Neuropsychology and Behavioral Neurology: Handbook of Clinical Neurology Vol 88

Foreword

This volume dedicated to neuropsychology and behavior is the eleventh to be published in the new series of the Handbook of Clinical Neurology. It is in line with the traditional attraction for ‘higher cortical functions’ of many neurologists, including some of the giants of our discipline. Derek Denny-Brown, Lord Brain, Jean and Franc¸ois Lhermitte as well as many others have provided seminal contributions to the field. The Editors of the earlier series, Pierre Vinken and George Bruyn, also dedicated volumes to this aspect. In the past few years, the field of neuropsychology and behavior has undergone major changes thanks to new discoveries, such as those related to imaging, as well as new approaches, such as the collaboration with other disciplines, for example cognitive psychology. Georg Goldenberg and Bruce Miller, editors of the present volume, are to be congratulated for bringing together a wide range of internationally acknowledged authorities to summarize these new developments in neuropsychology and behavior as well as their clinical implications. This ensures that this new volume will be an important and valuable resource for those interested in the fundamental aspects of neuropsychology and for those involved in the care of patients with these disorders. A separate volume devoted to dementia will be published shortly. We wish to express our gratitude to the many authors who contributed their time and expertise to summarize developments in their field and have helped to put together an outstanding volume that reflects the highest standards of scholarship and provides a critical appraisal and synthesis of current concepts concerning neuropsychology and behavior. As series editors, we have reviewed all the chapters included in this volume and have been greatly impressed by their scope and implications. We are proud that this new volume fully accords with our concept of the Handbook series in providing greater insight to the basic mechanisms of disease so that a greater appreciation is gained of the disorders encountered by clinicians. As always, we are also grateful to the team at Elsevier – and in particular to Ms Lynn Watt and Mr Michael Parkinson in Edinburgh – for their unfailing and expert assistance in the development and production of this volume. Michael J. Aminoff Franc¸ois Boller Dick F. Swaab

Preface

The first series of this Handbook, published in the late 1960s, and the second, published in the mid 1980s, each included two volumes devoted to behavioral neurology and neuropsychology. Remarkably current still, they established a high standard for future editions; chapters by the pioneers of the then-emerging field of behavioral neurology, such as Alexander Luria, Norman Geschwind, and Henri He´caen, provided a snapshot of the neural basis of memory, language, praxis, and visuoconstructive skills. Reflecting the technical possibilities of their time, the chapters discussed mostly evidence from clinical examination and postmortem anatomy, and there were no chapters devoted to the development of new methods for exploring relationships between brain and mind. Despite the forward thinking of the books’ authors, much has happened since 1985 and a new edition is overdue. Indeed, the twenty years since then have brought forward an explosion of research into the neural basis of cognition and behavior. New techniques of structural and functional imaging and of neurophysiology led to an enormous expansion of the database upon which theories on the brain–behavior relationship are founded. Against this background, our attempt to compile a comprehensive reference may appear overly ambitious. We nonetheless believe we have identified the main issues and have convinced leading experts to present them in chapters which are accessible to a broad readership of scientists and clinicians with an interest in the cognitive and neurochemical processes underlying human consciousness and behavior. In an attempt to define the major changes in the field of neuropsychology in the last two decades, three major forces have greatly affected the course of research: (1) the unprecedented rise of interdisciplinary work in cognitive neuroscience, which has led to a greater and more complete understanding of brain-related processes; (2) the discovery and application of new tools to investigate the neurochemical and neuroanatomical underpinnings of cognition; and (3) the wider and more focused use of neuropsychological testing in the characterization and diagnosis of neurodegenerative conditions. The findings that have resulted from the surge in research thanks to these forces are addressed throughout this new volume. We are delighted that we were able to attract leaders in neuropsychology from across North America and Europe to contribute to this new volume. There are new chapters on ‘Cortical neuroanatomy and cognition,’ ‘Functional neuroimaging of cognition,’ and two separate chapters that describe the influence of acetylcholine, glutamate, serotonin, and noradrenaline on cognition. Chapters on ‘Neuropsychology of aging and dementia’ and ‘Neuropsychological testing: bedside approaches’ offer practical guides to the clinician regarding how to approach the neuropsychological process. One remarkable development in modern neuropsychology has been the explosion of knowledge related to memory, a topic that can no longer be covered in a single chapter. Rather, the sheer volume of basic and clinical information regarding the cognitively and anatomically distinctive components of memory led us to include five memory chapters: there are authoritative contributions on amnesia, and semantic, implicit, and working memory. Chapters on the traditional topics of aphasia, alexia and agraphia, apraxia, number processing, and acalculia combine classic behavioral approaches to these dominant hemisphere functions with new data. Similarly, related to nondominant hemisphere syndromes and visually predominant processes, there are comprehensive discussions on ‘Hemispatial neglect,’ ‘Visuospatial and visuoconstructive deficits’, ‘Optic ataxia and Ba´lint’s syndrome’, and ‘Visual agnosia.’ Additionally, distinctive chapters on ‘Illusory perceptions of the human body and self,’ ‘The musical brain,’ ‘Visual art and the brain,’ and ‘Laboratory testing of emotion and frontal cortex’ are included for the first time. Finally, nothing has facilitated understanding of dementing disorders more than neuropsychology, and in this new edition, the topics of neuropsychological function in mild cognitive impairment, Alzheimer’s disease, frontotemporal lobar degeneration, dementia with Lewy bodies, and vascular dementia are eloquently described. Finally, we would like to give special thanks to some of the people who made this possible. First, we express gratitude to Handbook editors Michael J. Aminoff and Franc¸ois Boller who worked closely with us through the selection of topics and authors to the editing of chapters. Dr Miller would like to thank Tami Scott, his

x

PREFACE

administrative assistant, and Dr Indre Viskontas, his editorial assistant, who kept the chapters rolling and contributed innumerable hours to phone calls, emails, and editing related to this project. Additionally, he thanks his mother Harriet, wife Deborah and two children Hannah and Elliot. Dr Goldenberg wants to express his gratitude to Daniela and Anna for their infallible support of a husband and father whose favorite pastimes are writing papers and editing a Handbook. Georg Goldenberg Bruce L. Miller

List of Contributors

M. Albert Department of Neurology, Johns Hopkins University, Baltimore, MD, USA M.P. Alexander Harvard Medical School, Behavioral Neurology Unit, Beth Israel Deaconess Medical Center, Boston, MA, USA S. Arzy Laboratory of Cognitive Neuroscience, Brain Mind Institute, Ecole Polytechnique Fe´de´rale de Lausanne (EPFL), Lausanne and University Hospital, 1211 Geneva, Switzerland E. Ascher Department of Psychology, University of California, Berkeley, CA, USA W.B. Barr Department of Neurology and Psychiatry, New York University School of Medicine, New York, NY, USA M. Benoit Centre Me´moire de Resources et de Recherche CHU de Nice, Nice, France O. Blanke Laboratory of Cognitive Neuroscience, Brain Mind Institute, Ecole Polytechnique Fe´de´rale de Lausanne (EPFL), Lausanne, Switzerland M. Conson Neuropsychology Laboratory, Department of Psychology, Second University of Naples, Caserta, Italy K.R. Daffner Division of Cognitive and Behavioral Neurology, Departments of Neurology and Psychiatry, Brigham and Women’s Hospital, Boston, MA, USA

M. D’Esposito Henry H. Wheeler Jr Brain Imaging Center, Helen Wills Neuroscience Institute and University of California, Berkeley, CA, USA O. Devinsky Department of Neurology and Psychiatry, New York University School of Medicine, New York, NY, USA M.J. Farah Center for Cognitive Neuroscience, University of Pennsylvania, Philadelphia, PA, USA G. Gainotti Neuropsychology Service of the Catholic University of Rome, Rome, Italy Y.E. Geda Alzheimer’s Disease Research Center, Mayo Clinic College of Medicine, Rochester, MN, USA G. Goldenberg Neuropsychologische Abteilung, Krankenhaus Mu¨nchen Bogenhausen, Munich, Germany M. Goodkind Department of Psychology, University of California, Berkeley, CA, USA D.L. Greenberg Department of Psychology, University of California, Los Angeles, CA, USA A.E. Hillis Johns Hopkins School of Medicine, Departments of Neurology and Physical Medicine and Rehabilitation, Baltimore, MD, USA J.R. Hodges MRC Cognition and Brain Sciences Unit, Cambridge, UK

xii

LIST OF CONTRIBUTORS

M. Husain Institute of Neurology and Institute of Cognitive Neuroscience, University College London, London, UK D.I. Kaufer Department of Neurology, University of North Carolina School of Medicine, Chapel Hill, NC, USA

B.L. Miller Memory and Aging Center, University of California, San Francisco, CA, USA S. Negash Alzheimer’s Disease Research Center, Mayo Clinic College of Medicine, Rochester, MN, USA

C.M. Kipps MRC Cognition and Brain Sciences Unit, Cambridge, UK

H. Ota Institut National de la Sante´ et de la Recherche Me´dicale, Bron, France and Sapporo Medical University Hospital, Sapporo, Japan

J.A. Knibb MRC Cognition and Brain Sciences Unit, Cambridge, UK

K. Patterson MRC Cognition and Brain Sciences Unit, Cambridge, UK

B.J. Knowlton Department of Psychology, University of California, Los Angeles, CA, USA

D. Perani Vita-Salute San Raffaele University, San Raffaele Scientific Institute, Milan, Italy

M.D. Kopelman Academic Unit of Neuropsychiatry, Institute of Psychiatry, Kings College London, London, UK J.H. Kramer Memory and Aging Center, University of California, San Francisco, CA, USA T. Landis Department of Neurology, University Hospital, Geneva, Switzerland R.W. Levenson Department of Psychology, University of California, Berkeley, CA, USA A. Liu Memory and Aging Center, University of California, San Francisco, CA, USA H.J. Markowitsch Physiological Psychology, University of Bielefeld, Bielefeld, Germany M. McCarthy Department of Psychology, University of California, Berkeley, CA, USA B.R. Matthews Memory and Aging Center, University of California, San Francisco, CA, USA

R.C. Petersen Alzheimer’s Disease Research Center, Mayo Clinic College of Medicine, Rochester, MN, USA L. Pisella Institut National de la Sante´ et de la Recherche Me´dicale, Bron, and Universite´ Claude Bernard, Institut Fe´de´ratif des Neurosciences de Lyon (IFNL), Lyon, France L.A. Rabin Department of Psychology, Brooklyn College and the Graduate Center, City University of New York, Brooklyn, NY, USA N. Relkin Department of Neurology and Neuroscience, Weill Medical College of Cornell University, New York, NY, USA P.H. Robert Centre Me´moire de Resources et de Recherche, CHU de Nice, Nice, France H.J. Rosen Memory and Aging Centre, University of California, San Francisco, CA, USA Y. Rossetti Institut National de la Sante´ et de la Recherche Me´dicale, Bron; Universite´ Claude Bernard, Institut Fe´de´ratif des Neurosciences de Lyon (IFNL), and Hospices Civils de Lyon, Lyon, France

LIST OF CONTRIBUTORS D.P. Salmon Department of Neurosciences, University of California, San Diego, CA, USA A. Schnider Department of Clinical Neurosciences, University Hospital, Geneva, Switzerland M.M. Searl Harvard Medical School, Boston, MA, USA V. Sturm Department of Psychology, University of California, Berkeley, CA, USA P. Tanapat Research Consultant, Princeton, NJ, USA L. Trojano Neuropsychology Laboratory, Department of Psychology, Second University of Naples, Maugeri Foundation, IRCCS, Telese Terme, Italy A.I. Tro¨ster Department of Neurology, University of North Carolina School of Medicine, Chapel Hill, NC, USA

xiii

A. Vighetto Institut National de la Sante´ et de la Recherche Me´dicale, Bron; and Universite´ Claude Bernard, Institut Fe´de´ratif des Neurosciences de Lyon (IFNL); Hospices Civils de Lyon, Lyon, and Hoˆpital Henry Gabrielle, St Genis Laval, France I.V. Viskontas Memory and Aging Center, University of California, San Francisco, CA, USA K. Willmes Neurology Clinic, Neuropsychology University Hospital – RWTH Aachen University, Aachen, Germany K. Werner Department of Psychology, University of California, Berkeley, CA, USA M.E. Wetzel Department of Neurology, University of California, San Francisco, CA, USA W. Ziegler Entwicklungsgruppe Klinische Neuropsychologie, Munich, Germany

Handbook of Clinical Neurology, Vol. 88 (3rd series) Neuropsychology and behavioral neurology G. Goldenberg, B.L. Miller, Editors # 2008 Elsevier B.V. All rights reserved

Chapter 1

Cholinergic components of frontal lobe function and dysfunction LAURA A. RABIN1*, PATIMA TANAPAT2, AND NORMAN RELKIN3 1

Department of Psychology, Brooklyn College and the Graduate Center, City University of New York, Brooklyn, NY, USA 2

Research Consultant, Princeton, NJ, USA

3

Department of Neurology and Neuroscience, Weill Medical College of Cornell University, New York, NY, USA

1.1. Introduction Anatomically represented by cortical areas anterior to the central sulcus, the frontal lobes are richly and reciprocally interconnected with widespread brain regions through numerous pathways including the limbic (motivational/mnemonic) system, reticular activating (arousal) system, posterior association cortex (perceptual/cognitive processes and knowledge base), and motor (action) areas (Goldman-Rakic, 1987; Cummings, 1995). This broad pattern of connectivity underlies the significant control exerted over posterior cortical and subcortical systems by the frontal cortex. All areas of the frontal cortex receive substantial cholinergic innervation. Consequently, acetylcholine (ACh) plays a significant role in various aspects of frontal lobe function, particularly complex cognitive processes such as attention and memory. In this chapter, we will first review cholinergic anatomy, neurochemistry, and physiology related to frontal lobe function. Next, the contribution of cholinergic dysfunction to Alzheimer’s disease (AD) and other disorders associated with cognitive deterioration, as well as the use of drugs to enhance cholinergic activity under these conditions, will be discussed. Finally, imaging strategies such as functional MRI (fMRI) and positron emission tomography (PET), which are playing an increasingly important role in investigations of the human ACh system, will be reviewed. These techniques can be used to investigate effects of cholinergic agonists and antagonists on cognitive performance in healthy and compromised individuals and can assist in disease detection and monitoring of progression, treatment, and clinical outcome. *

Throughout the chapter, important findings related to the brain cholinergic system will be presented and directions for future research highlighted.

1.2. Acetylcholine The synthesis of ACh is the result of a chemical reaction involving the acetylation of choline by acetyl CoA. This reaction is catalyzed by choline acetyltransferase (ChAT), an enzyme that, because of its central role in catalyzing this reaction, is widely used as a marker of cholinergic activity. Although choline can be synthesized de novo in the brain, ACh is synthesized primarily from ingested choline, which is transported to the brain by the blood either free or in phospholipid form. Following its synthesis, ACh is then stored in synaptic vesicles. The level of ACh at any given time may be regulated by either feedback inhibition of ChAT, mass action, or the availability of acetyl CoA and/or choline. Additionally, there is some suggestion that intracellular levels of ACh play a role in regulating its rate of synthesis, thus limiting the maximum amount of the neurotransmitter that can be achieved in the brain, even with the administration of drug compounds (Klein et al., 1993). Upon depolarization of the cell membrane, the vesicles fuse with the cell membrane and ACh contained in presynaptically localized vesicles is released into the synaptic cleft to interact with both postsynaptic and presynaptic receptors. Postsynaptically, ACh receptor activation may result in a number of events that lead to changes in membrane potential of the postsynaptic cell whereas presynaptic receptor activation acts to inhibit further release

Correspondence to: Laura A. Rabin, Ph.D. Department of Psychology, Brooklyn College, City University of New York, 2900 Bedford Avenue, Brooklyn, NY 11210, USA. E-mail: [email protected], Tel: þ1-718-951-5601, Fax: þ1-718-951-4814.

2

L.A. RABIN ET AL.

of the neurotransmitter. Following its release into the synapse, unbound ACh is hydrolyzed by acetylcholinesterase (AChE) and, to a much lesser extent, by butyrylcholinesterase (BuChE). About 35–50% of the liberated choline is then transported back to the presynaptic terminal by a sodium-dependent, high-affinity active transport system to be re-utilized in ACh synthesis. The remaining fraction may be catabolized or incorporated into phospholipids, which can later be used as a source of choline. Although the role of BuChE historically has received much less attention than AChE, recent evidence suggests that BuChE may play an important role that is distinct from that of AChE. In contrast to AChE, which is localized primarily within neurons, BuChE tends to be associated not only with neurons, but also with glial and endothelial cells (Darvesh et al., 2003). At low neurotransmitter concentrations, BuChE is relatively inefficient at hydrolyzing ACh. At high concentrations, which tend to inhibit the actions of AChE, BuChE is very efficient. This suggests that during periods of high brain activity, characterized by synaptic levels of ACh that are likely to inhibit AChE, BuChE may be critically responsible for maintaining normal cholinergic function.

1.3. Neuroanatomy Damage to the cholinergic system is characteristic of a number of pathological conditions including Alzheimer’s disease (AD), vascular dementia (VaD), Parkinson’s disease (PD), dementia with Lewy bodies (DLB), and Down syndrome (DS), all of which are associated with substantial cognitive impairment (Perry, 1999; Roman and Kalaria, 2005). As a result, a great deal of attention has been focused upon understanding the cholinergic system’s influence on frontal cortical regions. The cholinergic system directly influences frontal cortex activity via projections from the nucleus basalis of Meynert (NBM) in the basal forebrain, as well as indirectly via the thalamus, which receives cholinergic input from NBM projections and midbrain tegmental nuclei, and via the basal ganglia. In the following section, the properties of these projections will be described in the context of their relevance to clinical neuropathology. Fig. 1.1 presents primary frontal lobe cholinergic pathways. 1.3.1. Direct cholinergic regulation by the nucleus basalis of Meynert (NBM) The cells of the NBM provide the primary extrinsic cholinergic innervation of the frontal cortex. These cells, which correspond to Ch4 cells as described by Mesulam and Geula (1988), can be divided into four

Panel 1: Direct cholinergic innervation of the frontal lobe originating in the basal forebrain: NCX, neocortex: NBM, nucleus basalis of Meynert Panel 2: Indirect cholinergic innervation of the frontal lobe originating in the podunculapontine and laterodorsal nuclei of the tegmentum: PF, prefrontal cortex; TH, thalamus; PMT, pontomesencephalotegmental system (pedunculopontine and laterodorsal tegmental nuclei) Panel 3: Cholinergic pathways influencing the frontal lobe that involve projections of the basal ganglia: AC, anterior cingulate cortex OF, orbitofrontal cortex; TH, thalamus; VS, ventral striatum; GP, globus pallidus (internal segment): SN, substantia nigra (pars reticulata); VTA, ventral tegmental area

Fig. 1.1. Frontal lobe cholinergic pathways.

CHOLINERGIC COMPONENTS OF FRONTAL LOBE FUNCTION AND DYSFUNCTION subregions based upon their location and target cells: (1) Ch4am (anteromedial) projects to cingulate cortex and basolateral amygdala; (2) Ch4al (anterolateral) projects to orbitofrontal cortex and opercular cortex; (3) Ch4id (intermediate) projects to lateral frontal, parietal, peristriate, temporal cortex; and (4) Ch4p (posterior) projects to superior temporal and temporopolar cortex. In individuals exhibiting various neurodegenerative diseases, a significant loss of cells in the NBM is observed consistently. Although the reasons underlying this damage are not yet fully understood, a number of age-related pathological processes that may be responsible have been identified. These processes include decreases in the calcium binding protein calbindin, deficits in neurotrophic factor protection, and the formation of amyloid plaques (Iacopino and Christakos, 1990; Wu et al., 1997; Geula et al., 1998; Chu et al., 2001; Wu et al., 2003). In spite of significant disagreement surrounding the etiology of the cognitive deficits associated with various neurodegenerative conditions, it remains clear that deterioration of cholinergic cells within the NBM is an important contributing factor. In general, the morphology, organization, and connectivity of cholinergic cells in the NBM suggest that they are well suited to integrating information from a diversity of sources and transmitting that information diffusely throughout neocortical target regions. These cholinergic cells tend to be characterized by extensive, overlapping dendritic arbors that contact myelinated fiber tracts in regions that contain corticofugal projections (Saper, 1984; Woolf, 1991). Cholinergic cells of the NBM are therefore capable of receiving information deriving from both neighboring cells and from cortical cell populations. Moreover, these cells tend to be organized into clusters. While the exact significance of this clustering phenomenon is unclear, this type of intimate intercellular association may provide the basis for an enhanced capacity for information processing (Bigl et al., 1982). Indeed, it has been noted that phylogenetically advanced animals possess larger aggregates of cells, leading to the postulation that these aggregates may form a physiological substrate for the type of information processing characteristic of more advanced species. With regard to their connectivity, cholinergic cells of the NBM have been shown to extend axons that are organized into discrete bundles and project to highly restricted telencephalic regions (Selden et al., 1998). In spite of the restrictive nature of their connectivity, however, cholinergic cells in the NBM projecting to very different areas are often observed adjacent to one another, indicating that the activation of a relatively small area in the NBM has the potential to affect a wide target area in the cortex (Bigl et al., 1982). Moreover,

3

this implies that damage to or degeneration of a small area may impact a number of behavioral functions. Like other cortical regions, the frontal cortex exhibits a rich density of cholinergic fibers. These fibers are for the most part unmyelinated, varicose, and form synapses on the perikarya, dendritic shafts, and spines of pyramidal and, to a lesser extent, non-pyramidal neurons (Wainer et al., 1984; Frotscher and Leranth, 1985). Cholinergic projections to the cortex are organized into a medial and lateral pathway, both of which provide innervation to frontal regions (Saper, 1984; Kitt et al., 1994; Selden et al., 1998). The greatest density of cholinergic fibers is exhibited in motor cortex with lower but significant densities in premotor and anterior cingulate cortex, as well as association areas of prefrontal cortex. At present, it is not known whether the increasing rostrocaudal gradient is functionally significant, or whether it is simply the result of the greater density of fiber projections present in the more caudal cortical regions. With regard to their laminar distribution, cholinergic fibers tend to be concentrated in layers I through upper III, as well as in layer V in agranular cortex, V and VI in motor and premotor regions, and I and V-VI in prefrontal regions (Mesulam et al., 1984; Lewis, 1991). Although the density of cholinergic fibers tends to vary significantly by region and laminar position, their widespread presence across all cortical areas and layers may underlie the spectrum of symptoms associated with conditions of cholinergic dysfunction. 1.3.2. Indirect cholinergic regulation via projections to the thalamus In addition to receiving direct cholinergic input from the NBM, the frontal cortex is indirectly influenced by cholinergic projections to the thalamus that derive from two different pathways. The first of these pathways originates in the pedunculopontine and laterodorsal nuclei of the tegmentum and, together with the direct projections from the NBM, is responsible for the vast majority of cholinergic innervation to the cortex. In contrast to the cholinergic cells of the NBM, however, cells of the pedunculopontine and laterodorsal nuclei act to inhibit gamma-aminobutyric acid (GABA) cell populations within the mediodorsal thalamus, which in turn provide the primary source of ascending thalamic input to prefrontal cortical regions (Sillito and Kemp, 1983). The second pathway by which the cortex receives indirect cholinergic input derives from a small population of cells in the NBM that project to the nucleus reticularis, a thalamic region known to play an important role in the synchronization of cortical activity (Hallanger et al., 1987; Levey et al., 1987; Steriade et al., 1987).

4

L.A. RABIN ET AL.

1.3.3. Indirect cholinergic regulation via the basal ganglia Although the cholinergic projections from the NBM and tegmental nuclei have been the primary focus of efforts to characterize cholinergic modulation of activity in the frontal cortex, increasing attention is being focused on the role of the basal ganglia. This interest has been fueled, at least in part, by the observation that patients with AD undergo a selective loss of cholinergic interneurons in the ventral striatum (Nagai et al., 1983; Steriade et al., 1984; Lehericy et al., 1989). Comprised of the ventral portions of the caudate nucleus, putamen, nucleus accumbens, and olfactory tubercle, the ventral striatum receives input from the ventral tegmental area and projects to the internal segment of the globus pallidus, the ventral pallidum, and substantia nigra pars reticulata. These three nuclei are responsible for input to the medial dorsal and ventral anterior thalamic nuclei, which in turn provide information to the anterior cingulate and orbitofrontal cortical regions. In addition to the ventral striatum, the substantia nigra pars compacta (SNc) also has been a focus of attention with regard to its relationship to the cholinergic system. Dopaminergic cells of the SNc receive cholinergic input originating from the reticular formation, an area involved in arousal, and these cells provide input to areas of the frontal cortex. Although the SNc is thought to play an important role in the regulation of movement, results of primate physiological experiments suggest that the activity of many of these neurons may be related to the salience of stimuli rather than to movement per se. This hypothesis has credence given that the SNc receives projections not only from the reticular formation but also from the amygdala, which is involved in motivation and emotion.

1.4. Physiology 1.4.1. Cholinergic regulation of activity in the frontal cortex The ascending cholinergic system originating in the NBM is responsible for maintaining a desynchronized pattern of cortical activity that is thought to enhance neuronal responsiveness to stimuli. Consistent with this assertion, single unit recording studies have demonstrated that under normal conditions, increased cholinergic activity in the NBM correlates with both neocortical desynchronization as well as behavioral activation (Buzsaki et al., 1988). Studies also have shown that pharmacological interference with cholinergic activity, which presumably prevents cortical desynchronization, negatively impacts an animal’s ability to respond to

appropriate stimuli. The administration of antimuscarinic drugs such as atropine and scopolamine appears to completely block responsiveness to stimuli, inducing slow wave EEG activity characteristic of the drowsy and sleep states. Likewise, surgical depletion of ACh originating from the NBM prevents cortical neurons in the visual cortex from responding appropriately to excitatory inputs, an effect that is readily reversible by the microionophoretic application of ACh (Sato et al., 1987). Despite the fact that the latter study describes the responsiveness of cells in the visual cortex, the mechanisms described are likely to be relevant to NBM modulation of the frontal cortical regions as well. Similar to the direct projections from the NBM to the neocortex, cholinergic projections that exert their influence via connections to the thalamus tend to have a somewhat diffuse effect on frontal cortical activity. The pedunculopontine and dorsolateral nuclei influence activity in the cortex by inhibiting cell populations within the dorsomedial thalamus, a region that provides innervation to the entire prefrontal cortex. As a result, the pedunculopontine and dorsolateral nuclei are essentially responsible for modulating the activity of all prefrontal cortical regions. Likewise, the nucleus reticularis plays an important role in processes that are somewhat generalized. Although this nucleus was originally believed to be important in activation-related cortical desynchronization, subsequent work has revealed that this region does not project directly to the cortex. The nucleus reticularis, however, does appear to play a role in neocortical rhythmic synchronization (Steriade et al., 1984; 1985; 1987), a phenomenon that is suppressed by cholinergic input originating from the NBM (Buzsaki et al., 1988). This observation implies that the cholinergic system plays a major role in neocortical activation not only via the direct activation of the neocortex, but also through its inhibitory effect on the RT-thalamocortical synchronizing system. Given the role of ACh in enhancing the cortical response to stimuli, it seems logical that interference with cholinergic input would have important consequences for processes requiring experiential input. Indeed, available evidence indicates that cholinergic input from the basal forebrain is critically involved in activity-dependent synaptic modifications in the visual, somatosensory, and auditory cortices (Gu, 2002). Likewise, for individuals with lesions to the NBM, the inability to respond appropriately to stimuli also prevents the formation of stimulus–reward associations (Roberts et al., 1990). 1.4.2. Cholinergic receptors Acetylcholine exerts its effects via nicotinic and muscarinic receptor subtypes, each of which is associated with a broad spectrum of downstream events. Through

CHOLINERGIC COMPONENTS OF FRONTAL LOBE FUNCTION AND DYSFUNCTION these downstream events, ACh appears to facilitate rather than initiate changes in membrane potential. Studies using immunohistochemical techniques, in situ hybridization, and receptor binding assays have found that the frontal cortical regions express both the muscarinic, and to a lesser extent nicotinic, subtypes of cholinergic receptor. Muscarinic receptors are slow response time (100–250 ms) G-protein coupled receptors that act either directly on ion channels or are linked to a second messenger system. At least five different subtypes have been designated (M1-M5). Activation of the M1-like receptors (M1, M3, and M5) stimulates the phosphoinositol pathway, which results in the closing of Kþ channels, opening of Ca2þ channels, and cell depolarization (Caulfield and Birdsall, 1998; LucasMeunier et al., 2003). These receptors are generally post-synaptic, acting to facilitate cholinergic transmission. The M1 subtype of receptors, which are expressed only modestly in the periphery, exist in great abundance in the brain. They are found in all major neocortical areas, including frontal regions, and it is believed that the major effect of ACh in these areas, i.e., rendering cortical neurons more responsive to other excitatory input, is mediated by the activation of M1 receptors (Cox et al., 1994). The M3 receptors also are observed in the brain; however, they are expressed at a relatively low level and extant studies have been unsuccessful at assigning them a clear phenotype (Bymaster et al., 2003). Although the M5 receptors have been identified in cerebral blood vessels, they represent only approximately two percent of the muscarinic receptors in the brain, and they have not been observed in neocortical regions (Elhusseiny et al., 1999; Phillips et al., 1997; Yasuda et al., 1993). In contrast to activation of the M1-like receptors, activation of the M2-like receptors (M2 and M4) inhibits adenylate cyclase, causing the inhibition of voltage-gated Ca2þ channels, and cell hyperpolarization (Egan and North, 1986). These receptors are pre-synaptic autoreceptors that decrease cholinergic activity. Although not as abundant as the M1 receptors, a significant level of M2 receptors is expressed in the frontal cortex (Li et al., 1991). Knockout studies indicate that the release of ACh in neocortical areas is mediated primarily by the M2 autoreceptors (Zhang et al., 2002). M4 autoreceptors, on the other hand, appear to be primarily involved in mediating ACh release in the striatum. Nicotinic receptors are fast acting pentameric ligandgated cation channels that may be composed of a combination of a and b subunits, or a subunits alone. Although other subunits exist, they are not expressed by neuronal cell types. At least nine a subunits and three b subunits have been identified thus far (Martin-Ruiz et al., 2003). The vast majority of neuronal nicotinic receptors

5

contain either the a4b2 subunits or the a7 subunit. The a4b2 receptors bind nicotine with very high affinity and demonstrate relatively slow rates of desensitization (Fenster et al., 1997). The a7 receptors, on the other hand, bind nicotine with a somewhat lower affinity, are effectively blocked by a-bungarotoxin, exhibit rapid desensitization, and are highly permeable to Ca2þ (Couturier et al., 1990; Seguela et al., 1993; Zhang et al., 1994; Castro and Albuquerque, 1995). Both the a7 and non-a7 type nicotinic receptors may be either presynaptically or postsynaptically located. Activation of the presynaptic receptors results in changes in intracellular Ca2þ concentrations, which are then capable of affecting neurotransmitter release. In contrast, postsynaptic receptors are capable of inducing a fast cationic inward current (Lucas-Meunier et al., 2003). Although there seems to be a relatively low expression of a4b2 receptors in neocortex, the a7 subtype appears to be significantly expressed in a number of areas that include the frontal regions (Geerts, 2005). Over the past few years, researchers have begun to explore the functional differences between the a4b2 and the a7 receptor subtypes. Results of these efforts indicate that the a7 receptors are specifically vulnerable to effects of abeta peptides. Given the putative role of a7 activation in cell survival (Geerts, 2005), this observation suggests a possible mechanism by which abeta may contribute to cell degeneration. Although various neurodegenerative conditions have been directly linked to cholinergic dysfunction within the frontal lobe, the relationship between these disorders and changes in cholinergic activity at the receptor level has yet to be fully elucidated. Broadly speaking, pathological conditions associated with cholinergic dysfunction tend to be characterized by similar changes in receptor pharmacology. In patients with AD, PD, and DLB, no changes in antagonist binding of M1 receptors have been observed, indicating that the expression of the receptor protein is unchanged (Aubert et al., 1992). However, the ability of the M1 receptor to form a high affinity agonist-receptor-G protein complex, and therefore its overall ability to bind ACh, may be compromised in patients with AD (Flynn and Mash, 1993). This observation is significant as it implies that therapeutic compounds targeting M1 receptor activation should take into consideration alterations in affinity in order to restore normal function. With regard to the muscarinic autoreceptors, several studies have identified an overall decrease in antagonist binding and immunoreactivity of the M2 receptor in AD and DLB patients (Flynn et al., 1995) but an increase in these parameters with M4 receptors. Given the decrease in cholinergic synaptic activity that results from depletion of the cholinergic cell

6

L.A. RABIN ET AL.

population, the decrease in the density of inhibitory M2 autoreceptors is not surprising. The significance of the upregulation of the M4 receptors, however, remains unclear. Several studies employing various antagonists have reported changes in nicotinic receptor pharmacology as well. Specifically, these studies report a decrease in the binding of presynaptic nicotinic receptors in the frontal cortex of patients with AD, PD, and DLB (Rinne et al., 1991; Perry et al., 1995; Court et al., 2000; Pimlott et al., 2004) that is likely due to a decrease in the number of cells expressing the receptor (Schroder et al., 1991; 1995). At least in the case of AD, the decrease in receptor density does not appear to be associated with a change in binding affinity (Aubert et al., 1992).

1.5. Neuroimaging 1.5.1. PET imaging of AChE Positron emission tomography (PET) can be used to measure AChE activity in vivo by imaging the human brain using 11C-labeled radiotracers such as N-[11C] methyl-4-piperidinyl acetate (AMP or MP4A) and N-[11C]methyl-4-piperidinyl propionate (PMP or MP4P). These esters serve as AChE substrates and are hydrolyzed to a hydrophilic product that is unable to cross the blood–brain barrier, and which therefore remains in the brain according to the distribution of AChE enzyme activity (Irie et al., 1994; Kikuchi et al., 2005; Shao et al., 2005). Subsequently, a quantitative estimate of regional AChE activity is provided through kinetic analysis of this radioactivity trapping. Statistically significant localized decreases in cortical hydrolysis rate of [11C] AMP or [11C]PMP can be observed in certain clinical populations (i.e., AD, PD, DLB) (Iyo et al., 1997; Kuhl et al., 1999; Shinotoh et al., 1999; 2003). Additionally, studies applying cross-sectional and longitudinal designs with healthy individuals can be used to investigate changes in AChE activity in cortical regions associated with the aging process (Namba et al., 2002). [11C]PMP also has been used to quantify AChE inhibition and to demonstrate the utility of PET radiotracers for AChE activity in evaluating the efficacy of cholinergic drugs and optimizing drug dosage schedules (Kilbourn et al., 1999; Kuhl et al., 2000; Shao et al., 2005). Current research is focused on developing and assessing the utility of F-labeled PMP analogs, which may permit longer imaging times, better image quality, and allow the use of radiotracers with slower pharmacokinetics. Additionally, the longer half-life of 18 F is convenient for long-time storage and transport, enabling preparation of radiotracer batches for multiple

patients and facilities, and making the technology more widely available (Zhang et al., 2003). Initial results in primate and rat studies have shown encouraging characteristics for a novel compound (N-[18F]fluoroethyl-4piperidinyl acetate), suggesting its future utility as a PET radiotracer for measuring brain AChE activity (Kikuchi et al., 2005; Shao et al., 2005). 1.5.2. Functional imaging in cognitively healthy and compromised humans Researchers are using functional magnetic resonance imaging (fMRI) and PET with increasing frequency to investigate the impact of pharmacologically induced neurochemical changes on human brain networks. These methods have elucidated the role of major neurotransmitter systems in cognitive function and the effects of neurotransmitter depletion or overexpression on brain function and behavior (Honey and Bullmore, 2004; Goekoop et al., 2006). The cholinergic system has been a focus study due to its innervation of key cortical and subcortical regions involved in cognition, particularly memory processes, in addition to its association with various neurological conditions. In most cases, administration of a drug or placebo occurs before participants undergo a cognitive task. A comparison between drug and placebo then reveals the drug’s action on taskrelated brain activity. The subsequent review of neuroimaging research includes a fairly heterogeneous body of work with regard to imaging modality (PET vs. fMRI), drug (cholinergic agonist vs. antagonist), dosing (acute vs. prolonged), participants (healthy vs. cognitively compromised), targeted memory systems or subprocesses (explicit vs. implicit, encoding, retrieval, or working memory), experimental design (within vs. between subjects) and task (e.g., blocked vs. event-related, visual vs. verbal modality). Table 1.1 outlines human neuroimaging studies focused on the cholinergic system along with a summary of key findings. Studies chosen for inclusion all contain results with significant involvement of frontal brain regions. 1.5.3. Impact of cholinergic manipulation on learning in cognitively healthy subjects Research has demonstrated an attenuation of learningrelated activity in healthy volunteers under scopolamine, a potent antagonist of muscarinic M2 ACh receptors. Sperling et al. (2002) examined alterations in brain activation associated with scopolamine induced memory impairment using a face–name associative learning paradigm in the context of a repeated-measures design. Participants were scanned on four consecutive occasions,

8

Table 1.1 (Continued) Study design and goals

Main findings and conclusions

Sperling et al. (2002)/scopolamine or placebo*/healthy, young adult males

Investigated effects of scopolamine on encoding-related activity in a double-blind using a block design, face-name associative learning task. Participants were scanned on four separate occasions (two weeks apart); they received placebo during the first two sessions and drug thereafter (60 min prior to scanning). Encoding-related brain activity was isolated by comparing face-name association learning with visual fixation. Investigated effects of donepezil hydrochloride on cognition brain activity in patients with MCI using a block design auditory 2-back WM task. Patients were scanned before initiating drug treatment and after stabilization (approx 11 weeks); unmedicated control participants were scanned at similar time intervals.

Results indicated a decrease in the extent and magnitude of activation in inferior prefrontal cortex, hippocampus, and fuisform gyrus with scopolamine as compared to placebo. Performance was impaired on postscan memory measures suggesting that medications that impair memory also diminish activation in critical brain regions subserving memory processes.

(n ¼ 10). *Participants received scopolamine during one session and lorazepam during another (cross-over design).

Saykin et al. (2004)/donepezil or no medication/older adults with MCI (n ¼ 9) healthy older adult controls (n ¼ 9).

Goekoop et al. (2004)/acute galantamine or prolonged galantamine or no medication/older adults with MCI (n ¼ 28).

Investigated cholinergic system reactivity to pharmacological challenge with galantamine in MCI using face-encoding and visual 2-back WM tasks (block design). Scans occurred at baseline and following single-dose and prolonged exposure (5 days) to drug. Baseline, acute, and prolonged regimes were randomized across scanning sessions, and washout periods separated acute and prolonged regimes.

Goekoop et al. (2006)/acute galantamine or prolonged galantamine or no medication/older adults with MCI (n ¼ 28) and AD (n ¼ 18).

Investigated differential response to cholinergic stimulation with galantamine in MCI and AD using an event-related face-recognition task. fMRI was performed at baseline and following single-dose and prolonged exposure (5 days) to galantamine. Baseline, acute, and prolonged regimes were randomized across scanning sessions, and washout periods separated acute and prolonged regimes.

At baseline, patients showed reduced activation of frontoparietal regions relative to controls. After stabilization on donepezil, patients showed increased frontal activity relative to unmedicated controls, which was positively correlated with improvement in task performance. Short-term treatment with donepezil appeared to enhance activity of frontal circuitry in MCI and this increase was related to improved cognition. Significant increases in brain activation from baseline were observed after prolonged exposure. For face encoding, increases occurred in left prefrontal areas, anterior cingulate gyrus, left occipital areas, and left posterior hippocampus. For WM, increased activation occurred in right precuneus and right middle frontal gyrus, coinciding with increased accuracy after treatment. Cholinergic treatment produced alterations in brain activation patterns in MCI related to improved cognition. In MCI, acute galantamine challenge enhanced brain activation in areas in prefrontal and other distributed cortical and subcortical regions. Prolonged exposure decreased activation in similar frontal and other brain regions. In AD, acute galantamine intake increased brain activation in regions other than frontal cortex (mainly medial temporal) and prolonged exposure decreased activation in these areas. Findings also suggested a preferential targeting of memory retrieval rather than encoding processes by galantamine.

L.A. RABIN ET AL.

Reference/drug/participants

Repeated measures of regional rCBF were made during auditory verbal memory tasks (with alternating short vs. long word lists). Memory-related brain activity involved a comparison of rCBF in the long vs. short condition. Participants underwent 6 scans, with no drug during scans 1–2 and drug or saline (with tasks) during scans 3–6.

Furey et al. (1997)/physostigmine or placebo (saline)/healthy adults. Drug (n ¼ 13) or Placebo (n ¼ 8).

Participants performed a visual WM task for faces. Memoryrelated brain activity was measured by comparing rCBF under task performance compared with a resting baseline. Participants underwent 10 scans, with saline administered during scans 1–2 and drug or saline (with tasks) during scans 3–10.

Furey et al. (2000a)/physostigmine or placebo (saline)/healthy adults. Drug (n ¼ 13) or placebo (n ¼ 13).

Participants performed a visual WM task for faces. Memoryrelated brain activity was measured by comparing rCBF under task performance with a resting baseline. Used a data set similar to that reported by Furey et al. (1997) (see above), with the additional goal of examining correlations between physostigmine-related changes in rCBF in all brain areas (not just right prefrontal cortex) and changes in RT.

Behaviorally, scopolamine reduced the number of words recalled from the long list. Neuronally, the drug attenuated memory-related rCBF in bilateral prefrontal cortex (predominantly middle frontal gyri) and right anterior cingulate, suggesting that the memory-impairing action may be due to disturbed activity in these frontal brain regions. Physostigmine improved WM efficiency (as indicated by faster RTs) and reduced task-related activity in anterior and posterior regions of the right midfrontal gyrus. The magnitude of drug-induced RT change correlated with rCBF reduction in a task-specific right prefrontal region. Enhancement of cholinergic function may improve processing efficiency and reduce effort required to perform a WM task. Cholinergically induced improvements in WM were related to alterations in neural activity in multiple cortical regions. Increased activity occurred in regions associated with early perceptual processing (medical occipital visual cortex) while decreases occurred in regions associated with attention, encoding, and memory maintenance (right frontal cortex, left temporal cortex, anterior cingulate, and left hippocampus). Cholinergic potentiation may improve cognition by enhancing perceptual processing in early visual areas or by improving signal-to-noise in memory processing at different sites (i.e., making relevant stimuli more salient by reducing background noise).

Note: rCBF ¼ regional cerebral blood flow; AD ¼ Alzheimer’s disease; fMRI ¼ functional magnetic resonance imaging; MCI ¼ mild cognitive impairment; MS ¼ multiple sclerosis; RT ¼ reaction time; WM ¼ working memory. Studies included both male and female participants unless otherwise noted. With the exception of Goekoop et al. (2004, 2006) and Rombouts et al. (2002), participants in all studies were noted to be right-handed.

CHOLINERGIC COMPONENTS OF FRONTAL LOBE FUNCTION AND DYSFUNCTION

Grasby et al. (1995)/scopolamine or placebo (saline)/healthy adult males. Drug (n ¼ 6) or placebo (n ¼ 6).

9

10

L.A. RABIN ET AL.

with a two-week interval between sessions. Results revealed decreases in extent and magnitude of activation in inferior prefrontal cortex, hippocampus, and fusiform gyrus with scopolamine relative to placebo during encoding as compared to visual fixation. Activation within all regions of interest was consistent across the two placebo scans during encoding. Additionally, performance was impaired on post-scan memory measures suggesting that medications that impair memory also diminish activation in critical brain regions subserving memory. Other researchers have identified activity reductions in frontal brain regions during both implicit (repetition priming) and explicit (word recall) memory paradigms with scopolamine (Grasby et al., 1995; Thiel et al., 2001). Taken together, these findings suggest that intact cholinergic neurotransmission in frontal brain regions may be crucial for successful functioning across memory processes. Research also has investigated the cerebral correlates of improved stimulus processing in healthy participants using a class of drug known as acetylcholinesterase inhibitors (AChEIs), which serve to enhance synaptic concentrations of ACh. Furey et al. (1997) examined changes in regional cerebral blood flow (rCBF) and behavioral performance associated with cholinergic stimulation during a working memory (WM) task for faces. Experimental participants received a saline infusion for the first 2 of 10 PET scans, followed by a continuous infusion of physostigmine; control participants received saline. Results indicated that the drug improved WM efficiency (as indicated by faster reaction times, RTs) and reduced WM task-related activity in anterior and posterior regions of the right midfrontal gyrus, a region associated with WM. The magnitude of this RT change correlated with right midfrontal rCBF. Reduction in prefrontal rCBF was interpreted as enhanced efficiency of WM processes on drug (i.e., less effort required to perform the task led to a reduced need to recruit prefrontal cortex). In a subsequent fMRI study, Furey et al. (2000b) investigated effects of physostigmine, again using a WM task for faces in a double-blind, placebo-controlled, cross-over design. Results indicated that physostigmine increased activation of extrastriate visual cortex and inferior frontal regions, particularly during the early, stimulus-encoding phase of each trial, with reduced activation in dorsal anterior prefrontal cortex. These neurophysiological effects again were associated with performance improvements. Enhancement of the ACh system was interpreted as augmenting perceptual processing of task-relevant stimuli during encoding, resulting in reduced processing demands for ‘executive’ anterior prefrontal regions. Together these and other findings (e.g., Furey et al., 2000a) suggest that cholinergic enhancement of WM serves to reduce

recruitment of prefrontal cortical tissue due to more efficient processing elsewhere.1 Overall, the body of cholinergic imaging work utilizing learning and memory paradigms with healthy individuals reveals several notable findings. First, across experiments, cholinergic modulation occurred in frontal areas typically activated in learning and memory paradigms, suggesting that memory impairing or promoting effects of cholinergic drugs may be linked to modulation of frontal cortical activity. The exact mechanism of such modulation, however, is not readily apparent because reduced activity was observed with both cholinergic blockade and stimulation. Further work is required to clarify and extend current findings. Results also suggested that cholinergic neurotransmission is modulated by activity in regions involved in processing task relevant stimuli (e.g., fusiform cortex, extrastriate regions, auditory cortex), suggesting a cholinergic role in stimulus processing and attentional function (Rosier et al., 1999; Furey et al., 2000a; Sperling et al., 2002; Thiel et al., 2002). Further research will be required to determine whether these extrastriate effects contribute to cholinergic modulation of frontal activity or whether frontal cortical activations are independent of extrastriate drug effects.2 Experimental designs that do not confound learning and stimulus processing will be required. 1

Physostigmine may improve behavioral performance by increasing visual attention mediated by cholinergic projections from NBM to widespread cortical regions. This would account for the observed correlation between RT reductions and rCBF increases in medial occipital visual cortex, and is consistent with work suggesting that cholinergic enhancement facilitates visual attention by increasing activity in extrastriate cortex (Furey et al., 2000a; Bentley et al., 2004). Another possibility is that the drug exerts a more direct effect on WM circuitry via the septohippocampal cholinergic system by facilitating the inhibitory effect of ACh on the hippocampus. As septal cholinergic fibers projecting to the hippocampus are inhibitory, physostigmine may decrease neuronal activity in this region while enhancing signal (i.e., improving signal-to-noise ratio and making relevant stimuli more salient). This would account for the observed relation between RT reductions and rCBF reductions in the hippocampus (Furey et al., 2000a). 2 See Thiel (2003) for additional studies related to modulation of learning and memory in cognitively intact humans. Of note, Bentley et al. (2003a; 2003b) used fMRI to investigate cholinergic modulation of responses to emotional stimuli, with the goal of mapping inputs to the frontoparietal cortex that influence allocation of attention to and priming of emotional information. Additionally, Ernst et al. (2001) used PET to study effects of nicotine gum (which binds exclusively to nicotinic receptors) on differences in cholinergic modulation of memory-related brain activity in smokers vs. non-smokers.

CHOLINERGIC COMPONENTS OF FRONTAL LOBE FUNCTION AND DYSFUNCTION Examples include utilization of the same drug within different cognitive paradigms or use of different cholinergic agents within a single experimental paradigm (Thiel, 2003).

11

demographically matched controls. After treatment, patients showed increased activity predominantly in the dorsolateral prefrontal cortex (see Fig. 1.3), which was positively correlated with baseline hippocampal

1.5.4. Functional changes observed in cognitively compromised populations Studies using neuroimaging to challenge the cholinergic system in clinical populations have focused on older adults with known memory deficits. Saykin et al. (2004) conducted a controlled fMRI study of WM in patients with amnestic mild cognitive impairment (MCI), thought to be a preclinical stage of dementia (Petersen et al., 2001), before and approximately 11 weeks after treatment with donepezil. The researchers utilized a blocked-design auditory 2-back task with conditions that make increasing demands on WM (see Fig. 1.2). At baseline, patients showed reduced activation of frontoparietal regions relative to unmedicated,

Fig. 1.2. Two-back auditory working memory task including an example of the three target conditions (0-, 1- and 2-back). The presentation was auditory with button press response recording.

Fig. 1.3. Statistical parametric maps displaying results of a group by time interaction analysis. These images show regions that were more activated in MCI patients (n ¼ 9) compared to healthy controls (n ¼ 9) after 11 weeks of treatment with donepezil compared to baseline performance on the working memory task. Shown are (A) a surface render and (B) an axial image with the anterior prefrontal region that had the greatest signal change (for display purposes, p < 0.01). Correlational analysis of the interaction data at the global maxima in the left frontal lobe revealed that the extent of increase in activation in that cluster of voxels was positively related to the extent to which accuracy improved on the working memory task across participants (twoback condition, r ¼ .49). Increased activation in this region also was positively related to baseline hippocampal volume (r ¼ .62) within the patient group.

12

L.A. RABIN ET AL.

volume. Findings suggested that treatment with donepezil led to enhanced activity of frontal circuitry in MCI, and this increase was associated with improved cognition. Goekoop et al. (2006) investigated differential responses to galantamine in MCI and AD during an event-related face recognition task at three time points: baseline, acute (single dose), and prolonged exposure (5 days). In MCI, the acute galantamine challenge enhanced brain activation in areas known to depend on cholinergic innervation including prefrontal and other distributed cortical and subcortical regions. Prolonged exposure decreased activation in similar frontal and other brain regions. In AD, acute galantamine increased brain activation in regions other than frontal cortex (mainly medial temporal), and prolonged exposure decreased activation in these areas. Thus, patients exhibited differential responses to acute versus prolonged exposure to drug, which may represent differences in nicotinic or muscarinic receptor sensitivities, disease-specific mechanisms, or a combination of factors. When combined with previous research (Rombouts et al., 2002; Goekoop et al., 2004), findings suggested a preferential targeting of memory retrieval rather than encoding processes by galantamine. The processspecific nature of cholinergic treatment has treatment implications to the extent that benefits arising from these drugs may be limited by existing pathology, which initially affects encoding of information (Grober and Kawas, 1997; Wang and Zhou, 2002; Honey and Bullmore, 2004; Goekoop et al., 2006). Results also revealed a differential response to cholinergic challenge in MCI and AD, possibly reflecting underlying differences in the functional status of the cholinergic system at these different disease stages. Researchers have begun to investigate cholinergic modulation of cognition in additional patient groups. In a pilot fMRI study, Parry et al. (2003) examined the effects of acute rivastigmine administration in patients with multiple sclerosis (MS) and healthy participants using a visual counting Stroop task. Prior to treatment investigators found greater activation in MS, primarily in left medial prefrontal cortex, despite comparable task performance; healthy controls showed greater activation in the right inferior frontal cortex. For MS patients, rivastigmine led to normalization of abnormal patterns of brain activation (i.e., reduction in fMRI activation of the left medial frontal region of interest and increase in the right prefrontal region). Recruitment of medial prefrontal cortex may represent adaptive brain plasticity, which helps compensate for processing deficits in MS patients. Further, this functional plasticity may be modulated by cholinergic agonism. Risch et al. (2001) performed a double-blind, placebo-controlled, crossover case study of donepezil augmentation in a patient

with schizoaffective disorder who was stabilized on the neuroleptic olanzapine. The patient manifested significant improvements in cognition and increased activation of prefrontal cortex and basal ganglia on functional MRI. Donepezil augmentation also resulted in reduced depression and improved functional abilities and quality of life. 1.5.5. Additional implications derived from pharmacological neuroimaging studies The small body of published clinical pharmacological neuroimaging studies is somewhat limited methodologically by: (a) poor design features such as no control group, use of cross-sectional design (all extant studies), and lack of randomized, placebo-controlled design; (b) low power; and (c) group differences in key demographic variables. Nonetheless, some conclusions can be drawn. Treatment with AChEIs can enhance activity of frontal circuitry (in addition to other brain areas) in clinical patients, and this regional increase in activity may be related to improved cognition. Research has yet to specify how AChEIs affect frontal brain systems, though current findings suggest possible mechanisms.3 Results also provided in vivo evidence for a differential involvement of the cholinergic system in MCI and AD (i.e., disease specificity). Longitudinal research with periodic follow-up of patients will help clarify whether early intervention in MCI utilizes different brain mechanisms from intervention during later neurodegenerative stages. In addition, pharmacological MRI challenge tests may prove valuable in clinical studies designed to monitor disease progression and predict outcome based on factors such as initial response to pharmacological therapy, structural brain integrity, and cognition. Results also revealed signal reactivity with respect to exposure duration, and further investigation of brain activation changes after acute versus prolonged treatment with AChEIs will be required to better characterize this phenomenon. Intraindividual stability of activation patterns also should be established for fMRI to be effective in disease tracking 3

Saykin et al. (2004) proposed several possible mechanisms by which AChEIs exert regionally specific effects on frontal regions in MCI including: (1) upregulation in frontal cortex that results from the comparatively dense representation of cholinergic receptors and fibers in brainstem regions that project to this area, (2) a drug-induced increase in frontal nicotinic receptors, (3) secondary upregulation of dopaminergic systems involving the frontal lobe, (4) sparing of frontal cortex in MCI (as compared to temporal and parietal regions) that provides greater structural integrity with which to support increased activation in response to medication, or (5) altered neurovascular coupling that contributes to the observed regional specificity on brain activity.

CHOLINERGIC COMPONENTS OF FRONTAL LOBE FUNCTION AND DYSFUNCTION and evaluation of treatments (Rosen et al., 2002; Saykin et al., 2004). Another direction for future research involves the use of pharmacological fMRI in the emerging field of pharmacogenetics. Saykin et al. (2006) showed that following donepezil treatment, MCI patients had increased right medial temporal activation during verbal encoding and increased right frontal activation during retrieval, compared to healthy older adults. Additionally, specific Apolipoprotein E and brain-derived neurotrophic factor (BDNF) genotypes (i.e., greater response seen in the absence of e4 allele and met allele of the val-66-met polymorphism) were associated with this increased activity. The authors suggested that a favorable genetic profile may be associated with increased activation following cholinergic medication in memory-relevant brain circuitry. Studies like this are important in establishing links between cognitive and fMRI measures of cholinergic-related drug effects, and in relating behavioral and physiological phenotypes to underlying allelic variation. Finally, dementia and other neuropsychiatric diseases are increasingly thought to result from compromised brain function in distributed and interconnected brain regions rather than from localized deficits. As such, the mechanism and action of treatments will necessarily involve the modulation of inter-regional functional connectivity. Recent studies have begun to characterize the effects of pharmacological treatment on integrative brain function. For example, Nahas et al. (2003) found that the addition of donepezil to current antipsychotic therapy provided a ‘functional normalization’ of fronto-temporal dysconnectivity in patients with schizophrenia. Another study demonstrated that acute pharmacological effects on functional connectivity can be detected in healthy older adults (Honey et al., 2003). The integration of pharmacological neuroimaging designs with multivariate data analysis of inter-regional connectivity is likely to gain importance in future research on drug treatment for neuropsychiatric conditions (Honey and Bullmore, 2004).

13

cholinergic receptor antagonists and agonists, respectively (for review see Sarter and Bruno, 1997; Van der Zee and Luiten, 1999; Auld et al., 2002; Gold, 2003). Additional research has shown that ACh modulates several forms of neural plasticity necessary for learning and memory (Gold, 1995; Weinberger, 1998; Disterhoft et al., 1999; Hasselmo, 1999; Gu, 2002; Warburton et al., 2003). While this body of work has tended to focus on pharmacological manipulation of the septohippocampal cholinergic system, some studies have shown increases in ACh release in the neocortex while animals performed tasks designed to engage attentional processing (Arnold et al., 2002; Sarter and Bruno, 2002) and novelty (Miranda et al., 2000), and in the striatum during performance of tasks associated with behavioral flexibility (Ragozzino, 2003). In their conceptualization of the central cholinergic system, Everitt and Robbins (1997) suggested that basal forebrain projections provide a common function, which is to boost signal-tonoise ratios in cortical target areas. In general, research designed to elucidate the function of cortical cholinergic inputs has consistently pointed to a role in attention, processing of behaviorally relevant sensory information, and detecting and selecting stimuli and associations for extended processing (Everitt and Robbins, 1997; Sarter et al., 2001; Arnold et al., 2002). It is also important to note that ACh acts in concert with many other neurotransmitters, and that complex cognitive processes reflect the combined functions of multiple neuromodulators and neural systems (Gold, 2003). The forthcoming sections will summarize evidence implicating the basal forebrain cholinergic system in pathological conditions, particularly neurodegenerative diseases, along with accompanying cognitive deficits. Treatment strategies aimed at alleviating cognitive and behavioral symptomatology by enhancing cholinergic functions will be highlighted. We will conclude with a look toward future treatment strategies and directions for research. When possible, discussions will focus on treatment approaches that exert their effects via the frontal lobe.

1.6. Cognitive functions and cholinergic therapies

1.6.1. Alzheimer’s disease

Given its widespread brain distribution, it is not surprising that the cholinergic system has been implicated in diverse behavioral and physiological regulatory activities including sensory processing, mood, sleep, arousal, biorhythms, aggression, ingestive behavior, thermoregulation, and sexual functions (Van der Zee and Luiten, 1999; Gu, 2002). Research also has established a cholinergic role in various cognitive processes. For example, pharmacological studies have provided evidence for impaired or enhanced learning and memory with

Damage to ACh-synthesizing neurons in the human basal forebrain is among the early pathological events in AD (Davies and Maloney, 1976; Whitehouse et al., 1982; Coyle et al., 1983). In addition to significant neuronal cell loss within this brain region, research has revealed decreases in ChAT activity (Whitehouse et al., 1982; DeKosky et al., 1992; Lehericy et al., 1993), high affinity choline uptake (Rylett et al., 1983), and nicotinic and muscarinic ACh receptor binding (Aubert et al., 1992; Nordberg et al., 1992; Perry et al., 1995) in post-mortem

14

L.A. RABIN ET AL.

brain tissue of AD patients compared to non-pathological controls brains (Auld et al., 2002). With regard to the frontal lobe specifically, Giacobini (2000) showed a 46% decrease in the ratio of synthesis/hydrolysis of ACh in the frontal cortex of AD patients compared to controls. Reductions in ChAT activity and ACh synthesis are known to correlate with cognitive impairments and behavioral disturbances in AD (DeKosky et al., 1992; Francis et al., 1994; Minger et al., 2000; Garcia-Alloza et al., 2005). Cholinergic neurons also appear to be involved in b-amyloid precursor protein (APP) processing, and subsequent manifestation of b-amyloid deposition and development of toxic neuritic plaques (Buccafusco and Terry, 2000). These clinical findings, together with evidence for impaired cognition in both animals and normal humans after cholinergic blockade, led to the development of the ‘cholinergic hypothesis of geriatric memory dysfunction,’ which relates deterioration of cognition in AD to a decline in basal forebrain cholinergic transmission (reviewed in Bartus et al., 1982; Auld et al., 2002). In modified form, this hypothesis still motivates investigation of the mechanisms that underlie systemically administered cholinergic agents that alter cognition and behavior in animals and humans (for review see Gallagher and Colombo, 1995; Lawrence and Sahakian, 1995). Common treatment approaches for AD have included increasing ACh production via supplementation with cholinergic precursors, directly stimulating post-synaptic muscarinic and nicotinic receptors, enhancing ACh release by acting on autoreceptors, and inhibiting synaptic ACh degradation. More recent strategies have aimed to prevent cholinergic neuronal death using trophic factors, grafts, or gene therapy (for reviews see Kasa et al., 1997; Winkler et al., 1998; Emilien et al., 2000; Auld et al., 2002; Lemstra et al., 2003; Giacobini, 2003a; 2003b; 2004). Initial attempts to alleviate the cholinergic deficit in AD focused on replacement therapy with ACh precursors such as choline or lecithin (Higgins and Flicker, 2000). Data from clinical trials have not supported use of ACh precursors, given their limited penetration across the blood–brain barrier, short duration of action, and the fact that precursor concentrations typically are not rate-limiting variables in the ACh synthetic pathway (Ducis, 1988; Kumar and Calache, 1991; Tucek, 1993; Sirvio, 1999; Auld et al., 2002). Researchers also have attempted to modulate cholinergic activity at the receptor level. For example, a potential target for muscarinic receptor intervention is the post-synaptic M1-subtype, which is relatively spared in brains of patients with AD (Araujo et al., 1988; Bodick et al., 1997). Though in vitro and in vivo studies with M1 muscarinic receptor agonists initially showed promise in alleviating cognitive

impairments and reducing t protein phosphorylation and APP/b-amyloid pathology, studies with clinical patients have revealed limited efficacy and a high incidence of side effects (Veroff et al., 1998; Ladner and Lee, 1999; Emilien et al., 2000; Fisher, 2000; Korczyn, 2000; Doggrell and Evans, 2003). Another treatment approach involves blocking presynaptic M2 muscarinic ACh autoreceptors, which exert negative feedback on ACh release (Quirion et al., 1994). Overall, research in animals has shown that potent and selective M2 antagonists can increase in vivo striatal ACh release and improve cognitive performance, and it remains to be seen whether these gains can be achieved in humans (Quirion et al., 1995; Cohen et al., 2000; Thal et al., 2000; Weiss et al., 2000; Carey et al., 2001; Lachowicz et al., 2001; Auld et al., 2002). Cholinesterase inhibitors are currently the most practical and beneficial method for enhancing cholinergic neurotransmission (Giacobini, 2000). Normally, ACh released from neurons is inactivated rapidly by AChE or more slowly by BuChE. Drugs that inhibit one or both of these enzymes serve to increase its concentration and duration of action (Sirvio, 1999). First- (tacrine, velnacrine, physostigmine) and second-generation (donepezil, rivastigmine, galantamine) AChEIs have yielded positive results in terms of ameliorating cognitive dysfunction associated with AD (Lanctot et al., 2003), and are considered the current standard of care.4 Though comprehensive review of the efficacy of AChEIs is beyond the scope of this chapter, meta-analyses generally report modest but significant therapeutic effects in 4

First generation AChEIs had a short duration of action and lacked specificity for AChE, and are rarely still used clinically (Thal, 1996; Lanctot et al., 2003). Second-generation drugs produce less severe side effects at effective doses and share the ability to inhibit AChE, but are distinguished by their pharmacologic variations (Giacobini, 2004). Donepezil inhibits AChE but not BuChE (Bryson and Benfield, 1997), the latter of which may be a component of neuritic plaques and tangles (Wright et al., 1993). Rivastigmine has central selectivity (Gottwald and Rozanski, 1999) and inhibits both enzymes involved in breaking down ACh, which may provide added clinical benefit (Ballard, 2002; Racchi et al., 2004). Galantamine provides allosteric modulation of nicotinic receptors (Scott and Goa, 2000; Sramek et al., 2000), a characteristic that may offer disease-modifying benefits (Coyle and Kershaw, 2001; Zarotsky et al., 2003). Some preliminary head-to-head trials have indicated slightly better response with donepezil than galantamine, and similar efficacy for donepezil and rivastigmine. Initial results also indicated higher tolerability for donepezil than for galantamine and rivastigmine (Wilkinson et al., 2002; Jones et al., 2004; Ritchie et al., 2004). Unfortunately, important issues such as openlabel design, dose of the comparator, and titration rate may account for observed findings (Lanctot et al., 2003).

CHOLINERGIC COMPONENTS OF FRONTAL LOBE FUNCTION AND DYSFUNCTION terms of cognition, function, and global outcome with these drugs relative to placebo in patients with mild to moderate AD (Lanctot et al., 2003; Ritchie et al., 2004). AChEIs also show modest benefit in neuropsychiatric and functional outcomes (Qizilbash et al., 1998; Trinh et al., 2003). Current cholinergic treatment approaches are primarily symptomatic because they do not halt the eventual progression of dementia. In AD, the notable presence of AChE in senile plaques has led to the hypothesis that this protein might bind ab and promote its deposition. In vitro work has shown that AChE promotes the formation of insoluble fibrils containing ab and AChE, which are more toxic to cells that ab alone (Inestrosa et al., 2005). Transgenic animal models have confirmed an increase in plaque formation when ab presents alongside increased levels of AChE (Rees et al., 2005). Overall, extant research indicates that AChEIs may modify the course of disease by interfering with the synthesis, deposition, and aggregation of toxic amyloid-b-peptides, slowing the neurodegenerative process (Rodriguez-Franco et al., 2005; Woodruff-Pak and Gould, 2002). This has led to speculation a dual-site compound with disease-modifying properties can be synthesized, which would target AChE at both its active (the mechanism of current agents) and peripheral sites, thus occupying the entire catalytic gorge. If developed, such dual binding agents might enhance cognitive function while simultaneously interfering with ab aggregation (Castro and Martinez, 2001; Dorronsoro et al., 2003; Martinez and Castro, 2006). Current research is focused on maximizing benefits attained with available AChEIs while developing variants of current drugs with additional features or innovative modes of administration such as intranasal delivery (e.g., NP-7557), transdermal administration (e.g., Tolserine, Thiatolserine), or injectable, sustained release formulations (e.g., ZT-1) (for review see Martinez and Castro, 2006). Novel agents such as hybrid compounds that simultaneously act in two different neurotransmitter systems (BGC-20–1259, which combines AChE and 5-HT transport inhibition) or that increase their potency in the single target (i.e., AChE) are under development as well (Martinez and Castro, 2006). Drug combinations also may prove to be a productive way to enhance treatment effects, such as using an AChEI together with a muscarinic or nicotinic agonist (with higher selectivity than those presently available) (Giacobini, 2000; 2004). Recent work also suggests a role for BuChE in ACh hydrolysis and as a contributor to the occurrence, symptoms, and progression of dementia (Mesulam et al., 2002). BuChE activity has been shown to progressively increase as the severity of dementia

15

advances due to an increase in glial cell activity, suggesting that inhibition of BuChE may provide additional treatment benefits, particularly in late disease stages (Giacobini, 2004). Preliminary work with rivastigmine suggests that central BuChE inhibition can improve cognition in AD (Giacobini et al., 2002), and this inhibition correlates more strongly with cognitive improvement than inhibition of AChE (Costa et al., 1999). Opinions differ, however, on whether selective inhibitors of AChE alone (e.g., donepezil) or nonselective inhibitors of both AChE and BuChE (e.g., rivastigmine, physostigmine) offer the best clinical outcome. Kuhl et al. (2006) used 11C-labeled radiotracers to measure in vivo BuChE and AChE activity in the cerebral cortices of AD and control participants at baseline and after treatment with donepezil or physostigmine. Results failed to reveal increased BuChE activity after months of selective AChE inhibition, making it unlikely that incremental BuChE contributes importantly to ACh hydrolysis in AD. Overall findings did not support the premise that AChEIs should target BuChE to prevent increased levels of BuChE from hydrolyzing ACh in the AD cerebral cortex. Another notable finding, that warrants replication, was that the in vivo AD brain did not demonstrate the increased BuChE activity consistently reported from in vitro studies of postmortem patients (Geula and Darvesh, 2004; Giacobini et al., 2002). The next sections will review current use of AChEIs in disease states other than AD, and consider the possibility that cognitive and behavioral benefits derived from these drugs may be mediated through inhibition of AChE activity in the frontal cortex. 1.6.2. Vascular dementia Vascular cognitive impairment and dementia (VaD) are no longer thought to be the primary cause of dementia in the elderly but may be a contributing factor in a larger percent of cases. VaD is associated with an abrupt onset and fluctuating or stepwise course, as well as more focal or patchy neurological and cognitive deficits and neuroimaging evidence of a cerebrovascular event in temporal proximity to the cognitive decline (Metter and Wilson, 1993; Dugue et al., 2003). Early treatment of hypertension and vascular disease can help prevent further progression. The term VaD actually comprises several heterogeneous conditions, including cortical (or multi-infarct), subcortical, and strategic infarct vascular dementia (Pirttila et al., 2003; Bullock, 2004). Additionally, the relationship between AD and VaD is complex, in part because AD and strokes are both common and coexist frequently, and because evidence suggests that small strokes or risk factors for vascular

16

L.A. RABIN ET AL.

disease may lead to increased clinical expression of AD (Kalaria and Ballard, 1999; Lopez et al., 2005). Research has confirmed that cholinergic dysfunction is important in the cognitive decline observed in VaD, and that reduction in cholinergic function is associated with decreased nicotinic receptors, particularly the a7 subtype (Wallin et al., 1989; Gottfries et al., 1994; Togashi et al., 1996; Ferrari et al., 1999). There are several published studies using AChEIs in patients with vascular-related cognitive impairment. The largest clinical trial of pure probable VaD included approximately 1200 participants recruited for a 24week randomized, placebo-controlled, multicenter and multinational study of donepezil, which was divided into two identical trials (Black et al., 2003; Wilkinson et al., 2003). Patients with pre-existing AD or AD plus cerebrovascular disease (CVD) were excluded. Combined analyses from the two studies indicated that the treatment groups showed significant improvements in cognition, global function, and activities of daily living. Donepezil was tolerated well, with low withdrawal rates due to adverse events, and treatment was not associated with increased incidence of cardiovascular events (Roman et al., 2005). With regard to galantamine, Erkinjuntti et al. (2002a) conducted a multicenter, randomized, double-blind, controlled 6-month trial in approximately 600 patients diagnosed with probable VaD or AD plus CVD. Galantamine demonstrated efficacy in terms of cognition, global functioning, behavioral symptoms, and activities of daily living as compared to placebo, though a subgroup analysis suggested that effects were less pronounced in the pure VaD group. In an open-label 6-month extension, the original galantamine groups with probable VaD and AD plus CVD showed similar sustained benefits in terms of maintenance or improvement in cognition, functional ability, and behavior (Erkinjuntti et al., 2003). An important study finding was galantamine’s beneficial effects in patients with AD with concomitant CVD, a group not typically studied despite the fact that it may represent the largest group actually seen clinically for dementia workup (Erkinjuntti et al., 2002b). Moretti et al. (2001; 2002) conducted a small study of rivastigmine treatment in patients with probable subcortical VaD. Results showed that long-term treatment (22 months) was associated with general stability of cognition and daily function, and improvements in aspects of executive function, neuropsychiatric function, and social conduct relative to a control group; reductions in caregiver stress also were noted. In a larger randomized, controlled, open 12-month study of subcortical VaD, the rivastigmine treatment group showed less decline in aspects of executive function and improved behavior compared to patients treated with

aspirin (Moretti et al., 2003). Side effects were tolerable in both studies. Another notable finding was that the observed cognitive improvements involved aspects of executive function and behavior, processes typically associated with frontal lobe functioning. These benefits may reflect rivastigmine’s dual inhibitory effects on the cholinergic system (i.e., AChE and BuChE), and its particular activity in frontal brain regions possibly due to a preferential affinity for the G1 isoform of AChE (Weinstock, 1999). It is also worth mentioning that in studies of AD patients, those with concurrent vascular risk factors have tended to show greater clinical benefit, particularly with regard to cognition, after treatment with rivastigmine (Kumar et al., 2000; Erkinjuntti et al., 2002b). Several explanations for this increase effect in patients with vascular risk factors are being considered including rivastigmine’s ability to increase cerebral blood flow, which would confer protection against focal ischemia or worsening of vascular pathology (Kumar et al., 2000). Overall, research indicates that AChEIs have efficacy in VaD and AD plus CVD, although difficulties remain with regard to differential diagnosis in these clinical populations (Bullock, 2004; Erkinjuntti et al., 2004). 1.6.3. Dementia with Lewy bodies Dementia with Lewy bodies accounts for approximately 20% of all autopsy-confirmed dementias in old age, making it the second most common cause of degenerative dementia after AD (Hansen et al., 1990; McKeith et al., 2000b). Diagnosis of DLB is complicated by the extensive overlap in symptoms and pathology with both AD and dementia occurring in the course of Parkinson’s disease PD (McKeith et al., 1996; McKeith and Burn, 2000; McKeith et al., 2004). Current consensus criteria suggest that a diagnosis of DLB should be reserved for patients in which dementia either precedes the clinical presence of parkinsonian motor symptoms or occurs within the first year after onset of Parkinsonism. Recent genetic findings related to the a-synuclein gene lend support to the concept of a unitary disease process (Poewe, 2005). Dementia in both DLB and PD is associated with cortical cholinergic disturbances including cholinergic denervation and reductions in ChAT activity, which have been correlated with severity of cognitive impairment and presence of hallucinations (Nakano and Hirano, 1984; Perry et al., 1990; 1993; Jellinger and Bancher, 1995; Perry and Perry, 1996). Additionally, research suggests that postsynaptic muscarinic receptors are relatively preserved in these disorders relative to AD, despite significantly diminished neocortical ChAT activity, suggesting the potential for significant cognitive benefit with cholinergic agents

CHOLINERGIC COMPONENTS OF FRONTAL LOBE FUNCTION AND DYSFUNCTION (Perry et al., 1994). For these reasons, AChEIs have been tried in both Parkinson’s disease dementia (PDD) and DLB with generally positive results (for review see Gustavson and Cummings, 2003; Maidment et al., 2005; Poewe, 2005). Several open-label studies and case reports using AChEIs (typically donepezil) in DLB have shown improvement in general cognitive function, deliriumlike features, behavioral disturbances, and/or psychotic symptoms (Kaufer et al., 1998; Shea et al., 1998; Fergusson and Howard, 2000; Lanctot and Herrmann, 2000; Skjerve and Nygaard, 2000; Rojas-Fernandez, 2001; Bullock and Cameron, 2002). In a small, openlabel study over 12 weeks, patients with probable DLB were treated with rivastigmine and showed reductions in delusions, apathy, agitation, and hallucinations. Some of the patients experienced significant clinical improvement that had not previously been achieved with other treatments including low-dose neuroleptics, and medication generally was well tolerated (McKeith et al., 2000b). A double-blind placebo-controlled study of rivastigmine in 120 mild to moderately impaired DLB patients broadly confirmed these findings, with prominent reductions in apathy, anxiety, and psychotic symptoms after 20 weeks of treatment. Participants on the drug also demonstrated enhanced processing speed, particularly on tasks with an attentional component; after discontinuation of rivastigmine, differences between the groups diminished (McKeith et al., 2000a). Two small-scale, open-label uncontrolled studies on the use of tacrine in DLB and AD had mixed results, though both reported mild cognitive improvements in a subset of DLB patients, most notably on tests of verbal initiation and attention (Lebert et al., 1998; Querfurth et al., 2000). Given the widely reported dangers associated with neuroleptic medications in this population (McKeith et al., 1992), drugs enhancing central cholinergic function appear to offer a rationally based therapeutic approach for DLB, though more large-scale, controlled studies are clearly warranted. Positive effects have been shown most consistently in aspects of cognition (particularly attention), alertness, apathy, behavioral disturbances, and hallucinations. It also should be noted that gastrointestinal adverse affects and worsened Parkinsonism were observed in many of the reviewed studies. 1.6.4. Parkinson’s disease Dementia develops in approximately 25% of patients with PD and increases in prevalence to over 50% with advancing age and overall disease severity (Mayeux

17

et al., 1992; Aarsland et al., 2001). Extant studies on the use of AChEIs in PDD include three randomized controlled trials (two evaluating donepezil and one rivastigmine) and numerous open-label trials and case reports. A pilot study using tacrine in seven severely impaired PD patients with dementia and psychosis noted improvements in hallucinations and MMSE scores in addition to significant motor improvements after two months of treatment (Hutchinson and Fazzini, 1996). Additional small, open-label series studies have claimed efficacy for several AChEIs in terms of improving cognition and/or ameliorating psychotic symptoms (Reading et al., 2001; Werber and Rabey, 2001; Bergman and Lerner, 2002; Giladi et al., 2003). Aarsland et al. (2002) conducted the first doubleblind, randomized and controlled, crossover study in 14 patients with PD and mild to moderate cognitive impairment. After 10 weeks of treatment, performance was improved on a test of general cognitive functioning (MMSE) and a clinician-based impression of cognition; no significant treatment effects were observed on measures of neuropsychiatric symptoms or motor skills. Leroi et al. (2004) enrolled 16 patients with PDD in a randomized, double-blind placebocontrolled study over approximately 15 weeks of treatment. Results indicated significant improvement in the treatment group on a measure of memory, with trends toward improvements in psychomotor speed and attention. A larger, placebo-controlled trial of rivastigmine in mild-to-moderate PDD showed modest but significant improvements on a global cognitive rating scale and a clinician’s global impression of change index after 24 weeks of treatment (Emre et al., 2004). Significant improvements also were noted with drugs relative to placebo on secondary efficacy variables including neuropsychiatric symptoms, activities of daily living, and cognition (i.e., general cognitive ability, attention, verbal fluency, and clock-drawing ability). Based largely on the results of this study, Rivastigmine was approved by the US Food and Drug administration for the treatment of dementia in PD in 2006. Overall, studies evaluating the efficacy and tolerability of AChEIs in PDD have shown mild improvements on some measures of cognition, global change, and psychiatric status. Key limitations to the extant body of research include variable diagnostic criteria, small sample sizes, and high dropout rates, in part due to adverse gastrointestinal and motor events that may limit utility of these agents with this population. Clearly, more information is needed regarding the longer-term efficacy of AChEIs to treat cognitive dysfunction in both DLB and PDD, including effects on cognitive trajectory, clinical

18

L.A. RABIN ET AL.

disability, and outcomes such as nursing home placement, daily functioning, and survival. 1.6.5. Down syndrome Down syndrome (DS) is the most frequent genetic cause of mild to moderate mental retardation, and is associated with various medical problems, deficits in adaptive functioning, and cognitive impairments (Kishnani et al., 1999). DS presents with neuropathological and neurochemical features similar to AD including loss of cholinergic neurons providing input to limbic structures and neocortex and accumulation of b-amyloid (Wisniewski et al., 1985; Heller et al., 2003). As in AD, a cholinergic deficit has been implicated in the progressive declines frequently observed in cognition and behavior, providing a rationale for use of AChEIs in this clinical population. Prasher et al. (2002) reported the first double blind, placebocontrolled investigation of donepezil in 27 adults with DS and mild to moderate AD. Over 24 weeks, donepezil proved safe and appeared to provide benefit in terms of global, cognitive, and adaptive functioning relative to placebo, though results failed to reach statistical significance. Follow-up work with this cohort showed a similar pattern of findings with rivastigmine (Prasher et al. 2005). A later pilot study in six patients with DS and moderate dementia found significant improvement in global dementia scores relative to an untreated control group over a five month period (Lott et al., 2002). Heller et al. (2003) conducted a 24-week, openlabel clinical trial of donepezil for treatment of language deficits in six adults with DS. Despite some methodological limitations including low power and lack of untreated control group, the main study result was an improvement in expressive language performance following drug therapy. In an earlier pilot study, these researchers had demonstrated benefits in global function over nine months of treatment with donepezil (Kishnani et al., 1999). Johnson et al. (2003) conducted a 12-week randomized, double-blind, placebo-controlled study of donepezil’s effects on various aspects of cognitive functioning in 19 DS patients without dementia. After treatment, patients attained higher scores on tests of language compared to placebo, with no improvement observed on other cognitive subtests, behavior scores, or caregiver ratings. Finally, in the first open-label clinical trial of donepezil in seven children with DS, Heller et al. (2004) found improvement in selective aspects of expressive language over a 16-week period. Overall, the small body of research in DS is quite heterogeneous with regard to patients sampled (e.g., adult vs. pediatric, dementia vs. no dementia), cognitive domain tested

(e.g., language vs. global cognitive ability), and study design. Nonetheless, results show some promise, particularly in the area of language ability, and suggest the need for large-scale controlled studies of AChEIs in both pediatric and adult populations. It is also important to note that therapy was well tolerated by most participants, though adverse effects (particularly urinary incontinence) were noted in some of the adult samples (Hemingway-Eltomey and Lerner, 1999; Prasher et al., 2002). 1.6.6. Prospects for cholinergic therapies AChEIs have been studied in a wide range of other neurologic and neuropsychiatric disorders, though not as extensively or systematically as in AD. Overall, findings suggest that cognitive, behavioral, and/or psychiatric benefits can be achieved in some patient groups (e.g., autism, delirium, multiple sclerosis, bipolar disorder, depression, Tourette’s, migraine, REM sleep behavior disorder, and post-stroke aphasia) but not others (progressive supranuclear palsy, Huntington’s disease). Results are mixed for some conditions, such as mild cognitive impairment, traumatic brain injury, and schizophrenia (for review see Griffin et al., 2003; Gustavson and Cummings, 2003; Craig and Birks, 2006). It is important to note that most extant work involves small, open-label studies or multiple-case observations, and placebo effects may confound findings. Additionally, case reports are typically limited to patients who show benefit, thus the number and characteristics of individuals for whom AChEIs are unhelpful remain unknown. Nonetheless, preliminary observations identify numerous conditions worthy of further study with these agents. In particular, disorders characterized by a presynaptic cholinergic deficit (e.g., AD, PDD), appear to show greater improvements with AChEIs than disorders with a known postsynaptic cholinergic deficit (e.g., supranuclear palsy, Huntington’s disease), consistent with the postulated mechanism of action of these drugs. Most disorders, however, cannot readily be incorporated into a pre- or postsynaptic cholinergic deficit framework because detailed information about the integrity of the cholinergic system is not presently available. Another important consideration is the degree to which observed benefits with cholinergic treatment are moderated via the frontal lobes. Evidence from neuroimaging (discussed above) and other research suggests that AChEIs may exert regionally specific effects on frontal regions in some circumstances (Saykin et al., 2004). For example, Nordberg et al. (1998) showed that treatment with high doses of tacrine in three mild AD patients improved mean EEG frequency in large brain areas, whereas short-term treatment consistently

CHOLINERGIC COMPONENTS OF FRONTAL LOBE FUNCTION AND DYSFUNCTION affected the frontal lobes; improvement on a neuropsychological test of attentional switching also was observed following treatment. Kaasinen et al. (2002) examined the direct effects of donepezil or rivastigmine in the frontal, temporal, and parietal cortices of 11 mild to moderate AD patients at baseline and after three months of treatment. Results for the combined treatment groups showed that treatment with AChEIs induced greater AChE inhibition in the frontal as compared to the temporal cortex in AD, likely due to the prominent temporoparietal reduction of AChE in AD. The researchers suggested that improvement in behavioral and attentional symptoms of AD after treatment may be associated with frontal AChE inhibition. This finding augments other research suggesting that agitation and aberrant motor behavior are correlates of greater neurofibrillary tangle pathology in the orbitofrontal cortex, while increased apathy relates to greater disease burden in the anterior cingulate (Tekin et al., 2001). Additionally, Nobili et al. (2002) evaluated brain perfusion changes on SPECT in mild to moderate AD during chronic AChEI therapy (average 15 months) in relation to cognitive status. For patients who declined cognitively over the course of the study, rCBF was significantly lower in the left lateral frontal cortex after treatment, whereas no change occurred in patients with stabilized cognitive performance, suggesting better preservation of rCBF in this region for treatment responders. Together these findings suggest that the effect of AChEI therapy is more likely to be found in areas that are less involved by disease process, such as frontal regions, at least in mild disease stages, and that AChEIs may influence cognition in part by upregulating frontal systems functioning. Research also suggests that aspects of cognition and behavior known to be mediated by the frontal lobes, particularly attentional control, can improve with pharmacologic stimulation of cholinergic receptors. It is important to keep in mind, however, that cholinergic projections are widespread and interact with other neurotransmitter systems, perhaps suggesting a more global alteration in brain activity with cholinergic therapy (Levin and Simon, 1998; Saykin et al., 2004; Thiel, 2003). Future research should further investigate regional differences in the effects of AChE inhibitors and the relation of these differences to observed clinical effects.

1.7. Additional treatment directions 1.7.1. Nicotinic cholinergic strategies Research has investigated relations between smoking, nicotine exposure, direct stimulation of nicotinic receptors and neurodegenerative diseases such as AD and PD (for review see Sabbagh et al., 2002), with the hope of

19

discerning any therapeutic potential. In addition to increasing cholinergic neurotransmission, nicotine may provide cascading effects via stimulation of the release of various other neurotransmitters involved in cognition and behavior including dopamine, norepinephrine, and glutamate (McGehee et al., 1995; Pauly, 1999). With regard to smoking, evidence is mixed concerning protective effects in AD, though smoking is clearly associated with reduced risk of PD, possibly due to the upregulation of dopaminergic neurotransmission (Morens et al., 1995). Trials involving subcutaneous administration of nicotine have revealed mild benefits in AD patients, particularly in the areas of visual attention and perception and reaction time (Sahakian et al., 1989; Jones et al., 1992). Small studies with the nicotine patch also have shown positive effects on learning or attention in AD, with no evidence of overall clinical improvement (Wilson et al., 1995; White and Levin, 1999). With regard to nicotinic receptor agonists, a question remains as to their utility in the treatment of neurodegenerative diseases. Lemay et al. (2004) found that transdermal nicotine was not effective in treating motor and cognitive deficits in PD, although a nicotinic agonist has shown cognitive and motor benefit in an animal model of PD (Schneider et al., 1999). Bontempi et al. (2001) reported that peripheral administration of a nicotinic acetylcholine receptor (nAChR) agonist that selectively binds the b4 subunit, improved performances in working memory tasks in aged mice and rhesus monkeys. Another selective nicotinic agonist (ABT-418), initially showed promise for boosting cognition in AD (Potter et al., 1999), but has not been the focus of follow-up study. Also unclear is whether the AChEI galantamine, with its effects at nicotinic receptors, confers advantage over agents that act exclusively at the level of cholinesterase enzyme inhibition. Effects of chronic nicotine exposure on abeta accumulation also have been studied in animal models, and with mixed results. For example, Nordberg et al. (2002) showed that chronic nicotine administration lowers plaque load in APP transgenic mice with extensive abeta pathology. Oddo et al. (2005), however, found that nicotine can significantly increase phosphorylation and aggregation of tau, suggesting that nicotinic treatment may have differential effects on abeta or tau. Overall, nicotinic strategies have not been studied extensively or systematically enough to warrant firm conclusions about their treatment efficacy in neurodegenerative processes with known cholinergic deficits. Additionally, many questions remain, including whether cognitive and/or neuroprotective benefits are mediated via acute, repetitive, or more chronic inactivation of nAChR or by some combination of these actions (Sabbagh et al., 2002).

20

L.A. RABIN ET AL.

1.7.2. Gene therapy Therapies reviewed thus far, which are aimed at enhancing neurotransmitter activity (e.g., cholinesterase inhibitors, neurotransmitter precursors), are likely to result in only short-term improvements under conditions where cell degeneration is persistent. In such cases, a more successful strategy might involve attempts to enhance cell survival directly. One strategy is gene therapy, which entails the use of retroviral vectors to genetically modify cells to produce neurotrophic factors at the site of cell degeneration. Once transfected and implanted, the cells are capable of delivering therapeutic substances in a highly targeted, site-specific manner for a prolonged period of time without additional manipulation (Tuszynski et al., 2005). The transfection can be performed either ex vivo or in vivo. Research thus far has focused on ex vivo techniques, which entail the acquisition of host cells that are transfected and grafted into a brain area of interest. Because the transfected cells are host-derived, this type of procedure is not subject to complications normally associated with an immune response to grafted tissue from a non-host source. Although such ex vivo gene therapy is highly effective for therapeutic delivery (Tuszynski et al., 2005), the associated cost and various logistic considerations have motivated researchers to begin examining in vivo methods. In vivo therapies involve direct introduction of viral vectors to the target brain region and therefore represent a relatively straightforward procedure. The safety of in vivo strategies, however, is somewhat unclear as retroviral incorporation into the host genome has the potential to lead to mutations, or the activation or inactivation of genes, and ultimately the transformation of host cells (Tuszynski and Blesch, 2004; Ebert and Svendsen, 2005). Gene therapy, as a strategy for preventing the progression of neurodegeneration, is as yet unproven but could play a future role in managing diseases such as AD, VaD, PD, DLB, and DS, all of which are characterized by cholinergic cell loss (Perry, 1999; Roman and Kalaria, 2005). Numerous studies already have demonstrated that trophic factors, whose size and chemical properties prevent them from crossing the blood–brain barrier, can be successfully delivered to target brain regions with the use of retroviral vectors (Tuszynski et al., 2005). To illustrate, a therapeutic approach to the treatment of AD involves the administration of nerve growth factor (NGF), which plays an important role in promoting cell survival and axon outgrowth during development. In the adult brain, NGF is secreted by cells within the cortex, and exerts an important neurotrophic influence on afferent basal forebrain cell populations. Experimental studies have

shown that NGF administration can prevent lesioninduced degeneration of basal forebrain cells (Hefti, 1986) and moreover, appears to have the ability to stimulate ACh production in the remaining population of cells (Dekker et al., 1991). In addition to having a significant impact on cholinergic cell survival and activity, NGF also has been shown to influence function, reducing age-associated impairments in learning and memory (Fischer et al., 1987). While it is clear that NGF has the potential to be of substantial therapeutic value, its administration has proven somewhat problematic. Because of the size and polarity of the protein, studies using NGF historically have involved administration via intracerebroventricular (ICV) infusion. Administration via this relatively nonspecific route, however, results in the activation of sensory nociceptive neurons, sympathetic neurons, and Schwann cells. These events in turn cause pain, weight loss, and the migration/proliferation of Schwann cells into the subpial space surrounding the brainstem and spinal cord. In order to circumvent these issues, researchers have investigated the use of gene therapy as an alternative means of NGF delivery. In a recent phase 1 clinical trial, cells that had been genetically altered to produce NGF were grafted in close proximity to the nucleus basalis of eight patients exhibiting early signs of AD (Tuszynski et al., 2005). Results indicated that the grafts successfully induced robust cholinergic axon sprouting into the site of NGF delivery as well as increases in glucose uptake by cortical neurons as revealed by PET. In addition, assessments performed using two common clinical measures of cognitive function in AD suggested that disease progression was reduced. Although it was impossible to determine whether the grafts enhanced cholinergic cell survival and activity in this study, previous observations of primates provide some support for these assertions (Tuszynski et al., 1990; 1996; 2002). In summary, advancements in the understanding of cholinergic dysfunction associated with various disease processes have led to novel treatments. Inhibition of AChE has emerged as the leading therapeutic target for the cognitive and functional problems experienced by patients, particularly those with AD. The emerging relationship between cholinergic neurotransmission and the metabolism of key proteins involved in AD and other disorders (b-amyloid and tau) has given new impetus to the cholinergic approach to therapy, and suggests that AChEIs may provide neuroprotective effects. Other approaches such as intracerebral administration of NGF and gene transfer to locally deliver NGF or ACh have shown promise in reversing behavioral and biochemical disruptions associated with compromised basal-cortical system functioning

CHOLINERGIC COMPONENTS OF FRONTAL LOBE FUNCTION AND DYSFUNCTION (Winkler et al., 1998). Continued research efforts with each of the strategies discussed above undoubtedly will provide new insights into how to reverse or curtail cholinergic deficits and consequent cognitive impairments in various patient populations.

1.8. Conclusions The current chapter reviewed cholinergic neuroanatomy, neurochemistry, and physiology related to frontal lobe function and dysfunction. The cholinergic system exerts its widespread influence on the frontal cortex via both direct and indirect projections. Direct projections from the NBM of the basal forebrain to frontal regions maintain a desynchronized pattern of activity that enhances neuronal responsiveness to stimuli. At the same time, a complementary population of NBM cells, which project to the nucleus reticularis, also contributes to neocortical activation by inhibiting the RTthalamocortical synchronizing system. Indirect cholinergic innervation of the frontal lobe originates primarily in the pedunculopontine and laterodorsal tegmental nuclei, which modulate prefrontal activity via their input to the mediodorsal thalamus. However, pathways that include the basal ganglia also have been identified as a source of indirect cholinergic influence on the frontal cortex. The ventral striatum, for example, projects to thalamic nuclei that provide information to the anterior cingulate and orbitofrontal cortices. Additionally, dopaminergic cells of the SNc provide input to frontal regions and receive cholinergic input originating from the reticular formation and amygdala. Given the nature of these afferents, dopaminergic cells of the SNc may play a role in processing the salience of stimuli. ACh acts via nicotinic and muscarinic receptor subtypes. Of the five muscarinic receptor subtypes, M1 is most abundant and may be responsible for rendering neurons in the frontal cortex more responsive to other excitatory input. Although not expressed as abundantly as the M1 receptor, M2 autoreceptors also are expressed in the frontal cortex and are primarily responsible for regulating ACh release in the neocortex. Broadly speaking, the activity of both receptors appears to be decreased under pathological conditions associated with cholinergic dysfunction. Of the nicotinic receptors, the most relevant to frontal lobe function may be the a7 subtype, which is thought to promote cell survival. Research suggests that the a7 subtype is specifically vulnerable to effects of abeta peptides and may contribute to cell degeneration. Consistent with this hypothesis, disorders involving cholinergic dysfunction are associated with decreased a7 receptor activity. It remains

21

unclear, however, whether nicotinic receptor activity changes are responsible for cholinergic system pathology or occur in response to this pathology. Direct evidence from functional brain imaging implicates the cholinergic system in frontally mediated aspects of arousal, attention, working memory, and executive function. Research in clinical populations, particularly dementia, has shown that treatment with acetylcholinesterase inhibitors can enhance or ‘normalize’ activity of frontal circuitry, and that regional changes in activation may be associated with improved cognition. Additionally, effects of pharmacological agents on brain function appear to be region-specific, process-specific, disease-specific, and may vary with age and cognitive capacity. While extant research has focused on localized effects of pharmacological manipulations, future studies likely will emphasize inter-regional function and interaction of cognitive, neurophysiological, and genetic mechanisms in disease processes. Pharmacological neuroimaging increasingly may be used to evaluate treatment mechanisms and predict response in various clinical populations, and the prospect of tailoring therapy to patients based on initial PET or fMRI assessment has great value from both an economic and clinical standpoint. Quantitative measurement of cortical AChE also is a potentially powerful tool for early diagnosis therapeutic monitoring of cholinergic medications. The reduction of AChE activity, known to be associated with various neurodegenerative processes, can be measured in vivo using PET with 11 C-labeled AChE substrates. Novel 18F-labeled radiotracers (currently under development), may confer advantages over extant substrates, including longer imaging times, better image quality, and ease of transport to other research and clinical facilities. ACh, in concert with other neurotransmitters, modulates various cognitive functions, including attention, learning, and memory. Degeneration of neurons in the NBM appears to occur early in the course of several disease processes, and is correlated with the severity of observed cognitive decline. Based on the ‘cholinergic hypothesis’ of memory, AChEIs were developed to ameliorate the cognitive symptoms of Alzheimer’s disease and other disorders including vascular dementia, dementia with Lewy bodies, Parkinson’s disease, and Down syndrome. These treatments often exert their most distinctive effects through modulation of the brain’s frontal systems. In addition to providing modest improvements in cognition, behavior, and global outcome, cholinergic drugs may confer neuroprotection through the activation of nicotinic receptors or through their effect on amyloid precursor protein abeta. Thus, evidence suggests that the cholinergic system is not

22

L.A. RABIN ET AL.

a neuropathological bystander, but that a reciprocal interaction exists between cholinergic neurons and the neurotoxic species of the beta amyloid peptide, which plays a critical role in the neurodegenerative process. Current research aims to produce agents that employ innovative modes of administration, simultaneously act on more than one neurotransmitter system, exert their inhibitory action in a selective or nonselective fashion with regard to AChE and BuChE, or involve the local delivery of nerve growth factor or ACh to individuals with compromised basal-cortical systems. These efforts undoubtedly will help prevent or reverse the cholinergic deficits associated with various human diseases and shed light on how observed treatment benefits are moderated via the frontal lobes.

References Aarsland D, Andersen K, Larsen JP, et al. (2001). Risk of dementia in Parkinson’s disease: A community-based prospective study. Neurology 56: 730–736. Aarsland D, Laake K, Larsen JP, et al. (2002). Donepezil for cognitive impairment in Parkinson’s disease: A randomized controlled study. J Neurol Neurosurg Psychiatry 72: 708–712. Araujo DM, Lapchak PA, Robitaille Y, et al. (1988). Differential alteration of various cholinergic markers and subcortical regions of human brain in Alzheimer’s disease. J Neurochem 50: 1914–1923. Arnold H, Burk J, Hodgson E, et al. (2002). Differential cortical acetylcholine release in rats performing a sustained attention task versus behavioral control tasks that do not explicitly tax attention. Neuroscience 114: 451–460. Aubert I, Araujo DM, Cecyre D, et al. (1992). Comparative alterations of nicotinic and muscarinic binding sites in Alzheimer’s and Parkinson’s diseases. J Neurochem 58: 529–541. Auld DS, Kornecook TJ, Bastianetto S, et al. (2002). Alzheimer’s disease and the basal forebrain cholinergic system: Relations to b-amyloid peptides, cognition, and treatment strategies. Prog Neurobiol 68: 209–245. Bartus RT, Dean RL, Beer B, et al. (1982). The cholinergic hypothesis of geriatric memory dysfunction. Science 217: 408–417. Bentley P, Husain M, Dolan RJ (2004). Effects of cholinergic enhancement on visual stimulation, special attention, and spatial working memory. Neuron 41: 969–982. Bentley P, Vuilleumier P, Thiel CM, et al. (2003a). Cholinergic enhancement modulates neural correlates of selective attention and emotional processing. Neuroimage 20: 58–70. Bentley P, Vuilleumier P, Thiel CM, et al. (2003b). Effects of attention and emotion on repetition priming and their modulation by cholinergic enhancement. J Neurophysiol 90: 1171–1181.

Bergman J, Lerner V (2002). Successful use of donepezil for the treatment of psychotic symptoms in patients with Parkinson’s disease. Clin Neuropharmacol 25: 107–110. Bigl V, Woolf NJ, Butcher LL (1982). Cholinergic projections from the basal forebrain to frontal, parietal, temporal, occipital, and cingulate cortices: A combined fluorescent tracer and acetylcholinesterase analysis. Brain Res Bull 8: 727–749. Black S, Roman GC, Geldmacher DS, et al. (2003). Efficacy and tolerability of donepezil in vascular dementia: Positive results of a 24-week, multicenter, international, randomized, placebo-controlled clinical trial. Stroke 34: 2323–2330. Bodick NC, Offen WW, Levey AI, et al. (1997). Effects of xanomeline, a selective muscarinic receptor agonist, on cognitive function and behavioral symptoms in Alzheimer’s disease. Arch Neurol 54: 465–473. Bontempi B, Whelan KT, Risbrough VB, et al. (2001). SIB1553A, (þ/-)-4-[[2-(1-methyl-2-pyrrolidinyl)ethyl]thio]phenol hydrochloride, a subtype-selective ligand for nicotinic acetylcholine receptors with putative cognitive-enhancing properties: Effects on working and reference memory performances in aged rodents and nonhuman primates. J Pharmacol Exp Ther 299: 297–306. Bryson HM, Benfield P. (1997). Donepezil. Drugs Aging 10: 234–239. Buccafusco JJ, Terry Jr. AV (2000). Multiple central nervous system targets for eliciting beneficial effects on memory and cognition. Perspect Pharmacol 295: 438–446. Bullock R (2004). Cholinesterase inhibitors and vascular dementia: Another string to their bow? CNS Drugs 18: 79–92. Bullock R, Cameron A (2002). Rivastigmine for the treatment of dementia and visual hallucinations associated with Parkinson’s disease: A case series. Curr Med Res Opin 18: 258–264. Buzsaki G, Bickford RG, Ponomareff G, et al. (1988). Nucleus basalis and thalamic control of neocortical activity in the freely moving rat. J Neurosci 8: 4007–4026. Bymaster FP, McKinzie DL, Felder CC, et al. (2003). Use of M1-M5 muscarinic receptor knockout mice as novel tools to delineate the physiological roles of the muscarinic cholinergic system. Neurochem Res 28: 437–442. Carey J, Billard W, Binch III H, et al. (2001). SCH-57790, a selective muscarinic M2 receptor antagonist, releases acetylcholine and produces cognitive enhancement in laboratory animals. Eur J Pharmacol 431: 189–200. Castro A, Martinez A (2001). Peripheral and dual binding site acetylcholinesterase inhibitors: Implications in treatment of Alzheimer’s disease. Mini Rev Med Chem 1: 267–272. Castro NG, Albuquerque EX (1995). alpha-Bungarotoxinsensitive hippocampal nicotinic receptor channel has a high calcium permeability. Biophys J 68: 516–524. Caulfield MP, Birdsall NJ (1998). International Union of Pharmacology. XVII. Classification of muscarinic acetylcholine receptors. Pharmacol Rev 50: 279–290.

CHOLINERGIC COMPONENTS OF FRONTAL LOBE FUNCTION AND DYSFUNCTION Chu Y, Cochran EJ, Bennett DA, et al. (2001). Down-regulation of trkA mRNA within nucleus basalis neurons in individuals with mild cognitive impairment and Alzheimer’s disease. J Comp Neurol 437: 296–307. Cohen VI, Jin B, McRee RC, et al. (2000). In vitro and in vivo M2 muscarinic subtype selectivity of some dibenzodiazepinones and pyridobenzodiazepinones. Brain Res 861: 305–315. Costa J, Anand R, Cutler N (1999). Correlation between cognitive effects and level of acetylcholinesterase inhibition in a trial of rivastigmine in Alzheimer’s patients. Proc Am Psych Assoc NR: 561. Court JA, Martin-Ruiz C, Graham A, et al. (2000). Nicotinic receptors in human brain: Topography and pathology. J Chem Neuroanat 20: 281–298. Couturier S, Bertrand D, Matter JM, et al. (1990). A neuronal nicotinic acetylcholine receptor subunit (alpha 7) is developmentally regulated and forms a homo-oligomeric channel blocked by alpha-BTX. Neuron 5: 847–856. Cox CL, Metherate R, Ashe JH (1994). Modulation of cellular excitability in neocortex: Muscarinic receptor and second messenger-mediated actions of acetylcholine. Synapse 16: 123–136. Coyle J, Kershaw P (2001). Galantamine, a cholinesterase inhibitor that allosterically modulates nicotinic receptors: Effects on the course of Alzheimer’s disease. Biol Psychiatry 49: 289–299. Coyle JT, Price DL, DeLong MR (1983). Alzheimer’s disease: A disorder of cortical cholinergic innervation. Science 219: 1184–1190. Craig D, Birks J (2006). Galantamine for vascular cognitive impairment. Cochrane Database Syst Rev 1: CD004746. Cummings JL (1995). Anatomic and behavioral aspects of frontal-subcortical circuits. Ann N Y Acad Sci 769: 1–13. Darvesh S, Hopkins DA, Geula C (2003). Neurobiology of butyrylcholinesterase. Nat Rev Neurosci 4: 131–138. Davies P, Maloney AJ (1976). Selective loss of central cholinergic neurons in Alzheimer’s disease. Lancet 2: 1403. Dekker AJ, Langdon DJ, Gage FH, et al. (1991). NGF increases cortical acetylcholine release in rats with lesions of the nucleus basalis. Neuroreport 2: 577–580. DeKosky ST, Harbaugh RE, Schmitt FA, et al. (1992). Cortical biopsy in Alzheimer’s disease: Diagnostic accuracy and neurochemical, neuropathological, and cognitive correlations. Ann Neurol 32: 625–632. Disterhoft JF, Kronforst-Collins M, Oh MM, et al. (1999). Cholinergic facilitation of trace eyeblink conditioning in aging rabbits. Life Sci 64: 541–548. Doggrell SA, Evans S (2003). Treatment of dementia with neurotransmission modulation. Expert Opin Investig Drugs 12: 1633–1654. Dorronsoro I, Castro A, Martinez A (2003). Peripheral and dual binding site inhibitors of acetylcholinesterase as neurodegenerative disease-modifying agents. Expert Opin Ther Targets 13: 1725–1732.

23

Ducis I (1988). The high-affinity choline uptake system. In: VP Whittaker (Ed.), The Cholinergic Synapse. Springer, Berlin, pp. 409–445. Dugue M, Neugroschl J, Sewell M, et al. (2003). Review of dementia. Mt Sinai J Med 70: 45–53. Ebert AD, Svendsen CN (2005). A new tool in the battle against Alzheimer’s disease and aging: Ex vivo gene therapy. Rejuvenation Res 8: 131–134. Egan TM, North RA (1986). Acetylcholine hyperpolarizes central neurones by acting on an M2 muscarinic receptor. Nature 319: 405–407. Elhusseiny A, Cohen Z, Olivier A, et al. (1999). Functional acetylcholine muscarinic receptor subtypes in human brain microcirculation: Identification and cellular localization. J Cereb Blood Flow Metab 19: 794–802. Emilien G, Beyreuther K, Masters ML, et al. (2000). Prospects for pharmacological intervention in Alzheimer’s disease. Arch Neurol 57: 454–459. Emre M, Aarsland D, Albanese A, et al. (2004). Rivastigmine for dementia associated with Parkinson’s disease. N Engl J Med 351: 2509–2518. Erkinjuntti T, Kurz A, Gauthier S, et al. (2002a). Efficacy of galantamine in probable vascular dementia and Alzheimer’s disease combined with cerebrovascular disease: A randomised trial. Lancet 359: 1283–1290. Erkinjuntti T, Kurz A, Small GW, et al. (2003). An openlabel extension trial of galantamine in patients with probable vascular dementia and mixed dementia. Clin Ther 25: 1765–1782. Erkinjuntti T, Roman G, Gauthier S (2004). Treatment of vascular dementia: Evidence from clinical trials with cholinesterase inhibitors. J Neurol Sci 226: 63–66. Erkinjuntti T, Skoog I, Lane R, et al. (2002b). Rivastigmine in patients with Alzheimer’s disease and concurrent hypertension. Int J Clin Pract 56: 791–796. Ernst M, Matochik JA, Heishman SJ, et al. (2001). Effect of nicotine on brain activation during performance of a working memory task. Proc Natl Acad Sci USA 98: 4728–4733. Everitt BJ, Robbins TW (1997). Central cholinergic systems and cognition. Annu Rev Psychol 48: 649–684. Fenster CP, Rains MF, Noerager B, et al. (1997). Influence of subunit composition on desensitization of neuronal acetylcholine receptors at low concentrations of nicotine. J Neurosci 17: 5747–5759. Fergusson E, Howard R (2000). Donepezil for the treatment of psychosis in dementia with Lewy bodies. Int J Geriatr Psychiatry 15: 280–281. Ferrari R, Frasoldati A, Leo G, et al. (1999). Changes in nicotinic acetylcholine receptor subunit mRNAs and nicotinic binding in spontaneously hypertensive stroke prone rats. Neurosci Lett 277: 169–172. Fischer W, Wictorin K, Bjorklund A, et al. (1987). Amelioration of cholinergic neuron atrophy and spatial memory impairment in aged rats by nerve growth factor. Nature 329: 65–68. Fisher A (2000). Therapeutic strategies in Alzheimer’s disease: M1 muscarinic agonists. Jpn J Pharmacol 84: 101–112.

24

L.A. RABIN ET AL.

Flynn DD, Ferrari-DiLeo G, Levey AI, et al. (1995). Differential alterations in muscarinic receptor subtypes in Alzheimer’s disease: Implications for cholinergic-based therapies. Life Sci 56: 869–876. Flynn DD, Mash DC (1993). Distinct kinetic binding properties of N-[3H]-methylscopolamine afford differential labeling and localization of M1, M2, and M3 muscarinic receptor subtypes in primate brain. Synapse 14: 283–296. Francis PT, Cross AJ, Bowen DM (1994). Neurotransmitters and neuropeptides. In: RD Terry, R Katzman, KL Bick (Eds.), Alzheimer Disease. Raven Press, New York, pp. 247–261. Frotscher M, Leranth C (1985). Cholinergic innervation of the rat hippocampus as revealed by choline acetyltransferase immunocytochemistry: A combined light and electron microscopic study. J Comp Neurol 239: 237–246. Furey ML, Pietrini P, Alexander GE, et al. (2000a). Cholinergic enhancement improves performance on working memory by modulating the functional activity in distinct brain regions: A positron emission tomography regional cerebral blood flow study in healthy humans. Brain Res Bull 51: 213–218. Furey ML, Pietrini P, Haxby JV (2000b). Cholinergic enhancement and increased selectivity of perceptual processing during working memory. Science 290: 2315–2319. Furey ML, Pietrini P, Haxby JV, et al. (1997). Cholinergic stimulation alters performance and task-specific regional cerebral blood flow during working memory. Proc Natl Acad Sci USA 94: 6512–6516. Gallagher M, Colombo PJ (1995). Aging: The cholinergic hypothesis of cognitive decline. Curr Opin Neurobiol 5: 161–168. Garcia-Alloza M, Gil-Bea FJ, Diez-Ariza M, et al. (2005). Cholinergic-serotonergic imbalance contributes to cognitive and behavioral symptoms in Alzheimer’s disease. Neuropsychologia 43: 442–449. Geerts H (2005). Indicators of neuroprotection with galantamine. Brain Res Bull 64: 519–524. Geula C, Darvesh S (2004). Butyrylcholinesterase, cholinergic neurotransmission and the pathology of Alzheimer’s disease. Drugs Today (Barc) 40: 711–721. Geula C, Mesulam MM, Saroff DM, et al. (1998). Relationship between plaques, tangles, and loss of cortical cholinergic fibers in Alzheimer disease. J Neuropathol Exp Neurol 57: 63–75. Giacobini E (2000). Cholinesterase inhibitor therapy stabilizes symptoms of Alzheimer disease. Alzheimer Dis Assoc Disord 14: S3–S10. Giacobini E (2003a). Cholinergic function and Alzheimer’s disease. Int J Geriatr Psychiatry 18: S1–S5. Giacobini E (2003b). Cholinesterases: New roles in brain function and in Alzheimer’s disease. Neurochem Res 28: 515–522. Giacobini E (2004). Cholinesterase inhibitors: New roles and therapeutic alternatives. Pharmacol Res 50: 433–440. Giacobini E, Spiegel R, Enz A, et al. (2002). Inhibition of acetyl- and butyryl-cholinesterase in the cerebrospinal fluid of patients with Alzheimer’s disease by rivastigmine:

Correlation with cognitive benefit. J Neural Transm 109: 1053–1065. Giladi N, Shabtai H, Gurevich T, et al. (2003). Rivastigmine (Exelon) for dementia in patients with Parkinson’s disease. Acta Neurol Scand 108: 368–373. Goekoop R, Rombouts SARB, Jonker C, et al. (2004). Challenging the cholinergic system in mild cognitive impairment: A pharmacological fMRI study. Neuroimage 23: 1450–1459. Goekoop R, Scheltens P, Barkhof F, et al. (2006). Cholinergic challenge in Alzheimer patients and mild cognitive impairment differentially affects hippocampal activation: A pharmacological fMRI study. Brain 129: 141–157. Gold PE (1995). Modulation of emotional and non-emotional memories: Same pharmacological systems, different neuroanatomical systems. In: JL McGaugh, NM Weinberger, GS Lynch (Eds.), Brain and Memory: Modulation and Mediation of Neural Plasticity. Oxford University Press, New York, pp. 41–74. Gold PE (2003). Acetylcholine modulation of neural systems involved in learning and memory. Neurobiol Learn Mem 80: 194–210. Goldman-Rakic P (1987). Circuitry of primate prefrontal cortex and regulation of behavior by representational memory. In: V Mountcastle, F Plum, S Geiger (Eds.), Handbook of Physiology: The Nervous System. American Physiological Society, Bethesda, MD, pp. 373–417. Gottfries CG, Blennow K, Karlsson I, et al. (1994). The neurochemistry of vascular dementia. Dementia 5: 163–167. Gottwald MD, Rozanski RI (1999). Rivastigmine, a brainregion selective acetylcholinesterase inhibitor for treating Alzheimer’s disease: Review and current status. Expert Opin Investig Drugs 8: 1673–1682. Grasby PM, Frith CD, Paulesu E, et al. (1995). The effect of the muscarinic antagonist scopolamine on regional cerebral blood flow during the performance of a memory task. Exp Brain Res 104: 337–348. Griffin S, van Reekum R, Masanic C (2003). A review of cholinergic agents in the treatment of neurobehavioral deficits following traumatic brain injury. J Neuropsychiatry Clin Neurosci 15: 17–26. Grober E, Kawas C (1997). Learning and retention in preclinical and early Alzheimer’s disease. Psychol Aging 12: 183–188. Gu Q (2002). Neuromodulatory transmitter systems in the cortex and their role in cortical plasticity. Neuroscience 111: 815–835. Gustavson AR, Cummings JL (2003). Cholinesterase inhibitors in non-Alzheimer dementias. J Am Med Dir Assoc 4: S165–S169. Hallanger AE, Levey AI, Lee HJ, et al. (1987). The origins of cholinergic and other subcortical afferents to the thalamus in the rat. J Comp Neurol 262: 105–124. Hansen L, Salmon D, Galasko D, et al. (1990). The Lewy body variant of Alzheimer’s disease: A clinical and pathologic entity. Neurology 40: 1–8. Hasselmo ME (1999). Neuromodulation: Acetylcholine and memory consolidation. Trends Cogn Sci 3: 351–359.

CHOLINERGIC COMPONENTS OF FRONTAL LOBE FUNCTION AND DYSFUNCTION Hefti F (1986). Nerve growth factor promotes survival of septal cholinergic neurons after fimbrial transections. J Neurosci 6: 2155–2162. Heller JH, Spiridigliozzi GA, Doraiswamy PM, et al. (2004). Donepezil effects on language in children with Down syndrome: Results of the first 22-week pilot clinical trial. Am J Med Genet 130A: 325–326. Heller JH, Spiridigliozzi GA, Sullivan JA, et al. (2003). Donepezil for the treatment of language deficits in adults with Down syndrome: A preliminary 24-week open trial. Am J Med Genet 116A: 111–116. Hemingway-Eltomey JM, Lerner AJ (1999). Adverse effects of donepezil in treating Alzheimer’s disease associated with Down syndrome. Am J Psychiatry 156: 1470–1471. Higgins JP, Flicker L (2000). Lecithin for dementia and cognitive impairment. Cochrane Database Syst Rev 2: CD001015. Honey G, Bullmore E (2004). Human pharmacological MRI. Trends Pharmacol Sci 25: 365–374. Honey GD, Suckling J, Zelaya F, et al. (2003). Dopaminergic drug effects on physiological connectivity in a human cortico-striato-thalamic system. Brain 126: 1767–1781. Hutchinson M, Fazzini E (1996). Cholinesterase inhibitors in Parkinson’s disease. J Neurol Neurosurg Psychiatry 61: 324–325. Iacopino AM, Christakos S (1990). Specific reduction of calcium-binding protein (28-kilodalton calbindin-D). Gene expression in aging and neurodegenerative diseases. Proc Natl Acad Sci U S A 87: 4078–4082. Inestrosa NC, Sagal JP, Colombres M (2005). Acetylcholinesterase interaction with Alzheimer amyloid b. Subcell Biochem 38: 299–317. Irie T, Fukushi K, Akimoto Y, et al. (1994). Design and evaluation of radioactive acetylcholine analogues for mapping brain acetylcholinesterase (AChE). in vivo. Nucl Med Biol 21: 801–808. Iyo M, Namba H, Fukushi K, et al. (1997). Measurement of acetylcholinesterase by positron emission tomography in the brain of healthy controls and patients with Alzheimer’s disease. Lancet 349: 1805–1809. Jellinger KA, Bancher CH (1995). Structural basis of mental impairment in Parkinson’s disease. Neuropsychiatr 9: 9–14. Johnson N, Fahey C, Chicoine B, et al. (2003). Effects of donepezil on cognitive functioning in Down syndrome. Am J Ment Retard 6: 367–372. Jones GM, Sahakian BJ, Levy R, et al. (1992). Effects of acute subcutaneous nicotine on attention, information processing and short-term memory in Alzheimer’s disease. Psychopharmacology (Berl) 108: 485–494. Jones RW, Soininen H, Hager K, et al. (2004). A multinational, randomised, 12-week study comparing the effects of donepezil and galantamine in patients with mild to moderate Alzheimer’s disease. Int J Geriatr Psychiatry 19: 58–67. Kaasinen V, Nagren K, Jarvenpaa T, et al. (2002). Regional effects of donepezil and rivastigmine on cortical

25

acetylcholinesterase activity in Alzheimer’s disease. J Clin Psychopharmacol 22: 615–620. Kalaria RN, Ballard C (1999). Overlap between pathology of Alzheimer’s disease and Vascular dementia. Alzheimer Dis Assoc Disord 13: 115–123. Kasa P, Rakonczay Z, Gulya K (1997). The cholinergic system in Alzheimer’s disease. Prog Neurobiol 52: 511–535. Kaufer DI, Catt KE, Lopez OL, et al. (1998). Dementia with Lewy bodies: Response of delirium-like features to donepezil. Neurology 51: 1512. Kilbourn MR, Sherman PS, Snyder SE (1999). Simplified methods for in vivo measurement of acetylcholinesterase activity in rodent brain. Nucl Med Biol 26: 543–550. Kikuchi T, Zhang MR, Ikota N, et al. (2005). N-[18F] Fluoroethylpiperidin-4ylmethyl acetate, a novel lipophilic acetylcholine analogue for PET measurement of brain acetylcholinesterase activity. J Med Chem 48: 2577–2583. Kishnani PS, Sullivan JA, Walter BK, et al. (1999). Cholinergic therapy for Down syndrome. Lancet 353: 1064–1065. Kitt CA, Hohmann C, Coyle JT, et al. (1994). Cholinergic innervation of mouse forebrain structures. J Comp Neurol 341: 117–129. Klein J, Gonzalez R, Koppen A, et al. (1993). Free choline and choline metabolites in rat brain and body fluids: Sensitive determination and implications for choline supply to the brain. Neurochem Int 22: 293–300. Korczyn AD (2000). Muscarinic M1 agonists in the treatment of Alzheimer’s disease. Expert Opin Investig Drugs 9: 2259–2267. Kuhl DE, Koeppe RA, Minoshima S, et al. (1999). In vivo mapping of central acetylcholinesterase activity in aging and Alzheimer’s disease. Neurology 52: 691–699. Kuhl DE, Koeppe RA, Snyder SE, et al. (2006). In vivo butyrylcholinesterase activity is not increased in Alzheimer’s disease synapses. Ann Neurol 59: 13–20. Kuhl DE, Minoshima S, Frey KA, et al. (2000). Limited donepezil inhibition of acetylcholinesterase measured with positron emission tomography in living Alzheimer cerebral cortex. Ann Neurol 48: 391–395. Kumar V, Anand R, Messian J (2000). An efficacy and safety analysis of Exelon in Alzheimer’s disease with concurrent vascular risk factors. Eur J Neurol 7: 159–169. Kumar V, Calache M (1991). Treatment of Alzheimer’s disease with cholinergic drugs. Int J Clin Pharmacol Ther 29: 23–27. Lachowicz JE, Duffy RA, Ruperto V, et al. (2001). Facilitation of acetylcholine release and improvement in cognition by a selective M2 muscarinic antagonist, SCH-72788. Life Sci 68: 2585–2592. Ladner CJ, Lee JM (1999). Reduced high-affinity agonist binding at the M1 muscarinic receptor in Alzheimer’s disease brain: Differential sensitivity to agonists and divalent cations. Exp Neurol 158: 451–458. Lanctot KL, Herrmann N (2000). Donepezil for behavioral disorders associated with Lewy bodies: A case series. Int J Geriatr Psychiatry 15: 338–345.

26

L.A. RABIN ET AL.

Lanctot KL, Herrmann N, Yau KK, et al. (2003). Efficacy and safety of cholinesterase inhibitors in Alzheimer’s disease: A meta-analysis. CMAJ 169: 557–564. Lawrence AD, Sahakian BJ (1995). Alzheimer disease, attention and the cholinergic system. Alzheimer Dis Assoc Disord 9: 43–49. Lebert F, Pasquier F, Souliez L, et al. (1998). Tacrine efficacy in Lewy body dementia. Int J Geriatr Psychiatry 13: 516–519. Lehericy S, Hirsch EC, Cervera P, et al. (1989). Selective loss of cholinergic neurons in the ventral striatum of patients with Alzheimer disease. Proc Natl Acad Sci USA 86: 8580–8584. Lehericy S, Hirsch EC, Cervera-Pierot P, et al. (1993). Heterogeneity and selectivity of the degeneration of cholinergic neurons in the basal forebrain of patients with Alzheimer’s disease. J Comp Neurol 330: 15–31. Lemay S, Chouinard S, Blanchet P, et al. (2004). Lack of efficacy of a nicotine transdermal treatment on motor and cognitive deficits in Parkinson’s disease. Prog Neuropsychopharmacol Biol Psychiatry 28: 31–39. Lemstra AW, Eikelenboom P, van Gool WA (2003). The cholinergic deficiency syndrome and its therapeutic implications. Gerontology 49: 55–60. Leroi I, Brandt J, Reich SG, et al. (2004). Randomized placebo-controlled trial of donepezil in cognitive impairment in Parkinson’s disease. Int J Geriatr Psychiatry 19: 1–8. Levey AI, Hallanger AE, Wainer BH (1987). Cholinergic nucleus basalis neurons may influence the cortex via the thalamus. Neurosci Lett 74: 7–13. Levin ED, Simon BB (1998). Nicotinic acetylcholine involvement in cognitive function in animals. Psychopharmacology (Berl) 138: 217–230. Lewis DA (1991). Distribution of choline acetyltransferaseimmunoreactive axons in monkey frontal cortex. Neuroscience 40: 363–374. Li M, Yasuda RP, Wall SJ, et al. (1991). Distribution of m2 muscarinic receptors in rat brain using antisera selective for m2 receptors. Mol Pharmacol 40: 28–35. Lopez OL, Kuller LH, Becker JT, et al. (2005). Classification of vascular dementia in the Cardiovascular Health Study Cognition Study. Neurology 64: 1539–1547. Lott IT, Osann K, Doran E, et al. (2002). Down syndrome and Alzheimer disease: Response to donepezil. Arch Neurol 59: 1133–1136. Lucas-Meunier E, Fossier P, Baux G, et al. (2003). Cholinergic modulation of the cortical neuronal network. Pflugers Arch 446: 17–29. Maidment ID, Fox C, Boustani M (2005). A review of studies describing the use of acetylcholinesterase inhibitors in Parkinson’s disease dementia. Acta Psychiatr Scand 111: 403–409. Martin-Ruiz CM, Haroutunian VH, Long P, et al. (2003). Dementia rating and nicotinic receptor expression in the prefrontal cortex in schizophrenia. Biol Psychiatry 54: 1222–1233. Martinez A, Castro A (2006). Novel cholinesterase inhibitors as future effective drugs for the treatment of Alzheimer’s disease. Expert Opin Investig Drugs 15: 1–15.

Mayeux R, Denaro J, Hemenegildo N, et al. (1992). A population-based investigation of Parkinson’s disease with and without dementia: Relationship to age and gender. Arch Neurol 49: 492–497. McGehee DS, Heath MJS, Gelber S, et al. (1995). Nicotine enhancement of fast excitatory synaptic transmission in CNS by presynaptic receptors. Science 269: 1692–1696. McKeith I, Burn D (2000). Spectrum of Parkinson’s disease, Parkinson’s dementia, and Lewy Body dementia. Neurol Clin 18: 865–902. McKeith I, Del Ser T, Spano P, et al. (2000a). Efficacy of rivastigmine in dementia with Lewy bodies: A randomized, double-blind, placebo-controlled international study. Lancet 356: 2031–2036. McKeith I, Fairbairn A, Perry R, et al. (1992). Neuroleptic sensitivity in patients with senile dementia of Lewy body type. BMJ 305: 673–678. McKeith I, Galasko D, Kosaka K, et al. (1996). Consensus guidelines for the clinical and pathologic diagnosis of dementia with Lewy bodies (DLB): Report of the Consortium on DLB International Workshop. Neurology 47: 1113–1124. McKeith I, Grace JB, Walker Z, et al. (2000b). Rivastigmine in the treatment of dementia with Lewy bodies. Int J Geriatr Psychiatry 15: 387–392. McKeith I, Mintzer J, Aarsland D, et al. (2004). Dementia with Lewy bodies. Lancet Neurol 3: 19–28. Mesulam MM, Geula C (1988). Nucleus basalis (Ch4) and cortical cholinergic innervation in the human brain: Observations based on the distribution of acetylcholinesterase and choline acetyltransferase. J Comp Neurol 275: 216–240. Mesulam MM, Guillozet A, Shaw P, et al. (2002). Widely spread butyrylcholinesterase can hydrolyze acetylcholine in the normal and Alzheimer brain. Neurobiol Dis 9: 88–93. Mesulam MM, Rosen AD, Mufson EJ (1984). Regional variations in cortical cholinergic innervation: chemoarchitectonics of acetylcholinesterase-containing fibers in the macaque brain. Brain Res 311: 245–258. Metter EJ, Wilson RS (1993). Vascular dementias. In: RW Parks, RF Zec, RS Wilson (Eds.), Neuropsychology of Alzheimer’s Disease and Other Dementias. Oxford, New York, pp. 416–437. Minger SL, Esiri MM, McDonald B, et al. (2000). Cholinergic deficits contribute to behavioral disturbance in patients with dementia. Neurology 55: 1460–1467. Miranda MI, Ramirez-Lugo L, Bermudez-Rattoni F (2000). Cortical cholinergic activity is related to the novelty of the stimulus. Brain Res 882: 230–235. Morens DM, Grandinetti A, Reed D, et al. (1995). Cigarette smoking and protection from Parkinson’s disease: False association or etiologic clue? Neurology 45: 1041–1051. Moretti R, Torre P, Antonello RM, et al. (2001). Rivastigmine in subcortical vascular dementia: A comparison trial on efficacy and tolerability for 12 months follow-up. Eur J Neurol 8: 361–362. Moretti R, Torre P, Antonello RM, et al. (2002). Rivastigmine in subcortical vascular dementia: An open 22-month study. J Neurol Sci 203: 141–146.

CHOLINERGIC COMPONENTS OF FRONTAL LOBE FUNCTION AND DYSFUNCTION Moretti R, Torre P, Antonello RM, et al. (2003). Rivastigmine in subcortical vascular dementia: A randomized, controlled, open 12-month study in 208 patients. Am J Alzheimers Dis Other Demen 18: 265–272. Nagai T, McGeer PL, Peng JH, et al. (1983). Choline acetyltransferase immunohistochemistry in brains of Alzheimer’s disease patients and controls. Neurosci Lett 36: 195–199. Nahas Z, George MS, Horner MD, et al. (2003). Augmenting atypical antipsychotics with a cognitive enhancer (donepezil) improves regional brain activity in schizophrenia patients: A pilot double-blind placebo controlled BOLD fMRI study. Neurocase 9: 274–282. Nakano I, Hirano A (1984). Parkinson’s disease: Neuron loss in the nucleus basalis without concomitant Alzheimer’s disease. Ann Neurol 15: 415–418. Namba H, Fukushi K, Nagatsuka SI, et al. (2002). Poistron emission tomography: A quantitative measurement of brain acetylcholinesterase activity using radiolabeled substrates. Methods 27: 22–250. Nobili F, Koulibaly M, Vitali P, et al. (2002). Brain perfusion follow-up in Alzheimer’s patients during treatment with acetylcholinesterase inhibitors. J Nucl Med 43: 983–990. Nordberg A, Alafuzoff I, Winblad B (1992). Nicotinic and muscarinic subtypes in the human brain: Changes with aging and dementia. J Neurosci Res 31: 103–111. Nordberg A, Amberla K, Shigeta M, et al. (1998). Long-term tacrine treatment in three mild Alzheimer patients: Effects on nicotinic receptors, cerebral blood flow, glucose metabolism, EEG, and cognitive abilities. Alzheimer Dis Assoc Disord 12: 228–237. Nordberg A, Hellstrom-Lindahl E, Lee M, et al. (2002). Chronic nicotine treatment reduces b-amyloidosis in the brain of a mouse model of Alzheimer’s disease. J Neurochem 81: 655–658. Oddo S, Caccamo A, Green KN, et al. (2005). Chronic nicotine administration exacerbates tau pathology in a transgenic model of Alzheimer’s disease. PNAS 102: 3046–3051. Parry AMM, Scott RB, Palace J, et al. (2003). Potentially adaptive functional changes in cognitive processing for patients with multiple sclerosis and their acute modulation by rivastigmine. Brain 126: 2750–2760. Pauly JR (1999). Nicotinic cholinergic receptor deficits in Alzheimer’s disease: Where’s the smoke? J Alzheimers Dis 1: 221–230. Perry EK (1999). Cholinergic components of frontal lobe function. In: BL Miller, JL Cummings (Eds.), Human Frontal Lobes: Functions and Disorders. Guilford Press, New York, pp. 568–583. Perry EK, Haroutunian V, Davis KL, et al. (1994). Neocortical cholinergic activities differentiate Lewy body dementia from classical Alzheimer’s disease. Neuroreport 5: 747–749. Perry EK, Irving D, Kerwin JM, et al. (1993). Cholinergic transmitter and neurotrophic activities in Lewy body dementia: Similarity to Parkinson’s and distinction from Alzheimer’s disease. Alzheimer Dis Assoc Disord 7: 69–79. Perry EK, Marshall E, Kerwin J, et al. (1990). Evidence of monaminergic-cholinergic imbalance related to visual

27

hallucinations in Lewy body dementia. J Neurochem 55: 1454–1456. Perry EK, Morris CM, Court JA, et al. (1995). Alteration in nicotine binding sites in Parkinson’s disease, Lewy body dementia, and Alzheimer’s disease: Possible index of early neuropathology. Neuroscience 64: 385–395. Perry EK, Perry RH (1996). Altered consciousness and transmitter signalling in Lewy body dementia. In: R Perry, I McKeith, E Perry (Eds.), Dementia with Lewy Bodies. Cambridge University Press, New York, pp. 397–413. Petersen RC, Stevens JC, Ganguli M, et al. (2001). Practice parameter: Early detection of dementia: Mild cognitive impairment (an evidence-based review): Report of the Quality Standards Subcommittee of the American Academy of Neurology. Neurology 56: 1133–1142. Phillips JK, Vidovic M, Hill CE (1997). Variation in mRNA expression of alpha-adrenergic, neurokinin and muscarinic receptors amongst four arteries of the rat. J Auton Nerv Syst 62: 85–93. Pimlott SL, Piggott M, Owens J, et al. (2004). Nicotinic acetylcholine receptor distribution in Alzheimer’s disease, dementia with Lewy bodies, Parkinson’s disease, and vascular dementia: in vitro binding study using 5-[(125)i]-a85380. Neuropsychopharmacology 29: 108–116. Pirttila T, Erkinjuntti T, Hachinski, V (2003). Vascular dementias and Alzheimer’s disease. In: V Olga, B Emery, TE Oxman (Eds.), Dementia: Presentations, Differential Diagnosis, and Nosology. 2nd edn, Johns Hopkins University Press, Baltimore, pp. 306–335. Poewe W (2005). Treatment of dementia with Lewy bodies and Parkinson’s disease dementia. Mov Disord 20: S77–S82. Potter A, Corwin J, Lang J, et al. (1999). Acute effects of the selective cholinergic channel activator (nicotinic agonist) ABT-418 in Alzheimer’s disease. Psychopharmacology (Berl) 142: 334–342. Prasher VP, Fung N, Adams C (2005). Rivastigmine in the treatment of dementia in Alzheimer’s disease in adults with Down syndrome. Int J Geriatr Psychiatry 20: 496–497. Prasher VP, Huxley A, Haque MS, et al. (2002). A 24-week, double-blind, placebo-controlled trial of donepezil in patients with Down syndrome and Alzheimer’s disease. Int J Geriatr Psychiatry 17: 270–278. Qizilbash N, Whitehead A, Higgins J, et al. (1998). Cholinesterase inhibition for Alzheimer disease: A meta-analysis of the tacrine trials. JAMA 280: 1777–1782. Querfurth HW, Allam GJ, Geffroy MA, et al. (2000). Acetylcholinesterase inhibition in dementia with Lewy bodies: Results of a prospective pilot trial. Dement Geriatr Cogn Disord 11: 314–321. Quirion R, Richard J, Wilson A (1994). Muscarinic and nicotinic modulation of cortical acetylcholine release monitored by in vivo microdialysis in freely moving adult rats. Synapse 17: 92–100. Quirion R, Wilson A, Rowe W, et al. (1995). Facilitation of acetylcholine release and cognitive performance by an M2muscarinic receptor antagonist in aged memory-impaired. J Neurosci 15: 1455–1462.

28

L.A. RABIN ET AL.

Racchi M, Mazzucchelli M, Porrello E, et al. (2004). Acetylcholinesterase inhibitors: Novel activities of old molecules. Pharmacol Res 50: 441–451. Ragozzino ME (2003). Acetylcholine actions in the dorsomedial striatum support the flexible shifting of response patterns. Neurobiol Learn Mem 80: 257–267. Reading P, Luce A, McKeith I (2001). Rivastigmine in the treatment of parkinsonian psychosis and cognitive impairment. Mov Disord 16: 1171–1174. Rees TM, Berson A, Sklan EH, et al. (2005). Memory deficits correlating with acetylcholinesterase splice shift and amyloid burden in doubly transgenic mice. Curr Alzheimer Res 2: 291–300. Rinne JO, Myllykyla T, Lonnberg P, et al. (1991). A postmortem study of brain nicotinic receptors in Parkinson’s and Alzheimer’s disease. Brain Res 547: 167–170. Risch SC, McGurk S, Horner MD, et al. (2001). A doubleblind placebo-controlled case study of the use of donepezil to improve cognition in a schizoaffective disorder patient: Functional MRI correlates. Neurocase 7: 105–110. Ritchie CW, Ames D, Clayton T, et al. (2004). Metaanalysis of randomized trials of the efficacy and safety of donepezil, galantamine, and rivastigmine for the treatment of Alzheimer disease. Am J Geriatr Psychiatry 12: 358–369. Roberts AC, Robbins TW, Everitt BJ, et al. (1990). The effects of excitotoxic lesions of the basal forebrain on the acquisition, retention and serial reversal of visual discriminations in marmosets. Neuroscience 34: 311–329. Rodriguez-Franco MI, Fernandez-Bachiller MI, Perez C, et al. (2005). Desing and synthesis of N-benzylpiperidine-purine derivatives as new dual inhibitors of actyl- and butyrylcholinesterase. Bioorg Med Chem 13: 6795–6802. Rojas-Fernandez C (2001). Successful use of donepezil for the treatment of dementia with Lewy bodies. Ann Pharmacother 35: 202–205. Roman GC, Kalaria RN (2005). Vascular determinants of cholinergic deficits in Alzheimer disease and vascular dementia. Neurobiol Aging 27: 1769–1785. Roman GC, Wilkinson DG, Doody RS, et al. (2005). Donepezil in vascular dementia: Combined analysis of two large-scale clinical trials. Dement Geriatr Cogn Disord 20: 338–344. Rombouts SARB, Barkhof F, van Meel CS, et al. (2002). Alterations in brain activation during cholinergic enhancement with rivastigmine in Alzheimer’s disease. J Neurol Neurosurg Psychiatry 73: 665–671. Rosen A, Bokde AL, Pearl A, et al. (2002). Ethical and practical issues in applying functional imaging to the clinical management of Alzheimer’s disease. Brain Cogn 50: 498–519. Rosier AM, Cornette L, Dupont P, et al. (1999). Regional brain activity during shape recognition impaired by a scopolamine challenge to encoding. Eur J Neurosci 11: 3701–3714. Rylett RJ, Ball MJ, Colhoun EH (1983). Evidence for high affinity choline transport in synaptosomes prepared from hippocampus and neocortex of patients with Alzheimer’s disease. Brain Res 289: 169–175. Sabbagh MN, Lukas RJ, Sparks DL, et al. (2002). The nicotinic acetylcholine receptor, smoking, and Alzheimer’s disease. J Alzheimers Dis 4: 317–325.

Sahakian B, Jones G, Levy R, et al. (1989). The effects of nicotine on attention, information processing, and shortterm memory in patients with dementia of the Alzheimer type. Br J Psychiatry 154: 797–800. Saper CB (1984). Organization of cerebral cortical afferent systems in the rat. II. Magnocellular basal nucleus. J Comp Neurol 222: 313–342. Sarter M, Bruno JP (1997). Cognitive functions of cortical acetylcholine: Toward a unifying hypothesis. Brain Res Rev 23: 28–46. Sarter M, Bruno JP (2002). The neglected constituent of the basal forebrain corticopetal projection system: GABAergic projections. Eur J Neurosci 15: 1867–1873. Sarter M, Givens B, Bruno JP (2001). The cognitive neuroscience of sustained attention: Where top-down meets bottom-up. Brain Res 35: 146–160. Sato H, Hata Y, Hagihara K, et al. (1987). Effects of cholinergic depletion on neuron activities in the cat visual cortex. J Neurophysiol 58: 781–794. Saykin AJ, Wishart HA, Rabin LA, et al. (2004). Cholinergic enhancement of frontal lobe activity in mild cognitive impairment. Brain 127: 1574–1583. Saykin AJ, Wishart HA, Rabin LA, et al. (2006). Psychogenetic imaging in preclinical Alzheimer’s disease: Candidate genes and response to cholinergic enhancement in amnestic MCI. Proceedings of the 34th Annual Meeting of the International Neuropsychological Society 2006: 54. Schneider JS, Tinker JP, Van Velson V, et al. (1999). Nicotinic acetylcholine receptor agonist SIB-1508Y improved cognitive functioning in chronic low-dose MPTP-treated monkeys. J Pharmacol Exp Ther 290: 731–739. Schroder H, de Vos RA, Jansen EN, et al. (1995). Gene expression of the nicotinic acetylcholine receptor alpha 4 subunit in the frontal cortex in Parkinson’s disease patients. Neurosci Lett 187: 173–176. Schroder H, Giacobini E, Struble RG, et al. (1991). Cellular distribution and expression of cortical acetylcholine receptors in aging and Alzheimer’s disease. Ann N Y Acad Sci 640: 189–192. Scott LJ, Goa KL (2000). Galantamine: A review of its use in Alzheimer’s disease. Drugs 60: 1095–1122. Seguela P, Wadiche J, Dineley-Miller K, et al. (1993). Molecular cloning, functional properties, and distribution of rat brain alpha 7: a nicotinic cation channel highly permeable to calcium. J Neurosci 13: 596–604. Selden NR, Gitelman DR, Salamon-Murayama N, et al. (1998). Trajectories of cholinergic pathways within the cerebral hemispheres of the human brain. Brain 121: 2249–2257. Shao X, Koeppe RA, Butch ER, et al. (2005). Evaluation of 18 F-labeled acetylcholinesterase substrates as PET radiotracers. Bioorg Med Chem 13: 869–875. Shea C, MacKnight C, Rockwood K (1998). Donepezil for treatment of dementia with Lewy bodies: A case series of nine patients. Int Psychogeriatr 10: 229–238. Shinotoh H, Aotsuka A, Fukushi K, et al. (2003). Brain acetylcholinesterase activity in dementia with Lewy bodies:

CHOLINERGIC COMPONENTS OF FRONTAL LOBE FUNCTION AND DYSFUNCTION Alzheimer’s disease and frontotemporal dementia. J Cereb Blood Flow Metab 23: S598. Shinotoh H, Namba H, Yamaguchi M, et al. (1999). Positron emission tomographic measurement of acetylcholinesterase activity reveals differential loss of ascending cholinergic systems in Parkinson’s disease and progressive supranuclear palsy. Ann Neurol 1: 62–69. Sillito AM, Kemp JA (1983). The influence of GABAergic inhibitory processes on the receptive field structure of X and Y cells in cat dorsal lateral geniculate nucleus (dLGN). Brain Res 277: 63–77. Sirvio J (1999). Strategies that support declining cholinergic neurotransmission in Alzheimer’s disease patients. Gerontology 45: S3–S14. Skjerve A, Nygaard HA (2000). Improvement in sundowning in dementia with Lewy bodies after treatment with donepezil. Int J Geriatr Psychiatry 15: 1147–1151. Sperling R, Greve D, Dale A, et al. (2002). Functional MRI detection of pharmacologically induced memory impairment. Proc Natl Acad Sci 99: 455–460. Sramek JJ, Frackiewicz EJ, Cutler NR, et al. (2000). Review of the acetylcholinesterase inhibitor galanthamine. Expert Opin Investig Drugs 9: 2393–2402. Steriade M, Deschenes M, Domich L, et al. (1985). Abolition of spindle oscillations in thalamic neurons disconnected from nucleus reticularis thalami. J Neurophysiol 54: 1473–1497. Steriade M, Domich L, Oakson G, et al. (1987). The deafferented reticular thalamic nucleus generates spindle rhythmicity. J Neurophysiol 57: 260–273. Steriade M, Parent A, Hada J (1984). Thalamic projections of nucleus reticularis thalami of cat: A study using retrograde transport of horseradish peroxidase and fluorescent tracers. J Comp Neurol 229: 531–547. Tekin S, Mega MS, Masterman DM, et al. (2001). Orbitofrontal and anterior cingulate cortex neurofibrillary tangle burden is associated with agitation in Alzheimer disease. Ann Neurol 49: 355–361. Thal LJ (1996). Cholinomimetic treatment of Alzheimer’s disease. Prog Brain Res 109: 299–309. Thal LJ, Forrest M, Loft H, et al. (2000). Lu25–109, a muscarinic agonist, fails to improve cognition in Alzheimer’s disease. Lu25–109 Study Group. Neurology 54: 421–426. Thiel CM (2003). Cholinergic modulation of learning and memory in the human brain as detected with functional neuroimaging. Neurobiol Learn Mem 80: 234–244. Thiel CM, Henson RNA, Dolan RJ (2002). Scopolamine but not lorazepam modulates face repetition priming: A psychopharmacological fMRI study. Neuropsychopharmacology 27: 282–292. Thiel CM, Henson RA, Morris JS, et al. (2001). Pharmacological modulation of behavioural and neuronal correlates of repetition priming. J Neurosci 21: 6846–6852. Togashi H, Kimura S, Matsumoto M, et al. (1996). Cholinergic changes in the hippocampus of stroke-prone spontaneously hypertensive rats. Stroke 27: 520–526. Trinh N-H, Hoblyn J, Mohanty S, et al. (2003). Efficacy of cholinesterase inhibitors in the treatment of neuropsychiatric

29

symptoms and functional impairment in Alzheimer disease: A meta-analysis. JAMA 289: 210–216. Tucek S (1993). Short-term control of the synthesis of acetylcholine. Prog Biophys Mol Biol 60: 59–69. Tuszynski MH, Blesch A (2004). Nerve growth factor: From animal models of cholinergic neuronal degeneration to gene therapy in Alzheimer’s disease. Prog Brain Res 146: 441–449. Tuszynski MH, Grill R, Jones LL, et al. (2002). Spontaneous and augmented growth of axons in the primate spinal cord: Effects of local injury and nerve growth factor-secreting cell grafts. J Comp Neurol 449: 88–101. Tuszynski MH, Roberts J, Senut MC, et al. (1996). Gene therapy in the adult primate brain: Intraparenchymal grafts of cells genetically modified to produce nerve growth factor prevent cholinergic neuronal degeneration. Gene Ther 3: 305–314. Tuszynski MH, Thal L, Pay M, et al. (2005). A phase 1 clinical trial of nerve growth factor gene therapy for Alzheimer disease. Nat Med 11: 551–555. Tuszynski MH, U HS, Amaral DG, et al. (1990). Nerve growth factor infusion in the primate brain reduces lesioninduced cholinergic neuronal degeneration. J Neurosci 10: 3604–3614. Van der Zee EA, Luiten PGM (1999). Muscarinic acetylcholine receptors in the hippocampus, neocortex, and amygdala: A review of immunocytochemical localization in relation to learning and memory. Prog Neurobiol 58: 409–471. Veroff AE, Bodick NC, Offen WW, et al. (1998). Efficacy of xanomeline in Alzheimer disease: Cognitive improvement measured using the Computerized Neuropsychological Test Battery (CNTB). Alzheimer Dis Assoc Disord 12: 304–312. Wainer BH, Bolam JP, Freund TF, et al. (1984). Cholinergic synapses in the rat brain: A correlated light and electron microscopic immunohistochemical study employing a monoclonal antibody against choline acetyltransferase. Brain Res 308: 69–76. Wallin A, Alafuzoff I, Carlsson A, et al. (1989). Neurotransmitter deficits in a non-multi-infarct category of vascular dementia. Acta Neurol Scand 79: 397–406. Wang QS, Zhou ZN (2002). Retrieval and encoding of episodic memory in normal aging and patients with mild cognitive impairment. Brain Res 924: 113–115. Warburton EC, Koder T, Cho K, et al. (2003). Cholinergic neurotransmission is essential for perirhinal cortical plasticity and recognition memory. Neuron 38: 987–996. Weinberger, NM (1998). Physiological memory in the primary auditory cortex: Characteristics and mechanisms. Neurobiol Learn Mem 70: 226–251. Weinstock, M (1999). Selectivity of cholinesterase inhibition. CNS Drugs 12: 307–323. Weiss C, Preston AR, Oh MM, et al. (2000). The M1 muscarinic agonist CI-1017 facilitates trace eyeblink conditioning in aging rabbits and increases the excitability of CA1 pyramidal neurons. J Neurosci 20: 783–790. Werber E, Rabey J (2001). The beneficial effect of cholinesterase inhibitors on patients suffering from Parkinson’s disease and dementia. J Neural Transm 108: 1319–1325.

30

L.A. RABIN ET AL.

White HK, Levin ED (1999). Four-week nicotine skin patch treatment effects on cognitive performance in Alzheimer’s disease. Psychopharmacology (Berl) 143: 158–165. Whitehouse PJ, Price DL, Struble RG, et al. (1982). Alzheimer’s disease and senile dementia: Loss of neurons in the basal forebrain. Science 215: 1237–1239. Wilkinson D, Doody R, Helme R, et al. (2003). Donepezil in vascular dementia: A randomized, placebo-controlled study. Neurology 61: 479–486. Wilson AL, Langley LK, Monley J, et al. (1995). Nicotine patches in Alzheimer’s disease: Pilot study on learning, memory, and safety. Pharmacol Biochem Behav 51: 509–514. Winkler J, Thal LJ, Gage FH, et al. (1998). Cholinergic strategies for Alzheimer’s disease. J Mol Med 76: 555–567. Wisniewski KE, Wisniewski HM, Wen GY (1985). Occurrence of neuropathological changes and dementia in Alzheimer’s disease and Down syndrome. Ann Neurol 17: 278–282. Woodruff-Pak DS, Gould TJ (2002). Neuronal nicotinic acetylcholine receptors: Involvement in Alzheimer’s disease and schizophrenia. Behav Cogn Neurosci Rev 1: 5–20. Woolf NJ (1991). Cholinergic systems in mammalian brain and spinal cord. Prog Neurobiol 37: 475–524. Wright CI, Geula C, Mesulam MM (1993). Neurological cholinesterases in the normal brain and in Alzheimer’s disease: Relationship to plaques, tangles, and patterns of selective vulnerability. Ann Neurol 34: 373–384.

Wu CK, Mesulam MM, Geula C (1997). Age-related loss of calbindin from human basal forebrain cholinergic neurons. Neuroreport 8: 2209–2213. Wu CK, Nagykery N, Hersh LB, et al. (2003). Selective agerelated loss of calbindin-D28k from basal forebrain cholinergic neurons in the common marmoset (Callithrix jacchus). Neuroscience 120: 249–259. Yasuda RP, Ciesla W, Flores LR, et al. (1993). Development of antisera selective for m4 and m5 muscarinic cholinergic receptors: Distribution of m4 and m5 receptors in rat brain. Mol Pharmacol 43: 149–157. Zarotsky V, Sramek JJ, Cutler NR (2003). Galantamine hydrobromide: An agent for Alzheimer’s disease. Am J Health Syst Pharm 60: 446–452. Zhang MR, Furutsuka K, Maeda J, et al. (2003). N-[18F] fluoroethyl-4-piperidyl acetate ([18F]FEtP4A): A PET tracer for imaging brain acetylcholinesterase in vivo. Bioorg Med Chem 11: 2519–2527. Zhang W, Basile AS, Gomeza J, et al. (2002). Characterization of central inhibitory muscarinic autoreceptors by the use of muscarinic acetylcholine receptor knock-out mice. J Neurosci 22: 1709–1717. Zhang ZW, Vijayaraghavan S, Berg DK (1994). Neuronal acetylcholine receptors that bind alpha-bungarotoxin with high affinity function as ligand-gated ion channels. Neuron 12: 167–177.

Handbook of Clinical Neurology, Vol. 88 (3rd series) Neuropsychology and behavioral neurology G. Goldenberg, B.L. Miller, Editors # 2008 Elsevier B.V. All rights reserved

Chapter 2

Neurochemistry of cognition: serotonergic and adrenergic mechanisms PHILLIPPE H. ROBERT* AND M. BENOIT Centre Me´moire de Resources et de Recherche CHU de Nice, Nice, France

2.1. Introduction Aminergic transmitter systems include the catecholamines, noradrenaline (NA), dopamine (DA) and adrenaline, the indoleamine serotonin (5-hydroxy-tryptamine; 5HT) and the biogenic amine acetylcholine (cf chapter 1). Aminergic transmitters belong to the class of slow-acting neurotransmitters that exert their effects through cascades of biochemical reaction as opposed to the class of fast synaptic neurotransmitters (e.g., glutamate). Slow neurotransmitters are essential for modulation and long-term regulation. The present chapter describes separately the biochemistry, neuroanatomy, functional role and clinical significance of NA, DA and 5HT neurons. In neuropsychiatry the majority of hypotheses about the therapeutic effects of the psychotropic drugs is based on their action at the pre- and postsynaptic receptors (Fig. 2.1). Neurotransmitters play the role of first messengers and interact with postsynaptic receptors to induce intracellular changes. They indirectly stimulate specific intracellular components called second messengers (e.g., calcium ion or adenosine monophosphate). Protein kinases modulate cellular activities and the second messengers activate several of them. Following the protein kinase activity, the phosphorylated proteins, also called third messengers, induce subsequent modifications in the cellular functioning. In the central nervous system, information is transferred via electrical impulses (action potentials) originating in the soma of neurons and progressing along the nerve’s axon and up to its terminal regions, where it is transformed into chemical information in the form of neurotransmitters. Most nerves release *

one neurotransmitter, although some nerves can release more (Shiloh et al., 2000). Neurotransmitters are stored in intracellular vesicles. Following the arrival of an action potential, they undergo exocytosis into the synaptic cleft in order to be available for postsynaptic interactions. The amount of neurotransmitters ready for exocytosis depends on several mechanisms including availability of neurotransmitter precursor, reuptake of the neurotransmitter into the presynaptic nerve and efficient metabolism of the neurotransmitter. In addition the rate of neurotransmitter release into the synaptic cleft is regulated by autoreceptors and heteroreceptors. Autoreceptors are located in the presynaptic nerve terminals or in the soma, dendrites and axons of central nervous system neurons. They interact with the neurotransmitter produced by the same nerve, and consequently suppress or stimulate the release of neurotransmitters. Heteroreceptors are activated by neurotransmitters different from those produced by the nerve they are on. They can either suppress or enhance the release of the neurotransmitter. Normal neuronal activity requires intact pre- and postsynaptic interactions between first messengers and their target receptors or transporters located on the extracellular membrane. Neurotransmitters bind with high affinity to postsynaptic receptors that are linked to either protein complexes, termed G-proteins, or ion channels. Synaptic responses mediated by receptor-gated channels and G-protein-linked receptors have considerably different time courses. The direct effects of ligand-gated channels are rapid and transitory, usually ending in less than one millisecond, whereas those mediated by G-protein-linked receptors are slower.

Correspondence to: Philippe H. Robert, Centre Me´moire de Resources et de Recherche CHU de Nice, Pavillon M, Hoˆpital Pasteur, 30 av de la Voie Romaine, 06002 Nice, France. E-mail: [email protected], Tel: þ33-4-92038002/ 37993, Fax: þ33-4-92038326.

32

P.H. ROBERT AND M. BENOIT

Fig. 2.1. Neurotransmitter at the pre- and postsynaptic nerves. (NT ¼ neurotransmitter; AR ¼ autoreceptor; HR ¼ heteroreceptor.)

Pharmacological treatment acting on neurotransmitter activities this way interacts with various membrane receptors and inevitably alters the functioning of second-messenger components.

2.2. Noradrenaline Noradrenaline (NA) is one of the most important mammal catecholamines chemically characterized by a benzene ring and a catechol nucleus. Stimulation of sympathetic nerves leads to release of a substance originally called ‘sympathin’ (Cannon and Uridil, 1921), subsequently identified as NA. 2.2.1. NA nuclei, pathway, receptors, and transmitter release Three main cell groups located in the pons and medulla are recognized. The locus coeruleus (LC) is the most important NA structure (Fig. 2.2), projecting both rostrally and caudally, and innervating essentially all parts of the telencephalon and diencephalons (e.g., all layers of the neocortex, hippocampus, amygdala, thalamus, and hypothalamus). The LC exerts a major influence on brain and behavioral responses. Neurons in the LC with their wide projections are central to NA release

and actions in the central nervous system. Interestingly, in parallel to the feedback controls between the frontal cortex–nucleus accumbens–A9/A10 areas, the LC is subjected to a reciprocal regulation from the prefrontal cortex by glutamatergic input (Jodo et al., 1998). The NA and adrenergic receptors all belong to the G-proteincoupled receptor superfamily. In the central nervous system, NA is concentrated and stored in synaptic vesicles by a vesicular transporter. The same transporter protein is found in DAergic, NAergic and 5-HTergic neurons, indicating that these three monoamines are concentrated by the same mechanism. In similarity to other neurotransmitters synaptically released, NA is released by depolarization of the nerve terminals. Release of NA is regulated by presynaptic a2 autoreceptors (Langer, 1974; Langer and Arbilla, 1990). NA released into the synaptic cleft is either metabolized or transported back into the neurons by a high-affinity transporter. The transporter is a presynaptically located glycoprotein, and this intraneuronal high affinity is called uptake. NA can also be taken extraneuronally by a different mechanism which has lower affinity and is less selective for NA (Amara and Kuhar, 1993). Many psychotropic drugs, such as the tricyclic antidepressants, and substance of abuse inhibit the uptake of NA.

NEUROCHEMISTRY OF COGNITION 5HT1A HTT1B 5HT2A 5HT2C

5HT3

5HT4

5HT6

5HT7

α 1Ad

α 2Ad

33 β Ad

D1

D2

D3

D4

Cortex Amygdala hippocampus, LS Nucleus accumbens caudate putamen Globus pallidus substantia nigra Thalamus locus ceruleus raphe nuclei

concentration ++++ +++ LS = limbic system

Fig. 2.2. Comparative distribution of receptors in different brain regions.

2.2.2. Functional role and clinical significance of brain NA neurons

2.3.1. DA nuclei, pathways, receptors, and transmitter release

The LC plays a role in the functioning of cortex, thalamus, hypothalamus, hippocampus, and amygdala, and the corresponding behavioral manifestations such as vigilance, arousal, fear stimulus discrimination, eating behavior, and learning (Aston-Jones et al., 1994, Ressler and Nemeroff, 2000). Furthermore a role in attentional functioning was confirmed and, in principle, the system may serve as a significance enhancer with respect to salient environmental stimuli (Foote et al., 1983). In Alzheimer’s disease there are consistent changes in the NA and to a lesser extent in the adrenergic system. The progressive loss of NA neurons in the LC has been documented using postmortem and biopsy tissue sample (Mann, 1988) but there is little relationship with cognitive deficit (Palmer et al., 1987; Palmer and DeKosky, 1993). The losses of NA may, however, contribute to behavioral disturbances, which are a common feature of the disease (Benoit et al., 2003). NA neurons have also been found to be involved in the mode of action of many antidepressant drugs as well as a number of antipsychotics, and drugs affecting wakefulness and attention, such as nicotine (Svensson and Engberg, 1980; Mitchell, 1993).

The best-known DA system, mostly identified with motor function, is the nigrostriatal system originating in the zona compacta of the substantia nigra (SN). The mesolimbic and mesocortical DA systems, which are more important for motivational and cognitive function, arise from the DA cells that are associated with the ventral tegmental area (VTA). Generally, the midbrain DA neurons receive glutamanergic, GABAergic, cholinergic, serotoninergic and noradrenergic inputs (for review see Svensson and Mathe´, 2002). There are currently five known DA receptor subtypes categorized according to structural, functional and pharmacological characteristics, and divided into two main families (D1-like and D2-like) based upon their sequence homology. The D1-like receptors (D1 and D5) activate adenylyl cyclase, whereas the D2-like receptors (D2, D3, and D4) inhibit adenylyl cyclase. Both the D1 and D2 families are found postsynaptically, whereas the presynaptic receptors are regarded to belong to the D2 family. Specifically, the D2 receptor has been found (Fig. 2.2) mainly in the striatum, in the olfactory tubercule and in the core of the nucleus accumbens (NAC). The D3 receptor is largely expressed in forebrain and limbic areas (Sokoloff et al., 1990) and the D4 receptor is predominantly expressed in the frontal cortex. Overall, D2 receptors are more prominently expressed in areas associated with motor control, while D3 and D4 receptors are more exclusively located in areas where the DA system is thought to serve a role in modulating emotion and cognition.

2.3. Dopamine DA was discovered as an independent neurotransmitter in the brain during the late 1950s (Carlsson et al., 1957; Carlsson, 1959).

34

P.H. ROBERT AND M. BENOIT

DA neurons in the SN and VTA show spontaneous spike firing. Generally, the discharge of the cells is an important determinant of the DA release process. The firing pattern of the DA neurons is characterized by two differential modes of firing: single-spike firing and burst firing (Grace and Bunney, 1984). Single-spike firing is a relatively regular, low-frequency firing pattern, i.e., 1–10 Hz. In contrast, burst firing is typically recognized as the transient high-frequency discharge of multiple action potentials. Such transient changes in impulse activity normally occur in relation to basic attentional and motivational processes in response to reward-predicting stimuli, and apparently serve to initiate goal-oriented behaviors (Nishino et al., 1987; Schultz et al., 1993; Schultz, 1998; 1999). Postsynaptic effects of DA are manifested both at the level of the individual postsynaptic neuron, with a cascade of intracellular transduction mechanisms being affected, and also include presynaptic effects and modulatory effects at the network level. In the striatum DA has mostly been found to decrease the excitability of neurons in both the dorsal striatum and the nucleus accumbens (NAC) by means of D1 receptor stimulation (Calabresi et al., 1987). In addition DA may modulate the postsynaptic response of striatal neurons to other neurotransmitters as well as the presynaptic regulation of transmitter release (Chergui et al., 1996). Finally DA also influences neuronal functioning in its target areas at the network level. In the prefrontal cortex the role of DA has attracted successively increased attention over the years but still remains somewhat controversial, although studies in vivo clearly demonstrate an inhibitory effect of DA on the prefrontal cortex neuronal firing. The D3 and D4 receptors are linked to the heteromodal association neocortex via their expression in the NAC and prefrontal cortex (Ross and Pearlson, 1996; Schwartz et al., 2000). These interconnected association areas are involved in higher integrative functions, such as executive tasks, speech, and focused attention. In the mediodorsal thalamus the dopaminergic input may generally contribute to the control of thalamocortical information processing (Lavin and Grace, 1998). Finally, in the ventral striatum DA contributes to influencing motivated behavior taking into account that this brain region represents an interface between the limbic and extrapyramidal systems. 2.3.2. Functional role and clinical significance of brain DA neurons DA is not a simple excitatory or inhibitory neurotransmitter. DA is also a neuromodulator that modifies the

responses of target neurons to other neurotransmitters (Girault and Greengard, 2004). DA exerts effects on its target neurons by modulating their responses and by altering synaptic plasticity. By this function DA is involved in different disease or disorders such as Parkinson’s disease, drug addiction, compulsive behavior, attentional deficit, and schizophrenia. Another important finding was the identification of its role in reward systems. Mesolimbic and neostriatal dopamine projection have been suggested to mediate reward. Reward and ‘positive reinforcer’ are frequently equivalently used in order to describe stimuli which an animal wants to obtain (Rolls, 1999). In this way reward is an object or event that elicits approach and is worked for. In a recent review Wise (2004) summarizes the different hypotheses concerning the implication of DA in reward and cognition processes. Incentive motivation refers primarily to the priming or drive-like effects of an encounter with an otherwise neutral stimulus that has acquired motivational importance through prior association with a primary reward. This external contribution to the motivation of the animal combines with internal drive states to determine the strength of goal-directed behavior. The dopamine hypothesis of reward proposes that dopamine is important not only in the reinforcement that follows the earning of a reward but also in the incentive motivation that precedes the earning of a reward. Berridge and Robinson (1998) argue that reward is a constellation of multiple processes, many of which can be separately identified in behavior. In animal studies this author (Berridge, 1996) has suggested that dopamine related neural systems mediate more specifically one component of reward. Their incentive salience hypothesis is built on earlier incentive theory formulation of motivation (Toates, 1986; Blackburn et al., 1989). Incentive salience transforms the brain’s neural representations of conditioned stimuli, converting an event or stimulus from a neutral representation into an attractive and wanted incentive that can ‘grab attention’ and is able to elicit voluntary action. Incentive salience can be dissociated into the complementary but separate components of ‘liking’ and ‘wanting,’ dopamine systems only mediating the later. In this theory wanting refers specifically to the underlying core process that instigates goal-directed behavior, attraction to an incentive stimulus, and consumption of the goal object with as behavioral manifestation the interest of the animal to the goal object and the initiative to obtain it. DA also appears to be important for learning, memory, and relationships with reward in most terminal

NEUROCHEMISTRY OF COGNITION fields of the nigrostriatal, mesolimbic, and mesocortical dopamine systems. In fact the majority of our motivations are motivations to return to the rewards we have experienced in the past and to the cues that mark the way to obtain such rewards. The ability of phasic dopamine release to augment the motivation that is induced by drives and conditioned stimuli is thought to involve dopamine’s actions in the NAC. Midbrain dopamine neurons devoted to error signals are involved in learning algorithms (Schultz and Dickinson, 2000) and suggested that brain dopamine is more responsive to predictors of reward than to the receipt of reward. At the cellular level reinforcing properties of D1 or D2 activation have been demonstrated in a number of cortical and limbic sites (Wise, 2004). At the behavioral level DA role in memory consolidation is suggested by studies in which DA agonist is given after a learning trial involving some other form of reinforcement (Messier and White, 1984; Packard and White, 1991; White and Viaud, 1991). Finally interconnection between prefrontal cortex and midbrain (Sesack et al., 2003) helps to understand that the activity of dopamine neurons in the midbrain is under both excitatory and inhibitory control of the prefrontal cortex (Seamans and Yang, 2004). These interactions are critical for motivated behavior, working memory (Williams and Goldman-Rakic, 1995), and reward-related learning, and have been proposed to contribute to the pathogenesis of several neuropsychiatric disorders, including schizophrenia. Using multitracer neuroimaging methodology in order to measure both regional cerebral blood flow and presynaptic DA functioning in human healthy subjects, specific interactions between prefrontal activity and midbrain dopaminergic synthesis (Meyer-Lindenberg et al., 2005) have recently been demonstrated. During a working memory challenge the regional cerebral blood flow in the prefrontal cortex was highly correlated with midbrain DA uptake. A common substitution in the gene for catecholamine-O-methyltransferase (COMT) which is an important enzyme regulating prefrontal dopamine turnover, predicted reduced DA synthesis in midbrain and qualitatively affected the interaction with prefrontal cortex.

2.4. Serotonin Serotonin or 5-hydroxy-tryptamine (5-HT), initially identified in peripheral tissues, was first detected in the mammalian central nervous system 40 years ago. Very rapidly its heterogeneous distribution suggested that this amine could be a cerebral neurotransmitter.

35

2.4.1. Serotonin nuclei, pathways, receptors, and transmitter release In evolutionary terms, 5-HT is one of the oldest neurotransmitters. 5-HT neurons arise from midbrain nuclei. 5-HT cell bodies are systematically organized in the median and dorsal raphe nuclei. Ascending fibers from the dorsal raphe project preferentially to the cortex and striatal regions, while the median raphe projects to the limbic regions (Jacobs and Azmitia, 1992). Cowen (1991) reported that each projecting 5-HT neuron sends over 500 000 terminals to the cerebral cortex. Indeed, the average density of 5-HT innervations in the cortex is greater than that of dopamine or noradrenaline. Most of the different 5-HT receptor subtypes are located on the postsynaptic targets of serotoninergic neurons. Furthermore, some receptors are located on the soma and dendrites (5-HT1A somatodendritic autoreceptors) or on the terminals (5-HT1B/5-HT1D presynaptic autoreceptors) of serotoninergic neurons (Hamon and Gozlan, 1993). 5-HT receptors with at least 14 members represent one of the most complex families of neurotransmitter receptors. 2.4.1.1. 5-HT1 receptors They were first identified in the course of radioligandbinding studies on brain homogenates with [3H] 5-HT (Peroutka and Snyder, 1979), through their high affinity for 5-HT. 5-HT1A receptors were located in limbic structures such as the hippocampus, septum, and amygdala but also in the frontal cortex (Radja et al., 1991, Biegon et al., 1986, Dillon et al., 1991), striatum and raphe nuclei. Activation of 5-HT1A receptors causes neuronal depolarization. The strongest concentration of 5-HT1B receptor binding sites was found in the basal ganglia, striatum and frontal cortex. 5-HT1B receptors serve as terminal autoreceptors and may also act as a terminal heteroreceptor controlling the release of other neurotransmitters, such as acetylcholine, glutamate, dopamine noradrenaline and gamma-aminobutyric acid (Pauwels, 1997). 2.4.1.2. 5-HT2 receptors 5-HT2A receptors are present in different regions of the cortex (Pazos et al., 1985; Hoyer et al., 1986; Cook et al., 1994) and the limbic system. They are situated on postsynaptic targets of serotoninergic neurons. 5HT2C receptor activation has been shown to exert a tonic, inhibitory influence upon frontocortical dopaminergic and adrenergic transmission (Jorgensen et al., 1999, Millan et al., 1998).

36

P.H. ROBERT AND M. BENOIT

2.4.1.3. 5-HT3 receptors Contrary to the receptors described above, which are all coupled to G proteins, 5-HT3 is an ‘ion-channel receptor’ whose stimulation opens a sodium/potassium channel (Yakel et al., 1990). In the central nervous system it is most abundant in the amygdala, the CA1 pyramidal cell layer in the hippocampus, and the entorhinal cortex (Laporte et al., 1992). 2.4.1.4. 5-HT4,6,7 receptors They are positively coupled to adenylate cyclase. 5-HT4 receptors appear to be present in the frontal cortex (Monferini et al., 1993). 5-HT4 receptors appear to modulate neurotransmitters release and enhance synaptic transmission. 5-HT6 receptors are located in the striatum, amygdala, nucleus accumbens, hippocampus, and cortex. Several studies indicate a potential role for 5-HT6 receptor in the control of central cholinergic function (Woolley et al., 2001). 5-HT7 receptors are located in the limbic system and thalamocortical regions. On a clinical point of view atypical antipsychotics such as clozapine and risperidone have high affinity for the 5-HT7 receptor (Roth et al., 1994) and a downregulation of 5-HT7 receptors occurs after chronic antidepressant treatment (Mullins et al., 1999). In neurons, 5-HT is stored in vesicles and released by exocytosis, a process by which the synaptic vesicle fuses with the cell membrane. Exocytosis, the main mechanism for release of transmitters, is triggered by depolarization (classically induced by Kþ) and involves membrane proteins, for example synapsin. Following release into the synaptic cleft 5-HT is either metabolized or actively transported back into the neuron by a highaffinity transporter which is a membrane polypeptide, located presynatically (Biessen et al., 1990). 2.4.2. Functional role and clinical significance of brain 5-HT neurons It is now clearly established that neurons that synthesize and release 5-HT participate in the control of many central functions, and that alterations of serotoninergic transmission are associated with various neuropsychiatric conditions such as depression, anxiety, impulsivity, and behavioral disorders in dementias (Robert et al., 1999). In addition, relations between serotonin and the dopaminergic system imply that serotonin is involved in schizophrenic disorders and in complex cognitive behavioral interactions. Recent functional brain imaging studies have shown the involvement of the orbitofrontal cortex and of the

ventral striatum in the prediction and perception of reward (Berns et al., 2001; Breiter et al., 2001; O’Doherty et al., 2003). In parallel, neural circuitry in the ventral prefrontal cortex has been implicated in cognitive domains such as decision-making and reversal learning, which are closely related with complex behavior (Clark et al., 2004). On a pharmacological point of view administration of fenfluramine to patients with conduct disorders reduces impulsive responding to the delayed reward paradigm (Cherek and Lane, 2000). This is in line with animal studies reporting an increase of impulsive responding at the same task after selective lesions of the ascending 5-HT projection (Mobini et al., 2000). The reversal-learning paradigm requiring the adaptation of behavior according to changes in stimulusreward contingencies is relevant to social and emotional behavior (Rolls, 1999). In pathologically impaired subjects, reversal learning has been attributed to the loss of inhibitory control of affective responding (Dias et al., 1996). Consistent with animal studies indicating that reversal learning is modulated by 5HT manipulations (Millan et al., 1998), two studies in healthy human volunteers showed that 5HT suppression by acute tryptophan depletion impairs reversal learning (Park et al., 1994, Rogers et al., 1999a). Therefore it seems that the serotoninergic system is also involved in the reward process but in a different way from the dopaminergic system. In this field, Tanaka et al. (2004) has demonstrated that when human subjects learned actions on the basis of immediate rewards, significant activity was observed in the lateral orbitofrontal cortex and the striatum, whereas when subjects learned to act in order to obtain large future rewards while incurring small immediate loss, the dorsolateral prefrontal cortex, inferior parietal cortex, dorsal raphe nucleus, and cerebellum were also activated. The authors suggest that different sub-loops of the corticobasal ganglia network are specialized for reward prediction at different time scales and that they are differently activated by the ascending serotoninergic system. This hypothesis is in line with studies underlining that low activity of the central serotoninergic system is associated with impulsive behavior in human (Rogers et al., 1999b) and that animals with lesions in the ascending serotoninergic pathway tend to choose small immediate rewards over large future reward (Evenden and Ryan, 1996).

2.5. The importance of aminergic interactions Animal and human studies have demonstrated the involvement of aminergic neurotransmitters in cognition (Robbins, 1997). The coeruleo-cortical NA system is particularly involved in attention, vigilance, and

NEUROCHEMISTRY OF COGNITION arousal. The mesolimbic and mesocortical DA systems play a major role in the cortical processing of signals affecting mnesic process and in the prediction and initiation of reward. The ascending 5-HT systems also play a role in reward and higher cognitive functions, most particularly in the inhibitory processes. However, it is difficult to always clearly differentiate the cognitive and behavioral aspects of their effects. In the same way our general understanding of the neurotransmitters role must also take into account their interactions. For instance the norepinephrine activity interacts with other neurotransmitters systems such as acetylcholine, histamine, or serotonin and switch from a low excitability state during drowsiness and slowwave sleep to a state of increased excitability and responsiveness during periods of waking, attentiveness facilitating cognition (Mc Cormick et al., 1991). Another example concern the cholinergic–DA interactions in different brain areas (Yeomans et al., 1985; 1993; Yeomans and Baptista, 1997; Zhou et al., 2002) which are particularly important in order to understand the relation between cognition, reward, and goal-directed behavior and to find treatment for symptoms such as apathy which are common in many neuropsychiatric disorders (Robert et al., 2002). There is also growing evidence for serotoninergic influences on dopamine transmission. The majority of studies demonstrated that 5-HT transmission plays an inhibitory role on dopaminergic activity (Korsgaard et al., 1985; Kapur and Remington, 1996; Sasaki-Adams and Kelley, 2001), but some studies also suggested the opposite view (Yoshimoto et al., 1996; De Deurwaerdere et al., 1996; Hallbus et al., 1997). These divergences could be partially explained by the variety of subtypes and actions of 5-HT receptors. For example, 5-HT2C agonists inhibit dopaminergic effects (Walsh and Cunningham, 1997), whereas 5-HT1B and 5-HT3 agonists enhance dopamine release (De Deurwaerdere et al., 1998). In schizophrenia, there is also evidence that atypical antipsychotics targeting some individual 5-HT receptor subtypes such as 5-HT1A partial agonists, 5-HT2A, 5HT6 antagonists and 5-HT4 partial agonists may improve cognition. Some of these drugs become available in clinical practice, and are generally also DA2 antagonists (Roth et al., 2004). These interactions are also important for frontal lobe function. The DA mesocortical system has numerous terminations in the prefrontal cortex. Their synapses are regulated by frontal 5-HT2 heteroreceptors activated by serotoninergic neurons projecting from the medial raphe (Ugedo et al., 1989). Serotoninergic projections also inhibit dopaminergic activity in the striatum. The repartition and interaction of dopaminergic

37

and serotoninergic neurons supports the hypothesis of a serotonin–dopamine balance, which plays a major role in the regulation of transmission between the prefrontal cortex and subcortical structures (Kapur et al., 1999). In fact, it seems possible to enhance dopaminergic activity in the prefrontal cortex with 5-HT2A and 5-HT2C inhibitors. This underlines the fact that aminergic neurotransmitters and their interaction with other aminergic transmitters as well as with fast neurotransmitters such as glutamate are a key factor for the understanding and mastery of neuropsychiatric pharmacotherapy.

References Amara SG, Kuhar MJ (1993). Neurotransmitter transporters: Recent progress. Annu Rev Neurosci 16: 73–93. Aston-Jones G, Rajkowski J, Kubiak P, et al. (1994). Locus coeruleus neurons in monkey are selectively activated by attended cues in a vigilance task. J Neurosci 14: 4467–4480. Benoit M, Staccini P, Brocker P, et al. (2003). Symptoˆmes comportementaux et psychologiques dans la maladie d’Alzheimer: Re´sultats de l’e´tude REAL. FR. Rev Med Interne 2003: 319–324. Berns GS, Mcclure SM, Pagnoni G, et al. (2001). Predictability modulates human brain response to reward. J Neurosci 21: 2793–2798. Berridge KC (1996). Food reward: Brain substrates of wanting and liking. Neurosci Biobehav Rev 20: 1–25. Berridge KC, Robinson TE (1998). What is the role of dopamine in reward: Hedonic impact, reward learning, or incentive salience. Brain Res Rev 28: 309–369. Biegon A, Kargman S, Snyder L, et al. (1986). Characterization and localization of serotonin receptors in human brain postmortem. Brain Res 363: 91–98. Biessen EA, Horn AS, Robillard GT (1990). Partial purification of the 5-hydroxytryptamine-reuptake system from human blood platelets using a citalopram-derived affinity resin [corrected]. Biochemistry 29: 3349–3354. Blackburn JR, Phillips AG, Jakubovic A, et al. (1989). Dopamine and preparatory behavior. Behav Neurosci: 15–23. Breiter HC, Aharon I, Kahneman D, et al. (2001). Functional imaging of neural responses to expectancy and experience of monetary gains and losses. Neuron 30: 619–639. Calabresi P, Mercuri N, Stanzione P, et al. (1987). Intracellular studies on the dopamine-induced firing inhibition of neostriatal neurons in vitro: Evidence for D1 receptor involvement. Neuroscience 20: 757–771. Cannon WB, Uridil JE (1921). Studies on the conditions of activity in endocrine glands. Am J Physiol 58: 353–354. Carlsson A (1959). The occurrence, distribution and physiological role of catecholamines in the nervous system. Pharmacol Rev 11: 490–493. Carlsson A, Lindqvist M, Magnusson T (1957). 3,4-Dihydroxyphenylalanine and 5-hydroxytryptophan as reserpine antagonists. Nature 180: 1200.

38

P.H. ROBERT AND M. BENOIT

Cherek DR, Lane SD (2000). Fenfluramine effects on impulsivity in a sample of adults with and without history of conduct disorder. Psychopharmacology (Berl) 152: 149–156. Chergui K, Nomikos GG, Mathe JM, et al. (1996). Burst stimulation of the medial forebrain bundle selectively increase Fos-like immunoreactivity in the limbic forebrain of the rat. Neuroscience 72: 141–156. Clark L, Cools R, Robbins TW (2004). The neuropsychology of ventral prefrontal cortex: Decision-making and reversal learning. Brain Cogn 55: 41–53. Cook EH, Fletcher KE, Wainwright M, et al. (1994). Primary structure of the human platelet serotonin 5-HT2A receptor: Identity with frontal cortex serotonin 5-HT2A receptor. J Neurochem 63: 465–469. Cowen PJ (1991). Serotonin receptor subtypes: Implications for psychopharmacology. Br J Psychiatry 159: 7–14. De Deurwaerdere P, Bonhomme N, Lucas G, et al. (1996). Serotonin enhances striatal dopamine outflow in vivo through dopamine uptake sites. J Neurochem 66: 210–215. De Deurwaerdere P, Stinus L, Spampinato U (1998). Opposite change of in vivo dopamine release in the rat nucleus accumbens and striatum that follows electrical stimulation of dorsal raphe nucleus: Role of 5-HT3 receptors. J Neurosci 18: 6528–6538. Dias R, Robbins TW, Roberts AC (1996). Dissociation in prefrontal cortex of affective and attentional shifts. Nature 380: 69–72. Dillon KA, Gross-Isseroff R, Israeli M, et al. (1991). Autoradiographic analysis of serotonin 1A receptor binding in the human brain postmortem: Effects of age and alcohol. Brain Res 554: 56–64. Evenden JL, Ryan CN (1996). The pharmacology of impulsive behaviour in rats: The effects of drugs on response choice with varying delays of reinforcement. Psychopharmacology (Berl) 128: 161–170. Foote SL, Bloom FE, Aston-Jones G (1983). Nucleus locus ceruleus: New evidence of anatomical and physiological specificity. Physiol Rev 63: 844–914. Girault JA, Greengard P (2004). The neurobiology of dopamine signaling. Arch Neurol 61: 641–644. Grace AA, Bunney BS (1984). The control of firing pattern in nigral dopamine neurons: Burst firing. J Neurosci 4: 2877–2890. Hallbus M, Magnusson T, Magnusson O (1997). Influence of 5-HT1B/1D receptors on dopamine release in the guinea pig nucleus accumbens: A microdialysis study. Neurosci Lett 225: 57–60. Hamon M, Gozlan H (1993). Les re´cepteurs centraux de la se´rotonine. Med Sci (Paris) 9: 21–30. Hoyer D, Pazos A, Probst A, et al. (1986). Serotonin receptors in the human brain II Characterisation and autoradiographic localisation of 5-HT1C and 5-HT2 recognition sites. Brain Res 376: 97–107. Jacobs BL, Azmitia EC (1992). Structure and function of the brain serotonin system. Physiol Rev 72: 165–229.

Jodo E, Chiang C, Aston-Jones G (1998). Potent excitatory influence of prefrontal cortex activity on noradrenergic locus coeruleus neurons. Neuroscience 83: 63–79. Jorgensen H, Knigge U, Kjaer A, et al. (1999). Adrenocorticotropic hormone secretion in rats induced by stimulation with serotonergic compounds. J Neuroendocrinol 11: 283–290. Kapur S, Remington G (1996). Serotonin-dopamine interaction and its relevance to schizophrenia. Am J Psychiatry 153: 466–476. Kapur S, Zipursky RB, Remington G (1999). Comparison of the 5-HT2 and D2 receptor occupancy of clozapine, risperidone, and olanzapine in schizophrenia: Clinical and theoretical implications. Am J Psychiatry 156: 286–293. Korsgaard S, Gerlach J, Christensson E (1985). Behavioral aspects of serotonin–dopamine interaction in the monkey. Eur J Pharmacol 118: 245–252. Langer SZ (1974). Presynaptic regulation of catecholamine release. Biochem Pharmacol 23: 1793–1800. Langer SZ, Arbilla S (1990). Presynaptic receptors on peripheral noradrenergic neurons. Ann NY Acad Sci 604: 7–16. Laporte AM, Kidd E, Verge D, et al. (1992). Autoradiographic mapping of central and peripheral 5-HT3 receptors. In AM Hamon (Ed.), Central and Peripheral 5-HT3 Receptors. Academic Press, London, pp. 157–187. Lavin A, Grace AA (1998). Dopamine modulates the responsivity of mediodorsal thalamic cells recorded in vitro. J Neurosci 18: 10566–10578. Mann JJ, McBride PA, Stanley M (1986). Postmortem serotonergic and adrenergic receptor binding to frontal cortex: Correlations with suicide. Psychopharma Bull 22(3): 647–649. Mc Cormick DA, Pape HC, Williamson A (1991). Action of norepinephrine in the cerebral cortex and thalamus: Implications for function of the central noradrenergic system. Prog Brain Res: 293–305. Messier C, White NM (1984). Contingent and non-contingent actions of sucrose and saccharin reinforcers: Effects on taste preference and memory. Physiol Behav 32: 195–203. Meyer-Lindenberg A, Kohn PD, Kolachana B, et al. (2005). Midbrain dopamine and prefrontal function in humans: Interaction and modulation by COMT genotype. Nat Neurosci 8: 594–596. Millan MJ, Dekeyne A, Gobert A (1998). Serotonin (5-HT) 2C receptors tonically inhibit dopamine (DA) and noradrenaline (NA), but not 5-HT, release in the frontal cortex in vivo. Neuropharmacology 37: 953–955. Mitchell SN (1993). Role of the locus coeruleus in the noradrenergic response to a systemic administration of nicotine. Neuropharmacology 32: 937–949. Mobini S, Chiang TJ, Ho MY, et al. (2000). Effects of central 5-hydroxytryptamine depletion on sensitivity to delayed and probabilistic reinforcement. Psychopharmacology (Berl) 152: 390–397. Monferini E, Gaetani P, Rodriguez Y, et al. (1993). Pharmacological characterization of the 5-HT receptor coupled to adenylyl cyclase stimulation in human brain. Life Sci 52: 61–65.

NEUROCHEMISTRY OF COGNITION Mullins UL, Gianutsos G, Eison AS (1999). Effects of antidepressants on 5-HT7 receptor regulation in the rat hypothalamus. Neuropsychopharmacology 21: 352–367. Nishino H, Ono T, Muramoto K, et al. (1987). Neuronal activity in the ventral tegmental area (VTA) during motivated bar press feeding in the monkey. Brain Res 413: 302–313. O’Doherty JP, Dayan P, Friston K, et al. (2003). Temporal difference models and reward-related learning in the human brain. Neuron 38: 329–337. Packard MG, White NM (1991). Dissociation of hippocampus and caudate nucleus memory systems by posttraining intracerebral injection of dopamine agonists. Behav Neurosci 105: 295–306. Palmer AM, Dekosky ST (1993). Monoamine neurons in aging and Alzheimer’s disease. J Neural Transm Gen Sect 91: 135–159. Palmer AM, Francis PT, Benton JS (1987). Presynaptic serotonergic dysfunction in patients with Alzheimer’s disease. J Neurochem 48: 8–15. Park SB, Coull JT, McShane RH, et al. (1994). Tryptophan depletion in normal volunteers produces selective impairments in learning and memory. Neuropharmacology 33: 575–588. Pauwels PJ (1997). 5-HT 1B/D receptor antagonists. Gen Pharmacol 29: 293–303. Pazos A, Cortes R, Palacios JM (1985). Quantitative autoradiographic mapping of serotonin receptors in the rat brain. Brain Res 346: 241–249. Peroutka SJ, Snyder SH (1979). Multiple serotonin receptors: Differential binding of [3H]5 hydroxytryptamine, [3H] lysergic acid diethylamide and [3H] spiroperidol. Mol Pharmacol 16: 687–699. Radja F, Laporte AM, Daval G, et al. (1991). Autoradiography of serotonin receptor subtypes in the central nervous system. Neurochem Int 18: 1–15. Ressler KJ, Nemeroff CB (2000). Role of serotonergic and noradrenergic systems in the pathophysiology of depression and anxiety disorders. Depress Anxiety 12: 2–19. Robbins TW (1997). Arousal systems and attentional processes. Biol Psychol: 57–71. Robert PH, Aubin-Brunet V, Darcourt G (1999). Serotonin and the frontal lobes. In JL Cummings, BL Miller (Eds.), The Frontal Lobes. The Guilford Press, New York, pp. 125–138. Robert PH, Clairet S, Benoit M, et al. (2002). The Apathy Inventory: Assessment of apathy and awareness in Alzheimer’s disease, Parkinson’s disease and mild cognitive impairment. Int J Geriatr Psychiatry 17: 1099–1105. Rogers RD, Blackshaw AJ, Middleton HC, et al. (1999a). Tryptophan depletion impairs stimulus–reward learning while methylphenidate disrupts attentional control in healthy young adults: Implications for the monoaminergic basis of impulsive behaviour. Psychopharmacology (Berl) 146: 482–491. Rogers RD, Everitt BJ, Baldacchino A, et al. (1999b). Dissociable deficits in the decision-making cognition of chronic

39

amphetamine abusers, opiate abusers, patients with focal damage to prefrontal cortex, and tryptophan-depleted normal volunteers: Evidence for monoaminergic mechanisms. Neuropsychopharmacology 20: 322–339. Rolls E (1999). The Brain and Emotion, Oxford, Oxford University Press. Ross CA, Pearlson GD (1996). Schizophrenia, the heteromodal association neocortex and development: Potential for a neurogenetic approach. Trends Neurosci 19: 171–176. Roth BL, Craigo SC, Choudhary MS, et al. (1994). Binding of typical and atypical antipsychotic agents to 5-hydroxytryptamine-6 and 5-hydroxytryptamine-7 receptors. J Pharmacol Exp Ther 268: 1403–1410. Roth BL, Hanizavareh SM, Blum AE (2004). Serotonin receptors represent highly favorable molecular targets for cognitive enhancement in schizophrenia and other disorders. Psychopharmacology (Berl) 174: 17–24. Sasaki-Adams DM, Kelley AE (2001). Serotonin–dopamine interactions in the control of reinforcement and motor behavior. Neuropsychopharmacology 25: 440–452. Schultz W (1998). Predictive reward signal of dopamine neurons. J Neurophysiol 80: 1–27. Schultz W (1999). The primate basal ganglia and the voluntary control of behaviour. J Consc Stud 6: 31–45. Schultz W, Apicella P, Ljungberg T (1993). Responses of monkey dopamine neurons to reward and conditioned stimuli during successive steps of learning a delayed response task. J Neurosci 13: 900–913. Schultz W, Dickinson A (2000). Neuronal coding of prediction errors. Annu Rev Neurosci 23: 473–500. Schwartz JC, Diaz J, Pilon C, et al. (2000). Possible implications of the dopamine D(3) receptor in schizophrenia and in antipsychotic drug actions. Brain Res Brain Res Rev 31: 277–287. Seamans JK, Yang CR (2004). The principal features and mechanisms of dopamine modulation in the prefrontal cortex. Prog Neurobiol 74: 1–58. Sesack SR, Carr DB, Omelchenko N, et al. (2003). Anatomical substrates for glutamate–dopamine interactions: Evidence for specificity of connections and extrasynaptic actions. Ann NY Acad Sci 1003: 36–52. Shiloh R, Nutt D, Weiszman A (2000). Atlas of Psychiatric Pharmacotherapy. Martin Dunitz, London. Sokoloff P, Giros B, Martres MP, et al. (1990). Molecular cloning and characterization of a novel dopamine receptor (D3) as a target for neuroleptics. Nature 347: 146–151. Svensson TH, Engberg G (1980). Effect of nicotine on single cell activity in the noradrenergic nucleus locus coeruleus. Acta Physiol Scand Suppl 479: 31–34. Svensson TH, Mathe´ AA (2002). Monoaminergic transmitter systems. In HA D’Haenen, JA Den Boer, P Willner (Eds.), Biological Psychiatry. Wiley, Chichester, pp. 45–66. Tanaka SC, Doya K, Okada G, et al. (2004). Prediction of immediate and future rewards differentially recruits cortico-basal ganglia loops. Nat Neurosci 7: 887–893. Toates F (1986). Motivational Systems. Cambridge University Press, Cambridge.

40

P.H. ROBERT AND M. BENOIT

Ugedo L, Grenhoff J, Svensson TH (1989). Ritanserin, a 5-HT2 receptor antagonist, activate midbrain dopamine neurons by blocking serotonergic inhibition. Psychopharmacology (Berl) 98: 45–50. Walsh SL, Cunningham KA (1997). Serotonergic mechanisms involved in the discriminative stimulus, reinforcing and subjective effects of cocaine. Psychopharmacology (Berl) 130: 41–58. White NM, Viaud M (1991). Localized intracaudate dopamine D2 receptor activation during the post-training period improves memory for visual or olfactory conditioned emotional responses in rats. Behav Neural Biol 55: 255–269. Williams GV, Goldman-Rakic PS (1995). Modulation of memory fields by dopamine D1 receptors in prefrontal cortex. Nature 376: 572–575. Wise RA (2004). Dopamine, learning and motivation. Nat Rev Neurosci 5: 483–494. Woolley ML, Bentley JC, Sleight AJ, et al. (2001). A role for 5-HT6 receptors in retention of spatial learning in the Morris water maze. Neuropharmacology 41: 210–219.

Yakel JL, Shao XM, Jackson MB (1990). The selectivity of the channel coupled to the 5-HT3 receptor. Brain Res 533: 46–52. Yeomans J, Baptista M (1997). Both nicotinic and muscarinic receptors in ventral tegmental area contribute to brainstimulation reward. Pharmacol Biochem Behav 57: 915–921. Yeomans JS, Kofman O, Mcfarlane V (1985). Cholinergic involvement in lateral hypothalamic rewarding brain stimulation. Brain Res 329: 19–26. Yeomans JS, Mathur A, Tampakeras M (1993). Rewarding brain stimulation: Role of tegmental cholinergic neurons that activate dopamine neurons. Behav Neurosci 107: 1077–1087. Yoshimoto K, Yayama K, Sorimachi Y, et al. (1996). Possibility of 5-HT3 receptor involvement in alcohol dependence: A microdialysis study of nucleus accumbens dopamine and serotonin release in rats with chronic alcohol consumption. Alcohol Clin Exp Res 20: 311A–319A. Zhou FM, Wilson CJ, Dani JA (2002). Cholinergic interneuron characteristics and nicotinic properties in the striatum. Neurobiology 53: 590–605.

Handbook of Clinical Neurology, Vol. 88 (3rd series) Neuropsychology and behavioral neurology G. Goldenberg, B.L. Miller, Editors # 2008 Elsevier B.V. All rights reserved

Chapter 3

Cortical neuroanatomy and cognition HOWARD J. ROSEN* AND INDRE V. VISKONTAS Memory and Aging Center, University of California, San Francisco, CA, USA

3.1. Introduction The human nervous system is organized in a hierarchical fashion, with basic processing performed by lower centers such as the brainstem and spinal cord and more complex functions organized in higher structures like the basal ganglia and cerebral cortex. In the last 150 years, it has become clear that higher brain structures do not perform all sensory and motor functions as a single, undifferentiated unit. Rather, the current predominant view of cerebral function is that the brain is organized into topographically distinct systems that perform relatively independent functions. Familiarity with the division of labor in the brain and its topography is required to understand and to predict the types of cognitive deficits that emerge with cerebral injury. The purpose of this chapter is to provide an overview of the cortical components of cognition and the functions they serve, and to prepare the reader for a deeper exploration of the specific cognitive deficits that result from dysfunction in each of these systems. The majority of cognitive processing begins with the interpretation of incoming sensory information, and it is in these sensory processing systems that the segregation of information is most apparent. Many syndromes of cognitive dysfunction can be easily understood in light of this topographical organization. The visual system has been the most intensely studied, and provides the best example of cortical specialization. For this reason, we begin our chapter by describing the cortical topography of visual processing, to be followed by a discussion of some of the other sensory modalities. Much of the power in our cognitive capacities comes from our ability to maintain sensory information over time (memory), to control our processing of sensory information (attention), to focus

our behavior so that we achieve our goals efficiently without distraction (executive functions) and to attach value to information, tailoring our actions accordingly (emotion and motivation). All of these functions deal with information in multiple sensory modalities, even if this information is altered from the way it was originally perceived (abstract processing). Accordingly, the cerebral cortex can be divided into regions that process information that is increasingly altered from its original sensory properties and integrated across sensory modalities (see Fig. 3.1).

3.2. Sensory processing and cognition Information about the world is brought to the brain through the sensory pathways. In general, sensory systems start with peripheral receptors that convert (transduce) sensory stimulation (light, heat, sound, etc.) into action potentials. Receptors vary in their complexity and the set of stimuli to which they respond, called the receptive field. Most sensory neurons send their information to subcortical relay regions, usually in the thalamus, and eventually to specific regions of the neocortex. 3.2.1. Vision 3.2.1.1. Neurophysiology and neuroanatomy of visual processing Regions and pathways involved in the processing of visual information occupy a large portion of the cerebral cortex. Felleman and Van Essen, based on cytoarchitectonics, connectivity, and the presence of separate visual topographical maps, have identified a total of 32 areas in occipital, temporal, and parietal cortex involved in visual processing. These regions comprise a huge

* Correspondence to: Howard Rosen MD, UCSF Department of Neurology, Memory and Aging Center, 350 Parnassus Avenue, Box 1207, Suite 706, San Francisco, CA 94143, USA. E-mail: [email protected], Website: www.memory. ucsf.edu, Tel: 415-476-2936, Fax: 415-476-4800.

42

H.J. ROSEN AND I.V. VISKONTAS

Fig. 3.1. Mesulam’s classification of the types of cerebral cortex into corticoid regions, allocortex, and mesocortex (all in green), neocortex (yellow and pink) and idiotypic isocortex (blue), with neocortex having unimodal (yellow) and polymodal (pink) association areas. The classification is superimposed on the cytoarchitectonic map of Brodmann, as indicated by the small numbers. Major anatomic subdivisions of the brain are denoted as follows: AA ¼ Auditory Association Cortex; AG ¼ Angular Gyrus; A1 ¼ Primary Auditory Cortex; CG ¼ Cingulate Cortex; INS ¼ Insula; IPL ¼ Inferior Parietal Lobule; IT ¼ Inferior Temporal Gyrus; MA ¼ Motor Association Cortex; MPO ¼ Medial Parieto-Occipital Area; MT ¼ Middle Temporal Gyrus; M1 ¼ Primary Motor Area; OF ¼ Orbitofrontal Region; PC ¼ Prefrontal Cortex; PH ¼ Parahippocampal Gyrus; PO ¼ Parolfactory Area; PS ¼ Peristriate Cortex; RS ¼ Retrosplenial Cortex; SA ¼ Somatosensory Association Cortex; SG ¼ Supramarginal Gyrus; SPL ¼ Superior Parietal Lobule; ST ¼ Superior Temporal Gyrus; S1 ¼ Primary Somatosensory Area; TP ¼ Temporopolar Cortex; VA ¼ Visual Association Cortex; V1 ¼ Primary Visual Cortex. Reprinted from Mesulam (1985) with permission from Oxford University Press.

proportion of cerebral neocortex—about 55% in monkeys (Felleman and Van Essen, 1991). Thus, it is no surprise that cerebral injury frequently causes visual deficits. Depending on the location of the injury, a problem in basic visual processing may occur, such as blindness, or a more complex problem may occur, such as the inability to see the spatial relationships between targets in the visual landscape. Many of these deficits can be understood from the organization of visual processing.

Visual processing starts at the retina, where photoreceptor cells are exposed to light coming into the eye through the iris and lens. The lens of the eye inverts the visual image so that the retina receives an upsidedown representation of the visual image. This relationship, where the lower parts of the neural apparatus process the superior portion of the visual image is maintained back into the primary visual cortical regions. From the retina, fibers pass backwards in the optic nerves to the optic chiasm. At this point, fibers from the nasal half of each retina cross to the opposite side of the chiasm to join the fibers from the temporal half of the opposite retina (see Fig. 3.2). Thus the optic tracts, which carry fibers back from the chiasm, contain all the fibers carrying information about the contralateral visual field. Fibers next arrive at the lateral geniculate nucleus (LGN), in the thalamus, where they synapse with cells that send fibers back, via the optic radiations, to the primary visual cortex (V1), or striate cortex (named for the dark stripe in the cortex which can be seen running parallel to the cortical surface in this area). Within striate cortex, information is retinotopically arranged, with peripheral stimuli being represented anterior to stimuli in the center of the visual field. After arrival at V1, information is passed on to

Overlap

Retina

Optic Nerve

Optic Chiasm

Optic Tract

Striate Cortex

Fig. 3.2. The visual pathways from the retina to the striate, or primary visual cortex. Fibers from the nasal portion of each retina pass to the contralateral hemisphere via the optic chiasm. Thus, the primary visual processing region receives all the retinal information pertaining to the contralateral visual field.

CORTICAL NEUROANATOMY AND COGNITION other regions in the temporal and parietal cortex. The temporal areas are sometimes collectively referred to as extrastriate cortex. As visual information passes from one stage of processing to another, stimulus features become increasingly segregated. This segregation begins at the retina, where several types of photoreceptor cells exist, some with large receptive fields, some with small ones. Each of these cell types communicates with a different cell type in the LGN. In V1, functional segregation becomes even more evident. V1 (comprised of BA 17 and BA 18) can be subdivided into several regions using cytochrome oxidase staining. Circular regions of heavy staining, called blobs, can be seen in area 17. Blob cells are very sensitive to color, and they communicate with an extrastriate region specialized for color processing, called V4. Cells in between the blobs (interblob cells) have linear receptive fields and are sensitive to the orientation of the stimuli. They appear to represent the beginning of the process of shape detection. In adjacent area 18, heavily staining thick and thin stripes can be seen. Cells in the thick stripe regions send their output to area V5 (also called area MT, for the middle temporal region in the monkey cortex), which is specialized to represent the direction of motion of a stimulus (Newsome et al., 1989). These separate regions and pathways concerned with an object’s color, form, and motion provide the rudiments for neurological systems devoted to object recognition and object location, separately represented in the temporal and parietal regions. In animals, lesions in the posterior parietal cortex impair spatial discrimination (Pohl, 1973), and lesions in the inferior temporal cortex impair object identification. This type of finding led Mishkin and Ungerleider to characterize separate pathways devoted to the analysis of object identity and object location, located in the inferior temporal and posterior parietal regions, respectively (Mishkin and Ungerleider, 1982). Neural physiology in these regions is consistent with this idea. Temporal lobe neurons have large receptive fields, and respond to the physical characteristics of objects, sometimes regardless of where they are in space. Some temporal neurons even respond to very specific stimuli, such as individual faces (Logothetis and Sheinberg, 1996). On the other hand neurons in the posterior parietal cortex have small receptive fields, consistent with a region that is sensitive to an object’s spatial location. In humans, functional imaging studies with PET have confirmed that spatial visual processing activates parietal regions while object form processing activates inferior occipitotemporal regions (Haxby et al., 1991). The anatomically distinct pathways carrying visual information into the temporal and parietal regions are often referred to as the ‘what’ (ventral stream) and ‘where’ (dorsal stream) pathways.

43

3.2.1.2. Lesions in striate and extrastriate cortex Many syndromes of visual dysfunction related to injury are predictable by the organization of the visual system. Lesions that affect fibers heading to the striate cortex, and most lesions in the striate cortex itself, cause loss of vision. Optic nerve injuries result in monocular visual loss, whereas optic tract lesions damage the fibers from the nasal portion of each retina, resulting in tunnel vision. Unilateral damage posterior to the chiasm affects vision in the contralateral visual hemifield. Inferior striate cortex lesions cause a defect in the superior visual quadrant (superior because of the inversion of the visual image on the retina), called superior quadrantanopsia. Similarly, superior occipital injury causes inferior quadrantanopsia, and lesions affecting the superior and inferior portions of the occipital lobe in one hemisphere cause a contralateral hemianopsia (see Fig. 3.2). Cortical blindness results from complete destruction of the occipital region. In some cases, this blindness is associated with a denial of deficit, called Anton’s syndrome. Whereas structures that process the form, color, and movement of visual stimuli are closely intermingled in the striate cortex, the physical separation between these pathways increases as the information is passed to the association cortex; damage to these ‘higher cortical regions’ causes deficits in some aspects of vision, such as movement perception, without total blindness. Lesions in the temporal–occipital regions, for instance, usually cause color vision (as in achromatopsia) deficits. Resultant vision is grayscale, with complete preservation of form. Inability to recognize an object based on its visual form is called visual agnosia. Visual agnosia exemplifies the extreme type of visual–perceptual deficit that emerges with bilateral injury to the ‘what’ system. Hans Teuber defined agnosia as ‘a percept stripped of its meaning.’ In the case of an ‘associative’ visual agnosia, an object can be copied precisely, yet the patient is unable to name or describe the function of the object. With a more pervasive ‘aperceptive’ agnosia, objects cannot be properly copied. One of the most dramatic deficits in form vision occurs in prosopagnosia, which is a deficit in face recognition. Patients with prosopagnosia are unable to recognize the subtle distinctions that differentiate one face from another, so that they are unable to recognize even themselves. They can easily identify a person from other cues, such as the voice, or an article of clothing. The deficit can extend to nonhuman faces and to inanimate objects, such as various makes and models of cars. According to Damasio, prosopagnosia always occurs in the setting of bilateral temporal–occipital lesions (Damasio, 1985). Prosopagnosia can be contrasted with a more general type of visual

44

H.J. ROSEN AND I.V. VISKONTAS

agnosia, in which patients are unable to recognize an object’s category. In contrast to patients with prosopagnosia, these patients are unable to tell that a face is a face and a car is a car. Patients with agnosia are often able to recognize objects upon touching them; in some cases, moving the object or slowly rotating it also improves recognition (Botez, 1975). Selective deficits in movement perception, with relative preservation of form vision, have also been observed. Zihl and coworkers described one such patient (Zihl et al., 1983). She complained that, when pouring tea, she could not stop at the right time because she was unable to perceive the rising of the fluid level in the cup. Crowded places disturbed her because ‘people were suddenly here or there’ and she could not see them moving. She could no longer judge the speed of moving cars, though she could identify the car itself. Basic visual acuity was preserved, as were tactile and auditory movement perception. This patient had bilateral lesions which included both parietal–occipital regions. A more complex deficit in the localization of visual objects is seen in Ba´lint’s Syndrome (Corsellis, 1976). The visual dysfunction in this disorder is called simultanagnosia; the patient cannot process an entire visual scene at once. Simultanagnosia is not related to simple visual loss, since the ‘seen’ portion of the visual field can be in different parts of the visual field at different times. Patients with Balint’s syndrome exhibit other related findings including optic ataxia (inability to manually localize items in the environment), sticky fixation (inability to shift gaze from one object to another), and varying degrees of ocular apraxia (voluntary gaze paresis). Clearly, these phenomena relate to the movement and location aspects of visual processing rather than to form or color perception. Patients with Balint’s syndrome usually have bilateral injury to the parietal–occipital region. Injury to areas of higher visual processing can also lead to visual distortions of objects, called metamorphopsias. Achromatopsia is one example of this, but other distortions can occur, such as image shrinkage (micropsia) or enlargement (macropsia), modification of object dimensions (stretching or flattening), blurring or fragmentation of contours, false impressions of movement or lack of appreciation of movement, or object perseveration (seeing two or more of an image, called palinopsia) (Hacaen and Albert, 1978). The latter condition is particularly noteworthy, as it highlights the fact that diplopia (double vision) can rarely be associated with cortical injury, as opposed to brainstem injury. Lastly, lesions or epileptic discharges in the extrastriate visual region can be associated with frank visual hallucinations, some of which can be quite complex.

3.2.1.3. Cerebral asymmetry and visuospatial cognition Many of the syndromes described above, including Ba´lint’s syndrome and agnosia, are caused by bihemispheric dysfunction, but visuospatial deficits also develop with unilateral non-dominant (right hemispheric) injury. Copying a drawing, fixing a machine, and dressing deteriorate following non-dominant parietal injury. The ability to distinguish ‘figure’ from ‘ground’ can be so impaired that even the simplest spatial functions such as eating are disrupted. This loss of spatial processing leads to serious deficits in the ability to navigate, a problem commonly seen with non-dominant parietal lobe dysfunction. In contrast, with dominant (left hemispheric) parietal injury, the deficits in spatial function are subtle and tend to involve loss of attention to details. Although prosopagnosia is thought to occur from bilateral lesions, non-dominant temporal lobe injury can cause face-recognition deficits for both familiar and unfamiliar faces. Another symptom frequently associated with nondominant parietal dysfunction is unilateral neglect. With inferior non-dominant parietal injury, a patient preferentially orients toward the spatial map organized by the contralateral hemisphere (in right-handers the right visual field). This orientation leads to neglect of the left side of the paper when a patient attempts to draw, or the left side of the body when a patient attempts to dress. The patient may draw only the right half of a clock or dress only the right side of the body. Neglect can be seen in multiple sensory modalities, including touch, vision, and hearing; for this reason, it may represent a global deficit in spatial attention. There is a close relationship between neglect and denial of illness, so-called ‘anosognosia.’ Many patients with non-dominant parietal lobe injury not only neglect the left side of the body, but even deny that a deficit is present. 3.2.2. Audition 3.2.2.1. Anatomy and physiology of auditory processing Auditory processing begins in the organ of corti, in the cochlea. Different portions of the organ of corti are sensitive to different frequencies, so it is here that the discrimination of sounds begins. Sound information ascends through the brainstem to the medial geniculate nucleus of the thalamus, making a number of synapses along the way in the cochlear nuclei, the superior olive, and the inferior colliculus. A great deal of auditory processing occurs in the brainstem and thalamus before information is finally passed on to the cerebral cortex. Most of the auditory fibers initially cross to the contralateral side of the brainstem in the trapezoid body, and

CORTICAL NEUROANATOMY AND COGNITION then ascend in the lateral lemniscus, although a substantial amount of auditory information ascends ipsilaterally, so that each hemisphere receives information from both ears (Brodal, 1981). The auditory cortex is located on the superior surface of the superior temporal gyrus, and occupies the region of the transverse temporal gyrus, or Heschl’s gyrus and part of the adjacent planum temporale, just posterior to Heschl’s gyrus (Brodmann’s areas 41 and 42) (see Fig. 3.3). Auditory cortex receives input primarily from the medial geniculate nucleus of the thalamus, and sends descending fibers to the thalamus, as well as to the midbrain and pons. Transcallosal communication exists between homologous regions of the auditory cortex (Diamond et al., 1968a), and output from the primary auditory cortex is sent to various regions in the frontal, temporal, and parietal lobes (Diamond et al., 1968b). The primary auditory processing area in the auditory cortex appears to be a collection of cytoarchitectonically distinct regions with a core region, called A1, surrounded by a collection of areas called the belt region, which is in turn surrounded by a collection of regions called the parabelt region (Kaas et al., 1999). Rather than simply recognizing sound frequencies, the primary auditory cortex appears to be more important for processing other aspects of sound, including intensity, source, and pattern. Lesions of the auditory cortex have demonstrated that it is not essential for basic frequency discrimination (Rauschecker et al., 1997). Instead, bilateral injury to the auditory cortex results in impairment of the perception of auditory patterns such as tone sequences (Kaas et al., 1999). Some neurons in the auditory cortex respond to the temporal aspects of stimuli, such as changes in frequency (Whitfield and Evans, 1965) or amplitude (Bieser and Muller-Preuss, 1996) over time; these neurons may even be sensitive

Fig. 3.3. Auditory cortex: Brodmann’s Areas 41 and 42.

45

to a particular frequency embedded in a complex auditory stimulus. In addition, neurons sensitive to intensity and frequency differences between the two ears appear to aid sound localization (Brugge and Merzenich, 1973; Wegener, 1973). The specific functions of auditory cortex subregions are still being delineated. While A1 is characterized by a strict tonotopic organization, the adjacent belt and parabelt regions have less detailed tonotopic organization and are more sensitive to complex stimuli such as narrowband noise (Rauschecker et al., 1995; 1997; Kosaki et al., 1997). Lateral belt neurons also fire more vigorously to species-specific vocalizations than to pure tones (Rauschecker et al., 1995). Although both auditory cortices receive input from both ears, their functions do not appear to be identical. Electrical stimulation of the auditory cortex in humans produces a perception of buzzing, ringing, or clicking, seemingly coming from the contralateral ear (Penfield and Jasper, 1954). In addition, anatomical studies have demonstrated that the left planum temporale is usually larger than the right in humans (Galaburda et al., 1978), consistent with the special relationship between the left auditory cortex and adjacent structures necessary for language processing. Dichotic listening experiments, in which subjects are asked to monitor different auditory stimuli entering each ear, have revealed a right ear (left hemisphere) advantage for verbal stimuli, complemented by a left ear (right hemisphere) advantage for musical stimuli (Kimura, 1961; 1964). 3.2.2.2. Lesions of the auditory cortex As a rule, lesions of the temporal lobe affecting the primary auditory regions do not cause deafness unless they are bilateral. Slight unilateral hearing loss and impairment in sound localization have been observed in conjunction with unilateral lesions (Brodal, 1981). The syndrome of auditory agnosia, or the inability to recognize sounds, such as the ringing of a telephone, or the sound of a running car, has been described following bilateral injury to the superior temporal lobe (Vignolo, 1969). Left temporal lobe lesions often have more profound effects on language function, particularly comprehension, than right temporal lobe lesions. Such deficits generally follow damage to Wernicke’s area, which is slightly posterior to the left-sided primary auditory region (see section 3.5). This pure word deafness syndrome is characterized by the inability to comprehend speech sounds, in the presence of intact hearing for other types of sounds, and intact written language comprehension. These symptoms can also be associated with bilateral auditory cortex injury, or sometimes with unilateral left-sided injury, if the

46

H.J. ROSEN AND I.V. VISKONTAS

language dominant left hemisphere is cut off from auditory input (Benson and Geschwind, 1985). Irritative lesions near the primary auditory cortex typically produce subjective auditory sensations, or tinnitus, in the form of ringing, buzzing, or clicking perceptions. Seizures emanating from the lateral temporal lobe can lead to these symptoms, but may also cause vertigo. Occasionally, more complex auditory hallucinations, such as hearing voices, have been described in conjunction with seizure activity in this region. 3.2.3. Somatosensory processing 3.2.3.1. Anatomy and physiology of the somatosensory system As with other cortical systems, most of the processing of somatic sensory information occurs at lower levels in the neuroaxis. At the most peripheral levels, different types of sensory information are processed by different types of receptors in the skin. For instance, Pacinian corpuscles are thought to convey information about vibration, while Meissner’s corpuscles convey light-touch information (Brodal, 1981). In the cortex, somatic sensory information arrives just behind the central sulcus, via two major ascending pathways: the anterolateral-spinothalamic tract (carrying information about pain and temperature) and the dorsal columnmedial lemniscus pathway (carrying information about light touch and proprioception). Dorsal column fibers form synapses in the nucleus gracillis and cuneatus in the medulla, whose output is sent primarily to the ventromedial nucleus of the thalamus and the cerebral cortex.

Primary somatosensory cortex, or S-I, is subdivided into four cytoarchitectonically distinct regions: Brodmann’s Areas (BAs) 3a and 3b, which receive most of the thalamic input, and BAs 1 and 2, which receive output from BAs 3a and 3b. Somatosensory cortex (SSC) also has extensive connections with primary motor cortex, and with other regions of parietal cortex (BAs 5 and 7) that receive inputs from other sensory modalities, particularly vision. Thus, these parietal regions integrate information from different sensory modalities. Anatomical mapping of BA 1 has demonstrated a somatotopic organization along the surface of the cerebral cortex in animals (Marshall, 1951) and humans (Penfield and Rasmussen, 1950), with the mouth and distal upper extremities represented laterally and inferiorly, and the legs and feet represented medially and superiorly (see Fig. 3.4). The physiologic organization in the SSC reflects the overall organization of the somatosensory system. Specific populations of cells are devoted to particular regions of the body, but are also attuned to particular types of receptors. Thus, some cells fire when Pacinian corpuscles are stimulated, while others fire when Meissner’s corpuscles are stimulated (Mountcastle, 1957). Although all the cortical sensory regions receive input from all parts of the skin, certain types of stimuli seem to be over-represented in particular regions; for instance, the dominant input to BA 2 is from deep pressure receptors, while the predominant input to BA 1 is from rapidly adapting cutaneous receptors (Kaas et al., 1981). This may relate to findings that lesions to BA 1 result in deficits specific to texture discrimination, whereas lesions to BA 2 result in deficits in size and shape discrimination (Kandel et al., 1995).

Fig. 3.4. The map indicating the areas of the human primary somatosensory and primary motor cortex at which electrical stimulation produces sensations or movement in various body parts. Note the relative size and position of the representation of various body parts (adapted Penfield and Rasmussen, 1950).

CORTICAL NEUROANATOMY AND COGNITION Physiological studies of the SSC have shown that, as information is passed from one region to the next, it becomes more abstract. For example, neurons in BAs 3a and 3b respond to punctate stimuli, whereas neurons in BAs 1 and 2 have larger receptive fields (Iwamura et al., 1985a; 1985b) and thus create a less detailed representation of the physical characteristics of the stimulus (Phillips et al., 1988). In contrast to neurons in BAs 3a and 3b, BAs 1 and 2 neurons respond to complex aspects of stimuli such as direction of motion (Warren et al., 1986). Inferior and slightly posterior to S-I is S-II, or secondary sensory cortex. The precise nature of the additional sensory processing which occurs in S-II is not clearly understood. Although the properties of S-II neurons are in many ways similar to the properties of neurons in S-I, S-II has been shown to contain neurons with bilateral receptive fields (Whitsel et al., 1969) and stimulation of S-II in humans can produce bilateral sensations (Penfield and Rasmussen, 1950). In animals, lesions of S-II result in deficits in texture and size/ shape discrimination. One unresolved question regards the role of the SSC in pain processing. In fact, a number of studies have demonstrated that injuries to the SSC frequently do not result in a deficit in pain perception (Marshall, 1951), although neurons in the SSC have been found which respond only to painful stimuli (Powell and Mountcastle, 1959). Although the exact role of the SSC in pain processing is yet to be defined, it appears that the SSC is much more directly related to the processing of touch, vibration, and position sense. 3.2.3.2. Lesions of the somatosensory cortex Damage to the SSC will result in loss of sensation in the opposite half of the body, with the location being predicted by the homunculus (see Fig. 3.4). Initially, the sensory loss may be complete for all modalities. Over time the sensory loss may resolve to a variable degree, sometimes leaving a patient with isolated abnormalities of fine discrimination, referred to as ‘cortical’ sensory loss. This deficit in tactile ability can result in difficulty recognizing complex stimuli, and sometimes it can be demonstrated that the threshold to basic touch stimuli seems unaffected, but that the appreciation of more complex sensory stimuli is impaired. Localization of tactile stimuli can be faulty as well. The loss of the ability to recognize objects by their tactile qualities has been referred to as astereognosis. Parietal injury, particularly on the left, can sometimes lead to subtle, bilateral sensory loss. Patients with cortical sensory loss may also have variable responses to sensory stimulation, which can sometimes lead the

47

examiner to conclude that the sensory complaints are factitious.

3.3. Higher cognitive functions of the cerebral cortex: integration of information from multiple modalities 3.3.1. Attention Our daily world provides us with much more information then we can possible take in at one time: attention is the mechanism by which the brain filters information for further processing. Attentional capacity varies not only between individuals but also within the same individual at different times or under different conditions. 3.3.1.1. Neuroanatomy and neurophysiology of attention Assigning ‘resources’ to particular aspects of the external world or the internal information processing occurring within the brain begins with general arousal. The central component of the arousal system is in the midbrain portion of the reticular activating system (Moruzzi and Magoun, 1949). This system, along with the noradrenergic locus coeruleus nucleus in the pons, sends widespread connections to the thalamus and cerebral cortex, establishing the overall level of arousal, which is required for attention. The thalamus also plays an important role in modulating attention, especially the pulvinar complex: cells in the pulvinar have been shown to respond more vigorously to stimuli that are targets of behavior than to those that seem to be ignored (Petersen et al., 1987). The pulvinar is well placed to play a role in attention, as it projects to the posterior parietal, temporal, and frontal cortices. Within the cerebral cortex, specific regions participate in directing attention and vigilance. These include the anterior cingulate region, the premotor region and the parietal regions posterior to primary sensory processing areas. Functional neuroimaging studies have suggested that each of these regions plays a specific role in attentional processing. For instance, studies requiring individuals to shift attention to various peripheral locations in the visual field activate regions in the superior posterior parietal cortex, around BA 7 (Corbetta et al., 1993). These regions are also important for attending to various aspects of visual stimuli, such as color or motion, and BA 7 is particularly active when shifting between stimulus features is required (Petersen et al., 1994). Damage to the posterior parietal region has been shown to impair performance on tasks that require disengagement, shifting or engagement of attention (Posner and Petersen, 1990). Frontal premotor responses

48

H.J. ROSEN AND I.V. VISKONTAS

are also seen in studies examining shifting of attention, but only when subjects use the information from peripheral visual stimuli to make a response, suggesting that they are responsible for sensorimotor integration. Anterior cingulate activity during tasks requiring directed attention has usually been associated with prefrontal responses, and has been interpreted as being related to response selection (Corbetta et al., 1991). The study of patients with cerebral lesions has revealed a particular role for the right parietal region in the direction of attention to various locations on either side of the body. Damage to this region can be associated with profound deficits in attention, particularly to the left half of the body and the part of the world on the left side of the patient (see also section 3.2.1).

Fig. 3.5. Brain regions involved in long-term declarative memory: medial temporal lobe and adjacent neocortex.

3.3.2. Memory 3.3.2.1. Episodic memory Learning occurs on a variety of timescales, from seconds to years. A simple model of memory processes might posit that memory depends on a single system which stores information over longer and longer periods. However, experimental observations, particularly in humans, have indicated that memory uses different brain systems depending on the type of information, the duration for which it will be stored, and how it will be used. One major distinction is between declarative memory, which refers to the conscious memory for facts and events, and non-declarative memory, which refers to non-conscious memory for skills, habits, or other manifestations of learning that can be expressed without awareness of what was learned. Studies of people with amnesia are widely recognized as providing the evidence for a dissociation between declarative (tested using explicit tests of memory, such as repeating a list of previously studied words) and non-declarative memories (tested using implicit tests of memory, such as running a familiar maze) (Squire, 1982). It is now a well-established finding that people with amnesia as a result of medial temporal lobe (MTL) damage are impaired on explicit but not implicit tests of memory (Squire, 1992) (see Fig. 3.5). Within the declarative memory system, Tulving (1972; 1983) further distinguished ‘episodic’ from ‘semantic’ memory. Episodic memory contains information about temporally dated episodes or events and temporal–spatial relations between them (Tulving, 1983). Semantic memory, in contrast, refers to knowledge about the world; generic information that is acquired across many different contexts and stored independent of the learning situation. As discussed below, this fractionation of declarative memory is supported by evidence that episodic and semantic memory may have unique neural underpinnings.

3.3.2.1.1. Anatomy of the episodic memory system Surrounding the hippocampal formation, the parahippocampal and perirhinal cortices receive projections from unimodal and polymodal association areas in the frontal, parietal, and occipital lobes, and send projections primarily to the entorhinal cortex (Insausti et al., 1987). Therefore, via the entorhinal cortex, the hippocampus receives processed information from many different sensory domains. Given these neuroanatomical connections, the hippocampus is well-placed to create associations between co-occurring stimuli in our sensory world. Key structures involved with episodic memory include the hippocampus (including the subiculum), parahippocampal gyrus (entorhinal cortex in particular), the mammillary bodies and thalamus (Zola-Morgan et al., 1986). These structures are organized into two anatomically connected systems required for maintenance of episodic memory, the septohippocampal and mammillothalamic tracts. A major cholinergic projection beginning in the septum travels via the fornix and enters the hippocampus through the entorhinal cortex (Everitt et al., 1988). This mammillothalamic circuit begins in the mammillary body and projects through the tract of Vic d’Azyr adjacent to the dorsomedial nucleus of the thalamus and then to the anterior thalamic nucleus (Papez, 1937). From the anterior thalamus, projections go to the cingulum in the frontal lobes and then project back to the hippocampus. In this way the mammillothalamic system is connected to the septohippocampal tract. Spatial processing appears to be an important component of hippocampally based memory function. The hippocampus has the unique ability to bind association between ‘what,’ ‘when,’ and ‘where’ together (Rolls, 1996). In the rat hippocampus, there are cells that fire

CORTICAL NEUROANATOMY AND COGNITION selectively when the animal is in a particular part of an environment (O’Keefe and Dostrovsky, 1971). Cells that fire when a specific object is seen in a specific place have also been found in this region in animals (Rolls, 1999). Human neuroimaging studies, however, have thus far failed to find a change in activity in the hippocampus during navigation (Aguirre et al., 1998). Instead, fMRI studies have shown that the parahippocampal cortex is activated when participants are navigating through a virtual maze (Aguirre et al., 1998). A region of the parahippocampal cortex known as the parahippocampal place area (PPA) has also been found to increase in activation during the viewing of indoor and outdoor scenes, as well as mental images of scenes (O’Craven and Kanwisher, 2000). Therefore, it seems that both the hippocampus and parahippocampal cortices may be involved in spatial memory in humans. 3.3.2.1.2. Lesions of the episodic memory system Injury anywhere along this septohippocampal pathway can lead to severe loss of episodic memory. Patients with this type of injury will have an anterograde amnesia, characterized by an inability to commit any new information to memory. Memories that were established before the injury (remote memories) are relatively preserved, although a retrograde amnesia, going back anywhere from minutes to years, will usually be present. Larger lesions cause a more extensive retrograde memory deficit (Squire and Alvarez, 1995). Also, as brain injury improves overtime, the retrospective memory impairment tends to lessen (Benson and Geschwind, 1967). The most common cause for entorhinal dysfunction is Alzheimer’s disease, which begins in the entorhinal cortex and then spreads to the hippocampus (Braak and Braak, 1991). Other mechanisms of hippocampal injury include traumatic injury (because the hippocampi sit adjacent to, and are easily pushed against, the bone in the middle cranial fossa) (Bigler et al., 1989), stroke (Benson et al., 1974), anoxia and infections, in particular herpes simplex encephalitis (Wilson et al., 1995). Severe loss of episodic memory can also be due to dysfunction in the mammillothalamic memory system. The amnesia of Korsakoff syndrome is due to injury from hemorrhage into the mammillary bodies and dorsomedial nuclei of the thalamus (Victor, 1987; Kopelman, 1995). Furthermore, recent studies of patients with stroke in the left dorsomedial nucleus of the thalamus suggest that injury here alone will precipitate a severe amnesia (Guberman and Stuss, 1983). The nature of recovery from a retrograde amnesia sheds light upon the process of consolidation, where episodic memories are slowly locked into our memory system over time. Dreaming and conscious revisiting

49

of a memory may be important for the process of consolidation. Many questions remain regarding anatomical localization of remote episodic memory. While the hippocampus appears to play a limited role, other regions, including the lateral temporal, posterior parietal, anterior temporal, and frontal regions have been implicated in the access of remote memory. 3.3.2.1.3. Material specificity in left and right hippocampi Verbal memory, the ability to remember verbally encoded information such as words, relies disproportionately on the left (or dominant) hippocampus. When the dominant hippocampus is lesioned these functions diminish. Hence, the ability to learn new vocabulary is lost. Beyond words, much of day-to-day new learning requires intact verbal memory. Often, the time or place of appointments, the names of friends, or the content of previous conversation are lost. Injury to the dominant (left) hippocampus and dorsomedial nucleus of the thalamus leads to more severe amnesia than will injury to the same regions on the right side (Abrahams et al., 1997). Damage to the right hippocampus seems to have a greater impact on memory for visual and spatial than for verbal information. 3.3.2.1.4. Emotion and episodic memory Emotion plays a key role in enhancing the ability to remember. Emotionally charged events are more easily remembered than emotionally neutral episodes, and highly vivid ‘flashbulb’ memories are often laid down during traumatic or emotional events. In humans the amygdala appears important for retaining information related to strong emotions (Canli et al., 2000). Various nuclei in the amygdala are connected to the hippocampus: the lateral nucleus, the accessory basal nucleus, and the periamygdaloid cortex all project to the hippocampus (Krettek and Price, 1977). In return, projections from the subiculum, CA1 field and entorhinal cortex reach the basal, lateral, and cortical nuclei (Ottersen, 1982). 3.3.2.2. Semantic memory Unlike episodic memory, with semantic memory the individual usually has no recollection of when or where the information was acquired. For example, when someone asks how many weeks are present in a year, most of us respond spontaneously with the answer ‘52.’ Beyond the simple repetition of a label or a fact, semantic memory is composed of rich knowledge sets about the world. Knowing that ‘52’ weeks are present in a year is possible because the brain holds a complex set of constructs that include an abstract awareness of what a week

50

H.J. ROSEN AND I.V. VISKONTAS

represents, and how many of these abstract units of time are present in another abstract time concept, the year. These ideas are held together in the semantic memory system. Little is known about semantic dementia from animal research. Evidence that semantic memories are independent of the septohippocampal and mammillothalamic memory systems comes from humans with MTL injury, who maintain their access to semantic knowledge. In contrast, patients with primarily anterior and lateral temporal lobe damage show intact episodic memory but impaired semantic memory (Warrington, 1975; Tulving et al., 1988; Hodges and Graham, 1998; Viskontas et al., 2000). There remains, however, considerable controversy in the literature concerning whether these two memory systems are in fact distinct, or whether semantic memory represents the abstraction of common elements from multiple episodic memories.

periods of time: from seconds to minutes (Baddeley and Della Sala, 1996). A classic example of a verbal working memory task is calling an operator and asking for a telephone number. Working memory allows us to hold these numbers while they are dialed into the telephone, and then to discard them. Baddeley’s conceptualization of short-term memory as ‘working memory’ emphasizes the fact that this memory system is also involved in manipulation of information (for instance, when reorganizing names in alphabetical order). He further proposes that there are four main components: a) a central executive that keeps track of and gathers information for the ‘slave’ systems, b) a visual ‘slave’ system called the visuospatial scratchpad that holds visual representations of objects, c) a phonological ‘slave’ system that holds verbal information and d) an episodic buffer that is capable of binding together information from different modalities into a coherent trace.

3.3.2.2.1. Lesions of the semantic memory system

3.3.2.3.1. Neuroanatomy, physiology, and lesions affecting working memory

In the condition called semantic dementia (a syndrome associated with neurodegenerative disease that begins in the anterior temporal lobes) both the simple labeling process (naming), and beyond this, knowledge about the identity of people and objects are lost. Patients with semantic dementia classify objects into increasingly superordinate categories. Hence, a hawk becomes a ‘hunting bird,’ then a ‘bird,’ then an ‘animal,’ then a ‘thing’ as the disease worsens. Eventually all objects are classified with a series of simple stereotyped phrases. Recent work in semantic dementia suggests that the hippocampus can store semantic memories for approximately two years following which these memories are transferred to the left temporal neocortex (Simons et al., 2002). Therefore, patients with semantic dementia can often remember recent events because their hippocampus is spared, but they may show profound impairment of remote memory, presumably because their temporal neocortex has degenerated. Bilateral temporal dysfunction is a prerequisite of semantic dementia, although the disorder affects the left temporal lobe more than the right. There are few other disorders that lead to this bilateral anatomic defect, as the anterior temporal lobes are rarely subjected to bilateral vascular lesions. One disorder that attacks this region is herpes simplex encephalitis, and semantic dementia has been described in patients recovering from this disorder. 3.3.2.3. Working memory Alan Baddeley first used the term working memory to describe a fluid memory process that allowed the individual to hold and manipulate information for short

Patricia Goldman-Rakic and others delineated, with single cell recording, a network of neurons in the posterior parietal and dorsolateral frontal lobes where activity is high only during periods when information is being held in memory for use in just a few seconds (GoldmanRakic, 1988). These neurons appear to provide an important functional basis for working memory. Similarly, functional imaging studies from humans show that the dorsolateral frontal lobes, particularly Brodmann area 46, are critical for working memory (Petrides et al., 1993; Grady, 1998). Lesions that disrupt the structure or function of the dorsolateral frontal or posterior parietal regions decimate working memory (Moscovitch, 1982; Milner et al., 1985). Deficits in working memory have a profound effect upon the organism, either by disrupting the learning process downstream to working memory, or by affecting activities that directly depend upon an intact working memory. In the classic amnesic syndrome, patients have intact working memory but cannot transfer information from working memory into a long-term store. 3.3.3. Executive function and the frontal lobes The frontal lobes, which make up 40% of the human cerebral cortex, are greatly expanded in humans compared to non-human primates (Stuss and Benson, 1986). Yet, only recently have researchers begun to elucidate the mysterious functions of the frontal lobes. Far from a monolithic structure with a single purpose, the frontal lobes are divided into multiple structurally,

CORTICAL NEUROANATOMY AND COGNITION physiologically, and functionally distinct regions with important functions related to movement, motor planning, language, intelligence, working memory, generation, inhibition, alternating sequences, drive, emotion, self-awareness, insight, and personality. Although tremendous progress has been made in characterizing the physiology of frontal lobe neurons (particularly in the motor systems), most of what we know about the role of the frontal lobes and cognition comes from studies of humans with brain injury. The cognitive functions most commonly attributed to the frontal lobes are higher order or executive processes which involve the organization of more basic cerebral processes to promote efficient task performance and establishment of associations beyond basic representation of incoming sensory information. Examples of important cognitive functions of the frontal lobes include abstraction, inhibition, and facilitating the shifting of cognitive sets (Luria, 1966; Fuster, 1997)—tasks often subsumed under the term executive function, and mediated by multiple frontal regions on the medial and lateral frontal surface (see Fig. 3.6). Also, the frontal lobes play a key role in attention, memory (particularly working memory), and language (these functions are described in other sections of this chapter). 3.3.3.1. Concentration and sustained mental activity Efficient, successful completion of tasks requires the ability to avoid distraction and to maintain mental effort on a given task until it is complete. These functions go beyond working memory, for they require an individual not just to hold information in mind, but to iteratively evaluate one’s progress toward a goal and repeat or alter our behavior until the goal is reached. Patients with frontal lobe damage are often impaired

51

in these functions, leading them to be distractible, disorganized, and very inefficient (Zakzanis, 1998). 3.3.3.2. Alternating tasks and inhibition Often we are required to maintain two or more tasks in mind simultaneously, and constantly shift between them. In addition, it is sometimes necessary to suppress the impulse to perform certain tasks to reach our goals. These functions are significantly impaired with frontal lobe injury (Luria, 1966) with profound consequences. For example, driving requires constant changes in established plans of action, and there are frequent shifts and conflicts that must be managed. If stopped at a red light we activate a complex set of movements to ‘go’ when the light turns green. Yet, if a young child runs in front of the car at the same moment that the light turns green, immediate inhibition of the ‘go’ response is required. Frontal lobe motor systems generate and inhibit complex movement. When a friend extends his hand we spontaneously begin a series of movements that will lead us to shake it; this is followed by a second series of movements that will lead us to stop shaking. The person unable to inhibit movements or speech is profoundly disabled. Lhermitte and colleagues (Lhermitte et al., 1985) discussed two aspects of the impaired inhibition seen in the daily activities of patients with frontal lobe injury, for which he coined the terms ‘utilization behavior’ and ‘environmental dependency.’ With utilization behavior, patients lose the ability to inhibit motor programs. Such patients, when given an empty cup, automatically drink, or when shown a hammer carry out a series of hammering movements even though no nail is present. The drive to use an object overwhelms any logic related to whether or not the object should

Fig. 3.6. Frontal regions involved in executive function. Cognitive processes include planning, organization, assessing and modulating social interactions, and working memory.

52

H.J. ROSEN AND I.V. VISKONTAS

be utilized. Environmental dependency (Lhermitte, 1986) describes the tendency to passively follow the cues and gestures of others, even though inhibition of the response to follow such cues would be more appropriate. If a person extends a hand, the environmentally dependent patient automatically shakes the hand, even if the physician says, ‘touch your ear.’ This manifestation of environmental dependency is called ‘echopraxia.’ Environmental dependency is common in the patient with bifrontal injury. 3.3.3.3. Abstraction Abstraction requires absorbing verbal or visual information and reflecting upon the meaning of this information beyond its surface features. To interpret a proverb like ‘wild colts make good horses,’ requires taking a step away from the simple words ‘wild,’ ‘colts,’ and horses.’ To correctly answer, the person must think about the features of wildness and youth that might translate into a positive factor in adulthood. Although the ability to verbally abstract is strongly influenced by education, individuals who lose this ability often have acquired frontal lobe lesions. Multiple brain regions participate in the process of abstraction, but the final pathway probably requires the frontal lobes. Many of the functions described above are associated with the dorsolateral portions of the frontal lobes. Generally, verbal tasks disproportionately tap left frontal functions, while visual tasks are more likely to use the right frontal lobe. Inhibition tasks seem to rely upon both the dorsolateral and the orbitofrontal region. A variety of disorders with selective subcortical involvement, like progressive supranuclear palsy, disconnect the frontal lobes from subcortical activation and lead to frontal lobe neuropsychological syndromes.

3.4. Emotion and social functions 3.4.1. Anatomy and physiology of emotion Many aspects of emotional processing occur in subcortical structures, including the amygdala, hypothalamus, and multiple regions in the brainstem in emotional processing (Panksepp, 1998). The way that the higher neocortical structures interact with these regions is less clear, but both human and animal studies have revealed an extensive network of regions in the frontal and temporal lobes involved in emotional and social processing. Papez was the first to posit an association between emotion and the limbic system, which traditionally included the hypothalamus (mammillary bodies), anterior thalamus, cingulate cortex, and hippocampus (Papez, 1937; MacLean, 1949). Over time, additional regions, in particular the amygdala, orbitofrontal

cortex, anterior temporal cortex, and portions of the basal ganglia, have been added to the list of structures involved in emotion and some limbic structures are now thought to play a much more important role in other functions (such as the hippocampus and memory). In a classic experiment by Kluver and Bucy, the anterior temporal lobes were removed from monkeys, resulting in a marked behavioral deficit including hypermetamorphosis (constant shifting of visual attention), placidity, altered feeding habits and sexual behavior, and hyperorality (Kluver and Bucy, 1937; 1939). Subsequently, more restricted lesions demonstrated that most of these behaviors were related to amygdala damage. Continued study of amygdala function, mostly in rodents but also in humans (LaBar et al., 1995), has focused on conditioned responding. The amygdala appears crucial for learning the association between a previously neutral stimulus (such as a light or tone, called a conditioned stimulus, or CS) and a biologically relevant reward or punishment (e.g., food or shock, both unconditioned stimuli, or USs), and for altering behavior to match these new associations (for an excellent review see Cardinal et al. (2002)). In humans, amygdala damage also leads to impaired recognition of specific facial expressions of emotion, with fear being the most affected (Adolphs et al., 1999). Several functional MRI studies have demonstrated that the amygdala is active during the processing of fear, but also other emotions, both pleasant and unpleasant, leading to the speculation that the amygdala is registering the emotional salience of a stimulus (Phan et al., 2002), or possibly is activating to make the animal vigilant to situations with potential importance for wellbeing (Davis and Whalen, 2001). These views are consistent with the animal literature indicating amygdala involvement in both aversive and appetitive learning. Although classically part of the limbic system, the hippocampus has been much more closely associated with episodic memory than emotion (see above section on episodic memory). However, the hippocampus does make contributions to emotional learning, specifically allowing the association of a conditioned stimulus with a context. For example, animals that acquire conditioned freezing in response to a tone associated with a shock will also learn to freeze in the box in which this learning occurred (contextual fear conditioning). Although hippocampal lesions do not abolish the freezing in response to the tone, they do abolish freezing in response to the box (Phillips and LeDoux, 1992). At the same time, hippocampal functions in episodic memory are affected by emotional content, making it likely that amygdala–hippocampal interactions are important for enhancement of memory.

CORTICAL NEUROANATOMY AND COGNITION The role of non-amygdala structures in processing of emotion has also been elucidated in some detail (for a review, again see Cardinal et al. (2002)). Another important structure is the nucleus accumbens (Ach), in the ventral striatum, which appears to mediate as well as modulate some amygdala dependent responses. The Ach consists of two regions, the core (AchC) and the shell (AchS). Lesions of the AchC abolish some behavioral responses to conditioned stimuli, particularly those involving movement toward them. Amphetamine infusion into the AchC potentiates an animal’s tendency to work for a conditioned stimulus that has been associated with a reward. The AchC is also important for animals to tolerate a delay to a reward. In contrast to the AchC, the AchS mediates responding to unconditioned stimuli, such that dopamine release in the AchS, but not the AchC, increases the response to unconditioned stimuli such as food. Overall, it appears that the Ach takes part in representing the current value of external stimuli, shaping our motivation and our behavioral responses. Several other cerebral structures, including the orbitofrontal cortex (OFC), the anterior cingulate cortex (ACC) and the anterior temporal neocortex, play an important role in emotional processing. The OFC, in addition to the amygdala, plays a role in conditioned responding. When continued exposure to a CS no longer predicts the US, OFC is critical for extinguishing the behavior that was previously developed in response to the CS (LeDoux, 1993; Cardinal et al., 2002). This function may reflect a general function of the OFC in maintaining the current value of stimuli. For example, OFC neurons responding to specific foods can rapidly change their firing pattern to this food once an animal has been sated with it (Rolls, 2000). In humans with OFC lesions, experimental ‘gambling’ paradigms reveal an inability to inhibit the drive to choose stimuli leading to large immediate rewards, even though it becomes increasingly clear that these choices are not advantageous in the long run (Bechara et al., 1996). This is consistent with an inability to change representations as more information is available. Such patients also do not show the normal autonomic responses when preparing to choose a stimulus with the potential for large penalties. It has been suggested that these autonomic responses normally function as a ‘somatic marker’ helping other brain systems to make decisions. OFC lesions also lead to difficulty recognizing facial expressions of emotions (Hornak et al., 1996). The ACC has at least two functional subdivisions: a more posterior part involved in cognitive and motor processing, and a more anterior part involved in affective processing and sensitivity to pain (Devinsky et al.,

53

1995; Vogt et al., 2003). The latter region is also connected with other regions important for emotional processing, including the amygdala, the nucleus accumbens, and subcortical structures involved in control of autonomic functioning (Amaral and Price, 1984). Lesion studies indicate that ACC plays a role in emotion recognition (Hornak et al., 2003). The ACC also has a role in mood. Increased blood flow and decreased volume in the ventral ACC is associated with familial depression, and flow in the region differentiates medication responders from non-responders (Drevets, 2000). Ventral ACC is also commonly activated by tasks associated with sadness (Phan et al., 2002). The affective part of the ACC also plays an important role in autonomic function. It has heavy connections with subcortical autonomic nuclei, and autonomic changes can be induced with stimulation of the ACC (Devinsky et al., 1995; Critchley, 2003). Functional MRI analyses have suggested that the ACC is active when emotional tasks are cognitively demanding (Phan et al., 2002), and ACC is particularly important when a response to one of several conditioned stimuli is required, prompting the speculation that the ACC directs responding to a particular CS, and prevents generalization of the response to similar CSs (Cardinal et al., 2002). Relatively little is known about the anterior temporal neocortex, in particular in animals. This multimodal cortex is at the end of the visual processing stream and likely carries very abstract information composed of visual, auditory, and possibly other sensory associations. It is important for semantic knowledge (see section 3.3.2.2), however, it also plays a role in social and emotional functioning. It is heavily interconnected with the amygdala (Amaral and Price, 1984). In addition, removal of the anterior temporal lobes without amygdala or hippocampus removal results in profound behavioral deficits in monkeys (Franzen and Myers, 1973). PET studies have demonstrated activation in this region when emotions are generated by films (external stimuli) (Lane et al., 1997; Reiman et al., 1997). In patients with neurodegenerative disease, atrophy in the right anterior temporal cortex plays is associated with impaired recognition of emotional facial expressions (Rosen et al., 2006). This area of the brain is difficult to study with fMRI for technical reasons (Ojemann et al. 1997; Gorno-Tempini et al., 2002). 3.4.2. The right hemisphere and emotion In general, lesions studies in humans have suggested that the right hemisphere plays a dominant role in emotional processing. Patients with injury to the right hemisphere are sometimes emotionally flat, and have

54

H.J. ROSEN AND I.V. VISKONTAS

difficulty understanding and expressing the normal emotional signals in the voice (variations in pitch, speed, etc., called prosody) and in facial gestures (Ross, 1997). Ross has suggested that such problems can be divided into expressive and receptive deficits, which can be associated with anterior and posterior right hemisphere injury. Despite being emotionally flat, such patients rarely complain of being depressed, and it is has been suggested that the emotional blunting can lead to an under-appreciation of the affective state of these individuals. Again, the pattern can be seen not only in patients with focal lesions related to tumor or stroke, but also in patients with focal degeneration. In patients with the temporal variant of frontotemporal dementia, emotional blunting is observed primarily in association with right temporal degeneration (Miller et al., 1993). Another approach to hemispheric specialization of emotional functions has posited that the right hemisphere is more involved in the processing of emotions characterized by withdrawal types of behavior (e.g., fear, sadness, disgust) while the left hemisphere is more involved with emotions characterized by approach (e.g., happiness and, in some cases, anger) (Davidson et al., 1990). Much of the evidence for this theory comes from EEG studies indicating that the right or left hemisphere is more active in the processing of withdrawal or approach emotions, respectively. In addition, patients with left hemispheric lesions are more likely to be depressed than patients with right hemisphere lesions. However, some of these observations are complicated, as patients with right hemisphere lesions do suffer from depression, and decreased insight may impair their ability to recognize and express their own feelings (Ott and Fogel, 1992). 3.4.3. Lesions of the social and emotional systems 3.4.3.1. Apathy Drive and motivation represent vital life forces that allow us to carry out goal-directed activities. Loss of these functions often accompanies lesions affecting the medial frontal or ventral striatal (caudate head, nucleus accumbens) regions (Craig et al., 1996). With large or bilateral lesions patients become inert and immobilized, and their concerns for the consequences of their actions diminish (abulia, or akinetic mutism) (Nielsen and Jacobs, 1951). Social withdrawal is an early manifestation of this loss of motivation, although family and friends often experience this withdrawal as selfishness. This is often the first behavioral symptom of neurodegenerative disease (Miller et al., 1997), and is a prominent feature of frontotemporal dementia (Liu et al., 2004). Frontal lobe apathy can be mistaken

for depression, but patients with this apathy syndrome often experience little self-concern or change in mood. 3.4.3.2. Social disinhibition Maintaining good judgment, honesty, and social appeal, understanding our place in social systems, and shaping and modifying our behavior in response to social cues are critical aspects of human function. The story of Phineas Gage (Harlow, 1868) serves as a reminder of how dramatically social skills diminish from brain injury. After a railway spike was driven through Gage’s medial and orbital frontal regions, he was transformed from a hard-working, church-going, railway man to a profane, irreverent drifter. Subsequently, other patients with lesions affecting the OFC from brain tumors, head trauma, anterior communicating artery aneurysms, and frontotemporal dementia have been reported with selective deficits in social behavior and relative sparing of drive and neuropsychological functions (Damasio et al., 1983). Benson and Blumer used the term ‘pseudopsychopathic personality disorder’ to describe the behavioral changes seen with orbitobasal frontal dysfunction (Blumer and Benson, 1975). This phrase emphasized that these patients are socially disinhibited, inappropriately friendly, unreliable, and in constant trouble. Unlike true psychopaths, they rarely show the systematic cruelty, or the careful planning of crimes. Rather, intermittent loss of emotional control followed by remorse is more typical. In our own work, nearly one-half of patients with frontotemporal dementia (dementia associated with bilateral frontal lobe dysfunction) committed antisocial behaviors that could, or did, lead to their arrest (Miller et al., 1997). Behavioral disturbances due to OFC damage tends to be associated with right sided pathology (Miller et al., 1993; Tranel et al., 2002; Rosen et al., 2005). 3.4.3.3. Changes in emotional reactivity Emotional changes, including depression and mania, are frequently associated with lesions of the prefrontal cortex. As noted above, depression may be more common with left rather than right frontal lobe injury (Robinson et al., 1984). In contrast, manic syndromes were more likely to occur with right frontal injury. Patients with frontal injury sometimes demonstrate a lower threshold for crying, or less frequently for laughing, called ‘pseudobulbar affect.’ In some cases the behavior may be elicited by a mild emotional stimulus, while in other cases, it can be apparently unrelated to any feelings of sadness or amusement. Careful anatomical studies have not yet demonstrated the precise anatomical localization of this symptom.

CORTICAL NEUROANATOMY AND COGNITION

3.5. Language and aphasic language disorders Because of the unique quality of human language as a form of communication, all our knowledge about the cerebral organization of language comes from the study of humans, mostly patients with aphasia (acquired language dysfunction) due to brain injury. Thus, our knowledge of the anatomy and physiology of human language is inextricably linked with the phenomenology of aphasia. Cerebral injury causes a variety of abnormalities in language, the pattern roughly correlating with lesion location. One aspect of impaired language in aphasia is the speech pattern. Speech production may be hesitant, with few words being produced, often called nonfluent speech. Such patients often simplify their speech, leaving out grammatical function words, such as prepositions (e.g., ‘I go store’). This type of speech is called agrammatic and, when characterized by preservation of important content words, is called telegraphic speech. Conversely, aphasia can be associated with an excessive amount of speech, and might sound normal to someone who did not know the language, a pattern that is described as fluent. Aphasia can also be characterized by deficits in language comprehension, usually assessed by giving the patient various questions or commands where they must respond with a yes/no answer or by carrying out an action. Abnormalities of word usage are another key feature of aphasia. Word-finding difficulty, or anomia, is characterized by the inability to produce a specific word and can be brought out by asking a patient to name various pictures or items in the room (confrontation naming). Paraphasias are substitutions of sounds or words. They are referred to as semantic when the word substitution is from the same category as the word required (e.g., calling a ‘helicopter’ an ‘airplane’) or when a superordinate category word is used in place of the specific word required (e.g., using ‘animal’ for ‘camel’). Paraphasias are called phonemic, or literal, when a sound is substituted within a word (e.g., saying ‘I had a stoke’ instead of ‘I had a stroke’). The most profound deficit in word usage is consistent use of meaningless utterances, which are sometimes combinations of other words (neologisms).

55

observations of Paul Broca and Carl Wernicke, it has been recognized that most aphasias occur with lefthemisphere, particularly perisylvian, injury (Broca, 1861; Wernicke, 1874) (see Fig. 3.7). Within the left hemisphere, Broca’s aphasia, a syndrome of non-fluent speech, phonemic paraphasias, and relatively intact language comprehension, is classically associated with a lesion in the posterior portion of the left inferior frontal gyrus. In contrast, lesions affecting the left parietal/ posterior temporal region are associated with fluent speech, nonsensical speech, comprehension difficulties and semantic paraphasias, a syndrome known as Wernicke’s aphasia. A milder syndrome of relatively isolated anomia can be produced with any left-hemisphere lesion, and many aphasic patients evolve from having a more severe syndrome immediately after their brain injury to an anomic aphasia at the final stage of recovery. Larger perisylvian lesions can result in global aphasia, or the complete inability to understand or produce language. In many aphasics (especially classical Broca’s or Wernicke’s aphasics), the ability to repeat speech is impaired to the same degree as the ability to speak spontaneously. Lesions more distant from the sylvian fissure can result in similar deficits, with sparing of repetition. The combination of features, including the speech pattern, word usage, and comprehension and repetition abilities have been used to describe several other aphasic syndromes with specific anatomies as well (Goodglass and Kaplan, 1972; Damasio, 1985). Lesions in the posterior regions of the brain can result in deficits in reading, such as alexia without agraphia, which classically occurs with a lesion in the left inferior occipital region and involves the splenium of the corpus callosum. These anatomical relationships are discussed in more details in another chapter.

3.5.1. Aphasic syndromes and the neuroanatomy of language Speech pattern, word usage, and comprehension are often co-associated in aphasia, so that a number of aphasic syndromes have been described, each of which is associated with a specific anatomy. Beginning with the

Fig. 3.7. Regions known to be involved in the production and comprehension of language.

56

H.J. ROSEN AND I.V. VISKONTAS

3.6. Complex motor behavior

3.6.1. Neuroanatomy of apraxia

Patients with neurological lesions have also taught us that cerebral injury can impair our ability to organize our motor skills. Apraxia is defined as the inability to perform a skilled motor activity that is not explicable on the basis of problems with basic motor function due to weakness, sensory loss, tremor, chorea or other movement disorders, or to deficits in attention, memory, or motivation. The most commonly described type of apraxia is referred to as ideomotor apraxia, where patients are unable to demonstrate, through pantomime, skilled movements such as the use of an object (e.g., a knife, toothbrush, or scissors), or learned limb movements not requiring the use of an object, such as waving goodbye or making the ‘OK,’ ‘victory,’ or ‘peace’ sign, though it may be observed that they can perform these actions spontaneously. Patients with apraxia may complain that they have lost the ability to manipulate commonly used tools, such as eating utensils, or they may complain that they have lost the ability to perform skilled complex motor tasks, such as knitting or sewing. The types of errors made by apraxic patients can include substitution of another skilled movement for the one requested (e.g., moving a hand up and down as opposed to back and forth sawing movements), incorrect configuration of the fingers or other body parts, incorrect timing, or movements at the wrong joints. Often, the patient will use the body part as the object, such as brushing the teeth with the index finger, even when specifically asked not to. Oral–buccal apraxia is a form of apraxia that involves the mouth and tongue, and is characterized by deficits in demonstrating learned movements with these structures, such as puckering the lips, whistling, or blowing out a match. Different varieties and degrees of apraxia have been delineated (Heilman et al., 1997). In dissociation apraxia, pantomiming to command is severely impaired, while imitation and object use are perfect. Conduction apraxia is characterized by impairments with imitation. Conceptual apraxia is defined as the inability to properly associate a particular use with a particular tool (e.g., making hammering movements when asked to demonstrate the use of a screwdriver). Ideational apraxia is the inability to properly sequence a series of skilled movements (such as putting a cigarette in the mouth, taking out a match, lighting it, and then lighting the cigarette). Limb kinetic apraxia seems to refer to the clumsiness seen with lesions of the pyramidal system, and thus may not represent an apraxia per se.

Apraxia is almost always described in the setting of left hemisphere injury, particularly after lesions in the left frontal or parietal lobe (Heilman and Valenstein, 1982; Rothi et al., 1985). In addition, it can also be seen with lesions in the corpus callosum, which prevent communication between the hemispheres. In such cases, apraxia limited to left arm can be seen, often associated with difficulties in using real objects (Watson and Heilman, 1983). One would hypothesize that injury to the components of the motor system may result in deficits in the execution of skilled movements. Consistent with this hypothesis is the finding that apraxia with use of either limb has been seen with lesions in the dorsomedial frontal lobes, where complex motor movements are coordinated (Watson et al., 1986). Frontal motor regions have extensive connections to specific parietal areas whose neuronal physiology reflects the sensory skills necessary to perform the task, which may explain the association of apraxia with parietal lesions. Apraxia can also be seen in the setting of neurodegenerative disorders, particularly those that affect the parietal lobes, such as Alzheimer’s disease. Apraxia is a major presenting symptom of corticobasal degeneration (Gibb et al., 1989).

References Abrahams S, Pickering A, Polkey CE, et al. (1997). Spatial memory deficits in patients with unilateral damage to the right hippocampal formation. Neuropsychologia 35: 11–24. Adolphs R, Tranel D, Hamann S, et al. (1999). Recognition of facial emotion in nine individuals with bilateral amygdala damage. Neuropsychologia 37: 1111–1117. Aguirre GK, Zarahn E, D’Esposito M (1998). Neural components of topographical representation. Proc Natl Acad Sci USA 95: 839–846. Amaral DG, Price JL (1984). Amygdalo-cortical projections in the monkey (Macaca fascicularis). J Comp Neurol 230: 465–496. Baddeley A, Della Sala S (1996). Working memory and executive control. Philos Philos Trans R Soc Lond B Biol Sci 351: 1397–1404. Bechara A, Tranel D, Damasio H, et al. (1996). Failure to respond autonomically to anticipated future outcomes following damage to prefrontal cortex. Cereb Cortex 6: 215–225. Benson D, Geschwind N (1967). Shrinking retrograde amnesia. J Neurol Neurosurg Psychiatry 30: 539–544. Benson DF, Marsden CD, Meadows JC (1974). The amnesic syndrome of posterior cerebral artery occlusion. Acta Neurol Scand 50: 133–145. Benson DF, Geschwind N (1985). Aphasia and related disorders: A clinical approach. In M-M Mesulam (Ed.),

CORTICAL NEUROANATOMY AND COGNITION Principles of Behavioral Neurology. F.A. Davis, Philadelphia, pp. 193–238. Bieser A, Muller-Preuss P (1996). Auditory responsive cortex in the squirrel monkey: Neural responses to amplitudemodulated sounds. Exp Brain Res 108: 273–284. Bigler ED, Rosa L, Schultz F, et al. (1989). Rey-Auditory Verbal Learning and Rey-Osterrieth Complex Figure Design performance in Alzheimer’s disease and closed head injury. J Clin Psychol 45: 277–280. Blumer D, Benson DF (1975). Personality changes with frontal and temporal lobe lesions. In DF Benson and D Blumer (Eds.), Psychiatric Aspects of Neurologic Disease. Grune & Stratton, New York, pp. 151–169. Botez MI (1975). Two visual systems in clinical neurology: Readaptive role of the primitive system in visual agnosic patients. Eur Neurol 13: 101–122. Braak H, Braak E (1991). Neuropathological stageing of Alzheimer-related changes. Acta Neuropathol 82: 239–259. Broca P (1861). Remarques sur le sie`ge de la faculte´ du langage articule´, suivies d’une observation d’aphemie. Bull Assoc Anat (Nancy) 2: 330–357. Brodal A (1981). Neurological Anatomy in Relation to Clinical Medicine. Oxford University Press, New York. Brugge JF, Merzenich MM (1973). Responses of neurons in auditory cortex of the macaque monkey to monaural and binaural stimulation. J Neurophysiol 36: 1138–1158. Canli T, Zhao Z, Brewer J, et al. (2000). Event-related activation in the human amygdala associates with later memory for individual emotional experience. J Neurosci 20: RC99. Cardinal RN, Parkinson JA, Hall J, et al. (2002). Emotion and motivation: The role of the amygdala, ventral striatum, and prefrontal cortex. Neurosci Biobehav Rev 26: 321–352. Corbetta M, Miezin FM, Dobmeyer S, et al. (1991). Selective and divided attention during visual discriminations of shape, color, and speed: Functional anatomy by positron emission tomography. J Neurosci 11: 2383–2402. Corbetta M, Miezin FM, Shulman GL, et al. (1993). A PET study of visuospatial attention. J Neurosci 13: 1202–1226. Corsellis JAN (1976). Ageing and the dementias. In W Blackwood, JAN Corsellis (Eds.), Greenfield’s Neuropathology. Year Book Medical Publishers, Chicago, pp. 796–848. Craig AH, Cummings JL, Fairbanks L, et al. (1996). Cerebral blood flow correlates of apathy in Alzheimer disease. Arch Neurol 53: 1116–1120. Critchley H (2003). Emotion and its disorders. Br Med Bull 65: 35–47. Damasio AR (1985). Disorders of complex visual processing: Agnosias, achromatopsia, Balint’s syndrome, and related difficulties of orientation and construction. In M-M Mesulam (Ed.) Principles of Behavioral Neurology. F.A. Davis, Philadelphia, pp. 259–288. Damasio AR, Graff-Radford NR, Damasio H (1983). Transient partial amnesia. Arch Neurol 40: 656–657.

57

Davidson RJ, Ekman P, Saron CD, et al. (1990). Approach– withdrawal and cerebral asymmetry: Emotional expression and brain physiology. J Pers Soc Psychol 58: 330–341. Davis M, Whalen PJ (2001). The amygdala: Vigilance and emotion. Mol Psychiatry 6: 13–34. Devinsky O, Morrell MJ, Vogt BA (1995). Contributions of anterior cingulate cortex to behaviour. Brain 118: 279–306. Diamond IT, Jones EG, Powell TPS (1968a). The association connections of auditory cortex of the cat. Brain Res 11: 560–579. Diamond IT, Jones EG, Powell TPS (1968b). Interhemispheric fiber connections of the auditory cortex of the cat. Brain Res 11: 177–193. Drevets WC (2000). Functional anatomical abnormalities in limbic and prefrontal cortical structures in major depression. Prog Brain Res 126: 413–431. Everitt BJ, Sirkia TE, Roberts AC, et al. (1988). Distribution and some projections of cholinergic neurons in the brain of the common marmoset, Callithrix jacchus. J Comp Neurol 271: 533–538. Felleman DJ, Van Essen DC (1991). Distributed hierarchical processing in the cerebral cortex. Cereb Cortex 1: 1–47. Franzen EA, Myers RE (1973). Neural control of social behavior: Prefrontal and anterior temporal cortex. Neuropsychologia 11: 141–157. Fuster J (1997). The Prefrontal Cortex. Raven Press, New York. Galaburda AM, LeMay M, Kemper TL, et al. (1978). Right– left asymmetries in the brain. Science 199: 852–856. Gibb WRG, Luthert PJ, Marsden CD (1989). Corticobasal degeneration. Brain 112: 1171–1192. Goldman-Rakic P (1988). Topography of cognition: Parallel distributed networks in primate association cortex. Annu Rev Neurosci 11: 137–156. Goodglass H, Kaplan E (1972). The Assessment of Aphasia and Related Disorders. Lea and Febiger, Philadelphia. Gorno-Tempini ML, Hutton C, Josephs O, et al. (2002). Echo time dependence of BOLD contrast and susceptibility artifacts. Neuroimage 15: 136–142. Grady C (1998). Neuroimaging and Activation of the Frontal Lobes. Guilford Press, New York. Guberman A, Stuss D (1983). The syndrome of bilateral paramedian thalamic infarction. Neurology 33: 540–546. Hacaen H, Albert M (1978). Human Neuropsychology. John Wiley and Sons, New York. Harlow JM (1868). Recovery from the passage of an iron bar through the head. Massachussets Med Soc Publ 2: 327–346. Haxby JV, Grady CL, Horwitz B, et al. (1991). Dissociation of object and spatial visual processing pathways in human extrastriate cortex. Proc Natl Acad Sci USA 88: 1621–1625. Heilman KM, Watson RT, Rothi LJG (1997). Disorders of skilled movements: Limb apraxia. In TE Feinberg, MJ Farah (Eds.), Behavioral Neurology and Neuropsychology. McGraw-Hill, New York.

58

H.J. ROSEN AND I.V. VISKONTAS

Heilman KR, Valenstein E (1982). Two forms of ideomotor apraxia. Neurology 32: 342–346. Hodges JR, Graham KS (1998). A reversal of the temporal gradient for famous person knowledge in semantic dementia: Implications for the neural organisation of long-term memory. Neuropsychologia 36: 803–825. Hornak J, Bramham J, Rolls ET, et al. (2003). Changes in emotion after circumscribed surgical lesions of the orbitofrontal and cingulate cortices. Brain 126: 1691–1712. Hornak J, Rolls ET, Wade D (1996). Face and voice expression identification in patients with emotional and behavioural changes following ventral frontal lobe damage. Neuropsychologia 34: 247–261. Insausti R, Amaral DG, Cowan WM (1987). The entorhinal cortex of the monkey: II. Cortical afferents. J Comp Neurol 264: 356–395. Iwamura Y, Tanaka M, Sakamoto M, et al. (1985a). Comparison of the hand and finger representation in areas 3, 1 and 2 of the monkey somatosensory cortex. Liss, New York. Iwamura Y, Tanaka M, Sakamoto M, et al. (1985b). Vertical neuronal arrays in the postcentral gyrus signalling active touch: A receptive field study in the conscious monkey. Exp Brain Res 58: 412–420. Kaas JH, Hackett TA, Tramo MJ (1999). Auditory processing in primate cerebral cortex. Curr Opin Neurobiol 9: 164–170. Kaas JH, Nelson RJ, Sur M, et al. (1981). Organization of Somatosensory Cortex in Primates. MIT Press, Cambridge, MA. Kandel ER, Schwartz JH, Jessell TM (1995). Essentials of Neural Science and Behavior. Appleton and Lange, Norwalk. Kimura D (1961). Cerebral dominance and the perception of verbal stimuli. Can J Psychol 15: 166–171. Kimura D (1964). Left–right differences in the perception of melodies. Q J Exp Psychol 16: 355–358. Kluver H, Bucy PC (1937). ‘Psychic Blindness’ and other symptoms following bilateral temporal lobectomy in rhesus monkeys. Am J Physiol 1937: 352–353. Kluver H, Bucy PC (1939). Preliminary analysis of functions of the temporal lobes in monkeys. Arch Neurol Psychiatry 42: 979–1000. Kopelman M (1995). The Korsakoff syndrome. Br J Psychiatry 166: 154–173. Kosaki H, Hashikawa T, He J, et al. (1997). Tonotopic organization of cortical auditory fields delineated by parvalbumin immunoreactivity in Macaque monkeys. J Comp Neurol 386: 304–316. Krettek JE, Price JL (1977). Projections from the amygdaloid complex to the cerebral cortex and thalamus in the rat and cat. J Comp Neurol 172: 687–722. LaBar KS, LeDoux JE, Spencer DD, et al. (1995). Impaired fear conditioning following unilateral temporal lobectomy in humans. J Neurosci 15: 6846–6855. Lane RD, Reiman EM, Ahern GL, et al. (1997). Neuroanatomical correlates of happiness, sadness, and disgust. Am J Psychiatry 154: 926–933. LeDoux JE (1993). Emotional memory systems in the brain. Behav Brain Res 58: 69–79.

Lhermitte F (1986). Human autonomy and the frontal lobes. Part II: Patient behaviour in complex and social situations: the ‘environmental dependency syndrome’. Ann Neurol 19: 335–343. Lhermitte F, Pillon B, Serdaru M (1985). Human autonomy and the frontal lobes. Part I: Imitation and utilization behaviour: A neuropsychological study of 75 patients. Ann Neurol 19: 326–334. Liu W, Miller BL, Kramer JH, et al. (2004). Behavioral disorders in the frontal and temporal variants of frontotemporal dementia. Neurology 62: 742–748. Logothetis NK, Sheinberg DL (1996). Visual object recognition. Annu Rev Neurosci 19: 577–621. Luria AR (1966). Human Brain and Psychological Processes. Harper Row, New York. MacLean PD (1949). Psychosomatic disease and the visceral brain: Recent developments bearing on the Papez theory of emotion. Psychosom Med 11: 338–353. Marshall J (1951). Sensory disturbances in cortical wounds with special reference to pain. J Neurol Neurosurg Psychiatry 14: 187–204. Mesulam M-M (1985). Principles of Behavioral Neurology. F.A. Davis, Philadelphia. Miller BL, Chang L, Mena I, et al. (1993). Progressive right frontotemporal degeneration: Clinical, neuropsychological and SPECT characteristics. Dementia 4: 204–213. Miller BL, Darby A, Benson DF, et al. (1997). Aggressive, socially disruptive and antisocial behaviour associated with fronto-temporal dementia. Br J Psychiatry 170: 150–154. Milner B, Petrides M, Smith ML (1985). Frontal lobes and the temporal organization of memory. Hum Neurobiol 4: 137–142. Mishkin M, Ungerleider LG (1982). Contribution of striate inputs to the visuospatial functions of parieto-preoccipital cortex in monkeys. Behav Brain Res 6: 57–77. Moruzzi G, Magoun H (1949). Brainstem reticular formation and activation of the EEG. Electroencephalogr Clin 1: 455–473. Moscovitch M (1982). Multiple dissociations of function in amnesia. In LS Cermak (Ed.), Human Memory and Amnesia. Erlbaum, Hillsdale, NJ, pp. 337–370. Mountcastle V (1957). Modality and topographic properties of single neurons of cat’s somatic sensory cortex. J Neurophysiol 20: 408–434. Newsome WT, Britten KH, Movshon JA (1989). Neuronal correlates of a perceptual decision. Nature 341: 52–54. Nielsen JM, Jacobs LL (1951). Bilateral lesions of the anterior cingulate gyri. Bull Los Angel Neuro Soc 16: 231–234. O’Craven KM, Kanwisher N (2000). Mental imagery of faces and places activates corresponding stimulus-specific brain regions. J Cogn Neurosci 12: 1013–1023. Ojemann JG, Akbudak E, Snyder AZ, et al. (1997). Anatomic localization and quantitative analysis of gradient refocused echo-planar fMRI susceptibility artifacts. Neuroimage 6: 156–167. O’Keefe J, Dostrovsky J (1971). The hippocampus as a spatial map. Preliminary evidence from unit activity in the freely-moving rat. Brain Res 34: 171–175.

CORTICAL NEUROANATOMY AND COGNITION Ott BR, Fogel BS (1992). Measurement of depression in dementia: Self vs. clinician rating. Int J Geriatr Psychiatry 7: 899–904. Ottersen OP (1982). Connections of the amygdala of the rat. IV: Corticoamygdaloid and intraamygdaloid connections as studied with axonal transport of horseradish peroxidase. J Comp Neurol 205: 30–48. Panksepp J (1998). Affective Neuroscience: The Foundations of Human and Animal Emotions. Oxford University Press, Oxford. Papez JW (1937). A proposed mechanism of emotion. Arch Neurol Psychiatry 387: 25–38. Penfield W, Jasper H (1954). Epilepsy and the Functional Anatomy of the Human Brain. Little, Brown, Boston. Penfield W, Rasmussen T (1950). The Cerebral Cortex of Man. Macmillan, New York. Petersen SE, Corbetta M, Miezin FM, et al. (1994). PET studies of parietal involvement in spatial attention: Comparison of different task types. Can J Exp Psychol 48: 319–338. Petersen SE, Robinson DL, Morris JD (1987). Contributions of the pulvinar to visual spatial attention. Neuropsychologia 25: 97–105. Petrides M, Alivisatos B, Meyer E, et al. (1993). Functional activation of the human frontal cortex during the performance of verbal working memory tasks. Proc Natl Acad Sci USA 90: 878–882. Phan KL, Wager T, Taylor SF, et al. (2002). Functional neuroanatomy of emotion: A meta-analysis of emotion activation studies in PET and fMRI. Neuroimage 16: 331–348. Phillips J, Johnson K, Hsiao S (1988). Spatial pattern representation and transformation in monkey somatosensory cortex. Proc Natl Acad Sci USA 85: 1317–1321. Phillips RG, LeDoux JE (1992). Differential contribution of amygdala and hippocampus to cued and contextual fear conditioning. Behav Neurosci 106: 274–285. Pohl W (1973). Dissociation of spatial discrimination deficits following frontal and parietal lesions in monkeys. J Comp Physiol Psychol 82: 227–239. Posner MI, Petersen SE (1990). The attention system of the human brain. Annu Rev Neurosci 13: 25–42. Powell TPS, Mountcastle VB (1959). Some aspects of the functional organization of the postcentral gyrus of the monkey: A correlation of findings obtained in a single unit analysis with cytoarchitecture. Bull Johns Hopkins Hosp 106: 133–162. Rauschecker JP, Tian B, Hauser M (1995). Processing of complex sounds in the macaque nonprimary auditory cortex. Science 268: 111–114. Rauschecker JP, Tian B, Pons T, et al. (1997). Serial and parallel processing in rhesus monkey auditory cortex. J Comp Neurol 382: 89–103. Reiman EM, Lane RD, Ahern GL, et al. (1997). Neuroanatomical correlates of externally and internally generated human emotion. Am J Psychiatry 154: 918–925. Robinson RG, Kubos KL, Starr LB, et al. (1984). Mood disorders in stroke patients: Importance of lesion location. Brain 107: 81–93. Rolls E (1996). A theory of hippocampal function in memory. Hippocampus 6: 601.

59

Rolls E (1999). The Representation of Space in the Primate Hippocampus, and its Role in Memory. Oxford University Press, Oxford. Rolls ET (2000). The orbitofrontal cortex and reward. Cereb Cortex 10: 284–294. Rosen HJ, Allison SC, Schauer GF, et al. (2005). Neuroanatomical correlates of behavioural disorders in dementia. Brain 128: 2612–2625. Rosen HJ, Wilson MR, Schauer GF, et al. (2006). Neuroanatomical correlates of impaired recognition of emotion in dementia. Neuropsychologia 44: 365–373. Ross ED (1997). The Aprosodias. In TE Feinberg, MJ Farah (Eds.), Behavioral Neurology and Neuropsychology. McGraw-Hill, New York. Rothi L, Heilman KM, Watson RT (1985). Pantomime comprehension and ideomotor apraxia. J Neurol Neurosurg Psychiatry 48: 207–210. Simons JS, Verfaellie M, Galton CJ, et al. (2002). Recollection-based memory in frontotemporal dementia: Implications for theories of long-term memory. Brain 125: 2523–2536. Squire LR (1982). The neuropsychology of human memory. Annu Rev Neurosci 5: 241–273. Squire LR (1992). Declarative and non-declarative memory: Multiple brain systems supporting learning and memory. J Cogn Neurosci 4: 232–243. Squire LR, Alvarez P (1995). Retrograde amnesia and memory consolidation: A neurobiological perspective. Curr Opin Neurobiol 5: 169–177. Stuss DT, Benson DF (1986). The Frontal Lobes. Raven Press, New York. Tranel D, Bechara A, Denburg NL (2002). Asymmetric functional roles of right and left ventromedial prefrontal cortices in social conduct, decision-making, and emotional processing. Cortex 38: 589–612. Tulving E (1972). Episodic and semantic memory. In E Tulving, W Donaldson (Eds.), Organisation of Memory. Academic Press, New York and London, pp. 381–403. Tulving E (1983). Elements of Episodic Memory. Clarendon Press, Oxford. Tulving E, Schacter DL, McLachlan DR, et al. (1988). Priming of semantic autobiographical knowledge: A case study of retrograde amnesia. Brain Cogn 8: 3–20. Victor M (1987). The irrelevance of mammillary body lesions in the causation of the Korsakoff amnesic state. Int J Neurol 88: 51–57. Vignolo L (1969). Auditory agnosia: A review and report of recent evidence. In A Benton (Ed.) Contributions to Clinical Neuropsychology. Aldine, Chicago, pp. 172–208. Viskontas IV, McAndrews MP, Moscovitch M (2000). Remote episodic memory deficits in patients with unilateral temporal lobe epilepsy and excisions. J Neurosci 20: 5853–5857. Vogt BA, Berger GR, Derbyshire SW (2003). Structural and functional dichotomy of human midcingulate cortex. Eur J Neurosci 18: 3134–3144. Warren S, Hamaleinen H, Gardner E (1986). Objective classification of motion- and direction sensitive neurons in primary

60

H.J. ROSEN AND I.V. VISKONTAS

somatosensory cortex of awake monkeys. J Neurophysiol 56: 598–622. Warrington EK (1975). The selective impairment of semantic memory. Q J Exp Psychol 27: 635–657. Watson RT, Fleet WS, Rothi LJG, et al. (1986). Apraxia and the supplementary motor area. Arch Neurol 43: 787–792. Watson RT, Heilman KM (1983). Callosal apraxia. Brain 106: 391–403. Wegener JG (1973). The sound-locating behavior of braindamaged monkeys. J Aud Res 13: 191–219. Wernicke K (1874). Der Aphasische Symtomencomplex Cohn & Weigert, Breslau. Whitfield IC, Evans EF (1965). Responses of auditory cortical neurons to changing frequency. J Neurophysiol 28: 655–672.

Whitsel BL, Petrucelli LM, Werner G (1969). Symmetry and connectivity in the map of the body surface in somatosensory area II in primates. J Neurophysiol 32: 170–183. Wilson BA, Baddeley AD, Kapur N (1995). Dense amnesia in a professional musician following herpes simplex virus encephalitis. J Clin Exp Neuropsychol 17: 668–681. Zakzanis KK (1998). Neurocognitive deficit in frontotemporal dementia. Neuropsychiatry Neuropsychol Behav Neurol 11: 127–135. Zihl J, Von Cramon D, Mai N (1983). Selective disturbance of movement vision after bilateral brain damage. Brain 106: 313–340. Zola-Morgan S, Squire LR, Amaral DG (1986). Human amnesia and the medial temporal region: Enduring memory impairment following a bilateral lesion limited to the CA1 field of the hippocampus. J Neurosci 6: 2950–2967.

Handbook of Clinical Neurology, Vol. 88 (3rd series) Neuropsychology and behavioral neurology G. Goldenberg, B.L. Miller, Editors # 2008 Elsevier B.V. All rights reserved

Chapter 4

Functional neuroimaging of cognition DANIELA PERANI* Vita-Salute San Raffaele University, San Raffaele Scientific Institute, Milan, Italy

‘It ought to be generally known that the source of our pleasure, merriment, laughter, and amusement, as of our grief, pain, anxiety, and tears, is none other than the brain. It is specially the organ which enables us to think, see, and hear, and to distinguish the ugly and the beautiful, the bad and the good, pleasant and unpleasant. It is the brain too which is the seat of madness and delirium, of the fears and frights which assail us, often by night, but sometimes even by day; it is there where lies the cause of insomnia and sleep-walking, of thoughts that will not come, forgotten duties, and eccentricities’ Hippocrates (460?–377 BCE)

4.1. Introduction One of the most important goals of neuroscience is to establish precise structure–function relationships in the brain. The question about how cognitive functions are organized in the brain originated from the very early lesions studies. Since the nineteenth century, a major scientific endeavor has been to associate structurally distinct cortical regions with specific cognitive functions. This was traditionally accomplished by correlating macro structurally defined areas with lesion sites found in patients with specific neuropsychological symptoms. It was also realized that cognitive impairments could arise from lesions that spared the functional centers themselves, but disconnected them from other centers. In the 1970s and 1980s, the advent of computerized tomography (CT) and later, magnetic resonance imaging *

(MRI), allowed the direct in vivo assessment of the structural lesions, with a consequent explosion of clinical–radiological observations. The simplest way of interpreting all these anatomoclinical associations was to conjecture that the normal function, impaired after brain damage, was localized within the lesioned region. During the late nineteenth and early twentieth centuries, functional localization began to be studied in the intact human brain by techniques providing indirect measurements of changes in cerebral blood flow when different cognitive tasks were performed (see for a review Marshall and Fink, 2003). One modest but elegant technique—cerebral thermometry—involved placing thermometers or more sensitive thermoelectric piles on different regions of the scalp and measuring the differential temperatures thereon in response to well-defined stimuli and tasks. Paul Broca, Angelo Mosso and Hans Berger were all devotees of the method. J.S. Lombard, in his 1879 monograph on ‘Experimental Researches on the Regional Temperature of the Head under Conditions of Rest, Intellectual Activity and Emotion,’ set out a very large number of sophisticated experiments of this sort. In the late twentieth century, these crude techniques gave way to positron emission tomography (PET), single photon emission computed tomography (SPECT), functional magnetic resonance imaging (fMRI), and magnetoencephalography (MEG). Functional neuroimaging techniques, such as PET and SPECT, with high spatial resolution, as well as the methods for fMRI acquisition, have provided a fundamental new approach, enabling non-invasive measurements of regionally specific changes of brain activity that are correlated with the components of a cognitive process. In parallel, the contribution of neurophysiology techniques, such as evoked related potentials (ERPs), EEG mapping and MEG to cognitive neuroscience cannot be neglected,

Correspondence to: Daniela Perani, Vita-Salute San Raffaele University and San Raffaele Scientific Institute, Via Olgettina 60, 20132 Milan, Italy. E-mail: [email protected], Tel: þ39-02-26432224, Fax: þ39-02-26415202.

62

D. PERANI

considering the value of a precise temporal resolution and the increasing reliability of source localization methods. The popularity of the study of cognition and functional brain activity is evident from the enormous number of studies published in the last 15 or so years that have used PET, fMRI, EEG, MEG, and also Transcranial magnetic stimulation (TMS) to investigate functional aspects of brain and cognition. The amount of resources devoted to these studies suggests that they are motivated by a viable and successful research program, and implies that substantial progress is being made. At the very least, the amount and vigor of such research implies that something significant is being learned. The progresses made in understanding the nature of functional specialization in the human brain made through the relatively precise spatial and temporal resolution of modern functional neuroimaging methods have raised a crucial question: do the functional localizations obtained by the anatomoclinical method converge with those implied by the functional neuroimaging of cognition in healthy volunteers? Considering functional imaging as a new phrenology, by itself, is clearly not going to reveal the principles that underlie the brain’s functional architectures. Functional neuroimaging has instead contributed to answering questions about organizational principles, in terms of distributed and coupled interactions among specialized brain systems. The issue concerns two fundamental principles of brain organization, namely functional specialization and functional integration, and how they rest on the anatomy and physiology of cortico-cortical connections in the brain (Friston and Price, 2001; Price and Friston, 2002). Convergent conclusions suggest that functional specialization is not such a fixed property of brain regions as previously supposed. Executive function, memory, or language are more distributed than located in just one area, and even the different subprocesses that compose each of these functions are supported by a network rather than a particular area. Functional neuroimaging contributes to this issue by answering the following questions: where, when, and how the activity is produced in the brain. The current available functional neuroimaging techniques under this view are the unique tools to describe the neural networks which support cognition. The domain of functional neuroanatomy in cognition has more recently expanded to the domain of neurochemical functional specialization. A particular cognitive process or behavior may be linked not only to a specific neural network, but also to particular neurochemical systems. The majority of work has been conducted in animals, or in postmortem in vitro studies

in humans; however, in recent years, pharmaceutical agents targeted at neurotransmitter systems (i.e., neurotransmitter receptors or enzymes) became available for in vivo studies in humans. Both PET and fMRI can contribute to this line of research. For example, with fMRI, the subjects are required to perform cognitive tasks in the scanner in the presence and absence of psychoactive agents. This approach allows measuring the modulatory effects of pharmacological agents on cognitive/behavioral brain systems. During the past decades PET/SPECT groups involved in the development of new radioligands for the in vivo imaging of human brain neurotransmission focused their attention on the sites of action (receptors), synthesis, or degradation of neurotransmitters. The method has been largely applied to the study of neurological and psychiatric disease conditions. For example, binding of the D1 receptor antagonist 11C-NNC-112 was reported to be increased in the dorsolateral prefrontal cortex of unmedicated schizophrenic patients compared to normal controls, and was correlated to poor performance in a test of verbal working memory (Abi-Dargham et al., 2002). More interestingly, PET with specific radioligands allows the direct, in vivo evaluation of the brain neurochemistry at work during sensorimotor and cognitive challenges. This method is an exciting complement to conventional functional activation studies. This chapter tackles the complex relationship between brain function and ‘high-order cognition,’ encompassing under this broad concept the different aspects of neuropsychology: language, memory, performance monitoring, decision-making, reasoning, and even ‘personality.’ Imaging experiments in normal subjects, as well as in patients with neurological diseases, provide an overview of the multiple methods available to the cognitive neuroscientists who dare to extend the scope of brain/mind relationship to such elusive conceptual entities. The possible theoretical implications of the functional localization of brain activity, but also the brain–cognition correlates in the case of functional derangement due to underlying pathology, indicate that a functional brain-based approach to high-order cognition has provided and will provide high quality findings, depending also upon the quality of the questions. To reduce to a single chapter the enormous amount of excellent evidence in the field is a challenge. Thus, this chapter cannot be but a ‘personal’ reflection on the state-of-the-art knowledge of how human cognition is instantiated in the brain, with highlights about the possible application of the knowledge obtained in normal humans to disease conditions, and implications for developmental disabilities and for recovery of function and the underlying mechanisms.

FUNCTIONAL NEUROIMAGING OF COGNITION

4.2. Methods The evolution of human brain mapping depended on much diverse expertise from physics and biology through mathematics and statistics, to neurology, neuropsychiatry, and neuropsychology. The realization of this dependence on the expertise of many individuals from many disciplines represents the basis of an enterprise focused on the understanding the functional (and structural) architecture of the human brain and the methodological developments that have supported their achievement. Structural MRI provides an in-depth evaluation of the central nervous system anatomy. The enhanced anatomical detail allowed by recent MRI scanners has outlined relatively specific patterns of different neurological diseases. A number of tools of varying technological complexity have been developed to rate the structural changes taking place in the brains of patients with cognitive impairment, ranging from simple subjective rating scales to sophisticated computerized algorithms. On the other hand, functional magnetic resonance imaging (fMRI) is a tool that, by exploiting the principles of traditional MRI, allows the function of brain to be mapped and studied, i.e., ‘looking at the brain while it works.’ It is a non-invasive technique, based on the measurement of MRI signal changes associated with alterations in local blood oxygenation levels (for a critical discussion, see Logothetis and Pfeuffer, 2004). The imaging methods of positron emission tomography (PET) and single photon emission computed tomography (SPECT) allow the in vivo measurement of several parameters of brain function. These include oxygenation levels, perfusion, metabolism, and also neurotransmission. Radiolabeled tracers for receptor occupancy or enzymatic activities represent a unique tool for the in vivo measurement of specific neurotransmission systems. Direct measures of therapeutic targets by PET may provide unique information on drug action in vivo, allowing studies of the effects in selected patient populations (Halldin et al., 2001). The instrumentations and reconstruction algorithms are different for PET and SPECT because of the properties of positron and gamma emissions. The availability of positron emitting radioisotopes, such as carbon, oxygen and fluorine, which can fit into biological relevant molecules without altering their biological properties, gives PET substantial advantages. Such tracers or radiopharmaceuticals closely share the properties of normally occurring brain substances. On the other hand SPECT, with gamma emitting elements like iodine or technetium, is more widely available. These methods are sensitive to modifications taking place at the cellular level, which are not necessarily reflected in morphological

63

abnormalities. They are thus providing a different type of information, in comparison with structural imaging such as MRI. 4.2.1. Emission tomography (PET and SPECT) Both PET and SPECT provide images and data that represent the distribution in the brain of a specific biochemical process. These functional measurements can detect modifications that occur at the cellular level and do not reflect gross focal structural changes. In neurology, this technique complements the structural imaging methods of CT and MRI. PET is based on the detection of coincident 511 keV gamma rays that originate from positron electron pair annihilation. At the core of PET scanners are scintillation detectors associated with coincidence electronics to detect the paired 511 keV gamma rays. Detectors made of scintillation crystals, such as bismuth germanate, are typically arranged as a hexagonal, octagonal or circular ring. The width of the detector ring is larger in whole body scanners than in dedicated brain scanners, and both can be used for brain studies. Modern scanners have axial fields of view of 12 to 15 cm at a nearly isotropic spatial resolution of 2.2 to 6 mm that allows scanning of the entire brain. Image reconstruction from the recorded coincident events by filtered back-projection or iterative procedures needs to take into account corrections for gamma ray attenuation, scatter, and isotope decay. Positron emitting isotopes, with typically nuclear masses that are smaller than those of stable isotopes, are very short lived. They can be applied at rather low effective biological radiation doses (Gatley, 1993). The physical half-lives of oxygen-15 (15O, 2 min) and carbon-11 (11C, 20 min) require an on-site cyclotron for tracer preparation, and therefore the availability of these tracers usually is limited to highly specialized research laboratories. Tracers labeled by fluorine-18 have longer half-lives (18F, 109 min). The most widely used tracer for brain studies is 18 F-2-fluoro-2-deoxy-D-glucose (18F-FDG) (Reivich et al., 1985), which is usually synthesized in a radiochemistry laboratory by a stereospecific procedure based on nucleophilic substitution (Hamacher et al., 1986). PET can provide steady-state measurements of brain functional parameters, such as oxygen consumption by inhaling 15O2, or glucose metabolism and blood flow by i.v. injection of 18F-FDG, and radioactive labeled water (H215O), respectively. H215O with PET is also used in functional activation studies to evaluate regional cerebral blood flow changes associated with cognitive performances, either in normal subjects or in patients (see section 4.2.1.1).

64

D. PERANI

PET radiolabeled tracers for receptor occupancy or enzymatic activities represent a unique tool for measurements of specific neurotransmission systems (see paragraph 8 in the present chapter). Research for receptor alterations, in particular dopaminergic and serotoninergic ones, as well as for enzymatic activity and receptor occupancy by drugs (i.e., neuroleptics) have been carried out. For example, dopadecarboxylase enzymatic activity can be measured by 18F-DOPA, postsynaptic dopamine receptor density by [11C]raclopride, and presynaptic dopamine activity by 11CFECIT. The general aim was to find a suitable tracer for assessing, in vivo, the pre- and postsynaptic components of a specific neurotransmitter system and for evaluating the effects of therapy. Among the main applications, there have been the neurodegenerative disorders and in particular Parkinson’s disease, but more recently also Alzheimer’s disease and other dementia conditions. Another important field of application is the psychiatry research. SPECT results partially parallel those obtained with PET when related biochemical processes (i.e., regional cerebral blood flow, neurotransmission parameters) are examined. SPECT relies on the three-dimensional reconstruction of gamma emitter distributions in the brain. The sensitivity of SPECT is reduced compared with PET, due to the lack of the advantage of the special geometry of positron annihilation into two photons traveling in opposite directions. Thus, the efficiency of PET scanners is substantially higher than that of SPECT scanners, resulting typically in high-count PET images with excellent signal-to-noise ratio. Other differences between PET and SPECT derive from the different radioactive half-life of the gamma and positron emitters: short half-lives of positron-emitters make several repeat examinations within a short period possible, while longer half-lives of gamma-emitters allow for the examination of metabolic or pharmacological processes that require longer periods to establish. Further, the replacement of carbon atoms of the ligand with the positron emitter 11C can generate radioligands with identical pharmacological properties, thus without any modification of the biological substance, whereas substitution with the gamma-emitters 123Iodine or 99m Technetium is likely to change the ligand’s chemical properties. Consequently, the generation of new SPECT ligands has proceeded at a disappointingly slow rate, partially because of the need to establish their pharmacological properties after synthesis. SPECT is especially used for ‘cerebral blood-flow’ studies. Two ligands are commercially available, hexamethyl-propylene amine oxime (HMPAO) and N0 -1,2-ethylenediy (bis-L-cysteine) diethyl ester (ECD). The cerebral distribution of these tracers offers an

indirect measurement of cerebral perfusion. The radioiodinated SPECT tracer iodobenzovesamicol (I123IBVM) was used as a marker of presynaptic vesicular acetylcholine transporter (Kuhl et al., 1996). Muscarinic cholinergic receptor distribution by the antagonist ligand (I123)-iodo-quinnuclidinyl benzilate (IQNB) has been applied in the study of AD (Weinberger et al., 1991) as well as the presynaptic dopaminergic ligand FP-CIT in dopaminergic degeneration in PD and parkinsonisms (Walker et al., 1999). 4.2.1.1. Data analysis PET and SPECT functional data have been extensively applied in neurological research. These methods offer the opportunity to improve diagnosis by providing regional functional measurements, which can be used to substantiate a clinical judgment. In Alzheimer’s disease, several well known neuropathological features result in a loss of synaptic activity. This dysfunction is readily reflected in regional decreases in cerebral metabolic activity and blood flow. The metabolic reductions measured with both oxygen and glucose consumption, which is coupled to a reduction in regional perfusion, are not simply a consequence of tissue loss (Ibanez et al., 1998). Technical aspects, in particular high-resolution scanners and advanced methods of data analysis, are crucial factors to take into account in the evaluation of the dysfunctional brain. Quantitative measurements of brain functional parameters, such as blood flow, oxygen consumption, glucose metabolism, semiquantitative assessment based on ratios of different regions of interest (ROIs) (Herholz et al., 1993), together with different statistical approaches and neural network classification, have been proposed for an improvement in the diagnostic accuracy of functional neuroimaging in neurodegenerative and dementia conditions (Kippenhan et al., 1992; Azari et al., 1993; Minoshima et al., 1995; Herholz et al. 2002; Zuendorf et al., 2003). Statistical Parametric Mapping (SPM) has been largely applied to PET and SPECT steady-state resting studies with the aim of providing automated voxel-based measurements of brain functional parameter changes in disease conditions (Imran et al., 1999; Signorini et al., 1999). In particular, SPM based comparisons with samples of matched normal subjects have significantly improved the study of patient groups and single cases (Signorini et al., 1999; Mosconi et al., 2005a). The resulting SPM foci in PET and SPECT perfusion or metabolism studies are characterized in terms of spatial extent and peak height according to a Gaussian distribution and usually refer to significant brain regional hypometabolism or hypoperfusion.

FUNCTIONAL NEUROIMAGING OF COGNITION PET and H215O have been successfully applied also to the study of sensorimotor and cognitive functions during ‘activation studies.’ To this aim i.v. injections of radiolabeled water (H215O) with several CBF measurements performed over 1–2 min are necessary. Following the injection, the radioactive water accumulates in the brain in direct proportion to the local blood flow. The greater the blood flow in a given brain region, the higher the radiation count recorded by PET. Since the local increases of blood flow associated to any cognitive demand are low (1–2% of the global), several measurements in a single subject are necessary. In addition, averaging of at least 12–15 subjects is required to obtain robust population effects. It is generally accepted that regional cerebral blood flow (rCBF) reflects synaptic activity. Increases in rCBF are necessary to replace the energy consumed by neurons. These changes in rCBF have been demonstrated to be closely related to changes in neural activity in both space and time (Sokoloff, 1979). The perfusion data are then compared to find areas where the experimental task is associated with increased cerebral blood flow with respect to the control task (see Friston et al. 1995, for taxonomy of experimental designs). Statistical Parametric Mapping (SPM, www.fil.ucl.ac.uk) is the most used method for data analysis, revealing statistically significant areas of increased perfusion that are typically referred to as ‘activations.’ SPM procedures, in which a voxel-by-voxel analysis is performed to test experiment-induced signal changes according to the general linear model, are spatially extended statistical processes that are used to characterize regionally specific effects in imaging data (Friston et al., 1995). All images are transformed into a

65

standard space (e.g., so-called ‘Talairach space’ (Talairach and Tournoux, 1988) or ‘Montreal Neurological Institute (MNI) space’ (Evans et al., 1993) in order to match each scan to a reference or template image that already conforms to the standard space. Then the analysis includes global activity as a confounding covariate and can therefore be regarded as an ANCOVA. To test hypotheses about regionally specific condition (or covariate) effects, the estimates are compared using linear compounds or contrasts. The resulting set of voxel values for each contrast constitutes a statistical parametric map of the t statistic SPM{t} (Fig. 4.1). 4.2.2. Functional MRI Functional magnetic resonance imaging (fMRI) is a tool that by exploiting the principles of traditional MRI, allows studying the brain while it works. The fundamentals of fMRI are well established, being based on a phenomenon known as Blood Oxygenation Level Dependent (BOLD). In response to neural activation, the rCBF increases to the relevant region, but for reasons that are still not well understood, the rCBF increases far more (by 30–50%) than the expected increase in oxygen demand (oxygen extraction increases by only 5%) (Ogawa et al., 1990). This leads to both local increase of oxyhemoglobin concentration, which has diamagnetic properties, and reduction of deoxyhemoglobin, which has paramagnetic properties. The presence of paramagnetic substances in the blood could act as vascular markers, featuring as a natural endogenous contrast agent. The BOLD effect is particularly manifested in the venous compartment, which

Fig. 4.1. Description of SPM method for spatial preprocessing and data analysis, see text for details (from the SPM website www.fil.ion.ucl.ac.uk).

66

D. PERANI

is only 60–70% saturated with oxygen at rest and hence has the capacity to get more oxygenated during the activation state, with a corresponding increase in MRI signal intensity. Kenneth Kwong and colleagues (1995) reported the time course of these oxygenation changes in humans during breath-holding. Afterwards, the use of fMRI in neuroscience exploded. Using this totally non-invasive method, it is possible to localize functional brain activation with an accuracy of millimeters and a temporal resolution of about one to two seconds. As such, the BOLD signal is an indirect marker of brain activity, as it evaluates only hemodynamic changes (Logothetis et al., 2001). A BOLD response to a given stimulation usually peaks with a delay of 6–9 seconds. BOLD signal changes are generated more by synaptic than neuronal body activity (Arthurs and Boniface, 2002) and this implies that the region(s) apparently active during fMRI experiments can be remote from the true site of neuronal activation. Logothetis and colleagues have analyzed the relationship between BOLD signal and local neural activity by simultaneously acquiring electrophysiological and fMRI data from monkeys, finding that the BOLD signal does reflect a local increase of neural activity, being thus due both to excitatory and inhibitory interneurons (Logothetis and Wandell, 2004; Logothetis and Pfeuffer, 2004). The fMRI technique has advantages in spatial and temporal resolution when compared to the PET technique and, in addition, the fact that no radionuclides are used makes it feasible to repeat experiments several times on the same subject. Using fMRI, it is therefore possible to take advantage of more complex experimental designs. However, fMRI imaging has some limits. For instance, there are interferences with the magnetic field in some structures of the brain, in particular the orbitofrontal inferior temporal regions and the temporal pole, because of the air enclosed in adjacent structures (the middle ear and the mastoid bone). This interference creates susceptibility artifacts, resulting in a loss of signal detection (Gorno-Tempini et al., 2002). 4.2.2.1. Data analysis Functional magnetic resonance imaging (fMRI) has become the most commonly used method to reveal neural correlates of specific sensorimotor, perceptual, and cognitive processes. Well-defined functions such as motor and sensory tasks give a relatively sharp fMRI signal, while cognitive tasks, due to slow and variable beginning, complexity and slow dying off, are more problematic. The detected fMRI signal, believed to be proportional to neuronal activation, is the difference between signal in the active task condition and that in

the rest or control condition. Activation maps are obtained for instance through subtraction among the experimental conditions (see Friston et al., 1995, for a taxonomy of experimental designs). A typical ‘block design’ experiment usually is based on registration of BOLD response lasting between 20 and 30 seconds, where between 6 and 9 seconds are needed to reach the activity peak, and between 8 and 20 to return to the baseline level (Matthews and Jezzard, 2004). On the other hand, the ‘event related design’ is a technique to detect hemodynamic responses to brief stimuli or events (Donaldson and Buckner, 2001). Individual, single trial events are measured rather than a temporally integrated signal, as it happens for the ‘block design.’ The main advantage of the event related design is that biases, such as habituation, anticipation, and strategy effects, are greatly limited, thus enhancing the possibility of drawing powerful inferences. Cognitive tasks can significantly influence the time course of hemodynamic response, and event-related fMRI provides a unique opportunity to merge spatial and temporal information in a single approach. However, the temporal resolution of event-related fMRI remains poor to date (in the range of 50 ms for one slice) even though further technological developments have been announced. The most important limitation comes from the slow kinetics of the hemodynamic response itself (typically peaking at 6 s after SOT). The search is clearly on for a sound mathematical model of EHRs, taking into account regional specificities (Josephs and Henson, 1999). As for PET activation studies, factorial designs can be used following a general method and dedicated software, such as Statistical Parametric Mapping (see section 4.2.1.1). This standard approach uses linear convolution models that relate experimentally designed inputs, through a hemodynamic response function, to observed blood oxygen level dependent (BOLD) signals. Although different statistical models have been suggested (see Bullmore et al. [2003] and Henson [2004] for recent reviews of different approaches), these standard models treat all voxels throughout the brain as isolated black boxes, whose input–output functions are characterized by BOLD responses evoked by various experimental conditions. It has been argued that these approaches were not sufficient to provide an understanding of the operational principles of a dynamic system such as the brain, but must be complemented by models based on general system theory (Friston, 2002). These models reflect the connectional structure of the nervous system and emphasize contextdependent couplings between the system elements in terms of effective connectivity. The brain appears indeed to adhere to two fundamental principles of

FUNCTIONAL NEUROIMAGING OF COGNITION functional organization, that is functional integration and functional specialization, where the integration within and among specialized areas is mediated by effective connectivity. Functional localization implies that a function can be localized in a cortical area, whereas specialization suggests that a cortical area is specialized for some aspects of perceptual or motor processing, in which this specialization can be anatomically segregated within the cortex. The cortical infrastructure supporting a single function may then involve many specialized areas whose union is mediated by the functional integration among them. Functional specialization and integration are not exclusive, but they are complementary. Functional specialization is only meaningful in the context of functional integration and vice versa (Ramnani et al., 2004). The usefulness of system models whose parameters are fitted to measured functional imaging data for testing hypotheses about structure–function relationships in the brain and their potential for clinical applications has been demonstrated by empirical and applicative examples (Stephan et al., 2004). Recently developed biophysical models of fMRI responses have focused on how BOLD responses are generated. These causal models deal either with the mechanisms that translate local neural dynamics into observed BOLD signals (the neurovascular coupling), and with the neural interactions of local responses with other brain regions. Such models of functional integration consider context-dependent causal interactions among remote areas in terms of effective connectivity (Stephan et al., 2004). Particular emphasis has been given to dynamic causal modeling for progress in the field of effective connectivity (Friston et al., 2003). It represents an emerging class of models that combine the biophysics of local responses and effective connectivity, including the neural state equations, the forward model for fMRI, and the Bayesian parameter estimation scheme. Thus, as a complement to existing models of ‘where’ brain responses are expressed, current effort is being invested in developing models of ‘how’ neuronal responses are caused. A promising strategy is to use comprehensive models with meaningful neurophysiological parameters that link experimental manipulations, via induced neural dynamics, to observed BOLD responses. In the near future, it is realistic that such models will greatly enhance the ability to investigate and to understand the neural systems that mediate specific cognitive processes. In summary, although there has been a shift from PET to fMRI over the last decade, each technique has its advantages for the study of cognitive functions. Greater spatial resolution is combined in fMRI with faster temporal resolution and no exposure of the subject

67

to radiation. Perhaps its major advantage is to study hemodynamic changes after perception or response to a single stimulus (event-related imaging), allowing true experimental randomization. The blocked designs necessary in PET, as one cerebral blood flow measurement is performed over 1–2 min, cannot distinguish between transient responses to repeated stimuli, which are summed over the scanning period, or a steady-state change (set shift) in readiness for the repeated stimuli and the responses to them. In addition and noteworthy, whatever the procedure for functional neuroimaging analysis may be, subject-specific parameters and task generic parameters of cognitive experiments have a profound, albeit frequently disregarded influence on the results.

4.3. Language Many anatomoclinical observations in aphasic patients, reported by neurologists during the nineteenth and the first part of the twentieth centuries, resulted in the delineation of a set of ‘language areas,’ located around the sylvian fissure of the left hemisphere of right-handed individuals. These ‘cerebral centers’ were originally defined in term of their specialization for a language activity: Broca’s area for speaking, Wernicke’s areas for comprehending, the angular gyrus for reading and writing. They are connected by fiber pathways, which are responsible for the transfer of linguistic information among centers, necessary for other tasks such as repetition and writing to dictation (Catani et al., 2005). This conception was in full agreement both with the available anatomical knowledge and with the associationist model of language function. Functional neuroimaging studies from their start have heavily depended on this knowledge, both in terms of study design and of data interpretation. However, imaging studies have actually shown that the neuropsychological method of relating the result of a deficit analysis to the location of a brain lesion is not necessarily the ‘gold standard’ for the location of the neural sub-systems involved in language processing. The added value that functional neuroimaging has brought to language research is in the delineation of distributed, large-scale networks, which are involved in specific aspects of language processing. PET and fMRI, as well as electrophysiological methods such as ERPs and MEG, made it possible to address crucial questions about the cerebral organization of language systems which go beyond the localization of a language activity. The integration of the electrophysiological and tomographic data is a powerful method of assessing the in vivo organization of cognitive processing, focusing either on the temporal or the anatomical

68

D. PERANI

dimension of the signal (see, for instance, Snyder et al., 1995; Thierry et al., 1998; 2003). 4.3.1. Studies in normal individuals Functional neuroimaging has been applied to the investigation of healthy subjects, with well-defined language backgrounds, using paradigms aimed at the characterization of the neural architecture of language. In particular, a large part of the research has been devoted to the identification of ‘modular’ language processors dedicated to phonology, lexical semantics, and morphosyntax. The modern concept of brain specialization for language has emerged as a consequence of the development of sophisticated experimental paradigms, allowing the study of these language subcomponents, together with their computational processing demands. The ‘language system’ appears to be specialized for specific components of language processing, rather than for specific activities, such as speaking, repeating, reading, and listening (Neville and Bavelier, 1998). A comprehensive review of the huge body of studies devoted to the investigation of language organization in the intact human brain is nowadays almost impossible. In general, imaging studies employing functional techniques have largely confirmed the anatomical knowledge gained from neuropsychological lesion studies, but more importantly, they have considerably enlarged and redefined the participation of brain systems in language processing (see for review Price, 1998; Indefrey and Levelt, 2000; Demonet et al., 2005). In the first place, language-related activations have been reported outside the classical perisylvian language areas of the left hemisphere, and right hemispheric activations have been observed during the performance of most language tasks. Functional neuroimaging has also shown that the areas related to linguistic processing in the normal human brain are less fixed than previously thought. For example, even when the task and the experimental design are held constant, changes in language-related brain activations can be observed as a consequence of increased familiarity or practice with the task (Raichle et al., 1994). More generally, several aspects of plasticity, related to development, exercise or brain lesions, can be investigated with functional imaging also in the language domain. Functional neuroimaging has provided relevant new information about the classic topic of hemispheric specialization for language. The concept of left hemispheric language dominance, a fundamental cornerstone of aphasiology for more than a century, has been further qualified by functional neuroimaging results, which have provided ample evidence for bilateral hemispheric activation during language tasks, even

in strictly right-handed individuals. There is evidence that the left-greater-than-right asymmetry is associated with auditory input rather than with visual input, with single-word rather than sentence level processing, and with comprehension rather than production task (Thompson-Schill et al., 1997). It is the nature of the task, rather than of the material, which is the crucial determinant of hemispheric asymmetry (Stephan et al., 2003). An important concept, proposed by Price and colleagues (Price et al., 1999), is that functional neuroimaging of language in normal subjects may show a set of brain regions whose activation is related to the task, but not actually ‘necessary’ for its performance. Only the study of lesion effects has the unique ability to reveal the regions which are actually required (necessary) for the task. The activations observed in the right hemisphere during language tasks may thus have a functional significance, without being necessary for their execution. In particular, they could reflect the persistent automatic activation of a subsidiary language system, whose function is inhibited by the preponderant leftsided system. This ‘dormant’ system could partially compensate for the effects of left-sided lesion and aphasia, at some stages of recovery (see below). What is the basis of the left-sided language dominance? Kimura (1973) proposed that the right-handedness could be related to the particularly efficient spatial and temporal motor programming abilities of the left premotor area, and that this basic specialization could enable language capacities. This theory of hemispheric specialization can be linked with the ‘temporal’ hypothesis, according to which the left hemisphere is specialized for the processing of rapidly changing acoustic signals, an ability which is crucial for speech comprehension. The temporal hypothesis, originally advanced by Tallal et al. (1993), has been recently explored using functional neuroimaging. For example, Zatorre and Belin (2001) described activation in the left superior temporal gyrus for rapidly changing auditory stimuli (over a period shorter than 80 ms), with a contralateral bias for more steady acoustic events. Poldrack et al. (2001b) reported similar findings in the inferior posterior frontal cortex, close to the left inferior frontal gyrus. A clear-cut left hemispheric predominance has been shown during phonological tasks (Zatorre et al., 1992). The left inferior frontal/anterior insula complex, an essential component of the neural system implicated in phonological processing, mouth motor planning, and articulation, showed a prevalent left-sided activation during silent lip-reading (Paulesu et al., 2003). This task requires the extraction of articulatory mouth movements by means of an integration of visual, phonological, and motor information. The left hemisphere

FUNCTIONAL NEUROIMAGING OF COGNITION has been proposed to store the long-term representations of phonemes, and is responsible for categorical perception. There is neuroimaging evidence for the activation of left hemispheric structures, such as the inferior frontal gyrus and supramarginal gyrus, during categorical perception of spoken syllables (Celsis et al., 1999) The brain correlates of single-word and sentencelevel processing have been studied in relation to input modalities (visual and auditory input) and output modalities (speech and written output). In the case of single-word processing, a large body of evidence has been collected, which can be linked to the levels of information processing hypothesized by the major cognitive models of language. Price, in a review focused on single-word processing (Price, 2000) summarized the ‘classical’ neurological model of single-word processing, as well as the recent functional imaging results, and proposed an anatomically constrained model of word processing, which attempts to reconcile the clinicoanatomical views of the nineteenth century neurologists with the twentieth century cognitive models. As predicted by classical neurological models, auditory and visual word processing engages the left posterior superior temporal and inferior frontal cortices. More specifically, the functional role that Wernicke and Broca assigned to the eponymous regions engages, respectively, the posterior superior temporal sulcus and the anterior insula. An additional region in the left posterior inferior temporal cortex was also found to be activated for word retrieval, and may be responsible for the lexical route to reading, predicted by cognitive models. It is noteworthy that functional imaging can reveal the involvement of discrete brain regions which have been missed by the nineteenth century neurologists only because they are seldom affected by selective damage. The results of imaging studies have indicated that the angular gyrus is not only involved in reading, but is part of a distributed semantic system, which can be accessed by objects and faces as well as by words. More specifically, a large number of studies has been devoted to the neural correlates of the processing of different classes of words: nouns referring to different semantic categories (biological entities, artifacts, people, or geographical names), as well as to actions and abstract concepts. These investigations have been primed by neuropsychological observations of selective disorders, affecting the processing of specific categories. The results are not fully consistent: however, taken together they indicate the presence of differential engagement of brain regions which may support the different aspects of conceptual representation, as well as of grammatical role, engaged by specific word

69

classes (Diller and Riley, 1993; Martin and Chao, 2001; Devlin et al., 2002; Cappa and Perani, 2003). For example, Saccuman et al. (2006) using fMRI showed the impact of semantic reference and word class on brain activity during a picture naming task. Participants named pictures of objects and actions that did or did not involve manipulation. The effects of word class on brain activity were limited; in contrast, extensive differences in activation were associated to the semantic dimension (manipulation). In the case of manipulable items, irrespective of word class, there were significant activations within a frontoparietal system subserving hand action representation. These results highlight the impact of the biologically crucial sensorimotor dimension of manipulability on the pattern of brain activity associated to picture naming (Fig. 4.2). Many findings from language studies indicate that the neural systems that control language processes appear to also subserve other crucially related cognitive functions. For example, the left inferior frontal cortex is involved in many language tasks, such as word generation, semantic and syntactic monitoring (Mummery et al., 1996; Thompson-Schill et al., 1997; Moro et al., 2001), but also generating and monitoring self-ordered sequences, learning of associations between stimuli, and maintenance in working memory (Owen et al., 1998). The prefrontal cortex is not homogeneous, encompassing many different cytoarchitectonic areas

Fig. 4.2. (A) Main effects of word class (verbs and nouns); (B) semantic reference (manipulability) see text for details. (Modified from Saccuman et al., 2006.)

70

D. PERANI

that exhibit their own unique pattern of connections with other cortical and subcortical areas (Petrides and Pandya, 1999). The different cognitive functions of these areas rely on specific pattern of connections with other brain regions, as well as on reciprocal connections. For example, the left inferior frontal cortex was shown not to be a single functional region, as it can be subdivided into distinct areas that contribute differently to word processing. The anterior left inferior frontal cortex (LIFC) is mainly linked to the meaning of words, whereas the processing of sound pattern of the words is associated with the posterior left inferior frontal cortex (see Cappa and Perani, 2006, for a review). Again, this double dissociation for the phonological and the semantic task in distinct subdivisions of the LIFC can be understood in terms of separable cortico-cortical connections linking the anterior LIFC to temporal pole regions associated with semantic memory and the posterior LIFC to temporoparietal regions involved in auditory speech processing. In the case of the other classical language area, i.e., Wernicke’s area in the left superior temporal gyrus, recent imaging studies have clarified its relationship with other auditory areas, resulting in a model of the neural mechanisms underlying speech perception. The studies by Wise and their coworkers have indicated the important role of anterolateral temporal cortex in speech perception, and have suggested the existence of two separate processing pathways

between the temporal lobe and Broca’s area: a rostral pathway, connecting anterolateral temporal areas and the rostral part of the inferior frontal gyrus via the uncinate fasciculus, responsible for word meaning, and a caudal pathway, connecting the posterior temporal areas with the caudal inferior frontal gyrus, via the arcuate fasciculus, dedicated to phonological processing (Wise, 2003). It is noteworthy that recent developments in diffusion tensor imaging techniques open new perspectives in the in vivo assessment of fiber pathways in the human brain (Catani et al., 2005). Functional imaging studies have addressed also the complex issue of sentence processing. While many studies have confirmed the role of Broca’s area which was predicated on the basis of the association between the clinical syndrome of agrammatism and the eponymous aphasia type (Caplan et al., 1998), there is ample evidence that a number of other structures are involved in syntactic processing. For example, syntactic error detection in monolinguals (Dapretto and Bookheimer, 1999; Moro et al., 2001) engages a selective deep component of Broca’s area, in addition to the left caudate nucleus, insula, and a right inferior frontal region, indicating their role in syntactic computation (Fig. 4.3). These findings provide in vivo evidence that all these brain structures constitute an integrated neural network selectively engaged in morphological and syntactic computation. A psycholinguistic and neurological

Fig. 4.3. Activations found in the syntactic condition (A): the frontal operculum, the right homologue of Broca’s area, the left caudate nucleus and insula; and in the morphosyntactic condition (B): comparable activation foci to those in A apart from the caudate nucleus. (Modified from Moro et al., 2001.)

FUNCTIONAL NEUROIMAGING OF COGNITION model of sentence comprehension has been described by Friederici (2002). The model represents a remarkable attempt to integrate evidence from behavioral studies with the results of imaging studies and neurophysiological investigation, providing a general framework of the temporal dynamics of sentence comprehension and of the localization of specific processes within a bilateral frontotemporal network, with the right hemisphere subserving prosodic aspects of linguistic processing. We can thus conclude that functional neuroimaging methods are playing an important role in building a new physiology of language. Further progresses in this area will depend on the deep integration of behavioral, computational anatomostructural, and neurophysiological approaches, including functional neuroimaging. 4.3.2. Bilingualism In recent years, functional techniques for measuring brain activity have shed new light on the neural basis of second language (L2) processing and its relationship to native language processing (L1). The current research is focused on the degree of functional integration or separation of the languages in the polyglot brain. Considering that L1 is acquired implicitly and mediated, according to many theorists, by innate learning mechanisms triggered during a critical period, whether or not the same neural mechanisms underlie the acquisition and processing of L2 remains an open question. Neuroimaging work on bilinguals has been motivated by the same ‘localizationist’ questions that run through the bilingual aphasia literature: whether multiple languages are represented in overlapping or in separate cerebral systems. For instance, in bilingual aphasics the observation of selective recovery of one language was often interpreted as evidence for differential neural representation of languages (Albert and Obler, 1978). However, there are limitations to the generalization of such lesion evidence to neurologically healthy individuals (Green and Price, 2001). Several environmental factors have been considered to affect the neural organization of language, in particular the age of language acquisition and degree of proficiency attained in each of the spoken languages. People who learn a language at later ages, particularly after late infancy or puberty, do not generally achieve the same level of proficiency as young learners (Birdsong, 1999; Johnson and Newport, 1989). Explanations range from the postulation of biologically based ‘critical periods’ to differences between infant and adult learning contexts (Lenneberg, 1967). Proficiency appears to play an important role in second language organization, too, as several psycholinguistic studies indicated (De

71

Groot and Kroll, 1997). It is possible that the increasing proficiency of late learners also entails a reorganization of language areas in the bilingual brain. Bilingual/multilingual subjects have been a fundamental model for the neuroimaging study of the interactions between a pre-wired neurobiological substrate and environmental, time-locked influences (Abutalebi et al., 2001; 2005). The most important contribution of functional neuroimaging on this issue is the observation of both aspects of invariance and aspects of plasticity. Indeed, the patterns of brain activation associated with tasks, which engage specific aspects of linguistic processing, such as phonology, lexicon, and grammar, are remarkably consistent across different languages and different speakers. Differences in the first and second language representations are only related to the specific computational demands, which may vary according to the age of acquisition, the degree of mastery, and the level of exposure to each language (Abutalebi et al., 2001; 2005). For example, during grammatical tasks in bilinguals the brain structures traditionally associated with grammatical processing (e.g., inferior frontal regions, including the operculum, basal ganglia) were involved at a comparable level when performing the tasks in both L1 and L2. Additional activation for L2, extending into areas adjacent to the areas subserving L1 grammar, was evident only in bilinguals with low proficiency and/or late acquisition (Wartenburger et al., 2003; Fig. 4.4). These results indicate the effects of these variables on the pattern of brain activation in bilinguals and suggest that the neural organization of languages depends on appropriate input during a biologically based ‘critical period’ and by the level of language mastery. It is likely that other factors, such as daily usage and exposure, might influence brain plasticity. More extensive brain activation in the left dorsolateral frontal cortex was found in a group of early high proficient bilinguals when generating words in their second language with less exposure during daily activities (Perani et al., 2003a). These findings suggest that a second language associated with lower environmental exposure is in need of additional neural resources. Similar findings have been reported in studies directly addressing L2 acquisition. Studies in adults using fMRI reported comparable evidence for shared computational brain devices underlying native language and the acquisition of a second language (Tettamanti et al., 2002; Musso et al., 2003). This happened irrespective of the differences in orthography, phonology, and syntax among languages. Structural MRI has been used to investigate brain plasticity in bilinguals (Mechelli et al., 2004). Evidence for structural plasticity was shown by whole-brain voxel-based morphometry in healthy right-handed

72

D. PERANI

Fig. 4.4. Comparison of grammatical judgment for the second acquired language and for the native language: no differences in the early-acquisition high-proficiency group (A), but significant differences in language-related regions in both the late-acquisition high-proficiency group (B) and the late-acquisition low-proficiency group (C). This demonstrates that age of acquisition specifically affects the cortical representation of grammatical processes. (Reproduced from Wartenburger et al, 2003 with permission from Elsevier.)

English and Italian bilinguals. Differences between monolinguals and bilinguals were found in the neural density of the left inferior parietal lobule. Early bilinguals had increased gray matter density within this area. Notably, late bilinguals might also have comparable gray matter density in this brain area, but only when L2 proficiency is high. There has been also an emphasis placed in particular on the importance of studying language-related cognitive functions in bilinguals. In particular, some memory components, such as working memory, show a clear-cut a relationship with language acquisition, on the basis of different sources of evidence (Vallar and Papagno, 2002). In normal development, phonological memory skills correlate both with existing vocabulary knowledge and with the ease of learning new vocabulary, either in native or foreign languages (Baddeley, 1998). Deficits of phonological short-term memory include developmental deficits, such as dyslexia. Many dyslexics indeed are impaired in foreign language acquisition (see section 4.7.2). These findings emphasize the

evolutionary role of the phonological loop component of verbal working memory as the main candidate for a ‘language acquisition device’ (Gathercole, 1999). In a recent paper, Chee et al. (2004) report differences in the patterns of brain activation/deactivation in bilinguals, who attained different levels of proficiency in L2. The most fascinating aspect of this research is that the authors addressed the issue of the neural basis of phonological working memory, which is crucial in language acquisition, in groups of bilinguals matched for the environmental variables, including age of acquisition and social pressure to learn languages. The results led the authors to suggest that a more readily available working memory system may correlate with the attainment of superior proficiency in second language. In summary, the available evidence supports a dynamic view of the neural basis of L2 processing. L2 seems to be acquired through the same neural devices responsible for L1 acquisition. The patterns of brain activation associated with tasks that engage specific aspects, such as phonology, syntax, and semantics, are

FUNCTIONAL NEUROIMAGING OF COGNITION remarkably consistent among different languages, which thus share the same brain language system. These relatively fixed brain patterns, however, are modulated by several factors. Proficiency, age of acquisition, and amount of exposure can affect the cerebral representations of each language, interacting in a complex way with the modalities of language performance. 4.3.3. Aphasia and recovery Functional imaging has also been applied to the investigation of the neural mechanisms underlying the spontaneous recuperation of aphasia and to its rehabilitation. During the early period, crucial mechanisms of clinical improvement are the disappearance of cerebral edema and of intracranial hypertension, the reabsorption of blood, the normalization of hemodynamics in ischemic penumbra areas, and the resolution of local inflammation. Another important mechanism is the regression of diaschisis (functional suppression) in non-injured areas connected to the damaged region (von Monakow 1914; Feeney and Baron, 1986). The mechanisms underlying recovery at later stages are less known. Recovery may be achieved by adopting novel cognitive strategies for performance. The effect of the ‘degeneracy of neural systems’ sustaining cognitive functions is a very interesting hypothesis (Noppeney et al., 2004). Edelman and colleagues have defined ‘degeneracy’ as ‘the ability of elements that are structurally different to perform the same function or yield the same output’ (Edelman and Gally, 2001). The human brain shows an amazing ability to maintain and recover cognitive functions after focal cortical damage. This resilience suggests that there might not be a one-to-one mapping between neuronal structures and cognitive functions, but that multiple neuronal systems might be capable of producing the same behavioral response. Degeneracy explains structure–function relationships in terms of neuronal mechanisms that can mediate behavioral compensation after focal cortical damage. True recovery of linguistic function has been attributed to the ‘reorganization’ of the cerebral substrate of language processing, with new brain areas taking over the function of damaged regions. The influential hypothesis proposed by Gowers (1895), is that the involvement of homologous areas of the contralateral hemisphere may subserve compensation. Recovery may be due to the recruitment of perilesional areas surrounding the lesioned region. In both cases, these areas may be part of redundant language networks, which are inhibited by the ‘primary’ language areas (Heiss et al., 2003). Modern neuroimaging techniques, in particular functional fMRI, have been used to test these hypotheses. A study by Weiller et al. (1995) supported the

73

capacity of the right hemisphere to take over the damaged dominant hemisphere. This was followed by several studies showing a better long-term recovery in patients who were able to reactivate preserved areas of the left hemisphere. Follow-up studies have shown a temporal gradient in the enrolment of cerebral reorganization mechanisms in vascular aphasia. The initial engagement of homologous areas of the right hemisphere is followed over time by a progressive increase of activity in left hemispheric perilesional areas. The right to left transfer is associated with language improvement (Karbe et al., 1998; Warburton et al., 1999; Perani et al., 2003b). The ‘right hemispheric recruitment’’ of the early stage may thus simply reflect the recruitment of additional cognitive resources, which are not required by normal subjects. There are only a small number of studies of the neural basis of training-induced modifications on language performance. In the study of Musso et al. (1999) intensive language comprehension training during the PET inter-scan intervals was positively correlated with the increase of rCBF in the right homologues of Wernicke’s area and of Broca’s area. Blasi et al. (2002) found that the learning of a stem-completion task was associated with specific response decrements in the right frontal and occipital cortex, rather than in the left-sided network engaged by normal subjects. Training-induced effects were prevalent in the right hemisphere also in a recent study of ‘intentional’ therapy (Crosson et al., 2005). Other investigations, however, suggest that the engagement of spared left hemispheric regions is also crucial. In the study of Belin et al. (1996) language training with Melodic Intonation Therapy (MIT) resulted in right hemisphere deactivation and in a significant increase in the left frontal areas. The complex interplay between right- and lefthemispheric activations is shown by the study of Vitali et al. (2003) with event-related fMRI (e-fMRI), in which two anomic patients were submitted to an intensive training of lexical retrieval. In both patients before training naming was mainly associated with activations in the non-dominant hemisphere. After training, perilesional areas of the dominant hemisphere were mainly activated in one patient, supporting their role for effective recovery. However, in the other patient, with a lesion involving Broca’s area, the right homologue was activated, indicating its potential to support successful naming. In summary, the process of language recovery after damage to the specialized left hemispheric network is based on a complex interplay between left-hemispheric mechanisms (restitution of reversible damage, reorganization in perilesional areas) and right hemispheric engagement. The role of these different mechanisms

74

D. PERANI

depends on many factors, such as the nature of the lesion, its location, its size, the condition of the intact brain, individual differences in brain organization, time post onset, and effects of training and rehabilitation. Given the large number of variables, it is not surprising that our comprehension of these mechanisms is in its infancy.

4.4. Memory Functional neuroimaging methods have provided fundamental insights into the neural basis of memory, extending the field of inquiry from the analysis of the functional consequences of brain lesions to the investigations of brain activity, either in patients with selective neuropsychological deficits or in normal subjects engaged in cognitive tasks. As these investigations illustrate, neuroimaging goes beyond asking ‘where’ activity is occurring, to ask questions concerned with ‘what’ functional role in memory processes the activity reflects. A review of the current status of neuroimaging studies of memory provides clear-cut evidence that a neuronal network perspective can lead to a better understanding of the multiple memory functions than a localizationist perspective. These results show that memory is subserved by a more widely distributed cortical network than expected (see for review Rugg, 2002). 4.4.1. [18F]FDG PET steady-states in patients The hippocampus belongs to the limbic lobe described by Broca, or to the Papez circuit, which were considered to be related to emotions. The observation that medial temporal lobe damage leads also to mnemonic dysfunction have been advanced greatly by the study of brain-damaged patients and by experimental animal studies. Functional imaging has also helped to change these historical concepts. Specific patterns of cerebral hypometabolism in neurological patients are associated with different profiles of memory deficits (Fazio et al., 1992; Perani et al., 1993a). These [18F]FDG PET studies have shown the association of episodic memory with the structures of Papez’s circuit as a whole, and have indicated correlations between short-term and semantic memory and the language areas. Subsequent comparable PET studies in the permanent amnesic syndrome, provided statistical maps of the brain regions with significantly impaired resting metabolism in comparison with control subjects. These regions include not only Papez’s circuit but also the left supramarginal gyrus, which may explain in part the retrograde amnesia present in most cases of amnesic syndrome. This approach was also used in transient global amnesia

where the defect of episodic memory is highly selective and occurs without permanent damage. The PET studies revealed the dysfunction of a distributed network, including the hippocampal region and the prefrontal cortex, with a different pattern individually. In Alzheimer’s disease, the study of the correlations between memory test scores and metabolic values across a sample of subjects provided a map of those brain structures whose synaptic dysfunction underlies the particular neuropsychological alteration. The distribution of the sites of correlations with specific memory deficits shows striking differences according to which memory system is involved (Eustache et al., 2000) and to the severity of the impairment (Desgranges et al., 2002). In fact, significant correlations involved bilaterally not only several limbic structures (the hippocampal/rhinal cortex regions, posterior cingulate gyrus and retrosplenial cortex), but also some temporo-occipital association areas. In the less severe subgroup, all significant correlations were restricted to the parahippocampal gyrus and retrosplenial cortex, in accordance with the known involvement of this network in normal and impaired memory function, while in the more severe subgroup they mainly involved the left temporal neocortex, which is known to be implicated in semantic memory. The authors suggest that, when episodic memory is mildly impaired, limbic functions are still sufficient to subserve the remaining performance, whereas with more severe memory deficit resulting from accumulated pathology, the neocortical areas become more functionally involved. This approach opens the way for the unraveling of the neurobiological substrates of both cognitive impairment and compensatory mechanisms in neurological diseases. Such studies in brain-diseased subjects are particularly useful for establishing cognitive and neurobiological models of human memory, because they allow the highlighting of the neural networks that are essential for memory function. From a cognitive neuroscience perspective, the functional neuropsychology of amnesia is, therefore, complementary to the activation paradigm in normal subjects, which identifies the cerebral structures that are involved with, but not necessarily indispensable for, the execution of the task. 4.4.2. Activation studies in normal subjects The identification of the anatomofunctional networks involved in specific components of memory function was the aim of several PET and fMRI activation studies in normal subjects. The results have converged on the observation that hippocampal or parahippocampal regions could be consistently activated in verbal or visuospatial memory paradigms. In addition, these

FUNCTIONAL NEUROIMAGING OF COGNITION functional neuroimaging studies have also stressed the importance of the prefrontal, temporal, and parietal cortical activations in memory processes. All together these findings are in agreement with ‘neural network’ models of the basis of memory, as complex functions subserved by multiple interconnected cortical and subcortical structures. Indeed, neuroimaging research of the neurobiological bases of learning and memory suggest that these processes are not unitary in nature, but rather that relatively independent neural systems appear to mediate different types of memory. There are multiple memory systems with different functions that can be classified according to time (from shortterm memory, lasting only seconds or minutes, to long-term memory, lasting months or years), and to phases of memory storage or retrieval. PET and fMRI studies have identified brain regions associated with the different forms of memory (see Cabeza and Nyberg, 2000); episodic memory encoding has been associated with the left prefrontal and medial temporal regions; episodic memory retrieval with the right prefrontal, posterior midline and medial temporal regions; semantic memory with the left prefrontal and temporal regions; working memory has been associated primarily with the bilateral prefrontal and parietal regions and implicit memory, such as skill learning, with motor, parietal, and subcortical regions. Studies of human classification learning using functional neuroimaging have suggested that basal ganglia and medial temporal lobe memory systems may interact during learning. For example, separable cognitive or ‘declarative’ and stimulus-response ‘habit’ memory systems that rely upon the medial temporal lobe (e.g., hippocampus) and basal ganglia (e.g., caudate–putamen), respectively, appear also to interact (Knowlton et al., 1996; Poldrack and Rodriguez, 2004). Effective connectivity analyses suggest also that interaction between basal ganglia and medial temporal lobe is mediated by the prefrontal cortex, rather than by direct connectivity between the regions. As possible neurobiological mechanisms, interactions may be driven by neuromodulatory systems, suggesting that memory system interactions may reflect multiple mechanisms that combine to optimize behavior based on experience (Poldrack et al., 2001a). Potential neurobiological mechanisms mediating such interactions include direct anatomical projections, indirect neuromodulatory influences of other brain structures and activity of neocortical brain regions involved in top-down response selection. Recent human neuroimaging research has also provided evidence in favor of competition and cooperation between memory systems (Hartley and Burgess, 2005). This is the case in Voermans and colleagues’ demonstration in Huntington’s disease of a remote effect of

75

dysfunction in one region (caudate) upon activation in a distant region (hippocampus), thus revealing functional interactions between regions (Voermans et al., 2004). A similar approach showed that amygdala pathology modulates both hippocampal involvement in encoding emotional memories (Richardson et al., 2004) and the response of the fusiform gyrus to the recognition of fearful faces (Vuilleumier et al., 2004). This research helps us to understand how memories are created and, conversely, how our memories can be influenced also by emotion and stress. Indeed, the amygdala is thought to constitute a third complementary memory system (Richardson et al., 2004), mediating learned associations between neutral stimuli and reinforces. Both interaction and competition may play a role in some tasks. Cooperation is possible because the parallel systems support compatible behaviors, whereas in other tasks they drive conflicting responses and must therefore compete to control behavior. Thus, converging evidence across species supports the hypothesis of interactive and competitive multiple memory systems in the mammalian brain. Neuroimaging studies have also provided higher specificity within the memory systems, by dissociating the neural correlates of different subcomponents of complex memory tasks, and the cognitive roles of different subregions of larger brain areas. For example, specific regions of the prefrontal cortex and medial temporal areas are implicated in the successful encoding of verbal material into episodic memory (Otten et al., 2001). On the other hand, regions of the prefrontal cortex (PFC) are typically activated in many different memory functions. In most studies, the focus has been on the role of specific PFC regions in specific cognitive domains, but more recently similarities in PFC activations across cognitive domains have been stressed. Such similarities may suggest that a region mediates a common function across a variety of tasks. In a study on memory, the activation patterns associated with tests of working memory, semantic memory and episodic memory were compared (Nyberg et al., 2003). The results converged on a general involvement of four regions across memory tests. These were located in left frontopolar cortex, left mid-ventrolateral PFC, left mid-dorsolateral PFC and dorsal anterior cingulate cortex. These findings provide evidence that some PFC regions are engaged during many different memory tests, and support theories about the functional contribution of the PFC regions in the architecture of memory. 4.4.3. Aging and mild cognitive impairment Much of the recent neuroimaging research on aging has focused on investigating the relationship between

76

D. PERANI

age-related changes in brain structure/function and concomitant changes in cognitive/behavioral abilities. Memory impairment is one of the hallmarks of aging, and the majority of neuroimaging studies in this area have focused on age-related changes during working memory (WM) and episodic memory (EM) task performance (Craik and Salthouse, 2000). Age-related deficits in WM and EM abilities are related to changes in prefrontal cortex (PFC) function (Gazzaley et al. 2005; Persson et al., 2005; Cabeza et al., 2005). It is noteworthy that these age-related changes in PFC activity were associated either with poorer performance of older subjects or with an absence of behavioral differences between elderly and young subjects (Rypma and D’Esposito, 2000). Reviews of these neuroimaging studies have generally concluded that with age there is a reduction in the hemispheric specialization of cognitive function in the frontal lobes and viewed the PFC as a homogeneous region. For example, Cabeza (2002) observed that there is reduced lateralized PFC activity across WM and EM tasks with age, and proposed the hemispheric asymmetry reduction in old adults (HAROLD) model, which has been supported by subsequent experimental findings. However, this model does not address whether these laterality effects are specific to particular brain regions or common to all brain regions and does not specify the underlying neural mechanisms for age-related reductions in lateralized activity. A comprehensive qualitative meta-analytic review of all the fMRI and PET aging studies of WM and episodic memory that report PFC activation, indicates that in normal aging distinct PFC regions exhibit different patterns of functional change, suggesting that age-related changes in PFC function are not homogeneous in nature (Rajah and D’Esposito, 2005). Specifically, the effects of aging that are related to neural degeneration and changes in neurotransmitter systems, will result both in functional deficits and in dedifferentiation of cortical function. These changes in turn result in functional compensation within other PFC regions. To explore neural correlates of cognitive decline in aging, Persson et al. (2005) used both structural and diffusion tensor imaging, and fMRI in a longitudinal behavioral study. There was a heterogeneous set of differences associated with cognitive decline: hippocampal volume showed significant reduction in those older adults with a declining memory performance, as did DTI-measured fractional anisotropy in the anterior corpus callosum. The use of fMRI during episodic encoding revealed increased activation in the left prefrontal cortex for both groups and an additional right prefrontal activation for the elderly subjects with the greatest decline in memory performance. Moreover,

mean DTI measures in the anterior corpus callosum correlated negatively with activation in the right prefrontal cortex. The authors conclude that cognitive decline is associated with differences in the structure as well as function of the aging brain, and suggest that increased activation is either caused by structural disruption or is a compensatory response to such disruption. There is growing interest in using fMRI to assess the integrity of medial temporal lobe function in very early AD. Studies conducted in patients with a clinical diagnosis of AD consistently show that medial temporal lobe activation is decreased in comparison to older controls (Small et al., 1999; Machulda et al., 2003). Some fMRI studies concern subjects whose cognitive function falls between that of normal aging and mild AD, as in mild cognitive impairment (MCI), and the results so far have been inconsistent (Small et al., 1999; Machulda et al., 2003; Dickerson et al., 2004). MCI is a heterogeneous condition and this clinical heterogeneity may, in part, explain differences among previous fMRI studies of MCI. An fMRI study investigated whether hippocampal and entorhinal activation during learning is altered in the earliest phase of mild cognitive impairment (Dickerson et al., 2005). The subjects with MCI performed similarly to controls on the fMRI recognition memory task, whereas patients with AD had poorer performance. There were no differences in hippocampal or entorhinal volumes, but significantly greater hippocampal activation was present in the MCI group compared to controls. In contrast, the AD group showed hippocampal and entorhinal hypoactivation and atrophy in comparison to controls. The authors hypothesize that there is a phase of increased medial temporal lobe activation early in the course of prodromal Alzheimer’s disease, followed by a subsequent decrease as the disease progresses. The results of cognitive activation studies in aging and MCI are complex to interpret, however, an important contribution is already starting to become clear. The largely implicit logic, which tended to associate a larger activation with a better performance, is clearly questionable. The situation appears to be more complex, with evidence of rearrangements and recruitment of additional resources in order to support performance (D’Esposito et al., 2003). The advent of functional neuroimaging methods has undoubtedly provided an opportunity to gain insight into memory systems. An understanding of the neurobiology of memory may stimulate health educators to consider how various teaching methods conform to the process of memory formation and may also lead to new ideas about how to maximize the long-term

FUNCTIONAL NEUROIMAGING OF COGNITION retention of information in health and disease. Functional neuroimaging techniques allowing the exploration of the biological correlates of normal aging and related changes in behavior, under specific cognitive activations, can assess synaptic plasticity, clinically apparent as cognitive reserve capacity.

4.5. Executive functions and reasoning The executive function is a collection of cognitive abilities that allow the anticipation and establishment of goals, the formation of plans and programs, the initiation of activities and mental operations, the auto-regulation of tasks, and the ability to carry them out efficiently. They provide the coordination of several subprocesses to achieve a particular goal. Neuroscience research demonstrates that executive functioning is characterized by a variety of unitary and different processes (Fuster, 1989; Petrides and Pandya, 2002). There is no strong evidence for regional specialization or double dissociation, and we know only a few such demonstrations, largely restricted to comparisons between extensive lesions of the orbital and lateral surfaces (Fuster, 1989). The common finding is that even restricted lesions produce some degree of deficit in a broad array of different tasks. Executive dysfunction has been associated with a range of disorders, and is generally attributed to structural or functional frontal pathology. Neuropsychological evidence indeed suggests that executive processing is intimately connected with the intact functioning of the frontal cortex (Stuss and Benson, 1984). Neuroimaging, with PET and fMRI, has confirmed the relationship; however, attempts to link specific aspects of executive functioning to discrete prefrontal systems have been rather inconclusive. Early imaging experiments aimed at dissociating component processes of executive function and attributing them to discrete prefrontal foci. Although there is some evidence for both functional and structural specificity in prefrontal cortices, it appears that this is more a matter of degree than the result of fixed and fundamental dissociations. It is also clear that the same prefrontal regions mediate very different executive functions. The emerging view is that executive function is mediated by dynamic and flexible networks that can be better characterized using functional integration and effective connectivity analyses (Elliot, 2003). More sophisticated analysis approaches to studying flexible and dynamic changes in effective and functional connectivity between brain regions will have dramatic implications for our understanding of normal and abnormal executive functions. A dynamic network approach could form the basis for disconnection models of neurological and psychiatric disorders

77

and for understanding the mechanisms of both disconnection and functional reorganisation. 4.5.1. Studies in normal subjects Previous neuroimaging investigations explored the neural substrates of executive function used task-specific analyses, which might not be the most appropriate approach due to the difficulty of precisely isolating the functional components of this construct. These studies explored the functional anatomy of a variety of cognitive processes subserved by the prefrontal cortex, and demonstrated that standard frontal tasks recruit a widely distributed network within the brain, of which the prefrontal cortex forms just a part. Crucially, comparable patterns of frontal-lobe activation are associated with a broad range of different cognitive demands, including response selection, executive control, working memory, episodic memory, and problem solving. These results show a striking regularity. A similar recruitment of mid-dorsolateral, midventrolateral and dorsal anterior cingulate cortex has been found for many tasks. Much of the remainder of the frontal cortex, including most of the medial and orbital surfaces, is largely insensitive to these demands. These results on one hand provide strong evidence for regional specialization of function within the prefrontal cortex, on the other hand, this specialization takes an unexpected form: a specific prefrontal network recruited in the solution of diverse cognitive problems (Duncan and Owen, 2000). The results are also in keeping with the notion that executive functions rely not only on anterior prefrontal brain areas, but also on posterior, mainly parietal, brain regions. Moreover, intervention of similar brain regions in a large number of different executive tasks suggests that higher-level cognitive functions may best be understood in terms of an interactive network of specialized anterior as well as posterior brain regions. Most recent neuroimaging studies implicate diverse prefrontal foci, and support their interaction within a wider network (see Aron et al., 2004). A PET activation study re-examined, by conjunction and interaction paradigms, the cerebral areas associated with three executive processes: updating, shifting, and inhibition (Collette et al., 2005). The reported results are in agreement with cognitive studies, demonstrating that executive functioning is characterized by both unity and diversity of processes within the frontal functions. The ability to monitor and compare actual performance with internal goals and standards is critical for optimizing behavior. Convergent evidence suggests that the posterior medial frontal cortex and lateral prefrontal cortex are important contributors to cognitive

78

D. PERANI

control. The outcome of a meta-analysis of midline foci of activation reported in thirty-eight fMRI studies, published between 1997 and 2004 investigating brain activity associated with pre-response conflict, decision uncertainty, response errors, and negative feedback, suggest a critical role for the posterior medial prefrontal cortex in performance monitoring and the implementation of associated adjustments in cognitive control (Ridderinkhof et al., 2004a). Other studies, however, have suggested a more executive role for the posterior medial prefrontal cortex in implementing control directly (Matsumoto and Tanaka, 2004). Adaptive goal-directed behavior involves monitoring of ongoing actions and performance outcomes, and subsequent adjustments of behavior and learning. Primate and human studies, along with a meta-analysis of the human functional neuroimaging literature suggest that the detection of unfavorable outcomes, response errors, response conflict, and decision uncertainty elicits largely overlapping clusters of activation foci in an extensive part of the posterior medial frontal cortex. In addition, a direct link is delineated between activity in this area and subsequent adjustments in performance through functional interactions between the posterior medial frontal cortex and the lateral prefrontal cortex (Ridderinkhof et al., 2004b). Activations in human dorsomedial frontal and cingulate cortices are often present in neuroimaging studies of decision making and action selection. Interpretations have emphasized the role of executive control, movement sequencing, error detection, and conflict monitoring. A recent review attempted to integrate the results of novel experimental approaches, using lesions, inactivation, and cell recording, with those from neuroimaging (Rushworth et al., 2004). The conclusions suggest that these different cognitive aspects are just components of the areas’ functions. More specifically, a medial superior frontal gyrus region centered on the pre-supplementary motor area is involved in the selection of action sets, whereas the anterior cingulate cortex has a fundamental role in relating actions to their consequences, both positive reinforcement outcomes and errors, and in guiding decisions about which actions are worth making. Further evidence indicates a tight link between activity in these areas and subsequent adjustments in performance, suggesting close interactions that can signal other brain regions that changes in cognitive control are needed. Frontal functions involve in particular cognitive control, the ability to coordinate thoughts and actions in relation with internal goals that subserve higher cognition processes, such as planning and reasoning. Cognitive control primarily involves the lateral prefrontal cortex and exerts its influence through top-down

interactions between lateral prefrontal regions and premotor or posterior associative cortices (Miller and Cohen, 2001; Fletcher and Henson, 2001). Using brain imaging in humans, Koechlin et al. (2003) showed that the lateral prefrontal cortex is organized as a cascade of executive processes. They suggest a unified modular model of cognitive control that describes the overall functional organization, postulating a hierarchy of representations that processes distinct signals involved in controlling the selection of appropriate stimulus– response associations (Koechlin et al., 2003). The model assumes a cascade of top-down controls from rostral to caudal lateral prefrontal cortex and premotor regions. In addition, the cascade model predicts that the increasing demands of sensory, contextual, and episodic controls have additive effects on behavior and on local brain activations as measured by fMRI (see Fig. 4.5). The key assumption is the distinction between control processes operating with respect to either the perceptual context or the temporal episode in which the person is acting (Baddeley, 2000). Reasoning is the central nucleus of thinking, and is essential in almost every aspect of mental activity, from text comprehension to problem solving and decision-making. While philosophical and psychological aspects of reasoning have been largely investigated over the years, its neurobiological substrate is still poorly understood. The contribution of traditional, lesion-based neuropsychology has led to controversial results (Wharton and Grafman, 1998; Shuren and Grafman, 2002), and only the advent of functional neuroimaging techniques has opened new venues for the investigation of the neural correlates of reasoning.

Fig. 4.5. A unified modular model of cognitive control that describes the overall functional organization, postulating a hierarchy of representations that processes distinct signals involved in controlling the selection of appropriate stimulus–response associations. (Modified from Koechlin et al., 2003.)

FUNCTIONAL NEUROIMAGING OF COGNITION Neuroimaging studies on reasoning investigated the neural basis of distinct normative models of reasoning (i.e., deductive vs. inductive) (Goel et al., 1998; Goel & Dolan, 2000; Knauff et al., 2002) and the differences between them (Goel et al., 1997; Osherson et al., 1998; Parsons and Osherson, 2001). The pattern of cerebral activation associated with logical reasoning appears to be strongly influenced by the content of the stimuli. In fact, arbitrary material without semantic content activates frontal and parietal regions in both hemispheres, with a left sided prevalence, while semantically meaningful material activates a left fronto-temporal system. Taken together, these studies have highlighted the crucial role of the prefrontal cortex, with activation seen predominantly in the left hemisphere. Different research approaches addressed the mental processes that underlie reasoning, such as the linguistic ones or spatial manipulation, using different kinds of stimuli (Goel et al., 2000; Goel and Dolan, 2001; 2003). Indeed, psychological studies of deductive reasoning have shown that subjects’ performance is significantly influenced by the content of the stimuli they are presented with. For example, subjects find it easier to reason about contexts and situations with a social content. In an fMRI study, the effect of content on brain activation was investigated while subjects were solving two versions of the Wason Selection Task, which previous behavioral studies have shown to elicit a significant content effect (Canessa et al., 2005). One version described an arbitrary relation between two actions in a descriptive way: ‘If someone does ..., then he

79

does ...’), while the other described a social exchange of goods between two persons (‘If you give me ..., then I give you ...’). Both tasks activated frontal medial cortex and left dorsolateral frontal and parietal regions, confirming the major role of the left hemisphere in deductive reasoning. In addition, although the two reasoning conditions were identical in logical form, the social-exchange task was also associated with right frontal and parietal activations, mirroring the left-sided activations common to both reasoning tasks (Fig. 4.6). These results suggest that the recruitment of the right hemisphere is dependent on the content of the stimuli presented. The activation of a left-sided network is consistent within the literature, indicating a major role of the left hemisphere in the processes underlying logical reasoning (Wharton and Grafman, 1998). Similar supporting evidence also comes from lesion-based neuropsychological studies using a variety of experimental paradigms and different kinds of reasoning tasks (Read, 1981; Gazzaniga, 1989; Langdon and Warrington, 2000). There is also independent evidence for a crucial role of the right hemisphere in social cognition. Tranel et al. (2002) have recently observed a marked deficit in social behavior, emotional functioning, and decision making in patients with lesions confined to the prefrontal regions of the right hemisphere, but not in patients with similar lesions in the left hemisphere. It is worth noting that the observation of right hemispheric areas which are preferentially activated by social content is, in general, consistent with the hypothesis of the existence of cerebral specializations for

Fig. 4.6. The figure shows lateral views of brain renderings with superimposed clusters of activation in the deductive (DES top) and in the social (SE bottom) reasoning tasks. The colored arrows link the right-hemispheric frontal and parietal clusters activated in the SE task with histograms indicating BOLD signal change percentage (amplitude of the hemodynamic response curve) in both the reasoning tasks (see text for details). (Modified from Canessa et al., 2005.)

80

D. PERANI

reasoning about the social sphere (Duchaine et al., 2001; Adolphs, 2003). The latter findings are also consistent with studies showing a major role of the right hemisphere in the processing of world knowledge during reasoning (Whitaker et al., 1991; Deglin and Kinsbourne, 1996), and in decision-making involving the social sphere (Tranel et al., 2002). 4.5.2. Studies in disease conditions The impairment of executive functions is a hallmark of the behavioral disorders associated with frontal type dementia. Neuroimaging studies in the field also provided some evidence for the functional role of distinct prefrontal regions in the different aspects of the syndrome (Grossman, 2002). In a multicenter study, FDG-PET images in a population of patients with frontotemporal dementia (FTD) were compared to controls of a similar age (Salmon et al., 2003). A conjunction analysis led to identification of the ventromedial frontopolar cortex as the single region affected in each and every FTD patients. This regional metabolic impairment can be related to neuropsychological research, showing that the ventromedial frontal cortex is critically involved in decision-making processes based on personal experience, feelings of rightness, or social knowledge, processes that are characteristically impaired in FTD. Some patients with FTD can also manifest sociopathic behavior. Sociopathy in FTD results from a combination of diminished emotional concern for the consequences of their acts and disinhibition, which might follow right frontotemporal dysfunction, as shown by neuroimaging (Mendez et al., 2005). Dysexecutive syndromes in psychopathy, mainly in the antisocial disorder of personality (Dinn and Harris, 2000), have also been considered as prototypes of frontal lobe damage (see Elliott, 2003). Personality disorders can be thought of as trait-like dysfunctional patterns in impulse control. These domains of dysfunction have been linked to specific neural circuits. The typical behaviors of psychopaths could be related with structural and functional brain alterations shown by the neuroimaging techniques (for review see Bassarath, 2001). These associated brain functional changes might be the neurological substrate of the inability of psychopaths to integrate reasoning processes with emotions, and of the presence of symptoms such as impulsivity, context dependency, pathological perseverations, and metacognitive alteration. In this context a relevant aspect is the close relationship between reasoning and emotion, and the disorder of executive functions could explain this connection. Indeed, functional and structural studies provide support for a dysfunction in

fronto-limbic circuits in antisocial personality disorder, whereas temporal lobe and basal striatal–thalamic dysfunction has been shown in schizotypal personality disorders (see for review McCloskey et al., 2005). 4.5.3. Neuroeconomics The nascent field of neuroeconomics seeks to ground economic decision making in the biological substrate of the brain. A number of researchers in economics and neuroscience have recently begun to examine how the theory of games might be used to analyze the neural architecture active when competitive and stochastic behaviors are produced. Kevin McCabe and colleagues (2001) pioneered this approach when they examined the brains of human subjects engaged in a strategic game using fMRI. They used a classic strategic conflict called trust and reciprocity, in which two players, only one of which is inside the scanner, work sequentially and interactively to earn money. When players encounter each other repeatedly, an optimal strategy can emerge. The two players can cooperate for future benefit, electing to trust one another in order to reach the best outcome on each play. What McCabe and his colleagues found was that humans turned out to be more cooperative with other humans than could be expected on purely rational grounds, as if their brains were performing a computation that assumed that the opponent would sooner or later be encountered again. However, when subjects were told that they faced a computer opponent, they often took a different, and more purely rational approach, i.e., they almost never cooperated. Whenever subjects chose to cooperate with a human opponent, a specific region in the prefrontal cortex was more active than when they decided to act rationally against the computer. These experimental findings are an important step, because they demonstrate that game theoretic approaches can be used to study the neurobiological basis of stochastic decision making. Behavioral economists have identified psychological and emotional factors that influence decisionmaking (Camerer and Loewenstein, 2004), thus suggesting that the decision-maker is not a perfectly rational cognitive machine. Standard decision theory postulates that the ambiguity about probabilities of winning should not affect choices. However, experiments show that many people are more willing to bet on risky outcomes than on ambiguous ones. This empirical aversion to ambiguity prompted Hsu et al. (2005) to search for neural distinctions between risk and ambiguity using fMRI. Several areas in the brain are more active under conditions of ambiguity than risk. Among these regions are the amygdala, the

FUNCTIONAL NEUROIMAGING OF COGNITION orbitofrontal cortex, and the dorsomedial prefrontal cortex. By contrast, the dorsal striatum is preferentially activated during the risky condition. As the dorsal striatum is implicated in reward prediction, the result indicates that ambiguity lowers the anticipated reward of decisions. Another fMRI study was applied to the investigation of the contributions of cognitive and emotional processes to human social decision-making (Sanfey et al., 2003). The Ultimatum game was used, in which two players split a sum of money: one player proposes a division and the other can accept or reject this. Players were scanned as they responded to fair and unfair proposals. Unfair offers elicited activity in brain areas related to both emotion (anterior insula) and cognition (dorsolateral prefrontal cortex). The results provide direct empirical support for economic models that acknowledge the influence of emotional factors on decision-making behavior. On the basis of participant reports, it appeared that low offers are often rejected after an angry reaction to what is perceived as unfair. Objecting to unfairness has been proposed as a fundamental adaptive mechanism by which we assert and maintain a social reputation (Nowak et al., 2000), and the negative emotions provoked by unfair treatment in the Ultimatum Game can lead people to sacrifice what is sometimes a considerable financial gain in order to punish their partner for the slight. The authors highlight the role of these biological quantitative measures that may be useful in constraining the social utility function in economic models. An fMRI study also showed that human decision can be shaped by predictions of emotions that ensue after choosing advantageously or disadvantageously (Coricelli et al., 2005). They demonstrated that anticipating regret is a powerful predictor of future choice. According to the experimental paradigm, the participants became increasingly regret-aversive, an effect that reflected an enhanced activity in the orbitofrontal cortex and amygdale. This activation pattern also reoccurred before the subjects made a choice, thus suggesting that this neural circuit mediates direct experience and its anticipation. The authors suggest that this adaptive emotion may provide a neural substrate that influences cost–benefit analysis in decision making. Implicit memory seems to contribute to individual economic decisions (Deppe et al., 2005). Participants were asked to make binary decisions between different brands of sensorily nearly undistinguishable consumer goods. Changes of brain activity comparing decisions in the presence or absence of a specific target brand were detected by fMRI. In particular, there was a reduced activation in brain areas associated with working memory and reasoning and, on the other hand, increased activation in areas involved in

81

processing of emotions and self-reflections during decision making. To summarize, the work in a number of laboratories has begun to suggest that functional imaging may play an increasing role in the field of neuroeconomics. It may soon be possible to view the nervous system as a representational process that solves the mathematically defined economic problems humans face by making efficient decisions. These developments in the neurobiological theory of choice, and the new schema they imply, form the subject of review articles by Glimcher (2002) and by Sugrue et al. (2005).

4.6. Functional neuroimaging in dementia Functional neuroimaging studies are playing an important role in neuropathological and neuropsychological research of dementia, including innovative aspects, such as cognitive activation and in vivo studies of neurotransmitter function. 4.6.1. Alzheimer’s disease Many neuroimaging studies have attempted to measure the neurophysiological correlates of age-related changes in the brain. The analysis of several parameters of cerebral function, including blood flow, oxygen consumption and cerebral blood volume, resulted in the finding of a linear decline with age. However, there is variability among these results, with age influencing one more than another functional value, and some researchers even reporting stability of brain physiologic parameters during normal aging (Salmon et al., 1991; Petit-Taboue et al., 1998). Cerebral volume loss resulting from the normal aging processes can cause underestimation of PET physiological measurements, despite great improvement in scanner resolution. Normal aging of the brain has been characterized mainly by using [18 F]FDG PET metabolic evaluation. In normal subjects, typical resting state gray matter values of glucose metabolism are in the range of 40 to 60 mmol glucose/100 g/ min, and they are around 15 mmol glucose/100 g/min in white matter. There are regional differences, with highest values in the striatum and parietal cortex close to the parieto-occipital sulcus. Some phylogenetically old brain structures such as the medial temporal cortex and cerebellum have metabolic rates below the gray matter average, but are still higher than normal white matter. There is probably a slight decline of glucose metabolism with age, most prominently seen in the frontal cortex (Zuendorf et al., 2003) but this has not been confirmed in all studies. When brain atrophy and brain volume have been considered, metabolic values do not decline with normal aging (Meltzer et al., 2000). This

82

D. PERANI

crucial aspect has been further supported by PET metabolic studies of Alzheimer’s disease, in which it has been clearly demonstrated that regional deficits in energy metabolism are not fully accounted by regional cerebral atrophy (Ibanez et al., 1998; Mega et al., 1996). The diagnosis of dementia is based on clinical evaluation, supplemented by neuropsychological findings (Corey-Bloom et al., 1995). However, PET and SPECT are playing an increasing role in the investigation of Alzheimer’s disease and other degenerative conditions (Herholz, 1995; Herholz et al., 2002). The most common form of dementia, Alzheimer’s disease (AD) is characterized by several well-known neuropathological features, which result in a loss of synaptic activity. This dysfunction is readily reflected in regional decreases of cerebral metabolic activity and blood flow that are not simply a consequence of tissue loss (Ibanez et al., 1998). The reduction of metabolism has a characteristic topographic distribution, involving the associative cortex in the temporoparietal areas of both hemispheres, with the angular gyrus usually being the centre of the metabolic impairment (Herholz et al., 2002) (Fig. 4.7). Frontolateral association cortex is also frequently involved to a variable degree (Haxby et al., 1988; Herholz et al., 2002). Primary motor, somatosensory, and visual cortical areas are relatively spared. This pattern corresponds in general to the clinical symptoms, with impairment of memory and high-order cognition, including complex perceptual processing and planning of action, but with relative preservation of primary motor and sensory function. These changes differ from those of normal aging, which leads to predominantly medial frontal metabolic decline and may cause some apparent dorsal parietal and frontotemporal (perisylvian) metabolic reduction due to partial volume effects caused by atrophy (Zuendorf et al., 2003; Moeller et al., 1996; Petit-Taboue et al., 1998). The hypometabolism appears to be related to amyloid deposition, at least in areas which are still metabolically viable (Mega et al., 1999). The histochemical correlate of reduced FDG is a pronounced decline in cytochrome oxidase activity in AD relative to controls, whereas adjacent motor cortex does not show such differences (Valla et al., 2001). Longitudinal studies have shown that the severity and extent of metabolic impairment in temporal and parietal cortex increases as dementia progresses, and frontal involvement becomes more prominent (Mielke et al., 1994). The decline of metabolism is in the order of 16 to 19% over 3 years in association cortices, which contrasts with an absence of significant decline in normal control subjects (Smith et al., 1992). Metabolic asymmetries and associated predominance of language

or visuospatial impairment tends to persist during progression (Haxby et al., 1990). Metabolic rates in basal ganglia and thalamus remain stable and are unrelated to progression (Smith et al., 1992). Thus, in late dementia, there is typically a pattern of severe hypometabolism in temporoparietal and frontal association cortices, with a relative sparing of primary cortical areas and subcortical structures. The cerebellum is also spared. A prospective study of FDG PET addressed the issue of progression rate of AD, which can vary considerably and is particularly difficult to predict in patients with mild cognitive impairment (Herholz et al., 1999). The cohort study included patients with possible or probable AD (respectively, 40% and 60%) most with presenile onset. Follow-up data were obtained from 73% of patients. In a cross-sectional analysis at entry, impairment of glucose metabolism in temporoparietal or frontal association areas measured with PET was significantly associated with dementia severity, clinical classification as possible vs. probable AD, presence of multiple cognitive deficits, and history of progression. A relatively simple standardized protocol provided clinically relevant prognostic and diagnostic information. Indeed, impairment of glucose metabolism in temporoparietal or frontal association areas, as measured by a previously developed metabolic ratio with PET (Herholz et al., 1993), was a prognostic indicator of clinical deterioration during follow-up (< 0.80 metabolic ratio that represents metabolic rates of glucose in typically most affected neocortical structures, temporoparietal and frontal association cortex, relative to typically least affected structures, primary sensory and motor cortices, striatum, and cerebellum). There was a highly significant correlation between initial metabolic ratio and subsequent decline of MMSE score during follow-up, which was particularly evident in mildly affected patients. Thus, impairment of glucose metabolism in temporoparietal and frontal association cortex is not only an indicator of dementia severity, but also predicts progression of clinical symptoms. Methods for automatic detection of abnormal metabolism on individual PET scans, providing unbiased measurements, have also been developed. They require appropriate reference data sets, spatial normalization of scans, and statistical algorithms to compare the voxels in scan data with normal reference data, and suitable display of the results (see section 4.2). Signorini et al. (1999) demonstrated that this can be achieved by adapting the statistical parametric mapping (SPM) software package (Fig. 4.8). Some commercial software packages provide similar approaches, but users should take care to check the validity of normal reference data, statistics and normalization procedures. Studies that

FUNCTIONAL NEUROIMAGING OF COGNITION

83

Fig. 4.7. The figure shows the typical metabolic pattern associated with Alzheimer’s Disease: regions that show reduced FDG uptake in patients with probable AD are marked by red overlay; regions that have relatively preserved FDG uptake in AD are marked by blue overlay. (Modified from Herholz et al., 2002.)

84

D. PERANI

Fig. 4.8. The figure shows the metabolism pattern found in a probable Alzheimer’s disease (AD) patient (A) and in a subject with amnesic mild cognitive impairment (aMCI) (B). Below the corresponding statistical parametric maps, demonstrating a wide temporoparietal and posterior cingulate involvement in the AD case, and a less extensive metabolic reduction in the MCI subject, mostly confined to the posterior cingulate cortex and precuneus.

used voxel-based comparisons to normal reference data clearly showed that the posterior cingulate gyrus and the precuneus are also impaired early in AD (Minoshima et al., 1997). Thus, this potential diagnostic sign is easily detected by automated analysis of FDG PET scans. More advanced approaches go beyond detection of abnormal voxels and aim at automatic recognition of the typical metabolic abnormalities in AD. For example, discriminant functions derived by multiple regression of regional data achieved 87% correct classification of AD patients versus controls (Azari et al., 1993), and a neural network classifier arrived at 90% accuracy (Kippenhan et al., 1994). The sum of abnormal t-values in regions that are typically hypometabolic in AD has been used as an indicator with 93% accuracy (Herholz et al., 2002). Patients with late-onset AD may show less difference between typically affected and non-affected brain regions than usually seen in early-onset AD, which could potentially lead to reduced diagnostic accuracy with FDG PET (Mosconi et al., 2005b). According to neuropathological studies, the earliest pathological changes in AD develop in the transentorhinal

and entorhinal regions. The neurofibrillary pathology then spreads into the hippocampus, and finally towards the neocortex (Braak and Braak, 1991). Medial temporal reduction in metabolism can thus be expected to be the earliest markers of the disease process. Perani et al. (1993a) reported a significant inverse correlation between glucose metabolism in these areas and episodic memory performance in AD. Yamaguchi et al. (1997) have shown that the reduction in cortical metabolism is significantly correlated with hippocampal atrophy, as shown with structural MR. Atrophy of hippocampus and parahippocampal structures is a main finding of structural imaging in AD. Therefore, one would expect also major functional changes of glucose metabolism in this brain area, but this has not generally been the case (Ishii et al., 1998b). It is difficult to identify hippocampal metabolic impairment on FDG PET scans, because this region has a lower resting metabolism than the neocortex, and pathological changes are not obvious by visual image analysis. However, by coregistration with MRI for accurate positioning of regions of interest onto the hippocampus in FDG PET scans a reduction, especially of entorhinal metabolism,

FUNCTIONAL NEUROIMAGING OF COGNITION has indeed been observed in MCI and AD (Mosconi et al., 2005b). In normal controls, glucose metabolism in the neocortex is correlated with entorhinal cortex across both hemispheres, whereas in AD patients these correlations are largely lost (Mosconi et al., 2004b). Metabolic impairment in the parahippocampal gyrus had also been noted in a previous study during activation using a simple memory task (Stein et al., 1998). As to be expected, hypometabolism in that region is associated with memory impairment (Desgranges et al., 2002).

4.6.2. MCI There is a widely accepted operational definition for ‘mild cognitive impairment’ (MCI) based on clinical and neuropsychological examination (Petersen et al., 2001). Clinically, mild cognitive impairment (MCI) is defined as impairment in one or more cognitive domains (typically memory, such as in amnesic MCI), or an overall mild decline across cognitive abilities that is greater than would be expected for an individual’s age or education, but that is insufficient to interfere with social and occupational functioning, as is required for a dementia syndrome. According to the criteria used, MCI can imply a pre-Alzheimer disease (AD) state, or a more general predementia state. The outcome of MCI in individual cases is however uncertain, as several subjects with MCI remain stable or even revert to a normal cognitive state (Luis et al., 2003). Subjects with a high premorbid cognitive level can experience a substantial decline of cognitive function before reaching the lower normal limit of standard neuropsychological tests. The contribution of PET is early diagnosis in patients presenting with a mild cognitive deficit, but before clinical dementia arises. Patients with MCI may have cognitive, behavioral, genetic, neuroanatomic (i.e., MRI), and metabolic (i.e., PET and SPECT) markers that either predict the likelihood of conversion to dementia, or are indices of change from the baseline. It is well documented that individuals with predominant severe memory impairment (amnesic MCI) are at special risk for AD that increases steeply with age. Even at an asymptomatic stage, impairment of cortical glucose metabolism has been observed in the preclinical stage in subjects at high risk for AD due to family history of AD and ApoE e4 homozygosity (Small et al., 2000; Reiman et al., 2004). In middle-aged and elderly asymptomatic ApoE e4-positive subjects temporoparietal and posterior cingulate glucose metabolism declines by about 2% per year (Reiman et al., 1996).

85

Medial temporal hypometabolism is often seen in AD patients with severe memory impairment, but also in MCI and other amnesic disorders (Perani et al., 1993a; Nestor et al., 2003). Depending on subject selection, it may also have prognostic impact. A longitudinal study of cognitively normal subjects indicated that cognitive decline to MCI within three years’ follow-up is related to metabolic reductions in the entorhinal cortex at entry, independent of e4 status (Mosconi, 2004a). Progression to dementia usually is associated with additional metabolic impairment in temporoparietal and posterior cingulate cortex. Data are accumulating that the presence of the AD metabolic pattern in MCI predicts conversion to clinical dementia of the Alzheimer type, and therefore indicates ‘incipient AD.’ Non-demented patients with mild cognitive impairment may indeed show metabolic impairment of association cortices, which is characteristic of AD. MCI patient groups when compared to normal controls typically show significantly impaired metabolism (Minoshima et al., 1997). Anchisi et al. (2005) have demonstrated that neuropsychological testing alone can identify subjects who are likely not to progress to dementia, because their memory deficit is relatively mild, thus providing a high negative predictive value with regard to progression. However, prediction based on neuropsychological testing is less reliable for MCI patients with more severe memory impairment. In these patients FDG PET adds significant information by separating those who will progress within the next twelve months from those who will remain stable (Fig. 4.9). Few studies so far compared FDG PET with other biomarkers. PET prediction accuracy was maximum (94%) within the e4þ group (Mosconi et al., 2004a). In another report, MCI subjects were followed over 16 months. The positive and negative predictive values of FDG PET for progression to AD were 85% and 94%, respectively, whereas corresponding values for the ApoE4 genotype were 53% and 77% only (Drzezga et al., 2005). By combination of the two indicators, predictive values increased to 100% in subgroups of patients with concurrent genetic and metabolic findings. When comparing phosphorylated tau protein in CSF with FDG PET in MCI, Fellgiebel and colleagues found similar findings with both tests (Fellgiebel et al., 2004). Some studies indicate that combining targeted neuropsychology testing and platelet amyloid precursor protein ratio with SPECT (Borroni et al., 2005, 2006) may reach a prediction accuracy close to 90%. All these very promising results have to be confirmed in larger studies before revising the current practice guidelines that rely on clinical judgment and neuropsychological testing.

86

D. PERANI

Fig. 4.9. SPM maps showing patterns of reduced FDG uptake in subjects with amnesic mild cognitive impairment (aMCI), superimposed on a standardized magnetic resonance imaging brain template. The aMCI subjects subsequently converted to AD (see text for details). (Modified from Anchisi et al., 2005.)

4.6.3. Dementia with Lewy bodies The clinical presentation of dementia with Lewy bodies (DLB) is a progressive cognitive decline with particular deficits of visuospatial ability as well as frontal executive function, accompanied by mildly to moderately severe Parkinsonism. Further accompanying features include spontaneous recurrent visual hallucinations and conspicuous fluctuations in alertness and cognitive performance (Verghese et al., 1999). The main differential diagnoses are with AD and Parkinson’s disease dementia (PDD). Ancillary investigations, particularly neuroimaging, can aid in differential diagnosis (Geser et al., 2005). Reduced FDG uptake is found to be very similar to AD, but it extends also to primary and associative visual cortex, which are usually spared in AD. In addition, at the same level of dementia severity, the global cerebral metabolic rate of glucose is lower in DLB than in AD (Ishii et al. 1998a). The impairment of glucose metabolism in the visual cortex may well be the correlate of the impairment of visual processing and visual hallucinations (Imamura et al., 1999). The medial temporal and cingulate glucose metabolism are lower in AD than in DLB, possibly explaining a different underlying pathology and the different memory profile (Imamura et al., 1997). A functional asymmetry is possible, with a corresponding clinical feature: Bashir et al (1998) described a DLB patient who initially complained of heaviness in the right upper extremity and subsequently developed a dense left homonymous hemianopsia during the course of a rapidly progressive dementia. A cerebral perfusion study with SPECT revealed a large area of right parietal-occipital and inferior temporal hypoperfusion. The patient exhibited a striking predominance of neurofibrillary tangles in the right inferior-temporal and occipital cortices. SPECT studies

with dopaminergic receptor ligands may help the clinical diagnosis of DLB (Walker et al. 1999). Another characteristic finding in DLB that is related to the parkinsonism is the change in dopaminergic activity shown in the putamen as a reduction of dopadecarboxylase activity, measured with F-18-DOPA (Hisanaga et al., 2001), and reduced dopamine transporters at the presynaptic level (Lucignani et al., 2002). 4.6.4. Frontotemporal dementia Clinically, frontotemporal dementia (FTD) may be heralded either by early and progressive change in personality, or by a progressive language impairment. According to widely accepted diagnostic criteria, three different clinical syndromes are delineated. The frontal variant of FTD is characterized by prevalent behavioral symptoms, with early change in personality and difficulty in modulating behavior, often resulting in inappropriate responses and activities; ‘semantic dementia’ is associated with prevalent semantic/cognitive impairment and ‘progressive aphasia’ is characterized by early non-fluent aphasia (Neary et al., 1998). FTD is readily identified on FDG PET or rCBF SPECT scans by a distinct frontal or frontotemporal functional impairment that is typically quite asymmetrical, centered in frontolateral cortex and the anterior pole of the temporal lobe (Fig. 4.10). Medial frontal metabolic impairment can be found in nearly every case of FTD (Salmon et al., 2003). Frequently there is also unilateral focal atrophy of the frontal and temporal lobe, corresponding to the metabolic deficit. In patients with the frontal variant of frontotemporal lobar degeneration, behavioral abnormalities may vary from apathy with motor slowness, to disinhibition with agitation. Apathetic and disinhibited behavioral syndromes are associated with different functional metabolic

FUNCTIONAL NEUROIMAGING OF COGNITION

87

Fig. 4.10. SPM maps showing the reduction of perfusion with SPECT in a single case with semantic dementia (A) and in a subject with non-fluent primary progressive aphasia (B).

patterns (Franceschi et al., 2005). This study showed that apathetic and disinhibited behavioral syndromes are associated with different functional metabolic patterns, the former showing a prevalent dorsolateral and frontal medial hypometabolism, the latter a selective hypometabolism in interconnected limbic structures, such as the cingulate cortex, hippocampus/amygdala, and nucleus accumbens (Fig. 4.11). In addition, the in vivo measurements of 5-HT2A receptor density revealed a significant reduction in orbitofrontal, frontal medial and cingulate cortex, thus suggesting that the serotoninergic system, tightly bound to the function of prefrontal cortex, is important for behavioral modulation. The selective

lateral prefrontal and frontal medial involvement in the apathetic syndrome and the prevalent hypometabolism in limbic structures in the disinhibited patients correspond to the dorsolateral and orbitofrontal syndrome, classically described in experimental and clinical series of focal lesions (Stuss and Benson, 1986). The syndrome, associated with lesions in the dorsolateral prefrontal cortex, is characterized by marked reduction in mental flexibility, verbal fluency, motor programming and planning, with increased apathy and abulia. The orbitofrontal syndrome is characterized by marked changes in personality with impulsivity, disinhibition, and poor judgment.

Fig. 4.11. Hypometabolism in two FTD patient groups compared with normal controls. Significant hypometabolic areas are shown in SPM maps in blue. Bilateral hypometabolism in the frontal medial and dorsolateral frontal cortex in apathetic patients (A), and bilateral hypometabolism in the medial temporal cortex (hippocampus/amygdala structures), thalamus, and ventral striatum in disinhibited patients (B), see text for details. (Modified from Franceschi et al., 2005.)

88

D. PERANI

Semantic dementia, a variant of FTD with similar histopathological features and tau protein deposition, is characterized by the progressive inability to comprehend common concepts, often associated with fluent aphasia. In the early stages there are less emotional disturbances and repetitive, compulsive behaviors than in the frontal variant (Hodges et al., 1992). Metabolic impairment is more focused on the left temporal, rather than the frontal lobes (Diehl et al., 2004). A similar condition also exists for the right hemisphere, clinically consisting of progressive prosopagnosia (Tyrrell et al., 1990). Primary progressive (non-fluent) aphasia is associated with left frontal and temporal hypometabolism (Kempler et al., 1990; Cappa et al., 1996) that may also affect additional brain areas to a lesser degree. Automatic methods have been explored in order to distinguish between FTD and AD. An analysis using multivariate methods such as principal components analysis (PCA) and partial least squares (PLS) regression achieved over 90% accuracy in a sample of 48 patients (Higdon et al., 2004). Preliminary results of a prospective study indicated that FDG PET may be more accurate than clinical judgment in predicting histopathological diagnosis (Foster et al., 2004), whereas there may be substantial overlap of the FTD pattern with frontotemporal impairment and the AD pattern with predominant temporoparietal impairment, especially in senile dementia patients (Herholz et al., 2004).

Several studies have suggested that a diffuse global reduction of cerebral glucose metabolism is a typical finding in vascular dementia, and that the degree of reduction in association cortex is similar to that seen in AD (Sultzer et al., 1995). In cases without gross cortical infarcts, the effects of white matter lesions are generalized, and frontal hypometabolism correlates with memory and executive impairment. The effects of subcortical cerebrovascular disease appear to converge on the frontal lobes, and are diffuse and of modest magnitude (Reed et al., 2004). Thus, the contrast between metabolic impairment in association areas and preserved metabolism in primary areas, basal ganglia and cerebellum, that is typical for AD but not for vascular dementia, seems to provide some distinction with FDG PET between these two types of dementia. Only large white matter lesions may cause moderate focal reductions of overlying cortical blood flow and metabolism (Herholz et al., 1990), as an effect of diaschisis/deafferentation. Vascular dementia may also be caused by strategic infarcts in structures that are essential for integrating higher cognitive functions, especially the thalamus. Even small thalamic lesions may lead to considerable deactivation of cortex, as demonstrated by FDG PET (Pappata et al., 1990; Baron et al., 1992). However, a definitive distinction between vascular dementia and AD, or the relative contribution of vascular and Alzheimer-type lesions in patients who have signs of both often remains uncertain, even after autopsy and histopathological examination.

4.6.5. Vascular dementia

4.6.6. Prion diseases

Vascular dementia (VaD) is a heterogeneous syndrome, and several vascular pathologies can lead to cognitive deterioration (Graham et al., 2004). In contrast to the striking deficits produced by cortical infarcts, lesions of the subcortical white matter are mainly associated with a non-specific slowing of behavior. AD and vascular dementia represent the extremes of the clinical spectrum of dementia conditions that includes various combinations of cerebrovascular and degenerative pathology. The relationship between cerebrovascular lesions, as shown by neuroimaging, and focal neuropsychological signs is difficult to define during clinical follow-up. A large multicentric study for the treatment of CVD and AD showed a slower progression rate of cognitive impairment in ‘pure’ vascular dementia in comparison to AD (Kurz et al., 2003). A specific neuropsychological profile, characterized by a prominent impairment of executive and visuospatial functions associated with a relative sparing of episodic memory, has been suggested to be typical of subcortical vascular dementia (Varma et al., 1999).

The typical regional pattern of metabolic impairment differs between major neurodegenerative diseases that may cause dementia. Thus, FDG PET also has the potential to improve an early differential diagnosis, and it may be used to monitor disease progression and treatment effects. Creutzfeldt-Jakob disease is clinically characterized by rapidly progressive dementia, often accompanied by insomnia, myoclonus and other extrapyramidal disorders. In all cases reported so far, cerebral glucose metabolism was severely reduced in a multifocal pattern (Holthoff et al., 1990; Goldman et al., 1993; Engler et al., 2003). The PET results were in accordance with histological findings and the patient’s clinical condition. Fatal familial insomnia (FFI) is an autosomal dominant prion disease clinically characterized by alterations of the sleep–wake cycle, dysautonomia and motor signs (Lugaresi et al., 1986). The histopathological hallmark of FFI is severe neuronal loss, especially in the anterior-ventral and medial-dorsal nuclei of the thalamus, associated with a variable involvement of

FUNCTIONAL NEUROIMAGING OF COGNITION the inferior olive, striatum, and cerebellum. In addition, a mild to moderate spongiform degeneration is present in the cerebral cortex of subjects with the longest disease duration (Parchi et al., 1995). [18F] FDG and PET consistently demonstrated glucose hypometabolism in the thalamus and cingulate cortex of homozygous patients in the early phase of the disease, while the involvement of other brain regions depends on disease duration (Perani et al., 1993; Cortelli et al., 1997). The thalamic hypometabolism demonstrated by [18F] FDG PET is a hallmarker of FFI and suggests a relationship between thalamic dysfunction and the associated long-term memory and attention impairment. Comparison between neuropathological and [18F] FDG PET findings showed that, although hypometabolic areas and areas with neuronal loss codistributed extensively, the hypometabolism was actually more widespread than neuronal loss, and significantly correlated with the presence of protease resistant prion protein. Knowing how and when the degenerative process starts is important in prion diseases. This issue was addressed in FFI by measuring PET cerebral metabolism over several years, in parallel with clinical and neuropsychological examinations, and EEG polysomnography in asymptomatic carriers of the D178N mutation and in non-carriers belonging to the same families (Cortelli et al., 2006). The cerebral glucose metabolism, as well as clinical and electrophysiological examinations, was normal in all cases at the beginning of the study. Four of the mutation carriers developed typical FFI during the study, but 18F-FDG PET and the clinical and electrophysiological examinations remained normal 63, 56, 32 and 21 months, respectively, before disease onset. The carrier whose tests were normal 32 months before disease onset was re-examined 19 months later. At that time, selective hypometabolism was detected in the thalamus, while spectral-EEG analysis disclosed an impaired thalamic sleep spindle formation. These data indicate that the neurodegenerative process associated with FFI begins in the thalamus between 13 and 21 months before the clinical presentation of the disease. These findings probably reflect the rapid course of FFI and other familial prion diseases (Kong et al., 2004) or the normal functioning of the mutated prion until it changes conformation to become PrPSc. 4.6.7. Activation studies Neurodegenerative disorders affect the normal activation pattern in a number of ways. As predictable, functional activation in AD patients is decreased in the areas most affected by the pathology. Some studies of

89

verb processing, verbal and non-verbal learning, and working memory have found a reduced activation of the areas which are activated by healthy persons to carry out the same task (Grossman et al., 2003). Interestingly, medial temporal activation patterns during a memory task have been found to be as much reduced in MCI patients as in AD patients, possibly suggesting a very early functional damage in the medial temporal lobe (Machulda et al., 2003). There is evidence that reduced activation of normally active areas is accompanied by cortical reorganization in AD and frontotemporal dementia (Rombouts et al., 2003). Defective hippocampal activation during face encoding has been shown in AD with fMRI; subjects with MCI had only a selective subicular dysfunction (Small et al., 1999). On the other hand, the recruitment of wider networks can also be evident in dementia. Activations larger than in normal controls have been found in the medial temporal lobe and other cortical areas during verbal and non-verbal learning, working memory, semantic, and visuospatial tasks (Kato et al., 2001; Prvulovic et al., 2002; Sperling et al., 2003). Becker et al. (1996) reported that probable AD patients, while engaged in subspan and supraspan auditory-verbal memory tasks during PET acquisition, had a more extensive pattern of cerebral activation in comparison to healthy age matched controls, including the activation of parietal areas, which was consistently absent in normal controls (Backman et al., 1999). The above described changes were interpreted as reflecting, respectively, defective performance and functional compensation. It is conceivable that compensatory mechanisms may be functional in the relatively early stages of the disease, while in later stages activation decreases (Dickerson et al., 2004). Some authors have suggested that measurement of cerebral blood flow or glucose metabolism during simple visual and auditory stimulation is a more sensitive index of dementia severity than the resting state assessment (Mentis et al., 1998; Pietrini et al., 1999). Another interesting finding obtained with fMRI and PET in the study of dementia disturbances concerns the involvement of the default networks (Lustig et al., 2003). This is a specific set of regions, which consistently shows deactivation during a wide range of tasks with different stimulus modalities in normal individuals (Gusnard and Raichle, 2001; Mazoyer et al., 2001). These commonly deactivated regions include large sections of the lateral parietal cortex, the medial parietal cortex (including posterior cingulate and precuneus), and the medial frontal cortex. The function of this default network has been attributed to monitoring the environment, the subject’s internal state and

90

D. PERANI

emotions, and various forms of undirected thought. The demonstrated impairment in the function of this default network in AD and other dementias may explain disorders of insight and awareness of own cognitive deficits and of the surrounding environment, and may contribute to the development of agitation following minor environmental stimulation, and to context-dependent performance in activities of daily living. Some issues should always be considered when interpreting fMRI data in neurodegenerative conditions. First, fMRI does not allow differentiating systems that can produce either activation or inhibition. This is a limit for tracking the cortical remodelling that likely takes place in AD and other neurodegenerative disorders. Second, in normal persons the same task may gives rise to lesser or greater activation, on the basis of difficulty (for example, cognitive tasks produce more brain activation in persons with lower IQ, the so-called ‘neural efficiency’ hypothesis (Gray and Thompson, 2004)). Thus, it is always crucial to examine patients who are able to perform the cognitive tasks, which might require an adjustment of difficulty.

4.7. Development A fundamental issue in cognitive neuroscience is the nature of developmental changes in human cerebral functional organization for higher cognitive functions. Developmental cognitive neuroscience is an evolving field that investigates the relationships between brain development and cognitive development at different points in life. A crucial question is how genetic and environmental factors interact during the course of development to shape the brain, mind, and behavior. Work in this area uses methods from all of the related disciplines, including behavioral studies, molecular genetics, computational modelling, neurochemical assays, neurophysiology, and neuroimaging. An emphasis is placed on complementarity that allows the evaluation of multiple aspects of developmental processes in typical and atypical development. Neuroimaging and neurophysiology are contributing evidence that cognition, emotion, perception, and motor functions are not nearly as separate as previously thought. They are fundamentally, multiply intertwined (see for review Paus, 2005). On the basis of structural MRI results, there is an emerging consensus on a continuous increase in the volume of white matter, both global and local, throughout adolescence. There is also evidence of asynchronous age-related decreases in the volume of gray matter in different cortical regions that might equally represent tissue loss (‘pruning’) or gain (intra-cortical myelination). Studies using fMRI have so far focused mostly on memory and executive

functions, such as working memory and behavioral inhibition (Casey et al., 1995; 1997; Thomas et al., 1999; Booth et al., 2000; Gaillard et al., 2000; Nelson et al., 2000; Luna et al., 2001; Adleman et al., 2002; Bunge et al., 2002; Kwon et al., 2002; Pine et al. 2002; Olesen et al., 2003; Casey et al., 2004), and also language development (Holland et al., 2001; Schlaggar et al., 2002; Gaillard et al., 2003; Booth et al., 2004; Schapiro et al., 2004; Brown et al., 2005). The method of choice has also been fMRI to measure neural activations in newborns during visual and acoustic stimulation (Born et al., 1998; Anderson et al., 2001; Tzourio-Mazoyer et al., 2002). Other elegant fMRI studies have shown the functional neuroanatomy of early language processes in infants (Dehaene-Lambertz et al., 2002; Brown et al., 2005); musical emotional perception in children (Koelsch et al., 2005); the different brain activity in children relative to adolescents and adults during cognitive tasks (Casey et al., 1997); differences between adults and school-age children in language processing (Schlaggar et al., 2002); and increased activity in frontal and parietal cortex that underlies the development of working memory capacity during childhood (Klingberg et al., 2002). In general, all these studies demonstrated the fundamental usefulness of fMRI in the investigation of the neural correlates of cognitive development. A recent interesting issue concerns the role of the mirror neuron system in the development of social cognition (Rizzolatti et al., 1996). The related neuroimaging results might contribute to the understanding of crucial developmental processes, such as the imitative behavior of infants, which requires the integration of perceived and performed actions (Meltzoff and Decety, 2003), the correlation between infants’ abilities to perform actions and to comprehend those actions in others (Woodward and Guajardo, 2002), and the development of empathy (understanding how another feels because you can identify with that feeling in yourself) (Carr et al., 2003). Evidence from developmental psychology, indeed, suggests that understanding other minds constitutes a special domain of cognition which includes an early-developing system for reasoning about goals, perceptions, and emotions, and a laterdeveloping system for representing the contents of beliefs. Neuroimaging reinforces this view, by providing evidence that domain-specific brain regions exist for representing belief contents, and these regions are apparently distinct from other regions engaged in reasoning about goals and actions (Saxe et al., 2004). The neural distinction between these processes is compatible with the hypothesis that belief attribution is subserved by a specialized neural system for theory of mind.

FUNCTIONAL NEUROIMAGING OF COGNITION 4.7.1. Developmental disorders The developmental disorders of childhood, such as autism, developmental language disorders, dyslexia, and attention deficit hyperactivity, affect the cognitive domains of language, visuospatial function, attention, and socialization. However, none of these disorders is associated with discrete focal lesions or recognized encephaloclastic processes. Since the advent of brain imaging, much effort has focused on identifying the brain–behavior correlates of these disorders (see for review Filipek, 1999; Greicius, 2003). By investigating atypical development, these researches can inform a variety of practical applications, such as earlier diagnosis and more effective treatment of these disorders. For example, we can compare brain activity in the mature system to brain activity in the immature system, both before and following extended experience. The technique of fMRI is currently being used to trace learningrelated changes in cortical areas and to investigate the impact of behavioral and cognitive interventions on developmental disorders like dyslexia (Simos et al., 2002) and obsessive–compulsive disorder (Viard et al., 2005; Nakao et al., 2005). In addition, altered cognitive processing might be revealed earlier through functional neuroimaging and neurophysiology than through behavioral observation (Weber et al., 2005). 4.7.2. Developmental dyslexia Developmental dyslexia (DD) is defined as a disorder manifested by difficulty in the acquisition of reading and writing, despite conventional instruction, adequate intelligence, and sociocultural opportunity ICD10 (1992). There is considerable evidence for a genetic basis for DD, and linkage studies have found evidence for the possible localization of genes for dyslexia on chromosomes 1, 2, 3, 6, 15 and 18 (for reviews see Fisher and DeFries, 2002; Demonet et al., 2004). There have been a number of hypotheses about the neurological and cognitive mechanisms responsible for dyslexia (for reviews see Habib, 2000; Ramus, 2003; Demonet et al., 2004). However, because of the variability of its behavioral manifestations, the nature of the neurological and cognitive basis of the disorder remains a matter of debate. There is strong cognitive evidence supporting the idea that dyslexia is the consequence of a language disorder involving specifically phonological processing (Snowling, 1981; Bradley and Bryant, 1985; Frith, 1998). Other suggested mechanisms of dyslexia include the rapid auditory processing theory (Tallal, 1980; Tallal et al., 1993), the magnocellular theory (Lovegrove et al., 1980; Stein and Walsh, 1997), and the automaticity/

91

cerebellar theory (Nicolson and Fawcett, 1990; Nicolson et al., 1995; Nicolson et al., 2001). There is considerable evidence of the presence of brain abnormalities in DD. The observations of anatomo-morphological alterations in dyslexia started with the postmortem observations of Galaburda et al. (1985). Structural neuroimaging techniques, such as voxel-based morphometry, providing a quantitative assessment of brain morphology, can reveal the modification of gray and white matter in DD (Brambati et al., 2004; Silani et al., 2005). Functional neuroimaging has complemented these morphological observations. The diffuse neurological abnormalities may affect cortico-cortical connectivity, as suggested by PET and fMRI studies (Paulesu et al., 1996; Klingberg et al., 2000). With the exception of a few investigations of the visual system (Eden et al., 1996; Demb et al., 1998), most functional neuroimaging studies in sporadic dyslexia were based on phonological tasks, and reported reduced activation of specific language areas, in particular in the temporoparietal regions (Paulesu et al., 1996; Shaywitz et al., 1998; Shaywitz et al., 2002; 2003; Temple et al., 2001). Reduced activation in temporoparietal regions were also found out in sporadic DD during reading tasks (Rumsey et al., 1997; Brunswick et al., 1999; Paulesu et al., 2000). These findings suggest that the difficulties in language related functions, such as reading, phonological awareness, and phonological memory, are associated with the dysfunction of a distributed temporoparietal and frontal network within the language system (Fig. 4.12). There is considerable agreement that the causal link between brain abnormalities and reading difficulties is the phonological processing deficit. Brain areas involved in phonological processing (i.e., left perisylvian cortices, left middle and inferior temporal cortex) have been found to be dysfunctional in many studies in DD (Rumsey et al., 1992; Paulesu et al., 1996; Salmelin et al., 1996; Rumsey et al., 1997; Shaywitz et al., 1998; Rumsey et al., 1999; Paulesu et al., 2001; Helenius et al., 2002; Ruff et al., 2002; Shaywitz et al., 2002). Dysfunction of processes not directly related to phonology has also been found in other neuroimaging studies. These include modifications of early sensory processing in the magnocellular visual and auditory pathways (Tallal and Piercy, 1973; Livingstone et al., 1991; Eden et al., 1996; Demb et al., 1998; Temple et al., 2000); dysfunction of the visuospatial attention system (Hari et al., 2001); and disorders of the motor system including altered cerebellar function (Nicolson and Fawcett, 1990; Fawcett and Nicolson, 1992; 1994; Nicolson and Fawcett, 1994; Nicolson et al., 1999). The universality and specificity of the DD syndrome has been discussed, because epidemiological studies

92

D. PERANI

Fig. 4.12. SPM activation foci using fMRI in developmental dyslexics (A) and normal controls (B) during word reading tasks.

have shown that the nature and prevalence of DD differs across languages and cultures (Landerl et al., 1997). The prevalence estimates in different countries seem to be related to the shallowness of the orthography. In a cross-cultural study involving DD from three different countries (UK, France, and Italy), Italian dyslexics, which are exposed to a shallow orthography which facilitates reading, perform better on reading tasks than English and French subjects. However, all dyslexics were equally impaired relative to their controls on reading and phonological tasks. PET scans during explicit and implicit reading showed the same reduced activity in a temporo-occipital region of the left hemisphere (Paulesu et al., 2001). The authors concluded for a universal neurocognitive basis for dyslexia and suggested that behavioral differences in reading performance among dyslexics of different countries are due to different orthographies. A strictly related neuroimaging study was used to assess the consistency among functional imaging and brain morphometry data in the same individuals with dyslexia from the three different countries (France, Italy, and UK) (Silani et al., 2005). It provides evidence that the altered activation observed within the reading system is associated with altered density of gray and white matter in specific brain regions, such as the left middle and inferior temporal gyri and the left arcuate fasciculus. This supports the view that DD is associated to both local gray matter dysfunction and to altered gray and white matter structure. The latter finding is consistent with diffusion tensor imaging data (Klingberg et al., 2000), and supports the idea that DD might be due to a perturbed

connectivity within the language network, in particular among phonological/reading areas. It is noteworthy that these differences were replicable across samples, supporting the view that the neurological modifications underlying dyslexia are the same across the cultures investigated. The claim for a universal and culture-independent neurocognitive basis of dyslexia, at least in western countries, is mitigated by a recent study of Siok and colleagues (2004), in an ideographic language. They showed that Chinese children with DD had reduced activity of the left middle frontal gyrus, which plays a crucial role in the Chinese reading system, but not in other western languages. This study thus raises the crucial issue of cultural constraints on biology, resulting in the possible engagement of different neural systems in different cultures. Structural and functional neuroimaging in combination, together with neurophysiological methods, allow the in vivo measurements of both function and connectivity within the developing brain. This is essential information for understanding how brain and behavior change in normal and pathological development.

4.8. Neurochemistry of physiology and cognition During the past decades, advances in radiotracer chemistry and emission tomography instrumentation have merged, making these techniques a powerful scientific tool in molecular biology (Fowler et al., 2003). PET and SPECT permit the in vivo assessment of brain

FUNCTIONAL NEUROIMAGING OF COGNITION biological processes with methods originally developed for preclinical studies. This opportunity is of primary interest in neurology, biological psychiatry, and in psychoactive drugs development. The feasibility and usefulness of these methods for research, including full quantification, kinetic modeling and tracer validation, has been clearly demonstrated. The main applications have been the neurodegenerative disorders, in particular Parkinson’s disease (Eckert and Eidelberg, 2005; Brooks, 2005), and more recently also dementia (Nordberg, 2004; Schmidt et al., 2005; Dickerson et al., 2005; Franceschi et al., 2005) (see Fig. 4.13). Another important field of application is psychiatry (Frankle and Laruelle, 2002; Smith et al., 2003; Pimlott, 2005). However, despite the increasing reliance of the biomedical sciences on imaging and the increasing need of functional information, the development of new radiotracers with the specificity and kinetic characteristics which are required for the quantitative analysis of neurotransmission in vivo remains a slow process. PET, but also SPECT groups involved in the development of new radioligands for in vivo imaging of human brain neurotransmission, have focused their attention on the sites of action (receptors), synthesis, or enzymatic degradation of neurotransmitters.

93

The general aim was to find a suitable tracer for assessing in vivo the integrity of the pre- and postsynaptic components of a specific neurotransmitter system, enzymatic activity, and degradation, and for evaluating the effects of therapy. Several studies have shown receptor alterations, in particular in the dopaminergic and serotoninergic systems, as well as receptor occupancy by drugs (neuroleptics, etc). In these studies, the endogenous neurotransmitter interaction with receptors was addressed by the use of high affinity radioligands. It is evident, however, that information on neurotransmission, especially concerning its functional role, could be improved only by direct access to the endogenous neurotransmitter itself. Thus, a new challenge for neuroimaging for the next decades will be the development of methods allowing the in vivo visualization of endogenous neurotransmitters in the human brain. Pioneering studies addressed this issue by proposing the use of PET-SPECT for the assessment of changes in endogenous synaptic dopamine levels. The basic idea of this method is to measure the competition between the endogenous neurotransmitter and the exogenous radioligand for the same site. The ‘occupancy’ model (Laruelle, 2000) predicts that increase in synaptic dopamine concentration, secondary to

Fig. 4.13. 5-Hydroxytryptamine-2A (5-HT2A) receptor distribution: SPM maps of [11C]MDL100,907 binding potentials (BP) using PET in the frontal variant of frontotemporal lobar degeneration patients compared with healthy control subjects. Significant BP reduction is shown in the medial frontal cortex (p < 0.001). (Modified from Franceschi et al., 2005.)

94

D. PERANI

pharmacological and/or cognitive challenge, should result in increased dopamine binding to D2 receptors, and consequent reduction of the availability of D2 receptors for the radiotracer. It results in a displacement of the total radioactive concentration and/or reduction of the binding potential (BP). This model is however based on an obvious oversimplification of the physiological, biochemical, and molecular mechanisms that regulate the interactions between exogenous radioligand, endogenous neurotransmitter and receptors, and it requires appropriate analysis of how to optimize the experimental protocol and how to take into account methodological limitations. These issues are discussed in detail in the recent review by Laruelle (2000). Using this approach numerous studies have provided new information on endogenous neurotransmitter changes during pharmacological challenge, and to a lesser extent, during cognitive activation. The dopaminergic system has been the most explored with PET/SPECT radiotracers. There are at least three reasons for this: 1) the dopaminergic system has been largely studied and the behavior of endogenous dopamine is relatively well known, on the basis of electrical and pharmacological manipulations, 2) several specific radioligands have been developed to this aim and some are suitable for these competition studies, 3) dopamine changes during neural system activation could be theoretically detected by PET-radioligand studies (Fisher et al., 1995). Only D2 antagonist radiotracers, and in particular [11C]raclopride, allow the measurement of these effects, while D1 receptor radiotracers are not suitable for revealing the increase in endogenous release of dopamine at the synaptic level (Chou et al., 1999). Thus [11C]raclopride provides measurements of the tracer competition with endogenous dopamine for binding to D2 receptors. 4.8.1. Pharmacological challenge Functional brain imaging with positron emission tomography (PET) allows the investigation of functional disturbances related to psychiatric disease, as well as the pharmacodynamic assessment of the effects of drug treatment in vivo. Different strategies for studying pharmacologic effects on the brain have been developed in recent years. The basic methods are to measure blood flow or glucose metabolism, and parameters of specific receptor binding, or characterize functional interactions of neurotransmitter systems by assaying drug-induced displacement of specific receptor ligands. Each of these can be performed either in a resting state or after a pharmacological challenge. Some studies have supported the use of PET for investigating the functional responsiveness of a specific neurotransmitter system to a

pharmacologic challenge in the living human brain (Dewey et al., 1990). Logan et al. (1991) discussed in detail the effects of endogenous dopamine on PET radioligands binding to D2 receptors during amphetamine load. This method was applied to test the effects of increased GABA-ergic transmission in primates (Dewey et al., 1992) and of blockade of cholinergic transmission in the human brain (Dewey et al., 1993). Researches were designed to measure the responsiveness of striatal dopamine release to central cholinergic blockade in normal volunteers, using high-resolution PET and [11C]raclopride, a D2 dopamine receptor antagonist. For example, [11C]raclopride scans were performed prior to and 30 min after systemic administration of the potent muscarinic cholinergic antagonist, scopolamine. After scopolamine administration, [11C] raclopride binding decreased in the striatum (specific binding) but not in the cerebellum (non-specific binding) resulting in a significant decrease, exceeding the test/retest variability of this ligand (5%), in the ratio of the distribution volumes of the striatum to the cerebellum (17%). These results are consistent with the known inhibitory influence that acetylcholine exerts on striatal dopamine release. Other studies with PET-11C-raclopride and SPECT- 123I-IBZM have been carried out to further provided data on pharmacological modulation of synaptic dopamine in the human brain (Parsey and Mann, 2003). PET and SPECT have also been extensively applied to the study of specific psychiatric disorders, including schizophrenia, anxiety disorders, and depression, and have opened potential future directions research in these areas. Thus far, fundamental observations have been made, detecting abnormalities in the availability of neurotransmitter transporter and receptor sites in psychiatric patients, and evaluating the relationship of these neurochemical measures to symptomatology. Further advances in instrumentation and radiotracer chemistry will enable investigators to conduct pre-clinical and clinical mechanistic studies focused on several neurotransmitters and neuromodulators. These data will also offer important insights into the neurochemical substrates of treatment response variability in psychiatric disorders that may be expected to have important implications for the improvement of pharmacotherapy (see for review Smith et al., 2003). Important applications in psychiatry highlight the role of PET and SPECT imaging to measure for example the modifications in basal endogenous dopamine levels in patients with schizophrenia and with major depression who were drug responders or non-responders (Abi-Dargham et al., 2000; Messa et al., 2003), and the pharmacokinetic and pharmacodynamic effects of drug abuse on the human brain (Volkow et al., 2003).

FUNCTIONAL NEUROIMAGING OF COGNITION Overall, this kind of study was highly informative on the modulation induced by different drugs interaction on endogenous neurotransmitter. These effects can, however, be complex and only indirectly informative on the modulation of neurotransmitter systems. 4.8.2. Physiological challenge The assessment of endogenous neurotransmitter release has also been investigated in the case of pain, as well as in pathological conditions such as epilepsy and movement disorders. Regional release of endogenous opioids as measured by [11C]carfentanil and PET has been measured in healthy human subjects undergoing sustained painful stimulation (Zubieta et al., 2001) (Fig. 4.14). Increased occupancy by endogenous opioid peptides during trigeminal pain has been suggested as an explanation of the observed increase in BP measured with PET and [11C]diprenorphine in the prefrontal, insular, perigenual, mid-cingulate and inferior parietal cortices, basal ganglia, and thalamus after surgical pain release (Jones et al., 1999). Possible release of endogenous opioids during a reading activation task in patients with reading epilepsy is suggested by the reduction of [11C]diprenorphine binding in cerebral regions involved in the task (i.e., the left parietotemporo-occipital cortex) (Koepp et al., 1998). Parkinson’s disease is associated with slowness, especially of sequential movements, and is characterized pathologically by degeneration of dopaminergic neurons, particularly targeting nigrostriatal projections. Nigrostriatal dopamine has been suggested to be critical for the execution of sequential movements. PET with [11C]raclopride was used to measure changes in regional brain levels of dopamine in healthy volunteers and Parkinson’s disease patients during the execution

95

of paced, stereotyped sequential finger movements (Goerendt et al., 2003). As reported above, striatal [11C]raclopride binding reflects dopamine D2 receptor availability and is influenced by synaptic levels of endogenous dopamine. During execution of a prelearned sequence of finger movements, a significant reduction in binding potential (BP) of [11C]raclopride was seen in both caudate and putamen in healthy volunteers compared with a resting baseline, consistent with release of endogenous dopamine. Parkinson’s disease patients, on the other hand, showed attenuated [11C]raclopride BP reductions during the same motor paradigm and only in striatal areas less affected by the disease process. This innovative methodological approach shows that dopamine release can be detected by PET during a behavioral manipulation. Indeed, these findings confirm that striatal dopamine release is a component of movement sequencing, and that its change is associated with Parkinson’s disease. [11C]raclopride and PET have been also used to measure changes in synaptic dopamine concentration in vivo after repetitive transcranial magnetic stimulation (rTMS) of the dorsolateral prefrontal cortex in healthy human subjects. A reduction in [11C]raclopride binding in the left dorsal caudate nucleus was found, in comparison to rTMS of the left occipital cortex. This finding suggests a possible link between the therapeutic use of rTMS in neurological and psychiatric disorders and dopamine release (Strafella et al., 2001). 4.8.3. Cognitive challenge Much more difficult is the measurement of the endogenous neurotransmitter release during sensorimotor and/or cognitive activity. This is because the expected changes are low and the time-permanence in the

Fig. 4.14. [11C]carfentanil and PET. The figure shows brain areas with significant m-opioid receptor system increase during painful stimulation (thalamus, nucleus accumbens, and amygdala ipsilateral to the stimulus), superimposed on an anatomically standardized MRI. The pseudocolor scale on the left represents Z scores of statistical significance. (Modified from Zubieta et al., 2001.)

96

D. PERANI

synaptic space is unknown; especially for cognitive tasks. Only the endogenous dopamine release has been studied with this approach. There is evidence that PET detection of endogenous dopamine release during cognitive activation is feasible (Fisher et al., 1995; Morris et al., 1995). The impact of such an approach for the understanding of cognitive functional neurochemistry is of course, major. Up to now, however, there are only very few published studies. In a pioneering study with PET and [11C]raclopride, Koepp et al. (1998) showed that endogenous dopamine release could be detected in the human striatum while subjects were engaged in a video-game task. The task involved visuomotor as well as cognitive functions and notably a financial reward was included. In this study, a dual scan approach, one during the rest condition and one during the activation, was used. The comparison revealed changes in BP in the basal ganglia that were considered to reflect changes in the synaptic level of endogenous dopamine during the activation task. This paradigm, however, did not allow the disentangling of the impact of the different cognitive (reward, attention) and sensorimotor task components on dopamine release. Another study with PET and [11C]raclopride in normal volunteers engaged in a purely monetary rewarded task that required a conscious effort showed changes in striatal synaptic dopamine concentration (Pappata et al., 2002, see Fig. 4.15). This study was also aimed at increasing the sensitivity for detection of these effects by two single-dynamic PET studies, combining the classic kinetic compartmental model with the general linear model of SPM. This provides statistical inference on changes in the [11C]raclopride time–activity curve due to endogenous dopamine release during two short periods of activation. Endogenous dopamine was released in the ventral striatum during periods of unexpected monetary gains, but not during periods of unexpected monetary loss. The experimental results are in line with the hypothesis of dopaminergic modulation of reward, although the amplitude of the effects due to dopamine release was moderate. The third experiment deals with working memory and is based on positron emission tomography with a recently developed high-affinity dopamine D2 receptor tracer, [11C]FLB (Aalto et al., 2005). Experimental studies on animals have shown that dopamine is a key neurotransmitter in the regulation of working memory functions in the prefrontal cortex. The authors explored frontal, temporal, and parietal D2 receptor availability in healthy volunteers while they were performing verbal working memory and sustained attention tasks. During the performance of both tasks, reduced D2 receptor availability was observed in the left ventral anterior cingulate, suggesting an attention

or arousal-related increase in dopamine release during these tasks. Compared with the sustained attention task, the verbal WM task reduced D2 receptor availability in the ventrolateral frontal cortex bilaterally and in the left medial temporal structures (amygdala, hippocampus), suggesting a role of endogenous dopamine release in these regions in working memory. In addition, correlation analyses indicated that increased dopamine release in the dorsolateral frontal cortex and anterior cingulate was associated with faster and more stable working memory performance. These findings suggest that regionally specific components of the frontotemporal dopaminergic network are functionally involved in working memory performance in humans. A further PET and [11C]raclopride activation study for the in vivo assessment of endogenous dopamine release specifically addressed language processing. Based upon the cognitive and electrophysiological profiles of patients suffering from neurological diseases affecting the basal ganglia, some neurolinguistic models postulated a role for the basal ganglia in syntactic and phonological processes. In a group of healthy subjects selective syntactic and phonological tasks were compared to closely matched non-linguistic tasks. Two significant effects were found. First, the level of accuracy in performing the phonological task significantly correlated with the amount of tracer binding potential in the left dorsal caudate nucleus. Second, the speed in performing the phonological task significantly correlated with the amount of tracer binding potential in the left dorsal putamen. These results indicate that better performances in phonological processing are associated with a diminished level of dopamine release in the left basal ganglia. These in vivo findings support the hypothesis that the striatal dopaminergic system plays an essential role in some compositional grammatical processes that constitute the core of human language. 4.8.4. Neurochemistry of personality traits The studies of the neurochemical substrates of personality traits offer new insight into human brain functioning. Neuroimaging, together with genetic studies, suggests that individual differences in the brain dopaminergic system contribute to the normal variability of human personality (e.g., social detachment and novelty seeking). In particular, it appears that dopamine function is associated with personality traits. Presynaptic dopamine synthesis capacity in the brain was measured with positron emission tomography and [18F]fluorodopa in healthy adults, and personality traits were assessed with personality scales (Laakso et al., 2003). High scores on the anxiety-related personality

FUNCTIONAL NEUROIMAGING OF COGNITION scales, and on one aggressivity-related scale were significantly associated with low [18F]fluorodopa uptake in the caudate. No statistically significant associations were observed between presynaptic [18F]fluorodopa uptake and the detachment scale or scales related to novelty-seeking behavior. The authors suggest a role for the dopaminergic system in the regulation of anxiety in healthy subjects, and indicate possible differential involvement of various components of the dopaminergic system in normal and pathological personality traits. On the other hand, dopamine has been suggested to be the primary neurotransmitter modulator of novelty seeking, a temperament trait characterized by impulsiveness and exploratory behavior. In young healthy subjects, a correlation between increased novelty seeking and decreased insular cortical dopamine D2 receptor availability has been reported (Suhara et al., 2001). In disease, such as in patients with Parkinson’s disease, a link between dopamine deficiency and reduction in novelty seeking has been suggested. A PET study indeed demonstrated a negative correlation between the novelty seeking score and the dopamine D2 availability bilaterally in the insular cortex, thus providing further evidence for a relationship between novelty seeking and insular D2 receptors (Kaasinen et al., 2004). An association between striatal postsynaptic D2 dopamine receptors and emotional detachment has been reported using PET and [11C]raclopride (Breier et al., 1998). Other findings indicate a link between the serotoninergic systems and harm avoidance (Bailer et al., 2004). Another study reports the relationship between the in vivo binding of 3-(20 -[18F]fluoroethyl)spiperone ([18F]FESP) to cortical 5HT2 serotonin receptors and striatal dopamine D2 receptors, and different personality dimensions (i.e., novelty seeking, reward dependence, and harm avoidance) (Moresco et al., 2002). It is noteworthy that harm avoidance showed a significant inverse correlation with [18F]FESP binding in the cerebral cortex, particularly in the frontal and parietal cortex, but not in the basal ganglia. Thus, in the cerebral cortex, high [18F]FESP binding values are associated with a high tendency to avoid danger, indicating involvement of the serotoninergic system and in particular 5HT2A receptors, in this personality trait. Neuroimaging research has also addressed personality disorders, which can be defined as trait-like dysfunctional patterns in cognitive, affective, and interpersonal domains and in impulse control. These domains of dysfunction have been linked to specific neural circuits. Developments in brain imaging techniques have allowed researchers to examine the neural integrity of these circuits in personality-disordered individuals. Some studies addressed in particular

97

borderline personality disorders, antisocial personality disorder (including psychopathy), and schizotypal personality disorder. These functional and structural studies provide support for the dysfunction of frontolimbic circuits in borderline and antisocial personality disorders, whereas temporal lobe and basal striatal– thalamic dysfunction is present in schizotypal personality disorder (see for review McCloskey et al., 2005). Together, the results of these studies on personality dimensions support the existence of a relationship between behavior and neurobiological factors. In addition, they support the hypothesis that the variability in PET data of neurotransmission may be due to neurochemical differences related to specific personality traits.

4.9. Genes and cognitive processes Now that the human genome has been fully sequenced, it is possible to identify specific genes that affect human cognition. Recent studies have found associations between common gene variants and specific cognitive processes (see Goldberg and Weinberger, 2004 for review). The interpretation of results is very complex, since a single gene can affect multiple processes, multiple genes can impact on a single process, and multiple cognitive processes are intercorrelated. More importantly, variation in normal human cognition is related to many factors including the environmental ones, and the sum of all genetic effects is not likely to be greater than 50% for many types of cognition (Bouchard and McGue, 2003). However, a novel and fascinating way to view cognition, based on constraints imposed by genomics and neurobiology, is now open. Many genetic mutations that have been associated with brain development have an impact on cognition and may be involved in the pathogenesis of dementia or mental retardation. This is the case of Williams syndrome, Down syndrome, Huntington’s disease (Battaglia and Carey, 2003), as well as of the effects of the APOE polymorphism and the allelic variants of presenilin in Alzheimer’s disease and of synuclein in Parkinson’s disease (Nussbaum and Ellis, 2003). The heritability of various cognitive functions has been highlighted recently (Bouchard and McGue, 2003), and linkage analysis has described candidate genes and allelic associations related to different psychological trait patterns. Candidate genes and allelic associations, together with linkage findings, constitute common genetic variants that affect cognitive functions. Genetic association studies, however, must take into account differences in age, education, gender, diseases, and psychiatric status, all of which can influence a variety of cognitive processes. Since genotype–phenotype

98

D. PERANI

associations are phenomenological and do not imply causation, only by placing the association in a neurobiological context can plausible and mechanistic models be constructed. A more complete and necessarily more complex account of gene–cognition relations must also take into consideration interactions among genes, gene–environment interactions, and stochastic factors that bear on the biology of the phenotype of interest. Functional neuroimaging may offer a powerful method to examine genotypic effects on cognitive processing in brain (Hariri and Weinberger, 2003), although there are important limits to be considered. It has been suggested that neurophysiology at the systems level as measured by PET or fMRI may be closer to the neurobiological effects of the genes than overt behavior. On the other hand, methodological factors unrelated to genotype might decrease the reliability of large-scale multi-site studies, although analysis procedures, such as SPM, provide corrections for the large numbers variables (see Mattay and Goldberg, 2004, for review). Attention, executive functions and memory have been the cognitive domains investigated with respect to the relationship between functional neuroimaging and genetics. Attention networks and aminergic genes have long been implicated in various components of attention processing, and catecholamimetic drugs are mainstays of treatment for disorders of arousal and attention. Fossella and colleagues (2002) have examined various aspects of attention in relation to common polymorphisms in the catecholamine-related candidate genes. These include those encoding the dopamine type-4 receptor (DRD4), and monoamine oxidase-A (MAOA), which are involved in diverse aspects of aminergic signaling in the brain (dopamine, norepinephrine, and serotonin systems). These genes showed significant associations with efficiency of handling conflict as measured by reaction time differences in an attention test. In a related fMRI study, Fan and colleagues (2003) examined whether the same genetic variation might contribute to differences in brain activation within the anterior cingulate cortex. Brain imaging data have repeatedly shown that the anterior cingulate cortex is an important node in the brain network mediating conflict. They found a polymorphism in which the allele associated with better behavioral performance was also associated with increased activation in the anterior cingulate cortex while performing the attention task. These findings suggest that genetic differences among individuals can be linked to differences in neuromodulators affecting the efficiency of the operation of an appropriate attentional network.

Dopamine has been prominently studied as a crucial neurotransmitter for tuning neuronal and network responses during executive processes, and recent studies indicate that genetic factors affect dopamine flux in the prefrontal cortex. In particular, a common variant in the COMT gene appears to account for significant variance in prefrontal cognitive function. Egan and colleagues (2001) also explored the association of the COMT genotype with performance on the N-Back task, a more specific assay of working memory and executive processing. Met allele load predicted a more efficient physiological response (i.e., less BOLD activation) in the prefrontal cortex in the Two-Back condition. Mattay et al. (2003) explored the effects of COMT polymorphism on the actions of amphetamine in the prefrontal cortex. They found that amphetamine enhanced the physiological efficiency as assayed by the fMRI BOLD response in prefrontal cortex of individuals who were Val homozygotes and who had presumably less synaptic dopamine at all levels of working memory load. By contrast, healthy subjects who were Met homozygotes showed deterioration in cortical function under amphetamine at high working memory loads. These pharmacogenetic results might shed light on the variable clinical effects of amphetamine treatment, in which some individuals demonstrate improvements in mood and information processing, whereas others become dysphoric, irritable, or lose mental acuity. Their findings also support the link between COMT genotype and dopamine-mediated prefrontal function. Zubieta and colleagues (2003) reported another negative aspect of the Met allele. Using PET m-opioid imaging with [11C]carfentanil in concert with questionnaires that assess pain-related sensory and affective qualities, they examined the hypothesis that the different levels of COMT activity related to val–met polymorphism might have an influence on other functions regulated by catecholamines, including the m-opioid system responses to noxious stimuli. They reported that, in contrast to heterozygous individuals, individuals homozygous for the met allele show a diminished m-opioid response in the thalamus and amygdala, together with higher sensory and affective ratings of pain, and a negative internal state. Homozygotes for the Val allele, on the other hand, showed the opposite response. This study not only illustrates a potential mechanism that drives the variable response to pain across individuals, but it also shows that the so-called efficient allele (met allele) confers a lower threshold for pain tolerance. In the field of memory, some authors have raised the hypothesis that a genetic alteration in brain-derived neurotrophic factor function could have implications for hippocampal based learning and memory (Egan et al., 2003). This was based on evidence from basic studies

FUNCTIONAL NEUROIMAGING OF COGNITION in slice preparations and in animals showing that brainderived neurotrophic factors play an important and direct role in long-term potentiation and hippocampal function during memory processing. In a large cohort study of human subjects (including normal individuals, schizophrenic patients, and their non-psychotic siblings), these authors evaluated the levels of n-acetyl aspartate, a putative in vivo measure of neuronal integrity and synaptic abundance, with magnetic resonance spectroscopic imaging, and found lower levels in the hippocampus of subjects with Met alleles. In addition, the Met/Met genotype group exhibited impaired verbal episodic memory in contrast to the Val/Val. In a related fMRI paradigm in normal subjects that measured BOLD signal during encoding of visual scenes (indoor vs. outdoor) and then again during recognition of these scenes mixed with foils (old vs. new), Hariri and colleagues (2003) found that Met carriers exhibited diminished hippocampal engagement in comparison to Val homozygotes during both encoding and retrieval. This study linked genotype, hippocampal physiology, and performance, thus completing the conceptual loop for the role of brain-derived neurotrophic factors in human mnemonic function. These translational findings in human memory and hippocampal function suggest that the mechanism by which the polymorphism initiates these effects relates to an alteration in intracellular trafficking and secretion of brain-derived neurotrophic factors. Imaging the influence of the apolipoprotein allele on brain function has supported the evidence for the role of the APOE e4 allele in increasing the risk for Alzheimer’s disease (AD). Smith et al. (1998) showed a reduced BOLD response in APOE e4 carriers in the inferotemporal region during fluency and object recognition tasks. Bookheimer and colleagues (2000), on the other hand, showed increased activity in response to memory tasks in subjects carrying the epsilon4 allele compared to those without this allele. Using fMRI during a working memory task in healthy non-demented elderly individuals, Petrella and colleagues (2002) demonstrated greater extent and magnitude of activation in the prefrontal cortex in the e4 carriers relative to the e3 carriers. Since APOE e4 confers increased susceptibility to age-related memory problems and cholinergic system abnormalities are associated with memory problems in the elderly and AD patients, Cohen et al. (2003) used a 18F labelled muscarinic-2 selective agonist with PET to measure directly the effect of APOE e4 on the muscarinic component of the cholinergic system. They found increased distribution volumes of the tracer in APOE e4 carrying older individuals relative to the non-carriers. The authors postulate that this observation reflects an increase in the number of unoccupied

99

muscarinic-2 receptors, probably caused by the lower synaptic acetylcholine concentration in the APOE e4 carriers. Taken together, data from these functional neuroimaging studies support the notion that the effects of the APOE e4 allele can be discerned even before clinical presentation of disease and that elderly subjects with this allele may be more susceptible to future cognitive decline. Finally, developmental dyslexia, which has a genetic basis, is also relevant to the present issue. Genetic linkage analyses have identified regions of the genome containing polymorphisms that may play a role in the acquisition of reading. Recent reviews of linkage studies related to reading showed positive and replicable effects in independent samples for loci on chromosomes 2, 3, 6, 15 and 18 (Fisher and DeFries, 2002). Thus, even if reading per se is unlikely to be under genetic control, further research studies will serve as a measurable proxy of this basic linguistic function. In summary, the investigation of the relation between genes and brain functions using functional brain imaging techniques is an emerging and promising area of research that will help to better characterize the influence of genes on cognition and behavior as well as the links between genetic susceptibility and neuropsychiatric disorders. Neurophysiological imaging provides information regarding the effect of genes on brain function at the level of information processing, and neurochemical imaging provides information on the intrinsic mechanisms on how these genes affect the brain response.

4.10. Conclusion Functional neuroimaging has radically influenced neuroscience research in the last decade. Our knowledge about how human thinking, feeling, and action are instantiated in the brain has largely increased. The methodological advances of the last years in image acquisition, preprocessing and analysis are huge. In addition, while the contribution of CT and structural MRI to clinical diagnosis remains ‘ancillary’ in the case of the most common cognitive disorders, the new developments of functional imaging with PET, SPECT, and fMRI are becoming important clinical and research tools in neurology. In the case of neuropsychology and cognitive neuroscience, these tools are providing important insights into the brain organization of cognitive functions, such as memory and language, and in the in vivo assessment of the functional modifications associated with normal aging and dementia. This progress is not only taking place at the traditional resolution level of brain areas: new, exciting perspectives are presently opening at the level of neurotransmitter function and

100

D. PERANI

of molecular processes. In particular, the high sensitivity and selectivity of positron emission tomography allows probing the neurochemical processes at the molecular level. The implications of these possibilities for the assessment of the effectiveness of therapeutic interventions in the field of normal and pathological aging are now starting, and remarkable progress may be expected in the coming years. Progress in unravelling these and other related issues will depend on the integration of behavioral, computational, and neurophysiological approaches, including neuroimaging. The future relies on the integration of spatially, namely PET and fMRI, and temporally resolved methods, such as EEG and MEG, evoked or spontaneous brain potentials. Mapping each type of functional signal onto the anatomy and exploring the relationship with their molecular basis into a common framework will lead to new discoveries, predictions and insight in neuroscience and neurology.

References (1994). Clinical and neuropathological criteria for frontotemporal dementia. The Lund and Manchester Groups. J Neurol Neurosurg Psychiatry 57: 416–418. Aalto S, Bruck A, Laine M, et al. (2005). Frontal and temporal dopamine release during working memory and attention tasks in healthy humans: A positron emission tomography study using the high-affinity dopamine D2 receptor ligand [11C]FLB 457. J Neurosci 25: 2471–2477. Abi-Dargham A, Mawlawi O, Lombardo I, et al. (2002). Prefrontal dopamine D1 receptors and working memory in schizophrenia. J Neurosci 22: 3708–3719. Abi-Dargham A, Rodenhiser J, Printz D, et al. (2000). Increased baseline occupancy of D2 receptors by dopamine in schizophrenia. Proc Natl Acad Sci USA 97: 8104–8109. Abutalebi J, Cappa SF, Perani D (2001). The bilingual brain as reveale by functional neuroimaging. Bilingualism: Language and Cognition 4: 179–190. Abutalebi J, Cappa SF, Perani D (2005). What can functional neuroimaging tell us about the bilingual brain? In: JF Kroll, AMB De Groot (Es.), Handbook of Bilingualism: Psycholinguistic Approaches. Oxford Univerity Press, Oxford. Adleman NE, Menon V, Blasey CM, et al. (2002). A developmental fMRI study of the Stroop color-word task. Neuroimage 16: 61–75. Adolphs R (2003). Cognitive neuroscience of human social behaviour. Nat Rev Neurosci 4: 165–178. Albert ML, Obler LK (1978). The Bilingual Brain. Academic Press, New York. Anchisi D, Borroni B, Francheschi M (2005). Heterogeneity of glucose brain metabolism in Mild Cognitive Impairment predicts clinical progression to Alzheimer’s Disease. Arch Neurol 62: 1728–1733. Anderson AW, Marois R, Colson ER, et al. (2001). Neonatal auditory activation detected by functional magnetic resonance imaging. Magn Reson Imaging 19: 1–5.

Aron AR, Robbins TW, Poldrack RA (2004). Inhibition and the right inferior frontal cortex. Trends Cogn Sci 8: 170–177. Arthurs OJ, Boniface S (2002). How well do we understand the neural origins of the fMRI BOLD signal? Trends Neurosci 25: 27–31. Azari NP, Pettigrew KD, Schapiro MB, et al. (1993). Early detection of Alzheimer’s disease: A statistical approach using positron emission tomographic data. J Cereb Blood Flow Metab 13: 438–447. Backman L, Andersson JL, Nyberg L, et al. (1999). Brain regions associated with episodic retrieval in normal aging and Alzheimer’s disease. Neurology 52: 1861–1870. Baddeley A (1998). Recent developments in working memory. Curr Opin Neurobiol 8: 234–238. Baddeley A (2000). The episodic buffer: A new component of working memory? Trends Cogn Sci 4: 417–423. Bailer UF, Price JC, Meltzer CC, et al. (2004). Altered 5-HT(2A) receptor binding after recovery from bulimia-type anorexia nervosa: Relationships to harm avoidance and drive for thinness. Neuropsychopharmacology 29: 1143–1155. Baron JC, Levasseur M, Mazoyer B, et al. (1992). Thalamocortical diaschisis: Positron emission tomography in humans. J Neurol Neurosurg Psychiatry 55: 935–942. Bashir K, Elble RJ, Ghobrial M, et al. (1998). Hemianopsia in dementia with Lewy bodies. Arch Neurol 55: 1132–1135. Bassarath L (2001). Neuroimaging studies of antisocial behaviour. Can J Psychiatry 46: 728–732. Battaglia A, Carey JC (2003). Diagnostic evaluation of developmental delay/mental retardation: An overview. Am J Med Genet C Semin Med 117: 3–14. Becker JT, Mintun MA, Aleva K, et al. (1996). Compensatory reallocation of brain resources supporting verbal episodic memory in Alzheimer’s disease. Neurology 46: 692–700. Belin P, Van Eeckhout P, Zilbovicius M, et al. (1996). Recovery from nonfluent aphasia after melodic intonation therapy: A PET study. Neurology 47: 1504–1511. Birdsong D (1999). Second language acquisition and the critical period hypothesis. Lawrence Erlbaum Associates, Mahwah, NJ. Blasi V, Young AC, Tansy AP, et al. (2002). Word retrieval learning modulates right frontal cortex in patients with left frontal damage. Neuron 36: 159–170. Bookheimer SY, Strojwas MH, Cohen MS, et al. (2000). Patterns of brain activation in people at risk for Alzheimer’s disease. N Engl J Med 343: 450–456. Booth JR, Burman DD, Meyer JR, et al. (2004). Development of brain mechanisms for processing orthographic and phonologic representations. J Cogn Neurosci 16: 1234–1249. Booth JR, MacWhinney B, Harasaki Y (2000). Developmental differences in visual and auditory processing of complex sentences. Child Dev 71: 981–1003. Born P, Leth H, Miranda MJ, et al. (1998). Visual activation in infants and young children studied by functional magnetic resonance imaging. Pediatr Res 44: 578–583. Borroni B, Perani D, Broli M, et al. (2005). Pre-clinical diagnosis of Alzheimer disease combining platelet amyloid

FUNCTIONAL NEUROIMAGING OF COGNITION precursor protein ratio and rCBF spect analysis. J Neurol 252: 1359–1362. Borroni B, Anchisi D, Paghera B, et al. (2006). Combined 99mTc-ECD SPECT and neuropsychological studies in MCI for the assessment of conversion to AD. Neurobiol Aging 27: 24–31. Bouchard Jr TJ, McGue M (2003). Genetic and environmental influences on human psychological differences. J Neurobiol 54: 4–45. Braak H, Braak E (1991). Neuropathological stageing of Alzheimer-related changes. Acta Neuropathol 82: 239–259. Bradley L, Bryant PE (1985). Rhyme and Reason in Reading and Spelling (I.A.R.L.D. Monographs No. 1). University of Michigan Press, Ann Arbor. Brambati SM, Termine C, Ruffino M, et al. (2004). Regional reductions of gray matter volume in familial dyslexia. Neurology 63: 742–745. Breier A, Kestler L, Adler C, et al. (1998). Dopamine D2 receptor density and personal detachment in healthy subjects. Am J Psychiatry 155: 1440–1442. Brooks DJ (2005). Positron emission tomography and singlephoton emission computed tomography in central nervous system drug development. NeuroRx 2: 226–236. Brown TT, Lugar HM, Coalson RS, et al. (2005). Developmental changes in human cerebral functional organization for word generation. Cereb Cortex 15: 275–290. Brunswick N, McCrory E, Price CJ, et al. (1999). Explicit and implicit processing of words and pseudowords by adult developmental dyslexics: A search for Wernicke’s Wortschatz? Brain 122: 1901–1917. Bullmore E, Fadili J, Breakspear M, et al. (2003). Wavelets and statistical analysis of functional magnetic resonance images of the human brain. Stat Methods Med Res 12: 375–399. Bunge SA, Dudukovic NM, Thomason ME, et al. (2002). Immature frontal lobe contributions to cognitive control in children: Evidence from fMRI. Neuron 33: 301–311. Cabeza R (2002). Hemispheric asymmetry reduction in older adults: The HAROLD model. Psychol Aging 17: 85–100. Cabeza R, Nyberg L (2000). Neural bases of learning and memory: Functional neuroimaging evidence. Curr Opin Neurol 13: 415–421. Cabeza R, Nyberg L, Park DC (2005). Cognitive Neuroscience of Aging. Oxford University Press, New York. Camerer C, Loewenstein G (2004). Advances in Behavioral Economics. In: C Camerer, G Loewenstein, M Rabin (Eds.), Princeton University Press, Princeton, NJ. Canessa N, Gorini A, Cappa SF, et al. (2005). The effect of social content on deductive reasoning: An fMRI study. Hum Brain Mapp 26: 30–43. Caplan D, Alpert N, Waters G (1998). Effects of syntactic structure and propositional number on patterns of regional cerebral blood flow. J Cogn Neurosci 10: 541–552. Cappa SF, Perani D (2003). The neural correlates of noun and verb processing. J Neurolinguistics 16: 183–189. Cappa SF, Perani D (2006). Broca’s area and lexical-semantic processing. In: Y Grodzinsky, K Amunts (Eds.), Broca’s Region. Oxford University Press.

101

Cappa SF, Perani D, Messa C, et al. (1996). Varieties of progressive non-fluent aphasia. Ann NY Acad Sci 777: 243–248. Carr L, Iacoboni M, Dubeau MC, et al. (2003). Neural mechanisms of empathy in humans: A relay from neural systems for imitation to limbic areas. Proc Natl Acad Sci USA 100: 5497–5502. Casey BJ, Cohen JD, Jezzard P, et al. (1995). Activation of prefrontal cortex in children during a nonspatial working memory task with functional MRI. Neuroimage 2: 221–229. Casey BJ, Davidson MC, Hara Y, et al. (2004). Early development of subcortical regions involved in non-cued attention switching. Dev Sci 7: 534–542. Casey BJ, Trainor R, Giedd J, et al. (1997). The role of the anterior cingulate in automatic and controlled processes: A developmental neuroanatomical study. Dev Psychobiol 30: 61–69. Catani M, Jones DK, ffytche DH (2005). Perisylvian language networks of the human brain. Ann Neurol 57: 8–16. Celsis P, Boulanouar K, Doyon B, et al. (1999). Differential fMRI responses in the left posterior superior temporal gyrus and left supramarginal gyrus to habituation and change detection in syllables and tones. Neuroimage 9: 135–144. Chee MW, Soon CS, Lee HL, et al. (2004). Left insula activation: A marker for language attainment in bilinguals. Proc Natl Acad Sci USA 101: 15265–15270. Chou YH, Karlsson P, Halldin C, et al. (1999). A PET study of D(1)-like dopamine receptor ligand binding during altered endogenous dopamine levels in the primate brain. Psychopharmacology (Berl) 146: 220–227. Cohen RM, Podruchny TA, Bokde AL, et al. (2003). Higher in vivo muscarinic-2 receptor distribution volumes in aging subjects with an apolipoprotein E-epsilon4 allele. Synapse 49: 150–156. Collette F, Van der Linden M, Laureys S, et al. (2005). Exploring the unity and diversity of the neural substrates of executive functioning. Hum Brain Mapp 25: 409–423. Corey-Bloom J, Thal LJ, Galasko D, et al. (1995). Diagnosis and evaluation of dementia. Neurology 45: 211–218. Coricelli G, Critchley HD, Joffily M, et al. (2005). Regret and its avoidance: A neuroimaging study of choice behavior. Nat Neurosci 8: 1255–1262. Cortelli P, Perani D, Montagna P, et al. (2006). Presymptomatic diagnosis in fatal familial insomnia: Serial neurophysiological and 18FDG-PET studies. Brain 129: 668–675. Cortelli P, Perani D, Parchi P, et al. (1997). Cerebral metabolism in fatal familial insomnia: Relation to duration, neuropathology, and distribution of protease-resistant prion protein. Neurology 49: 126–133. Craik FIM, Salthouse TA (2000). The Handbook of Aging and Cognition, 2nd edn. Lawrence Erlbaum Associates, Mahwah, NJ. Crosson B, Moore AB, Gopinath K, et al. (2005). Role of the right and left hemispheres in recovery of function during treatment of intention in aphasia. J Cogn Neurosci 17: 392–406.

102

D. PERANI

Dapretto M, Bookheimer SY (1999). Form and content: Dissociating syntax and semantics in sentence comprehension. Neuron 24: 427–432. De Groot AMB, Kroll JF (1997). Tutorials in Bilingualism: Psycholinguistic Perspectives. Lawrence Erlbaum Associates, Mahwah, NJ. Deglin VL, Kinsbourne M (1996). Divergent thinking styles of the hemispheres: How syllogisms are solved during transitory hemisphere suppression. Brain Cogn 31: 285–307. Dehaene-Lambertz G, Dehaene S, Hertz-Pannier L (2002). Functional neuroimaging of speech perception in infants. Science 298: 2013–2015. Demb JB, Boynton GM, Heeger DJ (1998). Functional magnetic resonance imaging of early visual pathways in dyslexia. J Neurosci 18: 6939–6951. Demonet JF, Taylor MJ, Chaix Y (2004). Developmental dyslexia. Lancet 363: 1451–1460. Demonet JF, Thierry G, Cardebat D (2005). Renewal of the neurophysiology of language: Functional neuroimaging. Physiol Rev 85: 49–95. Deppe M, Schwindt W, Kugel H, et al. (2005). Nonlinear responses within the medial prefrontal cortex reveal when specific implicit information influences economic decision making. J Neuroimaging 15: 171–182. Desgranges B, Baron JC, Lalevee C, et al. (2002). The neural substrates of episodic memory impairment in Alzheimer’s disease as revealed by FDG-PET: Relationship to degree of deterioration. Brain 125: 1116–1124. D’Esposito M, Deouell LY, Gazzaley A (2003). Alterations in the BOLD fMRI signal with ageing and disease: A challenge for neuroimaging. Nat Rev Neurosci 4: 863–872. Devlin JT, Moore CJ, Mummery CJ, et al. (2002). Anatomic constraints on cognitive theories of category specificity. Neuroimage 15: 675–685. Dewey SL, Brodie JD, Fowler JS, et al. (1990). Positron emission tomography (PET) studies of dopaminergic/cholinergic interactions in the baboon brain. Synapse 6: 321–327. Dewey SL, Smith GS, Logan J, et al. (1992). GABAergic inhibition of endogenous dopamine release measured in vivo with 11C-raclopride and positron emission tomography. J Neurosci 12: 3773–3780. Dewey SL, Smith GS, Logan J, et al. (1993). Effects of central cholinergic blockade on striatal dopamine release measured with positron emission tomography in normal human subjects. Proc Natl Acad Sci USA 90: 11816–11820. Dickerson BC, Salat DH, Bates JF, et al. (2004). Medial temporal lobe function and structure in mild cognitive impairment. Ann Neurol 56: 27–35. Dickerson BC, Salat DH, Greve DN, et al. (2005). Increased hippocampal activation in mild cognitive impairment compared to normal aging and AD. Neurology 65: 404–411. Diehl J, Grimmer T, Drzezga A, et al. (2004). Cerebral metabolic patterns at early stages of frontotemporal dementia and semantic dementia. A PET study. Neurobiol Aging 25: 1051–1056. Diller L, Riley E (1993). The behavioral management of neglect. In: IH Robertson, JC Marshall (Eds.), Unilateral

Neglect: Clinical and Experimental Studies. LEA, Hillsdale, NJ, pp. 293–308. Dinn WM, Harris CL (2000). Neurocognitive function in antisocial personality disorder. Psychiatry Res 97: 173–190. Donaldson DL, Buckner RL (2001). Effective paradigm design. In: P Jezzard, PM Matthews, SM Smith (Eds.), Functional MRI: An Introduction to Methods. Oxford University Press, Oxford, pp. 177–195. Drzezga A, Grimmer T, Riemenschneider M, et al. (2005). Prediction of individual clinical outcome in MCI by means of genetic assessment and FDG-PET imaging. J Nucl Med 46: 1625–1632. Duchaine B, Cosmides L, Tooby J (2001). Evolutionary psychology and the brain. Curr Opin Neurobiol 11: 225–230. Duncan J, Owen AM (2000). Common regions of the human frontal lobe recruited by diverse cognitive demands. Trends Neurosci 23: 475–483. Eckert T, Eidelberg D (2005). Neuroimaging and therapeutics in movement disorders. NeuroRx 2: 361–371. Edelman GM, Gally JA (2001). Degeneracy and complexity in biological systems. Proc Natl Acad Sci USA 98: 13763–13768. Eden GF, VanMeter JW, Rumsey JM, et al. (1996). Abnormal processing of visual motion in dyslexia revealed by functional brain imaging. Nature 382: 66–69. Egan MF, Goldberg TE, Kolachana BS, et al. (2001). Effect of COMT Val108/158 Met genotype on frontal lobe function and risk for schizophrenia. Proc Natl Acad Sci USA 98: 6917–6922. Egan MF, Kojima M, Callicott JH, et al. (2003). The BDNF val66met polymorphism affects activity-dependent secretion of BDNF and human memory and hippocampal function. Cell 112: 257–269. Elliott R (2003). Executive functions and their disorders. Br Med Bull 65: 49–59. Engler H, Lundberg PO, Ekbom K, et al. (2003). Multitracer study with positron emission tomography in CreutzfeldtJakob disease. Eur J Nucl Med Mol Imaging 30: 85–95. Eustache F, Desgranges B, Aupee AM, et al. (2000). Functional neuroanatomy of amnesia: Positron emission tomography studies. Microsc Res Tech 51: 94–100. Evans AC, Collins DL, Mills SR, et al. (1993). 3D statistical neuroanatomical models from 305 MRI volumes, Proc IEEE-Nuclear Science Symposium and Medical Imaging Conference: 1813–1817. Fan J, Fossella J, Sommer T, et al. (2003). Mapping the genetic variation of executive attention onto brain activity. Proc Natl Acad Sci USA 100: 7406–7411. Fawcett AJ, Nicolson RI (1992). Automatisation deficits in balance for dyslexic children. Percept Mot Skills 75: 507–529. Fawcett AJ, Nicolson RI (1994). Naming speed in children with dyslexia. J Learn Disabil 27: 641–646. Fazio F, Perani D, Gilardi MC, et al. (1992). Metabolic impairment in human amnesia: A PET study of memory networks. J Cereb Blood Flow Metab 12: 353–358. Feeney DM, Baron JC (1986). Diaschisis. Stroke 17: 817–830.

FUNCTIONAL NEUROIMAGING OF COGNITION Fellgiebel A, Siessmeier T, Scheurich A, et al. (2004). Association of elevated phospho-tau levels with Alzheimertypical 18F-fluoro-2-deoxy-D-glucose positron emission tomography findings in patients with mild cognitive impairment. Biol Psychiatry 56: 279–283. Filipek PA (1999). Neuroimaging in the developmental disorders: The state of the science. J Child Psychol Psychiatry 40: 113–128. Fisher RE, Morris ED, Alpert NM, et al. (1995). In vivo imaging of neuromodulatory synaptic transmission using PET: A review of relevant neurophysiology. Hum Brain Mapp 3: 24–34. Fisher SE, DeFries JC (2002).Nat Rev Neurosci 3(10): 767–780. Fletcher PC, Henson RN (2001). Frontal lobes and human memory: Insights from functional neuroimaging. Brain 124: 849–881. Fossella J, Sommer T, Fan J, et al. (2002). Assessing the molecular genetics of attention networks. BMC Neurosci 3: 14. Foster NL, Barbas NR, Heidebrink JL (2004). Adding FDGPET to clinical history and examination improves the accuracy of dementia diagnosis. Neurobiol Aging 25: S372. Fowler JS, Ding YS, Volkow ND (2003). Radiotracers for positron emission tomography imaging. Semin Nucl Med 33: 14–27. Franceschi M, Anchisi D, Pelati O, et al. (2005). Glucose metabolism and serotonin receptors in the frontotemporal lobe degeneration. Ann Neurol 57: 216–225. Francks C, MacPhie IL, Monaco AP (2002). The genetic basis of dyslexia. Lancet Neurol 1: 483–490. Frankle WG, Laruelle M (2002). Neuroreceptor imaging in psychiatric disorders. Ann Nucl Med 16: 437–446. Friederici AD (2002). Towards a neural basis of auditory sentence processing. Trends Cogn Sci 6: 78–84. Friston KJ (2002). Bayesian estimation of dynamical systems: An application to fMRI. Neuroimage 16: 513–530. Friston KJ, Harrison L, Penny W (2003). Dynamic causal modelling. Neuroimage 19: 1273–1302. Friston KJ, Holmes AP, Worsley KJ, et al. (1995). Statistical parametric maps in functional imaging: A general linear approach. Hum Brain Mapp 2: 189–210. Friston KJ, Price CJ (2001). Dynamic representations and generative models of brain function. Brain Res Bull 54: 275–285. Frith U (1998). Cognitive deficits in developmental disorders. Scand J Psychol 39: 191–195. Fuster JM (1989). The Prefrontal Cortex. Anatomy, Physiology, and Neuropsychology of the Frontal Lobe. Raven, New York. Gaillard WD, Hertz-Pannier L, Mott SH, et al. (2000). Functional anatomy of cognitive development: fMRI of verbal fluency in children and adults. Neurology 54: 180–185. Gaillard WD, Sachs BC, Whitnah JR, et al. (2003). Developmental aspects of language processing: fMRI of verbal fluency in children and adults. Hum Brain Mapp 18: 176–185.

103

Galaburda AM, Sherman GF, Rosen GD, et al. (1985). Developmental dyslexia: Four consecutive patients with cortical anomalies. Ann Neurol 18: 222–233. Gathercole SE (1999). Cognitive approaches to the development of short-term memory. Trends Cogn Sci 3: 410–419. Gatley SJ (1993). Estimation of upper limits on human radiation absorbed doses from carbon-11-labeled compounds. J Nucl Med 34: 2208–2215. Gazzaley A, Cooney JW, Rissman J, et al. (2005). Top-down suppression deficit underlies working memory impairment in normal aging. Nat Neurosci 8(10): 1298–1300. Gazzaniga MS (1989). Organization of the human brain. Science 245: 947–952. Geser F, Wenning GK, Poewe W, et al. (2005). How to diagnose dementia with Lewy bodies: State of the art. Mov Disord 20: S11–S20. Glimcher P (2002). Decisions, decisions, decisions: Choosing a biological science of choice. Neuron 36: 323–332. Goel V, Buchel C, Frith C, et al. (2000). Dissociation of mechanisms underlying syllogistic reasoning. Neuroimage 12: 504–514. Goel V, Dolan RJ (2000). Anatomical segregation of component processes in an inductive inference task. J Cogn Neurosci 12: 110–119. Goel V, Dolan RJ (2001). Functional neuroanatomy of threeterm relational reasoning. Neuropsychologia 39: 901–909. Goel V, Dolan RJ (2003). Reciprocal neural response within lateral and ventral medial prefrontal cortex during hot and cold reasoning. Neuroimage 20: 2314–2321. Goel V, Gold B, Kapur S, et al. (1997). The seats of reason? An imaging study of deductive and inductive reasoning. Neuroreport 8: 1305–1310. Goel V, Gold B, Kapur S, et al. (1998). Neuroanatomical correlates of human reasoning. J Cogn Neurosci 10: 293–302. Goerendt IK, Messa C, Lawrence AD, et al. (2003). Dopamine release during sequential finger movements in health and Parkinson’s disease: A PET study. Brain 126: 312–325. Goldberg TE, Weinberger DR (2004). Genes and the parsing of cognitive processes. Trends Cogn Sci 8: 325–335. Goldman S, Laird A, Flament-Durand J, et al. (1993). Positron emission tomography and histopathology in CreutzfeldtJakob disease. Neurology 43: 1828–1830. Gorno-Tempini ML, Hutton C, Josephs O, et al. (2002). Echo time dependence of BOLD contrast and susceptibility artifacts. Neuroimage 15: 136–142. Gowers W (1895). Malattie del Sistema Nervoso. Vallardi, Milan. Graham NL, Emery T, Hodges JR (2004). Distinctive cognitive profiles in Alzheimer’s disease and subcortical vascular dementia. J Neurol Neurosurg Psychiatry 75: 61–71. Gray JR, Thompson PM (2004). Neurobiology of intelligence: Science and ethics. Nat Rev Neurosci 5: 471–482. Green DW, Price C (2001). Functional imaging in the study of recovery patterns in bilingual aphasics. Bilingualism: Language and Cognition 4: 191–201. Greicius MD (2003). Neuroimaging in developmental disorders. Curr Opin Neurol 16: 143–146.

104

D. PERANI

Grossman M (2002). Frontotemporal dementia: A review. J Int Neuropsychol Soc 8: 566–583. Grossman M, Koenig P, DeVita C, et al. (2003). Neural basis for verb processing in Alzheimer’s disease: An fMRI study. Neuropsychology 17: 658–674. Gusnard DA, Raichle ME (2001). Searching for a baseline: Functional imaging and the resting human brain. Nat Rev Neurosci 2: 685–694. Habib M (2000). The neurological basis of developmental dyslexia: an overview and working hypothesis. Curr Pharm Des 12: 2373–2399. Halldin C, Gulyas B, Farde L (2001). PET studies with carbon-11 radioligands in neuropsychopharmacological drug development. Curr Pharm Des 7: 1907–1929. Hamacher K, Coenen HH, Stocklin G (1986). Efficient stereospecific synthesis of no-carrier-added 2-[18F]fluoro-2-deoxy-D-glucose using aminopolyether supported nucleophilic substitution. J Nucl Med 27: 235–238. Hari R, Renvall H, Tanskanen T (2001). Left minineglect in dyslexic adults. Brain 124: 1373–1380. Hariri AR, Goldberg TE, Mattay VS, et al. (2003). Brainderived neurotrophic factor val66met polymorphism affects human memory-related hippocampal activity and predicts memory performance. J Neurosci 23: 6690–6694. Hariri AR, Weinberger DR (2003). Imaging genomics. Br Med Bull 65: 259–270. Hartley T, Burgess N (2005). Complementary memory systems: Competition, cooperation and compensation. Trends Neurosci 28: 169–170. Haxby JV, Grady CL, Koss E, et al. (1988). Heterogeneous anterior–posterior metabolic patterns in dementia of the Alzheimer type. Neurology 38: 1853–1863. Haxby JV, Grady CL, Koss E, et al. (1990). Longitudinal study of cerebral metabolic asymmetries and associated neuropsychological patterns in early dementia of the Alzheimer type. Arch Neurol 47: 753–760. Heiss WD, Thiel A, Kessler J, et al. (2003). Disturbance and recovery of language function: Correlates in PET activation studies. Neuroimage 20: S42–S49. Helenius P, Salmelin R, Richardson U, et al. (2002). Abnormal auditory cortical activation in dyslexia 100 msec after speech onset. J Cogn Neurosci 14: 603–617. Henson RN (2004). Analysis of fMRI time series: Linear timeinvariant models, event-related fMRI, and optimal experimental design. In: R Frackowiack (Ed.), Human Brain Function, 2nd edn. Elsevier, San Diego, pp. 793–823. Herholz K (1995). FDG PET and differential diagnosis of dementia. Alzheimer Dis Assoc Disord 9: 6–16. Herholz K, Heindel W, Rackl A, et al. (1990). Regional cerebral blood flow in patients with leuko-araiosis and atherosclerotic carotid artery disease. Arch Neurol 47: 392–396. Herholz K, Nordberg A, Salmon E, et al. (1999). Impairment of neocortical metabolism predicts progression in Alzheimer’s disease. Dement Geriatr Cogn Disord 10: 494–504. Herholz K, Perani D, Salmon E, et al. (1993). Comparability of FDG PET studies in probable Alzheimer’s disease. J Nucl Med 34: 1460–1466.

Herholz K, Salmon EDP, Holthoff V, et al. (2004). Prospective multicenter study of the discrimination between dementia of Alzheimer and frontotemporal type by automatic pattern detection on FDG PET scans. J Nucl Med 25: 66P. Herholz K, Salmon E, Perani D, et al. (2002). Discrimination between Alzheimer dementia and controls by automated analysis of multicenter FDG PET. Neuroimage 17: 302–316. Higdon R, Foster NL, Koeppe RA, et al. (2004). A comparison of classification methods for differentiating frontotemporal dementia from Alzheimer’s disease using FDGPET imaging. Stat Med 23: 315–326. Hisanaga K, Suzuki H, Tanji H, et al. (2001). Fluoro-DOPA and FDG positron emission tomography in a case of pathologically verified pure diffuse Lewy body disease. J Neurol 248: 905–906. Hodges JR, Patterson K, Oxbury S, et al. (1992). Semantic dementia. Progressive fluent aphasia with temporal lobe atrophy. Brain 115: 1783–1806. Holland SK, Plante E, Weber Byars A, et al. (2001). Normal fMRI brain activation patterns in children performing a verb generation task. Neuroimage 14: 837–843. Holthoff VA, Sandmann J, Pawlik G, et al. (1990). Positron emission tomography in Creutzfeldt-Jakob disease. Arch Neurol 47: 1035–1038. Hsu M, Bhatt M, Adolphs R, Tranel D, et al. (2005). Neural systems responding to degrees of uncertainty in human decision-making. Science 310: 1680–1683. Ibanez V, Pietrini P, Alexander GE, et al. (1998). Regional glucose metabolic abnormalities are not the result of atrophy in Alzheimer’s disease. Neurology 50: 1585–1593. ICD10 (1992). International Statistical Classification of Diseases and Related Health Problems. 1989, Revision, Geneva, World Health Organization, 1992. Imamura T, Ishii K, Hirono N, et al. (1999). Visual hallucinations and regional cerebral metabolism in dementia with Lewy bodies (DLB). Neuroreport 10: 1903–1907. Imamura T, Ishii K, Sasaki M, et al. (1997). Regional cerebral glucose metabolism in dementia with Lewy bodies and Alzheimer’s disease: A comparative study using positron emission tomography. Neurosci Lett 235: 49–52. Imran MB, Kawashima R, Awata S, et al. (1999). Parametric mapping of cerebral blood flow deficits in Alzheimer’s disease: A SPECT study using HMPAO and image standardization technique. J Nucl Med 40: 244–249. Indefrey P, Levelt P (2000). The neural correlates of language production. In: MS Gazzaniga (Ed.), The New Cognitive Neurosciences. The MIT Press, Cambridge, pp. 845–865. Ishii K, Imamura T, Sasaki M, et al. (1998a). Regional cerebral glucose metabolism in dementia with Lewy bodies and Alzheimer’s disease. Neurology 51: 125–130. Ishii K, Sasaki M, Yamaji S, et al. (1998b). Relatively preserved hippocampal glucose metabolism in mild Alzheimer’s disease. Dement Geriatr Cogn Disord 9: 317–322. Johnson JS, Newport EL (1989). Critical period effects in second language learning: The influence of maturational

FUNCTIONAL NEUROIMAGING OF COGNITION state on the acquisition of English as a second language. Cognit Psychol 21: 60–99. Jones AK, Kitchen ND, Watabe H, et al. (1999). Measurement of changes in opioid receptor binding in vivo during trigeminal neuralgic pain using [11C] diprenorphine and positron emission tomography. J Cereb Blood Flow Metab 19: 803–808. Josephs O, Henson RN (1999). Event-related functional magnetic resonance imaging: Modelling, inference and optimization. Philos Trans R Soc Lond B Biol Sci 354: 1215–1228. Kaasinen V, Aalto S, Nagren K, et al. (2004). Insular dopamine D2 receptors and novelty seeking personality in Parkinson’s disease. Mov Disord 19: 1348–1351. Karbe H, Thiel A, Weber-Luxenburger G, et al. (1998). Brain plasticity in poststroke aphasia: What is the contribution of the right hemisphere? Brain Lang 64: 215–230. Kato T, Knopman D, Liu H (2001). Dissociation of regional activation in mild AD during visual encoding: A functional MRI study. Neurology 57: 812–816. Kempler D, Metter EJ, Riege WH, et al. (1990). Slowly progressive aphasia: Three cases with language, memory, CT and PET data. J Neurol Neurosurg Psychiatry 53: 987–993. Kimura D (1973). Manual activity during speaking. II. Lefthanders. Neuropsychologia 11: 51–55. Kippenhan JS, Barker WW, Nagel J, et al. (1994). Neuralnetwork classification of normal and Alzheimer’s disease subjects using high-resolution and low-resolution PET cameras. J Nucl Med 35: 7–15. Kippenhan JS, Barker WW, Pascal S, et al. (1992). Evaluation of a neural-network classifier for PET scans of normal and Alzheimer’s disease subjects. J Nucl Med 33: 1459–1467. Klingberg T, Forssberg H, Westerberg H (2002). Increased brain activity in frontal and parietal cortex underlies the development of visuospatial working memory capacity during childhood. J Cogn Neurosci 14: 1–10. Klingberg T, Hedehus M, Temple E, et al. (2000). Microstructure of temporo-parietal white matter as a basis for reading ability: Evidence from diffusion tensor magnetic resonance imaging. Neuron 25: 493–500. Knauff M, Mulack T, Kassubek J, et al. (2002). Spatial imagery in deductive reasoning: A functional MRI study. Brain Res Cogn Brain Res 13: 203–212. Knowlton BJ, Mangels JA, Squire LR (1996). A neostriatal habit learning system in humans. Science 273: 1399–1402. Koechlin E, Ody C, Kouneiher F (2003). The architecture of cognitive control in the human prefrontal cortex. Science 302: 1181–1185. Koelsch S, Fritz T, Schulze K, et al. (2005). Adults and children processing music: An fMRI study. Neuroimage 25: 1068–1076. Koepp MJ, Gunn RN, Lawrence AD, et al. (1998). Evidence for striatal dopamine release during a video game. Nature 393: 266–268. Koepp MJ, Richardson MP, Brooks DJ, et al. (1998). Focal cortical release of endogenous opioids during readinginduced seizures. Lancet 352: 952–955.

105

Kong Q, Surewicz WK, Petersen RB, et al. (2004). Inherited prion diseases. In: SB Prusiner (Ed.), Prion Biology and Diseases. Cold Spring Harbor Laboratory Press, New York, pp. 673–775. Kuhl DE, Minoshima S, Fessler JA, et al. (1996). In vivo mapping of cholinergic terminals in normal aging, Alzheimer’s disease, and Parkinson’s disease. Ann Neurol 40: 399–410. Kurz AF, Erkinjuntti T, Small GW, et al. (2003). Long-term safety and cognitive effects of galantamine in the treatment of probable vascular dementia or Alzheimer’s disease with cerebrovascular disease. Eur J Neurol 10: 633–640. Kwon H, Reiss AL, Menon V (2002). Neural basis of protracted developmental changes in visuo-spatial working memory. Proc Natl Acad Sci USA 99: 13336–13341. Kwong KK, Wanke I, Donahue KM, et al. (1995). EPI imaging of global increase of brain MR signal with breath-hold preceded by breathing O2. Magn Reson Med 33: 448–452. Laakso A, Wallius E, Kajander J, et al. (2003). Personality traits and striatal dopamine synthesis capacity in healthy subjects. Am J Psychiatry 160: 904–910. Landerl K, Wimmer H, Frith U (1997). The impact of orthographic consistency on dyslexia: A German–English comparison. Cognition 63: 315–334. Langdon D, Warrington EK (2000). The role of the left hemisphere in verbal and spatial reasoning tasks. Cortex 36: 691–702. Laruelle M (2000). Imaging synaptic neurotransmission with in vivo binding competition techniques: A critical review. J Cereb Blood Flow Metab 20: 423–451. Lenneberg EH (1967). Biological Foundations of Language. Wiley, New York. Livingstone MS, Rosen GD, Drislane FW, et al. (1991). Physiological and anatomical evidence for a magnocellular defect in developmental dyslexia. Proc Natl Acad Sci USA 88: 7943–7947. Logan J, Dewey SL, Wolf AP, et al. (1991). Effects of endogenous dopamine on measures of [18F]N-methylspiroperidol binding in the basal ganglia: Comparison of simulations and experimental results from PET studies in baboons. Synapse 9: 195–207. Logothetis NK, Pauls J, Augath M, et al. (2001). Neurophysiological investigation of the basis of the fMRI signal. Nature 412: 150–157. Logothetis NK, Pfeuffer J (2004). On the nature of the BOLD fMRI contrast mechanism. Magn Reson Imaging 22: 1517–1531. Logothetis NK, Wandell BA (2004). Interpreting the BOLD signal. Annu Rev Physiol 66: 735–769. Lovegrove WJ, Bowling A, Badcock D, et al. (1980). Specific reading disability: Differences in contrast sensitivity as a function of spatial frequency. Science 210: 439–440. Lucignani G, Gobbo C, Moresco RM, et al. (2002). The feasibility of statistical parametric mapping for the analysis of positron emission tomography studies using 11C-2-betacarbomethoxy-3-beta-(4-fluorophenyl)-tropane in patients with movement disorders. Nucl Med Commun 23: 1047–1055.

106

D. PERANI

Lugaresi E, Medori R, Montagna P, et al. (1986). Fatal familial insomnia and dysautonomia with selective degeneration of thalamic nuclei. N Engl J Med 315: 997–1003. Luis CA, Loewenstein DA, Acevedo A, et al. (2003). Mild cognitive impairment: Directions for future research. Neurology 61: 438–444. Luna B, Thulborn KR, Munoz DP, et al. (2001). Maturation of widely distributed brain function subserves cognitive development. Neuroimage 13: 786–793. Lustig C, Snyder AZ, Bhakta M, et al. (2003). Functional deactivations: Change with age and dementia of the Alzheimer type. Proc Natl Acad Sci USA 100: 14504–14509. Machulda MM, Ward HA, Borowski B, et al. (2003). Comparison of memory fMRI response among normal, MCI, and Alzheimer’s patients. Neurology 61: 500–506. Marshall JC, Fink GR (2003). Cerebral localization, then and now. Neuroimage 20: S2–S7. Martin A, Chao LL (2001). Semantic memory and the brain: Structure and processes. Curr Opin Neurobiol 11: 194–201. Matsumoto K, Tanaka K (2004). Neuroscience. Conflict and cognitive control. Science 303: 969–970. Mattay VS, Goldberg TE (2004). Imaging genetic influences in human brain function. Curr Opin Neurobiol 14: 239–247. Mattay VS, Goldberg TE, Fera F, et al. (2003). Catechol O-methyltransferase val158-met genotype and individual variation in the brain response to amphetamine. Proc Natl Acad Sci USA 100: 6186–6191. Matthews PM, Jezzard P (2004). Functional magnetic resonance imaging. J Neurol Neurosurg Psychiatry 75: 6–12. Mazoyer B, Zago L, Mellet E, et al. (2001). Cortical networks for working memory and executive functions sustain the conscious resting state in man. Brain Res Bull 54: 287–298. McCabe K, Houser D, Ryan L, et al. (2001). A functional imaging study of cooperation in two-person reciprocal exchange. Proc Natl Acad Sci USA 98: 11832–11835. McCloskey MS, Phan KL, Coccaro EF (2005). Neuroimaging and personality disorders. Curr Psychiatry Rep 7: 65–72. Mechelli A, Crinion JT, Noppeney U, et al. (2004). Neurolinguistics: Structural plasticity in the bilingual brain. Nature 431: 757. Mega MS, Chu T, Mazziotta JC, et al. (1999). Mapping biochemistry to metabolism: FDG-PET and amyloid burden in Alzheimer’s disease. Neuroreport 10: 2911–2917. Mega MS, Cummings JL, Fiorello T, et al. (1996). The spectrum of behavioral changes in Alzheimer’s disease. Neurology 46: 130–135. Meltzer CC, Cantwell MN, Greer PJ, et al. (2000). Does cerebral blood flow decline in healthy aging? A PET study with partial-volume correction. J Nucl Med 41: 1842–1848. Meltzoff AN, Decety J (2003). What imitation tells us about social cognition: A rapprochement between developmental psychology and cognitive neuroscience. Philos Trans R Soc Lond B Biol Sci 358: 491–500.

Mendez MF, Chen AK, Shapira JS, et al. (2005). Acquired sociopathy and frontotemporal dementia. Dement Geriatr Cogn Disord 20: 99–100. Mentis MJ, Alexander GE, Krasuski J, et al. (1998). Increasing required neural response to expose abnormal brain function in mild versus moderate or severe Alzheimer’s disease: PET study using parametric visual stimulation. Am J Psychiatry 155: 785–794. Messa C, Colombo C, Moresco RM, et al. (2003). 5-HT(2A) receptor binding is reduced in drug-naive and unchanged in SSRI-responder depressed patients compared to healthy controls: A PET study. Psychopharmacology (Berl) 167: 72–78. Mielke R, Herholz K, Grond M, et al. (1994). Clinical deterioration in probable Alzheimer’s disease correlates with progressive metabolic impairment of association areas. Dementia 5: 36–41. Miller EK, Cohen JD (2001). An integrative theory of prefrontal cortex function. Annu Rev Neurosci 24: 167–202. Minoshima S, Frey KA, Koeppe RA, et al. (1995). A diagnostic approach in Alzheimer’s disease using three-dimensional stereotactic surface projections of fluorine-18-FDG PET. J Nucl Med 36: 1238–1248. Minoshima S, Giordani B, Berent S, et al. (1997). Metabolic reduction in the posterior cingulate cortex in very early Alzheimer’s disease. Ann Neurol 42: 85–94. Moeller JR, Ishikawa T, Dhawan V, et al. (1996). The metabolic topography of normal aging. J Cereb Blood Flow Metab 16: 385–398. Moresco RM, Dieci M, Vita A, et al. (2002). In vivo serotonin 5HT(2A) receptor binding and personality traits in healthy subjects: A positron emission tomography study. Neuroimage 17: 1470–1478. Moro A, Tettamanti M, Perani D, et al. (2001). Syntax and the brain: Disentangling grammar by selective anomalies. Neuroimage 13: 110–118. Morris ED, Fisher RE, Alpert NM, et al. (1995). In vivo imaging of neuromodulation using positron emission tomography: Optimal ligand characteristics and task length for detection of activation. Hum Brain Mapp 3: 35–55. Mosconi L, Herholz K, Prohovnik I, et al. (2005a). Metabolic interaction between ApoE genotype and onset age in Alzheimer’s disease: Implications for brain reserve. J Neurol Neurosurg Psychiatry 76: 15–23. Mosconi L, Perani D, Sorbi S, et al. (2004a). MCI conversion to dementia and the APOE genotype: A prediction study with FDG-PET. Neurology 63: 2332–2340. Mosconi L, Pupi A, De Cristofaro MT, et al. (2004b). Functional interactions of the entorhinal cortex: An 18F-FDG PET study on normal aging and Alzheimer’s disease. J Nucl Med 45: 382–392. Mosconi L, Tsui WH, DeSanti S, et al. (2005). Reduced hippocampal metabolism in MCI and AD: Automated FDGPET image analysis. Neurology 64(11): 1860–1867. Mummery CJ, Patterson K, Hodges JR, et al. (1996). Generating ‘tiger’ as an animal name or a word beginning with T: Differences in brain activation. Proc Biol Sci 263: 989–995.

FUNCTIONAL NEUROIMAGING OF COGNITION Musso M, Moro A, Glauche V, et al. (2003). Broca’s area and the language instinct. Nat Neurosci 6: 774–781. Musso M, Weiller C, Kiebel S, et al. (1999). Training-induced brain plasticity in aphasia. Brain 122: 1781–1790. Nakao T, Nakagawa A, Yoshiura T, et al. (2005). Brain activation of patients with obsessive-compulsive disorder during neuropsychological and symptom provocation tasks before and after symptom improvement: A functional magnetic resonance imaging study. Biol Psychiatry 57: 901–910. Neary D, Snowden JS, Gustafson L, et al. (1998). Frontotemporal lobar degeneration: A consensus on clinical diagnostic criteria. Neurology 51: 1546–1554. Nelson CA, Monk CS, Lin J, et al. (2000). Functional neuroanatomy of spatial working memory in children. Dev Psychol 36: 109–116. Nestor PJ, Fryer TD, Smielewski P, et al. (2003). Limbic hypometabolism in Alzheimer’s disease and mild cognitive impairment. Ann Neurol 54: 343–351. Neville HJ, Bavelier D (1998). Neural organization and plasticity of language. Curr Opin Neurobiol 8: 254–258. Nicolson RI, Fawcett AJ (1990). Automaticity: A new framework for dyslexia research? Cognition 35: 159–182. Nicolson RI, Fawcett AJ (1994). Reaction times and dyslexia. Q J Exp Psychol A 47: 29–48. Nicolson RI, Fawcett AJ, Berry EL, et al. (1999). Association of abnormal cerebellar activation with motor learning difficulties in dyslexic adults. Lancet 353: 1662–1667. Nicolson RI, Fawcett AJ, Dean P (1995). Time estimation deficits in developmental dyslexia: Evidence of cerebellar involvement. Proc R Soc Lond B Biol Sci 259: 43–47. Nicolson RI, Fawcett AJ, Dean P (2001). Developmental dyslexia: The cerebellar deficit hypothesis. Trends Neurosci 24: 508–511. Noppeney U, Friston KJ, Price CJ (2004). Degenerate neuronal systems sustaining cognitive functions. J Anat 205: 433–442. Nordberg A (2004). PET imaging of amyloid in Alzheimer’s disease. Lancet Neurol 3: 519–527. Nowak MA, Page KM, Sigmund K (2000). Fairness versus reason in the ultimatum game. Science 289: 1773–1775. Nussbaum RL, Ellis CE (2003). Alzheimer’s disease and Parkinson’s disease. N Engl J Med 348: 1356–1364. Nyberg L, Marklund P, Persson J, et al. (2003). Common prefrontal activations during working memory, episodic memory, and semantic memory. Neuropsychologia 41: 371–377. Ogawa S, Lee TM, Kay AR, et al. (1990). Brain magnetic resonance imaging with contrast dependent on blood oxygenation. Proc Natl Acad Sci USA 87: 9868–9872. Olesen PJ, Nagy Z, Westerberg H, et al. (2003). Combined analysis of DTI and fMRI data reveals a joint maturation of white and gray matter in a fronto-parietal network. Brain Res Cogn Brain Res 18: 48–57. Osherson D, Perani D, Cappa S, et al. (1998). Distinct brain loci in deductive versus probabilistic reasoning. Neuropsychologia 36: 369–376.

107

Otten LJ, Henson RN, Rugg MD (2001). Depth of processing effects on neural correlates of memory encoding: Relationship between findings from across- and within-task comparisons. Brain 124: 399–412. Owen AM, Stern CE, Look RB, et al. (1998). Functional organization of spatial and nonspatial working memory processing within the human lateral frontal cortex. Proc Natl Acad Sci USA 95: 7721–7726. Pappata S, Dehaene S, Poline JB, et al. (2002). In vivo detection of striatal dopamine release during reward: A PET study with [(11)C]raclopride and a single dynamic scan approach. Neuroimage 16: 1015–1027. Pappata S, Mazoyer B, Tran Dinh S, et al. (1990). Effects of capsular or thalamic stroke on metabolism in the cortex and cerebellum: A positron tomography study. Stroke 21: 519–524. Parchi P, Castellani R, Cortelli P, et al. (1995). Regional distribution of protease-resistant prion protein in fatal familial insomnia. Ann Neurol 38: 21–29. Parsey RV, Mann JJ (2003). Applications of positron emission tomography in psychiatry. Semin Nucl Med 33: 129–135. Parsons LM, Osherson D (2001). New evidence for distinct right and left brain systems for deductive versus probabilistic reasoning. Cereb Cortex 11: 954–965. Paulesu E, Demonet JF, Fazio F, et al. (2001). Dyslexia: Cultural diversity and biological unity. Science 291: 2165–2167. Paulesu E, Frith U, Snowling M, et al. (1996). Is developmental dyslexia a disconnection syndrome? Evidence from PET scanning. Brain 119:143–157. Paulesu E, McCrory E, Fazio F, et al. (2000). A cultural effect on brain function. Nat Neurosci 3: 91–96. Paulesu E, Perani D, Blasi V, et al. (2003). A functional-anatomical model for lipreading. J Neurophysiol 90: 2005–2013. Paus T (2005). Mapping brain maturation and cognitive development during adolescence. Trends Cogn Sci 9: 60–68. Perani D, Abutalebi J, Paulesu E, et al. (2003a). The role of age of acquisition and language usage in early, high-proficient bilinguals: An fMRI study during verbal fluency. Hum Brain Mapp 19: 170–182. Perani D, Bressi S, Cappa SF, et al. (1993a). Evidence of multiple memory systems in the human brain. A [18F] FDG PET metabolic study. Brain 116: 903–919. Perani D, Cappa SF, Tettamanti M, et al. (2003b). A fMRI study of word retrieval in aphasia. Brain Lang 85: 357–368. Perani D, Cortelli P, Lucignani G, et al. (1993b). [18F]FDG PET in fatal familial insomnia: The functional effects of thalamic lesions. Neurology 43: 2565–2569. Persson J, Nyberg L, Lind J, et al. (2005). Structure–function correlates of cognitive decline in aging. Cereb Cortex 16: 907–915. Petersen RC, Doody R, Kurz A, et al. (2001). Current concepts in mild cognitive impairment. Arch Neurol 58: 1985–1992.

108

D. PERANI

Petit-Taboue MC, Landeau B, Desson JF, et al. (1998). Effects of healthy aging on the regional cerebral metabolic rate of glucose assessed with statistical parametric mapping. Neuroimage 7: 176–184. Petrella JR, Lustig C, Bucher LA, et al. (2002). Prefrontal activation patterns in subjects at risk for Alzheimer disease. Am J Geriatr Psychiatry 10: 112–113. Petrides M, Pandya DN (1999). Dorsolateral prefrontal cortex: Comparative cytoarchitectonic analysis in the human and the macaque brain and corticocortical connection patterns. Eur J Neurosci 11: 1011–1036. Petrides M, Pandya DN (2002). Comparative architectonic analysis of the human and macaque frontal cortex. In: F Boller, J Grafman (Eds.), Handbook of Neuropsychology. Elsevier, Amsterdam. Pietrini P, Furey ML, Alexander GE, et al. (1999). Association between brain functional failure and dementia severity in Alzheimer’s disease: Resting versus stimulation PET study. Am J Psychiatry 156: 470–473. Pimlott SL (2005). Radiotracer development in psychiatry. Nucl Med Commun 26: 183–188. Pine DS, Grun J, Maguire EA, et al. (2002). Neurodevelopmental aspects of spatial navigation: A virtual reality fMRI study. Neuroimage 15: 396–406. Poldrack RA, Clark J, Pare-Blagoev EJ, et al. (2001a). Interactive memory systems in the human brain. Nature 414: 546–550. Poldrack RA, Rodriguez P (2004). How do memory systems interact? Evidence from human classification learning. Neurobiol Learn Mem 82: 324–332. Poldrack RA, Temple E, Protopapas A, et al. (2001b). Relations between the neural bases of dynamic auditory processing and phonological processing: Evidence from fMRI. J Cogn Neurosci 13: 687–697. Price C (1998). The functional anatomy of word comprehension and production. Trends Cogn Sci 2: 281–288. Price CJ (2000). The anatomy of language: Contributions from functional neuroimaging. J Anat 197: 335–359. Price CJ, Friston KJ (2002). Degeneracy and cognitive anatomy. Trends Cogn Sci 6: 416–421. Price CJ, Mummery CJ, Moore CJ, et al. (1999). Delineating necessary and sufficient neural systems with functional imaging studies of neuropsychological patients. J Cogn Neurosci 11: 371–382. Prvulovic D, Hubl D, Sack AT, et al. (2002). Functional imaging of visuospatial processing in Alzheimer’s disease. Neuroimage 17: 1403–1414. Raichle ME, Fiez JA, Videen TO, et al. (1994). Practicerelated changes in human brain functional anatomy during nonmotor learning. Cereb Cortex 4: 8–26. Rajah MN, D’Esposito M (2005). Region-specific changes in prefrontal function with age: A review of PET and fMRI studies on working and episodic memory. Brain 128: 1964–1983. Ramnani N, Behrens TE, Penny W, et al. (2004). New approaches for exploring anatomical and functional connectivity in the human brain. Biol Psychiatry 56: 613–619.

Ramus F (2003). Developmental dyslexia: Specific phonological deficit or general sensorimotor dysfunction? Curr Opin Neurobiol 13: 212–218. Read DE (1981). Solving deductive-reasoning problems after unilateral temporal lobectomy. Brain Lang 12: 116–127. Reed BR, Eberling JL, Mungas D, et al. (2004). Effects of white matter lesions and lacunes on cortical function. Arch Neurol 61: 1545–1550. Reiman EM, Caselli RJ, Yun LS, et al. (1996). Preclinical evidence of Alzheimer’s disease in persons homozygous for the epsilon 4 allele for apolipoprotein E. N Engl J Med 334: 752–758. Reiman EM, Chen K, Alexander GE, et al. (2004). Functional brain abnormalities in young adults at genetic risk for lateonset Alzheimer’s dementia. Proc Natl Acad Sci USA 101: 284–289. Reivich M, Alavi A, Wolf A, et al. (1985). Glucose metabolic rate kinetic model parameter determination in humans: the lumped constants and rate constants for [18F]fluorodeoxyglucose and [11C]deoxyglucose. J Cereb Blood Flow Metab 5: 179–192. Richardson MP, Strange BA, Dolan RJ (2004). Encoding of emotional memories depends on amygdala and hippocampus and their interactions. Nat Neurosci 7: 278–285. Ridderinkhof KR, Ullsperger M, Crone EA, et al. (2004a). The role of the medial frontal cortex in cognitive control. Science 306: 443–447. Ridderinkhof KR, van den Wildenberg WP, Segalowitz SJ, et al. (2004b). Neurocognitive mechanisms of cognitive control: The role of prefrontal cortex in action selection, response inhibition, performance monitoring, and rewardbased learning. Brain Cogn 56: 129–140. Rizzolatti G, Fadiga L, Gallese V, et al. (1996). Premotor cortex and the recognition of motor actions. Brain Res Cogn Brain Res 3: 131–141. Rombouts SA, van Swieten JC, Pijnenburg YA, et al. (2003). Loss of frontal fMRI activation in early frontotemporal dementia compared to early AD. Neurology 60: 1904–1908. Ruff S, Cardebat D, Marie N, et al. (2002). Enhanced response of the left frontal cortex to slowed down speech in dyslexia: An fMRI study. Neuroreport 13: 1285–1289. Rugg MD (2002). Functional imaging of memory. In: AD Baddeley, MD Kopleman, BA Wilson (Eds.), Handbook of Memory Disorders. 2nd edn, John Wiley & Sons, Chichester, pp. 57–80. Rumsey JM, Andreason P, Zametkin AJ, et al. (1992). Failure to activate the left temporoparietal cortex in dyslexia. An oxygen 15 positron emission tomographic study. Arch Neurol 49: 527–534. Rumsey JM, Horwitz B, Donohue BC, et al. (1999). A functional lesion in developmental dyslexia: Left angular gyral blood flow predicts severity. Brain Lang 70: 187–204. Rumsey JM, Nace K, Donohue B, et al. (1997). A positron emission tomographic study of impaired word recognition

FUNCTIONAL NEUROIMAGING OF COGNITION and phonological processing in dyslexic men. Arch Neurol 54: 562–573. Rushworth MF, Walton ME, Kennerley SW, et al. (2004). Action sets and decisions in the medial frontal cortex. Trends Cogn Sci 8: 410–417. Rypma B, D’Esposito M (2000). Isolating the neural mechanisms of age-related changes in human working memory. Nat Neurosci 3: 509–515. Saccuman MC, Cappa SF, Bates EA, et al. (2006). The impact of semantic reference on word class: an fMRI study of action and object naming. Neuroimage 32: 1865–1878. Salmelin R, Service E, Kiesila P, et al. (1996). Impaired visual word processing in dyslexia revealed with magnetoencephalography. Ann Neurol 40: 157–162. Salmon E, Garraux G, Delbeuck X, et al. (2003). Predominant ventromedial frontopolar metabolic impairment in frontotemporal dementia. Neuroimage 20: 435–440. Salmon E, Maquet P, Sadzot B, et al. (1991). Decrease of frontal metabolism demonstrated by positron emission tomography in a population of healthy elderly volunteers. Acta Neurol Belg 91: 288–295. Sanfey AG, Rilling JK, Aronson JA, et al. (2003). The neural basis of economic decision-making in the Ultimatum Game. Science 300: 1755–1758. Saxe R, Carey S, Kanwisher N (2004). Understanding other minds: Linking developmental psychology and functional neuroimaging. Annu Rev Psychol 55: 87–124. Schapiro MB, Schmithorst VJ, Wilke M, et al. (2004). BOLD fMRI signal increases with age in selected brain regions in children. Neuroreport 15: 2575–2578. Schlaggar BL, Brown TT, Lugar HM, et al. (2002). Functional neuroanatomical differences between adults and schoolage children in the processing of single words. Science 296: 1476–1479. Schmidt B, Braun HA, Narlawar R (2005). Drug development and PET-diagnostics for Alzheimer’s disease. Curr Med Chem 12: 1677–1695. Shaywitz BA, Shaywitz SE, Pugh KR, et al. (2002). Disruption of posterior brain systems for reading in children with developmental dyslexia. Biol Psychiatry 52: 101–110. Shaywitz SE, Shaywitz BA, Fulbright RK, et al. (2003). Neural systems for compensation and persistence: Young adult outcome of childhood reading disability. Biol Psychiatry 54: 25–33. Shaywitz SE, Shaywitz BA, Pugh KR, et al. (1998). Functional disruption in the organization of the brain for reading in dyslexia. Proc Natl Acad Sci USA 95: 2636–2641. Shuren JE, Grafman J (2002). The neurology of reasoning. Arch Neurol 59: 916–919. Signorini M, Paulesu E, Friston K, et al. (1999). Rapid assessment of regional cerebral metabolic abnormalities in single subjects with quantitative and nonquantitative [18F]FDG PET: A clinical validation of statistical parametric mapping. Neuroimage 9: 63–80. Silani G, Frith U, Demonet JF, et al. (2005). Brain abnormalities underlying altered activation in dyslexia: A voxel based morphometry study. Brain 128: 2453–2461.

109

Simos PG, Fletcher JM, Bergman E, et al. (2002). Dyslexiaspecific brain activation profile becomes normal following successful remedial training. Neurology 58: 1203–1213. Siok WT, Perfetti CA, Jin Z, et al. (2004). Biological abnormality of impaired reading is constrained by culture. Nature 431: 71–76. Small GW, Ercoli LM, Silverman DH, et al. (2000). Cerebral metabolic and cognitive decline in persons at genetic risk for Alzheimer’s disease. Proc Natl Acad Sci USA 97: 6037–6042. Small SA, Perera GM, DeLaPaz R, et al. (1999). Differential regional dysfunction of the hippocampal formation among elderly with memory decline and Alzheimer’s disease. Ann Neurol 45: 466–472. Smith GS, de Leon MJ, George AE, et al. (1992). Topography of cross-sectional and longitudinal glucose metabolic deficits in Alzheimer’s disease. Pathophysiologic implications. Arch Neurol 49: 1142–1150. Smith GS, Koppel J, Goldberg S (2003). Applications of neuroreceptor imaging to psychiatry research. Psychopharmacol Bull 37: 26–65. Smith JD, Sikes J, Levin JA (1998). Human apolipoprotein E allele-specific brain expressing transgenic mice. Neurobiol Aging 19: 407–413. Snowling MJ (1981). Phonemic deficits in developmental dyslexia. Psychol Res 43: 219–234. Snyder AZ, Abdullaev YG, Posner MI, et al. (1995). Scalp electrical potentials reflect regional cerebral blood flow responses during processing of written words. Proc Natl Acad Sci USA 92: 1689–1693. Sokoloff L (1979). Mapping of local cerebral functional activity by measurement of local cerebral glucose utilization with [14C]deoxyglucose. Brain 102: 653–668. Sperling RA, Bates JF, Chua EF, et al. (2003). fMRI studies of associative encoding in young and elderly controls and mild Alzheimer’s disease. J Neurol Neurosurg Psychiatry 74: 44–50. Stein DJ, Buchsbaum MS, Hof PR, et al. (1998). Greater metabolic rate decreases in hippocampal formation and proisocortex than in neocortex in Alzheimer’s disease. Neuropsychobiology 37: 10–19. Stein J, Walsh V (1997). To see but not to read; the magnocellular theory of dyslexia. Trends Neurosci 20: 147–152. Stephan KE, Harrison LM, Penny WD, et al. (2004). Biophysical models of fMRI responses. Curr Opin Neurobiol 14: 629–635. Stephan KE, Marshall JC, Friston KJ, et al. (2003). Lateralized cognitive processes and lateralized task control in the human brain. Science 301: 384–386. Strafella AP, Paus T, Barrett J, et al. (2001). Repetitive transcranial magnetic stimulation of the human prefrontal cortex induces dopamine release in the caudate nucleus. J Neurosci 21: RC157. Stuss DT, Benson DF (1984). Neuropsychological studies of the frontal lobes. Psychol Bull 95: 3–28. Stuss DT, Benson DF (1986). The Frontal Lobes. Raven Press, New York.

110

D. PERANI

Sugrue LP, Corrado CS, Newsome VT, et al. (2005). Choosing the greater of two goods: Neural currencies for valuation and decision making. Nat Rev Neurosci 6: 363–375. Suhara T, Yasuno F, Sudo Y, et al. (2001). Dopamine D2 receptors in the insular cortex and the personality trait of novelty seeking. Neuroimage 13: 891–895. Sultzer DL, Mahler ME, Cummings JL, et al. (1995). Cortical abnormalities associated with subcortical lesions in vascular dementia. Clinical and position emission tomographic findings. Arch Neurol 52: 773–780. Talairach J, Tournoux P (1988). Co-Planar Stereotaxic Atlas of the Human Brain. Thieme Medical Publishers, New York. Tallal P (1980). Auditory temporal perception, phonics, and reading disabilities in children. Brain Lang 9: 182–198. Tallal P, Miller S, Fitch RH (1993). Neurobiological basis of speech: A case for the preeminence of temporal processing. Ann NY Acad Sci 682: 27–47. Tallal P, Piercy M (1973). Defects of non-verbal auditory perception in children with developmental aphasia. Nature 241: 468–469. Temple E, Poldrack RA, Protopapas A, et al. (2000). Disruption of the neural response to rapid acoustic stimuli in dyslexia: Evidence from functional MRI. Proc Natl Acad Sci USA 97: 13907–13912. Temple E, Poldrack RA, Salidis J, et al. (2001). Disrupted neural responses to phonological and orthographic processing in dyslexic children: An fMRI study. Neuroreport 12: 299–307. Tettamanti M, Alkadhi H, Moro A, et al. (2002). Neural correlates for the acquisition of natural language syntax. Neuroimage 17: 700–709. Thierry G, Cardebat D, Demonet JF (2003). Electrophysiological comparison of grammatical processing and semantic processing of single spoken nouns. Brain Res Cogn Brain Res 17: 535–547. Thierry G, Doyon B, Demonet JF (1998). ERP mapping in phonological and lexical semantic monitoring tasks: A study complementing previous PET results. Neuroimage 8: 391–408. Thomas KM, King SW, Franzen PL, et al. (1999). A developmental functional MRI study of spatial working memory. Neuroimage 10: 327–338. Thompson-Schill SL, D’Esposito M, Aguirre GK, et al. (1997). Role of left inferior prefrontal cortex in retrieval of semantic knowledge: A reevaluation. Proc Natl Acad Sci USA 94: 14792–14797. Tranel D, Bechara A, Denburg NL (2002). Asymmetric functional roles of right and left ventromedial prefrontal cortices in social conduct, decision-making, and emotional processing. Cortex 38: 589–612. Tyrrell PJ, Warrington EK, Frackowiak RS, et al. (1990). Progressive degeneration of the right temporal lobe studied with positron emission tomography. J Neurol Neurosurg Psychiatry 53: 1046–1050.

Tzourio-Mazoyer N, De Schonen S, Crivello F, et al. (2002). Neural correlates of woman face processing by 2month-old infants. Neuroimage 15: 454–461. Valla J, Berndt JD, Gonzalez-Lima F (2001). Energy hypometabolism in posterior cingulate cortex of Alzheimer’s patients: Superficial laminar cytochrome oxidase associated with disease duration. J Neurosci 21: 4923–4930. Vallar G, Papagno C (2002). Neuropsychological impairments of verbal short-term memory. In: A Baddeley, B Wilson, M Kopelman (Eds.), Handbook of Memory Disorders. 2nd edn. Wiley, Chichester. Varma AR, Snowden JS, Lloyd JJ, et al. (1999). Evaluation of the NINCDS-ADRDA criteria in the differentiation of Alzheimer’s disease and frontotemporal dementia. J Neurol Neurosurg Psychiatry 66: 184–188. Verghese J, Crystal HA, Dickson DW, et al. (1999). Validity of clinical criteria for the diagnosis of dementia with Lewy bodies. Neurology 53: 1974–1982. Viard A, Flament MF, Artiges E, et al. (2005). Cognitive control in childhood-onset obsessive-compulsive disorder: A functional MRI study. Psychol Med 35: 1007–1017. Vitali P, Tettamanti M., Abutalebi J., et al. (2003). Recovery from anomia: Effects of specific rehabilitation on brain reorganisation: An er-fMRI study in 2 anomic patients. Brain Lang 87: 126–127. Voermans NC, Petersson KM, Daudey L, et al. (2004). Interaction between the human hippocampus and the caudate nucleus during route recognition. Neuron 43: 427–435. Volkow ND, Fowler JS, Wang GJ (2003). Positron emission tomography and single-photon emission computed tomography in substance abuse research. Semin Nucl Med 33: 114–128. Von Monakow C (1914). Die Lokalisation in Grosshirn und der Abbau der Funktion durch Kortikale Herde. Bergmann, Wiesbaden. Vuilleumier P, Richardson MP, Armony JL, et al. (2004). Distant influences of amygdala lesion on visual cortical activation during emotional face processing. Nat Neurosci 7: 1271–1278. Walker Z, Costa DC, Ince P, et al. (1999). In-vivo demonstration of dopaminergic degeneration in dementia with Lewy bodies. Lancet 354: 646–647. Warburton E, Price CJ, Swinburn K, et al. (1999). Mechanisms of recovery from aphasia: Evidence from positron emission tomography studies. J Neurol Neurosurg Psychiatry 66: 155–161. Wartenburger I, Abutalebi J, Cappa SF, et al. (2003). Early setting of grammatical processing in the bilingual brain. Neuron 37: 159–170. Weber C, Hahne A, Friedrich M, et al. (2005). Reduced stress pattern discrimination in 5-month-olds as a marker of risk for later language impairment: Neurophysiologial evidence. Brain Res Cogn Brain Res 25: 180–187. Weiller C, Isensee C, Rijntjes M, et al. (1995). Recovery from Wernicke’s aphasia: A positron emission tomographic study. Ann Neurol 37: 723–732.

FUNCTIONAL NEUROIMAGING OF COGNITION Weinberger DR, Gibson R, Coppola R, et al. (1991). The distribution of cerebral muscarinic acetylcholine receptors in vivo in patients with dementia. A controlled study with 123IQNB and single photon emission computed tomography. Arch Neurol 48: 169–176. Wharton CM, Grafman J (1998). Deductive reasoning and the brain. Trends Cogn Sci 2: 54–59. Whitaker H, Markovits H, Savary F (1991). Inference deficits after brain damage. J Clin Exp Neuropsychol 13: 38–38. Wise RJ (2003). Language systems in normal and aphasic human subjects: Functional imaging studies and inferences from animal studies. Br Med Bull 65: 95–119. Woodward AL, Guajardo JJ (2002). Infants’ understanding of the point gesture as an object-directed action. Cogn Dev 83: 1–24. Yamaguchi S, Meguro K, Itoh M, et al. (1997). Decreased cortical glucose metabolism correlates with hippocampal atrophy in Alzheimer’s disease as shown by MRI and PET. J Neurol Neurosurg Psychiatry 62: 596–600.

111

Zatorre RJ, Belin P (2001). Spectral and temporal processing in human auditory cortex. Cereb Cortex 11: 946–953. Zatorre RJ, Evans AC, Meyer E, et al. (1992). Lateralization of phonetic and pitch discrimination in speech processing. Science 256: 846–849. Zubieta JK, Heitzeg MM, Smith YR, et al. (2003). COMT val158met genotype affects mu-opioid neurotransmitter responses to a pain stressor. Science 299: 1240–1243. Zubieta JK, Smith YR, Bueller JA, et al. (2001). Regional mu opioid receptor regulation of sensory and affective dimensions of pain. Science 293: 311–315. Zuendorf G, Kerrouche N, Herholz K, et al. (2003). Efficient principal component analysis for multivariate 3D voxelbased mapping of brain functional imaging data sets as applied to FDG-PET and normal aging. Hum Brain Mapp 18: 13–21.

Handbook of Clinical Neurology, Vol. 88 (3rd series) Neuropsychology and behavioral neurology G. Goldenberg, B.L. Miller, Editors # 2008 Elsevier B.V. All rights reserved

Chapter 5

Neuropsychology of aging and dementia DAVID P. SALMON* Department of Neurosciences, University of California, San Diego, CA, USA

5.1. Introduction As an increasing number of people survive into older age in most developed countries, there is growing clinical and research interest in the consequences of aging on cognition. Much of this interest has focused on the detection and characterization of cognitive deficits associated with age-related neurodegenerative diseases. The most common of these diseases is Alzheimer’s disease (AD), a degenerative brain disorder that usually begins in later life (e.g., ages 60–70) characterized by neuronal atrophy, synapse loss, and the abnormal accumulation of diffuse and neuritic plaques and neurofibrillary tangles. Age-related neurodegenerative diseases such as AD occur against the backdrop of relatively subtle cognitive changes that take place during the course of normal aging (for reviews, see Park et al., 2003; Hedden and Gabrieli, 2004). Age-related cognitive decline is particularly evident in information processing abilities such as effortful encoding of new information, processing speed, inductive reasoning, and working memory. In contrast, little age-related decline is evident in semantic knowledge and vocabulary, autobiographical remote memory, and automatic memory processes (e.g., priming). The nature of the cognitive decline that occurs with healthy aging has led to several psychological and neurological models to account for these changes. One influential psychological model (Salthouse, 1996) suggests that a general decline in processing speed underlies most of the cognitive decline that occurs with age. According to this model, an age-related decline in information processing speed reduces the ability to efficiently integrate and organize information and causes a decline in memory by reducing the efficiency of information encoding, rehearsal, and retrieval. Similar psychological models suggest that cognitive decline in *

healthy elderly is caused by decline in a single factor such as working memory, inhibitory processes, or sensory function (Park et al., 2003; Kramer et al., 2004). Neurologically based models of age-related cognitive decline suggest that specific aspects of the brain are particularly vulnerable to aging and their deterioration leads to a decline in the cognitive abilities they mediate. There is evidence, for example, that atrophy of the prefrontal cortex and loss of frontal white matter integrity occurs as a normal consequence of aging (West, 1996; Greenwood, 2000) and these changes result in age-related declines in so-called ‘frontal functions’ such as working memory, cognitive flexibility, verbal fluency, directed and divided attention, and self-monitoring performance (West, 1996; Grady and Craik, 2000; Raz, 2005). It has also been suggested that aging has a particularly adverse effect on white matter tracts that integrate brain regions to form neural networks (O’Sullivan et al., 2001; Bartzokis, 2004; Pfefferbaum et al., 2005; Raz, 2005). The general loss of white matter connectivity may lead to an age-related ‘disconnection’ syndrome that causes cognitive changes beyond those that are usually considered frontal lobe functions, such as memory and visuospatial abilities. It has also been suggested that decline in multiple neurological processes with different life-span trajectories may better explain cognitive changes associated with normal aging than any single neurobiological factor (Band et al., 2002; Buckner, 2004; Kramer et al., 2004). Given our growing knowledge of the cognitive changes that occur throughout the lifespan, research efforts in the neuropsychology of aging and dementia have focused on differentiating the cognitive deficits associated with various neurodegenerative disorders from normal aging. These efforts have led to increased knowledge about the particular neuropsychological

Correspondence to: David P. Salmon, Ph.D., Department of Neurosciences (0948), University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093-0948. E-mail: [email protected], Tel: (858)-622-5853, Fax: (858) 622-1012.

114

D.P. SALMON

deficits that occur in the earliest stages of an age-related dementing disorder such as AD, and have recently provided information concerning cognitive changes that appear to presage the development of dementia. These neuropsychological advances have greatly enhanced the ability to clinically diagnosis AD in its early stages and to differentiate AD from other neurological disorders that affect cognition and produce a dementia syndrome. This ability is particularly important given that there are currently no peripheral biological markers for AD and that neuroprotective agents designed to impede the disease’s progression are being developed (Thal, 1999). Accordingly, the present chapter reviews the current state of knowledge regarding the neuropsychological detection of early AD, the impact of aging on the ability to detect the disease, cognitive changes that might presage the development of dementia in those with ‘preclinical’ AD, and differences in the cognitive manifestations of AD and other neurodegenerative disorders that can aid differential clinical diagnosis and provide important information about the neurological basis of memory, language, executive functions, and visuospatial processes.

5.2. Neuropsychological detection of Alzheimer’s disease Given the prevalence and significance of memory dysfunction in dementia and AD, it is not surprising that this aspect of cognition has been the focus of extensive neuropsychological research on the early detection of the disease. Research with patients with AD has shown that measures of the ability to learn and retain new information are quite effective in differentiating between mildly demented patients and normal older adults (e.g., Storandt et al., 1984; Eslinger et al., 1985; Kaszniak et al., 1986; Huff et al., 1987; Bayles et al., 1989; Delis et al., 1991). In particular, measures of delayed recall have revealed abnormally rapid forgetting by patients with AD, a characteristic that has important clinical utility for the detection and differential diagnosis of the disease (e.g., Butters et al., 1988; Welsh et al., 1991; Locascio et al., 1995; but see RobinsonWhelan and Storandt, 1992). Several studies have shown that measures of rapid forgetting expressed as absolute delayed recall scores or ‘savings’ scores (i.e., amount recalled after the delay divided by the amount recalled on the immediate learning trial) can differentiate mildly demented AD patients from healthy elderly controls with approximately 85–90% accuracy (Butters et al., 1988; Knopman and Ryberg, 1989; Flicker et al., 1991; Morris et al., 1991; Welsh et al., 1991; Tro¨ster et al., 1993).

The abnormally rapid forgetting exhibited by patients with AD suggests that their memory impairment may be due to ineffective consolidation of information. This possibility is supported by studies that have shown that to-be-remembered information is not accessible after a delay even if retrieval demands are reduced by the use of recognition testing (e.g., Delis et al., 1991), and by studies that demonstrate an abnormal serial position effect in the episodic memory performance of patients with AD (Miller, 1971; Wilson et al., 1983; Spinnler et al., 1988; Pepin and Eslinger, 1989; Delis et al., 1991; Capitani et al., 1992; Massman et al., 1993; Carlesimo et al., 1995; Greene et al., 1996; Bayley et al., 2000). In these latter studies, patients with AD are consistently shown to have an attenuation of the primacy effect (i.e., recall of words from the beginning of a list) in the relatively early stages of the disease, suggesting that they cannot effectively transfer information from primary memory (i.e., a passive, time-dependent, limited capacity store that allows the most recent items to be better recalled than other items) to secondary memory (an actively accessed, long-lasting store that allows early list items that received the greatest amount of processing to be better recalled than other items), or they cannot maintain information in secondary memory after its successful transfer. This deficit has been incorporated into several widely used clinical tests of memory that can distinguish between primary (or short-term) and secondary (or long term) memory such as the Buschke Selective Reminding Test (Buschke, 1973; Buschke and Fuld, 1974). A deficient ability to initially encode information may also adversely affect AD patients’ performance on episodic memory tasks (Martin et al., 1985). Semantic encoding procedures (Dalla Barba and Goldblum, 1996; Goldblum et al., 1998) or the use of categorically organizable material that would allow for semantic encoding strategies (for review, see Ba¨ckman and Herlitz, 1996; Ba¨ckman and Small, 1998) are less effective for improving the episodic memory performance of patients with AD than for normal elderly individuals. Several effective clinical memory tests are based upon the difficulty patients with AD have in utilizing semantic information to improve encoding in episodic memory tasks (e.g., Knopman and Ryberg, 1989; Buschke et al., 1997). Another prominent feature of the memory deficit of patients with AD is an enhanced tendency to produce intrusion errors (i.e., when previously learned information is produced during the attempt to recall new material) on both verbal and non-verbal memory tests (Fuld et al., 1982; Fuld, 1983; Butters et al., 1987; Jacobs et al., 1990; Delis et al., 1991). The abnormal production

NEUROPSYCHOLOGY OF AGING AND DEMENTIA of intrusion errors has been interpreted as increased sensitivity to interference and/or decreased inhibitory processes in patients with AD, and is correlated with the number of neuritic plaques and amount of acetylcholine depletion found in the patients’ brains at autopsy (Fuld et al., 1982). Although intrusion errors are not a pathognomonic sign of AD (Jacobs et al., 1990), their prevalence can be a useful adjunct to other memory measures (e.g., total recall, recognition memory, rate of forgetting) in developing clinical algorithms for differentiating AD from other types of dementia (Delis et al., 1991; Massman et al., 1992). Semantic memory that underlies general knowledge and language (Tulving, 1983) is often disturbed relatively early in the course of AD (for reviews, see Bayles and Kaszniak, 1987; Nebes, 1989; Salmon and Chan, 1994; Hodges and Patterson, 1995). This disturbance is evident in AD patients’ reduced ability to recall overlearned facts (e.g., the number of days in a year; Norton et al., 1997), and in their impairment on tests of confrontation naming (Bayles and Tomoeda, 1983; Martin and Fedio, 1983; Huff et al., 1986; Bowles et al., 1987; Hodges et al., 1991) and verbal fluency (Martin and Fedio, 1983; Butters et al., 1987; Monsch et al., 1994). Consistent with an impairment of semantic memory, the spontaneous speech of patients with AD is frequently vague, empty of content words, and filled with indefinite phrases and circumlocutions (Nicholas et al., 1985). There is evidence to suggest that the semantic memory deficit of patients with AD reflects the loss of semantic knowledge for particular items or concepts during the course of the disease. Studies that have probed for knowledge of particular concepts across different modes of access and output (e.g., fluency, confrontation naming, sorting, word-to-picture matching, definition generation) showed that patients with AD were significantly impaired on all measures of semantic memory, regardless of the specific task, and had item-to-item correspondence so that when a particular stimulus item was missed (or correctly identified) in one task, it was likely to be missed (or correctly identified) in other tasks that accessed the information in a different way (Chertkow and Bub, 1990; Hodges et al., 1992). In another study, Norton and colleagues (1997) found a progressive decline in semantic knowledge in mildly demented patients with AD who were longitudinally followed with a test of general knowledge that had minimal language demands. Patients were highly consistent in the individual items they missed in each subsequent yearly test session, suggesting a true loss of knowledge (rather than deficient retrieval) over the course of the disease (also see Salmon et al., 1999).

115

Deficits in ‘executive’ functions responsible for concurrent mental manipulation of information, concept formation, problem solving, and cue-directed behavior occur early in the course of AD (see Perry and Hodges, 1999). The ability to perform concurrent manipulation of information appears to be particularly vulnerable, as a study by Lefleche and Albert (1995) demonstrated that very mildly demented patients with AD were significantly impaired relative to elderly normal control subjects on tests that required set-shifting, self-monitoring, or sequencing, but not on tests that required cue-directed attention or verbal problem solving. Furthermore, Bondi et al. (1993b) found that the number of categories achieved on a modified version of the Wisconsin Card Sorting Task, a test that assesses set-shifting and self-monitoring, provided excellent sensitivity (94%) and specificity (87%) for differentiating between mildly demented AD patients and normal elderly subjects. Patients with AD have also been shown to be impaired on difficult problem solving tests (e.g., Tower of London puzzle; Lange et al., 1995) and on various other clinical neuropsychological tests that involve executive functions such as the Porteus Maze Task, Part B of the Trail-Making Test, and the Raven Progressive Matrices Task (Grady et al., 1988). Patients with AD exhibit deficits in some aspects of attention relatively early in the course of the disease, particularly on dual-processing tasks, tasks that require the disengagement and shifting of attention, and working memory tasks that are dependent upon the control of attentional resources (for reviews, see Parasuraman and Haxby, 1993; Perry and Hodges, 1999). The ability to focus and sustain attention is usually only affected in later stages of the disease, as was shown by the essentially normal performance of mildly demented AD patients on the Attention/Concentration Index of the Wechsler Memory Scale-Revised (WMS-R), a measure derived from performance on tests of digit span (forwards and backwards), visual memory span (forwards and backwards), and mental control (Butters et al., 1988). Deficits in visuoperceptual abilities, visuospatial abilities, and constructional praxis occur in patients with AD, but they usually emerge after the early stages of the disease and may have little to contribute to the differentiation of early dementia from normal aging (e.g., Storandt et al., 1984; Locascio et al., 1995). Once beyond the early stages of dementia, patients with AD exhibit impaired performance on visuoconstructional tasks such as the Block Design Test (Larrabee et al., 1985; La Rue and Jarvik, 1987; Mohr et al., 1990; Villardita, 1993; Pandovani et al., 1995), the Clock Drawing Test (for review, see Freedman et al., 1994), or copying a complex figure (Mohr et al., 1990;

116

D.P. SALMON

Villardita, 1993; Locascio et al., 1995; Pandovani et al., 1995), and on tasks that require visuoperception and visual orientation such as the Judgement of Line Orientation test (Ska et al., 1990), the Left–Right Orientation test (Fischer et al., 1990), and the Money Road Map Test (Flicker et al., 1988; Liu et al., 1991; Locascio et al., 1995). The clinical utility of neuropsychological testing for differentiating between very early AD and normal aging was shown in a study by Salmon and colleagues (2002). Ninety-eight patients with AD who scored 24 or higher (out of 30) on the Mini-Mental State Exam (MMSE) were matched on the basis of gender, age, and years of education to 98 normal control subjects in order to compare their performances on a neuropsychological evaluation that included sensitive measures of learning and memory, executive abilities, language, and visuospatial abilities. The diagnosis of AD was verified in each of the AD patients by subsequent autopsy or longitudinal clinical evaluations that showed a typical course for the disease. Receiver Operating Characteristic (ROC) curve analyses of individual test data from the initial evaluation showed excellent sensitivity and specificity for the detection of very mild AD for the Mattis Dementia Rating Scale (sensitivity: 96%, specificity: 92%), learning and delayed recall measures from the California Verbal Learning Test (CVLT) (sensitivity: 95–98%, specificity: 88–89%), delayed recall from the Logical Memory Test (sensitivity: 87%, specificity: 89%), delayed recall from the Visual Reproduction Test (sensitivity: 87%, specificity: 86%), Category Fluency (sensitivity: 96%, specificity: 88%), and Part B of the Trail Making Test (sensitivity: 85%, specificity: 83%). The Block Design Test was an effective measure from the visuospatial domain (sensitivity: 78%, specificity: 79%) (Fig. 5.1). The clinical utility of combinations of neuropsychological test measures from the various cognitive domains was examined by subjecting the data to Classification Tree analysis, a non-parametric recursive partitioning procedure that considers all possible binary splits of the data in pursuit of optimal discrimination. Classification trees provide an intuitive classification process that can be readily applied to clinical diagnosis. The optimal diagnostic model obtained with the procedure included performance on the category fluency test and the delayed recall measure of the Visual Reproduction Test. A score < 39.5 on the Category Fluency Test and a score < 8.5 on the delayed recall measure from the Visual Reproduction Test indicated a high probability of having mild AD, whereas a score > 39.5 on the Category Fluency Test, or a score < 39.5 on this measure with a score > 8.5 on the delayed recall measure of the Visual

Reproduction Test, indicated a high probability of being normal. Performance on this combination of cognitive measures accurately classified 96% of the patients with AD and 93% of the elderly normal control subjects, a level of accuracy higher than achieved with any individual cognitive measure (Fig. 5.2).

5.3. The impact of aging on the neuropsychological detection of Alzheimer’s disease The clinical detection of AD is particularly difficult in very elderly individuals (e.g., over the age of 80) because many of the cognitive abilities affected by the disease are also detrimentally affected by normal aging (e.g., executive functions, memory processes). After performance is standardized to the age-appropriate normal cohort to reduce the impact of age-related changes in cognition, the prominence of specific deficits associated with AD may be less salient in very elderly individuals than in those who are younger. This may result in a less distinct and somewhat atypical cognitive deficit profile associated with AD in the very elderly compared to that of the typical AD patient. This was recently illustrated in a study that directly compared the neuropsychological test performance of AD patients who were over the age of 80 or below the age of 70 in terms of the raw scores they achieved on the tests and scores that were standardized to their respective age-appropriate normal control groups (Bondi et al., 2003). Despite similar raw scores on all neuropsychological measures, the patient groups differed significantly in the severity and pattern of cognitive deficits they exhibited in relation to their ageappropriate controls (Fig. 5.3). The AD patients below the age of 70 were generally more impaired than the patients over the age of 80 and showed a typical AD profile of particularly salient deficits in executive functions and the retention of episodic memories (i.e., savings scores) relative to deficits in other cognitive domains. The more elderly AD patients, in contrast, exhibited a similar level of impairment across all cognitive domains so that their deficit profile lacked the disproportionate saliency of memory and executive function deficits typical of the disease. Because the raw scores of the younger and older AD patients were comparable, the distinct cognitive profiles reflect differences in the respective age-matched normative cohorts. Indeed, the older control group performed significantly worse than the younger control group on nearly all cognitive tests, with the largest differences apparent on tests of memory, executive functions, and category fluency. It should also be noted that the variance associated with the various cognitive

NEUROPSYCHOLOGY OF AGING AND DEMENTIA

117

Fig. 5.1. Receiver Operating Characteristic (ROC) curves comparing sensitivity and specificity for the accurate diagnosis of Alzheimer’s disease (AD) achieved with the Trial 1–5 Learning measure from the California Verbal Learning Test (CVLT), the Category Fluency Test, Part B of the Trail-Making Test, and the Block Design Test. The maximally effective cutpoint for memory and executive function measures showed excellent sensitivity and specificity in distinguishing between very mild AD and normal aging (adapted from Salmon et al., 2002).

measures was similar for the two control groups, so it is unlikely that the ‘better’ z-scores of the older AD patients are an artifact of increased variability with aging. It is more likely that the better z-scores reflect lower mean performance in the older control group for tests of cognitive abilities that are vulnerable to normal age-related decline. The results of this study demonstrate that normal aging can significantly impact the severity and pattern

of neuropsychological deficits associated with early AD and reduce the saliency of these features as diagnostic markers of the disease. Clinicians run a particular risk of false negative diagnostic errors in very elderly AD patients if they expect to see the typical deficit pattern that has been described through studies of younger patients and healthy controls. A multifaceted approach to diagnosis that integrates neuropsychological assessment, neuroimaging, and genetic

118

D.P. SALMON

Fig. 5.2. A Classification and Regression Tree (CART) model that was maximally effective for differentiating between patients with mild Alzheimer’s disease (AD) and normal control (NC) subjects. The initial variables entered into the analysis were the total score from the DRS, delayed recall from the CVLT, delayed recall from the Visual Reproduction Test, delayed recall from the Logical Memory Test, time to complete Part B of the Trail-Making Test, and total correct on the Category Fluency Test. The final model showed excellent sensitivity and specificity in distinguishing between very mild AD and normal aging (adapted from Salmon et al., 2002).

Fig. 5.3. The average composite impairment score achieved by Alzheimer’s disease (AD) patients older than age 80 or younger than age 70 in the cognitive domains of language, visuospatial abilities, executive functions, and memory (savings scores). The presented scores are z-scores referenced to the patient groups’ respective age-appropriate healthy elderly control cohort (adapted from Bondi et al., 2003).

factors may be needed to identify early AD in patients over the age of 80, the fastest growing and most vulnerable segment of the population.

5.4. Neuropsychological detection of ‘preclinical’ Alzheimer’s disease One of the most active areas of neuropsychological research on AD is the attempt to identify cognitive

changes that occur during a so-called ‘preclinical’ phase that precedes the manifestation of the overt dementia syndrome. These efforts are based on the current view that the neurodegenerative changes of AD begin well before the clinical manifestations of the disease become apparent (e.g., Katzman, 1994). As the pathology of AD gradually progresses, a threshold for the initiation of the clinical symptoms of the dementia syndrome is eventually reached. Once this threshold

NEUROPSYCHOLOGY OF AGING AND DEMENTIA is crossed, the cognitive deficits associated with AD become evident and gradually worsen in parallel with continued neurodegeneration. When the cognitive deficits become global and severe enough to interfere with normal social and occupational functioning, established criteria (e.g., DSM-IV) for dementia and a clinical diagnosis of AD are met. Prospective studies of nondemented older adults have shown that a subtle decline in episodic memory often occurs prior to the emergence of the obvious cognitive and behavioral changes required for a clinical diagnosis of AD (Fuld et al., 1990; Bondi et al., 1994; Jacobs et al., 1995; Grober and Kawas, 1997; Howieson et al., 1997), possibly many years prior to the onset of dementia (Linn et al., 1995; Bondi et al., 1999; Small et al., 2000; Ba¨ckman et al., 2001; Kawas et al., 2003). In one such study, Bondi et al. (1999) compared the neuropsychological test performances of nondemented elderly individuals with or without at least one ApoE e4 allele. Because the e4 allele is a risk factor for AD, a higher percentage of individuals with ‘preclinical’ AD were presumably in the e4þ group than in the e4 group. Although the groups did not differ significantly in age, education, or global cognitive status, the e4þ subjects performed significantly worse than the e4 subjects on measures of delayed recall, but not on tests of other cognitive abilities. Cox proportional hazards analysis showed that ApoE e4 status and measures of delayed recall were significant independent predictors of subsequent conversion to AD, suggesting that poor recall is an early sensitive neuropsychological marker of AD and not a cognitive phenotype of the e4 genotype. Several studies have examined the course of episodic memory changes during the preclinical phase of AD (Rubin et al., 1998; Small et al., 2000; Ba¨ckman et al., 2001; Chen et al., 2001; Storandt et al., 2002). Small et al. (2000) and Ba¨ckman et al. (2001) found that episodic memory was mildly impaired six years prior to dementia onset, but changed little over the next three years. However, other studies showed a significant and steady decline in episodic memory in individuals with preclinical AD, beginning about three years prior to diagnosis (Chen et al., 2001; Lange et al., 2002). Thus, imminent conversion to dementia might be better predicted by an abrupt decline in memory rather than by poor but stable memory abilities. This state of poor memory performance in nondemented elderly individuals has been shown to predict the subsequent development of dementia and is known variously as ‘preclinical’ AD (Bondi et al., 1994), ‘questionable’ dementia (Albert et al., 2001), or Mild Cognitive Impairment (MCI; Petersen et al., 1995). After considerable research and clinical interest (for review, see Collie & Maruff, 2000), formal criteria

119

for MCI have been proposed (Petersen et al., 1995; 2001a) and recent practice parameters recommend systematically monitoring patients with MCI for subsequent conversion to possible or probable AD (Petersen et al., 2001b). Recent reviews suggest that the cognitive decline in the two or three years preceding a non-normal diagnosis is largely nonspecific. These reviews revealed that while memory was clearly impaired prior to development of the clinical dementia syndrome, so were executive functioning, perceptual speed, verbal ability, visuospatial skill, and attention (Ba¨ckman et al. 2004; 2005; Twamley et al., 2006). This broad-based decline in cognitive functioning mirrors evidence suggesting that multiple brain regions such as the medial temporal lobes, the frontal lobes, and the anterior cingulate are impaired in preclinical AD (Albert et al., 2001; Small et al., 2003). Consistent with this broader view, Jacobson et al. (2002) found that asymmetric cognitive profiles were a preclinical marker of AD in older, at-risk adults. Based upon prior research documenting lateralized cognitive deficits (e.g., greater verbal than visuospatial deficits, or vice versa) in subgroups of mildly demented patients with AD, these investigators reasoned that inconsistent findings of cognitive markers in at-risk groups may occur because subgroups of subjects have asymmetric deficits that cannot be appreciated with the use of a single test. Accordingly, Jacobson et al. compared 20 cognitively normal elderly adults who were in a preclinical phase of AD (i.e., they were diagnosed with AD approximately one year later) and 20 age- and education-matched normal control subjects on a number of cognitive tests and a derived score that reflected the absolute difference between verbal and visuospatial ability (i.e., a measure of cognitive asymmetry). The results showed that the groups performed similarly on individual cognitive tests of memory, language, and visuospatial ability, but that the preclinical AD patients exhibited consistent evidence of subtle dysfunction on the measure of cognitive asymmetry. These results suggest that there is a subgroup of preclinical AD patients who have asymmetric cognitive changes in either the verbal or visuospatial direction that may be obscured when cognitive scores are averaged over the entire group. Consideration of these non-memory changes, along with subtle declines in memory that have been noted in the preclinical phase of AD may improve the ability to detect AD in its earliest stages.

5.5. Distinguishing Alzheimer’s disease from other age-related causes of dementia Although AD is the leading cause of dementia in the elderly, it has been known for some time that dementia

120

D.P. SALMON

can arise from a wide variety of etiologically and neuropathologically distinct disorders that give rise to somewhat different patterns of relatively preserved and impaired cognitive abilities. This is quite evident in differences observed between dementia syndromes associated with neurodegenerative diseases that primarily involve regions of the cerebral cortex (e.g., AD and frontotemporal dementia) and those that have their primary locus in subcortical brain structures (e.g., Huntington’s disease, Parkinson’s disease, Progressive Supranuclear Palsy). Huntington’s disease (HD) and Parkinson’s disease (PD) are neurodegenerative diseases that produce a ‘subcortical’ dementia syndrome through their effects on basal ganglia and brainstem structures. Huntington’s disease is an inherited, autosomal dominant disease that results in the midlife (e.g., ages 30–40) development of movement disorder (e.g., chorea, dysarthria, gait disturbance, oculomotor dysfunction), behavioral changes (e.g., depression, irritability, and anxiety) and dementia due to progressive deterioration of the neostriatum (caudate nucleus and putamen) (Vonsattel et al., 1985; Folstein, 1989; Folstein et al., 1990). Parkinson’s disease is characterized by a loss of pigmented cells in the substantia nigra pars compacta (resulting in a major depletion of dopamine) and the presence of Lewy bodies (abnormal intracytoplasmic eosinophilic neuronal inclusion bodies) in the substantia nigra, locus ceruleus, dorsal motor nucleus of the vagus, substantia innominata (Jellinger, 1987; Jankovic, 1987; Hansen and Galasko, 1992), and in most cases the neocortex (Hughes et al., 1992). Parkinson’s disease usually begins in later life (e.g., ages 60–70) and is clinically identified by the classic motor-symptom triad of resting tremor, rigidity, and bradykinesia, with associated symptoms such as postural stooping, gait disturbances (shuffling gait), masked facies, micrographia, hypophonia, dysarthria, and poor prosody (monotoned speech) (Marsden, 1990). Parkinson’s disease is also associated with cognitive decline and a recent systematic review suggests that 24–31% are demented (Aarsland et al., 2005). The cognitive deficits associated with PD, HD, and other subcortical neurodegenerative diseases may be a consequence of damage to so-called ‘frontostriatal loops’ that are circuits consisting of projections from the frontal neocortex to the striatum, striatum to the globus pallidus, globus pallidus to thalamus, and thalamus back to specific neocortical regions of the frontal lobes (e.g., dorsolateral prefrontal, orbitofrontal, and anterior cingulate cortex) (Alexander et al., 1986). These circuits are believed to provide a subcortical influence on both motor control and higher cognitive functions, and damage to specific aspects of the circuits may explain subtle differences in the nature of the

cognitive impairment manifested in various neurodegenerative diseases that produce a subcortical dementia syndrome (Alexander et al., 1986). In contrast to the prominent amnesia, semantic memory loss (i.e., anomia and agnosia), and constructional apraxia that characterize cortical/limbic neurodegenerative diseases such as AD, the cognitive dysfunction associated with the subcortical dementia syndrome is broadly characterized by slowness of thought, impaired attention, poor learning, visuoperceptual and constructional deficits, and personality changes such as apathy and depression (Albert et al., 1974; McHugh and Folstein, 1975; Cummings and Benson, 1984). Both cortical and subcortical dementia syndromes are associated with significant executive dysfunction, but the character of this dysfunction differs in the two disorders. The ensuing sections of the chapter will describe the quantitative and qualitative differences between cortical (i.e., AD) and subcortical (i.e., HD and PD) dementia syndromes in terms of the deficits in learning and memory, language and semantic knowledge, attention, working memory and executive functions, and visuospatial abilities they entail. Knowledge of these differences can aid in differential diagnosis and lead to better understanding of the neurobiological basis of various cognitive disorders. 5.5.1. Learning and memory As mentioned previously, a severe deficit in episodic memory (i.e., the storage and recollection of temporally dated autobiographical events that depend upon temporal and/or spatial contextual cues for their retrieval) is characteristic of the cortical dementia syndrome of AD and has been attributed to ineffective consolidation (i.e., storage) of new information (Salmon, 2000). Patients with the subcortical dementia syndrome of HD, in contrast, exhibit a mild to moderate memory impairment that appears to result from a general deficit in the ability to initiate and carry out the systematic retrieval of successfully stored information (Butters et al. 1985; 1986; Moss et al., 1986). This distinction in the episodic memory deficits associated with the two disorders was illustrated in a study by Delis et al. (1991) that directly compared the performances of patients with AD and patients with HD on a rigorous test of verbal learning and memory, the California Verbal Learning Test (CVLT). The CVLT is a standardized memory test that assesses rate of learning, retention after short- and long-delay intervals, semantic encoding ability, recognition memory, intrusion and perseverative errors, and response biases. In the test, a list of 16 shopping items (four items in each of four categories) is presented verbally on five consecutive

NEUROPSYCHOLOGY OF AGING AND DEMENTIA presentation/free recall trials. A single interference trial with a different list of 16 items is then presented in the same manner. Immediately after this interference trial, free-recall and then cued-recall of the first list of shopping items is assessed. Twenty minutes later, freerecall and then cued-recall is again assessed, followed by a yes–no recognition test that consists of the 16 items on the first shopping list and 28 distractor items. The results of this study showed that despite comparable immediate and delayed free- and cued-recall deficits (based on age-corrected normative data), the HD and AD patients could be distinguished by two major differences in their performances. First, patients with AD were just as impaired on the recognition trial as they were on the immediate and delayed free recall trials, whereas patients with HD were less impaired on the recognition trial than on the various free recall trials. The significant improvement shown by the HD patients when memory was tested with a recognition procedure has been observed in a number of additional studies (Butters et al. 1985; 1986; but see Brandt et al., 1992), and suggests that when the need for effortful, strategic retrieval is reduced, the memory impairment exhibited by these patients is greatly attenuated. The second major difference observed by Delis and colleagues was that patients with AD exhibited significantly faster forgetting of information over the 20minute delay interval than did the patients with HD (see also Butters et al., 1988; Tro¨ster et al., 1993).

121

While patients with HD retained approximately 70% of the initially acquired information over the delay interval, patients with AD retained less than 20%. This pattern of performance is consistent with the notion that information is not effectively consolidated and rapidly dissipates in patients with the cortical–limbic damage that occurs in AD. In patients with the frontostriatal damage of HD, information appears to be successfully stored, but cannot be effectively retrieved either immediately or after a delay interval. Although the episodic memory deficits in cortical and subcortical dementia syndromes are broadly different, there is evidence that the distinction is more or less clear depending upon the neurodegenerative disease underlying the subcortical dementia syndrome. Massman et al. (1990) showed that the CVLT performances of patients with HD and PD were quite similar with a pattern indicative of a prominent retrieval deficit (e.g., both had mildly deficient encoding, normal retention over a delay, difficulty initiating systematic retrieval strategies), but that the two patient groups differed in the salience of this pattern. In general, patients with HD had a more severe free recall deficit and showed a greater improvement on recognition testing compared to free recall than patients with PD (Fig. 5.4). Zizak and colleagues (2005) recently extended these findings in a study that classified the CVLT performances of patients with HD or PD as demonstrating or not demonstrating a retrieval deficit profile (i.e., significantly

0

Mean Z-Score

−1

−2

−3

−4

Alzheimer's Disease Huntington's Disease Parkinson's Disease

−5 Delayed Recall

Delayed Recognition

Fig. 5.4. The mean age-corrected z-scores achieved by patients with Alzheimer’s disease (AD), Huntington’s disease (HD), or Parkinson’s disease (PD) on the 20-minute delayed recall and delayed recognition (i.e., discriminability) measures from the California Verbal Learning Test. The pattern of performance for AD (recognition < recall) suggests an encoding/storage deficit, whereas the pattern for HD and PD (recognition > recall) suggests a retrieval deficit (adapted from Delis et al., 1991 and Massman et al., 1990).

122

D.P. SALMON

higher standardized scores on CVLT recognition indices compared to free recall indices). The results showed that a clear retrieval deficit profile was more prevalent in patients with HD than those with PD, but only occurred in about 44% of the HD patients. In addition, the profile tended to occur in those patients who had at least a mildto-moderate level of global dementia. Several studies have shown that the memory performance of patients with PD can be quite variable and difficult to classify. Filoteo and colleagues (1997) found that about 25% of non-demented PD patients produced a CVLT memory profile indicative of a retrieval deficit (i.e., a subcortical dementia profile), 25% produced a profile indicative of a deficit in encoding and storage (i.e., a cortical dementia profile), and the remaining 50% had no memory impairment (for similar results, see Weintraub et al., 2004). The lack of a retrieval deficit in the memory performance of patients with PD has been reported by others (Higginson et al., 2005), primarily due to a high rate of false-positive errors on recognition tests, an occurrence not usually seen in patients with HD. 5.5.2. Retrograde amnesia A deficit in the ability to remember past events that were successfully remembered prior to a brain injury or the onset of a neurological disease is known as retrograde amnesia (RA). This form of memory impairment often occurs following circumscribed damage to medial temporal lobe (Squire et al., 1989) or diencephalic (Albert et al., 1979) brain structures, and can extend years or decades into the past. The RA associated with damage to the medial temporal–diencephalic memory system often follows a temporal gradient in which information from the distant past is less affected than information from the more recent past. This temporal gradient has been attributed to disruption of a long-term consolidation process (Squire, 1987; Zola-Morgan and Squire, 1990) which has been characterized by some investigators as shifting a memory from a hippocampally mediated episodic form to a cortically mediated semantic form (Cermak, 1984; Hodges, 1995; Kapur, 1999; Schmidtke and Vollmer, 1997). When circumscribed hippocampal–diencephalic damage occurs, there is a relative preservation of the older, more cortically instantiated memories (but see Nadel and Moscovitch, 1997 for a hippocampally mediated explanation of the temporal gradient in retrograde amnesia). Some degree of retrograde amnesia occurs after the onset of most neurodegenerative diseases that produce dementia (Wilson et al., 1981; Beatty et al., 1988b). Mildly demented patients with AD often exhibit a severe and temporally graded retrograde amnesia with

memories from the distant past better retained than memories from the more recent past (Beatty et al. 1988b; Sagar et al., 1988; Kopelman, 1989; Hodges et al., 1993). The temporal gradient is similar to the pattern of loss exhibited by patients with circumscribed amnesia and has been attributed to the interruption of a long-term consolidation process that is critically dependent upon the hippocampal–diencephalic memory system. The interpretation of the temporal gradient of retrograde amnesia in patients with AD is somewhat clouded by the insidious nature of the anterograde memory deficit associated with the disease. It may be the case that information from the most recent decade (or decades) just prior to the diagnosis of AD was not learned as well as more remote information because of a ‘preclinical’ anterograde memory impairment that often occurs before the development of the full dementia syndrome; however, this account is less likely to explain the discrepancy between the AD patients’ retrograde amnesia for information from early versus middle life epochs. The very severe retrograde amnesia exhibited by patients with AD for information from the most remote time periods may result from a combination of the episodic and semantic memory deficits that they suffer (for review, see Salmon, 2000). In AD, the temporal gradient related to the loss of remote episodic memory is superimposed upon a general semantic memory deficit that arises from damage to cortical association areas. This semantic memory loss reduces the amount of information available from all time periods, providing a low baseline level of performance on which to observe the temporal gradient. To explore the possibility that the retrograde amnesia of AD is due to a retrieval deficit rather than an inability to adequately consolidate information over time, Hodges et al. (1993) examined the performance of patients with AD on an updated version of the Famous Faces test that employed recognition and cuing formats. These latter conditions allowed remote memory to be assessed across decades while greatly reducing the retrieval demands of the task. Patients were first shown four faces simultaneously and asked to simply point out the one that was a famous person. They were then asked to name the person, then to identify the person if they could not name them, and then to name the person following the presentation of a semantic (e.g., an actor) or a phonemic (e.g., the person’s initials) cue. The results demonstrated that patients with AD were impaired on the Famous Faces test even when retrieval demands were minimized by using a recognition procedure. Furthermore, the retrograde amnesia that was evident on the recognition and phonemic cuing formats was temporally graded with information from the distant past better retained than information from the more recent past.

NEUROPSYCHOLOGY OF AGING AND DEMENTIA A different pattern of retrograde amnesia often occurs in demented patients with subcortical dysfunction due to HD (Albert et al., 1981; Beatty et al., 1988b), PD (Freedman et al., 1984; Sagar et al., 1988), Multiple Sclerosis (Beatty et al., 1988a), or HIV-associated dementia (Sadek et al., 2004). These patients exhibit a relatively mild retrograde amnesia that equally affects all time periods (Fig. 5.5). Presumably, episodic memory that was acquired in the past is successfully stored and retained over time by these patients, but retrieval of this information is generally deficient causing the remote memory deficit to be equally distributed across decades. This interpretation is bolstered by an analysis of cued retrieval in a remote memory task which indicated a preferential cueing benefit for patients with HD or HIV-associated dementia compared to patients with AD (Sadek et al., 2004). Such a retrieval deficit has been attributed to the frontostriatal dysfunction that characterizes those disorders.

5.5.3. Implicit memory While memory is usually thought of as a conscious process in which an individual explicitly attempts to learn, remember, and retrieve a specific bit of information, there are some forms of memory that can occur implicitly without conscious awareness (Schacter, 1987). This implicit memory is demonstrated through facilitation of performance due simply to prior exposure to the

123

stimuli or procedures of a given task. For example, an individual’s ability to detect a stimulus (or to identify it in a degraded form) might be enhanced upon its second presentation (i.e., priming), or they may show a gradual improvement in the performance of some motor or cognitive act with practice (i.e., motor or cognitive skill learning). There is considerable evidence that implicit memory is generally preserved in patients with circumscribed amnesia indicating that it is not dependent upon the hippocampal–diencephalic memory system that is damaged in these disorders (for review, see Squire, 1987). The neurological basis of implicit memory remains largely unknown; however, studies suggest that some forms of implicit memory are dependent upon the frontostriatal circuits that are damaged in patients with HD and PD while others may be dependent upon the activation of neocortical association areas damaged in AD. Dissociations in the performance of patients with cortical or subcortical dementia syndromes on various types of implicit priming and motor and cognitive skill learning tasks have been noted and may shed some light on the neural bases of these forms of memory. Several studies have shown that implicit priming is differentially affected in cortical and subcortical dementia syndromes. Shimamura et al. (1987) directly compared the performances of patients with AD and HD on a word-stem completion priming test. In this task, subjects were shown 10 words (e.g., MOTEL, ABSTAIN) one at a time and were asked to rate how

Fig. 5.5. The mean percentage of correct responses on the Remote Memory battery as a function of life epoch (left panel). Patients with Alzheimer’s disease exhibit a severe and temporally graded retrograde amnesia (RA), whereas patients with Huntington’s disease or HIV dementia exhibit a mild RA that is equally severe across life epochs. The temporally graded nature of the RA of patients with Alzheimer’s disease is more evident when the number of correct responses from each life epoch is shown as a proportion of all correct responses (right panel) (adapted from Sadek et al., 2004).

124

D.P. SALMON

much they liked each word on a 5-point scale. Following these presentation trials, the subjects were shown 20 three-letter word stems (e.g., MOT, ABS) and were asked to complete each stem with the first word that came to mind. Ten of the stems could be completed using study words, and the other 10 stems were used to assess baseline guessing rates (i.e., completing stems with target words that were not previously presented). Despite pronounced explicit memory deficits, patients with HD and patients with circumscribed amnesia (i.e., alcoholic Korsakoff’s syndrome) displayed significant priming by completing a greater proportion of stems with previously presented words than with non-presented words. Furthermore, the magnitude of their priming was the same as that of normal control subjects. Patients with AD exhibited impaired priming on this task, with little tendency to complete the word stems with the previously presented words. This word-stem completion priming deficit in AD has been replicated in a number of subsequent studies (Salmon et al., 1988; Heindel et al., 1989; Keane et al., 1991; Randolph, 1991; Bondi and Kaszniak, 1991; Perani et al., 1993; Russo and Spinnler, 1994; Fleischman and Gabrieli, 1998), and the disparate pattern of impaired priming in patients with AD and preserved priming in patients with HD has been generalized to several other priming paradigms, including semantic paired-associate priming (Salmon et al., 1988) and priming to enhance the identification of fragmented pictures (Heindel et al., 1990). Word-stem completion priming has also been shown to be normal in non-demented patients with PD (Heindel et al., 1989; Bondi and Kaszniak, 1991), but impaired in PD patients who are demented (Heindel et al., 1989). From a neurobiological perspective, these studies indicate that priming is not dependent upon the hippocampal– diencephalic structures damaged in patients with circumscribed amnesia, or the frontostriatal circuits that are damaged in HD and early PD. Rather, this aspect of implicit memory may be mediated by the neocortical association cortex that is damaged in AD (and that may be compromised by cortical Lewy bodies in PD), or from a deficiency in the level of steady-state cortical activation that could arise from damage to the ascending noradrenergic projection system (i.e., the locus ceruleus) (Sara, 1985) that may be damaged in AD and PD (see Salmon and Heindel, 1992). The ability to learn and retain a motor or cognitive skill with repeated practice is another form of implicit memory that is differentially affected in cortical and subcortical syndromes. This was initially illustrated in a study that directly compared the gradual development of the pursuit rotor motor skill in patients with AD, HD, or circumscribed amnesia. In the pursuit rotor task,

individuals learned over repeated 20-second trials to maintain contact between a hand-held stylus and a small metallic disk that rotated on a turntable (Heindel et al., 1988). Patients with AD and amnesic patients demonstrated rapid and extensive motor learning across trials that was equivalent to that of normal control subjects (for similar results, see Corkin, 1968; Eslinger and Damasio, 1986; Heindel et al., 1989; Bondi et al., 1993a). Patients with HD and demented patients with PD, in contrast, were impaired in learning the motor skills underlying pursuit rotor task performance (for similar results, see Gabrieli et al., 1997). Heindel and colleagues postulated that neostriatal damage leads to a deficiency in developing motor programs which forces reliance on an error-correction mode of performance rather than the more effective predictive mode of performance utilized by AD patients, amnesic patients, and normal control subjects. Importantly, the normal learning exhibited by the patients with AD or circumscribed amnesia show that this form of memory is not dependent upon the hippocampal memory system necessary for episodic memory, or the neocortical association areas that are thought to underlie priming. A number of subsequent studies have replicated this pattern of impaired motor skill learning in patients with HD or PD and preserved motor skill learning in mildly demented patients with AD using an adaptationmediated weight biasing task (Heindel et al., 1991), a perceptual adaptation task that required patients to learn to point to a target while wearing distorting prisms that shifted the perceived location of objects to the right or left (Paulsen et al., 1993), and a serial reaction time task that required implicit learning of a repeating 10-item sequence of key-press responses (Nissen and Bullemer, 1987; Knopman and Nissen, 1987; Grafman et al., 1991; Knopman and Nissen, 1991; Willingham and Koroshetz, 1993; Ferraro et al., 1993; Pascual-Leone et al., 1993). In addition, several studies have shown that patients with HD are impaired in implicitly acquiring the visuoperceptual skill of reading mirror-reversed text (Martone et al., 1984) or the cognitive skill necessary to solve complex problems such as the Tower of Hanoi puzzle (Butters et al., 1985; Saint-Cyr et al., 1988), even though similar deficits were not apparent in patients with AD (Perani et al., 1993; Deweer et al., 1993; 1994; Huberman et al., 1994) or circumscribed amnesia (for review, see Squire, 1987). Patients with HD and PD have also been shown to be impaired in implicitly learning the cognitive skills necessary to perform a probabilistic classification task (Knowlton et al., 1996a; 1996b). In this task, subjects must classify stimulus patterns as being associated with one of two outcomes which occur equally often. The stimulus patterns are composed of four stimuli which are

NEUROPSYCHOLOGY OF AGING AND DEMENTIA independently and probabilistically related to the two outcomes (i.e., correctly predicted one of the outcomes 25, 43, 57 or 75% of the time). The probabilistic structure of the task discourages attempts to explicitly learn the relationship between the stimuli and outcomes, but allows implicit learning of these relationships to take place. Although patients with circumscribed amnesia were able to learn the probabilistic relationship as well as normal control subjects, non-demented patients with PD and patients with HD were impaired in learning the probabilistic relationship between the stimuli and outcomes even though they had normal recall of the training episodes. Interestingly, patients with AD showed normal learning on this task (Colla et al., 2003), although performance was related to the degree of subcortical integrity as measured by magnetic resonance spectroscopy. Subsequent studies with HD and PD patients have extended these findings to show that HD patients are impaired in both rule-based category learning (e.g., learning that a line stimulus is in one category if it is long and another category if it is short) and information-integration category learning (e.g., learning that a line stimulus is in a particular category based upon integrated information from two or more stimulus components like length and orientation), whereas patients with PD tend to be impaired only in informationintegration category learning (Maddox and Filoteo, 2001; Filoteo et al., 2001a; 2005). Similar deficits were not apparent in patients with circumscribed amnesia (Filoteo et al., 2001b) which suggests that the striatum may be particularly important for implicitly learning complex rules. 5.5.4. Language and semantic knowledge A major distinction between cortical and subcortical dementia syndromes is the prominence of language and semantic knowledge (e.g., general knowledge of facts, concepts, and the meanings of words) deficits in cortical disorders such as AD, and the virtual absence of these deficits in subcortical disorders such as HD and PD. Patients with AD are noted for mild anomia and word finding difficulties in spontaneous speech, and a decline in the general structure and organization of semantic knowledge. In contrast, patients with HD and other forms of subcortical dementia are often dysarthric with a slow and reduced speech output (Murray, 2000; Murray and Lenz, 2001), but the semantic knowledge that underlies their language abilities appears to be relatively preserved. These differences in the language and semantic memory abilities of patients with AD and HD were shown in a series of studies of verbal fluency that directly compared their performances on letter fluency

125

tasks that required them to generate as quickly as possible (for 60 seconds) words that begin with the letters ‘F,’ ‘A,’ or ‘S,’ and category fluency tasks that required them to generate as quickly as possible (for 60 seconds) exemplars from a designated semantic category (e.g., animals, fruits, or vegetables) (Butters et al., 1987; Monsch et al., 1994). Patients with HD were severely and equivalently impaired on both types of fluency tasks, whereas patients with AD were more impaired on the category fluency task than on the letter fluency task. Indeed, in the study by Butters et al. (1987), the AD patients exhibited a significant category fluency deficit even though their performance on the letter fluency task was not significantly different from that of normal control subjects. The unique patterns of letter and category fluency performance observed in these studies have been replicated a number of times and confirmed in several meta-analytic studies (Henry et al., 2004; 2005). The pattern of performance of PD patients across types of fluency tasks is less clear, although a meta-analytic study suggests that these patients have slightly greater deficit on category than letter fluency tasks (Henry and Crawford, 2004). The results of these studies support the notion that qualitatively different processes underlie the verbal fluency deficits of AD and HD patients. The fact that patients with AD are more impaired on the fluency task that places greater demands on the integrity of semantic memory suggests that they have a loss of semantic knowledge, or a breakdown in the organization of semantic memory, rather than a general inability to retrieve or access semantic knowledge. A loss of knowledge of the attributes, exemplars, and organization that define a particular semantic category is thought to reduce the ability of patients with AD to efficiently generate words from a small and highly related set of exemplars. The equivalent deficit that patients with HD exhibit on the two fluency tasks suggests that their impairment reflects a general retrieval deficit that is not influenced by the demands the various tasks place on semantic memory. This interpretation of the disparate patterns is supported by a series of studies that examined the temporal dynamics of retrieval from semantic memory during the letter and category fluency tasks (Rohrer et al., 1995; 1999). According to well known random search models (McGill, 1963), if the set size for a particular semantic category is reduced due to a loss of semantic knowledge, mean latency should decrease and be lower than normal. If, on the other hand, the semantic set size remains intact but retrieval is slowed, mean latency should increase and be higher than normal. The results of these studies showed that patients with AD exhibited a lower than normal mean latency consistent with the notion that they

126

D.P. SALMON

suffer a loss of semantic knowledge. Patients with HD, in contrast, exhibited a higher than normal mean response latency which is consistent with the view that damage to frontal–subcortical circuits results in a disruption of retrieval processes. Differences in the language abilities of patients with cortical and subcortical dementia syndromes are apparent on tests of confrontation naming. Numerous studies have shown that patients with AD have a significant naming impairment (Bayles and Tomoeda, 1983; Huff et al., 1986; Bowles et al., 1987) that is not shared by patients with HD (Folstein et al., 1990; Hodges et al., 1991). Direct comparisons have shown that patients with AD are significantly worse than patients with HD on confrontation naming tasks, and that the two groups produce distinct patterns of naming errors (Hodges et al., 1991). Patients with AD make a greater proportion of semantically-based errors (e.g., superordinate errors such as calling a ‘camel’ an ‘animal’) than patients with HD, whereas patients with HD make a greater proportion of perceptually based errors (e.g., calling a ‘pretzel’ a ‘snake’) than patients with AD (Hodges et al., 1991). The tendency of patients with AD to make semantically based errors is consistent with a disruption of the structure and organization of semantic knowledge that may arise from damage to cortical association areas in the temporal, parietal, and frontal lobes. Chan and colleagues directly compared the structure and organization of semantic knowledge in cortical and subcortical dementia syndromes using cluster analysis and multidimensional scaling techniques to statistically model a spatial representation of the degree of association between concepts in semantic memory (for reviews, see Salmon and Chan, 1994; Chan et al., 1998). The degree of association between the various exemplars in the category ‘animals’ was estimated from their proximate position when generated in a verbal fluency task, or from the frequency with which they were paired in a triadic comparison task. The modeling showed that the network of semantic associations (i.e., the semantic network) for patients with HD was virtually identical to that of control subjects, whereas the semantic network of patients with AD was abnormal in several ways. First, AD patients focused primarily on concrete perceptual information (i.e., size) in categorizing animals, whereas control subjects stressed abstract conceptual knowledge (i.e., domesticity). Second, animals that were highly associated and clustered together for control subjects (e.g., cat and dog) were not strongly associated for patients with AD. Third, AD patients were less consistent than control subjects in utilizing the various attributes of animals in categorization (e.g., consistently considering dog a domestic animal). These results provide further evidence that

the cortical dementia syndrome of AD is characterized by a loss of semantic knowledge and semantic organization that does not occur in the subcortical dementia syndrome exhibited by patients with HD. 5.5.5. Attention, working memory, and executive functions Although deficits in attention, working memory, and executive functions occur in both cortical and subcortical dementia syndromes, they play a more prominent role in defining the latter syndrome. A deficit in attention, for example, is an early and prominent feature of cognitive decline in patients with HD or PD (Butters et al., 1978; Caine et al., 1978; Tweedy et al., 1982), but it is not a particularly salient feature of early AD (Huber et al., 1986). This discrepancy is apparent in studies that directly compared the performance of patients with HD or AD on the attention items of the MiniMental State Exam (Brandt et al., 1988), the attention subscale of the Mattis Dementia Rating Scale (Salmon et al., 1989), or the Wechsler Memory Scale-Revised (WMS-R) Attention/Concentration Index (Butters et al., 1988; Tro¨ster et al., 1989). In these latter studies, patients with HD were impaired on the Attention/ Concentration Index and scored significantly worse than equally demented patients with AD in both early and more advanced stages of the diseases. Specific aspects of attentional processing are differentially affected in cortical and subcortical dementia syndromes. Sahakian and colleagues (Lange et al., 1995; Lawrence et al., 1996) showed that patients with AD and mildly demented patients with HD were able to effectively shift attention between stimulus dimensions in a visual discrimination task in which first one stimulus dimension (e.g., color) and then another (e.g., shape) was reinforced as correct. Moderately-toseverely demented patients with HD, in contrast, were impaired in maintaining the proper response set and perseveratively returned to a previously correct response strategy when attention should have shifted. A deficit in shifting or allocating attention has been observed in other studies of patients with HD (Taylor and Hansotia, 1983; Hanes et al., 1995; Lange et al., 1995; Lawrence et al., 1996), and appears to be particularly evident when attentional shifts must be internally regulated (Sprengelmeyer et al., 1995). A similar deficit in maintaining response set and shifting attention across stimulus dimensions has been observed in patients with PD (Owen et al., 1993) or progressive supranuclear palsy (PSP) (Partiot et al., 1996), whereas patients with AD and patients with circumscribed frontal lobe lesions can maintain attention but not effectively disengage from a previous set (Owen et al., 1993; Filoteo et al., 1995).

NEUROPSYCHOLOGY OF AGING AND DEMENTIA Cortical and subcortical dementia syndromes also differ in the nature and severity of the working memory deficits they comprise. Working memory refers to a limited capacity memory system in which information that is the immediate focus of attention can be temporarily held in limited-capacity language-based (i.e., the phonological loop) or visual-based (i.e., the visuospatial scratchpad) buffers while being manipulated through a primary central executive system (Baddeley, 1986). The central executive system is critically responsible for strategic aspects of memory that facilitate the encoding and retrieval of information in long-term memory. The subcortical dementia syndrome of patients with HD or PD is characterized by early deficits in all aspects of working memory, including the maintenance of information in the temporary memory buffers (e.g., as evidenced by poor digit span performance), inhibition of irrelevant information, and the use of strategic aspects of memory (e.g., planning, organization) to enhance free recall (Caine et al., 1977; Butters et al., 1978; Bradley et al., 1989; Lange et al., 1995; Lawrence et al., 1996; Owen et al., 1997; Le Bras et al., 1999; Stebbins et al., 1999; Kensinger et al., 2003). The cortical dementia syndrome of AD, in contrast, is initially characterized by relatively mild working memory deficits that primarily involve disruption of the central executive with sparing of the phonological loop and visuospatial scratchpad (Baddeley et al., 1991; Collette et al., 1999). It is not until later stages of AD that all aspects of the working memory system become compromised (Baddeley et al., 1991; Collette et al., 1999) as they are in the early stages of most subcortical dementia disorders. The prominent deficits in attention and working memory associated with the subcortical dementia syndrome are accompanied by impairment of various ‘executive’ functions involved in planning and problem solving. These include deficits in goal-directed behavior, the ability to generate multiple response alternatives, the capacity to resist distraction and maintain response set, and the cognitive flexibility to evaluate and modify behavior (for reviews, see Folstein et al., 1990; Huber and Shuttleworth, 1990; Brandt and Bylsma, 1993). Deficits in these abilities are apparent on a variety of tests that require executive functioning such as the Wisconsin Card Sorting Test (Pillon et al., 1991; Paulsen et al., 1995; Peinemann et al., 2005; Ward et al., 2006), the Stroop Test (Paulsen et al., 1996; Peinemann et al., 2005; Ward et al., 2006), the Tower of London test (Lange et al., 1995), the Gambling Decision Making task (Stout et al., 2001), and tests of verbal concept formation (Hanes et al., 1995). These deficits are not unique to subcortical dementia, however, as extensive executive

127

dysfunction is also characteristic of the cortical dementia syndrome of AD (for review, see Perry and Hodges, 1999). It may be the case that specific aspects of executive dysfunction are more common in one syndrome than another, but there are few studies that have directly compared this aspect of cognition in the two disorders. 5.5.6. Visuospatial abilities Although visuospatial deficits are characteristic of both the cortical and subcortical dementia syndrome, few studies have directly compared the two conditions to determine if there are qualitative differences in the processes affected. Visuospatial abilities are often adversely affected early in the course of HD and decline as the disease progresses (Josiassen et al., 1983; Brouwers et al., 1984; Brandt and Butters, 1986; Caine et al., 1986; Lawrence et al., 2000; Ward et al., 2006). Patients with HD have been shown to be impaired compared to age-matched controls on many different tests of visuospatial function such as the Block Design subtest of the Wechsler Adult Intelligence Scale-Revised (Strauss and Brandt, 1985; Bamford et al., 1989), the Clock Drawing Test (Caine et al., 1986), and tests of the ability to follow a visual ‘map’ (Brouwers et al., 1984; Bylsma et al., 1992). Patients with AD have also been shown to be impaired on these and many other visuospatial tasks (for review, see Cronin-Golomb and Amick, 2001), but relatively little is known about the specific components of visuospatial processing that might be differentially affected in the two disorders. In one of the few studies to directly compare patients with AD and patients with HD on visuospatial tasks, Brouwers et al. (1984) found that patients with AD, but not those with HD, were impaired on tests of visuoconstructional ability that required extrapersonal orientation (e.g., copying a complex figure), whereas patients with HD, but not those with AD, were impaired on visuospatial tasks that required personal orientation (e.g., the Money Road Map Test). Thus, the distinct pattern of deficits produced by the two groups was interpreted as a dissociation between personal and extrapersonal spatial orientation abilities in cortical and subcortical dementia syndromes. This interpretation of the visuospatial deficits exhibited by patients with AD and patients with HD was supported by the results of a recent study that examined their ability to mentally rotate representations of objects (Lineweaver et al., 2005). Patients with HD were significantly slower than normal control subjects in performing mental rotation, but were as accurate as control subjects in making the rotation and reporting the correct side of the target. Patients with AD, in

128

D.P. SALMON

contrast, performed the mental rotation as quickly as control subjects, but were significantly impaired in making an accurate rotation and reporting the correct side of the target. These results suggest that HD patients can perform mental rotation of visual representations accurately, but suffer a general bradyphrenia (i.e., slowed thinking) that parallels the bradykinesia that characterizes the disorder. The impaired ability of AD patients to perform mental rotation may reflect a deficit in extrapersonal visual orientation secondary to neocortical damage in brain regions thought to be involved in processing visual motion (e.g., the middle temporal gyrus). A recent study by Festa et al. (2005) compared the performances of patients with AD and patients with HD on a visual sensory integration task that required subjects to detect the direction of coherently moving dots that could be segmented from randomly moving distractor dots by color (red versus green) or by luminance (light gray versus dark gray). Patients with HD were as effective as normal control subjects in integrating motion and color or motion and luminance information to enhance their ability to detect the direction of motion above baseline levels of performance (i.e., when color or luminance did not segment coherently moving dots). Patients with AD effectively used luminance information to enhance their motion detection, but they were impaired in their ability to use color information in the same way. This deficit was interpreted as an impaired ability to bind motion and color information that is processed in distinct cortical visual systems (the dorsal visual processing stream for motion information, the ventral visual processing stream for color information) because the cortical pathology in AD leads to the loss of effective interaction between distinct neocortical areas (De Lacoste and White, 1993). The ability to integrate motion and luminance information was not affected in the same way, presumably because both types of information are processed within the dorsal visual processing stream. At least one study has directly compared visuoconstructional deficits in cortical and subcortical dementia syndromes by examining the ability of patients with AD and patients with HD to draw-to-command and to copy clocks (Rouleau et al., 1992). In the command condition, patients were asked to ‘draw a clock, put in all the numbers, and set the hands to 10 past 11.’ In the copy condition, they were asked to copy a drawing of a clock. Both patient groups were impaired on both conditions of this task, but patients with AD were significantly worse in the command condition than in the copy condition, while patients with HD were equally impaired in both. A qualitative analysis of the types of errors produced also revealed a difference

between the patient groups. Patients with HD tended to make graphic, visuospatial, and planning errors in both the command and copy conditions, whereas patients with AD tended to make conceptual errors (e.g., misrepresenting the clock by drawing a face without numbers or with an incorrect use of numbers; misrepresenting the time by failing to include the hands; incorrectly using the hands; or writing the time in the clock face) in the command condition but not in the copy condition. These disparate patterns of deficits are thought to reflect distinct processing deficits in the cortical and subcortical dementia syndromes. The deficits exhibited by patients with HD appear to be a manifestation of the planning and motor deficits that accompany disruption of frontal–subcortical circuits, whereas those of patients with AD seem to reflect a deficit in accessing knowledge of the attributes, features, and meaning of a clock.

5.6. Summary The neuropsychological research described in this chapter clearly demonstrates that considerable progress has been made in differentiating between the cognitive changes that occur as a normal consequence of aging and those that signal the onset of a dementia syndrome associated with neurodegenerative disease. Among the important contributions of this research are the classification of specific neuropsychological deficits that occur in the earliest stages of AD, the most common cause of dementia in the elderly, and the identification of cognitive changes that may presage the development of dementia in nondemented elderly. In addition, recent research has begun to identify the impact of normal age-related cognitive changes on the ability to identify early dementia in the very elderly, a rapidly growing and particularly vulnerable segment of the population. Finally, considerable research progress has been made in delineating different patterns of relatively preserved and impaired cognitive abilities that distinguish between the cortical dementia syndrome associated with AD and the subcortical dementia syndrome associated with HD and PD. Appreciation of the cognitive distinctions between these disorders can aid in the development of better differential diagnosis and has important implications for the study of brain–behavior relationships underlying episodic memory, semantic memory, implicit memory (e.g., priming, motor skill learning, cognitive skill learning) and other cognitive abilities. As our knowledge of the neuropsychology of aging and dementia grows in coming years, further advances in our understanding of neural mediation of these and other cognitive processes should be possible.

NEUROPSYCHOLOGY OF AGING AND DEMENTIA

Acknowledgements The preparation of this chapter was supported, in part, by funds from NIA grants AG-05131 and AG-12963 to the University of California, San Diego.

References Aarsland D, Zaccai J, Brayne C (2005). A systematic review of prevalence studies of dementia in Parkinson’s disease. Mov Disord 20: 1255–1263. Albert ML, Feldman RG, Willis AL (1974). The ‘subcortical dementia’ of progressive supranuclear palsy. J Neurol Neurosurg Psychiatry 37: 121–130. Albert MS, Butters N, Brandt J (1981). Development of remote memory loss in patients with Huntington’s disease. J Clin Exp Neuropsychol 3: 1–12. Albert MS, Butters N, Levin J (1979). Temporal gradients in the retrograde amnesia of patients with alcoholic Korsakoff disease. Arch Neurol 36: 211–216. Albert MS, Moss MB, Tanzi R, et al. (2001). Preclinical prediction of AD using neuropsychological tests. J Int Neuropsychol Soc 7: 631–639. Alexander GE, DeLong MR, Strick PL (1986). Parallel organization of functionally segregated circuits linking basal ganglia and cortex. Annu Rev Neurosci 9: 357–381. Ba¨ckman L, Herlitz A (1996). Knowledge and memory in Alzheimer’s disease: A relationship that exists. In RG Morris (Ed.), The Cognitive Neuropsychology of Alzheimer’s Disease. Oxford University Press, Oxford, pp. 89–104. Ba¨ckman L, Jones S, Berger AK, et al. (2004). Multiple cognitive deficits during the transition to Alzheimer’s disease. J Intern Med 256: 195–204. Ba¨ckman L, Jones S, Berger AK, et al. (2005). Cognitive impairment in preclinical Alzheimer’s disease: A metaanalysis. Neuropsychology 19: 520–531. Ba¨ckman L, Small BJ (1998). Influences of cognitive support on episodic remembering: Tracing the process of loss from normal aging to Alzheimer’s disease. Psychol Aging 13: 267–276. Ba¨ckman L, Small BJ, Fratiglioni L (2001). Stability of the preclinical episodic memory deficit in Alzheimer’s disease. Brain 124: 96–102. Baddeley AD (1986). Working Memory. Clarendon Press, Oxford. Baddeley AD, Bressi S, Della Sala S, et al. (1991). The decline of working memory in Alzheimer’s disease: A longitudinal study. Brain 114: 2521–2542. Bamford KA, Caine ED, Kido DK, et al. (1989). Clinical– pathologic correlations in Huntington’s disease: Neuropsychology and computed tomography study. Neurology 39: 796–801. Band GP, Ridderinkhof KR, Segalowitz S (2002). Explaining neurocognitive aging: Is one factor enough? Brain Cogn 49: 259–267. Bartzokis G (2004). Age-related myelin breakdown: a developmental model of cognitive decline and Alzheimer’s disease. Neurobiol Aging 25: 5–18.

129

Bayles KA, Boone DR, Tomoeda CK, et al. (1989). Differentiating Alzheimer’s patients from the normal elderly and stroke patients with aphasia. J Speech Hear Disord 54: 74–87. Bayles KA, Kaszniak AW (1987). Communication and Cognition in Normal Aging and Dementia. College-Hill/Little, Brown and Company, Boston. Bayles KA, Tomoeda CK (1983). Confrontation naming impairment in dementia. Brain Lang 19: 98–114. Bayley PJ, Salmon DP, Bondi MW, et al. (2000). Comparison of the serial position effect in very mild Alzheimer’s disease, mild Alzheimer’s disease, and amnesia associated with electroconvulsive therapy. J Int Neuropsychol Soc 6: 290–298. Beatty WW, Goodkin DE, Monson N, et al. (1988a). Anterograde and retrograde amnesia in patients with chronic progressive multiple sclerosis. Arch Neurol 45: 611–619. Beatty WW, Salmon DP, Butters N, et al. (1988b). Retrograde amnesia in patients with Alzheimer’s disease or Huntington’s disease. Neurobiol Aging 9: 181–186. Bondi MW, Houston WS, Salmon DP, et al. (2003). Neuropsychological deficits associated with Alzheimer’s disease in the very old: Discrepencies in raw vs. standardized scores. J Int Neuropsychol Soc 9: 783–795. Bondi MW, Kaszniak AW (1991). Implicit and explicit memory in Alzheimer’s disease and Parkinson’s disease. J Clin Exp Neuropsychol 13: 339–358. Bondi MW, Kaszniak AW, Bayles KA, et al. (1993a). Contributions of frontal system dysfunction to memory and perceptual abilities in Parkinson’s disease. Neuropsychology 7: 89–102. Bondi MW, Monsch AU, Butters N, et al. (1993b). Utility of a modified version of the Wisconsin Card Sorting Test in the detection of dementia of the Alzheimer type. Clin Neuropsychol 7: 161–170. Bondi MW, Monsch AU, Galasko D, et al. (1994). Preclinical cognitive markers of dementia of the Alzheimer type. Neuropsychology 8: 374–384. Bondi MW, Salmon DP, Galasko D, et al. (1999). Neuropsychological function and apolipoprotein E genotype in the preclinical detection of Alzheimer’s disease. Psychol Aging 14: 295–303. Bowles NL, Obler LK, Albert ML (1987). Naming errors in healthy aging and dementia of the Alzheimer type. Cortex 23: 519–524. Bradley VA, Welch JL, Dick DJ (1989). Visuospatial working memory in Parkinson’s disease. J Neurol Neurosurg Psychiatry 52: 1228–1235. Brandt J, Butters N (1986). The neuropsychology of Huntington’s disease. Trends Neurosci 9: 118–120. Brandt J, Bylsma FW (1993). The dementia of Huntington’s disease. In RW Parks, RF Zec, RS Wilson (Eds.), Neuropsychology of Alzheimer’s Disease and Other Dementias. Oxford University Press, New York, pp. 265–282. Brandt J, Corwin J, Krafft L (1992). Is verbal recognition memory really different in Huntington’s and Alzheimer’s disease? J Clin Exp Neuropsychol 14: 773–784.

130

D.P. SALMON

Brandt J, Folstein SE, Folstein MF (1988). Differential cognitive impairment in Alzheimer’s and Huntington’s disease. Ann Neurol 23: 555–561. Brouwers P, Cox C, Martin A, et al. (1984). Differential perceptual–spatial impairment in Huntington’s and Alzheimer’s dementias. Arch Neurol 41: 1073–1076. Buckner RL (2004). Memory and executive function in aging and AD: Multiple factors that cause decline and reserve factors that compensate. Neuron 44: 195–208. Buschke H (1973). Selective reminding for analysis of memory and learning. J Verb Learn Verb Behav 12: 543–550. Buschke H, Fuld PA (1974). Evaluating storage, retention, and retrieval in disordered memory and learning. Neurology 24: 1019–1025. Buschke H, Sliwinski MJ, Kuslansky G, et al. (1997). Diagnosis of early dementia by the double memory test. Neurology 48: 989–997. Butters N, Granholm E, Salmon DP, et al. (1987). Episodic and semantic memory: A comparison of amnesic and demented patients. J Clin Exp Neuropsychol 9: 479–497. Butters N, Salmon DP, Cullum CM, et al. (1988). Differentiation of amnesic and demented patients with the Wechsler memory scale—revised. Clin Neuropsychol 2: 133–148. Butters N, Sax DS, Montgomery K, et al. (1978). Comparison of the neuropsychological deficits associated with early and advanced Huntington’s disease. Arch Neurol 35: 585–589. Butters N, Wolfe J, Granholm E, et al. (1986). An assessment of verbal recall, recognition and fluency abilities in patients with Huntington’s disease. Cortex 22: 11–32. Butters N, Wolfe J, Martone M, et al. (1985). Memory disorders associated with Huntington’s disease: Verbal recall, verbal recognition and procedural memory. Neuropsychologia 23: 729–743. Bylsma FW, Brandt J, Strauss ME (1992). Personal and extrapersonal orientation in Huntington’s disease patients and those at risk. Cortex 28: 113–122. Caine ED, Bamford KA, Schiffer RB, et al. (1986). A controlled neuropsychological comparison of Huntington’s disease and multiple sclerosis. Arch Neurol 43: 249–254. Caine ED, Ebert MH, Weingartner H (1977). An outline for the analysis of dementia: The memory disorder of Huntington’s disease. Neurology 27: 1087–1092. Caine ED, Hunt R, Weingartner H, et al. (1978). Huntington’s dementia: Clinical and neuropsychological features. Arch Gen Psychiatry 35: 377–384. Capitani E, Della Sala S, Logie R, et al. (1992). Recency, primacy, and memory: Reappraising and standardising the serial position curve. Cortex 28: 315–342. Carlesimo GA, Sabbadini M, Fadda L, et al. (1995). Different components in word-list forgetting of pure amnesics, degenerative demented and healthy subjects. Cortex 31: 735–745. Cermak LS (1984). The episodic/semantic distinction in amnesia. In LR Squire, N Butters (Eds.), The Neuropsychology of Memory. Guilford Press, New York, pp. 52–62. Chan AS, Salmon DP, Butters N (1998). Semantic network abnormalities in patients with Alzheimer’s disease. In RW Parks, DS Levine, DL Long (Eds.), Fundamentals of

Neural Network Modeling. MIT Press, Cambridge, MA, pp. 381–393. Chen P, Ratcliff G, Belle SH, et al. (2001). Patterns of cognitive decline in presymptomatic Alzheimer disease: A prospective community study. Arch Gen Psychiatry 58: 853–858. Chertkow H, Bub D (1990). Semantic memory loss in dementia of Alzheimer’s type. Brain 113: 397–417. Colla M, Ende G, Bohrer M, et al. (2003). MR spectroscopy in Alzheimer’s disease: Gender differences in probabilistic learning capacity. Neurobiol Aging 23: 545–552. Collette F, Van der Linden M, Bechet S, et al. (1999). Phonological loop and central executive functioning in Alzheimer’s disease. Neuropsychologia 37: 905–918. Collie A, Maruff P (2000). The neuropsychology of preclinical Alzheimer’s disease and mild cognitive impairment. Neurosci Biobehav Rev 24: 365–374. Corkin S (1968). Acquisition of motor skill after bilateral medial temporal-lobe excision. Neuropsychologia 6: 255–265. Cronin-Golomb A, Amick M (2001). Spatial abilities in aging, Alzheimer’s disease, and Parkinson’s disease. In F Boller, SF Cappa (Eds.), Handbook of Neuropsychology, 2nd edn, Vol 6: Aging and Dementia. Elsevier, Amsterdam, pp. 119–143. Cummings JL, Benson DF (1984). Subcortical dementia: Review of an emerging concept. Arch Neurol 41: 874–879. Dalla Barba G, Goldblum M (1996). The influence of semantic encoding on recognition memory in Alzheimer’s disease. Neuropsychologia 34: 1181–1186. De Lacoste M, White CL (1993). The role of cortical connectivity in Alzheimer’s disease pathogenesis: A review and model system. Neurobiol Aging 14: 1–16. Delis DC, Massman PJ, Butters N, et al. (1991). Profiles of demented and amnesic patients on the California verbal learning test: Implications for the assessment of memory disorders. Psychol Assess 3: 19–26. Deweer B, Ergis AM, Fossati P, et al. (1994). Explicit memory, procedural learning and lexical priming in Alzheimer’s disease. Cortex 30: 113–126. Deweer B, Pillon B, Michon A, et al. (1993). Mirror reading in Alzheimer’s disease: Normal skill learning and acquisition of item-specific information. J Clin Exp Neuropsychol 15: 789–804. Eslinger PJ, Damasio AR (1986). Preserved motor learning in Alzheimer’s disease: Implications for anatomy and behavior. J Neurosci 6: 3006–3009. Eslinger PJ, Damasio AR, Benton AL, et al. (1985). Neuropsychologic detection of abnormal mental decline in older persons. JAMA 253: 670–674. Ferraro FR, Balota DA, Connor LT (1993). Implicit memory and the formation of new associations in nondemented Parkinson’s disease individuals and individuals with senile dementia of the Alzheimer type: A serial reaction time (SRT) investigation. Brain Cogn 21: 163–180. Festa E, Insler RZ, Salmon DP, et al. (2005). Neocortical disconnectivity disrupts sensory integration in Alzheimer’s disease. Neuropsychology 19: 728–738. Filoteo JV, Delis DC, Roman MJ, et al. (1995). Visual attention and perception in patients with Huntington’s disease:

NEUROPSYCHOLOGY OF AGING AND DEMENTIA Comparison with other subcortical and cortical dementias. J Clin Exp Neuropsychol 17: 654–667. Filoteo JV, Maddox WT Davis JD (2001a). A possible role of the striatum in linear and nonlinear categorization rule learning: Evidence from patients with Huntington’s disease. Behav Neurosci 115: 786–798. Filoteo JV, Maddox WT, Davis JD (2001b). Quantitative modeling of category learning in amnesic patients. J Int Neuropsychol Soc 7: 1–19. Filoteo JV, Maddox WT, Salmon DP, et al. (2005). Information-integration category learning in patients with striatal dysfunction. Neuropsychology 19: 212–222. Filoteo JV, Rilling LM, Cole B, et al. (1997). Variable memory profiles in Parkinson’s disease. J Clin Exp Neuropsychol 19: 878–888. Fischer P, Marterer A, Danialczyk W (1990). Right–left disorientation in dementia of the Alzheimer type. Neurology 40: 1619–1620. Fleischman DA, Gabrieli JDE (1998). Repetition priming in normal aging and Alzheimer’s disease: A review of findings and theories. Psychol Aging 13: 88–119. Flicker C, Ferris SH, Crook T, et al. (1988). Equivalent spatial-rotation deficits in normal aging and Alzheimer’s disease. J Clin Exp Neuropsychol 10: 387–399. Flicker C, Ferris SH, Reisberg B (1991). Mild cognitive impairment in the elderly: Predictors of dementia. Neurology 41: 1006–1009. Folstein SE (1989). Huntington’s Disease: A Disorder of Families. Johns Hopkins University Press, Baltimore. Folstein SE, Brandt J, Folstein MF (1990). Huntington’s Disease. In JL Cummings (Ed.), Subcortical Dementia. Oxford University Press, New York, pp. 87–107. Freedman M, Leach L, Kaplan E, et al. (1994). Clock Drawing: A Neuropsychological Analysis. Oxford University Press, New York. Freedman M, Rivoira P, Butters N, et al. (1984). Retrograde amnesia in Parkinson’s disease. Can J Neurol Sci 11: 297–301. Fuld PA (1983). Word intrusions as a diagnostic sign of Alzheimer’s disease. Geriatric Med Today 2: 33–41. Fuld PA, Katzman R, Davies P, et al. (1982). Intrusions as a sign of Alzheimer dementia: Chemical and pathological verification. Ann Neurol 11: 155–159. Fuld PA, Masur DM, Blau AD, et al. (1990). Object-memory evaluation for prospective detection of dementia in normal functioning elderly: Predictive and normative data. J Clin Exp Neuropsychol 12: 520–528. Gabrieli JDE, Stebbins GT, Singh J, et al. (1997). Intact mirrortracing and impaired rotary-pursuit skill learning in patients with Huntington’s disease: Evidence for dissociable memory systems in skill learning. Neuropsychology 11: 272–281. Goldblum M, Gomez C, Dalla Barba G, et al. (1998). The influence of semantic and perceptual encoding on recognition memory in Alzheimer’s disease. Neuropsychologia 36: 717–729. Grady CL, Craik FI (2000). Changes in memory processing with age. Curr Opin Neurobiol 10: 224–231.

131

Grady CL, Haxby JV, Horwitz B, et al. (1988). Longitudinal study of the early neuropsychological and cerebral metabolic changes in dementia of the Alzheimer type. J Clin Exp Neuropsychol 10: 576–596. Grafman J, Weingartner H, Newhouse PA, et al. (1991). Implicit learning in patients with Alzheimer’s disease. Pharmacopsychiatry 23: 94–101. Greene JDW, Baddeley AD, Hodges JR (1996). Analysis of the episodic memory deficit in early Alzheimer’s disease: Evidence from the doors and people test. Neuropsychologia 34: 537–551. Greenwood PM (2000). The frontal aging hypothesis evaluated. J Int Neuropsychol Soc 6: 705–726. Grober E, Kawas C (1997). Learning and retention in preclinical and early Alzheimer’s disease. Psychol Aging 12: 183–188. Hanes KR, Andrewes DG, Pantelis C (1995). Cognitive flexibility and complex integration in Parkinson’s disease, Huntington’s disease, and schizophrenia. J Int Neuropsychol Soc 1: 545–553. Hansen LA, Galasko D (1992). Lewy body disease. Curr Opin Neurol 5: 889–894. Hedden T, Gabrieli JDE (2004). Insights into the ageing mind: A view from cognitive neuroscience. Nat Rev 5: 87–97. Heindel W, Butters N, Salmon D (1988). Impaired learning of a motor skill in patients with Huntington’s disease. Behav Neurosci 102: 141–147. Heindel WC, Salmon DP, Butters N (1990). Pictorial priming and cued recall in Alzheimer’s and Huntington’s disease. Brain Cogn 13: 282–295. Heindel WC, Salmon DP, Butters N (1991). The biasing of weight judgments in Alzheimer’s and Huntington’s disease: A priming or programming phenomenon? J Clin Exp Neuropsychol 13: 189–203. Heindel WC, Salmon DP, Shults CW, et al. (1989). Neuropsychological evidence for multiple implicit memory systems: A comparison of Alzheimer’s, Huntington’s, and Parkinson’s disease patients. J Neurosci 9: 582–587. Henry JD, Crawford JR (2004). Verbal fluency deficits in Parkinson’s disease: A meta-analysis. J Int Neuropsychol Soc 10: 608–622. Henry JD, Crawford JR, Phillips LH (2004). Verbal fluency performance in dementia of the Alzheimer’s type: A meta-analysis. Neuropsychologia 42: 1212–1222. Henry JD, Crawford JR, Phillips LH (2005). A meta-analytic review of verbal fluency deficits in Huntington’s disease. Neuropsychology 19: 243–252. Higginson CI, Wheelock VL, Carroll KE, et al. (2005). Recognition memory in Parkinson’s disease with and without dementia: Evidence inconsistent with the retrieval deficit hypothesis. J Clin Exp Neuropsychol 27: 516–528. Hodges JR (1995). Retrograde amnesia. In AD Baddeley, BA Wilson, FN Watts (Eds.), Handbook of Memory Disorders. John Wiley & Sons, New York, pp. 81–107. Hodges JR, Patterson K (1995). Is semantic memory consistently impaired early in the course of Alzheimer’s

132

D.P. SALMON

disease? Neuroanatomical and diagnostic implications. Neuropsychologia 33: 441–459. Hodges JR, Salmon DP, Butters N (1991). The nature of the naming deficit in Alzheimer’s and Huntington’s disease. Brain 114: 1547–1558. Hodges JR, Salmon DP, Butters N (1992). Semantic memory impairment in Alzheimer’s disease: Failure of access or degraded knowledge? Neuropsychologia 30: 301–314. Hodges JR, Salmon DP, Butters N (1993). Recognition and naming of famous faces in Alzheimer’s disease: A cognitive analysis. Neuropsychologia 31: 775–788. Howieson DB, Dame A, Camicioli R, et al. (1997). Cognitive markers preceding Alzheimer’s dementia in the healthy oldest old. J Am Geriatr Soc 45: 584–589. Huber SJ, Shuttleworth EC (1990). Huntington’s disease. In JL Cummings (Ed.), Subcortical Dementia. Oxford University Press, New York, pp. 71–86. Huber SJ, Shuttleworth EC, Paulson GW, et al. (1986). Cortical vs subcortical dementia: Neuropsychological differences. Arch Neurol 43: 392–394. Huberman M, Moscovitch M, Freedman M (1994). Comparison of patients with Alzheimer’s and Parkinson’s disease on different explicit and implicit tests of memory. Neuropsychiatry Neuropsychol Behav Neurol 7: 185–193. Huff FJ, Becker JT, Belle SH, et al. (1987). Cognitive deficits and clinical diagnosis of Alzheimer’s disease. Neurology 37: 1119–1124. Huff FJ, Corkin S, Growdon JH (1986). Semantic impairment and anomia in Alzheimer’s disease. Brain Lang 28: 235–249. Hughes AJ, Daniel SE, Killford L, et al. (1992). Accuracy of clinical diagnosis of idiopathic Parkinson’s disease: A clinico-pathological study of 100 cases. J Neurol Neurosurg Psychiatry 55: 181–184. Jacobs D, Salmon DP, Tro¨ster AI, et al. (1990). Intrusion errors in the figural memory of patients with Alzheimer’s and Huntington’s disease. Arch Clin Neuropsychol 5: 49–57. Jacobs DM, Sano M, Dooneief G, et al. (1995). Neuropsychological detection and characterization of preclinical Alzheimer’s disease. Neurology 45: 957–962. Jacobson MW, Delis DC, Bondi MW, et al. (2002). Do neuropsychological tests detect preclinical Alzheimer’s disease?: Individual-test versus cognitive discrepancy analyses. Neuropsychology 16: 132–139. Jankovic J (1987). Pathophysiology and clinical assessment of motor symptoms in Parkinson’s disease. In WC Koller (Ed.), Handbook of Parkinson’s Disease. Marcel Dekker, New York, pp. 99–126. Jellinger K (1987). The pathology of parkinsonism. In CD Marsden, S Fahn (Eds.), Neurology, Vol. 7. Movement Disorders 2. Butterworths, London, pp. 124–165. Josiassen RC, Curry LM, Mancall EL (1983). Development of neuropsychological deficits in Huntington’s disease. Arch Neurol 40: 791–796. Kapur N (1999). Syndromes of retrograde amnesia: A conceptual and empirical synthesis. Psychol Rev 125: 800–825.

Kaszniak AW, Wilson RS, Fox JH, et al. (1986). Cognitive assessment in Alzheimer’s disease: Cross-sectional and longitudinal perspectives. Can J Neurol Sci 13: 420–423. Katzman R (1994). Apolipoprotein E and Alzheimer’s disease. Curr Opin Neurobiol 4: 703–707. Kawas CH, Corrada MM, Brookmeyer R, et al. (2003). Visual memory predicts Alzheimer’s disease more than a decade before diagnosis. Neurology 60: 1089–1093. Keane MM, Gabrieli JDE, Fennema AC, et al. (1991). Evidence for a dissociation between perceptual and conceptual priming in Alzheimer’s disease. Behav Neurosci 105: 326–342. Kensinger EA, Shearer DK, Locascio JJ, et al. (2003). Working memory in mild Alzheimer’s disease and early Parkinson’s disease. Neuropsychology 17: 230–239. Knopman DS, Nissen MJ (1987). Implicit learning in patients with probable Alzheimer’s disease. Neurology 37: 784–788. Knopman DS, Nissen MJ (1991). Procedural learning is impaired in Huntington’s disease: Evidence from the serial reaction time test. Neuropsychologia 29: 245–254. Knopman DS, Ryberg S (1989). A verbal memory test with high predictive accuracy for dementia of the Alzheimer type. Arch Neurol 46: 141–145. Knowlton BJ, Mangels JA, Squire LR (1996a). A neostriatal habit learning system in humans. Science 273: 1399–1402. Knowlton BJ, Squire LR, Paulsen JS, et al. (1996b). Dissociations within nondeclarative memory in Huntington’s disease. Neuropsychology 10: 538–548. Kopelman MD (1989). Remote and autobiographical memory, temporal context memory and frontal atrophy in Korsakoff and Alzheimer patients. Neuropsychologia 27: 437–460. Kramer AF, Bherer L, Colcombe SJ, et al. (2004). Environmental influences on cognitive and brain plasticity during aging. Biol Sci Med Sci 59: 940–957. Lange KL, Bondi MW, Salmon DP, et al. (2002). Decline in verbal memory during preclinical Alzheimer’s disease: Examination of the effect of APOE genotype. J Int Neuropsychol Soc 8: 943–955. Lange KW, Sahakian BJ, Quinn NP, et al. (1995). Comparison of executive and visuospatial memory function in Huntington’s disease and dementia of Alzheimer type matched for degree of dementia. J Neurol Neurosurg Psychiatry 58: 598–606. Larrabee GL, Largen JW, Levin HS (1985). Sensitivity of age-decline resistant (‘Hold’) WAIS subtests to Alzheimer’s disease. J Clin Exp Neuropsychol 7: 497–504. La Rue A, Jarvik LR (1987). Cognitive function and prediction of dementia in old age. Int J Aging Hum Dev 25: 79–89. Lawrence AD, Sahakian BJ, Hodges JR, et al. (1996). Executive and mnemonic functions in early Huntington’s disease. Brain 119: 1633–1645. Lawrence AD, Watkins LH, Sahakian BJ, et al. (2000). Visual object and visuospatial cognition in Huntington’s disease:

NEUROPSYCHOLOGY OF AGING AND DEMENTIA Implications for information processing in corticostriatal circuits. Brain 123: 1349–1364. Le Bras C, Pillon B, Damier P, et al. (1999). At which steps of spatial working memory processing do striatofrontal circuits intervene in humans? Neuropsychologia 37: 83–90. Lefleche G, Albert MS (1995). Executive function deficits in mild Alzheimer’s disease. Neuropsychology 9: 313–320. Lineweaver TT, Salmon DP, Bondi MW, et al. (2005). Distinct effects of Alzheimer’s disease and Huntington’s disease on performance of mental rotation. J Int Neuropsychol Soc 11: 30–39. Linn RT, Wolf PA, Bachman DL, et al. (1995). The ‘preclinical phase’ of probable Alzheimer’s disease. Arch Neurol 52: 485–490. Liu L, Gauthier L, Gauthier S (1991). Spatial disorientation in persons with early senile dementia of the Alzheimer’s type. Am J Occup Ther 45: 67–74. Locascio JJ, Growdon JH, Corkin S (1995). Cognitive test performance in detecting, staging, and tracking Alzheimer’s disease. Arch Neurol 52: 1087–1099. Maddox WT, Filoteo JV (2001). Striatal contributions to category learning: Quantitative modeling of simple linear and complex nonlinear rule learning in patients with Parkinson’s disease. J Int Neuropsychol Soc 7: 710–727. Marsden CD (1990). Parkinson’s disease. Lancet 335: 948–952. Martin A, Brouwers P, Cox C, et al. (1985). On the nature of the verbal memory deficit in Alzheimer’s disease. Brain Lang 25: 323–341. Martin A, Fedio P (1983). Word production and comprehension in Alzheimer’s disease: The breakdown of semantic knowledge. Brain Lang 19: 124–141. Martone M, Butters N, Payne M, et al. (1984). Dissociations between skill learning and verbal recognition in amnesia and dementia. Arch Neurol 41: 965–970. Massman PJ, Delis DC, Butters N (1993). Does impaired primacy recall equal impaired long-term storage? Serial position effects in Huntington’s disease and Alzheimer’s disease. Dev Neuropsychol 9: 1–15. Massman PJ, Delis DC, Butters N, et al. (1990). Are all subcortical dementias alike? Verbal learning and memory in Parkinson’s and Huntington’s disease patients. J Clin Exp Neuropsychol 12: 729–744. Massman PJ, Delis DC, Butters N, et al. (1992). The subcortical dysfunction hypothesis of memory deficits in depression: Neuropsychological validation in a subgroup of patients. J Clin Exp Neuropsychol 14: 687–706. McGill WJ (1963). Stochastic latency mechanisms. In RD Luce, RR Brush, E Galanter (Eds.), Handbook of Mathematical Psychology, Vol. 1. Wiley, New York, pp. 309–360. McHugh PR, Folstein MF (1975). Psychiatric symptoms of Huntington’s chorea: A clinical and phenomenologic study. In DF Benson, D Blumer (Eds.), Psychiatric Aspects of Neurological Disease. Raven Press, New York, pp. 267–285. Miller E (1971). On the nature of memory disorder in presenile dementia. Neuropsychologia 9: 75–78. Mohr E, Litvan I, Williams J, et al. (1990). Selective deficits in Alzheimer and Parkinson dementia: Visuospatial function. Can J Neurol Sci 17: 292–297.

133

Monsch AU, Bondi MW, Butters N, et al. (1994). A comparison of category and letter fluency in Alzheimer’s disease and Huntington’s disease. Neuropsychology 8: 25–30. Morris JC, McKeel DW, Storandt M, et al. (1991). Very mild Alzheimer’s disease: Informant-based clinical, psychometric, and pathologic distinction from normal aging. Neurology 41: 469–478. Moss MB, Albert MS, Butters N, et al. (1986). Differential patterns of memory loss among patients with Alzheimer’s disease, Huntington’s disease and alcoholic Korsakoff’s syndrome. Arch Neurol 43: 239–246. Murray LL (2000). Spoken language production in Huntington’s and Parkinson’s diseases. J Speech Lang Hear Res 43: 1350–1366. Murray LL, Lenz LP (2001). Productive syntax abilities in Huntington’s and Parkinson’s diseases. Brain Cogn 46: 213–219. Nadel L, Moscovitch M (1997). Memory consolidation, retrograde amnesia and the hippocampal complex. Curr Opin Neurobiol 7: 217–227. Nebes R (1989). Semantic memory in Alzheimer’s disease. Psychol Bull 106: 377–394. Nicholas M, Obler L, Albert M, et al. (1985). Empty speech in Alzheimer’s disease and fluent aphasia. J Speech Hear Res 28: 405–410. Nissen MJ, Bullemer P (1987). Attentional requirements of learning: Evidence from performance measures. Cognit Psychol 19: 1–32. Norton LE, Bondi MW, Salmon DP, et al. (1997). Deterioration of generic knowledge in patients with Alzheimer’s disease: Evidence from the Number Information Test. J Clin Exp Neuropsychol 19: 857–866. O’Sullivan M, Jones DK, Summers PE, et al. (2001). Evidence for cortical ‘disconnection’ as a mechanism of agerelated cognitive decline. Neurology 57: 632–638. Owen AM, Iddon JL, Hodges JR, et al. (1997). Spatial and non-spatial working memory at different stages of Parkinson’s disease. Neuropsychologia 35: 519–532. Owen AM, Roberts AC, Hodges JR, et al. (1993). Contrasting mechanisms of impaired attentional set-shifting in patients with frontal lobe damage or Parkinson’s disease. Brain 116: 1159–1175. Pandovani A, Di Piero V, Bragoni M, et al. (1995). Patterns of neuropsychological impairment in mild dementia: A comparison between Alzheimer’s disease and multi-infarct dementia. Acta Neurol Scand 92: 433–442. Parasuraman R, Haxby JV (1993). Attention and brain function in Alzheimer’s disease. Neuropsychology 7: 242–272. Park HL, O’Connell JE, Thomson RG (2003). A systematic review of cognitive decline in the general elderly population. Int J Geriatr Psychiatry 18: 1121–1134. Partiot A, Verin M, Pillon B, et al. (1996). Delayed response tasks in basal ganglia lesions in man: Further evidence for a striato-frontal cooperation in behavioural adaptation. Neuropsychologia 34: 709–721. Pascual-Leone A, Grafman J, Clark K, et al. (1993). Procedural learning in Parkinson’s disease and cerebellar degeneration. Ann Neurol 34: 594–602.

134

D.P. SALMON

Paulsen JS, Butters N, Salmon DP, et al. (1993). Prism adaptation in Alzheimer’s and Huntington’s disease. Neuropsychology 7: 73–81. Paulsen JS, Como P, Rey G, et al. (1996). The clinical utility of the Stroop Test in a multicenter study of Huntington’s disease. J Int Neuropsychol Soc 2: 35. Paulsen JS, Salmon DP, Monsch AU, et al. (1995). Discrimination of cortical from subcortical dementias on the basis of memory and problem-solving tests. J Clin Psychol 51: 48–58. Peinemann A, Schuller S, Pohl C, et al. (2005). Executive dysfunction in early stages of Huntington’s disease is associated with striatal and insular atrophy: A neuropsychological and voxel-based morphometric study. J Neurol Sci 239: 11–19. Pepin EP, Eslinger PJ (1989). Verbal memory decline in Alzheimer’s disease: A multiple-processes deficit. Neurology 39: 1477–1482. Perani D, Bressi S, Cappa SF, et al. (1993). Evidence of multiple memory systems in the human brain. Brain 116: 903–919. Perry RJ, Hodges JR (1999). Attention and executive deficits in Alzheimer’s disease: A critical review. Brain 122: 383–404. Petersen RC, Doody R, Kurz A, et al. (2001a). Current concepts in mild cognitive impairment. Arch Neurol 58: 1985–1992. Petersen RC, Smith GE, Ivnik RJ, et al. (1995). Apolipoprotein E status as a predictor of the development of Alzheimer’s disease in memory-impaired individuals. JAMA 273: 1274–1278. Petersen RC, Stevens JC, Ganguli M, et al. (2001b). Practice parameter: Early detection of dementia: Mild cognitive impairment (an evidence-based review). Neurology 56: 1133–1142. Pfefferbaum A, Adalsteinsson E, Sullivan E (2005).Frontal circuitry degradation marks healthy adult aging: Evidence from diffusion tensor imaging. Neuroimage 26: 891–899. Pillon B, Dubois B, Ploska A, et al. (1991). Severity and specificity of cognitive impairment in Alzheimer’s, Huntington’s, and Parkinson’s diseases and progressive supranuclear palsy. Neurology 41: 634–643. Randolph C (1991). Implicit, explicit and semantic memory functions in Alzheimer’s disease and Huntington’s disease. J Clin Exp Neuropsychol 13: 479–494. Raz N (2005). The aging brain observed in vivo: Differential changes and their modifiers. In R Cabeza, L Nyberg, D Park (Eds.), Cognitive Neuroscience of Aging: Linking Cognitive and Cerebral Aging. Oxford University Press, New York, pp. 19–57. Robinson-Whelan S, Storandt M (1992). Immediate and delayed prose recall among normal and demented adults. Arch Neurol 49: 32–34. Rohrer D, Salmon DP, Wixted JT, et al. (1999). The disparate effects of Alzheimer’s disease and Huntington’s disease on semantic memory. Neuropsychology 13: 381–388.

Rohrer D, Wixted JT, Salmon DP, et al. (1995). Retrieval from semantic memory and its implications for Alzheimer’s disease. J Exp Psychol Learn Mem Cogn 21: 1–13. Rouleau I, Salmon DP, Butters N, et al. (1992). Quantitative and qualitative analyses of clock drawings in Alzheimer’s and Huntington’s disease. Brain Cogn 18: 70–87. Rubin EH, Storandt M, Miller JP, et al. (1998). A prospective study of cognitive function and onset of dementia in cognitively healthy elders. Arch Neurol 55: 395–401. Russo R, Spinnler H (1994). Implicit verbal memory in Alzheimer’s disease. Cortex 30: 359–375. Sadek JR, Johnson SA, White DA, et al. (2004). Retrograde amnesia in dementia: Comparison of HIV-associated dementia, Alzheimer’s disease and Huntington’s disease. Neuropsychology 18: 692–699. Sagar HJ, Cohen NJ, Sullivan EV, et al. (1988). Remote memory function in Alzheimer’s disease and Parkinson’s disease. Brain 111: 525–539. Saint-Cyr JA, Taylor AE, Lang AE (1988). Procedural learning and neostriatal dysfunction in man. Brain 111: 941–959. Salmon DP (2000). Disorders of memory in Alzheimer’s disease. In LS Cermak (Ed.), Handbook of Neuropsychology, 2nd edn, Vol. 2: Memory and Its Disorders. Elsevier, Amsterdam, pp. 155–195. Salmon DP, Chan AS (1994). Semantic memory deficits associated with Alzheimer’s disease. In LS Cermak (Ed.), Neuropsychological Explorations of Memory and Cognition: Essays in Honor of Nelson Butters. Plenum Press, New York, pp. 61–76. Salmon DP, Heindel WC (1992). Impaired priming in Alzheimer’s disease: Neuropsychological implications. In LR Squire LR, N Butters N (Eds.), Neuropsychology of Memory, 2nd ed. Guilford Press, New York, pp. 179–187. Salmon DP, Heindel WC, Lange KL (1999). Differential decline in word generation from phonemic and semantic categories during the course of Alzheimer’s disease: Implications for the integrity of semantic memory. J Int Neuropsychol Soc 5: 692–703. Salmon DP, Kwo-on-Yuen PF, Heindel WC, et al. (1989). Differentiation of Alzheimer’s disease and Huntington’s disease with the Dementia Rating Scale. Arch Neurol 46: 1204–1208. Salmon DP, Shimamura AP, Butters N, et al. (1988). Lexical and semantic priming deficits in patients with Alzheimer’s disease. J Clin Exp Neuropsychol 10: 477–494. Salmon DP, Thomas RG, Pay MM, et al. (2002). Alzheimer’s disease can be accurately diagnosed in very mildly impaired individuals. Neurology 59: 1022–1028. Salthouse TA (1996). The processing-speed theory of adult age differences in cognition. Psychol Rev 103: 403–428. Sara S (1985). The locus coeruleus and cognitive function: Attempts to relate noradrenergic enhancement of signal/noise in the brain to behavior. Physiol Psychol 13: 151–162. Schacter DL (1987). Implicit memory: History and current status. J Exp Psychol Learn Mem Cogn 3: 501–517.

NEUROPSYCHOLOGY OF AGING AND DEMENTIA Schmidtke K, Vollmer H (1997). Retrograde amnesia: A study of its relation to anterograde amnesia and semantic memory deficits. Neuropsychologia 35: 505–518. Shimamura AP, Salmon DP, Squire LR, et al. (1987). Memory dysfunction and word priming in dementia and amnesia. Behav Neurosci 101: 347–351. Ska B, Poissant A, Joanette Y (1990). Line orientation judgement in normal elderly and subjects with dementia of Alzheimer’s type. J Clin Exp Neuropsychol 12: 695–702. Small BJ, Fratiglioni L, Viitanen M, et al. (2000). The course of cognitive impairment in preclinical Alzheimer disease: three- and 6-year follow-up of a population-based sample. Arch Neurol 57: 839–844. Small BJ, Mobly JL, Laukka EJ, et al. (2003). Cognitive deficits in preclinical Alzheimer’s disease. Acta Neurol Scand Suppl 179: 29–33. Spinnler H, Della Sala S, Bandera R, et al. (1988). Dementia, aging, and the structure of human memory. Cogn Neuropsychol 5: 193–211. Sprengelmeyer R, Lange H, Homberg V (1995). The pattern of attentional deficits in Huntington’s disease. Brain 118: 145–152. Squire LR (1987). Memory and Brain. Oxford University Press, New York. Squire LR, Haist F, Shimamura AP (1989). The neurology of memory: Quantitative assessment of retrograde amnesia in two groups of amnesic patients. J Neurosci 9: 828–839. Stebbins GT, Gabrieli JDE, Masciari F, et al. (1999). Delayed recognition memory in Parkinson’s disease: A role for working memory. Neuropsychologia 37: 503–510. Storandt M, Botwinick J, Danziger WL, et al. (1984). Psychometric differentiation of mild senile dementia of the Alzheimer type. Arch Neurol 41: 497–499. Storandt M, Grant EA, Miller JP, et al. (2002). Rates of progression in mild cognitive impairment and early Alzheimer’s disease. Neurology 59: 1034–1041. Stout JC, Rodawalt WC, Siemers ER (2001). Risky decision making in Huntington’s disease. J Int Neuropsychol Soc 7: 92–101. Strauss ME, Brandt J (1985). Is there increased WAIS pattern variability in Huntington’s disease? J Clin Exp Neuropsychol 7: 122–126. Taylor HG, Hansotia P (1983). Neuropsychological testing of Huntington’s patients: Clues to progression. J Nerv Ment Dis 171: 492–496. Thal LJ (1999). Clinical trials in Alzheimer disease. In R Terry, R Katzman, KL Bick, SS Sisodia (Eds.), Alzheimer Disease. Raven Press, New York, pp. 423–439.

135

Tro¨ster AI, Butters N, Salmon DP, et al. (1993). The diagnostic utility of savings scores: Differentiating Alzheimer’s and Huntington’s diseases with the logical memory and visual reproduction tests. J Clin Exp Neuropsychol 15: 773–788. Tro¨ster AI, Jacobs D, Butters N, et al. (1989). Differentiation Alzheimer’s disease from Huntington’s disease with the Wechsler memory scale—revised. Clin Geriatr Med 5: 611–632. Tulving E (1983). Elements of Episodic Memory. Oxford University Press, New York. Twamley EW, Ropacki SAL, Bondi MW (2006). Neuropsychological and neuroimaging changes in preclinical Alzheimer’s disease. J Int Neuropsychol Soc 12: 707–735. Tweedy JR, Langer KG, McDowell FH (1982). The effect of semantic relations on the memory deficit associated with Parkinson’s disease. J Clin Neuropsychol 4: 235–247. Villardita C (1993). Alzheimer’s disease compared with cerebrovascular dementia. Acta Neurol Scand 87: 299–308. Vonsattel JP, Myers RH, Stevens TJ, et al. (1985). Neuropathological classification of Huntington’s disease. J Neuropathol Exp Neurol 44: 559–577. Ward J, Sheppard JM, Shpritz B, et al. (2006). A four-year study of cognitive functioning in Huntington’s disease. J Int Neuropsychol Soc 12: 445–454. Weintraub D, Moberg PJ, Culbertson WC, et al. (2004). Evidence for impaired encoding and retrieval memory profiles in Parkinson disease. Cogn Behav Neurol 17: 195–200. Welsh K, Butters N, Hughes J, et al. (1991). Detection of abnormal memory decline in mild cases of Alzheimer’s disease using CERAD neuropsychological measures. Arch Neurol 48: 278–281. West RL (1996). An application of prefrontal cortex function theory to cognitive aging. Psychol Bull 120: 272–292. Willingham DB, Koroshetz WJ (1993). Evidence for dissociable motor skills in Huntington’s disease patients. Psychobiology (Austin, Tex) 21: 173–182. Wilson RS, Bacon LD, Fox JH, et al. (1983). Primary and secondary memory in dementia of the Alzheimer type. Psychobiology (Austin, Tex) 5: 337–344. Wilson RS, Kaszniak AW, Fox JH (1981). Remote memory in senile dementia. Cortex 17: 41–48. Zizak VS, Filoteo JV, Possin KL, et al. (2005). The ubiquity of memory retrieval deficits in patients with fronto-striatal dysfunction. Cogn Behav Neurol 18: 198–205. Zola-Morgan S, Squire LR (1990). The primate hippocampal formation: Evidence for a time-limited role in memory storage. Science 250: 288–290.

Handbook of Clinical Neurology, Vol. 88 (3rd series) Neuropsychology and behavioral neurology G. Goldenberg, B.L. Miller, Editors # 2008 Elsevier B.V. All rights reserved

Chapter 6

Neuropsychological testing: bedside approaches ARMIN SCHNIDER* Department of Clinical Neurosciences, University Hospital, Geneva, Switzerland

6.1. Introduction Most physicians, including neurologists, are perfectly at ease when making a physical examination of a patient; they are much less so when it comes to mental disorders, i.e., failures of cognition, affect, and emotion. An old myth holds that mental disorders cannot be correctly evaluated with clinical means, but require extensive, standardized neuropsychological testing. The myth is false. Interested clinicians can learn to make a clinical evaluation of mental functions, which is as precise and meaningful as the physical neurological examination. Similar to the latter one, it aims to find the presence, severity, and anatomical meaning of dysfunctions in order to guide further evaluations, serve diagnosis, and observe the clinical course. The precise structure of the examination depends on the clinical question and is often adapted during history taking and even during the examination itself as a function of the patient’s responses. ‘Bedside testing,’ as used in this chapter, denotes a flexible, goal-oriented evaluation of mental function, for which the clinician will use—according to the clinical situation—prepared test material or ad hoc devised tests. Although different approaches may be advocated, most clinicians are interested in the anatomical significance of mental failures. This chapter first introduces an anatomical schema of cognitive failures and then proposes ways to test mental functions.

6.2. Anatomical significance of mental failures The testing of mental functions, be it through concise clinical tests or extensive neuropsychological batteries, has long been an important instrument for localizing brain lesions. For many decisions, structural and *

metabolic imaging have taken over this role. Nonetheless, mental testing, as performed by most behavioral neurologists, continues to be guided by anatomical considerations. This has several reasons: 1) Not all brain lesions are visible in structural imaging, e.g., some epileptogenic foci; 2) Neither structural nor metabolic imaging allows determination of whether a known lesion is symptomatic or not. In many cases, mental examination indicates widespread brain dysfunction indicating dementia when structural imaging is still normal; conversely, brain atrophy in structural imaging does not prove mental dysfunction. The approach described in the following will be based on the observation that most mental failures have a clear anatomical significance. Fig. 6.1 presents a simple schema of cognitive disorders and their association with damage of specific regions of the brain (Schnider, 2004). This schema serves as a guideline for the mental status testing discussed in the following. For in-depth discussion of the cognitive disorders, the reader is referred to the dedicated chapters of this Handbook. 6.2.1. Ascending reticular activating system Coherent thinking requires coordinated activation of large areas of the brain. Damage of the brainstem, the basal forebrain, or the thalamus may interfere with such coordinated activation. The anterior brainstem contains the production sites of many neurotransmitter systems projecting into the ascending part of the reticular formation. This system with its projections through the basal forebrain and the thalamus to wide areas of the hemispheres constitutes the ascending reticular activating system (Brodal, 1981; Parvizi and Damasio, 2003). Damage to the system, e.g., by a small mesencephalic lesion, may induce dysfunction of wide areas of the

Correspondence to: Armin Schnider, M.D. Professor and Chairman, Division of Neurorehabilitation, Department of Clinical Neurosciences, University Hospital of Geneva, CH-1211 Geneva 14, Switzerland. E-mail: [email protected].

138

A. SCHNIDER Frontal lobe dysfunction

L

R

1

aphasia agraphia alexia apraxia acalculia

hemispatial neglect Amnesia

2

2

4

finger agnosia right-leftconfusion

visuo-constructive disorders

topographagnosia

3

pure alexia associative agnosia colour anomia

Visuo-spatial disorders

Language-associated disorders

distractability, perseveration, ... lack of drive impulsiveness

prosopagnosia

Visual recognition disorders

2 1

3

3

4

1

Fig. 6.1. Anatomic significance of cognitive dysfunctions. Adapted from Schnider (2004) with permission from Thieme.

hemispheres, which often mimics severe frontal dysfunction (lack of drive, distractibility, perseveration). The evaluation of vigilance, arousal, and basic attention is therefore an essential initial step of the mental examination. 6.2.2. Prefrontal lobes The prefrontal lobes (area 1 in Fig. 6.1) constitute the core mental control apparatus allowing integrating diverse acts over time into meaningful behavior (Stuss and Benson, 1986; Fuster, 1997). Patients with damage to the prefrontal lobes may have difficulty in seizing concepts and making abstractions; they may lack flexibility and perseverate on motor or mental behaviors; they may fail to initiate acts, be distractible and overly guided by environmental cues. Social behavior may be driven by immediate interests rather than thoughtful anticipation. Although many of these dysfunctions do not have a strict anatomical significance, some disorders may nevertheless be localized (Cummings, 1993; Fuster, 1997): it appears that disorders of higher planning and

integration of behavior over time (working or active memory) are particularly dependent on the dorsolateral aspects of the prefrontal lobes. Paramedian lesions, by contrast, typically induce a lack of drive, in extreme cases akinetic mutism. Orbitofrontal lesions have often been said to induce disinhibition (Fuster, 1997), but this has not been confirmed by formal exploration (Hornak et al., 2003). However, pure cases of personality disorders with deranged social behavior, in the absence of other neuropsychological deficits, have been described after frontal polar lesions (Eslinger and Damasio, 1985; Anderson et al., 1999). The inability to select memories of current relevance (spontaneous confabulation syndrome) only occurs with posterior orbitofrontal lesions or disconnection (see 6.2.6. and 6.3.7.3.) (Schnider, 2003).

6.2.3. Left hemisphere Lesions in the pericentral area of the left hemisphere (area 2 in Fig. 6.1) often induce disorders of language or associated symbolic functions (Benson and Ardila,

NEUROPSYCHOLOGICAL TESTING: BEDSIDE APPROACHES 1996). The area indicated in Fig. 6.1 encompasses posterior parts of the frontal lobe, the insula, the parietal lobe and the lateral aspect of the temporal lobe. The precise characteristics of an aphasia depend on the lesion location and the time since onset of brain damage (Willmes and Poeck, 1993). In general, posterior temporal damage particularly impairs language comprehension, anterior lesions typically produce non-fluent output. Many aphasic patients also have difficulty in reading (alexia) and writing (agraphia), disorders that may also appear in isolation. Ideomotor apraxia is the inability to perform complex, artificial movements out of their natural context and is most evident in defective pantomime of tool use (Heilman and Gonzalez Rothi, 2003). This form of apraxia is very strictly associated with damage of the left hemisphere (Schnider et al., 1997). By contrast, ideational apraxia, the inability to perform a correct sequence of acts, has often been described as being specific to left parietal lesions but may also be seen in the context of frontal planning deficits (De Renzi and Lucchelli, 1988). The inability to make calculations (acalculia), to distinguish right and left in space and on one’s own body (right– left confusion) and to recognize one’s own fingers (finger agnosia) also typically occur after left hemisphere damage, in pure form after left inferior parietal damage. 6.2.4. Right hemisphere Lesion of the homologous area of the right hemisphere (right homologue of area 2 in Fig. 6.1) typically induces failures of visuospatial processing (De Renzi, 1982). The most dramatic manifestation is left-sided hemispatial neglect, an inability to integrate information of the left side of space, body, or both into one’s concept of space. Parietotemporal lesions particularly impair the ability to perceive stimuli coming from the left side; right prefrontal lesions appear to particularly impair the ability to act in the left hemispace (Bisiach et al., 1990). Many patients with hemispatial neglect do not realize that they cannot move the left side and even deny their hemiplegia (anosognosia) (Baier and Karnath, 2005). In contrast to hemispatial neglect, difficulties in copying complex designs or making three-dimensional constructions do not have strict anatomical significance; they may also occur after left parietal or frontal lesions (Kirk and Kertesz, 1994). The inability to orient oneself in familiar surroundings and to find one’s way around in a new setting (topographagnosia) is almost exclusively due to right hemisphere damage, be it parietal or the inferior medial temporo-occipital junction (Aguirre and D’Esposito, 1999).

139

6.2.5. Posterior hemispheric regions Damage to posterior regions of the hemispheres (area 3 in Fig. 6.1) induces disorders of visual perception or recognition (Farah, 1990; Gru¨sser and Landis, 1991). The area indicated in Fig. 6.1 includes the occipital lobes and the inferior temporal lobes. Apart from restrictions of the visual field, which will not be discussed here, such lesions may induce different forms of specific failures to recognize the meaning of visually perceived information. Apperceptive agnosia describes the inability to sort out the essential components of a complex visual scenario. The patients may have difficulty in recognizing overlapping, fractionated, or illusory contours or to recognize objects shown from an uncommon perspective. Associative agnosia describes the inability to recognize the meaning of visual information that has been correctly perceived and sorted out from its surroundings; the patients may see an object, perhaps even correctly draw it, but fail to understand its meaning and to pantomime its use (Schnider et al., 1994b). Many patients have elements of both types of agnosia. Both may be due to bilateral occipital lesions. Unilateral right-sided lesions more often produce apperceptive visual deficits, left sided lesions are typically associated with associative agnosia (Farah, 1990; Gru¨sser and Landis, 1991). This principle (right-sided lesion: apperceptive agnosia; left sided lesion: associative agnosia) can also be found in disorders of other senses, e.g., the recognition of environmental sounds (Schnider et al., 1994a) or the tactile recognition of objects (Bottini et al., 1991). Prosopagnosia, the inability to recognize the individuality of faces, always requires a right medial temporo-occipital lesion; most cases have bilateral lesions (De Renzi et al., 1994). 6.2.6. Paramedian limbic structures Dysfunction of limbic and paralimbic areas (area 4 in Fig. 6.1), that is, the medial temporal lobes (hippocampus and adjacent cortex), of the medial and anterior diencephalon (medial thalamus and hypothalamus) and of the connecting structures (fornix, mammillothalamic tract) may induce an inability to learn new information (anterograde amnesia) (Schnider, 2004; Squire, 2004). Severe anterograde amnesia may also ensue from lesions of the medial orbitofrontal cortex and basal forebrain (DeLuca and Diamond, 1995). This form of anterograde amnesia—in contrast to medial temporal amnesia—is typically characterized by lack of insight and, in the first weeks, often by flagrant confabulation and disorientation (spontaneous confabulation syndrome) (Schnider, 2003). Although the lesions of all of these paralimbic structures may also induce a

140

A. SCHNIDER

temporally limited loss of information acquired before the occurrence of brain damage (retrograde amnesia), long-term storage of information appears to depend on neocortical areas. Temporally unlimited loss of old information has been described in particular in patients with lesions of the convexity and pole of the temporal lobes (Kapur et al., 1992). The ability to learn new motor or cognitive skills (procedural learning) does not appear to depend on medial temporal structures; deficient learning of new skills has been described after basal ganglia lesions. Other forms of implicit memory do not depend on the medial temporal lobes either (Squire, 2004).

6.3. The mental examination Similar to the physical examination, the mental examination should probe for dysfunction of the diverse areas of the brain. In the following, some techniques to test mental functions will be described. However, the organization of the examination depends on the precise question and the clinical context. In a patient awakening from coma, the examination will concentrate on documenting vigilance, attention, and the capacity to cooperate, whereas in the ambulatory patient suspected of having Alzheimer’s dementia, extended evaluation to determine the precise pattern of cognitive and behavioral dysfunction is crucial. The following description and order of the components of the mental status examination is loosely related to the above anatomical considerations and represents one way of sequencing the components of the examination. For example, it is important to have an idea of the patients’ attention before testing their judgment; to verify intact language before testing their verbal memory, etc. 6.3.1. Taking the history As in any other medical activity, taking the patient’s history is the first step of the exploration; in the mental status examination, it plays a particularly important role and serves several purposes: 1. It allows one to sort out the precise complaints of the patient. What a patient calls ‘memory disturbance’ may be a naming problem; ‘blurred vision’ may be hemianopia or alexia. Very often, it is useful to have a family member present at the beginning of the discussion: patients with dementia may be unaware of their failures, which are all too obvious to the family; or relatives may have noticed changes of personality and behavior that are not evident in the setting of a medical evaluation. 2. History taking allows one to determine the severity and impact of a disorder. A ‘memory disorder’ has

an entirely different importance if a patient gets lost in their hometown than if they only have difficulty in finding the names of people. 3. It allows one to determine premorbid cognitive capacities. Difficulties with orthography or in drawing a three-dimensional cube do not necessarily indicate brain damage if a person has had little schooling. 4. History taking is part of mental status testing. The ease and precision with which the patient responds to questions are important measures of their language and memory functioning. Behavioral abnormalities may be more evident than during structured testing. A patient may play around with objects on the table, may appear verbally disinhibited, or fail to react to humorous hints by the examiner. Observations should be documented. 5. The observations during history taking allow one to adjust the components of the mental examination and to determine what cognitive areas require particular attention. 6.3.2. Attention and orientation Anything less than full, attentive cooperation during the whole consultation is indicative of brain dysfunction. Decreased attention, slowing of performance, or apparent distractibility should be documented. A good starting point to document a patient’s attention over prolonged periods is the testing of orientation. Four domains should be tested: orientation to person (name, date of birth, age, color of eyes, marital status), time (year, season, month, day of the week, date, time of day), place (city, county, building, unit, floor), and situation and circumstances (reason for the consultation, accompanying person, transport to the hospital and so on). The latter type of orientation is normally evaluated during history taking. In most cases of brain damage, orientation to time is most vulnerable, whereas orientation to person is most resistant and is usually only disturbed in a confusional state (High et al., 1990). It is important to test several items because orientation primarily depends on the selection of currently relevant information from memory, rather than simple information storage; this selection may rapidly vary (Schnider et al., 1996). Disorientation is typical for confusional state but is also seen in non-confused amnesic patients, especially with orbitofrontal lesions, and in dementia. A more direct measure of attention is the digit span (Wechsler, 1945). The examiner reads out an irregular series of numbers between 1 and 9 (2-7-4-8-. . .) and asks the patient to repeat the series. If the patient fails to perfectly repeat the series, a new series of the same length is presented. Digit span corresponds to the

NEUROPSYCHOLOGICAL TESTING: BEDSIDE APPROACHES longest series that the patient succeeds in reproducing on at least one of two trials. Normal digit span is at least 5. An additional, more demanding task is to repeat the series in reverse order. Reverse digit span is normally one less than the forward digit span. In a similar fashion, short-term retention of visuospatial material can be tested by drawing 9 circles in a random fashion on a paper and to designate an irregular series of locations that the patient has to reproduce. A comparably demanding test of attention is the serial 7s test (Smith, 1967; Luria, 1973). The patient is asked to subtract 7 from 100, and then to continue to subtract 7 from the obtained results. No more help must be provided and the series of responses should be noted. Performance is considered normal if the patient succeeds in making 5 correct successive subtractions. A comparable test is the backward spelling of a word (WORLD); of course, the test is only meaningful if the patient succeeds in correct forward spelling (Ettlin et al., 2000). A less difficult test of attention is the backward enunciation of the months of the year or the days of the week. Less demanding tasks which allow one to document severe disturbances of attention are the following tests: In the A-test, the patient is required to tap on the table or raise their arm whenever the examiner, who reads out an irregular series of letters, says the letter A (Strub and Black, 2000). In the go/no-go test, the patient is asked to tap twice when the examiner has tapped once and to tap once when the examiner has tapped twice (Drewe, 1975; Dubois et al., 2000). This first part tests the ability to suppress the interference of the conflicting instruction. After one minute, the patient is reinstructed to tap once when the examiner has tapped twice but not to tap when the examiner taps once. This second part measures inhibitory control. Finally, the brief retention and execution of a motor sequence can be tested with Luria’s hand sequences (Luria, 1980). The examiner shows a three-step hand sequence comprising initial tapping with the fist, then the edge of the open hand and then the palm of the open hand. After executing this sequence three times, the patient is asked to produce the same sequence. If the patient fails to reproduce the sequence, the examiner helps by indicating the rhythm of the sequence while performing it again (‘1-2-3-. . .’). If the patient still fails to produce the sequence, the examiner helps by describing the sequence (‘fist-cut-slap-. . .’). If the patient still does not succeed, the sequence is reduced to two steps. Perfect performance of this task is a reassuring sign of largely preserved motor flexibility. Elderly patients often have difficulty with the task and performance has to be interpreted in the context of the entire examination. Nonetheless, this task, like

141

the A-test and the go/no-go task, allows one to document an attentional capacity. Failure in the task is often seen in confused patients and appears to primarily reflect frontal dysfunction. Many patients with dementia and occasional patients with circumscribed frontal lesions fail in these tasks. Scoring systems have been proposed (Dubois et al., 2000; Ettlin et al., 2000). 6.3.3. Frontal lobe dysfunction The term ‘frontal dysfunction’ is used here synonymously with ‘executive failures’ and is meant to comprise such functions as planning, focused attention, and flexibility, but also behavioral failures, which—in pure form—typically reflect dysfunction of the prefrontal lobes. Severe frontal dysfunction also leads to impaired performance in the tasks described in the previous paragraph 6.3.2. There are innumerable ‘frontal bedside tests.’ Unfortunately, most bedside tests are quite insensitive to frontal dysfunction: higher order planning, the ability to maintain attention over a prolonged period, to plan actions with foresight over prolonged periods, and to adapt behavior to social signals are extremely important for human behavior but cannot be adequately measured with bedside tests. The examiner has to be particularly sensitive to indications of impairment in these capacities and must carefully observe behavioral aberrations during history taking and the examination. Sensitive evaluation of attention and planning requires standardized, often computerized testing. Tasks of social interaction are mostly still in the realm of experimental investigation. The clinical evaluation of frontal lobe functions depends at least as much on the history and behavioral observation as on the results of bedside tests. 6.3.3.1. Planning The patient’s ability to sequence the steps necessary to achieve a goal can be estimated on the basis of their performance in complex tasks such as the copying of a complex design (see 6.3.5.1). The recognition of a concept can be evaluated at the bedside with the coin test (Ettlin et al., 2000): the examiner moves a coin— out of sight—according to a fixed pattern from one hand to the other (e.g., L-L-R-L-L-R-) and the patient has to guess, upon each move, in which hand the examiner holds the coin. After 3 or 4 repetitions of the same sequence, the patient should be able to grasp the pattern. The ability to make abstractions, also a requirement for meaningful action planning, can be estimated on a basic level using logical sequences, where the patient is asked to complete a sequence initiated by the

142

A. SCHNIDER

examiner (1-3-5-7-. . .; A1-B2-C3-D. . .). Patients with severe frontal lobe dysfunction may fail to grasp the concept and fall into an inflexible, perseverative behavior (Fig. 6.2). Disorders of higher levels of abstraction may be evident throughout the examination, e.g., in a patient’s approach to calculation tasks. More formally, it may be evaluated with the interpretation of proverbs, where patients with frontal lobe damage tend to give a concrete explanation rather than abstract interpretation of proverbs (Benton, 1968; Luria, 1973). 6.3.3.2. Initiation and drive Especially after paramedian prefrontal lesions, patients may be profoundly impaired in their ability to initiate motor acts. They respond to commands very slowly and after long delays. Such behavior should be documented and situations be sought in which the patient succeeds in initiating an act. Oftentimes, such patients only react in an inflexible, stimulus bound way to objects within their reach: they aimlessly grasp objects (utilization behavior) (Lhermitte, 1983). Psychomotor slowness, the clinical manifestation of disturbed drive and initiation, may be evident throughout the examination and can be documented by noting the time taken to execute diverse tasks, e.g., the copying of line drawings or mental calculations. In a more formal way, verbal drive and flexibility can be measured with verbal fluency, also called controlled oral word association test or FAS-test (Thurstone and Thurstone, 1962). The patient is asked to produce during one minute as many words as possible that start with the letter F, then the letter A, and finally the letter S. A healthy person produces at least 10 to 12 words per minute. We prefer an adapted version, in which patients are asked to produce for 3 minutes words with a given letter and to respect certain rules: ‘Say all the words starting with the letter F, except proper names or geographic names; Frederic or France would not be

allowed.’ The examiner comments only the first occurrence of a repetition or a rule break (production of a name). Normal subjects produce at least 20 correct words in 3 minutes. Patients with frontal lobe dysfunction, e.g., due to frontotemporal degeneration, produce few words and make rule breaks. Amnesic patients tend to repeat the same words several times. The test is also very sensitive to aphasia and is indeed an excellent screening test for language dysfunction. Only when language is intact can the test be considered a ‘frontal lobe test,’ in particular for left frontal function. Nonverbal drive and flexibility can be explored with the 5-point test (Regard et al., 1982) in which patients have to produce for 3 minutes simple designs by combining 2 to 5 points in a fixed array of 5 points. Normal subjects produce at least 20 correct designs in 3 minutes. The test requires a prepared testing form (Spreen and Strauss, 1998). It is easy to score and very valuable in documenting especially right frontal dysfunction. 6.3.3.3. Focused attention Some techniques to explore a patient’s ability to concentrate on a task have been described in 6.3.2.: digit span forward and backward, spelling backward, and the serial 7s test measure focused attention. A disturbance may be clinically evident in a patient’s distractibility during the examination, distractibility which reflects increased susceptibility to interference. The go/no-go task described above is also a measure of such susceptibility. Rule breaks in verbal fluency testing may also indicate increased susceptibility to interference when the patient produces the words that have been explicitly interdicted by the examiner. More formally, susceptibility to interference may be tested with the Stroop paradigm (Stroop, 1935). As a measure of cognitive speed, patients first have to name the colors of an array of colored dots. In the interference condition, they have to indicate the colors in which the names of colors are written (e.g., word ‘red’ written in blue). Patients with frontal lobe dysfunction tend to succumb to this interference by reading the written word rather than indicating its color, and by slowing their performance. This test requires prepared material; a simplified version appropriate for clinical mental testing has been developed (Perret, 1974). 6.3.3.4. Cognitive flexibility

Fig. 6.2. Simple logical sequences. The examiner writes down the initial part of the sequence. The underlined part indicates the attempt to continue the sequences by a patient with frontotemporal degeneration. Adapted from Schnider (2004) with permission from Thieme.

The above-mentioned tests of verbal and nonverbal fluency are also measures of cognitive flexibility. The lack of flexibility, i.e., cognitive perseveration, can be seen when the patient continues to act according to rules that pertained to previous tasks. For example, a patient whose verbal fluency has just been tested (words

NEUROPSYCHOLOGICAL TESTING: BEDSIDE APPROACHES starting with a specific letter), may try to produce names starting with the same letter when asked to name as many animals as possible (a test of semantic memory, see 6.3.7.5). Fig. 6.3 gives an example of cognitive perseveration in a drawing task. Motor perseveration, which is independent of cognitive perseveration, may be tested with Luria’s loops and alternating sequences (Fig. 6.3) (Luria, 1980). Patients are asked to copy the three loop-designs and the alternating sequences, which they then have to continue until the end of the paper. Even a slight tendency to add additional loops or to produce a zigzag pattern are abnormal and indicate brain dysfunction. Fixed combination of some of these tests with elaborated scoring systems have been proposed (Dubois et al., 2000; Ettlin et al., 2000) and appear to be particularly useful for separating frontotemporal dementia from other forms of dementia (Mathuranath et al., 2000; Slachevsky et al., 2004). 6.3.4. Language-associated disorders The term ‘language-associated disorders’ is used here to denote failures of cognitive functions that often,

143

but not always, occur together with aphasic disorders and most of which preferentially, but not exclusively, occur after damage to the left hemisphere, particularly the pericentral area (see 6.2.2). 6.3.4.1. Spoken language If a patient expresses themselves precisely and with ease during history taking, it is very unlikely that they have a serious language disorder. There are occasional exceptions of patients with an aphasia characterized by word finding difficulties who have learned to circumvent these difficulties in spontaneous speech. Thus, naming ability should be tested specifically. The patient may be asked to name body parts (index, thumb, earlobe, etc.), objects (handkerchief, door handle, pencil, etc.) or line drawings. Preparing a series of drawings of objects (e.g., 12 drawings from Snodgrass and Vanderwart (1980)) has the advantage that the examiner does not depend on the availability of objects during testing and rapidly acquires the experience with the difficulty and ease that normal subjects have in naming the drawings. The examination is more sensitive when the search for relatively rare words describing exemplars of groups of items (‘index finger’ rather than ‘finger,’ ‘tulip’ or

Fig. 6.3. Motor perseveration. Patients are asked to copy the design and to continue it to the end of the sheet. Above: Luria’s loops (Luria, 1980). (A) Patient with frontal contusion who produces typical perseverative loops (more than 3 loops). (B) Severe perseveration in a patient with basal forebrain infarction due to spasms following subarachnoid hemorrhage from an aneurysm of the anterior communicating artery. (C) Patient with right dorsolateral prefrontal infarct due to spasms following hemorrhage from an aneurysm of the middle cerebral artery. Below: Alternating sequences (Luria, 1980). (D) A patient with right frontal contusion intermittently produces perseverative zigzag pattern. (E) Patient with bilateral prefrontal infarction following superior sagittal sinus thrombosis. (F) Same patient as (C); in addition to repetitive motor behavior, there is cognitive perseveration in that the patient continues a previous task of drawing a house. Reprinted from Schnider (2004) with permission from Thieme.

144

A. SCHNIDER

‘daisy’ rather than ‘flower’) and parts of objects (‘cap’ of a bottle rather than ‘bottle’) are tested. Naming capacity and verbal fluency (see 6.3.3.2) together are highly sensitive tests for the presence of language disturbances (Benson and Ardila, 1996). If a patient has difficulty in expressing themselves, the examiner should determine whether the language is nonfluent, i.e., hesitant and devoid of grammatical structure (motor aphasia) or whether it is fluent, i.e., with an easy flow of words but full of syllable or word confusions, sometimes composed of neologisms and incomprehensible jargon (sensory aphasia). It should be determined whether the patient produces words with substituted syllables (phonematic paraphasias) or confuses the words themselves (semantic paraphasias). These elements, together with testing of language comprehension and repetition, allow the classification of an aphasia and an estimation of the locus of the lesion (Benson and Ardila, 1996; Kreisler et al., 2000). If it is unclear whether a patient is really aphasic or merely dysarthric, the examination of written language may clarify the question. Repetition should be tested by having the aphasic patient repeat words and sentences, whereby sentences containing functors are particularly difficult for aphasic subjects to repeat (‘there are no ifs, ands or buts’). Comprehension should first be tested with simple sentences (‘close your eyes, stick out your tongue’). Patients with moderate to severe comprehension deficit will still be able to execute these simple orders, so that these commands can be used to establish communication. If the patient does not have obvious language deficits, one may immediately test complex commands like: ‘Touch your left ear with your right index finger; point to my right elbow after you have shown me your left eye.’ Execution of these commands requires many cognitive faculties beyond language comprehension: attention, immediate memory, recognition of body parts, differentiation between right and left etc. If the patient is suspected of having comprehension difficulties, increasingly complex pointing commands should be tried, starting with simple commands: ‘Point to the ceiling, to the door, the window’ etc.), then combined commands ‘Point to the floor, then to your nose. . .’ A patient should be able to execute four-step commands (Strub and Black, 2000). Then, questions should be asked which can be answered by ‘yes’ or ‘no’: ‘Is this a hotel? Are you a man/woman?’ etc. A sufficient number of items should be tested as 50% of the questions can be correctly answered by chance alone. 6.3.4.2. Written language For a brief exploration, it is sufficient to have the patient write a full sentence and read a brief text. If

there is suspicion of interhemispheric disconnection, the patient should also be asked to write a difficult word (e.g., electricity) with their non-dominant hand, together with testing for ideomotor apraxia (see 6.3.4.5) and tactile naming (Bogen, 1985). If the patient fails in writing a correct, full sentence, there is suspicion of agraphia. Their writing of single letters, digits and words should then be explored. If their problem is purely motor, the patient should be able to spell words. Alexia, the inability to read, is often part of an aphasia. Types of errors during reading (paralexias) should be noted to classify the reading disorder: there may be substitutions of syllables and letters (phonematic paralexias) or substitution of whole words (semantic paralexias). Pure alexia, the inability to read in the presence of intact oral language and writing, is typically characterized by letter-by-letter reading (Coslett et al., 1993). Such patients can nevertheless copy a text that they cannot read and understand words spelled to them. Alexia should be distinguished from other difficulties with reading: reading is often hesitant and effortful in hemianopia. Patients with hemispatial neglect may omit the beginning of words or lines of text. 6.3.4.3. Acalculia The ability to make mental and written calculations demands comprehension, retention and manipulation of information and thus involves language, working memory, and calculation skills. Some mental calculations (18 þ 23, 47  29, 13  4, 27  3) and written calculations (4386  2674), in which the patient themselves write the numbers down, should be part of any mental examination. Much cognition must be intact for swift execution of such tasks. If the patient fails, it should be evaluated whether the disorder is restricted to the act of calculation or whether the patient also fails to write and read the digits and calculation symbols (He´caen et al., 1961; Mayer et al., 2003). 6.3.4.4. Body and space Patients’ understanding of the spatial arrangement of their body can be tested by having them name fingers and other body parts that the examiner touches on their right or left side as the patients have their eyes closed (Coslett et al., 2002). Conversely, patients are asked to point to fingers and other body parts named by the examiner (‘show me your left index finger; point to my right elbow,’ etc). Although difficulties in such tasks can most often be attributed to an underlying aphasia, the inability to recognize the position and meaning of fingers (finger agnosia) and to distinguish between right and left on oneself and other people

NEUROPSYCHOLOGICAL TESTING: BEDSIDE APPROACHES (right/left-confusion) can also occur in the absence of an aphasia. Together with acalculia and agraphia, they constitute the Gerstmann syndrome, whose occurrence in pure form has been described after left parietal damage (Mayer et al., 1999).

145

or recognition problems, in dementia or in confusional states, ideational and conceptual apraxia can occur as isolated disorders and should be sought when a patient displays such difficulties in everyday life. 6.3.5. Visuospatial disorders

6.3.4.5. Ideomotor and other apraxias There are diverse forms of apraxia whose dissociations, clinical scope, and anatomical basis are still debated (see Chapter 16). Ideomotor apraxia can be defined as the inability to voluntarily perform skilled movements to command out of their natural context (Schnider et al., 1997; Heilman and Gonzalez Rothi, 2003). The failure must not be due to a primary motor or sensory disorder. It is easily tested by having the patient perform pantomimes of tool use to verbal command: ‘Show me how you use a toothbrush, comb, key,’ etc. Ideomotor apraxia is characterized by parapraxic errors: the most frequent error is the use of the hand as if it were the tool itself (body-part-as-object error) and which is not corrected on reinstruction. Less frequent errors concern the configuration of the hand or the whole extremity, inappropriate timing and speed of the movement or substitution or mixture with a movement denoting use of another tool. If language comprehension is impaired, the patient may be asked to imitate movements made by the examiner. The performance of meaningful symbolic gestures (‘salute like soldier, wave goodbye,’ etc.) is also often impaired. Buccofacial apraxia can be interpreted as an ideomotor apraxia concerning facial movements and is tested by verbal commands or imitation (‘frown, show your teeth, whistle,’ etc.). Ideomotor apraxia, in particular to verbal command, is highly specific to left hemisphere damage (Schnider et al., 1997); apraxia on imitation may also occur after right hemisphere damage (De Renzi et al., 1980; Goldenberg, 1996). Some patients may have apparently normal fine movements and sensibility of the hand contralateral to a hemispheric lesion but still fail to intentionally grasp fine objects, such as a coin from a table. The disorder is called limb-kinetic apraxia. Several authors proposed to distinguish between two forms of apraxia, which interfere with real use of objects and tools: in ideational apraxia, the patient fails to plan the correct sequence of an act necessary to perform a complex action, such as preparing a cup of coffee or cooking an egg (De Renzi et al., 1982; Poeck, 1983). In conceptual apraxia, they fail to select and correctly use the tool appropriate to handle an object (e.g., a screwdriver rather than a hammer to insert a screw) (Heilman et al., 1997; Goldenberg and Hagmann, 1998). Although difficulty in selecting and using tools are often seen together with other planning

Disorders of spatial processing do not only occur after right hemisphere damage; the Gerstmann syndrome (see 6.3.4.4) is an example of a spatial disorder induced by left hemisphere damage. Nonetheless, the right hemisphere appears to have a strong dominance for processing complex spatial relationships. Most are amenable to bedside testing. 6.3.5.1. Visuoconstructive and visuospatial disorders The inability to correctly copy complex twodimensional designs or three-dimensional constructions is often called constructional apraxia. The examiner should be aware that, in most cases, the problem reflects a spatial disorder rather than an apraxic one. Visuoconstructive abilities are particularly easy to document, but the exploration has to be adapted to the clinical context. In a confused patient, the copying of Luria’s loops or alternating sequences (see 3.3.4, Fig. 6.3) or a free design of a flower or a house give a first impression of the ability to cooperate and execute an intentional act; such documents are precious for the follow-up of a patient. In order to describe the severity of a visuoconstructive disorder, it is useful to demand the copying of some increasingly difficult designs (Fig. 6.4) (Schnider, 2004). For screening, at least the copying of a three-dimensional cube should be documented (Strub and Black, 2000). Patients with severe visuospatial disorders often fail to grasp the three-dimensional quality of the cube. The patient’s level of schooling has to be taken into account: the copying of a cube may be difficult for a person having less than three or four years of formal education. A test which is spatially easier but semantically more demanding, is the drawing of a clock (Freedman et al., 1994). The examiner draws a circle on a paper and asks the patient to put the numbers into the clock and to put the hands to 10 past 10. Standardized scoring procedures have been developed, but failure is mostly blatant. If the patient fails, the reading of an analog clock without numbers—real watch or pictures of clocks—should be tested to examine whether the patient perceives the spatial arrangement and orientation of lines, a capacity which is particularly dependent on right hemisphere contribution (Benton and Tranel, 1993). A most valuable test is the copying of Rey’s complex figure (Fig. 6.5) (Rey, 1941). It allows one not only to

146

A. SCHNIDER test patients’ ability to comprehend spatial relationships but also to evaluate their planning capacity and sense of abstraction. A normal person easily grasps the concept of the design and then proceeds with the details. Patients with planning deficits often just assemble bits and pieces of the figure. Such patients will have difficulty in reproducing the figure from memory after a 20 to 40 minutes’ delay. Indeed, the possibility of quantitatively evaluating nonverbal memory with the delayed recall of the complex figure makes it particularly valuable. It should therefore only be part of the bedside testing if the examiner can appropriately document, not only the copy, but also the delayed recall of the design (Lezak, 2004). Three-dimensional constructions are not normally part of bedside testing as most examiners do not have the necessary material available. The testing of threedimensional constructions does not normally add crucial information for clinical decision-making.

Fig. 6.4. Copying of increasingly difficult designs (by D.F. Benson, MD). (A) Patient with Alzheimer’s dementia (MMSE (Folstein et al., 1975) score of 22); (B) Patient with extensive right temporoparietal infarction. Adapted from Schnider (2004) with permission from Thieme.

6.3.5.2. Hemispatial neglect Difficulties in the visuoconstructive tasks mentioned above, inducing distortions and errors on both sides of the designs, occur with damage of both hemispheres. By contrast, hemispatial neglect very reliably indicates

Fig. 6.5. Copying of Rey’s complex figure (Rey, 1941; Spreen and Strauss, 1998). (A) Difficulties of a patient with bilateral frontal contusion. (B) Moderate deficit in a patient with right parietal hemorrhage. (C) Severely deficient copy by a patient having extensive right frontoparietal infarction due to spasms following hemorrhage from an aneurysm of the right posterior communicating artery. Reprinted from Schnider (2004) with permission from Thieme.

NEUROPSYCHOLOGICAL TESTING: BEDSIDE APPROACHES damage to the hemisphere opposite the neglected side, in most cases of the right hemisphere (Heilman et al., 2003; Karnath, 2003). In the acute phase, hemispatial neglect may be suspected when a patient fails to explore one side of space or to groom the side of the body contralateral to a hemispheric lesion. On questioning, patients may be unaware of or explicitly deny their hemiplegia (anosognosia) (Baier and Karnath, 2005). If there is no severe visual or sensory deficit, the presence of unilateral extinction alerts the examiner to the presence of hemispatial neglect: whereas the patient recognizes unilateral stimuli in both hemifields and on both sides of the body, the patient does not perceive the stimulus applied to the neglected side when stimuli are applied simultaneously to both sides. Hemispatial neglect may become evident in many tests and its expression often varies between tasks. When writing a sentence, patients with hemispatial neglect may write the text on only one side of the paper; in reading, they may neglect the beginning of the lines; in visuoconstructive tasks, they may omit or make more errors on the left side. Tasks of visuospatial search allow the formal documentation of hemispatial neglect. In Albert’s line cancellation task, the patient fails to mark lines on the neglected side (Albert, 1973). This test can easily be prepared by pseudorandomly distributing 12 lines on the left side and 12 lines on the right side of a horizontally oriented sheet of paper (Fig. 6.6a). After the acute phase, many neglect patients have no difficulty with this task anymore but still fail on finer tests, such as the cancellation of a given letter (e.g., ‘A’) in a cloud of letters; this test requires prepared testing material (Kaplan et al., 1991). Patients often also fail in bisecting lines arranged horizontally on a sheet of paper (Fig. 6.6b): they miss lines on the neglected side and bisect lines too much toward the intact hemifield (Bisiach et al., 1983). The test is more sensitive with longer lines, so that the normal sheet of paper should be oriented horizontally. Patients may fail on one, but not the other task (Kaplan et al., 1991). The neglect syndrome has many dissociations. Clinical testing normally only covers neglect within the reaching space, which may be based on a difficulty in perceiving elements from a hemispace or in acting into that space. In some cases, neglect only concerns the body; in other patients, neglect only concerns far space (Vuilleumier et al., 1998). The latter should be suspected when a patient omits elements on one side of space when asked to describe the ward’s hallway or to point to all people present in a spacious room. Some patients have neglect in thinking and visual imagery (representational neglect), which can be explored by having patients describe from memory a place known to them and the examiner (Bisiach et al., 1979). For

147

Fig. 6.6. Neglect tests. (A) Version of the line cancellation task (Albert, 1973) with 12 pseudorandomly distributed lines on the right and left half of the sheet. (B) Line bisection task (Bisiach et al., 1983); the patient is asked to mark each line’s midpoint. Adapted from Schnider (2004) with permission from Thieme.

clinical decision-making, the diagnosis of hemispatial neglect concerning the body, reaching space and far space is usually sufficient. 6.3.5.3. Topographical agnosia Hospitalized patients, who are not confused, may have disproportionate difficulties in finding their way around the ward. The problem may be due to an inability to learn new environments (topographamnesia; anterograde disorientation) or to a visuospatial disorder with an inability to relate one’s own body to space (apperceptive topographagnosia; egocentric disorientation) (Gru¨sser and Landis, 1991; Aguirre and D’Esposito, 1999). In some instances, however, the problem is disproportionate in comparison with other spatial problems. This pure disorder (landmark agnosia; associative topographagnosia) reflects inability to sense familiarity with an environment. The patients may even fail to orient themselves in a previously familiar environment, such as their own

148

A. SCHNIDER

home. The disorder is likely when patients have striking difficulty in orienting themselves in space in the face of only minimal constructive difficulties. When asked to draw a map of a specific environment that the patient should know (own apartment or hospital bedroom), they display much more difficulty than when asked to copy a design. Associative topographical agnosia has high localizing significance for a right medial temporo-occipital lesion (Landis et al., 1986). 6.3.6. Visual recognition disorders Patients with disorders of visual perception or recognition do not always realize their difficulties. Patients with acute cortical blindness may be entirely unaware of it and even confabulate on entirely invented perceptions (Anton syndrome). Higher visual functions should therefore always be tested, also in patients who do not complain about bad vision. The examination is usually rapid and reliable. However, there remain visual disorders which cannot be examined at the bedside with sufficient precision and which require specialized neuro-ophthalmological exploration. This concerns subtle scotomas or dysfunction of isolated physiologic channels inducing impaired perception of motion, color, contrast, or depth (Gru¨sser and Landis, 1991). Visual fields should be tested with fine finger movements in the four quadrants with intermittent simultaneous stimulation on both sides. Higher disorders of visual conception should be tested with prepared material such as proposed in Fig. 6.7. A healthy person immediately recognizes the displayed items. If a patient has difficulty in recognizing these items, further testing should be added to characterize the disorder according to the following considerations. 6.3.6.1. Apperceptive visual agnosia Apperceptive agnosia impairs the ability to instantly extract and bind the visual components necessary to recognize a visual scenario (Farah, 1990). Thus, a patient will have difficulty in recognizing overlapping, illusory, or fragmented information or objects shown from an uncommon perspective (Fig. 6.7). By contrast, the patient should not have difficulty when the same objects are shown separately from the typical perspective. Apperceptive agnosia may be a primary visual disorder presumably due to impaired binding, e.g., the automatic completion of bits of visual information into their coherent representation. This disorder is typically due to bilateral or right-sided posterior, in particular occipital or occipitotemporal damage (Warrington and Taylor, 1973). In other cases, the disorder is due to extremely limited visual attention, allowing perception

of only one visual component (simultanagnosia, ‘peacemeal perception’), the failure typical of Ba´lint’s syndrome. It is typically due to bilateral (superior) parietal damage and accompanied by optic ataxia in both visual fields, which interferes with the ability to make precise movements towards visual targets (Luria, 1959; Farah, 1990). Likewise, ocular saccades also lack precision, the component called ocular apraxia. 6.3.6.2. Associative agnosia Associative agnosia impairs the ability to attribute the correct meaning to an intact visual percept (Rubens and Benson, 1971; Farah, 1990). A patient with a pure form of this disorder would have difficulty in recognizing and naming the items displayed in Fig. 6.7 but would be able to indicate their outlines and to draw them. Likewise, the patient will be able to copy the drawing of an object which they fail to recognize or copy a text which they cannot read. Pure associative visual agnosia emanates from left temporo-occipital lesions which leave the splenium of the corpus callosum intact (Schnider et al., 1994b). In the acute stage, the patients may also fail to recognize objects in other than the visual modality. Associative agnosia impairs visual recognition of objects; the patient cannot name them, use them before touching them and cannot pantomime their use. Associative agnosia should be differentiated from other disorders. In anomia, the patient correctly uses objects that they cannot name, but they additionally fail to name objects presented in other modalities (e.g., tactile recognition) and cannot name the objects upon a verbal definition. Optic aphasia may represent like anomia limited to the visual modality, but it may also include the inability to point to named objects; objects have lost their verbal representation, but not their meaning. It is typically due to a lesion similar to associative agnosia but extending into the splenium of the corpus callosum. Using this anatomical criterion to separate cases, optic aphasia differs from associative agnosia by the preserved ability to pantomime the use of seen objects (Schnider et al., 1994b). Patients with semantic memory impairment have lost precise knowledge about objects leading to confusions or superficial identification of objects. The disorder extends to other than the visual modality and also impairs the ability to define objects (Warrington, 1975; Hodges et al., 1992). In summary, if a patient fails to name items such as those displayed in Fig. 6.7, objects should be shown in prototypical form. A patient should be asked to point to named objects, name tactilely presented objects, show the pantomime corresponding to shown objects, and name objects to verbal definition. This exploration

NEUROPSYCHOLOGICAL TESTING: BEDSIDE APPROACHES

149

Fig. 6.7. Screening for visual recognition disorder. (A) Masked words. (B) Illusory contours (square and 2 triangles) by Kanizsa (1979). (C) Color patches to test for color recognition (e.g., pink, brown, bright green). (D) Fragmented illustration of a dog by Street (1931). (E) Overlapping drawings by Poppelreuter (1917). (F) Photographic portrait of celebrities. (G) Masked contours of animals. Adapted from Schnider (2004) with permission from Thieme.

allows one to break down the previously mentioned disorders and is within the reach of bedside testing.

objects with a distinct color (tomato, banana, cigar, national flag, etc.).

6.3.6.3. Color agnosia

6.3.6.4. Prosopagnosia

The naming and recognition of colors may be selectively impaired (Gru¨sser and Landis, 1991). These capacities should be tested by having the patient name color sheets presented in the four quadrants of the visual field. A patient failing to name colors should be tested regarding the ability to color designs of

Prosopagnosia, the failure to recognize the individuality of faces, may explain bizarre behaviors of patients confusing people. It normally concerns the recognition of previously familiar faces and the learning of new faces. As a screening test, patients may be shown portraits of famous personalities. Alternatively, the examiner may

150

A. SCHNIDER

show a portrait of themselves. If patients’ failure to recognize celebrities is due to prosopagnosia, they should be able to name them upon verbal definition. Prosopagnosia is due to right-sided or bilateral damage of the area homologous with the one producing associative object agnosia, i.e., the right medial temporooccipital junction (De Renzi et al., 1994). It is often associated with topographagnosia (Farah, 1990). 6.3.7. Memory disorders Memory encompasses several distinct capacities with partially dissociated anatomical representation (Squire, 2004). Some forms allow us to store and use information that can be consciously exchanged between individuals. Defects of immediate memory, anterograde amnesia, retrograde amnesia, and semantic memory disorders concern this type of memory, which have been summarized as explicit or declarative memory. Other memory capacities concern abilities that each individual has to acquire by practice and repeat exposure. These forms of memory have been summarized as implicit or nondeclarative memory and encompass the increasingly efficacious processing of previously encountered information (priming), the acquisition of cognitive or motor skills (cognitive or motor skill learning), the acquisition of habits (habit learning), and different forms of conditioning. Whereas the search for non-declarative memory disorders normally requires sophisticated testing material, declarative memory disorders are well amenable to bedside testing. 6.3.7.1. Disorders of working memory Working memory describes the brief retention of information for immediate processing; information is immediately degraded by interfering information (Baddeley, 2003). A common everyday example is the retention of a telephone number kept in mind until the call is answered. The ability to retain verbal and visual information for processing are component capacities of working or active memory (Fuster, 1995), which encompasses in addition the integration of mental activities into thoughts and behaviors and which has been suggested to be supervised by a ‘central executive’ (Baddeley, 2003). This capacity depends on and forms one aspect of attention. The digit and visual span described above (see 6.3.2) are measures of working memory. 6.3.7.2. Anterograde amnesia Anterograde amnesia describes the impaired learning or access to new explicit information. Anterograde amnesia should only be diagnosed if the patient has

the cognitive capacities necessary for processing the information to be stored. Thus, attention should be sufficient and working memory (span) in the corresponding modality should be normal. If these conditions are met, learning can be explored particularly easily because the examiner can precisely define the learning conditions. The most common way of testing verbal memory is to have the patient learn a list of words, then to test recall and recognition of this information after a delay. For example, eight words of medium frequency (tulip, seventeen, belt, Toyota, cabbage, camel, goose, river) can be read to the patient who is then asked to repeat the list. This procedure is repeated five times. Healthy individuals show a fast increase of immediately recalled words with repeated trials (e.g., 3-5-7-8-8). After 20 to 40 minutes during which other tests or the physical exam is made, the patient is asked to reproduce the list (delayed free recall). Healthy individuals recall at least 6 items (persons aged at least 5) (Benson, 1996). If a patient cannot recall the items, a cue is provided (cued recall; ‘there was a type of flower’). If the patient still cannot recall the item, recognition is tested: ‘Was it: rose, tulip, or violet?’ Markedly improved performances on cued recall and recognition indicates that the information has at least partially been stored but is not accessible to free recall. A comparably efficient way of memory testing is by paired-associate learning, where patients learn to associate two words and are later requested to recall the second word when only one word of a pair is presented (Strub and Black, 2000). If there is suspicion of very severe anterograde amnesia, rapid documentation is possible by having the patient repeat three words read by the examiner. Learning trials are repeated until all words are correctly repeated. Delayed recall is then tested after an interfering task, which is cognitively demanding for the patient, e.g., serial-7s (see 6.3.2). A patient with severe memory disorder will fail to recall all three words after such an interference. Failure is very telling, but the test, which is part of the Mini Mental State Examination (Folstein et al., 1975), has little sensitivity. Another rapid documentation of severe memory impairment is possible by hiding four or five objects in the room while the patient is observing the examiner (Strub and Black, 2000). The objects should be clearly visible and be named to make sure that the patient has clearly perceived what objects are hidden. At the end of the examination, i.e., after interfering tasks, the patient is asked to indicate what objects had been hidden and where. Only severe memory disorders will be revealed with this task, which has the merit of sometimes demonstrating a dissociation between the memory for content (the patient does not remember what objects were hidden) from the memory

NEUROPSYCHOLOGICAL TESTING: BEDSIDE APPROACHES for space (the patient remembers the objects, but not where they are hidden). Testing visual memory is more time consuming because the learning procedure, typically the copying designs, takes more time. Having the patient produce from memory all drawings made during the testing (Luria’s loops and alternating sequences, geometric designs) gives an impression of the patient’s visual memory capacity (Schnider, 2004). Sensitive and reliable exploration requires more formal testing, e.g., the reproduction from memory of Rey’s complex figure, which the patient copied during the exploration of visuoconstructive abilities (Lezak, 2004). The described test, especially word list learning and the recall of drawings made during the examination, are sufficiently sensitive for most clinical questions but they may fail to seize subtle memory disturbances, e.g., due to depression. Diverse more sensitive, standardized tests are available (Lezak, 2004). 6.3.7.3. Confabulation and false recognition Patients may occasionally produce words on free recall that were not part of the presented word list. These intrusions, which represent provoked confabulations, are more frequent in brain-damaged subjects than in healthy individuals and mostly reflect a patient’s attempt to recollect more information from memory than is reliably stored (Schnider, 2003). These confabulations therefore do not prove a cognitive disorder beyond the memory disorder itself. By contrast, other patients may produce credible, but fictitious, stories of the recent past and plans for the future, which do not take their current hospitalization into account, and they occasionally act according to these false beliefs. These patients are also disoriented. This disorder, the spontaneous confabulation syndrome, is based on a confusion of reality in thinking and results from posterior orbitofrontal damage or disconnection (Schnider, 2003). There is no clinical bedside test to diagnose the disorder, but it is important to recognize the characteristic features of the syndrome as its behavioral manifestations are much more difficult to handle than common amnesia. 6.3.7.4. Retrograde amnesia Retrograde amnesia is the loss of explicit (declarative) memory acquired before the occurrence of brain damage. The term is normally used for memories associated with particular periods in time. It may concern specific public events or personal episodes (autobiographical memory). The mnestic processing of such information is thought by many to be different from the processing of information that has not been personally experienced and whose acquisition is not associated

151

with a specific period in time, i.e., semantic memory (Moscovitch et al., 2005). Testing is difficult because old memory is personal and there is no individually reliable way of determining what precise information a person should still remember. Nonetheless, marked retrograde amnesia can be explored at the bedside by having the patient recall the names of family members (grandchildren, cousins etc.), politicians, actors, or sport celebrities from different episodes (depending on the patient’s background and the examiner’s knowledge) and precise questions about personal events in the patient’s past (professional training, family celebrations, marriage, etc.). Although such testing is somewhat informal, the memory loss evidenced in this way can sometimes be astounding, especially when testing demented patients, even in early stages. Temporally limited retrograde amnesia, usually extending over some months or years, often accompanies anterograde amnesia (Schmidtke and Vollmer, 1997). By contrast, extended retrograde amnesia requires lesion extension beyond the medial temporal area, usually with extension into the neocortex, in particular the temporal pole or inferior temporal area (Markowitsch, 1995). 6.3.7.5. Semantic memory disorders As used here, this term denotes the loss of general knowledge, including the precise meaning of words, objects or other pieces of information. The patient has difficulty in defining words or understanding the similarity or differences between related words, and cannot precisely name shown objects, sounds, or other perceptions (Warrington, 1975; Hodges et al., 1992). Formal tests commonly require the patient to select from an array of designs those items that are related in meaning rather than form. During bedside testing, semantic memory impairment can be explored during the testing of naming and visual recognition (see 6.3.4.1 and 6.3.6), by asking the patient to define words or to draw objects with distinct features (draw a pyramid, a giraffe etc.). Verbal semantics can additionally be tested with semantic fluency: the patient is asked to name as many items from a specific category as possible during one minute (Lezak, 2004). For common categories like pieces of furniture, animals, car makes or fruits, normal subjects easily produce 15–18 items per minute. The ability to produce item names does not, however, prove that the patient precisely understands their meaning. 6.3.7.6. Non-declarative memory Various forms of non-declarative memory depend on repeated practice of an act or exposure to information and often require specific testing material; many forms

152

A. SCHNIDER

are therefore not reliably amenable to bedside testing. Luria’s hand sequences (see 6.3.2) allow the clinician to evaluate the acquisition of a motor skill. Cognitive skill learning, or quantified testing of motor skill acquisition and conditioning require elaborate tests.

6.4. Scoring and protocols The bedside tests described above are but suggestions that should be adapted to the clinical practice. Further ideas for bedside tests can be found in dedicated books (Hodges, 1994; Strub and Black, 2000; Schnider, 2004). Although it is wise to test all mentioned cognitive domains, the examiner should feel free to replace proposed tests by more difficult or easy items, according to the clinical situation. It may also be useful to include extracts from or complete standardized tests or to have a series of questions prepared to explore behavioral disorders (Cummings et al., 1994). Not all patients undergoing neurological evaluation are considered for mental testing. The following items constitute a very brief screening for the possible presence of mental disturbances. It is composed of observations during history taking and on targeted testing. The following items should be checked: 





 



Vigilance and cooperation are normal: the patient maintains attention and fully cooperates during the whole examination. Communication is normal: the patient expresses themselves easily with an appropriate vocabulary and precise indications regarding their history. Orientation is normal: the patient has precise knowledge about the time (year, month, day), the place (town, hospital, floor, unit) and the situation (reason for the consultation, accompanying person, referring physician, etc.). Copying a three-dimensional cube poses no problem. Reading of a sentence poses no problem; the patient fluently reads a text and understands its meaning. Writing of a sentence is correct.

If a patient fails on any of these items, mental status examination as described above should be performed. In a setting with recurring clinical questions, e.g., a dementia clinic, or in the context of scientific study, quantification of results may be necessary. Several quantitative scoring systems of bedside test have been proposed, the most common being the ‘Mini Mental State Examination’ (Folstein et al., 1975). More complete batteries covering diverse aspects of cognition have been proposed for clinical mental testing (Welsh et al., 1994;

Mathuranath et al., 2000; Strub and Black, 2000). Scores summarizing performance in test batteries may be useful but carry the risk of limiting one’s attention to the total score rather than the patient’s specific mental difficulties. The described examination satisfies most clinical situations. When precise comparison of a patient’s performance within a cognitive domain with age- and education-matched controls is necessary or when subtle cognitive deficits have to be quantified and followed, the described examination may need to be completed by standardized neuropsychological tests.

References Aguirre GK, D’Esposito M (1999). Topographical disorientation: A synthesis and taxonomy. Brain 122: 1613–1628. Albert ML (1973). A simple test of visual neglect. Neurology 23: 658–664. Anderson SW, Bechara A, Damasio H, et al. (1999). Impairment of social and moral behavior related to early damage in human prefrontal cortex. Nat Neurosci 2: 1032–1037. Baddeley A (2003). Working memory: Looking back and looking forward. Nat Rev Neurosci 4: 829–839. Baier B, Karnath HO (2005). Incidence and diagnosis of anosognosia for hemiparesis revisited. J Neurol Neurosurg Psychiatry 76: 358–361. Benson DF (1996). Approaches to intellectual and memory impairments. In WG Bradley, RB Daroff, GM Fenichel, CD Marsden (Eds.), Neurology in Clinical Practice. Principles of Diagnosis and Management, Vol. I. ButterworthHeinemann, Boston, pp. 71–81. Benson DF, Ardila A (1996). Aphasia. A Clinical Perspective. Oxford University Press, New York. Benton A, Tranel D (1993). Visuoperceptual, visuospatial, and visuoconstructive disorders. In KM Heilman, E Valenstein (Eds.), Clinical Neuropsychology, 3rd edn, Oxford University Press, New York, pp. 165–213. Benton AL (1968). Differential behavioral effects in frontal lobe disease. Neuropsychologia 6: 53–60. Bisiach E, Bulgarelli C, Sterzi R, et al. (1983). Line bisection and cognitive plasticity of unilateral neglect of space. Brain Cogn 2: 32–38. Bisiach E, Geminiani G, Berti A, et al. (1990). Perceptual and premotor factors of unilateral neglect. Neurology 40: 1278–1281. Bisiach E, Luzzatti C, Perani D (1979). Unilateral neglect, representational schema and consciousness. Brain 102: 609–618. Bogen JE (1985). Split-brain syndromes. In PJ Vinken, GW Bruyn, HL Klawans, JAM Frederiks (Eds.), Handbook of clinical neurology, Vol. 45, Clinical neuropsychology. Elsevier Science, Amsterdam, pp. 99–106. Bottini G, Cappa SF, Vignolo LA (1991). Somesthetic–visual matching disorders in right and left hemisphere-damaged patients. Cortex 27: 223–228. Brodal A (1981). Neurological Anatomy, 3rd edn. Oxford University Press, New York.

NEUROPSYCHOLOGICAL TESTING: BEDSIDE APPROACHES Coslett HB, Saffran EM, Greenbaum S, et al. (1993). Reading in pure alexia. The effect of strategy. Brain 116: 21–37. Coslett HB, Saffran EM, Schwoebel J (2002). Knowledge of the human body: A distinct semantic domain. Neurology 59: 357–363. Cummings JL (1993). Frontal–subcortical circuits and human behavior. Arch Neurol 50: 873–880. Cummings JL, Mega MS, Gray K, et al. (1994). The Neuropsychiatric Inventory: Comprehensive assessment of psychopathology in dementia. Neurology 44: 2308–2314. De Renzi E (1982). Disorders of Space Exploration and Cognition. John Wiley & Sons, New York. De Renzi E, Faglioni P Sorgato P (1982). Modalityspecific and supramodal mechanisms of apraxia. Brain 105: 301–312. De Renzi E, Lucchelli F (1988). Ideational apraxia. Brain 111: 1173–1185. De Renzi E, Motti F Nichelli P (1980). Imitating gestures. A quantitative approach to ideomotor apraxia. Arch Neurol 37: 6–10. De Renzi E, Perani D, Carlesimo GA, et al. (1994). Prosopagnosia can be associated with damage confined to the right hemisphere—an MRI and PET study and a review of the literature. Neuropsychologia 32: 893–902. DeLuca J, Diamond BJ (1995). Aneurysm of the anterior communicating artery: A review of neuroanatomical and neuropsychological sequelae. J Clin Exp Neuropsychol 17: 100–121. Drewe EA (1975). Go–no go learning after frontal lobe lesions in humans. Cortex 11: 8–16. Dubois B, Slachevsky A, Litvan I, et al. (2000). The FAB: a Frontal Assessment Battery at bedside. Neurology 55: 1621–1626. Eslinger PJ, Damasio AR (1985). Severe disturbances of higher cognition after bilateral frontal lobe ablation: Patient EVR. Neurology 35: 1731–1741. Ettlin TM, Kischka U, Beckson M, et al. (2000). A frontal lobe score. I: Construction of a mental status of frontal systems. Clin Rehabil 14: 260–271. Farah MJ (1990). Visual agnosia. Disorders of Object Recognition and What They Tell Us About Normal Vision. The MIT Press, Cambridge. Folstein MF, Folstein SE, McHugh PR (1975). Mini mental state. A practical method for grading the cognitive state of patients for the clinician. J Psychiatr Res 12: 189–198. Freedman M, Leach L, Kaplan E, et al. (1994). Clock Drawing. A Neuropsychological Analysis. Oxford University Press, New York. Fuster JM (1995). Memory in the Cerebral Cortex. MIT Press, Cambridge. Fuster JM (1997). The Prefrontal Cortex. Anatomy, Physiology, and Neuropsychology of the Frontal Lobes, 3rd edn. Raven Press, New York. Goldenberg G (1996). Defective imitation of gestures in patients with damage in the left or right hemispheres. J Neurol Neurosurg Psychiatry 61: 176–180.

153

Goldenberg G, Hagmann S (1998). Tool use and mechanical problem solving in apraxia. Neuropsychologia 36: 581–589. Gru¨sser OJ, Landis T (1991). Visual Agnosias and Other Disturbances of Visual Perception and Cognition. MacMillan, London. He´caen H, Angelergues R, Houillier S (1961). Les varie´te´s cliniques des acalculies au cours des le´sions re´trorolandiques: Approche statistique du proble`me. Rev Neurol (Paris) 105: 85–103. Heilman KM, Gonzalez Rothi LJ (2003). Apraxia. In KM Heilman, E Valenstein (Eds.), Clinical Neuropsychology, 4th edn. Oxford University Press, New York, pp. 215–235. Heilman KM, Maher LM, Greenwald ML, et al. (1997). Conceptual apraxia from lateralized lesions. Neurology 49: 457–464. Heilman KM, Watson RT, Valenstein E (2003). Neglect and related disorders. In KM Heilman, E Valenstein (Eds.), Clinical Neuropsychology, 4th edn, Oxford University Press, New York, pp. 296–346. High WM, Levin HS, Gary HE (1990). Recovery of orientation following closed head injury. J Clin Exp Neuropsychol 12: 703–714. Hodges JR, Salmon DP, Butters N (1992). Semantic memory impairment in Alzheimer’s disease: Failure of access or degraded knowledge? Neuropsychologia 30: 301–314. Hodges JR (1994). Cognitive Assessment for Clinicians. Oxford University Press, Oxford. Hornak J, Bramham J, Rolls ET, et al. (2003). Changes in emotion after circumscribed surgical lesions of the orbitofrontal and cingulate cortices. Brain 126: 1691–1712. Kanizsa G (1979). Organization in Vision. Essays on Gestalt perception. Praeger, New York. Kaplan RF, Verfaellie M, Meadows ME, et al. (1991). Changing attentional demands in left hemispatial neglect. Arch Neurol 48: 1263–1266. Kapur N, Ellison D, Smith MP, et al. (1992). Focal retrograde amnesia following bilateral temporal lobe pathology. Brain 115: 73–85. Karnath HO (2003). Neglect. In HO Karnath, P Thier (Eds.), Neuropsychologie, Springer, Berlin, pp. 217–230. Kirk A, Kertesz A (1994). Localization of lesions in constructional impairment. In A Kertesz, (Ed.), Localization and neuroimaging in neuropsychology, Academic Press, San Diego, pp. 525–544. Kreisler A, Godefroy O, Delmaire C, et al. (2000). The anatomy of aphasia revisited. Neurology 54: 1117–1123. Landis T, Cummings JL, Benson DF, et al. (1986). Loss of topographic familiarity: An environmental agnosia. Arch Neurol 43: 132–136. Lezak MD (2004). Neuropsychological Assessment, 4th edn. Oxford University Press, New York. Lhermitte F (1983). ‘Utilization behaviour’ and its relation to lesions of the frontal lobes. Brain 106: 237–255. Luria AR (1959). Disorders of ‘simultaneous perception’ in a case of bilateral occipito-parietal brain injury. Brain 82: 437–449.

154

A. SCHNIDER

Luria AR (1973). The Working Brain. An Introduction to Clinical Neuropsychology. Penguin-Allen Lane, New York. Luria AR (1980). Higher Cortical Functions in Man, 2nd edn. Basic Books, New York. Markowitsch HJ (1995). Which brain regions are critically involved in the retrieval of old episodic memory? Brain Res Brain Res Rev 21: 117–127. Mathuranath PS, Nestor PJ, Berrios GE, et al. (2000). A brief cognitive test battery to differentiate Alzheimer’s disease and frontotemporal dementia. Neurology 55: 1613–1620. Mayer E, Martory MD, Pegna AJ, et al. (1999). A pure case of Gerstmann syndrome with a subangular lesion. Brain 122: 1107–1120. Mayer E, Reicherts M, Deloche G, et al. (2003). Number processing after stroke: Anatomoclinical correlations in oral and written codes. J Int Neuropsychol Soc 9: 899–912. Moscovitch M, Rosenbaum RS, Gilboa A, et al. (2005). Functional neuroanatomy of remote episodic, semantic and spatial memory: A unified account based on multiple trace theory. J Anat 207: 35–66. Parvizi J, Damasio AR (2003). Neuroanatomical correlates of brainstem coma. Brain 126: 1524–1536. Perret E (1974). The left frontal lobe of man and the suppression of habitual responses in verbal categorical behavior. Neuropsychologia 12: 323–330. Poeck K (1983). Ideational apraxia. J Neurol 230: 1–5. Poppelreuter W (1917). Die psychischen Scha¨digungen durch Kopfschuss in Kriege 1914/16. Verlag von Leopold Voss, Leipzig. Regard M, Strauss E Knapp P (1982). Children’s production on verbal and non verbal fluency tasks. Percept Mot Skills 55: 839–844. Rey A (1941). L’examen psychologique dans les cas d’encephalopathie traumatique. Arch Psychol (Frankf) 112: 286–340. Rubens AB, Benson DF (1971). Associative visual agnosia. Arch Neurol 24: 305–316. Schmidtke K, Vollmer H (1997). Retrograde amnesia: A study of its relation to anterograde amnesia and semantic memory deficits. Neuropsychologia 35: 505–518. Schnider A (2003). Spontaneous confabulation and the adaptation of thought to ongoing reality. Nat Rev Neurosci 4: 662–671. Schnider A (2004). Verhaltensneurologie. Die neurologische ¨ rzte Seite der Neuropsychologie. Eine Einfu¨hrung fu¨r A und Psychologen, 2nd edn. Thieme, Stuttgart. Schnider A, Benson DF, Alexander DL, et al. (1994a). Nonverbal environmental sound recognition after unilateral hemispheric stroke. Brain 117: 281–287.

Schnider A, Benson DF, Scharre DW (1994b). Visual agnosia and optic aphasia: Are they anatomically distinct? Cortex 30: 445–457. Schnider A, von Da¨niken C, Gutbrod K (1996). Disorientation in amnesia: A confusion of memory traces. Brain 119: 1627–1632. Schnider A, Hanlon RE, Alexander DN, et al. (1997). Ideomotor apraxia. Behavioral and neuroanatomical dimensions. Brain Lang 58: 125–136. Slachevsky A, Villalpando JM, Sarazin M, et al. (2004). Frontal assessment battery and differential diagnosis of frontotemporal dementia and Alzheimer disease. Arch Neurol 61: 1104–1107. Smith A (1967). The serial sevens subtraction test. Arch Neurol 17: 78–80. Snodgrass JG, Vanderwart M (1980). A standardized set of 260 pictures: Norms for name agreement, image agreement, familiarity, and visual complexity. J Exp Psychol [Hum Learn] 6: 174–215. Spreen O, Strauss E (1998). A Compendium of Neuropsychological Tests. Administration, Norms, and Commentary, 2nd edn. Oxford University Press, New York. Squire LR (2004). Memory systems of the brain: A brief history and current perspective. Neurobiol Learn Mem 82: 171–177. Street RF (1931). A Gestalt Completion Test. Teachers College, Columbia University, New York. Stroop JR (1935). Studies of interference in serial verbal reactions. J Exp Psychol 18: 643–662. Strub R, Black FW (2000). The Mental Status Examination in Neurology, 4th edn. F.A. Davis, Philadelphia. Stuss DT, Benson DF (1986). The Frontal Lobes. Raven Press, New York. Thurstone LL, Thurstone TG (1962). Primary Mental Abilities (rev.). Science Research Associates, Chicago. Vuilleumier P, Valenza N, Mayer E, et al. (1998). Near and far visual space in unilateral neglect. Ann Neurol 43: 406–410. Warrington EK (1975). The selective impairment of semantic memory. Q J Exp Psychol 27: 635–657. Warrington EK, Taylor AM (1973). The contribution of the right parietal lobe to object recognition. Cortex 9: 152–164. Wechsler D (1945). A standardized memory scale for clinical use. J Psychol 19: 87–95. Welsh KA, Butters N, Mohs RC, et al. (1994). The Consortium to Establish a Registry for Alzheimer’s Disease (CERAD). Part V. A normative study of the neuropsychological battery. Neurology 44: 609–614. Willmes K, Poeck K (1993). To what extent can aphasic syndromes be localized? Brain 116: 1527–1540.

Handbook of Clinical Neurology, Vol. 88 (3rd series) Neuropsychology and behavioral neurology G. Goldenberg, B.L. Miller, Editors # 2008 Elsevier B.V. All rights reserved

Chapter 7

Anterograde amnesia HANS J. MARKOWITSCH* Physiological Psychology, University of Bielefeld, Bielefeld, Germany

7.1. Introduction An ‘a-mnesic’ is the opposite of Mnemosyne, the Greek muse of memory who was supposed to possess an exceptionally good memory, both with respect to remembering old (retrograde memory) and encoding fresh facts and events (anterograde memory). Charcot (1892) probably coined the expressions ‘anterograde amnesia’ and ‘retrograde amnesia,’ though already in 1763 amnesias were classified (Sauvages de la Croix, 1763; cited in Nicolas and Penel, 2001). Until the last two decades of the last century, clinicians tended to refer to the ‘global amnesic syndrome’ (e.g., Corkin, 1984) when they had a patient who was grossly deficient in both areas, the formation of new memories and the retrieval of old ones (Fig. 7.1). Furthermore, at that time, memory was principally considered to be a unity, though a few researchers of the old times had already pointed out that brain-damaged patients may be impaired in some domains of memory, but not in others (e.g., Schneider, 1912; 1928; see Markowitsch, 1992a for a review). Research on learning and memory was already common in the nineteenth century as the famous book of Ebbinghaus (1885) exemplifies. The oldest descriptions of patients with memory disorders came from Korsakoff (1889; 1890; Korsakow, 1890; 1891; Korsakow and Serbsky, 1892; a short portrait of Korsakoff was given by Kru¨ger and Bra¨unig, 2004), from other Russian scientists (Bechterew, 1900), and from a number of reports on dementia patients and patients with memory disturbances related to psychiatric disorders (e.g., Alzheimer, 1911; Donath, 1908; Pick, 1893; Tiling, 1892; see Markowitsch, 1992a for an overview). Expressions such as anterograde and retrograde amnesia were already in use in the nineteenth century (e.g., Boediker, 1896) as were relations between specific brain *

damage—for example in the hippocampal region (Bechterew, 1900; Bratz, 1898), specific toxins (Bonhoeffer, 1901), or hypoxia (Boediker, 1896; Lu¨hrmann, 1896; Schulz, 1908; Wagner, 1891)—and amnesia. It was also differentiated into brain loci whose damage results more probably in anterograde (Campbell, 1909) or in retrograde amnesia (Cowles, 1900; Paul, 1899). Freud’s (1898; 1899) work pointed to psychic origins of forgetfulness—that is to motivated amnesias; however, even his work had prominent predecessors (Kraepelin, 1886). Psychosurgery was attempted in a Swiss clinic before the turn of the twentieth century (Burckhardt, 1891) and infantile amnesia—the inability to retrieve memories from the earliest childhood as an adult—was a subject of debate (Potwin, 1901). In 1870 Ewald Hering formulated in an unsurpassed manner in a lecture given in the high session of the Imperial Academy of Sciences in Vienna what constitutes memory (Hering, 1870; English translation: Hering, 1895). He stated that memory unites the countless single phenomena to a whole and that without its binding power our consciousness would disintegrate into as many fragments as there are moments. This view on the power of memory for our personality seems to have foreseen what recent workers see as the uniqueness of human memory (Tulving, 1983; 2005; Tulving & Markowitsch, 1998) and what is described in case reports on patients who—after brain damage—lost the ability to glue together bits of newly incoming information.

7.2. Patient H.M. Patient H.M is considered to be the example par excellence of a subject who from one day to the next lost his ability to learn new information long term. William Scoville and Brenda Milner’s description (Scoville and

Correspondence to: Professor Dr Hans J. Markowitsch, Physiological Psychology, University of Bielefeld, Universita¨tsstr. 25, D-33615 Bielefeld, Germany. E-mail: [email protected], Tel.: þ49-521-106-4487, Fax: þ49-521-106-6049.

156

H.J. MARKOWITSCH

Fig. 7.1. Possible consequences of brain injury on old and new memories.

Milner, 1957) of this patient became a milestone for neuropsychological research which aimed to understand the functioning of the brain in long-term information storage. Shortly after the Second World War, the Canadian neurosurgeon Scoville performed a series of operations on patients with pharmacologically intractable epilepsies. One of these patients was a 23-yearold, right-handed man of normal intelligence (IQ above 100) who received a bilateral resection of major portions of his medial temporal lobes on September 1, 1953

(Fig. 7.2). This surgery reduced the frequency of his pre-operatively severe epileptic attacks and enabled their control by drugs. Surprisingly to the surgeon, the outcome of the tissue removal resulted in a severely adverse side-effect—H.M.’s permanent loss of his ability to form new stable memories. While still displaying adequate social skills and expressing himself verbally better than the majority, time appeared to have stopped for him. He could no longer keep up with the date of the year, or events happening in the world or in his

Fig. 7.2. Recent magnetic resonance images (MRI) of H.M.’s brain. Multiplanar views of 18 averaged T1-weighted MRI volumes showing preserved structures. The scan was made in December 1998 when H.M. was 72 years old (i.e., 46 years after medial temporal lobe surgery). Images were motion corrected. The asterisk marked the intersection of the 3 viewing planes, just caudal to the left medial temporal lobe resection which is seen best in the transaxial (‘horizontal’) view. In the top right picture the locations for the coronal (bottom left) and transaxial (bottom right) views are marked. Abbreviations: CS, collateral sulcus; EC, entorhinal cortex; H, hippocampus; L, left; PH, parahippocampal gyrus; R, right. (Fig. 1 of Corkin, 2002, with permission of the author.)

ANTEROGRADE AMNESIA microcosm. There was no ability to foresee what might happen in the next year, month, or even day. However, H.M. remained able to reflect on his condition by stating, for example: ‘Every day is alone, whatever enjoyment I’ve had, and whatever sorrow I’ve had’ (Milner et al., 1968, p. 217). At that time (and also much later still), such a condition was termed an amnesic syndrome. Amnesic syndromes in the classical sense are characterized by a preservation of general intellectual abilities together with a major loss of memory abilities. That is, intelligence, language, and emotional–social behavior principally remain in the range as they had prior to the brain damage (but see Aybek et al. (2005), who report emotional alterations as a separate consequence of stroke). Interestingly, and contrary to commonsense assumptions, the short-term memory (‘attention span’) remains intact (Fig. 7.3). While capacities such as reading, writing, and calculating are preserved as well (except when calculating requires more complex—longer—arithmetic), there is much more variance with respect to autobiographical episodes. Sometimes, there is a major loss of old memories—or, more precisely, a major

Fig. 7.3. Measurement of short-term memory in H.M. The graph summarizes the results of H.M. in one-trial recognition tasks; he had to indicate whether the second stimulus was the same as, or different from, the first. The score is the mean number of errors in 12 trials, so that 6 represents chance performance. At a delay of one minute, H.M.’s performance approaches chance performance—both with and without distraction. (After Fig. 5 in Milner, 1970 and Fig. 25.2 in Milner, 1972; original data from L. Prisko: Short-term memory in focal cerebral damage [Ph.D. Thesis], p. 126. McGill University, Montreal, 1963.)

157

inability to recall them consciously—sometimes, there is a general preservation of them (cf. Fig. 7.1). As scalable measurement instruments have been developed only lately and are still not regularly used, part of the variance may be attributable to inadequate assessment instruments (Markowitsch, 1992b). So for H.M. there is differing evidence with respect to the extent of his retrograde memory loss. While Milner et al. (1968) suggested that it covered only the last year prior to surgery, Corkin (1984) stated that objective tests ‘extend the limits of the deficit back to 1942, 11 years before the medial temporal-lobe resection’ (p. 257) and that all his personal memories were ‘from age 16 years or younger, even though his operation took place at age 27’ (p. 257). The statement of Marslen-Wilson and Teuber (1975) is in opposition to this view; these authors wrote that ‘a very extended series of biographical interviews with H.M. [. . .] yielded rich recollections for the first two decades-and-a-half of his life’ (p. 362) which would indicate that he had no autobiographical retrograde amnesia. Probably, the time point of measurement may have been of importance as well, as H.M. continued to take drugs against epilepsy (phenytoin) and as his anterograde amnesia might, with time, have had a negative influence on his old memories as well. The following episode is an example of H.M.’s confusion with past times. In 1967 (after the death of his father) he was brought to a rehabilitation center during weekdays where he performed simple work such as mounting lighters on cardboards. Even after 6 months of working there, while he had no conscious recollection of details of his workplace or his work, when once offered a car ride home from the center, he gave the address of where he had lived prior to his surgery—that is more than a decade ago. Fig. 7.4 provides the results of a more formal test on his retrograde memory (Marslen-Wilson and Teuber, 1975). While his test results on famous faces from different decades demonstrate the recognition of a few celebrities, such a test is of course never precise, as there is usually no absolute date when this person was mentioned in the media and when they disappeared from public attendance (Markowitsch, 1992b). Nevertheless, there is other evidence that H.M.’s anterograde amnesia was nearly, but not totally complete. He was able to record a few fragments of facts he had learned after surgery such as the assassination of a public figure named Kennedy, that astronauts travel in outer space and that rock music is ‘that new kind of music we have’ (Corkin, 1984). He also—after many repetitions—‘remembered’ or knew (see Blaxton and Theodore 1997; Hirano et al. 2002; or Wheeler and Stuss 2003 for the remember–know distinction) the death of his parents and of Pope Johannes XXIII. In my eyes this learning of new facts may have occurred

158

H.J. MARKOWITSCH

Fig. 7.4. Percentages of means of correct responses of H.M. (black columns), brain-damaged patients (gray columns), and non brain-damaged control subjects (white columns) when having to identify (name) portraits of famous persons from public life. Decades, when individuals became famous, are given on the abscissa (1950 ¼ decade from 1950–1959). It is evident that brain-damaged and normal subjects (of H.M.’s age) are more likely to identify persons from the last decades, while H.M. vice versa demonstrates superior results for the 1920s and 1930s, while for the decades after his brain surgery (1950s and 1960s) his performance fell rapidly due to his severe anterograde amnesia (data after Fig. 1 and Table 1 of Marslen-Wilson & Teuber, 1975).

via different, possibly limbic-system independent neural networks. There is evidence both from animal research and from studies on human subjects that led Kapur (1994) and McClelland (1994) to postulate the existence of a non-limbic, neocortical memory encoding system which they, however, considered to be slow and quite limited in its capacity; this system should be responsible for permanent information storage and should be more prone to encoding of frequently repeated facts than of episodes. H.M. was extensively studied over the last 50 years in the course of studies which reflect the increased theoretical sophistication in neuropsychological and neuroradiological research (e.g., Milner, 1966; 1967; Milner et al., 1968; Milner, 1970; Lackner, 1974; Corkin, 1984; Corkin et al., 1997; MacKay and James, 2002; Corkin, 2002; Manns, 2004; Steinvorth et al., 2005). In these studies it was found that H.M. was able to acquire and retain certain kinds of information under special circumstances of stimulus presentation and retrieval conditions (Freed and Corkin, 1988) or when more simple forms of memory were required (e.g., skill learning, priming, conditioning; see below) (Gabrieli et al., 1993; Woodruff-Pak, 1993). For instance, an example of preserved familiarity judgments was the fact that he became quite irritated and non-approachable and one day left his home after the death of his father. As it turned out an uncle had removed a gun from his father’s collection of which H.M. was very proud. When the gun was returned, H.M.’s moderate temperament returned.

Though H.M. behaved properly in social settings (Milner et al., 1968), he had a diminished capacity to interpret and report internal states (Hebben et al., 1985). An interesting experiment on the distinction between short-term and long-term memory was made by Richards (1973) who asked H.M. to reproduce time intervals ranging from 1 to 300 seconds. H.M. was quite accurate in estimating intervals under 20 s, but underestimated longer ones. For example, he estimated 1 hour as equivalent to approximately 3 minutes. He demonstrates perceptual memory (see 7.3) in a sense that he recognizes repeatedly perceived items or persons and is not ‘shocked’ or surprised when looking into the mirror (Corkin, 2002). With modern neuroradiological techniques such as magnetic resonance imaging (MRI) it was found that his brain damage was somewhat more circumscribed than the surgeon had inferred from his notes (Corkin et al., 1997; Corkin, 2002). 7.2.1. Predecessors of H.M. There are a number of descriptions of amnesic syndromes prior to the case of H.M. However, with the exception of case descriptions of Korsakoff’s patients (see 7.5.1), many were described more cursorily, discussed non-temporal damaged patients, or were written in languages other than English. One of the early examples, associating medial temporal lobe damage to amnesia, was provided by Bechterew (1900). He described a

ANTEROGRADE AMNESIA patient with a brain with destruction of the anterior and inner portions of the cerebral cortex of both temporal lobes. Bechterew emphasized that the bilateral damage to the uncinate and hippocampal gyri was accompanied by an ‘extraordinary weakness of his memory.’ As the patient had been presented as a Korsakoff’s psychotic to the Russian Society of Psychiatrists and Neurologists during his lifetime, Bechterew concluded that Korsakoff symptomatology may also occur after temporal lobe damage. In 1942 Gru¨nthal emphasized the role of the thalamic mediodorsal nucleus in memory (Gru¨nthal, 1942)—a role confirmed in many later studies (see below). In ¨ ber thalamische Demenz’ Gru¨nthal his article ‘U described a female patient whose most prominent brain damage was a symmetrical degeneration of the mediodorsal thalamus. Small parts of additional thalamic nuclei and the red nucleus were also degenerated. The damage had probably been caused by thrombosis in the arteria thalamo-perforata (paramedian artery). Gru¨nthal considered damage of the mediodorsal nucleus to be the most likely cause of the patient’s progressive dementia appearing during the last ten years of her stay in a psychiatric hospital. Speculations on a direct relationship between impaired memory functions and damage of the mediodorsal thalamic nucleus arose particularly from cases described by Smyth and Stern (1938) and by Stern (1939). Of the six case histories presented by Smyth and Stern (1938) it is most likely that three of them died from tumors which originated and spread outwards from the midline nuclei of the thalamus. In four patients, mental deterioration, particularly various forms of amnesia, were prominent. In a few of these cases other regions, including portions of the medial temporal lobe, were affected as well, as was pointed out already by Walker (1940). Other patients with circumscribed and frequently bilateral hippocampal damage were described by Gru¨nthal (1947), Conrad and Ule (1951), Ule (1951), Glees and Griffith (1952), and Hegglin (1953) (for more detailed descriptions see Markowitsch, 1992a).

7.3. Memory systems As mentioned in the introduction, memory is not a unique system, but has to be divided into several systems. Both researchers studying animals (Mishkin and Petri, 1984) and human subjects (Tulving, 1972; 1983) divided memory on the basis of content and material. Nowadays five long-term memory systems are central for a proper description of human behavior (Fig. 7.5). These memory systems are considered to be hierarchically ordered, starting with procedural memory as the lowest and ending with episodic (or episodic–

159

autobiographical) memory as the highest system. Procedural memory stands for motor-related skills (e.g., driving a car, riding a bike, swimming, playing cards or piano), priming stands for a higher likeliness to re-identify stimuli which one has perceived (unconsciously or subconsciously) in the same or a similar way at a previous time point. Perceptual memory refers to being familiar with a stimulus on the basis of presemantic features. Fact-like, context-free information is represented in the semantic memory system. Tulving (2005) sees the episodic memory system as the conjunction of subjective time, autonoetic consciousness, and the experiencing self; frequently it is affect-related. Tulving fines episodic memory in the following words: Episodic memory is a recently evolved, latedeveloping, and early-deteriorating brain/mind (‘neurocognitive’) memory system. It is oriented to the past, more vulnerable than other memory systems to neuronal dysfunction, and probably unique to humans. It makes possible mental time travel through subjective time—past, present, and future. This mental time travel allows the ‘owner’ of episodic memory (‘self ’), through the medium of autonoetic awareness, to remember one’s own previous ‘thought-about’ experiences, as well as to ‘think about’ one’s own possible future experiences. The operations of episodic memory require, but go beyond, the semantic memory system. Retrieving information from episodic memory (‘remembering’) requires the establishment and maintenance of a special mental set, dubbed episodic ‘retrieval mode.’ The neural components of episodic memory comprise a widely distributed network of cortical and subcortical brain regions that overlap with and extend beyond the networks subserving other memory systems. The essence of episodic memory lies in the conjunction of three concepts—self, autonoetic awareness, and subjective time. This definition makes clear that episodic memory will be most vulnerable to many kinds of brain damage. Principally, procedural memory and priming act on the subconscious or semi-conscious level, while the other three memory systems require conscious processing of information. Emotions are a central part of the episodic–autobiographical memory system: events that touch our hearts or that revolve our guts are seen as those which become burned into our brains and which influence our future decisions (Welzer and Markowitsch, 2005). The episodic–autobiographical memory system consequently is seen as determining our personality and as reflecting

160

H.J. MARKOWITSCH

Fig. 7.5. The five principal memory systems important for human information processing. The episodic memory system is context-specific with respect to time and place. It allows mental time travel. Examples are episodes such as the last vacation or the dinner of the previous night. Declarative memory is context-free and refers to general facts. It is termed semantic memory or the knowledge systems as well. Procedural memory is largely motor-based, but includes also sensory and cognitive skills (‘routines’). Priming refers to a higher likeliness of re-identifying previously perceived stimuli.

our history as an individual (Tulving and Markowitsch, 1998). When events are represented in an integrated manner, they can be ecphorized synchronically as an amalgamate of emotional and cognitive aspects. (Tulving (1983) used the term ‘ecphory’ to describe the process by which retrieval cues interact with stored information so that an image or a representation of the information in question appears.) However, when an individual is either in a grossly heightened or grossly reduced (‘pathological’) emotional mood, or when a particular event immediately evokes a gross change in a subject’s emotional state, the process of ecphorizing loses its character of synchrony and either the emotional or the cognitive aspect dominates and suppresses the other one.

All these elaborations point to the importance of a synchronously acting limbic system as a principal prerequisite for a successful long-term encoding of new events. I therefore will shortly outline the relevant regions and fiber connections of the limbic system.

7.4. Brain regions implicated in memory formation At present, there is accumulating evidence for distinct neural networks involved in the acquisition and consolidation of information, in its representation, and in its retrieval (Markowitsch, 2000; 2005). In line with this chapter’s title I will focus on the encoding part of

ANTEROGRADE AMNESIA information processing and on the semantic and episodic memory systems. The acquisition of new facts and events initially requires their short-term representation in buffer systems (Baddeley, 2000; 2001) which are seen in dorsolateral parts of the prefrontal (Jacobsen, 1936; Markowitsch and Pritzel, 1978; Belger et al., 1998; Courtney et al., 1998; Goldman-Rakic et al., 2000) and in, especially, left-hemispheric portions of the lateral parietal cortex (Brodmann areas 39, 40) (Warrington and Shallice, 1969; Markowitsch et al., 1999). Patients with damage to these regions may manifest problems in the initial online holding of information, while they may still be able to encode information long-term. More important therefore is the process of further evaluation of information that entered the brain newly. For this process structures of the expanded limbic system become central. While the term limbic system had its ups and downs during the last 50 years, it finally appears to be a valid, comprehensive description of an anatomically and functionally diverse conglomerate of areas, nuclei, and fiber connexions which have in common that they are principally non-motoric and nonsensoric in function and instead subserve to integrate emotional and mnemonic functions. Defined as the expanded limbic system (Nauta, 1979; Nieuwenhuys, 1996) they further provide a mediating system between evaluating allocortical (Stephan, 1975) and storing neocortical portions of the nervous system (Fig. 7.6). Especially data obtained with functional imaging methods have demonstrated that portions of the prefrontal cortex are crucially engaged in the successful encoding of new information (Tulving et al., 1994; Fletcher et al., 1997; 1998; Frey and Petrides, 2000; Devlin et al., 2003; Ko¨hler et al., 2004). 7.4.1. The limbic system Probably the most well known scientist of the last half century, working on the limbic system, is Paul MacLean (1949; 1990). He considered the uniqueness of the limbic brain structures implicated in memory processing as their crucial participation in ‘a feeling of individuality—a sense of self—that is basic to a consideration of neural mechanisms of memory’ (MacLean, 1990, p. 513). The limbic system is constituted of a mixture of cerebral cortical areas, telencephalic and diencephalic nuclei, and a number of interconnecting fibers. Some brainstem nuclei may be included as well (Fig. 7.6). Several structures stand in the centre as they are heavily interconnected and as they can be regarded as bottleneck structures through which information has to be pass in order to be stored long-term. These structures are combined as the Papez circuit (Papez, 1937)

161

Fig. 7.6. Overview over memory and emotion processing structures and connections of the expanded limbic system. Abbreviations: mtt ¼ mammillothalamic tract; n ¼ nucleus or nuclei; VTA ¼ ventral tegmental area. (Modified from Figs 1-13 of Mesulam, 2000).

and the basolateral limbic circuit (Livingston and Escobar, 1971; Sarter and Markowitsch, 1985a; 1985b) (Fig. 7.7). Within the Papez circuit the hippocampal formation is, since the days of H.M. (see 7.2.), seen as the key structure for the transfer of information from short-term to long-term memory. Within the basolateral limbic system two structures may be emphasized, the amygdala for its role in the emotional colorization of memory (Markowitsch et al., 1994; Markowitsch, 1998/ 99; Siebert et al., 2003; Zald, 2003) and the mediodorsal nucleus of the thalamus (and the surrounding midline nuclei; Fig. 7.6) for their roles in memory (Markowitsch, 1988) and consciousness (Dercum, 1925; Brown, 1990; Bogousslavsky et al., 1991; Koch, 1995; Bogen, 1997; Van der Werf et al., 2002) (also via their interconnexions with the frontal lobes; Wheeler et al., 1997). Due to its size and expansion in human beings the phylogenetically young pulvinaris complex should at least be mentioned as probably implicated in long-term information

162

H.J. MARKOWITSCH

Fig. 7.7. The medial (or Papez) and the basolateral limbic circuit. The medial circuit is probably more relevant for the cognitive acts of memory processing, the basolateral one for the affective evaluation of information. Both circuits interact with each other. The Papez circuit interconnects the hippocampal formation via the (postcommissural) fornix to the mammillary bodies, these via the mammillothalamic tract (or tractus Vicq d’Azyr) to the anterior thalamus, the anterior thalamus with its cortical projection targets reaches the cingulate gyrus and the subicular part of the hippocampal formation and the cingulum fibers in addition project back from the cingulate gyrus into the hippocampal formation. (The precommissural fornix in addition provides a bidirectional connection between the hippocampal formation and the basal forebrain.) The basolateral limbic circuit links the amygdala, mediodorsal thalamic nucleus, and area subcallosa with each other by distinct fiber projections, namely the ventral amygdalofugal pathway, the inferior thalamic peduncle, and the bandeletta diagonalis.

processing. Inferring from the magnitude of the area and locus of the cortical fields it covers by its projections (Markowitsch et al., 1985), this structure, which is rarely damaged selectively, should have a prominent role in memory processing (Guard et al., 1986; Kuljis, 1994). Indeed, Crosson et al. (1997) observed category-specific memory deficits after subtotal damage to the left pulvinar.

7.5. Syndromes associated with anterograde amnesia There are a number of etiologies which lead to severe memory deteriorations (Table 7.1). Most of these have been known for more than a century, for example the Korsakoff syndrome (Korsakoff, 1889) or the observation that patients with schizophrenia may appear as demented, which led Bleuler (1911) to create the expression ‘dementia praecox’ for schizophrenia. It was also known since the nineteenth century that there exists a relationship between hippocampal damage, epilepsy, and amnesia (Sommer, 1880; Alzheimer, 1897). 7.5.1. Korsakoff’s syndrome and other intoxications A wealth of data was published on Korsakoff’s syndrome and its consequences for memory (see Ch. 6: KORSAKOFF’S SYNDROME in Markowitsch, 1992a). Korsakoff’s syndrome is the result of a deficiency in

incorporating and metabolising vitamin B1, that is a thiamine deficiency. The usual etiology is chronic alcohol abuse. In rare instances, other etiologies, usually related to metabolic disturbances (e.g., Shimomura et al., 1998; Cirignotta et al., 2000; Deb et al., 2001/02) or acquired immune deficiency syndrome (Schwenk et al., 1990) can be found. Without going into detail, there was a general agreement that Korsakoff’s syndrome leads in particular to medial diencephalic damage—from the mediodorsal and adjacent non-specific nuclei down to the mammillary bodies (Mair et al., 1979; Victor et al., 1989)—and is accompanied by four classical symptoms (Bonhoeffer, 1901): anterograde amnesia, retrograde amnesia, disorientation with respect to time and place, and a tendency to confabulate. The last two symptoms may be consequence of the first two. Some other symptoms, related to frontal lobe pathology, may also be found (Snitz et al., 2002; Brand et al., 2003; 2005; Caulo et al., 2005). Functional imaging studies in Korsakoff’s patients were performed only rarely (Paller et al., 1997; Reed et al., 2003; Caulo et al., 2005). Caulo et al. (2005) suggested from their fMRI findings that there is a more widespread pathology: in addition to diencephalic involvement they also pointed to probable hippocampal–anterior thalamic and to ventrolateral prefrontal involvement. While retrograde amnesia may vary in severity (see the case descriptions of patient P.Z. by Butters (1985)

ANTEROGRADE AMNESIA Table 7.1 Overview of etiologies which commonly results in lasting memory disorders Patients with cerebral infarcts, aneurismal bleeding/surgery, or vascular diseases Trauma-based cases with cerebral concussions or compressions Patients with a status after anoxia or hypoxia (e.g., after heart attack or drowning) Patients with intracranial tumors Patients with bacterial or viral infections (e.g., herpes simplex encephalitis) Patients with intoxications, chronic alcohol abuse, Korsakoff’s syndrome Patients with deficiency diseases or avitaminoses (e.g., B1-deficiency) Patients with epilepsy Patients with degenerative diseases of the CNS (e.g., Alzheimer’s disease, Pick’s disease) Patients with organic insufficiencies (e.g., of liver, heart, kidneys) Psychiatric patients (e.g., patients with schizophrenia) Patients after drug addiction or as a consequence of drug usage (e.g., after taking anticholinergic or anticonvulsive substances, benzodiazepines, neuroleptics) Patients with transient global amnesia Patients with psychogenic or dissociative or functional amnesia Patients with mnestic block syndrome

and of patients E.A. and H.J. by Mair et al. (1979)), anterograde amnesia is consistently severe (Kessler et al., 1986; Victor et al., 1989). There is, however, evidence for a disproportionally better performance in recognition compared to free recall tasks (Markowitsch et al., 1984; 1986), a finding which corresponds to that of patients with prefrontal damage (Jetter et al., 1986) and therefore with damage of the cortical projection zone of the mediodorsal nucleus (Kuroda et al., 1998). That remnants of memory exist was already emphasized by Bonhoeffer in 1901. He wrote: ‘The inability to memorize is complete only exceptionally. Usually it is possible, even in cases with apparent total amnesia, to determine remains of a memory ability. For example, a patient was able to tell me a list of names of familiar distilleries even after a very long time, though he otherwise forgot nearly instantaneously simple, indifferent words, names, or two- or three-figure numbers.’ (Bonhoeffer, 1901, p. 126). Furthermore, Claparede (1911) already gave an example for implicit memory functions (priming) in a patient with Korsakoff’s psychosis. This was later named the ‘Claparede phenomenon’ and is based

163

on the event that Claparede had hidden a pin in his hand when shaking hands with the patient with the consequence that she later refused to shake hands, but was apparently unaware of a reason for this, or even of the fact that she had met him before. What clinicians of old times suggested, namely that the basic deficits of Korsakoff’s patients lie in a disturbed sense of time, or in disturbed consciousness of time or time duration (Krauss, 1930; Van der Horst, 1932), is most likely the essence of their deficit. According to Van der Horst (1932) Korsakoff’s patients work with ‘pieces of time’ and ‘time points’; their possibility of ordering the time is lost. 7.5.2. Patients with cerebral infarcts, aneurismal bleeding/surgery, or vascular diseases A variety of patients with major anterograde memory disorders are found after infarcts of cerebral arteries. Among them, two groups stand out—patients with diencephalic infarcts (Markowitsch, 1982; 1988) and patients with basal forebrain infarcts (Irle and Markowitsch, 1987). 7.5.2.1. Diencephalic infarcts The diencephalic vascular supply is quite complex and can vary considerably between individuals (Schlesinger, 1971; George et al., 1975; Percheron, 1976; Rosner et al., 1984) (Fig. 7.8). The symptomatology after bilateral symmetrical, vascular thalamic damage was classified in three clinical groups, (1) the amnesic syndrome, (2) the syndrome of thalamic dementia, and (3) the syndrome of akinetic mutism (Von Cramon, 1980, p. 1385). Diencephalic infarcts, affecting memory, are principally caused by damage to the paramedian or polar artery (Table 7.2). There is a wealth of case descriptions of patients with various forms of diencephalic infarcts (overviews in Markowitsch, 1988; 1991; 1992c). The syndrome picture is rarely uniform; as is the case with damage at other limbic loci, a major differentiation is the one between unilateral and bilateral damage. And, again as with other damaged loci, left hemispheric damage is more closely associated with verbal and right hemispheric damage with nonverbal memory deficits (Clarke et al., 1994). The wide ranging changes after bilateral diencephalic infarcts were, for instance, described by Bogousslavsky et al. (1991). They studied two patients who had a bilateral thalamo-mesencephalic infarct in the territory of the paramedian artery. Aside from ocular motility changes, both patients manifested massive behavioral disturbances without, however, being inferior in formal neuropsychological tests. They became apathetic, aspontaneous, indifferent and seemed

164

H.J. MARKOWITSCH Table 7.2 Principal symptoms after damage of the four thalamic arterial branches Arterial branch

Symptoms

Polar (tuberothalamic) artery Paramedian artery

dysphasia, hemineglect, visuospatial disturbances, anterograde amnesia disturbances of consciousness, anterograde amnesia, confusion, memory disturbances motor, sensory, and neuropsychological dysfunctions infarcts most frequent, usually preceded by transient ischemic attacks (TIAs), hemisensory defects, no neuropsychological disturbances, consciousness not disturbed

Posterior choroidal artery Inferolateral artery

Fig. 7.8. Major arteries and arterial branches of the diencephalon (see also Graff-Radford et al., 1985; Bogousslavsky et al., 1988; Chung et al., 1996). The tubero-thalamic artery is also named polar or premammillary artery; it reaches mostly the anterior nuclear group. The thalamo-perforated artery is also named paramedian or deep interpeduncular artery; it reaches the posterior portion of the mediodorsal nucleus and the pulvinar. Memory-relevant damage to the diencephalon occurs mainly after damage to one of these two arterial branches. The paramedian artery may affect the meso-diencephalic transition zone—leading to the so-called paramedian thalamus syndrome (Guberman and Stuss, 1983; Ko¨mpf et al., 1984; Katz et al., 1987), a major syndrome which sometimes may include dementia. (Translated and modified from Calabrese, 1997).

to have lost their drive on the motoric and affective level. If, however, repeatedly stimulated by others or reinforced to act, they became more active. This necessity of constant external programming, together with their lacking emotional reactivity, led them to appear robot-like in the eyes of the observers. Computer tomographic (CT) and magnetic resonance imaging (MRI)pictures indicated damage to the mediodorsal and the midline nuclei; single photon emission computed tomography (SPECT) furthermore revealed evidence for a frontomedial hypoperfusion. Bogousslavsky et al. (1991) assumed that the circuit from the striatum over the ventral pallidum to thalamus and frontomesial cortex was interrupted, resulting in the syndrome picture (Fig. 7.6). And, in the same year, Peper et al. described a female patient with a bilateral thalamic thrombosis and major depressive symptomatology (Peper et al., 1991). While the thalamic thrombosis shrank considerably over time so that clinicians prognosed a favorable

After data of Graff-Radford et al. (1985) and further studies.

outcome, her emotional situation remained in a labile and depressed condition for over 15 months after the onset of the illness so that even after this time she attempted suicide. A patient with quite selective, but severe and lasting anterograde amnesia was A.B., a former medical professor with above average intelligence (Markowitsch et al., 1993). A decade earlier he had suffered from a bilateral occlusion of the polar (premammillary) artery (Fig. 7.8). Aside from a number of neuroradiologic, including magnetic resonance imaging analyses, we gave him a number of tests and test batteries allowing a determination or evaluation of the areas of intelligence, attention, subjective memory, immediate retention, learning, performance of skills, problem solving, concept formation, cognitive flexibility, priming, and long-term memory. A.B.’s intelligence, short term memory, motivation, and attention were above average. Learning of skills (procedural memory; Fig. 7.5) and performance increases in priming tasks could be observed. On the other hand he had no knowledge or reflection of his deficits; he apparently had no insight into the massiveness of his anterograde amnesia, a fact reflected by his statements in the subjective memory evaluation. When asked about the condition of his memory, he stated: ‘Why do you ask—it’s normal,’ and when we insisted and asked him ‘Don’t you think that you have memory problems?’ he responded ‘Well, maybe, I easily forget my dreams and I do not remember jokes.’ A psychologist who had worked with him for a long time, remarked that he once stated ‘I have no memory at all, isn’t that terrible?’ but immediately

ANTEROGRADE AMNESIA thereafter had forgotten this statement and its consequences. In fact, he only was able to repeat the last few words of the short stories of the revised Wechsler Memory Scale and was unable to redraw anything of the Rey–Osterrieth Figure by heart after having it copied perfectly well just a minute before. Otherwise, A.B. appeared normally and socially adequate to other individuals. The example of this patient shows that anterograde amnesia may be so severe that conscious reasoning and reflection and mental time traveling (especially into the future) become impossible. Though we made every attempt to specify lesion locus and extent, this and related patients demonstrate that due to traversing fibers in the thalamic region (e.g., internal medullary lamina, mammillothalamic tract) the contribution of specific gray and white matter configurations cannot be determined with certainty and consequently the contribution of specific nuclei and fiber bundles for memory processing remains a matter of debate (see, e.g., Gentilini et al. (1987) who postulated from their analysis of eight patients with paramedian thalamic artery infarcts that damage to the mammillothalamic tract was responsible for the observed memory disorders). Thalamic/diencephalic amnesia may consequently best be understood as a disconnection syndrome (Warrington and Weiskrantz, 1982; Von Cramon and Markowitsch, 1992). A more extensive symptom picture may arise if the paramedian artery infarct affects structures at the mesencephalic–diencephalic junction area. Here the deficit symptomatology may even lead to general dementia (Meissner et al., 1986; Katz et al., 1987). Finally, it should be mentioned that diencephalic infarcts sometimes lead to various degrees of retrograde amnesia in addition to anterograde amnesia (Hodges and McCarthy, 1993), to numerous other deficits (Van der Werf et al., 2000; 2003), including in particular emotional changes (Peper et al., 1991; Clarke et al., 1994; Benke et al., 2002)—sometimes even childish behavior and a psychiatric-like symptomatology corresponding to the Ganser syndrome (Ganser, 1898; Fukatsu et al., 1997). Related to the changes in affective behavior are firstly that the mediodorsal thalamus constitutes a cornerstone in the basolateral limbic circuit and secondly that functional imaging studies found thalamic activation towards emotional stimuli (Fink et al., 1996; Lane et al., 1997; Reiman et al., 1997). Similarly, using a number of different analyses based on PET methodology, Szelies et al. (1991) were able to show how divergent even limited thalamic infarcts influence other areas of the brain. Primarily affected are structures with direct connections to the thalamus, such as limbic regions, the basal ganglia, and many cortical areas. The authors emphasize that even tiny thalamic lesions

165

demonstrate the massive network character and the dependence on other brain regions. 7.5.2.2. Basal forebrain damage Similarly to diencephalic infarcts, it is not precisely known which structures contribute what to anterograde memory impairments after infarct-based damage to the basal forebrain. This, of course, has to do with the nature of the infarct process, which for the basal forebrain is usually related to ruptures and/or repairs of the anterior communicating artery (Gade, 1982; Damasio et al., 1985b; Gade and Mortensen, 1990; Irle et al., 1992; Bo¨ttger et al., 1998; Goldenberg et al., 1999; Borsutzky et al., 2000). On the other hand, most of the basal forebrain structures possess cholinergic neurons whose axons distribute widely over the cerebral cortex (Fig. 7.6; Woolf, 1997) so that deficits in memory acquisition can be expected after damage of tissue belonging to the septal area, the basal nucleus of Meynert, or the diagonal band of Broca (Wenk, 1989; Morris et al., 1992; Von Cramon et al., 1993; Bo¨ttger et al., 1998; Von Cramon and Markowitsch, 2000). While Von Cramon et al. (1993) emphasized the contribution of the septal nuclei, Von Cramon and Schuri (1992) pointed to that of fiber tracts, connecting the basal forebrain with the hippocampal formation, and Irle et al. (1992) found that the basal ganglia may participate in memory formation as well. Bo¨ttger et al. (1998) suggested that both lesions of the medial septum and of the nucleus of the diagonal band of Broca are closely associated with the memory deficits after anterior communicating artery ruptures. Morris et al. (1992) described an amnesic patient whose brain damage was largely confined to the region of the diagonal band of Broca. Goldenberg et al. (1999) proposed that damage to the nucleus accumbens might cause amnesia, and Irle et al. (1992) suggested that the combined damage of the basal forebrain and the striatum might most likely lead to severe memory disturbances (see also Mayes, 1999). Generally spoken, the defects after basal forebrain damage are even less confined to anterograde amnesia and are frequently less severe than those after bilateral damage to diencephalic or medial temporal lobe structures. As is the case in patients with frontal lobe damage in general, there are disproportionally more severe deficits in recall compared to recognition memory, and the process of encoding may even be less affected than in diencephalic and temporal lobe amnesia (Fukatsu et al., 1998; Borsutzky et al., 2000). Consequently, recovery of amnestic functions is more common than in the other two forms of amnesia (D’Esposito et al., 1996). Usually transient confabulatory tendencies (Hashimoto et al., 2000) (which may affect consciousness; Woolf, 1997)

166

H.J. MARKOWITSCH

are common, and there may be deficits in executive functions (Diamond et al., 1997; Mavaddat et al., 2000) and attention (Bo¨ttger et al., 1998), too. 7.5.3. Intracranial tumors About 1% of cerebral tumors are of thalamic origin (McKissock and Paine, 1958; Cheek and Taveras, 1966). Due to this fact already a century ago the term ‘thalamic syndrome’ was coined (Dejerine and Roussy, 1906; Roussy, 1907). In 1902, Schuster reviewed three thalamic tumor cases with pure amnesia and preserved intelligence (Schuster, 1902). Numerous case descriptions were published during the next decades (reviewed in Markowitsch, 1992c). In 1954 Williams and Pennybaker emphasized on the basis of 180 cases that the most frequent, most prominent and most easily diagnosable behavioral changes after brain damage were those in which the damage lay at the basis or along the walls of the lateral ventricle (Williams and Pennybaker, 1954, p. 121). Major memory disturbances were described by McEntee et al. (1976) in a case with a bilateral metastatic tumor in the medial and posterior region of the thalamus; similary, Ziegler et al. (1977) found an abruptly occurring memory loss in a case with a glioma in the right thalamus. Altogether, cases with diencephalic tumors, especially colloid cysts and pituitary tumors, are quite frequent (Nitta & Symon, 1985; Guinan et al., 1998). They have confirmed that memory disturbances belong to the most prominent features, but—similarly to other neoplastic changes in the brain—they failed to reveal specific, detailed relationships between anatomy and function (Calabrese et al., 1995; McMackin et al., 1995). This statement holds above all for the numerous cases with ventricular cysts, which manifested after cyst removal a clear, sometimes total functional recovery (Beal et al., 1981; Apuzzo et al., 1982; Nitta and Symon, 1985; Bischoff et al., 1988; Hu¨tter et al., 1997). Descriptions of cases with cysts in the third ventricle furthermore demonstrate where regions in the diencephalon are situated which influence long-term information processing most directly, namely the neuronal and fibrous agglomerations situated along the ependymal walls of the third ventricle. Furthermore the surrounding anterior, medial, and posterior areas of the thalamus with the nuclei anteriores, mediodorsalis and pulvinaris have to be named, together with the (medial) mammillary nuclei on the hypothalamic level, and the fiber systems traversing within and between these regions (primarily the mammillothalamic tract and the internal medullary lamina), as well as the fornix, which runs above the thalamic region, but may be affected by cysts as well (McMackin et al., 1995; Aggleton et al., 2000).

Also surgical removal of cysts may lead to the cutting of fornix fibers. Some years ago we studied a juvenile patient who, due to such a surgical intervention, had major problems in his anterograde memory domain (Calabrese et al., 1995). His fornix was damaged bilaterally at the level of the fornical columns. The patient’s subsequent memory problems were most pronounced in tests using long delays (e.g., in the delayed recall index of the revised Wechsler Memory Scale). His anterograde amnesia was as prominent on the verbal as on the nonverbal level, while attention, concentration, and short-term memory abilities were preserved. Similarly, his cognitive flexibility, procedural and priming memory were principally unimpaired. There was no evidence of retrograde amnesia. We concluded from these results that the fornix constitutes a major link betweeen the three memory interfaces (medial diencephalon, medial temporal lobe, basal forebrain) and that its bilateral rupture anterior to the thalamic level may lead to lasting anterograde amnesia. Tumors in other memory-sensitive structures usually do not affect anterograde long-term memory, but are confined to either short-term and working memory disturbances (prefrontal areas) or to retrograde memory (retrosplenial area). Exceptions are encephalitis-based paraneoplastic changes (O’Connor et al., 1997; Bak et al., 2001). 7.5.4. Infectious processes Viral encephalitis relatively frequently leads to bilateral damage in the medial temporal and basal forebrain regions (Haymaker et al., 1958; Damasio et al., 1985a; Neeley et al., 1985), but only exceptionally to diencephalic damage (Ullmann and Berlit, 1986; Ullmann, 1988). Massive and permanent memory disturbances are usually accompanied by encephalitis-based brain damage (Damasio et al., 1985a; 1989; Verfaellie et al., 1995; Hokkanen et al., 1996a; 1996b; Hirayama et al., 2003; McCarthy et al., 2005). Damasio and van Hoesen (1985) assume that the cause for the impact on limbic temporal and (basal) frontal regions is less likely to be based on the infiltration by the virus via olfactory channels or meningeal branches of the trigeminus nerve, but can be seen in a special neurochemical or neuroimmunological affinity of the limbic cortex to the herpes type I virus. (Hokkanen et al. (1996a; 1996b) also considered other virus types to show an affinity to the temporal lobe region.) Sometimes carcinomas are associated with encephalitis (Alamowitch et al., 1997; Dorresteijn et al., 2002). The memory disturbances after other infectious or immunological diseases are more varying and depend on the extent of the damage and other variables. Among

ANTEROGRADE AMNESIA these disease conditions multiple sclerosis (Haupts et al., 1994; Markowitsch et al., 1996; Scarrabelotti and Carroll, 1999; Martin et al., 2003) and HIV infections (Ellis et al., 1997; Bell et al., 1998; Rourke et al., 1999; De Ronchi et al., 2002; Manji and Guiloff, 2003) are the more frequent ones. Neurosyphilis, bacterial, fungal, and other infections are comparatively more rarely found (Keil et al., 1997; Kaiser, 1999; Prange, 2003; see chapters in Brand et al., 2003). The most common of these, which is endemic in Latin America, India, Asia, and Africa, is neurocysticercosis. More than 50 millions of individuals in the world are affected by the taeniasis/cysticercosis complex. However, it seems that this disease does not increase existing cognitive deficits of such patients (Terra-Bustamante et al., 2005). 7.5.5. Degenerative diseases Degenerative conditions are very common and range from circumscribed thalamic degeneration (Stern, 1939; Martin, 1975; Martin et al., 1983; Katz et al., 1984; 1987; McDaniel, 1990) to widespread cortical degeneration as in Alzheimer’s disease and related disease conditions (Auld et al., 2002; Brenneis et al., 2004). Sometimes prion diseases are the cause of the degeneration (Federoff, 1997; Macchi et al., 1997; Prusiner, 1997; Chesebro, 1999; Hedge et al., 1999; Mallucci et al., 1999; Parchi et al., 1999; Knight and Will, 2003) and a genetic background is found (Katz et al., 1984; Lugaresi and Montagna, 1990; Markowitsch, 1993) (see 7.5.5.1). The thalamic degeneration is completely symmetrical with the consequence that the behavioral disturbances are severe so that frequently the expression thalamic dementia is used (Stern, 1939; Schulman, 1957; Hori et al., 1981; Katz et al., 1984; 1987; McDaniel, 1990). As there are several chapters on conditions of dementia in this Handbook, I will refer only briefly to some of the consequences for memory disorders. Seen in general, nearly all of the dementias result in major and over time increasing anterograde memory disturbances. This holds above all for the major group of Alzheimer’s patients (Carlesimo and Oscar-Berman, 1992; Ba¨ckman et al., 1999; 2001; Demadura et al., 2001; Desgranges et al., 2002; Adak et al., 2004). Of course, memory deficits, which appear already at an early stage of Alzheimer’s disease (Braak et al., 1999; Eustache et al., 2001), mild cognitive impairment (MCI) (Bennett et al., 2005; Kantarci et al., 2005), vascular forms of dementia (Jellinger, 2005), frontotemporal dementia (Graham et al., 2005), and other dementia forms, all are related to early (usually bilateral) degenerations in medial temporal lobe structures. Caine et al. (2001), for example, described a patient with extensive

167

hippocampal degeneration and rapidly progressive frontotemporal dementia, extending thereby the link between anterograde amnesia and (left) hippocampal damage to frontotemporal dementia. Similarly, Csernansky et al. (2004) demonstrated significant correlations between antemortem hippocampal volumes, dementia severity and density of hippocampal neurofibrillary tangles. Parkinson’s disease patients with anterograde memory disturbances similarly seem to have limbic damage, or, as Testa et al. (1998) formulated, probably show a bilateral destruction of tracts connecting isocortex and hippocampal formation. 7.5.5.1. Spongiform encephalopathies/prion diseases More recently, an increasing number of prion related diseases—neurodegenerative diseases with a usually rapid fatal consequence—has been reported. They are divided into familial (genetic), sporadic (spontaneous) and acquired (transmitted) prion diseases. Many, though not all of them, lead to cortical degeneration. Creutzfeldt–Jakob disease (CJD) and its variant (vCJD) are well known, Kuru disease, Gerstmann–Stra¨ussler– Scheinker syndrome and fatal familial insomnia are examples (for overview see Knight and Will, 2003; see also Lasme´zas et al., 2001; Arnold and Wilesmith, 2003). While anterograde amnesia is common, usually a number of further intellectual deficits are observed as well. 7.5.5.2. Epilepsies Epileptic foci are frequent in the medial temporal lobe area and are usually accompanied by hippocampal sclerosis (Dam, 1982; Jefferys, 1999). (Benbadis et al., 2000, even reported evidence for mesial temporal sclerosis in patients with psychogenic nonepileptic seizures.) Consequently, anterograde memory deficits are common (Ojemann and Dodrill, 1985; Gloor, 1990; Miller et al., 1993; Hermann et al., 1995; Fuerst et al., 2001; Martin et al., 2002; Lawn et al., 2004). Nevertheless, as epileptic foci frequently appear already early in childhood, functional plasticity may occur (Jokeit et al., 1996; 1997a; Jokeit and Markowitsch, 1999). Jokeit et al. (1997b) found that a subset of patients with medial temporal epilepsy show an additional prefrontal hypometabolism which results in more severe memory impairments than found in patients without this additional prefrontal abnormality (‘remote lesion effects’; see also Goldenberg et al., 1991). 7.5.5.3. Hypoxia, Anoxia Neurodegenerative processes caused by insufficient oxygen supply are most closely related to hippocampal degeneration (or to degeneration of specific

168

H.J. MARKOWITSCH

hippocampal sectors) (Sommer, 1880) and are accompanied by severe anterograde amnesia (Mackenzie and Hodges, 1997; Markowitsch, 1998; Mecklinger et al., 1998). A condition after heart attack is most frequent (Markowitsch et al., 1997c), but drowning, hanging (Markowitsch, 1992d), perinatal damage, and respiratory problems are causes as well. Already many decades ago cases with carbon monoxide intoxications were described (Schulz, 1908; Gru¨nthal, 1947). Broman et al. (1997) described a patient whom they had followed up for more than 19 years and who had had respiratory failure at age eight. His mnestic condition corresponded to that of patient H.M. (see section 2). On the other hand, Calabrese and Markowitsch (1995) had a patient with a condition after heart attack who regained much of his memory abilities after extensive training of more than one year of duration. And Stuss et al. (1997) emphasized that chronic obstructive pulmonary disease may have consequences for memory performance. Interestingly, in this field a number of glucose PET studies were done (Markowitsch et al., 1997c; de Reuck et al., 2003). Vargha-Khadem et al. (1997) described three cases with bilateral hippocampal damage since birth or childhood and episodic–autobiographical amnesia. Two of their three patients had hypoxia-related damage of the hippocampus proper. Their semantic memory, on the other hand, was largely preserved. The authors argue that the findings in their juvenile patient provide evidence not only for the distinction between episodic and semantic memory, but also for that between the hippocampus—as a structure necessary for encoding and consolidation of episodic memory—and the surrounding medial temporal structures which they consider relevant for semantic memory processing. Interestingly, and in line with data from Maguire et al. (2000), bilateral vestibular nerve loss may lead to hippocampal atrophy and selective spatial memory impairments, while general memory functions (as measured, e.g., with the Wechsler Memory Scale-revised) may be preserved (Brandt et al., 2005). These results point to a preservation of phylogenetically old hippocampal functions in the spatial domain and reinforce the view of a functional shift from space to time later in evolution (Tulving and Markowitsch, 1994).

temporal lobe region, bilaterally confined to the amygdaloid region (Tranel and Hyman, 1990; Markowitsch et al., 1994; Cahill et al., 1995; Siebert et al., 2003). While we originally had the possibility to study a brother and a sister with this disease in Germany, we later were able to test a larger number of these patients in South Africa. While all of them were characterized by distinct bilateral damage to the amygdaloid regions (Fig. 7.9), their behavior varied considerably and was apparently related to their early education and to their social background (Siebert et al., 2003). Most consistently, we found an improper processing of negative affective facial stimuli, a finding which I later confirmed in a test situation where emotionally arousing movies were presented (unpublished data). In an earlier study we had found that Urbach–Wiethe patients may have problems in differentiating between more or less emotionally significant material which then affects their memory as well (Cahill et al., 1995). Also personality dimensions were affected, demonstrating a heightened agitation and tendency towards depression (Markowitsch et al., 1994). The findings in these patients and emotionally ‘opposite’ findings we obtained in a patient with selective bilateral damage of the septal region (Von Cramon et al., 1993; Von Cramon and Markowitsch, 2000) lets us conclude that the amygdala and the septal nuclei act at least in part in an opposite manner: amygdala activity increases emotional sensitivity while septal activity dampens it. By doing so, both structural complexes affect the processing of memories.

7.5.5.4. Urbach–Wiethe disease A very rare, but most interesting disease condition is Urbach–Wiethe disease (lipoid proteinosis). It is a hereditary systemic disorder characterized by the deposition of hyaline material in the skin and mouth–larynx areas. About one half to two-thirds of the affected patients furthermore show a mineralization in the medial

Fig. 7.9. Example of the amygdaloid brain damage of a patient with Urbach–Wiethe disease (Siebert et al., 2003).

ANTEROGRADE AMNESIA 7.5.6. Traumatic brain damage Traumatic brain injury is the leading cause of death and disability in young adults of industrialized countries (Salazar et al., 2003). Within neuropsychology a number of cases became well known. In 1968 Teuber and coworkers introduced the case of a trauma-caused diencephalic lesion in a patient, abbreviated as N.A. (Teuber et al., 1968). This patient received a stab wound by a fencing foil which entered the nose and ended in the left mediodorsal nucleus of the thalamus. N.A. in the following years was intensily investigated by Squire and coworkers (Squire and Moore, 1979; Kaushall et al., 1981; Squire et al., 1989). A more recent, but very similar case was introduced by Dusoir et al. (1990). A billard cue entered this patient’s nose and destroyed the mammillary bodies, but not any thalamic areas. The patient was tested neuropsychologically 21 months after the accident. Even at this time he had a massive verbal memory disturbance which in severity was comparable to that of other amnesics. On the nonverbal level his difficulties were less obvious. There was no evidence for a frontal lobe syndrome, and otherwise he manifested average or supra-average performance in the cognitive field. This case deserves special attention as it emphazizes again the role of the mammillary bodies in memory processing which long ago had been stressed by Gudden (1896), Gamper (1928) and other early authors. (However, there is ongoing discussion of the role of the mammillary bodies in memory; see Kapur et al., 1998; Victor et al., 1989.) Another patient, whose anterograde as well as retrograde amnesia was documented repeatedly, is K.C. K.C. had a traffic accident with various cortical and white matter injuries, including bilateral hippocampal damage (see Fig. 1 in Tulving et al., 1988 and Fig. 20-1 in Tulving, 2002); thereafter he became amnesic and has continued to be so for decades. Research on him has recently been summarized by Rosenbaum et al. (2005). Case K.C. provides an example for the problems frequently inherent in patients with traumatic brain injury. Though trauma conditions frequently lead to severe—in particular, severe retrograde autobiographical amnesia (e.g., Levine et al., 1998)—the contribution of psychogenic components to amnesia prolongation and exacerbation should not be negated (Binder, 1994). Furthermore, more widespread damage, including white matter, may lead to various behavioral deteriorations aside from memory. Examples are the head injured American Vietnam fighters of Grafman et al. (1988), of whom 96 had right hemispheric, 78 left hemispheric, and 89 bilateral brain damage, and Jarho’s (1973) Finnish war veterans with penetrating cranial injuries.

169

Jarho had, however, among his patients two dense amnesics with lesions restricted to the area of the mammillothalamic tract. 7.5.7. Therapeutically induced lesions resulting in amnesia The most well known example of therapeutically induced anterograde amnesia is patient H.M., described in section 7.2. Along with him, Scoville and Milner (1957) described a number of related patients. Less well known is a—usually more transient—anterograde amnesic symptomatology after diencephalic lesions. Circumscribed thalamic lesions have been used for pain reduction (Sugita et al., 1972), to control aggressive (Poblete et al., 1970; Na´dvornı´k et al., 1973), or compulsive behavior (Wada, 1951; Wada and Endo, 1951; Spiegel et al., 1953; Hassler and Dieckmann, 1967; 1973), or epilepsy (Wada, 1951; Wada and Endo, 1951). Though part of these surgeries included the mediodorsal nucleus, there was little discussion of possible memory disturbances, this all the more as the stereotaxic invasions were aimed to change the patient’s emotional behavior. Even in 1987 Na´dvornı´k and Drlickova´ wrote that memory constitutes ‘a new dimension in surgeries’ (Na´dvornı´k and Drlickova´, 1987, p. 73). On the other hand there is evidence for at least short-term amnesic syndromes which Hassler and Dieckmann (1967) attributed to the additional lesion of the mammillothalamic tract. ‘Severe amnesias’ were reported by the same authors in 1973 in two of their six cases with bilateral coagulation of the mediodorsal and the intralaminar nuclei (Hassler and Dieckmann, 1973). For Spiegel et al. (1956) the above mentioned chronotaraxis, a disorientation in time, was the characteristic symptom after mediodorsal thalamotomy. Orchinik (1960) tested 46 thalamotomized patients pre- and postsurgery by using the Wechsler Memory Scale. He found that the deteriorations observable immediately postoperatively had disappeared after a few months. All these data are difficult to interpret as not much complementary data were available. Premorbid intelligence status, mood state, functions of attention and concentration, etc. could have contributed to the varying outcome (Markowitsch, 2003a). 7.5.8. Patients with transient global amnesia Transient global amnesia is an amnesic condition which is mainly found in the elderly and which is considered to be principally benign. The incidence of the disease is rated between 10 and 32 per 100 000. Contrary to the assumption found repeatedly in the literature, recurrent attacks may be less rare than assumed (Markowitsch,

170

H.J. MARKOWITSCH

1983). The etiology of transient global amnesias (TGAs) is still little understood which is in part due to the defining characteristics of the phenomenon, its short duration ( 2 errors: (score ¼ 1), Patient taps like the examiner at least four consecutive times: (score ¼ 0). 5. Go–No Go (inhibitory control): ‘Tap once when I tap once.’ To be sure that the patient has understood the instruction, a series of three trials is run: 1-1-1. ‘Do not tap when I tap twice.’ To be sure that the patient has understood the instruction, a series of three trials is run: 2–2-2. The examiner performs the following series: 1-1-2-1-2-2-2-1-1-2. SCORE No error: (score ¼ 3), 1-2 errors: (score ¼ 2), > 2 errors: (score ¼ 1), Patient taps like the examiner at least four consecutive times: (score ¼ 0). 6. Prehension behavior (environmental autonomy) ‘Do not take my hands.’ The examiner is seated in front of the patient. Place the patient’s hands palm up on his/her knees. Without saying anything or looking at the patient, the examiner brings his/ her hands close to the patient’s hands and touches the palms of both the patient’s hands, to see if he/she will spontaneously take them. If the patient takes the hands, the examiner will try again after asking him/her: ‘Now, do not take my hands.’ SCORE Patient does not take the examiner’s hands: (score ¼ 3), Patient hesitates and asks what he/she has to do: (score ¼ 2), Patient takes the hands without hesitation: (score ¼ 1), Patient takes the examiner’s hand even after he/she has been told not to do so: (score ¼ 0). Population

n

Controls Patients PD MSA CBD PSP FTD

42 121 24 6 21 47 23

Age 58.0  14.4a 64.4  9.3a 59.4  12.9cg 65.0  10.5 67.4  8.1bc 66.9  7.0gh 60.3  8.5bh

MMSE 28.9  0.8a 25.5  4.8a 28.0  1.9ij 25.7  3.9j 26.4  3.8b 26.2  3.7h 20.7  6.3bhi

Mattis DRS 141  2.4a 118.0  19.1a 134.0  15.2cgi 127.0  16.2e 123.7  15.0bc 117.7  15.2gh 101.5  20.0behi

FAB 17.3  0.8a 10.3  4.7a 15.9  3.8cgi 13.5  4.0ef 11.0  3.7bcd 8.5  3.4dfg 7.7  4.2bei

PD ¼ Parkinson’s disease; MSA ¼ multiple system atrophy; CBD ¼ corticobasal degeneration; PSP ¼ progressive supranuclear palsy; FTD ¼ frontotemporal dementia. Values are presented as mean  SD. Significantly different at p < 0.05 for: acontrols and patients; bFTD and CBD patients; cPD and CBD patients; dPSP and CBD patients; eFTD and MSA patients; fPSP and MSA patients; gPD and PSP patients; h FTD and PSP patients; iPD and FTD patients; jPD and MSA patients. MMSE ¼ Mini-Mental State Examination; DRS ¼ Dementia Rating Scale; FAB ¼ Frontal Assessment Battery.

estimation, abstraction, mental flexibility, planning, strategy generation and execution, monitoring, and ability to conduct a strategic search. The entire battery requires 40 minutes for administration and can be given to adults between the ages of 16 and 87.

12.6.3.4. The executive control battery (ECB) This battery is based on work done by Goldberg et al. (2000) with Alexander Luria in patients with prefrontal lesions. The battery consists of four subtests: graphical sequences, competing programs, manual postures, and

THE DYSEXECUTIVE SYNDROMES motor sequences and is designed to reveal deficits in initiation, persistence, set-shifting, inhibition, and motor programming. This battery can be administered to adults in approximately one hour.

12.7. Management of dysexecutive syndromes There are pharmacological and behavioral strategies to help individuals with dysexecutive functioning. A detailed review of potential interventions is beyond the scope of this chapter and has been addressed by the authors elsewhere (Daffner and Wolk, 2004). Patients with dysexecutive syndromes often have limited cognitive reserve and are vulnerable to the side effects of medications or to being inadequately treated for concurrent medical or psychiatric illness. Clinicians need to serve as advocates for their patients who are at risk for not receiving optimal treatment. 12.7.1. Pharmacological management Before initiating therapy for executive dysfunction, all concurrent illnesses should be evaluated and treated (e.g., toxic-metabolic state, infection, pain, constipation, sleep disturbance). Neuropsychiatric symptoms and disorders that may be contributing (e.g., depression, anxiety, hypomania/mania, thought disorder) should be identified and treated. All medicines should be reviewed. Nonessential medications should be eliminated. There are no medications that have been developed specifically for the treatment of dysexecutive syndromes. However, as briefly reviewed below, several classes of medications may help to ameliorate some symptoms. If a clinician is interested in trying potentially helpful medications, it is prudent to inform the patient (and caregiver) of the known indications for the medication, the logic of the proposed trial, its potential risks and benefits, and the need to closely monitor the patient. Pharmacologic therapies for executive dysfunction are aimed at the modulation of dopaminergic, noradrenergic, or cholinergic systems. Dopamine is probably the best characterized neurotransmitter associated with the executive functions (Cohen and Servan-Schreiber, 1992). It contributes to the appropriate activity of working memory (Williams and Goldman-Rakic, 1995; Goldman-Rakic, 1996) and helps to regulate motivational states and reward systems (Horvitz et al., 1997; Schultz et al., 1997; Wickelgren, 1997). Evidence in animals points to there being an ‘optimal’ amount of dopamine, which follows an inverted ‘ushaped’ curve. Too much or too little dopamine is detrimental to working memory performance (Arnsten, 1997). Dopamine originates from structures in the

261

midbrain, including the ventral tegmental area (VTA), that project to frontal cortex. In rats, lesions to either midbrain VTA cell bodies or frontal cortical areas result in similar behavioral effects (hyperactivity) (Pycock et al., 1980). In monkeys, destruction of dopamine terminals leads to impaired performance on the delayed alternation task in a manner similar to that seen after destruction of the frontal cortex itself (Brozoski et al., 1979). Norepinephrine, released from neurons originating in the brain stem’s locus ceruleus, serves as a central neurotransmitter mediating arousal and vigilance, and helps to improve the ratio of signal-to-noise (Foote et al., 1975; Tucker and Williamson, 1984; Craik et al., 1987; Posner and Petersen, 1990; Foote et al., 1991; Usher et al., 1999; Mesulam, 2000; Nieuwenhuis et al., 2005). Alpha-2a noradrenergic receptors in the prefrontal cortex are important in the modulation of focused attention (Arnsten, 1997). Disruption of these receptors can lead to increased distractibility. Alpha2a autoreceptors on neurons in the locus ceruleus also may modulate its discharge rates, leading to improved attention (Taylor and Russo, 2001). Acetylcholine is released by neurons projecting from basal forebrain to frontal cortex and hippocampus in response to behaviorally significant or novel events (Acquas et al., 1996). This neurotransmitter has been strongly implicated in the modulation of selective attention (Posner and Petersen, 1990). PET studies in healthy volunteers have suggested that inhibition of cholinesterase activity is associated with more efficient working memory (faster reaction times and more circumscribed activation of the right PFC) (Furey et al., 1997; 2000; Freo et al., 2005). Consistent with these observations, pharmacological interventions that have been employed to improve arousal, motivation, attention, and executive functions include stimulant medications, catecholamine ‘boosters,’ alpha-2 agonists, dopaminergic agents, modafinil, and cholinergic agents. The most common dysexecutive syndrome for which therapeutic trials have been reported is ADHD. However, data also exist regarding the impact of some of these classes of medications on patients with dysexecutive functions due to other disorders such as head injury and Alzheimer’s disease, and on attention and working memory in healthy individuals. Stimulant medications increase the availability of catecholamines (dopamine and norepinephrine). They may improve arousal level, motivational tone, and attentional focus (Chiarello and Cole, 1987; Marin et al., 1995; Wilens et al., 1995; Greenhill and Osmon, 2000; Taylor and Russo, 2001). Recent studies also indicate that certain stimulants can improve spatial working

262

K.R. DAFFNER AND M.M. SEARL

memory, sustained attention, and inhibitory control (Mehta et al., 2004; Freo et al., 2005; Turner et al., 2005). Stimulants have been studied most extensively in patients with attention deficit hyperactivity disorders (ADHD), but also have been used with variable success for other disorders that lead to dysexecutive syndromes (Marin et al., 1995; Watanabe et al., 1995; Galynker et al., 1997; Mahalick et al., 1998; Challman and Lipsky, 2000; Whyte et al., 2004; Rahman et al., 2005; Siddall, 2005). Non-stimulant medications that boost norepinephrine (e.g., atomoxetine) or norepinephrine and dopamine (e.g., buproprion) have been shown to be efficacious in the treatment of ADHD (Maidment, 2003; Michelson et al., 2003; Simpson and Plosker, 2004; Adler et al., 2005). Buproprion may be particularly appropriate in patients who are suffering both from depression and compromised executive functions. Alpha-2 agonists, such as clonidine and guanfacine, have been beneficial for patients with ADHD (Connor et al., 1999; Taylor and Russo, 2001). However, there is evidence that this class of medication may be less effective than stimulants in improving the motivational state of patients (Taylor and Russo, 2001). Another alternative to stimulants, modafinil, does not appear to work directly via noradrenergic or dopaminergic systems. Modafinil may activate hypothalamic and tuberomamillary nucleus pathways involving hypocretin (orexin) from the lateral hypothalamus and/or histaminergic neurons from the tuberomamillary nucleus that have excitatory projections to cortex (Lin et al., 1996; Scammell et al., 2000). Initial reports emphasized modafinil’s ability to promote wakefulness and treat narcolepsy and other sleep-related disorders. More recent studies have suggested that modafinil may also be effective in the treatment of the patients with diminished attention and executive functions (Taylor and Russo, 2000; Muller et al., 2004; Turner et al., 2004). Dopaminergic agents (e.g., pramipexole, bromocriptine, selegiline, L-dopa) are most often prescribed for the treatment of Parkinson’s disease. However, these medications also have been used to help improve motivation, diminish apathy, and to augment working memory and other executive functions (Luciana et al., 1992; Muller and von Cramon, 1994; Marin et al., 1995; Luciana and Collins, 1997; McDowell et al., 1998; Muller et al., 1998). Interestingly, in neurologically healthy individuals, activation of D1 dopamine receptors may be more important than activation of D2 receptors and dopamine agonists may be more effective in improving working memory performance in those individuals who have a low working memory capacity than those with high working memory capacity (Kimberg et al., 1997; Muller et al., 1998).

Cholinesterase inhibitors (e.g., donepezil, rivastigmine, galantamine), that increase the availability of acetylcholine, were developed for the symptomatic treatment of probable Alzheimer’s disease. This class of medication appears to have modest effects not only on cognition and memory, but also on aspects of executive functions, attention, and neuropsychiatric wellbeing (Acquas et al., 1996; Furey et al., 1997; 2000; Yesavage et al., 2002; Zhang et al., 2004; Bohnen et al., 2005; Khateb et al., 2005). A recent PET study in patients with probable AD suggested that the degree of cortical enzyme inhibition correlated with improvements on tests of executive function and attention (Bohnen et al., 2005). In patients with mild cognitive impairment (amnestic type), donepezil increased frontal activity, which correlated with the degree of improvement on an n-back working memory task (Saykin et al., 2004). Reports have been mixed regarding whether cholinesterase inhibitors can improve executive functioning and cognitive performance in healthy adults (Yesavage et al., 2002; Beglinger et al., 2004). Regardless of which medication is initiated, it is essential that clinicians identify target symptoms, develop close communication with reliable informants, and try to quantify the impact of their interventions. If there is no clear benefit from the treatment or if there is evidence that side effects are outweighing benefits, it makes sense to discontinue the medication and consider alternatives. 12.7.2. Environmental and behavioral modifications Patients with executive dysfunction often require increased structure to their environment, which helps to serve as their ‘external executive system.’ They may be able to carry out tasks if each step is made explicit and cues are frequently provided during the process. Wilson et al. (2001) conducted a study using a paging system to help patients with brain injury compensate for deficits in memory and executive abilities (e.g., planning). They reported that over 80% of the patients who completed the trial of receiving electronic prompts to carry out specific tasks improved significantly in the execution of daily activities, including self care, administration of medicines, and keeping appointments. Individuals with subtle disruptions of executive functions may be helped by learning organizational strategies and time management techniques. Patients with more severe behavioral symptoms may benefit from clear, consistent, concrete rewards and punishments that are immediately linked to their behaviors. Alderman (1996) found that performance on a dualtask experiment, but not other neuropsychological

THE DYSEXECUTIVE SYNDROMES tests, discriminated between patients who showed a positive response to behavior modification (reinforcement, extinction, time-out) and patients who did not. He argued that impairments of central executive functioning lead to the inability to allocate attentional resources to concurrent stimulus sets necessary for successful reinforcement and other operant methods. It may prevent the kind of monitoring necessary to account for cues that signal a behavior as inappropriate and requiring modification. An alternative strategy for assisting such patients may be immediate (verbal) feedback that is tightly linked to their performance. It is essential that caregivers and family members are educated regarding a patient’s disabilities to help them understand that the inappropriate or frustrating actions of their loved ones most often reflect brain disease and not moral turpitude. In addition, caregivers can learn how to assist patients by cueing them and by providing them with external structure and very consistent responses. Patients with severe dysexecutive syndromes tend to do best when following very stable, predictable routines. Since such patients often are incapable of planning for their own future personal and financial wellbeing, it is essential that family members address these issues. Safety is a high priority for individuals at risk for behavioral dyscontrol. There is a need to protect the patient from self-harm and the caregivers from injurious behaviors. An effort should be made to reduce excessive environmental stimulation. The establishment of a calm and predictable environment can be beneficial. Attempting to augment the sensory fidelity of a patient (e.g., with glasses or hearing aids) should be pursued when feasible. In addition, efforts to improve sleep hygiene and ensure adequate fluids and nutrition are essential (Inouye et al., 1999). Behaviors also may improve with the establishment of a modest exercise program (Colcombe and Kramer, 2003). Cognitive, occupational, and behavioral therapists may offer techniques for augmenting executive and organizational skills, for creating conditions that facilitate improved behaviors, and for educating caregivers about how they can be most helpful to their loved ones. A social work consultation can aim to promote adequate safety, establish plans for the future, and provide necessary caregiver support.

12.8. Summary Executive functions are among the most valued components of being human. When executive functions fail, the cost to individuals and those who care for them can be extraordinary. The past decades have witnessed a greater understanding of the neuroanatomy, physiology,

263

and cognitive processing that underlies executive functions. There has been a growth of clinical assessment tools, diagnostic procedures, and environmental and pharmacological strategies to manage executive dysfunction. We anticipate that future research will lead to increasingly effective treatments that will improve the quality of life of our patients with executive dysfunction.

References Acquas E, Wilson C, Fibiger HC (1996). Conditioned and unconditioned stimuli increase frontal cortical and hippocampal acetylcholine release: Effects of novelty, habituation, and fear. J Neurosci 16: 3089–3096. Adler LA, Spencer TJ, Milton DR, et al. (2005). Long-term, open-label study of the safety and efficacy of atomoxetine in adults with attention-deficit/hyperactivity disorder: An interim analysis. J Clin Psychiatry 66: 294–299. Alderman N (1996). Central executive deficit and response to operant conditioning methods. Neuropsychol Rehabil 6: 161–186. Alexander GE, DeLong MR, Strick PL (1986). Parallel organization of functionally segregated circuits linking basal ganglia and cortex. Annu Rev Neurosci 9: 357–381. Anderson MC, Ochsner KN, Kuhl B, et al. (2004). Neural systems underlying the suppression of unwanted memories. Science 303: 232–235. Anderson SW, Bechara A, Damasio H, et al. (1999). Impairment of social and moral behavior related to early damage in human prefrontal cortex. Nat Neurosci 2: 1032–1037. Andre´s P (2003). Frontal cortex as the central executive of working memory: Time to revise our view. Cortex 39: 871–896. Arnsten AF (1997). Catecholamine regulation of the prefrontal cortex. J Psychopharmacol 11: 151–162. Aron AR, Fletcher PC, Bullmore ET, et al. (2003). Stopsignal inhibition disrupted by damage to right inferior frontal gyrus in humans. Nat Neurosci 6: 115–116. Aron AR, Poldrack RA (2005). The cognitive neuroscience of response inhibition: Relevance for genetic research in attention-deficit/hyperactivity disorder. Biol Psychiatry 57: 1285–1292. Baddeley AD, Bressi S, Della Sala S, et al. (1991). The decline of working memory in Alzheimer’s disease. A longitudinal study. Brain 114: 2521–2542. Baddeley AD, Hitch GJ (1974). Working memory. In G Bower (Ed.), Vol VIII. Academic Press, New York, pp. 47–89. Banks G, Short P, Martinez J, et al. (1989). The alien hand sydrome: Clinical and post-mortem findings. Arch Neurol 46: 456–459. Barris RW, Schuman HR (1953). Bilateral anterior cingulate gyrus lesions; syndrome of the anterior cingulate gyri. Neurology 3: 44–52. Bechara A, Damasio AR, Damasio H, et al. (1994). Insensitivity to future consequences following damage to human prefrontal cortex. Cognition 50: 7–15.

264

K.R. DAFFNER AND M.M. SEARL

Bechara A, Tranel D, Damasio H, et al. (1996). Failure to respond autonomically to anticipated future outcomes following damage to prefrontal cortex. Cereb Cortex 6: 215–225. Beglinger LJ, Gaydos BL, Kareken DA, et al. (2004). Neuropsychological test performance in healthy volunteers before and after donepezil administration. J Psychopharmacol 18: 102–108. Bianchi L (1922). The Mechanism of the Brain and the Function of the Frontal Lobes. E&S Livingstone, Edinburgh. Bohnen NI, Kaufer DI, Hendrickson R, et al. (2005). Degree of inhibition of cortical acetylcholinesterase activity and cognitive effects by donepezil treatment in Alzheimer’s disease. J Neurol Neurosurg Psychiatry 76: 315–319. Botvinick MM, Braver TS, Barch DM, et al. (2001). Conflict monitoring and cognitive control. Psychol Rev 108: 624–652. Botvinick MMC, Carter CS (2004). Conflict monitoring and anterior cingulate cortex: An update. Trends Cogn Sci 8: 539–546. Brass M, Derrfuss J, Forstmann B, et al. (2005). The role of the inferior frontal junction area in cognitive control. Trends Cogn Sci 9: 314–316. Brown JW, Braver TS (2005). Learned predictions of error likelihood in the anterior cingulate cortex. Science 307: 1118–1121. Brozoski TJ, Brown RM, Rosvold HE, et al. (1979). Cognitive deficit caused by regional depletion of dopamine in prefrontal cortex of rhesus monkey. Science 205: 929–932. Castellanos FX, Tannock R (2002). Neuroscience of attention-deficit/hyperactivity disorder: The search for endophenotypes. Nat Rev Neurosci 3: 617–628. Challman TD, Lipsky JJ (2000). Methylphenidate: Its pharmacology and uses. Mayo Clin Proc 75: 711–721. Chiarello RJ, Cole JO (1987). The use of psychostimulants in general psychiatry. A reconsideration. Arch Gen Psychiatry 44: 286–295. Cohen JD, Servan-Schreiber D (1992). Context, cortex, and dopamine: A connectionist approach to behavior and biology in schizophrenia. Psychol Rev 99: 45–77. Cohen RA, Kaplan RF, Zuffante P, et al. (1999). Alteration of intention and self-initiated action associated with bilateral anterior cingulotomy. J Neuropsychiatry Clin Neurosci 11: 444–453. Colcombe SJ, Kramer AF (2003). Fitness effects on the cognitive function of older adults. Psychol Sci 14: 125–130. Connor DF, Fletcher KE, Swanson JM (1999). A meta-analysis of clonidine for symptoms of attention-deficit hyperactivity disorder. J Am Acad Child Adolesc Psychiatry 38: 1551–1559. Courtney SM, Ungerleider LG, Keil K, et al. (1996). Object and spatial visual working memory activate separate neural systems in human cortex. Cereb Cortex 6: 39–49. Craik RL, Hand PJ, Levin BE (1987). Locus coeruleus input affects glucose metabolism in activated rat barrel cortex. Brain Res Bull 19: 495–499. D’Esposito M, Aguirre GK, Zarahn E, et al. (1998). Functional MRI studies of spatial and nonspatial working memory. Brain Res Cogn Brain Res 7: 1–13.

D’Esposito M, Postle BR, Ballard D, et al. (1999). Maintenance versus manipulation of information held in working memory: An event-related fMRI study. Brain Cogn 41: 66–86. Daffner K, Wolk D (2004). Behavioral neurology and dementia. In M Samuels (Ed.), Manual of Neurologic Therapeutics. Philadelphia, Lippincott, Williams &Wilkins, pp. 410-448. Damasio AR (1996). The somatic marker hypothesis and the possible functions of the prefrontal cortex. Philos Trans R Soc Lond B Biol Sci 351: 1413–1420. Damasio AR, Tranel D, Damasio H (1990). Individuals with sociopathic behavior caused by frontal damage fail to respond autonomically to social stimuli. Behav Brain Res 41: 81–94. Damasio H, Grabowski T, Frank R, et al. (1994). The return of Phineas Gage: Clues about the brain from the skull of a famous patient. Science 264: 1102–1105. Delis D, Kaplan E (2001). Delis-Kaplan Executive Function System (DKEFS). Psychological Corporation, San Antonio, Texas. Dubois B, Slachevsky A, Litvan I, et al. (2000). The FAB: A Frontal Assessment Battery at bedside. Neurology 55: 1621–1626. Eslinger PJ, Damasio AR (1985). Severe disturbance of higher cognition after bilateral frontal lobe ablation: Patient EVR. Neurology 35: 1731–1741. Falkenstein M, Hohnsbein J, Hoormann J, et al. (1991). Effects of crossmodal divided attention on late ERP components. II. Error processing in choice reaction tasks. Electroencephalogr Clin Neurophysiol 78: 447–455. Foote SL, Berridge CW, Adams LM, et al. (1991). Electrophysiological evidence for the involvement of the locus coeruleus in alerting, orienting, and attending. Prog Brain Res 88: 521–532. Foote SL, Freedman R, Oliver AP (1975). Effects of putative neurotransmitters on neuronal activity in monkey auditory cortex. Brain Res 86: 229–242. Freo U, Ricciardi E, Pietrini P, et al. (2005). Pharmacological modulation of prefrontal cortical activity during a working memory task in young and older humans: A PET study with physostigmine. Am J Psychiatry 162: 2061–2070. Furey ML, Pietrini P, Haxby JV (2000). Cholinergic enhancement and increased selectivity of perceptual processing during working memory. Science 290: 2315–2319. Furey ML, Pietrini P, Haxby JV, et al. (1997). Cholinergic stimulation alters performance and task-specific regional cerebral blood flow during working memory. Proc Natl Acad Sci USA 94: 6512–6516. Fuster J (1997). The Prefrontal Cortex: Anatomy, Physiology, and Neuropsychology of the Frontal Lobe. Raven Press, New York. Fuster JM, Alexander GE (1971). Neuron activity related to short-term memory. Science 173: 652–654. Galynker I, Ieronimo C, Miner C, et al. (1997). Methylphenidate treatment of negative symptoms in patients with dementia. J Neuropsychiatry Clin Neurosci 9: 231–239.

THE DYSEXECUTIVE SYNDROMES Gaymard B, Rivaud S, Cassarini J, et al. (1998). Effects of anterior cingulate cortex lesions on ocular saccades in humans. Exp Brain Res 120: 173–183. Gioia G, Isquith P, Guy S, et al. (2000). Behavior Rating Inventory of Executive Function. Psychological Assessment Resources, Inc., Odessa, FL. Goldberg E, Podel K, Bilder R, et al. (2000). The Executive Control Battery. PsychPress, Melbourne. Goldman-Rakic P (1987). Circuitry of primate prefrontal cortex and regulation of behavior by representational memory. In FMV Plum, ST Geiger (Eds.), The Handbook of Physiology, Section 1: The Nervous System, Volume V. Higher Functions of the Brain, Part 1. Bethesda, American Physiological Society, chap. 9, pp. 373–417. Goldman-Rakic PS (1996). Regional and cellular fractionation of working memory. Proc Natl Acad Sci USA 93: 13473–13480. Goldstein K, Scheerer M (1941). Abstract and concrete behavior. Psychol Monogr 53: 110–130. Grace JMalloy P (2001). Frontal Systems Behavior Scale (FrSBe). Psychological Assessment Resources, Lutz, FL. Greenhill L, Osmon B (2000). Ritalin: Theory and Practice. Mary Ann Liebert, New York. Harlow J (1868). Recovery from the passage of an iron bar through the head. Mass Med Soc Publ 2: 327–346. Hashimoto R, Tanaka Y (1998). Contribution of the supplementary motor area and anterior cingulate gyrus to pathological grasping phenomena. European neurology 40: 151–158. Horvitz JC, Stewart T, Jacobs BL (1997). Burst activity of ventral tegmental dopamine neurons is elicited by sensory stimuli in the awake cat. Brain Res 759: 251–258. Inouye SK, Bogardus ST, Jr., Charpentier PA, et al. (1999). A multicomponent intervention to prevent delirium in hospitalized older patients. N Engl J Med 340: 669–676. Ito S, Stuphorn V, Brown JW, et al. (2003). Performance monitoring by the anterior cingulate cortex during saccade countermanding. Science 302: 120–122. Jackson JH (1932). Selected Writings of John Hughlings Jackson, Vol 2. Hodder and Stoughton, London. Jacobsen CF (1935). Functions of frontal association areas in primates. Arch Neurol Psychiatry 33: 558–569. Jenkins IH, Jahanshahi M, Jueptner M, et al. (2000). Selfinitiated versus externally triggered movements. II. The effect of movement predictability on regional cerebral blood flow. Brain 123: 1216–1228. Khateb A, Ammann J, Annoni JM, et al. (2005). Cognitionenhancing effects of donepezil in traumatic brain injury. European neurology 54: 39–45. Kimberg DY, D’Esposito M, Farah MJ (1997). Effects of bromocriptine on human subjects depend on working memory capacity. Neuroreport 8: 3581–3585. Konishi S, Nakajima K, Uchida I, et al. (1999). Common inhibitory mechanism in human inferior prefrontal cortex revealed by event-related functional MRI. Brain 122: 981–991. Lau HC, Rogers RD, Haggard P, et al. (2004). Attention to intention. Science 303: 1208–1210.

265

Lau H, Rogers RD, Passingham RE (2006). Dissociating response selection and conflict in the medial frontal surface. Neuroimage 29:446–451 [epub 2005]. Liddle PF, Kiehl KA, Smith AM (2001). Event-related fMRI study of response inhibition. Hum Brain Mapp 12: 100–109. Lin JS, Hou Y, Jouvet M (1996). Potential brain neuronal targets for amphetamine-, methylphenidate-, and modafinil-induced wakefulness, evidenced by c-fos immunocytochemistry in the cat. Proc Natl Acad Sci USA 93: 14128–14133. Luciana M, Collins P (1997). Dopaminergic modulation of working memory for spatial but not object cues in normal humans. J Cogn Neurosci 9: 330–347. Luciana M, Depue R, Arbisi P, et al. (1992). Facilitation of working memory in humans by a D2 dopamine receptor agonist. J Cogn Neurosci 4: 58–68. Macmillan M (2002). An Odd Kind of Fame: Stories of Phineas Gage. MIT Press, Cambridge. Mahalick DM, Carmel PW, Greenberg JP, et al. (1998). Psychopharmacologic treatment of acquired attention disorders in children with brain injury. Pediatr Neurosurg 29: 121–126. Maidment ID (2003). The use of antidepressants to treat attention deficit hyperactivity disorder in adults. J Psychopharmacol 17: 332–336. Marin RS, Fogel BS, Hawkins J, et al. (1995). Apathy: A treatable syndrome. J Neuropsychiatry Clin Neurosci 7: 23–30. McDowell S, Whyte J, D’Esposito M (1998). Differential effect of a dopaminergic agonist on prefrontal function in traumatic brain injury patients. Brain 121: 1155–1164. Mehta MA, Goodyer IM, Sahakian BJ (2004). Methylphenidate improves working memory and set-shifting in AD/ HD: Relationships to baseline memory capacity. J Child Psychol Psychiatry 45: 293–305. Mesulam M-M (1986). Frontal cortex and behavior. Ann Neurol 19: 320–325. Mesulam M-M (1990). Large-scale neurocognitive networks and distributed processing for attention, language, and memory. Ann Neurol 28: 597–613. Mesulam M-M (2000). Behavioral neuroanatomy. In M-M Mesulam (Ed.), Principles of Behavioral and Cognitive Neurology. Oxford University Press, Oxford, pp. 1–120. Meythaler JM, Peduzzi JD, Eleftheriou E, et al. (2001). Current concepts: Diffuse axonal injury-associated traumatic brain injury. Arch Phys Med Rehabil 82: 1461–1471. Michelson D, Adler L, Spencer T, et al. (2003). Atomoxetine in adults with ADHD: Two randomized, placebo-controlled studies. Biol Psychiatry 53: 112–120. Miller EKCohen JD (2001). An integrative theory of prefrontal cortex function. Annu Rev Neurosci 24: 167–202. Miller EK, Erickson CA, Desimone R (1996). Neural mechanisms of visual working memory in prefrontal cortex of the macaque. J Neurosci 16: 5154–5167. Muller N, Machado L, Knight RT (2002). Contributions of subregions of the prefrontal cortex to working memory: Evidence from brain lesions in humans. J Cogn Neurosci 14: 673–686.

266

K.R. DAFFNER AND M.M. SEARL

Muller U, Steffenhagen N, Regenthal R, et al. (2004). Effects of modafinil on working memory processes in humans. Psychopharmacology (Berl) 177: 161–169. Muller U, von Cramon DY (1994). The therapeutic potential of bromocriptine in neuropsychological rehabilitation of patients with acquired brain damage. Prog Neuropsychopharmacol Biol 18: 1103–1120. Muller U, von Cramon DY, Pollmann S (1998). D1- versus D2receptor modulation of visuospatial working memory in humans. J Neurosci 18: 2720–2728. Nemeth G, Hegedus K, Molnar L (1988). Akinetic mutism associated with bicingular lesions: Clinicopathological and functional anatomical correlates. Eur Arch Psychiatry Neurol Sci 237: 218–222. Nieuwenhuis S, Aston-Jones G, Cohen JD (2005). Decision making, the P3, and the locus coeruleus–norepinephrine system. Psychol Bull 131: 510–532. Niki H, Watanabe M (1979). Prefrontal and cingulate unit activity during timing behavior in the monkey. Brain Res 171: 213–224. O’Doherty J, Kringelbach ML, Rolls ET, et al. (2001). Abstract reward and punishment representations in the human orbitofrontal cortex. Nat Neurosci 4: 95–102. Owen AM, McMillan KM, Laird AR, et al. (2005). N-back working memory paradigm: A meta-analysis of normative functional neuroimaging studies. Hum Brain Mapp 25: 46–59. Passingham D (1995). The Frontal Lobes and Voluntary Action. Oxford University Press, Oxford. Paus T (2001). Primate anterior cingulate cortex: Where motor control, drive and cognition interface. Nat Rev Neurosci 2: 417–424. Perry RJ, Hodges JR (1999). Attention and executive deficits in Alzheimer’s disease. A critical review. Brain 122: 383–404. Petrides M (2000). Dissociable roles of mid-dorsolateral prefrontal and anterior inferotemporal cortex in visual working memory. J Neurosci 20: 7496–7503. Posner MI, Petersen SE (1990). The attention system of the human brain. Annu Rev Neurosci 13: 25–42. Price BH, Daffner KR, Stowe RM, et al. (1990). The comportmental learning disabilities of early frontal lobe damage. Brain 113: 1383–1393. Pycock CJ, Kerwin RW, Carter CJ (1980). Effect of lesion of cortical dopamine terminals on subcortical dopamine receptors in rats. Nature 286: 74–76. Rahman S, Robbins TW, Hodges JR, et al. (2005). Methylphenidate (‘Ritalin’) can ameliorate abnormal risk-taking behavior in the frontal variant of frontotemporal dementia. Neuropsychopharmacology 31:651–658 (also 2006). Ridderinkhof KR, Ullsperger M, Crone EA, et al. (2004). The role of the medial frontal cortex in cognitive control. Science 306: 443–447. Rolls ET (1996). The orbitofrontal cortex. Philos Trans R Soc Lond B Biol Sci 351: 1433–1443; discussion 1443–1444. Royall DR, Cabello M, Polk MJ (1998). Executive dyscontrol: An important factor affecting the level of care received by older retirees. J Am Geriatr Soc 46: 1519–1524.

Rypma B, Prabhakaran V, Desmond JE, et al. (1999). Loaddependent roles of frontal brain regions in the maintenance of working memory. Neuroimage 9: 216–226. Saykin AJ, Wishart HA, Rabin LA, et al. (2004). Cholinergic enhancement of frontal lobe activity in mild cognitive impairment. Brain 127: 1574–1583. Scammell TE, Estabrooke IV, McCarthy MT, et al. (2000). Hypothalamic arousal regions are activated during modafinil-induced wakefulness. J Neurosci 20: 8620–8628. Schultz W, Dayan P, Montague PR (1997). A neural substrate of prediction and reward. Science 275: 1593–1599. Shallice T (1982). Specific impairments of planning. Philos Trans R Soc Lond B Biol Sci 298: 199–209. Shimamura A (2000). The role of the prefrontal cortex in dynamic filtering. Psychobiology (Austin, Tex) 28: 207–218. Siddall OM (2005). Use of methylphenidate in traumatic brain injury. Ann Pharmacother 39: 1309–1313. Simpson D, Plosker GL (2004). Atomoxetine: A review of its use in adults with attention deficit hyperactivity disorder. Drugs 64: 205–222. Slachevsky A, Villalpando JM, Sarazin M, et al. (2004). Frontal assessment battery and differential diagnosis of frontotemporal dementia and Alzheimer disease. Arch Neurol 61: 1104–1107. Smith EE, Jonides J, Koeppe RA (1996). Dissociating verbal and spatial working memory using PET. Cereb Cortex 6: 11–20. Stephan KM, Binkofski F, Halsband U, et al. (1999). The role of ventral medial wall motor areas in bimanual coordination. A combined lesion and activation study. Brain 122: 351–368. Stroop JR (1935). Studies in interference in serial verbal reactions. J Exp Psychol 18: 643–661. Taylor FB, Russo J (2000). Efficacy of modafinil compared to dextroamphetamine for the treatment of attention deficit hyperactivity disorder in adults. J Child Adolesc Psychopharmacol 10: 311–320. Taylor FB, Russo J (2001). Comparing guanfacine and dextroamphetamine for the treatment of adult attention-deficit/hyperactivity disorder. J Clin Psychopharmacol 21: 223–228. The Lund, Manchester Groups (1994). Clinical and neuropathological criteria for frontotemporal dementia. J Neurol Neurosurg Psychiatry 57: 416–418. Tucker DM, Williamson PA (1984). Asymmetric neural control systems in human self-regulation. Psychol Rev 91: 185–215. Turner DC, Blackwell AD, Dowson JH, et al. (2005). Neurocognitive effects of methylphenidate in adult attention-deficit/hyperactivity disorder. Psychopharmacology (Berl) 178: 286–295. Turner DC, Clark L, Dowson J, et al. (2004). Modafinil improves cognition and response inhibition in adult attention-deficit/hyperactivity disorder. Biol Psychiatry 55: 1031–1040. Ullsperger M, von Cramon DY (2004). Neuroimaging of performance monitoring: Error detection and beyond. Cortex 40: 593–604.

THE DYSEXECUTIVE SYNDROMES Usher M, Cohen JD, Servan-Schreiber D, et al. (1999). The role of locus coeruleus in the regulation of cognitive performance. Science 283: 549–554. Wager TD, Smith EE (2003). Neuroimaging studies of working memory: A meta-analysis. Cogn Affect Behav Neurosci 3: 255–274. Wager TD, Sylvester CY, Lacey SC, et al. (2005). Common and unique components of response inhibition revealed by fMRI. Neuroimage 27: 323–340. Wagner AD, Maril A, Bjork RA, et al. (2001). Prefrontal contributions to executive control: fMRI evidence for functional distinctions within lateral prefrontal cortex. Neuroimage 14: 1337–1347. Watanabe MD, Martin EM, DeLeon OA, et al. (1995). Successful methylphenidate treatment of apathy after subcortical infarcts. J Neuropsychiatry Clin Neurosci 7: 502–504. Werring DJ, Frazer DW, Coward LJ, et al. (2004). Cognitive dysfunction in patients with cerebral microbleeds on T2*weighted gradient-echo MRI. Brain 127: 2265–2275. Whyte J, Hart T, Vaccaro M, et al. (2004). Effects of methylphenidate on attention deficits after traumatic brain injury: A multidimensional, randomized, controlled trial. Am J Phys Med Rehabil 83: 401–420. Wickelgren I (1997). Getting the brain’s attention. Science 278: 35–37. Wilens TE, Biederman J, Spencer TJ, et al. (1995). Pharmacotherapy of adult attention deficit/hyperactivity disorder: a review. J Clin Psychopharmacol 15: 270–279.

267

Willcutt EG, Doyle AE, Nigg JT, et al. (2005). Validity of the executive function theory of attention-deficit/hyperactivity disorder: A meta-analytic review. Biol Psychiatry 57: 1336–1346. Williams GV, Goldman-Rakic PS (1995). Modulation of memory fields by dopamine D1 receptors in prefrontal cortex. Nature 376: 572–575. Wilson B, Alderman N, Burgess P, et al. (1996). Behavioural Assessment of the Dysexecutive Syndrome. Thames Valley Test Company, Suffolk. Wilson BA, Emslie HC, Quirk K, et al. (2001). Reducing everyday memory and planning problems by means of a paging system: A randomised control crossover study. J Neurol Neurosurg Psychiatry 70: 477–482. Wilson FAW, Scalaidhe SPO, Goldman-Rakic PS (1993). Dissociation of object and spatial processing domains in primate prefrontal cortex. Science 260: 1955–1958. Wozniak RH (1999). John Hughlings Jackson: Evolution and Dissolution of the Nervous System, 1881–7, collected 1932. Classics in Psychology, 1855–1914: Historical Essays. London, Thoemes Continuum. Yesavage JA, Mumenthaler MS, Taylor JL, et al. (2002). Donepezil and flight simulator performance: Effects on retention of complex skills. Neurology 59: 123–125. Zhang L, Plotkin RC, Wang G, et al. (2004). Cholinergic augmentation with donepezil enhances recovery in short-term memory and sustained attention after traumatic brain injury. Arch Phys Med Rehabil 85: 1050–1055.

Handbook of Clinical Neurology, Vol. 88 (3rd series) Neuropsychology and behavioral neurology G. Goldenberg, B.L. Miller, Editors # 2008 Elsevier B.V. All rights reserved

Chapter 13

Apraxia of speech WOLFRAM ZIEGLER* Entwicklungsgruppe Klinische Neuropsychologie, Munich, Germany

13.1. History and terminology The term apraxia of speech dates back to the 1960s, when F.L. Darley borrowed it from the ideas of H. Liepmann to describe an impairment of the capacity to program the movements of the articulators for the purpose of speaking (Darley, 1968). Liepmann (1900, p. 129) used the term ‘Apraxie der Sprachmuskeln’ (apraxia of the language muscles) to characterize the ‘motor aphasia’ of his patient ‘T.’ The history of this disorder is characterized by terminological confusions and theoretical disputes, mainly originating from strong dissents concerning relationship and interface between the linguistic and motor aspects of speaking. Broca had studied several patients who, after left inferior-frontal lesions, were unable to speak, but had normal or virtually normal comprehension, normal intelligence, and whose speech muscles were not significantly paretic. He coined the term aphemia to describe this disorder, and characterized it as a loss of the faculty of articulate language, i.e., an inability to coordinate the movements pertaining to the articulation of syllables and words (Broca, 1861; 1865). On another occasion Broca characterized the syndrome as a loss of ‘the memory of the processes required for the articulation of words’ (‘. . .le souvenir du proce´de´ qu’il faut suivre pour articuler les mots’; cf. Liepmann (1913, p. 490)). Later, in Wernicke’s and Lichtheim’s theory, the terms motor aphasia and Broca’s aphasia were used to refer to this disorder, which was then considered to result from a destruction of speech motor images (‘Sprechbewegungsbilder’) located in the left anterior perisylvian region (Lichtheim, 1885). Associating the motor with the linguistic aspects of speech was not a sacrilege in these times, and a few terminological relicts from this era, such as the labels pure motor aphasia or subcortical *

motor aphasia, have survived until more recently (cf. Kertesz, 1985, in the latest issue of this Handbook). At the beginning of the twentieth century P. Marie introduced the term anarthria to underscore his conviction that the impairment initially described by Broca is a motor syndrome which must strictly be kept separate from aphasia (cf. Alajouanine et al., 1939). This position more or less anticipated the theoretical stance prevailing in the second half of the last century, when aphasia was seen as a dysfunction of the ‘linguistic module’ and, as such, entirely independent of cognition, perception, and motor functions. In this view, disordered language production could be either aphasic (i.e., linguistic), or dysarthric (i.e., motor), and the proponents of this dualism consequently used the terms dysarthria or cortical dysarthria when they referred to Broca’s aphemia (e.g., Bay, 1957; Schiff et al., 1983). As a consequence, the disorder—which had been the starting point of modern aphasiology—disappeared from the screen of the new aphasiology school, because, in a strict sense, it was no longer related to the ‘language organ’ proper. A source of confusion within the syndromal theory of these days was that ‘articulatory agility’ nonetheless constituted an important criterion for the differential diagnosis of the aphasic syndromes, especially for the diagnosis of Broca’s aphasia (Kaplan et al., 1983). Darley’s understanding of the disorder, on the contrary, emerged from a neurological taxonomy of movement disorders which distinguished between ‘elementary’ motor syndromes, such as paresis, ataxia, or akinesia, and an impairment of hierarchically higher aspects of motor planning or programming, i.e., ideomotor apraxia (Darley et al., 1975). His introduction of the term apraxia of speech was guided by phenomenological similarities of the speech disorder with limb apraxia, such as its attribution to left-hemisphere

Correspondence to: Wolfram Ziegler, PhD, Entwicklungsgruppe Klinische Neuropsychologie, Dachauer Strasse 164, D 80992. Mu¨nchen, Germany. E-mail: [email protected], Phone: þ49-89-1577474, Fax: þ49-89-156781.

270

W. ZIEGLER

damage, its error inconsistency, or the helpless appearance and groping behavior of apraxic patients who are confronted with a (speech or motor) task they are unable to perform (see Chapter 16). On clinical grounds, Darley’s taxonomic distinction between the dysarthrias and apraxia of speech stood the test of time, since in many clinical respects, including therapeutic approaches, dysarthric patients are fundamentally different from patients with apraxia of speech.

13.2. Definition A definition relating apraxia of speech to theories of spoken language production postulates that it is an impairment of the phonetic encoding of words and sentences. Accordingly, apraxic speakers have (a) a preserved knowledge of the phonological form of the words they intend to produce (i.e., ‘how the words sound’), and (b) no significant paresis, ataxia, akinesia, or other motor execution problem which would prevent them from performing the required speech movements. Instead, their problem is to transform the more abstract representations of word forms into the motor commands that guide the articulators, or, in the terms used by Darley, to program the positioning of speech organs and the sequencing of articulations (Darley, 1968; Code, 1998). This definition suffers from the drawback that it relies on model-based terms, such as phonetic encoding or motor programming, whose semantics is not sufficiently clear to make the definition clinically useful. Instead, an operational definition of the disorder would focus on the most salient symptoms of apraxia of speech, i.e., disfluent, groping, and effortful speech with phonetic distortions and phonemic paraphasias, and a frequent occurrence of false starts and restarts (see 13.3). Effortful and phonetically distorted speech are considered suggestive of the motor nature of the disorder, the presence of silent groping movements and of self-initiated corrections indicates that the patient struggles for the realization of some stable phonological target he/she has in mind, and the fact that the symptoms are variable and inconsistent is taken as evidence against more elementary, dysarthric pathomechanisms, such as paresis, ataxia, akinesia, dyskinesia/dystonia, etc. However, these symptoms are far from unequivocal and clinicians do not always agree on their presence or absence, which often creates uncertainty in the differential diagnosis of apraxia of speech vs. aphasic phonological impairment or vs. dysarthria. Within the ICF classification system of the World Health Organization (2005), apraxia of speech is listed among the disturbances of ‘specific mental functions of sequencing and coordinating complex, purposeful movements’ (World Health Organization, 2005, b176).

13.3. Clinical presentation Patients with apraxia of speech may present with a broad variety of clinical signs, depending on the severity of their speech impairment and the pattern of accompanying aphasic symptoms. In its most severe form, apraxia of speech may result in a total inability to voluntarily produce even a single word, syllable, or speech sound (apraxic mutism). In stroke patients this stage is frequently confined to the first few hours or days postonset and is then followed by a transition into the characteristic pattern of apraxic speech (see below). In rare cases, apraxic mutism after a left hemisphere lesion may extend over several weeks (Lecours and Lhermitte, 1976; David and Bone, 1984). Persisting mutism combined with oral–facial apraxia was observed in patients with bilateral opercular lesions (Groswasser et al., 1988; Pineda and Ardila, 1992). Since the complete loss of speech in these cases was not ascribable to paresis of the speech musculature or to severe linguistic impairment, a speech-apraxic mechanism has been considered as the underlying cause. In less severe cases, patients with apraxia of speech are able to pronounce isolated syllables or words or even short phrases. They produce many speech errors, both of a phonemic and a phonetic type (see Table 13.1). The term phonemic error refers to substitutions, omissions, or additions of speech sounds, such as *gog for dog, *cocodie for crocodile, or *clat for cat. (An asterisk indicates that the linguistic form that follows is not a real word.) Typically, these aberrations sound well-articulated, as if the patient had erroneously created a nonexistent string of sounds, but pronounced the wrong form smoothly and adequately. Most often the resulting nonword is phonemically close to the intended word, and substituted phonemes share many features with their target phonemes; e.g., if cow is pronounced as *gow, the target phoneme /k/ and its substitute /g/ are both produced by forming a complete closure with the back of the tongue in the posterior palatal region, and they differ only by their timing of the laryngeal gesture (adduction of the vocal folds occurring earlier in /g/ than in /k/). Another frequent type of phonemic error is deletion of a consonant in consonant clusters, such as *fog for frog or *tone for stone, most often at the onset of a word or a syllable (Aichert and Ziegler, 2004). The mechanism causing these errors has usually been described as articulatory simplification (Romani and Calabrese, 1998). The term phonetic distortion, on the other hand, refers to an error type in which the integrity and wellformedness of speech sounds is destroyed (Table 13.1). For instance, a phonetically distorted /f/ neither sounds like a proper /f/, nor like a /v/ or /p/ or like any other

APRAXIA OF SPEECH

271

Table 13.1 The symptoms of AOS Segmental impairment: Errors concerning the segments (phonemes) of words Phonemic paraphasias Phonetic distortions categorical aberration from target phoneme gradual aberration from target phoneme phonemes sound well-articulated phonemes sound awkward, ill-formed Error variability Errors are inconsistent: a patient may produce the same sound accurately or inaccurately, and multiple inaccurate productions may have different qualities. Islands of unimpaired speech: Even severely impaired speakers may at times produce entirely accurate words or phrases. Prosodic impairment: Disturbances concerning the flow and melody of speech Speech is hesitant and halting, with many pauses between syllables or words, with false starts, repairs, and repetitive attempts at initiating speech. Pauses are often accompanied by prolonged articulatory groping. Disfluent articulation corrupts the regular rhythm and melody of speech.

consonant of the patient’s native language. Likewise, transitions between phonemes or syllables may sound awkward, as if the patient had lost the ability of smoothly moving from one articulatory position to the next. The fact that phonetically distorted sounds no longer pertain to the phoneme inventory of the patient’s native language is taken as evidence for an obvious motor basis of phonetic distortions. On closer inspection of the error patterns of apraxic speakers, a structural relationship can often be observed between gradual (phonetic) and categorical (phonemic) errors, which suggests that the two types of errors may result from a common motor mechanism (Ziegler and Cramon, 1986; Ziegler, 1987; Table 13.2). For instance, phonetic denasalizations of nasal consonants (i.e., /m/ or /n/ sound as if the nasal passage were obstructed) often go together with a frequent occurrence of nasal-to-oral phoneme substitutions (i.e., /m/, /n/ or /ng/ are substituted by /b/, /d/ or /g/), suggesting a problem with the interplay between velar adjustments and the articulations of the lips and the tongue in both error types. Alternatively, audible over-aspiration of voiceless plosives (e.g., /t/ sounds like /thhh/) often cooccurs with a prominence of voiced-voiceless paraphasias (substitutions of /b/by /p/, /d/ by /t/, or /g/ by /k/), indicating an impairment of the appropriate timing of laryngeal adductory and abductory movements relative to supralaryngeal articulations as the mechanism underlying both gradual and categorical voicing aberrations. Table 13.2 lists more examples to illustrate similar relationships between phonetic and phonemic errors. However, it must be admitted that more complex phonemic errors may also occur in apraxia of speech, which cannot be traced back straightforwardly to such simple motor mechanisms. A salient property of apraxic speech is that the pattern of phonetic impairment lacks any apparent consistency. As an example, the consonant /s/ may be

produced correctly in one instance, sound like a voiced /z/ in another instance, hover somewhere between /s/ and /sh/ on a third occasion, or even be completely unidentifiable in a fourth incidence. Or, the transitions from /s/ to /a/ to /m/ in the word some may sound fluent and smooth on one occasion, but laborious and clumsy on the next. The variability of the error pattern may even go so far that severely distorted stretches of speech are sometimes interspersed by ‘islands’ of entirely fluent and well-formed articulation. During administration of a word repetition test, for instance, a patient who is virtually unable to pronounce any of the test tokens, may unexpectedly come out with a fluent and completely intelligible comment or with a clearly articulated expression of her frustration (Table 13.1). The phonetic and phonemic aberrations in apraxic speech are usually overarched by a halting and disfluent manner of speaking. Patients often require several attempts at initiating an utterance, they may produce off-target onsets and re-starts and may separate the syllables of a word by pauses or by vocalic intrusions (Table 13.1). Hesitations are often accompanied by a visible groping or by sounds resulting from searching movements of the larynx and the articulatory organs (Hoole et al., 1997). These events interrupt the flow of speech in a way that orderly rhythmical and intonational patterns are no longer recognizable. In less severe cases speech may be reasonably fluent and only retain some scanning, syllable-by-syllable rhythm with occasional phonemic and phonetic errors (McNeil et al., 1997; Croot, 2002).

13.4. Etiologies The primary cause of apraxic speech impairment is left hemisphere stroke. The great majority of patients with apraxia of speech have suffered from infarction or hemorrhage of the left middle cerebral artery (central cortical

272

W. ZIEGLER

Table 13.2 Phonetic vs. phonemic errors: examples of common articulatory-based error mechanisms Phonetic distortions*

Phonemic paraphasias

Oral–nasal distinction (elevation vs. lowering of the soft palate) ball ! mball, bmall, ~ball (b sounds partly or completely nasalized, but still sounds different from m) insufficient, ill-timed, or missing elevation movement of the soft palate nail ! dnail, ndail, ~dail (n sounds partly or completely de-nasalized, but still sounds different from d) insufficient, ill-timed, or missing lowering movement of the soft palate Voiced–voiceless distinction (adduction vs. abduction of vocal folds) dull ! dull _ insufficiently voiced, but still sounds different from t) (d sounds insufficient adduction or premature abduction of glottis tail ! dail _ insufficiently unvoiced, but still sounds different from d) (t sounds insufficient abduction or premature adduction of glottis

ball ! mall nail ! dail

dull ! tull tail ! dail

*While phonemic paraphasias can be transcribed orthographically, a formal description of phonetic distortions requires phonetic transcription symbols. Here, a simplified transcription style was chosen for the sake of readability.

branch) and its perforating arteries, or of the left lateral lenticulostriate arteries. A few cases of apraxia of speech after right hemisphere strokes have also been reported, both in right-handers (‘crossed apraxia of speech’; Delreux et al., 1989; Balasubramanian and Max, 2004) and in left-handed persons (Tanji et al., 2001). Other etiologies can also cause apraxia of speech, e.g., traumatic brain injury (Pellat et al., 1991), hematoma caused by arteriovenous malformation (Ruff and Arbit, 1981), or brain tumor (Mori et al., 1989). Moreover, apraxia of speech may be among the initial symptoms of primary progressive aphasia (Nestor et al., 2003) and of frontal cortical atrophy syndromes (Broussolle et al., 1996), including Pick’s disease (Sakurai et al., 1998).

13.5. Localization Broca’s attempt at localizing the ‘faculty of articulate language’ has often been considered as the birth of modern neuropsychology. His examinations of the brains of several patients with aphemia had led him to postulate that (a) speech, like other skilled motor activities, is in most people controlled by the left hemisphere (Broca, 1865), and (b) the seat of this faculty is the posterior part of the (left) inferior frontal convolution—the region which later was named after Broca (Broca, 1861). Since then, the classic model has repeatedly been challenged, mainly by case studies demonstrating that circumscribed lesions to Broca’s area did not result in persisting speech problems (Alexander et al., 1990). For instance, a number of patients were reported who, after complete ablation of the posterior part of left inferior frontal cortex, had no or

virtually no speech or language impairment (see Hecaen and Consoli (1973), for a review). It was also noted that the patients originally described by Broca had large lesions which included far more than the posterior part of the inferior frontal convolution (Mohr et al., 1978). Basing on such considerations, several alternative models have been proposed during the course of time. 13.5.1. Subcortical white matter In Dejerine’s view, the pure motor form of Broca’s aphemia, which he had termed subcortical motor aphasia, resulted from lesions to fibers connecting Broca’s area with the motor centers in the brainstem (Dejerine, 1891) (‘. . .rupture des fibres qui relient la circonvolution de Broca aux noyaux bulbaires. . .’ (Dejerine 1891, p. 161)). Dejerine’s interpretation nowadays is at odds with the widely accepted view that the cortico-bulbar projections implicated in speaking are organized bilaterally and that one-sided lesions to this system can be compensated for within short time (Muellbacher, Artner, and Mamoli, 1999). However, the hypothesis of a subcortical mechanism has been upheld until very recently. For instance, in their review of 13 cases from the literature and their presentation of four new cases, Schiff et al. (1983) identified the white matter deep to the inferior motor strip and the opercular part of the inferior frontal gyrus, including the anterior limb of the internal capsule of the dominant hemisphere, among the regions responsible for the ‘organization of simultaneous and sequential motor actions into well-articulated speech’ (p. 726). In a

APRAXIA OF SPEECH comprehensive analysis of the subcortical pathways implicated in severe non-fluency in aphasia, Naeser, Palumbo, Helm-Estabrooks, Stiassny-Eder, and Albert (1989) postulated a significant role of two distinct subcortical regions in the genesis of persisting articulatory impairment, i.e., (1) the ‘medial subcallosal fasciculus’ area, located deep to Broca’s area, and (2) the middle portion of the periventricular white matter area, located deep to the mouth and face area of primary sensory-motor cortex, both in the left hemisphere. In a recent fMRI-study of four patients with severe persisting nonfluent speech, presumably including verbal apraxia, Naeser et al. (2005) suggested that white matter lesions in these areas may be responsible for a transcallosal disinhibition of right motor cortical and right SMA activity causing severe nonfluency and speech motor problems. The idea that deep-reaching lesions may prevent recovery of speech functions through transcallosal (as well as intrahemispheric) mechanisms, however, is much older, and originally goes back to Kleist (for a discussion cf. Mohr et al., 1978; Ruff and Arbit, 1981). 13.5.2. The ‘lenticular zone’ Pierre Marie, after a re-examination of Broca’s most prominent cases and a review of several new cases, denied that the left posterior inferior frontal gyrus plays any specific role in language. Marie ascribed the syndrome he called anarthria to lesions within the ‘lenticular zone,’ i.e., a rectangular area, extending—on a horizontal brain section—from the anterior to the posterior aspect of the insula and comprising the insular cortex and the subcortical structures deep to it (extreme capsule and claustrum, caudate and lenticular nuclei), in either the left or the right hemisphere (Alajouanine et al., 1939; Lecours and Lhermitte, 1976). This hypothesis, which—at least in its most general form— was disproved by numerous observations reported later on (Liepmann, 1907), is no longer valid. However, the ‘lenticular zone’ in the left hemisphere includes brain structures which are still considered relevant in apraxia of speech today, i.e., the white matter areas discussed above, the anterior insular region (see 13.5.4), or, according to a small number of single case reports, the basal ganglia (Peach and Tonkovich, 2004). 13.5.3. Left inferior motor cortex In several case studies, lesions to the inferior portion of the left precentral gyrus, i.e., the face, mouth, and larynx region of left primary motor cortex, were mentioned as a potential cause of apraxia of speech (Lecours and Lhermitte, 1976; Tonkonogy and Goodglass, 1981; Schiff

273

et al., 1983, cases 1, 2; Kushner et al., 1987; Mori et al., 1989; LeRoux et al., 1991; Tanji et al., 2001). According to the classical model, left motor cortical lesions should result in a unilateral upper motor neuron syndrome (Urban et al., 2001). Consequently, Bay (1957) suggested that the syndrome (which he termed cortical dysarthria) results from a spastic movement disorder. Yet, the symptoms characterizing apraxia of speech are not explainable by the mechanisms underlying the spastic syndrome, i.e., increased tone, reduced force, and reduced dexterity. Moreover, the severity and persistence of the disorder in many apraxic speakers cannot be reconciled with the fact that important parts of the corticobulbar system are organized bilaterally and that unilateral lesions to this system can usually be compensated for within a few days or weeks (Muellbacher et al., 1999). In a different view, the left inferior precentral region (together with the opercular portion of the inferior frontal gyrus and underlying white matter) is considered part of a specialized motor network which integrates ‘simultaneous and sequential motor actions into wellarticulated speech’ (Schiff et al., 1983). It is known that prerolandic motor cortical regions are functionally reorganized during long-term practice of specific motor skills (Karni et al., 1995; Elbert et al., 1995; Ungerleider et al., 2002). Since adult speech is the result of extensive long-term motor learning, such mechanisms may account for a specific role of the left inferior motor cortex and the regions immediately anterior to it in speaking. Destruction of this network would produce a complex disturbance of the interplay between articulatory gestures rather than merely a hemiparesis of the oral and facial muscles of the right side. 13.5.4. Left anterior insular cortex Left insular cortex, which is part of P. Marie’s ‘lenticular zone’ (see above), has often been mentioned as a potential locus of speech motor impairments (Mohr et al., 1978; Shuren et al., 1995). A comprehensive lesion study was conducted by Dronkers (1996), who compared overlaps of CT- or MRI-documented focal lesions of 25 patients with apraxia of speech (AOS) with those of 19 patients who were not apraxic. All patients had suffered single left-hemisphere infarcts and were more than one year post-onset. The lesions of the AOS patients overlapped in a small region within the left precentral gyrus of the insula, and, at the same time, this region was spared in the overlap of the 19 non-apraxic patients. In the years following publication of Dronkers’ investigation several single case studies of patients with apraxia of speech after left anterior insular lesions were reported (Kumabe et al., 1998; Nagao et al., 1999;

274

W. ZIEGLER

Duffau et al., 2001; Nestor et al., 2003). More recently, Dronkers and Ogar (2004) extended their findings by reporting on 23 patients with left anterior insular lesions, all of whom had apraxia of speech. A role of left anterior insular cortex in articulation was also corroborated by functional imaging studies (Wise et al., 1999; Riecker et al., 2000) and by an MEG-study (Kuriki et al., 1999). However, the fMRI data reported by Riecker et al. (2000) suggested that the implication of left anterior insular cortex is confined to the actual execution of speech movements (‘overt performance’) and is absent during covert speech. The conclusion that AOS might result from a lesion to this area is not compatible with the view that the apraxic speech impairment extends to covert articulation as well, especially that it also abolishes the covert rehearsal processes involved in verbal short-term memory tasks (Waters et al., 1992; see 13.8.3). 13.5.5. Broca’s area, revisited More recently the pendulum swung back again towards Broca’s original model. Hillis et al. (2004) studied 80 patients with left hemisphere, non-lacunar strokes, 40 with and 40 without insular damage. One crucial aspect of their approach was that they examined patients with acute infarcts, i.e., within 24 hours after stroke, with the aim of identifying patients with transient speech impairments after small infarcts—a group which may have gone unnoticed in lesion studies of patients with chronic AOS. A second specialty of this study was that Hillis et al. (2004) used diffusion- and perfusion-weighted MRI methods, with the hope of identifying—over and above the structurally lesioned brain regions—those areas which may be dysfunctional as a consequence of hypoperfusion. No association was found between the occurrence of AOS and left anterior insular lesions in the large patient sample of this investigation. However, there was a statistically significant association between the presence of AOS and a hypoperfusion or structural lesion of Broca’s area, as well as a strong association between the absence of AOS and the absence of infarcts or hypoperfusion in Broca’s area. Hillis et al. (2004) speculated that the association of AOS with anterior insular damage reported by Dronkers (1996)—though statistically reliable—was not causative, but was rather due to the fact that chronic apraxia of speech usually results from large MCA infarctions, and that—by virtue of the distribution of cerebral blood flow—the insula is very likely within the overlap region of large MCA strokes. Basing on the presumed validity of their combined diffusion/perfusion-weighted imaging method and their inclusion of patients with and without AOS early after onset,

Hillis et al. (2004) claimed that the left posterior inferior frontal gyrus is crucially involved in articulation. Their findings were consistent with the results of three earlier PET experiments examining oral reading and word repetition in normal subjects (Price et al., 2003), in which speech-related activation was found in Broca’s area, but not in the anterior insula. The results of a PET study of patients with recovered apraxia of speech suggested that it is especially the posterior portion of the left pars opercularis which is responsible for motor control aspects of speech production (Blank et al., 2003). Indirect neurobiological evidence for a role of Broca’s area in speech motor control has only recently been presented by Petrides et al. (2005). These authors showed that, in macaque monkeys, the cortical region lying anterior to the ventral part of premotor cortical area 6 is cytoarchitectonically comparable to dysgranular human cortical area 44, and that the cytoarchitectonics of its bordering cortical regions is comparable, rostrally, to human cortical area 45 (granular) and, caudally, to human cortical area 6V (agranular). Most importantly, intracortical microstimulation within this area elicited complex oral–facial, lingual, and respiratory movements, suggesting that BA 44 might have evolved as an area exercising high-level control over the motor system involved in spoken language communication. 13.5.6. The localization of apraxia of speech: tentative conclusions The inconsistency of the neuroanatomic findings related to apraxia of speech may be attributable to several sources, such as (1) divergent taxonomies or inconsistent definitions of the speech impairment in the reported cases (Mohr et al., 1978), (2) individual variability in gyral patterning and a lacking reliability of sulcal contours as cytoarchitectonic landmarks in left anterior perisylvian cortex (Amunts et al., 1999), or (3) individual variability in structure–function relationships in this region (Hillis et al., 2004). Despite these uncertainties, a few tentative conclusions can be drawn. It is safe to say that AOS is a syndrome of the dominant hemisphere and that it occurs after lesions to the anterior perisylvian region. Within this region, parts of Broca’s area and eventually also its caudally neighboring primary motor cortical region seem to play an important role, at least initially. A causative role of left anterior insular cortex still waits to be proven. One might speculate that the process of speech motor learning, which extends over more than the first decade of our life, creates a large, left-lateralized representation area dedicated to the planning and/or programming of speech movements. This region extends anteriorly from the

APRAXIA OF SPEECH face/mouth/larynx region of left rolandic motor cortex to premotor cortex and potentially also includes insular cortex. The different parts of this network may subserve specific functions in speech motor control, and lesions to different subunits may create subtypes of speech impairment which we have so far been unable to differentiate. Small cortical lesions alone are probably not sufficient to cause severe, persisting AOS. Involvement of a larger part of the network or of communicating fibers may aggravate the problem and prevent a functional reorganization of articulation, eventually through mechanisms of transcallosal disinhibition.

13.6. Differential diagnosis 13.6.1. Apraxia of speech vs. dysarthria The dysarthrias comprise speech disorders whose underlying pathomechanisms correspond to one of the neuromotor pathologies known from limb motor control, such as paresis, akinesia, rigidity, ataxia, dyskinesia/dystonia, etc. Accordingly, the speech patterns of dysarthric patients are characterized by predictable and virtually constant disturbances of speech breathing, phonation, and articulation, causing symptoms such as increased frequency of inspirations, deviant voice quality, altered pitch or loudness, undershooting articulation, hypernasality, reduced articulation rate, etc. Unlike apraxic speakers with their variable articulatory skills, patients with moderate or severe dysarthria constantly demonstrate the same quality of their phonetic distortions, and their output is never entirely symptom-free. Moreover, as a consequence of their constant symptom pattern, dysarthric patients rarely make attempts at correcting themselves or repairing their vocal or articulatory deviations. Hence, they do not show disfluencies and initiation problems related to self-initiated repairs—a symptom which is typical of apraxic speech. Another important clinical criterion is that persisting dysarthric conditions of a significant degree have rarely been observed after unilateral hemispheric lesions (Urban et al., 2001). 13.6.2. Apraxic mutism vs. akinetic or paralytic mutism In the absence of any verbal utterances, the apraxic nature of a mutistic state cannot be diagnosed with certainty. Mutism may also occur as a sign of complete akinesia, e.g., after mesodiencephalic or after left or bilateral medial–frontal lesions (Alexander, 2001; Nagaratnam et al., 2004), where it is seen as a consequence of reduced cortical ‘arousal’ or as an impaired activation of the speech motor system (Choudhari, 2004). A behavioral sign which can be useful to distinguish apraxic from akinetic

275

mutism is that the former is usually associated with effortful struggling and a visible groping for articulation, whereas patients with akinetic mutism often make no forceful attempts at speaking. Recovery from akinetic mutism after left ACA-infarction is often characterized by transient hypophonia and hypokinetic articulations, sometimes also by stuttering, and by transcortical motor aphasia (Kumral et al., 2002). Mutism may also result from a complete bilateral paralysis of the speech muscles, e.g., in patients with a Foix–Chavany–Marie or bilateral anterior operculum syndrome, but this state is distinguishable from apraxic mutism by visible signs of increased tone or a generalized paresis of the oral and facial muscles. The fullblown syndrome of pseudobulbar mutism is often also accompanied by pathologic laughter or crying (Mao et al., 1989). 13.6.3. Apraxia of speech vs. phonological impairment The distinction between apraxia of speech and phonological impairment (as it is seen, for instance, in conduction aphasia) may cause considerable problems in clinical diagnosis. Confusions will usually not occur in patients who present with a fluent phonemic jargon, i.e., who produce severely distorted, often unrecognizable word forms and create new words (‘neologisms’), and whose output nonetheless sounds well articulated and comes out fluently. Phonemic jargon, which can be part of a severe Wernicke’s aphasia, has no similarities with the clinical pattern of apraxia of speech (see Chapter 14). Other aphasic patients may produce fewer phonemic errors and generate word forms which are much closer to their targets. When articulation in these patients sounds accurate and when they speak fluently, without demonstrating the typical groping and self-correcting behavior of apraxic speakers, they are diagnosed as phonologically impaired. Phonological impairment may be part of any aphasic syndrome, and it is the major symptom of conduction aphasia (see Chapter 14). Confusion with apraxia of speech may result from the fact that disfluencies resembling those seen in apraxic speakers may also occur in patients with aphasic–phonological problems, where they indicate word finding difficulties or a phonological ‘conduite d’approche’—behavior rather than a speech motor problem. It has been speculated that phonological impairment afflicts word and syllable endings more than word and syllable onsets, whereas the reverse is true for apraxia of speech (Aichert and Ziegler, 2004), but there is still too little empirical evidence for such a distinction.

276

W. ZIEGLER

According to a more traditional criterion, patients with apraxia of speech ‘know what they want to say and how it should sound.’ Despite their speech impairment they should therefore be able to resolve silent meta-phonological tasks, e.g., recognize rhymes, estimate word lengths, or dissect syllables or words into their phonemes. However, in clinical practice this is not a safe diagnostic indicator (see 13.8.3). Another criterion which has often been mentioned in the traditional literature is based on the claim that patients with phonological impairment, in addition to their speech problem, also have a writing impairment, whereas patients with ‘pure’ apraxia of speech have preserved writing. As a matter of fact, in some of the AOS patients reported in the literature writing was considerably better than speech, or was even completely preserved (e.g., Lecours and Lhermitte, 1976). However, brain lesions causing apraxia of speech may, by virtue of their size and location, also destroy the circuitries specific to writing, hence impaired writing can certainly co-occur with apraxia of speech. Moreover, since written language can be produced along multiple separate routes, preserved writing is not necessarily incompatible with phonological impairment (e.g., Mohr et al., 1978; Ellis et al., 1983). 13.6.4. Other related syndromes Foreign accent syndrome (FAS) is a rare condition of acute onset, mostly after stroke, in which a patient speaks with an audible foreign accent, as if she/he were non-native. Often, the accent cannot unambiguously be assigned to some specific foreign language (Christoph et al., 2004), but in some of the reports listeners agreed in saying that the accent was French, German, Irish, etc. The first case description was of a young Czech butcher who, after a stroke, sounded as if he were Polish (Pick, 1919). A further prominent case was a Norwegian woman who, during a German bomb attack in World War II, suffered traumatic brain injury and developed a German accent (Monrad-Krohn, 1947). Many of the patients reported in the literature have never been exposed to the particular language their accent was reminiscent of, or even to any other foreign language earlier in their life, while in others a language learned during childhood reappeared as a foreign accent (e.g., Roth et al., 1997). The syndrome is distinct from apraxia of speech in that FAS patients do not primarily make phonemic or phonetic errors, except for the relatively constant deviations characterizing their accent. These deviations, which have sometimes been characterized as dysarthric, afflict the segmental aspects and the prosody of the patients’ speech output in a specific and constant

manner, thereby causing the impression of a foreign accent (Pick, 1919; Ingram et al., 1992; Kurowski et al., 1996). Mild aphasic impairment such as wordfinding difficulties or agrammatism may also contribute to this impression (Roth et al., 1997; Christoph et al., 2004). In several cases, FAS occurred as a transient or a persisting state during recovery from a global aphasia or a Broca’s aphasia, or from muteness (e.g., MonradKrohn, 1947; Avila et al., 2004). Reported etiologies are ischemic or hemorrhagic stroke (Roth et al., 1997; Fridriksson et al., 2005), traumatic brain injury (Moonis et al., 1996; Lippert-Gruener et al., 2005), or multiple sclerosis (Bakker et al., 2004). FAS may also be associated with schizophrenic psychosis (Reeves and Norton, 2001). Most cases had left hemisphere lesions, either of the inferior perirolandic cortex and its underlying white matter (Graff-Radford et al., 1986; Blumstein et al., 1987; Takayama et al., 1993; Christoph et al., 2004; Avila et al., 2004) or of the basal ganglia (Kurowski et al., 1996; Gurd et al., 2001; Fridriksson et al., 2005). Callosal infarction was also reported as the cause of a foreign accent syndrome (Hall et al., 2003). Acquired neurogenic stuttering (ANS) denotes a speech disorder, secondary to some acquired neurologic condition, which is predominantly characterized by disfluent articulation, most typically with frequent involuntary repetitions of phonemes or syllables rather than with prolongations or cessations of sound. The ANS syndrome can be distinguished from apraxia of speech by the absence of visible groping behavior and by the observation that the disfluencies seen in ANS, unlike those occurring in AOS, are not related to phonemic or phonetic errors or to the self-initiated repairs of such errors. The major etiologic condition leading to ANS is stroke (Grant et al., 1999), but stuttering can also be caused by traumatic brain injury (Ludlow et al., 1987) or by Parkinson’s disease (Hertrich et al., 1993); it may occur with epileptic seizures (Michel et al., 2004) and during migraine attacks (Perino et al., 2000), and it has been observed after application of pharmacological agents (Movsessian, 2005). ANS usually occurs in patients with left-hemisphere lesions, with or without concomitant aphasia (Helm et al., 1978), but has also been described in right-handers with right hemisphere infarctions (Fleet and Heilman, 1985; Ardila and Lopez, 1986), or after bilateral lesions (Helm et al., 1978; Balasubramanian et al., 2003). A great variety of different intrahemispheric lesion sites have been suggested as being responsible for ANS, such as left anterior medial cortex (Ackermann et al., 1996; Ziegler et al., 1997; Chung et al., 2004), left parietal cortex (Turgut et al., 2002), the basal ganglia and thalamus (Ludlow et al., 1987; Sorokeret al., 1990; Andy and Bhatnagar, 1991;

APRAXIA OF SPEECH 1992; Carluer et al., 2000; Ciabarra et al., 2000; Van Borsel et al., 2003), or the corpus callosum (Hamano et al., 2005). It is not sufficiently clear if the observations of ANS in all these cases pertain to a unique syndrome, or if they constitute different pathological conditions. HelmEstabrooks et al. (1986) explained stuttering by a lack of unilateral dominance in the control of the speech musculature, Soroker et al. (1990) by a disturbance of the cross-talk between hemispheres. The fact that a remarkable number of cases with subcortical lesions were observed may suggest that the striatal–thalamocortical motor circuit plays a role in the genesis of acquired neurogenic stuttering. An important diagnostic detail is if a patient has already been stuttering during childhood, since in this case the symptom may be explainable by a decompensation of a developmental disorder which had been compensated for successfully until the brain lesion occurred (Mouradian et al., 2000). Developmental apraxia of speech (DAS) occurs during speech development in early childhood. It resembles AOS in that it is characterized by a corruption of the phonological make-up of spoken words, with distorted articulation, phonemic errors, and severe disfluency (Shriberg et al., 1997). A comparison between AOS and DAS is hampered by the problem that DAS interferes with the early motor learning stage of speech acquisition, with the consequence that a normal development of speech perception and of phonological, lexical, or syntactic aspects of language is prevented (Maassen, 2002). A retrospective analysis of speech acquisition in children with DAS often reveals that they had delayed or reduced babbling and reduced oral motor capabilities during infancy. Hence, the contributions of auditory–perceptual, general oral motor, and speechspecific factors to the genesis of the disorder cannot easily be disentangled (Groenen et al., 1996). Although a neurogenic basis of the disorder is assumed, there are no consistent findings regarding the localization of a potentially underlying structural lesion, and in many cases neuroanatomical findings were unremarkable (Horwitz, 1984). Today, a genetic origin of DAS is hypothesized, basing on the discovery of a mutation of the FOXP2 gene in the DAS-afflicted members of a family which, over three generations, has shown a high incidence of the disorder (Vargha-Khadem et al., 2005). Variants of this mutation have meanwhile been discovered in DAS patients originating from other families (MacDermot et al., 2005). Oral–facial apraxia describes a condition in which a patient is unable to perform nonverbal movements of the facial, oral, or laryngeal muscles on imitation or on command (see Chapter 16). It is, by definition, different from apraxia of speech, since its diagnosis is tied to

277

impaired performance on nonverbal motor tasks, whereas AOS is a speech disorder (Ziegler, 2003; 2006). Most patients with apraxia of speech also have face apraxia, but the two conditions often show different clinical courses (Alajouanine and Lhermitte, 1960). Apraxic speakers who have no or a completely recovered oral–facial apraxia have repeatedly been described (Lecours and Lhermitte, 1976; Ruff and Arbit, 1981; Kushner et al., 1987; Mori et al., 1989; Tanji et al., 2001). The reverse condition, i.e., facial apraxia with preserved speech, has been reported less frequently, but it occurs as well (Alajouanine and Lhermitte, 1960; Kramer et al., 1985; Bizzozero et al., 2000). In a study of 33 patients with left intracerebral hemorrhage Maeshima et al. (1997) found no differences in speech impairment between patients with and without oral–facial apraxia.

13.7. Natural course and treatment Systematic observations of the natural course of apraxia of speech have, to my knowledge, not yet been published. Probably depending on the size and the site of the lesion (see 13.5), AOS may occur as a transient syndrome in some patients, and as a persisting, severe speech problem in others. The treatment of persisting apraxia of speech is a notorious therapeutic challenge. In clinical practice, speech therapists dispense a variety of well established treatment techniques, but there is only little empirical support for their effectiveness. In a recent Cochrane meta-analysis of non-drug interventions for apraxia of speech after stroke, no studies fulfilling the criteria of a randomized controlled trial were found (West et al., 2005). However, the results of several studies with small patient groups suggest that behavioral treatments based on speech motor exercises may lead to substantial improvements in these patients (Wambaugh, 2002; Brendel and Ziegler, in press). Pharmacological trials on patient groups characterized as ‘nonfluent aphasic’ may also be relevant to the issue of AOS treatment. Several trials have been made with bromocriptine (Gupta et al., 1995; Bragoni et al., 2000) and with amphetamine (Walker-Batson et al., 2001), though without any convincing, or even consistent, results.

13.8. Theoretical accounts 13.8.1. AOS and the task-specific nature of speech motor control One of the theoretical questions relating to apraxia of speech is whether the disorder is confined to the control

278

W. ZIEGLER

of speech movements, or if volitional oral motor control is afflicted more generally, i.e., for nonlinguistic purposes as well. If a strongly dualistic distinction between linguistic and motor processes is drawn, speaking is viewed as one out of many different activities of a multipurpose motor apparatus, and the relation of speech motor control to the linguistic domain is solely determined by the circumstance that it consumes the input provided by a linguistic (i.e., phonological) apparatus. Assuming that apraxia of speech is a motor impairment this model would predict that it is not confined to the act of speaking, but that its underlying mechanism afflicts all skilful motor actions of the involved muscles, verbal or nonverbal. Ballard et al. (2000) claimed that a co-incidence of verbal and nonverbal apraxic impairment can be demonstrated if nonverbal motor skills are examined whose motor demands are comparable to speaking. In their view, the observation that some apraxic speakers have only little or no oral–facial apraxia is ascribable to the fact that the motor tasks probed in examinations of oral apraxia are not sufficiently demanding. As mentioned above, however, there is no close relationship between oral–facial apraxia and speech impairment in patients with left hemisphere lesions (Maeshima et al., 1997), and there are also no convincing experimental data in support of such a relationship (for a review see Ziegler, 2003). The assumption of a strong dualism between linguistic and motor components of language production raises the problem of how a strictly linguistic, nonmotor system can get its information across to a strictly nonlinguistic motor processing device. Therefore, an alternative view was proposed by Liberman and Whalen (2000) in which the organization of the speech motor system is considered to be shaped significantly by the specific task it subserves, i.e., speaking. The idea that the motor system implied in speaking is not a multipurpose tool, but is specific to the production of language, is based on a number of fundamental properties distinguishing speech motor control from all other motor skills of the facial–oral–laryngeal motor apparatus (Ziegler, 2003). Two of them are theoretically most important, namely (1) speech movements are organized within an acoustic reference frame, and (2) speaking is an outstandingly skilful motor activity which is practiced extensively throughout lifetime. With respect to the idea that speech movements, unlike mouth movements elicited in imitation or visual tracking tasks, are guided by an auditory–acoustic reference frame was already contained in Wernicke’s and Lichtheim’s theory, which assumed that the motor images of speaking are closely connected to the acoustic images of words (Lichtheim, 1885). Liepmann (1913)

emphasized that the role played by an ‘acoustic scheme’ in speaking is similar to that of an ‘optical scheme’ in hand movements. Meanwhile, this thinking is formulated rather explicitly in computational phonetic models of speech production and is supported by a considerable amount of experimental evidence (Guenther et al., 1998). A neurophysiological basis of the close integration of auditory–sensory and articulatory–motor processes is seen in the ‘dorsal stream’ of the perisylvian language area, a structure linking auditory cortical regions in the superior temporal lobe with inferior parietal cortex and with premotor regions in the posterior inferior frontal cortex of the left hemisphere (Hickok et al., 2000; Hickok and Poeppel, 2004; Watkins and Paus, 2004). The neurons in the anterior target region of the dorsal stream can be considered to specifically subserve motor functions which are guided by auditory linguistic goals. They may therefore be specific to the motor task of speaking, and destruction of these neuron pools may impair speech, but leave other oral motor functions unimpaired. With respect to the link between auditory and motor regions of left perisylvian cortex, this also forms the basis of vocal learning in children. The capacity to imitate acoustic patterns by vocal tract movements is specific to humans and to very few other species, e.g., songbirds, but is absent in nonhuman primates (Fitch, 2000). Imitation of the vocal patterns of adult speech starts early in infancy (Kuhl and Meltzoff, 1996), and the emerging speech movements are exercised extensively throughout childhood and early adolescence. It is known from other motor domains, e.g., string instrument playing (Elbert et al., 1995) or juggling (Draganski et al., 2004), that such learning processes lead to alterations in the size and the organization of cortical areas implied in motor control. An extensive amount of literature has meanwhile been accumulated which demonstrates that motor practice has a structural substrate and that one and the same movement may have different neural representations, depending on whether it is part of a learned or an unlearned motor activity (Ungerleider et al., 2002). Although the evidence relating to learning-induced brain plasticity was obtained from studies of hand motor control and is therefore not directly related to the vocal motor system, it suggests by analogy that speech motor control in adults must be based on a highly specific neural organization and can be impaired differentially. Hence, it appears plausible to assume that the pathomechanism underlying apraxia of speech may leave other face and mouth movements unimpaired (Ziegler, 2006). The bifurcation of the developmental course of verbal and nonverbal motor skills occurs rather early in childhood (Moore, 2004). Nonetheless, this does not

APRAXIA OF SPEECH necessarily entail that a neural network specifically devoted to speech motor control exists from birth on. On the contrary, data from patients with genetically based developmental apraxia of speech suggest that mutation of a specific gene, FOXP2, results in an abnormal development of volitional oral motor control more generally (Alcock et al., 2000) and that, probably on the basis of this, a development of normal speech is prevented as well. Hence, the acquisition of speech motor skills presumably depends on the genetic endowments underlying general oral motor capacities and vocal learning potentials. 13.8.2. Psycholinguistic models of AOS and the units of phonetic encoding Levelt et al. (1999) proposed a model of spoken language production which, on a coarse-grained scale, distinguishes between a conceptual level comprising prelinguistic, semantic, and syntactic aspects of the formulation of a verbal message, and a motor level comprising the different processing stages by which the phonological form of words and sentences is retrieved and transformed into motor commands (Fig. 13.1; see Levelt (2000) for this particular view). On an early stage

Fig. 13.1. Left: organization of spoken language production at an early stage of language development. Each concept is associated with a holistic speech motor pattern, e.g., the concept ANIMAL with the articulatory gestures for ‘dog.’ Right: tripartite model of the phonological–motor component in adults: phonological encoding (unfilled), phonetic encoding (shadowed), and motor execution (hatched). After Levelt (1998; 2000).

279

of language acquisition, one-to-one relationships exist between a small number of concepts in the child’s repertoire, on the one hand, and an equally small number of holistic motor patterns to articulate them, on the other. When, in a later developmental stage, the child’s lexicon undergoes a dramatic ‘spurt,’ this principle can no longer be maintained, and the speech motor system is reorganized by fractionating the holistic motor patterns of words into smaller, sublexical building blocks (Levelt, 1998). When a word is articulated, its motor program must be assembled from the precompiled motor programs pertaining to these smaller bits. Such a generative principle allows, among other things, for a fast acquisition of new words and for a flexible adaptation of spoken words to their environment. Levelt’s theory postulates that, in the mature system, the primitives of speech motor programs are of the size of syllables (Levelt et al., 1999; Cholin et al., 2006). Most languages typically consist of several thousands of syllables, and a relatively small proportion of them suffice to generate the major part of the lexical repertoire of a language (e. g., in English and German, less than 200 syllables make up more than 70% of the vocabulary used in everyday communication). Since these high-frequency syllables are used over and over again during a lifetime, the Levelt model assumes that they attain the status of precompiled motor routines which are stored in a repository of motor programs. During speaking these routines must be retrieved and buffered sequentially while they are being articulated (Fig. 13.1). If, in the case of low-frequency syllables, no ready-made motor program exists, a syllabic program must be assembled from smaller, sub-syllabic units (e.g., phonemes). The store of motor programs, the process of their retrieval, and their short-term buffering are subsumed under the term phonetic encoding (Cholin et al., 2006). Long-term storage of the motor patterns of words in a word form lexicon is, in Levelt’s theory, based on more abstract representations, with phonemes as their basic underlying units. Phonological representations of words provide a link between sensory (auditory) and motor (articulatory) processes, and their specifications are sufficiently abstract to allow for diverse morphological adaptations, for gesturally different, but functionally equivalent articulations, and for rhythmical adaptations to the specific context in which a word occurs. Several processing steps are required for these representations to hook up with the rhythmical units of speaking, i.e., the motor programs of syllables. These processing steps are referred to by the term phonological encoding (Fig. 13.1). The tripartite organization of the processes transforming words and sentences into audible speech, as sketched in Fig. 13.1, suggests allocation of the different

280

W. ZIEGLER

syndromes of impaired speech production to the three components of this model: aphasic–phonological impairment to the phonological encoding component, apraxia of speech to the phonetic encoding component, and the dysarthrias to the motor execution or articulation component (Code, 1998). Regarding apraxia of speech, Broca’s early assumption that ‘the memory of the processes required for the articulation of words’ is lost (see 13.1), translates, in this theory, into a loss of the ‘memory’ of syllabic motor routines, or of a disturbance of their retrieval or their short-term buffering. Whiteside and Varley (1998) proposed that a corruption of stored syllabic speech motor programs forces apraxic speakers to circumvent the syllable lexicon and assemble syllables from smaller programming units. Since their hypothesis was based on weak empirical grounds, Aichert and Ziegler (2004) examined whether the distorted speech output of AOS patients contains any clues indicating if syllabic units still play a role in their speech. This study revealed that syllables with particularly high frequencies of occurrence were relatively preserved in patients suffering from apraxia of speech, and that the apraxic error mechanism was constrained by the between-syllable boundaries in a word. In a further investigation of a large sample of speech materials from AOS patients it was found that these patients’ probability of failing on a word was strongly influenced by the word’s hierarchical, nonlinear architecture (Ziegler, 2005). According to this model, the motor programs

conducting the articulation of words decompose, in a tree-like architecture, into rhythmical units (i.e., metrical feet), syllables, subsyllabic units (such as syllable rhymes), and phonemes (Fig. 13.2). The error profiles of apraxic speakers reflect that their words are not disintegrated into linear sequences of phonemes. Instead, these patients obviously rely on integration mechanisms above the level of the segment. A clinical consequence of this finding is that preserved suprasegmental motor mechanisms should be exploited in the treatment of apraxic speakers (Ziegler, 2005; Brendel and Ziegler, in press). 13.8.3. AOS and ‘inner speech’ From early on, discussions about the nature of the syndrome which is now termed apraxia of speech were dominated by questions about the status of internal language. Broca had already made a clear distinction between general linguistic capabilities independent of any specific modality of expression, on the one hand, and the ‘faculty of articulate language’ on the other, by underscoring the fact that his aphemic patients had normal language comprehension and only their speech was affected. Lichtheim made this point more explicit when he distinguished between aphasic patients whose ‘inner words’ are either preserved or impaired (Lichtheim, 1885). He probed the preservation of the sound patterns of words by asking aphasic patients to

Fig. 13.2. Units of phonetic encoding/speech motor programming of the word ‘prestigious.’ Inserts (A) and (B) illustrate linear models with a sequential ordering of (A) phonemes or (B) syllables as the primitives of encoding. The nonlinear model, (C) on the opposite, parses the word’s phonetic code (Wd) into a nested sequence of hierarchically ordered subunits: prestigious decomposes into a ‘trochaic foot’-program, tigious, and a syllable-program, pres, the phonetic code of the trochaic foot is composed of two syllable-sized codes, ti and gious, each syllable consists of an onset- and a rhyme-program (e.g., pres of pr and es) and rhymes are composed of phonetic codes for a vocalic nucleus and (eventually) a consonantal coda (e.g., e and s in the syllable pres). Wd: word, Ft: foot, Sy: syllable, Rh: rhyme, On: onset, Nc: nucleus, Cd: coda. A modelling of apraxic error-data from a field of 72 words with different phonological structures and from a large number of testings (N ¼ 100) yielded significantly better results for model (C) as compared to linear models, such as (A) and (B), suggesting that apraxic speakers dispose of hierarchically nested motor representations of words. Double lines indicate representational levels where a particularly strong integration of phonetic subunits was found in apraxic speakers. Adapted from German; after Ziegler (2005).

APRAXIA OF SPEECH tap the number of syllables of an object name with their unimpaired hands (‘Lichtheim probe’). If a patient with impaired speech performed this task accurately, he concluded that only the motor images of words, but not the ‘inner words’ themselves, are lost. This was probably the first example of a task measuring ‘phonological awareness,’ i.e., the capacity of processing phonological information without overt speech. A number of different tasks have later been introduced to measure phonological awareness, such as rhyme or onset decision tasks (‘do the names of two objects rhyme/begin with the same phoneme?’) or inversion tasks (‘cap’ is converted into ‘pack’). A similar diagnostic role was always ascribed to writing, with the idea that written language production is parasitic of the phonological processing steps implied in speech, but uses a different motor system (for a discussion see Mohr et al., 1978). The concept of ‘pure anarthria’ or ‘pure apraxia of speech’ (e.g., Lecours and Lhermitte, 1976) was based on the assumption that although speech is severely impaired, the capacity to perform metaphonological tasks or to write words should be preserved. This thinking is faced with several theoretical problems. First, the tasks probing metaphonological skills, with the inclusion of writing, comprise a multitude of processing requirements which are not necessary for speaking. For instance, most of these tasks have a high working memory load, e.g., when the names of two objects must be buffered for a certain period during which their phonological information is compared for rhyming. Moreover, skills which are crucial to solve explicit phonological tasks like ‘first phoneme deletion’ (e.g., break is transformed into rake) can hardly be imagined to be part of the chain of implicit, automatized phonological encoding steps implied in speaking. As a matter of fact, it is known that performance on such tasks is strongly dependent on specific skills, some of which are more related to literacy than to speaking. In a recent study of illiterate, partly literate, and literate healthy adults, Loureiro et al. (2004) found, for instance, that the ‘readers’ included in their study differed from ‘non-readers’ on a number of metaphonological tasks, e.g., rhyme identification or initial phoneme deletion, although the two groups obviously did not differ in their speaking skills. Similarly, comparative studies of children who have acquired alphabetic or logographic writing systems have revealed that these groups differed systematically in their phonological awareness, although all of them were good speakers (Cheung et al., 2001). From the results of a brain imaging study of illiterate adults CastroCaldas et al. (1998) concluded that with the acquisition of alphabetic script a new language processing network is established which subserves metaphonological

281

functions (including nonword repetition), but there is no reason to assume that this network also influences the natural, automatized functions of the language production apparatus. As a consequence, the fact that an aphasic patient is impaired on metaphonological tasks does not allow us to infer that the phonological encoding system required for speaking is impaired as well. Second, even if one assumes that the processes implied in speaking overlap with some of the processing steps implied in writing or in rhyme decisions etc., their temporal requirements may vary considerably between these tasks. In speaking, phonological representations are necessarily short-lived, and a slowing of phonological encoding processes will have dramatic implications for the quality of a patient’s speech. Writing and metaphonological tasks, on the contrary, are based on a ‘frozen’ phonology and are performed within a larger time-frame (see Berg (2005), for the case of writing). A slowing of such processes in aphasic patients will therefore have less dramatic consequences for these tasks than it has for speaking. Hence, if writing, rhyme decisions, segmentation, etc. are relatively preserved in a patient with impaired speech, we cannot conclude with certainty that the patient’s phonology is preserved in speaking. Third, the fact that metaphonological tasks avoid overt speaking does not necessarily entail that speech motor representations are not implicated in such tasks. It has already been mentioned that most of these tasks draw on working memory resources. In the model developed by Baddeley (1998) the phonological loop of the working memory system is based on speech motor representations of words, since it uses articulatory rehearsal processes to refresh the information held in a phonological store. The inferior part of Broca’s area (BA 44/6), which is assumed to play a role in speech motor planning, is also part of the neuroanatomical system subserving verbal working memory (Paulesu et al., 1993). Hence, phonological tasks which depend on working memory resources can be infiltrated by speech motor impairments if one assumes that these impairments also afflict covert articulation. The mechanism underlying apraxia of speech is known to interfere with verbal working memory (Rochon et al., 1990; Waters et al., 1992). Therefore, tasks probing phonological awareness may also be impaired in apraxic speakers, even though no overt speech production is required. In conclusion, there is currently no clinically useful method which would allow us, on the basis of ‘inner speech tasks,’ to distinguish safely between disturbances of the phonological and the phonetic encoding stage of speech production, i.e., between phonological impairment and apraxia of speech.

282

W. ZIEGLER

References Ackermann H, Hertrich I, Ziegler W, et al. (1996). Acquired dysfluencies following infarction of the left mesiofrontal cortex. Aphasiology 10: 409–417. Aichert I, Ziegler W (2004). Syllable frequency and syllable structure in apraxia of speech. Brain Lang 88: 148–159. Alajouanine T, Lhermitte F (1960). Les troubles des activite´s expressives du langage dans l’aphasie. Leurs relations avec les apraxies. Rev Neurol (Paris) 102: 604–629. Alajouanine T, Ombredane A, Durand M (1939). Le Syndrome de De´sinte´gration Phone´tique dans l’Aphasie. Masson, Paris. Alcock KJ, Passingham RE, Watkins KE, et al. (2000). Oral dyspraxia in inherited speech and language impairment and acquired dysphasia. Brain Lang 75: 17–33. Alexander MP (2001). Chronic akinetic mutism after mesencephalic-diencephalic infarction: Remediated with dopaminergic medications. Neurorehabil Neural Repair 15: 151–156. Alexander MP, Naeser MA, Palumbo C (1990). Broca’s area aphasias: Aphasia after lesions including the frontal operculum. Neurology 40: 353–361. Amunts K, Schleicher A, Bu¨rgel U, et al. (1999). Broca’s region revisited: Cytoarchitecture and intersubject variability. J Comp Neurol 412: 319–341. Andy OJ, Bhatnagar SC (1991). Thalamic-induced stuttering (surgical observations). J Speech Hear Res 34: 796–800. Andy OJ, Bhatnagar SC (1992). Stuttering acquired from subcortical pathologies and its alleviation from thalamic perturbation. Brain Lang 42: 385–401. Ardila A, Lopez MV (1986). Severe stuttering associated with right-hemisphere lesion. Brain Lang 27: 239–246. Avila C, Gonzalez J, Parcet MA, et al. (2004). Selective alteration of native, but not second language articulation in a patient with foreign accent syndrome. Neuroreport 15: 2267–2270. Baddeley A (1998). Recent developments in working-memory. Curr Opin Neurobiol 8: 234–238. Bakker JI, Apeldoorn S, Metz LM (2004). Foreign accent syndrome in a patient with multiple sclerosis. Can J Neurol Sci 31: 271–272. Balasubramanian V, Max L (2004). Crossed apraxia of speech: A case report. Brain Cogn 55: 240–246. Balasubramanian V, Max L, Van Borsel J, et al. (2003). Acquired stuttering following right frontal and bilateral pontine lesion: A case study. Brain Cogn 53: 185–189. Ballard KJ, Granier JP, Robin DA (2000). Understanding the nature of apraxia of speech: Theory, analysis, and treatment. Aphasiology 14: 969–995. Bay E (1957). Die corticale Dysarthrie und ihre Beziehungen zur sog. motorischen Aphasie. Dtsch Z Nervenheilkd 176: 553–594. Berg T (2005). A structural account of phonological paraphasias. Brain Lang 94: 104–129. Bizzozero I, Costato D, Della Sala S, et al. (2000). Upper and lower face apraxia: Role of the right hemisphere. Brain 123: 2213–2230.

Blank SC, Bird H, Turkheimer F, et al. (2003). Speech production after stroke: The role of the right pars opercularis. Ann Neurol 54: 310–320. Blumstein SE, Alexander MP, Ryalls JH, et al. (1987). On the nature of the foreign accent syndrome: A case study. Brain Lang 31: 215–244. Bragoni M, Altieri M, Di P, et al. (2000). Bromocriptine and speech therapy in non-fluent chronic aphasia after stroke. Neurol Sci 21: 19–22. Brendel B, Ziegler W (in press). Effectiveness of Metrical Pacing in the Treatment of Apraxia of Speech. Aphasiology. Broca P (1861). Remarques sur le sie`ge de la faculte´ du langage articule´; suives d’une observation d’aphe´mie. Bull Assoc Anat (Nancy) 6: 330–357. Broca P (1865). Sur le sie`ge de la faculte´ du langage articule´. Bull Mem Soc Anthropol Paris 6: 377–393. Broussolle E, Bakchine S, Tommasi M, et al. (1996). Slowly progressive anarthria with late anterior opercular syndrome—a variant form of frontal cortical atrophy syndromes. J Neurol Sci 144: 44–58. Carluer L, Marie RM, Lambert J, et al. (2000). Acquired and persistent stuttering as the main symptom of striatal infarction. Mov Disord 15: 343–346. Castro-Caldas A, Petersson KM, Reis A, et al. (1998). The illiterate brain—learning to read and write during childhood influences the functional-organization of the adult brain. Brain 121: 1053–1063. Cheung H, Chen H-C, Lai CY, et al. (2001). The development of phonological awareness: Effects of spoken language experience and orthography. Cognition 81: 227–241. Cholin J, Levelt WJ, Schiller NO (2006). Effects of syllable frequency in speech production. Cognition 99: 205–235. Choudhari KA (2004). Subarachnoid haemorrhage and akinetic mutism. Br J Neurosurg 18: 253–258. Christoph DH, Freitas GRd, Santos DPd, et al. (2004). Different perceived foreign accents in one patient after prerolandic hematoma. European neurology 52: 198–201. Chung SJ, Im JH, Lee JH, et al. (2004). Stuttering and gait disturbance after supplementary motor area seizure. Mov Disord 19: 1106–1109. Ciabarra AM, Elkind MS, Roberts JK, et al. (2000). Subcortical infarction resulting in acquired stuttering. J Neurol Neurosurg Psychiatry 69: 546–549. Code C (1998). Models, theories and heuristics in apraxia of speech. Clin Linguist Phon 12: 47–65. Croot K (2002). Diagnosis of AOS: Definition and criteria. Semin Speech Lang 23: 267–280. Darley FL (1968). Apraxia of speech: 107 years of terminological confusion Paper presented at the Annual Convention of the ASHA. Darley FL, Aronson AE, Brown JR (1975). Motor Speech Disorders. W.B. Saunders, Philadelphia. David AS, Bone I (1984). Mutism following left hemisphere infarction. J Neurol Neurosurg Psychiatry 47: 1342–1344. Dejerine MJ (1891). Contribution a` l’e´tude de l’aphasie motrice sous-corticale et de la localisation ce´re´brale des

APRAXIA OF SPEECH centres larynge´s (muscles phonateurs). Compte Rendu des Se´ances de la Socie´te´ de Biologie 43: 155–162. Delreux V, Partz MPd KL, Callewaert A (1989). Aphasie croise´e chez un droitier. Rev Neurol (Paris) 145: 725–728. Draganski B, Gaser C, Busch V, et al. (2004). Neuroplasticity: Changes in grey matter induced by training. Nature 427: 311–312. Dronkers N (1996). A new brain region for coordinating speech articulation. Nature 384: 159–161. Dronkers N, Ogar J (2004). Brain areas involved in speech production. Brain 127: 1461–1462. Duffau H, Bauchet L, Lehe´ricy S, et al. (2001). Functional compensation of the left dominant insula for language. Neuroreport 12: 2159–2163. Elbert T, Pantev C, Wienbruch C, et al. (1995). Increased cortical representation of the fingers of the left hand in string players. Science 270: 305–307. Ellis AW, Miller D, Sin G (1983). Wernicke’s aphasia and normal language processing: A case study in cognitive neuropsychology. Cognition 15: 111–144. Fitch WT (2000). The evolution of speech: A comparative review. Trends Cogn Sci 4: 258–267. Fleet WS, Heilman KM (1985). Acquired stuttering from a right hemisphere lesion in a right-hander. Neurology 35: 1343–1346. Fridriksson J, Ryalls J, Rorden C, et al. (2005). Brain damage and cortical compensation in foreign accent syndrome. Neurocase 11: 319–324. Graff-Radford NR, Cooper WE, Colsher PL, et al. (1986). An unlearned foreign ‘accent’ in a patient with aphasia. Brain Lang 28: 86–94. Grant AC, Biousse V, Cook AA, et al. (1999). Stroke-associated stuttering. Arch Neurol 56: 624–627. Groenen P, Maassen B, Crul T, et al. (1996). The specific relation between perception and production errors for place of articulation in developmental apraxia of speech. J Speech Hear Res 39: 468–482. Groswasser Z, Korn C, Groswasser-Reider I, et al. (1988). Mutism associated with buccofacial apraxia and bihemispheric lesions. Brain Lang 34: 157–168. Guenther FH, Hampson M, Johnson D (1998). A theoretical investigation of reference frames for the planning of speech movements. Psychol Rev 105: 611–633. Gupta SR, Mlcoch AG, Scolaro C, et al. (1995). Bromocriptine treatment of nonfluent aphasia. Neurology 45: 2170–2173. Gurd JM, Coleman JS, Costello A, et al. (2001). Organic or functional? A new case of foreign accent syndrome. Cortex 37: 715–718. Hall DA, Anderson CA, Filley CM, et al. (2003). A French accent after corpus callosum infarct. Neurology 60: 1551–1552. Hamano T, Hiraki S, Kawamura Y, et al. (2005). Acquired stuttering secondary to callosal infarction. Neurology 64: 1092–1093. Hecaen H, Consoli S (1973). Analyse des troubles du langage au cours des lesions de l’aire de Broca. Neuropsychologia 11: 377–388. Helm NA, Butler RB, Benson DF (1978). Acquired stuttering. Neurology 28: 1159–1165.

283

Helm-Estabrooks N (1986). Diagnosis and management of neurogenic stuttering in adults. In: KO St Louis (Ed.), The Atypical Stutterer. Principles and Practices of Rehabilitation. Academic Press, Orlando, pp. 193–217. Hertrich I, Ackermann H, Ziegler W, et al. (1993). Speech iterations in Parkinsonism: A case study. Aphasiology 7: 395–406. Hickok G, Erhard P, Kassubek J, et al. (2000). A functional magnetic resonance imaging study of the role of left posterior superior temporal gyrus in speech production: Implications for the explanation of conduction aphasia. Neurosci Lett 287: 156–160. Hickok G, Poeppel D (2004). Dorsal and ventral streams: A framework for understanding aspects of the functional anatomy of language. Cognition 92: 67–99. Hillis AE, Work M, Barker PB, et al. (2004). Re-examining the brain regions crucial for orchestrating speech articulation. Brain 127: 1479–1487. Hoole P, Schro¨ter-Morasch H, Ziegler W (1997). Patterns of laryngeal apraxia in two patients with Broca’s aphasia. Clin Linguist Phon 11: 429–442. Horwitz SJ (1984). Neurological findings in developmental verbal apraxia. Semin Speech Lang 5: 111–118. Ingram JCL, McCormack PF, Kennedy M (1992). Phonetic analysis of a case of foreign accent syndrome. J Phonetics 20: 457–474. Kaplan E, Goodglass H, Weintraub S (1983). The Boston Naming Test. Lea & Febiger, Philadelphia. Karni A, Meyer G, Jezzard P, et al. (1995). Functional MRI evidence for adult motor cortex plasticity during motor skill learning. Nature 377: 155–158. Kertesz A (1985). Aphasia. In: JAM Frederiks (Ed.), Handbook of Clinical Neurology, Vol 1(45): Clinical Neuropsychology. Elsevier, Amsterdam, pp. 287–331. Kramer JH, Delis DC, Nakada T (1985). Buccofacial apraxia without aphasia due to a right parietal lesion. Ann Neurol 18: 512–514. Kuhl DE, Meltzoff AN (1996). Infant vocalizations in response to speech: Vocal imitation and developmental change. J Acoust Soc Am 100: 2425–2438. Kumabe T, Nakasato N, Suzuki K, et al. (1998). Two-staged resection of a left frontal astrocytoma involving the operculum and insula using intraoperative neurophysiological monitoring—case-report. Neurol Med Chir (Tokyo) 38: 503–507. Kumral E, Bayulkem G, Evyapan D, et al. (2002). Spectrum of anterior cerebral artery territory infarction: Clinical and MRI findings. Eur J Neurol 9: 615–624. Kuriki S, Mori T, Hirata Y (1999). Motor planning centre for speech articulation in the normal human brain. Neuroreport 10: 765–769. Kurowski KM, Blumstein SE, Alexander MP (1996). The foreign accent syndrome: A reconsideration. Brain Lang 54: 1–25. Kushner M, Reivich M, Alavi A, et al. (1987). Regional cerebral glucose metabolism in aphemia: A case report. Brain Lang 31: 201–214. Lecours AR, Lhermitte F (1976). The ‘pure form’ of the phonetic disintegration syndrome (pure anarthria):

284

W. ZIEGLER

Anatomo-clinical report of a historical case. Brain Lang 3: 88–113. LeRoux PD, Berger MS, Haglund MM, et al. (1991). Resection of intrinsic tumors from nondominant face motor cortex using stimulation mapping: Report of two cases. Surg Neurol 36: 44–48. Levelt WJM (1998). The genetic perspective in psycholinguistics or where do spoken words come from. J Psycholinguist Res 27: 167–180. Levelt WJM (2000). Producing spoken language: A blueprint of the speaker. In: CM Brown, P Hagoort (Eds.), The Neurocognition of Language. University Press, Oxford, pp. 83–122. Levelt WJM, Roelofs A, Meyer AS (1999). A theory of lexical access in speech production. Behav Brain Sci 22: 1–38. Liberman AM, Whalen DH (2000). On the relation of speech to language. Trends Cogn Sci 4: 187–196. Lichtheim L (1885). Ueber Aphasie. Aus der medicinischen Linik in Bern. Dtsch Arch Klin Med 36: 204–268. Liepmann H (1900). Das Krankheitsbild der Apraxie (‘motorischen Asymbolie’) auf Grund eines Falles von einseitiger Apraxie (II). Monatsschr Psychiatr Neurol VIII: 102–132. Liepmann H (1907). Zwei Fa¨lle von Zersto¨rung der unteren linken Stirnwindung. Psychol Neurol IX: 279–289. Liepmann H (1913). Motorische Aphasie und Apraxie. Monatsschr Psychiatr Neurol XXXIV: 485–494. Lippert-Gruener M, Weinert U, Greisbach T, et al. (2005). Foreign accent syndrome following traumatic brain injury. Brain Inj 19: 955–958. Loureiro CS, Braga LW, Souza LN, et al. (2004). Degree of illiteracy and phonological and metaphonological skills in unschooled adults. Brain Lang 89: 499–502. Ludlow CL, Rosenberg J, Salazar A, et al. (1987). Site of penetrating brain lesions causing chronic acquired stuttering. Ann Neurol 22: 60–66. Maassen B (2002). Issues contrasting adult acquired versus developmental apraxia of speech. Semin Speech Lang 23: 257–266. MacDermot KD, Bonora E, Sykes N, et al. (2005). Identification of FOXP2 truncation as a novel cause of developmental speech and language deficits. American journal of human genetics 76: 1074–1080. Maeshima S, Truman G, Smith DS, et al. (1997). Buccofacial apraxia and left cerebral haemorrhage. Brain Inj 11: 777–782. Mao C-C, Coull BM, Golper LAC, et al. (1989). Anterior operculum syndrome. Neurology 39: 1169–1172. McNeil MR, Robin DA, Schmidt RA (1997). Apraxia of speech: Definition, differentiation and treatment. In: MR McNeil (Ed.), Clinical Management of Sensorimotor Speech Disorders. Thieme, New York, Stuttgart, pp. 311–344. Michel V, Burbaud P, Taillard J, et al. (2004). Stuttering or reflex seizure? A case report. Epileptic Disord 6: 181–185. Mohr JP, Pessin MS, Finkelstein S, et al. (1978). Broca aphasia: Pathologic and clinical. Neurology 28: 311–324. Monrad-Krohn GH (1947). Dysprosody or altered ‘melody of language.’ Brain 70: 405–415. Moonis M, Swearer JM, Blumstein SE, et al. (1996). Foreign accent syndrome following a closed head injury: Perfusion

deficit on single photon emission tomography with normal magnetic resonance imaging. Neuropsychiatry Neuropsychol Behav Neurol 9: 272–279. Moore CA (2004). Physiologic development of speech production. In: B Maassen, R Kent, H Peters, P van Lieshout, W Hulstijn (Eds.): Speech Motor Control in Normal and Disordered Speech. Oxford University Press, Oxford, New York, pp. 191–209. Mori E, Yamadori A, Furumoto M (1989). Left precentral gyrus and Broca’s aphasia: A clinicopathologic study. Neurology 39: 51–54. Mouradian MS, Paslawski T, Shuaib A (2000). Return of stuttering after stroke. Brain Lang 73: 120–123. Movsessian P (2005). Neuropharmacology of theophylline induced stuttering: The role of dopamine, adenosine and GABA. Med Hypotheses 64: 290–297. Muellbacher W, Artner C, Mamoli B (1999). The role of the intact hemisphere in recovery of midline muscles after recent monohemispheric stroke. J Neurol 246: 250–256. Naeser MA, Martin PI, Nicholas M, et al. (2005). Improved picture naming in chronic aphasia after TMS to part of right Broca’s area: An open protocol study. Brain Lang 93: 95–105. Naeser MA, Palumbo CL, Helm-Estabrooks N, et al. (1989). Severe nonfluency in aphasia. Role of the medial subcallosal fasciculus and other white matter pathways in recovery of spontaneous speech. Brain 112: 1–38. Nagao M, Takeda K, Komori T, et al. (1999). Apraxia of speech associated with an infarct in the precentral gyrus of the insula. Neuroradiology 41: 356–357. Nagaratnam N, Nagaratnam K, Ng K, et al. (2004). Akinetic mutism following stroke. J Clin Neurosci 11: 25–30. Nestor PJ, Graham NL, Fryer TD, et al. (2003). Progressive non-fluent aphasia is associated with hypometabolism centred on the left anterior insula. Brain 126: 2406–2418. Paulesu E, Frith CD, Frackowiak RSJ (1993). The neural correlates of the verbal component of working memory. Nature 362: 342–345. Peach RK, Tonkovich JD (2004). Phonemic characteristics of apraxia of speech resulting from subcortical hemorrhage. J Commun Disord 37: 77–90. Pellat J, Gentil M, Lyard G, et al. (1991). Aphemia after a penetrating brain wound: A case study. Brain Lang 40: 459–470. Perino M, Famularo G, Tarroni P (2000). Acquired transient stuttering during a migraine attack. Headache 40: 170–172. Petrides M, Cadoret G, Mackey S (2005). Orofacial somatomotor responses in the macaque monkey homologue of Broca’s area. Nature 435: 1235–1238. ¨ nderungen des Sprachcharakters als ¨ ber A Pick A (1919). U Begleiterscheinung aphasischer Sto¨rungen. Z Gesamte Neurol Psychiatr 45: 230–241. Pineda D, Ardila A (1992). Lasting mutism with buccofacial apraxia. Aphasiology 6: 285–292. Price CJ, Winterburn D, Giraud AL, et al. (2003). Cortical localisation of the visual and auditory word form areas: A reconsideration of the evidence. Brain Lang 86: 272–286.

APRAXIA OF SPEECH Reeves RR, Norton JW (2001). Foreign accent-like syndrome during psychotic exacerbations. Neuropsychiatry Neuropsychol Behav Neurol 14: 135–138. Riecker A, Ackermann H, Wildgruber D, et al. (2000). Opposite hemispheric lateralization effects during speaking and singing at motor cortex, insula and cerebellum. Neuroreport 11: 1997–2000. Rochon E, Caplan D, Waters G (1990). Short-term memory processes in patients with apraxia of speech: Implications for the nature and structure of the auditory verbal shortterm memory system. J Neurolinguistics 5: 237–264. Romani C, Calabrese A (1998). Syllabic constraints in the phonological errors of an aphasic patient. Brain Lang 64: 83–121. Roth EJ, Fink K, Cherney LR, et al. (1997). Reversion to a previously learned foreign accent after stroke. Arch Phys Med Rehabil 78: 550–552. Ruff RL, Arbit E (1981). Aphemia resulting from a left frontal hematoma. Neurology 31: 353–356. Sakurai Y, Murayama S, Fukusako Y, et al. (1998). Progressive aphemia in a patient with Pick’s disease: A neuropsychological and anatomic study. J Neurol Sci 159: 156–161. Schiff HB, Alexander MP, Naeser MA, et al. (1983). Aphemia. Clinical-anatomic correlations. Arch Neurol 40: 720–727. Shriberg LD, Aram DM, Kwiatkowski J (1997). Developmental apraxia of speech: I. Descriptive and theoretical perspectives. J Speech Lang Hear Res 40: 273–285. Shuren JE, Schefft BK, Yeh H-S, et al. (1995). Repetition and the arcuate fasciculus. J Neurol 242: 596–598. Soroker N, Bar-Israel Y, Schechter I, et al. (1990). Stuttering as a manifestation of right-hemispheric subcortical stroke. European neurology 30: 268–270. Takayama Y, Sugishita M, Kido T, et al. (1993). A case of foreign accent syndrome without aphasia caused by a lesion of the left precentral gyrus. Neurology 43: 1361–1363. Tanji K, Suzuki K, Yamadori A, et al. (2001). Pure anarthria with predominantly sequencing errors in phoneme articulation: A case report. Cortex 37: 671–678. Tonkonogy J, Goodglass H (1981). Language function, foot of the third frontal gyrus, and rolandic operculum. Arch Neurol 38: 486–490. Turgut N, Utku U, Balci K (2002). A case of acquired stuttering resulting from left parietal infarction. Acta Neurol Scand 105: 408–410. Ungerleider LG, Doyon J, Karni A (2002). Imaging brain plasticity during motor skill learning. Neurobiol Learn Mem 78: 553–564. Urban PP, Wicht S, Vukurevic G, et al. (2001). Dysarthria in acute ischemic stroke. Lesion topography, clinicoradiologic correlation, and etiology. Neurology 56: 1021–1027.

285

Van Borsel J, van der Made S, Santens P (2003). Thalamic stuttering: A distinct clinical entity? Brain Lang 85: 185–189. Vargha-Khadem F, Gadian DG, Copp A, et al. (2005). FOXP2 and the neuroanatomy of speech and language. Nat Rev Neurosci 6: 131–138. Walker-Batson D, Curtis S, Natarajan R, et al. (2001). A double-blind, placebo-controlled study of the use of amphetamine in the treatment of aphasia. Stroke 32: 2093–2098. Wambaugh JL (2002). A summary of treatments for apraxia of speech and review of replicated approaches. Semin Speech Lang 23: 293–308. Waters GS, Rochon E, Caplan D (1992). The role of highlevel speech planning in rehearsal: Evidence from patients with apraxia of speech. J Mem Lang 31: 54–73. Watkins K, Paus T (2004). Modulation of motor excitability during speech perception: The role of Broca’s area. J Cogn Neurosci 16: 978–987. West C, Hesketh A, Vail A, et al. (2005). Interventions for apraxia of speech following stroke. Cochrane Database Syst Rev: Issue 4. Art. No.: CD004298. DOI: 10.1002 / 14651858. CD004298.pub2. Whiteside SP, Varley RA (1998). A reconceptualization of apraxia of speech: A synthesis of evidence. Cortex 34: 221–231. Wise RJS, Greene J, Buchel C, et al. (1999). Brain-regions involved in articulation. Lancet 353: 1057–1061. World Health Organization (2005). The International Classification of Functioning, Disability and Health—ICF http:// www3.who.int/icf/. Ziegler W (1987). Phonetic realization of phonological contrast in aphasic patients. In: JH Ryalls (Ed.), Phonetic Approaches to Speech Production in Aphasia and Related Disorders. College Hill Press, Boston, pp. 163–179. Ziegler W (2003). Speech motor control is task-specific. Evidence from dysarthria and apraxia of speech. Aphasiology 17: 3–36. Ziegler W (2005). A nonlinear model of word length effects in apraxia of speech. Cogn Neuropsychol 22: 603–623. Ziegler W (2006). Distinctions between speech and nonspeech motor control. A neurophonetic view. In: M Tabain, J Harrington (Eds.), Speech Production. Psychology Press, Oxford. Ziegler W, Cramon DYv (1986). Timing deficits in apraxia of speech. Eur Arch Psychiatry Neurol Sci 236: 44–49. Ziegler W, Kilian B, Deger K (1997). The role of the left mesial frontal cortex in fluent speech: Evidence from a case of left supplementary motor area hemorrhage. Neuropsychologia 35: 1197–1208.

Handbook of Clinical Neurology, Vol. 88 (3rd series) Neuropsychology and behavioral neurology G. Goldenberg, B.L. Miller, Editors # 2008 Elsevier B.V. All rights reserved

Chapter 14

Aphasia MICHAEL P. ALEXANDER1* AND ARGYE E. HILLIS2 1

Harvard Medical School, Behavioral Neurology Unit, Beth Israel Deaconess Medical Center, Boston, MA, USA 2

Johns Hopkins School of Medicine, Departments of Neurology and Physical Medicine and Rehabilitation, Baltimore, MD, USA

14.1. Introduction The history of the study of aphasia has often been reviewed and summarized, so often that another review, even in a comprehensive text, is thoroughly unnecessary. Like American politicians consulting the Constitution or religious scholars consulting the Bible, aphasiologists have always found layers of interpretation in the writings of the early observers of aphasia. Every aphasiologist appears to have found support for his or her beliefs about aphasia in those seminal reports, whether worshipping at the connectionist or the critical center churches. The contributions of investigators up to the modern era were enormous: trenchant case reports, well-designed experiments and models fruitful for motivating further study have led us to the current era. In the last 20 years the paradigm has shifted somewhat. The goal now is not to reconcile connectionist and center models, say in their most straightforward versions the connectionist model of Geschwind (1965) and functional center model of Luria (1973), but to integrate several classes of study. Analysis of chronic, stable disorders informs us about durable, critical, and largely consistent relationships between lesion site and linguistic functions. Variations in those relationships inform us about the effects on the neural basis of language of age, gender, the linguistic structure of individual languages, and the potential anomalies partly marked by handedness. Analysis of acute, evolving disorders informs us about the roles of redundancy and plasticity in the neural basis of language. Analysis of the functional maps of language in intact brains informs us about the participation of brain structures in language operations, and the numerous ingenious functional experiments have *

begun to tell us about the local and distributed networks that serve language and about how they interact in real time. A single chapter cannot properly cover all of this territory, but respect can be paid to all by the following structure: 1. prototypical clinical syndromes: their essential components, their natural history, and their lesion correlates over that natural history; 2. acute clinical profiles: where they converge and diverge from the chronic, prototypical syndromes, how they evolve into the chronic syndromes, and the implications for redundancy and recovery; 3. the essential linguistic capacities: as they are revealed by clinical studies and by functional studies; 4. treatment: the implications for redundancy and plasticity.

14.2. Prototypical syndromes The named syndromes of clinical aphasiology are a mixture of eponyms and an early, unprovable theory about aphasia: ‘transcortical’ mechanisms of language impairment. The syndromes were defined by differences in fairly coarse measures of language: output, repetition, and comprehension, all considered as normal, or nearly so, and the assumption that word retrieval was abnormal in all aphasias. 14.2.1. Aphasia assessment Output impairment has been described over the years by a series of terms that were either irrelevant to

Correspondence to: Michael P. Alexander, MD, Behavioral Neurology, KS 253, Beth Israel Deaconess Medical Center, 330 Brookline Avenue, Boston, MA 02215, USA. E-mail: [email protected].

288

M.P. ALEXANDER AND A.E. HILLIS

language—motor—or ambiguous—expressive or nonfluent. Nevertheless, aphasic populations can usually be divided into those with impoverished output and those with relatively rich output (Howes and Geschwind, 1964). The criteria for impoverished output are reduced sentence or phrase length and reduced grammatical complexity although these two measures are not independent (Goodglass, 1993). Some patients have terse, unelaborated output, but their best utterances are normal and even their short utterances respect grammatical rules. The most rigorously demonstrated criterion for normal utterance length is seven words in the best-formed utterance out of ten elicited propositional (meaningful) utterances (Goodglass, 1993). Nonpropositional utterances are not considered, whether the lengthy, stereotyped variety or echoed, even partially echoed, replies. We prefer the terms fluent and nonfluent while acknowledging that ‘nonfluency’ is also used to describe stuttering (a motor deficit) and ‘fluency’ is also used to describe a word generation task (an executive deficit). The fluency/nonfluency dichotomy does not include any judgment about the content of the utterance—just its structure. Any aphasic patient who makes any propositional utterances may have a number of abnormalities of content. It is generally held that all aphasic patients have some degree of impaired word retrieval deficit— anomia—although this can be quite variable between aphasic patients who have otherwise similar aphasia profiles. There are also cases of isolated alexia, isolated agraphia, and rare cases of impaired sentence construction without anomia. (The mechanism of each of these is considered below.) The manifestations of anomia can be quite different in different aphasia syndromes and even within the output of a single patient (Kohn and Goodglass, 1985): output that simply stops at the retrieval deficit, a long latency of retrieval, substitutions of less specific general words (‘thing,’ ‘it,’ ‘one,’ etc), substitutions of descriptive phrases (circumlocutions), gestures (of varying communication accuracy). Word retrieval and production deficits are often marked by incorrect word selection: semantic paraphasias—usually a related word, often higher frequency or more general (‘food’ or ‘peas’ when ‘lentils’ intended). Phonemic paraphasias are substitutions of a phoneme within a word. Phonemes are the smallest linguistically meaningful elements of language, thus, ‘pentils’ when ‘lentils’ was intended. The phonemic paraphasias often represent anticipations and perseverations, even forming Spoonerisms from nearby words in an utterance: ‘I like pentils with lork.’ Phonemic paraphasias are not articulation errors, i.e., they are not motor misrepresentation of an intended target; they are the correct production of an intended but incorrectly selected (or

programmed) phonemic target. Neologistic paraphasias are word-like productions that are not real words although the relationship to a real target word—correct or not—can sometimes be determined. One or two phonemic substitutions into a semantic paraphasia may produce a neologism. Meaning to say ‘ambulance,’ word retrieval produces ‘hospital’ that is transformed by phonemic substitutions, one a perseveration from earlier trying to say heart attack, into ‘haspitrack.’ The mechanisms of phonemic paraphasia and neologism occasionally produce an actual real world, but not one in any way related to the original target: in the same example, ‘hatrack’ is produced. This accidental production of a real word out of paraphasias is called formal verbal paraphasia. Auditory comprehension can be measured along many dimensions and the dimension most impaired differs across aphasic syndromes (Goodglass and Wingfield, 1993; Dronkers et al., 2004). Word discrimination is comprehension of single words, usually as a multiplechoice task, but the choices can be finite—an array of objects—or nearly unlimited—body parts or objects in the environment. The choices can vary in frequency and in part–whole complexity: watch vs. timepiece or watch vs. dial. Comprehension at sentence length can be tested as object identification to a spoken functional or perceptual description. It can also be tested by yes/no questions: Do I wear eyeglasses to improve my eyesight? Is it raining today? For patients with very restricted output, some effort may be required to establish reliable yes/no signals before reaching conclusions about yes/no comprehension. Sentence length comprehension can also be tested with commands. Interpretation of comprehension of commands requires two preliminary steps. First, the elements of the command must be individually assessed: ‘Put the pencil in the cup’ involves two objects and an action/location element. A patient could use one or two wrong items and/or do the wrong action or locate the action incorrectly: putting a comb on top of the watch. Second, failure to carry out a command that directs a learned movement such as ‘make a fist,’ ‘wave goodbye,’ or ‘pretend to hammer,’ may be due to ideomotor apraxia (IMA), not failure to understand (Alexander et al., 1992a). Recognition of IMA is facilitated if performance resembles the requested act. Prompt improvement when done as imitation suggests but does not prove a comprehension impairment. In the classic aphasia syndromes, comprehension of object names, body part names, commands, and sentence length questions is reduced to a single distinction as abnormal or normal, or perhaps abnormal or not too abnormal. There are other elements of comprehension— actions, locations, order, colors, numbers, and grammar— that are obviously important but rarely figure into

APHASIA the overall sense of good or bad comprehension. Comprehension of specific grammatical and syntactic elements plays a major role in Broca’s aphasia (Berndt and Caramazza, 1999; Caramazza et al., 2001). Repetition is straightforward although stimulus selection and error interpretation may not be. For the prototypical syndrome assignments, patients are asked to repeat a few words or sentences, and again, a decision is made about abnormal or nearly normal. Repetition is sometimes useful to define the nature of the paraphasias that are heard in spontaneous speech because, with repetition, the target is known to the examiner, and errors are easier to map back to target. In the practical matter of stimulus selection, the important variables are word span and phonological complexity. The well-worn stimulus ‘No ifs, ands, or buts’ is essentially useless for characterizing output impairments from repetition. Repetition failure can occur for many reasons: related to motor speech impairments, perseveration of response, elision of grammatical words, phonemic substitutions, word substitutions, and span effect (phonological or auditory–verbal short-term memory). These three coarse measures, all marked as abnormal or (nearly) normal are used to generate the eight prototypical syndrome diagnoses. In the summary to follow: 1) nonfluent means a best phrase length of three or fewer words; 2) impaired comprehension means poor performance on all aspects of testing including word discrimination; 3) impaired repetition means a deficit other than in motor speech or purely span errors. Clinical evidence supports the actual existence of each syndrome, even when many patients have elements of more than one (Kertesz and Phipps, 1977; Mazzocchi and Vignolo, 1979). Patients are not frozen into one syndrome. Many patients rapidly evolve through two or more (Kertesz and McCabe, 1977). Some syndromes are encountered in acute presentation; some require time to emerge (Mohr et al., 1978; Kreisler et al., 2000; Godefroy et al., 2002). Each of these factors: the individual features underlying syndromes and the common patterns of presentation and evolution will be emphasized in turn in the discussions to follow. 14.2.2. The classic aphasia syndromes Each can be described on the same template: common profile of output, comprehension, and repetition, typical lesion (location and etiology) and usual associated signs. 14.2.2.1. Broca’s aphasia Output is nonfluent: 1–2 word utterances with no grammatical structure, sometimes referred to as telegraphic.

289

Semantic and phonemic paraphasias are common. Hesitant language initiation and perseveration are also frequent. There is little or no improvement in output with repetition. Recitation of some overlearned sequences may be possible. Comprehension at the object word level and for most conversation is good. When specifically probed, a variety of impairments in understanding grammar and syntax may be found (Caramazza et al., 1981; Berndt and Caramazza, 1999). The most common lesion profile is a subacute or chronic infarction centered in the left frontal operculum but extensively involving middle frontal cortex, lower motor cortex, anterior, superior insula, anterior, inferior parietal lobule, white matter deep to these structures, often down to the ventricle, and the putamen and the dorsal head of the caudate nucleus (Mohr et al., 1978; Naeser and Hayward, 1978). This infarct is usually the territory of the superior division of the middle cerebral artery (MCA) with or without the involvement of the lenticulostriate branches. Rather than full cortical damage, much of the lesion may be restricted to subcortical white matter. Common associated signs: 1) slow, dystonic or spastic articulation; 2) poor prosody; 3) hemiparesis, at least central facial paresis; 4) facial apraxia; 5) limb ideomotor apraxia. Frustration about communication struggles is very common, and frank depression also frequently occurs (Sinyor et al., 1986; Starkstein et al., 1991). 14.2.2.2. Wernicke’s aphasia Output is fluent, sometimes pressured, with considerable grammatical and sentence structure. All types of paraphasias are heard, and the cascade of paraphasias occurring in apparently propositional utterances using a rich range of grammar can sound as though the patient is speaking an unknown language—jargonaphasia. Content may be so disrupted that grammar becomes indecipherable—pronouns do not seem to agree with any identifiable referent, subject–verb agreement becomes hard to establish, relative clauses appear without clear reference. This is called paragrammatism. Perseveration is pervasive at every level of language (Shindler et al., 1984). Awareness of the severity of the language deficit is quite variable. Patients are often unaware that their output is incomprehensible to others (anosognosia). Comprehension is poor at all levels. Repetition may be hard to assess if the patients fail to understand that they are supposed to be repeating, but, when it can be tested, it is very abnormal with paraphasias and perseveration. The most common lesions are an infarct centered in the left superior temporal gyrus (STG) but extending to involve the middle temporal gyrus (MTG), posterior supramarginal gyrus (SMG) and inferior angular gyrus

290

M.P. ALEXANDER AND A.E. HILLIS

(AG) or a hemorrhage in the posterior temporal lobe (Naeser and Hayward, 1978; Mazzocchi and Vignolo, 1979; Knepper et al., 1989). SMG is continuous with posterior STG, and inferior AG is continuous with posterior MTG. Common associated signs: 1) right visual field defect; 2) pervasive perseveration. Irritability over communication failures may evolve into paranoia or depression if awareness improves. 14.2.2.3. Conduction aphasia Output is fluent, well constructed with few paragrammatic utterances. Prominent phonemic paraphasias are the dominant abnormality in addition to word retrieval deficits. Phonemic paraphasias are particularly common on phonologically complex substantive words. Patients have clear lexical targets and will make many attempts to correct phonemic paraphasias (conduit d’approche), not always leading them closer to the target. Comprehension is good. Repetition is poor, but not necessarily worse than spontaneous speech. Using phonologically complex substantive targets (Presbyterian preacher) will demonstrate the problem most clearly. The span of repetition, even simple forward digit span, may be reduced even when no paraphasias are produced. The lesion that produces conduction aphasia is almost always an embolic infarct in the SMG and the posterior, superior insula with variable extent into lower sensory and motor cortex, superior parietal lobule, and deep parietal white matter (Palumbo et al., 1992). There is no special role of the arcuate fasciculus. Associated signs: 1) contralateral sensory loss; 2) central facial paresis; 3) partial right visual field defect or extinction; 4) limb IMA. Many patients have no associated signs. Mood deficits are rare. 14.2.2.4. Transcortical motor aphasia (TCMA) Output is nonfluent by length criterion but not always by grammar criterion. Utterances may be short but with preserved grammatical structure within the limits allowed by length (Nadeau, 1988). TCMA often has the greatest discrepancy between the typical utterance and the best utterance. Some degree of incorporation of a question into the response, if not frank echolalia, is also common. Comprehension is good at the word and the personal yes/no levels. Repetition is normal, and recitation, even of lengthy over-learned material, is often normal. The usual lesion is a left ventrolateral frontal infarct (branch of superior division of MCA) or intracerebral hemorrhage often involving frontal operculum but centered on more anterior and dorsal frontal cortex

(Freedman et al., 1984). A similar, although usually milder, profile is also seen with large subcortical lesions centered in the periventricular white matter (PVWM) anterior to the anterior limb internal capsule (ALIC) and in the dorsal head of the caudate; this is the common chronic aphasia syndrome associated with capsulostriatal infarcts or hemorrhage (Mega and Alexander, 1994; D’Esposito and Alexander, 1995). This is the aphasia presentation of left prefrontal tumors (Costello and Warrington, 1989) and of the frontal variant of frontotemporal dementia (FTD) (Hodges and Miller, 2001), including those with progressive supranuclear palsy (Esmonde et al., 1996). Large medial frontal lesions, usually infarction in the distal territory of the left anterior cerebral artery (ACA), can also cause TCMA (Rubens, 1976; Masdeu et al., 1978; Bogousslavsky et al., 1987). A similar pattern of reduced speech output with preserved repetition has been described with anterior thalamic lesions (Graff-Radford et al., 1985). Some patients with left thalamic lesions have relatively fluent but severely disorganized output (Chatterjee et al., 1997). Associated signs are variable depending on the lesion. The dorsolateral frontal lesion may have no associated signs, but mild contralateral grasp reflex and paratonia, or ataxic paresis are common. The subcortical lesion usually produces hypophonia and hypokinetic dysarthria, hemiparesis and postural instability. The medial lesion is also accompanied by mild contralateral grasp reflex and paratonia, but with inverted hemiparesis, leg more affected than arm. Patients with TCMA are often generally abulic, i.e., lack behavioral as well as speech spontaneity, particularly with anterior thalamic lesions. The thalamic lesion may also cause significant episodic memory impairment (Graff-Radford et al., 1985). 14.2.2.5. Transcortical sensory aphasia (TCSA) Language ouput is fluent but extremely empty. Semantic paraphasias may occur but phonemic paraphasias are uncommon. Repetition is preserved, but prompting long recitation is more difficult. Patients differ in how aware they appear to be of the content of what they are repeating (Coslett et al., 1987). Comprehension is impaired, and patients often seem worse at comprehension of single words than conversation. There are two typical lesion locations: a large infarct in the territory of the left posterior cerebral artery (PCA) including the inferior temporal gyrus (ITG) or a hemorrhage in the ITG (Coslett et al., 1987; Alexander et al., 1989). Traumatic contusions also commonly involve the ITG and may produce TCSA (Kertesz and McCabe, 1977). Although the nature of

APHASIA aphasia after thalamic lesions is disputed, TCSA has been reported after damage in a variety of thalamic locations (McFarling et al., 1982; Bogousslavsky et al., 1986; Nicolai and Lazzarino, 1991). Associated signs depend upon the lesion location. If restricted to the ITG, the only deficit may be a partial right visual field defect. If due to a PCA territory infarct, associated signs can include visual field defect, visual object agnosia (Alexander et al., 1989), alexia (Damasio and Damasio, 1983), amnesia (parahippocampal lesion) (von Cramon et al., 1988), hemiparesis (cerebral peduncle lesion) or abulia (polar thalamus) (Graff-Radford et al., 1985). 14.2.2.6. Global aphasia Output is entirely nonpropositional, consisting of perseverative single words (verbal stereotypes, most commonly ‘no’), nonwords (nonverbal stereotypes, most commonly consonant–vowel pairings that may vary slightly over utterances), and short, stereotyped phrases (often obscenities or a meaningless phrase such as ‘I don’t know’). Comprehension is severely impaired although some single words, perhaps particularly geographic place names (Goodglass and Wingfield, 1993), simple conversation and commands (most commonly ‘close your eyes’) may be understood. There is no repetition although occasionally emphatic exclamations (‘boo,’ ‘ouch’) can be repeated. The typical lesion of chronic global aphasia is a large infarct of perisylvian cortex and the subcortical white matter (Naeser and Hayward, 1978; Mazzocchi and Vignolo, 1979). A sufficiently large subcortical lesion can also cause global aphasia, and a surprising number of global aphasics have little or no temporal damage (Vignolo et al., 1986). Many patients with much smaller acute lesions present as global aphasia but rapidly evolve depending upon the actual territory of ischemic injury (discussed below). Associated signs: 1) hemiparesis; 2) hemisensory loss; 3) visual field defect or extinction; 4) postural instability. The associated signs, other than central facial paresis, are entirely due to the subcortical extent of the lesions, and so-called global aphasia without hemiparesis merely indicates the absence of extension into the periventricular white matter motor and sensory pathways (Hanlon et al., 1999). Depression, at least as inferred by observers, is common. 14.2.2.7. Mixed transcortical aphasia (MTA) Propositional output is very reduced, often similar to global aphasia, although stereotyped utterances are less frequent. Echolalia is prominent, and, thus, repetition

291

is relatively preserved. Some patients with abundant echolalia, oddly, cannot be modeled or prompted to repeat as a task. Comprehension is severely impaired with the same type of variability as described for global aphasia. The anticipated lesion would be a combination of the frontal lesion of TCMA and the temporal lesion of TCSA, and occasionally multiple emboli or a large borderzone infarction will present as MTA, but the most typical lesion is actually a very large prefrontal injury with deep extension (Bogousslavsky et al., 1988; Rapcsak et al., 1990; Maeshima et al., 2002). ICH is a common cause, but large anterior, superior division MCA infarcts can also produce MTA. Therefore, MTA is usually an early presentation of what will eventually be severe TCMA. Acute anterior (polar) thalamic lesions also present as MTA but evolve quickly into anomic aphasia. The comprehension problem may be due to such severe impairment of attention and executive function that patients are not able to grasp the nature of the comprehension tasks. Associated signs depend upon the lesion type. Large frontal lesions may have no signs or the combination of grasp, paratonia, postural instability, and mild ataxic paresis may be seen. Abulia is common. Polar thalamic lesions may also cause significant executive impairment and amnesia. 14.2.2.8. Anomic aphasia Language output is fluent and normal except for word finding deficits that may be marked by pauses, circumlocutions, and frequent resort to nonspecific filler words, such as ‘thing’ or ‘it’ for nouns and ‘does’ or ‘goes’ for actions. Comprehension and repetition are normal. There is no usual lesion site as chronic anomic aphasia is the residual state of most other mild acute aphasias. Depending on lesion site, there may be idiosyncratic category specific anomia: possibly limited to colors (Damasio et al., 1979), letters, numbers, actions (Damasio et al., 2001) or some natural categories (Warrington and Shallice, 1984). The lesion site associated with predominant anomia from presentation is damage to ITG, often small traumatic contusions or intracerebral hemorrhage. Anomic aphasia is the common aphasic presentation of tumors anywhere in the language zone. It is the aphasia presentation of Alzheimer’s disease (Cummings et al., 1985; Garrard et al., 2005a; 2005b) and the left temporal form of FTD (semantic dementia) (Gorno-Tempini et al., 2004; Hodges et al., 2004). Associated signs are obviously as variable as the lesion sites. Patients with only anomia often complain of ‘memory loss,’ but examination demonstrates that

292

M.P. ALEXANDER AND A.E. HILLIS

the only memories lost are for words and names, not for experiences. 14.2.2.9. Aphasic alexia and agraphia Disorders of reading and writing are considered in a separate chapter, but a few observations about written language are deserved here. Most patients with aphasia will have generally parallel impairments in spoken and written tests. There are, however, a few factors that can generate discrepancies. Most patients with Broca’s aphasia or global aphasia will have paresis of the preferred right hand. Writing with the left hand adds the additional problem that production of letters will be under the direction of a motor system not previously trained in writing, resulting in written output even more limited than spoken. In other patients with global or Broca’s aphasia, motor speech may be so impaired that almost no propositional language can be produced. Written output emerges under no time constraints, and some severely nonfluent patients can slowly write enough words or word fragments that some communication is possible. In either case, the structure of written output will still be fundamentally agrammatic and telegraphic. Writing is the least predictably developed language skill in normal populations, but written language in aphasia usually parallels the structure of spoken: fluent speakers are fluent writers. In either conduction aphasia, or less commonly in Wernicke’s aphasia, extension of lesion into the more superior portion of the parietal lobe may cause further disruption of writing, adding impaired letter formation (orthography) to the abnormal language structure typical of each aphasia. Reading comprehension relies on a visual discrimination system that resides in the left ventral occipitotemporal region, largely posterior to but mapping on to the perisylvian and middle and inferior temporal regions essential for language. The placement of temporal lesions will determine if comprehension of either written or spoken language is disproportionately affected. Thus, patients with large PCA territory infarcts will have relatively much greater reading than spoken comprehension deficits, but patients with superior temporal lesions will have a reverse pattern. Reading aloud requires the same system of phonological production as repetition and will typically parallel repetition profiles. This is seen most clearly in conduction aphasia in which reading comprehension can be normal despite phonemic paraphasias (paralexias) in oral reading. The agrammatical production of Broca’s aphasia is usually also present in oral reading, as it is in repetition, although the overall pattern of oral reading impairment in Broca’s aphasia may be quite a lot more complex.

14.2.3. Modality specific syndromes Even the brief review of alexia and agraphia in aphasia highlights the last facet of the classic aphasia syndromes, the disorders restricted to one of the sensory pathways in to or motor pathways out of the language system: speech, writing, hearing, and reading. Each of these syndromes is frequently embedded in one or more of the larger aphasia syndromes, but each may be impaired in relative isolation with an appropriate lesion with minimal or no evidence for a language disorder. 14.2.3.1. Speech A speech disorder without any associated aphasia may follow a wide variety of lesions, but only one occurs with a lesion within the cortex of the language zone or its immediate outflow. Speech is slow and dystonic, i.e., associated with awkward control of the musculature of articulation. The melodic line (prosody) of the utterance is distorted with broken transitions between words and even within words although the prosodic manipulations and resonance necessary to define affective intent are preserved. Volume is usually normal. The prototypical lesion is a small embolic infarct in the left lower motor cortex, posterior frontal operculum (FOP) and anterior, superior insula (branch of superior division of MCA) (Schiff et al., 1983; Dronkers, 1996). In the acute epoch, language is mildly abnormal, usually with elements of Broca’s aphasia—effortful unelaborated output with mild anomia, agrammatism, and phonemic paraphasia (see discussion in next section) (Alexander et al., 1990). When aphasic elements clear, chronic articulatory–prosody impairment remains. It is likely that the dysarthria commonly reported with a variety of small subcortical lesions (lacunar syndromes) is caused by damage to the descending pathways from lower motor cortex/operculum—in the corona radiata deep to operculum, in the genu of the internal capsule, and possibly even in the pons. Associated signs of the cortical lesion are few: central facial paresis and rarely sensory loss; transient facial apraxia. Associated signs of the subcortical lesion depend on the extent of lesion into adjacent structures. Given the common co-occurrence of this speech disorder with nonfluent aphasia, facial apraxia, facial paresis, and damage to putamen, it is not surprising that both the existence of an articulatory impairment due to a restricted cortical lesion and what to call it—if it exists—have been debated. Emphasizing location of lesion, cortical dysarthria, cortical dysprosody, or subcortical dysarthria, and presumptive mechanisms, anarthria or apraxia of speech, have all been suggested. Because lesion location is not determinative, because

APHASIA there are other disorders that might more profitably be labeled cortical dysprosody, the term ‘aphemia’— agnosic about location of lesion and mechanism of impairment—seems safer although apraxia of speech seems to be most popular at the time of this writing. 14.2.3.2. Writing Agraphias are considered in a later chapter, but there is evidence that writing—or as it is sometimes called, written spelling, to distance it from oral spelling (both are produced one letter at a time)—can be impaired in isolation from aphasia. It is usually called ‘apractic agraphia,’ based on the observation that patients have lost the spatial motor program for writing in the absence of any basic defect in motor or sensory function (Roeltgen and Heilman, 1983; Maeshima et al., 2003). The small number of modern cases have had infarcts in the superior parietal lobule (Roeltgen and Heilman, 1983; Alexander et al., 1992b; Maeshima et al., 1998). Extension of lesions of the perisylvian region into the superior parietal lobule (SPL) may account for disproportionate agraphia in some cases of conduction aphasia and Broca’s aphasia. Patients are unable to produce letters correctly except with intense visual feedback. Script is more impaired than print. This form of agraphia is sometimes considered an isolated ideational apraxia for writing (DeRenzi and Lucchelli, 1988). Patients have lost the spatial temporal representations for writing movements. The classic localization of isolated agraphia was the posterior premotor frontal cortex, and patients with that lesion as well with lesions deep to midfrontal cortex down to the dorsal striatum may have writing problems out of proportion to aphasia. Writing is slow and effortful, often small, but letters are actually written correctly. This is agraphia due to disturbed frontostriatal network for learned motor procedures. Some patients with TCMA demonstrate this pattern of writing. Associated signs in cases of isolated parietal apraxic agraphia have included hemisensory loss, visual extinction, impaired visually guided reaching, and, not improbably but not inevitably, limb apraxia. 14.2.3.3. Hearing Given the bilateral, but asymmetrical, distribution of the ascending auditory pathways to the STG, hearing loss is not observed after even large unilateral STG lesions, but some loss of discrimination of the speech signal occurs with left STG lesions. With small lesions of the left auditory cortex, the speech discrimination signal may be disturbed sufficiently to impair language comprehension even when pure tone hearing is not impaired. Patients complain that speech sounds fuzzy but not that

293

they cannot hear speech. If they can repeat the speech stimulus correctly, they will always be able to understand it. (This is the opposite pattern of TCSA, where patients can always repeat but often do not understand what has been said.) Bilateral lesions of the auditory cortex or its subcortical ascending pathways are even likelier to disrupt speech discrimination, so-called auditory acuity (Auerbach et al., 1982), but patients may complain of poor hearing generally, not restricted to speech. This disorder has traditionally been called ‘pure word deafness’ (Coslett et al., 1984). Essentially by definition, this disorder rarely has any associated signs. 14.2.3.4. Reading Inability to read in the absence of aphasia or agraphia has been recognized for almost as long as debates about the nature of aphasia have raged. Classically attributed to large infarcts (PCA territory) of the left occipital lobe producing right hemianopia and the corpus callosum preventing passage of the right hemisphere’s visual information to the left perisylvian language zone, this syndrome has been the epitome of dysconnection syndromes (Geschwind and Fusillo, 1966; Damasio and Damasio, 1983). At its most severe, patients cannot identify any letters, but with milder cases or with improvement, patients can read letters and most words accurately, but they are slow and read one letter at a time, spelling the word out to themselves. Word length is the major factor in reading accuracy and speed. This disorder has been variously, and for obvious reasons, labeled pure word blindness, agnosic alexia, alexia without agraphia, letter-by-letter reading, and pure alexia. It is rarely ‘pure.’ Associated signs depend on lesion size but often include right visual defect and impaired color naming (Damasio and Damasio, 1983) and may include impaired naming objects by sight (visual anomia) or even visual associative agnosia (Alexander et al., 1989). If the infarct involves the medial temporal branches of the PCA, amnesia is also frequent (von Cramon et al., 1988). 14.2.4. ‘Subcortical aphasias’ It has been customary in the last 15 years to include a section on aphasia due to lesions focused on the capsulostriatal region (Alexander et al., 1987; Nadeau and Crosson, 1995) and on the thalamus (Cappa et al., 1989; Chatterjee et al., 1997; Crosson, 1999). We do not believe that there are any unique aphasia syndromes associated with these structures. In acute cases (see below) much of the aphasia is either due to transient ischemic effects on cortical function (Godefrey et al., 1992; Hillis and Heidler, 2002) or due to disruption

294

M.P. ALEXANDER AND A.E. HILLIS

of cortical networks (diaschisis). In chronic cases, there may be a specific set of impairments related to striatal (D’Esposito and Alexander, 1995; Mega and Alexander, 1994) or thalamic (Graff-Radford et al., 1985) lesion site, but the aphasias are often fairly subtle or secondary to more pervasive executive deficits in the case of striatal or anterior thalamic lesions or secondary to mild deficits in semantic activation after thalamic lesions. Just as ‘subcortical aphasia’ may be due to cortical involvement or disconnection, most ‘cortical’ aphasias are due to lesions with extensive damage to subcortical white matter and often to striatum, and large lesions in subcortical white matter are probably critical to classic syndromes. Where a specific subcortical lesion is key to a characteristic aphasia profile, it is included in the discussion of the aphasia syndrome (above) or in the review of specific language capacities (below). 14.2.5. Anomalous syndromes All of the foregoing has assumed a right-handed patient with a left hemisphere lesion. What of left-handers and what about aphasia after right hemisphere lesions? It is customary to consider these questions separately, but modern evidence suggests that they are two aspects of the same phenomenon: anomalous cerebral dominance. In a large population of left-handers—or more accurately ‘non-right-handers’—who become aphasic about 30% will have a right hemisphere lesion and 70% a left hemisphere lesion (Goodglass and Quadfasel, 1954; Basso et al., 1990). In a large population of right-handers who become aphasic 1–10% are reported to have a right hemisphere lesion, so-called crossed aphasics (Annett and Alexander, 1996; Marien et al., 2004). In both groups—left-handers (with left or right sided lesion) and crossed aphasics—there is a remarkable excess of anomalous organization of language and other cognitive operations as compared to the modal right-hander’s brain (Alexander and Annett, 1996). There are two other patient populations that have anomalous organization. In a group of right-handers with aphasia after left hemisphere lesions, a significant portion have very atypical impairments for the demonstrated lesion sites— approximately 14% in one large, well-described population (Basso et al., 1985). The pattern is usually much less overall but much more focal impairment than anticipated. There are right-handers with large left hemisphere lesions who have no aphasia but who demonstrate a classic ‘right hemisphere syndrome’: anosognosia, severe hemispatial neglect, and severe visuospatial impairment (Fischer et al., 1991). The frequency of this phenomenon is not known, but these patients surely have the same anomalous organization as crossed aphasics. They are

likely reported less commonly because their anomaly is failing to have the expected aphasia. Within these atypical aphasia–lesion correlations (Alexander and Annett, 1996; Marien et al., 2004), there are patients whose impairments are simply anomalously lateralized, i.e., the relationship of lesion site to deficits is reasonably typical, simply in the ‘wrong’ hemisphere for right-handers (considered mirror-image cases) and in the less common hemisphere for lefthanders. There are also patients whose impairments have anomalous localization, i.e., the relationship of lesion site to deficits is not typical, whichever hemisphere the lesion is in—right for crossed aphasics, left or right for left-handers, and left for atypical patients, such as in the Basso et al. study. When all of the patients with anomalous localization are considered together, they include a large number of cases with deficits limited to phonology despite very large perisylvian lesions (Alexander and Annett, 1996). In addition, analysis of cases of transcortical aphasias selected for language findings, independent of lesion consideration, has demonstrated a surprising number of crossed aphasics and a large number of large perisylvian lesions, both left and right hemisphere, even in patients with TCSA (Alexander and Annett, 1996; Berthier et al., 1991). This suggests that these patients have preserved phonology in the contralateral hemisphere. The two observations together imply that the second form of atypicality may arise when phonological and semantic capacities have lateralized to different hemispheres. There is no evidence that anomalous aphasias recover better than typical ones of comparable initial severity. There are other anomalies in all of these cases. Significant hemispatial neglect (a` la typical right hemisphere lesions) is much more common in crossed aphasia than in standard aphasia and is also common in left-handers with left hemisphere lesions and aphasia. Limb apraxia is much less common in crossed aphasia than in standard aphasia. Taken as a whole there are three conclusions from these populations. First, these anomalous phenomena are more common than common wisdom indicates. In a large stroke service with a few hundred admissions a year approximately 15% of patients are potentially anomalous if handedness is ignored. When clinical findings do not match lesion sites, consider an anomalous organization. Second, they fall into patterns of anomalous lateralization, anomalous localization, and combined. Third, the basic biological mechanisms for lateralization and localization of handedness and for cognitive functions are unknown. One theory suggests a single (unknown) gene could be sufficient to account for these patterns of typical and atypical organization (Annett and Alexander, 1996). It is not unlikely that

APHASIA general answers to lateralization could emerge from these populations. Based on the review thus far, a clinician could diagnose and localize any of the classic, chronic aphasia disorders. She/he might, however, be puzzled by the aphasia–lesion relationships of many patients with acute lesions. He/she probably could not define the fundamental linguistic deficits that may or may not be present in one or more of the syndromes. She/he could have almost no sense of the natural history or of the possible treatments of the aphasia. Those aspects are to be considered next.

14.3. Aphasia in the acute presentation Aphasia has not been studied as extensively in the acute stage, hours to days after onset, of stroke or other brain injury. Patients are, or at least are felt to be, ‘too sick’ or ‘too upset’ to be studied. There is also a common belief or concern that patients with acute stroke have an impaired level of consciousness. Most strokes (at least ischemic strokes) do not however cause overwhelming deficits, medical instability, or altered consciousness. Many patients with a recent stroke are medically stable and after the first few busy hours of testing are left alone and quite willing to participate in language studies. Therefore, investigating aphasia in the acute stage is feasible, but is it worthwhile? The most frequently cited reason for not studying aphasia in the acute phase is that language impairment in the first few days after stroke often seems to be a ‘moving target.’ This fluctuation of language impairment has generally been considered a nuisance to investigators who hope for stable, reliable performance on tests, but the variability of aphasia in early ischemic stroke is also informative if it reflects changes in cerebral blood flow that affect neural function. The symptoms and signs of stroke are generally sudden in onset, but the ischemic injury may evolve over hours or even days to weeks. In the acute stroke there is a core area of damaged tissue (infarct), surrounded by a larger area of marginally perfused tissue that is getting just enough blood to survive, but not enough to function. The dysfunctional region contributes, however, to the clinical picture. Furthermore, this area of ‘hypoperfused’ tissue (areas where the blood flow is insufficient to support neural function) may expand or contract depending on the status of the clot or obstruction in the vessel supplying that area and on the patient’s blood pressure. When the hypoperfused region enlarges, the patient’s condition, including potentially the aphasia, may worsen. When blood flow is partially or wholly restored to the hypoperfused area, either spontaneously or as a result of medical or

295

surgical intervention, the area of hypoperfusion becomes smaller, and the patient’s deficits improve. This concept of an ‘ischemic penumbra’ of dysfunctional, but salvageable, brain tissue surrounding the core infarct was developed in the 1970s with animal studies, but now underlies much of the rationale for acute stroke treatment. The role of hypoperfused or penumbral tissue in acute aphasia has only recently been investigated. The development of MRI and CT methods for measuring blood flow without use of radiographically active compounds has facilitated the study of language deficits due to low blood flow (even in the absence of structural damage). Magnetic resonance perfusion weighted imaging (PWI) and CT perfusion measure the difference between the time to arrival and the time to clearance of a bolus of intravenous contrast material. PWI shows areas of relative hypoperfusion; CT shows areas of quantitatively abnormal perfusion. When combined with structural imaging, these perfusion images have revealed some demonstrably reliable associations between the site of lesion, including the hypoperfused region, and specific aphasic phenomena in the acute stage (Hillis et al., 2002). The correlations between aphasic signs and lesion sites in acute stroke mirror those identified in studies of chronic stroke, but in a very specific manner. The correlations of acute aphasia, including the classic aphasia syndromes, with lesion site when area of hypoperfusion is included in the defined site match the correlations of chronic aphasia when lesion site is the chronic infarct. For instance, hypoperfusion and/or infarct of the territory of the superior division of the left middle cerebral artery—centered on Broca’s area—results in the classic presentation of Broca’s aphasia. What differs is permanence or stability of the Broca’s aphasia. These classic aphasia syndromes in the acute stage due to the combination of infarcted and ischemic tissues have also been reported in patients with infarcts restricted to subcortical areas. Several studies of patients with purely subcortical infarcts have demonstrated that damage to subcortical structures alone, at least in the acute stage, does not cause frank aphasia unless accompanied by cortical hypoperfusion (Skyhj-Olsen et al., 1986; Vallar et al., 1988; Hillis et al., 2002). One study of patients with purely subcortical infarcts went on to show that the type of aphasia observed after subcortical stroke depends on the site of cortical hypoperfusion (Hillis et al., 2004a). Low blood flow in the entire distribution of the superior division of the middle cerebral artery (MCA) caused classic Broca’s aphasia and the associated symptoms (Fig. 14.1). In contrast, patients with comparable subcortical infarcts, but low perfusion in the entire territory of the inferior division of the left MCA, caused Wernicke’s

296

M.P. ALEXANDER AND A.E. HILLIS

Fig. 14.1. Diffusion-weighted MRI demonstrates diffusion abnormality in the periventricular white matter of the left frontal lobe (left). The perfusion scan demonstrates that impaired perfusion actually involves an extensive region of the left frontal lobe (right) including frontal operculum (lower right). The patient’s acute aphasia profile was entirely compatible with the perfusion scan and recovery was good because there was no infarction in that territory. Cases of this type render uncertain clinical correlations of purely subcortical lesions with only standard MRI.

aphasia. When the subcortical infarct is associated with hypoperfusion of the entire area supplied by the middle cerebral artery, global aphasia is typically observed. When blood flow to the cortex can be at least partially restored, there is at least partial resolution of aphasia, even with no change in the the area of subcortical infarct (Hillis et al., 2002). When perfusion is restored to Wernicke’s area, word discrimination and other aspects of comprehension improve. When blood flow is restored

to the frontal operculum, speech articulation improves. These cases indicate that the cortical hypoperfusion, rather than the subcortical infarct, are responsible for the speech and language deficits in the acute stage. Chronic subcortical infarct may be associated chronic hypoperfusion of the cortex, reduced metabolism of the cortex, and/or microscopic damage (cellular loss) in the cortex, which may not be visible on structural imaging but may nevertheless cause aphasia.

APHASIA These studies of acute aphasia confirm the brain/language relationships defined by studies of chronic stroke, but acute aphasia can also reveal new insights into the neural basis of language functions. Studying acute aphasia can illuminate the effects of small lesions or small regions of hypoperfusion on language. Patients with small strokes are rarely studied in the chronic stage because they generally recover normal language within a few weeks, but small, discrete lesions may result in impairments in selective language functions that are otherwise hard to investigate. The capacity to study specific language functions repeatedly over a short time when areas of dysfunctional tissue due to low blood flow become functional again by restoring blood flow—‘temporary lesions’ are reversed allows very precise aphasia–lesion correlations. Strong evidence that a particular area of the brain is essential for a given language function is obtained when a function is impaired when a particular area is hypoperfused, and the function resolves immediately when that area is reperfused, This sort of investigation has revealed some of the subparts of vascular territories that are critical for subsets of each of the classic aphasia syndromes. As illustrated below, the co-occurrence of various deficits within each classic aphasia syndrome might be explained by the proximity of regions essential for various language processes. 14.3.1. Broca’s aphasia As noted, classic Broca’s aphasia includes: production of 1–2 word phrases with little or no grammatical structure; effortful, poorly articulated speech (aphemia); impaired sentence structure and poor spelling in written production; and difficulty understanding syntactically complex sentences. Phonemic and semantic paraphasias are prominent, and naming is often more impaired for verbs than nouns. It is implausible that a single underlying deficit is responsible for the diverse symptoms. Rather, it is likely that these language functions rely on adjacent areas of the brain within the same vascular territory, so that compromise of blood flow from that vessel can cause dysfunction of each of these adjacent areas and can thereby result in all of the symptoms. Consistent with this hypothesis are the observations that lesions of Broca’s area do not cause the entire syndrome of Broca’s aphasia. Only lesions of a more extensive region that includes Broca’s area produces the entire syndrome of Broca’s aphasia, and hypoperfusion of this extensive area also causes the complete syndrome, albeit transiently. Each of the discrete signs of Broca’s aphasia, including articulation impairment, can be due to hypoperfusion of part of Broca’s area (Hillis et al., 2004b). Even selective

297

impairment of naming of verbs, can be caused by hypoperfusion of part of Broca’s area, and reperfusion of this part of Broca’s area reverses the verb naming deficit (Hillis et al., 2003). 14.3.2. Wernicke’s aphasia Wernicke’s aphasia, with fluent, grammatical, empty and paraphasic language results from either damage (chronic) or hypoperfusion (acute) in the territory of the inferior division of the left MCA, including Wernicke’s area (superior temporal gyrus), the inferior and middle temporal gyri and the angular gyrus. Isolated hypoperfusion of just the posterior inferior/middle temporal and fusiform gyri results in impaired oral and written naming but intact comprehension. Reperfusion of this region (Brodmann’s area 37) results in recovery of oral and written naming (Fig. 14.2). When this same region (BA 37) is initially normal but becomes hypoperfused or infarcted, naming deteriorates. If it remains hypoperfused for a few days after stroke, even if not structurally damaged, naming remains impaired. By contrast, infarction of left, posterior superior temporal gyrus (Wernicke’s area) causes impaired word comprehension and so does hypoperfusion acutely. The severity of hypoperfusion of Wernicke’s area is strongly correlated with the severity of word discrimination impairment (Hillis et al., 2001b), and reperfusion in acute stroke (Fig. 14.2) results in improved word comprehension (Hillis and Heidler, 2002). 14.3.3. Transcortical aphasia One case of acute mixed transcortical aphasia had an infarct in the borderzone territory between the left anterior cerebral artery (ACA) and MCA plus hypoperfusion of Wernicke’s area. When Wernicke’s area was reperfused in this patient, comprehension, including word discrimination, improved, resulting in evolution to transcortical motor aphasia, compatible with the area of infarction (Hillis et al., 2001a). Acute transcortical sensory aphasia (TSA) has been described in cases of infarction of the left thalamus but associated with hypoperfusion and/or hypometabolism of the PCA territory. In six patients with chronic epilepsy, electrical stimulation of multiple posterior cortical sites demonstrated a clear double dissociation suggesting a disconnection between left hemisphere phonology and lexical–semantics (Boatman et al., 2000). Stimulation of the posterior superior and middle temporal gyri resulted in reversible TSA. Stimulation in adjacent posterior, superior sites resulted in Wernicke’s aphasia in the same patients.

298

M.P. ALEXANDER AND A.E. HILLIS

Fig. 14.2. Perfusion scan demonstrates acute perfusion defects in the left superior temporal gyrus. This defect was associated with acute impairments in comprehension that did not persist because the area did not go on to actual infarction. This case exemplifies one mechanism of recovery from acute aphasic deficits.

14.3.2. Global aphasia Acute global aphasia results from hypoperfusion of the entire MCA territory, and typically evolves to Broca’s aphasia if Wernicke’s area can be reperfused. Thus, restoration of blood flow, either by spontaneous recanalization of the inferior division of the MCA or interventions, can explain early recovery of word discrimination observed in about 25% of cases in the first few days. In other cases of global aphasia caused by poor blood flow in the entire left MCA distribution, reperfusion of Broca’s area results in evolution to Wernicke’s aphasia. 14.3.3. Anomic aphasia As noted above, acute, isolated impaired oral and written naming is associated with hypoperfusion and/or infarction of the left posterior inferior and middle temporal gyri (BA 37), and reperfusion results in recovery of anomia (Fig. 14.2). The fact that anomia is often the residual language deficit in all forms of aphasia underscores that naming is a complex process that depends on several brain regions, including BA 37 for word retrieval, Wernicke’s area for linking words to their meanings, and Broca’s area for articulating the word. 14.3.4. Conduction aphasia Acute conduction aphasia must be rare, if it occurs. In a series of 200 patients studied within 24 hours of stroke,

there was not a case. No patient had more impaired repetition than other forms of spoken output. This is not, however, necessarily the most defining feature of conduction aphasia. As described above, the combination of impaired phonological output and preserved comprehension may be the key features. Nevertheless, most patients who will show conduction aphasia in the post-acute phase probably reach criteria for Wernicke’s aphasia (Palumbo et al., 1992) or, rarely, Broca’s aphasia in the acute phase (Alexander et al., 1990). Cases of pure alexia, pure agraphia, and alexia with agraphia in the acute stage are described in a separate chapter.

14.4. The neural representation of language processes The prototypical aphasia syndromes—acute and chronic—described above are based on the anatomical relationship of the neural structures and networks that represent language. Because of spatial propinquities some combinations of deficits are more common than others, but the fundamental operations of the language system can be detected through the multidimensional syndromes. The enormous literature on functional imaging also illuminates some of these fundamental operations and will be judiciously called upon to clarify the operations. This brief review will proceed from the perception and motor boundaries of language to intrinsic

APHASIA linguistic operations to the more complex procedures of language. This trip will move in a centrifugal direction from perisylvian structures outward to more dorsal frontal and parietal and more ventral temporal structures. 14.4.1. Perception and production 14.4.1.1. Perception to language Auditory discrimination is essential for spoken language comprehension, and, as noted above, Heschel’s gyrus in the superior temporal gyrus is the site of the earliest cortical representation of phonetic discrimination. Damage to the auditory cortex will impair speech discrimination whatever the other deficits produced by additional injury. Damage to auditory cortex alone is rare, but small lesions of STG involving HG may have pure word deafness. Exactly the same analysis can be made for visual input. The perceptual unit is the letter (or common word fragments or short words) (Tarkiainen et al., 1999; Cohen et al., 2002). Lesion studies (discussed above and in the separate chapter on reading) and functional imaging studies point to a critical region of left temporo-occipital junction as essential for the letter/word recognition (Leff et al., 2001; Cohen et al., 2002). 14.4.1.2. Language to production The motor production of speech requires control of complex articulatory movements of the upper airway and oral cavity. It also requires control of voicing: amplitude (volume), timbre (affect), and coordination of breathing with the planned utterance length. Articulatory control is centered in the lowest portions of the left lower motor cortex (LMC), the immediately adjacent posterior frontal operculum (FOP) and the subjacent anterior superior insula (ASI). These areas represent the learned motor recruitment patterns for speech movements embedded in the final corticobulbar output (Dronkers, 1996). Through constant feedback with the auditory system, infants and children slowly learn to control the motor pathways to make sounds that match what they hear. Much babbling is probably ‘practicing.’ To gain this voluntary control, potent, primitive vegetative reflexes—rooting, sucking—must be inhibited in parallel with improving control. When damaged, articulation is slow and lacks dexterity, isolation of precise movements is contaminated by dystonic overflow, and transitions between speech elements are poorly coordinated. Control of the same musculature for other tasks is either not affected—singing—or only transiently affected—swallowing. This is a lateralized motor control deficit specific to a language operation. There are obviously numerous other motor disorders that can affect speech, and bilateral opercular–lower motor

299

cortex lesions exaggerate this deficit dramatically. Putaminal lesions reduce the amplitude of movements and may cause a decline in intelligibility. Voice control is more complex. Prosody may be determined by linguistic demands—the rising voice that marks a question, the alterations in timbre or pitch that mark emphasis, a parenthetical insertion, etc. Impairments to these aspects of prosody may occur with lesions in the same area discussed above for articulation control, usually in concert with dysarthria (Danly and Shapiro, 1982). Prosody may also be determined by nonlinguistic contexts—the rising pitch of alarm, the rate and emphasis characteristics of sarcasm, the timbre and volume changes of sadness, etc. (Pell, 1999). These appear represented in the homologous portion of the right posterior frontal lobe (Ross and Mesulam, 1979). Perhaps because they are not rehearsed nearly so much in early life, control of these voice capacities develops more slowly and, in some, incompletely. Lesions leave linguistic emphasis relatively unimpaired, but affective prosody reduced, giving the voice a flat, unemotional quality. Patients are often unable to produce melody (Nicholson et al., 2003). Dysprosody may be heard in all domains of speech with putaminal lesions or diseases, and it will have the same general properties as other motor impairments. The deficits are in amplitude, rate, or coordination. The motor production of writing is considered in another chapter. Here we will just point out the parallels with speech. As with the cortical representations for reading, control of writing is centered fairly remotely from perisylvian structures—for writing in the left superior parietal lobe (Menon and Desmond, 2001). These areas represent the learned motor recruitment patterns for all complex unimanual movements, and this lateralization is what is customarily meant by handedness. Motor control of writing requires representations of the complex movements of the fingers and hand that produce characteristic letter forms, initially with slow visual and proprioceptive feedback but eventually without absolute necessity for either. Writing has spatial elements that speaking lacks, as speaking has temporal elements that writing lacks. There are other spatially demanding motor systems for language production—American Sign Language (Hickok et al., 1996) and semaphore. 14.4.1.3. Phonological representations As noted above, from infancy, if not earlier, the human auditory cortex is exposed to those sounds that recur in the language environment. Not all sounds and sound combinations are meaningful in every language. The ones that are make up the structure of the language, and the members of this set are phonemes. The combination

300

M.P. ALEXANDER AND A.E. HILLIS

of auditory and some proprioceptive feedback and motor rehearsal eventually maps the meaningful phonemes into neural representations. Access to these phonological representations seems to depend on posterior STG and SMG (Demonet et al., 1992; Vandenberghe et al., 1996; Thierry et al., 1998; MacSweeney et al., 2002; Friederici et al., 2003; Muller et al., 2003), and on motor representations that become entwined with the motor programs in FOP, LMC and ASI (Thierry et al., 1998). Thus, damage to much of the perisylvian cortex can disrupt phoneme selection or production. This presumably underlies the clinical phenomenon that perisylvian lesions are all marked by impaired repetition. The linkage of SMG and FOP through the arcuate fasciculus was traditionally emphasized as the critical connection for production of phonology, but recent imaging techniques of dissecting connectivity with diffusion tensor weighting have demonstrated that there are both long and short association pathways connecting STG to SMG and SMG to FOP (Catani et al., 2005). The posterior SMG is the key locus of representation on phonological form. With FOP/LMC/ASI lesions production errors (phonemic paraphasias) often co-occur with motor production errors and the combination produces remarkable variability of phoneme output, sometimes called ‘apraxia of speech.’ Others use ‘apraxia of speech’ as the term for just the motor programming deficits (Dronkers, 1996), the profile we have labeled ‘aphemia’ (Schiff et al., 1983). With STG lesions phonemic errors are often combined with lexical–semantic errors, and the combination can produce well-articulated utterances that have the sound structure of real words but are not recognizable words (neologistic paraphasias). With SMG lesions, the phonemic errors occur in relative isolation. They are most frequent on words of high phonemic complexity (i.e., hippopotamus) or on runs of words with similar phonemic structures (i.e., tongue twisters). They often represent transpositions or perseverations between syllables or words that might be neighbors or at some distance in the utterance (‘My cog dates cates’ or ‘The book is on the bining toom table.’) Some phonemic paraphasias ‘accidentally’ create real, but unintended words (‘The cook is on the dining room cable’) referred to as formal verbal paraphasias. The reason for some of the phenomenology of Broca’s, Wernicke’s, and conduction aphasias should be obvious. This phonological system is also the neural basis for verbal STM, the ability to hold an utterance in mind, absent interfering verbal distractions, for a few seconds. It is usually believed to have two components within perisylvian cortex: a phonological trace held in SMG and a capacity for silent rehearsal requiring FOP/LMC (Wildgriber et al., 1999; Henson et al.,

2000). Thus, patients with lesions in this phonological system may have trouble with repetition for two reasons: 1) an inability to produce a target because of phonological substitutions or 2) loss of a lengthy trace due to the interference of output. The response ‘pistohotamus’ represents the first; reduced simple digit span, the second. 14.4.1.4. Lexical–semantic representations Modern notions of language identify two broad neural structures: a mental lexicon that represents all of the perceptual and associational experience that underlies the meaning of words, and a set of combinatorial procedures that allows the construction of an infinite variety of utterances to achieve the goal of communication. There is evidence that the mental lexicon is centered in the left temporal lobe and the multimodal association cortex of the SMG/AG region. The mental lexicon is not an orderly file cabinet or dictionary. A lifetime of visual perceptual, tactile, proprioceptive, kinematic, auditory, emotional, and lexical experience forms associative bonds that come to represent our semantic knowledge of things—the weight, feel, use, and look of tools; the movement, colors, locations, sounds of birds—and of concepts—the feeling, context, institutions, personal history of charity; the symptoms, signs, laboratory findings, etiologies of stroke. These forms of semantic knowledge are represented, or at least come to be represented, independently of the memory of the experiences of learning them. (There are, obviously, large realms of motor skills that have these properties, but that is a subject for the chapter on praxis.) Semantic knowledge is, then, not instantiated in a few neurons that ‘know’ about hammers. It is instantiated in networks of cortical regions, the weight of whose connections represent knowledge. These networks appear to have different critical neural loci depending on their various combinations of perceptual, tactile, etc. foundations. The fundamental structure of these networks is a matter of controversy (McClelland and Rumelhart, 1985). Is there a single semantic system that incorporates all domains of knowledge with differently weighted connections to different perceptual, proprioceptive, etc. representations (Lambon Ralph et al., 1999)? Or are there separable semantic systems based in those perceptual, proprioceptive, etc. representations (Warrington and Shallice, 1984)? Or is there a single semantic system driven by evolutionary exigencies to weight different domains differently (Caramazza and Shelton, 1998)? We are unable to wade into this controversy intelligently, but clinical and imaging studies indicate that the critical loci are somewhat different for different categories of semantic knowledge. The

APHASIA categories of living things that are differentiated by visual perceptual features—animals, vegetables, faces, facial expressions, topographic structure, etc.—appear to have critical loci in the inferior temporal and occipital regions. The representations are bilateral but asymmetrical: faces, facial expressions, and topographic structures more to the right (Evans et al., 1995) and other categories more to the left. The categories of meaningful movements and implements that are differentiated by a combination of visual, proprioceptive, and kinematic features appear to have a critical locus more parietal (DeRenzi and Lucchelli, 1988). Categories that incorporate more encyclopedic knowledge—historical facts and figures—may have critical loci in more anterior temporal regions. Knowledge of personally familiar people appears to have some of the properties of historical figures but also a great deal more personal experiential memory and emotional experience (Giovanello et al., 2003). There is some evidence that the more ‘singular’ the item represented—a particular person, a pet dog versus dogs in general, the Empire State Building as opposed to buildings in general, etc.—the more left lateralized the critical node in temporal structures will be (Gorno-Tempini and Price, 2001). But where do the words to represent semantic knowledge come from? This is another source of controversy. Words are a singular representation of knowledge, and proper names are the most singular representation. Semantic knowledge may permit progressive differentiation of numerous forms of animals: the category of small four-legged furry animals down to the category of dogs down to specific breeds down to personal pets within that breed down to their individual names. At each level there is associated encyclopedic knowledge that includes words: ‘animal,’ ‘dog,’ ‘Cavalier’ and finally ‘Gizmo.’ Thus, words are the result of a cascade of experience, learning, frequency of use, and specificity. Most observations suggest that words are represented in phonological forms that are embedded in the semantic representations and activated by the semantic context of retrieval. Thus, in aphasic patients, anomia may arise at many levels. It may on occasion be specific to one perceptual modality if that modality or its projections to the temporal lobe are damaged; thus, impaired naming of visually presented objects with left occipitotemporal lesions (‘visual anomia’ or ‘optic aphasia’). It may be due to damage to the critical semantic nodes such that inadequate semantic knowledge is activated to activate, in turn, phonological forms. (If semantic knowledge is sufficiently damaged, even providing the lexical form may not be sufficient for the patient to associate it with meaning.) It may be due to weakened associations between semantic and phonological representations, leading to production of related, usually

301

higher frequency or more familiar words, than the target. This observation underlies the terminological change of verbal paraphasia to semantic paraphasia. It may be due to damage to the phonological representation of the word despite normal activation of phonology from semantics, leading to phonemic paraphasias. It may be due to damage to the motor representations of the phonemes, leading to a variable mix of phonemic paraphasias and articulatory errors. It may be due, of course, to multiple levels of damage in the same patient. (There is a prefrontal form of anomia as well, discussed below.) The relationship of this model of lexical– semantics to the clinical phenomenology described above should be transparent: perception in sensory association cortices maps to semantic representations in association cortices maps to phonological representations in STG/SMG maps to motor programs in FOP/ LMC/ASI. The anomia common in some degenerative diseases is also due to damage to this system: early Alzheimer’s disease involves posterior association cortex diffusely; early semantic dementia (left temporal variant of FTD) specifically involves anterior temporal association cortex; one form of primary progressive aphasia—also probably a variant of frontotemporal dementia appears to involve FOP/SMG. 14.4.1.5. Combinatorial procedures of language As children develop language capacity they learn both broader and more specific semantic–lexical representations: from ‘juice’ meaning all liquid drinks to meaning a particular class of drink to methods of modifying ‘juice’ to specify type, temperature, amount, or timing. They develop the capacity to form sentences that capture even more specificity about juice: when it was or might be consumed, who provided it to whom, etc. Some of this complexity becomes represented in new lexical– semantic forms—locative and chronological prepositions, pronouns of various types, restricted rule-bound transformations (tense and number). Some of the complexity is due to learning procedures for assembling words in longer but specific forms; these are syntactical procedures—compound sentences, relative clauses, verb voicing, perfect tense structures (Pinker, 1991). Even higher forms of complexity come from learning procedures for assembling sentences into goal-directed discourse—telling stories, giving instructions, reporting a medical history. As verbal productions become more and more elaborate they require incorporation of more and more extra-linguistic capacities: recall from memory, expanded working memory, the ability to modify the narrative based on a computation of a listener’s knowledge or emotional reaction—what to leave in, what to omit, what to repeat, etc. (Reilly et al., 1998; Chapman et al.,

302

M.P. ALEXANDER AND A.E. HILLIS

2003). With practice and feedback we develop these capacities to quite variable extent and often in quite idiosyncratic domains. Much of secondary education is spent learning the general rules and techniques for production of narrative forms. Much of higher education is spent learning the rules and techniques for domain-specific narrative forms—a business prospectus, a medical history, a legal argument, etc. With experience—and there is nothing most humans practice as much in their lifetimes as narratives—many of the procedures of sentence and narrative become relatively independent of attention; they become automatically accessible to a larger communication goal. These procedures are represented in frontal structures and their discrete networks of striatal and cerebellar connections. Clinical studies have provided considerable illumination on the neural loci of these procedures. The more fundamental assembly—or combinatorial—procedures appear centered in posterior frontal regions (Crozier et al., 1999), and with increasing complexity, the procedures are centered more anteriorly, and the impairments become less transparently ‘aphasic’ (Alexander, 2003). They may be better viewed as impairments of the execution of communication goals—a form of executive impairment. There are clinical profiles associated with progressively more anterior lesions, but the boundaries between these disorders are fuzzy. TCMA is due to damage to the most fundamental assembly procedures; lesions are centered in left FOP and posterior MFG (Freedman et al., 1984). Dynamic aphasia is due to damage to a higher level of assembly of syntax; lesions are centered in left MFG and connections deep to MFG (Costello and Warrington, 1989). Discourse impairment (at least one form of it) is due to an inability to assemble goal-directed complex utterances; lesions are centered in left prefrontal cortex (Novoa and Ardila, 1987; Chapman et al., 1992). Somewhere along that spectrum, patients are no longer heard as ‘aphasic,’ but they are heard as vague, confused, hard to follow, etc. The role of subcortical structures in these procedures of language assembly is not as clear. Evidence from Parkinson’s disease, Huntington’s disease and functional imaging supports the claim that there is maintenance of topographic distinctions between the different levels of procedure (Crosson et al., 2001). The evidence for a cerebellar role comes from functional imaging and from the effects of childhood injuries on development of complex language skills (Riva and Giorgi, 2000). The striatal and cerebellar representations may be necessary for the procedures to become automatic, i.e., independent of attention. Lesions of left dorsal caudate (Mega and Alexander, 1994) and right

ventrolateral neocerebellum (Silveri et al., 1994) both disrupt narrative procedures in a manner very similar to prefrontal lesions. The final procedure necessary for narrative is context-specific word retrieval. When word retrieval is a naming task—a presented object—or is tightly embedded in a specific semantic structure—a familiar topic in a familiar setting, frontal lesions do not cause anomia. When word retrieval is in a novel context without external structure, word retrieval may be impaired by frontal and prefrontal lesions. Word list generation is often impaired despite normal confrontation naming. In an unfolding narrative, specific words must be retrieved in a very timely manner; frontal lesions impair this retrieval causing hesitations and struggle that may derail the entire narrative. Both clinical studies and functional imaging have demonstrated clear roles for the striatum and the contralateral ventrolateral cerebellum in these situations of rapid retrieval without external structure. If this chapter has been successful, the relationship between the fundamental operations of the brain’s language systems and the clinical phenomenology as well as the acute and chronic clinical–anatomical correlations should be clear.

14.5. Treatment Studies of aphasia in the first few days of stroke indicate that very early recovery of language occurs largely because of restoration of blood flow to areas that support various components of language (Hillis et al., 2001a; Hillis and Heidler, 2002). The most complete recovery appears to be recovery that occurs quickly, much as described above in the section on acute aphasia (Kertesz and McCabe, 1977; Holland et al., 1985). Subsequent recovery, weeks to months (Kertesz and McCabe, 1977; Wade et al., 1986; Enderby et al., 1987) after stroke, and more slowly after that (Pashek and Holland, 1988; Naeser et al., 1990), likely occurs as a result of partial injury to key areas (Vignolo et al., 1986; Naeser et al., 1990) and also reorganization of structure–function relationships (Weiller et al., 1995). It is well known that undamaged areas, including homologous areas of the right hemisphere (Doesborgh et al., 2004) and perilesional areas in the left hemisphere (Warburton et al., 1999) can assume the function of the damaged brain region. Where functional imaging has been able to identify the neural processes underlying, it appears that recovery based on reorganization of ipsilesional cortex is superior to contralateral control (Wade et al., 1986; Weiller et al., 1995). This reorganization might be facilitated by

APHASIA intense practice or retraining of language through speech and language therapy. Various therapy approaches have been shown to facilitate language recovery. Some therapies are aimed directly at the language impairment with progressive stimulation and shaping of responses. One strategy is use of a cuing hierarchy to evoke a desired utterance then progressively reducing the cues (Linebaugh, 1983). A related approach is to determine which cuing structure is most effective (semantic or phonemic) and then using that strategy to train a set of targets that are useful for the patient’s functional communication. In another approach, the response may be directly modeled, even with direct imitation, before eliciting the target response (Helm, 1981). These types of strategies appear to have a common basis: facilitating a correct response with less and less external structure. Their effectiveness implies a retained but damaged function that can be augmented with careful attention to training. It is likely that the basic facets of effective neurological training—errorless learning and massed practice—are the basis for effect. The only therapy that is labeled effective by the American Academy of Neurology is Melodic Intonation Therapy for severe nonfluent aphasia (Albert et al., 1973; AAN, 1994). Here the principle appears to be avoiding a profoundly blocked output system— articulated speech—by using a parallel output that does not require that system, in this case, placing propositional utterances into novel melodies, beginning with unison singing and progressing to independent intoned production. There is evidence that right hemisphere lesions can interfere with the efficacy of MIT (Naeser and Helm-Estabrooks, 1985), but there is also evidence that response to the technique hinges on reactivation of left hemisphere systems for output (Belin et al., 1996). There are other approaches that attempt to improve output by a similar strategy of circumventing a profoundly blocked avenue with a more intact one such as using writing to facilitate spoken output (Bruce and Howard, 1987) or relying on relatively spared components of the language task to compensate for the damaged components (e.g., using relatively intact access to word meaning to provide a self-generated semantic cue). An entirely different approach to therapy is to focus on pragmatic communication without any treatment directed at specific language impairments. The bestknown version of this approach is Promoting Aphasics Communication Effectiveness (PACE) (Aten et al., 1982). The patient is given a message that he/she must communicate to the therapist with whatever alternative method works—drawing, gestures, pointing to pictures or words, etc. when language is impaired.

303

Many of these interventions have been shown to be efficacious for individual patients in carefully designed single-case experiments, such as studies with multiple baseline across-behaviors design or crossover studies. A meta-analysis of efficacy of language therapy concluded that there was a moderate positive effect of therapy compared to no therapy (Robey, 1998). Two large studies of language therapy versus no therapy from Italy appear to indicate benefit as measured with standard aphasia tests (Basso et al., 1975; 1979), but in neither case was the nature of the therapy or even the method of determining optimal, individualized therapy described. In neither study was the assignment to therapy random. The large VA cooperative study on language therapy was randomized although unblinded and concluded that therapy (again structure was unspecified) was effective overall (Wertz et al., 1986). The control group received language stimulation from nonprofessionals and also showed improvement. A Cochrane Database review, however, concluded that trained nonprofessionals did not produce as much improvement as trained language therapists (Greener et al., 2000). In addition, the VA study could not demonstrate that there was a benefit of early therapy over delayed therapy. This finding probably reflects the reorganization under stimulation that is the basis for late treatment and recovery. There is some evidence that intensity of training can be a factor in response to treatment (Bhogal et al., 2003; Doesborgh et al., 2004). The details of these language therapies are beyond the scope of this chapter, but the interested reader may refer to recent volumes devoted to interventions for aphasia (Chapey, 2001; Hillis, 2002; 2005). There is a long history of drug trials for aphasia, dating back at least to Luria and the anticholinesterase, neostigmine (Luria, 1973), and there is some evidence that therapy can be augmented with medications. The most convincing benefit has been with use of amphetamines (Walker-Batson et al., 2001). Benefit was not lost when treatment was stopped. Numerous case reports of benefit with bromocriptine (Albert et al., 1988; MacLennan et al., 1991; Muller and von Cramon, 1994; Sabe et al., 1992) have not been confirmed in small controlled studies (Sabe et al., 1995). The nootropic agent piracetam had a modest benefit in chronic aphasia (Huber, 1999), but the effects were lost when the medication was stopped (Kessler et al., 2000). Cholinesterase inhibitors have been reported to have a small benefit (Greener et al., 2001; Berthier et al., 2003). Transcranial magnetic stimulation to the right homologue of Broca’s area facilitates language production in chronic nonfluent aphasia, but the effect is transient (Naeser et al., 2005).

304

M.P. ALEXANDER AND A.E. HILLIS

These studies imply that not all aphasic deficits reflect fixed structural limitations in language. There must be some stimulable structure that responds to the medication. Amphetamine may boost norepinephrine through auxillary pathways from locus ceruleus via the cerebellum. Cholinesterase inhibitors may augment acetylcholine at cortical receptors that have lost projections from nucleus basalis because of deep lesions; the majority of cholinergic pathways run in the external capsule and would be damaged by MCA infarcts that spared much of the target cortex. Dopaminergic agonists could act in a similar manner on medial frontal cortical targets, and at least reduce bradykinesia of speech. Alternatively, adrenergic agonists, cholinesterase inhibitors, and dopaminergic agonists may facilitate reorganization of structure–function relationships by augmenting synaptic plasticity (Hillis, 2005). What medications are most effective, and at what times and in what combinations and in what synergy with behavioral therapies, is simply unknown at present. A recent review covers these controversies thoroughly (Berthier, 2005). A major component of effective language therapy may be education of patient and family to use of adaptive behaviors. This may reduce communication frustration, caregiver stress, and dependence.

14.6. Conclusion The classic aphasia syndromes represent common patterns of language disorder. They have a great deal of consistency because the organization of language functions in the adult brain has a considerable consistency. When diseases begin with an acute destructive lesion, the initial profile of language impairment and its correlation with lesion site may or may not comply with the classic syndromes. In the acute phase, there may be more impaired neural function than is evident on structural imaging. Potentially reversible ischemia may account for early divergence between clinical picture and structural lesion. Damage to connections of a wide neural network involved in a language function may produce impairment at a distance from the structural lesion. Early recovery of language functions is no doubt due to resolution of some of these acute effects. This is an important window for neuromedical and neuroprotective intervention. Some of the anomalies of acute presentation are due to differences in the pathophysiology of different etiologies. Because tumors are slowly infiltrative, brain networks have considerable time to adapt, and even large, central tumors may present with modest anomic aphasia. Traumatic contusions have a propensity for inferior temporal regions, so anomic aphasia or TCSA are more

common after trauma than other etiologies. Intracerebral hemorrhages (ICH) may occur in distributions that are not constrained by vascular territories and, thus, may produce deficits that are perfectly compatible with lesion site but not common after infarctions. ICH may also have local effects beyond tissue destruction—edema, mass effect, inflammation, etc.—that produce an initial phase that appears excessively severe but allows for substantially greater late improvement. Other anomalous aphasic profiles may represent actual anomalous cerebral organization, either of lateralization or localization or both. These are relatively more common in left-handers, but perhaps absolutely nearly as common in right-handers. There are just a few rules for recognizing these patterns of anomalous organization. Some language functions appear quite tightly organized in limited cerebral structures, and, thus, they may be relatively severely impaired with a critical small lesion or part of more complex aphasia when subsumed in a larger lesion. Cortical systems for speech mechanisms (aphemia), phonetic discrimination (pure word deafness) and perhaps phonology (conduction aphasia) are examples. They may also be the most striking residual deficit after language systems that are more diffusely distributed recover, thus aphemia out of acute Broca’s aphasia. Other language systems appear more diffusely organized in networks, and, thus, are likelier to be impaired after a wide localization of lesions, the mechanisms for discourse (prefrontal, striatal, and even cerebellum) and word comprehension (variously temporal, parietal, occipital, even bilaterally) are examples. As the distributed networks for these operations reorganize after partial damage, there may be considerable late recovery. Such a mechanism may account for the gradual recovery of comprehension after incomplete injury to temporoparietal structures, marked by the evidence that perilesional and contralateral structures play a role in recovery. The plasticity of these networks may allow for structured stimulation—i.e., language therapy—to accelerate reorganization although, presumably, the therapy must be properly structured to support learning—reorganization—of the targeted function. The several ascending subcortical systems— noradrenergic, serotinergic, and cholinergic—appear to play a significant role in facilitating reorganization of some or all of these networks although the mechanisms and possible interactions are not known. When this Handbook is revised for a third edition in 20 years, the mechanisms of early recovery and late plasticity, the targets of pharmacological intervention, and the proper structure of behavioral therapy are all likely to be much clearer.

APHASIA

References AAN (1994). Assessment: melodic intonation therapy. Report of the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology. Neurology 44: 566–568. Albert ML, Bachman D, Morgan A, et al. (1988). Pharmacotherapy for aphasia. Neurology 38: 877–879. Albert ML, Sparks RW, Helm NA (1973). Melodic intonation therapy for aphasia. Arch Neurol 29: 130–131. Alexander MP (2003). Transcortical motor aphasia: A disorder of language production. In: M D’Esposito (Ed.), Neurological Foundations of Cognitive Neuroscience. Cambridge, Mass, The MIT Press, pp. 165–174. Alexander MP, Annett M (1996). Crossed aphasia and related anomalies of cerebral organization: Case reports and a genetic hypothesis. Brain Lang 55: 213–239. Alexander MP, Baker E, Naeser MA, et al. (1992a). Neuropsychological and neuroanatomical dimensions of ideomotor apraxia. Brain 115: 87–107. Alexander MP, Fischer RS, Friedman R (1992b). Lesion localization in apractic agraphia. Arch Neurol 49: 246–251. Alexander MP, Hiltbrunner B, Fischer RS (1989). Distributed anatomy of transcortical sensory aphasia. Arch Neurol 46: 885–892. Alexander MP, Naeser MA, Palumbo C (1987). Correlations of subcortical CT lesion sites and aphasia profiles. Brain 110: 961–991. Alexander MP, Naeser MA, Palumbo C (1990). Broca’s area aphasia. Neurology 40: 353–362. Annett M, Alexander MP (1996). Atypical cerebral dominance: Predictions and tests of the right shift theory. Neuropsychologia 34: 1215–1227. Aten JL, Caligiuri MP, Holland AL (1982). The efficacy of functional communication therapy for chronic aphasic patients. J Speech Hear Disord 47: 93–96. Auerbach SH, Allard T, Naeser M, et al. (1982). Pure word deafness. Analysis of a case with bilateral lesions and a defect at the prephonemic level. Brain 105: 271–300. Basso A, Capitani E, Vignolo LA (1979). Influence of rehabilitation on language skills in aphasic patients. A controlled study. Arch Neurol 36: 190–196. Basso A, Faglioni P, Vignolo LA (1975). [Controlled study of language re-education in aphasia: Comparison between treated and untreated aphasics]. Rev Neurol (Paris) 131: 607–614. Basso A, Farabola M, Grassi MP, et al. (1990). Aphasia in left-handers. Comparison of aphasia profiles and language recovery in non-right-handed and matched right-handed patients. Brain Lang 38: 233–252. Basso A, Lecours AR, Moraschini S, et al. (1985). Anatomoclinical correlations of the aphasias as defined through computerized tomography: Exceptions. Brain Lang 26: 201–229. Belin P, Van Eeckhout P, Zilbovicius M, et al. (1996). Recovery from nonfluent aphasia after melodic intonation therapy: A PET study. Neurology 47: 1504–1511.

305

Berndt RS, Caramazza A (1999). How ‘regular’ is sentence comprehension in Broca’s aphasia? It depends on how you select the patients. Brain Lang 67: 242–247. Berthier ML (2005). Poststroke aphasia: Epidemiology, pathophysiology, and treatment. Drugs Aging 22: 163–182. Berthier ML, Hinojosa J, Martin Mdel C, et al. (2003). Openlabel study of donepezil in chronic poststroke aphasia. Neurology 60: 1218–1219. Berthier ML, Starkstein SE, Leiguarda R, et al. (1991). Transcortical aphasia. Importance of the nonspeech dominant hemisphere in language repetition. Brain 114: 1409–1427. Bhogal SK, Teasell R, Speechley M (2003). Intensity of aphasia therapy, impact on recovery. Stroke 34: 987–993. Boatman D, Gordon B, Hart J, et al. (2000). Transcortical sensory aphasia: Revisited and revised. Brain 123: 1634–1642. Bogousslavsky J, Assal G, Regli F (1987). [Infarct in the area of the left anterior cerebral artery. II. Language disorders]. Rev Neurol (Paris) 143: 121–127. Bogousslavsky J, Regli F, Assal G (1986). The syndrome of unilateral tuberothalamic artery territory infarction. Stroke 17: 434–441. Bogousslavsky J, Regli F, Assal G (1988). Acute transcortical mixed aphasia. A carotid occlusion syndrome with pial and watershed infarcts. Brain 111: 631–641. Bruce C, Howard D (1987). Computer-generated phonemic cues: An effective aid for naming in aphasia. Br J Disord Commun 22: 191–201. Cappa SF, Vignolo LA, Papagno C, et al. (1989). Thalamic aphasia. Neurology 39: 874. Caramazza A, Berndt RS, Basili AG, et al. (1981). Syntactic processing deficits in aphasia. Cortex 17: 333–348. Caramazza A, Capitani E, Rey A, et al. (2001). Agrammatic Broca’s aphasia is not associated with a single pattern of comprehension performance. Brain Lang 76: 158–184. Caramazza A, Shelton JR (1998). Domain-specific knowledge systems in the brain: The animate–inanimate distinction. J Cogn Neurosci 10: 1–34. Catani M, Jones DK, ffytche DH (2005). Perisylvian language networks of the human brain. Ann Neurol 57: 8–16. Chapey R (2001). Language Intervention Strategies in Aphasia and Related Neurogenic Communication Disorders. Williams and Wilkens, Baltimore. Chapman SB, Culhane KA, Levin HS, et al. (1992). Narrative discourse after closed head injury in children and adolescents. Brain Lang 43: 42–65. Chapman SB, Max JE, Gamino JF, et al. (2003). Discourse plasticity in children after stroke: Age at injury and lesion effects. Pediatr Neurol 29: 34–41. Chatterjee A, Yapundich R, Mennemeier M, et al. (1997). Thalamic thought disorder: On being ‘a bit addled’. Cortex 33: 419–440. Cohen L, Lehericy S, Chochon F, et al. (2002). Languagespecific tuning of visual cortex? Functional properties of the Visual Word Form Area. Brain 125: 1054–1069. Coslett HB, Brashear HR, Heilman KM (1984). Pure word deafness after bilateral primary auditory cortex infarcts. Neurology 34: 347–352.

306

M.P. ALEXANDER AND A.E. HILLIS

Coslett HB, Roeltgen DP, Gonzalez Rothi L, et al. (1987). Transcortical sensory aphasia: Evidence for subtypes. Brain Lang 32: 362–378. Costello AL, Warrington EK (1989). Dynamic aphasia. The selective impairment of verbal planning. Cortex 25: 103–114. Crosson B (1999). Subcortical mechanisms in language: Lexical–semantic mechanisms and the thalamus. Brain Cogn 40: 414–438. Crosson B, Sadek JR, Maron L, et al. (2001). Relative shift in activity from medial to lateral frontal cortex during internally versus externally guided word generation. J Cogn Neurosci 13: 272–283. Crozier S, Sirigu A, Lehericy S, et al. (1999). Distinct prefrontal activations in processing sequence at the sentence and script level: An fMRI study. Neuropsychologia 37: 1469–1476. Cummings JL, Benson F, Hill MA, et al. (1985). Aphasia in dementia of the Alzheimer type. Neurology 35: 394–397. D’Esposito M, Alexander MP (1995). Subcortical aphasia: Distinct profiles following left putaminal hemorrhage. Neurology 45: 38–41. Damasio AR, Damasio H (1983). The anatomic basis of pure alexia. Neurology 33: 1573–1583. Damasio AR, McKee J, Damasio H (1979). Determinants of performance in color anomia. Brain Lang 7: 74–85. Damasio H, Grabowski TJ, Tranel D, et al. (2001). Neural correlates of naming actions and of naming spatial relations. Neuroimage 13: 1053–1064. Danly M, Shapiro B (1982). Speech prosody in Broca’s aphasia. Brain Lang 16: 171–190. Demonet JF, Chollet F, Ramsay S, et al. (1992). The anatomy of phonological and semantic processing in normal subjects. Brain 115: 1753–1768. DeRenzi E, Lucchelli F (1988). Ideational apraxia. Brain 111: 1173–1185. Doesborgh SJ, van de Sandt-Koenderman MW, Dippel DW, et al. (2004). Effects of semantic treatment on verbal communication and linguistic processing in aphasia after stroke: A randomized controlled trial. Stroke 35: 141–146. Dronkers NF (1996). A new brain region for coordinating speech articulation. Nature 384: 159–161. Dronkers NF, Wilkins DP, Van Valin RD, Jr., et al. (2004). Lesion analysis of the brain areas involved in language comprehension. Cognition 92: 145–177. Enderby PM, Wood VA, Wade DT, et al. (1987). Aphasia after stroke: A detailed study of recovery in the first three months. Int Rehabil Med 9: 162–165. Esmonde T, Giles E, Xuereb J, et al. (1996). Progressive supranuclear palsy presenting with dynamic aphasia. J Neurol Neurosurg Psychiatry 60: 403–410. Evans JJ, Heggs AJ, Antoun N, et al. (1995). Progressive prosopagnosia associated with selective right temporal atrophy: A new syndrome? Brain 118: 1–13. Fischer RS, Alexander MP, Gabriel C, et al. (1991). Reversed lateralization of cognitive functions in right handers. Brain 114: 245–261.

Freedman M, Alexander MP, Naeser MA (1984). Anatomic basis of transcortical motor aphasia. Neurology 34: 409–417. Friederici AD, Ruschemeyer SA, Hahne A, et al. (2003). The role of left inferior frontal and superior temporal cortex in sentence comprehension: Localizing syntactic and semantic processes. Cereb Cortex 13: 170–177. Garrard P, Lambon Ralph MA, Patterson K, et al. (2005a). Semantic feature knowledge and picture naming in dementia of Alzheimer’s type: A new approach. Brain Lang 93: 79–94. Garrard P, Maloney LM, Hodges JR, et al. (2005b). The effects of very early Alzheimer’s disease on the characteristics of writing by a renowned author. Brain 128: 250–260. Geschwind N (1965). Disconnexion syndromes in animals and man. II. Brain 88: 585–644. Geschwind N, Fusillo M (1966). Color-naming defects in association with alexia. Arch Neurol 15: 137–146. Giovanello KS, Alexander MP, Verfaellie M (2003). Differential impairment of person-specific knowledge in a patient with semantic dementia. Neurocase 9: 15–26. Godefroy O, Dubois C, Debachy B, et al. (2002). Vascular aphasias: Main characteristics of patients hospitalized in acute stroke units. Stroke 33: 702–705. Godefrey O, Rousseaux M, Leys D, et al. (1992). Frontal lobe dysfunction in unilateral lenticulostriate infarcts: Prominent role of cortical lesions. Arch Neurol 49: 1285–1289. Goodglass H (1993). Understanding Aphasia. Academic Press, San Diego. Goodglass H, Quadfasel FA (1954). Language laterality in left-handed aphasics. Brain 77: 521–548. Goodglass H, Wingfield A (1993). Selective preservation of a lexical category in aphasia: Dissociations in comprehension of body parts and geographical place names following focal brain lesion. Memory 1: 313–328. Gorno-Tempini ML, Dronkers NF, Rankin KP, et al. (2004). Cognition and anatomy in three variants of primary progressive aphasia. Ann Neurol 55: 335–346. Gorno-Tempini ML, Price CJ (2001). Identification of famous faces and buildings: A functional imaging study of semantically unique items. Brain 124: 2087–2097. Graff-Radford NR, Damasio H, Yamada T, et al. (1985). Nonhaemorrhagic thalamic infarction. Clinical, neuropsychological and electrophysiological findings in four anatomical groups defined by computerized tomography. Brain 108: 485–516. Greener J, Enderby P, Whurr R (2000). Speech and language therapy for aphasia following stroke. Cochrane Database Syst Rev 2: CD000425. Greener J, Enderby P, Whurr R (2001). Pharmacological treatment for aphasia following stroke. Cochrane Database Syst Rev 4: CD000424. Hanlon R, Lux W, Dromerick A (1999). Global aphasia without hemiparesis: Language profiles and lesion distribution. J Neurol Neurosurg Psychiatry 66: 365–369. Helm N (1981). Helm Elicited Language Program for Syntax Stimulation. Pro-Ed, Austin, TX.

APHASIA Henson RN, Burgess N, Frith CD (2000). Recoding, storage, rehearsal, and grouping in verbal short-term memory: An fMRI study. Neuropsychologia 38: 426–440. Hickok G, Bellugi U, Klima ES (1996). The neurobiology of sign language and its implications for the neural basis of language. Nature 381: 699–702. Hillis AE (2002). Handbook of Adult Language Disorders: Integrating Cognitive Neuropsychology, Neurology, and Rehabilitation. Psychology Press, Philadelphia. Hillis AE (2005). For a theory of rehabilitation: Progress in the decade of the brain. In: P Halligan, D Wade (Eds.), Effectiveness of Rehabilitation of Cognitive Deficits. Oxford University Press, Oxford, UK, pp. 271–280. Hillis AE, Barker P, Beauchamp N, et al. (2001a). Restoring blood pressure reperfused Wernicke’s area and improved language. Neurology 56: 670–672. Hillis AE, Barker PB, Wityk RJ, et al. (2004a). Variability in subcortical aphasia is due to variable sites of cortical hypoperfusion. Brain Lang 89: 524–530. Hillis AE, Heidler J (2002). Mechanisms of early aphasia recovery: Evidence from MR perfusion imaging. Aphasiology 16: 885–896. Hillis AE, Wityk RJ, Barker PB, et al. (2002). Subcortical aphasia and neglect in acute stroke: The role of cortical hypoperfusion. Brain 125: 1094–1104. Hillis AE, Wityk RJ, Barker PB, et al. (2003). Neural regions essential for writing verbs. Nat Neurosci 6: 19–20. Hillis AE, Wityk RJ, Tuffiash E, et al. (2001b). Hypoperfusion of Wernicke’s area predicts severity of semantic deficit in acute stroke. Ann Neurol 50: 561–566. Hillis AE, Work M, Breese EL, et al. (2004b). Re-examining the brain regions crucial for orchestrating speech articulation. Brain 127: 1479–1487. Hodges JR, Davies RR, Xuereb JH, et al. (2004). Clinicopathological correlates in frontotemporal dementia. Ann Neurol 56: 399–406. Hodges JR, Miller B. (2001). The neuropsychology of frontal variant frontotemporal dementia and semantic dementia. Introduction to the special topic papers: Part II. Neurocase 7: 113–121. Holland AL, Miller J, Reinmuth OM, et al. (1985). Rapid recovery from aphasia: A detailed language analysis. Brain Lang 24: 156–173. Howes D, Geschwind N. (1964). The brain and disorders of communication. Quantitative studies of aphasic language. Res Publ Assoc Res Nerv Ment Dis 42: 229–244. Huber W (1999). The role of piracetam in the treatment of acute and chronic aphasia. Pharmacopsychiatry 32: 38–43. Kertesz A, McCabe P (1977). Recovery patterns and prognosis in aphasia. Brain 100: 1–18. Kertesz A, Phipps JB (1977). Numerical taxonomy of aphasia. Brain Lang 4: 1–10. Kessler J, Thiel A, Karbe H, et al. (2000). Piracetam improves activated blood flow and facilitates rehabilitation of poststroke aphasic patients. Stroke 31: 2112–2116. Knepper LE, Biller J, Tranel D, et al. (1989). Etiology of stroke in patients with Wernicke’s aphasia. Stroke 20: 1730–1732.

307

Kohn SE, Goodglass H (1985). Picture-naming in aphasia. Brain Lang 24: 266–283. Kreisler A, Godefroy O, Delmaire C, et al. (2000). The anatomy of aphasia revisited. Neurology 54: 1117–1123. Lambon Ralph MA, Graham KS, Patterson K, et al. (1999). Is a picture worth a thousand words? Evidence from concept definitions by patients with semantic dementia. Brain Lang 70: 309–335. Leff AP, Crewes H, Plant GT, et al. (2001). The functional anatomy of single-word reading in patients with hemianopic and pure alexia. Brain 124: 510–521. Linebaugh C (1983). Treatment of anomic aphasia. In: C Perkins (Ed.), Current Therapies for Communication Disorders: Language Handicaps in Adults. Thieme-Stratton, New York. Luria AR (1973). The Working Brain. Basic Books, New York. MacLennan DL, Nicholas LE, Morley GK, et al. (1991). The effects of bromocriptine on speech and language function in a man with transcortical motor aphasia. Clin Aphasiol 21: 145–155. MacSweeney M, Woll B, Campbell R, et al. (2002). Neural systems underlying British Sign Language and audiovisual English processing in native users. Brain 125: 1583–1593. Maeshima S, Sekiguchi E, Kakishita K, et al. (2003). Agraphia with abnormal writing stroke sequences due to cerebral infarction. Brain Inj 17: 339–345. Maeshima S, Toshiro H, Sekiguchi E, et al. (2002). Transcortical mixed aphasia due to cerebral infarction in left inferior frontal lobe and temporo-parietal lobe. Neuroradiology 44: 133–137. Maeshima S, Yamaga H, Masuo O, et al. (1998). [A case of agraphia due to cerebral infarction in the left parietal lobe]. No Shinkei Geka 26: 431–437. Marien P, Paghera B, De Deyn PP, et al. (2004). Adult crossed aphasia in dextrals revisited. Cortex 40: 41–74. Masdeu JC, Schoene WC, Funkenstein HH (1978). Aphasia following infarction of the left supplementary motor area. Neurology 28: 1220–1223. Mazzocchi F, Vignolo LA (1979). Localisation of lesions in aphasia: Clinical-CT scan correlations in stroke patients. Cortex 15: 627–653. McClelland JL, Rumelhart DE (1985). Distributed memory and the representation of general and specific information. J Exp Psychol 114: 159–188. McFarling D, Rothi LJ, Heilman KM (1982). Transcortical aphasia from ischaemic infarcts of the thalamus: A report of two cases. J Neurol Neurosurg Psychiatry 45: 107–112. Mega MS, Alexander MP (1994). The core profile of subcortical aphasia. Neurology 44: 1824–1829. Menon V, Desmond JE (2001). Left superior parietal cortex involvement in writing: Integrating fMRI with lesion evidence. Brain Res Cogn Brain Res 12: 337–340. Mohr JP, Pessin M, Finkelstein S, et al. (1978). Broca aphasia: Pathologic and clinical aspects. Neurology 28: 311–324.

308

M.P. ALEXANDER AND A.E. HILLIS

Muller RA, Kleinhans N, Courchesne E (2003). Linguistic theory and neuroimaging evidence: An fMRI study of Broca’s area in lexical semantics. Neuropsychologia 41: 1199–1207. Muller U, von Cramon DY (1994). The therapeutic potential of bromocriptine in neuropsychological rehabilitation of patients with acquired brain damage. Prog Neuropsychopharmacol Biol Psychiatry 18: 1103–1120. Nadeau S (1988). Impaired grammar with normal fluency and phonology. Brain 111: 1111–1137. Nadeau S, Crosson B (1995). Subcortical aphasia. Brain Lang 58: 355–402. Naeser MA, Gaddie A, Palumbo CL, et al. (1990). Late recovery of auditory comprehension in global aphasia. Improved recovery observed with subcortical temporal isthmus lesion vs Wernicke’s cortical area lesion. Arch Neurol 47: 425–432. Naeser MA and Hayward RW (1978). Lesion localization in aphasia with cranial computed tomography and the Boston Diagnostic Aphasia Exam. Neurology 28: 545–551. Naeser MA, Helm-Estabrooks N (1985). CT scan lesion localization and response to melodic intonation therapy with nonfluent aphasia cases. Cortex 21: 203–223. Naeser MA, Martin PI, Nicholas M, et al. (2005). Improved picture naming in chronic aphasia after TMS to part of right Broca’s area: An open-protocol study. Brain Lang 93: 95–105. Nicholson KG, Baum S, Kilgour A, et al. (2003). Impaired processing of prosodic and musical patterns after right hemisphere damage. Brain Cogn 52: 382–389. Nicolai A, Lazzarino LG (1991). Language disturbances from paramedian thalamic infarcts: A CT method for lesion location. Rev Neurol (Paris) 61: 86–91. Novoa OP and Ardila A. Linguistic abilities in patients with prefrontal damage. Brain Lang 30: 206–225.. Palumbo CL, Alexander MP, Naeser M (1992). CT scan lesion sites associated with conduction aphasia. In: SE Kohn (Ed.), Conduction Aphasia. Lawrence Erlbaum, Hillsdale, NJ, pp. 51–75. Pashek GV, Holland AL (1988). Evolution of aphasia in the first year post-onset. Cortex 24: 411–423. Pell MD (1999). The temporal organization of affective and non-affective speech in patients with right-hemisphere infarcts. Cortex 35: 455–477. Pinker S (1991). Rules of language. Science 253: 530–535. Rapcsak SZ, Krupp LB, Rubens AB, et al. (1990). Mixed transcortical aphasia without anatomic isolation of the speech area. Stroke 21: 953–956. Reilly JS, Bates EA, Marchman VA (1998). Narrative discourse in children with early focal brain injury. Brain Lang 61: 335–375. Riva D, Giorgi C (2000). The cerebellum contributes to higher functions during development. Evidence from a series of children surgically treated for posterior fossa tumours. Brain 123: 1051–1061. Robey RR (1998). A meta-analysis of clinical outcomes in the treatment of aphasia. J Speech Lang Hear Res 41: 172–187.

Roeltgen DP, Heilman KM (1983). Apractic agraphia in a patient with normal praxis. Brain Lang 18: 35–46. Ross ED, Mesulam MM (1979). Dominant language functions of the right hemisphere? Prosody and emotional gesturing. Arch Neurol 36: 144–148. Rubens AB (1976). Transcortical motor aphasia. Studies in Neurolinguistics 1: 293–306. Sabe L, Leiguarda R, Starkstein S (1992). An open-labeled trial of bromocriptine in nonfluent aphasia. Neurology 42: 1637–1638. Sabe L, Salvarezza F, Cuerva AG, et al. (1995). A randomized, double-blind, placebo-controlled study of brmocriptine in nonfluent aphasia. Neurology 45: 2272–2274. Schiff HB, Alexander MP, Naeser MA, et al. (1983). Aphemia. Clinical-anatomic correlations. Arch Neurol 40: 720–727. Shindler AG, Caplan LR, Hier DB (1984). Intrusions and perseverations. Brain Lang 23: 148–158. Silveri MC, Leggio MG, Molinari M (1994). The cerebellum contributes to linguistic production: A case of agrammatic speech following a right cerebellar lesion. Neurology 44: 2047–2050. Sinyor D, Jacques P, Kaloupek DB (1986). Post stroke depression and lesion location. Brain 109: 537–546. ¨ berg RG (1986). Cortical hypoSkyhj-Olsen T, Bruhn P, O perfusion as a possible cause of ‘subcortical aphasia.’ Brain 106: 393–410. Starkstein SE, Bryer JB, Berthier ML, et al. (1991). Depression after stroke: The importance of cerebral hemisphere asymmetries. J Neuropsychiatry Clin Neurosci 3: 276–285. Tarkiainen A, Helenius P, Hansen PC, et al. (1999). Dynamics of letter string perception in the human occipitotemporal cortex. Brain 122: 2119–2132. Vallar G, Perani D, Cappa SF, et al. (1988). Recovery of aphasia and neglect after subcortical stroke: Neuropsychological and cerebral perfusion study. J Neurol Neurosurg Psychiatry 51: 1269–1276. Vandenberghe R, Price C, Wise R, et al. (1996). Functional anatomy of a common semantic system for words and pictures. Nature 383: 254–256. Vignolo LA, Boccardi E, Caverni L (1986). Unexpected CTscan findings in global aphasia. Cortex 22: 55–69. von Cramon DY, Hebel N, Schuri U (1988). Verbal memory and learning in unilateral posterior cerebral infarction. A report on 30 cases. Brain 111: 1061–1077. Wade DT, Langton Hewer R, David RM, et al. (1986). Aphasia after stroke: Natural history and associated deficits. J Neurol Neurosurg Psychiatry 49: 11–16. Walker-Batson D, Curtis S, Natarajan R, et al. (2001). A double-blind, placebo-controlled study of the use of amphetamine in the treatment of aphasia. Stroke 32: 2093–2098. Warburton E, Price CJ, Swinburn K, et al. (1999). Mechanisms of recovery from aphasia: Evidence from positron emission tomography studies. J Neurol Neurosurg Psychiatry 66: 155–161.

APHASIA Warrington EK, Shallice T (1984). Category specific semantic impairments. Brain 107: 829–854. Weiller C, Isensee C, Rijntjes M, et al. (1995). Recovery from Wernicke’s aphasia: A positron emission tomographic study. Ann Neurol 37: 723–732. Wertz RT, Weiss DG, Aten J, et al. (1986). Comparison of clinic, home, and deferred language treatment for aphasia:

309

A Veteran’s Administration cooperative study. Arch Neurol 43: 653–658. Wildgriber D, Kischka U, Ackermann H, et al. (1999). Dynamic pattern of brain activation during sequencing of word strings evaluated by fMRI. Cogn Brain Res 7: 285–294.

Handbook of Clinical Neurology, Vol. 88 (3rd series) Neuropsychology and behavioral neurology G. Goldenberg, B.L. Miller, Editors # 2008 Elsevier B.V. All rights reserved

Chapter 15

Cognitive processes underlying reading and writing and their neural substrates ARGYE E. HILLIS* Johns Hopkins University School of Medicine, Johns Hopkins Hospital, Baltimore, MD, USA

15.1. Introduction Reading and writing are language functions that are increasingly important in everyday living. Communication via e-mail, internet shopping, learning via webbased courses, paying bills through web sites, searching for information on the internet are all common daily activities. Stroke (or other focal brain injury) can selectively impair the ability to read and/or write, impeding these daily interactions. This chapter will focus on such impairments in reading—alexia (also called acquired dyslexia) and writing—agraphia (also called acquired dysgraphia) that result from neurological disorders. Although alexia and agraphia are not always identified in the traditional neurological examination, they are frequent, disabling, and dehumanizing consequences of stroke. In fact, alexia and agraphia are among the most common residual deficits after partial recovery of language after stroke (Beeson et al., 2005). Furthermore, alexia can be the only clinically important manifestation of strokes involving the left posterior cerebral artery (PCA) territory or posterior watershed area between the left PCA and left middle cerebral artery (MCA) (Binder and Mohr, 1992; Cohen et al., 2004; Hillis et al., 2005b); and agraphia may be the only manifestation of strokes in the territory of the superior division of the left MCA (Hillis et al., 1999; 2004b). Reading and writing deficits may also be the earliest manifestations of dementias, such as Alzheimer’s disease (Hillis et al., 1995; Luzzatti et al., 2003; Groves-Wright et al., 2004; Garrard et al., 2005), primary progressive aphasia (Graham et al., 2004; Hillis et al., 2004c), or posterior cortical atrophy (Mendez and Cherrier, 1998; Charles and Hillis, 2005). *

Although the prevalence of acquired reading and writing impairments is not known, it approaches or exceeds the combined prevalence of aphasia and dementia, since aphasia and dementia only rarely spare written language skills. It is estimated that one million people in the United States alone have aphasia (http://aphasia.org/NAAfact sheet.html). Although stroke and focal dementias are the most common causes of alexia and agraphia, other common neurological disorders, such as traumatic brain injury, multiple sclerosis, and brain tumors can also affect these skills. Therefore, assessment of reading and writing functions should be an important part of neurological and neuropsychological examinations. Although reading and writing skills may be influenced by genetics as well as education, these variables are likely to influence development of these skills more than loss of the acquired skills. The focus of this chapter will be on alexia and agraphia that occur as a result of brain damage, assuming previous proficiency of reading and writing. Of course, the extent to which one has become proficient, and perhaps the method of education that leads to proficiency, will interact with the effects of neurological disease or injury. Genetic factors also influence the risk of particular types of stroke, dementia, and other neurological disorders that cause acquired alexia and agraphia, but these factors are beyond the scope of this chapter. Instead, the emphasis will be on the location of injury within the brain that results in impairment of particular cognitive processes underlying reading and/or spelling. Evidence that damage to specific brain regions causes impairment of specific components of reading and writing provides some evidence for the neural regions that are required for these complex tasks. Evidence from functional imaging of normal

Correspondence to: Argye E. Hillis, MD, MA, Professor of Neurology, Johns Hopkins University School of Medicine, Johns Hopkins Hospital, Meyer 6-113, 600 N. Wolfe Street, Baltimore, MD 21287, USA. E-mail: [email protected], Tel: (410)-614-2381, Fax: (410) 955-0672.

312

A.E. HILLIS

subjects regarding the neural regions engaged in reading and spelling, which complement evidence from lesion/ deficit association studies, will also be briefly reviewed. Clinical evaluation and treatment of acquired reading and spelling disorders is a broad and exciting topic, which has been reviewed elsewhere (e.g., Beeson and Hillis, 2001; Hillis and Heidler, 2005).

15.2. Cognitive processes underlying reading and spelling Written language comprehension and production are complex tasks that require a number of cognitive processes, some of which are shared by verbal language comprehension and production. For example, reading aloud and understanding a written word requires, at the very least, the following cognitive processes: (1) computation of a series of increasingly abstract representations of the visual stimulus, beginning with a retinotopic representation of the variations in light intensities that encodes the visual features and culminates in a word-centered representation of the series of graphemes that no longer encodes location, orientation, case, or font (Hillis and Caramazza 1990; 1995; McCandliss et al., 2003); (2) access to learned orthographic information (the stored spelling of the word) that allows recognition of the word as a familiar word; (3) access to a lexical–semantic representation—the meaning of the word; (4) access to, or assembly of, the pronunciation of the word; (5) motor planning and programming of the movements of the jaw, lips, palate, tongue, vocal folds, and respiratory muscles required to articulate the word, and (6) movements of the articulators themselves (see Ellis and Young, 1988; Rapp et al., 2000; Hillis, 2003, for review). These cognitive processes underlying reading are schematically represented in Fig. 15.1. Similarly, writing a familiar word

to dictation engages, at the very least, the following cognitive processes: (1) auditory processing of the spoken word, culminating in access to a learned phonological representation that allows recognition of the spoken word as a familiar word; (2) access to the lexical–semantic representation of the word; (3) access to, or assembly of, an orthographic representation (the series of graphemes that constitute the learned spelling of the word); (4) access to the specific letter shapes or letter shape-specific motor plans, that support writing the word in a particular font or case; (5) motor planning and programming of the movements of the fingers, wrist, and arm required to write; and (6) implementing the actual movements (Beeson and Hillis, 2001; Hillis, 2001; Rapp, 2002; see Fig. 15.2). The extent to which the spelling process is simply the reverse of the reading process, engaging the same representations but in the opposite order, remains controversial. However, the available evidence suggests that at least the stored phonological representations (learned word pronunciations), lexical–semantic representations (learned meanings of words), and orthographic representations (learned spellings) are shared by reading aloud and writing to dictation (Hillis and Rapp, 2004). Both reading aloud and spelling to dictation of unfamiliar words can also be accomplished by ‘phonics’—applying knowledge of orthography-to-phonology correspondence (for reading) and phonology-to-orthography correspondence (for spelling) to assemble a plausible response. For example, such processes are used in trying to pronounce or spell unfamiliar surnames. Although it would seem most efficient for one to be simply the reverse of the other, such simplicity is not found in English. For example, the sound /s/ can be spelled with either the letters s or c, and the letter c can be read as /s/ or /k/ depending on the subsequent vowel; but the letter k cannot be pronounced as /s/. Therefore, cake has only one plausible Writing

Reading Letter-shape–Grapheme Conversion

words

unfamiliar words

Phonologic Input Lexicon Orthographic Input Lexicon

Semantic System OPC

Semantic System

Modality-Independent Lexical Representation Phonologic Output Lexicon unfamiliar words

unfamiliar words

Fig. 15.1. A schematic representation of the cognitive processes underlying reading.

Modality-Independent Lexical Representation

POC

Orthographic Lexicon Graphemic Buffer Grapheme-Letter-shape Conversion

Fig. 15.2. A schematic representation of the cognitive processes underlying writing.

COGNITIVE PROCESSES UNDERLYING READING AND WRITING pronunciation, while ‘cake’ has several plausible spellings (e.g., kake, kacke, caik). Nevertheless, both processes require parsing the stimulus, converting from one modality to the other, and short-term storage of the assembled pronunciation or spelling during motor output. Some of these subcomponents of sublexical processes might be common to reading and writing, while other subcomponents might be distinct for the two tasks. For example, reading an unfamiliar word also requires ‘blending’ the sounds, but writing does not require blending of the letters, except perhaps in script.

15.3. Neural regions essential for cognitive processes underlying reading and spelling 15.3.1. Spatial attention and computation of a word-centered graphemic description Models of written word recognition often assume that word recognition, like object recognition, requires computation of a series of representations of the visual stimulus that are increasingly abstract, culminating in a word-centered (‘object-centered’) representation of the stimulus word that is independent of location of the printed word with respect to the viewer, and independent of the case, font, or orientation of the printed word (Monk, 1985; Caramazza and Hillis, 1990; McCandliss et al., 2003). That is, such a representation specifies the series of abstract letter identities, or graphemes, in the stimulus. This ‘graphemic description’ would be identical for the stimulus chair written in the far left corner of the page, the stimulus CHAIR written vertically across the center of the page, or even the stimulus chair written upside down on the right side of the page. Computation of such a grapheme description can be impaired by spatial attention deficits, particularly hemispatial neglect— impaired attention to the side contralateral to brain damage. This deficit is most common after damage to the nondominant (usually right) hemisphere, affecting attention to the left. Hemispatial neglect can impair computation of early, retinotopic representations of the visual stimulus (typically resulting in impaired reading of stimuli on the left side of the page), a stimulus-centered representation of the word (typically resulting in errors on the left side of the individual written words, regardless of their location with respect to the viewer), or computation of a word-centered grapheme description (resulting in errors on the contralesional side of the canonical representation of the word). Evidence for these patterns of hemispatial neglect in reading has been reviewed previously (Hillis and Caramazza, 1990; 1995). Illustrative cases of each type are described below.

313

A recent study of 76 patients with acute, ischemic stroke indicated that these different patterns of ‘neglect dyslexia’ result from damage to different brain regions. For example, patients with viewer-centered or ‘egocentric’ neglect dyslexia, characterized by errors in reading that increased as a function of how far the word is presented to the left of the viewer, was associated with acute infarcts and/or hypoperfusion (poor blood flow, resulting in dysfunction) of the right angular gyrus (Hillis et al., 2005c). For example, a patient with viewer-centered neglect dyslexia made significantly more errors in reading the left, contralesional sides of words when words were presented on the left side of the page or the left side of her body than when the words were presented on the right side of the page or right side of her body. She also omitted the initial words on each line in reading a paragraph. This patient showed hypoperfusion in the right angular gyrus and inferior frontal gyrus. In contrast, stimulus-centered or ‘allocentric’ neglect dyslexia resulted from acute infarct or hypoperfusion of the right temporal gyrus. For example, a patient with stimulus-centered neglect dyslexia made errors on the left side of the word (the initial letters; e.g., chair ! fair) on about 50% of words, whether words were presented on the left or right of her body. She also made errors on the left side of the stimulus, now the final letters of the word (e.g., chair ! chain), in reading words in mirror-reversed or upside-down print. Her left stimulus-centered neglect dyslexia was associated with hypoperfusion of right superior and inferior temporal gyrus. Object- (word-) centered neglect dyslexia was rare, and only occurred in left-handed patients with damage to the left temporal gyrus. For instance, a patient with object-centered neglect dyslexia was left-handed, non-aphasic, and made errors on the right sides (final letters) of the canonical representations of words in reading standard and mirror-reversed print (e.g., huge ! hug; undo ! under), recognizing words spelled aloud (e.g., eastward ! eastwest; considerate ! consideration) and in spelling (e.g., thin ! thing; huge ! hugh; speaking ! speath). Her right objectcentered neglect was associated with hypoperfusion of left superior and inferior temporal gyrus. Together, these results were interpreted as consistent with the view that the dorsal stream of visual processing (including parietal cortex) is critical for planning responses to stimuli in particular locations with respect to the viewer, whereas the ventral stream (including temporal cortex) is critical for determining the identity of stimuli, including written words, irrespective of their location (Hillis et al., 2005a). Of note, the viewer-centered and stimulus-centered spatial representations need not be computed for certain reading tasks (e.g., recognition of words spelled aloud to the patient) or spelling tasks (e.g., oral spelling).

314

A.E. HILLIS

However, a word-centered graphemic description would be computed in these latter tasks, and held in a ‘buffer’ while the grapheme description is matched to a stored representation for recognition (in reading) or while the letters are written (in spelling). Patients with word-centered neglect dyslexia therefore also have word-centered neglect dysgraphia (spelling errors on the contralesional side of the canonical representation of the word; e.g., Baxter and Warrington, 1983; Barbut and Gazzaniga, 1987; Hillis and Caramazza, 1990; Warrington, 1991; Hillis and Caramazza, 1995). In contrast, patients with stimulus-centered or viewercentered neglect dyslexia do not make spelling errors on the contralesional side of the word, but do make errors such as failure to cross t’s or dot i’s, or make perseverative stroke errors (e.g., 3þ humps in the letter m), due to poor visual monitoring of their writing, especially on the left (Ellis et al., 1987). Functional imaging studies of reading also indicate that computation of a word-centered graphemic description, independent of font, case, or location, results in activation of left or bilateral midfusiform gyrus (part of BA 37) (Cohen et al., 2000; Gros et al., 2001; Cohen et al., 2002; Polk et al., 2002; McCandliss et al., 2003; Cohen and Dehaene, 2004). However, Price and colleagues (Price et al., 2003; Price and Devlin, 2003; 2004) argue that left midfusiform gyrus shows activation in modality-independent lexical processing. In fact, both hypotheses might be correct. In a study of reading and oral and written naming of 80 patients with acute left hemisphere stroke, infarct and/or hypoperfusion of left midfusiform gyrus alone did not impair reading comprehension or written lexical decision (reading tasks that require computation of a word-centered graphemic representation for written word recognition, but that do not require lexical output), but did impair modalityindependent lexical output (Hillis et al., 2005c). Although these results suggest that left midfusiform gyrus is not essential for computation of a word-centered grapheme description or other component of written word recognition, they do not rule out the possibility that this area is consistently engaged in computing a word centered graphemic description. In fact, other lesion studies and functional imaging studies indicate that either left or right midfusiform gyrus is necessary for computing a word-centered graphemic description for written word recognition. If only the right midfusiform gyrus is available for this process, the splenium of the corpus callosum is essential for transferring this representation to the left hemisphere for other components of reading. For instance, a patient with an acute infarct including left midfusiform gyrus was still able to compute a word-centered graphemic description (e.g., for spelling) but was unable to recognize or read words when the splenium was hypoperfused (Marsh

and Hillis, 2005). When the splenium was reperfused, his written word recognition (written lexical decision and reading comprehension) recovered. However, he still had a mild impairment in modality-independent lexical output (naming), probably due to the infarct of the left midfusiform gyrus. These results suggest that right midfusiform gyrus might be able to assume the role of left midfusiform gyrus in computing a word-centered graphemic description, but not the role of left midfusiform gyrus in accessing a modality-independent lexical representation for output (see below for more evidence of the role of this area in lexical output). 15.3.2. Access to stored orthography for orthography-to-phonology conversion or phonology-to-orthography conversion As mentioned earlier, orthography-to-phonology conversion (OPC) for reading phonically, and phonology-toorthography conversion (POC) for spelling phonically, are complex processes. There is considerable debate as to whether these processes are really distinct from lexical reading and spelling, or whether there is a continuum of mappings between orthographic units (from single letters through syllables and words) and phonological units. Computational models of reading have been developed that do not include a separate orthographic lexicon (Seidenberg and McClelland, 1989; Plaut and Shallice, 1993). Although these models can account for many patterns of impaired reading that result from brain damage, they have trouble accounting for the clearest dissociations between word and pseudoword reading. For example, there are patients who can read words relatively well, but have virtually no ability to assemble a plausible pronunciation for a pseudoword (classically ascribed to impaired sublexical OPC, with intact orthographic lexicon, or ‘phonological alexia’; Shallice, 1988; Ellis and Young, 1988). There are also patients who can assemble plausible pronunciations of words and pseudowords, but mispronounce irregular words (e.g., read bear as ‘beer’), classically ascribed to impaired access to the orthographic or phonological lexicon, with intact OPC mechanisms, or ‘surface dyslexia’ (Patterson et al., 1985). Similar, but less ‘pure’ dissociations can be observed after ‘lesioning’ a computational model of reading without separate OPC mechanisms and lexicons, however. This debate is not settled. By either hypothesis, some knowledge about orthographic units, and their correspondence with phonological units (through the word level, to explain correct reading of uniquely spelled words such as yacht) must be learned and stored. Studies of alexia after acute and chronic stroke (Benson, 1979; Black and Behrmann, 1994; Hillis et al.,

COGNITIVE PROCESSES UNDERLYING READING AND WRITING 2001a; Love et al., 2002; Hillis et al., 2005b) indicate that the left angular gyrus is critical for access to learned orthography. This area may be especially critical for sublexical assembly of plausible pronunciations of unfamiliar written words (through ‘phonics’). For example, in a large study of acute stroke patients, reading of pseudowords that was significantly more impaired than reading of real words was associated with acute infarct and/or hypoperfusion of the left angular gyrus (Hillis et al., 2001a). However, all patients with this pattern had some trouble in reading real words as well. For example, the patient whose scans are shown in Fig. 15.3 had impaired reading of words and pseudowords, although he made significantly more errors on pseudowords, after an acute infarct and hypoperfusion of left angular gyrus. In fact, impaired reading of real words was also significantly associated with infarct and/or hypoperfusion of the left angular gyrus in this study. There is some evidence from functional imaging of reading development in normal and dyslexic children that the left angular gyrus is engaged in reading words early in the development of reading, and continues to be engaged in reading of pseudowords (Pugh et al., 2001). However, in good readers, activation associated with real word reading will shift to the left occipitotemporal regions (fusiform gyrus) during development. Furthermore, another fMRI study of reading demonstrated correlated activity between left angular gyrus and extrastriate occipital and temporal lobe regions during word reading (Horwitz et al., 1998), indicating a role of this region in reading. Other fMRI studies have

315

more directly shown activation in left angular gyrus during these aspects of reading (Joubert et al., 2004). Assembling an orthographic response using sublexical or lexical phonology-to-orthographic (POC) mechanisms for spelling may also depend on the function of the left angular gyrus. Among patients with acute stroke, impairment in spelling pseudowords relative to words was associated with acute infarct and/or hypoperfusion of left angular gyrus and supramarginal gyrus (Hillis et al., 2002). Consistent with the hypothesis that POC mechanisms may not be completely distinct from access to orthographic representations, lesions involving left angular gyrus have also been found to be associated with impairments in accessing orthographic representations for spelling in chronic stroke (Dejerine, 1892; Beauvois and Derouesne, 1981; Roeltgen and Heilman, 1984; Goodman and Caramazza, 1986; Rapcsak and Beeson, 2002) as well as in acute stroke (Hillis et al., 2001a). Furthermore, in a study of patients with Alzheimer’s disease, impaired access to orthographic representations for spelling (as manifest by impaired spelling of irregular, but not regular, words) was found to be associated with reduced metabolism in left angular gyrus (Peniello et al., 1995). Functional imaging studies of spelling also reveal significant spelling-specific activation in left angular gyrus in most individual subjects studied (Beeson et al., 2003; Hsieh and Rapp, 2004). Together, results from lesion studies and functional imaging studies indicate that the left angular gyrus

Fig. 15.3. Magnetic resonance diffusion-weighted images and perfusion-weighted images of a patient with impaired reading of words and pseudowords, but significantly more errors on pseudowords, after an acute infarct and hypoperfusion of left angular gyrus.

316

A.E. HILLIS

may be essential for accessing learned orthographic knowledge necessary for sublexical and lexical reading and spelling. Some patients with left angular gyrus lesions studied in the chronic stage of stroke are impaired only in reading or only in spelling, probably because they recovered either reading or spelling function (through reorganization of structure/function relationships, with or without rehabilitation). Both lesion studies of alexia and functional imaging of reading development also implicate left posterior, inferior frontal gyrus in later stages of OPC that require assembly of a phonological representation for articulatory output (Pugh et al., 2001; Hillis et al., 2004d). Left posterior, inferior frontal gyrus may also be essential for phonological segmentation required for assembling a plausible spelling response using POC mechanisms. Lesions of this area interfere with pseudoword spelling in patients studied in the chronic period after stroke (Rapcsak and Beeson, 2002), and this area shows activation in normal subjects during fMRI studies of spelling (Beeson et al., 2003; Hsieh and Rapp, 2004). 15.3.3. Access to lexical semantics Lesions involving a wide range of areas in the left temporal and parietal lobes can influence performance on lexical–semantic tasks. Likewise, functional imaging studies of semantic tasks (e.g., word association tasks) show activation in many areas in frontal, temporal, and parietal tasks. Nevertheless, some of these areas may not be necessary or even engaged in the accessing lexical–semantic representations (the meanings of words; e.g., what makes a ‘tiger’ different from a ‘lion’), but rather engaged in other aspects of the task (e.g., a role of the posterior frontal lobe in evaluating the relationship between meanings of two words or selecting a response; see Bookheimer, 2002; and Hart et al., 2002 for review). Other areas of left temporal and parietal cortex may represent features of the conceptual representation (e.g., color, shape, function). Linking word meanings (distributed lexical–semantic representations) to word forms (lexical–orthographic and lexical– phonological representations) seems to require adequate function of the left superior temporal gyrus (Wernicke’s area). For example, spoken and written word comprehension are disrupted by acute lesions or poor blood flow in Wernicke’s area (Hillis et al., 2001b; 2004a), chronic lesions in Wernicke’s area (Hart and Gordon, 1990) and cortical stimulation of Wernicke’s area (Lesser et al., 1986). PET studies show activation of Wernicke’s area in word comprehension tasks as well (Wise et al., 1991; Whatmough and Chertkow, 2002), although fMRI studies inconsistently show activation in Wernicke’s area in comprehension tasks. One possible reason that functional imaging studies do not

consistently show activation in this area during task relative to baseline or control tasks is that Wernicke’s area may also be activated during the ‘control task’ or rest (since subjects generally think in meaningful ‘words,’ even during control tasks). 15.3.4. Access to lexical representations for output Oral reading and spelling also require access to lexical representations for output. Several studies indicate that lesions or hypoperfusion in posterior, inferior temporal gyrus and fusiform gyrus (BA 37) are associated with impaired access to modality-independent lexical representations for output in reading, spelling, and naming in acute stroke, as indicated earlier (Hillis et al., 2001a; 2002; 2005b) and chronic stroke (Raymer et al., 1997; Foundas et al., 1998). Furthermore, early damage to this area can result in developmental dyslexia with impaired access to the lexical representations for reading, but spared sublexical reading (Samuelsson, 2000). Chronic stroke patients with damage to left BA 37 were found to make more errors on irregular than regular words in spelling, indicating they also relied more on sublexical spelling (Rapcsak and Beeson, 2004). Likewise, Pugh and colleagues reported that as children improve in reading by developing lexical representations, activation shifts from left angular gyrus to left BA 37 (Pugh et al., 2001). Functional neuroimaging studies have often reported activation in BA 37 during tasks that require access to lexical representations for spelling (Petrides et al. 1995; Beeson et al., 2003; Hsieh and Rapp, 2004; Rapcsak and Beeson, 2004) or reading (see Cohen and Dehaene, 2004 for review). But since other functional neuroimaging studies have reported activation in this area when words are presented auditorily (Buckner et al., 2000; Chee et al., 1999; Demonet et al., 1992; 1994; Giraud and Price, 2001; Wise et al., 2001), or presented in the tactile modality with blind subjects (Buchel et al., 1998), or with sign language in the deaf (Corina et al., 2007), this region may engage in modality-independent lexical processing as well as computation of a location-independent graphemic representation, as discussed above. 15.3.5. Access to modality-specific representations for reading and spelling Reading a word aloud requires access to not only a modality-independent lexical representation (sometimes called a ‘lemma’), but also a lexical–phonological representation—the learned pronunciation of the word. Likewise, spelling a word requires access to both a lemma representation and a lexical–orthographic representation (the learned spelling of the word). Some patients are selectively impaired in accessing lexical–

COGNITIVE PROCESSES UNDERLYING READING AND WRITING phonological representations or the lexical–orthographic representations of verbs with spared access to nouns and spared access to verbs in the other modality. That is, some reported patients have impaired spelling of verbs (to dictation and written naming) but spared spelling of nouns and spared oral reading and oral naming of both nouns and verbs, while others have impaired oral reading and oral naming of verbs but spared oral reading and oral naming of nouns and relatively spared spelling of both nouns and verbs (e.g., Caramazza and Hillis, 1991). The fact that such patients can spell or read aloud nouns in the impaired modality rules out a more peripheral impairment in production (e.g., speech articulation or motor writing skills). These results indicate that there may be separate brain regions necessary for accessing modality-specific representations for output in reading and spelling. For example, left posterior inferior

317

frontal gyrus (PIFG) may be more important for accessing the lexical orthographic and lexical phonological representations of verbs than nouns in reading and spelling, as well as naming. To illustrate, two patients with hypoperfusion of left PIFG (Broca’s area) were selectively impaired in written naming of verbs; written naming of nouns and oral naming of both nouns and verbs were spared. Importantly, written naming of verbs improved when blood flow was restored in Broca’s area, thereby providing further evidence that this region was crucial for accessing orthographic representations of verbs for output (Hillis et al., 2003; see also Fig. 15.4, Panel A). Other patients with acute stroke showed similar evidence that this region is critical for accessing modality-specific lexical representations for output in reading, writing, and naming, that is more important for verbs than nouns (e.g., Hillis et al., 2004b for

Fig. 15.4. Panel A. MRI scans of two patients with pure agraphia, with impaired access to orthographic representations for output (affecting verbs more than nouns) and impaired use of POC but relatively intact oral naming. A T2 scan of one patient with an infarct in left Broca’s area (BA 44/45) is shown on the left; DWI and PWI scans of the other patient, with hypoperfusion of Broca’s area (BA 44/45), are shown on the right. Panel B. Left: CT scan of a patient with a focal hemorrhage in BA 6, associated with acute onset of selectively impaired written spelling (with intact oral spelling) and impaired conversion between upper and lower case letters. Right: DWI and PWI scans of a second patient with the same pattern of spelling after acute ischemic stroke in roughly the same area.

318

A.E. HILLIS

evidence from spelling). Therefore, patients with Broca’s aphasia (usually associated with damage to Broca’s area) typically have trouble naming verbs relative to nouns (Miceli et al., 1984; Berndt et al., 1997; Zingeser and Berndt, 1990). Damage to this region results in greater difficulty reading verbs than nouns (Nadeau et al., 2000). It is possible that this region may be necessary for selecting a particular morphological form of a verb (e.g., walks versus walking), whereas other regions are essential for accessing the orthographic representation of the stem (e.g., walk) for both nouns and verbs. 15.3.6. Access to letter shape-specific representations or motor programs for spelling

font and case, and a motor program for producing the shape) or just access to a letter-shape specific motor program (Rapcsak and Beeson, 2002). Nevertheless, recent studies of patients with pure agraphia in acute stroke indicate that hypoperfusion and/or infarct in BA 6 may be associated with impaired production of specific letter shapes, indicated by (1) better oral spelling than written spelling, and (2) impaired transcoding of upper to lower case and vice versa (Fig. 15.3, panel B, right) (Hillis et al., 2002; 2004b). Furthermore, this pattern of performance in spelling, in a patient with pure written agraphia but intact oral spelling, was observed in a patient with a highly focal hemorrhage in BA 6 (Fig. 15.4, Panel B, left).

15.4. Summary Once an orthographic representation of a word is accessed or computed from sublexical POC mechanisms, the abstract letter identities, or graphemes, must be converted to specific letter shapes. There is some controversy over whether this process requires two steps (access to a stored representation of the letter shape, in a particular

There is a convergence of evidence from studies of lesions (and areas of dysfunctional brain tissue) associated with alexia and agraphia and from functional imaging studies of reading and spelling in normal subjects that these complex processes require a network of

Fig. 15.5. Areas of activation (increased BOLD signal on fMRI) during a task that required knowledge of the spellings of words (adapted from Hsieh and Rapp, 2004). (A) BA44 showed activation in 6/6 subjects; (B) left BA37 showed activation in 4/6 subjects; (C) left BA39 showed activation in 3/6 subjects.

COGNITIVE PROCESSES UNDERLYING READING AND WRITING

319

Fig. 15.6. (A) Neural regions where damage (indicated by DWI and/or conventional MRI or CT) or hypoperfusion (indicted by PWI or PET) is associated with impaired reading and spelling. (B) Neural regions where activation (increased BOLD effect) is associated with spelling in normal subjects (data from a single representative subject shown). (C) Neural regions where activation is associated with reading in normal subjects (adapted from a meta-analysis by Turkeltaub et al., 2002).

interacting brain regions, each with a distinct role in reading and/or writing. For example, Fig. 15.5 shows the areas of activation revealed by fMRI during a task that required knowledge of the spellings of words (adapted from Hsieh and Rapp, 2004). The functional imaging data and evidence from stroke patients together suggest some specialization of neural regions for particular cognitive processes underlying these complex tasks of reading and spelling, and that damage to any one of these regions can disrupt reading and/or spelling, albeit in different ways. Fig. 15.6(A), shows the areas of brain that when damaged (as indicated by DWI and/ or conventional MRI or CT) or hypoperfused (as indicated by PWI or PET) result in impaired reading and spelling as reviewed above. Fig. 15.6(B) shows the areas of activation in response to spelling tasks in normal subjects (data from one representative subject shown). Fig. 15.6(C) shows a meta-analysis of areas of activation in response to reading in normal subjects

(adapted from Turkeltaub et al., 2002). Together, these studies indicate that at least the following regions are necessary, and perhaps sufficient, for reading and spelling: left PIFG (BA 44), left dorsal lateral prefrontal gyrus (BA 6), left posterior STG (BA 22), and left inferior temporal/fusiform gyrus (BA 37). Although there is striking convergence of data from various methodologies that these areas comprise a network of neural regions involved in reading and spelling, the precise roles of each of these areas are just beginning to be defined.

Acknowledgements Many of the studies reported in this paper were supported by NIH through RO1 DC05375 and RO1 NS047691. I gratefully acknowledge this support. I am also thankful to the patients who cheerfully participated in this research and to Brenda Rapp for many contributions.

320

A.E. HILLIS

References Barbut D, Gazzaniga MS (1987). Disturbances in conceptual space involve language and speech. Brain 110: 1487–1496. Baxter DM, Warrington EK (1983). Neglect dysgraphia. J Neurol Neurosurg Psychiatry 46: 1073–1078. Beauvois MF, Derouesne J (1981). Lexical or orthographic agraphia. Brain 104: 21–49. Beeson P, Hillis AE (2001). Comprehension and production of written words. In R Chapey (Ed.), Language Intervention Strategies in Aphasia and Related Neurogenic Communication Disorders, 4th edn. Williams and Wilkins, Baltimore, pp. 572–604. Beeson PM, Magliore JG, Robey RR (2005). Letter-by-letter reading: Natural recovery and response to treatment. Behav Neurol 16: 191–202. Beeson PM, Rapcsak SZ, Plante E, et al. (2003). The neural substrates of writing: A functional magnetic resonance imaging study. Aphasiology 17: 647–665. Benson DF (1979). Aphasia, Alexia, and Agraphia. Churchill Livingstone, New York. Berndt RS, Mitchum CC, Haendiges AN, et al. (1997). Verb retrieval in aphasia. Brain Lang 56: 68–106. Binder JR, Mohr JP (1992). The topography of callosal reading pathways. A case-control analysis. Brain 115: 1807–1826. Black S, Behrmann M (1994). Localization in alexia. In A Kertesz (Ed.), Localization and Neuroimaging in Neuropsychology. Academic Press, San Diego. Bookheimer S (2002). Functional MRI of language: New approaches to understanding the cortical organization of semantic processing. Annu Rev Neurosci 25: 151–188. Buchel C, Price C, Friston K (1998). A multimodal language region in the ventral visual pathway. Nature 394: 274–277. Buckner RL, Koutstal W, Schacter DL, et al. (2000). Functional MRI evidence for a role of frontal and inferior temporal cortex in amodal components of priming. Brain 123: 620–640. Caramazza A, Hillis AE (1990). Levels of representation, coordinate frames, and unilateral neglect. In MJ Riddoch, (Ed.), Neglect and the Peripheral Dyslexias. Special Issue, Cogn Neuropsychol: 391–445. Caramazza A, Hillis AE (1991). Lexical organization of nouns and verbs in the brain. Nature 349: 788–790. Charles R, Hillis AE (2005). Posterior cortical atrophy: Clinical presentation and cognitive deficits compared to Alzheimer’s disease. Behav Neurol 16: 15–24. Chee MWL, O’Craven KM, Bergida R, et al. (1999). Auditory and visual word processing studied with fMRI. Hum Brain Mapp 7: 15–28. Cohen L, Dehaene S (2004). Specialization within the ventral stream: The case for the visual word form area. Neuroimage 22: 466–476. Cohen L, Dehaene S, Naccache L, et al. (2000). The visual word form area: Spatial and temporal characterization of an initial stage of reading in normal subjects and posterior split-brain patients. Brain 123: 291–307.

Cohen L, Henry C, Dehaene S, et al. (2004). The pathophysiology of letter-by-letter reading. Neuropsychologia 42: 1768–1780. Cohen L, Lehericy S, Chochon F, et al. (2002). Languagespecific tuning of visual cortex? Functional properties of the visual word form area. Brain 125: 1054–1069. Corina D, Chiu YS, Knapp H, et al. (2007). Neural correlates of human action observation in hearing and deaf subjects. Brain Res 1152: 111–129. Dejerine J. (1892). Contribution a` l’e´tude anatomo-pathologique et clinique des diffe´rentes varie´te´s de ce´cite´ verbale. Mem Soc Biol 4: 61–90. Demonet J-F, Chollet F, Ramsay S, et al. (1992). The anatomy of phonologic and semantic processing in normal subjects. Brain 115: 1753–1768. Demonet J-F, Price C, Wise R, et al. (1994). Differential activation of right and left posterior sylvian regions by semantic and phonological tasks: A positron-emission tomography study in normal human subjects. Neurosci Lett 182: 25–28. Ellis AW, Flude BM, Young AW (1987). ‘Afferent dysgraphia’ in a patient and normal subjects. Cogn Neuropsychol 4: 465–486. Ellis AW, Young A (1988). Human Cognitive Neuropsychology. Lawrence Erlbaum, London. Foundas A, Daniels SK, Vasterling JJ (1998). Anomia: Case studies with lesion localization. Neurocase 4: 35–43. Garrard P, Maloney LM, Hodges JR, et al. (2005). The effects of very early Alzheimer’s disease on the characteristics of writing by a renowned author. Brain 128: 250–260. Giraud AL, Price CJ (2001). The constraints functional neuroimaging places on classical models of auditory word processing. J Cogn Neurosci 13: 754–765. Goodman RA, Caramazza A (1986). Phonologically plausible errors: Implications for a model of the phoneme– grapheme conversion mechanism in the spelling process. In G Augst (Ed.), Proceedings of the International Colloquium on Graphemics and Orthography, pp. 300–325. Graham NL, Patterson K, Hodges JR (2004). When more yields less: Speaking and writing deficits in nonfluent progressive aphasia. Neurocase 10: 141–155. Gros H, Boulanouar K, Viallard G, et al. (2001). Eventrelated functional magnetic resonance imaging study of the extrastriate cortex response to a categorically ambiguous stimulus primed by letters and familiar geometric figures. J Cereb Blood Flow Metab 21: 1330–1341. Groves-Wright K, Neils-Strunjas J, Burnett R, et al. (2004). A comparison of verbal and written language in Alzheimer’s disease. J Commun Disord 37: 109–130. Hart J, Gordon B (1990). Delineation of single-word semantic comprehension deficits in aphasia, with anatomical correlation. Ann Neurol 27: 226–231. Hart J, Moo LR, Segal JB, et al. (2002). Neural Substrates of Semantics. In AE Hillis (Ed.), Handbook of Adult Language Disorders: Integrating Cognitive Neuropsychology, Neurology, and Rehabilitation. Psychology Press, Philadelphia.

COGNITIVE PROCESSES UNDERLYING READING AND WRITING Hillis AE (2001). The organization of the lexical system. In BC Rapp (Ed.), The Handbook of Cognitive Neuropsychology. Psychology Press, Philadelphia, pp. 185–210. Hillis AE (2003). Alexia. In R Kent (Ed.), MIT Encyclopedia of Communication Disorders. MIT Press, Cambridge, pp. 236–240. Hillis AE, Barker PB, Wityk RJ, et al. (2004a). Variability in subcortical aphasia is due to variable sites of cortical hypoperfusion. Brain Lang 89: 524–530. Hillis AE, Benzing L, Epstein C, et al. (1995). Cognitive gains and losses of patients with Alzheimer’s Disease during frequent practice. Am J Speech Lang Pathol 4: 150–156. Hillis AE, Caramazza A (1990). The effects of attentional deficits on reading and spelling. In A Caramazza (Ed.), Cognitive Neuropsychology and Neurolinguistics: Advances in Models of Cognitive Function and Impairment. LEA, London. Hillis AE, Caramazza A (1995). A framework for interpreting distinct patterns of hemispatial neglect. Neurocase 1: 189–207. Hillis AE, Chang S, Breese E, et al. (2004b). The crucial role of posterior frontal regions in modality specific components of the spelling process. Neurocase 10: 157–187. Hillis AE, Heidler J (2005). Contributions and limitations of the ‘Cognitive neuropsychological approach’ to treatment: Illustrations from studies of reading and spelling therapy. Aphasiology 19: 985–993. Hillis AE, Kane A, Barker P, et al. (2001a). Neural substrates of the cognitive processes underlying reading: Evidence from Magnetic Resonance Perfusion Imaging in hyperacute stroke. Aphasiology 15: 919–931. Hillis AE, Kane A, Tuffiash E, et al. (2002). Neural substrates of the cognitive processes underlying spelling: Evidence from MR diffusion and perfusion imaging. Aphasiology 16: 425–438. Hillis AE, Newhart M, Heidler J, et al. (2005a). Anatomy of spatial attention: Insights from perfusion imaging and hemispatial neglect in acute stroke. J Neurosci 25: 3161–3167. Hillis AE, Newhart M, Heidler J, et al. (2005b). The roles of the ‘visual word form area’ in reading. Neuroimage 24: 548–559. Hillis AE, Newhart M, Heidler J, et al. (2005c). The neglected role of the right hemisphere in spatial representation of words for reading. Aphasiology 19: 225–238. Hillis AE, Oh S, Ken L (2004c). Deterioration of naming nouns versus verbs in primary progressive aphasia. Ann Neurol 55: 268–275. Hillis AE, Rapp BS (2004). Cognitive and neural substrates of written language comprehension and production. In M Gazzaniga (Ed.). The New Cognitive Neurosciences, 3rd edn. MIT Press, Cambridge. Hillis AE, Rapp BC, Caramazza A (1999). When a rose is a rose in speaking but a tulip in writing. Cortex 35: 337–356. Hillis AE, Wityk R, Barker PB, et al. (2003). Neural regions essential for writing verbs. Nat Neurosci 6: 19–20.

321

Hillis AE, Wityk RJ, Tuffiash E, et al. (2001b). Hypoperfusion of Wernicke’s area predicts severity of semantic deficit in acute stroke. Ann Neurol 50: 561–566. Hillis AE, Work M, Breese EL, et al. (2004d). Re-examining the brain regions crucial for orchestrating speech articulation. Brain 127: 1479–1487. Horwitz B, Rusey JM, Donohue BC (1998). Functional connectivity of the angular gyrus in normal reading and dyslexia. Proc Natl Acad Sci USA 95: 8939–8944. Hsieh L, Rapp BR (2004). Functional magnetic resonance imaging of the cognitive components of the spelling process. Brain Lang 91: 41–42. Joubert S, Beauregard M, Walter N, et al. (2004). Neural correlates of lexical and sublexical processes in reading. Brain Lang 89: 9–20. Lesser R, Luders H, Morris HH, et al. (1986). Electrical stimulation of Wernicke’s area interferes with comprehension. Neurology 36: 658–663. Love T, Swinney D, Wong E, et al. (2002). Perfusion imaging and stroke: A more sensitive measure of the brain bases of cognitive deficits. Aphasiology 16: 873–883. Luzzatti C, Laiacona M, Agazzi D (2003). Multiple patterns of writing disorders in dementia of the Alzheimer type and their evolution. Neuropsychologia 41: 759–772. Marsh EB, Hillis AE (2005). Cognitive and neural mechanisms underlying reading and naming: Evidence from letter-by-letter reading and optic aphasia. Neurocase 11: 325–318. McCandliss BD, Cohen L, Dehaene S (2003). The visual word form area: Expertise for reading in the fusiform gyrus. Trends Cogn Sci 7: 293–299. Mendez MF, Cherrier MM (1998). The evolution of alexia and simultanagnosia in posterior cortical atrophy. Neuropsychiatry Neuropsychol Behav Neurol 11: 76–82. Miceli G, Silveri MC, Villa G, et al. (1984). On the basis of agrammatic’s difficulty in producing main verbs. Cortex 20: 217–220. Monk AF (1985). Co-ordinate systems in visual word recognition. Q J Exp Psychol A 37: 613–625. Nadeau SE, Gonzalez Rothi LJ, Crosson B (2000). Aphasia and Language: Theory to Practice. The Guilford Press, New York. Patterson KE, Coltheart M, Marshall JC (1985). Surface Dyslexia. LEA, London. Peniello M-J, Lambert J, Eustache F, et al. (1995). A PET study of the functional neuroanatomy of writing impairment in Alzheimer’s disease: The role of the left supramarginal and angular gyri. Brain 118: 697–707. Petrides M, Alivisatos B, Evans AC (1995). Functional activation of the human ventrolateral frontal cortex during mnemonic retrieval of verbal information. Proc Nat Acad Sci USA 92: 5803–5807. Plaut D, Shallice T (1993). Deep dyslexia: A case study in connectionist neuropsychology. Cogn Neuropsychol 10: 377–500. Polk TA, Stallcup M, Aguirre GK, et al. (2002). Neural specialization for letter recognition. J Cogn Neurosci 14: 145–159.

322

A.E. HILLIS

Price CJ, Devlin JT (2003). The myth of the visual word form area. Neuroimage 19: 473–481. Price CJ, Devlin JT (2004). The pros and cons of labeling a left occipitotemporal region: The visual word form area. Neuroimage 22: 477–479. Price CJ, Winterburn D, Giraud AL, et al. (2003). Cortical localization of the visual and auditory word form areas: A reconsideration of the evidence. Brain Lang 86: 272–286. Pugh KR, Mencl WE, Jenner AR, et al. (2001). Neurobiological studies of reading and reading disability. J Commun Disord 34: 479–492. Rapcsak SZ, Beeson PM (2002). Neuroanatomical correlates of spelling and writing. In AE Hillis (Ed.), Handbook of Adult Language Disorders: Integrating Cognitive Neuropsychology, Neurology, and Rehabilitation. Psychology Press, Philadelphia, pp. 71–99. Rapcsak SZ, Beeson PM (2004). The role of the left inferior temporal cortex in spelling. Neurology 662: 2221–2229. Rapp BC (2002). Uncovering the cognitive architecture of spelling. In AE Hillis (Ed.), Handbook of Adult Language Disorders: Integrating Cognitive Neuropsychology, Neurology, and Rehabilitation. Psychology Press, Philadelphia. Rapp BC, Folk JR, Tainturier MJ (2000). Word reading. In BC Rapp (Ed.), The Handbook of Cognitive Neuropsychology. Psychology Press, Philadelphia. Raymer A, Foundas AL, Maher LM, et al. (1997). Cognitive neuropsychological analysis and neuroanatomical correlates in a case of acute anomia. Brain Lang 58: 137–156.

Roeltgen DP, Heilman KM (1984). Lexical agraphia: Further support for the two strategy hypothesis of linguistic agraphia. Brain 107: 811–827. Samuelsson S (2000). Converging evidence for the role of occipital regions in orthographic processing: A case of developmental surface dyslexia. Neuropsychologia 38: 351–362. Seidenberg M, McClelland JL (1989). A distributed, developmental model of visual word recognition and naming. Psychol Rev 96: 523–568. Shallice T (1988). From Neuropsychology to Mental Structure. Cambridge University Press, Cambridge. Turkeltaub PE, Eden GF, Jones KM, et al. (2002). Meta-analysis of the funcitonal neuroanatomy of singleword reading: Method and validation. Neuroimage 16: 765–780. Warrington EK (1991). Right neglect dyslexia: A single case study. Cogn Neuropsychol 8: 191–212. Whatmough C, Chertkow H (2002). Neuroanatomical aspects of naming. In AE Hillis (Ed.), Handbook of Language Disorders. Psychology Press, Philadelphia. Wise R, Chollet F, Hadar U, et al. (1991). Distribution of cortical neural networks involved in word comprehension and word retrieval. Brain 114: 1803–1817. Wise RJS, Scott SK, Blank C, et al. (2001). Separate neural subsystems within ‘Wernicke’s area.’ Brain 124: 83–95. Zingeser LB, Berndt RS (1990). Retrieval of nouns and verbs in agrammatism and anomia. Brain Lang 39: 14–32.

Handbook of Clinical Neurology, Vol. 88 (3rd series) Neuropsychology and behavioral neurology G. Goldenberg, B.L. Miller, Editors # 2008 Elsevier B.V. All rights reserved

Chapter 16

Apraxia GEORG GOLDENBERG* Neuropsychologische Abteilung, Krankenhaus Mu¨nchen Bogenhausen, Munich, Germany

16.1. Introduction In his description of the famous case ‘Tantan,’ Paul Broca noted that this severely aphasic patient was unable to manifest his ideas or desires other than by movements of the left hand but frequently made incomprehensible gestures (Broca, 1861). Ten years later the German psychiatrist Finkelnburg described an aphasic woman who had been raised as a devout Catholic but now failed to make the sign of the cross after the grace. ‘When asked by her surrounding to make it, she hesitantly reached sometimes behind the ear, sometimes to the neck until it was demonstrated to her. Then she imitated it exactly’ (Finkelnburg, 1870). From this and numerous other observations of nonverbal communicative impairment of aphasic patients, Finkelnburg concluded that these patients suffer not merely from loss of speech but from a more profound inability of conceptual thinking which he termed ‘asymbolia.’ Shortly after Finkelnburg’s influential publication the German linguist Steinthal described an aphasic and anarthric patient who had ‘preserved his intellect. But when he wanted to write he grasped the pen wrongly; he also grasped spoon and fork as if he had never used them before’ (Steinthal, 1881, p 458; the first edition of Steinthal’s book which apparently already contained this paragraph was published in 1871). He concluded that ‘this apraxia is an obvious aggravation of aphasia’ and distinguished it from the ‘aggravation of aphasia to a general lack of recognition of signs’ described by Finkelnburg. The early history of apraxia culminated in Liepmann’s seminal writings which have retained direct influence on research and theorizing on apraxia until today (Goldenberg, 2003a). Liepmann corroborated the anecdotal descriptions of defective use of communicative gestures *

and of tools in aphasia through systematic exploration of both single cases and groups of brain damaged patients, identified a further clinical manifestation, and placed all of them into a novel theoretical context. The new clinical observation was that, in contrast to Finkelnburg’s asymbolic Catholic, many other patients also have difficulties with the imitation of demonstrated gestures. The new theoretical context was motor control. Liepmann proposed that there are apraxic patients who have a correct concept of what they ought to do but cannot transform the image of the intended action into appropriate motor commands. He insisted that apraxia can occur independently from aphasia but noted in a group study comparing patients with right and left hemisphere damage that it is invariably associated with left brain damage (Liepmann, 1908). This led him to postulate a dominance of the left hemisphere for deliberate motor control above and beyond its dominance for speech. I will argue in this chapter that Liepmann’s model of motor control and the taxonomy of apraxia derived from that model have not withstood the test of 100 years of progress in neuropsychology. Nonetheless, his conception of apraxia as a disturbance at the interface between cognition and motor control sets the stage upon which research on apraxia still takes place.

16.2. Definition and scope of apraxia A widely accepted definition of apraxia describes it as a ‘disorder of skilled movement not caused by weakness, akinesia, deafferentation, abnormal tone or posture, movement disorders (such as tremors or chorea), intellectual deterioration, poor comprehension, or uncooperativeness’ (Heilman and Rothi, 1993). The somewhat cumbersome enumeration of alternative motor or cognitive diagnoses highlights that apraxia is conceived as

Correspondence to: Georg Goldenberg, MD, Neuropsychologische Abteilung, Krankenhaus Mu¨nchen Bogenhausen, Englschalkingerstrasse 77, D 81925 Munich, Germany. E-mail: [email protected], Tel: þ49-899270-2106, Fax: þ49-89-9270-2089.

324

G. GOLDENBERG

being neither a motor nor a cognitive disorder. It thus reiterates Liepmann’s postulate of a disturbance at the interface between cognition and motor control. This theoretical stance gives little practical help for restraining the scope of faulty actions deserving a diagnosis of apraxia. Indeed the term apraxia has been used for disturbances of widely different actions ranging from lid closure and gait to dressing and spatial constructions. There is, however, a core of clinical manifestations which had been in the focus of the historical development of the concept (see above) and which continue to be generally accepted as deserving a diagnosis of apraxia. They concern three domains of human actions: the imitation of gestures, the performance of communicative gestures, and the use of tools and objects. All of them occur predominantly after left brain lesions and are frequently, though not invariably, associated with aphasia. Another common point is that in contrast to genuinely ‘motor’ disturbances they affect not only the side of the body opposite to the cerebral lesion but also the ipsilateral side. Most of the actions considered in research on apraxia are manual, but some actions in each of the domains can be made by legs, face, or trunk. In this chapter I will concentrate on manual apraxia but consider foot postures and axial movements in the section on imitation. Face apraxia will be considered in a short separate section. Its relationship to speech disorders will be discussed in the chapter on apraxia of speech.

16.3. Imitation of gestures From a clinical point of view testing imitation is attractive because its essentially nonverbal nature liberates the examination from a confounding influence of accompanying aphasia. The independence from language is particularly obvious when imitation is tested for meaningless gestures which bear no verbal label. Meaningless gestures do not form part of the repertoire of habitual gestures and are hence essentially novel. Novelty of the imitated action is considered crucial for speaking of imitation in evolutionary and comparative psychology where imitation is being discussed as a possible basis for the transmission of novel behavioral skills (Tomasello et al., 1993; Whiten, 2000; Byrne et al., 2004; Zentall, 2004). We will come back to the different mechanisms enabling imitation of meaningful and meaningless gestures but retain now that genuine imitation can reliably be assessed only with meaningless gestures. 16.3.1. Clinical presentation Defective imitation will rarely be conspicuous in spontaneous behavior but can easily be demonstrated in the clinical examination. As with all manifestations of

apraxia the limbs ipsilateral to the lesion should be tested to exclude contamination of results by the effects of hemiparesis. Usually the examiner sits opposite the patient and demonstrates the model of the gesture ‘like a mirror,’ that is with the right hand if the patient uses the left one. Mirroring of the acting hands conforms to the spontaneous preference of normal persons (Schofield, 1976). The difficulties and errors of severely apraxic patients are impressive and pose little problem for a reliable diagnosis, but things become more intricate when subtle deviations from normality are considered or when qualitative categorization of errors is attempted (Haaland and Flaherty, 1984; Roy et al., 1996; Rothi et al., 1997b; Roy et al., 2000). Hesitation or self-correction which eventually leads to a correct final position is difficult to quantify by mere observation. Kinematic analysis of imitation of meaningless gestures revealed that such abnormalities are quite common in apraxic patients but that their severity does not correlate with the severity of apraxia as assessed by spatial errors of the final position (Hermsdo¨rfer et al., 1996). As will be discussed in the following sections the results of imitation testing depend on the kind of gestures used. Computation of a sum score from performance on different kinds of gestures (e.g., De Renzi et al., 1980; Lehmkuhl et al., 1983) may be useful for screening whether there is any difficulty with imitation at all but may veil dissociations between different kinds of gestures. For detecting dissociations between meaningful and meaningless gestures it is preferable to present them in distinct blocks rather than intermingled, as otherwise subjects may be inclined to make a strategic choice to treat all of them as if they were meaningless (Tessari and Rumiati, 2004). 16.3.2. Localization The following discussion will consider first the laterality of lesions and then the intrahemispheric location of left-sided lesions. 16.3.2.1. Laterality of lesions The association of defective imitation with left brain damage depends on the nature of the imitated gesture. One property to be considered is whether imitation is probed for single gestures or sequences of several gestures. A proposal that imitation of sequences is particularly sensitive to left brain damage (Kimura and Archibald, 1974; Kimura, 1977) has not been confirmed by subsequent studies. Imitation of single gestures and sequences was found to be strongly correlated in patients with left sided lesions (De Renzi et al., 1983), whereas

APRAXIA defective imitation of gesture sequences contrasting with normal imitation of single gestures was demonstrated in patients with right hemisphere lesions, Parkinson’s disease, or supranuclear palsy (Goldenberg et al., 1986; Canavan et al., 1989; Roy et al., 1991; Soliveri et al., 2005). It thus appears that left brain damage affects imitation of single gestures and sequences equally, but that sequences are also vulnerable to lesions elsewhere. Another feature of the imitated gesture which may be important for laterality is the body part involved. There has been a lively debate as to whether imitation of whole body and axial movements is generally spared in patients with left brain damage who commit errors on imitation of limb gestures (Poeck et al., 1982; Geschwind and Damasio, 1985; Howes, 1988). The debate has been settled by the conclusion that imitation of axial movements like bending down the head or raising the shoulders is indeed less error prone than imitation of limb movements due to the lower complexity of the axial gestures. There are much fewer degrees of freedom for axial postures than there are for postures of the limbs (Hanlon et al., 1998). A dissociation that can less easily be referred to different task difficulty has been demonstrated between gestures of the fingers, the whole hand, and the foot (see Fig. 16.1). Patients with left brain damage have difficulties with the imitation of hand and foot postures while imitation of finger postures is less compromised and can even be completely normal. By contrast, patients with right brain damage have severe difficulties with finger postures and some difficulties with foot postures but imitate hand postures nearly as perfectly as normal controls (Goldenberg, 1996; 1999; Goldenberg and Strauss, 2002). 16.3.2.1. Intrahemispheric location of left-sided lesions Left hemisphere lesions interfering with imitation need not necessarily be located in regions contributing to language processing: defective imitation without aphasia has repeatedly been observed in left brain damage (De Renzi et al., 1980; Agostini et al., 1983; Papagno et al., 1993; Goldenberg and Hagmann, 1997). Group studies using CT or MRI consistently found parietal lesions to be the most important though not the only possible cause of defective imitation (Basso et al., 1980; De Renzi et al., 1983; Basso et al., 1987; Haaland et al., 2000). Lesions are also found in premotor cortex, basal ganglia and white matter, but for subcortical lesions it is questionable whether the lesion itself or associated dysfunction of overlying cortex are causal (Weiller et al., 1993; Hillis et al., 2002). The importance of the parietal lobes for genuine imitation is underscored by

325

the observation of patients with left parietal lesions who display a selective deficit for imitation of meaningless gestures, which contrasts with perfect execution of meaningful gestures both on command and in imitation. (Mehler, 1987; Goldenberg and Hagmann, 1997; Cubelli et al., 2000; Peigneux et al., 2000). This combination has been termed visuoimitative apraxia. The distinction between hand and finger position may be important not only for lateralization to the left hemisphere but also for localization within it. Haaland et al. (2000) examined imitation of gestures combining hand and finger postures but observed ‘target errors’ affecting the position of the whole hand only with parietal lesions, whereas ‘internal hand position’ errors affecting the configuration of the fingers occurred also with premotor lesions. In a patient with a parietal lesion and visuoimitative apraxia from defective imitation of hand positions contrasted with perfect imitation of finger configurations (Goldenberg and Hagmann, 1997). 16.3.3. Theoretical accounts Disturbed imitation yielded the main support for Liepmann’s contention that patients were unable to transmit a correct concept or image of the intended gesture into appropriate motor commands. The view that defective imitation indicates a problem of motor execution has been upheld by influential modern authors (Barbieri and De Renzi, 1988; Roy and Hall, 1992). For example, De Renzi (1990, p. 246) wrote: ‘Since the examiner provides the model of the action and the patient must simply copy it, errors can only be due to an executive deficit.’ As defective motor execution would affect gestures independently of their origin patients who have problems with imitation should also fail when motor actions of similar complexity are retrieved from long term memory as, for example, when patients demonstrate pantomimes of tool use. This prediction is refuted by the already discussed observation of patients with visuoimitative apraxia who fail imitation of meaningless gestures but flawlessly perform pantomimes of object use or other symbolic gestures on command (Mehler, 1987; Goldenberg and Hagmann, 1997; Cubelli et al., 2000; Peigneux et al., 2000). Rothi and coworkers proposed a cognitive model of apraxia which can account for visuoimitative apraxia (Rothi et al., 1991; 1997a). They distinguished two routes from vision to replication of the demonstrated gesture. A ‘direct’ route from vision to motor control enables replication of the external shape of the gesture. This route can accommodate both meaningful and meaningless gestures. The ‘indirect’ route is confined to familiar meaningful gestures. Their imitation can be achieved by first recognizing the gesture and then producing a

326

G. GOLDENBERG

Fig. 16.1. Examples of finger, hand, and foot postures which show differential vulnerability to lesions in the left or right hemisphere (reprinted from Goldenberg and Strauss, 2002, with permission from Lippincott Williams and Wilkins).

corresponding gesture out of the repertoire of familiar gestures (Rothi et al., 1991; Goldenberg and Hagmann, 1997; Cubelli et al., 2000; Tessari and Rumiati, 2004). The selective interruption of the direct route gives rise to visuoimitative apraxia where disturbed imitation of meaningless gestures contrasts with perfect performance of meaningful gestures on command or imitation. There is, however, evidence that the ‘direct’ route involves intermediate steps of cognitive processing. Patients who commit errors when imitating meaningless gestures commit errors also when asked to replicate these

gestures on a manikin or to match photographs of meaningless gestures demonstrated by different persons and seen under different angles of view (Goldenberg, 1995; 1999; Peigneux et al., 2000). A direct route from vision to execution of gestures would be expected to connect identical motor actions, but the motor actions of manipulating a manikin or pointing to pictures are basically different from those required for executing the gestures themselves. If the deficit can manifest itself in very different motor actions its source has to be sought in processing stages preceding motor execution.

APRAXIA Morlaas (1928) proposed that the particular difficulty of imitating meaningless gestures concerns the comprehension and reproduction of body centered spatial relationships. This idea gained popularity for some time and was defended in the first series of this handbook (De Ajuriaguerra and Tissot, 1969) but was then overshadowed by a resurrection of Liepmann’s model of motor control. However, some recent theoretical approaches elaborate very similar ideas (Goldenberg, 1995; Meltzoff and Moore, 1997; Buxbaum et al., 2000; Goldenberg and Strauss, 2002; Chaminade et al., 2004; Peigneux et al., 2004). One variant of these proposals (Goldenberg, 1995; Goldenberg and Strauss, 2002) hypothesizes that the crucial cognitive step interpolated between perception and replication of meaningless gestures is a coding of the demonstrated gesture with reference to classification of body parts and knowledge of the boundaries defining them. Body part coding reduces the multiple visual features of the demonstrated gesture to simple relationships between a limited set of body parts and produces equivalence between demonstration and imitation which is independent of the different modalities and perspectives of perceiving one’s own and other persons’ bodies. According to this proposal a second crucial difficulty of imitation of novel gestures concerns their perceptual analysis. The difficulty of body part coding increases with the increasing number and diversity of body parts involved in the gesture (see Fig. 16.1). Positions of the hand relative to parts of the head demand access to knowledge about the determining features and boundaries of a multitude of very different body parts like chin, lips, back and tip of the nose, cheek, or ears. Because of their diversity these body parts are easy to discriminate perceptually. By contrast, finger configurations pose exceptionally low demands on knowledge about body parts because, with the possible exception of the thumb, they are constituted by a set of uniform elements which differ only in their serial position, but for the same reasons their perceptual discrimination is difficult. Imitation of foot gestures may be vulnerable to disturbances of both components. They involve a number of conceptually different parts like ankle, heel, calf, big toe, and little toe which are, however, perceptually less salient than the parts of the face which were used to determine hand positions. On the assumption that body part coding is bound to integrity of the left parietal lobe while perceptual analysis involves more widespread and right hemisphere regions, the varying demands on body part coding and perceptual analysis can accommodate the differential impact of left parietal and other lesions on imitation of different kinds of meaningless gestures. As the crucial difficulty is sought in cognitive and perceptual operations preceding motor execution it can

327

also account for defective replication of gestures on a manikin and for defective matching of gestures. The link between defective imitation and defective access to cognition of body structures gains plausibility by consideration of autotopagnosia. Patients with autotopagnosia commit errors when asked to point to body parts on themselves, on another person, or on a model of the human body. Their lesions always affect the left inferior parietal lobe. Defective imitation of meaningless gestures is a regular feature of autotopagnosia (De Renzi and Scotti, 1970; Poncet et al., 1971; Assal and Butters, 1973; Ogden, 1985; Denes et al., 2000; Buxbaum and Coslett, 2001; Felician et al., 2003) and may contrast with preserved execution of meaningful gestures on command (De Renzi and Scotti, 1970; Assal and Butters, 1973; Denes et al., 2000).

16.4. Communicative gestures Gestures accompanying or replacing speech are a pervasive feature of human face to face communication. A substantial body of research has been devoted to their classification and to elucidation of their communicative and cognitive functions (Ekman and Friesen, 1969; McNeill, 1992; Kendon, 2004; Goldin-Meadow and Wagner, 2005), but research on apraxia has traditionally concentrated on only a small sector of their wide variety: emblematic gestures which convey a conventionally defined message like thumb up for approval or the nose thumb for mockery, and pantomimes of object use where use of an object is demonstrated with the empty hand. As a further restriction, diagnosis of apraxia is based on performance of these gestures in response to an explicit command to demonstrate them which disrobes them of their genuine communicative role. This restriction is remarkable as historically the concept of apraxia arose out of the observation of deficient spontaneous use of communicative gestures (see above). 16.4.1. Clinical presentation The artificiality of demonstrating communicative gestures out of their natural communicative context presumably contributes to aphasic patients’ difficulties with comprehension of the instructions. For emblematic gestures patients must understand both the general instruction and the verbal designation of the individual gestures. For pantomime of object use, the identity of the individual objects can be made clear by showing the object or a picture of it. This may be one reason why clinical diagnosis and most research on communicative gestures in apraxia concentrate on pantomime of object use. Nonetheless, aphasic patients with severe

328

G. GOLDENBERG

comprehension problems may fail to comprehend the instruction at all and in others the nature of errors may raise doubts about full comprehension. Failure of comprehension is rather obvious when patients try to grasp the object for actual use, try to name or describe it (‘verbal overflow’ Goodglass and Kaplan, 1963) or outline with the finger a more or less recognizable shape on the table. The diagnosis gets more difficult, however, when they outline the shape at the place where the object would be used (e.g., a pipe before the mouth) or when they use the hand for symbolizing the object (‘body part as object’: e.g., opening and closing index and middle finger for scissors). Normal subjects use such strategies too and frequently prefer them to pure pantomime when communicating their needs to someone whose language they do not speak. They can switch to pure pantomime when explicitly asked to do so (Duffy and Duffy, 1989; Heilman and Rothi, 1993) but when patients with aphasia persist, it remains arguable whether they understood the request to switch to the less efficient strategy. Independence of apraxic errors from language comprehension becomes obvious when patients make searching movements for the correct grip or movement or when their pantomime displays some but not all distinctive features of the intended pantomime (e.g., pantomiming drinking from a glass with a narrow grip not accommodated to the width of the pretended glass). In severe cases patients may produce stereotyped circling or swaying movements of the hand which might be taken to indicate but not specify movement of the object in peripersonal space. Not only the distinction between apraxia and other sources of faulty pantomime but also the distinction between faulty and correct pantomime may be equivocal. There is considerable variety in how exactly the pantomimes of normal subjects replicate hand shapes and movements of actual manipulation. In clinical practice some experience with examination of normal subjects suffices for recognition of significant aberrations, but for research purposes a list of defined features of the pantomime with normative data on their presence in normal subjects’ performance is indispensable (Roy et al., 1998; Goldenberg et al., 2003). 16.4.2. Localization As in the previous section we will consider first the laterality of lesions and then the intrahemispheric location of left-sided lesions. 16.4.2.1. Laterality of lesions The association between defective pantomime and left brain damage is tight but not absolute. Pantomime

impairment of patients with right brain damage is so mild that it usually escapes clinical observation but comes forward by application of rigorous scoring criteria. In systematic group studies about one third of patients with right brain damage are rated lower than controls, but their scores are very close to the control range, whereas deficiencies of patients with left brain damage and aphasia are distinctly more severe (Barbieri and De Renzi, 1988; Roy et al., 1998; 2000; Goldenberg et al., 2003). 16.4.2.2. Intrahemispheric location of left-sided lesions Defective pantomime without aphasia has been reported only in patients in whom other aspects of the clinical picture point to deviations of hemisphere dominance from the normal organization of right-handed persons (Selnes et al., 1991). Conversely the combination of aphasia with intact pantomime is found in 5–50% of patients with left brain damage (Barbieri and De Renzi, 1988; Roy et al., 1998; 2000; Goldenberg et al., 2003) suggesting that either the areas needed for pantomime are a subset of those needed for language or that language is more sensitive than pantomime to lesions in a common territory. A recent study using MRI lesion subtraction found the maximal difference of lesion frequency between patients with defective and normal pantomime in inferior frontal lobe and adjacent white matter (Goldenberg et al., in press). The preservation of pantomime in patients with visuoimitative apraxia from parietal lobe damage supports the implication that parietal lobe damage does not have the same importance for pantomime as for imitation (Mehler, 1987; Goldenberg and Hagmann, 1997). 16.4.3. Theoretical accounts Two opposing hypotheses have been proposed for the basic deficit underlying defective pantomime of object use in patients with left brain damage and aphasia. One, originating from Finkelnburg’s ‘asymbolia,’ sees defective pantomime as a manifestation of a general inability to create and use communicative signs which is heightened by the request to produce them outside their natural context (Finkelnburg, 1870; Bay, 1962; Duffy and Duffy, 1981; Duffy et al., 1994). Pantomime of object use is particularly challenging because the gestures are not conventional but must be created with the arbitrary restriction that only hand movements which also occur in real object use must be used to symbolize the object and its use, which excludes the possibility to indicate the object by drawing it in ‘in the air’ or by demonstrating a body part as if it were the object (see

APRAXIA above) (Goldenberg et al., 2003; Goldenberg, 2003b). The importance of the non-conventional nature of pantomime is emphasized by the observation that aphasic patients whose language comprehension suffices for understanding the instructions have less difficulties with demonstration of conventional emblematic gestures than with pantomime of object use (Goodglass and Kaplan, 1963; Raade et al., 1991). The alternative hypothesis derives from Liepmann’s concept of apraxia as an inability to transform a concept of the intended action into appropriate motor commands. On this view the particular difficulty of pantomime of object use originates from the need to perform the motor actions of object use without support from visual and tactile feedback of object properties (Liepmann, 1908; De Renzi et al., 1982; Bartolo et al., 2003). Indeed most patients who fail pantomime of object use improve dramatically when allowed to demonstrate use with the object in hand (De Renzi et al., 1982; Goldenberg and Hagmann, 1998b). However, the claim that tactile feedback from a handle suffices for eliciting a correct pantomime has not been confirmed in a systematic study of the effect of tactile feedback (Graham et al., 1999; Wada et al., 2000; Goldenberg et al., 2004) and failure of pantomime in combination with intact use of real objects is also compatible with the ‘asymbolia’ account, because real object use does not demand creation of a symbolic representation of the object and its use. Support for this interpretation comes from studies in normal subjects demonstrating that their pantomimes of grasping do not replicate the complete kinematics of real grasping but retain only features necessary for depicting the object and the action (Goodale et al., 1994; Laimgruber et al., 2005).

16.5. Use of single conventional tools and objects I will divide discussion of tool and object use in two sections. This one is devoted to the use of single conventional tools and objects and the following one to multi-step actions with multiple objects including technical devices. 16.5.1. Clinical presentation Misuse of everyday tools and objects is an impressive manifestation of apraxia: patients try to cut paper with closed scissors, to eat soup with a fork, or to write with the wrong end of the pencil. They bite on the toothbrush but do not brush, press the knife into the loaf without moving it to and fro, press the hammer upon the nail without hitting, and close the paper punch on top of the sheet without inserting the sheet. As many

329

of these patients have right sided hemiplegia one may be inclined to ascribe their errors to the ineptness of the non-dominant left hand, but it is easy to convince oneself of their pathological nature by observing healthy persons using the tools with the non-dominant hand or doing so oneself. The patients’ difficulties are not confined to the testing situation but are observed in their activities of daily living as well (Foundas et al., 1995; Goldenberg and Hagmann, 1998a). 16.5.2. Localization Misuse of everyday tools and objects can be a symptom of dementia caused, for example, by degenerative disease or anoxic brain damage. If caused by unilateral lesions they are invariably left-sided, large, and associated with severe aphasia (De Renzi et al., 1968; Goldenberg and Hagmann, 1998b). Probably the parietal lobe must be included (Poeck and Lehmkuhl, 1980) but circumscribed parietal lesions are unlikely to interfere with basic tool use. Experimental investigations of single components of tool and object use (see below) point to differential involvement of parietal and temporal regions within the left hemisphere. The ability to infer possible functions from structural properties of objects depends on the parietal lobe whereas retrieval of semantic knowledge specifying the purpose of a tool and the typical recipients of its action is bound to temporal lobe integrity (Hodges et al., 1999; 2000; Spatt et al., 2002). 16.5.3. Theoretical accounts Most authors (but see Zangwill, 1960; Poeck, 1982 for exceptions) agree that defective use of tools and objects indicates loss of knowledge about their proper use. This loss has been conceived by Morlaas (1928) as ‘agnosia of utilization.’ He insisted that this agnosia selectively affects recognition of the ‘practical, pragmatic significance’ of tools and objects but spares recognition of other aspects. Modern elaborations of this basic idea are controversial with respect to the diversification of ‘pragmatic’ knowledge and its embedment in general semantic memory. Concerning the diversification of pragmatic knowledge a distinction has been made between knowledge of a tool’s purpose and of its manipulation. Indeed typical errors of apraxic patients, like pressing down the knife on the loaf without the sawing movement, give the impression that patients still know the purpose of the action (dividing the loaf) but not how to reach it. Other errors, however, are more ambiguous. For example, when patients try to eat soup with a fork they seem to retain the purpose of the soup but not that of the fork.

330

G. GOLDENBERG

In spite of the insecurity of the border between both kinds of knowledge it has been postulated that they constitute distinct compartments of semantic memory and can be lost independently from each other (Buxbaum and Saffran, 2002; Boronat et al., 2005). An alternative hypothesis proposes that knowledge of a tool’s purpose and of its manipulation are closely associated in semantic memory, but a second, nonsemantic, route enables inference of possible functions from structural properties of objects. Whereas semantic functional knowledge is basically restricted to the prototypical use of familiar tools, the nonsemantic route permits detection of functions of novel tools as well as of nonprototypical applications of familiar tools (Vaina and Jaulent, 1991; Goldenberg and Hagmann, 1998b; Rumiati and Humphreys, 1998; Hodges et al., 1999; 2000). Support for the existence of such a division comes from double dissociations between patients who have lost one or the other of these routes to action. There are patients with pervasive deterioration of semantic memory who have lost any knowledge about familiar tools and objects are able to manipulate them in a sensible way which, however, may not achieve the usual purpose of that tool. For example, they may find out that a nail-clipper can be used for cutting but not that it is used for cutting nails (Sirigu et al., 1991; Hodges et al., 2000). Conversely, there are patients who have retained knowledge about the prototypical use of familiar objects but can neither detect the function of novel tools nor ways for achieving a given purpose (e.g., fixing a screw) in the absence of the usual tool by nonprototypical application of other familiar tools or objects (e.g., a coin; Heilman et al., 1997; Goldenberg and Hagmann, 1998b; Hodges et al., 1999; Spatt et al., 2002). Application of the nonsemantic route from vision to action is restricted to tools with transparent mechanical structure–function relationship. As most conventional tools fulfill this condition the second route can at least partially compensate loss of semantic knowledge of their appropriate use. Consequently, failure to use familiar conventional tools and objects should become manifest only in patients in whom both routes to action are compromised by brain damage, and this seems indeed to be the case in patients with apraxia from left brain damage (Goldenberg and Hagmann, 1998b).

16.6. Multi-step actions In daily life one rarely encounters a situation like that in testing for use of single tools and objects where one is handed a tool and asked to perform its prototypical action on an adequately prepared recipient. Usually the use of the single tool is embedded in a chain of actions involving several tools and objects, frequently

including technical devices, and aiming at a superordinate goal transgressing and modulating the purposes of each single action step. Although failure on tests of single tool use predicts difficulties with such naturalistic actions, the reverse is not necessarily the case, and more patients fail on naturalistic action than on use of single conventional tools and objects. 16.6.1. Clinical presentation Errors in application of single tools and objects which are detectable in explicit testing are likely to show up also in the course of multi-step actions, and the distraction by the additional demands of multi-step actions may bring forward insecurity and failure in use of single tools which have not been manifest in their isolated testing. In addition to these ‘misuse’ errors there are other types of errors specific to multi-step actions. The most important of them are mislocation, omission, toying, and perplexity (see Mayer et al., 1990; Rumiati et al., 2001; Schwartz et al., 2002 for more extensive error classifications). Mislocation refers to a correct action performed with the wrong recipient like pouring water into the cup rather than the reservoir of the coffee maker for preparing coffee with a drip coffee maker. Omission of a step is equivalent to the premature performance of another action step which should be initiated only after completion of the omitted one, as for example when turning on the heating of the coffee maker without having inserted water. Toying and perplexity could in principle also affect the isolated examination of single tool use but are much more prevalent in multi-step actions. Toying refers to touching or brief lifting of objects not followed by goal-oriented manipulations. Perplexity is diagnosed when patients hesitate unduly before commencing an action or fail to proceed with actions at all. 16.6.2. Localization In contrast to the exclusive association of defective use of single familiar tools with left brain damage multi-step actions are affected also by lesions in the right hemisphere (Buxbaum et al., 1998; Humphreys and Forde, 1998; Schwartz et al., 1998; 1999; Goldenberg et al., 2005; Hartmann et al., 2005). Although clinical experience and detailed descriptions of single cases (Poeck and Lehmkuhl, 1980; Humphreys and Forde, 1998; Rumiati et al., 2001; Forde et al., 2004) suggest more severe aberrations from the normal course of action in patients whose brain damage affects the left hemisphere, group studies corroborated neither this clinical impression nor the inference that errors of misuse, which on isolated testing of single tool use occur exclusively in

APRAXIA patients with left brain damage, are more common in patients with left brain damage than in those without (Goldenberg et al., 2003; Schwartz et al., 1999). There is no unequivocal evidence concerning intrahemispheric location specificity of lesions interfering with multi-step actions (Hartmann et al., 2005). 16.6.3. Theoretical accounts There are two ways to explain the uniform affection of naturalistic actions by lesions in either hemisphere. It may be due to depletion of attentional resources which are not bound to any specific location but depend on the integrity of the whole brain (Pick, 1905; Schwartz et al., 1999). Alternatively, the errors may have different causes in patients with damage to different locations, but these differences do not show up in the error profile because functional interactions between the multiple tools and objects constrain the range of possible errors and render observation of errors opaque as to the causes of failure (Hartmann et al., 2005). Support for the importance of general attentional depletion is provided by the repeatedly observed association between number of errors and severity of hemineglect in patients with right brain damage. There is no preponderance of errors in the left side of working space or of objects (Schwartz et al., 1999; Goldenberg et al., 2003) suggesting that both severity of hemineglect and errors on multi-step actions are expression of an underlying nonspatial reduction of attentional resources (Husain and Rorden, 2003). Different specific causes of errors were suggested by the finding of a strong correlation between errors in making coffee and linguistic abilities in patients with left brain damage and aphasia (Hartmann et al., 2005). The observation that patients with right brain damage whose language is unimpaired nonetheless make coffee no better than the aphasic patients suggests different causes of errors in both groups. Other approaches to naturalistic multi-step actions interpret task demands and causation of errors in the framework of executive function and the supervisory control of action (Humphreys and Forde, 1998; Cooper and Shallice, 2000; Rumiati et al., 2001; Forde et al., 2004; Goldenberg et al., 2005). Finally, a promising approach is computational modeling of the interactions between the multiple cognitive components contributing to success on such mundane tasks as preparing coffee, tea, or orange juice (Cooper and Shallice, 2000; Botvinick and Plaut, 2004; Cooper, 2005).

16.7. Ideational and ideomotor apraxia Having discussed the core manifestations of apraxia I will now turn to their classification as ‘ideational’ or

331

‘ideomotor.’ This dichotomy was originally elaborated by Liepmann (Liepmann, 1908; Goldenberg, 2003a). It was based on a distinction between non-localizable ‘psychic’ and localizable sensory and motor function of the cerebral cortex. Liepmann’s aim was to push forward the limits of localizable function into the realm of the psychic. He admitted that the generation of ideas of intended actions is a non-localizable psychic function depending on integrity of the whole cortex but postulated an ‘ideomotor’ step where ideas are transformed into appropriate muscular actions. (In fact Liepmann used the term ‘ideo-kinetic’ and considered ‘ideomotor’ to be synonymous with ‘ideational.’) This step should be intermediate between purely motor and purely psychic functions and depend on integrity of only the left hemisphere. A hundred years later even exquisitely ‘psychic’ functions like religious beliefs, empathy, or risk-taking are no longer exempted from cerebral localization. This undermines the theoretical basis of the dichotomy but not necessarily its clinical utility. Thus the theoretical framework of Wernicke’s classification of aphasia hardly corresponds with modern accounts of language, but the types of aphasia he described have proven to be clearly distinguishable clinical entities. A review of criteria proposed by different authors for discriminating ideational from ideomotor apraxia shows much less clarity. Defective imitation of meaningless gestures has been considered as ‘not really related to the understanding of apraxia’ by two influential authors (Geschwind and Damasio, 1985). It has been acknowledged as a core manifestation of ideomotor apraxia by others (Morlaas, 1928; Kimura and Archibald, 1974; De Renzi et al., 1980; Kimura, 1993), but this acknowledgement is made problematic by the evidence, reviewed above, that patients fail imitation because of insufficient perceptual and conceptual processing of demonstrated gestures rather than insufficient motor execution. Defective performance of communicative gestures on command has been said to emanate either from inability to retrieve the gesture from semantic memory, which would classify as ideational, or from defective motor execution, which would classify as ideomotor (Barbieri and De Renzi, 1988; De Renzi, 1990; Roy and Hall, 1992; Heilman and Rothi, 1993). The ambiguity should be resolved by observation of the types of errors. ‘Distorted movements’ (Poeck, 1982) which ‘do not concern the general configuration of the gesture’ (De Renzi, 1990) were considered indicative of ideomotor apraxia, but the decision whether or not an error distorts the general configuration or only a detail of a gesture may leave considerable space for divergence of interpretation. Defective use of single tools and objects has

332

G. GOLDENBERG

been considered as being due to insufficient motor execution and hence ideomotor apraxia by some authors (Poeck, 1982; Zangwill, 1960) and as the hallmark of ideational apraxia by others (Morlaas, 1928; De Renzi and Lucchelli, 1988). Omissions and confusions in the sequential ordering of multi-step actions were core symptoms of the original description of ideational apraxia (Pick, 1905; Liepmann, 1908; 1920; Lehmkuhl and Poeck, 1981; Poeck, 1982), but have recently been considered as constituting an ‘action disorganization syndrome’ distinct from apraxia (Buxbaum et al., 1998; Humphreys and Forde, 1998). A proposal to call difficulties with single tools and objects ‘conceptual apraxia’ and those with multi-step actions ‘ideational apraxia’ (Heilman and Rothi, 1993; Raymer and Ochipa, 1997) adds to the nomenclatorial confusion without clarifying the nature of their differences. Given that the theoretical fundament is questionable and the clinical application uncertain I plead for relegating the dichotomy of ideational and ideomotor apraxia to the history of neuropsychology and to replace it by unprejudiced inquiries into the mechanisms and cerebral substrates of each of the domains affected. Liberating imitation of gestures, production of communicative gestures, and use of tools and objects from their forced unification into a hierarchy of ideational and ideomotor apraxia will have advantages both for clinical practice and scientific research. For clinical practice equivocal classifications will be replaced by usable descriptions of what patients can and cannot do. For research abandoning the traditional classification clears the stage for discussing the differences and communalities between the cognitive and neuronal basis of the affected domains of action.

16.8. Apraxia and handedness Liepmann reasoned that the left hemisphere becomes dominant for deliberate motor control because it directly controls the more skilful right hand. According to this argument dominance for praxis should shift to the right hemisphere of left-handed persons. By contrast, approaches which emphasize the intimate link between gestures and language (Finkelnburg, 1870; Geschwind, 1975; Duffy and Duffy, 1981; Geschwind and Damasio, 1985) would predict that the laterality of praxis varies in accordance with the lateralization of language. As long as handedness and speech dominance are in concordance both hypotheses make the same predictions, but they dissociate in a substantial proportion of left-handed and a minority of right-handed persons (Knecht et al., 2000). Studies of apraxia in such patients support neither of the proposed associations. An obligatory association with handedness is refuted by observations

of left-handed patients who have both aphasia and apraxia from lesions of the left hemisphere (Hecaen et al., 1981; Kimura, 1983) and of right-handed handed patients who have ‘crossed’ aphasia and apraxia from right hemisphere lesions (Basso et al., 1985; Rapcsak et al., 1987; Alexander and Annet, 1996; Raymer et al., 1999; Coppens et al., 2002; Bartha et al., 2004). The concordance between lateralization of apraxia and aphasia is more difficult to refute as left sided lesions can cause apraxia without aphasia or the reverse dissociation in right-handed persons who have no evidence of atypical lateralization (Kertesz et al., 1984), but it is called into doubt by the lower frequency of apraxia in patients with aphasia from lesions ipsilateral to the dominant hand than in patients with concordant lateralization of handedness and language (Coppens et al., 2002; Marien et al., 2004). The doubts on an obligatory link between lateralization of apraxia and aphasia are enhanced by observations of single patients in whom very large lesions of the hemisphere opposite the dominant hand led to apraxia without aphasia (Margolin, 1980; Junque et al., 1986; Selnes et al., 1991; Verstichel et al., 1994). Before concluding that lateralization of apraxia is independent of both handedness and speech dominance one must consider methodological shortcomings of the reviewed studies. Most of them did not systematically explore which domains of actions were affected but based the diagnosis of apraxia either exclusively on performance of communicative gestures on command or on a compound scores combining performance of communicative gestures on command with imitation of the same gestures. This leaves open the possibility of more regular relationships between only one of the manifestations of apraxia and either handedness or language.

16.9. Callosal apraxia Liepmann’s first patient, the ‘imperial counselor,’ displayed apraxia of only one hand (Liepmann, 1900). Autopsy revealed among other lesions a partial destruction of the corpus callosum and Liepmann contended that the subsequent functional division of the hemispheres explained the unilaterality of apraxia. In this famous case the right hand was apraxic and interfered with appropriate actions of the left hand. At the time he published this case Liepmann had not yet developed the hypothesis of left hemisphere dominance for deliberate motor control. Later he tried to accommodate the aberrant laterality of this patient by the suggestion that he was not entirely right-handed (see Goldenberg 2003a for discussion of this case). In the subsequent years a number of cases were described in whom

APRAXIA autopsy proven callosal lesions had rendered only the left hand apraxic (Bonhoeffer, 1914; Goldstein, 1908; Goldstein, 1909; Hartmann, 1907; Liepmann and Maas, 1907; Van Vleuten, 1907), but around the middle of the twentieth century the conclusion that callosal disconnection had deprived the right hemisphere of the left hemisphere’s contribution to motor control fell into disgrace (Hecaen and Gimeno-Alava, 1960; De Ajuriaguerra and Tissot, 1969). This refusal was an expression of the then prevailing skepticism against ‘diagram making,’ of which the disconnection account of callosal apraxia was a prime example. When the pendulum swung back to acceptance of disconnection accounts of neuropsychological disorders the skepticism against callosal apraxia found new support in studies of patients who had undergone surgical section of the corpus callosum for relief of epileptic seizures. It seemed that effects on deliberate motor control were restricted to an inability to move the fingers of the left hand on verbal command but affected neither imitation nor object use (Gazzaniga et al., 1967; Zaidel and Sperry, 1977; Volpe et al., 1982). Since then, however, numerous reports of patients with natural lesions of the corpus callosum have confirmed the reality of left hand apraxia for imitation of gestures, performance of communicative gestures on command, and sometimes also object use (Goldenberg et al., 1985; Graff-Radford et al., 1987; Yamodori et al., 1988; Tanaka et al., 1990; Kazui and Sawada, 1993; Giroud and Dumas, 1995; Tanaka et al., 1996; Marangolo et al., 1998; Goldenberg et al., 2001). Recently disturbance of imitation of meaningless gestures and of pantomime of object use have been demonstrated also by careful re-examination of surgical split brain patients (Lausberg et al., 2003; Lausberg and Cruz, 2004). In all patients where left sided apraxia was caused by partial destruction of the corpus callosum the lesion included its middle portion connecting sensorimotor cortex. The lesions encroached upon the adjacent mesial frontal cortex in nearly all reported cases, but a proposal that these additional lesions are necessary for the emergence of apraxia (Goldenberg et al., 1985) has been disconfirmed by single cases with left sided apraxia from purely callosal lesions (GraffRadford et al., 1987; Goldenberg et al., 2001).

333

movements like licking the upper lip, pressing the tongue against one check, clicking with the tongue, or clear the throat, they search for the correct movement and eventually replace it by less differentiated movements like opening of the mouth or by unarticulated phonations. The failure is independent of whether the required movements are meaningful or not and whether the command is specified verbally or by imitation. It is said to contrast with flawless spontaneous performance of oral movements of similar complexity or even the same movements. Thus a patient who is unable to lick the upper lip on command will do so without thinking about it after a meal. Until now, however, the postulated dissociation between voluntary and automatic motor control is based on clinical impression rather than on systematic assessment of behavior outside the testing situation. The general agreement that face apraxia concerns mainly oral and articulatory movements and is a symptom of left brain damage has been challenged by a group study which applied a refined scoring system to a wide variety of lower and upper face gestures and found impairment on both of them in left and in right brain damaged patients (Bizzozero et al., 2000). In patients with left brain damage face and limb apraxia can co-occur but their association is not all mandatory. Their independence is corroborated by differential intrahemispheric locations. Impaired imitation of oral gestures is almost always associated with lesions of the anterior insula and adjacent frontal and central operculum but does not, in contrast to impaired imitation of limb movements, result from parietal lesions (Tognola and Vignolo, 1980; Raade et al., 1991).

16.11. Conclusion A major lesson of hundred years of research on apraxia seems to be that apraxia is not a unitary disorder and that there is no single locus of the brain responsible for all manifestations of apraxia. Further research into the neural and cognitive mechanisms underlying disturbances of imitation, of the production of communicative gestures, and of using tool and objects is likely to provide important insights into principles of cerebral localization of function.

16.10. Face apraxia References Face apraxia has also been labeled oral apraxia and buccofacial apraxia because most of the movements assessed concern mouth, tongue, and vocal cords (Alajouanine and Lhermitte, 1960; De Renzi et al., 1966; Tognola and Vignolo, 1980; Lehmkuhl et al., 1983; Raade et al., 1991). When asked to perform oral

Agostini E, Coletti A, Orlando G, et al. (1983). Apraxia in deep cerebral lesions. J Neurol Neurosurg Psychiatry 46: 804–808. Alajouanine T, Lhermitte F (1960). Les troubles des activite´s expressives du langage dans l’aphasie. Rev Neurol (Paris) 102: 604–629.

334

G. GOLDENBERG

Alexander MP, Annet M (1996). Crossed aphasia and related anomalies of cerebral organization: Case reports and a genetic hypothesis. Brain Lang 55: 213–239. Assal G, Butters J (1973). Troubles du sche´ma corporel lors des atteintes he´misphe´riques gauches. Schweiz Rundsch Med Prax 62: 172–179. Barbieri C, De Renzi E (1988). The executive and ideational components of apraxia. Cortex 24: 535–544. Bartha L, Marien P, Poewe W, et al. (2004). Linguistic and neuropsychological deficits in crossed conduction aphasia. Report of three cases. Brain Lang 88: 83–95. Bartolo A, Cubelli R, Della Sala S, et al. (2003). Pantomimes are special gestures which rely on working memory. Brain Cogn 53: 483–494. Basso A, Capitani E, Della Sala S, et al. (1987). Recovery from ideomotor apraxia—a study on acute stroke patients. Brain 110: 747–760. Basso A, Capitani E, Laiacona M, et al. (1985). Crossed aphasia: One or more syndromes? Cortex 21: 25–45. Basso A, Luzzatti C, Spinnler H (1980). Is ideomotor apraxia the outcome of damage to well defined regions of the left hemisphere? J Neurol Neurosurg Psychiatry 43: 118–126. Bay E (1962). Aphasia and non-verbal disorders of language. Brain 85: 411–426. Bizzozero I, Costato D, Della Sala S, et al. (2000). Upper and lower face apraxia: Role of the right hemisphere. Brain 123: 2213–2230. Bonhoeffer K (1914). Klinischer und anatomischer Befund zur Lehre von der Apraxie und der ‘motorischen Sprachbahn,’. Monatsschr Psychiatr Neurol 35: 113–128. Boronat CB, Buxbaum LJ, Coslett HB, et al. (2005). Distinctions between manipulation and function knowledge of objects: Evidence from functional magnetic resonance imaging. Cogn Brain Res 23: 361–373. Botvinick M, Plaut DC (2004). Doing without schema hierarchies: A recurrent connectionist approach to normal and impaired routine sequential actions. Psychol Rev 111: 395–429. Broca P (1861). Perte de la parole, ramollissement chronique et destruction partielle du lobe ante´rieur gauche du cerveau. Communication Socie´te´ d’Anthropologie: Se´ance du 18 avril 1861. Buxbaum LJ, Coslett HB (2001). Specialised structural descriptions for human body parts: Evidence from autotopagnosia. Cogn Neuropsychol 18: 289–306. Buxbaum LJ, Giovannetti T, Libon D (2000). The role of the dynamic body schema in praxis: Evidence from primary progressive apraxia. Brain Cogn 44: 166–191. Buxbaum LJ, Saffran EM (2002). Knowledge of object manipulation and object function: Dissociations in apraxic and nonapraxic patients. Brain Lang 82: 179–199. Buxbaum LJ, Schwartz MF, Montgomery MW (1998). Ideational apraxia and naturalistic action. Cogn Neuropsychol 15: 617–644. Byrne RW, Barnard PJ, Davidson I, et al. (2004). Understanding culture across species. Trends Cogn Sci 8: 341–346.

Canavan AGM, Passingham RE, Marsden CD, et al. (1989). Sequencing ability in Parkinsonians, patients with frontal lobe lesions and patients who have undergone unilateral temporal lobectomies. Neuropsychologia 27: 787–798. Chaminade T, Meltzoff AN, Decety J (2004). An fMRI study of imitation: Action representation and body schema. Neuropsychologia 43: 115–127. Cooper R, Shallice T (2000). Contention scheduling and the control of routine activities. Cogn Neuropsychol 17: 297–338. Cooper RP (2005). Tool use and related errors in ideational apraxia: The quantitative simulation of patient error profiles. Cortex 43: 319–337. Coppens P, Hungerford S, Yamaguchi S, et al. (2002). Crossed aphasia: An analysis of the symptoms, their frequency, and a comparison with left hemisphere aphasia symptomatology. Brain Lang 83: 425–463. Cubelli R, Marchetti C, Boscolo G, et al. (2000). Cognition in action: Testing a model of limb apraxia. Brain Cogn 44: 144–165. De Ajuriaguerra J, Tissot R (1969). The apraxias. In: PJ Vinken, GW Bruyn (Eds.), Handbook of Clinical Neurology, Vol. 4. North Holland, Amsterdam, pp. 48–66. De Renzi E (1990). Apraxia. In: F Boller, J Grafman (Eds.), Handbook of Clinical Neuropsychology, Vol. 2. Elsevier, Amsterdam, New York, Oxford, pp. 245–263. De Renzi E, Faglioni P, Lodesani M, et al. (1983). Performance of left brain-damaged patients on imitation of single movements and motor sequences. Frontal and parietalinjured patients compared. Cortex 19: 333–344. De Renzi E, Faglioni P, Sorgato P (1982). Modality-specific and supramodal mechanisms of apraxia. Brain 105: 301–312. De Renzi E, Lucchelli F (1988). Ideational apraxia. Brain 111: 1173–1185. De Renzi E, Motti F, Nichelli P (1980). Imitating gestures— A quantitative approach to ideomotor apraxia. Arch Neurol 37: 6–10. De Renzi E, Pieczuro A, Vignolo LA (1966). Oral apraxia and aphasia. Cortex 2: 50–73. De Renzi E, Pieczuro A, Vignolo LA (1968). Ideational apraxia: A quantitative study. Neuropsychologia 6: 41–55. De Renzi E, Scotti G (1970). Autotopagnosia: Fiction or reality? Arch Neurol 23: 221–227. Denes G, Cappelletti JY, Zilli T, et al. (2000). A categoryspecific deficit of spatial representation: The case of autotopagnosia. Neuropsychologia 38: 345–350. Duffy RJ, Duffy JR (1981). Three studies of deficits in pantomimic expression and pantomimic recognition in aphasia. J Speech Hear Res 14: 70–84. Duffy RJ, Duffy JR (1989). An investigation of body part as object (BPO) responses in normal and brain-damaged people. Brain Cogn 10: 220–236. Duffy RJ, Watt JH, Duffy JR (1994). Testing causal theories of pantomimic deficits in aphasia using path analysis. Aphasiology 8: 361–379. Ekman P, Friesen WV (1969). The repertoire of nonverbal behavior: Categories, origins, usage, and coding. Semiotica 1: 49–89.

APRAXIA Felician O, Ceccaldi M, Didic M, et al. (2003). Pointing to body parts: A double dissociation study. Neuropsychologia 41: 1307–1316. Finkelnburg FC (1870). Sitzung der Niederrheinischen Gesellschaft in Bonn. Medizinische Section, Ber Klin Wochenschr 7: 449–450, 460–462. Forde EME, Humphreys GW, Remoundou M (2004). Disordered knowledge of action order in action disorganisation syndrome. Neurocase 10: 19–28. Foundas AL, Macauley BL, Raymer AM, et al. (1995). Ecological implications of limb apraxia: Evidence from mealtime behaviour. J Int Neuropsychol Soc 1: 62–66. Gazzaniga MS, Bogen JE, Sperry RW (1967). Dyspraxia following division of the cerebral commissures. Arch Neurol 16: 606–612. Geschwind N (1975). The apraxias: Neural mechanisms of disorders of learned movements. Am Sci 63: 188–195. Geschwind N, Damasio AR (1985). Apraxia. In: JAM Frederiks (Ed.), Handbook of Clinical Neurology, Vol 1(49): Clinical Neuropsychology. Elsevier, Amsterdam, New York, pp. 423–432. Giroud M, Dumas R (1995). Clinical and topographical range of callosal infarction: A clinical and radiological correlation study. J Neurol Neurosurg Psychiatry 59: 238–242. Goldenberg G (1995). Imitating gestures and manipulating a mannikin—the representation of the human body in ideomotor apraxia. Neuropsychologia 33: 63–72. Goldenberg G (1996). Defective imitation of gestures in patients with damage in the left or right hemisphere. J Neurol Neurosurg Psychiatry 61: 176–180. Goldenberg G (1999). Matching and imitation of hand and finger postures in patients with damage in the left or right hemisphere. Neuropsychologia 37: 559–566. Goldenberg G (2003a). Apraxia and beyond—life and works of Hugo Karl Liepmann. Cortex 39: 509–525. Goldenberg G (2003b). Pantomime of object use: A challenge to cerebral localization of cognitive function. Neuroimage 20: S101–S106. Goldenberg G, Hagmann S (1997). The meaning of meaningless gestures: A study of visuo-imitative apraxia. Neuropsychologia 35: 333–341. Goldenberg G, Hagmann S (1998a). Therapy of activities of daily living in patients with apraxia. Neuropsychol Rehabil 8: 123–142. Goldenberg G, Hagmann S (1998b). Tool use and mechanical problem solving in apraxia. Neuropsychologia 36: 581–589. Goldenberg G, Hartmann K, Schlott I (2003). Defective pantomime of object use in left brain damage: Apraxia or asymbolia? Neuropsychologia 41: 1565–1573. Goldenberg G, Hartmann-Schmid K, Su¨rer F, et al. (2005). The impact of dysexecutive syndrome on use of tools and technical equipment. Cortex 43: 424–435. Goldenberg G, Hentze S, Hermsdo¨rfer J (2004). The effect of tactile feedback on pantomime of object use in apraxia. Neurology 63: 1863–1867.

335

Goldenberg G, Hermsdo¨rfer J, Glrindernam R, et al. (in press). Pantomime of tool use depends on integrity of left inferior frontal cortex. Cereb cortex DOI: 10. 1093/cercor/bhm004. Goldenberg G, Hermsdo¨rfer J, Laimgruber K (2001). Imitation of gestures by disconnected hemispheres. Neuropsychologia 39: 1432–1443. Goldenberg G, Strauss S (2002). Hemisphere asymmetries for imitation of novel gestures. Neurology 59: 893–897. Goldenberg G, Wimmer A, Auff E, et al. (1986). Impairment of motor planning in patients with Parkinson’s disease: Evidence from ideomotor apraxia testing. J Neurol Neurosurg Psychiatry 49: 1266–1272. Goldenberg G, Wimmer A, Holzner F, et al. (1985). Apraxia of the left limbs in a case of callosal disconnection: The contribution of medial frontal lobe damage. Cortex 21: 135–148. Goldin-Meadow S, Wagner SM (2005). How our hands help us to learn. Trends Cogn Sci 9: 234–241. Goldstein K (1908). Zur Lehre von der motorischen Apraxie. J Psychol Neurol 11: 169–187, 270–283. Goldstein K (1909). Der makroskopische Hirnbefund in meinem Fall von linksseitiger Apraxie. Neurol Zentralbl 28: 898–906. Goodale MA, Jakobson LS, Keillor JM (1994). Differences in the visual control of pantomimed and natural grasping movements. Neuropsychologia 32: 1159–1178. Goodglass H, Kaplan E (1963). Disturbance of gesture and pantomime in aphasia. Brain 86: 703–720. Graff-Radford NR, Welsh K, Godersky J (1987). Callosal apraxia. Neurology 37: 100–105. Graham NL, Zeman A, Young AW, et al. (1999). Dyspraxia in a patient with corticobasal degeneration: The role of visual and tactile inputs to action. J Neurol Neurosurg Psychiatry 67: 334–344. Haaland KY, Flaherty D (1984). The different types of limb apraxia errors made by patients with left versus right hemisphere damage. Brain Cogn 3: 370–384. Haaland KY, Harrington DL, Knight RT (2000). Neural representations of skilled movement. Brain 123: 2306–2313. Hanlon RE, Mattson D, Demery JA, et al. (1998). Axial movements are relatively preserved with respect to limb movements in aphasic patients. Cortex 34: 731–742. Hartmann F (1907). Beitraege zur Apraxielehre. Monatsschr Psychiatr Neurol 21: 97–118, 248–270. Hartmann K, Goldenberg G, Daumu¨ller M, et al. (2005). It takes the whole brain to make a cup of coffee: The neuropsychology of naturalistic actions involving technical devices. Neuropsychologia 43: 625–637. Hecaen H, De Agostini M, Monzon-Montes A (1981). Cerebral organization in left handers. Brain Lang 12: 261–284. Hecaen H, Gimeno-Alava A (1960). L’apraxie unilaterale gauche. Rev Neurol (Paris) 102: 648–653. Heilman KM, Maher LM, Greenwald ML, et al. (1997). Conceptual apraxia from lateralized lesions. Neurology 49: 457–464.

336

G. GOLDENBERG

Heilman KM, Rothi LJG (1993). Apraxia. In: KM Heilman, E. Valenstein (Eds.), Clinical Neuropsychology. Oxford University Press, New York, Oxford, pp. 141–164. Hermsdo¨rfer J, Mai N, Spatt J, et al. (1996). Kinematic analysis of movement imitation in apraxia. Brain 119: 1575–1586. Hillis AE, Wityk RJ, Barker PB, et al. (2002). Subcortical aphasia and neglect in acute stroke: The role of cortical hypoperfusion. Brain 125: 1094–1104. Hodges JR, Bozeat S, Lambon Ralph MA, et al. (2000). The role of conceptual knowledge in object use—evidence from semantic dementia. Brain 123: 1913–1925. Hodges JR, Spatt J, Patterson K (1999). ‘What’ and ‘how’: Evidence for the dissociation of object knowledge and mechanical problem-solving skills in the human brain. Proc Natl Acad Sci USA 96: 9444–9448. Howes DH (1988). Ideomotor apraxia: Evidence for the preservation of axial commands. J Neurol Neurosurg Psychiatry 51: 593–598. Humphreys GW, Forde EME (1998). Disordered action schema and action disorganisation syndrome. Cogn Neuropsychol 15: 771–812. Husain M, Rorden C (2003). Non-spatially lateralized mechanisms in hemispatial neglect. Nat Rev Neurosci 4: 26–36. Junque C, Litvan I, Vendrell P (1986). Does reversed laterality really exist in dextrals? A case study. Neuropsychologia 24: 241–254. Kazui S, Sawada T (1993). Callosal apraxia without agraphia. Ann Neurol 33: 401–403. Kendon A (2004). Gesture—Visible Action as Utterance. Cambridge University Press, Cambridge, New York. Kertesz A, Ferro JM, Shewan CM (1984). Apraxia and aphasia: The functional–anatomical basis for their dissociation. Neurology 34: 40–47. Kimura D (1977). Acquisition of a motor skill after left-hemisphere damage. Brain 100: 527–542. Kimura D (1983). Speech representation in an unbiased sample of left-handers. Hum Neurobiol 2: 147–154. Kimura D (1993). Neuromotor Mechanisms in Human Communication Oxford University Press–Clarendon Press, New York, Oxford. Kimura D, Archibald Y (1974). Motor functions of the left hemisphere. Brain 97: 337–350. Knecht S, Dra¨ger B, Deppe M, et al. (2000). Handedness and hemispheric language dominance in healthy humans. Brain 123: 2512–2518. Laimgruber K, Goldenberg G, Hermsdo¨rfer J (2005). Manual and hemispheric asymmetries in the execution of actual and pantomimed prehension. Neuropsychologia 43: 682–692. Lausberg H, Cruz RF (2004). Hemispheric specialisation for imitation of hand–head positions and finger configurations: A controlled study in patients with complete callosotomy. Neuropsychologia 42: 320–334. Lausberg H, Cruz RF, Kita S, et al. (2003). Pantomime to visual presentation of objects: Left hand dyspraxia in patients with complete callosotomy. Brain 126: 343–360.

Lehmkuhl G, Poeck K (1981). A disturbance in the conceptual organization of actions in patients with ideational apraxia. Cortex 17: 153–158. Lehmkuhl G, Poeck K, Willmes K (1983). Ideomotor apraxia and aphasia: An examination of types and manifestations of apraxic symptoms. Neuropsychologia 21: 199–212. Liepmann H (1900). Das Krankheitsbild der Apraxie (motorische Asymbolie) auf Grund eines Falles von einseitiger Apraxie. Monatsschr Psychiatr Neurol 8: 15–44, 102– 132, 182–197. Liepmann H (1908). Drei Aufsa¨tze aus dem Apraxiegebiet. Karger, Berlin. Liepmann H (1920). Apraxie. In: H Brugsch (Ed.), Ergebnisse der Gesamten Medizin. Urban & Schwarzenberg, Wien, Berlin, pp. 516–543. Liepmann H, Maas O (1907). Fall von linksseitiger Agraphie und Apraxie bei rechtsseitiger Laehmung. J Psychol Neurol 10: 214–227. Marangolo P, De Renzi E, Di Pace E, et al. (1998). Let not thy left hand know what thy right hand knoweth. The case of a patient with an infarct involving the callosal pathways. Brain 121: 1459–1467. Margolin DI (1980). Right hemisphere dominance for praxis and left hemisphere dominance for speech in a left-hander. Neuropsychologia 18: 715–719. Marien P, Paghera B, De Deyn PP, et al. (2004). Adult crossed aphasia in dextrals revisited. Cortex 40: 41–74. Mayer NH, Reed E, Schwartz MF, et al. (1990). Buttering a hot cup of coffee: An approach to the study of errors of action in patients with brain damage. In: DE Tupper, KD Cicerone (Eds.), The Neuropsychology of Everyday Life: Assessment and Basic Competencies. Kluwer Academic Publishers, Boston, Dordrecht, London, pp. 259–284. McNeill D (1992). Hand and Mind. The University of Chicago Press, Chicago, London. Mehler MF (1987). Visuo-imitative apraxia. Neurology 37: 129. Meltzoff AN, Moore MK (1997). Explaining facial imitation: A theoretical model. Early Development and Parenting 6: 179–192. Morlaas J (1928). Contribution a` l’e´tude de l’apraxie. Ame´de´e Legrand, Paris. Ogden JA (1985). Autotopagnosia. Occurrence in a patient without nominal aphasia and with an intact ability to point to parts of animals and objects. Brain 108: 1009–1022. Papagno C, Della Sala S, Basso A (1993). Ideomotor apraxia without aphasia and aphasia without apraxia: The anatomical support for a double dissociation. J Neurol Neurosurg Psychiatry 56: 286–289. Peigneux P, Van der Linden M, Andres-Benito P, et al. (2000). Exploration neuropsychologique et par imagerie fonctionelle ce´re´brale d’une apraxie visuo-imitative. Rev Neurol (Paris) 156: 459–472. Peigneux P, Van der Linden M, Garraux G, et al. (2004). Imaging a cognitive model of apraxia: The neural substrate of gesture-specific cognitive processes. Hum Brain Mapp 21: 119–142.

APRAXIA Pick A (1905). Studien zur motorischen Apraxia und ihr nahestende Erscheinungen; ihre Bedeutung in der Symptomatologie psychopathischer Symptomenkomplexe. Franz Deuticke, Leipzig und Wien. Poeck K (1982). The two types of motor apraxia. Arch Ital Biol 120: 361–369. Poeck K, Lehmkuhl G (1980). Das Syndrom der ideatorischen Apraxie und seine Lokalisation. Nervenarzt 51: 217–225. Poeck K, Lehmkuhl G, Willmes K (1982). Axial movements in ideomotor apraxia. J Neurol Neurosurg Psychiatry 45: 1125–1129. Poncet M, Pellissier JF, Sebahoun M, et al. (1971). A propos d’un cas d’autotopagnosie secondaire a` une le´sion parie´tooccipitale de l’he´misphe`re majeur. Encephale 61: 1–14. Raade AS, Rothi LJG, Heilman KM (1991). The relationship between buccofacial and limb apraxia. Brain Cogn 16: 130–146. Rapcsak SZ, Rothi LJG, Heilman KM (1987). Apraxia in a patient with atypical cerebral dominance. Brain Cogn 6: 450–463. Raymer AM, Merians AS, Adair JC, et al. (1999). Crossed apraxia. Cortex 35: 183–200. Raymer AM, Ochipa C (1997). Conceptual praxis. In: LJG Rothi, KM Heilman (Eds.), Apraxia: The Neuropsychology of Action. Psychology Press, Hove, pp. 51–61. Rothi LJG, Ochipa C, Heilman KM (1991). A cognitive neuropsychological model of limb praxis. Cogn Neuropsychol 8: 443–458. Rothi LJG, Ochipa C, Heilman KM (1997a). A cognitive neuropsychological model of limb praxis and apraxia. In: LJG Rothi, KM Heilman (Eds.), Apraxia: The Neuropsychology of Action. Psychology Press, Hove, pp. 29–50. Rothi LJG, Raymer AM, Heilman KM (1997b). Limb praxis assessment. In: LJG Rothi, KM Heilman (Eds.), Apraxia: The Neuropsychology of Action. Psychology Press, Hove, pp. 61–74. Roy EA, Black SE, Blair N, et al. (1998). Analysis of deficits in gestural pantomime. J Clin Exp Neuropsychol 20: 628–643. Roy EA, Black SE, Winchester TR, et al. (1996). Gestural imitation following stroke. Brain Cogn 30: 343–346. Roy EA, Hall C (1992). Limb apraxia: A process approach. In: L Proteau, D Elliott (Eds.), Vision and Motor Control. Elsevier, Amsterdam, pp. 261–282. Roy EA, Heath M, Westwood D, et al. (2000). Task demands in limb apraxia and stroke. Brain Cogn 44: 253–279. Roy EA, Square-Storer P, Hogg S, et al. (1991). Analysis of task demands in apraxia. Int J Neurosci 56: 177–186. Rumiati RI, Humphreys GW (1998). Recognition by action: Dissociating visual and semantic routes to action in normal observers. J Exp Psychol Hum Percept Perform 24: 631–647. Rumiati RI, Zanini S, Vorano L, et al. (2001). A form of ideational apraxia as a selective deficit of contention scheduling. Cogn Neuropsychol 18: 617–642. Schofield WN (1976). Do children find movements which cross the body midline difficult? Q J Exp Psychol 28: 571–582.

337

Schwartz MF, Buxbaum LJ, Montgomery MW, et al. (1999). Naturalistic action production following right hemisphere stroke. Neuropsychologia 37: 51–66. Schwartz MF, Lee SS, Coslett HB, et al. (1998). Naturalistic action impairment in closed head injury. Neuropsychology 12: 13–28. Schwartz MF, Segal M, Veramonti T, et al. (2002). The naturalistic action test: A standardised assessment for everyday action impairment. Neuropsychol Rehabil 12: 311–339. Selnes OA, Pestronk A, Hart J, et al. (1991). Limb apraxia without aphasia from a left sided lesion in a right handed patient. J Neurol Neurosurg Psychiatry 54: 734–737. Sirigu A, Duhamel JR, Poncet M (1991). The role of sensorimotor experience in object recognition—a case of multimodal agnosia. Brain 114: 2555–2573. Soliveri P, Piacentini M, Girotti F (2005). Limb apraxia in corticobasal degeneration and progressive supranuclear palsy. Neurology 64: 448–453. Spatt J, Bak T, Bozeat S, et al. (2002). Apraxia, mechanical problem solving and semantic knowledge—Contributions to object usage in corticobasal degeneration. J Neurol 249: 601–608. Steinthal H (1881). Abriss der Sprachwissenschaft, 2nd edn. Ferd. Du¨mmlers Verlagsbuchhandlung Harrwitz und Gossmann, Berlin. Tanaka Y, Iwasa H, Obayashi T (1990). Right hand agraphia and left hand apraxia following callosal damage in a righthander. Cortex 26: 665–671. Tanaka Y, Yoshida A, Kawahata N, et al. (1996). Diagonistic dyspraxia: Clinical characteristics, responsible lesion and possible underlying mechanism. Brain 119: 859–873. Tessari A, Rumiati RI (2004). The strategic control of multiple routes in imitation of action. J Exp Psychol [Hum Percept Performance] 30: 1107–1116. Tognola G, Vignolo LA (1980). Brain lesions associated with oral apraxia in stroke patients: A clinico-neuroradiological investigation with the CT scan. Neuropsychologia 18: 257–272. Tomasello M, Savage-Rumbaugh S, Kruger AC (1993). Imitative learning of actions on objects by children, chimpanzees, and enculturated chimpanzees. Child Dev 64: 1688–1705. Vaina LM, Jaulent MC (1991). Object structure and action requirements: A compatibility model for functional recognition. Int J Intelligent Syst 6: 313–336. Van Vleuten CF (1907). Linksseitige motorische Apraxie – Ein Beitrag zur Physiologie des Balkens. Zeitschrift fu¨r Psychiatrie 64: 203–239, 389. Verstichel P, Cambier J, Masson C, et al. (1994). Apraxie et autotopagnosie sans aphasie ni agraphie, mais avec activite´ compulsive de langage au cours d’une le´sion he´misphe´rique droite. Rev Neurol (Paris) 150: 274–281. Volpe BT, Sidtis JJ, Holtzmann JD, et al. (1982). Cortical mechanisms involved in praxis: Observations following partial and complete section of the corpus callosum in man. Neurology 32: 645–650.

338

G. GOLDENBERG

Wada Y, Nakagawa Y, Nishikawa T, et al. (2000). Role of somatosensory feedback from tools in realizing movements by patients with ideomotor apraxia. European neurology 41: 73–78. Weiller C, Willmes K, Reiche W, et al. (1993). The case of aphasia or neglect after striatocapsular infarction. Brain 116: 1509–1525. Whiten A (2000). Primate culture and social learning. Cogn Sci 24: 477–508. Yamodori A, Osumi Y, Imamury T, et al. (1988). Persistent left unilateral apraxia and a disconnection theory. Behav Neurol 1: 11–22.

Zaidel D, Sperry RW (1977). Some long term motor effects of cerebral commissurotomy in man. Neuropsychologia 15: 193–204. Zangwill OL (1960). Le probleme de l’apraxie ideatoire. Rev Neurol (Paris) 102: 595–633. Zentall TR (2004). Action imitation in birds. Learn Behav 32: 15–23.

Handbook of Clinical Neurology, Vol. 88 (3rd series) Neuropsychology and behavioral neurology G. Goldenberg, B.L. Miller, Editors # 2008 Elsevier B.V. All rights reserved

Chapter 17

Acalculia KLAUS WILLMES* Neurology Clinic, Neuropsychology University Hospital—RWTH Aachen University, Aachen, Germany

17.1. Introduction It is hard to imagine what it would be like not to be fully able to comprehend the transactions at the cashier when going shopping, to check the veracity of a special offer, to assess the balance of one’s bank account, to use numbers in approximate calculations or for estimation of numerosities, distances, discounts, or to even simply understand or convey a telephone number and the time of the day. This loss or impairment of the ability to carry out calculation tasks and to handle numbers consequent to acquired brain pathology is called acalculia. Although acalculia constitutes a frequent and incapacitating disorder, the term itself was coined only several decades later than aphasia by Henschen (1919) and its scientific inquiry has been much less intense than for other major neuropsychological conditions (Ardila and Rosselli, 2002) until the 1990s. Nevertheless a chapter was devoted to it by Boller and Grafman (1985) in the revised edition of volume 45 of this Handbook (Vinken et al., 1985) and a chapter by Grafman (1988) in the first edition of the Handbook of Neuropsychology (Boller and Grafman, 1988). Lewandowsky and Stadelmann are generally considered to be the first authors to have given a detailed report on a patient with calculation disorders (Lewandowsky and Stadelmann, 1908) showing that these disorders may be distinct from language disturbances. Henschen (1925) also provided the first comprehensive compilation of patients presenting with disorders of calculation that could not be considered to be the consequence of language impairments. Moreover, Henschen identified candidate brain areas taken to subserve arithmetic processes: the third frontal convolution for uttering numbers, angular gyrus and intraparietal sulcus for reading numbers, angular gyrus for *

writing numbers, inferior parietal areas for mental calculation. In case of large left-hemispheric lesions the right hemisphere was assumed to take over certain calculation functions. It was also pointed out that these areas are close to anatomical centers for language and musical abilities. Along a similar line Berger (1926) proposed to distinguish between primary acalculia—as a loss of numerical concepts and an inability to comprehend or carry out even basic numerical operations—and a secondary form, in which deficits of other cognitive functions like attention, short or long-term memory, language, reading, writing, as well as spatial abilities lead to specific problems in handling numbers or arithmetic. Subsequently, existence of the primary form of acalculia has been under scrutiny from different perspectives. On the one hand, the Gerstmann syndrome has been proposed as an obligatory association between primary acalculia and the three other symptoms agraphia, right–left disorientation, and finger agnosia (Gerstmann, 1940) seen in patients with left posterior parietal lesions; whereas Benton (1992) has argued for a spurious association due to anatomofunctional vicinity in adjacent inferior parietal regions. On the other hand, it soon became obvious that disorders of calculation are not homogeneous and that subtypes should be introduced leading to the proposition of several clinically oriented classifications. The most prominent was the tripartite grouping by He´caen et al. (1961) discerning ‘anarithmetia’ (anarithme´tie) as the primary form and two secondary forms ‘alexia and agraphia for digits and numbers’ as well as ‘spatial acalculia.’ Boller and Grafman (1983) differentiated calculation problems proper further into impaired knowledge and use of mathematical facts as compared to problems with conceptual knowledge of mathematical concepts and operations.

Correspondence to: Klaus Willmes, PhD, Neurological Clinic, Neuropsychology University Hospital—RWTH, Aachen, Germany. E-mail: [email protected], Tel: 0241/80–89970, Fax: 0241/80–82444.

340

K. WILLMES

Acalculia has to be distinguished from developmental dyscalculia, designating a specific learning difficulty about numbers and arithmetic in childhood, resulting in a failure to achieve adequate proficiency in arithmetic despite normal intelligence, scholastic opportunity, emotional stability, and sufficient motivation (Shalev and Gross-Tsur, 2001; Butterworth, 2005). A more fundamental and detailed appreciation of the various patterns of acquired impairments was feasible with the formulation of explicit (neuro-)cognitive modular number processing and calculation models starting with the so-called single-route model by McCloskey et al. (1985). In this model, comprehension mechanisms for Arabic numbers and spoken as well as written number words feed into a central semantic (symbolic) representation of number meaning that is linked bidirectionally to stored arithmetic facts and stored calculation procedures and that relates the results of mental transcoding and calculation to an output system with separate subsystems for the production of (strings of) Arabic digits, as well as spoken and written number words, with an organization homologous to the input systems. This model of normal processing was very influential in characterizing different forms of impairment in a multitude of single-case studies of patients suffering from acquired acalculia with isolated or associated disorders of number processing and calculation (Caramazza and McCloskey, 1987; McCloskey et al., 1991). There is however a principled and ongoing debate about the number and properties of mental representations of number since dissociations between exact and approximate processing were reported, such as the famous case D.R.C. studied by Warrington (1982). In line with and elaborating on this distinction, Dehaene and coworkers proposed their influential triple-code model (Dehaene, 1992), in which three interrelated major internal mental representations for numbers are assumed. The central semantic representation is a quantitative analog magnitude code for number, employed in number comparison and approximate calculation; but see Nuerk et al. (2001) presenting a modification for two-digit numbers that also entails separate, digit-position based representations. It is linked with a visual– Arabic code that provides a string of identified digit symbols and an auditory–verbal code that provides a pre-phonological word form, both without meaning. Both latter codes are employed as an interface for input and output processes. The model became even more interesting for neuropsychology and functional imaging research when it was augmented into an anatomofunctional model (Dehaene and Cohen, 1995; Dehaene, 1997) specifying brain areas and cerebral networks assumed to subserve the different number representations and number processing and calculation processes.

In particular, introduction of the quantitative magnitude representation, comparable to a left-to-right oriented metaphorical ‘mental number line’ with increasing numerical magnitude and supposed to be subserved by brain tissue around the (horizontal part of) the intraparietal sulcus (IPS) bilaterally, was pivotal in understanding patients’ performance patterns in which number comparison of Arabic numbers was feasible, but not the comprehension and production of number words or simple mental arithmetic (see below). In the most recent version of the model (Dehaene et al., 2003), based on a meta-analysis of the available body of functional activation studies and neuropsychological evidence, a further functional partition of the inferior parietal cortex has been proposed: The horizontal IPS (hIPS) has been identified as the structure which gets active whenever numbers in whatever symbolic or nonsymbolic notation are manipulated mentally, in particular when numerical quantity has to be processed. This brain area is distinct from a left angular gyrus area which is assumed to support the manipulation of numbers in verbal format in connection with other lefthemisphere perisylvian areas (e.g., for the retrieval of number fact knowledge), and a bilateral system in the posterior superior parietal lobe (PSPL) that regulates attentional orientation in general and presumably also along the mental number line. Since elementary abilities in discerning (and possibly summating) small numerosities and quantities have been reported for birds, mammals, and primates (Hauser et al., 2003) as well as for newborns and babies (Feigensohn et al., 2004) it is tempting to postulate an inborn ‘number sense’ (Dehaene, 1997) or ‘number module’ (Butterworth, 1999) subserving the preverbal representation of quantitative number magnitude or numerosity, since Nieder and Miller (2004) reported on the detection of numerosity sensitive neurons in a visual numerosity judgment task in the monkey, indicating a parietofrontal network for the processing of numerosity. The debate about whether elementary numerical cognition and calculation require a differentiated number word vocabulary has been fuelled by recent reports on indigenous Amazon tribes speaking languages with a very limited number word vocabulary and with very limited exact calculation abilities but showing good approximate skills when dealing with nonsymbolic numerosities e.g., in comparison tasks (Gordon, 2004; Pica et al., 2004). Finally, the host of different symbolic notations used in the history of mankind (Ifrah, 1985) and their differences with respect to suitability for computations raises very general questions about the relations between external notations and internal representation (Zhang and Norman, 1995) and the relation between language and thought per se.

ACALCULIA

17.2. Mental operations and representations Even without explicit recourse to a specific neurocognitive number processing and calculation model, a short characterization of the most important mental operations involved in dealing with numbers and their organization will be helpful in providing a conceptual framework for the delineation of clinically relevant patterns of symptoms. 17.2.1. Mental representations Knowledge about numbers is available in at least three formats related to different mental codes: (i) sequences of Arabic digits; (ii) sequences of number words composed of elements from a limited lexicon with specific syntactic–morphological combination rules, which may encompass inversion of unit and decade numbers for teens-numbers in English and two-digit numbers in general in German or Dutch (‘46’ is equivalent to ‘sechsundvierzig,’ literally ‘sixandforty’ instead of ‘fortysix’); (iii) (abstract) quantity or numerosity not tied to a specific notation. Culturally specific and culturally transmitted symbolic notational systems allow for the exact encoding of any number, in principle, irrespective of their flexibility and transparency. The quantitative representation, preferably modeled as a left-to-right oriented mental number line is only approximate showing a decrease in precision with increasing numerical quantity (Dehaene et al., 2003). Particular numbers may additionally be related to specific aspects of episodic or declarative memory such as ‘1789,’ ‘1945,’ ‘747,’ personal year of birth or age. A recent discussion of what is known about the relations between the different mental representations is provided by Fayol and Seron (2005). 17.2.2. Input/output Spoken and written number words are identified as well as spoken and written like other words. Numbers in Arabic format can be identified and written in the visual modality. Interestingly, every single digit already bears a semantic meaning (i.e., numerical magnitude) contrary to individual letters of the alphabet. A collection of visual objects like line marks, finger patterns, even hand gestures, or dots on a dice lend themselves easily to nonlinguistic encoding or expression of numerosity or numerical quantity (Fayol and Seron, 2005). 17.2.3. Transcoding Different number codes can be transformed into each other according to fixed sets of rules. For example, when reading an Arabic number, the individual digits

341

and their relative position in the sequence of digits have to be identified; next—e.g., for ‘46’—a specific element (in this case the fourth) from the set/stack of decade words has to be selected as well as a specific element from the set/stack of units words and both have to be concatenated. In German (or Dutch) the inversion rule has to be applied first before the two words are allotted with the particle ‘und’ inserted between them (‘sechsundvierzig’). Brysbaert (2005) has given a scholarly presentation and discussion about the commonalities and differences of how numbers are encoded and processed in their different formats, concentrating on analog displays (dots, tallies, bar graphs, etc.), verbal numerals, and Arabic numerals. 17.2.4. Calculation The three number codes introduced before contribute to mental or written calculation in different ways. Multiplication tables are assumed to be highly overlearned in adults. Visual presentation of ‘6
8’ is assumed to invoke transcoding into a verbal representation ‘six times eight’ which in turn triggers retrieval of the stored representation of the result in a verbal format ‘forty-eight’ that may be uttered, written down (rarely) or transcoded into an Arabic number. There is debate about whether multiplication tables of one-digit numbers only require (fast) retrieval from a store or whether some computations are required to obtain a result. Solving arithmetic problems with bigger numbers usually has to rely on more or less overlearned computational routines that make use of the unique properties of the ingenious place–value notational system of Arabic numbers (Zhang and Norman, 1995). In approximate calculation or numerical magnitude comparisons (of two numbers) the quantitative magnitude representation is employed, resulting in faster reaction times and less errors with increasing numerical distance among numbers (so called distance effect)—a pattern of results that is compatible with the assumption of analog quantity representation of number magnitude. With increasingly complex calculation tasks there is an increasing challenge of (verbal) working memory as well as attentional and executive functions (cf. a comprehensive model by Grafman, 1988). 17.2.5. Conceptual mathematical thinking Apart from facts and procedures, conceptual knowledge constitutes the third main type of arithmetic knowledge. Conceptual knowledge encompasses an understanding of arithmetic operations and principles like commutativity in addition and multiplication (Delazer, 2003). Thus, conceptual arithmetic knowledge is required to

342

K. WILLMES

draw inferences and combine different pieces of information in arithmetic. This type of knowledge is flexible; it can be adapted and applied to novel tasks. It is also involved when instead of simply trying to retrieve e.g., the result of ‘7
9’ from memory one may employ the following calculations: 7
10 ¼ 70; 70  7 ¼ 63, i.e., application of a specific instance of the distributive law 7
(10  1) ¼ 70  7 ¼ 63. Semenza (2002) has again pointed out that successful schematic application of the heterogeneous set of procedures comprising complex calculation does not necessitate conceptual understanding of all procedural steps in a calculation and that it can thus be applied only to familiar types of computations. Even in case of profound semantic dementia it is possible that rather complex calculation skills may be preserved (cf. patient B.E.T. of Crutch and Warrington, 2002). It may be that an individual subcomponent is memorized only within a learned context. Thus, 0
n may be solved correctly in the context of some complex multidigit calculation but answered as 0
n ¼ n when asked to solve the task in isolation. 17.2.6. Spatial representation of numbers For a certain percentage of normal adult persons numbers have a visuospatial representation (Seron et al., 1992), as already described by Galton (1880) and called ‘number form.’ Galton was also the first to report on its heritability (Boller, 1982). The idea of a linear analog representation termed the ‘mental number line’ has been proposed by Moyer and Landauer (1967) to account for a distance effect obtained in a singledigit number magnitude comparison task: reaction time increased with decreasing distance. This mental number line is assumed to have a left-to-right orientation since the experimental demonstration of the so-called SNARC effect by Dehaene et al. (1993): in a parity (odd vs. even) decision task for digits from 0 to 9 participants responded faster to smaller numbers with a left-hand response key as well as faster to larger numbers with the right-hand response key. Thus there was a ‘Spatial Numerical Association of Response Codes’ pointing to activation of a spatial number representation in most subjects even in a task where number magnitude is not involved explicitly. Fias and Fischer (2005) have reviewed the evidence for the SNARC effect as an index of the spatial properties of numerical magnitude in the form of an oriented mental number line. This metaphor should not be taken literally since there is no indication of a topographic arrangement of number-selective neurons in the (monkey) brain (Nieder and Miller, 2004) but of a flexible and strategic use of these spatial associations with respect to different reference frames that are also task-dependent and

culturally determined (e.g., reversed SNARC effect in right-to-left reading and writing societies). Another spatial association has been reported by Nuerk et al. (2004) such that odd numbers are associated with left side and even numbers with right side of space. Another line of evidence for spatial aspects of number representation is related to the responses of patients with right brain damage neglecting the left side of space when having to indicate which number is midway between two other numbers in a so-called number bisection task. Zorzi et al. (2002) found a systematic shift of the reported midpoint to the right (e.g., responding ‘6’ to the interval 2–8) attributing this deviation to a (representational) neglect of the left side of the mental number line. Moreover the patients also showed a crossover effect with responses to the left of the middle for small intervals, just as for physical line bisection with short lines. A recent report by Doricchi et al. (2005) complicated the picture in that physical and mental number bisection could dissociate after right brain damage. In that report damage to right prefrontal spatial working memory regions was considered the main cause of rightward neglect bias for number bisection.

17.3. Clinical presentation Acalculia symptomatology can be grossly divided into (i) transcoding impairments, e.g., concerning the auditory comprehension of number words or reading (aloud) and writing of Arabic numbers, (ii) impairments of a (quantitative) magnitude representation, e.g., when comparing numbers, (iii) calculation impairments (oral or written) including the processing of arithmetical signs, and (iv) impairments of conceptual mathematical thinking. 17.3.1. Transcoding impairments Noe¨l (2000) provides a comprehensive overview about neuropsychological studies in which selective and associated impairments of the six different transcoding routes between the three major symbolic representations of numbers: Arabic numbers, spoken number words, and written number words have been reported. As an example, impairments of reading aloud Arabic numbers will be presented in some more detail. This mode of transcoding subserved by the (left) language dominant hemisphere requires at least three sequential processing stages: identification (encoding) of strings of digits, (mental) transformation into a sequence of (number) words, and utterance of that compound sequence. Models of transcoding differ in whether a semantic interpretation of the encoded digit string is assumed necessary or not.

ACALCULIA 17.3.2. Identification of digit strings Impairments in the identification process are present in cases of pure alexia. Nevertheless, these patients— typically suffering from unilateral damage of medially centered occipitotemporal lesions effecting a disconnection between language system and direct visual input— are still (almost) flawless in number magnitude comparison even of multidigit numbers (Dehaene and Cohen, 1995). Cohen and Dehaene (2000) report about another patient who was unimpaired in deciding which of two numbers was the larger, or whether a number was odd or even, even with two-digit numerals for which she made almost 90% reading errors. In arithmetic the patient, though unable to read aloud correctly the operands of visually presented problems, could still produce the exact result of the same problems verbally (e.g., reading ‘8  6’ as ‘five minus four,’ but uttering the correct result ‘two’). Such ‘calculating without reading’ was observed in subtraction, addition, and division, but not in multiplication. Since the right hemisphere—in accord with the triple-code model—is capable of encoding Arabic numbers as well as appreciating their (approximate) magnitude in the right-hemisphere IPS, there is no need for this approximate number magnitude information to be processed further in the left hemisphere magnitude system after having passed the corpus callosum in a section anterior to the splenium. In case the semantic information gets transferred to perisylvian language areas only transcallosally, the approximate, fuzzy representation of a number’s exact numerical magnitude will often lead to errors in selecting the appropriate sequence of number words to be uttered. 17.3.3. Transcoding process Transcoding of a (semantically interpreted) digit string into a (complex) number word may lead to basically different types of errors. Lexical errors are characterized by substitution of one or several lexical constituents with other exemplars of the same lexical number word class being either units (one-nine), teens (eleven-nineteen) or decades (ten, twenty,. . ., ninety) and preserving the overall morphosyntactic structure of the number word, e.g., ‘48’ ! ‘sixty-seven,’ ‘312’ ! ‘three hundred and eleven’ or ‘658’ ! ‘six hundred and fifty-four.’ It is interesting to note that these substitutions always comprise other number words and not other lexical elements. Preservation of the overall structure is in line with the detailed description by McCloskey (1992) of the steps assumed to be involved in this transcoding process: first a syntactic frame is derived from the internal symbolic representation closely mirroring the base-ten place– value system of Arabic numerals: e.g., ‘658’ ! {6}

343

EXP2 {5}EXP1 {8}EXP0 ! ‘__hundred and __-__.’ Next, every slot is filled with a specific lexical element from the respective lexical class and then the concatenated string of (phonological) word-forms is uttered. Further transformations during or after filling the slots may be required, e.g., with teens numbers, or in case of languages with an inverted decade-unit number word sequence. In an influential asemantic transcoding model (Deloche and Seron, 1987) a set of transcoding rules employing only four functional processing components (parsing, categorization of primitives, transcoding, and production) was specified without assuming a semantic representation as in the model above. An improved version of the model that can account also for developmental and learning processes has recently been proposed by Barrouillet et al. (2004). Lexical errors are conceptualized as so-called ‘stack-position’ errors characterized by selecting a lexical element from the wrong position in the correct stack. With syntactic errors, however, a wrong frame (‘stack’ error) is specified and the correct lexical elements corresponding to the ‘misplaced’ semantic representations of digit values are chosen from the respective lexical class, e.g., ‘{4}EXP1 {8} EXP0’ ! ‘__ hundred and __’ ! ‘four hundred and eight.’ In languages with an inversion of the sequence of decade and unit in two-digit and multidigit numbers in the transcoding process between number words and Arabic numbers, like in German or Dutch, inversion errors are another frequent error type, e.g., ‘48’ ! ‘vierundachtzig (fourandeighty).’ When reading multidigit numbers, the so-called multiplicator words ‘hundred,’ ‘thousand,’ ‘million,’ etc. may be left out. For the reverse transcoding route of writing Arabic numbers to dictation there is an additional frequent specific type of syntactic error which can be labeled ‘term-by-term’ transcoding or literal transcription error, e.g., ‘five thousand four hundred and sixtyeight’ ! 500040068; with this error type, the additive composition principle of multidigit numbers is not followed correctly in that the so-called overwrite rule for one or more zeros is disregarded. The literal transcription error is often only partial, e.g., ‘four thousand three hundred twenty’ ! ‘4000320.’ Furthermore, errors concerning the multiplicative relation are also of a term-by-term transcoding form, e.g., ‘three hundred’ ! ‘3100’ or ‘five thousand’ ! ‘51000.’ In addition, one frequently finds lexical errors (‘three’ ! ‘5’; ‘thirty’ ! ‘40’) as well as (lexical) errors that reflect an erroneous appreciation of the place assignment of the digit derived from the number word (e.g., ‘thirty’ ! ‘13’ or ‘3’; ‘two’ ! ‘20’ or ‘12’). Barrouillet et al. (2004) also provide a detailed reanalysis of the error patterns of three published cases suggesting that the transcoding difficulties of these

344

K. WILLMES

patients are the consequence of some specific deterioration of one part of the hypothesized production system in the two stroke cases or the consequence of more general impairments that limit the overall functioning after suspect Alzheimer’s disease in the third case. It is important to note that the authors of this new asemantic transcoding model do not deny that possibly a semantic representation is established in parallel but it is not employed to construct the output form. One frequently observed dissociation in more severely impaired aphasic patients is a major problem with reading aloud (even one-digit) Arabic numbers but (almost) intact comprehension of the same numbers as inferred from a number magnitude comparison task. Besides the numerical magnitude meaning of a number other declarative knowledge about a number may be activated and lead to an utterance that is indicative of an exact apprehension of the number presented; e.g., ‘1945’ ! ‘war over.’ Similar to deep dyslexia the semantic system gets activated via a nonlexical route leading to the more easy activation of a semantically related word or utterance. Cohen et al. (1994) reported on a patient presenting with deep dyslexia for Arabic numbers who could read them better or at least identify them correctly in a set of alternatives when the number had an entry in declarative or episodic memory, like ‘504’ as a brand name of a Peugeot car or ‘1789’ as a famous French Revolution date. In the recent model of number recognition in verbal, analog, and Arabic format by Brysbaert (2005, p. 40) it is assumed that after visual feature analysis stored mental images of familiar numerals are activated that can directly trigger associated memories in semantic and episodic memory. Similarly, Delazer and Girelli (1997) could show that correct semantic information provided before having to read an Arabic number led to better reading aloud of Arabic numbers in an Italian patient suffering from aphasia and dyslexia: reading the words ‘Alfa Romeo’ facilitated the reading of the number ‘164’ (a particularly popular brand name in Italy) but not of an equally complex number without that type of reference. Patients with severe naming disorders often use a ‘counting upwards from one’ strategy—mostly in case of small numbers—to facilitate production of the target number word. Usually the patients do not count beyond the target number. Alternatively, fingers are used in a compensatory fashion to indicate the correct number value or to facilitate utterance of the number word when looking at the appropriate set of fingers. Occasionally the digit finger is used to ‘write’ the Arabic number in an imaginary fashion on the table or in the air. These latter strategies are not only used in transcoding tasks but whenever the oral production of a number is required, like e.g., in a mental calculation task.

17.3.4. Production of number words The final stages of number word utterances are assumed to be subserved by general language production processes, although also for this stage performance (double) dissociations have been reported. Marangolo et al. (2005) review the few case reports with a putative dissociation between processing verbal number words and words from other semantic domains. Usually there are also number transcoding deficits in conditions of aphasia. But Cohen et al. (1997) examined a patient presenting with neologistic jargon. When having to produce spoken number words the patient committed predominantly lexical substitution errors compared to phonological substitutions when having to utter nonnumber words that had been matched for length and frequency. Several objections have been raised arguing that number words are different from other (complex) words in several compositional and semantic aspects. With the case of Marangolo et al. (2005), these other explanations could be ruled out convincingly, thus allowing the interpretation as a clear case of numberspecific anomia. There was an impairment concerning the spoken production of numbers already at the singledigit level, whereas the written production was unimpaired for Arabic and verbal notation and numerical knowledge itself was intact as well. Since the patient could repeat well and made no phonological substitution errors the impairment could not be at a postlexical stage. Errors were also not of a syntactic nature. Rather the patient had selective difficulties in filling the correctly generated syntactic number word frame with the correctly chosen phonological lexical elements, thus pointing at an impaired selection of numerals within the phonological (output) lexicon. Domahs et al. (2006) provide a comprehensive review of the evidence that number words can be selectively impaired or spared at post-semantic stages of processing, i.e., at lexical and more peripheral oral and written production levels. They also state that no equivalent dissociations have been encountered so far at pre-semantic input levels and present an impressive case of primary progressive aphasia with a category-specific preservation of numerals functionally located at a processing level between the semantic system and the input and output lexical systems in all modalities.

17.3.5. Clinical examples Acalculia and aphasia are often associated. Nevertheless, problems in number processing (and calculation problems) seen in aphasic patients need not be reducible to the language impairment (Basso et al.,

ACALCULIA 2005)—even though impairments of receptive and expressive number processing are frequent in aphasia (Noe¨l, 2000), usually in combination with general reading and writing problems. But the latter two may be dissociated as well. In a frequently cited study, Benson and Denckla (1969) have reported on a case of jargon aphasia with good comprehension of number words when assessed via having to select the correct Arabic numeral or set of dots corresponding to the numerosity presented aurally as a number word. When having to name Arabic digits and numbers the patient produced only paraphasias. More frequently one can observe that an aphasic patient is better at choosing the larger number from a pair of Arabic multidigit numbers than from a pair of spoken or written number words. In the case of Broca’s aphasia syntactic as compared to lexical transcoding errors tend to be more frequent, whereas no systematic difference can be found in the case of Wernicke’s aphasia. In a more recent group study by Delazer et al. (1999), the sample of Italian speaking patients with Broca’s aphasia similarly committed more syntactic errors in reading aloud Arabic numbers, whereas the group with Wernicke’s aphasia produced relatively more lexical errors. Transcoding errors may also be found in neuropsychological conditions different from aphasia. In case of reduced digit span, writing to dictation of multidigit Arabic numerals with different digits that are all different from zero is often truncated after a few digits. Patients with visuoconstructive disorders tend to reduce or augment the number of embedded zeros in multidigit numbers. Visual processing disorders like hemianopia or visual neglect can result in leaving out the leftmost digits (He´caen et al., 1961) even without a similar problem in semantically adequate texts. Patients suspected of suffering from Alzheimer’s disease have been reported to reproduce parts of the source code also in the target code like ‘3247’ ! ‘3thousand four hundred47’ (Kessler and Kalbe, 1996), possibly due to insufficient cognitive control mechanisms. This empirical finding could however not be reproduced by Della Sala et al. (2000), challenging the validity of that task as a screening instrument for early signs of suspect Alzheimer’s disease. Visuospatial or visuoconstructive impairments may hamper written arithmetic that requires a particular positioning of digits (Hartje, 1987). Adding up a set of multidigit numbers may be impaired due to problems with a column-wise right-adjusted alignment of digits according to the number of digits involved. Long multiplication may be impaired due to erroneous or missing alignment of intermediate results.

345

17.4. Impairments of the quantitative magnitude representation Problems with processing abstract numerical magnitude have been observed much less frequently than language related errors. The postulated bilateral cortical representation of abstract numerical quantity may make it less vulnerable under conditions of focal brain damage. There are only a few patients on record suffering from lesions in the intraparietal region of the hemisphere dominant for language who revealed problems in dealing with abstract quantities (Dehaene and Cohen, 1997; Delazer and Benke, 1997; Lemer et al., 2003). Reading aloud of numbers, transcoding of numerical symbols like dot patterns of dice as well as the production of automatized number series when counting or reciting multiplication tables from memory were well preserved. To the contrary, number magnitude comparison of Arabic numerals was much less than perfect as well as ‘number bisection’ (e.g., ‘Which integer number represents the numerical middle between the two outer integer numbers 23_?_29 ?’). Even quite simple subtraction tasks—not assumed to be solved via retrieval of the correct result from memory—led to erroneous or no responses. Approximate calculation was impossible. Since number magnitude comparison of irregularly placed sets of dots was impaired as well, the number semantic problems of the patient were not notation specific. A well documented case of bilateral posterior cortical atrophy was reported by Delazer et al. (2005) as well as a review of the reported cases. The patient made errors in both a production and a receptive version (‘Is the middle number of an ordered triplet also the numerical middle?’ e.g., ‘33_36_39’; ‘32_34_38’) of the number bisection task. Many errors were also seen in approximate calculation tasks in which the better suited alternative had to be selected quickly from two wrong solutions to an arithmetic problem. Furthermore, numerical estimation of physical size, weight, numerosity, time-duration as well as semantic declarative numerical knowledge of numerosities or prices of everyday objects or utensils were impaired without a general disorder of semantic knowledge. Finally, numerical tasks loading on visuospatial abilities were impaired like counting dot collections in the range 11–30 and placing a mark on an analog scale from 0–100 or 0–50 corresponding to the numerical magnitude of an Arabic number. There is also evidence from single-case studies that numerical knowledge can dissociate from non-numerical knowledge at the level of semantic processing. The most impressive case has been reported by Cipolotti et al. (1991). Although completely dysgraphic and dyslexic for all kinds of material there was preserved

346

K. WILLMES

oral performance for words but strikingly not for numerals above four. The patient could not discriminate Arabic digits from meaningless shapes or numerals from nonwords; she could not produce the direct ‘neighbors’ of a number word presented aurally or do numerical magnitude comparisons for number words nor even count above four. A clear dense semantic dementia case with spared numerical abilities is also on record (Butterworth et al., 2001).

17.5. Impairments of calculation Problems with calculation proper can be broadly classified into (i) impairments of arithmetical facts retrieval, (ii) impairments of procedural arithmetic knowledge, and (iii) impairments of conceptual arithmetic knowledge. These capacities can be affected independently— as already claimed by Peritz (1918), Henschen (1919), or Warrington (1982)—and there have been several convincing single-case reports to demonstrate these performance dissociations (e.g., Caramazza and McCloskey, 1987; McCloskey et al., 1991; Sokol et al., 1991; Delazer and Bartha, 2001) as summarized e.g., by Domahs and Delazer (2005). 17.5.1. Arithmetic facts retrieval Arithmetic facts are usually assumed to be stored and retrieved directly from declarative long-term memory (Ashcraft, 1995; for a recent review see Domahs and Delazer, 2005), but there are also deviant conceptualizations (Baroody, 1994). Impairments of arithmetic facts retrieval comprise errors in simple addition and subtraction with a number range below 20, in simple multiplication for arithmetical tables from 2
2 up to 9
9, and possibly some simple divisions like division by 2. There are also studies that challenge the view that simple problems are always retrieved from memory (Lefevre et al., 1996a; 1996b) and there is considerable interindividual variability although verbal self-reports about the way of solution are hard to validate. Usually, for a healthy adult person, there is no need to carry out a sequence of mental computations; rather the result is retrieved from declarative long-term memory, just like other highly overlearned facts. Domahs and Delazer (2005) have also pointed out that a precise definition of what constitutes a number fact is not available. Multiplication with zero or one—possibly also with 10—is considered to be rule-based and has been shown to dissociate from ‘proper’ multiplication tables (Pesenti et al., 2000). Erroneous responses to simple multiplication tasks tend to be from the same multiplication table or a close entry from another table (McCloskey et al., 1985; e.g., ‘7
8 ¼ 48’ or ‘7
8 ¼ 54,’ so called

within-tables errors) and not from a more distant entry or even an out-of-table response. Problems with arithmetic facts retrieval, e.g., in simple addition, need not be related to higher error rates only; they can also manifest themselves in substantially longer response times, indicating the use of calculation routines or strategies in case of hampered or impossible facts retrieval (Warrington, 1982). There is ongoing controversy about the format in which arithmetic facts are stored in memory. The influential ‘sound-based’ phonological storage hypothesis (Dehaene and Cohen, 1995) contends that arithmetic facts are stored in memory exclusively in a phonological form such that accessing an arithmetic fact from memory required a phonological representation of the problem. This assumption implies that when a patient translates a multiplication problem in Arabic notation erroneously into a wrong phonological representation then the corresponding solution to the wrong form will be retrieved from memory, e.g., ‘5
9’ gets misnamed as ‘four times six’ and is answered as ‘24’ or ‘twenty-four.’ This type of error is even more compelling when the patient provides the correct answer to misnamed problems for arithmetic operations other than multiplication. Whalen et al. (2002) discuss the evidence and provide counter evidence against storage in a purely phonological form. They also delineate other hypotheses stating that arithmetic facts are addressed and retrieved in (i) an abstract-meaningbased form (McCloskey and Macaruso, 1995), (ii) in multiple formats (Campbell, 1994), or (iii) in a preferred code (Noel and Seron, 1993). 17.5.2. Calculation routines Impairments in carrying out multi-step calculation routines or in mastering calculation procedures are characterized by the incorrect or incomplete application of a calculation algorithm. Frequent, typical errors in written addition or subtraction are problems with carrying or borrowing (McCloskey et al., 1985). Another type of error in addition and multiplication of multidigit numbers consists of writing down the whole number result of intermediate computations, thus disregarding the rule that only the unit digit of an intermediate result has to be written down and the decade digit to be kept in working memory or written down somewhere to reduce verbal working memory load, and only to be included in the next computational step (Head, 1926; McCloskey et al., 1985). In written division tasks, sometimes the division process is started for the rightmost digit(s) instead of starting from the leftmost part of the dividend. One may also observe that an intermediate subtraction before the next division step in the division routine is left out completely.

ACALCULIA 17.5.3. Conceptual arithmetic Conceptual knowledge in mathematics implies understanding of arithmetical operations and principles pertaining to these operations. Conceptual knowledge varies greatly in the normal population and is strongly dependent on education, a fact to be accounted for when studying patients with brain damage. Conceptual knowledge may be preserved even in case of impaired simple number facts knowledge (Hittmair-Delazer et al., 1994). On the other hand, highly overlearned arithmetical knowledge may be preserved without any conceptual knowledge about number facts and procedures. 17.5.4. Clinical examples 17.5.4.1. Arithmetic signs In aphasic patients there may be impaired processing of arithmetic signs such that in an aurally presented calculation task comprehension of the corresponding word is impossible or it gets confused with another sign. There is also an aphasic patient on record who confused visually presented addition and multiplication signs (Ehrenwald, 1931). This type of problem is usually interpreted as a consequence of aphasia; but in a famous single-case report Ferro and Botelho (1980) presented a patient who had a selective impairment for visually presented arithmetic signs not extending to the comprehension of other visual symbols. In a group study by Dahmen et al. (1982) patients with Wernicke’s aphasia performed poorer on average than patients with Broca’s aphasia in an arithmetic task where the correct operation sign had to be inserted (‘3 ? 3 ¼ 6’). This type of arithmetic task had been identified as the one arithmetic task in the collection of tasks administered that required imagery of spatial relations. 17.5.4.2. Counting Wynn (1998) has conceptualized counting as an ontogenetic precursor of addition and subtraction ability. Problems with counting in aphasic patients have been reported as early as 1918 by Peritz (see also Head, 1926). Impairments in producing counting sequences can be observed frequently, mostly starting only with two-digit numbers even in cases of severe aphasia. Patients produce paraphasic or neologistic utterances or leave out one or several numbers in a row. Non-aphasic patients with acalculia usually have no problems in counting forwards. Problems with counting backwards in steps of one are more frequent since this task puts a stronger additional load on verbal working memory and executive control not to continue counting forward in an automatized fashion. Occasionally, a more specific error is found in counting backwards when crossing

347

a decade boundary in that the decade digit is reduced by one and not the unit digit. 17.5.4.3. Calculation Performance in arithmetic tasks may be impaired completely or selectively for individual arithmetical operations. Patients with severe aphasia may be unable to carry out even very simple arithmetic (Barbizet et al., 1967) or may master just some simple addition problems, but only after visual presentation in Arabic notation. In case of less severe aphasia, addition and subtraction may be better preserved; but there may be consistent errors of borrowing in subtraction tasks (Girelli and Delazer, 1996). Multiplication tables may be more strongly or even selectively impaired (McCloskey et al., 1985) since in this case direct retrieval from verbal memory is more frequent. Kashiwagi et al. (1987) also reported impaired performance for simple multiplication in conditions of aphasia. Even after massive practice the patients could not regain mastery of multiplication with aural presentation and verbal responses. The patients could only demonstrate fact knowledge with visual presentation and answers in the written modality. Such patterns of responses are taken as evidence (Campbell and Epp, 2005; for a recent summary of this view) that the representations underlying multiplication facts may involve multiple codes that are differentially called upon depending on the surface format. Along similar lines Deloche and Willmes (2000)—employing stringent inferential statistical procedures for the delineation of single-case performance dissociations—have reported on several patients who presented with format effects for the multiplication verification task presenting all items from small multiplication tables (2
2—9
9) either as spoken number words or in visual Arabic format. Selective impairments of division have already been reported by Lewandowsky and Stadelmann (1908) as well as Berger (1926); combined impairments of subtraction and division by Sittig (1920), Berger (1926), and Krapf (1937). Selective sparing of subtraction was found by Lampl et al. (1994) as well as in a detailed report by Pesenti et al. (1994). Format specific dissociations other than for multiplication have also been reported, e.g., by Cipolotti et al. (1995), for an aphasic patient who could successfully deal with simple addition and subtraction problems when written number word input was combined with oral output or when the items were in Arabic notation throughout. Problems—as indexed by more errors and slower response times—showed up when Arabic input was combined with oral output. McNeil and Warrington (1994) even reported evidence for a deficit that seemed to be modality and operation specific. They extensively

348

K. WILLMES

examined a right homonymous hemianopic patient with all four combinations of spoken verbal and visual Arabic input and output with single-digit addition, subtraction, and multiplication tasks. Impairments were registered only for Arabic digit input for addition and multiplication but not for subtraction. On the other hand there has been an impressive single-case study by Sokol et al. (1991) about a patient with multiplication deficits, lending support to the view that these arithmetic or multiplication facts are stored in declarative memory in a format independent code. All nine input/output combinations of Arabic digits, written number words and dot patterns were assessed with a striking similarity in the percentage of errors (11.7–13.8%) committed for all input or output codes with errors predominantly being either operant errors, table-related errors or no responses at all. Campbell and Epp (2005), however, also review some studies that demonstrate substantial effects of format on the specific errors being committed. Among them are intrusion errors which designate operands that appear again in the result (e.g., ‘two plus nine ¼ nine’; ‘nine times six ¼ thirty-six’); these errors have been found to be much more frequent with number words than with Arabic digits stimuli. Operation errors (e.g., 2 þ 4 ¼ ‘eight’; 2
4 ¼ ’six’), however, have been found to be more frequent with the Arabic code. Furthermore, erroneous responses to Arabic digit problems tended to be ‘near’ errors, i.e., the responses would be correct if one of the two operants were reduced or augmented by just 1; errors with number words did not follow the numerical distance effect (e.g., Dehaene, 1992). Whether selective impairment or sparing as well as associated impairments are possible for all combinations of the four basic arithmetic operations is a matter of ongoing debate (van Harskamp and Cipolotti, 2001). Based on the triple-code model, Lemer et al. (2003) and Dehaene et al. (2004) have argued that small addition and multiplication problems are solved via verbal routines and verbally mediated retrieval of overlearned arithmetic facts from memory, whereas subtraction, approximate calculation, and estimation rely on the analog magnitude representation. A case report about a patient with posterior cortical atrophy by Delazer et al. (2005) is also revealing with respect to the status of the different arithmetical operations. The patient was able to do mental calculation of simple addition and multiplication with almost no errors, in contrast to simple subtraction and division. Recent group studies of aphasic patients comprising transcoding and calculation tasks have revealed that patients with Broca’s aphasia were particularly impaired in simple multiplication facts, presumably because of verbal mediation in the retrieval process.

Patients with global or Wernicke’s aphasia, however, were relatively more impaired with written calculation procedures. Studies about transcoding and calculation impairments in conditions of aphasia (Delazer and Bartha, 2001) have repeatedly raised the question of the functional relationship between language and numerical cognition. The spectrum of claims reaches from an obligatory mediation of numerical cognition via lexical and syntactic language processes to the proposition that in the adult brain calculation may be independent of language. Indeed there have been case reports such as the one by Rossor et al. (1995) of a patient with severe global aphasia who presented with an unusual preservation of calculation skills. Basso et al. (2000) have argued— based on a large retrospective study—that language functions and calculation are independent. They also reported that selective acalculia may be found after a left hemispheric lesion; on the other hand, aphasia without acalculia was seen in a substantial proportion of Broca’s (50%) and Wernicke’s (39%) aphasia. At the group level there was also no significant difference— both quantitatively and qualitatively—for patients with vs. without acalculia. Interestingly, the same group of researchers came to a different conclusion when analyzing an enlarged database with more refined methodology (Basso et al., 2005): about 60% (36/61) of the right-handed patients with a single unilateral lefthemispheric lesion presented with a ‘significant association,’ but there were selective impairments in the remaining 25 patients (19 aphasic, 6 acalculic). The authors point out that the observed association may be a simple artifact of the vascularization of the brain, since adjacent cortical regions in the supply area of the posterior branch of the left middle cerebral artery may be jointly affected by a lesion even if anatomical separability of areas subserving language and calculation functions were the case. A recent study by Varley et al. (2005) about three severely expressively and receptively language-impaired chronic aphasic patients with extended middle cerebral artery infarcts covering perisylvian temporal, parietal, and frontal cortical areas revealed that these patients could handle ‘syntactic’ principles like recursivity and bracketing in arithmetic tasks (e.g., ‘50  ((4 þ 7)
4)’) that require dispensing with a linear left-to-right processing routine. In a purely linguistic context analogous operations were not or not fully available.

17.6. Pathophysiology and functional neuroanatomy Impairments in dealing with numbers, in mental computing, and in conceptual processing of numbers and

ACALCULIA formulas of different kinds and complexity can be found for all types and etiologies of acquired focal and diffuse brain damage. Girelli and Delazer (2001) provide an overview about numerical abilities in dementia. They state that number processing and numerical difficulties are among the early signs of dementia but go on to stress that in the course of the disease there is substantial interindividual variability in the pattern of impairments, ranging from highly selective problems in single processing mechanisms to general problems covering almost all aspects of numerical abilities. Similar to acquired disorders after circumscribed brain lesions this is indicative of potential dissociations among multiple functional stages and components in numerical cognition. Depending on type, localization, and size of a lesion these impairments may be isolated or more frequently be associated with other higher cognitive functions like attention, working memory, visuospatial, visuoconstructive, and executive functions. This state of affairs does not come as a surprise since even rather simple, often practiced written calculations require the correct execution and sequencing of a large set of specific processes that put different degrees of processing load on subprocesses of working memory as well as monitoring and mental control. Despite their incapacitating consequences, no precise epidemiological data concerning acalculia are available (Girelli and Seron, 2001). Because of the frequent association between aphasia and acalculia after left-hemispheric lesions and associations with other cognitive impairments it is plausible that a proportion of brain damaged patients similar to aphasia suffers from substantial problems in dealing with numbers and in calculation, both in the acute and in the chronic stage. According to the historical review of Kahn and Whitaker (1991) frontal, temporal, parietal (angular gyrus, IPS), temporoparietal as well as parieto-occipital predominantly left-hemispheric lesions, but also similar regions in the right hemisphere as well as subcortical structures have been associated with impairments in numerical cognition. Grafman (1988) states that acalculia follows left-hemisphere lesions typically comprising the angular gyrus. In case of problems with reading and writing of numbers lesions are typically encompassing left temporoparietal areas whereas calculation problems proper occur subsequent to left posterior lesions. Even though more recent lesion studies and functional imaging group studies of healthy participants and individual brain damaged patients still do not allow for a complete picture, a substantial increase in detailed knowledge has been accomplished. Since aural and written number words constitute a specific lexical class and since complex number words are formed according to a fixed set of morphosyntactic

349

rules, they are processed in perisylvian language areas of the hemisphere dominant for language. The left angular gyrus seems to play a prominent role in the retrieval of verbally coded calculation facts (multiplication table facts in particular) and in exact calculations subserved by language. Corticosubcortical loops connected to cortical language areas seem to be involved in the retrieval of highly overlearned multiplication facts (Dehaene and Cohen, 1997; Delazer et al., 2004). The identification of Arabic digits seems to be based on bilateral occipitotemporal cortex, in particular the fusiform gyrus, similar to the identification of visual objects and written number words (Cohen et al., 2000b). As mentioned before, bilateral cortex around the horizontal part of the intraparietal cortex (hIPS) seems to subserve the nonlinguistic abstract quantitative semantic number magnitude representation. This claim is predominantly based on recent PET and fMRI studies (Simon et al., 2002; Dehaene et al., 2003; Pinel et al. 2004). More sophisticated experimental fMRI paradigms, e.g., varying the numerical distance in number comparisons, contrasting approximate and exact addition or subtraction vs. highly overlearned multiplication facts that led to variation in IPS and/or angular gyrus activations (Stanescu-Cosson et al., 2000) have strengthened the view that parts of the IPS subserve number magnitude processing (see also Kaufmann et al., 2005). Direct cortical stimulation before tumor operation has also revealed acalculia sites in the region of the angular gyrus and close to the IPS (Roux et al., 2003). Researchers have also started to use transcranial magnetic stimulation (TMS) to probe the necessity of specific parietal activations for subserving a particular numerical task. Andres et al. (2005) have shown that the left IPS seems to be pivotal for more precise processing of number magnitude whereas approximate comparisons can be processed by either posterior parietal cortex area. Whether these areas are more specifically or even exclusively devoted to number processing or whether they form part of a more general system capable of processing different kinds of quantities like time and space as well (cf. Walsh, 2003, and his ATOM—a theory of magnitude—hypothesis) or numerical–spatial interactions (Hubbard et al., 2005) is part of ongoing research. Wood et al. (2006) have shown differential parametric BOLD signal variation in distinct left and right anterior hIPS areas in a number magnitude comparison task of two-digit number pairs that were varied with respect to decade and unit distance, additionally distinguishing between numbers in which the magnitude relation of unit numbers was compatible vs. incompatible with the overall number magnitude relation. This variation in the decade–unit magnitude relation has revealed consistent reaction time differences and has

350

K. WILLMES

been termed the ‘compatibility effect’ (Nuerk and Willmes, 2005). Also the well-established approach of studying split-brain patients has revealed that both hemispheres in a complete callotomy patient were able to make magnitude comparisons and to show a numerical distance effect about two simultaneously presented number stimuli (Colvin et al., 2004) regardless of their identical or different presentation format as Arabic numbers, number words, and dot arrays. There was only a left-sided superiority in accuracy when number words were involved. Furthermore, both hemispheres were equally able to enumerate briefly presented sets of one to four stimuli in a subitizing task (Gallistel and Gelman, 2000), a finding paralleled by bilateral extrastriate middle occipital and intraparietal fMRI activation reported by Piazza et al. (2002) postulated to form a common network for both subitizing and counting.

17.7. Model-oriented neuroscience study of acalculia In a single-case study Cohen et al. (2000a) demonstrate in an exemplary fashion how a processing model based explanation of an individual performance and impairment pattern—backed up by a functional–anatomical model and knowledge about functional (fMRI) activation patterns as well as assumption about cortical plasticity in the adult brain—can account for the activation pattern observed in that patient. The 55-year-old patient had suffered from a left-hemispheric stroke affecting the superior temporal gyrus, parts of the middle temporal gyrus, the supramarginal and the anterior half of the angular gyrus. The lesion thus covered language-related parts of perisylvian tissue. The medial part and posterior sections of the lateral aspect of the intraparietal sulcus were spared. Based on the anatomofunctional triplecode model one can expect that the patient should be impaired in all tasks that also recruit language functions in transcoding and calculation but not in tasks that only need a nonverbal quantitative semantic number representation. When seen two years post-stroke for the activation study, the patient still suffered from aphasic symptoms as well as reading and writing impairments similar to deep dyslexia. According to the classification system of He´caen and coworkers a combination of alexia and agraphia for numbers as well as a core primary arithmetic problem even with simple arithmetic problems were diagnosed. The patient was impaired in all tasks involving spoken or written numerals. Quite to the contrary, she could do number comparisons of Arabic numbers and other tasks relying on a quantitative number representation almost flawlessly. Comprehensive additional experimental examinations including response time measurements revealed that

subtraction and addition were much less affected than multiplication facts even in a decision task where the correctness of a displayed arithmetic fact had to be decided on. This performance dissociation (Willmes, 2003) is compatible with the assumption of the triplecode model that tasks involving multiplication facts may be solved primarily via stored verbally coded associations between multiplication problem and related solution in an automatic fashion. Subtraction and to a lesser degree addition problems would encompass more the manipulation of quantities on the internal mental number line and—according to the reformulation of the triple-code model (Dehaene et al., 2003)—exact computations in a language code would be assumed to be subserved by the left angular gyrus, the posterior half of which was spared by the lesion. In a standard box-car fMRI design with visual presentation of Arabic digits the patient was supposed to press a response button with the left hand for a correct solution in blocks of either subtraction or multiplication verification tasks. Control conditions were letter matching and rest periods. According to the structural lesion, the revised version of the triple-code model and the behavioral performance pattern it was expected that the patient would show bilateral activations around the IPS. Comparing both numerical operations against rest, almost all regions mentioned in the triple-code model showed significant activations: IPS and adjacent parietal areas bilaterally, inferior more posterior temporal regions bilaterally subserving the visual number form representation, bilateral dorsolateral prefrontal and inferior frontal areas as well as anterior cingulated cortex areas assumed to be involved in more general control, decision, and attentional processes. Notably, there were left-sided perilesional activations that were also found in homologous right hemisphere areas extending into lateral IPS and lateral inferior parietal lobe areas. It must be pointed out, however, that only a rather small fraction of these parietal activations were more specific when compared to the letter matching task: these more specific areas were comparable to the right-hemisphere horizontal IPS regions forming the center of the quantitative semantic number magnitude circuit from the meta-analysis of activation studies by Dehaene et al. (2003). An additional small activation focus was also present in the left posterior intraparietal cortex and covered by the angular gyrus activation foci assumed to be recruited for exact arithmetic operations carried out in a language code within the second parietal circuit identified by Dehaene and coworkers. When contrasting the two arithmetic operations, only a portion of the right hIPS survived the significance criterion, yielding stronger activation for subtraction. The reverse contrast revealed a stronger activation for multiplication in the left posterior IPS

ACALCULIA region. According to Cohen and coworkers the bilateral specific IPS activations—as compared to letter matching—are indicative of a bilateral network subserving arithmetic verification tasks in the patient studied. This interpretation has to accommodate the behavioral performance discrepancy in the scanner where subtraction (66% correct) was more impaired than multiplication (82% correct). The authors argue that the rather short time reserved for the solution of an item may have left the patient with time for only incomplete solutions in a considerable number of the items. With this assumption, one can accommodate stronger right-sided IPS activation for subtraction under conditions of the sizeable left perisylvian lesion extending into the anterior half of left inferior parietal cortex, following the argument of Price and Friston (2002) concerning interpretability of patient activation data. The intact capacity for number magnitude comparisons also indicates that the lesion cannot be responsible for calculation problems due to a number semantic disorder; however, it may well be that the calculation problems are due to the impaired language processes involved. Another study by Lee (2000) provides a similar line of argument in that the different arithmetic operations are subserved by different cognitive mechanisms—retrieval of semantic information from a long-term store vs. mental manipulation of numerical quantities—subserved by different brain circuits in turn. Similar model-guided studies about lesion–behavior correlation should be supplemented by training studies of healthy subjects, as in the pioneering work of Delazer et al. (2003a) to detect training-induced changes in activation patterns paralleled by performance alterations. Volunteers were massively trained on a set of complex multiplication problems. An fMRI study was carried out to compare activation patterns of trained and matched non-trained items presented in separate blocks that were interspersed with number matching and fact retrieval blocks. Left hemispheric activations were dominant in the two contrasts between untrained and trained condition, suggesting lateralized learning processes in arithmetic. Comparison of untrained versus trained problems revealed significant activation in the left IPS, in the inferior parietal lobule and in left inferior frontal gyrus, the latter activation possibly indicating higher working memory demands for untrained problems. Stronger left angular gyrus activation for trained problems is in line with predictions from the triple-code model suggesting that a shift of activation from the IPS to the left angular gyrus indicates a processing shift from quantity-based processing to more automatic retrieval. This study also shows that the left angular gyrus is not only involved in simple arithmetic requiring simple fact retrieval, but also as

351

a consequence of short but massive training of more complex calculations.

17.8. Assessment Compared to other cognitive functions and despite the high incidence of numerical deficits in neurological patients relatively little emphasis has been put on developing specific standardized diagnostic tools for acalculia. The vast majority of published reports on acquired numerical disorders, both single-case and group studies, do not use standardized performance measures. Intelligence test batteries usually comprise single subtests (e.g., WAIS subtests Arithmetic and Digit Span), mostly on arithmetic; but the items contained in them are heterogeneous from a cognitive neuropsychological perspective tapping on different and dissociable processing components. Moreover, these subtests do not provide a sufficiently comprehensive testing of the most relevant numerical cognitive functions. Furthermore, there is a host of math achievement tests available for different grades. These instruments however have a curricular perspective comprising item sets that are not homogeneous with respect to the cognitive numerical processes involved. The paucity of standardized tests may also be attributed in part to the methodological approach in cognitive neuropsychology advocating the detailed analysis of patterns of performance in individual patients leading to a processing model oriented and criterion-referenced perspective (Willmes, 2003) of discerning impaired and preserved abilities in search of performance dissociations. Jackson and Warrington (1986) have published the Graded Difficulty Arithmetic Test (GDA) that only contains 12 speeded addition and subtraction items each graded according to complexity. Normative data from 100 healthy subjects have been collected and a scaled score is provided only for the total score correct. Grafman and Rickard (1997) have proposed a set of tasks and an error-analysis approach to be used in a general but comprehensive assessment of number processing and calculation. Delazer et al. (2003b) review the better known processing model oriented assessment batteries, e.g., the Johns Hopkins Acalculia Battery (McCloskey et al., 1991) all of which are assigned only limited clinical value because of a lack of normative data. The Number Processing and Calculation Battery (NPC) by Delazer et al. (2003b) is an attempt to amalgamate both assessment perspectives. On the one hand, it comprises tasks that may be directly related to processing components and involvement of mental number representations discerned in the McCloskey and in the triple-code model; on the other hand it provides a cut-off score (10th percentile rank) per subtest allowing for a distinction between average

352

K. WILLMES

performance and below average performance, taking age and educational level into account whenever necessary. Although encompassing 35 subtests the overall administration time is still clinically feasible. These subtests represent a careful selection of tasks that allow for the detection of most of the dissociations reported in the literature assessing different counting abilities, various aspects of number comprehension such as parity and magnitude judgments, numerical transcoding, calculation, arithmetic reasoning, and conceptual knowledge. The highlight of the NPC battery is the assessment of different calculation abilities, including simple fact retrieval, rule based processing, mental calculation, and written calculation in all four operations. Even text problem solving is assessed as well as the understanding of arithmetic principles, tasks that are lacking in other batteries. Compared to the EC 301 battery proposed by Deloche et al. (1994) and cross-culturally standardized (Dellatolas et al., 2001) the NPC allows a more reliable and differentiated assessment of calculation skills, both for simple fact retrieval and more complex mental calculation. 17.8.1. Differential diagnosis A more comprehensive diagnostic examination for acalculia should always also comprise language functions, reading and writing, visuospatial processing, different attentional functions like alertness, selective, divided, and sustained attention, verbal and nonverbal working memory, as well as executive functions. Ardila and Rosselli (2002) provide an extensive clinically oriented description of the different manifestations of acalculia as well as the problems with number processing and calculation in case of another neuropsychological symptomatology. The group of researchers around Dehaene has revitalized the discussion about the Gerstmann syndrome with its symptom combination of acalculia, disorder of right–left orientation, agraphia, and finger agnosia. The notion of a spurious association between these symptoms due to spatial contiguity of anatomical regions in inferior parietal areas subserving the different functions has been substituted by the notion that a functional communality may be seen in the inferior parietal lobe subserving more general spatial and sensorimotor functions (Hubbard et al., 2005). This view is backed up by several functional imaging studies (e.g., Simon et al., 2002) revealing activations in and around the intraparietal cortex in calculation tasks, pointing and grasping movements using the individual index finger or the hand, as well as spatial orienting of attention. The type of acalculia seen in cases of a ‘pure’ Gerstmann syndrome without aphasia, in

particular, is compatible with a semantic deficit in processing numerical magnitude information subserved by brain tissue around the horizontal part of the intraparietal sulcus (hIPS; Dehaene et al., 2003; Wood et al., 2006). Moreover, in case of number processing its anatomical vicinity with inferior parietal language areas and superior parietal areas subserving spatial processing makes more complicated patterns of impairments plausible. From a developmental perspective, Fayol and Seron (2005) point out the possibility that the link between preverbal number knowledge and language may be mediated by an already established link in children between number concepts and the use of fingers and hands.

17.9. Rehabilitation A recent review by Girelli and Seron (2001) has claimed that acquired deficits due to brain damage in number transcoding and calculation have frequently been neglected, in particular when compared to the treatment of aphasia. Likewise, studies on the spontaneous course of recovery from acalculia are scarce. The largest study has been reported by Basso et al., (2005) comprising patients with unilateral left-hemisphere vascular lesions seen in the first five months after onset and retested five months later on average with a small set of written calculation tasks comprising the four basic arithmetical operations. Longitudinally, there was spontaneous improvement. The amount of improvement was positively correlated with the initial severity of impairment; it was highly variable and rarely leading to unimpaired performance. As for recovery of other cognitive functions this behavioral study did not allow one to conclude whether improvement without therapy is tied to re-establishing coordinated neural activity in perilesional left-hemispheric brain areas or to recruitment of contralesional homologous brain tissue. A successful pioneering single-case treatment study of transcoding abilities by Deloche et al. (1989) had shown improved transcoding skills between number words and Arabic digits, employing techniques borrowed from aphasia therapy using graded systematic cues that were reduced gradually with reduced processing problems. There is a principled distinction in neuropsychological rehabilitation methodology between approaches aiming at the restitution of the original impaired function, those that target a reorganization of functions employing other less impaired or unimpaired cognitive functions and those that try to compensate for the permanent loss of a function. Lochy et al. (2005) provide an up-to-date and comprehensive review of studies of

ACALCULIA rehabilitation for transcoding and calculation as well as the learning principles underlying the approaches, giving a balanced account of the pros and cons of these different rehabilitation methods. Many patients do not show highly selective deficits that can be trained in isolation. Rather, setting up a more or less individualized hierarchy from simple and fundamental skills up to more complex tasks is suggested, e.g., relearning of multiplication facts my be backed up by turning a multiplication into a repeated addition. 17.9.1. Rehabilitation of arithmetic facts and calculation skills Massive practice is usually considered to be the proper approach to restitution of function. Massive practice or drill aims at re-establishing temporarily lost knowledge about transcoding rules and the retrieval of stored arithmetic fact knowledge. Such exercises are expected to form a strong association between the particular arithmetic problem and its associated correct response relying on associative-learning principles (Campbell, 1987; Siegler, 1988; Ashcraft, 1995). In order not to establish wrong associations after erroneous responses the principle of errorless learning (Glisky et al., 1986), initially promoted for memory rehabilitation, is also relevant here employing instant feedback or presenting the calculation problem together with the correct answer. Similar to the long and arduous initial acquisition during pre-school and school years, analogous expectations have been put forward for training of arithmetic facts after brain injury. Girelli and Seron (2001) reviewed the small number of single-case and group studies that have resulted in improvement of transcoding skills, of arithmetic facts knowledge as well as of calculation routines, up to the however short-lived improvement of arithmetic problem solving skills in verbal arithmetic tasks. One drawback of the reported studies is that the training material usually consisted of the same type of items as contained in the control tests focusing the impairment level. Another problem is that training effects may be specific to the trained problems; in particular, n
m need not generalize to m
n. In cases of severe disorders, an intermediate step in the rehabilitation process may be a shift in the quality of errors from grossly deviant non-table responses or omissions to close operand errors. In milder cases a decrease in response latencies may indicate a shift from more effortful back-up strategies to successful retrieval. Domahs et al. (2004) used additional color coding of multiplication problems. Multiplication facts with the same unit digit of the product were presented in the same color which facilitated retrieval accuracy and speed during training and also at the end of the training period when

353

color coding was removed again. Interestingly, there was no generalization across operations. There are also successful applications of a conceptual arithmetic training approach on record (Girelli et al., 2002; Domahs et al., 2003) that resulted in good generalization and even a creative use of strategies indicating superior flexibility of conceptual knowledge. There is also the view (Baroody, 2003) that both conceptual and procedural knowledge should be combined in an iterative fashion. Another interesting implication from the triple-code model is that, in the case of problems with arithmetic facts, intact approximation based on the quantitative number magnitude system may be pivotal to use self-monitoring in detecting grossly deviant responses as for patient N.A.U. (Dehaene and Cohen, 1991). Rehabilitation of calculation skills themselves has been studied less frequently. Massive practice of the application of solution algorithms is a viable method. It is important to note that accurate execution of a calculation routine does not imply conceptual understanding of the underlying arithmetical principles. Authors also stress large premorbid differences in calculation skills due to education and activities required in different professions that have to be accounted for and taken into consideration when planning rehabilitation and vocational rehabilitation for acalculia, in particular. Rehabilitation of complex arithmetic text problems in patients with severe head trauma using a cueing technique have been pioneered by Delazer et al. (1998) as well. 17.9.2. Rehabilitation of transcoding Rehabilitation studies of numerical transcoding were among the first for acalculia. Deloche et al. (1989) reported successful application of a hierarchically organized program with colored cues and presentation of the number word lexicon organized in panels of units, teens, and decade panels to exercise writing of number words to Arabic digits input. In line with the restitution approach stepwise reteaching of a limited and fixed set of rules was employed, based on the asemantic model proposed by Deloche and Seron (1987) and following errorless learning and vanishing cues principles. In a later study a massive stimulation approach as compared to explicit teaching was tried out, simply presenting written number words with the patient only having to decide whether this was a legal sequence (Deloche et al., 1992). As expected, covert training was more item-specific and overt training of rules was more rule-specific, also transferring to reading aloud of visually presented Arabic numbers. Written assistance

354

K. WILLMES

frames have been used repeatedly for the transcoding of Arabic numbers into spoken or written number words. Multiplicator words ‘hundred’ or ‘thousand’—as well as the particle ‘und’ between unit and decade number word, e.g., in German—were presented visually with appropriately placed empty slots that had to be filled with either Arabic digits and/or unit, teens, or decade number words to be selected from a number word ‘lexicon’ organized in different panels. Initially, slots and related panels might be given identical color with a gradual reduction in cues provided (see the review by Lochy et al., 2005). Ablinger et al. (2006) employed predominantly phonetic cues, aural presentation of the precursor number word up to joint repetition of the two- to five-digit target number word together with the patient in a chronic severely impaired aphasic patient. Substantial training effects were obtained and proved to be stable over a period of six months with considerable transfer to the reverse transcoding of spoken and written number words into Arabic numbers.

17.10. Concluding remarks The last two decades have witnessed substantial theoretical and empirical advances in delineating and understanding the multifaceted nature of numerical cognition. Likewise, the neuropsychological analysis of number processing and calculation disturbances has become more refined with the availability of more articulated processing models, diagnostic procedures, and more readily available experimental paradigms. This will lead to a more comprehensive characterization and understanding of individual patients’ patterns of preserved and impaired processing components and routes also employing neuroscience methods like functional imaging and TMS. More refined diagnostic methods will also reveal the high frequency of more or less subtle impairments both in acquired focal and degenerating brain pathology. Progress is also expected for the development of training and therapy methods that go beyond pure drill for the procedural (re-)learning of calculation routines, e.g., fostering conceptual understanding. This may also be relevant for vocational training and adult life-long learning in post-industrial societies that are in need of well educated employees, even though not so optimistic views with regard to actual everyday calculation skills in adults have been articulated as well, as far as mental calculation skills are concerned, given the ubiquitous availability of real and personal computer implemented pocket calculators. Finally, it is expected that an interest in computational modeling of numerical cognition will grow such

that more refined and comprehensive models will be put forward based on the recent advances for modeling smaller numbers with semantic (e.g., numerosity code for representing cardinal meaning) and symbolic representations as well as more elementary number processing and arithmetic tasks (for review, see Zorzi et al., 2005). These modeling approaches will also become of interest for the neuropsychology of numerical cognition the more the ‘behavior’ of ‘lesioned’ models resembles that of neuropsychological patients.

References Ablinger I, Weniger D, Willmes K, et al. (2006). Treating number transcoding difficulties in a chronic aphasic patient. Aphasiology 20: 37–58. Andres M, Seron X, Olivier E (2005). Hemispheric lateralization of number comparison. Cogn Brain Res 25: 283–290. Ardila A, Rosselli M (2002). Acalculia and dyscalculia. Neuropsychol Rev 12: 179–231. Ashcraft MH (1995). Cognitive psychology and simple arithmetic: A review and summary of new directions. Math Cogn 1: 3–34. Barbizet J, Bindefeld N, Moaty F, et al. (1967). Persistence of the possibilities of elementary calculation during massive aphasia. Rev Neurol (Paris) 116: 170–178. Baroody AJ (1994). An evaluation of evidence supporting fact-retrieval models. Learn Indiv Diff 6: 1–36. Baroody AJ (2003). The development of adaptive expertise and flexibility: The integration of conceptual and procedural knowledge. In: AJ Baroody, A Dowker (Eds.), The Development of Arithmetic Concepts and Skills: Constructive Adaptive Expertise. Erlbaum, Hillsdale, pp. 1–34. Barrouillet P, Camos V, Perruchet P, et al. (2004). ADAPT: A developmental, asemantic, and procedural model for transcoding from verbal to Arabic numerals. Psychol Rev 111: 368–394. Basso A, Burgio F, Caporali A (2000). Acalculia, aphasia and spatial disorders in left and right brain-damaged patients. Cortex 36: 265–280. Basso A, Caporali A, Faglioni P (2005). Spontaneous recovery from aphasia. J Int Neuropsychol Soc 11: 99–107. Benson DF, Denckla MB (1969). Verbal paraphasia as a source of calculation disturbance. Arch Neurol 21: 96–102. Benton A (1992). Gerstmann’s syndrome. Arch Neurol 49: 445–449. ¨ ber Rechensto¨rungen bei HerderkrankunBerger H (1926). U gen des Großhirns. Arch Psychiatr Nervenkr 78: 238–263. Boller F (1982). Number form. Neurogenic directory. In: MC Myrianthopoulos, PJ Vinken, JW Bruyn (Eds.), Handbook of Clinical Neurology, Vol. 43. Elsevier, Amsterdam, pp. 224–225. Boller F, Grafman J (1983). Acalculia: Historical development and current significance. Brain Cogn 2: 205–223. Boller F, Grafman J (1985). Acalculia. In: JAM Frederiks (Ed.), Handbook of Clinical Neurology, Vol. 1. Elsevier, Amsterdam, pp. 473–481(45).

ACALCULIA Boller F, Grafman J (1988). Handbook of Neuropsychology. Elsevier, Amsterdam. Brysbaert M (2005). Number recognition in different formats. In: JID Campbell (Ed.), Handbook of Mathematical Cognition. Psychology Press, New York and Hove, pp. 23–42. Butterworth B (1999). The Mathematical Brain. Macmillan, London. Butterworth B (2005). The development of arithmetic abilities. J Child Psychol Psychiatry 46: 3–18. Butterworth B, Cappeletti M, Kopelman M (2001). Category specificity in reading and writing: The case of number words. Nat Neurosci 4: 784–786. Campbell JID (1987). Network interference and mental multiplication. JEP: LMC 13: 109–123. Campbell JID (1994). Architecture for numerical cognition. Cognition 53: 1–44. Campbell JID, Epp LJ (2005). Architectures for arithmetic. In: JID Campbell (Ed.), Handbook of Mathematical Cognition. Psychology Press, New York and Hove, pp. 347–360. Caramazza A, McCloskey M (1987). Dissociations of calculation processes. In: G Deloche, X Seron (Eds.), Mathematical Disabilities. A Cognitive Neuropsychological Perspective. Lawrence Erlbaum Associates, Hillsdale, NJ, pp. 221–256. Cipolotti L, Butterworth B, Denes F (1991). A specific deficit for numbers in a case of dense acalculia. Brain 114: 2619–2637. Cipolotti L, Warrington E, Butterworth B (1995). Selective impairment in manipulating Arabic numerals. Cortex 31: 73–86. Cohen L, Dehaene S (2000). Calculating without reading: Unsuspected residual abilities in pure alexia. Cogn Neuropsychol 17: 563–583. Cohen L, Dehaene S, Chochon F, et al. (2000a). Language and calculation within the parietal lobe: A combined cognitive, anatomical and fMRI study. Neuropsychologia 38: 1426–1440. Cohen L, Dehaene S, Naccache L, et al. (2000b). The visual word form area: Spatial and temporal characterization of an initial stage of reading in normal subjects and posterior split-brain patients. Brain 123: 291–307. Cohen L, Dehaene S, Verstichel P (1994). Number words and number non-words. A case of deep dyslexia extending to Arabic numerals. Brain 117: 267–279. Cohen L, Verstichel P, Dehaene S (1997). Neologistic jargon sparing numbers: A category specific phonological impairment. Cogn Neuropsychol 14: 1029–1061. Colvin MK, Funnell MG, Gazzaniga MS (2004). Numerical processing in the two hemispheres: Studies of a split-brain patient. Brain Cogn 57: 43–52. Crutch S, Warrington E (2002). Preserved calculation skills in a case of semantic dementia. Cortex 38: 389–399. Dahmen W, Hartje W, Buu¨ssing A, et al. (1982). Disorders of calculation in aphasic patients. Spatial and verbal components. Neuropsychologia 20: 145–153. Dehaene S (1992). Varieties of numerical abilities. Cognition 44: 1–42.

355

Dehaene S (1997). The Number Sense: How the Mind Creates Mathematics. Oxford University Press, New York. Dehaene S, Bossini S, Giraux P (1993). The mental representation of parity and number magnitude. JEP: Gen 122: 371–396. Dehaene S, Cohen L (1991). Two mental calculation systems: A case study of severe acalculia with preserved approximation. Neuropsychologia 29: 1045–1074. Dehaene S, Cohen L (1995). Towards an anatomical and functional model of number processing. Math Cogn 1: 83–120. Dehaene S, Cohen L (1997). Cerebral pathways for calculation: Double dissociation between rote verbal and quantitative knowledge of arithmetic. Cortex 33: 219–250. Dehaene S, Molko N, Cohen L, et al. (2004). Arithmetic and the brain. Curr Opin Neurobiol 14: 218–224. Dehaene S, Piazza M, Pinel P, et al. (2003, 2005). Three parietal circuits for number processing. Cogn Neuropsychol 20: 487–506; also in: JID Campbell (Ed.), Handbook of Mathematical Cognition. Psychology Press, New York and Hove, pp. 433–453. Delazer M (2003). Neuropsychological findings on conceptual knowledge of arithmetic. In: AJ Baroody, A Dowker (Eds.), The Development of Arithmetic Concepts and Skill: Constructing Adaptive Expertise. Erlbaum, Hillsdale, pp. 385–408. Delazer M, Bartha L (2001). Transcoding and calculation in aphasia. Aphasiology 15: 649–680. Delazer M, Benke T (1997). Arithmetic facts without meaning. Cortex 33: 697–710. Delazer M, Bodner T, Benke T (1998). Rehabilitation of arithmetical text problem solving. Neuropsychol Rehabil 8: 401–412. Delazer M, Domahs F, Bartha L, et al. (2003a). Learning complex arithmetic—An fMRI study. Cogn Brain Res 18: 76–88. Delazer M, Domahs F, Lochy A, et al. (2004). Number processing in basal ganglia dysfunction. Neuropsychologia 42: 1050–1062. Delazer M, Girelli L (1997). When ‘Alfa Romeo’ facilitates 164: Semantic effects in verbal number production. Neurocase 3: 461–475. Delazer M, Girelli L, Grana A, et al. (2003b). Number processing and calculation—Normative data from healthy adults. Clin Neuropsychol 17: 331–350. Delazer M, Girelli L, Semenza C, et al. (1999). Numerical skills and aphasia. J Int Neuropsychol Soc 5: 1–9. Delazer M, Karner E, Zamarian L, et al. (2005). Number processing in posterior cortical atrophy—A neuropsychological case study. Neuropsychologia 44: 36–51. Della Sala S, Gentileschi V, Gray C, et al. (2000). Intrusion errors in numerical transcoding by Alzheimer patients. Neuropsychologia 38: 768–777. Dellatolas G, Deloche G, Basso A, et al. (2001). Assessment of calculation and number processing using the EC 301 battery: Cross-cultural normative data and application to left- and right-brain damaged patients. J Int Neuropsychol Soc 7: 840–859.

356

K. WILLMES

Deloche G, Ferrand I, Naud E, et al. (1992). Differential effects of covert and overt training of the syntactical component of verbal number processing and generalisations to other tasks: A single-case study. Neuropsychol Rehabil 2: 257–281. Deloche G, Seron X (1987). Numerical transcoding: A general production model. In: G Deloche, X Seron (Eds.), Mathematical Disabilities: A Cognitive Neuropsychological Perspective. Erlbaum, Hillsdale, pp. 137–170. Deloche G, Seron X, Ferrand I (1989). Reeducation of number transcoding mechanisms: A procedural approach. In: X Seron, G Deloche (Eds.), Cognitive Approach in Neuropsychological Rehabilitation. Erlbaum, Hillsdale, pp. 247–271. Deloche G, Seron X, Larroque C, et al. (1994). Calculation and number processing assessment battery: Role of demographic factors. J Clin Exp Neuropsychol 16: 195–208. Deloche G, Willmes K. (2000). Cognitive neuropsychological models of adult calculation and number processing: The role of the surface format of numbers. Eur Child Adolesc Psychiatry 9: 27–40. Domahs F, Bartha L, Lochy A, et al. (2006). Number words are special: Evidence from a case of primary progressive aphasia. J Neurolinguistics 19: 1–37. Domahs F, Bartha L, Delazer M (2003). Rehabilitation of arithmetic abilities: Different intervention strategies for multiplication. Brain Lang 87: 165–166. Domahs F, Delazer M (2005). Some assumptions and facts about arithmetic facts. Psychol Sci 47: 96–111. Domahs F, Lochy A, Eibl G, et al. (2004). Adding color to multiplication: Rehabilitation of arithmetic fact retrieval in a case of traumatic brain injury. Neuropsychol Rehabil 14: 303–328. Doricchi F, Guariglia P, Gasparini M, et al. (2005). Dissociation between physical and mental number line bisection in right hemisphere brain damage. Nat Neurosci 8: 1663–1665. Ehrenwald H (1931). Sto¨rung der Zeitauffassung, der ra¨umlichen Orientierung, des Zeichnens und des Rechnens bei einem Hirnverletzten. Z Gesamte Neurol Psychiatr 132: 518–569. Fayol M, Seron X (2005). About numerical representations: Insights from neuropsychological, experimental, and developmental studies. In: JID Campbell (Ed.), Handbook of Mathematical Cognition. Psychology Press, New York and Hove, pp. 3–22. Feigensohn L, Dehaene S, Spelke E (2004). Core systems for number. Trends Cogn Sci 8: 307–314. Ferro JM, Botelho MAS (1980). Alexia for arithmetical signs. A cause of disturbed calculation. Cortex 16: 175–180. Fias W, Fischer MH (2005). Spatial representations of numbers. In: JID Campbell (Ed.), Handbook of Mathematical Cognition. Psychology Press, New York and Hove, pp. 43–54. Gallistel CR, Gelman R (2000). Non-verbal numerical cognition: From reals to integers. Trends Cogn Sci 4: 59–65. Galton F (1880). Visualized numerals. Nature 21: 252–256, 323, 494–495.

Gerstmann J (1940). Syndrome of finger agnosia, disorientation for right and left, agraphia, and acalculia. Arch Neurol Psychiatry 44: 398–408. Girelli L, Delazer M (1996). Subtraction bugs in an acalculic patient. Cortex 32: 547–555. Girelli L, Delazer M (2001). Numerical abilities in dementia. Aphasiology 15: 681–694. Girelli L, Seron X (2001). Rehabilitation of number processing and calculation skills. Aphasiology 15: 695–712. Girelli L, Bartha L, Delazer M (2002). Strategic learning in the rehabilitation of semantic knowledge. Neuropsychol Rehabil 12: 41–61. Glisky EL, Schacter DL, Tulving E (1986). Learning and retention of computer-related vocabulary in amnesic patients: Method of vanishing cues. J Clin Exp Neuropsychol 8: 292–312. Gordon P (2004). Numerical cognition without words: Evidence from Amazonia. Science 306: 496–499. Grafman J (1988). Acalculia. In: F Boller, J Grafman (Eds.), Handbook of Neuropsychology, Vol. 1. Elsevier, Amsterdam, pp. 414–430. Grafman J, Rickard T (1997). Acalculia. In: MJ Farah, TE Feinberg (Eds.), Patient Based Approaches to Cognitive Neuroscience. MIT Press, Cambridge, pp. 345–351. Hartje W (1987). The effect of spatial disorders on arithmetic skills. In: G Deloche, X Seron (Eds.), Mathematical Disabilities. A Cognitive Neuropsychological Perspective. Lawrence Erlbaum Associates, Hillsdale, NJ, pp. 121–135. Hauser MD, Tsao F, Garcia P, et al. (2003). Evolutionary foundations of number: Spontaneous representation of numerical magnitudes by cotton-top tamarins. Proc Royal Soc B: Biol Sciences 270: 1441–1446. Head H (1926). Aphasia and Kindred Disorders of Speech, Vols. 1–2. Cambridge University Press, Cambridge. He´caen H, Angelergues R, Houillier S (1961). Les varie´te´s cliniques des acalculies au cours des le´sions re´trorolandiques: Approche statistique du probleme. Rev Neurol (Paris) 105: 85–103. ¨ ber Sprach-, Musik- und RechenmeHenschen SE (1919). U chanismen und ihre Lokalisation im Großhirn. Z Gesamte Neurol Psychiatr 52: 273–298. Henschen SE (1925). Clinical and anatomical contributions on brain pathology. Arch Neurol Psychiatry 13: 226–249. Hittmair-Delazer M, Semenza C, Denes G (1994). Concepts and facts in calculation. Brain 117: 715–728. Hubbard EM, Piazza M, Pinel P, et al. (2005). Interactions between number and space in parietal cortex. Nat Rev Neurosci 6: 435–448. Ifrah G (1985). From One to Zero: A Universal History of Numbers. Viking Press, New York. Jackson M, Warrington EK (1986). Arithmetic skills in patients with unilateral cerebral lesions. Cortex 22: 611–620. Kahn HJ, Whitaker HA (1991). Acalculia: An historical review of localization. Brain Cogn 17: 102–115. Kashiwagi A, Kashiwagi T, Hasegawa T (1987). Improvement of deficits in mnemonic rhyme for multiplication in Japanese aphasics. Neuropsychologia 25: 443–447.

ACALCULIA Kaufmann L, Koppelstaetter F, Delazer M, et al. (2005). Neural correlates of distance and congruity effects in a numerical Stroop task: An event-related fMRI study. Neuroimage 25: 888–898. Kessler J, Kalbe E (1996). Written numeral transcoding in patients with Alzheimer’s disease. Cortex 32: 755–761. ¨ ber Akalkulie. Neurol Psychiatr (Bucur) Krapf E (1937). U 39: 330–334. Lampl Y, Eshel Y, Gilad R, et al. (1994). Selective acalculia with sparing of the subtraction process in a patient with left parietotemporal hemorrhage. Neurology 44: 1759–1761. Lee KM (2000). Cortical areas differentially involved in multiplication and subtraction: A functional magnetic resonance imaging study and correlation with a case of selective acalculia. Ann Neurol 48: 657–661. Lefevre J, Bisanz J, Daley KE, et al. (1996a). Multiple routes to solution of single-digit multiplication problems. JEP: Gen 125: 284–306. Lefevre J, Sadesky GS, Bisanz J (1996b). Selection of procedures in mental addition: Reassessing the problem-size effect in adults. JEP: LMC 22: 216–230. Lemer C, Dehaene S, Spelke E, et al. (2003). Approximate quantities and exact number words: Dissociable systems. Neuropsychologia 41: 1942–1958. ¨ ber einen bemerLewandowsky M, Stadelmann E (1908). U kenswerten Fall von Hirnblutung und u¨ber Rechensto¨rungen bei Herderkrankungen des Gehirns. Z Neurol Psychiat 2: 249–265. Lochy A, Domahs F, Delazer M (2005). Rehabilitation of acquired calculation and number processing disorders. In: JID Campbell (Ed.), Handbook of Mathematical Cognition. Psychology Press, New York and Hove, pp. 469–485. Marangolo P, Piras F, Fias W (2005). ‘I can write seven but I can’t say it’: A case of domain-specific phonological output deficit for numbers. Neuropsychologia 43: 1177–1188. McCloskey M (1992). Cognitive mechanisms in numerical processing: Evidence from acquired dyscalculia. Cognition 44: 107–157. McCloskey M, Aliminosa D, Sokol SM (1991). Facts, rules, and procedures in normal calculation: Evidence from multiple single-patient studies of impaired arithmetic fact retrieval. Brain Cogn 17: 154–203. McCloskey M, Caramazza A, Basili A (1985). Cognitive mechanisms in number processing and calculation: Evidence from dyscalculia. Brain Cogn 4: 171–196. McCloskey M, Macaruso P (1995). Representing and using numerical information. Am Psychol 50: 351–363. McNeil JE, Warrington EK (1994). A dissociation between addition and subtraction with written calculation. Neuropsychologia 32: 717–728. Moyer RS, Landauer TK (1967). Time required for judgments of numerical inequality. Nature 215: 1519–1520. Nieder A, Miller EK (2004). A parieto-frontal network of visual numerical information in the monkey. Proc Nat Acad Sci 1001: 7457–7462.

357

Noe¨l M-P (2000). Numerical cognition. In: B Rapp (Ed.), The Handbook of Cognitive Neuropsychology. Psychology Press, Philadelphia, pp. 495–518. Noel M-P, Seron X (1993). Arabic number reading deficit: A single case study or when 236 is read (2036) and judged superior to 1258. Cogn Neuropsychol 10: 317–339. Nuerk H-C, Iversen W, Willmes K (2004). Notational modulation of the SNARC and MARC (linguistic markedness of response codes) effect. QJEP 57A: 835–863. Nuerk H-C, Weger U, Willmes K (2001). Decade breaks in the mental number line? Putting the tens and units back in different bins. Cognition 82: B25–B33. Nuerk H-C, Willmes K (2005). On the magnitude representations of two-digit numbers. Psychol Sci 47: 52–72. Piazza M, Mechelli A, Butterworth B, et al. (2002). Are subitizing and counting implemented as separate or functionally overlapping processes? Neuroimage 15: 435–446. Peritz G (1918). Zur Pathopsychologie des Rechnens. Dtsch Z Nervenheilkd 61: 234–340. Pesenti M, Depoorter N, Seron X (2000). Noncommutability of the N þ 0 arithmetical rule: A case study of dissociated impairment. Cortex 36: 445–454. Pesenti M, Seron X, van der Linden M (1994). Selective impairment as evidence for mental organisation of arithmetic facts: BB, a case of preserved subtraction? Cortex 30: 661–671. Pica P, Lemer C, Izard V, et al. (2004). Exact and approximate arithmetic in an Amazonian indigene group. Science 306: 499–503. Pinel P, Piazza M, Le Bihan D, et al. (2004). Distributed and overlapping cerebral representations of number, size, and luminance during comparative judgements. Neuron 41: 1–20. Price C, Friston K (2002). Functional imaging studies of neuropsychological patients: Applications and limitations. Neurocase 8: 345–354. Rossor N, Warrington E, Cipolotti L (1995). The isolation of calculation skills. J Neurol 242: 78–81. Roux F-E, Boetto S, Sacko O, et al. (2003). Writing, calculation, and finger recognition in the region of the angular gyrus: A cortical stimulation study of Gerstmann syndrome. J Neurosurg 99: 716–727. Semenza C (2002). Conceptual knowledge in arithmetic: The core of calculation skills. Cortex 38: 285–288. Seron X, Pesenti M, Noel M-P, et al. (1992). Images of numbers, or ‘when 98 is upper left and 6 sky blue.’ Cognition 44: 159–196. Shalev RS, Gross-Tsur V (2001). Developmental dyscalculia. Review article. Pediatr Nephrol 24: 337–342. Siegler RS (1988). Strategy choice procedures and the development of multiplication skill. JEP: Gen 117: 258–275. Simon O, Mangin JF, Cohen L, et al. (2002). Topographical layout of hand, eye, calculation, and language-related areas in the human parietal lobe. Neuron 33: 475–487. Sittig O (1920). Sto¨rung des Ziffernschreibens und Rechnens bei einem Hirnverletzten. Monatsschr Psychiatr Neurol 49: 299–306.

358

K. WILLMES

Sokol SM, McCloskey M, Cohen NJ, et al. (1991). Cognitive representations and processes in arithmetic: Inferences from the performance of brain-damaged subjects. JEP: LMC 17: 355–376. Stanescu-Cosson R, Pinel P, van de Moortele P-F, et al. (2000). Understanding dissociations in dyscalculia: A brain imaging study of the impact of number size on the cerebral networks for exact and approximate calculation. Brain 123: 2240–2255. van Harskamp NJ, Cipolotti L (2001). Selective impairments for addition, subtraction, and multiplication. Implications for the organization of arithmetical facts. Cortex 37: 363–388. Varley RA, Klessinger NJC, Romanowski CAJ, et al. (2005). Agrammatic but numerate. Proc Natl Acad Sci USA: Early Edition 040747002, doi 10.1073. Vinken PJ, Bruyn GW, Klawans HL, et al. (1985). Handbook of Clinical Neurology. Clinical Neuropsychology, Vol. 45. Elsevier, Amsterdam. Walsh V (2003). A theory of magnitude: Common metrics of time, space and quantity. TICS 7: 483–488. Warrington EK (1982). The fractionation of arithmetical skills: A single case study. Q J Exp Psychol 34A: 31–51.

Whalen J, McCloskey M, Lindermann M, et al. (2002). Representing arithmetic table facts in memory: Evidence from acquired impairments. Cogn Neuropsychol 19: 505–522. Willmes K (2003). The methodological and statistical foundations of neuropsychological assessment. In: PW Halligan, U Kischka, JC Marshall (Eds.), Handbook of Clinical Neuropsychology. Oxford University Press, Oxford, pp. 27–47. Wood G, Nuerk H-C, Willmes K (2006). Neural representations of two-digit numbers: A parametric study. Neuroimage 29: 358–367. Wynn K (1998). Psychological foundations of number: numerical competence in human infants. Trends Cogn Sci 2: 296–303. Zhang J, Norman DA (1995). A representational analysis of numeration systems. Cognition 57: 271–295. Zorzi M, Priftis K, Umilta` C (2002). Neglect disrupts the mental number line. Nature 417: 138–139. Zorzi M, Stoianov I, Umilta` C (2005). Computational modeling of numerical cognition. In: JID Campbell (Ed.), Handbook of Mathematical Cognition. Psychology Press, New York and Hove, pp. 67–83.

Handbook of Clinical Neurology, Vol. 88 (3rd series) Neuropsychology and behavioral neurology G. Goldenberg, B.L. Miller, Editors # 2008 Elsevier B.V. All rights reserved

Chapter 18

Hemispatial neglect MASUD HUSAIN* Institute of Neurology and Institute of Cognitive Neuroscience, University College London, London, UK

18.1. Introduction Hemispatial neglect is a common and disabling condition following unilateral brain damage, particularly right-hemisphere stroke (Stone et al., 1991). Patients with neglect often fail to be aware of or acknowledge objects on their contralesional side (left side for patients with right brain damage), attending instead to ipsilesional items (right side for right-hemisphere stroke patients). Neglect may be so profound that patients are unaware of large objects—even people—in extrapersonal space (Brain, 1941; McFie et al., 1950). It may also involve personal space, with patients failing to acknowledge their own contralesional body parts in daily life (Bisiach et al., 1986a; Zoccolotti and Judica, 1991; Beschin and Robertson, 1997). Some patients display a striking failure to use their contralesional limbs, even if they have little or no weakness—so called ‘motor neglect’ (Laplane and Degos, 1983; Vallar et al., 2003). Importantly, many neglect patients may be unaware that they suffer from any of these problems (anosognosia), denying that there is anything wrong with their perception or control of movement (Bisiach et al., 1986b; Vallar et al., 2003). Although neglect appears to improve in many patients shortly after their acute stroke, some individuals continue to demonstrate persistent neglect (Stone et al., 1991) while others show ipsilesional biases in their behavior even if they no longer have frank neglect on clinical testing. Enduring neglect holds a poor prognosis for long-term functional independence following stroke (Denes et al., 1982; Fullerton et al., 1988; Robertson and Halligan, 1999; Jehkonen et al., 2000; Cherney et al., 2001; Nys et al., 2005). Current views of the neglect syndrome consider it to be a heterogeneous condition (Robertson and Marshall, *

1993; Driver and Mattingley, 1998; Mesulam, 1999; Bisiach and Vallar, 2000; Heilman and Watson, 2001; Kerkhoff, 2001; Bartolomeo and Chokron, 2002; Karnath et al., 2002b; Husain and Rorden, 2003), consistent with the multiple lesion sites associated with the condition (Heilman et al., 1983; Mesulam, 1999; Vallar, 2001; Husain and Rorden, 2003). Experimental investigations of neglect have been important in the development of concepts regarding the normal functions of these brain regions, as well as informing theories regarding the cognitive neuroscience of perception, attention, and action (Duncan et al., 1997; Driver and Mattingley, 1998; Rees, 2001; Corbetta and Shulman, 2002). Conversely, new developments in cognitive neuroscience are likely to play an increasing role in the development of behavioral and drug therapies for patients with neglect. This review commences with clinical assessment of patients, before discussing anatomy, possible underlying mechanisms, and treatment options.

18.2. Clinical assessment 18.2.1. Visual neglect Patients with severe unilateral neglect are obvious from a distance. Individuals with a large right middle cerebral artery (MCA) territory infarct assessed soon after their stroke often have their head and eyes turned to the right, very rarely directing their gaze to the left. When presented with food or a newspaper to read, they may restrict their interest only to items to their right, ignoring those to their left. Similarly, when approached by people from their left they may fail to acknowledge them or, if spoken to, orientate themselves to the right, replying with their gaze directed away from the person they are addressing. This type of behavior would be very unusual for a patient who has a pure hemianopia

Correspondence to: Masud Husain, Institute of Neurology and Institute of Cognitive Neuroscience, UCL, 17 Queen Square, London WC1N 3AR,UK. Email: [email protected]

360

M. HUSAIN

(without neglect) but, as discussed below, the distinction between neglect and neglect plus hemianopia is not always straightforward. Although clinical observation of a patient’s behavior is vital, many patients with moderate or mild neglect may not be identified using this method alone. Furthermore, it is increasingly becoming important to quantify the severity of neglect to track the progress of the patient, and to determine whether interventions are effective. Many stroke patients with neglect improve within a few weeks, but some continue to demonstrate persistent neglect. Early identification of these individual may facilitate their referral to specialized rehabilitation units, or allow more intensive occupational or physiotherapy to be directed towards them. A number of simple bedside screening tests have been developed for the assessment of neglect. Although object-copying (Fig. 18.1A) and clockdrawing (Fig. 18.1B) tests are widely known, they are not very sensitive on their own, though they may be helpful when used with other tests (Azouvi et al., 2002). Furthermore, right-hemisphere patients with constructional apraxia perform poorly on these tasks, even though they may not demonstrate any spatial neglect. Fortunately, there are a number of other relatively simple tests available that are frequently used. Batteries of such tests have been developed (Wilson et al., 1987; Pizzamiglio et al., 1989; Black et al., 1990; Azouvi et al., 1996), largely because no single test alone is able to detect neglect in all patients (Halligan et al., 1989; Azouvi et al., 1996; 2002). Moreover, there are many reports of clear dissociations with some patients showing neglect on some tasks, but not on

others (Binder et al., 1992; Azouvi et al., 1996; Ferber and Karnath, 2001). One of the most useful types of test for identifying neglect is the cancellation task. There are several different versions available, all of them requiring patients to find and cancel (visibly mark with a pen) targets distributed on an A4-sized sheet of paper placed directly in front of them. Some cancellation tasks have only target items, e.g., the Albert’s task (Albert, 1973) or line cancellation from the Behavioural Inattention Test (BIT) battery (Wilson et al., 1987). However, most have targets embedded in an array of many different types of distractor objects, e.g., the Bells test (Gauthier et al., 1989), star cancellation from the BIT (Wilson et al., 1987) and the Mesulam shape cancellation test (Mesulam, 1985). Many right hemisphere patients with left neglect cancel items on only the right side of cancellation tasks, omitting targets to the left (see Fig. 18.2). An important clue to the presence of neglect is that most such patients start to search from the right of the array (Azouvi et al., 2002), whereas most healthy individuals who read left-to-right start on the left. Most clinicians find that dense cancellation tasks with distractors are usually better and more sensitive in detecting neglect than the simpler cancellation tasks that have no distractor items (Halligan et al., 1989). Moreover, they identify neglect far more frequently than any other single test (Halligan et al., 1989; Azouvi et al., 1996; Ferber and Karnath, 2001), although there are a few patients who perform cancellation well but show neglect on other tasks (Halligan and Marshall, 1992). Hence the necessity to use more than one screening measure for neglect.

Fig. 18.1. Right-hemisphere patients with left neglect may omit elements to the left when copying simple objects (A) or drawing a clock face (B).

HEMISPATIAL NEGLECT

361

18.2.2. Hemianopia plus neglect or pure hemianopia?

Fig. 18.2. Performance of a right-hemisphere patient with left neglect on a dense cancellation task, with targets embedded among many distractors. In this case, the patient demonstrates severe left neglect, finding targets only on the right-hand edge of the array.

In addition to cancellation, many clinicians use another simple pen-and-paper task: line bisection. A long horizontal line marked on an A4 sheet of paper is placed in front of the patient who is asked to mark the midpoint of the line. Many right hemisphere patients with left neglect, particularly those with posterior lesions (Azouvi et al., 2002; Binder et al., 1992), tend to place their bisection mark well to the right of the true midline. Individuals with left hemianopia but without neglect tend to bisect the line slightly to the left, perhaps because they are aware of their visual deficit and attempt to compensate for it (Barton and Black, 1998). A similar contralesional bias in performance can also be seen in left neglect patients if the line to be bisected is small (the so-called ‘cross-over’ effect) (Halligan and Marshall, 1988). Recent work suggests that such paradoxical crossing-over to the left occurs only in patients who have neglect plus hemianopia (Doricchi et al., 2005). In normal clinical practice large horizontal lines (18–20 cm long) are usually used, so the crossover phenomenon is not a confounding factor, though the mechanisms underlying it remain of considerable interest. Asking patients to report ten objects in the room around them provides another rapid and useful measure (Patterson and Zangwill, 1944; Stone et al., 1991). Provided that the patient is not situated to the extreme edge of a room, this test may reveal a spatial bias, with neglect patients often reporting items only or mostly to their ipsilesional side. By contrast, patients with pure hemianopia tend to compensate by shifting their gaze towards contralesional space. Moreover, unlike many patients with neglect, those with pure hemianopia are typically aware of their deficit.

Many patients suffer from hemianopia as well as neglect (Vallar and Perani, 1986; Muller-Oehring et al., 2003). In addition, there are individuals who suffer from pure hemianopia (without neglect), and patients who show neglect on bedside testing but have full visual fields to confrontation (Halligan et al., 1991). It is usually operationally straightforward to confirm the presence of neglect—by using the tests we describe above. Furthermore, in the absence of neglect, the presence of a contralesional field defect which shows a strict demarcation at the vertical meridian in both eyes is easy to classify as homonymous hemianopia. The real problem is deciding whether a failure by a patient to report a contralesional stimulus during confrontation testing is due to neglect alone, or neglect plus hemianopia. Disentangling ‘absolute’ field defects from neglect is not always easy and some authors question the validity of making such a distinction (Halligan and Marshall, 2002). But the fact that two distinct syndromes may co-occur within the same patient is perhaps best illustrated by individuals who have complete loss of vision in the lower contralesional quadrant, but are nevertheless able to report a salient stimulus in the upper quadrant, and in addition demonstrate neglect on standard tests (Malhotra et al., 2004b). Such a patient has an absolute sensory defect (an inferior quadrantanopia), plus neglect. Assessment of field defects is probably best performed by careful clinical assessment at the bedside, rather than by the use of automated perimetry which tends to overestimate the apparent ‘absolute’ field defect (Muller-Oehring et al., 2003). If there is evidence of a field defect on initial testing with small targets (e.g., white hatpin), I repeat testing with larger targets (e.g., fingers) before I am fully satisfied of the presence of an ‘absolute’ field defect. Even under these circumstances, it is sometimes difficult clinically to distinguish dense neglect from neglect plus hemianopia (Halligan and Marshall, 2002). But it is worth persisting with the clinical examination because the identification of patients with neglect plus hemianopia is important. Many of these patients have severe difficulties in everyday life and identifying them early may allows more therapy time to be devoted to them. 18.2.3. Personal neglect and motor neglect All the tests discussed so far depend heavily on vision or visuomotor control. Some patients with neglect

362

M. HUSAIN

may perform normally on such tasks, yet demonstrate personal neglect (ignoring the contralesional side their body) or motor neglect (failing to use their contralesional limbs despite the fact that strength in these may be intact or only mildly reduced). Personal neglect may be detected formally by asking the patient to gesture how they would groom themselves, e.g., comb their hair, put on make-up or shave (Zoccolotti and Judica, 1991; McIntosh et al., 2000). Alternatively, patients may be asked to remove pieces of adhesive paper that have been attached to their clothing, with the number of pieces omitted on the contralesional side being used as a measure of personal neglect—the socalled ‘fluff test’ (Cocchini et al., 2001). Often, however, such neglect is often picked up by carers who notice the lack of interest to the contralesional side of the body. Similarly, motor neglect (Laplane and Degos, 1983; Vallar et al., 2003) is also most often detected by therapists or carers who remark on the lack of use of a contralesional limb, despite it being strong. 18.2.4. Auditory neglect In addition to visual, personal, and motor neglect, many patients with the neglect syndrome show neglect for contralesional auditory stimuli (particularly when there are competing ipsilesional sounds), or mislocalization of contralesional auditory stimuli, perceiving them to originate from more ipsilesional locations (Heilman and Valenstein, 1972; Bisiach et al., 1984; Bellmann et al., 2001; Pavani et al., 2004). These deficits may correlate quite well with the severity of visual inattention across individuals (Bisiach et al., 1984; Pavani et al., 2004). Thus far there are no standardized, objective bedside tests that are used to assess audiospatial neglect, but clinicians sometimes assess report of sounds (e.g., rubbing of fingers) presented separately to each ear, compared to bilaterally. Some patients show ‘extinction’ of contralesional stimuli, failing to report them when there is a competing ipsilesional stimulus, but not when they are presented alone (Bender, 1952).

component of the neglect syndrome. Finally, it is also worth noting that extinction may also be cross-modal, e.g., with a visual stimulus to the right ‘extinguishing’ a tactile stimulus on the left (Driver and Spence, 1998). The significance of extinction for understanding the possible competitive attentional mechanisms underlying neglect is discussed later. 18.2.6. Representational neglect Many neglect patients also demonstrate lateralized spatial deficits on tests of representational neglect, e.g., if they are asked to recall a familiar scene from memory right hemisphere neglect patients may fail to recollect places or items on the left side (Bisiach and Luzzatti, 1978; Denis et al., 2002). Standardized tests for use in the clinical environment have not been developed but some clinicians like to use clock-drawing from memory as a test of representational neglect. The problem with this test, however, is that lateralized deficits may be due to perceptual, oculomotor, and limb control dysfunction rather than representational neglect alone. Nevertheless, it may still be useful to have clock-drawing in a battery of tests for neglect, provided the examiner is aware that it may not detect simply representational neglect. 18.2.7. Anosognosia Although patients with severe anosognosia are often identified through conversation at the bedside, many individuals may not reveal unawareness of one or more of their neurological deficits so easily. There are a number of relatively simple structured instruments (Bisiach et al., 1986b; Starkstein et al., 1992) that can be helpful in screening for such deficits, although they may not be sensitive enough to detect mild forms of anosognosia. Neglect, as defined by the bedside tests already discussed, may occur without anosognosia, and vice versa; many patients suffer from both conditions (Starkstein et al., 1992; Vallar et al., 2003) which may have an important impact on functional recovery and/or rehabilitation potential.

18.2.5. Visual extinction 18.2.8. Summary Extinction also occurs in the visual domain (Bender, 1952; Mattingley, 2002). Many patients with unilateral brain damage—on the left or right side—demonstrate extinction, but do not show neglect on standard tests. Some consider this to be a mild type of neglect or a sign of ‘inattention.’ But it is important to appreciate that many patients with neglect also demonstrate some degree of extinction, and it may be argued that the mechanisms underlying extinction in fact comprise one

Clearly, a large number of tests are available to investigate whether a patient has neglect at the bedside. However, in the clinical setting, where time is often limited, it would not be practical to use all of these. A dense cancellation task, plus clock drawing and figure copying may be sufficient to pick up over 70 percent of neglect patients (Azouvi et al., 2002). In our experience, 90% of patients with neglect can be

HEMISPATIAL NEGLECT picked up with the combination of a dense cancellation test, line bisection and naming ten objects around the room (Malhotra et al., 2004a). If more time is available, more detailed assessments of neglect in daily life may be helpful (Azouvi et al., 1996; 2002).

18.3. Anatomy of the neglect syndrome Lesions of the right hemisphere are far more likely to lead to severe and enduring neglect than left hemisphere damage (Stone et al., 1992; Bowen et al., 1999), perhaps because of the specialization of the latter for language. Cortical damage involving the right inferior parietal lobe (IPL) or nearby temporoparietal junction (TPJ) has classically been implicated in causing neglect (Vallar and Perani, 1986). But it has become apparent that the syndrome may also follow focal lesions of the inferior frontal lobe (Husain and Kennard, 1997; Vallar, 2001) (Fig. 18.3). More commonly, however, large MCA strokes involve both parietal and frontal regions, resulting in a severe and persistent neglect syndrome that has a profound impact on the daily behavior of patients. One recent anatomical study has challenged the conventional view that IPL or TPJ lesions are the critical posterior cortical locations associated with neglect (Karnath et al., 2001). The authors proposed instead that the key region is the mid superior temporal gyrus (STG).

Fig. 18.3. Right hemisphere regions involved in lesions of patients with neglect. The intraparietal sulcus (Ips) separates the superior parietal lobe (SPL) from the inferior parietal lobe (IPL), which consists of the angular gyrus (Ang) and supramarginal gyrus (Smg). The temporoparietal junction (TPJ) is a zone that lies between the IPL and the temporal lobe. The middle frontal gyrus (MFG) and inferior frontal gyrus (IFG) are anterior areas that may also be involved in neglect patients.

363

A subsequent investigation, using higher resolution lesion-mapping, identified the angular gyrus of the IPL as the critical brain region associated with neglect in MCA stroke. Although the STG was involved in many neglect patients (50% of the sample), damage to this region was neither necessary nor sufficient on its own (without angular gyrus involvement) to cause neglect (Mort et al., 2003). Other subsequent investigations, using a variety of techniques, have also not found good evidence to substantiate the claim for a special role for the STG (Doricchi and Tomaiuolo, 2003; Buxbaum et al., 2004; Farne et al., 2004). However, a follow-up study by Karnath and colleagues has claimed, once again, that the STG is a critical site (Karnath et al., 2004). The debate continues (Karnath et al., 2004; Mort et al., 2004). It is likely that no single lesion location necessarily ‘explains’ the neglect syndrome. Rather, there may be sites that are commonly affected in many patients, e.g., angular gyrus of IPL, but the heterogeneity of the syndrome is likely to be explained also by the involvement of nearby regions, and disruption of their functions. Studies of healthy individuals using functional imaging have demonstrated that many different functions are subserved by subregions within even the IPL (Rizzolatti et al., 2000; Robertson, 2001; Corbetta and Shulman, 2002; Husain and Rorden, 2003). Each of these functions may well contribute to the clinical presentation of the neglect syndrome, with the precise combination of underlying deficits varying from patient to patient, and presumably being determined by the precise location and extent of brain damage (see Husain and Rorden (2003) for further discussion). Thus far, I would argue, there is no compelling reason to consider a special role of lesions to the STG in neglect. In addition to cortical damage, subcortical ischemic lesions in the territory of the MCA involving the right basal ganglia or thalamus may also produce neglect (Vallar, 2001; Karnath et al., 2002a), but this is most likely due to diaschisis or hypoperfusion in overlying parietal and frontal regions, as demonstrated by both SPECT and MR perfusion (Perani et al., 1987; Hillis et al., 2002). More recent studies have begun to investigate whether different types of neglect deficit following subcortical damage are associated with differential hypoperfusion of inferior parietal vs. superior temporal gyrus regions (Hillis et al., 2005), echoing the debate that has developed for the critical cortical location associated with neglect. Finally, some patients with posterior cerebral artery (PCA) territory stroke also suffer from neglect, although these individuals have been less well studied. Some groups have observed that while small lesions involving the occipital lobe lead to only hemianopia, larger strokes

364

M. HUSAIN

extending into the medial temporal lobe lead in addition to neglect (Vallar and Perani, 1986; Cals et al., 2002; Mort et al., 2003). Specifically, it has recently been demonstrated that the key medial temporal area damaged in these patients is the parahippocampal region (Mort et al., 2003), a region that has strong connections with the parietal cortex (Ding et al., 2000; Burwell and Witter, 2002), and may be considered an important gateway for parietal information to the hippocampus. Although lesions of the right parahippocampal region are traditionally associated with topographical disorientation, there are reports of patients who also demonstrate neglect (Takahashi and Kawamura, 2002). What remains to be determined is whether neglect following extensive PCA infarction is in fact due to diaschisis in parietal cortex, or is a separate disorder with unique underlying component deficits.

18.4. Mechanisms underlying the neglect syndrome Given the variety and widespread nature of the lesions— both cortical and subcortical—in neglect, it is perhaps not surprising that many different mechanisms are considered to contribute to the syndrome. Some recent studies, involving large groups of patients tested with a battery of experimental tasks, confirm this view (Buxbaum et al., 2004; Farne et al., 2004). Moreover, functional imaging studies in healthy volunteers have demonstrated that several different functions are subserved by subregions of the parietal and frontal regions commonly implicated in neglect (Rizzolatti et al., 2000; Robertson, 2001; Corbetta and Shulman, 2002; Husain and Rorden, 2003). Increasingly, the neglect syndrome is considered to consist of a number of component deficits, with the precise combination varying from patient to patient. A second critical concept that has emerged is that the mechanisms underlying neglect need not be specific to the syndrome: they may occur separately, on their own, in patients without neglect (Robertson, 2001; Husain and Rorden, 2003). But when combined with other component deficits they may lead to neglect. These perspectives have important implications not only for understanding the neglect syndrome but also for treating it. 18.4.1. Spatially lateralized deficits in directing attention A number of investigators have considered the possibility that there may be a ‘core’ deficit in the ability to direct attention—the focus of visual processing—to the left in right-hemisphere patients with neglect. Some consider this to be due to an intrinsic, graded bias to

direct attention rightwards following right-hemisphere damage (Kinsbourne, 1993), and there is clear evidence for such a gradient of neglect, with reaction times for visual stimuli gradually increasing from contra- to ipsilesional space (Smania et al., 1998). Other investigators, who have used the Posner cueing task as their experimental paradigm, propose that in both left-sided extinction and neglect there is a specific deficit in disengaging attention and shifting it leftward (Posner et al., 1984; Losier and Klein, 2001; Bartolomeo and Chokron, 2002). Consistent with this view functional imaging in healthy humans shows activation of the right temporoparietal junction when attention needs to be disengaged and shifted from invalidly cued locations (Corbetta et al., 2000). However, as discussed below, such activation may not be specific to disengagement of attention but rather occur whenever some unexpected or unusual salient event is detected. An alternative model for a lateralized attentional deficit in left-sided neglect casts the disorder in the context of the ‘biased competition model’ developed for understanding normal attention function (Desimone and Duncan, 1995). According to this view, in patients with right-hemisphere lesions, items on the right invariably ‘win’ over objects to the left in the competition for selection. A similar argument has also been advanced for left-sided visual extinction (Driver et al., 1997; Duncan et al., 1997). Increases in the number of items to the right in a visual scene or search array lead to increased leftward neglect (Eglin et al., 1989; Kaplan et al., 1991). The greater the clutter to the right, the more that visual attention or search appears to be tied up to that side, at the expense of exploring leftward space. Even irrelevant items briefly presented on the right can lead to deficits in visual processing on the left (Geeraerts et al., 2005), with the neural basis for such effects identified as being localized in the mid-intraparietal sulcus, lying just above the IPL (Vandenberghe et al., 2005). 18.4.2. A failure of space representation Several investigators have also raised the possibility that neglect may result from an impaired representation of space (Bisiach and Luzzatti, 1978; Karnath, 1997), which may be in multiple frames of reference (e.g., retinotopic, head-centered, trunk-centered) or be specific to near or far space (Halligan and Marshall, 1991; Cowey et al., 1994; Vuilleumier et al., 1998). Most researchers in this field would agree that patients with neglect have a distorted representation of space, but the real debate concerns whether this is the primary deficit, or whether it might be secondary to other deficits, e.g., a bias to direct attention to the right or difficulty in shifting it leftward.

HEMISPATIAL NEGLECT Some recent studies have also suggested that neglect patients may encounter difficulty in remapping spatial locations across eye or head movements (Husain et al., 2001; Wojciulik et al., 2001; 2004; Malhotra et al., 2005; Mannan et al., 2005). Each time we shift our gaze, the retinotopic locations of static objects (i.e., their position on the retina) is altered, but our percept of their spatial locations remains stable, and objects do not appear to move every time we move our eyes. Such ‘space constancy’ is considered to involve brain regions taking into account gaze shifts, or ‘remapping’ the spatial locations of salient items across saccades so that their positions remain invariant despite changes in their retinotopic locations (Duhamel et al., 1992a). Lesions involving posterior parietal cortex appear to lead to problems with such remapping (Duhamel et al., 1992b; Heide et al., 1995). Moreover, such a remapping deficit may be one mechanism that contributes to right-hemisphere neglect patients returning to previously fixated locations on the right (Fig. 18.4), and erroneously considering them to be newly inspected ones (Husain et al., 2001; Wojciulik et al., 2001; 2004; Mannan et al., 2005). This revisiting of locations, when combined with rightward attentional biases, may explain why some neglect patients recursively search items on the right at the expense of those on the left. The critical lesion locations associated with such behavior in neglect patients includes the intraparietal sulcus and inferior frontal lobe (Mannan et al., 2005). As discussed in the section below, remapping

365

deficits across saccades may not be the only factor contributing to such recursive rightward search in patients with left neglect. Impairments in retaining locations across short periods of time (spatial working memory) may also play a role. 18.4.3. Impaired spatial working memory It has been proposed that one mechanism underlying poor representation of contralesional space in neglect patients is impaired working memory for spatial locations (Ellis et al., 1996). If memory for objects in contralesional space is deficient, then durable representations of those objects cannot be formed, hence neglect of contralesional space. The difficulty with this hypothesis is that it is not easy to test. Because most neglect patients have degraded perception of contralesional locations, one might argue that any apparent impairment in spatial working memory is in fact due to degraded perception or poor encoding of locations. However, there are some rare cases who show little evidence of contralesional perceptual impairment but nevertheless demonstrate a deficit in retaining memories of contralesional objects (Denis et al., 2002). Other investigators have suggested that impairments in maintaining the locations of objects might, when combined with ipsilesional biases in attention, contribute to the recursive ipsilesional search behavior (Fig. 18.4) displayed by some neglect patients (Husain et al., 2001; Wojciulik et al., 2001; 2004; Mannan et al., 2005). Neglect patients with right parietal and frontal lesions show a profound reduction in spatial working memory capacity (Pisella et al., 2004), even when asked to remember locations on a vertical array (Malhotra et al., 2005). What is unclear is the extent to which such deficits in keeping track of spatial locations are due to impairments in simply retaining locations across time, or across eye movements, or both. As discussed in the section on space representation, trans-saccadic spatial remapping impairments may also contribute to such recursive ipsilesional search. Further research in this exciting area should help to clarify the contributions of impaired memory across time and across saccades to the neglect syndrome. 18.4.4. Spatial and directional motor deficits

Fig. 18.4. Scan paths of a patient with a right parietal stroke searching for Ts among distractor Ls. The patient not only neglected leftward items, but also recursively refixated targets to the right, erroneously indicating that he considered these to be new discoveries.(Reproduced from Husain et al. (2001), by permission from Oxford University Press.) A group study using this paradigm has also been performed (see Mannan et al., 2005).

Neglect may not only be perceptual. Some patients also appear to demonstrate a directional motor impairment, experiencing difficulty in initiating or programming contralesional eye or limb movements (Heilman et al., 1985; Bisiach et al., 1990). Although it has been suggested that such patients with motor planning deficits may have frontal lesions, more recent work has

366

M. HUSAIN

challenged that view, demonstrating that right parietal neglect patients have impairments in initiating leftward reaches (Mattingley et al., 1998; Husain et al., 2000). Importantly, however, these investigations also revealed that the directional deficit appears to interact with the hemispatial deficit in neglect: in right parietal neglect patients there is evidence for impaired initiation of leftward reaches specifically to targets in left hemispace, but not for leftward reaches to targets in right hemispace. 18.4.5. Nonspatial deficits in neglect In addition to spatial deficits, it is increasingly becoming apparent that non-spatial mechanisms might also contribute to neglect (Robertson, 2001; Husain and Rorden, 2003). For example, impairments in sustained attention are more common in right hemisphere neglect patients than non-neglect control stroke patients (Robertson et al., 1997). Selective attention capacity is also reduced, either at central fixation (Husain et al., 1997) or in both visual fields (Duncan et al., 1999; Battelli et al., 2001; Peers et al., 2005). Furthermore, many neglect patients demonstrate a striking bias to local features in the visual scene (Robertson et al., 1988; Rafal, 1994; Doricchi and Incoccia, 1998) and some investigators have shown a severe constriction of the effective visual field bilaterally, but worse to the contralesional side, when patients perform attentionally demanding tasks at fixation (Russell et al., 2004). None of these nonspatial deficits would traditionally be considered to be specific to the neglect syndrome. Instead, they might have been viewed as coexisting deficits, since they may occur independently in patients without neglect, i.e., they are ‘doubly dissociable’ from the neglect syndrome. However, several investigators argue that when such nonspatial deficits combine with spatial ones, they exacerbate any contralesional deficit and thereby have a significant impact on the neglect syndrome, reducing the potential for recovery (Samuelsson et al., 1998; Robertson, 2001; Husain and Rorden, 2003). Such a view of neglect has two important consequences. First, it brings to bear insights from other branches of cognitive neuroscience—such as the mechanisms underlying sustained attention and selective attention capacity—that have hitherto not been considered to be important for understanding neglect. Second, it raises the possibility of targeting treatments towards specific component deficits that may not be neglect-specific, but nevertheless are important in determining the severity of neglect. The full potential for such treatments has yet to be tested but recent work suggests this may be a promising avenue (see section 18.5).

Finally, this view of the neglect syndrome has led to a testable model relating component deficits—spatial and nonspatial—to specific lesion locations. Such a model also has potentially important implications for understanding the normal functions of these brain regions. 18.4.6. Relating spatial and nonspatial deficits to lesion locations Husain and Rorden (2003) have proposed that the spatial deficits associated with neglect may be due to stroke lesions affecting the dorsal regions of the right parietal lobe—the superior parietal lobe and/or intraparietal sulcus. In contrast, the nonspatial deficits associated with neglect may be due to damage to more ventral regions involving the right inferior parietal lobe and/or intraparietal sulcus. There may be similar dorsal–ventral distinctions in the functions of the right frontal lobe. This model incorporates data from functional imaging experiments in healthy humans and behavioral experiments in patients with focal lesions. It provides a neuroanatomical basis for understanding the diversity of spatial and nonspatial deficits that have been reported in patients with neglect. A different view of the functions of dorsal–ventral regions in the right hemisphere has been offered by Corbetta and Shulman (2002).

18.5. Treatment and rehabilitation 18.5.1. Scanning therapy and hemianopic patching Initial attempts to rehabilitate neglect attempted to encourage patients to shift their gaze contralesionally by cueing them to scan in that direction (see for example Diller and Weinberg, 1977; Weinberg et al., 1977). These approaches have shown some success in improving the spatial bias on a particular task, e.g., in reading (Weinberg et al., 1977). However, most neglect patients demonstrate little or no generalization of their improved scanning behavior to tasks outside the training environment (Robertson and Halligan, 1999), perhaps because they fail to adopt a generalized strategy to redirect their gaze, regardless of the specific context or environment they are in. A recent alternative method uses spectacles that occlude the ipsilesional (good) side of vision in each eye, forcing neglect patients to direct their gaze contralesionally (Beis et al., 1999), whatever the visual environment. Although such ‘hemianopic patching’ seems promising, the reported benefits are modest (Zeloni et al., 2002). Moreover, in our limited experience, patient compliance with these spectacles is not

HEMISPATIAL NEGLECT good, presumably because the natural inclination of neglect patients is to look towards the (now-occluded) ipsilesional side.

367

length of hospital stay in patients with neglect (Kalra et al., 1997). 18.5.3. Prism adaptation

18.5.2. Postural manipulations or cueing to induce contralesional shifts Many investigators have attempted to have a more direct effect on altering the impaired representation of space in neglect. The methods used include caloric, or vestibular, stimulation (Rubens, 1985), contralesional limb activation (Robertson and North, 1993), trunk rotation (Karnath et al., 1991), neck muscle vibration (Karnath, 1995; Schindler et al., 2002) and electrical stimulation of the neck (Vallar et al., 1995). Although the mechanisms underlying these different techniques vary, they have all been shown to produce an improvement in some aspects of neglect. Furthermore, they all produce an automatic (‘bottom-up’) change in behavior, or recalibration of the sensorimotor mechanisms recruited, that do not depend upon patients adopting (‘top-down’) a new control strategy to look leftwards. Perhaps, as a consequence, improvements in performance have been shown, at least in some cases, to generalize to tasks that were not used in training. However, not all these methods are very practical. For example, caloric stimulation by applying cold water to the contralesional ear (or warm water to the ipsilesional ear), causes a transient vestibular-induced contralesional shift during and after application (for 10–15 minutes) across a range of tasks. But the short duration of its effects, together with the discomfort of application, makes it impractical for clinical rehabilitation. Perhaps more clinically relevant is the procedure used by Schindler et al. (2002). Vibration of the contralesional neck muscles reduces leftward omissions when right-hemisphere neglect patients are required to report briefly presented stimuli (Karnath et al., 1993). When patients were treated with neck muscle vibration in combination with scanning training a long-lasting (> 2 months) improvement was observed, even on visuomotor tasks that had not been used in initial training (Schindler et al., 2002). Active movements of part of a contralesional body part (e.g., a finger) have also been reported to lead to improvements in neglect (Robertson and North, 1992; 1993; Robertson et al., 1998a). Although this spatiomotor cueing technique is effective in patients with contralesional limb weakness (Frassinetti et al., 2001), the prevalence of severe hemiparesis and sensory loss in neglect patients may limit the number of individuals who might benefit. Nevertheless, the findings from one trial suggest that spatiomotor cueing may be associated with significantly reduced

Prism adaptation is new type of treatment which has attracted a great deal of interest (Rossetti et al., 1998). Right-hemisphere patients with neglect wear rightward-displacing prisms and repeatedly point (for 50 trials) to visual targets either side of the body midline. Immediately after adaptation it has been reported that neglect may be ameliorated and this improvement may last for several hours after a single procedure (Rossetti et al., 1998), or weeks after brief prism adaptation twice a day for two weeks (Frassinetti et al., 2002). Some studies have also demonstrated that prism adaptation is associated with improvements in representational neglect (Rode et al., 1998; 2001), neglect dyslexia (Farne et al., 2002), postural imbalance in hemiparesis (Tilikete et al., 2001) haptic neglect (McIntosh et al., 2002), as well as tactile extinction (Maravita et al., 2003). However, the mechanisms that underlie the effectiveness of prism adaptation are not yet precisely understood. 18.5.4. Treating nonspatially lateralized deficits Some studies have attempted to examine whether increasing a patient’s alertness might lead to an improvement in their spatial bias. This has been done using experimental paradigms with phasic alerting tones (Robertson et al., 1998b), or a behavioral technique that is more appropriate for treating sustained attention deficits in clinical settings (Robertson et al., 1995). While carrying out some relatively simple tasks, e.g., sorting coins, neglect patients were intermittently reminded by the experimenter to maintain attention. Patients were then gradually trained to prompt themselves subvocally. The eight patients who were studied showed considerable improvements, a day after training, in tests of sustained attention and spatial neglect (Robertson et al., 1995). However, this intervention requires patients to be aware of their deficit, as well as the situations in which it is necessary to alert themselves. The degree to which neglect patients are able to do this may limit the general applicability of the technique. An alternative to behavioral approaches for the treatment of nonspatial cognitive deficits might be pharmacological interventions. Specifically, impaired sustained attention could be targeted using drugs that modulate the noradrenergic system, which is known to modulate vigilance levels in healthy volunteers (Smith and Nutt, 1996). By contrast, spatial working memory deficits might be targeted using dopaminergic drugs.

368

M. HUSAIN

Physiological evidence suggest that memory for spatial locations is modulated by dopamine D1-receptor agents (Williams and Goldman-Rakic, 1995). Previous studies using bromocriptine, a dopamine agonist, have reported both positive and negative results (Fleet et al., 1987; Geminiani et al., 1998; Grujic et al., 1998). These conflicting findings may partly be due to the heterogeneity of patients studied, as well as the fact that bromocriptine acts predominantly on D2 dopamine receptors. In the future, agents that primarily target D1 receptors may be tested on selected neglect patients with spatial working memory deficits. Finally, it is likely that combinations of behavioral and pharmacological approaches will be used in forthcoming attempts to treat the neglect syndrome.

Acknowledgements This work is funded by The Wellcome Trust. I am grateful to John Driver, Paresh Malhotra, and Andrew Parton for discussions on many of the issues presented here.

References Albert M (1973). A simple test of visual neglect. Neurology 23: 658–664. Azouvi P, Marchal F, Samuel C, et al. (1996). Functional consequences and awareness of unilateral neglect: study of an evaluation scale. Neuropsychol Rehabil 6: 133–150. Azouvi P, Samuel C, Louis-Dreyfus A, et al. (2002). Sensitivity of clinical and behavioural tests of spatial neglect after right hemisphere stroke. J Neurol Neurosurg Psychiatry 73: 160–166. Bartolomeo P, Chokron S (2002). Orienting of attention in left unilateral neglect. Neurosci Biobehav Rev 26: 217–234. Barton JJ, Black SE (1998). Line bisection in hemianopia. J Neurol Neurosurg Psychiatry 64: 660–662. Battelli L, Cavanagh P, Intriligator J, et al. (2001). Unilateral right parietal damage leads to bilateral deficit for highlevel motion. Neuron 32: 985–995. Beis JM, Andre JM, Baumgarten A, et al. (1999). Eye patching in unilateral spatial neglect: Efficacy of two methods. Arch Phys Med Rehabil 80: 71–76. Bellmann A, Meuli R, Clarke S (2001). Two types of auditory neglect. Brain 124: 676–687. Bender MB (1952). Disorders in Perception. Thomas, Springfield. Beschin N, Robertson IH (1997). Personal versus extrapersonal neglect: A group study of their dissociation using a reliable clinical test. Cortex 33: 379–384. Binder J, Marshall R, Lazar R, et al. (1992). Distinct syndromes of hemineglect. Arch Neurol 49: 1187–1194. Bisiach E, Cornacchia L, Sterzi R, et al. (1984). Disorders of perceived auditory lateralization after lesions of the right hemisphere. Brain 107: 37–52.

Bisiach E, Geminiani G, Berti A, et al. (1990). Perceptual and premotor factors of unilateral neglect. Neurology 40: 1278–1281. Bisiach E, Luzzatti C (1978). Unilateral neglect of representational space. Cortex 14: 129–133. Bisiach E, Perani D, Vallar G, et al. (1986a). Unilateral neglect: Personal and extra-personal. Neuropsychologia 24: 759–767. Bisiach E, Vallar G (2000). Unilateral neglect in humans. In: G Rizzolatti (Ed.), Handbook of Neuropsychology, Vol 1. Elsevier, Amsterdam, pp. 459–502. Bisiach E, Vallar G, Perani D, et al. (1986b). Unawareness of disease following lesions of the right hemisphere: Anosognosia for hemiplegia and anosognosia for hemianopia. Neuropsychologia 24: 471–482. Black SE, Vu B, Martin D, et al. (1990). Evaluation of a bedside battery for hemispatial neglect in acute stroke. J Clin Exp Neuropsychol 12: 102. Bowen A, McKenna K, Tallis RC (1999). Reasons for variability in the reported rate of occurrence of unilateral spatial neglect after stroke. Stroke 30: 1196–1202. Brain RW (1941). Visual disorientation with special reference to lesions of the right cerebral hemisphere. Brain 64: 244–272. Burwell RD, Witter MP (2002). Basic anatomy of the parahippocampal region in monkeys and rats. In: M Witter, F Wouterlood (Eds.), The Parahippocampal Region. Oxford University Press, Oxford. Buxbaum LJ, Ferraro MK, Veramonti T, et al. (2004). Hemispatial neglect: Subtypes, neuroanatomy, and disability. Neurology 62: 749–756. Cals N, Devuyst G, Afsar N, et al. (2002). Pure superficial posterior cerebral artery territory infarction in The Lausanne Stroke Registry. J Neurol 249: 855–861. Cherney LR, Halper AS, Kwasnica CM, et al. (2001). Recovery of functional status after right hemisphere stroke: Relationship with unilateral neglect. Arch Phys Med Rehabil 82: 322–328. Cocchini G, Beschin N, Jehkonen M (2001). The fluff test: A simple task to assess body representation neglect. Neuropsychol Rehabil 11: 17–31. Corbetta M, Kincade M, Ollinger JM, et al. (2000). Voluntary orienting is dissociated from target detection in human posterior parietal cortex. Nat Neurosci 3: 292–297. Corbetta M, Shulman GL (2002). Control of goal-directed and stimulus-driven attention in the brain. Nat Rev Neurosci 3: 215–229. Cowey A, Small M, Ellis S (1994). Left visuo-spatial neglect can be worse in far than in near space. Neuropsychologia 32: 1059–1066. Denes G, Semenza C, Stoppa E, et al. (1982). Unilateral spatial neglect and recovery from hemiplegia: A follow-up study. Brain 105: 543–552. Denis M, Beschin N, Logie RH, et al. (2002). Visual perception and verbal descriptions as sources for generating mental representations: Evidence from representational neglect. Cogn Neuropsychol 19: 97–112. Desimone R, Duncan J (1995). Neural mechanisms of selective visual attention. Annu Rev Neurosci 18: 193–222.

HEMISPATIAL NEGLECT Diller L, Weinberg J (1977). Hemi-inattention in rehabilitation: The evolution of a rational remediation program. Adv Neurol 18: 63–82. Ding SL, Van Hoesen G, Rockland KS (2000). Inferior parietal lobule projections to the presubiculum and neighboring ventromedial temporal cortical areas. J Comp Neurol 425: 510–530. Doricchi F, Guariglia P, Figliozzi F, et al. (2005). Causes of cross-over in unilateral neglect: Between-group comparisons, within-patient dissociations and eye movements. Brain 128: 1386–1406. Doricchi F, Incoccia C (1998). Seeing only the right half of the forest but cutting down all the trees? Nature 394: 75–78. Doricchi F, Tomaiuolo F (2003). The anatomy of neglect without hemianopia: A key role for parietal–frontal disconnection? Neuroreport 14: 2239–2243. Driver J, Mattingley JB (1998). Parietal neglect and visual awareness. Nat Neurosci 1: 17–22. Driver J, Mattingley JB, Rorden C, et al. (1997). Extinction as a paradigm measure of attentional bias and restricted capacity following brain injury. In: P Thier, H-O Karnath (Eds.), Parietal Lobe Contributions to Orientation in 3D space. Springer-Verlag, Heidelberg. Driver J, Spence C (1998). Crossmodal links in spatial attention. Philos Trans R Soc Lond B Biol Sci 1998: 1319–1331. Duhamel JR, Colby C, Goldberg ME (1992a). The updating of the representation of visual space in parietal cortex by intended eye movements. Science 1992: 90–92. Duhamel JR, Goldberg ME, Fitzgibbon EJ, et al. (1992b). Saccadic dysmetria in a patient with a right frontoparietal lesion. The importance of corollary discharge for accurate spatial behaviour. Brain 115: 1387–1402. Duncan J, Bundesen C, Olson A, et al. (1999). Systematic analysis of deficits in visual attention. J Exp Psychol Gen 128: 450–478. Duncan J, Humphreys G, Ward R (1997). Competitive brain activity in visual attention. Curr Opin Neurobiol 7: 255–261. Eglin M, Robertson LC, Knight RT (1989). Visual search performance in the neglect syndrome. J Cogn Neurosci 1: 372–385. Ellis A, Della Sala S, Logie R (1996). The bailiwick of visuospatial working memory: Evidence from unilateral spatial neglect. Cogn Brain Res 3: 71–78. Farne A, Buxbaum LJ, Ferraro M, et al. (2004). Patterns of spontaneous recovery of neglect and associated disorders in acute right brain-damaged patients. J Neurol Neurosurg Psychiatry 75: 1401–1410. Farne A, Rossetti Y, Toniolo S, et al. (2002). Ameliorating neglect with prism adaptation: Visuo-manual and visuoverbal measures. Neuropsychologia 40: 718–729. Ferber S, Karnath H (2001). How to assess spatial neglect— line bisection or cancellation tasks? J Clin Exp Neuropsychol 23: 599–607. Fleet WS, Valenstein E, Watson RT, et al. (1987). Dopamine agonist therapy for neglect in humans. Neurology 37: 1765–1770.

369

Frassinetti F, Angeli V, Meneghello F, et al. (2002). Long-lasting amelioration of visuospatial neglect by prism adaptation. Brain 125: 608–623. Frassinetti F, Rossi M, Ladavas E (2001). Passive limb movements improve visual neglect. Neuropsychologia 39: 725–733. Fullerton KJ, Mackenzie G, Stout RW (1988). Prognostic indices in stroke. Q J Med 66: 147–162. Gauthier L, Dehaut F, Joanette Y (1989). The Bells test. J Clin Neuropsychol 11: 49–54. Geeraerts S, Lafosse C, Vandenbussche E, et al. (2005). A psychophysical study of visual extinction: Ipsilesional distractor interference with contralesional orientation thresholds in visual hemineglect patients. Neuropsychologia 43: 530–541. Geminiani G, Bottini G, Sterzi R (1998). Dopaminergic stimulation in unilateral neglect. J Neurol Neurosurg Psychiatry 65: 344–347. Grujic Z, Mapstone M, Gitelman DR, et al. (1998). Dopamine agonists reorient visual exploration away from the neglected hemispace. Neurology 51: 1395–1398. Halligan PW, Cockburn J, Wilson B (1991). The behavioural assessment of visual neglect. Neuropsychol Rehabil 1: 5–32. Halligan PW, Marshall JC (1988). How long is a piece of string? A study of line bisection in a case of visual neglect. Cortex 24: 321–328. Halligan PW, Marshall JC (1991). Left neglect for near but not far space in man. Nature 350: 498–500. Halligan PW, Marshall JC (1992). Left visuo-spatial neglect: a meaningless entity? Cortex 28: 525–535. Halligan PW, Marshall JC (2002). Primary sensory deficits after right brain damage—An attentional disorder by any other name? In: HO Karnath, AD Milner, G Vallar (Eds.), The Cognitive and Neural Bases of Spatial Neglect. Oxford, Oxford University Press, pp. 327–340. Halligan PW, Marshall JC, Wade DT (1989). Visuospatial neglect: Underlying factors and test sensitivity. Lancet II: 908–911. Heide W, Blankenburg M, Zimmermann E, et al. (1995). Cortical control of double-step saccades: Implications for spatial orientation. Ann Neurol 38: 739–748. Heilman KM, Bowers D, Coslett B, et al. (1985). Directional hypokinesia: Prolonged reaction times for leftward movements in patients with right hemisphere lesions and neglect. Neurology 35: 855–859. Heilman KM, Valenstein E (1972). Auditory neglect in man. Arch Neurol 26: 32–35. Heilman KM, Valenstein E, Watson RT (1983). Localization of Neglect. Localization in Neurology. New York, Academic Press, pp. 471–492. Heilman KM, Watson RT (2001). Neglect and related disorders. In: KM Heilman, E Valenstein (Eds.), Clinical Neuropsychology. New York, OUP, pp. 243–293. Hillis AE, Newhart M, Heidler J, et al. (2005). Anatomy of spatial attention: Insights from perfusion imaging and hemispatial neglect in acute stroke. J Neurosci 25: 3161–3167.

370

M. HUSAIN

Hillis AE, Wityk RJ, Barker PB, et al. (2002). Subcortical aphasia and neglect in acute stroke: The role of cortical hypoperfusion. Brain 125: 1094–1104. Husain M, Kennard C (1997). Distractor-dependent frontal neglect. Neuropsychologia 35: 829–841. Husain M, Mannan S, Hodgson T, et al. (2001). Impaired spatial working memory across saccades contributes to abnormal search in parietal neglect. Brain 124: 941–952. Husain M, Mattingley JB, Rorden C, et al. (2000). Distinguishing sensory and motor biases in parietal and frontal neglect. Brain 123: 1643–1659. Husain M, Rorden C (2003). Non-spatially lateralized mechanisms in hemispatial neglect. Nat Rev Neurosci 4: 26–36. Husain M, Shapiro K, Martin J, et al. (1997). Abnormal temporal dynamics of visual attention in spatial neglect patients. Nature 385: 154–156. Jehkonen M, Ahonen JP, Dastidar P, et al. (2000). Visual neglect as a predictor of functional outcome one year after stroke. Acta Neurol Scand 101: 195–201. Kalra L, Perez I, Gupta S, et al. (1997). The influence of visual neglect on stroke rehabilitation. Stroke 28: 1386–1391. Kaplan RF, Verfaellie M, Meadows ME, et al. (1991). Changing attentional demands in left hemispatial neglect. Arch Neurol 48: 1263–1266. Karnath H, Ferber S, Himmelbach M (2001). Spatial awareness is a function of the temporal not the posterior parietal lobe. Nature 411: 950–953. Karnath H-O (1995). Transcutaneous electrical stimulation and vibration of neck muscles in neglect. Exp Brain Res 105: 321–324. Karnath H-O (1997). Spatial orientation and the representation of space with parietal lobe lesions. Philos Trans R Soc Lond B Biol Sci 352: 1411–1419. Karnath HO, Christ K, Hartje W (1993). Decrease of contralateral neglect by neck muscle vibration and spatial orientation of trunk midline. Brain 116: 383–396. Karnath HO, Fruhmann Berger M, Kuker W, et al. (2004). The anatomy of spatial neglect based on voxelwise statistical analysis: A study of 140 patients. Cereb Cortex 14: 1164–1172. Karnath H-O, Himmelbach M, Rorden C (2002a). The subcortical anatomy of human spatial neglect: Putamen, caudate nucleus and pulvinar. Brain 125: 350–360. Karnath H-O, Milner AD, Vallar G (2002b). The Cognitve and Neural Bases of Spatial Neglect. Oxford University Press, Oxford. Karnath HO, Schenkel P, Fischer B (1991). Trunk orientation as the determining factor of the ‘contralateral’ deficit in the neglect syndrome and as the physical anchor of the internal representation of body orientation in space. Brain 114: 1997–2014. Kerkhoff G (2001). Spatial hemineglect in humans. Prog Neurobiol 63: 1–27. Kinsbourne M (1993). Orientational bias model of unilateral neglect: Evidence from attentional gradients within hemispace. In: IH Robertson, JC Marshall (Eds.), Unilateral

Neglect: Clinical and Experimental Studies. Lawrence Erlbaum, Hove, pp. 63–86. Laplane D, Degos JD (1983). Motor neglect. J Neurol Neurosurg Psychiatry 46: 152–158. Losier BJ, Klein RM (2001). A review of the evidence for a disengage deficit following parietal lobe damage. Neurosci Biobehav Rev 25: 1–13. Malhotra P, Greenwood R, Husain M (2004a). The diagnosis of spatial neglect in acute stroke. J Neurol Neurosurg Psychiatry 75: 521. Malhotra P, Jager HR, Parton A, et al. (2005). Spatial working memory capacity in unilateral neglect. Brain 128: 424–435. Malhotra P, Mannan S, Driver J (2004b). Impaired spatial working memory: One component of the visual neglect syndrome? Cortex 40: 667–676. Mannan S, Mort D, Hodgson T, et al. (2005). Revisiting previously searched locations in visual neglect: Role of right parietal and frontal lesions in misjudging old locations as new. J Cogn Neurosci 17: 340–354. Maravita A, McNeil J, Malhotra P, et al. (2003). Prism adaptation can improve contralesional tactile perception in neglect. Neurology 60: 1829–1831. Mattingley JB (2002). Spatial extinction and its relation to mechanisms of normal attention. In: H-O Karnath, AD Milner, G Vallar (Eds.), The Cognitive and Neural Bases of Spatial Neglect. Oxford University Press, Oxford, pp. 289–309. Mattingley JB, Husain M, Rorden C, et al. (1998). Motor role of human inferior parietal lobe revealed in unilateral neglect patients. Nature 392: 179–182. McFie J, Piercy MF, Zangwill OL (1950). Visual–spatial agnosia associated with lesions of the right cerebral hemisphere. Brain 73: 167–190. McIntosh RD, Brodie EE, Beschin N, et al. (2000). Improving the clinical diagnosis of personal neglect: A reformulated comb and razor test. Cortex 36: 289–292. McIntosh RD, Rossetti Y, Milner AD (2002). Prism adaptation improves chronic visual and haptic neglect: A single case study. Cortex 38: 309–320. Mesulam M-M (1985). Principles of Behavioural Neurology. Tests of Directed Attention and Memory. Davis, Philadelphia. Mesulam M-M (1999). Spatial attention and neglect: Parietal, frontal and cingulate contributions to the mental representation and attentional targeting of salient extrapersonal events. Philos Trans R Soc Lond B Biol Sci 354: 1325–1346. Mort DJ, Malhotra P, Mannan SK, et al. (2003). The anatomy of visual neglect. Brain 126: 1986–1997. Mort DJ, Malhotra P, Mannan SK, et al. (2004). Reply to: Using SPM normalization for lesion analysis in spatial neglect. Brain 127: E11. Muller-Oehring EM, Kasten E, Poggel DA, et al. (2003). Neglect and hemianopia superimposed. J Clin Exp Neuropsychol 25: 1154–1168. Nys GM, van Zandvoort MJ, de Kort PL, et al. (2005). The prognostic value of domain-specific cognitive abilities in acute first-ever stroke. Neurology 64: 821–827.

HEMISPATIAL NEGLECT Patterson A, Zangwill O (1944). Disorders of visual space perception associated with lesions of the right cerebral hemisphere. Brain 67: 331–358. Pavani F, Husain M, Ladavas E, et al. (2004). Auditory deficits in visuospatial neglect patients. Cortex 40: 347–365. Peers PV, Ludwig CJ, Rorden C, et al. (2005). Attentional functions of parietal and frontal cortex. Cereb Cortex 15: 1469–1484. Perani D, Vallar G, Cappa S, et al. (1987). Aphasia and neglect after subcortical stroke. A clinical/cerebral perfusion correlation study. Brain 110: 1211–1229. Pisella L, Berberovic N, Mattingley JB (2004). Impaired working memory for location but not for colour or shape in visual neglect: A comparison of parietal and non-parietal lesions. Cortex 40: 379–390. Pizzamiglio G, Judica A, Razzano C, et al. (1989). Toward a comprehensive diagnosis of visual–spatial disorders in unilateral brain-damaged patients. Psychol Assess 5: 199–218. Posner MI, Walker JA, Friedrich FJ, et al. (1984). Effects of parietal injury on covert orienting of attention. J Neurosci 1984: 1863–1874. Rafal RD (1994). Neglect. Curr Opin Neurobiol 4: 231–236. Rees G (2001). Neuroimaging of visual awareness in patients and normal subjects. Curr Opin Neurobiol 11: 150–156. Rizzolatti G, Berti A, Gallese V (2002). Spatial neglect: Neurophysiological bases, cortical circuits and theories. In: G Rizzolatti, (Ed.), Handbook of Neuropsychology, Vol 1. Elsevier, Amsterdam, pp. 503–537. Robertson IH (2001). Do we need the ‘lateral’ in unilateral neglect? Spatially nonselective attention deficits in unilateral neglect and their implications for rehabilitation. Neuroimage 14: S85–S90. Robertson IH, Halligan PW (1999). Spatial Neglect: A Clinical Handbook for Diagnosis and Treatment. Psychology Press, Hove. Robertson IH, Hogg K, McMillan TM (1998a). Rehabilitation of unilateral neglect: Improving function by contralesional limb activation. Neuropsychol Rehabil 8: 19–29. Robertson IH, Manly T, Beschin N, et al. (1997). Auditory sustained attention is a marker of unilateral spatial neglect. Neuropsychologia 35: 1527–1532. Robertson IH, Marshall JC (1993). Unilateral Neglect: Clinical and Experimental Studies. Lawrence Erlbaum, Hove. Robertson IH, Mattingley JB, Rorden C, et al. (1998b). Phasic alerting of neglect patients overcomes their spatial deficit in visual awareness. Nature 395: 169–172. Robertson IH, North N (1992). Spatio-motor cueing in unilateral left neglect: The role of hemispace, hand and motor activation. Neuropsychologia 30: 553–563. Robertson IH, North N (1993). Active and passive activation of left limbs: Influence on visual and sensory neglect. Neuropsychologia 31: 293–300. Robertson IH, Tegner R, Tham K, et al. (1995). Sustained attention training for unilateral neglect: Theoretical and rehabilitation implications. J Clin Exp Neuropsychol 17: 416–430.

371

Robertson LC, Lamb MR, Knight RT (1988). Effects of lesions of temporal–parietal junction on perceptual and attentional processing in humans. J Neurosci 8: 3757–3769. Rode G, Rossetti Y, Boisson D (2001). Prism adaptation improves representational neglect. Neuropsychologia 39: 1250–1254. Rode G, Rossetti Y, Li L, et al. (1998). Improvement of mental imagery after prism exposure in neglect: A case study. Behav Neurol 11: 251–258. Rossetti Y, Rode G, Pisella L, et al. (1998). Prism adaptation to a rightward optical deviation rehabilitates left hemispatial neglect. Nature 395: 166–169. Rubens AB (1985). Caloric stimulation and unilateral visual neglect. Neurology 35: 1019–1024. Russell C, Malhotra P, Husain M (2004). Attention modulates the visual field in healthy observers and parietal patients. Neuroreport 15: 2189–2193. Samuelsson H, Hjelmquist E, Jensen C, et al. (1998). Nonlateralized attentional deficits: An important component behind persisting visuospatial neglect? J Clin Exp Neuropsychol 20: 73–88. Schindler I, Kerkhoff G, Karnath H-O, et al. (2002). Neck muscle vibration induces lasting recovery in spatial neglect. J Neurol Neurosurg Psychiatry 73: 412–419. Smania N, Martini MC, Gambina G, et al. (1998). The spatial distribution of visual attention in hemineglect and extinction patients. Brain 121: 1759–1770. Smith A, Nutt D (1996). Noradrenaline and attention lapses. Nature 380: 291. Starkstein SE, Fedoroff JP, Price TR, et al. (1992). Anosognosia in patients with cerebrovascular lesions. A study of causative factors. Stroke 23: 1446–1453. Stone SP, Patel P, Greenwood RJ, et al. (1992). Measuring visual neglect in acute stroke and predicting its recovery: The visual neglect recovery index. J Neurol Neurosurg Psychiatry 55: 431–436. Stone SP, Wilson B, Wroot A, et al. (1991). The assessment of visuo-spatial neglect after acute stroke. J Neurol Neurosurg Psychiatry 54: 345–350. Takahashi N, Kawamura M (2002). Pure topographical disorientation—the anatomical basis of landmark agnosia. Cortex 38: 717–725. Tilikete C, Rode G, Rossetti Y, et al. (2001). Prism adaptation to rightward optical deviation improves postural imbalance in left-hemiparetic patients. Curr Biol 11: 524–528. Vallar G (2001). Extrapersonal visual unilateral spatial neglect and its neuroanatomy. Neuroimage 14: S52–S58. Vallar G, Bottini G, Sterzi R (2003). Anosognosia for leftsided motor and sensory deficits, motor neglect, and sensory hemiinattention: is there a relationship? Prog Brain Res 142: 289–301. Vallar G, Perani D (1986). The anatomy of unilateral neglect after right-hemisphere stroke lesions. A clinical/CT-scan correlation study in man. Neuropsychologia 24: 609–622. Vallar G, Rusconi ML, Barozzi S, et al. (1995). Improvement of left visuo-spatial hemineglect by left-sided transcutaneous electrical stimulation. Neuropsychologia 33: 73–82.

372

M. HUSAIN

Vandenberghe R, Geeraerts S, Molenberghs P, et al. (2005). Attentional responses to unattended stimuli in human parietal cortex. Brain 128: 2843–2857. Vuilleumier P, Valenza N, Mayer E, et al. (1998). Near and far visual space in unilateral neglect. Ann Neurol 43: 406–410. Weinberg J, Diller L, Gordon WA, et al. (1977). Visual scanning training effect on reading-related tasks in acquired right brain damage. Arch Phys Med Rehabil 58: 479–486. Williams GV, Goldman-Rakic PS (1995). Modulation of memory fields by dopamine D1 receptors in prefrontal cortex. Nature 376: 572–575. Wilson B, Cockburn J, Halligan PW (1987). Behavioural Inattention test. Thames Valley, Bury St. Edmunds.

Wojciulik E, Husain M, Clarke K, et al. (2001). Spatial working memory deficit in unilateral neglect. Neuropsychologia 39: 390–396. Wojciulik E, Rorden C, Clarke K, et al. (2004). Group study of an ‘undercover’ test for visuospatial neglect: Invisible cancellation can reveal more neglect than standard cancellation. J Neurol Neurosurg Psychiatry 75: 1356–1358. Zeloni G, Farne A, Baccini M (2002). Viewing less to see better. J Neurol Neurosurg Psychiatry 73: 195–198. Zoccolotti P, Judica A (1991). Functional evaluation of hemineglect by means of a semistructured scale: Personal extrapersonal differentiation. Neuropsychol Rehabil 1: 33–34.

Handbook of Clinical Neurology, Vol. 88 (3rd series) Neuropsychology and behavioral neurology G. Goldenberg, B.L. Miller, Editors # 2008 Elsevier B.V. All rights reserved

Chapter 19

Visuospatial and visuoconstructive deficits LUIGI TROJANO* AND MASSIMILIANO CONSON Neuropsychology Laboratory, Department of Psychology, Second University of Naples, Caserta, Italy

19.1. Operational definitions The knowledge of spatial location of one’s own body is the prerequisite of any action: to get around through city streets, to do any manual job, to play any sport would be impossible without a spatial processing system. Although this concept is intuitive, conceptualization and scientific investigation of spatial competences are less straightforward. Actually, exhaustive and widely accepted theories for visuospatial processes, and for more complex spatial activities, such as drawing, have not yet developed. For this reason research in the field resorts to operational definitions that most often do not explicitly refer to a specific theoretical framework. In this chapter we will first outline operational definitions of visuospatial and visuoconstructive disturbances. Then we will present clinical and experimental findings regarding visuospatial and constructional disorders, and their possible relationships. Moreover, we will outline available cognitive models and some relevant neuroimaging findings aimed at comprehending the mechanisms of constructional disabilities. Last, we will offer a brief description of several constructional phenomena quite frequent in clinical practice.

19.1.1. Visuospatial disturbances Visuospatial abilities can be intended as those highorder, non-verbal cognitive abilities which operate upon perceptual stimuli and mental images and allow individuals to interact with the environment. Although this definition is prima facie acceptable, it remains quite vague: it does not clarify what visuospatial processes are and is not capable of identifying ‘pure’ visuospatial defects. From an operational point of view, *

De Renzi (1982) suggested using the term spatial perception in reference to elementary processing stages, while the term spatial cognition could designate more complex mental abilities requiring the use of mental (‘internal’) representations. Examples of spatial perception processes are those that allow location of points in space, and appreciation of dimensions, orientation, or distance of an object, while examples of spatial cognition abilities are recognition of shapes, maze learning, or mental rotation (De Renzi, 1982). In clinical practice, only some aspects of visuospatial processing are usually assessed, often limited to the bidimensional space defined by a sheet of paper or a computer screen. The most used test to assess visuospatial abilities is the judgment of line orientation test (JLOT), in which subjects are required to identify, among several alternatives, the lines that are at the same orientation as those presented as stimuli (Benton et al., 1975). Other visuospatial tasks are enclosed in the Visual Object and Space Perception battery (VOSP; Warrington and James, 1991): position discrimination tasks (to judge whether a dot in a square occupies the same position as in the target square, and to identify the location occupied by a digit in a square), and a task assessing spatial ‘representational’ skills (to count the number of cubes embedded in complex three-dimensional figures). These, and other similar tasks, have been included in a computerized assessment procedure (Kerkhoff and Marquardt, 1998). A set of eight visuospatial tasks, adapted from several experimental paradigms, is enclosed in the Battery for Visuospatial Abilities (BVA, known in Italy as TERADIC; Angelini and Grossi, 1993; Trojano et al., 2004), which taps both simple ‘perceptual’ and complex ‘representational’ visuospatial abilities. The four ‘perceptual’ tasks

Correspondence to: Luigi Trojano, Neuropsychology Labotatory, Second University of Naples, Via Vivaldi 43, 81100 Caserta, Italy. E-mail: [email protected], Tel/Fax: þ39-0823-274774.

374

L. TROJANO AND M. CONSON

enclosed in the battery are: line length and line orientation judgments, angle width judgment, point position discrimination. The four ‘representational’ tasks are: mental rotation task, recognition of nonsense shapes, identification of geometric patterns embedded in complex figures, mental construction. All these tasks but one have the format of fourchoice recognition, and subjects have to point to the only item identical to the stimulus, without time constraints. The mental construction task has a different arrangement: the display shows four subcomponents of the stimulus and subjects are required to identify with which side the four components are contiguous in the stimulus. All such tests share the need for spatial processing and minimize requirements of verbal processing, but their development and choice remain quite arbitrary. Often patients fail more than one single visuospatial test, but even in this case the specific consequences of these defective performances on more complex visuospatial skills (e.g., drawing) are not clear-cut. In other terms, it is not clear whether failure on some spatial tests may configure specific clinical syndromes. Before going on to characterize clinical pictures in which visuospatial processes are specifically impaired, it is important to underline that visuospatial disorders have to be distinguished from other defects of visual processing. First, although elementary visual sensory defects may impair performances on several visual tasks (Kempen et al., 1994), they are not sufficient to determine ‘high-order’ visuospatial defects (Ratcliffe and Ross, 1981). At least some visuospatial abilities (e.g., location and orientation senses) rely on specialized neural structures (Westheimer, 1996). Second, selective disorders of visual recognition are doubly dissociated from disorders of space perception. Patients who cannot recognize well-known faces, places or familiar objects by their visual appearance usually perform well on spatial perceptual and representational tests (Farah, 2003). In particular, patients with visual agnosia for objects may fail to recognize an item but can depict it and copy drawings correctly, although with a painstaking and slow procedure (see below). On the contrary, patients affected by several kinds of spatial disorders usually can identify objects they cannot reach or draw. This double dissociation represents the strongest clinical evidence supporting the distinction between two visual pathways: the ‘ventral’ occipitotemporal pathway would mainly be involved in visual object recognition, while the ‘dorsal’ occipitoparietal pathway would be devoted to visuospatial processing (Ungerleider and Mishkin, 1982). Third, different kinds of spatial impairments may dissociate from each other. The prototypical clinical picture

in which different kinds of spatial disorders occur in association is the Ba´lint–Holmes syndrome (Ba´lint, 1909; Holmes, 1918). The full clinical presentation of the syndrome (see Chapter 20 for a in-depth discussion) includes the inability to perceive more than one object at a time (simultanagnosia), to shift gaze voluntarily to objects of interest despite preserved reflex saccadic eye movements (psychic paralysis of gaze, or gaze apraxia), and to reach out objects under visual guidance despite normal limb strength (optic ataxia). However, Ba´lint–Holmes syndrome does not meet all the criteria of a syndrome; the operational definition of the different components vary across studies and the main symptoms are represented by broad categories that underlie more specific defects (Rizzo and Vecera, 2002). Moreover, the different components of the syndrome are frequently reported in isolation; disorders of the voluntary control of eye movement are the least common and most transient aspects of the syndrome (Coslett and Chatterjee, 2003), while simultanagnosia or optic ataxia are doubly dissociable (Damasio et al., 2000). Simultanagnosia has been interpreted in terms of an impaired disengagement of attention (Rizzo and Vecera, 2002), although more recent reports underline the complex interactions between oculomotor control and restriction of the attentional focus (Nyffeler et al., 2005). Optic ataxia is particularly relevant for the present issue, because reaching objects is an exquisite spatial behavior. Even within this specific field, there is some variability: whereas some patients show misreaching with only one hand in one side of space other patients show the deficit with both hands in both sides of space (De Renzi, 1982). Since patients usually exhibit adequate reaching towards targets in the center of the visual field and misreach peripheral targets, the traditional interpretation of the phenomenon in terms of a generic disconnection of motor and spatial systems needs further refinement (Coslett and Chatterjee, 2003). Several studies have shown that patients with optic ataxia not only have difficulty reaching in the correct direction, but they also show deficits in their ability to adjust the orientation of their hand when reaching toward an object, even though they have no difficulty in verbally describing the orientation of the object (Perenin and Vighetto, 1988). Such patients are also unable to adapt their grasp to the size of an object they are asked to pick up, although their perceptual estimates of object size remain quite accurate (Goodale et al., 1993). Taken together, these findings would suggest that the deficits in these patients cannot be described in terms of a defect of spatial vision (Goodale and Humphrey, 1998). These findings led to a reconsideration of the classical view of the dual visual pathways, since they are more consistent with the idea that the two neural pathways

VISUOSPATIAL AND VISUOCONSTRUCTIVE DEFICITS differ in the operations performed upon visual information (Goodale and Milner, 1992). Both streams process information about object features and their spatial locations, but whereas the ventral stream uses visual information to extract viewer-independent (allocentric) properties of environment and to identify objects (‘vision-for-perception’), the dorsal stream uses such visual information to represent object location in egocentric coordinates to plan reaching movements (‘vision-for-action’; Goodale et al., 2004). This interpretative framework would fit with the observation that optic ataxia has often been ascribed to lesions of the superior parietal lobule (SPL) and the intraparietal sulcus, although such a direct relationship has been recently challenged (Karnath and Perenin, 2005). However, it has to be underlined that visual cognition, and in particular visuospatial processing, is far more complex than a dual-route model can accommodate (Rizzolatti and Matelli, 2003; Jeannerod and Jacob, 2005), and that the range of spatial computations we address in the present chapter are distinct from visually guided reaching. Actually, as it has been already mentioned, patients with selective optic ataxia can perform visuospatial perceptual tasks without relevant errors, and defects of spatial perception and representation may occur in the absence of defects of visuomotor coordination. For instance, a patient with bilateral posterior cortical atrophy (Stark et al., 1996) failed at all spatial subtests of the VOSP, and in copying figures, but did not show disorders of low-level visual perception, space exploration, or spatially guided reaching. The authors suggested that the visuospatial defect in their patient disrupted the elaboration of a three-dimensional supramodal spatial representation in an egocentric coordinate system (Stark et al., 1996). Within this context, representation related to different spatial axes may dissociate. Actually, in another patient with primary degenerative dementia the ability to code spatial relationships along the horizontal axis was selectively impaired, with the appreciation of vertical and radial dimensions being spared (e.g., the patient was able to discriminate and copy vertical but not horizontal segments correctly), independently from visual exploration or eye movement disorders (Grossi et al., 1998). However, conditions in which a specific visuospatial defect may be held responsible for a certain clinical picture have been rarely reported. 19.1.2. Visuoconstructional disturbances The specific inability to construct a complex object, arranging its component elements in their correct spatial relationships, was recognized by Kleist (1934). According to Kleist, this syndrome, called ‘constructional

375

apraxia’ (CA), was related to ‘a disturbance in the activities of drawing, assembling and building, in which the spatial form of the product proves to be unsuccessful without there being an apraxia for single movements.’ Kleist proposed that CA derived from ‘an alteration in the connections between visual functions, that is visuospatial, and the kinetic engrams that control manual activity,’ thus distinguishing it from motor planning disorders (e.g., ideomotor apraxia) and elementary visuoperceptual deficits (Kleist, 1934). However, in subsequent years, it gradually became customary to use the term irrespective of the putative nature of the disorder. In other words, Kleist’s original definition has been substantially ignored and CA is used as a single diagnostic category which operationally identifies all disturbances observed during drawing, assembling, and building complex models (Gainotti, 1985). However, these activities cannot be considered equivalent: some researchers have noted a significant correlation between drawing, three-dimensional object construction, and visuospatial tasks (Arrigoni and De Renzi, 1964) in focal brain-damaged patients, but other studies have yielded contrasting data (e.g., Benton and Fogel, 1962). Furthermore, cases of patients who fail at graphomotor tasks but not at three-dimensional constructional tasks and vice versa have also been reported (Dee, 1970; Kashiwagi et al., 1994). CA is a neuropsychological symptom which is easily recognizable even at the patient’s bedside, and frequently observed in brain damaged patients. In clinical practice, constructional abilities may be assessed by asking the patient to assemble a two-dimensional model by arranging component elements (e.g., sticks) in given spatial relationships (Benson and Barton, 1970). The block design subtest of the WAIS (Wechsler, 1981)— where the person has to reconstruct a two-dimensional pattern using multicolored cube faces—is used for the same purpose, yet it is perhaps the clearest example of how a constructional test taps attentional, planning, and visuospatial perceptual and motor mechanisms. Three-dimensional constructional tasks (Benton and Fogel, 1962; Trojano et al., 1997) are used seldom, because only a few researchers recommend testing both two- and three-dimensional constructional competence (Benton, 1989). Drawing tasks are those most widely used to assess constructional abilities, but, unlike the above-mentioned tests, they rely on graphomotor skills. Not even copying and free drawing can be considered equivalent. Free drawing, or drawing from memory—in which the patient is asked to draw a named object (e.g., a clock, a face and so on)—is perhaps the most immediate test of constructional skills (Fig. 19.1). It reveals information about the patient’s ability to draw complete shapes or a tendency

376

L. TROJANO AND M. CONSON brain-damaged patients and in right brain-damaged patients, and were likely due to lexical–semantic deficits rather than to visual–constructional disorders. Similarly, Grossman (1988) observed that brain-damaged patients may fail in associating shape with appropriate size when drawing single objects, revealing a disorder not purely constructional in nature. For this reason, drawing from memory has been recently used as a sensitive nonverbal way of assessing peoples’ knowledge about concepts. Of course, this is possible in presence of sufficient premorbid drawing skills and when subjects are not affected by relevant constructional disturbances; even in these cases, however, specific scoring techniques are needed that focus on the content of each drawing and minimize the influence of drawing skills (Bozeat et al., 2003). Copying tasks directly assess the patient’s ability to reproduce a figure. Simple shapes, e.g., circles and squares, or complex designs, e.g., the Rey–Osterreith Complex Figure (ROCF; Osterreith, 1944), can be used for assessing constructional abilities (Figs. 19.2–19.4), but for diagnosis of CA it is crucial to adopt a standardized task, since copying tasks are affected by age, educational level, and even cultural background (see Rosselli and Ardila, 2003 for a review).

19.2. Constructional disturbances in clinical neurology 19.2.1. Visuospatial and visuoconstructional deficits in focal brain lesions

Fig. 19.1. Drawing a clock face on an empty circle. (A,B) Drawings by left focal brain-damaged patients often show loss of semantic knowledge or simplification of hour position. Typically, drawings by right brain-damaged patients show left-sided omissions (C) or allochiria (D). (E–H) Drawings by demented patients usually show planning errors, perseverations, simplifications, and gross alterations due to loss of semantic knowledge.

to omit parts and ability to organize the figure as a whole, with its component elements in their correct spatial relationships (for a detailed analysis of clock drawing, see Freedman et al., 1994). Even so, this task does not easily lend itself to standardization and relies on nonconstructional cognitive abilities, in terms particular on lexical– semantic knowledge and imagery abilities (see Trojano and Grossi, 1994, for a discussion). Gainotti et al., (1983) demonstrated that free drawing abilities were more compromised in aphasics than in non-aphasic left

It is often maintained that the right hemisphere is specialized in visuospatial processing, but findings on traditional tasks in brain-lesioned patients are not so clearcut as might be expected. A specific defect of right brain-damaged patients (RBD) on the JLOT has been repeatedly reported (see Hamsher et al., 1992), but in most studies no effort was made to disentangle the contribution of defective visual exploration (unilateral spatial neglect, see Chapter 18). Mehta et al. (1987) and Mehta and Newcombe (1991) demonstrated that, if patients affected by overt defects of visual exploration or of general intelligence are excluded, left braindamaged patients (LBD) achieve defective performances on an orientation judgment task, while RBD patients are impaired in an angle matching task with respect to normal controls. A recent study, in which line orientation judgments have been assessed in RBD and LBD not affected by unilateral spatial neglect or aphasia, has confirmed the trend of RBD to achieve scores lower than LBD on the JLOT, but without significant differences between the two groups (Ng et al., 2000). A specific study on the JLOT (Treccani et al., 2005) has confirmed that RBD and LBD achieve similar results, if RBD with neglect are not considered for the analysis.

VISUOSPATIAL AND VISUOCONSTRUCTIVE DEFICITS

377

Fig. 19.2. Copying of geometrical drawings: cube (model on the top). Drawings by left brain-damaged patients (first row) usually show simplifications and distortions, but with relatively spared spatial relationships; very rare are right-sided omissions (on the right). Drawings by right brain-damaged patients (second row) usually show left-sided omissions and frequent visuospatial defects. Drawings by demented patients (lower rows) show gross spatial distortions, perseverations, errors of perspective, simplifications, and different forms of closing-in (bottom figures).

Treccani et al. (2005) demonstrated also that the JLOT comprises lines on the left side that are easier to judge than lines on the right, suggesting that stimuli might add a spatial bias in performance of LBD and RBD. In line with these observations, a different line orientation test, included in the BVA, did not reveal significant differences in LBD and RBD matched for general intellectual abilities, and not affected by space exploration defects (Trojano et al., 2004). Therefore, in the absence of neglect, performance of RBD and LBD might not be overtly different on line orientation processing tasks.

Performances on perceptual spatial location tasks have also been related to right hemisphere processes (Warrington and Rabin, 1970; Hannay et al.,1976), but again, once patients with space exploration disorders are excluded, RBD and LBD might not show reliable differences (Trojano et al., 2004). In a specific study on position discrimination in LBD and RBD with posterior lesions, Postma et al. (2000) did not find differences between the two patient groups that were both impaired with respect to normal controls. Only more demanding task conditions (e.g., no visibility of visual

378

L. TROJANO AND M. CONSON

Fig. 19.3. Copying of geometrical drawings: novel figure (model on the top). Simplifications and distortions in drawings by left brain-damaged patients (first row); left-sided omissions and gross visuospatial defects in drawings by right brain-damaged patients (second row). Drawings by demented patients (lower rows) may show gross spatial distortions, perseverations, simplifications, and closing-in (right bottom figure).

background), particularly if combined with the requirement of a motor response, could elicit a larger impairment in RBD with respect to LBD. Analogous considerations about hemispheric lateralization apply to constructional disorders. Kleist’s original work (1934) drew attention to a link between CA and dominant parietal lesions, but early studies on broader samples of patients with focal lesions demonstrated that

CA seemed to be more prevalent and severe in RBD than in LBD (see Piercy et al., 1960; Piercy and Smyth, 1962; Warrington et al., 1966). Other studies, however, attributed the higher incidence of CA in RBD patients to severity of the lesion (Arrigoni and De Renzi, 1964) or to neglect errors (Gainotti and Tiacci, 1970). In fact, more recent studies, which have controlled these variables, demonstrate a similar prevalence of CA following

VISUOSPATIAL AND VISUOCONSTRUCTIVE DEFICITS

379

Fig. 19.4. Copying of Rey complex figure (model on the top). Drawings by left brain-damaged patients (upper row), by right brain-damaged patients without hemineglect but with gross visuospatial defects (second row), and by demented patients (lower row). Note in the right bottom figure that the reproduction of the single subcomponents is relatively spared, but spatial relationships among them are lost.

lesions to either hemisphere (Villa et al., 1986; Kirk and Kertesz, 1989; Carlesimo et al., 1993; Trojano et al., 2004), giving less weight to the ‘dominant right hemisphere’ hypothesis and reinforcing the idea that there could be qualitative differences in CA between the two groups of brain-damaged patients. Duensing (1953) was the first to maintain that RBD patients failed at copying tasks because of defective visuospatial mechanisms (a spatial agnosic form of

CA), whilst LBD patients were affected by an ideational form of CA. This hypothesis was triggered by the observation that right brain-damaged patients tend to produce drawings with wrong orientation and disorganized spatial relationships between component parts, whilst patients with left-sided lesions tend to simplify the model, omitting some details but preserving the original spatial relationships. Numerous studies have confirmed these characteristics in the drawings of brain-damaged

380

L. TROJANO AND M. CONSON

patients (see Gainotti and Tiacci, 1970), although many patients do not conform to this general rule (Figs. 19.2–19.4). The majority of the following studies revealed comparable visuospatial disorders in patients with rightand left-sided lesions, while the presence of a specific executive disorder or motor programming deficit in left hemisphere apraxic patients has not been demonstrated consistently (see Gainotti, 1985). To demonstrate interhemispheric differences in the mechanisms of CA, several experiments have tried to identify skills that correlate with constructional performance in one patient group but not in the other. Kirk and Kertesz (1989), for instance, noted that performance on a free drawing task correlated strongly with scores on a visuoperceptual task in RBD patients whilst correlating more strongly with tests of verbal comprehension and severity of hemiparesis in the left hemisphere group. Kirk and Kertesz concluded that CA can originate from a visuospatial deficit in RBD patients while it could be linked to semantic or elementary motor disorders in LBD patients. A study on a copying task (Carlesimo et al., 1993) confirmed these conclusions only partially: drawing ability in RBD patients was correlated significantly with a spatially guided motor task (a tracking task in which patients had to follow a track with a pencil), and only marginally with a line orientation test; on the other hand, constructional performance correlated strongly with performance on a simple motor task (tapping) in LBD patients. The authors suggested that the basic disturbance in right hemisphere apraxics may ascribed to an impaired ability to carry out spatial manipulations more than to a visuospatial deficit, whilst in LBD patients a disorder at the elementary motor level (and in particular the lack of deftness in patients drawing with their left, non-preferred hand) could play a more crucial role. The most recent study aimed at verifying whether constructional disabilities are correlated with different cognitive mechanisms in patients with focal brain lesions (Trojano et al., 2004) demonstrated that, when patients with general intellectual deficits or space exploration defects are excluded, LBD and RBD do not differ in their performance on the ROCF copying test. However, drawing accuracy was significantly correlated with scores on some spatial perceptual and representational tests of the BVA in RBD, but not in LBD patients. Therefore, it seems possible to retain the lateralization hypothesis only in a ‘weak’ version. In RBD patients, a deficit in visuospatial analysis appears to predominate, whilst in left-lesioned patients visuoconstructional disabilities probably have more complex origins—in movement planning disorders, but also in general intellectual deficits or disorders of visuospatial analysis (De Renzi, 1980).

As regards the intrahemispheric locus of CA, it is generally accepted that CA is more frequently associated with parieto-occipital lesions (De Renzi, 1982), although it can also be observed in patients with frontal lesions. Severity of constructional disturbances does not seem to differ in patients with anterior or posterior lesions (Black and Bernard, 1984). As in the case of the left–right issue, it has been argued that lesions with different intrahemispheric loci give rise to qualitatively different types of constructional disabilities. Luria and Tsvetkova (1964), for example, proposed that CA in patients with posterior lesions (parieto-occipital) is caused by a defect in the analysis of spatial relations whilst a deficit in movement planning could underlie CA of frontal lesion origin. A series of studies seemed to confirm, on the one hand, the role of caudal regions in visuospatial analysis and, on the other hand, the role of the frontal lobes in the programming of drawing (Pillon, 1981; see Gainotti, 1985, for a review). However, subsequent studies failed to support the crucial role of intrahemispheric localization in determining the nature of CA (e.g., Kirk and Kertesz, 1989). Subcortical structures do contribute to the drawing process and it is possible to observe selective constructional defects after a single right subcortical lesion (Grossi et al., 1996). No distinctive features seem to characterize constructional disorders of subcortical origin (Kirk and Kertesz, 1993), but Marshall et al. (1994) observed in a series of patients with focal right hemisphere damage that subcortical anterior lesions gave rise to a disability, regardless of the presence or absence of neglect while constructional disabilities were, as a rule, associated with neglect in the case of posterior lesions. 19.2.2. Constructional apraxia in dementia Some clinical and experimental studies attributed a causal role in the genesis of constructional disabilities to general intellectual deterioration in patients with focal brain damage, because apraxic patients often show intellectual abilities which are inferior to those of non-apraxic patients with focal lesions (Arrigoni and De Renzi, 1964). Adding weight to the argument, other studies have noted that constructional disorders represent an index for diffuse cognitive deterioration, both in left (Borod et al., 1982) and right (Benowitz et al., 1990) brain-damaged patients. On the other hand, CA is considered one of the most common behavioral alterations in different kinds of dementia. In principle, constructional disorders in these cases might be ascribed to the failure of visuospatial processing, but also to an impairment of planning and logical abstractive abilities, since constructional tasks,

VISUOSPATIAL AND VISUOCONSTRUCTIVE DEFICITS particularly those implying new or complex models, can be considered as sort of problem solving tasks. In the course of Alzheimer’s disease (AD) CA has been described from the early stages of the disease, with increasing severity as the illness progresses (Ajuriaguerra et al., 1960). An attempt at a systematic description of AD patients’ errors in a free drawing task (Kirk and Kertesz, 1991) has shown the frequent occurrence of simplifications, spatial alterations, and lack of perspective (Fig. 19.1). Patients’ scores did not correlate with performance on language or memory tests, suggesting that constructional disabilities develop relatively independently during the course of the illness; in fact, individual patients may not show constructional disabilities even in the advanced stages of AD (Denes and Semenza, 1982). However, free drawing poses a heavy load on semantic memory, and errors on this task (e.g., simplifications in drawing a house) may derive from impaired access to semantic knowledge or to impaired visuoperceptual processing (Grossman et al., 1996). For this reason, spontaneous drawing could be impaired in the early stages of AD, while copying may deteriorate later (Rouleau et al., 1996). The reproduction of complex figures is particularly sensitive to the progression of the disease (Binetti et al., 1998). For instance, the ROCF may be reproduced in a simplified way, with single constitutive elements put one after the other, even in early AD (Fig. 19.4). In these cases patients seem to be able to recognize and reproduce single well-known elements (as if they resorted to motor subroutines stored in a specialized long-term memory store—a sort of constructional lexicon) but are unable to reproduce complex spatial relationships correctly. Another ‘simplification’ error may consist in the reproduction of more familiar or simpler figures instead of more complex ones (e.g., a square instead of a diamond; see Fig. 19.2). As the disease progresses, patients usually become unable even to draw simple figures correctly, as they no longer had access to well-consolidated motor subroutines. The constructional impairment in AD patients may stem from different cognitive mechanisms. Binetti et al. (1998) found that whereas object perception was impaired from the early stages of the disease, a specific spatial impairment became evident only later, at a moderate level of severity. Moreover, the authors found a strict relation between the progression of visuoperceptual spatial impairment, measured on the spatial tasks of the VOSP, and the progressive deterioration of the performance on copying the ROCF. Gue´rin et al. (2002) examined the cognitive mechanisms underlying the constructional performance of AD patients at different stages of the disease by means of a copying task and of visuospatial tasks measuring spatial exploration

381

(visual search tasks), judgment of spatial relations, and planning abilities. The results suggested that cognitive defects underlying constructional impairment in patients with AD involved the early phases of spatial– constructional processing, likely exploration, and judgment of spatial relationships, rather than the late stage of planning. Rizzo et al. (2000) reported that mild AD usually spares basic visual sensory processes and affects all high-order visual processes, both occipitotemporal (ventral) and occipitoparietal (dorsal). A specific investigation of ventral and dorsal visual functions has been conducted by Caine and Hodges (2001) in two separate studies. In the former, the authors assessed AD patients on JLOT, on object-based visuoperceptual tests, and on semantic tests (picture naming). The authors found a great heterogeneity in the profile of patients’ performance at the early stages of the disease, with only a few patients showing visuospatial deficits. In the latter study, Caine and Hodges (2001) further explored visuospatial processing by administering AD patients with the entire VOSP battery. Again, only a small proportion of patients were impaired on visuospatial tasks. Taken together, Caine and Hodges’ findings would demonstrate that in very early stages of AD a small group of patients may be identified with prominent visuospatial disorders; these patients could be regarded as forming a continuous spectrum at the other end of which are patients affected by a focal degenerative dementia involving occipitoparietal cortex, the socalled posterior cortical atrophy (Benson et al., 1988; Ross et al., 1996; Hof et al., 1997; Suzuki et al., 2003). Studies on patients affected by focal degeneration of posterior cortical areas have proliferated in recent years, but its nosological status remains uncertain, also for the lack of consistent pathological findings: most cases present the pathology of AD, but also subcortical white matter gliosis, or pathological findings of the Creutzfeldt-Jacob disease (Victoroff et al., 1994; Della Sala et al., 1996; Zakzanis and Boulos, 2001). The clinical picture is characterized by early and prominent visuospatial impairment and relative preservation of episodic memory, insight, and verbal fluency with respect to typical AD (Mendez et al., 2002). The visuospatial defects may cover a wide range of disorders, all of which associated with occipitoparietal lesions: optic ataxia, gaze apraxia, simultanagnosia, topographical disorientation, visuospatial disorders, constructional apraxia, but also limb apraxia and disorders of reading (letter-by-letter alexia) and writing (Caine, 2004). These disorders gradually develop in the course of the disease, and constitute a quite homogeneous clinical picture, in which the impairment in visual perception of space and of higher-order spatial cognition can be considered

382

L. TROJANO AND M. CONSON

as the core feature (Della Sala et al., 1996). At the same time, the specific symptomatology can differ from case to case, likely due to the different underlying pathological disorder. CA and visuospatial disorders are typically found in other degenerative dementias too. In particular, visuospatial difficulties are often early and prominent in dementia with diffuse Lewy bodies (McKeith et al., 1996). Visuospatial tasks, such as object size discrimination, form discrimination, overlapping figure identification, and visual counting tasks may reveal more impaired performances in DLB than in AD, and these defects likely contribute to the disproportionate impairment in constructional tasks in DLB patients (Mori et al., 2000). In line with these observations, it has been suggested that DLB patients may show parallel impairments in free drawing and in figure copying since early stages of the disease (Gnanalingham et al., 1996; Ala et al., 2001), at variance with AD patients, who would show relative sparing of figure copying (but see Swanwick et al., 1996; Della Sala et al., 2002). In the most recent paper on this issue, Cormack et al. (2004) have confirmed that DLB patients show significantly lower performance in copying geometrical figures with respect to AD; moreover, while in AD the impairment in copying figures was correlated with general cognitive deterioration, in DLB patients drawing was correlated only with visuospatial tasks, thus suggesting the existence of a specific defect in this disease. A prominent visuospatial and constructional impairment is frequently observed also in less common degenerative dementias, such as corticobasal degeneration (Graham et al., 2003) and supranuclear progressive palsy (Aarsland et al., 2003), but definition of clinical features and of differential diagnostic value of CA in these disorders have not yet been studied in enough detail. The relative preservation of visuospatial and constructional abilities, instead, is suggested to be among critical features distinguishing frontotemporal dementia (FTD) from other degenerative dementias and, notably, from AD (Neary et al., 1998). As for patients with prominent frontal degeneration, these observations have been confirmed in recent clinical studies in which either patients with behavioral disorders (frontal variant FTD; Perri et al., 2005), or patients with specific language deficits (nonfluent progressive aphasia; Gorno-Tempini et al., 2004) have been examined by means of ROCF immediate reproduction. However, a study that compared frontal variant FTD and AD patients on a specific visuospatial battery (BVA), and on copying ROCF and simple geometrical drawings, failed to find significant differences between the two groups (Grossi et al., 2002). In particular, the groups did not differ on any

visuospatial test and showed comparable constructional performances both on quantitative and qualitative evaluation. Since the study enrolled mild to moderate FTD and AD patients, Grossi et al. (2002) suggested that the relative preservation of visuospatial abilities in FTD may be found only in early stages of the disease. This hypothesis has found support in a recent meta-analysis, suggesting that constructional abilities assessed on copying the ROCF quickly deteriorate as FTD progresses (Elderkin-Thompson et al., 2004). It is worth mentioning that FTD patients with prominent temporal involvement (semantic dementia) usually do not show visuospatial defects or impaired copying abilities in the early stages of the disease (Neary et al., 1998). For this reasons, these patients represent good candidates to use drawing from memory to explore their semantic defects. A recent paper assessed drawing of 64 living and nonliving items from their names in six patients affected by semantic dementia (Bozeat et al., 2003). Some patients refused to depict several items because they had no idea what the name meant, or produced some drawings that were recognizable as items other than those they had been asked to produce. Moreover, a specific scoring system could demonstrate patients’ drawings lacked distinctive features, presented incorrect features, or were ‘prototypical’ and simplified representations of the desired items. In three of these patients drawing from memory was compared with immediate copying and delayed copying of the same 64 items. Results showed that performance accuracy was significantly affected by the kind of task and by severity of disease; intruding features were more frequent for living than nonliving items, and were most likely to come from the pool of properties that are shared across domain. Therefore, Bozeat et al. (2003) suggested that results from the drawing from memory task parallel those from other semantic tasks, and that drawing from memory and delayed copying paradigms may be used to reveal fine gradations of patients’ knowledge about physical properties of living and nonliving items. 19.2.3. Neural and cognitive basis of drawing The study of visuospatial and visuoconstructional abilities in brain-lesioned patients has been complemented in recent years by the modern functional neuroimaging techniques that could provide new evidence about brain–behavior relationships. In this chapter there is not enough room to discuss this continuously expanding database, but we will mention only some findings, more related to clinical and theoretical aspects. As mentioned above, visuospatial processes appear not to be strongly lateralized, although the right hemisphere could play a more prominent role depending

VISUOSPATIAL AND VISUOCONSTRUCTIVE DEFICITS on specific task requirements. Consistent with this consideration, Ng et al. (2000) demonstrated a strong bilateral activation of the superior parietal cortex during a modified version of the JLOT, but the right parietal cortex appeared to be activated earlier than the left. Such findings suggest that the right hemisphere specialization could be related only to some aspects of visuospatial tasks. The different specialization of the two hemispheres is foreseen by the model of Kosslyn and coworkers (Kosslyn, 1987; Kosslyn and Koenig, 1992), who suggest the existence of two kinds of parallel processing, categorical and coordinate, that compute distinct aspects of spatial perception. The categorical processes define the basic and invariant properties of spatial relations, representing them in general and abstract codes. The coordinate processes, instead, specify the metric features of spatial relations and compute precise location of objects in space and exact distances among them. According to the model, categorical and coordinate representations are differentially dealt with by the two cerebral hemispheres: categorical information would be computed by the left hemisphere, while coordinate information would be mainly processed by the right hemisphere (Kosslyn, 1987). Neuroimaging and functional findings (Baciu et al., 1999; Trojano et al., 2002; Trojano et al., 2006) and neuropsychological studies on focal brain damaged patients (Laeng 1994) have lent support to the hypothesis that both parietal lobes operate upon visuospatial information, and that the relative contribution of the two hemispheres may be modulated by the specific requirements of the task being solved. As for visuoconstructional skills, it is worth underlining that because the concept itself rests mainly on operative definitions, functional neuroimaging studies and cognitive models have focused on the most widely used constructional task, i.e., drawing. An fMRI study in which subjects had to trace clock hands with their fingers, compared with a control condition in which subjects had to trace horizontal and vertical lines, has demonstrated the activation of a bilateral frontoparietal network (Ino et al., 2003). Such findings are consistent with clinical evidence showing defective performances on clock drawing tasks in patients with frontal or parietal lesions (Shulman, 2000). A further fMRI study on the copying of objects, compared with a condition in which subjects had to observe and name the same objects, has demonstrated that drawing relies on a wide network of cortical and subcortical structures (Makuuchi et al., 2003). Makuuchi et al. (2003) suggest that in copying visually presented objects, information is mainly transferred to the parietal lobe via the visual dorsal pathway; the parietal lobe selects the drawing

383

strokes to construct a representation of the object. This representation is transmitted to the dorsal premotor area (BA 6) and the ventral premotor area (BA 44), and hence to motor areas, and to motor subcortical structures, i.e., basal ganglia and cerebellum. In parallel, the ventral stream processes properties of objects and this information may be implemented in the drawing plan. Functional neuroimaging data are thus consistent with the view that drawing is a multicomponent process, based on a widely distributed neural network. The individual mental processes involved in drawing have been addressed by several cognitive models (Roncato et al., 1987; van Sommers, 1989; Grossi, 1991). All of them distinguish some fundamental stages in the process of drawing and, although differentiated in terms of formal characteristics, depth of analysis, and certain theoretical aspects, they share the idea that visuospatial processes, dedicated planning abilities, and general control processes are all involved in drawing (for a review, see Grossi and Trojano, 1999). None of these models have, at present, gained general acceptance, in the absence of solid clinical and experimental evidence about their heuristic value. However, each model presents some interesting hints at a comprehension of different facets of drawing. It is worth mentioning that Grossi and Angelini (Grossi, 1991) propose the existence of two copying procedures: a ‘lexical’ route which predominantly involves activation of familiar constructional schemata (for example, in drawing a square or a face) and a ‘line-by-line’ procedure, based on a spatial analysis which does not use constructional representations (activated when copying a doodle, for example). Both procedures may be adopted for copying complex pictures, but some patients might be constrained to use either one or the other. Here, the reader is reminded of the slow, slavish ‘line-by-line’ copying procedure adopted by visual agnosic patients (Wapner et al., 1978; Trojano and Grossi, 1992), who cannot access the lexical route for familiar objects. On the contrary, focal brain-damaged patients (Grossi et al., 1996; Trojano and Grossi, 1998) or patients affected by degenerative dementia (see above), may draw simple figures successfully without integrating correctly shaped simple elements in a coherent whole. Such a clinical picture could be ascribed to planning or visuospatial defects in presence of relatively spared abilities to activate motor subroutines for drawing well-known figures. This kind of procedural memory might be conceived as a sort of ‘constructional lexicon,’ which develops as a result of formal education and personal aptitudes. In a theoretical review, Gue´rin et al. (1999) argue that drawing is a multicomponent process that relies on at least three cognitive systems: visual perception, visual

384 L. TROJANO AND M. CONSON procedures; for example, it is possible to reproduce first imagery, and graphic production. Gue´rin et al. (1999) the main rectangle of the ROCF or to draw the model by suggest that Kosslyn and Koenig’s model (1992) promentally segmenting it in small subunits. Such a decivides a good conceptualization of visuospatial percepsion will have a great impact on the process of drawing tual processes involved in drawing, but the problem and also influence type and number of errors. A clear remains to define which, and to what extent, perceptual example of the influence of constructional strategies visuospatial abilities are correlated with constructional on the performance comes from neglect literature: Ishiai performances (Grossi and Trojano, 2002). Moreover, et al. (1997) recently demonstrated that the choice of Gue´rin and coworkers suggest that visual imagery different constructional strategies may even abolish would be involved in drawing unfamiliar objects, while neglect phenomena in drawing (omissions). drawing familiar objects (which are strictly related to No systematic study is available about consistency the drawer’s premorbid abilities) may proceed by the of constructional strategies: common observation, activation of motor procedural memory, and this could however, suggests that the same subject can use differcorrespond to what we have called a sort of construcent constructional strategies in different tasks, and even tional lexicon. Moreover, Gue´rin et al. suggest that a in two successive attempts at reproducing the same kind of planning (similar to that required by other prodrawing. Only in some cases the choice of a specific blem solving tasks) is necessary to produce novel or strategy seems to be forced by other cognitive defects, unfamiliar drawings; this planning component would as in the case of visual agnosic patients who resort to be not specific to drawing and, similarly, maintain that slavish line-by-line drawing procedures (Wapner damage to an action programming subsystem could et al., 1978; Trojano and Grossi, 1992). result in the associated picture of CA and gestural Several studies have aimed to establish whether apraxia. In summary, Gue´rin and coworkers agree that focal brain lesions may alter constructional strategies. model-based neuropsychological studies may provide The first formalized observations of copying perfornew insights on CA, but also cast some doubts about mance were those of Osterreith (1944) who presented the specificity of the cognitive abilities thought to be brain-damaged patients with the ROCF. It has been necessary to draw. asserted that observation of copying strategies in certain patients reveals the presence of a constructional 19.3. Peculiar constructional phenomena in disability more effectively and accurately than analysis clinical neurology of the final result (Kaplan, 1983; 1988). Semenza et al. (1978) noted that in copying tasks RBD and non-apha19.3.1. The problem of error analysis sic LBD patients tended to use a global strategy, similar to that adopted by normal subjects, whereas aphasics Most cognitive models for verbal and nonverbal abilities used a more analytical strategy, copying the model piehave been developed on the basis of a qualitative analysis cemeal. At variance, Binder (1982) demonstrated that, of errors made by patient, such that a specific mistake in copying the ROCF, patients with both right- and could be attributed to one or another cognitive failure. left-sided lesions broke the task down into successive Unfortunately, the analysis of constructional errors is steps, while control subjects tended to use a global not a straightforward procedure. The amount and the type strategy. Analogous results have been obtained by Troof errors may greatly vary within the same subject and jano et al. (1993) on a sample of focal brain-damaged only a few attempts have been made at a systematic anapatients without severe constructional disabilities. This lysis of single patients’ drawings errors. This is partly study confirmed that regardless of the lesion locus, explained by the fact that, for instance, the reproduction brain-damaged patients adopt a line-by-line in copying of a line in wrong orientation may be equally ascribed the ROCF, likely in response to the difficulties posed to faulty visuospatial perceptual processes, or to impaired by the task. An alteration in drawing strategies (i.e., motor execution, or to defects in planning drawing. Only in planning the copy) is therefore not sufficient to a few patients have been described who made systematic induce a constructional disability; other cognitive and consistent errors across several visuospatial and anomalies have to be present to determine a clinical constructional tasks, in such a way to allow attempts at picture of CA. coherent theoretical explanations (e.g., Grossi et al., 1998 for the dissociation of vertical and horizontal space 19.3.2. Omissions and ‘constructional allochiria’ in processing; for cognitively oriented diagnosis of CA, see unilateral spatial neglect Roncato et al., 1987; Trojano and Grossi, 1998). The analysis of constructional errors is further One exception to the poor explanatory value of concomplicated by the effect of constructional strategies. structional errors is seen in focal brain-damaged patients One can plan to reproduce a figure through different

VISUOSPATIAL AND VISUOCONSTRUCTIVE DEFICITS affected by Unilateral Spatial Neglect (USN). Drawing tasks, and in particular drawing from memory, have been considered a relatively independent measure of neglect with respect to other tests such as cancellation and line bisection and may provide an insight into the nature of the disorder (Halligan and Marshall, 2001). In the absence of gross constructional disorders, which are indeed often associated with USN, neglect patients typically show unilateral omissions in reproducing elements of a perceived or imagined model (Figs. 19.1–19.4). In a copying task the model is given by the examiner, and omissions may derive from a faulty perceptual appreciation of its figural components. However, such an explanation cannot account for a range of phenomena; for example, in a study by Ishiai et al. (1996) neglect patients were able to detect the absence of left-sided leaves on a sunflower, and yet failed to draw them in a subsequent copying task. These findings are not consistent with the presence of a visuoperceptual defect and might suggest an interaction between attentional mechanisms and the process of drawing. Typically, unilateral omissions occur during spontaneous drawing too, when no visually presented model is available and subjects have to resort to their long-term visual representations. In this case, omissions might suggest that patients’ mental representations are impaired in the neglected hemifield (as foreseen by several interpretative accounts of neglect; see Bisiach et al., 1979) and that the patients’ reproductions are the direct byproduct of these defects. Alternatively, it can be hypothesized these errors are due to a tendency to operate upon a limited part of the ‘drawing space,’ therefore reproducing only some parts of items that patients can entirely represent in their mind. Anderson (1993) demonstrated that a neglect patient who made omissions in copying and spontaneous drawing of a clock face, could draw it correctly if she was instructed to close her eyes, see the clock in her mind and draw what she saw with her eyes shut. A dramatic reduction of omissions when perceptual feedback is reduced or removed has been reported in a manual exploration task (Chedru, 1976) and in constructional and cancellation tasks (Mesulam, 1985; Marshall and Halligan, 1993; Halligan and Marshall, 1994). A recent study, in which six neglect patients were required to draw symmetric and asymmetric objects from memory with their eyes open or closed, confirmed that the suppression of the visual feedback may determine a general improvement of graphic productions, with an increase of details drawn in the left part of constructional space (Chokron et al., 2004). Although this effect was not present in all patients, it would suggest that visual control may determine a strong engagement of attention to the right,

385

ipsilesional space. Therefore, lateralized errors in neglect patients’ drawing from memory might result from a defect in representing the contralateral side of imaginal space, but also from an inability to direct attention and action towards the contralesional space, or from an interaction between these factors (Halligan and Marshall, 2001). Another drawing error often reported in neglect patients is the tendency to locate on the ipsilesional side stimuli occurring in the neglected, contralesional side (see Fig. 19.1). This phenomenon, called allochiria or spatial transposition, may be observed in several modalities (tactile, auditory, olfactory, visual), but is particularly evident in copying and spontaneous drawing (Halligan et al., 1992). According to an attentional account of allochiria in constructional tasks, patients start drawing from the right side and then may be unable to disengage their attention from the rightmost stimuli; this hypothesis has received direct support from a single case study in which transpositions in clock drawing disappeared when the patient was asked to write hours, one at a time, each on a blank dial (Di Pellegrino, 1995). The alternative, representational, hypothesis ascribes allochiria to an impairment in the mental representation of space (Bisiach et al., 1981; Mijovic, 1991; Grossi et al., 1999). Bisiach et al. (1981) suggested that both omissions and spatial transpositions in imaginal and drawing tasks had to be attributed to an alteration of the left side of patients’ mental representations, whereas Mijovic (1991) observed that the whole mental representation of the space might be defective, as if its right side had been more ‘receptive,’ in order to ‘host’ left-sided stimuli. Recently, Lepore et al. (2003) reported a neglect patient who showed allochiria in copying and drawing a clock from memory, even in writing each single hour on a blank dial. In another single case study, spatial transpositions could be elicited in different drawing and imaginal tasks where stimulus processing, response modality (graphic, manual, or verbal) or both were manipulated (Lepore et al., 2004). The presence of spatial transpositions across tasks and response modalities is consistent with the hypothesis that, al least in some patients, transpositions may derive from of a defect in the mental representation of space. A different picture has been observed in two neglect patients (Grossi et al., 2004; Lepore et al., 2005) who showed spatial transpositions on constructional tasks, but towards multiple (even opposite) directions depending on task instructions or on the relative positions of the model to be reproduced. Taken together, these recent findings suggest that ‘constructional allochiria’ may be caused by two different cognitive mechanisms, i.e., attentional or representational.

386

L. TROJANO AND M. CONSON

It is worth mentioning that neglect patients are usually unable to check their graphic productions for accuracy, and to detect omissions, distortions or spatial transpositions in their drawings. This kind of defective awareness may dissociate from other awareness disturbances that characterize USN (Berti et al., 1996). This defect is particularly striking because patients could criticize their drawing mistakes on the basis of available semantic information (for a related issue see Bartolomeo and Chokron, 2001). Halligan and Marshall (1994) suggested that this peculiar defect of awareness may be ascribed to a completion phenomenon, i.e., to the tendency to mentally fill in graphic productions on the basis of spared semantic information. This pathological process would allow the patients to believe that a distorted clock face is, on the contrary, normal. Therefore, theoretical interpretation of lack of awareness for drawing disturbances, as well as of the other neglect-related constructional phenomena, points to close relationships between attentional mechanisms, space representation, and the drawing processes. 19.3.3. Perseveration, rotation, and closing-in: frontal phenomena? Other qualitative phenomena observed in drawing tasks deserve some brief comments, because of their frequency and of their potential localizing value. Generally speaking, perseveration can be considered among ‘productive’ (or ‘positive’) pathological signs, since it consists in iterative behavioral responses, not adequate to the current stimulus (Vallar, 1998; 2001). Perseverations in drawing are of frequent observation in clinical practice: for instance, patients may produce the same figure repeatedly, in response to only one stimulus, or replicate stimuli’s elements (continuous perseveration, according to Sandson and Albert, 1987; see Fig. 19.3); on other occasions, patients may inappropriately draw figures already drawn in previous trials, instead of reproducing the current stimulus (recurrent perseveration; Sandson and Albert, 1987). A specific kind of perseveration is observed in clock drawing, when patients produce repeatedly the same numbers, or start numeration over and over (Fig. 19.1). These errors in clock drawings have been described in a small proportion of AD patients (Rouleau et al., 1992), but would increase in moderate-tosevere stages of the disease (Rouleau et al., 1996). A study on drawing to command and copying clocks (Cosentino et al., 2004) revealed that perseveration and closing-in (see below) in AD or vascular dementia were more frequent in patients with a higher number of white matter lesions and with more marked impairment on executive frontal tasks. These findings suggested

that executive impairment associated with frontal-subcortical dysfunction seems to contribute to the genesis of perseveration in clock drawing in dementia. These data would be consistent with a study reporting that perseverations are rare in typical AD patients on a cancellation task (Rusconi et al., 2002). At variance with AD patients, FTD patients would frequently show perseveration errors from the early stages (Snowden et al., 1996; but see Grossi et al., 2002), while specific disturbances in reproducing spatial relationships would become evident later during the course of the disease. In Rusconi et al.’s study (2002), perseverations were frequent in RBD neglect patients with a frontal or a subcortical lesion, in agreement with other recent findings (Na et al., 1999). Taken together, these findings would suggest that perseverative behavior in graphic tasks would be related to frontal-subcortical lesions, although more precise definition of perseverative phenomena is necessary to better define their cognitive and neural mechanisms. Rotation, albeit rare, is another constructional phenomenon with potential localizing value. In copying stimuli, some patients may respect spatial relationships among constituent elements but reproduce a model with general orientation different from the stimulus, usually by rotating the reproduction by 90 degrees. From a consecutive unselected series of 240 neurological patients, Solms et al. (1998) identified 16 patients who reproduced Rey’s or Taylor’s complex figures with their major axis rotated vertically rather than horizontally. In these cases, the model may be reproduced with correct inner spatial relationships, but the whole copy is rotated. This finding could suggest that the ability to reproduce the correct spatial disposition of a model is functionally distinct from the ability to correctly organize reciprocal relationships among model’s parts. Seven of these patients had diffuse cerebral involvement, but all remaining cases showed a lesion involving frontal regions. The authors suggest that this behavior could reflect the lack of planning and verification abilities of frontal patients (Solms et al., 1998). However, rotated drawing has been also described in patients with deficits in recognizing orientation of objects, despite intact recognition of misoriented objects. This clinical condition, termed orientation agnosia, is another example of the functional dissociation between spatial processing and object-identity processing, and has been rarely described in focal brain-damaged patients with posterior lesions (Turnbull et al. 1995; Fujinaga et al., 2005), and also in patients with posterior cortical atrophy (Harris et al., 2001). In these patients rotated drawings are the expression of a faulty appreciation of spatial properties of visually perceived stimuli.

VISUOSPATIAL AND VISUOCONSTRUCTIVE DEFICITS More frequent is the tendency either to trace the pencil over the lines of the model, producing a scrawl (see Fig. 19.2), or to overlap the copy with the model or to draw starting from one or more of the model’s elements (Figs. 19.2 and 19.3). Such behavior, termed ‘closingin,’ has often been reported in demented patients (Mayer-Gross, 1935; Ajuriaguerra et al., 1960; Gainotti, 1972), particularly in late stages of AD (Ober et al., 1991; Rouleau et al., 1996), but also in patients with relatively selective posterior atrophy (Suzuki et al., 2003). Some authors consider this phenomenon as a primitive reflex in patients with diffuse cognitive deterioration (Gainotti, 1972); patients might be strongly attracted by the model and be unable to detach from it. In some cases, however, a simple verbal instruction may suffice to avoid this constructional error. Other authors suggest that closing-in occurs when patients who are unable to structure an empty space look for a reference point to solve difficult constructional dilemmas (De Renzi, 1959). In these cases patients might be unable to generate a bidimensional frame in the copying paper (i.e., they cannot identify a ‘drawing space’), and try to use already existing frames, for example the border of the model or, in other cases, the edge of the paper (‘margination’ of the copy, seen also in children). The presence of closing-in seems consistent with a diagnosis of primary degenerative dementia (Gainotti et al., 1992), and could enhance sensitivity and specificity of diagnosis of AD versus subcortical vascular dementia (Kwak, 2004). Rarely, closing-in may be observed in patients with focal lesions (Gainotti, 1972); in a patient with a right subcortical lesion, the closing-in phenomenon was ascribed to a specific deficit in localizing points in space (Grossi et al., 1996). However, the observation that the prevalence of closing-in may increase in copying complex rather than simple figures challenges an interpretation based on a pure visuospatial defect (Lee et al., 2004). Indeed, figure complexity increases demands on executive processes and, in case of a specific frontal impairment, the patient could become unable to inhibit attention and action towards salient stimuli. This hypothesis would tie in with observation on spatial transpositions generated by attentional mechanisms, but further research is needed to understand cognitive and neural basis of closing-in (Kwak, 2004).

References Aarsland D, Litvan I, Salmon D, et al. (2003). Performance on the dementia rating scale in Parkinson’s disease with dementia and dementia with Lewy bodies: Comparison with progressive supranuclear palsy and Alzheimer’s disease. J Neurol Neurosurg Psychiatry 74: 1215–1220.

387

Ajuriaguerra J, Muller M, Tissot R (1960). A propos de quelques proble`mes pose´s par l’apraxie dans les de´mences. Encephale 49: 275–401. Ala TA, Hughes LF, Kyrouac GA, et al. (2001). Pentagon copying is more impaired in dementia with Lewy bodies than in Alzheimer’s disease. J Neurol Neurosurg Psychiatry 70: 483–488. Anderson B (1993). Spared awareness for the left side of internal images in patients with left-sided extrapersonal neglect. Neurology 43: 213–216. Angelini R, Grossi D (1993). La Terapia Razionale dei Disordini Costruttivi. Centro di Riabilitazione S. Lucia, Roma. Arrigoni C, De Renzi E (1964). Constructional apraxia and hemispheric locus of lesion. Cortex 1: 170–197. Baciu M, Koenig O, Vernier MP, et al. (1999). Categorical and coordinate spatial relations: fMRI evidence for hemispheric specialization. Neuroreport 10: 1373–1378. Ba´lint R (1909). Seelenla¨hmung des Schauens, optische Ataxie, rau¨mliche Sto¨rung der Aufmerksamkeit. Monatsschr Psychiatr Neurol 25: 51–81. Bartolomeo P, Chokron S (2001). Levels of impairment in unilateral neglect. In: F Boller, J Grafman (Eds.), Handbook of Neuropsychology, 2nd edn, Vol. 4. Elsevier Science Publishers, Amsterdam, pp. 67–98. Benowitz LI, Moya KL, Levine DN (1990). Impaired verbal reasoning and constructional apraxia in subjects with right hemisphere damage. Neuropsychologia 28: 231–241. Benson DF, Barton M (1970). Disturbances in constructional ability. Cortex 6: 19–46. Benson DF, Davis RJ, Snyder BD (1988). Posterior cortical atrophy. Arch Neurol 45: 789–793. Benton AL (1989). Constructional apraxia. In: F Boller, J Grafman (Eds.), Handbook of Neuropsychology, Vol. 2. Elsevier, Amsterdam, pp. 387–394. Benton AL, Fogel ML (1962). Three-dimensional constructional praxis: A clinical test. Arch Neurol 7: 347–354. Benton A, Hannay HJ, Varney NR (1975). Visual perception of line direction in patients with unilateral brain disease. Neurology 25: 907–910. Berti A, La`davas E, Della Corte M (1996). Anosognosia for hemiplegia, neglect dyslexia, and drawing neglect: Clinical findings and theoretical considerations. J Int Neuropsychol Soc 2: 426–440. Binder LM (1982). Constructional strategies of complex figure drawings after unilateral brain damage. J Clin Neuropsychol 4: 51–58. Binetti G, Cappa S, Magni E, et al. (1998). Visual and spatial perception in the early phase of Alzheimer’s disease. Neuropsychology 12: 29–33. Bisiach E, Capitani E, Luzzatti C, et al. (1981). Brain and conscious representation of outside reality. Neuropsychologia 19: 543–551. Bisiach E, Luzzatti C, Perani D (1979). Unilateral neglect, representational schema and consciousness. Brain 102: 609–618. Black FW, Bernard BA (1984). Constructional apraxia as a function of lesion locus and size in patients with focal brain damage. Cortex 20: 111–120.

388

L. TROJANO AND M. CONSON

Borod JC, Carper M, Goodglass H (1982). WAIS performance IQ in aphasia as a function of auditory comprehension and constructional apraxia. Cortex 18: 212–220. Bozeat S, Lambon Ralph MA, Graham KS, et al. (2003). A duck with four legs: Investigating the structure of conceptual knowledge using picture drawing in semantic dementia. Cogn Neuropsychol 20: 27–47. Caine D (2004). Posterior cortical atrophy: A review of the literature. Neurocase 10: 382–385. Caine D, Hodges JR (2001). Heterogeneity of semantic and visuospatial deficits in early Alzheimer’s disease. Neuropsychology 15: 155–164. Carlesimo GA, Fadda L, Caltagirone C (1993). Basic mechanisms of constructional apraxia in unilateral braindamaged patients: Role of visuo-perceptual and executive disorders. J Clin Exp Neuropsychol 15: 342–358. Chedru F (1976). Space representation in unilateral spatial neglect. J Neurol Neurosurg Psychiatry 39: 1057–1061. Chokron S, Colliot P, Bartolomeo P (2004). The role of vision in spatial representation. Cortex 40: 281–290. Cormack F, Aarsland D, Ballard C, et al. (2004). Pentagon drawing and neuropsychological performance in Dementia with Lewy Bodies, Alzheimer’s disease, Parkinson’s disease and Parkinson’s disease with dementia. Int J Geriatr Psychiatry 19: 371–377. Cosentino S, Jefferson A, Chute DL, et al. (2004). Clock drawing errors in dementia: Neuropsychological and neuroanatomical considerations. Cogn Behav Neurol 17: 74–84. Coslett HB, Chatterjee A (2003). Ba´lint’s syndrome and related disorder. In: TE Feinberg, MJ Farah (Eds.), Behavioural Neurology and Neuropsychology, 2nd edn. McGraw-Hill, New York, pp. 325–335. Damasio AR, Tranel D, Rizzo M (2000). Disorders of complex visual processing. In: M-M Mesulam (Ed.), Principles of Behavioral and Cognitive Neurology, 2nd edn.Oxford University Press, New York, pp. 332–372. Dee HL (1970). Visuoconstructive and visuoperceptive deficits in patients with unilateral cerebral lesions. Neuropsychologia 8: 305–314. Della Sala S, Spinnler H, Trivelli C (1996). Slowly progressive impairment of spatial exploration and visual perception. Neurocase 2: 299–323. Della Sala S, Turnbull O, Beschin N, et al. (2002). Orientation agnosia in pentagon copying. J Neurol Neurosurg Psychiatry 72: 129–130. Denes G, Semenza C (1982). Sparing of constructional abilities in severe dementia. European neurology 21: 161–164. De Renzi E (1959). Osservazioni semeiogenetiche in tema di aprassia costruttiva. Rivista Sperimentale di Freniatria 58: 231–256. De Renzi E (1980). L’aprassia costruttiva. In: E Bisiach, G Denes, E De Renzi (Eds.), Neuropsicologia Clinica. Franco Angeli, Milano. De Renzi E (1982). Disorders of Space Exploration and Cognition. Wiley and Sons, New York. Di Pellegrino G (1995). Clock-drawing in a case of left visuospatial neglect: A deficit of disengagement? Neuropsychologia 33: 353–358.

Duensing F (1953). Raumagnostische und ideatorische-apraktische Storung des gestalten den Handelns. Dtsch Z Nervenheilkd 170: 191–204. Elderkin-Thompson V, Boone KB, Hwang S, et al. (2004). Neurocognitive profiles in elderly patients with frontotemporal degeneration or major depressive disorder. J Int Neuropsychol Soc 10: 753–771. Farah MJ (2003). Visual perception and visual imagery. In: TE Feinberg, MJ Farah (Eds.), Behavioural Neurology and Neuropsychology, 2nd edn. McGraw-Hill, New York, pp. 227–232. Freedman M, Leach L, Kaplan E, et al. (1994). Clock Drawing: A Neuropsychological Analysis. Oxford, New York. Fujinaga N, Muramatsu T, Ogano M, et al. (2005). A 3-year follow-up study of ‘orientation agnosia.’ Neuropsychologia 43: 1222–1226. Gainotti G (1972). A quantitative study of the ‘closing-in’ symptom in normal children and in brain-damaged patients. Neuropsychologia 10: 429–436. Gainotti G (1985). Constructional apraxia. In: JAM Fredericks (Ed.), Handbook of Clinical Neurology, Vol 45. Elsevier, Amsterdam, pp. 491–506. Gainotti G, Parlato V, Monteleone D, et al. (1992). Neuropsychological markers of dementia on visuospatial tasks: A comparison between Alzheimer’s type and vascular forms of dementia. J Clin Exp Neuropsychol 14: 239–252. Gainotti G, Silveri MC, Villa G, et al. (1983). Drawing from memory in aphasia. Brain 106: 613–622. Gainotti G, Tiacci C (1970). Patterns of drawing disability in right and left hemispheric patients. Neuropsychologia 8: 379–384. Gnanalingham KK, Byrne EJ, Thornton A (1996). Clock-face drawing to differentiate Lewy body and Alzheimer type dementia. Lancet 347: 696–697. Goodale MA, Humphrey GK (1998). The objects of action and perception. Cognition 67: 181–207. Goodale MA, Milner AD (1992). Separate visual pathways for perception and action. Trends Neurosci 15: 20–25. Goodale MA, Murphy K, Meenan J-P, et al. (1993). Spared object perception but poor object-calibrated grasping in a patient with optic ataxia. S Abstr Soc Neurosci 19: 775. Goodale MA, Westwood DA, Milner AD (2004). Two distinct modes of control for object-directed action. Prog Brain Res 144: 131–144. Gorno-Tempini ML, Dronkers NF, Rankin KP, et al. (2004). Cognition and anatomy in three variants of primary progressive aphasia. Ann Neurol 55: 335–346. Graham NL, Bak TH, Hodges JR (2003). Corticobasal degeneration as a cognitive disorder. Mov Disord 18: 1224–1232. Grossi D (1991). La Riabilitazione dei Disturbi della Cognizione Spaziale. Masson, Milano. Grossi D, Correra G, Calise C, et al. (1996). Selective constructional disorders after right subcortical stroke. A neuropsychological premorbid and follow-up study. Ital J Neurol Sci 14: 23–33.

VISUOSPATIAL AND VISUOCONSTRUCTIVE DEFICITS Grossi D, Di Cesare G, Trojano L (2004). Left on the right or viceversa: A case of ‘alternating’ constructional allochiria. Cortex 40: 511–518. Grossi D, Fragassi NA, Chiacchio L, et al. (2002). Do visuospatial and constructional disturbances differentiate frontal variant of frontotemporal dementia and Alzheimer’s disease? An experimental study of a clinical belief. Int J Geriatr Psychiatry 17: 641–648. Grossi D, Fragassi NA, Giani E, et al. (1998). The selective inability to draw horizontal lines: On a peculiar constructional disorder. J Neurol Neurosurg Psychiatry 64: 795–798. Grossi D, Lepore M, Esposito A, et al. (1999). Neglect-associated constructional disorders: A paradoxical phenomenon? Neuropsychologia 37: 589–594. Grossi D, Trojano L (1999). Constructional apraxia. In: G Denes, L Pizzamiglio (Eds.), Handbook of Clinical and Experimental Neuropsychology. Psychology Press, Hove, pp. 441–450. Grossi D, Trojano L (2002). Constructional and visuospatial disorders. In: M Behrmann (Ed.), Handbook of Neuropsychology, 2nd edn, Vol. 4. Elsevier, Amsterdam, pp. 99–120. Grossman M (1988). Drawing deficits in brain-damaged patients’ freehand pictures. Brain Cogn 8: 189–205. Grossman M, Mickanin J, Onishi K, et al. (1996). Freehand drawing impairments in probable Alzheimer’s disease. J Int Neuropsychol Soc 2: 226–235. Gue´rin F, Belleville S, Ska B (2002). Characterization of visuoconstructional disabilities in patients with probable dementia of Alzheimer’s type. J Clin Exp Neuropsychol 24: 1–17. Gue´rin F, Ska B, Belleville S (1999). Cognitive processing of drawing abilities. Brain Cogn 40: 464–478. Halligan PW, Marshall JC (1994). Completion in visuo-spatial neglect: A case study. Cortex 30: 685–694. Halligan PW, Marshall JC (2001). Graphic neglect—more than the sum of the parts. Neuroimage 14: S91–S97. Halligan PW, Marshall JC, Wade DT (1992). Left on the right: Allochiria in a case of left visuo-spatial neglect. J Neurol Neurosurg Psychiatry 55: 717–719. Hamsher K, Capruso DX, Benton A (1992). Visuospatial judgment and right hemisphere disease. Cortex 28: 493–495. Hannay HJ, Varney NR, Benton AL (1976). Visual localization in patients with unilateral brain disease. J Neurol Neurosurg Psychiatry 39: 307–313. Harris IM, Harris JA, Caine D (2001). Object orientation agnosia: A failure to find the axis? J Cogn Neurosci 13: 800–812. Hof PR, Vogt BA, Bouras C, et al. (1997). Atypical form of Alzheimer’s disease with prominent posterior cortical atrophy: A review of lesion distribution and circuit disconnection in cortical visual pathways. Vision Res 37: 3609–3625. Holmes G (1918). Disturbances of visual orientation. Br J Ophthalmol 2: 449–506. Ino T, Asada T, Ito J, et al. (2003). Parieto-frontal networks for clock drawing revealed with fMRI. Neurosci Res 45: 71–77.

389

Ishiai S, Seki K, Koyama Y, et al. (1996). Mechanisms of unilateral spatial neglect in copying a single object. Neuropsychologia 34: 965–971. Ishiai S, Seki K, Koyama Y, et al. (1997). Disappearance of unilateral spatial neglect following a simple instruction. J Neurol Neurosurg Psychiatry 63: 23–27. Jeannerod M, Jacob P (2005). Visual cognition: A new look at the two-visual systems model. Neuropsychologia 43: 301–312. Kaplan E (1983). A process approach to neuropsychological assessment. In: T Boll, BK Bryant (Eds.), Clinical Neuropsychology and Brain Function: Research, Measurement and Practice. APA, Washington, pp. 129–167. Kaplan E (1988). Process and achievement revisited. In: S Wapner, B Kaplan (Eds.), Toward a Holistic Developmental Psychology. Erlbaum, Hillsdale, pp. 143–156. Karnath HO, Perenin MT (1994). Cortical control of visually guided reaching: Evidence from patients with optic ataxia. Cereb Cortex 15: 1561–1569. Kashiwagi T, Kashiwagi A, Kunimori Y, et al. (1994). Preserved capacity to copy drawings in severe aphasics with little premorbid experience. Aphasiology 8: 427–442. Kempen JH, Krichevsky M, Feldman ST (1994). Effect of visual impairment on neuropsychological test performance. J Clin Exp Neuropsychol 16: 223–231. Kerkhoff G, Marquardt C (1998). Standardised analysis of visual–spatial perception after brain damage. Neuropsychol Rehabil 8: 171–189. Kirk A, Kertesz A (1989). Hemispheric contributions to drawing. Neuropsychologia 27: 881–886. Kirk A, Kertesz A (1991). On drawing impairment in Alzheimer’s disease. Arch Neurol 48: 73–77. Kirk A, Kertesz A (1993). Subcortical contributions to drawing. Brain Cogn 21: 57–70. Kleist K (1934). Gehirnpathologie. Barth, Leipzig. Kosslyn SM (1987). Seeing and imagining in the cerebral hemispheres: A computational approach. Psychol Rev 94: 148–175. Kosslyn SM, Koenig O (1992). Wet Mind: The New Cognitive Neuroscience. The Free Press, New York. Kwak YT (2004). ‘Closing-in’ phenomenon in Alzheimer’s disease and subcortical vascular dementia. BMC neurology 4: 3. Laeng B (1994). Lateralization of categorical and coordinate spatial functions: A study of unilateral stroke patients. J Cogn Neurosci 6: 189–203. Lee BH, Chin J, Kang SJ, et al. (2004). Mechanism of the closing-in phenomenon in a figure copying task in Alzheimer’s disease patients. Neurocase 10: 393–397. Lepore M, Conson M, Ferrigno A, et al. (2004). Spatial transpositions across tasks and response modalities: Exploring representational allochiria. Neurocase 10: 386–392. Lepore M, Conson M, Grossi D, et al. (2003). On the different mechanisms of spatial transpositions: A case of representational allochiria in clock drawing. Neuropsychologia 41: 1290–1295. Lepore M, Conson M, Grossi D, et al. (2005). Multidirectional transpositions suggesting pathologic approach behavior after frontal stroke. Neurology 64: 1615–1617.

390

L. TROJANO AND M. CONSON

Luria AR, Tsvetkova LS (1964). The programming of constructive activity in local brain injuries. Neuropsychologia 2: 95–108. Makuuchi M, Kaminaga T, Sugishita M (2003). Both parietal lobes are involved in drawing: A functional MRI study and implications for constructional apraxia. Cogn Brain Res 16: 338–347. Marshall JC, Halligan PW (1993). Imagine only the half of it. Nature 364: 193–194. Marshall RS, Lazar RM, Binder JR, et al. (1994). Intrahemispheric localization of drawing dysfunction. Neuropsychologia 32: 493–501. Mayer-Gross W (1935). Some observations on apraxia. Proc R Soc Med 28: 1203–1212. McKeith IG, Galasko D, Kosaka K, et al. (1996). Consensus guidelines for the clinical and pathologic diagnosis of dementia with Lewy bodies (DLB): Report of the consortium on DLB international workshop. Neurology 47: 1113–1124. Mehta Z, Newcombe F (1991). A role for the left hemisphere in spatial processing. Cortex 27: 153–167. Mehta Z, Newcombe F, Damasio H (1987). A left hemisphere contribution to visuospatial processing. Cortex 23: 447–461. Mendez MF, Ghajarania M, Perryman KM (2002). Posterior cortical atrophy: Clinical characteristics and differences compared to Alzheimer’s disease. Dement Geriatr Cogn Disord 14: 33–40. Mesulam M-M (1985). Attention, confusional states and neglect. In: M-M Mesulam (Ed.), Principles of Behavioral Neurology. F.A. Davis, Philadelphia, pp. 125–168. Mijovic D (1991). Mechanisms of visual spatial neglect. Absence of directional hypokinesia in spatial exploration. Brain 114: 1575–1593. Mori E, Shimomura T, Fujimori M, et al. (2000). Visuoperceptual impairment in dementia with Lewy bodies. Arch Neurol 57: 489–493. Na DL, Adair MD, Kang Y, et al. (1999). Motor perseverative behaviour on a line cancellation task. Neurology 52: 1569–1576. Neary D, Snowden JS, Gustafson L, et al. (1998). Frontotemporal lobar degeneration: A consensus on clinical diagnostic criteria. Neurology 51: 1546–1554. Ng VW, Eslinger PJ, Williams SC, et al. (2000). Hemispheric preference in visuospatial processing: A complementary approach with fMRI and lesion studies. Hum Brain Mapp 10: 80–86. Nyffeler T, Pflugshaupt T, Hofer H, et al. (2005). Oculomotor behaviour in simultanagnosia: A longitudinal case study. Neuropsychologia 43: 1591–1597. Ober BA, Jagust WJ, Koss E, et al. (1991). Visuoconstructive performance and regional cerebral glucose metabolism in Alzheimer’s disease. J Clin Exp Neuropsychol 13: 752–772. Osterreith P (1944). Le test de copie d’une figure complexe. Arch Psychol (Frankf) 30: 206–356. Perenin M-T, Vighetto A (1988). Optic ataxia: A specific disruption in visuomotor mechanisms. I. Different aspects of the deficit in reaching for objects. Brain 111: 643–674.

Perri R, Koch G, Carlesimo GA, et al. (1962). Alzheimer’s disease and frontal variant of frontotemporal dementia. A very brief battery for cognitive and behavioural distinction. J Neurol 252: 1238–1244. Piercy M, Smyth VOG (1962). Right hemisphere dominance for certain nonverbal intellectual skills. Brain 85: 775–790. Piercy M, He´caen H, Ajuriaguerra J (1960). Constructional apraxia associated with unilateral cerebral lesions. Left and right sided cases compared. Brain 83: 225–242. Pillon B (1981). Troubles visuo-constructifs et methodes de compensation: Resultats de 85 patients atteints de lesions cerebrales. Neuropsychologia 19: 375–383. Postma A, Sterken Y, de Vries L, et al. (2000). Spatial localization in patients with unilateral posterior left or right hemisphere lesions. Exp Brain Res 134: 220–227. Ratcliffe G, Ross J (1981). Visual perception and perceptual disorders. Br Med Bull 37: 181–186. Rizzo M, Anderson SW, Dawson J, et al. (2000). Vision and cognition in Alzheimer’s disease. Neuropsychologia 38: 1157–1169. Rizzolatti G, Matelli M (2003). Two different streams form the dorsal visual system: Anatomy and functions. Exp Brain Res 153: 146–157. Rizzo M, Vecera SP (2002). Psychoanatomical substrates of Ba´lint’s syndrome. J Neurol Neurosurg Psychiatry 72: 162–178. Roncato S, Sartori G, Masterson J, et al. (1987). Constructional apraxia: An information processing analysis. Cogn Neuropsychol 4: 113–129. Ross SJM, Graham N, Stuart-Green L, et al. (1996). Progressive biparietal atrophy: An atypical presentation of Alzheimer’s disease. J Neurol Neurosurg Psychiatry 9: 191–224. Rosselli M, Ardila A (2003). The impact of culture and education on non-verbal neuropsychological measurements: A critical review. Brain Cogn 52: 326–333. Rouleau I, Salmon DP, Butters N (1996). Longitudinal analysis of clock drawing in Alzheimer’s disease patients. Brain Cogn 31: 17–34. Rouleau I, Salmon DP, Butters N, et al. (1992). Quantitative and qualitative analyses of clock drawings in Alzheimer’s and Huntington’s disease. Brain Cogn 18: 70–87. Rusconi ML, Maravita A, Bottini G, et al. (2002). Is the intact side really intact? Perseverative responses in patients with unilateral neglect: A productive manifestation. Neuropsychologia 40: 594–604. Sandson J, Albert ML (1987). Perseveration in behavioural neurology. Neurology 37: 1736–1741. Semenza C, Denes G, D’Urso V, et al. (1978). Analytical and global strategies in copying designs by unilaterally braindamaged patients. Cortex 14: 404–410. Shulman KI (2000). Clock-drawing: Is it the ideal cognitive screening test? Int J Geriatr Psychiatry 15: 548–561. Snowden JS, Neary D, Mann DM (1996). Fronto-temporal Lobar Degeneration: Fronto-temporal Dementia, Progressive Aphasia, Semantic Dementia. Churchill Livingstone, New York, pp. 49–50.

VISUOSPATIAL AND VISUOCONSTRUCTIVE DEFICITS Solms M, Turnbull OH, Kaplan-Solms K, et al. (1998). Rotated drawing: The range of performance and anatomical correlates in a series of 16 patients. Brain Cogn 38: 358–368. Stark M, Coslett B, Saffran EM (1996). Impairment of an egocentric map of locations: Implications for perception and action. Cogn Neuropsychol 13: 481–523. Suzuki K, Otsuka Y, Endo K, et al. (2003). Visuospatial deficits due to impaired visual attention: Investigation of two cases of slowly progressive visuospatial impairment. Cortex 39: 327–342. Swanwick GRJ, Coen RF, Maguire CP, et al. (1996). Clockface drawing to differentiate dementia syndrome. Lancet 347: 1115. Treccani B, Torri T, Cubelli R (2005). Is judgement of line orientation selectively impaired in right brain damaged patients? Neuropsychologia 43: 598–608. Trojano L, Angelini R, Gallo P, et al. (1997). An ‘ecological’ constructional task. Percept Mot Skills 85: 51–57. Trojano L, Conson M, Matei R, et al. (2006). Categorical and coordinate spatial processing in the imagery domain investigated by rTMS. Neuropsychologia 44: 1569–1574. Trojano L, De Cicco G, Grossi D (1993). Copying procedures of Rey complex figure in normal subjects and braindamaged patients. Ital J Neurol Sci 14: 23–33. Trojano L, Fragassi NA, Chiacchio L, et al. (2004). Relationships between constructional and visuospatial abilities in normal subjects and in focal brain-damaged patients. J Clin Exp Neuropsychol 26: 1103–1112. Trojano L, Grossi D (1992). Impaired drawing from memory in a patient with visual associative agnosia. Brain Cogn 20: 327–344. Trojano L, Grossi D (1994). A critical review of mental imagery defects. Brain Cogn 24: 213–243. Trojano L, Grossi D (1998). ‘Pure’ constructional apraxia. A cognitive analysis of a single case. Behav Neurol 11: 43–49. Trojano L, Grossi D, Linden DEJ, et al. (2002). Coordinate and categorical judgments in spatial imagery. An fMRI study. Neuropsychologia 40: 1666–1674.

391

Turnbull OH, Laws KR, McCarthy RA (1995). Object recognition without knowledge of object orientation. Cortex 31: 387–395. Ungerleider LG, Mishkin M (1982). Two cortical visual systems. In: DJ Ingle, MA Goodale, RJW Mansfield (Eds.), Analysis of Visual Behavior. MIT Press, Cambridge, pp. 549–586. van Sommers P (1989). A system for drawing-related neuropsychology. Cogn Neuropsychol 6: 117–164. Vallar G (1998). Spatial hemineglect in humans. Trends Cogn Sci 2: 87–97. Vallar G (2001). Extrapersonal visual unilateral spatial neglect and its neuroanatomy. Neuroimage 14: S52–S58. Victoroff J, Ross GW, Benson DF, et al. (1994). Posterior cortical atrophy. Neuropathologic correlations. Arch Neurol 51: 269–274. Villa G, Gainotti G, De Bonis C (1986). Constructive disabilities in focal brain-damaged patients: Influence of hemispheric side, locus of lesion and coexistent mental deterioration. Neuropsychologia 24: 497–510. Wapner W, Judd T, Gardner H (1978). Visual agnosia in an artist. Cortex 14: 343–364. Warrington EK, James M (1991). VOSP, The Visual Object and Space Perception Battery. Thames Valley Test Company, Bury St. Edmunds. Warrington EK, James M, Kinsbourne M (1966). Drawing disability in relation to laterality. Brain 89: 530–582. Warrington EK, Rabin P (1970). Perceptual matching in patients with cerebral lesions. Neuropsychologia 8: 475–487. Wechsler D (1981). Wechsler Adult Intelligence Scale— Revised. Harcourt Brace Jovanovic, New York. Westheimer G (1996). Location and line orientation as distinguishable primitives in spatial vision. Proc Biol Sci 263: 503–508. Zakzanis KK, Boulos MI (2001). Posterior cortical atrophy. Neurologist 7: 341–349.

Handbook of Clinical Neurology, Vol. 88 (3rd series) Neuropsychology and behavioral neurology G. Goldenberg, B.L. Miller, Editors # 2008 Elsevier B.V. All rights reserved

Chapter 20

Optic ataxia and Ba´lint’s syndrome: neuropsychological and neurophysiological prospects LAURE PISELLA1,2, HISAAKI OTA1,3, ALAIN VIGHETTO1,2,4,5, AND YVES ROSSETTI1,2,5,6* 1

Institut National de la Sante´ Et de la Recherche Me´dicale, Bron, France

2

Universite´ Claude Bernard, Institut Fe´de´ratif des Neurosciences de Lyon (IFNL), Lyon, France 3

Sapporo Medical University Hospital, Sapporo, Japan

4 5

Hospices Civils de Lyon, Hoˆpital Neurologique, Lyon, France

Mouvement et Handicap, Plateforme IFNL-HCL, Institut Fe´de´ratif des Neurosciences de Lyon (IFNL) and Hospices Civils de Lyon, Lyon, France 6

Hospices Civils de Lyon, Hoˆpital Henry Gabrielle, St Genis Laval, France

20.1. Introduction Ba´lint’s syndrome is a clinical entity that combines variously a set of complex spatial behavior disorders following bilateral damage to the occipitoparietal junction. The core syndrome is a triad, composed of ‘optische Ataxie’— a defect of visually guided hand movements—‘Seelenla¨hmung des Schauens’—often referred to as psychic paralysis of gaze or spasm of fixation—and ‘ra¨umliche Storung der Aufmerksamkeit’—spatial disorder of attention. While optic ataxia has been isolated from the two other symptoms, a set of visuospatial perception deficits are associated with the two latter. Both diversity of terminology used in literature and bias in clinical descriptions, which often reflect a particular opinion of the authors on underlying mechanisms, add to the difficulty in describing and comprehending this rare and devastating syndrome. As the components are not elementary symptoms, and as they are not necessarily present in each case, indicating that they do not rely upon a single brain mechanism, the validity of the complex as a syndrome has been questioned (Rizzo and Vecera, 2002). Despite these flaws, Ba´lint’s syndrome can be identified with bedside examination and it allows a robust anticipation of lesion localization (Fig. 20.1).

*

The first reports of a deficit in grasping movements towards normally perceived objects appeared in the late nineteenth century (Crouigneau, 1884; Badal, 1888; Pick, 1898; see also De Renzi, 1989; Rizzo, 1993; Rizzo and Vecera, 2002). Ba´lint (1909) coined the term ‘optische Ataxie’ and described the case of a patient impaired when having to perform visually guided actions, especially with the right hand. The deficit is apparent in central vision but it is widely exacerbated in peripheral vision and the left hand remains skilful. Hence a visual origin can be discarded, as well as apraxia. As this ataxia can be compensated by a somatosensory exploration of the object like a blind person (e.g., Rondot et al., 1977; Perenin and Vighetto, 1988; see Fig. 20.2), it can be described as specifically ‘optic.’ In addition to this ataxia, Ba´lint’s patient presented with two other symptoms. ‘Seelenla¨hmung des Schauens’ was described as an extreme spatial restriction of visual attention. Although his patient exhibited no visual field defect and no oculomotor paralysis, he manifested no attention for visual events appearing in his peripheral visual field. This apparently concentric shrinking of visual attention (Michel and He´naff, 2004) allowed the patient to see only one object at a time and this remained true regardless of its size. Last, a lateralized ‘spatial

Correspondence to: Yves Rossetti, Institut National de la Sante´ Et de la Recherche Me´dicale, U864, Espace et Action, 16 avenue Le´pine, F-69676 Bron, France. E-mail: [email protected].

394

L. PISELLA ET AL.

Fig. 20.1. A typical bilateral lesion responsible for Ba´lint’s syndrome. The watershed infarct involved both medial part of the posterior parietal cortex (upper lesion) and lateral part of the occipital cortex (lower lesion). This patient exhibited an initial full Ba´lint’s syndrome which gradually resolved such that his final symptoms can mainly be accounted for by a unilateral left optic ataxia.

attention disorder’: orientation of attention in the extrapersonal space to the right of the body midline and neglect for stimuli lying to the left of the point he was fixating (De Renzi, 1989) which can now be described as unilateral neglect. Interestingly the optic ataxia was already thought to be independent from these two attentional disorders. These three symptoms constitute Ba´lint’s syndrome (Husain and Stein, 1988). Ba´lint’s patient had a bilateral parieto-occipital lesion and his lack of motor coordination was interpreted as the interruption of visual projections to the hand motor center. A related ‘visual disorientation’ syndrome was described a few years later by Holmes (Smith and Holmes, 1916; Holmes, 1918) in soldier patients with bilateral parietal lesions (see also Inouye, 1900, cited in Rizzo and Vecera, 2002). These patients exhibited a particular oculomotor disorder: wandering of gaze in search of peripheral objects and a difficulty in maintaining fixation. This gaze ataxia or apraxia was accompanied by a visual localization deficit, and by a complete deficit for visually guided reach-to-grasp movements, even when performed in central vision. This condition was viewed by Holmes as a visual orientation disorder resulting from a retinal or an extraocular muscle position sense deficit. The three elements of Ba´lint’s triad have been subjected to numerous interpretations. Ba´lint himself clearly interpreted optic ataxia as being an autonomous

symptom, and this was confirmed much later. His description of ‘Seelenla¨hmung des Schauens’ included both a difficulty of patients in finding visual targets with their eyes (wandering of gaze) and a visual capture by the target once fixated (spasm of fixation). The lateralized aspects of the attentional deficit can now easily be ascribed to unilateral neglect. As emphasized by De Renzi (1989), Holmes (1918) added to his description of patients with parietal lesions a deficit in oculomotor functions, which had been excluded by Ba´lint for his patient. This oculomotor deficit described by Holmes (1918) has often been incorporated into Ba´lint’s syndrome, and confounded with the ‘Seelenla¨hmung des Schauens’ most often translated in English as a ‘psychic paralysis of gaze.’ Hence the attentional disorders that were initially associated with this element of the triad have been grouped together with the attentional deficits resulting from unilateral neglect (He´caen and Ajuriaguerra, 1954). As De Renzi (1989) pointed out, ‘psychic paralysis of gaze’ appears to be an erroneous translation of Ba´lint’s description. The alternative translation proposed by He´caen and Ajuriaguerra (1954)—psychic paralysis of visual fixation, also known as spasm of fixation—provides an alternative emphasis to this symptom, and suggests that it can be clearly dissociated from intrinsic oculomotor disorders, as already argued by Ba´lint. Husain and Stein’s translation of Ba´lint’s description of the psychic paralysis of gaze corresponds to a restriction of the patient’s ‘field of view, or we can call it the psychic field of vision’ (Husain and Stein, 1988). Altogether these apparent subtleties have given rise to several systematizations of the oculomotor, perceptual, and attentional aspects of the syndrome. For example, He´caen and Ajuriaguerra (1954) distinguished the ‘psychic paralysis of fixation’ (or inability to look towards a peripheral target) from the disturbance of attention. However, these authors further distinguished between two types of attention disorders. They first outlined a general impairment of attention that corresponded to a selective perception of foveal stimuli. But they also emphasized the presence of a lateralized component of the attention deficit which can now be described as unilateral neglect. Alternatively, De Renzi (1989) distinguished two types of visual disorders in Ba´lint’s description. One of these corresponds to the lateralized deficit known as unilateral neglect, and the other to a nonlateralized restriction of visual attention which can be partly interpreted as simultanagnosia. His interpretation of the ‘Ba´lint–Holmes syndrome’ excluded the presence of intrinsic visuo-oculomotor deficits. Rizzo and Vecera (Rizzo, 1993; Rizzo and Vecera, 2002) on their side, focused their analysis on a ‘spatial disorder of attention,’ corresponding to simultanagnosia (Wolpert, 1924), and on the ‘psychic

´ LINT’S SYNDROME OPTIC ATAXIA AND BA

395

Fig. 20.2. The clinical examination of optic ataxia patients. The clinician stands behind the patient and asks them to fixate straight ahead. The clinician then successively presents target objects in the patient’s peripheral field of vision to be grasped with one hand or the other. This patient with right optic ataxia exhibits a gross deficit when reaching to right-sided objects with his left hand. Once he has missed the object, he exhibits exploratory movements comparable to blind subjects. This poor visuomotor performance can be contrasted with the ability of the patient to describe the object and his normal ability to reach towards central targets (from Vighetto, 1980).

paralysis of gaze,’ which they distinguished from oculomotor deficits and assimilated to ‘spasm of fixation’ or ‘ocular apraxia.’ With these three symptoms the authors associated a unilateral neglect and a concentric restriction of the attentive field. Our following analysis of the three elements of Ba´lint’s syndrome will first attempt to provide a coherent systematization and interpretation of the various disorders that correspond

to the spatial perception and attention aspects of the syndrome. Ba´lint’s syndrome is not just a rare neurological curiosity. It is gaining new interest from progresses in visual neurosciences as it provides some insight into the functional roles assigned to the neuronal populations of the occipitoparietal region. These functions include spatial perception, gating, and directing spatial attention, as

396

L. PISELLA ET AL.

well as spatial coding of eye and hand movements in the immediate extrapersonal space. In particular, numerous papers have focused their attention on isolated optic ataxia, as a human model for studying visuomotor transformations processed in the dorsal visual stream, presumably because of both clinical and scientific reasons. First, optic ataxia is more frequently encountered than Ba´lint’s syndrome and appears to be the most resistant symptom of the triad. Among minor forms of Ba´lint’s syndrome, those resulting from unilateral lesions mainly result in impaired visually guided manual reaching, a symptom ascribed to general visual disorientation in Holmes’ description (Riddoch, 1935; Brain, 1941), or as optic ataxia—a specific visuomotor disorder—following Ba´lint’s view (Garcin et al., 1967; Perenin and Vighetto, 1988). Second, optic ataxia has gained much interest since the two cortical streams of visual processing have been described and visuomotor functions have been ascribed to the parietal cortex. Rizzo has provided recent detailed reviews about the clinical validity of Ba´lint’s syndrome (Rizzo, 1993; Rizzo and Vecera, 2002). Both reviews emphasized the complexity of the syndrome and of its interpretation. Following De Renzi, our analysis of Ba´lint’s syndrome will only distinguish between visuoattentional disorders and optic ataxia. We will therefore focus our analysis on the need to clarify the attentional and perceptual contributions to the oculomotor disorders described by Ba´lint. No extensive review has recently been devoted to the interpretation of optic ataxia, despite the increasing interest in this disorder which has given rise to new approaches and stimulating steps forward. Therefore the present chapter will also attempt to synthesize these recent accounts of optic ataxia and to consider them in the framework of Ba´lint’s syndrome. Classic and recent data will be examined in order to address the following important issues: what is the basic pathophysiology of the oculomotor disturbances observed in Ba´lint’s syndrome; how does Ba´lint’s syndrome fit in with neurophysiological accounts of the parietal lobe; which aspects of action are impaired in optic ataxia; is it visuomotor or spatial in nature; is there a temporal dimension to optic ataxia; is optic ataxia an attentional or perceptual disorder?

20.2. The interdependency of perception, attention, and eye movements 20.2.1. Intrinsic oculomotor deficit after parietal lobe lesions? Eye movement disorders have been variously labeled ‘psychic paralysis of gaze’ (Ba´lint, 1909), ‘oculomotor disorders’ (Holmes, 1918), ocular motor apraxia

(Cogan and Adams, 1953), or psychic paralysis of fixation (He´caen and Ajuriaguerra, 1954). These nebulous terms reflect the difficulty in assigning these ocular motor disorders to a well-defined dysfunction, as well as the variety of eye movement problems observed from case to case. Gaze apraxia is characterized by severe abnormalities of generation of eye movements in response to visual targets in space, in the absence of ocular motor palsy, ascertained by full reflexive eye movements. Saccadic behavior is abnormal in rich (natural) environment array, which requires continuous selection between concurrent stimuli, but it may be normal in a simplified context, when for example the task is to direct the eyes to a peripheral LED in the dark (Guard et al., 1984). Eye movement recordings usually show several abnormalities, such as prolonged latency, fragmentation and hypometria of saccades, fixation drift, and absence of smooth pursuit (Michel et al., 1963; Girotti et al., 1983). The pattern of oculomotor scanning is highly abnormal during scene exploration (Zihl, 2000). Both accuracy of fixation and saccadic localization are impaired, and spatiotemporal organization of eye displacements does not fit with the spatial configuration of the scene to be analyzed (Tyler, 1968). The issue of whether the parietal lobe is specifically involved in oculomotor processes per se is recalled by the more recent literature about patients described with specific lesion of a ‘parietal eye field,’ with unilateral neglect or optic ataxia. Pierrot-Deseilligny and Mu¨ri (1997) have observed increased reaction times and hypometria for contradirectional reflexive saccades after lesion of the inferior parietal lobule. They have therefore postulated the existence of an oculomotor parietal region (Parietal Eye Field, see also Mu¨ri et al., 1996) whose lesion specifically affects the processes of planning and triggering of contradirectional reflexive saccades. These authors mention that the increase in reaction time for contradirectional saccades is shorter when the fixation point vanishes about 200 ms before the presentation of the target in the contralesional visual field (‘gap paradigm’) than in a condition of ‘overlap’ between the two visual locations. This effect suggests that the deficit may be linked to the attentional deficit of ‘visual extinction’ that consists of a preferential attention to the ipsilesional stimulus in conditions of attentional competition between two visual targets presented simultaneously. Consequently, the contralesional stimulus is not reported (Mattingley et al., 2000) or reported to appear later in a temporal order judgment task (Rorden et al., 1997). Patients with unilateral neglect have also been reported to exhibit late and hypometric leftward saccades (Girotti et al., 1983; Walker and Findlay,

´ LINT’S SYNDROME OPTIC ATAXIA AND BA 1997), when their saccadic accuracy is reported normal elsewhere (Behrmann et al., 1997). Finally, Niemeier and Karnath (2000) have shown that hypometry can be observed casually only for reflexive saccades triggered in response to left peripheral target presentation, leftward and rightward saccades being equivalent in amplitude in condition of free ocular exploration of visual scenes. By contrast, the strategy of exploration is clearly impaired in patients with unilateral neglect (Ishiai, 2002). No available result seems to rule out that these temporal and strategic deficits in neglect patients may result from a deficient allocation of attention to visual targets in the left periphery. Finally, patients with pure optic ataxia consecutive to damage of the superior parietal lobule are, by definition, impaired in visuomanual reach and grasp guidance within their peripheral visual field, without primary visual, proprioceptive, and motor deficits (Garcin et al., 1967; Jeannerod, 1986); this definition is supposed to also exclude oculomotor deficits. Altogether there seems to be no direct evidence that lesions of the parietal lobe can be responsible for intrinsic oculomotor deficit. This point is directly connected to the issues debated by Ba´lint and Holmes themselves. The following section proposes that deficits lying at higher levels may account for these apparent oculomotor deficits. 20.2.2. Cognitive origins for oculomotor symptoms? In our view, two main oculomotor disorders emerge from the clinical descriptions: one in time and one in space. First, the most constant observation in these patients is—in the case of unilateral lesions—an increase of latency for saccades in contralesional direction or—in the case of bilateral lesions—a poverty of eye movements, that may culminate in a condition often referred to as spasm of fixation, or visual grasp reflex. Patients stare open-eyed, with the gaze being locked to the place they are fixating, and they may only be able to disrupt such sticky fixation after a blink. Second, patients are usually able to move their eyes ‘spontaneously’ or on verbal command, while they are impaired in performing visually guided saccades. The more attention and complex visual processing the eye movement requires, the less it is likely to be performed. In this line, visual search behavior is particularly vulnerable. Accordingly, inactivation of the parietal saccadic region in monkeys (lateral intraparietal area: LIP) does not affect direct saccades to single targets (Li et al., 1999; Wardak et al., 2002). Hence, when patients are asked to move their eyes to a target suddenly appearing in the peripheral field, they may generate no movement,

397

or initiate wandering eye movements, that consist in erratic, and usually hypometric displacement of eyes in space, ending with incidental acquisition of the target. These two categories of eye movement disorder may indeed be attributed to a single deficit. Spatial disorder of attention (Ba´lint, 1909), restriction (De Renzi, 1989) or shrinkage of attention field (Michel and He´naff, 2004), or disorder of simultaneous perception (Luria, 1959) are equivalent terms designating a complex symptom, which can be viewed as a symmetrical limitation of visuospatial attentional resources. Patients do not seem to perceive visual targets located away from a small area, which is usually the area of foveation, despite preserved visual fields. They exhibit a reduction of ‘useful field of vision,’ operationally defined as the field of space that can be attended to while keeping central fixation (Rizzo and Vecera, 2002). This can be tested by asking patients either to direct their eyes or their hand to, or to name, objects presented extrafoveally. Evaluation using a motor response may be affected by concurrent optic ataxia and gaze apraxia, while verbal response more directly probes conscious/attentive perception. Generally, responses are more likely to be given after verbal encouragement, a finding that indicates that the deficit is not a consequence of a reduction of the visual fields but of attention scanning for noncentral events. Shrinkage of the attention field reduces detection of multiple objects and may restrict patients’ perception to one item at a time. Ba´lint’s patient was not able to perceive the light of a match while focusing on a cigarette until he felt a burning sensation. This limited capacity of attentive vision for only one object at a time does not depend upon the size of the object. This is another distinction from a visual field deficit. As a general consequence, patients fail to perceive at any time the totality of the items forming a visual scene. Performance in counting objects is accordingly altered. Description or copying of complex figures is laborious and slow, patients focusing serially on details, apprehending portions of the pictures with a piecemeal approach, but failing to switch attention from local details to global structures. Copying of images is accordingly composed of tiny elements of the original figure without perception of the whole scene. Using Posner’s paradigm, it was shown that parietal patients exhibit a defect in shifting spatial attention (Verfaellie et al., 1990), or in disengaging attention from fixated objects (Rizzo and Vecera, 2002), a difficulty which may be central for the visual grasp reflex to occur. Michel and He´naff (2004) have provided a comprehensive examination of a patient with bilateral PPC lesion whose initial Ba´lint’s syndrome had been reduced 20 years post onset to bilateral optic ataxia and a variety of attentional deficits that

398

L. PISELLA ET AL.

could all be interpreted as a concentric shrinking of the attentional field. Patients not only explore working space in a disorganized fashion but may also focus several times on the same object. This ‘revisiting behavior’ in unilateral neglect patients has been recently ascribed to an impairment of short-term memory for spatial location of items already explored (Husain et al., 2001; Driver and Husain, 2002) or visual remapping impairment (Pisella and Mattingley, 2004). Such impairment may lead for example to counting more dots than are presented on a test sheet (VSOP test: personal observation on patient C.F.). Alexia is often prominent, with difficulties in assembling words in a text, while letters and isolated words are usually well identified. Note also that even when a target is incidentally found in a visual scene, the target may be lost due to fuzzy perception and instability of fixation, and a new search pattern has to be activated. Perception has been reported as ‘vanishing’ in patients with simultanagnosia (Rizzo and Hurtig, 1987; Rizzo and Robin, 1990). When these patients foveate a steadily illuminated LED, during fixation time the LED rapidly disappears from conscious perception. We have proposed elsewhere (Pisella and Mattingley, 2004) that this phenomenon of intermittent perception in dorsal simultanagnosia may result from impairments of visual remapping mechanisms. During fixation, the target of visual fixation is processed within the ventral visual stream but may disappear from awareness. However this visual target may be being overwritten by other attended objects as a consequence of wandering visual attention when the patient is searching for other targets. Although blinking in these patients is often reduced, some patients learn unconsciously to close their eyes either to enhance perception of a vanishing object being fixated, or conversely to break fixation from one object so they can look at another (Gottlieb et al., 1991). In summary, it is very tempting to view both the visual grasp reflex and the wandering of gaze as direct consequences of the shrinking of the visual field. It is quite obvious that if one does not perceive any visual target in the periphery, one should not perform automatic saccade to these targets. Hence the gaze should remain anchored on a target once acquired (visual grasp reflex). Then if one is forced to find a specific target in the visual scene, then one would have to make blind exploratory movements as would be the case in tunnel vision. The shrinking of the visual field would therefore also account for the wandering of gaze. We therefore propose to identify three aspects of the posterior parietal symptomatology that exclude oculomotor disorders as a specific category of deficit. First, the orientation to the right described in Ba´lint’s report can obviously be viewed as a consequence of left neglect. Second, the

wandering of gaze and the visual grasp reflex appear to depend on the concentric shrinking of the attentional field, called simultanagnosia. This second component may appear as unilateral visual extinction in the case of unilateral lesions. Other symptoms such as visual vanishing, recently studied in patients with simultanagnosia (Rizzo and Hurtig, 1987; Rizzo and Robin, 1990) may be attributable to other functions, namely spatial working memory or remapping impairment. Indeed, even if this component has been described in patients with left neglect, this deficit appears not to be lateralized and to be linked to neglect consecutive to parietal lesion (Pisella et al., 2004). However, the question whether lateralized and unlateralized components (see Chapter 18) of parietal neglect result from the same region or nearby dissociable functional regions need to be further investigated. 20.2.3. Neurophysiology of parietal lobe functions In parallel to the study of neurological patients, functions of the parietal lobe have been experimentally investigated in the monkey. Milner and Dijkerman (1998) consider the report of Ferrier (1890) as the first lesion study that has revealed a role of the posterior parietal cortex (PPC) in visual functions. Following studies have reported in humans three types of deficits described as visuospatial, visuomotor and attentional. As emphasized by Milner and Dijkerman (1998), ‘landmark’ tests in which the spatial location of a cue indicated where the food could be found have been first used by Ettlinger and colleagues (Ettlinger and Wegener, 1958; Bates and Ettlinger, 1960) and later made popular by Pohl (1973) and Ungerleider and Mishkin (1982). After a bilateral lesion of the PPC, the monkeys were not able to find the food and they got lost even in a familiar environment. These deficits were designated as ‘visuospatial’ and considered to concern topographic orientation and estimation of relative spatial locations. Second, the monkeys showed deficits in reaching and grasping objects under visual control. Ettlinger and Wegener (1958) already mentioned that the deficit is not motor in nature since when the food has been grasped the monkeys perform accurate movements toward their mouth. Ettlinger and Kalsbeck (1962) concluded that the deficit is visuomotor (and not visuospatial) since only the contralesional hand is affected in both visual fields after unilateral posterior parietal lesions. Third, after bilateral PPC lesion, the monkeys also exhibited what the authors called ‘inattention to visual environment’ (Ettlinger, 1990). This shrinking of visual attention has been suggested later to be able to explain the deficits in the ‘landmark’ tests, since it should affect the comparison of the relative location of

´ LINT’S SYNDROME OPTIC ATAXIA AND BA the cue-object and the two positions, usually quite far from each other, where the food could be placed (Lawler and Cowey, 1987). Consequently, Ettlinger (1990) himself concluded that altogether these studies lead one to ascribe to the PPC both the function of visuomanual guidance (‘how’) and the function of visual attention but not the function of ‘spatial perception’ (‘where’). However, unilateral PPC lesion leads to an ipsidirectional bias of selective attention (Lynch and McLaren, 1989) which it is less easy to give as a possible explanation of the visuospatial deficits in the ‘landmark’ tests, also observed after right unilateral lesion in humans. A hemispheric specialization for space of the right hemisphere is usually advocated in humans to explain the rightward bias in the ‘landmark’ test after unilateral (right) lesion, the line bisection and the perceptual ‘landmark’ test being a specific test to diagnose unilateral spatial neglect. Accordingly, brain imaging (Fink et al., 2000) and TMS (Fierro et al., 2000) studies have revealed that this task involved in humans a specialized and lateralized network including the right inferior parietal lobule and the left cerebellum. By contrast, TMS applied unilaterally on the superior parietal lobule symmetrically causes an ipsidirectional bias of selective attention known in humans as ‘contralesional visual extinction’ (Pascual-Leone et al., 1994). One can further postulate that bilateral lesion of the superior parietal lobule in humans may cause the Ba´lint’s symmetrical shrinkage of attention.

20.3. Diverging or converging accounts of optic ataxia 20.3.1. ‘Optische ataxie’ and ‘ataxie optique’ Following Ba´lint, further reports about optic ataxia either referred to Ba´lint’s syndrome or to Holmes’ visual disorientation, but failed to acknowledge this symptom as a real entity (Riddoch, 1935; Brain, 1941; Stenvers, 1961). It is only in 1967 that optic ataxia was identified as a specific entity. ‘Ataxie optique’ was first empirically isolated from Ba´lint’s syndrome by Garcin et al. (1967) who proposed a number of conditions necessary for diagnosing ‘ataxie optique’: 1) The visual field should be spared in the area concerned by the visuomotor deficit. Objects presented in this visual field have to be seen, recognized, and named by the patient, and no binocular stereopsis deficit should be detected. 2) Proprioception should be spared. 3) There should be no intrinsic motor (and oculomotor) and no cerebellar deficit. Interestingly interest in this neurological condition has been raised following the discovery of actionblindsight (see review in Danckert and Rossetti, 2005) and the exploration of parietal functions in the behaving

399

monkey (Mountcastle et al., 1975; Faugier-Grimaud et al., 1978). Clinically patients with optic ataxia present with posterior parietal lesions and a deficit in reaching at visual goals presented in their peripheral visual field. Importantly this symptom is not frequently obvious to clinical observation as it can be compensated for easily by foveating the goal prior to movement (see also Rossetti et al., 2003). This visuomotor difficulty becomes obvious when it is properly tested and has often been contrasted with the intact visual capacities of the patients, as they can discriminate between objects and recognize visual stimuli readily (Rondot et al., 1977). The term ‘ataxie optique’ was initially used in French (Garcin et al., 1967) to describe pure cases with unilateral lesions and deficits restricted to the peripheral visual field, whereas ‘optische ataxie’ was used for patients with Ba´lint’s syndrome, where praxic aspects are difficult to disentangle from ataxic symptoms, including visuomotor problems in central vision. When optic ataxia is part of Ba´lint’s syndrome, the visuomotor deficit of the patient is apparent on both sides of their visual fixation. When optic ataxia is observed following a unilateral lesion, the symptoms predominate on the contralesional side, where both hands may be impaired for reaching. Unilateral optic ataxia is characterized by large errors produced when pointing to targets presented in the peripheral visual field contralateral to the lesion (‘field effect’). These motor errors are additionally found to be larger when the action is to be performed with the contralesional hand (‘hand effect’) (Perenin and Vighetto, 1988). Alternative names have been proposed for optic ataxia, such as visuomotor ataxia (Rondot et al., 1977), but the original term has persisted. Interestingly the distinction between ‘optische ataxie’ and ‘ataxie optique’ has been further emphasized in Japan by large group studies. Hirayama (1982) introduced the difference between ‘ataxie optique’ and ‘optische Ataxie’ in Japanese for the first time. As the individual terms themselves are identical, he recommended using the original expressions to discriminate between two neurological conditions (Hirayama, 1982). Patients with ‘optische Ataxie’ show misreaching with their contralesional hand in foveal and peripheral vision as in Ba´lint’s patient (see also Buxbaum and Coslett, 1998). In contrast, the most frequent patients with ‘ataxie optique’ have problems reaching in the contralesional visual field (Hirayama did not mention about hand effect in his definitions). Other researchers have subsequently referred to this distinction (Yamadori, 1985; Kawamura, 2001; Ishihara and Kawamura, 2004). Hirayama et al. investigated hemispheric differences for reaching behavior in a group of 11 optic ataxia patients (Hirayama et al., 1983; Hirayama, 1993). The results revealed that right-handed

400

L. PISELLA ET AL.

patients with right brain damage manifested misreaching in the left (contralesional) visual field with both hands, whereas patients with left brain damage showed misreaching for peripheral targets in the right visual field with only the right hand, as also reported by Perenin and Vighetto (1988). Another interesting group study reported by Maeshima et al. (1991) carefully evaluated 20 patients with ataxie optique resulting either from cerebrovascular accident or brain tumor. All but two patients manifested optische Ataxie in the acute stage. Results from lesion analyses showed no difference between patients with optische Ataxie or with ataxie optique only, nor could they find behavioral differences related to the laterality of lesions. The movement disorders of optic ataxia patients have been well documented. Several spatiotemporal abnormalities of visual guidance of hand movement have been described from clinical observations and kinematic recordings. The whole movement is both delayed and slowed. The trajectory of hand movement is grossly impaired in terms of direction and amplitude, while the hand is held largely open, the posture grip being inadequate with respect to the form and orientation of the target object. Movement usually fails to reach the goal, although corrections may be possible with groping movements until a contact eventually elicits grasping. Jeannerod (1986) reported that visually directed reaching movements made by these patients are inaccurate, and often systematically in one direction (usually considered to be to the side of the lesion). In addition, the kinematics of these movements is altered: their duration is increased, their peak velocity is lower, and their deceleration phase is longer. This alteration of movement kinematics becomes particularly apparent when vision of the hand prior to and during the movement is prevented. Restoration of visual feedback reduces reaching errors, but movements remain slower than normal. Object grasping is also altered by posterior parietal lesions. Patients misplace their fingers when they have to visually guide their hand to a slit (Perenin and Vighetto, 1988). During prehension of objects, they open their finger grip too wide with no or poor preshaping, and they close their finger grip when they are in contact with the object (Jeannerod, 1986; Jakobson et al., 1991). They exhibit deficits not only in their ability to reach to the object, but also in adjusting the hand orienting and shaping during reaching. In contrast, they seem to remain able to indicate the orientation of a stimulus by a wrist movement that is not aimed at the stimulus (matching task) (Jeannerod et al., 1994; Milner et al., 2001). These results strongly suggest that the posterior parietal cortex plays a crucial role in the organization of object-oriented actions, whether the visual processing required for a given action is concerned with spatial

vision (location) or with object vision (size or shape) (Jeannerod, 1988; Jeannerod and Rossetti, 1993; Milner and Goodale, 1995; Rossetti, 1998). One interpretation of optic ataxia has been that patients present a deficit in programming hand movements (Jakobson et al., 1991). Recent evidence rather suggests that deficits result primarily from a disruption of online visuomotor processing (Pisella et al., 2000; Gre´a et al., 2002). Difficulty in navigating around and avoiding obstacles may be related to the same dysfunction (Schindler et al., 2004). Altogether patients with optic ataxia may show optische Ataxie in the initial stages but most of them exhibit only ataxie optique at the chronic stage. The visually guided reaching behavior is obviously perturbed only when it is specifically searched for. The deficit affects both the hand transport phase of the action and the hand adaptation to the target object (wrist orientation and grip formation), and is most obvious when the contralesional hand reaches into the contralesional visual field. 20.3.2. Optic ataxia and functional areas of the parietal lobe As for anatomical substrates, the superimposition of the lesions of 6 left brain-damaged and 2 right braindamaged patients with pure optic ataxia using CT scans (Perenin and Vighetto, 1988) revealed a symmetrical converging region including the superior parietal lobule, in and above the intraparietal sulcus, and sparing the human inferior parietal lobule. The localization of the lesion causing optic ataxia led to this trouble being considered an impairment of the visual dorsal stream. Therefore it is often contrasted with visual agnosia as an impairment of the ventral stream. More recently, Karnath and Perenin (2005) have used a computerized method of superimposition of lesion scans and proposed a more ventral and posterior locus for optic ataxia, namely: the parieto-occipital junction (POJ) close to monkey PO (see Fig. 20.3) or V6a (Galletti et al., 1997). The lesion analysis provided by Hirayama et al. already suggested that the corticosubcortical area in the parieto-occipital lobe is the crucial focus for ataxie optique (Hirayama et al., 1983; Hirayama, 1993). He emphasized that the retinal signal is used for peripheral reaching while information about both the retinal and the eye position is used for reaching in central vision. Specifically, the angular gyrus integrates somatosensory, retinal, and eye-position information for visually guided movement. Based on this hypothesis, he proposed that ataxie optique may occur if the retinal information was not sent to the angular gyrus. In contrast, when both the retinal and the eye-position information

´ LINT’S SYNDROME OPTIC ATAXIA AND BA SC

401 BS

Eye

FEF, SEF V3d PO MIP 7a

AIP POa,LIP, VIP V1

MT

Post. Parietal

V3a periphV4 V2 V3v

FST MST S.T.S

7b

PFv (12)

PMd

Cing. SMA

Arm M1

AIP PMv

Hand Face

Frontal STP

Hipp.

V4

Pre-striate

PFd (46)

TEO Inf. Temporal

TE

Fig. 20.3. Overview of the visual-to-motor network. This illustration displays the possible substrates for dissociation and interactions between ventral and dorsal pathways driving information from V1 to M1. The dorsal and the ventral streams are depicted here in plain and dotted lines respectively. Bold arrows arise from areas receiving convergent dorsal and ventral inputs, either directly or indirectly. Further projections from areas receiving these mixed convergent inputs have also been represented in bold. Even though the posterior parietal cortex and the inferior temporal cortex receive a single direct projection from each other, they were not considered as mixed recipient areas. By contrast, areas in the frontal lobe receive parallel dorsal, ventral, and mixed projections. Specifically M1 receives only bold inputs, i.e., no pure dorsal projection. Abbreviations: AIP: anterior intraparietal area; BS: brainstem; Cing. Cingulate motor areas; d: dorsal; FEF: frontal eye field; FST: floor of the superior temporal sulcus; Hipp.: Hippocampus; LIP: lateral intraparietal area; M1: primary motor cortex; MIP: mesial intraparietal area; PIP: posterior intraparietal area; MST: medial superior temporal area; MT: mediotemporal area; PF: prefrontal cortex; PM: premotor cortex; SC: superior colliculus; SEF: supplementary eye field; SMA: supplementary motor area; STS: superior temporal sulcus, STP: superior temporal polysensory area; TE: temporal area; TEO: temporo-occipital area; v: ventral; V1: primary visual cortex, VIP: ventral intraparietal area. (Adapted from Rossetti et al. (2000) and Rossetti and Pisella (2002)—derived from Morel and Bullier, 1990; Schwartz, 1994; Schall et al., 1995; Tanne´ et al., 1995; Van Hoesen, 1982.)

were interrupted, this may lead to optische Ataxie. In the group of 20 patients described by Maeshima et al. (1991), the lesion analysis of 12 stroke patients showed that there was no apparent difference between two groups of patients with either optische Ataxie (n ¼ 10) or ataxie optique (n ¼ 2) in the acute stage. However, all but one ischemic patient were analyzed in terms of bleeding amount. This revealed that the patients with optische Ataxie had bled much more than those with ataxie optique. The common lesion of both stroke and tumor patients with ataxie optique was centered on the superior parietal lobule and it extended to the subcortical area in the angular gyrus. As compared to those with optische Ataxie, patients whose ataxie optique disappeared within three months had smaller lesions, located around the same focus. The production of typical visuomotor deficits by lesions and the recording of typical sensorimotor activities in the monkey posterior parietal cortex strengthened the conception of a dorsal visual system specialized for action (review in Jeannerod and Rossetti, 1993; Sakata

and Taira, 1994; Milner and Goodale, 1995; Jeannerod et al., 1995; Sakata et al., 1997; Rossetti, 1998; Milner and Dijkerman, 2000; Pisella and Rossetti, 2000). Mountcastle et al. (1975) described in monkey areas 5 and 7 three types of neurons (motor, visual, and visuomotor) confirming the role of the PPC in visuomotor transformations. Visual cells responded to the presentation of an object in their receptive field. The activity of visuomotor cells was more temporally correlated to the motor event than to the visual event and was specific to the presentation in their receptive field of an object only when it corresponded to the target of a reach movement. Motor cells rather coded for the direction of reaching arm movements (also described by Hyvarinen and Poranen, 1974). Consistent with the properties of neuronal populations recorded in this cortical region, Faugier-Grimaud et al. (1978; 1985) reported that the contralesional hand movements are impaired during reach and grasp movements after lesions limited to the monkey area 7. Similarly, after lesion of monkey area 5, deficits of reach and of manipulation of visual objects have been described (Stein,

402

L. PISELLA ET AL.

1978a; 1978b; Johnson et al., 1996). However, area 5 mainly receives proprioceptive afferences. Rushworth et al. (1997) reported that this area is rather crucial for movements toward tactile and proprioceptive targets and for movements guided in the dark. Since visuomotor guidance involves the integration of both visual and proprioceptive information (Rossetti et al., 1995; Desmurget et al., 1998), this does not exclude its participation in visually guided movements. The issue of the underlying visuomotor modules within the monkey and human PPC has later reached an even more detailed scale with the identification of multiple functional areas within the intraparietal and the occipitoparietal sulci. For example, Taira et al. (1990) and Sakata et al. (1995) described a population of cells in the anterior part of the intraparietal sulcus (AIP), selectively activated during the grasping phase and the manipulation of objects by the animal. Galletti et al. (1997) and Fattori et al. (2005) identified reachrelated neurons in an area V6a within the occipitoparietal sulcus. This area is now part of the ‘parietal reach region’ defined by Snyder et al. (2000) which also involved the medial part of the intraparietal sulcus (MIP). However, it does not appear to simply correspond to a posterior vs. anterior segregation for reach and grasp, respectively. Indeed, Galletti et al. (2003) and Fattori et al. (2004) have revealed both reach and grasp activities in area V6a. In addition, an area CIP has been identified in the caudal part of the intraparietal sulcus and related to grasping (Tsutsui et al., 2001 in humans; Tanne´-Garie´py et al., 2002 in monkeys). This may explain why an isolated grasping impairment has been reported in the human literature after anterior lesion of the PPC (Binkofski et al., 1998) but not an isolated reaching deficit after a more posterior lesion of the PPC. The visuomotor cells of the PPC also have a neuronal activity which can be correlated in different ways to the motor event. For example, many authors have reported that they are active specifically before movement initiation and they have consequently been ascribed to visuomotor planning (protocols involving a long period of time between presentation of the target and the go-signal: Andersen et al., 1997). Other authors mentioned that the activity of visuomotor cells increases during movement execution (McKay, 1992; Rushworth et al., 1998), activity which can be related to visuomotor control of an ongoing motor response. Finally, the issue of the reference frame used for visuomanual transformation within the PPC is currently the subject of many electrophysiological studies in monkeys putting forward the eye-centered reference frame (Batista et al., 1999; Buneo et al., 2002; Andersen and Buneo, 2002). As detailed below, similar debates concerning

interpretations (Where vs. How vs. visuomotor control) and reference frame of the visuomanual deficit consecutive to PPC lesion is presently emerging in human neuropsychology. 20.3.3. Visuomotor vs. visuospatial origin? Eye–hand coordination is necessary for reaching to visual objects in order to interact with the environment. Whether this functional link between saccade and reach (Neggers and Bekkering, 2001) implies common neural substrates within the posterior parietal cortex (PPC) remains a crucial question in the debate about the PPC being devoted to visuomotor programming (‘How’) or spatial visual processing (‘Where’) and attention (Andersen and Buneo, 2002; and Colby and Goldberg, 1999, respectively). Historically, the parietal Ba´lint– Holmes syndrome described concomitant ‘gaze’ and reach impairments, with the same interpretations of a visuomotor disconnection (‘How’; Ba´lint, 1909) or a ‘visual disorientation’ (‘Where’; Holmes, 1918). These two main types of interpretations are still current in literature on optic ataxia. On the one hand it has been argued that optic ataxia (OA) cannot be explained exclusively in terms of a solely visual or motor perturbation but rather involves the transformation of visual input into motor output (‘How’; Ba´lint, 1909; Garcin et al., 1967; Rondot et al., 1977; Vighetto, 1980; Vighetto and Perenin, 1981; Perenin and Vighetto, 1988; Milner and Goodale, 1995; Battaglia-Mayer and Caminiti, 2002; Rossetti and Pisella, 2002). The ‘How’ interpretation has been heralded on the basis of studies (Garcin et al., 1967; Vighetto, 1980; Vighetto and Perenin, 1981; Perenin and Vighetto, 1988) which have progressively demonstrated that visuomotor deficits for peripheral targets can occur independently from perceptual disorders, rather supporting the ‘optic ataxia’ definition of Ba´lint (1909). The case described by He´caen and Ajuriaguerra (1954) also argued for a dissociation between optic ataxia and the other symptoms of the triad. Despite a massive deficit of ocular fixation over the whole visual field, one of their bilaterally lesioned patient exhibited optic ataxia only with his left hand. Rondot et al. (1977) described the first group of patients with optic ataxia without Ba´lint’s syndrome and also argued for the visuomotor nature of the deficit. In particular, description of cases with optic ataxia specific to the contralesional hand supported the view that it cannot be attributed to a visual deficit. They proposed to use the term visuomotor ataxia rather than ‘optic ataxia,’ which they argued suggested the existence of an intrinsic sensory deficit. Interpretation of optic ataxia as a specific visuomotor disorder was further reinforced by the careful study of reaching

´ LINT’S SYNDROME OPTIC ATAXIA AND BA behavior by Vighetto (Vighetto, 1980; Vighetto and Perenin, 1981; Perenin and Vighetto, 1988). First, testing aurally guided movements showed that optic ataxia appears as a modality-specific reaching impairment (but see Guard et al., 1984). Second, although verbal discrimination of dot position was impaired in some patients, a direct causal link between these subtle deficits in visual space perception and the gross misreaching errors was excluded by the authors. Finally, patients showed reaching errors related to either or both a visual field effect and a hand effect. This combination of sensory and motor influences, as well as the localization of the underlying lesion in between the visual and the motor areas, supported the idea that the deficit lies at the visuomotor interface rather than solely at either the sensory or motor level. On the other hand, other authors have argued that the basic deficit of optic ataxia patients rather lies at the visual space representation level (‘Where’; Holmes, 1918; Godwin-Austen, 1965; Ratcliff and Davies-Jones, 1972; Kase et al., 1977; Ratcliff, 1990). Ratcliff (1990) emphasized that most visually guided reaching errors occur in the space contralateral to the parietal cortex lesion independent of a motor component and argued that a visual mislocalization remains the best explanation for optic ataxia. Indeed, Ratcliff and Davies-Jones (1972) had observed that the errors produced by unilateral OA patients show a clear spatial pattern, regardless of the arm used, but note that most of their patients exhibited no pure visual deficit (most of them also presented with associated symptoms such as somatosensory defects, apraxia, or unilateral neglect). In addition, no direct comparison in the same patient was provided between the reaching errors produced by the contralesional and the ipsilesional hands in the contralesional field. Furthermore, the ‘visual’ interpretation proposed by Ratcliff (1990)—that information derived from the contralesional visual field was systematically distorted as the result of the lesion—was definitely ruled out by a recent experiment performed in patients with optic ataxia, by differentiating the location of the target with respect to the gaze axis at the time of target encoding and at the time of the manual response. Khan et al. (2005) have compared the accuracy of manual pointing made to targets seen only in peripheral vision, seen only in central vision, and then virtually projected into the contralesional versus ipsilesional field, or even seen only in one field and then virtually projected into the opposite field. The projection of a given internalized target into another position relative to gaze was achieved by an eye movement bringing the target location away from the fovea or even into the opposite field. Pointing errors were observed only in conditions when the target was located in the contralesional visual field,

403

independent of its position at the time of encoding, hence independent of visual input. By contrast, the presence of similar increases of hypometry with target eccentricity for saccade and reach movements (Blangero et al. 2006a; Gaveau et al., 2007) suggests a common visuospatial deficit for eye and hand effectors and could be seen as a novel argument in favor of a ‘where’ interpretation. However, this deficit may still be specific for action and spare perception, as suggested by Perenin and Vighetto’s (1988) report of the relatively good performance of an optic ataxia patient on a task of location discrimination in peripheral vision. In brief, the former authors have built up their arguments on the highlighting of the ‘hand effect’ and the latter on the highlighting of the ‘field effect.’ As we will argue in our conclusion, these two components of optic ataxia—hence these two lines of interpretations—are not mutually exclusive. 20.3.4. ‘How’ vs. immediate visuomotor control? Following Perenin and Vighetto (1988), who argued that optic ataxia consists of a general impairment of visuomotor transformations, research on optic ataxia has been conceptually constrained by the visual brain in action theory (the ‘How’ interpretation), according to which optic ataxia was a specific visuomotor disconnection syndrome (Jeannerod and Rossetti, 1993; Milner and Goodale, 1995). However, many arguments have raised the necessity of determining more precisely the exact visuomotor process that is impaired in these patients and thus the precise role of the human dorsal stream in goal-directed action. The main new feature of these studies was to introduce the temporal dimension in the analysis of optic ataxia. As a matter of fact, it had been suggested earlier that dorsal stream processing was characterized by short-lived representations (Rossetti, 1998; Rossetti and Pisella, 2002). Also, a deficit of online visuomotor transformation has been highlighted (Pisella et al., 2000; Milner et al., 2001; Gre´a et al., 2002; Rossetti and Pisella, 2003; Milner et al., 2003; Rossetti et al., 2003; 2005). Recent studies have questioned the specificity of the deficits for peripheral targets and looked for abnormalities in reaching to central targets (Pisella et al., 2000). A patient with a bilateral optic ataxia (I.G.) due to a bilateral PPC lesion was shown to be able to reach accurately to targets presented in free vision (not only for pointing, but also for grasping: Milner et al., 2001; Gre´a et al., 2002). However I.G. was strongly impaired in the same free vision condition, when these targets or objects were experimentally displaced at the onset of her pointing or grasping movement (see Fig. 20.4). She could eventually reach the final target position only after

404

L. PISELLA ET AL.

Reach C

Saccade CR

B

A *

Target jumps at reach onset

Target jumps at saccade onset

Target jumps from C to CR

Target jumps from A to B or C Horizontal Position (deg.)

Control

30

B 20

A C

10

0

−10

0

Patient I.G.

30

200

400

600

800

200

400

600

Time (ms)

B

20 A

C

10

0

−10

0

Fig. 20.4. Analysis of hand and eye online visuomotor control in bilateral optic ataxia (patient I.G.). This figure describes the performance of a control subject and a patient with bilateral optic ataxia (I.G.) in two experimental conditions. First, static objects were presented in central vision and all subjects were able to reach appropriately to grasp them in either position C or R. Second, when the object was quickly moved at the time of movement onset controls were able to alter their ongoing trajectory and reach for the final location of the object. The patient with bilateral optic ataxia was specifically impaired in this condition and produced a serial behavior. She performed a whole movement to the first location of the object (C), then followed by a secondary movement towards the second location (R). The time of target grasping was subsequently delayed with respect to stationary targets and control performance (from Gre´a et al., 2002; see also Pisella et al., 2000). Similarly, her saccadic behavior (on the right: from Gaveau et al., 2007) consisted of two corrective saccades, in addition to the primary saccade. The first ‘corrective’ saccade generated was directed to the initial target location (A) with no reaction time increase (i.e., as if the target had not been displaced), then a second late corrective saccade achieved visual capture of the target with a delay with respect to stationary targets and control performance. This pathological behavior (shown by a black arrow, to be compared to the control performance shown by a red arrow) reveals a core deficit of online integration of visual target location.

completing her initially programmed movement and using slow and intentional corrective processes (Pisella et al., 2000; Gre´a et al., 2002). In addition, the fast unwilled corrections produced by normal subjects in response to the target jumps (i.e., by ‘automatic pilot’; Pisella et al., 2000) were fully suppressed in I.G. The same pattern of impairment has been confirmed in a second patient with bilateral optic ataxia (patient A.T.; Rossetti and Pisella, 2003). To summarize, these experiments demonstrate that, at least in ecological conditions where patients can see their hand, the main deficit of

optic ataxia may result from an impairment of real-time visuomotor transformation sustained by the dorsal stream, which can be expressed as a deficit in automatic visuomotor adjustments or in visuomotor programming under high temporal constraints (Rossetti et al., 2003). A related paradoxical improvement of visuomotor performance in these patients was observed for pointing actions (Milner et al., 1999; Rossetti et al., 2005) as well as for the grasp component (Milner et al., 2001; 2003). This improvement (opposite to the effect of delays in normal subjects) was postulated to result from a ventral

´ LINT’S SYNDROME OPTIC ATAXIA AND BA stream contribution to action (Milner et al., 2001; but see Rossetti et al., 2003). An interesting question that leads from this is whether it is possible to generate a conflict between this sustained cognitive representation and short-lived motor representations. An experiment was designed in which an object was presented for 2 s, then hidden behind a panel for 8 s, then shown again. This procedure improved her grip scaling and pointing accuracy with respect to an immediate action condition (Milner et al., 2001; Rossetti and Pisella, 2002; 2003; Rossetti et al, 2005). Then a special session was performed in which, in some trials, a small object could be unexpectedly replaced by a large one, or vice versa. In other sessions, the target to be pointed at could be displaced during the memory delay. The specific question was whether the grip formed by I.G. would follow the size of the present object or that of the internal representation formed after the presentation of the initial object in the same trial. Analysis of the pointing trajectories and of the grip formation profiles clearly showed that her actions were initially tailored to her internal representation rather than to the actual external world (Rossetti et al., 2005). Control subjects tested in the same conditions produced delayed actions that were adapted to the object present in front of them. These results clearly confirm that dorsal and ventral visuomotor representations have different time constraints and that optic ataxia corresponds to a specific disruption of immediate visuomotor control mechanisms (see Rossetti et al., 2003). In sum, optic ataxia appears to be modulated by two main factors. It is overall most characteristic to the peripheral visual field and to immediate visually guided actions. Interestingly these two conditions exert a common pressure on action control; in both cases the motor program is not optimally specified and therefore online control plays a crucial role in accuracy control. As we have seen earlier, patients with optic ataxia exhibit an online motor control deficit (Pisella et al., 2000; Gre´a et al., 2002) that may explain why this syndrome is associated with the visual periphery and immediacy and improved in central vision and in delayed conditions (Rossetti et al., 2003). 20.3.5. A double dissociation between optic ataxia and visual agnosia? It follows from the previous sections that optic ataxia cannot be simply taken as a deficit of visual action in general. Although it has been grossly associated with a vision-for-action system that can be distinguished from a vision-for-perception system, patients remain typically accurate under ecological conditions, i.e., when the object to be grasped can be seen centrally

405

(Rossetti et al., 2003). As a matter of fact, there are only rare occasions in everyday life when actions are performed using peripheral vision (e.g., the first and last step of a staircase, dual tasks like reading while drinking coffee, power gearing, shaking hands, or fast responses). Hence patients with pure optic ataxia exhibit virtually no deficit in everyday life. Further, the idea that optic ataxia (OA) and visual agnosia (VA) can be considered as forming a double dissociation has been largely challenged recently. Convincing neuropsychological evidence is best provided by an anatomical ‘double dissociation,’ where a lesion of structure X disrupts function A while sparing function B, and a lesion of structure Y affects function B while function A remains intact. Teuber (1955) argued that a double dissociation indicates some specificity of function, e.g., between anterior and posterior brain lesions. These definitions imply that double dissociated patients have to be tested in identical conditions. Let us consider here the case of optic ataxia and visual agnosia in the light of the results presented in Fig. 20.4, which can be examined in two ways. First, one can look at within-pathology dissociations between perception and action. If we consider visual agnosia, there is good evidence that patients are impaired for object recognition (by definition) in natural exploration condition, whereas it has been shown that they may exhibit preserved visuomotor ability when simple goal-directed actions are performed in central vision under simple laboratory conditions (Goodale et al., 1991). Therefore it can be concluded that visual agnosia may be viewed as an instance of dissociated vision-for-perception and vision-for-action systems. In fact, lesion of the ventral stream certainly impairs visual recognition but also has heavy consequences for action (see the description of case S.B. in Leˆ et al., 2002), sometimes even more than optic ataxia itself that can be easily compensated by foveating the target goal objects and slowing the goal-directed movements (see review in Rossetti et al., 2003). Now let us consider the case of optic ataxia. It is widely acknowledged that these patients are impaired in reaching to visual objects (by definition) but this deficit is mostly observed in peripheral vision even in bilateral patients (Perenin and Vighetto, 1988; Ratcliff, 1990; Milner et al., 1999; Rossetti et al., 2003; 2005). Unfortunately visual perception has not been extensively explored in these patients. Formally, it is not warranted to claim that optic ataxia is an action-specific impairment, as action and perception have mainly been explored under different conditions. Actually, two recent studies indicate that perception is impaired in the peripheral visual field of optic ataxia patients (Michel and He´naff, 2004; Rossetti et al., 2005). If these results are confirmed

406

L. PISELLA ET AL.

Object recognition Reaching Grasping Delayed reaching Delayed grasping Pantomimed grasping

Vision

Optic ataxia

Central Peripheral Central Peripheral Central Peripheral Central Peripheral Central Peripheral Central Peripheral

Preserved ? Impaired ? Preserved IMPAIRED Preserved IMPAIRED Impoverished Improved ? Improved ? Improved

Visual agnosia IMPAIRED ? Preserved ? Preserved ? Impoverished ? Impoverished ? Impaired ?

? ?

Fig. 20.5. Summary of the impairment found in optic ataxia and visual agnosia. The canonical deficits found for the two conditions are depicted in capital letters. The bold boxes show the complementary abilities usually contrasted with these deficits. Black arrows are thus suggestive of dissociations, but white arrows point out missing data that are necessary to validate such dissociations.

then optic ataxia cannot be taken as evidence for dissociated perceptual and motor functions. One possible alternate view is that optic ataxia can be viewed as a dissociation between central and peripheral vision (Rossetti et al., 2003). Second, one can examine between-patients dissociation and analyze how they relate to the perception–action issue. As highlighted in bold in Fig. 20.5, impairment for action is emphasized in optic ataxia and a deficit for visual recognition in visual agnosia. But is this evidence sufficient to make the case for a proper double dissociation? Patients with optic ataxia do not exhibit obvious deficits in object recognition in central vision. Therefore one can argue for a simple dissociation: patients with visual agnosia are impaired in visual object recognition in central vision while patients with optic ataxia are not. Note that object recognition has never been tested in peripheral vision either in optic ataxia or in visual agnosia. When vision-for-action is considered, it is obvious that the two types of patients have not been tested in identical conditions. While reaching movements are impaired in peripheral viewing conditions in optic ataxia, testing is only available in central vision for visual agnosia (see pointing and reaching lines in Fig. 20.5). The visuomotor abilities of patients with optic ataxia in central vision has shown no or subtle visuomotor reach-and-grasp deficits under basic conditions (Milner et al., 2001; Gre´a et al., 2002). Deficit of automatic/online visuomotor control were revealed in central vision when a target jump was synchronized with the start of reach-and-grasp movement execution and asked for visuomotor adjustments with high temporal constraint. Overall, these studies have confirmed that, in addition to central/peripheral vision, time is another crucial factor influencing the visuomotor abilities of optic ataxia patients.

Evidence coming from both human neuropsychology and monkey data casts further doubts on the validity of a simple double dissociation between perception and action because they argue for a far more complex organization with multiple parallel visual-to-motor connections (Pisella et al., 2006): 1. a dorso-dorsal pathway (involving the most dorsal part of the parietal and premotor cortices): for immediate visuomotor control, with OA as the typical disturbance; 2. a ventral stream–prefrontal pathway (connections from the ventral visual stream to prefrontal areas, bypassing the parietal areas): for immediate control (involving spatial or temporal transpositions), with VA as the typical disturbance; preserved visuomanual guidance in patients with VA is restricted to immediate goal-directed guidance; they exhibit deficits for delayed or pantomimed actions; 3. a ventro-dorsal pathway (involving the more ventral part of the parietal lobe and the premotor and prefrontal areas): for complex planning and programming relying on high representational levels with a more bilateral organization or an hemispheric lateralization and with mirror apraxia, limb apraxia, and spatial neglect as representatives. The different temporal constraints, reference frames, and integrative capabilities of these three parallel visuomotor pathways are keys to interpreting the neuropsychological deficits. 20.3.6. Reference frames for optic ataxia? Initial papers about optic ataxia only provided a qualitative description of the visuomotor deficit. In unpublished experiments, Vighetto (1980) was the first

´ LINT’S SYNDROME OPTIC ATAXIA AND BA researcher to describe pointing accuracy to a target array of 6 targets arranged along the frontoparallel axis, two in the ipsilesional visual field, four in the contralesional visual field. It was shown that patients committed undershoot pointing errors in the contralesional visual field and overshoot pointing errors in the ipsilesional visual field, that have been interpreted by Jeannerod (1986) to be toward the side of the lesion. Further investigations have been restricted to this frontoparallel axis but have quantitatively described pointing errors performed across several locations of the visual field. They all reported a reliable increase of absolute error with target eccentricity (Milner et al., 1999; Rossetti and Pisella, 2002; Revol et al., 2003; Milner et al., 2003; Rossetti et al., 2005). A specific description of the target eccentricity effect was provided in Rossetti et al. (2005). It was shown that the absolute and the angular errors (measured in body coordinates) increased together with target eccentricity. Interestingly the amplitude of the reaches was not affected by target eccentricity. This description suggested that pointing biases observed in optic ataxia may correspond to an underestimation of the target eccentricity with respect to the body midline. Ratcliff and Davies-Jones (1972) described 24 patients with unilateral or bilateral lesions, of which a few only exhibited a pure optic ataxia. In their report they presented an illustration of the consistent pointing pattern obtained in two of these patients. Most of their error vectors converged towards the central fixation point (Ratcliff and Davies-Jones, 1972: figures 3 and 4). We recently tested pointing performed with left and right hands by pure unilateral optic ataxia patients with a bidimensional target array (Ota et al., 2002; 2003; 2007). Targets were presented on a 24-dot virtual matrix comprising 12 points on each side of a central fixation point. The 2D direction and the amplitude of the error vectors were recorded. This design allowed us to disentangle the egocentric (contraction of pointing towards the sagittal body axis) and the retinotopic (contraction of pointing towards the eye fixation) hypotheses. We confirmed in a group of four left brain-damaged and three right brain-damaged optic ataxia patients that error vectors are oriented toward the fixation point (i.e., towards the fovea). This observation fits with recent data showing that the ocular position is a major reference frame for sensorimotor transformation within the PPC. Indeed, monkey electrophysiology and functional magnetic resonance imaging findings suggest that in the PPC each hemisphere represents contralateral space for pointing in eye-centered coordinates (Batista et al., 1999; Sereno et al., 2001; Medendorp et al., 2003), which predicts that a PPC lesion could produce spatial deficits that are retinotopic. Recently, Khan et al.

407

(2005) confirmed in two unilateral optic ataxia patients that the visuomotor errors corresponding to the field effect depend on the updated target location with respect to the instantaneous eye position, hence expressed in an oculocentric reference frame. Gaveau et al. (2007) recently addressed the saccadic behavior of bilateral OA patients using a ‘look and point’ task in which the need for fast motor control was stressed by a target jump synchronized to primary saccade onset. The main aspect of their saccadic deficit was the impaired fast control of the saccadic sequence (see Fig. 20.6). Indeed, in control subjects, an update of the visual error takes place within a time gap of only about 150 ms, between the end of the primary saccade and the initiation of the corrective saccade (Prablanc et al., 1979; Becker and Ju¨rgens, 1979; Gaveau et al., 2007). By contrast, patient I.G. presented in most trials an increased number of corrective saccades to achieve capture of the displaced visual target (‘serial’ behavior). Strikingly in these trials, her first ‘corrective’ saccade was generated with no reaction time increase and was directed towards the initial (extinguished) target location. Clearly, this observation indicated that the oculomotor system did not have immediate access to the new retinal target location. Interestingly, the ‘serial’ saccadic behavior exhibited by patient I.G. is directly comparable to her reaching behavior described in Pisella et al. (2000) and Gre´a et al. (2002) (see Fig. 20.6). The second aspect of the oculomotor deficits described by Gaveau et al. (2007) in OA patients was the hypometry of primary saccades that increases with target eccentricity. Again, pointing data from previous studies involving patients I.G. and A.T. also revealed hand movement hypometric errors that increased with target eccentricity (Milner et al., 1999; 2003; Rossetti et al., 2005). This similarity between the saccadic and the reach deficits in OA also supports the use of the oculocentric reference frame in both visuo-ocular and visuomanual transformation. Taken altogether, the similar saccade and reach deficits concerned the initial target localization in peripheral vision (pathological increase of eye and hand hypometry with target eccentricity) and the fast updating of target localization in perifoveal vision (absence of fast corrections both for hand and eye movements). Interestingly, the POJ region, which has recently been proposed as the focus of lesions in a large group of OA patients (Karnath and Perenin, 2005), is specifically activated in relation to reaching movements performed by normal subjects in peripheral vision (Prado et al., 2005). Furthermore, the same POJ region has been involved in dynamic updating of the eye-centered spatial representation of peripheral pointing targets (Medendorp et al., 2003). Therefore, POJ is a potential anatomical

408

L. PISELLA ET AL.

LEFT HAND

RIGHT HAND

150

150

100

100

50

50

y (mm)

y (mm)

Control subjects

0 −50

−100 −150 −300

0 −50

−100 −200

−100

0 x (mm)

100

200

300

−150 −300

−200

−100

0 x (mm)

100

200

300

−200

−100

0 x (mm)

100

200

300

−200

−100

0 x (mm)

100

200

300

150

150

100

100

50

50

y (mm)

y (mm)

Right-hemisphere lesion patients

0 −50

−100 −150 −300

0 −50

−100 −200

−100

0 x (mm)

100

200

300

−150 −300

150

150

100

100

50

50

y (mm)

y (mm)

Left-hemisphere lesion patients

0 −50

−100 −150 −300

0 −50

−100 −200

−100

0 x (mm)

100

200

300

−150 −300

Fig. 20.6. An oculocentric reference frame. Optic ataxia has been extensively studied for unidimensional target arrays. However Ratcliff’s (1990) description suggested that patients with parietal lesions (and optic ataxia associated with several other deficits) may exhibit peculiar patterns of pointing errors in a frontal 2D target array. Ota et al. (2002; 2007) have investigated seven patients with pure optic ataxia and found that they all produced consistent pointing errors to peripheral visual targets. This figure depicts the group analysis of 2D pointing in the frontal plane. The red squares represent the targets, the green diamond indicates the fixation point, the ellipses illustrate the subjects’ variability (95% confidence). The matrix linking the dots actually reached by the subjects allows the visualization of the distortion resulting from visuomotor transformations. The first two graphs are for the control group, the next two for the right-hemisphere lesion patients and the last two for the left-hemisphere lesion patients. Graphs on the left side of the figure correspond to pointing with the left hand and graphs on the right side to pointing with the right hand. The control group shows an accurate pointing to all targets, whereas the two optic ataxia groups exhibit a clear undershooting of their visuomanual performances in the contralesional hemifield for both hands. This result shows that the direction of the errors was clearly directed towards the fovea and that the magnitude of these errors increased with target eccentricity. These results are compatible with the idea that optic ataxia is mainly expressed in an oculocentric reference frame.

´ LINT’S SYNDROME OPTIC ATAXIA AND BA

409

False alarms

20

detection

30

False alarms

40

correction

50

Occurrence

candidate to subserve a core visuospatial mechanism (‘where’) whose lesion would similarly affect eye and hand movements. However, such a unified ‘where’ interpretation is not sufficient to explain that visuomotor errors also appear in the ipsilesional visual field with the contralesional hand (hand effect of optic ataxia). Even if most OA cases exhibit both field and hand effects, a single-case observation of isolated hand effect suggests that they can be dissociated (see Pisella et al., 2006). Accordingly, we wish to propose that the historical functional interpretations of the OA deficits (‘Where’ versus ‘How’) are not incompatible. Along this line, Gaveau et al. (2007) argued that OA impairment corresponds to the addition of two dissociable components: 1) a visuospatial ‘updating’ deficit common to eye and hand movements, and 2) a specific visuomanual deficit (hand effect) corresponding to a proprioceptive mislocalization of the ataxic hand (Blangero et al., 2007). These deficits could correspond to the impairment of two anatomical modules demonstrated in normal subjects by Prado et al. (2005): 1) an ‘accessory’ module located at the POJ and specifically activated in relation to reaching movements performed in peripheral vision, and 2) a ‘main’ reach-related module located more anteriorly and always activated for reaching in central as well as in peripheral vision. The POJ may also correspond to the posterior region correlated with saccades and lying within the parietal reach region (Schluppeck et al., 2005) and with covert attentional shifts (Silver et al., 2005). Gaveau et al. (2007) proposed that this POJ region codes target location in oculocentric coordinates, and that the resulting visuospatial signal is used directly for the planning of the sequence of saccades and also for ‘updating’ the manual reach plans. The observation of pointing errors in OA patients depending on the target location in an oculocentric reference frame (Ota et al., 2002; 2003; 2007; Khan et al., 2005; Fig. 20.7) and the case of a parietal patient systematically pointing toward eye fixation (‘magnetic misreaching’: Carey et al., 1997) are compatible with such a hypothetical model of visuomanual transformation. This visuomanual transformation involving an updating of the reach plan based on the target–eye error may be particularly relevant for fast visuomotor control. The demonstration of high-level proprioceptive impairment in OA (mislocalization of the ataxic hand: Blangero et al., 2007) allows us to interpret misreaching consecutive to PPC damage as resulting from an impaired spatial integration of both visual (target) and proprioceptive (hand) position information. This result further demonstrates that the eye-centered representations used for visuomanual planning within the PPC (Buneo et al., 2002; Medendorp et al., 2003) can integrate proprioceptive as well as visual information and thus correspond to

10 0 Trajectory updating

Verbal report

Fig. 20.7. Perceptual vs. motor deficit in optic ataxia. Patients with optic ataxia were tested for their ability to process visual information for online motor control. They were shown a visual target for 2 s in the peripheral visual field. The target was then hidden for 5 s and was shown again. The patients were instructed to point at it immediately after the second presentation. Following a first block of trials during which the first and the second locations of the target were identical, a second block of trial included (20%) incongruent trials, in which the two locations differed by up to 30 degrees. Healthy controls were not affected by the presence of the first target and reacted only to the second location. Three patients were tested. One unilateral patient exhibited no deficit for either visuomotor or perceptual responses. The two bilateral patients initiated their reaches on the basis of the memorized information rather than the present target location. One bilateral patient performed a limited amount of trajectory updating but never perceived the target changes in location during the memory delay. The performance of the other patient is given here for kinematic and verbal reactions to the target jump. The patient performed numerous trajectory corrections for incongruent trials with respect to congruent trials, but her perceptual performance appeared to be even poorer.

visuoproprioceptive interfaces. Altogether, converging views from neuropsychology and neurophysiology lead to call attention to the contribution of the oculocentric reference frame to visuomanual transformations and to present the ‘where’ and ‘how’ interpretations of optic ataxia as complementary rather than exclusive.

20.4. Future prospects Boundaries between the symptoms of Ba´lint’s syndrome have been repeatedly questioned. Rizzo emphasized the complexity of Ba´lint’s syndrome and of its interpretation, and underlined the need for further investigating its attentional dimension, contributing working memory, or remapping deficits (Husain et al., 2001; Wojciulik et al., 2001; Pisella and Mattingley, 2004) and associated eye movement signals as well as object

410

L. PISELLA ET AL.

structure identification deficits (Rizzo, 1993; Rizzo and Vecera, 2002). Interestingly a shrinking of the functional visual field was precisely defined in Ba´lint’s case report and well documented by Michel and He´naff (2004). This symptom will require further investigation to be disentangled (or not) from simultanagnosia. It is fair to acknowledge that recent research on optic ataxia has focused on the visuomotor function. Not only has the perception–action dichotomy tentatively matched onto the ventral–dorsal visual pathways played a crucial role over the last 15 years by suggesting that optic ataxia was the archetype of pure visuomotor deficits (Jeannerod and Rossetti, 1993; Milner and Goodale, 1995), but the main aim of most previous analyses of optic ataxia was to isolate a pure visuomotor symptomatology from the complex Ba´lint’s syndrome (Rondot et al., 1977). Most of the recent studies of optic ataxia have emphasized the contrast between preserved perception and impaired visuomotor behavior. It should be underlined however that the severe deficit described for immediate actions does not appear to be specific to visuomotor functions. The findings that patients may also be unable to perceptually process the change in object location (Rossetti et al. 2005, Fig. 7) and the description of perceptual deficits in a bilateral case (Michel and He´naff, 2004) claim for a reconsideration of the pure visuomotor status of optic ataxia. In some cases with bilateral lesions, disordered visuomotor coordination may interfere with several daily activities, such as drawing, writing, eating, or filling a glass. For example, patients may be unable to draw a line between two points or to pick up a piece of food with a fork. Such deficits may simply result from the visuospatial deficits described earlier, that are frequently associated with bilateral optic ataxia. Future experiments should investigate whether these findings are specific to bilateral cases or whether optic ataxia per se may be accompanied by perceptual deficits. Recent data suggest that unilateral perceptual deficits can be found in unilateral patients when specifically tested in peripheral vision (Blangero et al., 2006b). Whether these perceptual deficits can be accounted for by a defective covert orientating of focal visual attention remains to be tested (Striemer et al., 2006). In the Ba´lint (1909) report it was stated that there was no visual memory deficit. However no recent investigation appears to have specifically addressed this issue in optic ataxia patients. Taken altogether the recent findings made in optic ataxia tend to lower the boundary drawn between optic ataxia and the other symptoms of Ba´lint’s syndrome. The question about the very definition of ‘visual disorientation’ remains open nowadays and the near future should provide interesting answers to this question by coupling investigations of arm and eye movements

with attentional and perceptual testing in the contralesional visual field of unilateral optic ataxia patients. Finally, although optic ataxia is described as a specific visuomotor transformation deficit, it may also be demonstrated for non-visually guided movements. In contrast to movements directed to visual targets, patients can point precisely with a finger to their body parts that are touched by the examiner, indicating that somesthetic–motor coordination is spared. However, recent investigations have shown that once proprioceptive targets are to be located as targets in space—to be pointed to with the other hand—patients with optic ataxia produce large pointing errors that follow the field effects described for visual targets (Blangero et al., 2007). The exclusion of higher-level proprioceptive integration deficits in OA is usually based upon the patients’ ability to grasp their thumb or their nose with their eyes closed. This calls for grossly locating targets in body coordinates, whereas proprioceptive pointing experiments (Blangero et al., 2007) permitted a more quantitative evaluation of reaching errors and allowed us to test for a specific impairment in the spatial transformation of proprioceptive information, which may be considered as a stimulus of peripersonal space. In addition, identification of the nature of the optic ataxia hand effect predicts errors linked to the use of the contralesional ataxic hand, independent of the nature of the target stimulation, hence ataxic errors also toward targets of different modalities reaching without vision of the hand may be even more impaired than reaching under visual feedback, and some patients may show in addition auditory ataxia (Guard et al., 1984). Performance may vary according to the hand, the sensory or crosssensory modality, but also to the action space related to the body (Valenza et al., 2004). These observations indicate that optic ataxia may be understood as a dysfunction of supramodal sensorimotor transformation control of movements in the immediate peripersonal space. In patients with unilateral lesions harboring optic ataxia, functional consequence is modest, as visuospatial functions are mostly spared and reaching is normal when performed in the natural, central fixation. On the other hand, consequences of full Ba´lint’s syndrome are devastating. Functional prognosis is poor, as a result of bilaterality or diffusion of lesions that usually precludes significant recovery. However, spontaneous recovery can occur, after a delay ranging from weeks to years (Allison et al., 1969; Montero et al., 1982; Pisella et al., 2000; Michel and He´naff, 2004). Even in these cases, recovery is partial (Michel and He´naff, 2004), leaving impaired simultaneous perception and reading difficulties (Allison et al., 1969). Evaluation of treatment procedures is to be developed. Reports of

´ LINT’S SYNDROME OPTIC ATAXIA AND BA beneficial retraining are scarce and mostly limited to single cases (Perez et al., 1996; Al-Khawaja and Haboubi, 2001; Kerkhoff, 2001; Rosselli et al., 2001). Visual exploration and fixation has partly improved after systematic training of oculomotor functions in three patients with Ba´lint’s syndrome (Zihl, 2000). This improvement seems transferable to daily activities, as these patients have gained better ability to find their way in familiar surroundings. These data should encourage development of rehabilitation programs but emphasize the need for further pathophysiological clarifications of the syndrome.

Acknowledgements The authors with to thank Dr Franc¸ois Cotton (CREATIS) for providing the 3D MRI reconstruction shown in Fig. 20.1, Ferdinand Binkofski, Annabelle Blangero, Vale´rie Gaveau, Denis Pe´lisson, Patrice Revol, and Philippe Vindras for stimulating discussions. This work was supported by INSERM and Hospices Civils de Lyon.

References Al-Khawaja I, Haboubi NH (2001). Neurovisual rehabilitation in Ba´lint’s syndrome. J Neurol Neurosurg Psychiatry 70: 416. Allison RS, Hurwitz LJ, et al. (1969). A follow-up study of a patient with Ba´lint’s syndrome. Neuropsychologia 7: 319–333. Andersen RA, Buneo CA (2002). Intentional maps in posterior parietal cortex. Annu Rev Neurosci 25: 189–220. Andersen RA, Snyder LH, Bradley DC, et al. (1997). Multimodal representation of space in the posterior parietal cortex and its use in planning movements. Annu Rev Neurosci 20: 303–330. Badal J (1888). Contribution a` l’e´tude des ce´cite´s psychiques: Alexie, agraphie, he´mianopsie infe´rieure, trouble du sens de l’espace. Arch Ophthalmol 140: 97–117. Ba´lint R (1909). Seelenla¨hmung des Schauens, optische Ataxie, rau¨mliche Sto¨rung der Aufmerksamkeit. Monatsschr Psychiatr Neurol 25: 51–81. Bates JAV, Ettlinger G (1960). Posterior parietal ablations in the monkey. Arch Neurol 3: 177–192. Batista AP, Buneo CA, Snyder LH, et al. (1999). Reach plans in eye-centered coordinates. Science 285: 257–260. Battaglia-Mayer A, Caminiti R (2002). Optic ataxia as a result of the breakdown of the global tuning fields of parietal neurones. Brain 125: 225–237. Becker W, Ju¨rgens R (1979). An analysis of the saccadic system by means of double-step stimuli. Vision Res 19: 967–983. Behrmann M, Watt S, Black SE, et al. (1997). Impaired visual search in patients with unilateral neglect: An oculographic analysis. Neuropsychologia 35: 1445–1458.

411

Binkofski F, Dohle C, Posse S, et al. (1998). Human anterior intraparietal area subserves prehension. A combined lesion and fMRI study. Neurology 50: 1253–1259. Blangero A, Delporte L, Vindras P, et al. (2007). Optic ataxia is not only ‘optic’: Impaired spatial integration of proprioceptive information. Neuroimage 36: 61–68. Blangero A, Gaveau V, Pe´lisson D, et al. (2006a). Visuospatial and Visuo-manual Deficit in Optic Ataxia Revealed by Online Control Motor Performance. Sensori-motor Foundation of Higher Cognition. Attention and Performance. Pizay, France. Blangero A, Rossetti Y, Pisella L (2006b). Saccade Planning, Pre-saccadic Perceptive Facilitation and Covert Attention: Dissociated Processes in Posterior Parietal Patients. Abstract CNS, San Francisco. Brain R (1941). Visual discrimination with special reference to lesions of the right hemisphere. Brain 64: 244–272. Buneo CA, Jarvis MR, Batista AP, et al. (2002). Direct visuomotor transformations for reaching. Nature 416: 632–636. Buxbaum LJ, Coslett HB (1998). Spatio-motor representations in reaching: Evidence for subtypes of optic ataxia. Cogn Neuropsychol 15: 279–312. Carey DP, Coleman RJ, Della Salla S (1997). Magnetic misreaching. Cortex 33: 639–652. Cogan DG, Adams RD (1953). A type of paralysis of conjugate gaze (ocular motor apraxia). Arch Ophthalmol 50: 434–442. Colby CL, Goldberg ME (1999). Space and attention in parietal cortex. Annu Rev Neurosci 22: 319–349. Crouigneau G (1884). Etude Clinique et Expe´rimentale de la Vision Mentale. Devillaire ed., Paris. Danckert J, Rossetti Y (2005). Blindsight in action: What can the different sub-types of blindsight tell us about the control of visually guided actions? Neurosci Biobehav Rev 29: 1035–1046. De Renzi E (1989). Ba´lint–Holmes syndrome. In: Classic Cases in Neuropsychology. Hove, Psychology Press, pp. 123–143. Desmurget M, Pe´lisson D, Rossettiet Y, et al. (1998). From eye to hand: Planning goal directed movements. Neurosci Biobehav Rev 22: 761–788. Driver J, Husain M (2002). The role of spatial working memory deficits in pathological search by neglect patients. In: HO Karnath, AD Milner, G Vallar (Eds.), The Cognitive and Neural Bases of Spatial Neglect. Oxford University Press, Oxford, pp. 351–364. Ettlinger G (1990). ‘Object vision’ and ‘spatial vision’: The neuropsychological evidence for the distinction. Cortex 26: 319–341. Ettlinger G, Kalsbeck JE (1962). Changes in tactile discrimination and in visual reaching after successive and simultaneous bilateral posterior parietal ablations in the monkey. J Neurol Neurosurg Psychiatry 25: 256–268. Ettlinger G, Wegener J (1958). Somaesthetic alternation, discrimination and orientation after frontal and parietal lesions in monkeys. Q J Exp Psychol 10: 177–186. Fattori P, Breveglieri R, Amoroso K, et al. (2004). Evidence for both reaching and grasping activity in the medial

412

L. PISELLA ET AL.

parieto-occipital cortex of the macaque. Eur J Neurosci 20: 2457–2466. Fattori P, Kutz DF, Breveglieri R, et al. (2005). Spatial tuning of reaching activity in the medial parieto-occipital cortex (area V6A) of macaque monkey. Eur J Neurosci 22: 956–972. Faugier-Grimaud S, Frenois C, Peronnet F (1985). Effects of posterior parietal lesions on visually guided movements in monkeys. Exp Brain Res 59: 125–128. Faugier-Grimaud S, Frenois C, Stein DG (1978). Effects of posterior parietal lesions on visually guided behavior in monkeys. Neuropsychologia 16: 151–168. Fierro B, Brighina F, Oliveri M, et al. (2000). Contralateral neglect induced by right posterior parietal rTMS in healthy subjects. Neuroreport 11: 1519–1521. Fink GR, Marshall JC, Shah NJ, et al. (2000). Line bisection judgments implicate right parietal cortex and cerebellum as assessed by fMRI. Neurology 54: 1324–1331. Galletti C, Fattori P, Kutz DF, et al. (1997). Arm movementrelated neurons in the visual area V6A of the macaque superior parietal lobule. Eur J Neurosci 9: 410–413. Galletti C, Kutz DF, Gamberini M, et al. (2003). Role of the medial parieto-occipital cortex in the control of reaching and grasping movements. Exp Brain Res 153: 158–170. Garcin R, Rondot P, de Recondo J (1967). Ataxie optique localise´e aux deux he´michamps visuels homonymes gauches. Rev Neurol (Paris) 116: 707–714. Gaveau V, Pe´lisson D, Blangero A, et al. (2007). Saccadic control and eye–hand coordination in optic ataxia. Neuropsychologia. In revision. Girotti F, Casazza M, Musicco M, et al. (1983). Oculomotor disorders in cortical lesions in man: The role of unilateral neglect. Neuropsychologia 21: 543–553. Godwin-Austen RB (1965). A case of visual disorientation. J Neurol Neurosurg Psychiatry 88: 585–644. Goodale MA, Milner AD, Jacobson LS, et al. (1991). A neurological dissociation between perceiving objects and grasping them. Nature 349: 154–156. Gottlieb D, Calvanio R, Levine DN (1991). Reappearance of the visual percept after intentional blinking in a patient with Ba´lint’s syndrome. J Clin Neuroophthalmol 11: 62–65. Gre´a H, Pisella L, Rossetti Y, et al. (2002). A lesion of the posterior parietal cortex disrupts on-line adjustments during aiming movements. Neuropsychologia 40: 2471–2480. Guard O, Perenin MT, Vighetto A, et al. (1984). Syndrome parie´tal bilate´ral ressemblant au syndrome de Ba´lint. Rev Neurol (Paris) 140: 358–367. He´caen H, De Ajuriaguerra J (1954). Ba´lint’s syndrome (psychic paralysis of visual fixation) and its minor forms. Brain 77: 373–400. Hirayama K (1982). Optic ataxia (ataxie optique de GarcinRondot): Clinical observation and its possible mechanism [in Japanese with English summary]. Higher Brain Function Research 2: 196–205. Hirayama K (1993). Ataxie optique. In: H Torii (Ed.), Neuropsychology. Psychiatry Book No. 27 [in Japanese]. Tokyo, Kanehara-shuppan, pp. 162–169.

Hirayama K, Toma S, Hiyama Y, et al. (1983). Optic ataxia—semiological observation and review of the literature [in Japanese]. Rinsho Shinkeigaku 23: 605–612. Holmes G (1918). Disturbances of visual orientation. Br J Ophthalmol 2: 449–468, 506–518. Husain M, Stein J (1988). Reszo¨ Ba´lint and his most celebrated case. Arch Neurol 45: 89–93. Husain M, Mannan S, Hodgson T, et al. (2001). Impaired spatial working memory across saccades contributes to abnormal search in parietal neglect. Brain 124: 941–952. Hyvarinen J, Poranen A (1974). Function of the parietal associative area 7 as revealed from cellular discharges in the alert monkey. Brain 97: 673–692. Ishiai S (2002). Perceptual and motor interaction in unilateral spatial neglect. In: HO Karnath, AD Milner, G Vallar (Eds.), The Cognitive and Neural Bases of Spatial Neglect. Oxford University Press, Oxford, pp. 181–195. Ishihara K, Kawamura M (2004). Ataxie optique following parietal lobe lesion [in Japanese with English summary]. Shinkei Kenkyu No Shimpo 48: 611–618. Jakobson LS, Archibald YM, Carey DP, et al. (1991). A kinematic analysis of reaching and grasping movements in a patient recovering from optic ataxia. Neuropsychologia 29: 803–809. Jeannerod M (1986). Mechanisms of visuo-motor coordination: A study in normals and brain-damaged subjects. Neuropsychologia 24: 41–78. Jeannerod M (1988). The neural and behavioural organization of goal-directed movements. Motor control: concepts and issues, J. Wiley (Ed). New York, pp. 277–291. Jeannerod M, Arbib MA, Rizzolatti G, et al. (1995). Grasping objects: The cortical mechanisms of visuomotor transformation. Trends Neurosci 18: 314–320. Jeannerod M, Decety J, Michel F (1994). Impairment of grasping movements following bilateral posterior parietal lesion. Neuropsychologia 32: 369–380. Jeannerod M, Rossetti Y (1993). Visuomotor coordination as a dissociable function: Experimental and clinical evidence. In: C Kennard (Ed.), Visual Perceptual Defects. Baille`re’s Clinical Neurology, International Practice and Research. Ballie`re Tindall, London, pp. 439–460. Johnson PB, Ferraina S, Bianchi L, et al. (1996). Cortical networks for visual reaching: Physiological and anatomical organization of frontal and parietal lobe arm regions. Cereb Cortex 6: 102–118. Karnath HO, Perenin MT (2005). Cortical control of visually guided reaching: Evidence from patients with optic ataxia. Cereb Cortex 15: 1561–1569. Kase CS, Troncoso JF, Court JE, et al. (1977). Global spatial disorientation. Clinico-pathologic correlations. J Neurol Sci 34: 267–278. Kawamura M (2001). Ataxie optique [in Japanese]. Clin Neurosci Res 19: 1236–1237. Kerkhoff G (2001). Neurovisual rehabilitation in Ba´lint’s syndrome: Reply. J Neurol Neurosurg Psychiatry 70: 416. Khan A, Pisella L, Vighetto A, et al. (2005). Optic ataxia errors depend on remapped, not viewed target location. Nat Neurosci 8: 418–420.

´ LINT’S SYNDROME OPTIC ATAXIA AND BA Lawler KA, Cowey A (1987). On the role of posterior parietal and prefrontal cortex in visuo-spatial perception and attention. Exp Brain Res 65: 695–698. Leˆ S, Cardebat D, Boulanouar K, et al. (2002). Seeing, since childhood, without ventral stream: A behavioural study. Brain 125: 58–74. Li CS, Mazzoni P, Andersen RA (1999). Effect of reversible inactivation of macaque lateral intraparietal area on visual and memory saccades. J Neurophysiol 81: 1827–1838. Luria AR (1959). Disorders of ‘simultaneous’ perception in a case of occipito-parietal brain injury. Brain 82: 437–449. Lynch JC, McLaren JW (1989). Deficits of visual attention and saccadic eye movements after lesions of parieto-occipital cortex in monkeys. J Neurophysiol 61: 74–90. Maeshima S, Komai N, Shigeno K, et al. (1991). A clinical study of optic ataxia [in Japanese with English summary]. Higher Brain Function Research 11: 131–139. Mattingley JB, Pisella L, Rossetti Y, et al. (2000). Visual extinction in retinotopic coordinates: A selective bias in dividing attention between hemifields. Neurocase 6: 465–475. McKay WA (1992). Properties of reach-related neuronal activity in cortical area 7a. J Neurophysiol 67: 1331–1345. Medendorp WP, Goltz HC, Vilis T, et al. (2003). Gaze-centered updating of visual space in human parietal cortex. J Neurosci 23: 6209–6214. Michel F, He´naff MA (2004). Seeing without the occipitoparietal cortex: Simultagnosia as a shrinkage of the attentional visual field. Behav Neurol 15: 3–13. Michel F, Jeannerod M, Devic M (1963). Un cas de de´sorientation visuelle dans les trois dimensions de l’espace (A propos du syndrome de Ba´lint et du syndrome de´crit par G Holmes). Rev Neurol (Paris) 108: 983–984. Milner AD, Dijkerman HC (1998). Visual processing in the primate parietal lobe. In: AD Milner (Ed.), Comparative Neuropsychology. Oxford University Press, Oxford, pp. 70–95. Milner AD, Dijkerman HC (2000). Direct and indirect visual routes for action. In: B De Gelder, EHF de Haan, CA Heywood (Eds.), Varieties of Unconscious Processing: New Findings and New Comparisons. Oxford University Press. Milner AD, Dijkerman HC, McIntosh RD, et al. (2003). Delayed reaching and grasping in patients with optic ataxia. In: D Pelisson, C Prablanc, Y Rossetti (Eds.), Progress in Brain Research Series: Neural Control of Space Coding and Action Production. Elsevier, Amsterdam, pp. 142, 225–242. Milner AD, Dijkerman HC, Pisella L, et al. (2001). Grasping the past: Delay can improve visuomotor performance. Curr Biol 11: 1–20. Milner AD, Goodale MA (1995). The Visual Brain in Action. Oxford University Press, Oxford. Milner AD, Paulignan Y, Dijkerman HC, et al. (1999). A paradoxical improvement of misreaching in optic ataxia: New evidence for two separate neural systems for visual localization. Proc R Soc Lond B Biol Sci 266: 2225–2229. Montero J, Pena J, Genis D, et al. (1982). Ba´lint’s syndrome. Report of four cases with watershed parieto-occipital

413

lesions from vertebrobasilar ischemia or systemic hypotension. Acta Neurol Belg 82: 270–280. Morel A, Bullie J (1990). Anatomical segregation of two cortical visual pathways in the macaque monkey. Vis Neurosci 4: 555–578. Mountcastle VB, Lynch JC, Georgopoulos A, et al. (1975). Posterior parietal association cortex of the monkey: Command functions for operations within extrapersonal space. J Neurophysiol 38: 871–908. Mu¨ri RM, Iba-Zizen MT, Derosier C, et al. (1996). Location of the human posterior eye field with functional magnetic resonance imaging. J Neurol Neurosurg Psychiatry 60: 445–448. Neggers SF, Bekkering H (2001). Gaze anchoring to a pointing target is present during the entire pointing movement and is driven by a non-visual signal. J Neurophysiol 86: 961–970. Niemeier M, Karnath HO (2000). Exploratory saccades show no direction-specific deficit in neglect. Neurology 54: 515–518. Ota H, Blangero A, Vindras P, et al. (2007). Systematic retinotopic error vectors in unilateral optic ataxia: The visuomotor field test. In preparation. Ota H, Fujii T, Otake H, et al. (2002). Deviation towards fixation: Performance from patients with optic ataxia. Paper presented at: Euroconference and Ebbs Workshop on Cognitive and Neural Mechanisms of Visuomotor Control. La Londe (France), 5th to 8th September 2002. Ota H, Pisela L, Rode G, et al. (2003). Spatial Miscomputation in Optic Ataxia. Paper presented at Tennet xiv, June 23, 2003, Montreal. Pascual-Leone A, Gomez-Tortosa E, Grafman J, et al. (1994). Induction of visual extinction by rapid-rate transcranial magnetic stimulation of parietal lobe. Neurology 44: 494–498. Perenin M-T, Vighetto A (1988). Optic ataxia: A specific disruption in visuomotor mechanisms. I. Different aspects of the deficit in reaching for objects. Brain 111: 643–674. Perez FM, Tunkel RS, Lachmann EA, et al. (1996). Ba´lint’s syndrome arising from bilateral posterior cortical atrophy or infarction: Rehabilitation strategies and their limitation. Disabil Rehabil 18: 300–304. Pick A (1898). Beitrage zur Pathologie und pathologischen Anatomie des zentral nerven Systems. Karger, Berlin, pp. 185–207. Pierrot-Deseilligny C, Mu¨ri R (1997). Posterior parietal cortex control of saccades in humans. In: P Their, H-O Karnath (Eds.), Parietal Lobe Contributions to Orientation in 3D Space. Springer-Verlag, Heidelberg, pp. 135–148. Pisella L, Berberovic N, Mattingley JB (2004). Impaired working memory for location but not for colour or shape in visual neglect: A comparison of parietal and non-parietal lesions. Cortex 40: 379–390. Pisella L, Binkofski F, Lasek K, et al. (2006). No doubledissociation between optic ataxia and visual agnosia: Multiple sub-streams for multiple visuo-manual integrations. Neuropsychologia 44: 2734–2748.

414

L. PISELLA ET AL.

Pisella L, Gre´a H, Tilikete C, et al. (2000). An automatic pilot for the hand in the human posterior parietal cortex toward a reinterpretation of optic ataxia. Nat Neurosci 3: 729–736. Pisella L, Mattingley JB (2004). The contribution of spatial remapping impairments to unilateral visual neglect. Neurosci Biobehav Rev 28: 181–200. Pisella L, Rossetti Y (2000). Interaction between conscious identification and non-conscious sensori-motor processing: Temporal constraints. In: Y Rossetti, A Revonsuo (Eds.), Beyond Dissociation: Interaction Between Dissociated Implicit and Explicit Processing. Benjamins, Amsterdam, pp. 129–152. Pohl W (1973). Dissociation of spatial discrimination deficits following frontal and parietal lesions in monkeys. J Comp Physiol Psychol 82: 227–239. Prablanc C, Echallier JF, Komilis E, et al. (1979). Optimal response of eye and hand motor systems in pointing at a visual target. I. Spatio-temporal characteristics of eye and hand movements and their relationships when varying the amount of visual information. Biol Cybern 35: 113–124. Prado J, Clavagnier S, Otzenberger H, et al. (2005). Two cortical systems for reaching in central and peripheral vision. Neuron 48: 849–858. Ratcliff G (1990). Brain and Space: Some deductions from the clinical evidence. In: J Paillard (Ed.), Brain and Space. Oxford University Press, Oxford, pp. 237–250. Ratcliff G, Davies-Jones GA (1972). Defective visual localization in focal brain wounds. Brain 95: 49–60. Revol P, Rossetti Y, Vighetto A, et al. (2003). Pointing errors in immediate and delayed conditions in unilateral optic ataxia. Spat Vis 16: 347–364. Riddoch G (1935). Visual disorientation in homonymous half-fields. Brain 58: 376–382. Rizzo M (1993). ‘Ba´lint syndrome’ and associated visuo-spatial disorders. Baillieres Clin Neurol 2: 415–437. Rizzo M, Hurtig R (1987). Looking but not seeing: Attention, perception, and eye movements in simultanagnosia. Neurology 37: 1642–1648. Rizzo M, Robin DA (1990). Simultanagnosia: A defect of sustained attention yields insights on visual information processing. Neurology 40: 447–455. Rizzo M, Vecera SP (2002). Psychoanatomical substrates of Ba´lint’s syndrome. J Neurol Neurosurg Psychiatry 72: 162–178. Rondot P, de Recondo J, Ribadeau-Dumas JL (1977). Visuomotor ataxia. Brain 100: 355–376. Rorden C, Mattingley JB, Karnath HO, et al. (1997). Visual extinction and prior entry: Impaired perception of temporal order with intact motion perception after unilateral parietal damage. Neuropsychologia 35: 421–433. Rosselli M, Ardila A, Beltran C (2001). Rehabilitation of Ba´lint’s syndrome: A single case report. Appl Neuropsychol 8: 242–247. Rossetti Y (1998). Implicit short-lived motor representations of space in brain damaged and healthy subjects. Conscious Cogn 7: 520–558.

Rossetti Y, Desmurget M, Prablanc C (1995). Vectorial coding of movement: Vision, proprioception, or both? J Neurophysiol 74: 457–463. Rossetti Y, McIntosh RM, Revol P, et al. (2005). Visually guided reaching: Posterior parietal lesions cause a switch from visuomotor to cognitive control. Neuropsychologia 43: 162–177. Rossetti Y, Pisella L (2002). Tutorial: Several ‘vision for action’ systems: A guide to dissociating and integrating dorsal and ventral functions. In: W Prinz, B Hommel (Eds.), Attention and Performance XIX: Common Mechanisms in Perception and Action. Oxford University Press, Oxford, pp. 62–119. Rossetti Y, Pisella L (2003). Mediate responses as direct evidence for intention: Neuropsychology of Not to-, Not nowand Not there- tasks. In: S Johnson (Ed.), Cognitive Neuroscience Perspectives on the Problem of Intentional Action. MIT Press, pp. 67–105. Rossetti Y, Pisella L, Pe´lisson D (2000). New insights on eye blindness and hand sight: Temporal constraints of visuomotor networks. Vis cogn 7: 785–808. Rossetti Y, Vighetto A, Pisella L (2003). Optic ataxia revisited: immediate motor control versus visually guided action. Exp Brain Res 153: 171–179. Rushworth MFS, Johansen-Berg H, Young SA (1998). Parietal cortex and spatial–postural transformation during arm movements. J Neurophysiol 79: 478–482. Rushworth MFS, Nixon PD, Passingham RE (1997). Parietal cortex and movement I & II. Movement selection and reaching & spatial representation. Exp Brain Res 117: 292–323. Sakata H, Taira M (1994). Parietal control of hand action. Curr Opin Neurobiol 4: 847–856. Sakata H, Taira M, Kusunoki M, et al. (1997). The parietal association cortex in depth perception and visual control of hand action. Trends Neurosci 20: 350–356. Sakata H, Taira M, Murata A, et al. (1995). Neural mechanisms of visual guidance of hand action in the parietal cortex of the monkey. Cereb Cortex 5: 429–438. Schall JD, Morel A, King DJ, et al. (1995). Topography of visual cortex connections with frontal eye field in macaque: Convergence and segregation of processing streams. J Neurosci 15: 4464–4487. Schindler I, Rice NJ, McIntosh RD, et al. (2004). Automatic avoidance of obstacles is a dorsal stream function: Evidence from optic ataxia. Nat Neurosci 7: 779–784. Schluppeck D, Glimcher P, Heeger DJ (2005). Topographic organization for delayed saccades in human posterior parietal cortex. J Neurophysiol 94: 1372–1384. Schwartz AB (1994). Distributed motor processing in cerebral cortex. Curr Opin Neurobiol 4: 840–846. Sereno MI, Pitzalis S, Martinez A (2001). Mapping of contralateral space in retinotopic coordinates by a parietal cortical area in humans. Science 294: 1350–1354. Silver MA, Ress D, Heeger DJ (2005). Topographic maps of visual spatial attention in human parietal cortex. J Neurophysiol 94: 1358–1371.

´ LINT’S SYNDROME OPTIC ATAXIA AND BA Smith S, Holmes G (1916). A case of bilateral motor apraxia with disturbance of visual orientation. BMJ 1: 437–441. Snyder LH, Batista AP, Andersen RA (2000). Intentionrelated activity in the posterior parietal cortex: A review. Vision Res 40: 1433–1441. Stein J (1978a). Effects of parietal lobe cooling on manipulative behavior in the monkey. In: G Gordon (Ed.), Active Touch. Pergamon Press, Oxford, pp. 79–90. Stein JF (1978b). Space and the parietal association areas. In: J Paillard (Ed.), Brain and Space. Oxford University Press, Oxford, pp. 185–222. Stenvers HW (1961). Les Re´actions Opto-motrices. Paris, Masson. Striemer C, Blangero A, Rossetti Y, et al. (2007). Deficits in peripheral visual attention in patients with optic ataxia. Neuroreport 18: 1171–1175. Taira M, Mine S, Georgopoulos AP, et al. (1990). Parietal cortex neurons of the monkey related to the visual guidance of hand movement. Exp Brain Res 83: 29–36. Tanne´ J, Boussaoud D, Boyer-Zeller N, et al. (1995). Direct visual pathways for reaching movements in the macaque monkey. Neuroreport 7: 267–272. Tanne´-Garie´py J, Rouiller EM, Boussaoud D (2002). Parietal inputs to dorsal versus ventral premotor areas in the macaque monkey: Evidence for largely segregated visuomotor pathways. Exp Brain Res 145: 91–103. Teuber HL (1955). Physiological psychology. Annu Rev Psychol 6: 267–296. Tsutsui K, Jiang M, Yara K, et al. (2001). Integration of perspective and disparity cues in surface-orientationselective neurons of area CIP. J Neurophysiol 86: 2856–2867. Tyler HR (1968). Abnormalities of perception with defective eye movements (Ba´lint’s syndrome). Cortex 4: 154–171. Ungerleider LG, Mishkin M (1982). Two cortical visual systems. In: DJ Ingle, MA Goodale, RJW Mansfield (Eds.),

415

Analysis of Visual Behavior. MIT Press, Cambridge, pp. 549–586. Valenza N, Murray MM, Ptak R, et al. (2004). The space of senses: Impaired crossmodal interactions in a patient with Ba´lint syndrome after bilateral parietal damage. Neuropsychologia 42: 1737–1748. Van Hoesen GW (1982). The parahippocampal gyrus: New observations regarding its cortical connections in the monkey. Trends Neurosci: 345–350. Verfaellie M, Rapcsak SZ, Heilman KM (1990). Impaired shifting of attention in Ba´lint’s syndrome. Brain Cogn 12: 195–204. Vighetto A (1980). Etude neuropsychologique et psychophysique de l’ataxie optique. The`se, Universite´ Claude Bernard Lyon I. Vighetto A, Perenin MT (1981). Optic ataxia: Analysis of eye and hand responses in pointing at visual targets. Rev Neurol (Paris) 137: 357–372. Walker R, Findlay JM (1997). Eye movement control in spatial- and object-based neglect. In: P Their, H-O Karnath (Eds.), Parietal Lobe Contributions to Orientation in 3D Space. Springer Verlag, Heidelberg, pp. 201–218. Wardak C, Olivier E, Duhamel JR (2002). Saccadic target selection deficits after lateral intraparietal area inactivation in monkeys. J Neurosci 22: 9877–9884. Wojciulik E, Husain M, Clarke K, et al. (2001). Spatial working memory. Coding of intention in the posterior parietal cortex. Nature 386: 167–170. Wolpert T (1924). Die simultanagnosie. Z Gesamte Neurol Psychiatr 93: 397–415. Yamadori A (1985). Higher brain dysfunction of visual perception. In: Introduction to Neuropsychology [in Japanese]. Tokyo, Igaku-shoin, pp. 56–91. Zihl J (2000). Rehabilitation of visual disorders after brain injury. In: Neuropsychological Rehabilitation: A Modular Handbook. Psychology Press, Hove.

Handbook of Clinical Neurology, Vol. 88 (3rd series) Neuropsychology and behavioral neurology G. Goldenberg, B.L. Miller, Editors # 2008 Elsevier B.V. All rights reserved

Chapter 21

Visual agnosia ORRIN DEVINSKY1*, MARTHA J. FARAH2, AND WILLIAM B. BARR1 1

Departments of Neurology and Psychiatry, New York University School of Medicine, New York, NY, USA 2

Center for Cognitive Neuroscience, University of Pennsylvania, Philadelphia, PA, USA

21.1. Introduction The word for agnosia is Greek for ‘not knowing’ and refers to a class of neuropsychological disorders in which patients fail to recognize familiar objects despite seemingly adequate perception, cognition, and intellectual ability. The very idea that a patient could ‘not know’ an object or face by sight, for example, yet retain other prerequisite abilities seems paradoxical to some and was once fiercely contested in the neurological literature. As recently as the 1950s, it was suggested that pure visual agnosia did not exist but was simply a result of a combination of subtle perceptual difficulty with an underlying impairment in general intellectual functions. However, advances in the neuroscience of visual perception led to an understanding of the cognitive and neuroanatomic features of visual agnosia. Perception involves many levels of internal representation, ranging from lower-level sensory images to more abstract representations of real objects such as a face, or complex sensory streams such as music. Each sensory modality is organized both hierarchically and in parallel, with feed-forward and feedback connections between multiple representations of each sensory world. Recognition of sensory stimuli requires modalityspecific association cortices. For each sensory modality, there are discreet but overlapping networks that mediate different aspects of recognizing and categorizing sensory stimuli. Dysfunctions and lesions in various neural components of these networks can give rise to different agnosias within a sensory modality. In this chapter, we provide an overview of the clinical types of visual agnosia and related syndromes, the anatomic systems underlying normal and abnormal

*

visual processing, and information regarding clinical assessment of these conditions.

21.2. Types of visual agnosia Understanding of visual agnosia began in 1890, when Lissauer first suggested that disorders of visual identification could be divided into two types, apperceptive agnosia and associative agnosia. According to this early distinction, apperceptive agnosia is a disorder of complex visual perceptual processing. Individuals with this condition are not blind since they can describe their visual experience, yet they do not have sufficient higher-level visual perception to accurately recognize objects. In contrast to apperceptive agnosia, Lissauer suggested that perception itself could be normal in associative agnosia. The problem in that condition was placed downstream in the process of associating a perception with more general knowledge-based representations. As stated by Teuber (1968), an individual with visual associative agnosia experiences ‘a normal percept stripped of its meaning.’ The apperceptive–associative dichotomy is useful insofar as it distinguishes between two broad but fairly distinct classes of patients: those with frank perceptual impairments and those without. However, the underlying theoretical assumption that perception is at fault only in the apperceptive group is no longer held; many cases labeled as associative agnosia are believed to result from the loss of higher-level visual processes. For this reason, our discussion of visual agnosias will be made with the visual form–associative classification system (Farah, 2004).

Correspondence to: Orrin Devinsky, MD, NYU Comprehensive Epilepsy Center, 403 East 34th Street, EPC—4th Floor, New York, NY 10016, USA. E-mail: [email protected], Tel: þ1-(212)-263-8871, Fax: þ1-(212)-263-8342.

418

O. DEVINSKY ET AL.

21.2.1. Visual form agnosia The term apperceptive agnosia was used loosely in the past to refer to any failure of object recognition in which perceptual impairments appeared to contribute. However, recent studies show that different types of perceptual processes can result in different agnosias with pronounced perceptual impairment. For clarity, we advocate the term visual form agnosia, first introduced by Benson and Greenberg (1969), to refer to a subgroup of these perceptually based agnosias. Patients with visual form agnosia may complain of blurred or unclear vision but, on formal examination, their acuity and other perceptual functions are more than adequate to recognize objects. However, they cannot recognize, copy, match, or discriminate simple visual stimuli, and cannot recognize even simple shapes such as triangles or circles. Some may have achromatopsia, in which case they cannot match stimuli by color. The key to diagnosing visual form agnosia is the dissociation between preserved primary visual functions but impaired shape perception and therefore object recognition seems disproportionately impaired. Patients with visual form agnosia may do better with recognition of real objects than those that are drawn. However, even with real objects, they are impaired and their recognition may be based on non-morphological features, such as color, size, or texture. They may recognize objects by tracing the shape with their fingers or hands, but their tracing and recognition of contours demonstrate a dependence on local continuity. They are distracted by irrelevant lines or details and cannot ‘connect’ relevant features. For example, a patient with visual form agnosia incorrectly reads a stimulus with discontinuous lines (Fig. 21.1) (Landis et al., 1982). The patient’s ability to recognize and point to the object may be improved if the object is moving (De Renzi, 2000). This is true whether the motion is of the whole object or whether a simple shape, such as a geometric figure or letter, is drawn in the air with a finger.

Fig. 21.1. A stimulus consistently read as “7415” by a patient with agnosia, who processed only the continuous lines. (From Landis et al., 1982. Reprinted with permission of Cambridge University Press.)

The perception of structure when an object is moving may create a sequence of correlated local motions that can be grouped or synthesized by different neural substrates than those that perceive static contour (Marcar and Cowey, 1992). Patients may display normal object imagery, but are unable to relate individual elements to a whole (Shelton et al., 1994). The inability to ‘group’ and ‘integrate’ object components into a whole may underlie visual form agnosia. Local features such as contour, color, and depth are normally grouped to create a more global structure of an image—this is where these agnosics fail. 21.2.2. Associative visual agnosia Associative visual agnosia refers to a visual object recognition impairment that cannot be attributed to a more basic perceptual deficit, as seen in visual form agnosia, nor to a higher-order disorder of language, communication, intellectual impairment, or other deficits (Feinberg et al., 1994). Unlike the individual with visual form agnosia, associative visual agnosics can make good copies of objects that they cannot recognize. The adequacy of visual perception is also judged by the patient’s description of the visual world. Since language function is normal or near-normal, the patient should be able to describe the visual stimuli in detail (i.e., shape, size, edges and contour, position, and number of stimuli). Many patients with visual agnosia have achromatopsia, easily identified by asking patients to describe colors, which should be tested in each hemifield. Copying of a complex figure, matching of similar figures, or matching of an object with a drawing of the object may be used to test normal visual perception. Patients with associative visual agnosia often use a slow, laborious line-by-line strategy to make detailed copies of a figure (Riddoch and Humphreys, 1987). This reconstruction of a copy, fragment by fragment, is quite distinct from normal object recognition in which the entire object is seen simultaneously or a series of rapid saccades and percepts are synthesized rapidly. Despite the accurate verbal descriptions, drawing, and successful matching of visual stimuli, subtle defects in visual perception may contribute to impaired recognition (Fig. 21.2) (Levine and Calvanio, 1989; Farah, 1990). Patients with associative visual agnosia may be misdiagnosed with anomic aphasia (inability to name), and those with anomic aphasia may be misdiagnosed with visual agnosia. Thus, one must use both verbal and nonverbal tests of object recognition. First, the patient should be asked to verbally describe in detail what they see. Associative visual agnosics report the features and shape of an object, but fail to recognize it. When shown a picture of a dog, for example, they are unable to state

VISUAL AGNOSIA

419

Fig. 21.2. A retired physician with associative visual agnosia copied four line drawings. (The original figures are the top ones of each set, except the original key, which is on the right.) He could not identify any of the objects but copied each item well. (From Rubens and Benson, 1971. Reprinted with permission of the American Medical Association.)

what the object is, whether it is animate or inanimate, or what sound it makes. In contrast, patients with anomia, when shown the same picture, might say, ‘It’s that pet thing, you know, the one that barks.’ Patients with anomia ‘understand the object’ and can relate it to general knowledge but cannot name the object. After verbal testing, nonverbal assessments are made using such tasks as matching pictures with functionally related objects. Anomic patients do better on nonverbal than verbal tasks (e.g., they easily match pictures of

a hammer and a nail). In contrast, patients with agnosia fare poorly on both verbal and nonverbal tests that tap knowledge of the object. In associative visual agnosia the impairment of recognition may be incomplete, as recognition may range, in order of decreasing difficulty, from line drawings, to photographs and then to real (actual) objects, reflecting a progressive wealth in visual detail (Levine and Calvanio, 1989). Common objects, such as a pen or watch, may be more easily recognized than uncommon

420

O. DEVINSKY ET AL.

or complex objects, such as a city skyline or stethoscope. These patients can recognize objects by using other sensory data. For example, a dog can be recognized by its bark and a person may be recognized by the smell of their perfume or sound of their gait. 21.2.3. Related syndromes 21.2.3.1. Simultanagnosia Visual form agnosia may be confused with simultanagnosia, a disturbance of visual attention in which patients recognize only one element in the visual scene. In both disorders, despite normal or mildly impaired visual fields, acuity, and color perception, patients may appear blind, often bump into objects in their environment as they maneuver, and make prominent searching movements with their eyes. Careful examination may be required to detect preserved basic visual perception. The key difference is that patients with simultanagnosia can recognize single objects, but those with visual form agnosia cannot. Simultanagnosics usually see only with macular vision, which provides good acuity but views only a tiny area of the visual field. These patients experience unpredictable jumping of their visual focus from region to region, which denies them detailed or systematic analysis of a particular region or object. In contrast to some visual form agnosics, rapidly or erratically moving targets are much harder for them to see. While watching an auto race on television, a simultanagnosic could see a stationary advertisement in the background but never see the moving cars (Girotti et al., 1982). Threatening visual stimuli directed toward their face fail to elicit responses (Holmes, 1918; Holmes and Horrax, 1919; Farah, 1990), while threatening auditory stimuli or the examiner taking the patient’s own hand and thrusting it suddenly toward their face evoke quick responses (Holmes, 1918). Simultanagnosia can be divided into dorsal and ventral forms. In dorsal simultanagnosia, patients have an attentional disorder that does not permit them to see more than one object at a time. In some instances, their attention focuses on one part of an object, causing them to misidentify the object. The relation to visual form agnosia is slight since when they can attend to an object these patients quickly recognize and identify it accurately. Further, unlike visual form agnosics, when they make errors about objects or parts of objects, they are able to provide much more detail about the global structure of a single object than visual form agnosics. In ventral simultanagnosia, patients can recognize an entire object, but they are limited in how many objects can be recognized in a certain time. When viewing a complex scene, they provide descriptions that are slow

and piecemeal. However, unlike visual form agnosics, their perception of single shapes is normal. In contrast to the dorsal simultanagnosics, visual form agnosics have a disorder of recognition per se, not in detection of multiple stimuli. The perception of patients with ventral simultanagnosia is better than those with either visual agnosia or dorsal simultanagnosia. 21.2.3.2. Prosopagnosia Prosopagnosia is the inability to recognize familiar faces or to learn and recognize new faces. In severe cases, patients may not recognize spouses, siblings, or even their own images in a mirror. Prosopagnosics can identify the mouth, eyes, nose, cheeks, and recognize that the image is a face. Thus, they have not lost the concept of a face. They are unable to identify specific faces. Their ability to identify real faces or photographs or line drawings of faces is impaired. One prosopagnosic provided an illustrative description: I can see the eyes, nose and mouth quite clearly but they just don’t add up. They all seem chalked in, like on a blackboard. I have to tell by the clothes or voice whether it is a man or woman, as the faces are all neutral, a dirty grey colour (he also had achromatopsia). The hair may help a lot, or if there is a moustache. . . All the men appear unshaven. . . I cannot recognize people in photographs, not even myself. At the club I saw someone strange staring at me and asked the steward who it was. You’ll laugh at me. I’d been looking at myself in the mirror. . . I later went to London and visited several cinemas and theatres. I couldn’t make head or tail of the plots. I never knew who was who. . . I can shut my eyes and can well remember what my wife looked like or the kids. . . (Pallis, 1955). The disorder in prosopagnosia extends to other classes of visually related stimuli. Thus, many prosopagnosics are impaired in their visual identification of friends and relatives, but also in distinguishing specific types of objects in a class, as in discriminating an apple from a pear (fruit), a sparrow from a raven (birds), or a Lexus from a Ford (cars). In contrast to some other patients with agnosia, prosopagnosics can distinguish the class of visual stimuli (e.g., fruit, bird, car). Depending on the extent and location of the lesion, patients may fail to recognize the specific face but identify facial expression and emotion, sex, and age correctly (Pallis, 1955). In contrast to prosopagnosics, patients with

VISUAL AGNOSIA bilateral amygdala lesions cannot recognize facial emotions or judge whether a face looks approachable and trustworthy but they can recognize and learn new faces (Damasio et al., 2000). In most cases, prosopagnosia develops suddenly, and the patient realizes that a familiar person’s face appears unfamiliar. Patients identify their relatives and friends by voice, clothing, body shape, perfume, or other features. However, they experience their faces as foreign. The ability of patients to recognize familiar individuals by nonvisual or nonfacial visual clues indicates that attention, memory, and intelligence are relatively preserved. Some patients may recognize a familiar face by identifying a specific and characteristic element (e.g., crooked nose) but cannot recognize the face by viewing it is a ‘whole.’ In some cases, facial memories are lost as patients cannot visually describe objects from memory, especially faces and animals. Other disorders, including constructional apraxia, left-sided hemianopia, left-sided neglect, or topographic disorientation, may coexist with prosopagnosia. Patients with topographic disorientation are unable to identify correct spatial relations. Prosopagnosia results from a lesion in the structures that process, store, and recognize facial templates and memories, located in the mesial occipitotemporal visual association cortex (lingual and fusiform gyri) (Dailey and Cottrell, 1999). Interference with the arrival of visual input at that system, or from its destruction, can cause prosopagnosia. Patients often know that they are viewing a face and can see the details, but cannot match the whole image with stored memories. This ability to recognize a ‘generic’ face (or car or bird) may result from use of the object recognition system, not the facial template system. Although patients with prosopagnosia cannot recognize individual faces, some patients generate a large electrodermal skin conductance response when they see familiar faces (Tranel and Damasio, 1985). No such response is detected when they view unfamiliar faces. The mounting of an autonomic response suggests the nonconscious recognition of familiar facial features, suggesting that an early phase of recognition occurs and influences behavior, even though the data and process are not accessible to consciousness. Studies using correct face–name pairs (larger amplitude of the skin conductance response) and incorrect face–name pairs or eye movement scan paths for familiar versus novel faces provide additional evidence that prosopagnosic patients can nonconsciously recognize some faces (Rizzo and Hurtig, 1987; Bauer and Verfaellie, 1988). Alternatively, these autonomic findings in patients with impaired facial recognition may be accounted for by residual functioning of a damaged, but not destroyed

421

face recognition system. Such a system may retain the ability to support certain types of performance and autonomic signs (Farah, 2003). 21.2.3.3. Perceptual categorization deficit Warrington described a disorder of perceptual categorization originally under the umbrella of apperceptive agnosia (Warrington, 1982). However, this deficit is distinct from traditional definitions of apperceptive agnosia (see above). Patients with perceptual categorization deficits perform poorly at recognizing or matching objects seen from unusual views or illuminated in ways that produce confusing shadows. This disorder was considered a deficit in object shape constancy, impairing the processes that allow us to recognize the equivalence of an object’s three-dimensional appearance when viewed from different perspectives and different lighting conditions. However, the deficit is usually apparent only when an object is seen from an unusual view that eliminates important features and is often identified in patients who have no problems with object recognition in their normal environments. Impairment of perceptual categorization may therefore be considered an abnormality in the systems that solve visual problems, perform mental rotation, and support visual imagination—not in the visual systems that mediate object recognition. Warrington and James (1986) suggested that the term apperceptive visual agnosia be restricted to a very small group of patients with right posterior quadrant lesions, usually involving the posterior inferior parietal lobe, in whom visual recognition is impaired when the perspective is unusual or lighting is uneven (i.e., perceptual categorization impairment). Warrington has argued that the traditional apperceptive visual agnosia is a ‘pseudoagnosia’ since these patients have a defect in complex cortical visual processing as well as a milder defect in basic visual perceptual functions (Warrington, 1985; Warrington and James, 1986). However, current views consider this a separate disorder, not apperceptive visual agnosia.

21.3. Neuroanatomic factors 21.3.1. Anatomy and function of cortical visual areas The occipital lobe contains primary visual cortex (V1) and much of the visual association cortex (V2-V8) (Fig. 21.3; Table 21.1). V1 provides the most detailed, high-resolution cortical map of our visual field, and is critical in orientation selectivity and combining visual information from the two eyes for stereopsis. Primary visual (striate) cortex is comprised of columnar units, each with its own receptive field and containing simple

422

O. DEVINSKY ET AL.

Fig. 21.3. Principal visual areas in humans. (A) Lateral view and (B) medial view. VP: ventral posterior area. (From Devinsky and D’Esposito, 2004. Reprinted with permission of Oxford University Press.)

and complex cells. Simple cells respond to illumination and orientation, complex cells receive input from simple cells but have a larger receptive field and respond to more specifically oriented stimuli (e.g., sharp dark–light contrasts). Hypercomplex cells, located in visual association cortex (BA 18, 19), respond to more specific visual stimuli with input from multiple complex cells. V2 (BA 18) (Fig. 21.3) is the largest visual association area in the occipital lobe. V2 neurons respond to orientation, motion, wavelength, and depth. V2 neurons have larger receptive fields and are activated by lower spatial frequencies than those in V1. The next hierarchical level is formed by V3, V3a, and the ventral posterior (VP) area, that are an intermediate processing level between V1/V2 and higher visual areas (Felleman et al., 1997). The two visual streams of ‘where’ (dorsal;

V3 and V3a) and ‘what’ (ventral; VP) begin their bifurcation here. Visual agnosias result from disorders in the ventral pathway. V3 lies superior to V2 in the superior occipital cortex..V3 neurons respond mainly to spatial orientation, direction, and depth (Zeki, 1978; Poggio et al., 1988). V3 lesions can impair motion and depth perception, and form analysis, especially at low contrast levels. V3a lies superior to V3 and is very sensitive to contrast and motion (Tootell et al., 1997; Bundo et al., 2000). The VP area in the inferior occipital lobe plays a role in the early stages of form perception (Fig. 21.3). The ventral area V4 (V4v), in the lingual sulcus and fusiform gyrus, is involved in hue perception, intermediate form vision, and visual attention in the contralateral superior quadrant (Fig. 21.3). Functional imaging studies in healthy subjects show activation of V4v with

VISUAL AGNOSIA

423

Table 21.1 Visual cortical and related areas Visual area

Location

Function

Comment

Primary visual cortex (V1) Visual association cortex V2

Medial occipital lobe

Surrounds V1

V3

Surrounds V2

Involved in orientation, selectivity, and binocularity Involved in form, motion, color, and depth analysis Cells respond to all major visual modalities –

V4

Lingual and fusiform gyri (temporal lobe) Lateral junction of temporal, parietal, and occipital lobes ?Caudal aspect of superior parietal lobe* Ventromedial occipital lobe

Initial cortical analysis of visual input Specialized analysis of visual information ?Higher-order processing of data than V1 Motion and depth perception, form analysis at low contrast Size estimation, color perception Motion detection

Bilateral lesions cause akinetopsia –

V5 V6 V8 Related areas Frontal eye field Lateral temporal Parietal

Lateral occipital lobe

Caudal portion of middle frontal gyrus Middle and inferior temporal gyri Posterior and superior parietal lobes

Self-motion, 3-D features, target selection in visual searches Color perception

Volitional eye movements Object identification Object location

–

Bilateral lesions cause achromatopsia Saccades directed toward contralateral space “What” system “Where” system, directing visual attention

Areas V4, V5, and V6 are located outside the occipital lobe; area V7 is not clearly defined in humans. *As defined in monkeys, not human. (From Devinsky and D’Esposito, 2004. Reprinted with permission of Oxford University Press).

awareness of an object’s identity and the dominant V4v is activated during visual word processing (Bar and Biederman, 1999; Tarkiainen et al., 1999). The dorsal area V4 (V4d) (Fig. 21.3A) may be involved in size estimation. Mental transformations of size activate the dorsal occipitoparietal areas, including V4d (Larsen et al., 2000). Distance perception may result from comparative data from ‘nearness’ and ‘farness’ neurons that occur in all cortical visual areas (Allman, 1999). V5, the ‘motion area,’ is located near the junction of the lateral temporoparieto-occipital junction (Tootell et al., 1995; Dumoulin et al., 2000) (Fig. 21.3A). V5 responds to motion, detecting binocular disparity, and speed and direction of a moving stimulus (Beckers and Zeki, 1995; Rizzo et al., 1995). V6 and V7 are not well characterized in humans. V6 is in the superior parietal lobule and is activated by visual analysis of three-dimensional features, self-motion, target selection during visual searching, and arm-reaching movements toward nonfoveated targets (Sakata et al., 1997; Galletti et al., 1999). V8 (overlapping with V4v), the ‘color area,’ is located in the fusiform gyrus (Fig. 21.3). The main

function of this area is to compute color constancy, the invariance of object color over changes in luminance (Zeki, 1993; Hadjikhani et al., 1998; Allman, 1999). Lesions of the fusiform gyrus can cause achromatopsia. The color area is close to the area that mediates facial recognition (see above) (Fig. 21.3B). In both achromatopsia and prosopagnosia, patients cannot distinguish between items in the same perceptual category (Desimone et al., 1989). 21.3.2. Neuropathology of the visual agnosias The lesions in visual form agnosia are typically diffuse and posterior. The prominence of white matter lesions suggests that disconnection, often of very local intralaminar connections, rather than neuronal loss, often causes the visual deficit. Stroke, anoxia, carbon monoxide poisoning, are common causes of the disorder; demyelination, tumor, and mercury poisoning are uncommon causes (Landis et al., 1982; Shelton et al., 1994; De Renzi, 2000). The most common cause of associative visual agnosia is bilateral infarction of the posterior cerebral arteries.

424

O. DEVINSKY ET AL.

Demyelination, hemorrhage, and tumor are uncommon causes. Bilateral lesions involving the inferior temporo-occipital junction and subjacent white matter are the most common anatomic lesions associated with this associative visual agnosia (De Renzi, 2000). However, this disorder can also occur with unilateral damage to the left or right temporo-occipital region (McCarthy and Warrington, 1986; Farah, 1994). The disorder is often a result of both neuronal loss of higher-order visual association areas and disconnection. Destruction of higher-order visual association cortices in the temporo-occipital region can cause associative visual agnosia (McCarthy and Warrington, 1986; Damasio et al., 2000). Neuronal templates that match a visual stimulus with a visual memory are stored primarily in ventral visual association cortex (Riddoch and Humphreys, 1987; Damasio et al., 2000). Long-term follow-up of a visual agnosia patient suggests that perceptual and mnemonic processes have strong interactive relations (Riddoch et al., 1999). Disconnection can produce or contribute to an associative visual agnosia from a lesion that interrupts the connections between visual association and temporolimbic memory areas (Feinberg, 1995; Damasio et al., 2000). The inferior longitudinal fasciculus, which connects the occipital (visual) association and medial temporal (memory) areas, is usually destroyed bilaterally in associative visual agnosia (Damasio et al., 2000). Selective bilateral temporo-occipital white matter lesions can disconnect visual association and temporolimbic memory areas without disrupting the recognition of familiar visual stimuli, but impairing visual learning. The brain damage that causes dorsal simultanagnosia is bilateral and usually encompasses the parietal and superior occipital regions. In a few cases, damage was confined to the occipital regions (Girotti et al., 1982; Rizzo and Hurtig, 1987), although in another case, only the superior parietal lobes were damaged (Kase et al., 1977). Etiologies likely to result in this configuration of damage, with perseveration of ventral visual system areas, include the penetrating head injuries originally studied by Holmes (1918) and ‘watershed’ infarction, in which a drop in blood pressure affects the most distal, or watershed, territory between the middle and posterior cerebral arteries. Middle cerebral artery strokes, although they commonly cause parietal damage, are not often the cause of dorsal simultanagnosia because of the need for bilateral lesions. In such cases, there is often involvement of language, praxis, and other areas, and identification of the simultanagnosia is problematic. The lesions responsible for ventral simultanagnosia affect the left posterior temporal or temporo-occipital cortex, and the disorder has been considered a localizing sign for damage there (Kinsbourne and Warrington,

1963). This localization accords well with the results of functional neuroimaging studies, which show selective activations within this zone (Petersen et al., 1990; Polk and Farah, 2002; Price et al., 1994). The precise location of orthography-specific activation varies somewhat from imaging study, perhaps as a result of different materials and experimental design. Lesions causing prosopagnosia occupy the bilateral inferomesial visual association cortices (lingual and fusiform gyri) and subjacent white matter (Fig. 21.4), territory similar to that occupied by lesions causing visual object agnosia, but the lesions in prosopagnosia are usually less extensive (Dailey and Cottrell, 1999). Neocortical neuronal populations in fusiform and lingual gyri selectively respond to different faces, differentiate novel from familar faces, and are critical for facial recognition and recall (Seeck et al., 1993; Kim et al., 1999). The fusiform face area is selective for faces. During functional magnetic resonance imaging (fMRI), for example, the response of the fusiform face area was strongest to stimuli containing human faces, slightly weaker to human heads, and weakest to stimulus categories of whole humans, animal heads, and whole animals (Kanwisher et al., 1999). Rarely, isolated right mesial occipitotemporal lobe lesions produce permanent prosopagnosia (Nachson, 1995). Unilateral leftsided lesions do not cause prosopagnosia. Most patients with unilateral, right-sided lesions and prosopagnosia have transient, mild-to-moderate deficits. The right hemisphere is superior to the left in recognizing and matching faces, as well as other sensory information that cannot be adequately differentiated with a verbal description (Gazzaniga and Smylie, 1983). Focal right temporal lobe atrophy may cause isolated, progressive prosopagnosia, which is analogous to progressive fluent aphasia resulting from left temporal lobe atrophy (Snowden et al., 1992; Evans et al., 1995; Hodges, 2001). Prosopagnosia usually follows embolic infarction of the posterior cerebral artery distribution. After a right hemisphere infarct, the deficit usually resolves within months. Often, a unilateral stroke in the posterior cerebral artery is followed months or years later by a contralateral infarct that causes prosopagnosia, visual object agnosia, or cortical blindness. Butterfly gliomas traversing the splenium of the corpus callosum to involve the posterior white matter bilaterally may cause prosopagnosia. 21.3.3. Clinical assessment of visual agnosia By definition, a patient with visual agnosia will have normal or near-normal visual capacity. This needs to be demonstrated by normal or near-normal performance

VISUAL AGNOSIA

425

Fig. 21.4. Region of brain lesions (shaded areas) in a patient with prosopagnosia. (From Devinsky and D’Esposito, 2004. Reprinted with permission of Oxford University Press.)

on measure of refraction and acuity and in testing of the visual fields. Bedside neurobehavioral testing should proceed with presenting a series of photographs and drawings of objects, animals, faces, colors, and complex visual scenes. Identification of patients with simultanagnosia and prosopagnosia will become apparent by their differential impairment on the more complex tasks and by those limited to facial recognition. Differentiation between visual form agnosia and associative visual agnosia can be made by instructing the patient to copy drawings of simple objects. Those with associative visual agnosia will produce more accurate representations. It is important to differentiate an associative visual agnosia from a naming disturbance. The patient with naming disturbance will be able to identify the object through a verbose description (circumlocution) or by pantomime. The person with the associative visual agnosia will often be able to identify the object more readily through another modality such as sound or by tactile recognition. Other useful information can be

obtained by having patients attempt to match various pictures according to their semantic or functional similarity. Patients with visual form agnosia typically make errors according to visual similarities whereas patients with other forms of semantic memory impairment make errors based on conceptual similarities. Neuropsychological testing can help formally document the clinical features of visual agnosia. Most features of these conditions will not be elicited through routine neuropsychological testing using the Wechsler scales (Wechsler, 1997a; 1997b) or the Halstead– Reitan Battery (Reitan and Wolfson, 1993). Information from more detailed visual perceptual testing using Benton’s tests can help document basic difficulties in spatial and perceptual abilities (Benton et al., 1994). The Facial Recognition Test, in particular, is useful for identifying perceptual deficits underlying prosopagnosia and other disorders affecting facial perception. The cueing conditions included in the Boston Naming Test provide a formal method for making the distinction between a basic naming disorder versus a

426

O. DEVINSKY ET AL.

visual associative agnosia (Kaplan et al., 1983). Presentation of a complex scene, such as that provided by the ‘Cookie Theft’ picture from the Boston Diagnostic Aphasia Test (Goodglass and Kaplan, 1983) can be useful in eliciting isolation errors typical of the patient with simultanagnosia. More detailed tests of visual and perceptual processing are often needed to make distinctions among the various types of visual agnosia. A battery of tests of higher-order visual perceptual processing (Visual Object and Space Perception Battery—VOSP) has been developed by Warrington and James (1991). This test is useful for demonstrating deficits in object and space perception. A similar test, focusing on object recognition (Birmingham Object Recognition Battery—BORB), is also available (Riddoch and Humphreys, 1993). The Pyramids and Palm Trees Test is another measure that assesses the ability to access semantic representations from words and from pictures (Howard and Patterson, 1992). While these tests provide formal methods of characterizing various perceptual components underlying visual recognition impairments, a comprehensive neurobehavioral evaluation often requires the clinician to be creative and innovative in the approach to their examination of the patient with visual agnosia.

References Allman JM (1999). Evolving Brains. Scientific American Library, New York. Bar M, Biederman I (1999). Localizing the cortical region mediating visual awareness of object identity. Proc Natl Acad Sci USA 96: 1790–1793. Bauer RM, Verfaellie M (1988). Electrodermal discrimination of familiar but not unfamiliar faces in prosopagnosia. Brain Cogn 8: 240–252. Beckers G, Zeki S (1995). The consequences of inactivating areas V1 and V5 on visual motion perception. Brain 118: 49–60. Benson DF, Greenberg JP (1969). Visual form agnosia. A specific defect in visual discrimination. Arch Neurol 20: 82–89. Benton AL, Sivan AB, Hamsher KD, et al. (1994). Contributions to Neuropsychological Assessment. A Clinical Manual, 2nd edn. Oxford, New York. Bundo M, Kaneoke Y, Inao S, et al. (2000). Human visual motion areas determined individually by magnetoencephalography and 3D magnetic resonance imaging. Hum Brain Mapp 11: 33–45. Dailey MN, Cottrell GW (1999). Prosopagnosia in modular neural network models. Prog Brain Res 121: 165–184. Damasio AR, Tranel D, Rizzo M (2000). Disorders of complex visual processing. In: MM Mesulam (Ed.), Principles of Behavioral and Cognitive Neurology, 2nd edn. Oxford University Press, New York, pp. 332–372.

De Renzi E (2000). Disorders of visual recognition. Semin Neurol 20: 479–485. Desimone R, Ungerleider LG (1989). Neural mechanisms of visual processing in monkeys. In: AR Damasio (Ed.), Handbook of Clinical Neuropsychology, Vol. 2, Section 4, Disorders of Visual Behavior. Elsevier, New York, pp. 267–299. Devinsky O, D’Esposito M (2004). Neurology of Cognitive and Behavioral Disorders. Oxford, New York, pp. 124, 125, 145. Dumoulin SO, Bittar RG, Kabani NJ, et al. (2000). A new anatomical landmark for reliable identification of human area V5/MT: A quantitative analysis of sulcal patterning. Cereb Cortex 10: 454–463. Evans JJ, Heggs AJ, Antoun N, et al. (1995). Progressive prosopagnosia associated with selective right temporal lobe atrophy. Brain 118: 1–13. Farah MJ (1990). Visual Agnosia. MIT Press, Cambridge. Farah MJ (1994). Perception and awareness after brain damage. Curr Opin Neurobiol 4: 252–255. Farah MJ (2003). Prosopagnosia. In: TE Feinberg and MJ Farah (Eds.), Behavioral Neurology and Neuropsychology, 2nd edn. New York, McGraw Hill, pp. 233–238. Farah MJ (2004). Visual Agnosia, 2nd edn. MIT Press/Bradford Books, Cambridge. Feinberg TE, Dyckes-Berke D, Miner CR, et al. (1995). Knowledge, implicit knowledge and metaknowledge in visual agnosia and pure alexia. Brain 118: 789–800. Feinberg TE, Schindler RJ, Ochoa E, et al. (1994). Associative visual agnosia and alexia without prosopagnosia. Cortex 30: 395–411. Felleman DJ, Burkhalter A, Van Essen DC (1997). Cortical connections of areas V3 and VP of macaque monkey extrastriate visual cortex. J Comp Neurol 379: 21–47. Galletti C, Fattori P, Gamberini M, et al. (1999). The cortical visual area V6: Brain location and visual topography. Eur J Neurosci 11: 3922–3936. Gazzaniga MS, Smylie CS (1983). Facial recognition and brain asymmetries: Clues to underlying mechanisms. Ann Neurol 13: 536–540. Girotti F, Milanese C, Casazza M, et al. (1982). Oculomotor disturbance in Balint’s syndrome: Anatomoclinical findings and the electrooculographic analysis in a case. Cortex 18: 603–614. Goodglass H, Kaplan E (1983). The Assessment of Aphasia and Other Neurological Disorders. Williams and Wilkins, Baltimore. Hadjikhani N, Liu AK, Dale AM, et al. (1998). Retinotopy and color sensitivity in human visual cortical area V8. Nat Neurosci 1: 235–241. Hodges JR (2001). Frontotemporal dementia (Pick’s disease): Clinical features and assessment. Neurology 56: S6–S10. Holmes G (1918). Disturbances of vision by cerebral lesions. Br J Ophthalmol 2: 353–384. Holmes G, Horrax G (1919). Disturbances of spatial orientation and visual attention, with loss of stereoscopic vision. Arch Neurol Psychiatry 1: 385–407.

VISUAL AGNOSIA Howard D, Patterson K (1992). Pyramids and Palm Trees: A Test of Semantic Access from Pictures and Words. Thames Valley Test Company, Bury St Edmunds. Kanwisher N, Stanley D, Harris A (1999). The fusiform face area is selective for faces not animals. Neuroreport 10: 183–187. Kaplan EF, Goodglass H, Weintraub S (1983). The Boston Naming Test, 2nd edn. Lea & Febiger, Philadelphia. Kase CS, Troncoso JF, Tapia FJ, et al. (1977). Global spatial disorientation. J Neurol Sci 34: 267–278. Kim JJ, Andreasen NC, O’Leary DS, et al. (1999). Direct comparison of the neural substrates of recognition memory for words and faces. Brain 122: 1069–1083. Kinsbourne M, Warrington EK (1963). A study of visual perseveration. J Neurol Neurosurg Psychiatry 26: 468–475. Landis T, Graves R, Benson DF, et al. (1982). Visual recognition through kinaesthetic mediation. Psychol Med 12: 515–531. Larsen A, Bundesen C, Kyllingsbaek S, et al. (2000). Brain activation during mental transformation of size. J Cogn Neurosci 12: 763–774. Levine DN, Calvanio R (1989). Prosopagnosia: A defect in visual configural processing. Brain Cogn 10: 149–170. Marcar VL, Cowey A (1992). The effect of removing superior temporal cortical motion areas in the macaque monkey. II. Motion discrimination using random dot displays. Eur J Neurosci 4: 1228–1238. McCarthy RA, Warrington EK (1986). Visual associative agnosia: A clinico-anatomical study of a single case. J Neurol Neurosurg Psychiatry 49: 1233–1240. Nachson I (1995). On the modularity of face recognition: The riddle of domain specificity. J Clin Exp Neuropsychol 17: 256–275. Pallis CA (1955). Impaired identification for faces and places with agnosia for colours. J Neurol Neurosurg Psychiatry 18: 218. Petersen SE, Snyfer AZ, Raichle ME (1990). Activation of extrastriate and frontal cortical areas by visual words and word-like stimuli. Science 249: 1041–1044. Poggio GF, Gonzales F, Drause F (1988). Stereoscopic mechanisms in monkey visual cortex, binocular correlation and disparity selectivity. J Neurosci 8: 4531–4550. Polk TA, Farah MJ (2002). Functional MRI evidence for an abstract, not perceptual, word-form area. J Exp Psychol Gen 131: 65–72. Price CJ, Wise RJS, Watson JDG, et al. (1994). Brain activity during reading: The effects of exposure duration and task. Brain 117: 1255–1269. Reitan RM, Wolfson D (1993). The Halstead–Reitan Neuropsychological Test Battery: Theory and Clinical Interpretation, 2nd edn. Neuropsychology Press, South Tucson. Riddoch GW, Humphreys GW (1987). A case of integrative visual agnosia. Brain 110: 1431–1462. Riddoch MJ, Humphreys GW (1993). Birmingham Object Recognition Battery (BORB). Psychology Press, London.

427

Riddoch MJ, Humphreys GW, Gannon T, et al. (1999). Memories are made of this: The effects of time on stored visual knowledge in a case of visual agnosia. Brain 122: 537–559. Rizzo M, Hurtig R (1987). Looking but not seeing: Attention, perception, and eye movements in simultanagnosia. Neurology 37: 1642–1648. Rizzo M, Nawrot M, Zihl J (1995). Motion and shape perception in cerebral akinetopsia. Brain 118: 1105–1127. Rubens AB, Benson DF (1971). Associative visual agnosia. Arch Neurol 24: 310. Sakata H, Taira M, Kusunoki M, et al. (1997). The parietal association cortex in depth perception and visual control of hand action. Trends Neurosci 20: 350–357. Seeck M, Mainwaring N, Ives J, et al. (1993). Differential neural activity in the human temporal lobe evoked by faces of family members and friends. Ann Neurol 34: 369–372. Shelton PA, Bowers D, Duara R, et al. (1994). Apperceptive visual agnosia: A case study. Brain Cogn 25: 1–23. Snowden JS, Neary D, Mann DM, et al. (1992). Progressive language disorder due to lobar atrophy. Ann Neurol 31: 174–183. Tarkiainen A, Helenius P, Hansen PC, et al. (1999). Dynamics of letter string perception in the human occipitotemporal cortex. Brain 122: 2119–2132. Teuber HL (1968). Alteration of perception and memory in man. In: L Weiskrantz (Ed.), Analysis of Behavioral Change. Harper & Row, New York, pp. 268–328. Tootell RB, Mendola JD, Hadjikhani NK, et al. (1997). Functional analysis of V3A and related areas in human visual cortex. J Neurosci 17: 7060–7078. Tootell RB, Reppas JB, Dale AM, et al. (1995). Visual motion aftereffect in human cortical area MT/V5 revealed by functional magnetic resonance imaging. Nature 375: 139–141. Tranel D, Damasio AR (1985). Knowledge without awareness: An autonomic index of facial recognition by prosopagnosics. Science 228: 1453–1454. Warrington EK (1982). Neuropsychological studies of object recognition. Philos Trans R Soc Lond B Biol Sci 298: 15–33. Warrington EK (1985). A disconnection analysis of amnesia. Ann NY Acad Sci 444: 72–77. Warrington EK, James M (1986). Visual object recognition in patients with right-hemisphere lesions: Axes or features. Perception 15: 355–366. Warrington EK, James M (1991). Visual Object and Space Perception Battery. Thames Valley Test Company, Bury St Edmunds. Wechsler D (1997a). WAIS-III administration and scoring manual. The Psychological Corporation, San Antonio. Wechsler D (1997b). Weschsler Adult Intelligence Scale-III. The Psychological Corporation, San Antonio. Zeki SM (1978). The third visual complex of rhesus monkey prestriate cortex. J Physiol 277: 245–272. Zeki S (1993). A Vision of the Brain. Blackwell, Oxford.

Handbook of Clinical Neurology, Vol. 88 (3rd series) Neuropsychology and behavioral neurology G. Goldenberg, B.L. Miller, Editors # 2008 Elsevier B.V. All rights reserved

Chapter 22

Illusory reduplications of the human body and self OLAF BLANKE1,2*, SHAHAR ARZY1,2, AND THEODOR LANDIS2 1

Laboratory of Cognitive Neuroscience, Brain Mind Institute, Ecole Polytechnique Fe´de´rale de Lausanne (EPFL), Lausanne, Switzerland 2

Department of Neurology, University Hospital, Geneva, Switzerland

For my part, when I enter most intimately into what I call myself, I always tumble, on some particular perception or other, of heat or cold, light or shade, love or hatred, pain or pleasure. I can never catch myself at any time without a perception, and never can observe anything but the perception. David Hume, A Treatise of Human Nature (1711–1776)

22.1. Doubles Illusory reduplications of the patient’s own body refer to complex manifestations during which human subjects experience a second own body or self in their environment. Here we refer to this illusory second own body or self as a double. Doubles may be seen, felt, or heard, may be multiple or even concern the inner organs of the patient. Doubles have fascinated mankind from time immemorial and—often under the term autoscopic phenomena—several distinct forms have been described that can be separated based on phenomenological, functional, and anatomical criteria. The main forms of doubles are the visual own-body reduplications: autoscopic hallucination, heautoscopy, and out-of-body experience (out-of-body experience) as well as the rarer forms including polyopic heautoscopy and inner heautoscopy. These are referred to here as visual doubles. Other own body reduplications include feeling of a presence (sensorimotor doubles), hearing of a presence (auditory doubles), and negative heautoscopy (negative doubles). *

Doubles are abundant in folklore, mythology, and spiritual experiences (Rank, 1925; MenningerLerchenthal, 1946; Todd and Dewhurst, 1962; Sheils, 1978; Arzy et al., 2005; Metzinger, 2005). In more recent times, doubles became a frequent and popular topic in the romantic literary movement of the nineteenth century (Rank, 1925; Dewhurst and Pearson, 1955; McCulloch, 1992). Reflecting these popular trends, detailed case descriptions (Muldoon and Carrington, 1929; Yram, 1972; Alvarado, 1992) and medical reports (Du Prel, 1886; Fe´re´, 1891; Sollier, 1903a) began to appear. Since then, doubles have been repeatedly described in patients suffering from neurological or psychiatric disease (Menninger-Lerchenthal, 1935; 1946; Lhermitte, 1939; He´caen and Ajuriaguerra, 1952; Todd and Dewhurst, 1955; Lukianowicz, 1958; Leischner, 1961; Fredericks, 1969; Devinsky et al., 1989b; Gru¨sser and Landis, 1991; Dening and Berrios, 1994; Brugger et al., 1997). Doubles have been related to various neurological diseases such as epilepsy, migraine, neoplasia, infarction, and infection (Menninger-Lerchenthal, 1935; 1946; Lippman, 1953; Devinsky et al., 1989a; Gru¨sser and Landis, 1991; Dening and Berrios, 1994; Brugger et al., 1997; Podoll and Robinson, 1999) and psychiatric diseases such as schizophrenia, depression, anxiety, and dissociative disorders (Menninger-Lerchenthal, 1935; Lhermitte, 1939, Bychowski, 1943; He´caen and Ajuriaguerra, 1952; Todd and Dewhurst, 1955; Lukianowicz, 1958; Dening and Berrios, 1994; Simeon, 2004; Bu¨nning and Blanke, 2005; Mohr and Blanke, 2005). Yet, despite this large number of observations of doubles in neurological disease they occupy a neglected position in neurobiology and behavioral neurology.

Correspondence to: Olaf Blanke, MD, PhD, Laboratory of Cognitive Neuroscience, Brain–Mind Institute, Ecole Polytechnique Fe´de´rale de Lausanne (EPFL), 1015 Lausanne, Switzerland. E-mail: [email protected], Tel: þ41-21-6939621, Fax: þ41-216939625.

430

O. BLANKE ET AL.

In addition, given the rarity of these manifestations, the widespread neurological literature, and the complex phenomenology, doubles have only recently been investigated systematically. This is surprising when looking at the large number of studies investigating visual and nonvisual illusory reduplication of body parts such as phantom limbs (Ramachandran and Hirstein, 1998; Halligan, 2002), which has led to the neuroscientific investigation and description of many of the underlying neurocognitive mechanisms for body part reduplications. Importantly, these latter findings have not only enhanced our understanding of phantom limbs, but have also improved our models of corporeal awareness and bodily processing (Botvinick and Cohen, 1998; Ramachandran and Hirstein, 1998; Brugger et al., 2000; Halligan, 2002; Ehrsson et al., 2004). The scientific value of a thorough understanding of visual illusory reduplication that affects not only body parts, but the entire body can thus not be overstated given its potential importance in understanding the central mechanisms of global corporeal awareness and embodiment, as well as global self-consciousness (Ehrsson, 2007; Lenggenhager et al., 2007). Here we will first review phenomenological, functional, and anatomical similarities and differences of the three main forms of visual reduplication: out-ofbody experience, autoscopic hallucination, and heautoscopy. The separation into three distinct autoscopic phenomena was initially developed by Devinsky et al. (1989a) and subsequently extended by Gru¨sser and Landis (1991), Brugger and colleagues (Brugger et al., 1997; Brugger, 2002), and Blanke et al. (2004). These authors agreed that the combined classification of the popularly phenomenon of out-of-body experience with the less known phenomena of autoscopic hallucination and heautoscopy is important, since during all three autoscopic phenomena the subject has the impression of seeing a second own body (or double) in extrapersonal space. It has been speculated that these phenomenological characteristics point to similar as well as distinct neurocognitive mechanisms in the different forms of autoscopic phenomena (Brugger et al., 1997; Blanke et al., 2004). Second, we will review the rarer forms of autoscopic phenomena including multiple visual doubles (polyopic heautoscopy) and inner visual doubles (inner heautoscopy). The description of these visual doubles is followed by a discussion of sensorimotor doubles (feeling of a presence), auditory doubles (hearing of a presence), and negative doubles (negative heautoscopy) due to neurological disease. The feeling of a presence is defined as the convincing feeling that there is another person close by without actually seeing that person (Brugger et al., 1996; Blanke et al., 2003) and has been referred to previously as ‘leibhafte

Bewusstheit’ (Jaspers, 1913), ‘hallucination du compagnon’ (Lhermitte, 1939) or ‘feeling of a presence’ (Brugger et al., 1996; Blanke et al., 2003). Although several patients with the feeling of a presence due to focal brain damage have been described (for review see Brugger et al., 1996), we do not consider the feeling of a presence as an autoscopic phenomenon because it is characterized by a nonvisual body reduplication as opposed to the three main forms of autoscopic phenomena which are all characterized by a visual body reduplication (see below; for alternative classifications of autoscopic phenomena see: Sollier, 1903a; Menninger-Lerchenthal, 1935; Lhermitte, 1939; He´caen and Ajuriaguerra, 1952; Gru¨sser and Landis, 1991; Brugger et al., 1997).

22.2. Visual doubles 22.2.1. Out-of-body experience During an out-of-body experience people seem to be awake and feel that their ‘self,’ or center of awareness, is located outside of the physical body and somewhat elevated. It is from this elevated extrapersonal location that the subjects experience seeing their body and the world (Blackmore, 1982; Irwin, 1985; Devinsky et al., 1989a; Brugger, 2002; Blanke et al., 2004). The subjects’ reported perceptions are organized in such a way as to be consistent with this elevated visuospatial perspective. The following example from Lunn (1970, case 1) illustrates what individuals commonly experience during an out-of-body experience: ‘Suddenly it was as if he saw himself in the bed in front of him. He felt as if he were at the other end of the room, as if he were floating in space below the ceiling in the corner facing the bed from where he could observe his own body in the bed. [. . .] he saw his own completely immobile body in the bed; the eyes were closed.’ An out-of-body experience can thus be defined as the presence of the following three phenomenological elements: the feeling of being outside one’s physical body (disembodiment); the presence of a distanced and elevated visuospatial perspective; and the seeing of one’s own body (autoscopy) from this elevated perspective. These three aspects are shown graphically in Fig. 22.2C. 22.2.2. Autoscopic hallucination During an autoscopic hallucination people experience seeing a double of themselves in extrapersonal space without the experience of leaving their body (no disembodiment). As compared to out-of-body experiences, individuals with autoscopic hallucination see the world from their habitual visuospatial perspective and experience their ‘self,’ or center of awareness inside their physical body (Fig. 22.2A). The following example of

432

O. BLANKE ET AL.

Case Study 22.2 Autoscopic hallucination Zamboni et al. (2005) The present case description of an autoscopic hallucination illustrates how much visual detail may be contained in the illusory image (of the autoscopic body) that patients experience to see. Somewhat atypically the autoscopic hallucination in this case was not paroxysmal, but persisted for several months allowing for the patient to describe the autoscopic body in great detail. A 30-year-old, right-handed female reported seeing in a permanent fashion her own image as though she was looking into a mirror. Wherever she looked, this mirror image was always in front of her, at a distance of about one meter. If a solid object was placed between the autoscopic image and the patient, she said that she can still see the image, but nearer to her, on the surface of the object. She described that the autoscopic image was transparent, yet somewhat blurred, setting ‘on a sheet of glass’ resting against whatever object she was looking at. The image was life-sized and usually included head and shoulders, but could extend as far as the legs if the patient explored it by moving

an autoscopic hallucination is taken from Ko¨lmel (1985, case 6). ‘. . . the patient suddenly noticed a seated figure on the left. ‘It wasn’t hard to realize that it was I myself who was sitting there. I looked younger and fresher than I do now. My double smiled at me in a friendly way.’’ 22.2.3. Heautoscopy The third form of autoscopic phenomena is heautoscopy, which is an intermediate form between autoscopic hallucination and out-of-body experience. Individuals experiencing a heautoscopy also have the experience of seeing a double of themselves in extrapersonal space. However, it is difficult for the subject to decide whether he/she is disembodied or not and whether the self is localized within the physical body or in the autoscopic body (Blanke et al., 2004). In addition, the subjects often report seeing, in an alternating or simultaneous fashion, from different visuospatial perspectives (physical body, double’s body) as reported by patient 2B in Blanke et al. (2004) (see Fig. 22.2). ‘[The patient] has the immediate impression as if she

the gaze downward over the figure. It was always dressed exactly like the patient. Like a real mirror image, the autoscopic image or body replicated her bodily movements, in particular her face and arm movements. Interestingly, while one of the examiners put his hand on the patient’s shoulder the patient reported that she could perceive something on the image’s shoulder similar to a hand. The image disappeared when she closed her eyes. The autoscopic hallucination was not associated with an emotional state and the patient appeared somewhat indifferent to its presence and disappeared progressively after 3 months. The patient suffered from hemorraghic infarction to the occipital poles extending to the right parietooccipital junction (as demonstrated by magnetic resonance imaging) due to gestosis and eclampsia, three months before the above described hallucination. The neurological examination during the period of the autoscopic hallucination showed right lower limb weakness, left visuospatial hemineglect, optic ataxia, ocular apraxia, impaired depth perception, severe object agnosia, prosopagnosia, and alexia.

were seeing herself from behind herself. She felt as if she were ‘standing at the foot of my bed and looking down at myself.’ Yet, [. . .] the patient also has the impression of ‘seeing’ from her physical [or bodily] visuospatial perspective, which looked at the wall immediately in front of her. Asked at which of these two positions she thinks herself to be, she answered that ‘I am at both positions at the same time.’’ To summarize, the three forms of autoscopic phenomena differ with respect to the three phenomenological characteristics of disembodiment, visuospatial perspective, and autoscopy. Whereas there is no disembodiment in autoscopic hallucination and always disembodiment in out-of-body experiences, subjects with heautoscopy generally do not report clear disembodiment, but are often unable to localize their self. Thus, in some patients with heautoscopy the self is localized either in the physical body, or in the autoscopic body, and sometimes even at multiple positions. Accordingly, the visuospatial perspective is body-centered in autoscopic hallucination, extracorporeal in out-of-body experience, and at an extracorporeal and body-centered position in heautoscopy.

ILLUSORY REDUPLICATIONS OF THE HUMAN BODY AND SELF

433

Fig. 22.2. Phenomenology of autoscopic phenomena. (A) Autoscopic hallucination: experience of seeing one’s body in extracorporeal space (as a double) without disembodiment (experiencing the self as localized outside one’s physical body boundaries). The double (right figure) is seen from the habitual egocentric visuospatial perspective (left figure). (B) Heautoscopy: an intermediate form between autoscopic hallucination and out-of-body experience; the subject experiences seeing their body and the world in an alternating or simultaneous fashion both from an extracorporeal perspective and from their bodily visuospatial perspective; often it is difficult for the subject to decide whether the self is localized in the double or in their own body. (C) Out-of-body experience: during an out-of-body experience the subject appears to ‘see’ themselves (bottom figure) and the world from a location above their physical body (extracorporeal location and visuospatial perspective; top figure). The self is localized outside one’s physical body (disembodiment). The directions of the subject’s visuospatial perspective during the AP are indicated by the arrows (modified from Blanke, 2004).

Case Study 22.3 Heautoscopy Brugger et al. (1994) The following heautoscopy case underlines that heautoscopy is not only associated with a reduplication of the patients’ body, but also by a reduplication of the self as these patients often cannot indicate in which of the two experienced bodies their self is localized and often claim to be localized at two positions simultaneously or in rapid alternation. Reduplication of the self is not present in autoscopic hallucination and out-of-body experience. A 21-year-old right-handed man woke up one morning and described the following experience. When he got up with a feeling of dizziness, he turned around and saw himself still lying in bed. He was angry about ‘this guy who I knew was myself and who would not get up and thus risked being late at work.’ He tried to wake up the body in the bed first by shouting at it then by trying to shake it and then by repeatedly jumping on the autoscopic body in the bed. His double did not show any reaction. Only then did the patient realize that

he should be puzzled about his double and became more and more scared by the fact that he did not know any more who of the two bodies he really was (or where his self was located). This was especially due to the fact that he experienced his self-location to be alternating between the two bodies. Thus, several times he experienced being the one lying in bed and having the double look down on him from above the bed and even beating him. His only intention was described as trying to become one person again: standing next to the window (from where he could still see his other body lying in bed) he decided to jump out the window ‘in order to stop the intolerable feeling of being divided into two’ hoping that ‘this desperate action would frighten the one in bed and thus urge him to merge with me again.’ The next thing he remembers is waking up in the hospital. This patient was known for complex partial seizures since the age of 15 years due to a dysembryoblastic neuroepithelial tumor in the mediobasal part of the left temporal lobe. The neurological examination revealed diminished right-sided hand agility, a severe deficit in verbal memory, but not in visuospatial memory.

434

O. BLANKE ET AL.

The impression of seeing one’s own body is present in all autoscopic phenomena (for further details see Brugger et al., 1997; Blanke et al., 2004). Only during autoscopic hallucination does the subject immediately realize the hallucinatory nature of the experience, whereas heautoscopy and out-of-body experiences are generally described as highly realistic experiences (Brugger et al., 1994; Brugger, 2002; Blanke et al., 2004). In a recent study Blanke and Mohr (2005) analyzed a larger number of neurological cases with out-of-body experiences, heautoscopy, and autoscopic hallucinations related to confirmed brain damage. These authors systematically analyzed 113 reported medical autoscopic phenomena cases from the English, German, French, and Italian literature and finally considered 41 cases with autoscopic phenomena (20 cases with autoscopic hallucination, 10 with heautoscopy, 11 with out-of-body experience) allowing a more detailed analysis of phenomenology (especially of the autoscopic body), associated neurological findings, etiology, and lesion site for out-of-body experience, autoscopic hallucination, and heautoscopy separately. With respect to phenomenology, these authors observed that a partially seen autoscopic body and its position in the visual field differed between the different forms of autoscopic phenomena. First, a partial autoscopic body was mostly experienced by patients with autoscopic hallucinations (63%) who always saw the upper part of the autoscopic body including head, neck, and upper trunk (while arms, legs, and lower trunk were missing). Second, in autoscopic hallucination the position of the autoscopic body in the visual field was frequently lateralized to the side of other visual hallucinations and hemianopia (Brugger et al., 1996), whereas the autoscopic body in heautoscopy and out-of-body experience was generally in the central visual field. Thus, these data do not agree with Green (1968) and Brugger et al. (1996) who observed a frequent lateralization of the autoscopic body also for out-of-body experiences. This might be due to several reasons. Green (1968) carried out her study in healthy subjects Blanke and Mohr (2005) only investigated neurological patients with confirmed brain damage that was mostly unilateral. As Brugger et al. (1996) studied psychiatric and neurological patients, and also included neurological patients with nonfocal brain damage as well as patients without confirmed brain damage, differences in patient selection might explain the phenomenological differences between the different studies. Finally, the autoscopic body is seen as standing or sitting in autoscopic hallucination and heautoscopy, whereas it is in supine position in out-of-body experiences (Blanke et al., 2004). These body positions were also found for the actual body position of the patient prior to the

autoscopic phenomena, suggesting that the position in which the patient experiences seeing the autoscopic body directly reflects the patient’s own body position prior to and during out-of-body experience, heautoscopy, and autoscopic hallucination. A supine body position was also found by Green (1968) in 75% of her out-of-body experience subjects and, interestingly, most techniques that are used to voluntarily induce out-of-body experiences propose that subjects use a supine and relaxed position (Blackmore, 1982; Irwin, 1985). On the contrary, the data of Blanke and Mohr (2005) confirmed the mainly upright body position in patients with autoscopic hallucinations and heautoscopy, as found by Dening and Berrios (1994). Whereas the above described variables allow the differentiation of autoscopic hallucination from heautoscopy and out-of-body experience, the following five phenomenological characteristics of the autoscopic body allow distinguishing out-of-body experience and heautoscopy. First, whereas patients with out-of-body experiences and autoscopic hallucinations experience seeing the autoscopic body in front-view, patients with heautoscopy often see the autoscopic body in sideor back-views. Ionasescu’s (1960, case 7) patient, who was a hairdresser, experienced rotating around his customer (while cutting his hair) and then saw his autoscopic body from the side. Blanke et al.’s patient (2004, case 2b) saw herself from behind as did Devinsky et al.’s patient (1989a, case 9). Brugger et al. (1994) describe a patient who saw the autoscopic body in many different views. Second, this variability of views of the autoscopic body in heautoscopy is also reflected in the various motor actions that the latter is experienced performing. Thus, patients with heautoscopy report that the autoscopic body walks, runs, sits down, even shouts at the patient, and beats him with his fists (for a very vivid description of a patient’s experience see case study 22.3). On the contrary, the autsocopic body during outof-body experience and autoscopic hallucination does not move or act. Third, heautoscopy is often associated with the experience of sharing thoughts, words, or actions, which are less frequent in out-of-body experiences and autoscopic hallucinations. Indeed, patients with heautoscopy experience hearing the autoscopic body talk to them (Brugger et al., 1994) or that both bodies communicate by thought (Blanke et al., 2004, case 5). Others patients stated that the autoscopic body is performing the actions they were supposed to do (Devinsky et al., 1989a, case 9) or fights with other people that could be of potential danger to the patient (Blanke et al., 2004, case 5). Fourth, whereas the visuospatial perspective was unambiguously localized and experienced as unitary by all patients with autoscopic hallucinations and out-of-body experiences (as was

ILLUSORY REDUPLICATIONS OF THE HUMAN BODY AND SELF used to classify both phenomena), patients with heautoscopy frequently experience seeing from several different visuospatial perspectives (Brugger, 2002; Blanke et al., 2004). Indeed, patients 2b, 4, and 5 of Blanke et al. (2004) experienced seeing from two different physical positions as did Brugger et al.’s patient (1994). Finally, patients with heautoscopy frequently report to ‘be split into two parts or selves’ or feel as if ‘I were two persons’ (Pearson and Dewhurst, 1954). Others reported that they were localized at two places at the same time (bilocation; Blanke et al., 2004, cases 2b, 5). In Brugger et al.’s patient (1994) bilocation occurred in rapid succession between the autoscopic and physical body, and Lunn’s patient (1970) describes himself (during heautoscopy) as a ‘split personality.’ The latter five variables of the autoscopic double (different views; actions; sharing of thoughts, words, or actions; multiple visuospatial perspectives; bilocation or splitting of the self) were all associated with heautoscopy. Thus, although out-of-body experience and heautoscopy share many associated hallucinations and some aspects of the autoscopic body, they differ in these latter five, more complex, variables suggesting that they are caused by different central mechanisms. These phenomenological differences are corroborated by functional and anatomical differences. 22.2.4. Clinical presentation Although most of the aforementioned authors agree that autoscopic phenomena relate to a pathology of own body perception and/or corporeal awareness, it is not known which of the many involved corporeal senses are primarily involved in the generation of autoscopic phenomena and whether there are differences between the different forms of autoscopic phenomena. Whereas many authors have argued that autoscopic phenomena are due to a multisensory disturbance or disintegration, most authors have argued that autoscopic phenomena are caused by different sensory disturbances classifying autoscopic phenomena as visual disorders, proprioceptive disorders, vestibular disorders, or body schema disorders. Some authors postulated a dysfunction of visual processing (Fe´re´, 1891; Naudascher, 1910). Visual theories considered autoscopic phenomena to be visual or ‘specular’ hallucinations based on the fact that they were experienced and described by most patients spontaneously as visual manifestations (Fe´re´, 1891; Naudascher, 1910). In addition, especially autoscopic hallucinations may sometimes be lateralized in the visual field and are frequently experienced as visual pseudohallucinations (Brugger et al., 1997; Brugger, 2002; Blanke et al., 2004). However, a number of

435

arguments show that a purely visual explanation cannot account for autoscopic phenomena in general. First, although all three forms of autoscopic phenomena are described spontaneously as visual, they are frequently experienced as veridical (especially heautoscopy and out-of-body experience) and not as pseudohallucinations (Menninger-Lerchenthal, 1935; 1946; He´caen and Ajuriaguerra, 1952; Brugger et al., 1997; Blanke et al., 2004). Secondly, patients and healthy people reported that the impression of reality and self-recognition is preserved even if visual details of the autoscopic body during the autoscopic phenomena differ from the patient’s actual appearance (such as clothes, age, haircut, size, coloring of the body (Sollier, 1903a; 1903b; Lhermitte, 1939; Lukianowicz, 1958; Crookall, 1964; Green, 1968; Irwin, 1985; Ko¨lmel, 1985; for discussion see Blanke et al., 2004). In some patients, self-recognition may even be immediate if the patient only sees their back during the autoscopic phenomena (Devinsky et al., 1989a; Blanke et al., 2004). These data point to the importance of nonvisual, body-related, mechanisms in autoscopic phenomena, such as proprioceptive and/or kinaesthetic processing, as already argued by Sollier (1903a; for later discussions see also Menninger-Lerchenthal, 1935; Lhermitte, 1939; Brugger et al., 1997; Blanke et al., 2004). In line with phenomenological differences, these authors proposed that the involvement of disturbed processing may differ between the different forms of autoscopic phenomena. Paul Sollier (1903a) for instance differentiated heautoscopy (or ‘autoscopie dissemblable’) from autoscopic hallucination (or ‘autoscopie spe´culaire’) of previous authors such as Fe´re´ (1891) suggesting that both autoscopic phenomena forms might relate to different cerebral mechanisms. He postulated the latter to be a mere visual hallucination, whereas he assumed the former to be a proprioceptive– kinaesthetic disturbance associated with a strong psychological affinity between the patient’s and the autoscopic body. For proprioceptive–kinaesthetic processing he coined the term ‘ce´nesthesia’ (for the body’s visceral and deep sensations) stating that autoscopic hallucination and heautoscopy are due to different degrees of the ‘projection of the body’s visceral and deep sensations in the space on the outside of the body’ (Sollier, 1903a, pp. 34–44). Several authors have also highlighted the role of proprioception and kinesthesia in autoscopic phenomena by noting that some patients report shared movements between their physical and autoscopic body (autoscopic echopraxia; MenningerLerchenthal, 1935; Lhermitte, 1939; He´caen and Ajuriaguerra, 1952; Lukianowicz, 1958; Brugger et al., 1997). Another sensory system, which has been linked to autoscopic phenomena, is the vestibular system that

436

O. BLANKE ET AL.

conveys sensations of the body’s orientation in threedimensional space to the brain. Whereas Bonnier (1904) and Skworzoff (1931) noted the frequent association of vestibular sensations of either peripheral or central origin with autoscopic phenomena, others proposed that a central vestibular dysfunction might be an important mechanism for the actual generation of autoscopic phenomena (Menninger-Lerchenthal, 1935; 1946; Gru¨sser and Landis, 1991; Brugger et al., 1997). Menninger-Lerchenthal (1935) extended this view and pointed to the importance of vestibular disorders in the generation of visual illusions and visual dysfunctions, as well as autoscopic phenomena. Blanke et al. (2004) suggested, on clinical grounds, a differential implication of vestibular processing in the different forms of autoscopic phenomena. These authors suggested systematic differences in the strength of vestibular dysfunction in autoscopic hallucination, heautoscopy, and out-of-body experiences. The potential role of the vestibular system for autoscopic phenomena is also supported by descriptions of vestibular sensations during autoscopic phenomena in healthy populations (i.e., Crookall, 1964; Green, 1968; Yram, 1972; Blackmore, 1982; Irwin, 1985; Metzinger, 2003). Blanke et al. (2004) suggested that out-of-body experiences were associated with a gravitational (otholithic) vestibular disturbance, whereas the vestibular dysfunction in patients with heautoscopy was more variable and often characterized by rotational components, and vestibular dysfunction was absent in patients with AS. Finally, many patients with autoscopic phenomena also experience paroxysmal visual body-part illusions (Ehrenwald, 1931; Menninger-Lerchenthal, 1935; Lhermitte, 1939; He´caen and Ajuriaguerra, 1952; Ionasescu, 1960; Lunn, 1970; Dening and Berrios, 1994) and this has led several authors to argue for a similar or closely related functional and anatomical origin of visual body part illusions and visual illusions of the entire body (MenningerLerchenthal, 1935; 1946; Lhermitte, 1939; He´caen and Ajuriaguerra, 1952; Ionasescu, 1960; Brugger et al., 1997). Recent findings from Blanke and Mohr (2005) suggest that different patterns of hallucinations and neurological deficits are associated with out-of-body experience, heautoscopy, and autoscopic hallucination arguing for different functional mechanisms in each form. Thus, vestibular hallucinations and body schema disturbances, as well as the absence of hemianopia were associated with out-of-body experiences and heautoscopy, whereas lateralized visual hallucinations and hemianopia without vestibular hallucinations and no body schema disturbances were associated with autoscopic hallucination. In addition, the visual hallucinations of patients with autoscopic hallucinations were

lateralized to the side of hemianopia. Auditory hallucinations were mainly observed in patients with out-ofbody experiences. Other manifestations such as tactile hallucinations, aphasia, and sensorimotor deficits were infrequent in all autoscopic phenomena. Based on this pattern of associated hallucinations and neurological deficits, Blanke and Mohr (2005) argued that it is possible to differentiate the mainly visual autoscopic hallucinations from out-of-body experience and heautoscopy confirming earlier case descriptions of autoscopic hallucination as a visual or ‘specular’ hallucination or pseudohallucination by Fe´re´ (1891) and Paul Sollier (1903a). Next to a confirmation of Fe´re´’s earlier theory of visual mechanisms in autoscopic hallucination, Blanke and Mohr’s (2005) analysis also provided evidence for a vestibular and body schema pathology. However, this was not found for all autoscopic phenomena, but specifically for heautoscopy and out-of-body experiences (Menninger-Lerchenthal, 1935; 1946; Brugger et al., 1997; Blanke et al., 2004). 22.2.5. Etiology In comparison with the rich phenomenology of the above mentioned studies, much less information is available about the etiology and especially anatomy of autoscopic phenomena, which is partly due to the fact that many cases were reported in the first half of the twentieth century. With respect to etiology, autoscopic phenomena have been reported in various focal and generalized diseases of the central nervous system. Generalized neurological etiologies include cerebral infections such as meningitis and encephalitis, intoxications, as well as generalized epilepsies (MenningerLerchenthal, 1935; Lhermitte, 1939; Bychowski, 1943; He´caen and Ajuriaguerra, 1952; Lukianowicz, 1958; Devinsky, 1989a; Dening and Berrios, 1994; Brugger et al., 1997; Blanke et al., 2004). Autoscopic phenomena following focal brain damage also emerge from a large variety of etiologies, including focal epilepsy (Devinsky, 1989a), traumatic brain damage (Todd and Dewhurst, 1955), and migraine (Lippman, 1953), vascular brain damage (Ko¨lmel, 1985), neoplasia (Todd and Dewhurst, 1955), dysembryoblastic neuroepithelial tumor (Blanke et al., 2004) and arteriovenous malformation (Devinsky et al., 1989a). 22.2.6. Anatomy Regarding their underlying anatomy, autoscopic phenomena of focal origin primarily implicate posterior brain regions and with respect to lobar anatomy most studies found the temporal, parietal, or occipital lobe to be involved (He´caen and Ajuriaguerra, 1952; Todd

ILLUSORY REDUPLICATIONS OF THE HUMAN BODY AND SELF and Dewhurst, 1955; Lunn, 1970; Devinsky et al., 1989a; Blanke et al., 2004; Blanke and Arzy, 2005). Some of these authors have either suggested a predominance of temporal lobe involvement (Devinsky et al., 1989a; Gru¨sser and Landis, 1991), a predominance of parietal lobe involvement (Menninger-Lerchenthal, 1935; 1946; He´caen and Ajuriaguerra, 1952), or no brain localization at all (Lhermitte, 1939). MenningerLerchenthal (1935) even speculated on different anatomical substrates for the different autoscopic phenomena, suggesting that autoscopic hallucination originate at the junction of the parietal and occipital lobe (junction of Brodmann’s areas 21 and 40), heautoscopy from the angular and supramarginal gyrus (Brodmann’s areas 40 and 41), and out-of-body experiences from the superior parietal lobule (Brodmann’s area 7). These anatomical dissociations have been partly confirmed by Blanke et al. (2004) showing that autoscopic phenomena might be related to damage to the temporoparietal junction (TPJ; Fig. 22.3). Unfortunately, the small number of analyzed patients in this latter study did not allow lesion analysis for each of the three forms of autoscopic phenomena. With regard to predominant hemispheric involvement the reported data are quite divergent. Some authors found no hemispheric predominance for autoscopic phenomena (He´caen and Ajuriaguerra, 1952; Fredericks, 1969; Devinsky et al., 1989a; Dening and Berrios, 1994), while others have suggested a right hemispheric predominance for autoscopic phenomena (Menninger-Lerchenthal, 1935; 1946; Gru¨sser and Landis, 1991; Brugger et al., 1997). For autoscopic phenomena in psychiatric disease see Bu¨nning and Blanke (2005) and Mohr and Blanke (2005). An analysis of 41 cases with autoscopic phenomena shared that all three autoscopic phenomena have been reported following damage to either the right or the left hemispheric brain lesions (Blanke and Mohr, 2005) although there were differences with respect to primarily involved hemisphere and brain region. Out-of-body experiences were mostly due to right hemispheric brain damage (67%), whereas more frequent left hemispheric brain damage was found for patients with heautoscopy (67%). The fact that previous studies have analyzed the lesion location for all autoscopic phenomena together, might thus explain why some authors reported no hemispheric predominance (He´caen and Ajuriaguerra, 1952; Fredericks, 1969; Devinsky et al., 1989a; Dening and Berrios, 1994). Regarding the intrahemispheric lesion site of autoscopic phenomena a high predominance of temporal lobe involvement in all autoscopic phenomena (55–82%) was found by Blanke and Mohr (2005) corroborating older literature (Devinsky et al., 1989a; Gru¨sser and Landis, 1991; Dening and Berrios,

437

Fig. 22.3. Lesion location in patients with autoscopic phenomena. Autoscopic phenomena are linked to interference with the temporoparietal junction. The figure shows the results of lesion overlap analysis in the five patients with autoscopic phenomena from Blanke et al. (2004). Each patient is indicated in a separate color. The area of lesion overlap (patient 1,5,6), of intracranial seizure onset (patient 2), or of the site of electrical cortical stimulation (patient 3) of each patient is mapped onto the right hemisphere of Patient 6. Lesion overlap for all patients centred on the temporoparietal junction (area indicated by dashed white line). Thick black lines indicate the sylvian fissure and the central sulcus; thin lines indicate superior temporal sulcus, postcentral sulcus and intraparietal sulcus. Modified with permission from Blanke et al. (2004).

1994). The parietal lobe was also found frequently and equally often involved in all forms of autoscopic phenomena (45–55%; Blanke and Mohr, 2005). Only patients with autoscopic hallucinations had significantly more involvement of the occipital lobe concordant with the above described association with visual hallucinations and hemianopia. Occipital lobe involvement in autoscopic hallucinations is compatible with frequent bright coloring of the autoscopic body in autoscopic hallucinations that contrasted with the colorless, pale, and misty appearance of the autoscopic body in heautoscopy (Brugger et al., 1997). Based on this it might be suggested that patients with autoscopic hallucination might have more posterior brain damage in occipitoparietal and occipitotemporal cortex, whereas patients with heautoscopy and out-of-body experience have rather left temporoparietal lesions including the

438

O. BLANKE ET AL.

TPJ and patients with out-of-body experiences have right temporoparietal lesions including the TPJ. 22.2.7. Theoretical considerations These data suggest that autoscopic phenomena may result from a disintegration in personal space (due to conflicting tactile, proprioceptive, kinesthetic, and visual information) and a second disintegration between personal and extrapersonal space (due to conflicting visual and vestibular information) (Blanke et al., 2004; Bu¨nning and Blanke, 2005; Mohr and Blanke, 2005). These authors proposed that, while disintegration in personal space was present in all three forms of autoscopic phenomena, differences between the different forms of autoscopic phenomena were mainly due to differences in strength and type of the vestibular dysfunction. Indeed, Blanke et al. (2004) suggested that out-of-body experiences were associated with a strong vestibular disturbance, whereas heautoscopy was associated with a moderate and more variable vestibular disturbance and autoscopic hallucinations only with a mild or even absent vestibular disturbance. The here reviewed phenomenological, neurological, and anatomical data suggest the importance of a vestibular dysfunction and body schema disturbance in heautoscopy and out-ofbody experience and suggests that a vestibular dysfunction is absent or only weakly present in autoscopic hallucination. Moreover, the high frequency of visual hallucinations and of hemianopia in autoscopic hallucination suggests that deficient visual processing rather than vestibular processing might be the main causative factor for disintegration in personal space and/or extrapersonal space. This is also in agreement with the anatomical findings showing that patients with autoscopic hallucinations have significantly more occipital lobe involvement as compared to patients with heautoscopy or out-of-body experiences. The phenomenological differences between heautoscopy and out-of-body experience suggest that both autoscopic phenomena rely on different neurocognitive mechanisms. These more complex phenomenological differences were found despite the highly similar sensory hallucinations and neurological deficits that were associated with heautoscopy and out-of-body experience. Yet, in contrast to out-of-body experiences, heautoscopy was associated with the presence of many different views of the autoscopic body, many actions, the sharing of thoughts, words, and agency, multiple visuospatial perspectives, and bilocation of the self. We therefore suggest that the association of greater phenomenological variability of the autoscopic body (with respect to views and actions) with the increased frequency of shared thoughts, voices, and

agency between autoscopic and (the patient’s) physical body (i.e., echopraxia) might be due to a greater (or more variable) implication of abnormal kinesthetic/ proprioceptive information processing in heautoscopy. This is contrasted in out-of-body experiences by the silent and static autoscopic body, the disembodiment, the 180  inversion and the elevated and distanced visuospatial perspective of the self (with respect to the extracorporeal environment) that are probably related to vestibular disturbances (Blanke et al., 2004; Bu¨nning and Blanke, 2005; Mohr and Blanke, 2005). Thus, it seems to the subject with an out-of-body experience that their body position and visuospatial perspective is distanced (about 2–3 meters) and rotated (by 180  ) with respect to the actual physical position (Fig. 22.2C). In addition, during heautoscopy, the sharing of thoughts, voices, and agency might make it difficult for the patient to decide where the physical agent (Gallagher, 2000; Decety and Sommerville, 2003) is localized (i.e., in the physical body or in the autoscopic body). This is increased by two visuospatial perspectives that either alternate or are simultaneously present between autoscopic and physical body in heautoscopy. This situation makes it almost impossible for the heautoscopy patient to decide where the observing self is localized and might lead to the experience of two ‘observing’ selves (Blanke et al., 2004, case 2b). It might thus be argued that heautoscopy is not only an experience characterized by the reduplication of one’s body, but also by a reduplication of one’s self. As strikingly reported by Brugger et al. (1994) the high risk of suicide during this terrifying experience cannot be overstated as some of these patients with heautoscopy try by all means to re-establish their unitary self.

22.3. Multiple visual doubles 22.3.1. Clinical presentation Polyopic autoscopic hallucination or polyopic heautoscopy is present when patients report seeing more than one autoscopic double in extracorporeal space, that is, a multiple rather than a single reduplication of one’s own body. Probably the first account of polyopic heautoscopy is to be found in Mu¨ller’s (1826) seminal work on visual hallucinations. Returning home late from work, this exhausted university professor suddenly found himself in front of 15 persons, all clearly recognized as doubles of himself although being of different ages and wearing different clothes he himself had used to wear in former times (quoted after Brugger et al., 2005). A case of an autoscopic hallucination with multiple optical images is also reported by Roubinovitch (1893; quoted by Menninger-Lerchenthal, 1935). This author’s patient

ILLUSORY REDUPLICATIONS OF THE HUMAN BODY AND SELF saw three identical mirror images of himself, which he compared to the reflections he would have seen standing in front of a mirror with three wings. Other early autoscopic phenomena of polyopic nature can be found in Oesterreich (1910) and Leischner (1961). As analyzed recently by Brugger et al. (2006) polyopic autoscopic phenomena are described as

439

follows. In a third of the cases autoscopic phenomena were characterized by either two or three doubles, but most often by a large number of doubles that, in some cases, filled up the entire room (Mayer-Gross, 1928) or the interior of the patient’s body (Heintel, 1965). If polyopic autoscopic phenomena are characterized by a large number of doubles they are generally seen as quite

Case Study 22.4 Polyopic heautoscopy Brugger et al. (2006) This case highlights that heautoscopy is not only associated with a single reduplication of the patient’s body (as in autoscopic hallucination, heautoscopy, or out-ofbody experience). Same patients may also experience seeing multiple autoscopic bodies with varying degrees of physical resemblance and psychological affinities. A 41-year-old right-handed pottery maker woke up one night and noticed that he had split into three distinct parts: there was the left half of his body which felt quite normal, a right half which, physically and psychologically, felt detached from the left, and a man adjacent to his right side, which he felt to be a part of himself. It was as if he and the man were ‘sharing the same soul.’ This feeling was very convincing despite the fact that there was no similarity in physical appearance (for instance, the man was blond while the patient’s hair is black). Puzzled by this, the patient began to walk up and down in his bedroom. As he did so, he at once discovered what he later referred to as ‘the family.’ He gives the following account: ‘When I walked around, I repeatedly looked towards the gentleman on my side and wondered if I could recognize his face. This was impossible since on looking towards the right side he also turned his head to the right. I could note however, that the man was blond and about 50 years old. All of a sudden, I noticed that, even more to the right, there was a whole group of people. At a distance of 2 meters I saw an approximately 50-year-old lady with blond braids. Still another 4 meters away, there were two girls [both approximately age 20] and some 20 meters from me, still in a straight line with all the other persons, there was a boy [unspecified age]. I knew right from the beginning that these persons were intimately linked with one another, they were father, mother, daughters and son.’ [In reality, the

patient’s wife was younger and had dark short hair. His only two children were two sons, aged 10 and 16]. The patient reported that, with the appearance of the ‘family,’ the gap between left and right halves of his body ceased to exist. He continued to feel a strong sense of belonging towards the man at his right side, which gradually expanded also to the woman and, to a lesser extent, to the girls. The boy was only vaguely seen and sometimes vanished in the darkness of the far right end of the bedroom. Notably, all ‘family’ members imitated the patient’s movements, yet the ‘daughters’ and the ‘son’ were also able to move on their own. The patient described: ‘When I walked, the family walked with me; when I bent my knees, the others bent theirs; when I looked to the right, so did all the others. The girls were talking to one another, and sometimes they would look towards me waving their hands as if inviting me to join their world. . . Naturally, I could not see the persons any longer on closing my eyes, but the feeling remained that pieces of myself were located in those places I knew them to stay. It was a feeling of being awfully frittered away!’ When his ‘real’ wife was sitting at his right side, the ‘family’ would temporarily vanish and he perceived himself to be one person in one place again. However, he noted a clumsiness and weakness of the entire right half of his body. As soon as his wife moved from his side, the imaginary persons would immediately reappear in their respective places. According to the patient’s wife account, the patient’s speech was barely understandable throughout the experience and contained many neologisms. The patient suffered from partial seizures due to a left insular astrocytoma that extended into the adjacent frontotemporal cortex (as demonstrated by computed tomography). Neurological examination revealed a mild right-sided sensory hemisyndrome, logorrhea, an elevated mood with fluctuating denial of illness, and an isolated deficit in the recall of verbal material.

440

O. BLANKE ET AL.

small in size (Dewhurst and Pearson, 1955), whereas the cases with a smaller number of doubles are mostly experienced as having the same size as the patient. Echopraxia (or sharing of action between the autoscopic bodies and the patient’s body) was noted by two previously reported patients with autoscopic phenomena (Staudenmaier, 1912/1968; Lance, 1976). The doubles are generally localized in the central visual field (lateralization in the visual field was only described by three patients: (Ley and Stauder, 1950; Dewhurst and Pearson, 1955; Brugger et al., 2006). If mentioned, the perceived distance of the double from the patient was generally very small and thus in the peripersonal or personal space as is the case in most patients with autoscopic phenomena. With respect to etiology about two thirds of the cases were of neurological origin, a third due to psychiatric disease (one case was reported during puerpurium). Of the neurological cases, the large majority were of focal origin either due to vascular infarction or focal epilepsy. In these focal neurological cases the lesion was localized as often in the right as in the left hemisphere. The recent case reported by Brugger et al. (2006) corroborated the importance of nonvisual, body-related, mechanisms, also for polyopic heautoscopy (Sollier, 1903a; 1903b; Menninger-Lerchenthal, 1935; Lhermitte, 1939; He´caen and Ajuriaguerra, 1952; Brugger et al., 1997; Blanke et al., 2004) by showing an alteration of own-body awareness (or depersonalization), detachment of parts or of the entire left half of the patient’s body (or dyssomatognosia), and vestibular illusions. Interestingly, Brugger et al.’s patient report confirmed that self-recognition and self-identification, as well as psychological affinity between patient and double occurs even if visual details of the body’s double differ from the patient’s actual appearance. There were only few physical similarities between this patient and the closest double (Case Study 22.4). Yet, the patient felt a strong psychological affinity towards him, as if the double were a part of him, and as if they were to share thoughts and feelings. Self-recognition, self-identification, and psychological affinity depended on the distance between the patient and the experienced location of the double. Thus, the doubles at greater distances (from the patients’s body) were perceived initially as different people and not as part of his own body. Only later, once this patient experienced the doubles as a group as well as closer with respect to his body did he state that he experienced them as part of his self (Brugger et al., 2006). It might thus be suggested that the visuospatial characteristics of the experienced scene such as the distance between patient and double relates to such psychological processes as self-recognition, self-identification, and psychological affinity with the double. This relation might become especially evident

in polyopic heautoscopy where multiple doubles with different characteristics are experienced simultaneously at different locations and distances from the patient’s body. What are the functional mechanisms leading to the perception of multiple visual doubles? Very little clinical information is currently available on this rare autoscopic phenomenon as is also the case for other body disturbances such as multiple supernumerary phantom arms (Ehrenwald, 1930). The patient described by Brugger et al. (2006) initially observed only one single right-sided double, but discovered the other more distant right-sided doubles upon moving his eyes onto the closest double. This potential relationship between eye movements and polyopic heautoscopy might be important, especially since eye movement related mechanisms are considered one of the major pathomechanisms in classical polyopia (Bender, 1945; but see Cornblath et al., 1998).

22.4. Inner visual doubles 22.4.1. Inner heautoscopy A number of patients have been described that claim to see the inner organs of their own body and this experience has been called inner heautoscopy. Schilder (1935), He´caen and Ajuriaguerra (1952), and Dening and Berrios (1994) only briefly mentioned inner heautoscopy, whereas Menninger-Lerchenthal (1935) and Lhermitte (1951) and especially Sollier (1903b) discussed several cases of inner heautoscopy in greater detail. There is a histrionic element to inner heautoscopy and most cases have been described about hundred years ago (Comar, 1901; Bain, 1903; Sollier, 1903a; 1903b). Patients with inner heautoscopy claim to see their inner organs in extracorporeal space (Bain, 1903; Sollier, 1903a; 1903b) or rarely within their own body from an extracorporeal visuospatial perspective (Heintel, 1965). Modern accounts of inner heautoscopy are rare (Carlson, 1977, case #4; Magri and Mocchetti, 1967; Peto, 1969). Internal heautoscopy may also be encountered during shamanic rituals (Eliade, 1951/ 1964, p. 62; cited in Brugger et al., 1997) and has been reported in certain populations. (Irwin, 1985 reported that Eskimos see their body as a skeleton under certain conditions). With respect to medical reports, Comar (1901; case #1) described an 18-year-old female patient who reported seeing her heart, and another patient (case #2) who claimed seeing her hip joint. Brugger et al. (1997) described a patient who saw the interior of his torso, including blood circulating in vessels and another patient who saw his skeleton. The case described by Heintel (1965) is interesting as she did not describe

ILLUSORY REDUPLICATIONS OF THE HUMAN BODY AND SELF seeing her inner organs in extracorporeal space, but many different mirror images of her own body (of different sizes) inside her body. It thus seems as if this patient experienced seeing doubles inside her body from a disembodied visuospatial perspective that is generally reported by subjects with an out-of-body experience. Paul Sollier (1903b) described several patients who experienced autoscopic hallucination or heautoscopy in association with inner heautoscopy. He described inner heautoscopy as ‘becoming conscious of one’s inner organs, in their form, their placement, their structure, [and] their functioning (p. 45)’ and described a patient claiming to see at different times her heart, lungs, intestines, uterus, muscles, and even her brain (Sollier, 1903a, pp. 68–79). Sollier thought inner heautoscopy to be functionally related to other autoscopic phenomena such as autoscopic hallucination and heautoscopy. Recently, Bradford (2005) suggested a relationship between inner heautoscopy and Cotard syndrome. Critchley (1950, p. 338) characterized ‘hysterical inner heautoscopy’ as ‘a pathological accentuation of the body-image.’ Bradford (2005) summarized the observations in several patients with inner heautoscopy generally as a ‘late middle-aged, usually female [patient], pacing the wards of public psychiatric hospitals, describing and bemoaning the extraction or diseased state of their viscera, and, in keeping with their complaints of damnation to Hell, occasionally complaining of excessive bodily heat (‘I am burning. . . I am on fire’).’ He adds that ‘morbid transformations of the viscera are reported more commonly than changes in the skeletal structure.’ Lhermitte (1939) mentions that inner heautoscopy might be related to sensations of referred pain (Sinclair et al., 1948). In referred pain, pain of inner organs is experienced at distinct spatial positions on the patient’s body surface (Lhermitte, 1939, pp. 228–232). Thus, cardiac pain is often experienced in the left hand and arm, pain from the gall bladder in the right shoulder, and kidney pain in the testes. Cardiac pain may even be experienced in phantom limbs (Cohen and Jones, 1943; cited in Lukianowicz, 1958). One could thus assume that inner heautoscopy is related to pathological interference with shared representations of visceral and somatosensory body area in the brain. Clinical evidence suggests that the insular cortex and the superior temporal gyrus might harbour such shared representations. Thus, the conscious (nonvisual) experience of one’s inner organs is frequently reported by patients with temporal lobe epilepsy (Isnard et al., 2000). This includes a variety of ‘visceral sensations’ (Penfield and Jaspers, 1954) such as epigastric sensations, abdominal aura, palpitations, and more rarely nausea, vomiting, suffocation sensation, thirst, or constipation. Given that the insula contains cortical

441

representations of the inner organs (Ostrowsky et al., 2000; Shelley and Trimble, 2004; Isnard and Maugie`re, 2005), that visceral sensations have been induced by electrical stimulation of the insula and the superior temporal gyrus (Penfield and Jaspers, 1954; Ostrowsky et al., 2000; Isnard and Maugie`re, 2005), and the fact that the lesion site of autoscopic hallucination, heautoscopy, and out-of-body experience most often affects the temporal lobe, one might suggest that inner heautoscopy may be related functionally and anatomically to a dysfunction of these shared cortical representations of inner organs with certain parts of the body surface and the entire body. The description of patient A.Ki. might be relevant in this respect as electrical stimulation at various points of his right insula induced sensations that included large parts of the body surface as well as visceral (abdominal) sensations (Penfield and Jaspers, 1954, pp. 426–431). Also, as reviewed by Dorpat (1971), not only the amputation of a limb, but also the resection of inner organs such as uterus, stomach, and rectum may lead to phantom sensations for the removed inner organs. Inner heautoscopy may thus be considered a visualized phantom sensation for inner organs, due to disturbed central mechanisms with respect to visceral own body representations, much as autoscopic hallucinations and phantom limb sensations are due to disturbed central mechanisms of body and limb representations. Finally, it might also be relevant concerning the involved mechanisms in inner heautoscopy to mention that the insula is a key region of the vestibular cortex (Guldin and Gru¨sser, 1998; Brandt and Dieterich, 1999) as it has been argued that disturbed vestibular processing is a key mechanism in autoscopic phenomena. With respect to etiology, inner heautoscopy has most often been described in patients suffering from hysteria (Comar, 1901; Bain, 1903; Sollier, 1903a; 1903b). Dening and Berrios (1994) mentioned that inner heautoscopy is often associated with agitated depression (Dening and Berrios, 1994), but may also be observed in patients with neurosyphilis and psychiatric disease (Lhermitte, 1939; He´caen and Ajuriaguerra, 1952). To our best knowledge, internal heautoscopy has not been reported in neurological patients with circumscribed brain damaged. We conclude that (1) the histrionic element in inner heautoscopy, (2) the rarity of cases and especially recent descriptions, and (3) the absence of cases with confirmed brain damage and detailed neuropsychological examination does not justify classifying inner heautoscopy with the other autoscopic phenomena. These observations also make clear that—at this point—any functional theory is pure speculation, although many associations–such as with other autoscopic phenomena, referred pain, phantom sensations of inner organs, and

442

O. BLANKE ET AL.

Cotard syndrome, as well as visceral representations in temporal and insular cortex—might be meaningful. 22.4.2. Negative heautoscopy and negative doubles Negative heautoscopy is defined as the failure to see one’s own body when looked at either directly or in a mirror (Menninger-Lerchenthal, 1935; Lhermitte, 1951; He´caen and Ajuriaguerra, 1952; Devinsky et al., 1989a; Dening and Berrios, 1994; Brugger et al., 1997). As for inner heautoscopy, case descriptions in neurological patients are rare, although a few reports of negative heautoscopy due to focal brain damage exist. Negative heautoscopy is discussed separately below (see negative doubles).

22.5. Sensorimotor doubles 22.5.1. Feeling of a presence The ‘feeling of a presence’ refers to the illusion that somebody is close by although nobody is around (Jaspers, 1913; Lhermitte, 1939; Critchley, 1950; 1955; Brugger et al., 1996). It is defined as the convincing feeling that there is another person close by without the patient actually being able to see that person (Brugger et al., 1996; Blanke et al., 2003) and was initially described by Karl Jaspers as ‘leibhafte Bewusstheit’ (Jaspers, 1913). Later, authors have named this experience of a sensorimotor double ‘hallucination du compagnon’ (Lhermitte, 1939), idea of a presence (Critchley, 1950), or more

recently ‘feeling of a presence’ (Brugger et al., 1996; Blanke et al., 2003; Arzy et al., 2006). This experience of feeling another human person close by is often described as highly realistic and vivid, but may also be experienced as dreamlike and ephemeral. It is mostly a transient experience, yet might sustain for a longer time. It often disappears when patients try to ascertain themselves that there is ‘nobody there’ by looking towards the felt location of the ‘presence.’ Although the patients do not experience seeing the ‘presence,’ they are convinced of the presence of the somatosensory double and can classically describe its spatial localization very accurately (James, 1961; Brugger et al., 1996). Indeed, the ‘presence’ is almost always experienced on one side of the patient’s body (Fe´re´, 1891; Jaspers, 1913; Menninger-Lerchenthal, 1935; Lippman, 1953; Critchley, 1955; Williams, 1956; Lukianowicz, 1960; Brugger et al., 1996; Blanke et al., 2003; Arzy et al., 2006), in peripersonal space, and most often less than 1 m from the patient’s body (Brugger et al., 1996; Blanke et al., 2003). Importantly, some patients may also mention a psychological affinity with the ‘presence’ (Critchley, 1955; Brugger et al., 1996), or a sharing of actions (or echopraxia) or that the presence has the same body position as the patient (Jaspers, 1913; Engerth and Hoff, 1929; Brugger et al., 1996; Blanke et al., 2003; Arzy et al., 2006). These latter points have led most previous authors to consider the feeling of a presence as a disorder of own body perception and led to its inclusion with other illusory own body reduplications

Case Study 22.5 Feeling of a presence Brugger et al. (1996, case 2) A 55-year-old right-handed woman reported several times a day the brief sensation of having ‘a shadow’ in her right peripersonal space. She described that ‘the shadow is always in front of me, about 50 cm to the right. I feel that it is very familiar to me, and I kind of know that it is a male shadow.’ She did not see the shadow yet she could ‘feel’ it, although she knew that there is nothing there. The shadow was described as stable or stationary, was not experienced as performing any action, did not talk to the patient and never imitated the patient’s movements. The experience was not occurring during or after

the patient’s epileptic seizures. Often the feeling of a presence was associated by feelings of dizziness, vertigo, and headache. Notably, while her husband died some month afterwards, the patient began to refer to the presence as her deceased husband. Six months before admission the patient developed headaches, rotational vertigo, and left-sided motor seizures. The neurological examination revealed leftsided hypoesthesia, a visuospatial memory deficit, mild apraxia, perseveration, and visual agnosia. Computed tomography demonstrated a space occupying lesion in the right temporal lobe. Surgical treatment rendered the patient seizure-free under anticonvulsant treatment. She continued to daily experience the feeling of a presence at least for a period of 6 months.

ILLUSORY REDUPLICATIONS OF THE HUMAN BODY AND SELF by most authors (Menninger-Lerchenthal, 1935; Lhermitte, 1939; Lippman, 1953; He´caen and Ajuriaguerra, 1952; Critchley, 1955; Williams, 1956; Lukianowicz, 1960; Brugger et al., 1996; 1997; Blanke et al., 2003; Arzy et al., 2006). Despite the fact that the patients deny seeing the double it is often described as ‘a shadow’ or as a ‘black man’ at the brink of vision (Critchley, 1950; Brugger et al., 1996; Blanke et al., 2003; Arzy et al., 2006) that can be associated with autoscopic phenomena (Lukianowicz, 1960, case 2; Maack and Mullen, 1983; Brugger et al., 1996; Blanke et al., 2004, cases 3 and 5). Concerning associated hallucinations, vestibular hallucinations (Brugger et al., 1996, cases 2, 3, and 4; Blanke et al., 2004, case 5) and body schema disturbances have been observed quite often, whereas visual, tactile, and auditory hallucinations were only rarely noted. With respect to associated neurological deficits, the feeling of a presence is often associated with hemiparesis or hemiplegia (Fe´re´, 1891; Gloning et al., 1957; Nightingale, 1982; Brugger et al., 1996, case 1) as well as somatosensory deficits (Hall, 1918; Gloning et al., 1957; Brugger et al., 1996, cases 1 and 2). In addition, patients with feeling of a presence may suffer from hemineglect (Critchley, 1979, case b; Brugger et al., 1996, case 1) or aphasia (Hall, 1918; Brugger et al., 1996, case 1; Blanke et al., 2003). Often other body schema disturbances such as limb disconnection, displacement, asomatognosia (Critchley, 1979, case b; Brugger et al., 1996, cases 1 and 4; Blanke et al., 2003), or somatoparaphrenia are present (see below). Some patients have also been reported to suffer from hemianopia (or quadrananopia) (Critchley, 1979, case b; Brugger et al., 1996, cases 1 and 4; Blanke et al., 2003). 22.5.2. Etiology Feeling of a presence was described in various neurological disturbances, mostly epilepsy (Fe´re´, 1891; Critchley, 1950; 1955; Williams, 1956; Gloning et al., 1957; Critchley, 1979; Hermann and Chhabria, 1980; Benson et al., 1986; Ardila and Gomez, 1988; Brugger et al., 1996; Blanke et al., 2003) but also migraine (Lippman, 1953; Todd and Dewhurst, 1955), neoplasm (He´caen and Ajuriaguerra, 1952; Nightingale, 1982; Brugger et al., 1996), head injury (Lukianowicz, 1960), or acute hypoxia (Sherrard, 1978; Messner, 1980). In psychiatry it was described in patients with schizophrenia (Jaspers, 1913; Havens, 1962; Mahaluf et al., 1987), depression (Lukianowicz, 1960) and organic psychosis (Nightingale, 1982). However, it may also be present in normal subjects, especially during long periods of loneliness and exhaustion such as in mountaineers, explorers, sailors, and castaways (Smythe, 1934; Critchley, 1950; Suedfeld and Mocellin, 1987; Brugger et al., 1999; Kellehear, 1990).

443

22.5.3. Anatomy Several patients have been described in whom feeling of a presence occurred in association with focal brain damage. Although it has been observed in patients with damage to any lobe, it is most often associated with posterior parietal damage (Kurth, 1941, case 2; Critchley, 1950; 1953; He´caen and Ajuriaguerra, 1952; Gloning et al., 1957; Nightingale, 1982; Brugger et al., 1996, cases 1, 3 and 4; Blanke et al., 2003). However, other lobes such as the occipital or temporal lobe were also implicated, mostly in association with parietal lobe damage (He´caen and Ajuriaguerra, 1952; Critchley, 1979, case b; Brugger et al., cases 1, 3, and 4). Finally, several patients with temporal lobe epilepsy and feeling of a presence have been described (Williams, 1956, case 7; Brugger et al., 1996, case 2). With regard to predominant hemispheric involvement the reported data are quite divergent. Some authors found no hemispheric predominance for feeling of a presence (Brugger et al., 1996), others have suggested a right hemispheric predominance (Fe´re´, 1891; Kurth, 1941) or left hemispheric predominance (Hall, 1918; He´caen and Ajuriaguerra, 1952; Arzy et al., 2006).

22.5.4. Theoretical considerations A number of observations support the assumption that the ‘presence’ is actually related to abnormal own body perception. Thus, a feeling of familiarity or close psychological affinity, as is often found in heautoscopy, is frequently mentioned (Critchley, 1955; Brugger et al., 1996). The patient also experiences the ‘presence’ in close proximity to their body (Strindberg, 1897; Critchley, 1950; Brugger et al., 1996; Blanke et al., 2003) and even as imitating the patient’s own body movements (Jaspers, 1913; Engerth and Hoff, 1929; Brugger et al., 1996). The ‘presence’ is by some patients described as their ‘alter ego’ (Critchley, 1950; 1955) and patients might even refer explicitly to the ‘presence’ as their own double (Engerth and Hoff, 1929; Critchley, 1950). Feeling of a presence thus shares many phenomenological and clinical characteristics with autoscopic phenomena like autoscopic hallucination and heautoscopy and in some patients both phenomena are observed (Lukianowicz, 1960; Maack and Mullen, 1983; Brugger et al., 1996; Blanke et al., 2004). Other patients might find it difficult to clearly state whether they see their double or whether they feel a presence. In the following we will discuss four conditions that are functionally associated with the feeling of a presence: autoscopic phenomena, phantom limbs, somatoparaphrenia, and delusional misidentifications.

444

O. BLANKE ET AL.

22.5.4.1. Autoscopic phenomena

22.5.4.2. Phantom limbs

Concerning the relation with autoscopic phenomena, Menninger-Lerchenthal (1935) referred to the feeling of a presence as ‘heautoscopy without optical image’ and Bychowski (1943) also compared the experience of an autoscopic body or visual double to a ‘visual feeling of a presence.’ Of the autoscopic phenomena, the feeling of a presence shares many characteristics with heautoscopy. This concerns the psychological affinity (Critchley, 1955; Brugger et al., 1996) and the sharing of action that is reported by some patients between their bodies and the ‘presence’ (Jaspers, 1913; Engerth and Hoff, 1929; Brugger et al., 1996; Blanke et al., 2003). Also, both latter illusory body reduplications are frequently associated with other body schema disturbances. Temporoparietal damage is often found in both conditions. Despite these similarities with heautoscopy, the feeling of a presence also shares some aspects with autoscopic hallucination, as both conditions are often lateralized (Fe´re´, 1891; Jaspers, 1913; Menninger-Lerchenthal, 1935; Lippman, 1953; Critchley, 1955; Williams, 1956; Lukianowicz, 1960; Brugger et al., 1996) and may be associated with hemianopia (Critchley, 1979; Brugger et al., 1996; Blanke et al., 2003). Despite these similarities with autoscopic phenomena several differences should also be mentioned. During the feeling of a presence the double is not experienced visually and it is for this reason that we have classified it among nonvisual doubles and not with autoscopic phenomena. Also, the feeling of a presence, in the cases that we have analyzed here, is always lateralized, whereas the autoscopic body in autoscopic hallucination is only lateralized in 50% of patients and almost never lateralized in heautoscopy (Blanke and Mohr, 2005). In addition, the feeling of a presence is frequently associated with contralesional deficits in somatosensory and motor function (Brugger et al., 1996) that have only infrequently been found in autoscopic phenomena (Blanke and Mohr, 2005). Based on the shared phenomenological and neurological characteristics with autoscopic phenomena we suggest that the feeling of the presence also relates to a double disintegration of multisensory information (Blanke et al., 2004). As most characteristics are shared with heautoscopy for which a primary dysfunction in proprioceptive processing has been proposed (Blanke and Mohr, 2005) and based on the observation that the feeling of a presence is often associated with sensorimotor deficits we suggest that it is associated with a dysfunction of proprioceptive and motor (sensorimotor) mechanisms. This is also compatible with the reported damage to parietal cortex.

Feeling of a presence has been associated with phantom limb phenomena by most authors reporting on the feeling of a presence (Menninger-Lerchenthal, 1935; Lhermitte, 1939; He´caen and Ajuriaguerra, 1952; Brugger et al., 1996). Phantom limbs are the vivid impression that a missing body part is not only still present and in some cases even painful (Ramachandran and Hirstein, 1998). Phantom phenomena were long considered to derive from irritation in severed axon terminals in the stump by the presence of scar tissue and neuromas (for review see Melzack, 1990). However, there is now a wealth of empirical evidence demonstrating cortical reorganization following limb amputation leading to disintegration of multisensory information (Ramachandran and Hirstein, 1998) as also proposed for autoscopic phenomena (Blanke et al., 2004). Moreover, although phantom limb phenomena most often occur in pathology, different phantom sensations and related phenomena might be easily induced in normal subjects. Examples are the Pinocchio effect (Lackner, 1988; Ramachandran and Hirstein, 1998) or the rubber hand illusion (Botvinick and Cohen, 1998) arising through multisensory conflict and relying on information processing in parietal and frontal cortices (Ehrsson et al., 2004; 2005). In these own body illusions, visual sensations and psychological affinity (or feelings of ownership) are projected onto parts of the external world through ambiguous multisensory input (Ramachandran and Hirstein, 1998). It has been speculated that the brain is required to homogenize these different multisensory sensations to one coherent body representation and treat the discrepant or ambiguous information as noise (Ramachandran et al., 1995). If the discrepancy is not corrected, a phantom limb (or supernumerary phantom limb or self-attributed rubber hand on healthy subjects) may occur. If interference is rather with central mechanisms that represent the entire body of the subject, phantoms of the entire body may occur and this may be experienced as a sensorimotor double (feeling of a presence) or as a visual double (autoscopic phenomena) (Blanke et al., 2004; Brugger, 2005). 22.5.4.3. Somatoparaphrenia Previous authors suggested that autoscopic phenomena might share functional and neural mechanisms with somatoparaphrenia (Menninger-Lerchenthal, 1935; Hoff and Po¨tzl, 1935/1988; He´caen and Ajuriaguerra, 1952; Gloning et al., 1963; Brugger, 2005). Although somatoparaphrenia most often affects only certain (mostly contralesional) body parts such as the hand and arm of

ILLUSORY REDUPLICATIONS OF THE HUMAN BODY AND SELF the patient, we here present several neurological cases which reveal that somatoparaphrenia may also concern the contralesional half of a patient’s body and even their entire body. We will draw especially on these latter cases to highlight some potential similarities between the feeling of a presence and somatoparaphrenia. The term somatoparaphrenia was coined by Josef Gerstmann (1942) in an attempt to isolate it from two other phenomena, anosognosia and asomatognosia, that are often associated in patients with visuospatial neglect. (In Gerstmann’s terminology asomatognosia was called autosomatoagnosia.) Gerstmann defined somatoparaphrenia as ‘specific psychic elaborations (marked by formation of illusions, confabulations, and delusions) with respect to the affected members or side of the body.’ Following Gerstmann’s definition, somatoparaphrenia should be distinguished from asomatognosia that he defined as the patient’s ‘imperception of the affected limbs or body half, in various degrees from simple forgetting to obstinate denial of their existence.’ Here we will not discuss the third symptom that Gerstmann discussed, anosognosia. Anosognosia has been defined in many variants, but the most common and most related in the present context is neurological patients’ unawareness or nonexperience of contralesional hemiplegia (Babinski, 1914; Gerstmann, 1942; Cutting, 1978). Somatoparaphrenia is characterized by a number of apparently strange perceptions and beliefs with respect to the patient’s extremities or body half of which the most common are that patients believe that their own arm or body half belongs to another person

445

or that they another person’s arm belongs to the patient. Gerstmann’s classification was only partly adapted by subsequent authors especially with respect to the distinction between asomatognosia and somatoparaphrenia (He´caen and Ajuriaguerra, 1952; Feinberg et al., 1990). This is probably due to the many intermediate forms as well as the presence of asomatognosia and somatoparaphrenia in the same patient (He´caen and Ajuriaguerra, 1952). Here, we will concentrate on patients with somatoparaphrenia that affect the entire body in order to stress its potential link with illusory reduplications of the entire body. Po¨tzl (1925), Hoff and Po¨tzl (1935/1988), Menninger-Lerchenthal (1935), and later Gerstmann (1942) and Gloning et al. (1963) proposed that somatoparaphrenia may not only affect a limb or body part, but also a body half of the patient and even lead to limb or whole body reduplication. For instance, Lhermitte (1939, p. 130) described somatoparaphrenia in a patient with visuospatial neglect due to right hemisphere brain damage who perceived her left own hand as the hand of somebody else. Yet, as many of these patients, she also claimed that this hand belonged to (the body) of a person that is close by and that she assumed to be in her hospital room. Most often patients with somatoparaphrenia will thus claim that their own extremity is not just an unknown extremity, but the extremity of another person. And this extremity belongs generally to a neighbor in the hospital room (Lhermitte, 1939), a doctor (Gerstmann, 1942), the husband (Assal, 1983), or other family members or friends

Case Study 22.6 Feeling of a presence associated with somatoparaphrenia Po¨tzl (1925) In addition to somatoparaphrenia this patient also felt the presence of another person in his bed (feeling of a presence) suggesting that both phenomena might share functional and neural mechanisms. This 56-year-old male patient repeatedly reported that his left hand and arm belonged to somebody else. This was especially the case when his hand was held in front of him and he mentioned that it was the hand of a stranger that he sees, probably belonging to another patient in the room. He also

stated that ‘I don’t know how this hand got here’ or ‘the hand seems so long, so lifeless, as dead as a snake.’ He also claimed that there was an unknown person that was lying in his bed (to his left side) and that this person wants to push him out of the bed. This 56-year-old male patient suffered from hemorrhagic brain damage to the right inferior parietal lobule, including supramarginal and angular gyri, parts of the superior temporal gyrus and insula, as well as underlying white matter. Autopsy also revealed an older right thalamic lesion. The neurological examination revealed left-sided plegia and hemianesthesia without hemianopia and severe hemineglect associated with anosognosia.

446

O. BLANKE ET AL.

(Weinstein et al. 1954, case 1). Thus, these patients indirectly attribute the somatoparaphrenic hand to another person in spatial (and emotional) proximity. Other patients have mentioned the presence of another person that is close by more directly. Thus, Po¨tzl (1925; patient #1; Case Study 22.6) described a patient with left-sided hemiplegia and somatoparaphrenia who not only claimed that his left arm belonged to an unknown person, but also that there was another person lying in his bed to his left and that this person tried to push him out of the bed (p. 119). Po¨tzl (1925) described a second patient with left-sided hemiplegia and somatoparaphrenia also claiming that his left arm belonged to a stranger. As this patient also claimed that there was a supernumerary left arm (see also Ehrenwald, 1930; Halligan et al., 1993), Po¨tzl (1925) and later Hoff and Po¨tzl (1935/1988) argued that reduplication of an extremity and of an entire body in patients with somatoparaphrenia may share functional mechanisms and that the delusional other in somatoparaphrenia is closely related to the feeling of a presence. Further such cases with somatoparaphrenia and the feeling of a presence can be found in the literature. Engerth and Hoff (1929) describe a 71-year-old man with left-sided hypoesthesia, hemianopia (with hemianopic hallucinations), and anosognosia who experienced a constant left-sided person who was most often localized next or behind the patient. In addition, the patient noted that this person had the patient’s posture and size and only appeared when the patient was standing or walking. This

dependence on posture and action of the patient has also been described in recently reported patients with feeling of a presence (Blanke et al., 2003) and, notably, heautoscopy (Blanke and Mohr, 2005). Lhermitte (1939) described a 72-year-old female patient with left-sided hemiplegia and hemianesthesia that claimed that her left body half belonged to another person that was lying in the same bed as she. More such patients with the association of somatoparaphrenia and the feeling of a presence were reported by Anton (1898), Zingerle (1913), Halligan (1995), and Cereda et al. (2002). The fact that this ‘stranger’s body’ is experienced in a highly realistic fashion is underlined by the fact that many of these patients are afraid or annoyed by the presence of this stranger. By trying to throw them out of the bed these patients often find themselves on the floor. This difficulty to distinguish between self and other is reminiscent of severe cases of heautoscopy (see Case Study 22.3) where the patient desperately tries to get rid of the unwanted stranger by often very dangerous (selfmutilating) actions. Some patients with somatoparaphrenia not only report sensorimotor doubles, but report seeing their double (autoscopic phenomena) on the contralesional side (Hoff, 1931). Still other patients may even describe that another person’s body (such as their father) has partly invaded one half of their body (Nightingale, 1982, Case Study 22.7). Based on these observations and the association of somatoparaphrenia with parietal lobe damage we argue that doubles that are reported by patients with

Case Study 22.7 Somatoparaphrenia Nightingale (1982) Somatoparaphrenia is mostly confined to the patient’s upper extremity and patients claim that their generally plegic arm belongs to another (most often familiar) person. The present case illustrates that somatoparaphrenia may also affect an entire half of the patient’s body and may be associated with illusory reduplication of the entire body. A 46-year-old right-handed man felt that the left side of his body was different from the right half. He explained that the left side of his body had slipped behind the right side so that the latter became more prominent than the former. Moreover, the left side seemed to him somewhat evil and controlled by external agents (such as the devil or his father). The right side of his

body was perceived as ‘self’ and ‘good.’ These two sides were in constant conflict about his behavior. The left body side tried to instruct him to perform evil acts that his ‘self’ or right body side felt to be incorrect. These experiences were accompanied by the patient hearing compelling voices, coming from his left extracorporeal space. Rarely, he experienced left-sided complex visual hallucinations and the presence of another person to his left (feeling of a presence). This patient suffered from complex partial seizures with secondary generalization since the age of 30 years. Despite removal of a parasagittal meningioma that was adjacent to right parietal cortex and anticonvulsant treatment the patient continued to have frequent seizures. The patient is known for a period of moderate depression following the death of his father at the age of 40 years. There were no signs of schizophrenia.

ILLUSORY REDUPLICATIONS OF THE HUMAN BODY AND SELF somatoparaphrenia may relate phenomenologically, functionally, and anatomically to the feeling of a presence. As somatoparaphrenia is strongly associated with right hemispheric brain damage, whereas the feeling of a presence is encountered with damage to either hemisphere, it is likely that the mostly left-sided sensorimotor doubles in somatoparaphrenia and rightsided sensorimotor doubles relate to different functional mechanisms (Brugger et al., 1996; 1997). 22.5.4.4. Delusional misidentification syndromes Finally, some authors (Signer, 1987) have proposed that the feeling of a presence (as well as autoscopic phenomena) may relate functionally to delusional misidentifications syndromes concerning the patient’s body and self, either as imposter or double. These include the syndrome of subjective doubles (Christodoulou, 1978a; Case Study 22.8) and a subtype of the Capgras syndrome (Berson, 1983; Kamanitz et al., 1989; Silva and Leong, 1991; Silva et al., 1993; Feinberg and Roane, 2005). Patients with the syndrome of subjective doubles are convinced that another person is posing as the patient, whereas patients with Capgras syndrome may claim that not only other persons, but also they themselves, are replaced by

447

identical substitutes (Capgras and Reboul-Lachaux, 1923; Kamanitz et al., 1989; Silva and Leong, 1991; Silva et al., 1993). Other forms may also include patients who fail to recognize themselves in a mirror (He´caen and Ajuriaguerra, 1952; Ajuriaguerra et al., 1963; Foley and Breslau, 1982) and, in addition, mistake their mirror reflection for an imposter (Gluckman, 1968; Feinberg and Shapiro, 2000). Other authors thought it important to distinguish between delusional misidentification syndromes and autoscopic phenomena based on several clinical differences (Sims, 1986). Thus, Sims mentions that autoscopy (or autoscopic phenomena in general) (1) has a perceptual element, which is generally absent in delusional misidentification syndromes, (2) that the autoscopic patient experiences the double as ‘their real self’ whereas the Capgras patient is convinced that the double is an imposter, and that (3) autoscopy is a pseudohallucination, which delusional misidentification syndromes are not. Yet, as discussed in this review, we would like to underline here that only some illusory reduplications are experienced as pseudohallucinations (autoscopic hallucinations) and the double is only rarely experienced as the location of the ‘real self.’ Weinstein

Case Study 22.8 Subjective doubles syndrome Christodoulou (1978b) Patients suffering from subjective doubles syndrome claim that another person has taken on the same appearance as the patient, but has kept the other person’s character traits and leads a life of their own. Some patients stated that several others have taken on their appearance. Other patients claim that another person with their habitual appearance has taken the same personality as the patient. Both subtypes are probably related to the more common syndromes of Capgras and Fre´goli. An 18-year-old woman developed insomnia, agitation, depression, loosening of associations, lack of sexual inhibition, and experience of de´ja` ve´cu. Yet, she also stated that a female neighbor acquired physical characteristics identical to the patient’s characteristics. The subjective double was described as having the ‘same face, same build, same clothes, same everything.’ The patient also stated that the neighbor accomplished this by wearing special make-up, a wig, and a

mask. In another episode, while the patient was hospitalized, she insisted that at least two other female patients had transformed themselves into her by taking on the patient’s appearance. The patient even attacked one of them trying to ‘pull the mask’ off the other patient’s face. In a letter to her father she explained: ‘In here there is a girl as fat and as tall as I am. At night when everyone is asleep, she puts on a wig and a mask and walks from room to room stealing things in order to incriminate me. One night I woke up and saw her with my own eyes. It is unfortunate that due to my confusion I failed to run to the window to shout to the people, ‘look here, this is me, and this is my double with a wig and a mask.’’ The patient had an unspecified seizure disorder since the age of 8 years. Before the above described hospitalization her psychiatric history was unremarkable. A paternal uncle suffered from a paranoid schizophrenia. Neurological examination, routine laboratory check, cerebrospinal fluid and computed tomography were normal.

448

O. BLANKE ET AL.

et al. (1954) and, more recently, Signer (1987) even speculated about common mechanisms between reduplicated body parts, bodies, and paramnesias for place and event (Ro¨hrenbach and Landis, 1995). Yet, although it is likely that some common mechanisms may be involved between delusional misidentication syndromes, delusional mirror recognition and misidentification, and paramnesias, we have not elaborated this any further here due to the many clinical differences of the latter conditions with illusory own body reduplications. In conclusion, these observations on the feeling of a presence suggest that it shares phenomenological, functional, and neural mechanisms with supernumerary phantom limbs, visual doubles (especially heautoscopy) and delusional doubles (somatoparaphrenia) and is probably due to multisensory mechanisms and sensorimotor disintegration. It might thus be speculated that the investigation of these three conditions through detailed neuropsychological examination is likely to further our understanding of the central mechanisms of own body representations, self processing, and self–other distinction as previous research helped elucidate the nature of (supernumerary) phantom limbs.

22.6. Auditory doubles 22.6.1. Hearing of a presence Are there auditory doubles? Have there been reports of neurological patients who claim to have the highly realistic experience of hearing a double of themselves or another person in extracorporeal space? Menninger-Lerchenthal (1935) and Gloning et al. (1963) have suggested that illusory own body reduplications should also exist in the auditory domain, yet have not presented clinical evidence for this nor further developed this hypothesis. Audition like vision, balance, and somatosensation is involved in the construction of the body image (La`davas, 2002; Blanke et al., 2003; Pavani et al., 2003; Holmes and Spence, 2004). Moreover, electrophysiological studies in the macaque at the subcortical level (Stein et al., 1993) and in parietal and temporal cortex (Duhamel et al., 1998; Bremmer et al., 2001; Schroter-Kunhardt, 2002) suggest that several cerebral areas combine auditory signals with tactile, proprioceptive, and visual information in a coordinated reference frame for personal and extrapersonal space. This has also been found by neuroimaging work (Bremmer et al., 2001; Foxe et al., 2002; Holmes and Spence, 2004) and behavioral studies in brain damaged and healthy subjects (La`davas et al., 2001; La`davas, 2002; Pavani et al., 2003; Holmes and Spence, 2004) in humans. In light of these findings and the earlier speculations by MenningerLerchenthal (1935) and Gloning et al. (1963), it might

thus be hypothesized that neurological damage to temporoparietal areas might not only lead to visual and sensorimotor doubles, but also to auditory doubles. 22.6.2. Clinical presentation, etiology, anatomy Auditory hallucinations cover a variety of elementary experiences such as hearing noises or sounds (humming, buzzing, tapping, ringing, etc) and complex experiences such as voices, conversations, or music (Cole et al., 2002). Complex auditory hallucinations are most often characterized by the hearing of a voice or voices that are generally called auditory verbal hallucinations. About 70% of schizophrenic and a variety of other psychiatric and neurological patients suffer from auditory verbal hallucinations (Stephane et al., 2001). Voices during auditory verbal hallucinations are most often experienced as addressing the subject directly and called 2nd person auditory verbal hallucinations (Frith, 1996). Less frequently voices during auditory verbal hallucinations may be experienced as the subject’s own voice (1st person auditory verbal hallucinations) or as hearing two or more other people taking to each other (3rd person auditory verbal hallucinations). The content of auditory verbal hallucinations may vary as does the localization of the voice which may be at varying positions in personal or extrapersonal space. In addition, most patients experience these variably localized auditory verbal hallucinations as voices and not as a present person that speaks to them. Auditory verbal hallucinations in neurological patients have been reported most often in spontaneous seizures and been localized to the temporal cortex (Bancaud, 1987). Auditory verbal hallucinations may also be evoked directly by electrical cortical stimulation in patients with pharmacoresistant epilepsy (Penfield and Perot, 1963; Halgren et al., 1978; 1983), which has the advantage of greater spatial precision and experimental control. The electrically induced experiences were reported to be highly similar to those described by psychiatric patients (2nd person auditory verbal hallucinations) and mostly characterized by hearing voices inside the head or at varying locations. Yet very few patients reported a precise extra-personal localization of the auditory source as well as hearing a talking person. Penfield and Perot (1963) reported this in two of 21 patients with stimulation-induced and seizure-induced auditory verbal hallucinations (case 12 and 29). Both epileptic patients reported that they not just heard a localized ‘voice,’ but heard a physically present person in the contralateral space or in the backspace that spoke to them. Moreover, the ‘heard persons’ had a precise location and distance from the patient’s body and in both patients either the feeling of a presence (case 12) or

ILLUSORY REDUPLICATIONS OF THE HUMAN BODY AND SELF the visual experience of a second body (case 29) were noted as well. One may wonder whether this was an autoscopic body, although this is not further detailed. Thus, a 24-year-old woman (case 12) had seizures since the age of 20 years characterized by a sensation (of something or somebody) in her back, complex auditory and visual hallucinations, and fear followed by secondary generalization. She described hearing a man that spoke behind her and that she could not understand what he was saying. Her seizure focus was localized to the left parietal lobe (arteriovenous malformation). Electrical cortical stimulations at the left posterior aspects of the superior temporal gyrus (at the temporoparietal junction) induced hearing of a presence described as ‘I could hear someone talking’ and ‘there was [somebody] talking or murmuring, but I could not understand it.’ During further stimulations she detailed that she heard a man who was standing behind her and who was once identified as her father. Note that somatoparaphrenic doubles or extremities are also often identified as relatives of the patient. The second patient of Penfield and Perot (1963) with hearing of a presence was a 25-year-old man (case 29) who had suffered from seizures since the age of 19 years characterized by vertigo and auditory verbal hallucinations (a voice calling him by his first name). (Interestingly,

449

several authors have suggested that 2nd person auditory verbal hallucination of being called by one’s first name relates to autoscopic phenomena (Menninger-Lerchenthal, 1935, pp. 131–132; Schilder, 1914). See Perrin et al. (2005) for a recent neuroimaging study on the neurobiology of hearing one’s first name.) His seizure focus was localized to the perisylvian region including temporal and parietal cortex (arteriovenous malformation). Electrical cortical stimulations at the right posterior (and middle) aspects of the superior temporal gyrus induced hearing of a presence. This was described as ‘it is just like someone [is] whispering in my left ear’ and ‘again someone [is] trying to speak to me, a single person,’ ‘I could not understand what he said.’ Interestingly stimulations at the superior temporal gyrus also lead to the visual impression of seeing of a person in front of him (‘someone was there in front of me’). Other stimulations at sites on the superior temporal gyrus and middle temporal gyrus led to different auditory hallucinations and experiential phenomena. Hearing of a presence was also reported by Gloor et al. (1982, case 3). More recently, Blanke et al. (2003) also described a patient with hearing of a presence probably due to epileptic seizures following hemorrhagic brain damage at the left TPJ (Case Study 22.9).

Case Study 22.9 Hearing of a presence Blanke et al. (2003) A right-handed 65-year-old nun reported complex auditory hallucinations characterized by the impression of hearing for various periods one or two people talking behind her. During one especially impressive and long period she was sitting in the hospital church when she suddenly had the feeling that she heard two ‘people’ whispering behind her. Both ‘people’ were sitting on a bench approximately one meter behind her and on her right. She could not understand what they were saying. She could not indicate the gender of these ‘people’ or any other character of their voices. While turning around she noticed that there was no one sitting behind her. Yet, after she turned her head back forward, she continued to hear two people whispering behind her back on the right side. This persisted until she left the hospital church. She reported similar experiences in her hospital room (and after hospital discharge for a period of several years). These instances were always characterized by the auditory perception as if someone was

suddenly standing behind her and to her right and talking in an incomprehensible manner to her. In addition, she suffered from simple auditory hallucinations characterized by humming or buzzing also localized on the right side (either lateral or behind her) or bilaterally. She also experienced several times a day a ‘shadow’ on her right side (feeling of a presence) and other right side dyssomatognosic illusions. The patient developed complex partial seizures with secondary generalization due to a hematoma at the left parietotemporo-occipital junction at the age of 60 years. When hospitalized for the hearing of a presence, the neurological examination revealed right-sided auditory spatial agnosia (deficit in the localization of auditory targets), moderate aphasia with semantic and phonological paraphasias, severe alexia, and moderate agraphia. There were no signs of apraxia or of visual agnosia. MRI did not show any new lesion, but EEG revealed frequent interictal epileptic activity characterized by spikewaves, sharp waves and slow waves over the left midto-posterior temporal region. In one instance, rhythmic discharges over the occipitotemporal region were noted.

450

O. BLANKE ET AL.

With respect to the underlying anatomy, Penfield and Perot (1963) localized auditory verbal hallucinations to the superior and middle temporal gyri of either hemisphere with a left-sided predominance. Others have confirmed these findings, but also induced auditory verbal hallucinations by electrical cortical stimulation of inferior temporal and mesial temporal structures (Penfield and Perot, 1963; Halgren et al., 1978; 1983). 22.6.3. Theoretical considerations The four cases with hearing of a presence (Penfield and Perot, 1963; Gloor et al., 1982; Blanke et al., 2003) closely resemble each other and are in contrast to classically reported auditory verbal hallucinations in epileptic patients. In addition, they suggest that learning of a presence can phenomenologically be dissociated from other auditory verbal hallucinations. Indeed, psychotic patients often find it difficult to say whether the ‘voice’ is inside or outside their head (Nayani and David, 1996; David, 1999) and mostly experience auditory verbal hallucinations inside their head or body (Junginger and Frame, 1985; Chadwick and Lowe, 1994; Nayani and David, 1996). This was also found for most stimulation-induced auditory verbal hallucinations in epileptic patients (Penfield and Perot, 1963) and differs from the phenomenology described by the four patients described here who localized a talking person (or persons) at a precise location in their backspace. This auditory lateralization and auditory distance from the patient’s body was corroborated by neuropsychological findings showing that the heard person(s) were localized on the side where spatial auditory agnosia and other dyssomatognosic sensations were found (Blanke et al., 2003). Although, some psychotic patients are able to describe characteristics of the voice such as content, affective tone, and identity, they usually lack spatial attributes such as location in extrapersonal space (Junginger and Frame, 1985; Chadwick and Lowe, 1994). This has even led to the proposition that auditory verbal hallucinations of psychotic origin classically lack any localization (Strauss, 1962). Even if in rare instances external auditory verbal hallucinations may be lateralized and localized in psychiatric patients, their spatial attributes are extremely variable. They are experienced at variable distances and variable locations from the patients’ bodies and often described at delusional locations (Chadwick and Lowe, 1994; Nayani and David, 1996; David, 1999). Based on these differences and neuropsychological findings, Blanke et al. (2003) suggested that the hearing

of a presence might relate to auditory–spatial disorders rather than auditory disorders (related to the identification of the nonspatial characteristics of a sound). The coappearance of hearing of a presence and feeling of a presence in three of the here presented four patients as well as previously reported four patients with feeling of a presence (Jaspers, 1913; Critchley, 1954; Gru¨sser and Landis, 1991; Brugger et al., 1996) also suggests their close functional relationship. It could be argued that the hearing of a presence is not a disorder of own body perception (referring to disorders in the perception and cognition of the patient’s own body), since these four patients never experienced their ‘own voice’ or their ‘own body’ as talking behind themselves. Similar arguments have been proposed for the feeling of a presence. Yet, as noted by Brugger et al. (1996) and others (Jaspers, 1913; Menninger-Lerchenthal, 1935), although patients suffering from feeling of a presence also do not feel their own body at two locations at the same time, the felt (or heard) body is always experienced in a very persuasive way (at the fringe of vision) and is often associated with a strong feeling of a strangeness towards one’s own body (depersonalization; Dening and Berrios, 1994; Brugger et al., 1997) and a psychological affinity with the felt body. In addition, in rare instances the feeling of a presence is associated with autoscopy (Brugger et al., 1996; 1997) suggesting a close link between visual and nonvisual body reduplications. Several functional and neural mechanisms have been proposed to account for auditory verbal hallucinations. Research proposed that auditory verbal hallucinations might be due to either an auditory dysfunction (McKay et al., 2000), a language dysfunction (Hoffmann, 1986; Frith and Done, 1988), a failure to monitor inner speech (McGuire et al., 1995), or dysfunctional reality monitoring (Bentall, 1990). Based on the rare, but concordant phenomenological and neuropsychological data in patients with hearing of a presence we speculate that it might result from a paroxysmal failure to integrate auditory bodyrelated information with somatosensory and visual body-related information. This information is needed in order to create neural representations of personal and peripersonal auditory space (di Pellegrino et al., 1997; La`davas et al., 2001; Farne` and La`davas, 2002) and the mechanisms of hearing of a presence are probably related to, but distinct from, mechanisms causing more common forms of auditory verbal hallucinations. These data suggest that within the group of illusory own body reduplications that concern the whole body, one should discern between visual doubles (autoscopic phenomena), sensorimotor doubles (feeling of a presence), and auditory doubles (hearing of a presence: the persuasive hearing of a person nearby).

ILLUSORY REDUPLICATIONS OF THE HUMAN BODY AND SELF

22.7. Negative doubles Negative heautoscopy is defined as the failure to see one’s own body either when looked at directly or in a mirror (Menninger-Lerchenthal, 1935; Lhermitte, 1951; He´caen and Ajuriaguerra, 1952; Devinsky et al., 1989a; Dening and Berrios, 1994; Brugger et al., 1997). Although negative heautoscopy is not an own body reduplication in the strict sense it is classically grouped among autoscopic phenomena. This is due to the fact that negative heautoscopy shares many phenomenological characteristics with other forms of autoscopic phenomena. Yet most authors mentioned negative heautoscopy only briefly with respect to other forms of autoscopic phenomena (Lhermitte, 1951; He´caen and Ajuriaguerra, 1952; Devinsky et al., 1989a; Dening and Berrios, 1994), some mentioned that negative heautoscopy is a distinct autoscopic phenomenon (Bradford, 2005; Blanke and Mohr, 2005), whereas others have included it more prominently (Gru¨sser and Landis, 1991; Brugger et al., 1997; Brugger, 2005). This may largely be due (as for inner heautoscopy) to the fact that case descriptions, especially recent ones in neurological patients, are rare. Yet a few reports of negative heautoscopy due to focal brain

451

damage do exist. As we will argue in the remainder of this section negative heautoscopy may have functional links with other neurological conditions such as asomatognosia and depersonalization. 22.7.1. Clinical presentation The most well-known description has probably been given by Guy de Maupassant in his short story ‘Le Horla’ (Maupassant, 1886/1961) and was quoted by Lhermitte, Critchley, and many other neurological authors. After describing many instances of persecution, fear, and hallucinations Maupassant writes ‘I could not see myself in the mirror! It was empty, transparent, deep [. . .] I was not reflected in it [. . .] and I was standing in front of it.’ A medical report with negative heautoscopy has been described by von Stockert (1934). This patient was ‘alarmed by the sudden impression of the left half of his body being absent. When he would look at himself with horror, he would indeed notice that the left half was not there. At these moments he felt somewhat comforted by the visual confirmation [of not seeing his left body] of his somatosensory impressions’ (cited in Brugger et al., 1997). Interestingly, this patient claimed not onlythat he could no longer see his own left

Case Study 22.10 Negative heautoscopy Arzy et al. (2006) Negative heautoscopy refers to failure to perceive one’s own body either in a mirror or when looked at directly. Given the rarity of negative heautoscopy for the entire body we detail here the experience of a recently reported patient in whom negative heautoscopy only affected one extremity. We suggest that the involved pathomechanisms are similar and might further relate to those involved in asomatognosia. A 51-year-old, right-handed woman, without neurological or psychiatric antecedents reported that for several minutes she did not see her left arm and left hand any more while she did normally see all other parts of her body. While at work she suddenly felt dizzy and noticed that parts of her left arm had ‘disappeared.’ She thus did not see her left upper extremity from her elbow on downwards. She was quite frightened, but realized to her astonishment that she could

see the table on which she had rested her ‘disappeared’ arm as if she could see the table ‘through the left arm.’ She saw her left arm only above her elbow where she saw a clear cut border. In addition, she could not move her left arm or hand while being normally able to move her right arm. She noted no changes with respect to any other body parts. Only after several minutes did she experience that her left arm and hand changed again, being progressively ‘restored’ until the arm was ‘complete’ again and occluding the table beneath it. Only some minutes later was she able to move her arm normally again. The neurological examination showed moderate left-sided hypoesthesia for arm and lower face, a mild executive deficit in Luria’s alternating sequences test, verbal semantic fluency, and in the mental rotation of human body parts. There were no signs of visuospatial neglect. Magnetic resonance imaging showed two small ischemic lesions in the premotor and the primary motor cortices.

452

O. BLANKE ET AL.

body half, but also noted that, when looking at other people that they lacked the right side of their bodies. Sollier (1903a) reports a case of negative heautoscopy in a 14-year-old hysteric patient and Magri and Mocchetti (1967) describe a 61-year-old patient who suffered from complex partial seizures and reported that he could not see his mirror reflection anymore. Brugger et al. (1997) note that some patients have been described who suffer from negative heautoscopy in association with other autoscopic phenomena. A more recent patient was briefly mentioned by Brugger (2005; unpublished observation). This female patient suffered from panic attacks consisting of episodes during which she could not see the left half of her body (negative heautoscopy for her left hemibody). EEG revealed abortive spike-wave complexes over the right parietocentral area and carbamazepine treatment seemed to have abolished all symptoms. Other patients have been described that noted that parts of their body or the autoscopic body were detached, missing, or invisible with respect to the rest of their body. Indeed, Gloning et al. (1954) described a patient with simple partial seizures and left-sided sensorimotor deficits who noted that during his simple partial seizures his right body half was one meter in front of his normally localized left-sided body. Brugger et al. (2006) describe a patient who noticed that his body was split along the midline with an empty area between both body parts. Finally, Blanke et al. (2002; 2004) described a patient who during an out-of-body experience only saw the lower parts of her body (autoscopic body). Whereas this partial vision of the autoscopic body is rather rare during out-of-body experiences and heautoscopy, it is quite frequent during autoscopic hallucinations and concerns generally the lower body (for review see Blanke and Mohr, 2005). It might thus be proposed that these latter partially negative illusory own body reduplications reflect central mechanisms with negative heautoscopy. Negative heautoscopy is thus in all these cases partial and restricted to certain body parts. This was also reported recently by Arzy et al. (2006; Box 10). This 51-year-old female patient stated that she could not see-for several minutes—her left arm and forearm anymore, while she clearly saw all other parts of her body. Interestingly she could also see the part of the table that should have been hidden by her left arm and hand. Negative heautoscopy disappeared progressively as the arm and hand were experienced to be restored progressively (see case study 22.10). The authors argued that this patient’s negative experience shares many characteristics with asomatognosia and may be defined as a visual form of asomatognosia. Extending Arzy et al.’s (2006) argumentation to the entire body (as in negative heautoscopy), one might argue that

the entire visually perceived body may also be missing, disappear, or ‘fall out of corporeal awareness.’ The above reviewed cases suggest that negative heautoscopy may affect the entire body, but mostly seems to affect only one half of the patient’s body or only a certain body part (mostly the upper extremity; Gru¨sser and Landis, 1991; Brugger et al., 1997; Bradford, 2005). It should also be noted that the autoscopic body in autoscopic hallucinations are not infrequently seen as missing certain body parts (Noue¨t, 1923; Genner, 1947; Maximov, 1973; Blanke et al., 2002; 2004; for review see Blanke and Mohr, 2005). 22.7.2. Etiology and anatomy Bradford (2005) writes that negative heautoscopy is an ‘instance of conversion reaction, a hysteria driven and attenuated form of asomatognosia.’ Critchley (1953, p. 240) stated that negative heautoscopy is ‘very rare’ and may be an ‘expression of a psychotic illness.’ Yet, a few cases due to focal brain damage have also been reported. Although most lesions affected the right hemisphere, lesion sites included parietal and frontal cortex, thalamus, and splenium. For instance, von Stockert’s (1934) patient suffered from a right-sided thalamic tumor that invaded the splenium and the patient described by Magri and Mocchetti (1967) suffered from complex partial seizures with secondary generalization due to a calcification in her right parietal lobe. The patient reported by Arzy et al. (2006) suffered from two small ischemic lesions in right motor and premotor cortex and Brugger’s patient (2005) showed abnormalities over the right centroparietal region. 22.7.3. Theoretical considerations 22.7.3.1. Asomatognosia These above mentioned cases suggest that negative heautoscopy might share some functional mechanisms with asomatognosia (Magri and Mocchetti, 1967; Devinsky et al., 1989a). This might have also been the reason why Devinsky et al. (1989a) and Magri and Mocchetti (1967) proposed the name asomatoscopy for negative heautoscopy. Patients with asomatognosia generally describe that an arm or leg or an entire body half seems to be ‘missing’ or that ‘the affected body parts may seem to disappear or to fall out of corporeal awareness’ (Critchley, 1953, pp. 237–238). Evidence from patients with focal brain damage suggests that asomatognosia is linked to posterior parietal (or temporoparietal) lesions, especially in the right hemisphere (Critchley, 1953; He´caen and David, 1945; David et al., 1946; Feinberg et al., 1990; Leiguarda et al., 1993; Feinberg et al., 2000; Sierra et al. 2002; So and Schauble, 2004).

ILLUSORY REDUPLICATIONS OF THE HUMAN BODY AND SELF Experimental findings in patients with asomatognosia are rare, but several case studies have shown that asomatognosia may be modified by touching the ‘missing’ body part or by looking at it suggesting multisensory mechanisms in asomatognosia and autoscopic phenomena (Critchley, 1953; Newport et al., 2001). Thus, an asomatognosic patient described by Carp (1952) lost her sensation for the right half of her body and had to verify continuously its existence by looking at it. Whereas the missing body part in asomatognosia is generally experienced as a somatosensory loss (Critchley, 1953; He´caen and David, 1945; David et al., 1946; Feinberg et al., 1990; Leiguarda et al., 1993; Feinberg et al., 2000; Sierra et al. 2002; So and Schauble, 2004) the above mentioned cases of von Stockert (1934) and Arzy et al. (2006) suggest that asomatognosia may also exist as a visual loss. One might thus classify these cases either as partial negative heautoscopy or as visual asomatognosia. Khazaal et al. (2005) considered asomatognosia a special form of hemi-depersonalization (quoted after Brugger, 2005). The association between depersonalization and negative heautoscopy as well as other forms of autoscopic phenomena will be briefly considered next. 22.7.3.2. Depersonalization Many authors have pointed out that autoscopic phenomena (except autoscopic hallucinations) are often associated with depersonalization (Menninger-Lerchenthal, 1935; He´caen and Ajuriaguerra, 1952; Leischner, 1961; Devinsky et al., 1989a; Gru¨sser and Landis, 1991; Dening and Berrios, 1994; Brugger et al., 1997). Depersonalization is one of the four major dissociative disorders and defined as ‘an alteration in the experience of the self so that one feels detached from, and as if one is an outside observer of, one’s mental processes or body’ (DSM-IV, American Psychiatric Association). Dissociation including depersonalization is most common after severe stress, as for example in military combat and automobile accidents (DSM-IV, American Psychiatric Association) that are also common precipitating factors of autoscopic phenomena (Devinsky et al., 1989a). As stated recently by Simeon (2004) not much is known about the neuroanatomical mechanisms involved in depersonalization. Penfield and Jaspers (1954), Gloor et al., (1982), and Devinsky and colleagues linked autoscopic phenomena (Devinsky et al., 1989a) and dissociative states (including depersonalization) (Devinsky et al., 1989b) to temporal lobe structures and epilepsy. Sierra and Berrios (1998) postulated that depersonalization is related to a widespread disturbance including prefrontal hyperactivation, limbic hypoactivation, and parietal dysfunction (Sierra et al., 2002).

453

Simeon et al. (2000) linked activation at the right TPJ including right middle and superior temporal gyri, the right inferior parietal lobule as well as left occipital cortex to depersonalization. Patients with autoscopic phenomena often suffer from depersonalization, probably by being confronted with the experience of seeing one or more second own body or bodies in extracorporeal space (autoscopic hallucinations, heautoscopy, polyopic heautoscopy), of having the sensation of disembodiment (out-of-body experience), or of not feeling or seeing their body anymore (negative heautocopy, asomatognosia). Depersonalization may be especially strong when the patient does not see his own body (or body parts) through direct inspection or as reflected in a mirror as was the case in the patient reported by Arzy et al. (2006). This was also mentioned by Critchley (1953, p. 240) who stated that especially negative heautoscopy is ‘a severe example of the depersonalization syndrome.’ In conclusion, these observations on negative heautoscopy suggest that it shares several phenomenological, functional, and neural mechanisms with autoscopic phenomena and asomatognosia. We speculate that negative heautoscopy is also due to multisensory disintegration in parietal or temporoparietal cortex, especially in the right hemisphere, and that its neurological investigation might shed some light on depersonalization and dissociative states.

22.8. Conclusion In science the most challenging phenomena are often the ones we take for granted in our everyday lives. Excellent examples are the self and the experienced spatial unity between self and body and thus the everyday experience of being spatially embodied. Both folk and psychological notions are challenged by the experience of one or more second own bodies or doubles that neurological patients describe in several multisensory and sensorimotor forms. The reviewed evidence from neurological patients experiencing these striking dissociations between self and body suggests that AP are culturally invariant phenomena, which can be investigated scientifically to further our understanding of the functional and neural mechanisms of corporeal awareness and self consciousness. Importantly, these findings will also help physicians in diagnosing and treating affected patients. The neuroscientific study of the self is in its infancy and there are currently no established models, very little data, and often not even the vocabulary to describe neuroscientific notions of the self, self consciousness and selfhood as well as their relation to the subject’s body. This complexity is especially evident when patients describe doubles to their physicians. We believe that the investigation of the

454

O. BLANKE ET AL.

phenomenological, functional, and neural mechanisms leading to the experience of a double in neurological patients (and healthy subjects) is likely to improve our self-related neuroscientific models of embodiment, selfhood, and subjectivity.

References Ajuriaguerra J, Strejilevitch M, Tissot R (1963). A propos de quelques conduites devant le miroir de sujets atteints de syndromes dementiels de grand age. Neuropsychologia 1: 59–72. Alvarado CS (1992). The psychological approach to out-ofbody experiences: A review of early and modern developments. J Psychol 126: 237–250. ¨ ber Herderkrankungen des Gehirns, die Anton G (1898). U vom Patienten selbst nicht wahrgenommen werden. Wien Klin Wochenschr 11: 227. Ardila A, Gomez J (1988). Paroxysmal ‘feeling of somebody being nearby.’ Epilepsia 29: 188–189. Arzy S, Idel M, Landis T, et al. (2005). Speaking with one’s self. Autoscopic phenomena in writings from the ecstatic Kabbalah. J Consciousness Studies 12: 4–30. Arzy S, Overney L, Landis T., et al. (2006). Neural mechanisms of embodiment: Asomatognosia due to premotor cortex damage. Arch Neurol 63: 1022–1025. Arzy S, Seeek M, Spinelli L, et al. (2006). Induction of an illsory shadow person. Nature 443: 287. Assal G (1983). Non, je ne suis pas paralyse´e, c’est la main de mon mari. Arch Suisses Neurol Neuroschir Psychiatr 133: 151–157. Babm Ski J (1914). Contribution a l’e´tude des troubles mentaut doms l’he´mipe´gie organ lque (anosoqnosie). Rev Neurol (Paris) 27: 845–848. Bain A (1903). De l’Autorepresentation chez les Hysteriques Vigot, Paris. Bancaud J (1987). [Clinical symptomatology of epileptic seizures of temporal origin]. Rev Neurol (Paris) 143: 392–400. Bender MB (1945). Polyopia and monocular diplopia of cerebral origin. Arch Neurol Psychiatry 54: 323–338. Benson DF, Miller BL, Signer SF (1986). Dual personality associated with epilepsy. Arch Neurol 43: 471–474. Bentall RP (1990). The illusion of reality: A psychological model of hallucinations. Psychol Bull 107: 82–95. Berson RJ (1983). Capgras’ syndrome. Am J Psychiatry 140: 969–978. Blackmore SJ (1982). Beyond the Body. An Investigation of Out-Of-Body Experiences. Heinemann, London. Blanke O (2004). Illusions visuelles. In: AB Safran, A Vighetto, T Landis, E Cabanis (Eds.), Neurophtalmologie. Masson, Paris, pp. 147–150. Blanke O, Arzy S (2005). The out-of-body experience: Disturbed self-processing at the temporo-parietal junction. Neuroscientist 11: 16–24. Blanke O, Mohr C (2005). Out-of-body experience, heautoscopy, and autoscopic hallucination of neurological origin.

Implications for neurocognitive mechanisms of corporeal awareness and self-consciousness. Brain Res Rev 50: 184–199. Blanke O, Landis T, Spinelli L, et al. (2004). Out-of-body experience and autoscopy of neurological origin. Brain 127: 243–258. Blanke O, Ortigue S, Coeytaux A, et al. (2003). Hearing of a presence. Neurocase 9: 329–339. Blanke O, Ortigue S, Landis T, et al. (2002). Stimulating illusory own-body perceptions. Nature 419: 269–270. Bonnier P (1904). Le Vertige Masson, Paris. Botvinick M, Cohen J (1998). Rubber hands ‘feel’ touch that eyes see. Nature 391: 756. Bradford D (2005). Autoscopic hallucinations and disordered self-embodiment. Acta Neuropathol 3: 120–189. Brandt T, Dieterich M (1999). The vestibular cortex. Its location, functions, and disorders. Ann NY Acad Sci 871: 293–312. Bremmer F, Schlack A, Duhamel JR, et al. (2001). Space coding in primate posterior parietal cortex. Neuroimage 14: S46–S51. Brugger P (2002). Reflective mirrors: Perspective taking in autoscopic phenomena. Cogn Neuropsychol 7: 179–194. Brugger P (2005). From mirror neurons to mirror. Acta Neuropathol 3: 190–201. Brugger P, Agosti R, Regard M, et al. (1994). Heautoscopy, epilepsy, and suicide. J Neurol Neurosurg Psychiatry 57: 838–839. Brugger P, Blanke O, Regard M, et al. (2006). Polyopic heautoscopy: Case report and review of the literature. Cortex 42: 666–674. Brugger P, Kollias SS, Mu¨ri RM, et al. (2000). Beyond remembering: Phantom sensations of congenitally absent limbs. Proc Nat Acad Sci 97: 6167–6772. Brugger P, Regard M, Landis T (1996). Unilaterally felt presences: The neuropsychiatry of one’s invisible doppelga¨nger. Neuropsychiatry Neuropsychol Behav Neurol 9: 114–122. Brugger P, Regard M, Landis T (1997). Illusory reduplication of one’s own body: Phenomenology and classification of autoscopic phenomena. Cogn Neuropsychol 2: 19–38. Brugger P, Regard M, Landis T, et al. (1999). Hallucinatory experiences in extreme-altitude climbers. Neuropsychiatry Neuropsychol Behav Neurol 12: 67–71. Bu¨nning S, Blanke O (2005). The out-of-body experience: Precipitating factors and neural correlates. Prog Brain Res 150: 331–350. Bychowski G (1943). Disorders of the body-image in the clinical pictures of psychoses. J Nerv Ment Dis 97: 310–335. Capgras J, Reboul-Lachaux J (1923). L’illusion des ‘sosies’ dans un delire syste´matise´ chronique. Bull Soc Clin Med Ment 11: 6–16. Carlson DA (1977). Dream mirrors. Psychoanal Q 46: 38–70. Carp E (1952). Troubles de l’image du corps. Acta Neurol Psychiatr Belg 52: 461–475. Cereda C, Ghika J, Maeder P, et al. (2002). Strokes restricted to the insular cortex. Neurology 59: 1950–1955.

ILLUSORY REDUPLICATIONS OF THE HUMAN BODY AND SELF Chadwick PD, Lowe CF (1994). A cognitive approach to measuring and modifying delusions. Behaviour research and therapy 32: 355–367. Christodoulou GN (1978a). Course and prognosis of the syndrome of doubles. J Nerv Ment Dis 166: 68–72. Christodoulou GN (1978b). Syndrome of subjective doubles. Am J Psychiatry 135: 249–251. Cohen H, Jones HW (1943). Reference of cardiac pain to a phantom left arm. Br Heart J 2: 67. Cole MG, Dowson L, Dendukuri N, et al. (2002). The prevalence and phenomenology of auditory hallucinations among elderly subjects attending an audiology clinic. Int J Geriatr Psychiatry 17: 444–452. Comar G (1901). L’autorepresentation de l’organisme chez quelques hysteriques. Rev Neurol (Paris) 9: 490–495. Cornblath WT, Butter CM, Barnes LL, et al. (1998). Spatial characteristics of cerebral polyopia: A case study. Vision Res 38: 3965–3978. Critchley M (1950). The body-image in neurology. Lancet 1: 335–340. Critchley M (1953). The Parietal Lobes. Edward Arnold, London. Critchley M (1954). Parietal syndromes in ambidextrous and left-handed subjects. Zentralbl Neurochir 14: 4–16. Critchley M (1955). The idea of a presence. Acta Psychiatr Neurol Scand 30: 155–168. Critchley M (1979). The Divine Banquet of the Brain and other Essays. Raven Press, New York. Crookall R (1964). More Astral Projections. Analyses of Case Histories. Aquarian Press, London. Cutting J (1978). Study of anosognosia. J Neurol Neurosurg Psychiatry 41: 548–555. David AS (1999). Auditory hallucinations: Phenomenology, neuropsychology and neuroimaging update. Acta Psychiatr Scand Suppl 395: 95–104. David M, He´caen H, Passouant P, et al. (1946). Asomatognosie partielle et algie paroxystique, seuls signes cliniques d’un angiome parie´tal partiellement calcifie´. Gue´rison apre`s extirpation chirurgicale. Rev Neurol (Paris) 78: 236–238. Decety J, Sommerville JA (2003). Shared representations between self and other: A social cognitive neuroscience view. Trends Cogn Sci 7: 527–533. Dening TR, Berrios GE (1994). Autoscopic phenomena. Br J Psychiatry 165: 808–817. Devinsky O, Feldmann E, Burrowes K, et al. (1989a). Autoscopic phenomena with seizures. Arch Neurol 46: 1080–1088. Devinsky O, Putnam F, Grafman J, et al. (1989b). Dissociative states and epilepsy. Neurology 39: 835–840. Dewhurst K, Pearson J (1955). Visual hallucinations of the self in organic disease. J Neurol Neurosurg Psychiatry 18: 53–57. di Pellegrino G, Ladavas E, Farne A (1997). Seeing where your hands are. Nature 388: 730. Dorpat TL (1971). Phantom sensations of internal organs. Compr Psychiatry 12: 27–35. Duhamel JR, Colby CL, Goldberg ME (1998). Ventral intraparietal area of the macaque: Congruent visual and somatic response properties. J Neurophysiol 79: 126–136.

455

Du Prel C (1886). Der Doppelga¨nger. Monatsschrift der u¨bersinnlichen Weltanschauung. 1. Jahrgang. Ehrenwald C (1931). Anosognosie und Depersonalisation. Nervenarzt 4: 681–688. Ehrenwald H (1930). Vera¨ndertes Erleben des Ko¨rperbildes mit konsekutiver Wahnbildung bei linksseitiger Hemiplegie. Z Neurol 118: 89–97. Ehrsson HH, Spence C, Passingham RE (2004). That’s my hand! Activity in premotor cortex reflects feeling of ownership of a limb. Science 305: 875–877. Ehrsson HH, Holmes NP, Passingham RE (2005). Touching a rubber hand: Feeling of body ownership is associated with activity in multisensory brain areas. J Neurosci 25: 10564–10573. Eliade M (1951/1964). Shamanism. Archaic Techniques of Ecstasy. Routledge & Kegan Paul, London. Engerth G, Hoff H (1929). Ein Fall von Halluzinationen im hemianoptischen Gesichtsfeld. Beitrag zur Genese der optischen Halluzinationen. Monatsschr Psychiatr Neurol 74: 246–256. Feinberg TE, Haber LD, Leeds NE (1990). Verbal asomatognosia. Neurology 40: 1391–1394. Feinberg TE, Roane DM (2005). Delusional misidentification. Psychiatr Clin North Am 28: 665–683, 678–669. Feinberg TE, Roane DM, Ali J (2000). Illusory limb movements in anosognosia for hemiplegia. J Neurol Neurosurg Psychiatry 68: 511–513. Feinberg TE, Shapiro TE (2000). Misidentification-Reduplification and the right hemisphere. Neuropsychiatry Neuropsychol Behav Neurol 2: 39–48. Fe´re´ C (1891). Note sur les hallucinations autoscopiques ou spe´culaires et sur les hallucinations altruistes. C R Hebdo Seances Me´m Soc Biol 3: 451–453. Foley JM, Breslau L (1982). A new syndrome of delusional misidentification. Ann Neurol 12: 76. Foxe JJ, Wylie GR, Martinez A, et al. (2002). Auditory-somatosensory multisensory processing in auditory association cortex: An fMRI study. J Neurophysiol 88: 540–543. Fredericks JAM (1969). Disorders of the body schema. In: PJ Vinken, GW Bruyn (Eds.), Disorders of Speech, Perception, and Symbolic Behavior. Amsterdam, North Holland, pp. 207–240. Frith C (1996). The role of the prefrontal cortex in selfconsciousness: The case of auditory hallucinations. Philos Trans R Soc Lond B Biol Sci 351: 1505–1512. Frith CD, Done DJ (1988). Towards a neuropsychology of schizophrenia. Br J Psychiatry 153: 437–443. Gallagher II (2000). Philosophical conceptions of the self: implications for cognitive science. Trends Cogn Sci 4: 14–21. Genner T (1947). Das Sehen des eigenen Spiegelbildes als epi¨ quivalent. Wien Klin Wochenschr 59: 656–658. leptisches A Gerstmann J (1942). Problem of imperception of disease and of impaired body territories with organic lesions. Arch Neurol Psychiatry 48: 890–913. Gloning I, Gloning K, Weingarten K (1954). Der Einfluss von kina¨sthetischen Impulsen auf Ko¨rperschemasto¨rungen. Wien Z Nervenheilkd Grenzgeb 9: 481–495.

456

O. BLANKE ET AL.

Gloning I, Gloning K, Weingarten K (1957). [A case of corporeal metamorphognosy]. Wien Z Nervenheilkd Grenzgeb 14: 228–235. ¨ ber einen Gloning IG, Jellinger K, Tschabiter H (1963). U obduzierten Fall von optischer Ko¨rperschemasto¨rung und Heautoskopie. Neuropsychologia 1: 217–231. Gloor P, Olivier A, Quesney LF, et al. (1982). The role of the limbic system in experiential phenomena of temporal lobe epilepsy. Ann Neurol 12: 129–144. Gluckman LK (1968). A case of Capgras syndrome. Aust N Z J Psychiatry 2: 39–43. Green CE (1968). Out-of-Body Experiences. Hamish Hamilton, London. Gru¨sser OJ, Landis T (1991). The splitting of ‘I’ and ‘me’: Heautoscopy and related phenomena. In: OJ Gru¨sser, T Landis (Eds.), Visual Agnosias and other Disturbances of Visual Perception and Cognition. MacMillan, Amsterdam, pp. 297–303. Guldin WO, Gru¨sser OJ (1988). Is there a vestibular cortex? Trends Neurosci 21: 254–259. Halgren E, Walter RD, Crandall PH (1983). Experiential phenomena of temporal epilepsy. Ann Neurol 14: 93–94. Halgren E, Walter RD, Cherlow DG, et al. (1978). Mental phenomena evoked by electrical stimulation of the human hippocampal formation and amygdala. Brain 101: 83–117. Hall PF (1918). Experiments in astral projection. J Am Soc Psychosom Dent Med 12: 39–60. Halligan PW (2002). Phantom limbs: The body in mind. Cognit Neuropsychiatry 7: 251–268. Halligan PW, Marshall JC, Wade DT (1993). Three arms: A case study of supernumerary phantom limb after right hemisphere stroke. J Neurol Neurosurg Psychiatry 56: 159–166. Havens LL (1962). The placement and movement of hallucinations in space: Phenomenology and theory. Int J Psychoanal 43: 426–435. He´caen H, Ajuriaguerra J (1952). L’Heautoscopie, Meconnassiances et hallucinations corporelles, Masson, Paris, pp. 310–343. He´caen HD, David M (1945). Syndrome parie´tal traumatique: Asymbolie tactile et he´miasomatognosie paroxystique et douloureuse. Rev Neurol (Paris) 77: 113–124. Heintel H (1965). Heautoskopie bei traumatischer Psychose. Zugleich ein Beitrag zur Pha¨nomenologie der Heautoskopie. Arch Psychiatr Nervenkr 206: 727–735. Hermann BP, Chhabria S (1980). Interictal psychopathology in patients with ictal fear. Examples of sensory-limbic hyperconnection? Arch Neurol 37: 667–668. Hoff H (1931). Zur Frage der formalen Gestaltung optischer Halluzinationen im hemianopischen Gesichtsfeld Zeit ges. Neurol Psychiatr (Bucur) 137: 453–457. Hoff H, Po¨tzl O (1935/1988). Transformations between body image and external world. In: JW Brown (Ed.), Agnosia and Apraxia: Selected Papers of Liepmann, Lange, and Po¨tzl. Lawrence Erlbaum, Hillsdale, NJ, pp. 251–262. Hoffmann RE (1986). Verbal hallucinations and language production processes in schizophrenia. Behav Brain Sci 9: 503–548.

Holmes NP, Spence C (2004). The body schema and the multisensory representation(s) of peripersonal space. Cogn Process 5: 94–105. Ionasescu V (1960). Paroxysmal disorders of the body image in temporal lobe epilepsy. Acta Psychiatr Scand 35: 171–181. Irwin HJ (1985). Flight of Mind: A Psychological Study of the Out-Of-Body Experience. Scarecrow Press, Metuchen, NJ. Isnard J, Guenot M, Ostrowsky K, et al. (2000). The role of the insular cortex in temporal lobe epilepsy. Ann Neurol 48: 614–623. Isnard J, Maugie`re F. (2005). [The insula in partial epilepsy]. Rev Neurol (Paris) 161: 17–26. James W (1961). The Variety of Religious Experience. Coller McMillan, New York. ¨ ber leibhaftige Bewusstheiten (BewusJaspers K (1913). U sheitsta¨uschungen), ein psychopathologisches Elementarsymptom. Zeitschrift fu¨r Psychopathologie 2: 150–161. Junginger J, Frame CL (1985). Self-report of the frequency and phenomenology of verbal hallucinations. J Nerv Ment Dis 173: 149–155. Kamanitz JR, El-Mallakh RS, Tasman A (1989). Delusional misidentification involving the self. J Nerv Ment Dis 177: 695–698. Kellehear A (1990). The near-death experience as status passage. Soc Sci Med 31: 933–939. Khazaal Y, Zimmermann G, Zullino DF (2005). [Depersonalization–current data]. Can J Psychiatry 50: 101–107. Ko¨lmel HW (1985). Complex visual hallucinations in the hemianopic field. J Neurol Neurosurg Psychiatry 48: 29–38. Kurth W (1941). Pseudohalluzination bei organischen Krankheiten. Acta Psychiatrica Nervenkr 112: 90–100. Lackner JR (1988). Some proprioceptive influences on the perceptual representation of body shape and orientation. Brain 111: 281–297. La`davas E (2002). Functional and dynamic properties of visual peripersonal space. Trends Cogn Sci 6: 17–22. La`davas E, Pavani F, Farne A (2001). Auditory peripersonal space in humans: A case of auditory-tactile extinction. Neurocase 7: 97–103. Lance JW (1976). Simple formed hallucinations confined to the area of a specific visual field defect. Brain 99: 719–734. Leiguarda R, Starkstein S, Nogues M, et al. (1993). Paroxysmal alien hand syndrome. J Neurol Neurosurg Psychiatry 56: 788–792. Leischner A (1961). [Autoscopic hallucinations (heautoscopy).]. Fortschr Neurol Psychiatr 29: 550–585. Ley H, Stauder KH (1950). Zur Neurologie und Psychopathologie des Morbus Bang. Zugleich ein Beitrag zum Pha¨nomen der sogenannten ‘Ichverdoppelung.’ Arch Psychiatr Zeit Neurol 183: 564–580. Lhermitte J (1939). Les phenome`nes he´autoscopiques, les hallucinations spe´culaires et autoscopiques. In: L’image de notre corps. L’Harmattan, Paris, pp. 170–227. Lhermitte J (1951). Les phenome`nes he´autoscopiques, les hallucinations spe´culaires. In: G Doin (Ed.), Les Hallucinations. Clinique et Physiopathologie. Cie, Paris, pp. 124–168.

ILLUSORY REDUPLICATIONS OF THE HUMAN BODY AND SELF Lippman CW (1953). Hallucinations of physical duality in migraine. J Nerv Ment Dis 117: 345–350. Lukianowicz N (1958). Autoscopic phenomena. AMA Arch Neurol Psychiatry 80: 199–220. Lukianowicz N (1960). Visual thinking and similar phenomena. J Ment Sci 106: 979–1001. Lunn V (1970). Autoscopic phenomena. Acta Psychiatr Scand 46: 118–125. Maack LH, Mullen PE (1983). The doppelganger, disintegration and death: A case report. Psychol Med 13: 651–654. Magri R, Mocchetti E (1967). [Partial asomatoscopy (negative autoscopy) in epileptics. Nosographic classification and clinical contribution]. Arch Psicol Neurol Psichiatr 28: 572–585. Mahaluf J, Canales G, Cattenaci M (1987). Heautoscopia: Description de un caso clinico. Revue Psychiatrico Clinico 24: 35–39. Maupassant G de (1986/1961). Le Horla. In: E Boyd, S Jameson (Eds.), 88 More Stories by Guy de Maupassant. Cassell, London. Maximov K (1973). Epilepsie occipitale avec hallucinations he´autoscopiques. Acta Neurol Belg 73: 320–323. Mayer-Gross W (1928). Psychopathologie und Klinik der Trugwahrnehmungen. In: O Bumke (Ed.), Handbuch der Geisteskrankheiten, Vol. I, Pt 1. Berlin, Springer, pp. 427–507. McCulloch WH (1992). A certain archway: Autoscopy and its companions seen in Western writing. Hist Psychiatry 3: 59–78. McGuire PK, Silbersweig DA, Wright I, et al. (1995). Abnormal monitoring of inner speech: A physiological basis for auditory hallucinations. Lancet 346: 596–600. McKay CM, Headlam DM, Copolov DL (2000). Central auditory processing in patients with auditory hallucinations. Am J Psychiatry 157: 759–766. Melzack R (1990). Phantom limbs and the concept of a neuromatrix. Trends Neurosci 13: 88–92. Menninger-Lerchenthal E (1935). Das Truggebilde der Eigenen Gestalt. Karger, Berlin. Menninger-Lerchenthal E (1946). Der Eigene Doppelga¨nger Bern. Messner R (1980). Alleingang Nanga Parbat. Knaur, Munchen. Metzinger T (2003). Being No One. MIT Press, Cambridge. Metzinger T (2005). Out of body experiences as the origin of the concept of a ‘soul.’ Mind and Matter 3: 57–84. Mohr C, Blanke O (2005). The demystification of autoscopic phenomena. Experimental propositions. Curr Psychiatry Rep 7: 189–195. Muldoon S, Carrington H (1929). The Projection of the Astral Body. Rider, London. ¨ ber phantastische Gesichtserscheinungen. Mu¨ller J (1826). U Verlag, Koblenz, 79. Naudascher MG (1910). Trois cas d’hallucinations spe´culaires. Ann Med Psychol (Paris) 68: 284–296. Nayani TH, David AS (1996). The auditory hallucination: A phenomenological survey. Psychol Med 26: 177–189. Newport R, Hindle JV, Jackson SR (2001). Links between vision and somatosensation. Vision can improve the felt position of the unseen hand. Curr Biol 11: 975–980.

457

Nightingale S (1982). Somatoparaphrenia: A case report. Cortex 18: 463–467. Noue¨t H (1923). Hallucination speculaire et traumatisme craˆnien. Encephale 18: 327–329. Oesterreich TK (1910). Die Pha¨nomenologie des Ich in ihren Grundproblemen. Barth, Leipzig. Ostrowsky K, Isnard J, Ryvlin P, et al. (2000). Functional mapping of the insular cortex: Clinical implication in temporal lobe epilepsy. Epilepsia 41: 681–686. Pavani F, La`davas E, Driver J (2003). Auditory and multisensory aspects of visuospatial neglect. Trends Cogn Sci 7: 407–414. Pearson J, Dewhurst K (1954). [Two cases of heautoscopic phenomena following organic lesions.] Encephale 43: 166–172. Penfield W, Jaspers H (1954). Epilepsy and the Functional Anatomy of the Human Brain. Churchill, London. Penfield W, Perot P (1963). The brain’s record of auditory and visual experience. A final summary and discussion. Brain 86: 595–696. Perrin F, Maquet P, Peigneux P, et al. (2005). Neural mechanisms involved in the detection of our first name: A combined ERPs and PET study. Neuropsychologia 43: 12–19. Peto A (1969). Terrifying eyes. A visual superego forerunner. Psychoanal Study Child 24: 197–212. Podoll K, Robinson D (1999). Out-of-body experiences and related phenomena in migraine art. Cephalalgia 19: 886–896. ¨ ber Sto¨rungen der Selbstwahrnehmung bei Po¨tzl O (1925). U linksseitiger Hemiplegie. Zeit ges Neurol Psychiatr 93: 117–168. Ramachandran VS, Hirstein W (1998). The perception of phantom limbs. The DO Hebb lecture. Brain 121: 1603–1630. Ramachandran VS, Rogers-Ramachandran D, Cobb S (1995). Touching the phantom limb. Nature 377: 489–490. Rank O (1925). Der Doppelga¨nger. Eine psychoanalytische Studie. Internationaler Psychoanalytischer Verlag, Leipzig. Ro¨hrenbach C, Landis T (1995). Dreamjourneys: Living in woven realities, the syndrome of reduplicative paramnesia. In: R Campbell, MA Conway (Eds.), Broken memories: Case studies in memory impairment. Blackwell, Oxford, pp. 93–99. ¨ ber Autoskopie, u¨ber die Lokalisation Schilder P (1914). U des Denkens und u¨ber die ‘Ichverdoppelungen’ der Hysterie. In: Selbstbewusstsein und Perso¨nlichkeitsbewusstsein. Eine psychopathologische Studie. Springer, Berlin, pp. 229–246. Schilder P (1935). The Image and Appearance of the Human Body. Georg Routledge and Sons, Regan Paul Trench, Trubner & Co, London. Schroter-Kunhardt M (2002). [Heautoscopy. Capgras phenomenon and rare hallucinations of own being. Comments on the contribution by D. Arenz]. Nervenarzt 73: 298–299; author reply 299. Sheils D (1978). A cross-cultural study of beliefs in out-ofthe-body experiences, waking and sleeping. J Soc Psychol 49: 697–741.

458

O. BLANKE ET AL.

Shelley BP, Trimble MR (2004). The insular lobe of Reil—its anatamico-functional, behavioural and neuropsychiatric attributes in humans—a review. World J Biol Psychiatry 5: 176–200. Sherrard C (1978). The Everest message. J Soc Psychol 49: 797–804. Sierra M, Berrios GE (1998). Depersonalization: Neurobiological perspectives. Biol Psychiatry 44: 898–908. Sierra M, Lopera F, Lambert MV, et al. (2002). Separating depersonalisation and derealisation: The relevance of the ‘lesion method.’ J Neurol Neurosurg Psychiatry 72: 530–532. Signer SF (1987). Capgras’ syndrome: The delusion of substitution. J Clin Psychiatry 48: 147–150. Silva JA, Leong GB (1991). A case of ‘subjective’ Fregoli syndrome. J Psychiatr Res 16: 103–105. Silva JA, Leong GB, Weinstock R (1993). Delusions of transformation of the self. Psychopathology 26: 181–188. Simeon D, Guralnik O, Hazlett EA, et al. (2000). Feeling unreal: A PET study of depersonalization disorder. Am J Psychiatry 157: 1782–1788. Simeon D. (2004). Depersonalisation disorder: A contemporary overview. CNS Drugs 18: 343–354. Sims A (1986). Psychopathology of schizophrenia with special reference to delusional misidentification. Bibl Psychiatr 164: 30–39. Sinclair DC, Weddell G, Feindel WH (1948). Referred pain and associated phenomena. Brain 71: 184–209. Skworzoff K (1931). Doppelga¨nger-Halluzinationen bei Kranken mit Funktionssto¨rungen des Labyrinths. Zeitschr Nervenheilk 133: 762–766. Smythe FS (1934). Everest 1933. Hodder & Stoughton, London. So EL, Schauble BS (2004). Ictal asomatognosia as a cause of epileptic falls: Simultaneous video, EMG, and invasive EEG. Neurology 63: 2153–2154. Sollier P (1903a). Les phe´nome`nes d’autoscopie. Fe´lix Alcan, Paris.

Sollier P (1903b). L’autoscopie interne. Rev Philos Louv 55: 1–41. Staudenmaier L (1912/1968). Die Magie als experimentelle Naturwissenschaft. In: Darmstadt Wissenschaftliche Buchgesellschaft, 106. Stein BE, Meredith MA, Wallace MT (1993). The visually responsive neuron and beyond: Multisensory integration in cat and monkey. Prog Brain Res 95: 79–90. Stephane M, Barton S, Boutros NN (2001). Auditory verbal hallucinations and dysfunction of the neural substrates of speech. Schizophr Res 50: 61–78. Strauss EW (1962). Phenomenology of hallucinations. In: LJ West (Ed.), Hallucinations. Grune and Stratton, New York. Strindberg A (1897). Inferno. Penguin Books, New York. Suedfeld P, Mocellin JS (1987). The sensed presence in unusual environment. Environ Behav 19: 33–52. Todd J, Dewhurst K (1955). The double: Its psycho-pathology and psycho-physiology. J Nerv Ment Dis 122: 47–55. Todd J, Dewhurst K (1962). The significance of the Doppelganger (hallucinatory double) in folk-lore and neuro-psychiatry. Practitioner 188: 377–382. von Stockert FG (1934). Lokalisation und klinische Differenzierung des Symptoms der Nichtwahrnehmung einer Ko¨rperha¨lfte. Dtsch Z Nervenheilkd: 1–13. Weinstein EA, Kahn RL, Malitz S, et al. (1954). Delusional reduplication of parts of the body. Brain 77: 45–60. Williams D (1956). The structure of emotions reflected in epileptic experiences. Brain 79: 29–67. Yram (1972). Practical Astral Projection. Samuel Weiser, New York. Zamboni G, Budriesi C, Nichelli P (2005). ‘Seeing oneself’: A case of autoscopy. Neurocase 11: 212–215. ¨ ber Sto¨rungen der Wahrnehmung des Zingerle H (1913). U eigenen Ko¨rpers bei organischen Gehirnerkrankungen. Monatsschr Psychiatr Neurol 34: 3–36.

Handbook of Clinical Neurology, Vol. 88 (3rd series) Neuropsychology and behavioral neurology G. Goldenberg, B.L. Miller, Editors # 2008 Elsevier B.V. All rights reserved

Chapter 23

The musical brain BRANDY R. MATTHEWS* Memory and Aging Center, University of California, San Francisco, CA, USA

23.1. Introduction The presence of music in the lives of humans is ubiquitously seen in a diverse array of forms across many cultures (Cross, 2003) and has a long history in the archeological records. In one compelling example, a bone flute was discovered in Slovenia in 1995 and was determined to be nearly 50,000 years old (Turk, 1997). The appearance of music in association with human evolution has led experts to speculate that music confers some evolutionary advantage to humans (Huron, 2001) while others maintain the claim that music is a nonadaptive activity (Pinker, 1997). Still other theorists suggest that music is a homologue of language, both having evolved from an ancestral ‘musilanguage’ system (Brown, 2000). While discussions of the potential evolutionary themes of music use for mate selection (Darwin, 1872), social cohesion (Roederer, 1984), and motor (PascualLeone, 2001) or perceptual (Pantev et al., 1998) development remain speculative, it is impossible to deny the importance of music in daily human activity. Historically, musical trends have helped to define esthetic culture in the Western world from the monophonic chants of Gregorian monks to the operas of Mozart, both of which maintain popularity even in modernity. US Census Bureau (2006) statistics affirm the importance of musical activities in modern life with 14.1% of Americans attending a live musical performance in the year 2004. In the same survey, 7.8% of adult respondents reported playing a musical instrument as a leisure activity. Attempts to understand the neurobiological basis for music go back more than a century (Bouillaud, 1865). Theoretical accounts of ‘amusias’ as described by Knoblach in the late nineteenth century have served as preliminary framework within which neuroscientists *

have made a detailed cognitive study of music tenable (Wertheim, 1969; Johnson and Graziano, 2003). Additionally, there have been studies of the neural substrates of music production based upon changes in talented musicians with neurodegenerative illness (Alajouanine, 1948; Baeck, 1996; Alonso and Pascuzzi, 1999; Amaducci et al., 2002; Marins, 2002). Other investigators have studied the genetic condition Williams syndrome, in which gene carriers exhibit an intense interest in music in association with deficits in other cognitive domains (Hopyan et al., 2001; Levitin et al., 2004; Deruelle et al., 2005; Levitin, 2005). While certainly not species-specific, given the diverse musical expressions of animals from birds to whales (Fitch, 2006), humans have developed an approach to musical creation that is distinct from other animals. The available evidence suggests that there are a complex array of neural circuits underlying human music perception and creation. While early pathological correlations of ‘musical agnosia’ were noted in association with lesions in one or both anterior temporal lobes (Brodmann, 1914), more detailed musical networks are being increasingly investigated with structural and functional neuroimaging, electrophysiology, psychoacoustics, and neuropsychological testing. The results offer exciting implications for the neuroscience of learning, memory, language, neurodevelopment, and neurodegeneration.

23.2. Music perception At its simplest, musical perception is dependent upon sound perception, which is optimal with an intact mechanical and neuroanatomic auditory apparatus. For humans, the perception of sound begins when sound waves contact the ear’s tympanic membrane

Correspondence to: Brandy R. Matthews, MD, Memory and Aging Center, Department of Neurology, University of California, San Francisco, 350 Parnassus Ave, Suite 706, San Francisco, CA 94117. E-mail: [email protected].

460

B.R. MATTHEWS as the perceptual correlate of intensity, a conversion of sound wave amplitude-dependent pressure at the tympanic membrane.

resulting in a vibration and a cascade of motion within the small bones of the middle ear. In order to be audible to humans, the sound waves must oscillate in a specific frequency range, measured in cycles per second or Hertz (Hz), within a specific peak to trough amplitude range, measured in decibels (dB). Human sound frequency perception spans an approximate range of 20 to 20,000 Hz, with the human vocal production range between 100 and 1700 Hz. The simplified perceptual correlate of frequency is pitch. The log-based decibel scale sets 0 dB as the human threshold of audibility with an upper limit of 130 dB, when pain and deafness begin to develop. This scale reflects loudness

23.2.1. Neuroanatomic considerations Beyond the mechanical transduction of sound waves, the type I, frequency-responsive, hair cells of the inner ear’s cochlea respond in a tonotopic arrangement with lower frequencies stimulating the hair cells situated at the apex, and higher frequencies stimulating those located at the cochlear base. Tonotopy is preserved throughout the auditory pathway (see Fig. 23.1) with

Primary Auditory Cortex (BA 41)

Temporal Lobe

higher frequencies lower frequencies

Thalamus

Medial Geniculate Bodies

Midbrain Inferior Colliculi Cochlea

Pontomedullary Junction

Dorsal and Ventral Cochlear Nuclei

Fig. 23.1. Tonotopic representation throughout human auditory pathway from cochlea to cortex. Schematic representation of human auditory pathway (represented only ipsilaterally for simplicity) illustrating preservation of tonotopic representation. Regions responsive to high frequencies are indicated by the solid line ascending from the treble clef at the base of the cochlea to the posteromedial transverse temporal gyrus. Regions responsive to lower frequencies are indicated by the dashed line ascending from the bass clef at the apex of the cochlea to the anterolateral transverse temporal gyrus.

THE MUSICAL BRAIN higher frequencies represented in the dorsal cochlear nuclei and lower frequencies represented in the ventral cochlear nuclei. The pattern is reversed in the central nuclei of the inferior colliculi, where higher frequencies are represented ventromedially and lower frequencies dorsolaterally, and in the ventral division of the medial geniculate nucleus of the thalamus, where higher and lower frequencies remain distinctly segregated from medial to lateral (Brazis et al., 2001). In primary auditory cortex (Heschl’s gyrus, BA 41), higher frequencies have been demonstrated to activate the posteromedial region while lower frequencies result in anterolateral activity with magnetoencephalography (MEG) and implanted electroencephalography (EEG) electrodes (Liegeois-Chauvel et al., 1991; Pantev et al., 1988). The primary auditory cortex is activated via a dual pathway, with columns of neurons excited by binaural stimuli intercalated with columns of neurons excited by the contralateral ear and inhibited by the ipsilateral ear. This arrangement of adjacent columns maintains frequency-specificity. The binaural pathways are represented in both hemispheres as a result of a functional decussation at the brainstem trapezoid body near the superior olivary complex, which acts as an integration center (Henkel, 1997). Beyond the transversely oriented primary auditory cortex in the temporal lobe, sound processing continues in adjacent association areas, including the secondary auditory cortex (BA 42) as well as more distant frontal and parietal regions. These association areas demonstrate variable lateralization of function in higher order sound processing and integration, likely due to rich connections transmitting sound information across the corpus callosum. Helmholtz pioneered investigation of such higher order sound processing around the time of the first reported case of amusia (Helmholtz, 1863/1954), with subsequent reports suggesting the potential for dissociation of music processing from the higher order processing of speech and environmental sounds (Vignolo, 2003). However, in humans all such processing is thought to preferentially involve the frontal and temporal lobes (Tramo and Braida, 2002; Gorno-Tempini et al., 2004; Dronkers et al., 2004; Lewis et al., 2004). There is clearly a discrepancy between the detailed understanding of the connectivity and neural underpinnings of basic auditory anatomy and physiology and the oftentimes conflicting evidence regarding higher order sound processing, including musical perception. However, as investigational methods continue to be refined, the study of human musical abilities may offer a unique opportunity to better understand human perception and brain–behavior relationships.

461

23.2.2. Musical models There is a growing body of literature on patients with focal lesions related to deficits in music perception that is complemented by new approaches using novel functional neuroimaging and electrophysiological paradigms to investigate music perception. Current cognitive theories of music perception emphasize a modular approach (Baeck, 2002; Peretz and Coltheart, 2003; Koelsch and Friederici, 2003). This theoretical framework is similar to historic theoretical models which emphasized the distinction between ‘sensory’ (i.e., melody deafness, musical alexia, etc.) and ‘motor’ (i.e., avocalia, musical agraphia, etc.) musical deficits (Wertheim, 1969; Johnson and Graziano, 2003). Other models have adopted aphasia terminology, referring to separable ‘receptive’ and ‘expressive’ musical deficits (Wertheim and Botez, 1961). Arguably, previously termed motor or expressive musical deficits are subject to enormous individual differences as a result of musical pursuits and training (i.e., classical composer versus tribal percussionist versus jazz vocalist) and associated neurological deficits (i.e., hemianopsia versus hemiparesis versus orobuccal apraxia). This renders such deficits less likely to be ‘pure’ or dissociable and, consequently, motor deficits have been more difficult to precisely characterize. Therefore, the focus of the following discussion will be deficits in music perception, supplemented by a general discussion of neurological findings in musicians versus non-musicians. 23.2.3. Investigating musical functions Musical variables which may be parsed from the experience of music perception include, but are not limited to: pitch, melody, scale, harmony, timbre, rhythm, and meter (for a detailed discussion see Tramo et al., 2001; Peretz et al., 2003) . Each of these components of music will be described in light of evidence for lateralization or localization from the neurological patient, lesion-based literature and from activations cited in published functional neuroimaging and electrophysiological studies. Baseline individual variability and the overlap of deficits in music perception with language or auditory processing deficits continue to confound attempts to generalize findings in this field. Fortunately, cross-sectional studies and case series in which a group of patients with similar lesions are subjected to formal music testing have been greatly facilitated by the introduction of standardized musical assessment batteries (Seashore et al., 1960; Wertheim, 1969; Peretz et al., 2003). Functional magnetic resonance imaging (fMRI), positron emission tomography

462

B.R. MATTHEWS

(PET) and electrophysiological investigations such as event related potentials (ERP), EEG, and MEG have advanced the field of study by demonstrating regions or networks of activity, but such methods cannot confirm the necessary and sufficient activations involved in musical tasks (Warren, 2004). 23.2.3.1. Pitch and melody Pitch is experienced as the height or depth of a sound as determined by the frequency of a complex of sound waves. Sounds perceived as pitch rather than noise are comprised of mixtures of pure frequencies that are harmonically related. The lowest audible frequency in the pitch is referred to as the fundamental frequency, with the associated harmonic tones being integerrelated multiples of that fundamental frequency vibrating with comparatively reduced amplitude. The ability to perceive differences between discrete pitches may be assessed by simply requesting a ‘same’ or ‘different’ response as exemplified in the Montreal Battery of Evaluation of Amusia (MBEA) (Peretz et al., 2003). Evidence from the evaluation of brain injured patients suggests that bilateral lesions in the primary auditory cortex or the associated subcortical white matter pathways (Mendez and Geehan, 1988; Tramo et al., 1990), or bilateral insulae (Habib et al., 1995) may result in acquired pitch discrimination deficits. Similarly, in a study of 20 patients with cerebrovascular insult isolated to either the left or right hemisphere, none of the patients demonstrated deficits on a pitch discrimination task, despite clear deficits in the performance of other music perception tasks (Schuppert et al., 2000). A PET study using a different pitch discrimination task demonstrated significant and asymmetric activation lateralized to the left hemisphere, in particular the precuneus (Platel et al., 1997). By presenting several notes in succession, this task may have assessed a more complex ability. Termed pitch interval discrimination, this perceptual task requires discerning the relative distance of one pitch from another when exposed to successive pitches. In another PET study, subjects engaged in pitch interval determination of temporally adjacent stimuli, revealing significant activations in the right inferior, middle, and superior frontal gyri and midline cerebellum (Zatorre et al., 1992; 1994). Lesion studies suggest that determining whether a second pitch is ‘higher’ or ‘lower’ is impaired following right temporoparietal (Mackworth-Young, 1983), bilateral temporoparietal (Tanaka et al., 1987), inferior collicular (Johkura et al., 1998) or even cerebellar insult (Parsons, 2001). Deficits in pitch interval perception were reported in both right- and left-sided temporal lobe excisions for a series of 62 patients

undergoing surgery for intractable epilepsy; however, only patients with right-sided excisions demonstrated a deficit in the ability to detect the direction of pitches relative to another over time in a melody, a musical variable referred to as contour (Liegeois-Chauvel et al., 1998). This result is similar to those demonstrated in two groups of 20 patients with unilateral cerebrovascular insults (Peretz, 1990; Ayotte et al., 2000). In sum, these findings are interpreted as consistent with a theory of right-hemisphere localized melodic contour processing as prerequisite to lefthemisphere pitch interval processing (Peretz, 1990). 23.2.3.2. Scale and harmony Closely related to pitch and melody, yet more difficult to accurately define, is musical scale. Theoretically, it is a small subset of pitches (in Western musical tradition most commonly seven, referred to as a diatonic scale, rather than twelve notes of an octave, or a chromatic scale), which is composed of a tonic pitch for which the scale is named and several closely related pitches. The mathematical properties inherent in a scale generate expectancies in listeners based on pitch relationships. Practically, violations of scale are perceived as being ‘out of tune’ (Peretz and Coltheart, 2003). In assessments of scale perception using the MBEA, neither left hemisphere cerebrovascular insult nor epilepsy with left temporal lobectomy resulted in below normal performance; however, deficits were revealed in the ability to detect scale violation with injury to the right hemisphere or bilateral hemispheres (Liegeois-Chauvel et al., 1998; Ayotte et al., 2000). Case reports have suggested dissociation of pitch interval or contour processing from tonal pattern recognition inherent in scale perception (Tramo et al., 1990; Peretz, 1993) while an fMRI investigation has suggested a rostromedial prefrontal activation while performing a task of scale analysis (Janata et al., 2002). The perception of the relationship of pitches in the vertical rather than horizontal dimension describes harmony. Similar to scale, harmony is determined by mathematical relationships initially investigated by Pythagoras and uses chords, three or more pitches played simultaneously, as its musical unit. Investigators have proposed that Western harmonic chord sequences also generate expectancies, as discrete perceptual elements in a structured, hierarchical sequence, forming an important component of musical syntax (Koelsch and Friederici, 2003). Musical syntax has been investigated by presenting research subjects with series of chords in which the expected tonal relationships are violated by the insertion of consonant

THE MUSICAL BRAIN chords containing two key-violating notes (Neapolitan chords). The Neapolitan chords are inserted in locations in the chord sequence where musical expectancies are known to vary (i.e., certain (tonic) chords are expected at the conclusion of a musical phrase.) Musical syntax has not yet been the subject of extensive investigation; however, related deficits in language syntax are well characterized with neuroimaging and electrophysiological studies, suggesting a dominant-hemisphere lateralization and an inferior frontal lobe localization of function (Patel, 2003; Dronkers et al., 2004; Jentschke et al., 2005) corresponding to the brain region referred to as Broca’s area (BA 44/45) (Caplan et al., 1999; Caplan, 2001). Available localization studies modeling musical syntax suggest a bilateral inferior frontal activation, with functional imaging and electrophysiology studies using chord sequence stimuli demonstrating a trend toward greater activation in the right hemisphere homologue of BA 44/45 (Maess et al., 2001; Koelsch et al., 2002; Levitin and Menon, 2003; Koelsch et al., 2004; Koelsch et al., 2005b). 23.2.3.3. Timbre Timbre, also known as ‘tone color,’ is a differential quality of sound perceived even as frequency, intensity, and duration across sound generators are held constant. Physically, timbre results from differing harmonic intensities and temporal periodicities associated with a fundamental frequency, while perceptually it may be as distinctive as a note from Louis Armstrong’s trumpet compared to Maria Callas’ coloratura. Perhaps most consistently of all the musical variables, timbre has demonstrated a right-hemisphere lateralization. Evidence includes: a left ear advantage in dichotic listening tasks (Boucher and Bryden, 1997), deficits in patients with right temporal lobe resection (Samson and Zatorre, 1994; Samson et al., 2002), deficits in patients with right-hemisphere cerebrovascular insult (Chobor and Brown, 1987), and EEG activation in the right temporo-occipital region when performing a timbre discrimination task (Auzou et al., 1995). Functional PET imaging data suggest activation in the right superior and middle frontal gyri in a timbre discrimination task administered in sequence with other musical tasks (Platel et al., 1997) while an fMRI paradigm likewise revealed right temporal lobe increased signal with a timbre-related task (Samson, 2003). 23.2.3.4. Rhythm and meter Rhythm is segmentation of temporal groups on the basis of durational value; whereas, meter is the underlying periodicity of an ongoing sequence, corresponding to the strength of accented beats, independent of

463

note durations. Temporal processing has been clearly demonstrated to be dissociable from pitch processing in multiple subjects with music perception deficits (Polk and Kertesz, 1993; Peretz et al., 1994). One of the widely accepted modular representations of music suggests that the temporal characteristics of music, meter and rhythm, are respectively analogous to the ‘global’ contour of successive pitches and the ‘local’ pitch interval (Peretz, 1990; Schuppert et al., 2000). However, deficits in temporal discrimination may involve multiple sensory modalities including vision and pain sensation (Tanaka et al., 1987), thereby revealing a potential limitation of this analogy as representative of music-specific neural circuits. Also in departure from the hierarchical model is evidence that, while right hemisphere cerebrovascular damage results in both rhythm and meter perceptual impairment, such deficits appear to be independent and dissociable in isolated left hemisphere damage (Schuppert et al., 2000). Similarly, evidence from other lesion-based accounts suggests that perception of meter may be spared even when rhythm perception is impaired, with the latter being referable to either hemisphere (Peretz, 1990; Ayotte et al., 2000). Evidence in temporal lobectomy patients has been variable, demonstrating a right-hemisphere lateralization for meter perception (Kester et al., 1991) in one series, with a nonspecific lateralization but specific localization to the anterior superior temporal gyrus in another series (Liegeois-Chauvel et al., 1998). Functional imaging evidence with PET scanning in healthy volunteers revealed increased activation in the left insula, contiguous with Broca’s area (BA44/45) during a rhythm discrimination task (Platel et al., 1997), while fMRI investigation demonstrated increased blood flow in the left prefrontal and parietal regions for simpler rhythms and a similar pattern in the right hemisphere for more complex rhythmic associations (Sakai et al., 1999). While a hierarchical model depicting global musical features of melodic contour and meter as necessary for accurate perception of the local features of pitch interval and rhythm is theoretically appealing, the localization of neuroanatomic networks involved in such a model has been complicated by inconsistent findings across investigative modalities. Synthesizing and simplifying the preceding evidence, accurate pitch discrimination seems to require bilateral primary auditory cortex while pitch interval determination is most likely lateralized to the left hemisphere and dependent on accurate melodic contour perception, which is most likely a function of right frontotemporal regions. Accurate perception of scale and harmony appear to be dependent on bilateral inferior frontal regions, possibly

464

B.R. MATTHEWS

lateralized more to the right than the left hemisphere. Timbre discrimination is strongly suggested to be dependent on right hemisphere integrity. With regard to temporal variables in music perception, both rhythm and meter may have bilateral hemispheric representation and appear to be mutually dissociable while also dissociable from the melodic variables.

23.3. Musicians versus non-musicians Beyond music perception, humans possess the ability to create music with an enormous variety of instruments including the self-contained voice for singing, upper limbs for transcribing composition, and the entire body for conducting other instrumentalists. Such variability in method of performance has rendered generalizations regarding localization difficult, but interesting differences in the neuroanatomy and lateralization of function during musical tasks in musicians versus non-musicians have emerged. Structural imaging has demonstrated a relatively increased volume of the corpus callosum (Schlaug et al., 1995a), motor cortex, posterior perisylvian region, and cerebellum in musically trained individuals (Schlaug, 2001; Gaser and Schlaug, 2003). Functional assessment of musicians suggests a relative left-hemisphere lateralization for various music perceptual and performance tasks (Mazziotta et al., 1982; Pantev et al., 1998; Tzortzis et al., 2000; Ohnishi et al., 2001) which has been ascribed to a more analytic approach with increasing musical sophistication. Learning to play a stringed instrument has been associated with structural reorganization of the sensorimotor cortical representation of the fingers via fMRI, TMS, and electrophysiological methods (Kim et al., 2004; Hashimoto et al., 2004). Similarly, a MEG investigation demonstrated crossmodal reorganization of cortical lip representation in trumpeters (Schulz et al., 2003). Using diffusion tensor imaging to investigate the effects of extensive piano practicing, investigators suggested a positive correlation with myelination in pyramidal white matter tracts (Bengtsson et al., 2005). MEG evidence suggests that the age at which musicians began to practice is positively correlated with an enlarged cortical representation of tones of the musical scale (Pantev et al., 1998). Another functional investigation revealed instrument-specific enlarged representations for timbre in trumpeters and violinists (Pantev et al., 2001). In addition to enhanced cortical representation for music-related tasks, musical training may also positively impact other neurological domains such as psychomotor speed (Gruhn et al., 2003), spatial reasoning (Rauscher et al., 1995; 1997), and tactile discrimination (Ragert et al., 2004).

Absolute pitch is a unique musical skill. Defined as the ability to identify or demonstrate a pitch in the absence of a reference tone, it is identified in 5–20% of musicians (Gregersen et al., 1999; Hamilton et al., 2004). Structural imaging in musicians has revealed greater than expected left-sided asymmetry in the planum temporale, a posterior region of Heschl’s gyrus (Schlaug et al., 1995b; Zatorre et al., 1998; Keenan et al., 2001). Such structural difference and absolute pitch ability have been controversially correlated with musical training which commences in early childhood (Ross et al., 2003), while other studies suggest a genetic predisposition to absolute pitch (Baharloo et al., 1998; 2000). Further experimental imaging with fMRI has demonstrated overlap between increased activation in the left planum temporale during language and music tasks in musicians with absolute pitch, in contrast to a right hemisphere or bilateral activation in non-musicians and musicians without absolute pitch (Schlaug, 2001). Musician’s dystonia, a type of task-specific focal movement disorder which selectively affects skilled musicians, is characterized by sustained contraction of muscles resulting in involuntary tremor or abnormal postures. Rapid, repetitive movements involved in musical performance may contribute to the development of dystonia by several mechanisms, including: the activation of sensory pathways involved in motor programming (Byl et al., 1996; Elbert et al., 1998), imbalance in local cortical inhibition and excitation (Ridding et al., 1995; Ikoma et al., 1996), or peripheral nerve entrapment and soft tissue injury (Charness et al., 1996). In an fMRI study of musician’s dystonia elicited by guitar playing, increased activation in the primary sensorimotor cortex and relatively decreased activation in the premotor region was observed in comparison to musicians without dystonia (Pujol et al., 2000). Fortunately, with the refinement of therapies for taskspecific dystonia, a recent study of 144 musicians found that over half responded favorably to various interventions, ranging from behavioral therapy to ergonomic improvements to medical treatments such as botulinum toxin. However, nearly 30% of the musicians surveyed reported a change of career following the development of their neurological condition (Jabusch et al., 2005).

23.4. Music and emotion The human experience of music perception and performance certainly exceeds acoustical pattern extraction, analysis, and production. For many people, music is unique in its connection with both emotional

THE MUSICAL BRAIN perception and emotional experience. As such, in investigations of the neural correlates of music and emotion, it is important to conceptualize a distinction between the identification of the affective character of music and the resultant emotional experience associated with music. For example, a tragic aria is perceived as conveying negative affective valence but many listeners derive pleasure from the experience (Siegwart and Scherer, 1995), and such stimuli may even result in the exceptionally positive musical emotion, ‘thrills’ or ‘chills’ (Blood and Zatorre, 2001; Panksepp and Bernatzky, 2002). Of note, research subjects are more likely to experience musically and emotionally induced ‘chills’ when listening to personally preferred and familiar tunes (Panksepp, 1995), while subjects rate musical taste as one of the most revealing preferences or activities in attributing personal qualities to themselves and others (Rentfrow and Gosling, 2003). Such reports highlight the role of personal experience as a determinant in the emotional response to music and reveal potential confounds in attempts to systematically investigate the relationship. The ability to determine the intended affect of musical excerpts is less variable across subjective experience and has been correlated with precise developmental ages in children. When manipulating the musical variables of mode (i.e., major–minor key) and tempo (beats per unit time), music presented in major keys and with faster tempi is interpreted as ‘happy’ while melodies in minor keys and with slower tempi are interpreted as ‘sad’ (Dalla Bella et al., 2001a; 2001b). Responses are remarkably consistent across subjects with advancing age, regardless of musical background or personal musical preferences. An fMRI paradigm investigating the perceptual correlates of manipulations of mode and tempo on assessment of affective intent revealed increased blood flow in the left medial and superior frontal gyri and the posterior cingulate cortex bilaterally (Khalfa et al., 2005). The preservation of emotional response to music after the development of severe deficits in other aspects of music perception has been reported (Peretz et al., 1998). Conversely, preserved cognitive processing of music with loss of the emotional response to music has also been demonstrated (Griffiths et al., 2004). This double dissociation supports the possibility of separate acoustic and emotional neural circuits functioning not only in sequence but also in parallel during the music perceptual experience, and is asserted by many current theoretical models of music processing (Baeck, 2002; Koelsch and Friederici, 2003; Peretz and Coltheart, 2003; Peretz et al., 2003). Emotional responses to music have been quantified with psychophysiology such that the positive valence

465

(i.e., pleasantness) of a musical excerpt is associated with increased respiratory rate and skin conductance response (Gomez and Danuser, 2004). Likewise, a positive arousal rating (i.e., stimulating) of a musical excerpt, regardless of the valence, is associated with increases in heart rate, respiratory rate, and skin conductance response (Khalfa et al., 2002; Baumgartner et al., 2005). Such findings demonstrate the impact of emotional response to music on the autonomic nervous system. Additional neurophysiological investigation has suggested lateralization of emotional responses to music consistent with theoretical models based on valence as generated by other perceptual modalities. For example, increased left and right frontal EEG response correlated with happy (positive valence) and sad (negative valence) musical excerpts, respectively (Tsang et al., 2001; Altenmuller et al., 2002). Such lateralization related to valence has also been seen with PET imaging using a dissonance paradigm to generate unpleasant stimuli with associated activation in the right parahippocampal and precuneus regions (Blood et al., 1999). Investigations of the neural correlates of pleasurable responses to music with PET demonstrate activation of reward circuitry (Cardinal et al., 2002) including the ventral striatum, midbrain, amygdala, orbitofrontal cortex, and ventral medial prefrontal cortex (Blood et al., 1999; Blood and Zatorre, 2001). In particular the nucleus accumbens (NAc), ventral tegmental area (VTA), hypothalamus, and anterior insula have demonstrated increased perfusion when subjects reported experiencing music-related pleasure in one fMRI paradigm (Menon and Levitin, 2005). Another study demonstrated overlapping findings but emphasized increased blood flow in the rolandic operculum, interpreted as suggestive of an observation–execution matching function in this region for the sound processing domain (Koelsch et al., 2005a). Neurochemically, the involvement of reward circuitry suggests activation of the dopaminergic and opioid neurochemical systems, with dopamine release in the VTA having been associated with NAc opioid transmission (Kelley et al., 2002; Zhang et al., 2003). Interestingly, the potential role for opioid mediation in music-associated pleasure was suggested prior to modern functional imaging techniques as subjects reported a decrease in their positive emotional reaction to musical stimuli after administration of a known opioid antagonist, naloxone (Goldstein, 1980). Involvement of the endogenous opioid system may be further suggested by opioid receptor prominence in the inferior colliculus, a rudimentary yet important component of the auditory processing system in

466

B.R. MATTHEWS

humans, which has been implicated in mediating affective responses related to non-musical sound perception (Panksepp and Bernatzky, 2002).

23.5. Future directions Continued theoretical modeling of musical perception and its functional neuroanatomic correlates will certainly propel the scientific study of music forward; yet, the therapeutic potential of music, reliant upon its intimate association with human emotion and cognition, also deserves further attention. In an instructive neurochemical example, an animal model exposed to daily music demonstrated significantly increased brain norepinephrine levels when compared to control animals (Panksepp, 1986), suggesting music as a potential for treatment of attentional deficits and mood disorders. Similarly, in a neuroendocrine model, following presentation of stressful stimuli, salivary cortisol levels were noted to decline more rapidly in human subjects exposed to pleasant music when compared to subjects exposed to silence (Khalfa et al., 2003) suggesting the potential for music to modulate harmful effects of chronic stress on the brain (Sapolsky, 1996). Patients with Alzheimer’s disease are able to demonstrate a normal familiarity preference pattern for novel tunes, suggesting a route to access implicit memory and improve quality of life (Quoniam et al., 2003) while children with dyslexia demonstrate improvement in spelling and phonics when engaged in classroom musical programs (Overy, 2003). In but a few examples, one can envision music as a tool not only to investigate the complexities, but also to expand the capacities of the human brain.

Acknowledgements The author would like to thank Julene Johnson, PhD for her thoughtful review and comments on this manuscript.

References Alajouanine T (1948). Aphasia and artistic realization. Brain 74: 229–241. Alonso RJ, Pascuzzi RM (1999). Ravel’s neurological illness. Semin Neurol 19: 53–57. Altenmuller E, Schurmann K, Lim VK, et al. (2002). Hits to the left, flops to the right: Different emotions during listening to music are reflected in cortical lateralisation patterns. Neuropsychologia 40: 2242–2256. Amaducci L, Grassi E, Boller F (2002). Maurice Ravel and right-hemisphere musical creativity: Influence of disease on his last musical works? Eur J Neurol 9: 75–82.

Auzou P, Eustache F, Etevenon P, et al. (1995). Topographic EEG activations during timbre and pitch discrimination tasks using musical sounds. Neuropsychologia 33: 25–37. Ayotte J, Peretz I, Rousseau I, et al. (2000). Patterns of music agnosia associated with middle cerebral artery infarcts. Brain 123: 1926–1938. Baeck E (1996). Was Maurice Ravel’s illness a corticobasal degeneration? Clin Neurol Neurosurg 98: 57–61. Baeck E (2002). The neural networks of music. Eur J Neurol 9: 449–456. Baharloo S, Johnston PA, Service SK, et al. (1998). Absolute pitch: An approach for identification of genetic and nongenetic components. American journal of human genetics 62: 224–231. Baharloo S, Service SK, Risch N, et al. (2000). Familial aggregation of absolute pitch. American journal of human genetics 67: 755–758. Baumgartner T, Esslen M, Jancke L (2005). From emotion perception to emotion experience: Emotions evoked by pictures and classical music. Int J Psychophysiol 60: 34–43. Bengtsson SL, Nagy Z, Skare S, et al. (2005). Extensive piano practicing has regionally specific effects on white matter development. Nat Neurosci 8: 1148–1150. Blood AJ, Zatorre RJ (2001). Intensely pleasurable responses to music correlate with activity in brain regions implicated in reward and emotion. Proc Natl Acad Sci U S A 98: 11818–11823. Blood AJ, Zatorre RJ, Bermudez P, et al. (1999). Emotional responses to pleasant and unpleasant music correlate with activity in paralimbic brain regions. Nat Neurosci 2: 382–387. Boucher R, Bryden MP (1997). Laterality effects in the processing of melody and timbre. Neuropsychologia 35: 1467–1473. Bouillaud J (1865). Sur la faculte du language articule. Bull Acad Natl Med 30: 752–768. Brazis P, Masdeu J, Biller J (2001). Cranial Nerve VIII. Localization in Clinical Neurology. Lippincott Williams & Wilkins, Philadelphia, pp. 309–329. Brodmann K (1914). Physiologie des Gehirns. Deutsche Verlagsgesellschaft, Stuttgart. Brown S (2000). The ‘musilanguage’ model of music evolution. In: NL Wallin, B Merker, S Brown (Eds.), The Origins of Music. MIT Press, Cambridge, MA, pp. 271–300. Byl NN, Merzenich MM, Jenkins WM (1996). A primate genesis model of focal dystonia and repetitive strain injury: I. Learning-induced dedifferentiation of the representation of the hand in the primary somatosensory cortex in adult monkeys. Neurology 47: 508–520. Caplan D (2001). Functional neuroimaging studies of syntactic processing. J Psycholinguist Res 30: 297–320. Caplan D, Alpert N, Waters G (1999). PET studies of syntactic processing with auditory sentence presentation. Neuroimage 9: 343–351. Cardinal RN, Parkinson JA, Hall J, et al. (2002). Emotion and motivation: The role of the amygdala, ventral striatum, and prefrontal cortex. Neurosci Biobehav Rev 26: 321–352.

THE MUSICAL BRAIN Charness ME, Ross MH, Shefner JM (1996). Ulnar neuropathy and dystonic flexion of the fourth and fifth digits: Clinical correlation in musicians. Muscle Nerve 19: 431–437. Chobor KL, Brown JW (1987). Phoneme and timbre monitoring in left and right cerebrovascular accident patients. Brain Lang 30: 278–284. Cross I (2003). Music as a biocultural phenomenon. Ann NY Acad Sci 999: 106–111. Dalla Bella S, Peretz I, Rousseau L, et al. (2001a). A developmental study of the affective value of tempo and mode in music. Cognition 80: B1–B10. Dalla Bella S, Peretz I, Rousseau L, et al. (2001b). Development of the happy–sad distinction in music appreciation. Does tempo emerge earlier than mode? Ann NY Acad Sci 930: 436–438. Darwin C (1872). The Expression of Emotion in Man and Animals. Murray, London. Deruelle C, Schon D, Rondan C, et al. (2005). Global and local music perception in children with Williams syndrome. Neuroreport 16: 631–634. Dronkers NF, Wilkins DP, Van Valin RD, Jr., et al. (2004). Lesion analysis of the brain areas involved in language comprehension. Cognition 92: 145–177. Elbert T, Candia V, Altenmuller E, et al. (1998). Alteration of digital representations in somatosensory cortex in focal hand dystonia. Neuroreport 9: 3571–3575. Fitch WT (2006). The biology and evolution of music: A comparative perspective. Cognition 100: 173–215. Gaser C, Schlaug G (2003). Gray matter differences between musicians and nonmusicians. Ann NY Acad Sci 999: 514–517. Goldstein A (1980). Thrills in response to music and other stimuli. Physiol Psychol 8: 126–129. Gomez P, Danuser B (2004). Affective and physiological responses to environmental noises and music. Int J Psychophysiol 53: 91–103. Gorno-Tempini ML, Dronkers NF, Rankin KP, et al. (2004). Cognition and anatomy in three variants of primary progressive aphasia. Ann Neurol 55: 335–346. Gregersen PK, Kowalsky E, Kohn N, et al. (1999). Absolute pitch: Prevalence, ethnic variation, and estimation of the genetic component. American journal of human genetics 65: 911–913. Griffiths TD, Warren JD, Dean JL, et al. (2004). ‘When the feeling’s gone’: A selective loss of musical emotion. J Neurol Neurosurg Psychiatry 75: 344–345. Gruhn W, Galley N, Kluth C (2003). Do mental speed and musical abilities interact? Ann NY Acad Sci 999: 485–496. Habib M, Daquin G, Milandre L, et al. (1995). Mutism and auditory agnosia due to bilateral insular damage—role of the insula in human communication. Neuropsychologia 33: 327–339. Hamilton RH, Pascual-Leone A, Schlaug G (2004). Absolute pitch in blind musicians. Neuroreport 15: 803–806. Hashimoto I, Suzuki A, Kimura T, et al. (2004). Is there training-dependent reorganization of digit representations in area 3b of string players? Clin Neurophysiol 115: 435–447.

467

Helmholtz H (1863/1954). On the Sensations of Tone. Dover, New York. Henkel C (1997). The auditory system. In: D Haines (Ed.), Fundamental Neuroscience. Churchill Livingstone, New York, pp. 285–301. Hopyan T, Dennis M, Weksberg R, et al. (2001). Music skills and the expressive interpretation of music in children with Williams–Beuren syndrome: Pitch, rhythm, melodic imagery, phrasing, and musical affect. Child Neuropsychol 7: 42–53. Huron D (2001). Is music an evolutionary adaptation? Ann NY Acad Sci 930: 43–61. Ikoma K, Samii A, Mercuri B, et al. (1996). Abnormal cortical motor excitability in dystonia. Neurology 46: 1371–1376. Jabusch HC, Zschucke D, Schmidt A, et al. (2005). Focal dystonia in musicians: Treatment strategies and longterm outcome in 144 patients. Mov Disord 20: 1623–1626. Janata P, Birk JL, Van Horn JD, et al. (2002). The cortical topography of tonal structures underlying Western music. Science 298: 2167–2170. Jentschke S, Koelsch S, Friederici AD (2005). Investigating the relationship of music and language in children: Influences of musical training and language impairment. Ann NY Acad Sci 1060: 231–242. Johkura K, Matsumoto S, Hasegawa O, et al. (1998). Defective auditory recognition after small hemorrhage in the inferior colliculi. J Neurol Sci 161: 91–96. Johnson JK, Graziano AB (2003). August Knoblauch and amusia: A nineteenth-century cognitive model of music. Brain Cogn 51: 102–114. Keenan JP, Thangaraj V, Halpern AR, et al. (2001). Absolute pitch and planum temporale. Neuroimage 14: 1402–1408. Kelley AE, Bakshi VP, Haber SN, et al. (2002). Opioid modulation of taste hedonics within the ventral striatum. Physiol Behav 76: 365–377. Kester DB, Saykin AJ, Sperling MR, et al. (1991). Acute effect of anterior temporal lobectomy on musical processing. Neuropsychologia 29: 703–708. Khalfa S, Bella SD, Roy M, et al. (2003). Effects of relaxing music on salivary cortisol level after psychological stress. Ann NY Acad Sci 999: 374–376. Khalfa S, Isabelle P, Jean-Pierre B, et al. (2002). Eventrelated skin conductance responses to musical emotions in humans. Neurosci Lett 328: 145–149. Khalfa S, Schon D, Anton JL, et al. (2005). Brain regions involved in the recognition of happiness and sadness in music. Neuroreport 16: 1981–1984. Kim DE, Shin MJ, Lee KM, et al. (2004). Musical traininginduced functional reorganization of the adult brain: Functional magnetic resonance imaging and transcranial magnetic stimulation study on amateur string players. Hum Brain Mapp 23: 188–199. Koelsch S, Friederici AD (2003). Toward the neural basis of processing structure in music. Comparative results of different neurophysiological investigation methods. Ann NY Acad Sci 999: 15–28.

468

B.R. MATTHEWS

Koelsch S, Fritz T, von Cramon DY, et al. (2006). Investigating emotion with music: An fMRI study. Hum Brain Mapp: . Koelsch S, Gunter TC, von Cramon DY, et al. (2002). Bach speaks: A cortical ‘language-network’ serves the processing of music. Neuroimage 17: 956–966. Koelsch S, Gunter TC, Wittfoth M, et al. (2005). Interaction between syntax processing in language and in music: An ERP Study. J Cogn Neurosci 17: 1565–1577. Koelsch S, Kasper E, Sammler D, et al. (2004). Music, language and meaning: Brain signatures of semantic processing. Nat Neurosci 7: 302–307. Levitin DJ (2005). Musical behavior in a neurogenetic developmental disorder: Evidence from Williams syndrome. Ann NY Acad Sci 1060: 325–334. Levitin DJ, Cole K, Chiles M, et al. (2004). Characterizing the musical phenotype in individuals with Williams Syndrome. Child Neuropsychol 10: 223–247. Levitin DJ, Menon V (2003). Musical structure is processed in ‘language’ areas of the brain: A possible role for Brodmann Area 47 in temporal coherence. Neuroimage 20: 2142–2152. Lewis JW, Wightman FL, Brefczynski JA, et al. (2004). Human brain regions involved in recognizing environmental sounds. Cereb Cortex 14: 1008–1021. Liegeois-Chauvel C, Musolino A, Chauvel P (1991). Localization of the primary auditory area in man. Brain 114: 139–151. Liegeois-Chauvel C, Peretz I, Babai M, et al. (1998). Contribution of different cortical areas in the temporal lobes to music processing. Brain 121: 1853–1867. Mackworth-Young CG (1983). Sequential musical symptoms in a professional musician with presumed encephalitis. Cortex 19: 413–419. Maess B, Koelsch S, Gunter TC, et al. (2001). Musical syntax is processed in Broca’s area: An MEG study. Nat Neurosci 4: 540–545. Marins EM (2002). Maurice Ravel and right hemisphere creativity. Eur J Neurol 9: 320–321. Mazziotta JC, Phelps ME, Carson RE, et al. (1982). Tomographic mapping of human cerebral metabolism: Auditory stimulation. Neurology 32: 921–937. Mendez MF, Geehan GR, Jr. (1988). Cortical auditory disorders: Clinical and psychoacoustic features. J Neurol Neurosurg Psychiatry 51: 1–9. Menon V, Levitin DJ (2005). The rewards of music listening: Response and physiological connectivity of the mesolimbic system. Neuroimage 28: 175–184. Ohnishi T, Matsuda H, Asada T, et al. (2001). Functional anatomy of musical perception in musicians. Cereb Cortex 11: 754–760. Overy K (2003). Dyslexia and music. From timing deficits to musical intervention. Ann NY Acad Sci 999: 497–505. Panksepp J (1986). The neurochemical control of behavior. Annu Rev Psychol 37: 77–107. Panksepp J (1995). The emotional sources of ‘chills’ induced by music. Music Perception 13: 171–207.

Panksepp J, Bernatzky G (2002). Emotional sounds and the brain: The neuro-affective foundations of musical appreciation. Behav Processes 60: 133–155. Pantev C, Hoke M, Lehnertz K, et al. (1988). Tonotopic organization of the human auditory cortex revealed by transient auditory evoked magnetic fields. Electroencephalogr Clin Neurophysiol 69: 160–170. Pantev C, Oostenveld R, Engelien A, et al. (1998). Increased auditory cortical representation in musicians. Nature 392: 811–814. Pantev C, Roberts LE, Schulz M, et al. (2001). Timbre-specific enhancement of auditory cortical representations in musicians. Neuroreport 12: 169–174. Parsons LM (2001). Exploring the functional neuroanatomy of music performance, perception, and comprehension. Ann NY Acad Sci 930: 211–231. Pascual-Leone A (2001). The brain that plays music and is changed by it. Ann NY Acad Sci 930: 315–329. Patel AD (2003). Language, music, syntax and the brain. Nat Neurosci 6: 674–681. Peretz I (1990). Processing of local and global musical information by unilateral brain-damaged patients. Brain 113: 1185–1205. Peretz I (1993). Auditory atonalia for melodies. Cogn Neuropsychol 10: 21–56. Peretz I, Champod AS, Hyde K (2003). Varieties of musical disorders. The Montreal Battery of Evaluation of Amusia. Ann NY Acad Sci 999: 58–75. Peretz I, Coltheart M (2003). Modularity of music processing. Nat Neurosci 6: 688–691. Peretz I, Gagnon L, Bouchard B (1998). Music and emotion: Perceptual determinants, immediacy, and isolation after brain damage. Cognition 68: 111–141. Peretz I, Kolinsky R, Tramo M, et al. (1994). Functional dissociations following bilateral lesions of auditory cortex. Brain 117: 1283–1301. Pinker S (1997). How the Mind Works. W.W. Norton, New York. Platel H, Price C, Baron JC, et al. (1997). The structural components of music perception. A functional anatomical study. Brain 120: 229–243. Polk M, Kertesz A (1993). Music and language in degenerative disease of the brain. Brain Cogn 22: 98–117. Pujol J, Roset-Llobet J, Rosines-Cubells D, et al. (2000). Brain cortical activation during guitar-induced hand dystonia studied by functional MRI. Neuroimage 12: 257–267. Quoniam N, Ergis AM, Fossati P, et al. (2003). Implicit and explicit emotional memory for melodies in Alzheimer’s disease and depression. Ann NY Acad Sci 999: 381–384. Ragert P, Schmidt A, Altenmuller E, et al. (2004). Superior tactile performance and learning in professional pianists: Evidence for meta-plasticity in musicians. Eur J Neurosci 19: 473–478. Rauscher FH, Shaw GL, Ky KN (1995). Listening to Mozart enhances spatial–temporal reasoning: Towards a neurophysiological basis. Neurosci Lett 185: 44–47.

THE MUSICAL BRAIN Rauscher FH, Shaw GL, Levine LJ, et al. (1997). Music training causes long-term enhancement of preschool children’s spatial–temporal reasoning. Neurol Res 19: 2–8. Rentfrow PJ, Gosling SD (2003). The do re mi’s of everyday life: The structure and personality correlates of music preferences. J Pers Soc Psychol 84: 1236–1256. Ridding MC, Sheean G, Rothwell JC, et al. (1995). Changes in the balance between motor cortical excitation and inhibition in focal, task specific dystonia. J Neurol Neurosurg Psychiatry 59: 493–498. Roederer J (1984). The search for a survival value of music. Music Perception 1: 350–356. Ross DA, Olson IR, Gore JC (2003). Absolute pitch does not depend on early musical training. Ann NY Acad Sci 999: 522–526. Sakai K, Hikosaka O, Miyauchi S, et al. (1999). Neural representation of a rhythm depends on its interval ratio. J Neurosci 19: 10074–10081. Samson S (2003). Neuropsychological studies of musical timbre. Ann NY Acad Sci 999: 144–151. Samson S, Zatorre RJ (1994). Contribution of the right temporal lobe to musical timbre discrimination. Neuropsychologia 32: 231–240. Samson S, Zatorre RJ, Ramsay JO (2002). Deficits of musical timbre perception after unilateral temporal-lobe lesion revealed with multidimensional scaling. Brain 125: 511–523. Sapolsky RM (1996). Stress, glucocorticoids, and damage to the nervous system: The current state of confusion. Stress 1: 1–19. Schlaug G (2001). The brain of musicians. A model for functional and structural adaptation. Ann NY Acad Sci 930: 281–299. Schlaug G, Jancke L, Huang Y, et al. (1995a). Increased corpus callosum size in musicians. Neuropsychologia 33: 1047–1055. Schlaug G, Jancke L, Huang Y, et al. (1995b). In vivo evidence of structural brain asymmetry in musicians. Science 267: 699–701. Schulz M, Ross B, Pantev C (2003). Evidence for traininginduced crossmodal reorganization of cortical functions in trumpet players. Neuroreport 14: 157–161. Schuppert M, Munte TF, Wieringa BM, et al. (2000). Receptive amusia: Evidence for cross-hemispheric neural networks underlying music processing strategies. Brain 123 : 546–559. Seashore C, Lewis D, Saetveit JG (1960). Manual of Instructions and Interpretations for the Seashore Measures of Musical Talents. Psychological Corporation, New York.

469

Siegwart H, Scherer KR (1995). Acoustic concomitants of emotional expression in operatic singing: The case of Lucia in Ardi gli incensi. J Voice 9: 249–260. Tanaka Y, Yamadori A, Mori E (1987). Pure word deafness following bilateral lesions. A psychophysical analysis. Brain 110: 381–403. Tramo MJ, Bharucha JJ, Musiek FE (1990). Music perception and cognition following bilateral lesions of auditory cortex. J Cogn Neurosci 2: 195–212. Tramo MJ, Cariani PA, Delgutte B, et al. (2001). Neurobiological foundations for the theory of harmony in western tonal music. Ann NY Acad Sci 930: 92–116. Tramo MJS, Shah GD, Braida LD (2002). Functional role of auditory cortex in frequency processing and pitch perception. J Neurophysiol 87: 122–139. Tsang CD, Trainor LJ, Santesso DL, et al. (2001). Frontal EEG responses as a function of affective musical features. Ann NY Acad Sci 930: 439–442. Turk I (1997). Mousterian ‘Bone Flute’ and Other Finds from Divje Babe 1 Cave Site in Slovenia. Zalozba ZRC, Ljubljana. Tzortzis C, Goldblum MC, Dang M, et al. (2000). Absence of amusia and preserved naming of musical instruments in an aphasic composer. Cortex 36: 227–242. US Census Bureau (2006). US Census Bureau Abstract of the United States, p. 9. Vignolo LA (2003). Music agnosia and auditory agnosia. Dissociations in stroke patients. Ann NY Acad Sci 999: 50–57. Warren J (2004). The Amusias. In: FC Rose (Ed.), Neurology of the Arts. Imperial College Press, London, pp. 275–305. Wertheim N (1969). The amusias. In: PJ Vinken, A Brun (Eds.), Handbook Of Clinical Neurology. John Wiley & Sons, New York, pp. 195–206. Wertheim N, Botez MI (1961). Receptive amusia: A clinical analysis. Brain 84: 19–30. Zatorre RJ, Evans AC, Meyer E (1994). Neural mechanisms underlying melodic perception and memory for pitch. J Neurosci 14: 1908–1919. Zatorre RJ, Evans AC, Meyer E, et al. (1992). Lateralization of phonetic and pitch discrimination in speech processing. Science 256: 846–849. Zatorre RJ, Perry DW, Beckett CA, et al. (1998). Functional anatomy of musical processing in listeners with absolute pitch and relative pitch. Proc Natl Acad Sci USA 95: 3172–3177. Zhang M, Balmadrid C, Kelley AE (2003). Nucleus accumbens opioid, GABAergic, and dopaminergic modulation of palatable food motivation: Contrasting effects revealed by a progressive ratio study in the rat. Behav Neurosci 117: 202–211.

Handbook of Clinical Neurology, Vol. 88 (3rd series) Neuropsychology and behavioral neurology G. Goldenberg, B.L. Miller, Editors # 2008 Elsevier B.V. All rights reserved

Chapter 24

Visual art and the brain ANLI LIU AND BRUCE L. MILLER* Memory and Aging Center, University of California, San Francisco, CA, USA

24.1. What is art? Uniquely human, art, language, and music represent the highest forms of creativity of our species. Art, in contrast to language and music, has proven difficult to study and the neurological underpinnings of art appreciation and production are still poorly understood. Our prehistoric ancestors began to cover the walls of caves with pictures of animals as early as 40,000 years ago suggesting something very old, intrinsic, and universal about our capacity for art (Harth, 1999; Janson and Janson, 1997; Miller and Hou, 2004). Despite the fact that these paintings were produced by humans living in a very different cultural milieu, it is easy for even the most modern of humans to appreciate these early efforts at art. What is art? While artistic preferences are steeped in culture, our discussion must begin with a common agreement about the core features of visual art. In the History of Art, Janson and Janson propose that the art begins with a mental image, be it either realistic or improbable, past or present (Janson and Janson, 1997). During the creative process, the artist manipulates materials to actualize this mental image. This aspect of ‘human intervention’ distinguishes natural objects such as flowers or landscape from art, unless they are purposefully exhibited as objects worthy of special consideration (e.g., found art). Manipulation of images occurs within the mind as well as with material. Furthermore, like language, art is a means of communication. Art delivers messages and impressions that cannot be expressed through words alone. Finally, art is original. The originality of the work is what separates art from craft—the latter can be mass produced. As truly original art only declares itself over time, this quality is often the most difficult feature to determine (Janson and Janson, 1997). *

Chatterjee (2004) proposes a framework for understanding artwork, and by extension, how it changes. The first axis involves purpose and may be either descriptive or expressive. In any given work, an artist may choose to accurately represent the real world or communicate an internal state. Both are valid goals and have been more or less celebrated in art history. The entire brain participates in the production of an artistic piece, but research suggests that the process of copying an ‘accurate representation of the real world’ relies strongly on the nondominant parietal lobe, while pulling up internal images activates memory systems in the temporal areas. The second axis describes the content matter, which may be more perceptual or conceptual in scope. Perceptually based content includes more sensory information, including light, color, form, texture, faces, and scenes. Conceptually based content, on the other hand, may be abstracted, symbolic, and simplified. This division between perception and concept contrasts the strengths of the nondominant versus the dominant hemisphere. In relation to the above definition of art, our goal is to articulate the state of the research on visuospatial perception, visual imagery, motor memory, and interest as it applies to the artistic process, through the lens of lesion studies and different categories of neurodegenerative illness. While the primary goal of this chapter is not to explain the cognitive basis of visual processing, it is important to discuss the visual systems used by artists as they conceptualize and then produce an artistic product.

24.2. The nature of research on art and the brain The fields of neurology, psychology, psychiatry, and cognitive science lend diverse and complementary

Correspondence to: Bruce L. Miller, MD, A.W. & Mary Margaret Distinguished Professor, UCSF Department of Neurology, Memory and Aging Center, 350 Parnassus Ave., Box 1207, Suite 706, San Francisco, CA 94143–1207, USA. E-mail: bmiller@ memory.ucsf.edu, Tel: 415-476-6880, Fax: 415-476-4800.

472

A. LIU AND B.L. MILLER

perspectives on art and the brain. The bulk of our understanding rests upon case reports of artists and non-artists who suffer from localized brain injury. Some argue that following the natural history of established artists provides a richer understanding of the neurological substrate of art-making (Marsh and Philwin, 1978; Kaplan and Gardner, 1989). Indeed, preand postmorbid comparisons can be more readily made in this cohort. With structural and functional imaging it is now possible to study brain activity and structure as it develops normally in an artist. Yet much of what we have learned about art and the brain still comes from the compelling stories of artists and non-artists who have had focal brain injuries that have influenced their visual creativity. Additionally, there have been numerous case reports of non-artists, usually with left frontal or temporally predominant brain degeneration, who demonstrate a newfound interest in the visual arts. The case-based nature of the bulk of the research has certain limits. Perhaps most importantly, humans vary enormously regarding their premorbid ability to produce and understand art. This is particularly evident when trying to compare a talented artist to an individual who lacks visual artistic ability. Individual variability has made it difficult to produce standardized batteries that quantify art in the same way that aphasia batteries have been organized. Also, localization of specific brain regions to art is limited by the variations in human neuroanatomy. For example, V5 motion area varies by as much as three centimeters in location from one person to another. Furthermore, much variation in cerebrovascular territories exists (Watson et al., 1993). Finally, some degree of subjectivity in interpretation is inherent in research on art and the brain. For example, over 150 physicians and art historians have retrospectively diagnosed Vincent van Gogh (1853– 1890) with temporal lobe epilepsy, Meniere’s disease, porphyria, depression, bipolar illness, and absinthe poisoning, to name a few (Arenberg et al. 1991; Morrant, 1993; Blumer, 2002).

unskilled artists and children have a preconceived notion of a table: a rectangle with one leg attached to each of its four corners. Thus, the novice may draw a flat representation of the table, with little regard to foreshortening or perspective. However, trained artists not only have an abundance of schemas but have acquired a set of skills that allow them to draw more flexibly, even when faced with novel stimuli (Wapner et al., 1978). Snyder and colleagues have suggested that the linguistic layering and labeling of objects in the world prevents non-artists from seeing the visual world as it is (Snyder and Thomas, 1997; Snyder et al., 2003). Paradoxically, learning how to become an artist requires the unlearning of these verbal and symbolic approaches to perception. Snyder’s theory may partially explain the emergence of visual creativity in the setting of semantic dementia, a degenerative disorder of the left anterior temporal lobe where semantic knowledge of the world disintegrates (Miller et al., 1996). Similarly, his theory yields insight into the behavior of artistic savants, who are prolific in visual expression but devastated in linguistic skills. A basic assumption of neuroscience is that learning a skill leads to specific neuroanatomical and neurophysiological brain changes. An EEG study comparing professional artists and laymen showed significantly stronger delta band synchronization between frontal and temporo-occipital electrodes in the former group. Nonartists however, only showed enhancement in gamma band synchronization primarily in frontal regions. Together, these findings suggest that artists may display greater functional cooperation between cortical regions and that the prefrontal cortex plays an important role in creative tasks (Bhattacharya and Petsche, 2005). Consistent with popular belief, strong right hemispheric dominance in terms of synchronization was also found among the artists (Bhattacharya and Petsche, 2005).

24.3. How do artists differ from non-artists?

Because of the limits of imaging at the time, early research could only make crude associations between lesion site and functional deficits. However, lesion and dementia studies from the 1970s to the present offer a valuable window into the relative hemispheric contribution to artistry, particularly the relationship between details versus form. As early as 1948, Alajouanine recognized the hemispheric specialization for linguistic, musical, and visual arts (Alajouanine, 1948). He described a writer (Valery Larbaud), a musician (Ravel), and an artist, each with devastating injury to the dominant (left) hemisphere. For the writer and musician, the dominant hemisphere injury had a devastating and permanent

In distinguishing the novice from the expert artist, it may be helpful to describe what happens during art training. Just as learning syntax and grammar is essential to good writing, acquiring basic perceptual skills is foundational to making art. In fact, for art educators, one of the most persistent problems in teaching students how to draw is encouraging them to draw what they see instead of what they think they see. Edwards calls this challenge ‘overcoming the tenacious set of symbols or schemata that every person develops from the age of three and ten (Edwards, 1988).’ For example, most

24.4. Hemispheric contributions to art-making

VISUAL ART AND THE BRAIN effect, while for the artist the effect was minimal. Fiftyseven years later, Boller (2005) identified the artist as Paul-Elie Gernex and confirmed that the aphasia did not stop painting. However, poststroke work appeared less poetic and spontaneous. The story of hemispheric specializations for art is quite complex. 24.4.1. Details vs. form Beginning with German neurologist Richard Jung’s collection of the work of four major German artists who suffered from right hemisphere injury (Jung, 1974), there have been several studies comparing patients with isolated hemispheric damage. Not surprisingly, patients with left-brain damage (LBD) produced drawings with a relative neglect of the (right) side of the canvas. Also, they tended to draw in a more simplistic and primitive manner. Contours were favored over details and their work was compared to children’s drawings. A preserved right hemisphere appears capable of maintaining the overall gestalt in drawing (Gardner, 1982; Kaplan and Gardner, 1989). In contrast, patients with right-brain damage (RBD) lost the overall contour of the subject matter but demonstrated fastidious attention to detail. Their drawings appeared more scattered, fragmented, and disorganized as a whole (Kaplan and Gardner, 1989; Gardner, 1982; Swindell et al., 1988). In another study of a visual artist with a right hemisphere stroke, the loss of the ability to draw and profound neglect was accompanied by the appearance of words onto pictures (Schnider et al., 1993). Together, these studies support Kaplan’s theory that the left hemisphere attends to details while the right hemisphere perceives the overall form and composition of the subject (Kaplan, 1980). Furthermore, in a task calling subjects to categorize artwork, aphasic patients were better at grouping paintings by artistic style. On the other hand, right-sided injury patients tended to group by subject matter (Gardner, 1975). Of related interest, one longitudinal study found that the LBD group recovered more rapidly and completely than RBD patients, as evidenced by their steady improvement in drawing (Swindell et al., 1988). Jung’s four German painters also demonstrated a definite shift in style with the onset of right-hemisphere damage (Jung, 1974; Gardner, 1982). As exemplified by the German painter Anton Ra¨derscheidt’s (1892–1970) self portraits made before and after his right-sided stroke, paintings become more free and expressive. Critics noted a similar shift in style of another famous German painter and printer Lovis Corinth (1858– 1925), but attributed the change to psychological reasons. More likely, the shift was due to the righthemisphere stroke he sustained in 1911 (Jung, 1974;

473

Gardner, 1982). Other examples of artists who demonstrated a shift in style include Reynold Brown, whose artwork was exhibited and discussed at an ‘Art and the Brain’ symposium in Chicago, 1994, and Loring Hughes (Heller, 1994). Gardner suggests such stylistic transformation may be due to ‘the release of an inhibitory mechanism’ (Gardner, 1982). Color perception is discussed in more detail later in this chapter, but its relevance to hemispheric specialization is noted here. In a comprehensive study of color deficits following right versus left brain injury, De Renzi and Spinnler (1967) demonstrated that patients with right brain damage were more likely to demonstrate deficits in color perception (dyschromatopsia), while patients with left brain injury demonstrated more problems with color naming and with conjuring up an image of object’s colors. The influence of these primary deficits on the production of paintings remains unknown. 24.4.2. Symbolic art The devastation of copying and realistic art with right hemisphere injury is well-established, but there is little research on the types of deficits that are seen when artists suffer left brain injury. In one study, Kaczmarek described a highly symbolic abstract artist who suffered a dominant hemisphere stroke (1991). This individual was able to successfully carry out accurate copies of visual scenes, but completely lost his ability to produce symbolic work. As will be discussed, patients with left anterior temporal or left frontal lobar degeneration lose symbolic components of language yet often produce elegant realistic or surrealistic art. Additionally, several studies suggest that left hemisphere lesions may be associated with loss of primary visual functions that could impair the artistic process. Bay (1962), Gainotti et al. (1983), and Goldenberg et al. (2003) reported that aphasic patients had difficulty with drawing objects from memory. 24.4.3. Distribution of function between left and right hemispheres In summary, lesion studies demonstrate that the left hemisphere attends to symbolic meaning in artwork, tends to appreciate art by its literal meaning or subject matter, and focuses on the detail of the subject matter. The right hemisphere, in contrast, perceives overall form and composition of the subject matter and responds to and generates the style of artwork. However, there is some evidence for handedness affecting the distribution of function between hemispheres. In general, left-handers appear to be

474

A. LIU AND B.L. MILLER

over-represented among visual artists suggesting a hemispheric advantage for spatial tasks in this group (Peterson, 1979). In MRI-based studies of brain volumes related to handedness, left-handers tend to have a more symmetrical brain in the temporal lobe regions (Geschwind et al., 2002), raising the intriguing possibility of symmetry offering an advantage in the visual tasks associated with art. 24.4.4. The nature of neglect Neglect following right hemisphere stroke, usually centered in the inferior parietal or superior temporal areas, is a fairly well-documented phenomenon (Vallar, 1993; Karnath et al., 2001; Bartolomeo and Chokron, 2002). One study cites unilateral neglect in over 80% of patients with acute right hemisphere stroke. Defined as failure to attend to objects in the left field of view, the disorder is usually associated with a poor prognosis (Roberson and Marshall, 1993; Halligan and Marshall, 1997). Furthermore, neglect may be person-centered or object-centered (Chatterjee, 1994; Ota et al., 2001). In person-centered neglect, the left side of the field of view in relation to the patient is relatively ignored, whereas in object-centered neglect, the left side of each object is overlooked. The famous filmmaker Federico Fellini, also a distinguished painter and cartoonist, suffered a right parietal stroke which left him with a left-field visual neglect (Cantagallo and Della Sala, 1998). When given linebisection drawing tasks, he demonstrated more stimulus-bounded neglect, whereas another patient with more anterior-medial damage demonstrated person-centered neglect (Ota et al., 2001). For example, he would always draw on the right side of the line (Fig. 24.1B). Unlike many of the other artists that Jung studied with righthemisphere strokes, Fellini was unique in his awareness of his deficit. In fact, a few of his cartoons feature characters that cleverly demonstrate his insight (Fig. 24.1A and C). Fellini’s performance on visuospatial tasks and preserved insight suggest that his stroke left him with relative impairment of this visuospatial working memory but spared his long-term visual memory, suggesting that these two functions exist independently. However, another interpretation may be that he suffered from hemianopia, not hemineglect. Other artists who have suffered right hemispheric strokes and exhibited left-sided field deficits include German realist painter Anton Ra¨derscheidt, German painter and printer Lovis Corinth, German painter and draftsman Otto Dix, British painter and sculptor Tom Greenshields, and Italian painter Guglielmo Lusignoli. Lovis Corinth (1858–1925) for example, continued to paint portraits after his stroke, but with missing or

displaced contours and details on the left side of the canvas (Chatterjee, 1994). Halligan and Marshall (1997) report another 75-year-old painter and sculptor with a right hemisphere stroke and resulting left-sided neglect. Not only did he demonstrate space-based and object-based neglect in his drawing, but also in his sculpting (Fig. 24.2). In comparison to the high degree of representational likeness that the patient’s premorbid life sculptures demonstrated, his postmorbid sculptures revealed a clumsily articulated, poorly formed left side, even though he could rotate his work on a turnstile. His example demonstrates that neglect can occur in three-dimensional space as well (Chatterjee, 2004). Like Fellini, this artist was frustrated with his postmorbid work, revealing an awareness of his deficits. While there remained traces of the hemineglect in his later sculptures, the artist’s greatest deficits eventually resolved. With these two exceptional case studies of artists demonstrating gradual improvement, one wonders whether the process of making art can facilitate recovery. There are no definitive studies to suggest that art therapy is an effective way to treat right or left brain injury. However, more formal controlled studies are underway. There are a few case studies suggesting that representational and visuospatial neglect are two distinct deficits, presumably caused by two anatomically distinct lesions (Marshall and Halligan, 1993). In Bisiach and Luzzatti’s case study (1978), two Italian subjects with left unilateral neglect were asked to recall a familiar place, the Piazza del Duomo in Milan. First these subjects were asked to pretend that they were looking toward the Duomo. They enthusiastically and elaborately describe the shops and landmarks from the right side of the square, but not from the left side. When the subjects were asked to pretend that they were at the Duomo and looked toward the town, they described the side of the road (previously left but now right) that they had previously neglected and neglected the side that they had previously described. Guariglia et al. report a 59-year-old right-handed man with a stroke in the right frontal area who demonstrated left-sided neglect when asked to perform an imagery task, but not when asked to perform visual tasks. Finally, a third case study reported a professional cartoonist who produced a whole image when drawing from memory, but neglected the left side when drawing from life (Halligan et al., 2003). Taken together, these studies suggest that the ability to imagine a scene exists separately from the ability to perceive a scene, such that hemineglect can affect the two independently. Most case studies of neglect have been in right-brain damaged patients. Bartolomeo and colleagues’ quantitative studies of neglect concluded that most patients

VISUAL ART AND THE BRAIN

475

Fig. 24.1. This triad of Fellini’s cartoons demonstrates the nature of his left-sided neglect, as well as his insight into his deficit. (A) The man, running to the left side of the page, shouts, ‘Where is the left?’ (B) All of his characters fall to the right side of the line. (C) An elephant, drawn on the left side of the page, exclaims to the man sitting on the right side, ‘Can I stay here, doctor?’ Notice that the defining feature of the elephant, its trunk, is missing from the left side. (Reprint with permission from Cortex, Cantagallo and Della Sala (1998), Figs. 3a, 6, 9).

experienced only isolated visuospatial neglect and that representational neglect tends to occur in only righthemisphere injured patients (Bartolomeo et al., 1994). The severe left-sided neglect that RBD patients experience may explain Marr’s observation of these patients’ difficulty depicting items in three dimensions (Marr, 1982). Patients with left-hemisphere injury do not experience the same severity of neglect (Kaplan and Gardner, 1989). There is one case report of an artist with right-sided neglect, caused by a left-hemisphere stroke

(Peru and Pinna, 1997). Furthermore, one study in humans suggests that the right superior temporal cortex is the key neuroanatomical site for spatial neglect, not the posterior parietal lobe (Karnath et al., 2001).

24.5. The neuroanatomy of visual imagery and color imagery The cerebral processing of visual information occurs in two pathways. The first carries information from the

476

A. LIU AND B.L. MILLER

Fig. 24.2. Demonstrates the painter and sculptor described in Halligan and Marshall’s case study before (A) and after a right hemisphere stroke (B). The left side of the postmorbid sculpture, as seen by the patient and viewer, is less well-formed than the right side, and the entire work is a more crude representational style than the premorbid bust. (C) Drawing made after the same artist’s stroke. (Reprinted from Halligan and Marshall (1997), with permission from Elsevier.)

VISUAL ART AND THE BRAIN retina to the lateral geniculate nucleus and finally to the striate cortex (area V1), located in the calcarine fissure of the occipital lobes. Lesions in the optic tracts or the striate cortex produce predictable topographic deficits in the contralateral hemifield. The second pathway begins from the striate cortex and radiates out into multiple inter-related areas of the extrastriate cortex. Over 40 specialized extrastriate regions have been identified in the monkey. These regions are responsible for highly specific aspects of the visual experience—including color, shape, and face recognition (Barton, 2004). Within the extrastriate cortex, intact visual perception requires the functioning of two visual streams: the ventral stream, responsible for recognizing ‘what’ is seen, and the dorsal stream, responsible for recognizing ‘where’ subjects are perceived (Ungerleider and Mishkin, 1982; Goodale, 1993; Goodale and Westwood, 2004). This separation of visual function suggests two anatomically distinct pathways of vision. 24.5.1. Ventral stream The ventral stream projects from the striate to temporal cortex (Goodale and Westwood, 2004; Barton, 2004). This pathway encodes the enduring characteristics of objects, thereby permitting long-term identification and recognition (Goodale and Westwood, 2004). Whether an artist is drawing in representational fashion or is culling from the bank of images stored over a lifetime to produce abstract or symbolic work, an intact ventral stream is needed to perceive these subjects. Visual perception must be able to divorce the spatial placement and metric information from the essential characteristics of the object itself. Damage to the ventral stream produces problems such as agnosia and dyschromatopsia. 24.5.1.1. Damage to the ventral stream—agnosia Visual agnosia is the inability to recognize an object by sight in the setting of relatively spared vision. Patients lose understanding of the seen object’s context or use (Barton, 2004). In contrast, these patients often identify objects presented to them in a tactile or auditory manner (Barton, 2004). One 73-year-old left-handed male artist described by sustaining an occipital infarction in the 1970s developed a visual agnosia (Wapner et al., 1978). The deficits suggested by his presentation and initial imaging suggest a deficit mainly in the left occipitoparietal region, in the region of the left posterior cerebral artery and possibly the right posterior cerebral artery (Chatterjee, 2004). The patient was unable to recognize faces and approximately 75% of the inanimate objects presented to him. Without a sense of the meaning of the subject matter,

477

he tended to focus on drawing its details instead of its defining features (Fig. 24.3). He often lost his place while drawing. To compensate, he would describe the object aloud to try and deduce the identity of the object. However, when asked to draw an object he recognized, he no longer maintained the same fastidious attention to detail. Interestingly, despite his stroke, his pre- and postmorbid drawings retained the same style. He maintained the same techniques of perspective, shadowing, and texture to copy designs and objects with good accuracy. This patient’s course suggests that his visual agnosia was associated with deficits in visual imagery and visual memory. However, visuomotor and verbal pathways were preserved and activated as part of a compensatory process (Chatterjee, 2004). There are a number of reports of a double dissociation between visual perception and imagery. One 34year-old patient who suffered focal cortical damage in the ventral portion of the lateral occipital region (primarily in Brodmann’s areas 18 and 19), also exhibited extreme deficits in visuospatial perception but had relatively spared visual imagery (Servos and Goodale, 1995). She had difficulty recognizing objects when presented as line drawings, but could draw common objects and write the alphabet from memory. Furthermore, the patient reported vivid visual dreams with well-structured objects (Servos et al., 1993; Servos and Goodale, 1995). Another interesting dissociation was the patient’s preserved ability to use perception to make skilled grasping motions (i.e., adjusting her hand to the appropriate width and position). In two remarkable case studies, Goldenberg and colleagues explored two patients with cortical blindness, one with loss of both visual imagery and visual knowledge (Goldenberg, 1992) and the other with complex and vivid visual imagery in whom visual loss was profound (Goldenberg et al., 1995). The second case strongly suggests that visual imagery can occur independent of an intact primary visual cortex. Additionally, preservation of visual imagery and visuomotor memory lends theoretical support to the idea of the ventral and dorsal stream as the perception vs. action stream. Based on the relative functional deficits of the patient and her neuroanatomical lesions, Servos and Goodale (1995) suggest the occipitotemporal pathway’s central importance in generating visual images. One SPECT regional cerebral blood flow study lends evidence that visual imagery is associated with increased blood flow in the left inferior occipital and left thalamic regions (Goldenberg et al., 1991). From this case study and other research in monkeys, Servos and Goodale also suggest that the posterior parietal system, the ‘action stream,’ may be further divided into two functional regions. The superior parietal system may

478

A. LIU AND B.L. MILLER

Fig. 24.3. Wapner et al. describe an artist who developed a visual agnosia following a left occipitoparietal stroke. (A) Demonstrates the overriding attention paid to detail, such that the overall contour of the object is lost. Nevertheless, techniques such as perspective and shading are maintained (e.g., the legs are rendered differently such that leg drawn on the right side of the page demonstrates foreshortening). (B) Similarly shows the preference of detail over gestalt, such that the various parts of the airplane are detached from the body, and the nose of the machine is entirely missing. (Reprinted with permission from Cortex, Wapner et al. (1978), Figs. 3 and 6.)

be more responsible for visuomotor control, and the ventral regions more responsible for mental manipulation of objects (Servos and Goodale, 1995). Taken together, the research suggests that the bank of visual imagery exists separately from visual perception. Theoretically, artists and patients with new deficits in their visual pathways may still produce art from mental imagery. New avenues of research might compare the breadth of visual imagery of people who are blinded at birth or during childhood to professional artists. 24.5.1.2. Damage to the ventral stream— dyschromatopsia Oliver Sacks, the well known neurologist and writer, describes an artist who developed achromatopsia after brain trauma (Sacks, 1995). Patients with cerebral achromatopsia can suffer deficits in both hue and saturation, viewing the world in shades of gray. Other kinds of disturbance in color perception include dyschromatopsia, or a reduced ability to perceive hue. Some people report seeing the world through a colored filter or see color spilling beyond its object boundaries.

Finally, hemiachromatopsia, or decreased color perception in the contralateral hemifield, is typically asymptomatic and therefore underdiagnosed (Zeki, 1990; Rizzo et al., 1993; Merigan et al., 1997). Which regions of the brain appear to be involved in color recognition and imagery? Lesions in the lingual and fusiform gyri have been associated with achromatopsia. Functional MRI has confirmed the participation of the middle third of the lingual gyrus or white matter behind the posterior tip of the lateral ventricle to be involved in normal color perception. A unilateral lesion would be associated with a hemiachromatopsia, whereas a bilateral lesion would be necessary for a complete achromatopsia. The latter is most parsimoniously caused by a PCA infarct (Zeki, 1990; Rizzo et al., 1993; Merigan et al., 1997). A few case reports suggest that the ability to imagine color exists separately from the ability to perceive it (Shuren et al., 1996; Bartolomeo et al., 1997; 1998). One 63year-old right-handed man with bilateral infarcts of the temporo-occipital region, affecting the lingual and fusiform gyri, developed a verbal and nonverbal amnesia as well as a significant deficit in color perception. However,

VISUAL ART AND THE BRAIN he did well on tasks that required him to name the color of objects with uncommon color associations (e.g., ‘Color of a US postal mailbox?’), compare verbal pairs of colors (e.g., ‘Which has more red in it, plum or eggplant?’), and distinguish the member in a verbal triad with dissimilar color (Shuren et al., 1996). Generally speaking, assessment of a patient’s color imagery, or memory for color, is difficult because common associations exist between certain objects and color (e.g., ‘apples are red’). As in the story behind visual imagery, the research suggests the existence of both a top-down and bottom-up process for color imagery and perception. The two processes can be dissociated. In most cases, patients who develop achromatopsia are left with a permanent deficit, but most employ compensatory strategies in visual tasks. 24.5.2. Dorsal stream The dorsal stream, running from the striate cortex to the occipitoparietal region, processes spatial relationships between objects (Goodale and Westwood, 2004; Barton, 2004). Because movement requires such visuospatial information, another name for this pathway is the ‘action’ stream. Damage to the dorsal stream produces defects such as akinetopsia (inability to perceive moving objects, despite ability to see stationary ones), optic ataxia (the inability to reach for an object despite being able to see it), ocular apraxia (inability to move one’s eyes toward an object despite possessing full range of eye movements and normal visual fields), and simultanagnosia (inability to recognize the whole despite perceiving the details), or a combination of the three, as seen in Ba´lint’s syndrome (Smith et al., 2003; Barton, 2004). Artists may use information from the dorsal stream to think about composition, or the placement of an object on the page and its relationship to other objects on the page. Injury to the dorsal stream may decrease the artist’s ability to perceive relationships between objects within the field of view (Smith et al., 2003). 24.5.2.1. Damage to the dorsal stream— simultanagnosia Simultanagnosia is the inability to process a complex scene, despite being able to attend to individual elements. Neuroimaging suggests that simultanagnosia may be related to lesions in Brodmann’s areas 18 and 19 of the dorsal occipital lobes (Rizzo and Robin, 1990), although prefrontal damage has also been associated with an inability to interpret complex scenes. In one case study, an 87-year-old artist sustaining a top-of-the-basilar artery embolic stroke, resulting in a posterior circulation defect, developed a simultanagnosia with no associated field deficits or hemineglect. In the

479

immediate period following her stroke, her paintings and drawings of the same flowers-in-vase still life reveal a selective attention to parts of the still life, with less attention given to background. Two years after her stroke, she had made a full recovery and was painting in similar fashion to her premorbid state, incorporating the entire still life and rich background into her work (Smith et al., 2003).

24.6. Art in neurodegenerative disease, savants, and migraine 24.6.1. Alzheimer’s disease The most common form of dementia in the aging population, Alzheimer’s disease (AD), is characterized by deterioration in memory, language, and visuospatial ability (Cummings, 2004). The inability to recognize faces or to read an analog clock represent typical daily deficits that occur from loss of visuospatial function characteristic of AD. In a comparison of thirty AD patients with controls, Mendez and colleagues found that AD patients showed preserved visual acuity and color recognition, but decreased ability to visually recognize common objects and famous faces, make figure–ground distinctions, and evaluate complex figures (Mendez et al., 1990). The deterioration of AD patients’ drawing abilities is common and has been well-documented (Henderson et al., 1989; Kirk and Kertesz, 1991). Case reports of artists with AD reveal a declining ability to represent subject matter in a representational fashion (Cummings and Zarit, 1987; Espinel, 1996; Crutch et al., 2001; Maurer and Prvulovic, 2004). Without necessarily diminishing in artistic quality, art becomes more abstract. Some of the painter Willem de Kooning’s (1904–1997) most celebrated works were made after the onset of his AD (Espinel, 1996). While difficult to quantify the effect that de Kooning’s illness had on his art, later paintings made during the advanced stages of his AD were composed of formless sheets of color and lines. One of our AD patients, a female artist with particularly prominent right parieto-occipital disease, noted to us, ‘I am no longer interested in form and shape, but colors now fascinate me.’ Artwork, shown in Fig. 24.4, demonstrates the abstract, formless nature characteristic of a patient with AD. There are several case reports that describe individuals with AD in whom artistic changes, many in the positive direction, were noted. One consideration with these reports is that many of the individuals never had autopsy confirmation of the type of dementing disorder. Similarly, in several reports the dementia is described without consideration of the anatomical correlates of the brain degeneration. Therefore some of these patients

480

A. LIU AND B.L. MILLER

Fig. 24.4. These paintings made in 2002 by one of our female patients with AD demonstrates the abstract, relatively formless style characteristic of the artwork of patients with AD. The progression of AD has been associated with decreased visuospatial function. (Reproduced with permission.)

described below may have suffered from frontotemporal dementia or, perhaps, a highly asymmetric left frontally or temporally predominant form of AD. The self-portraits of London-based professional artist William Utermohlen offers a rare and insightful perspective on the progression of his dementia. His large repertoire of paintings, his wife’s profession as an art historian, and longitudinal neuropsychological testing permit a veridical interpretation of his artistic

evolution. Fig. 24.5A, as selected by his wife, represents the style and method characteristic of Utermohlen’s portraiture in his premorbid state. As shown in the series of portraits in Fig. 24.5, perhaps the most striking change was in his visuospatial skills. As most clearly seen in the progression from Fig 24.5A–D, the structure and relative positioning of the features on his face and head become increasingly distorted (Crutch et al., 2001). Such distortion was consistent with his declining

VISUAL ART AND THE BRAIN

481

Fig. 24.5. Series of self-portraits of William Utermohlen as his Alzheimer’s disease progressed. A is typical of his premorbid portraiture style regarding his brushwork, color use, and expression. B and C showed increasing difficulty with spatial relationships, particularly with position of features on the face and head. As a result, his portraits look increasingly distorted. His later portraits become increasingly simplified and abstract, such that E and F carry very few features that permit identification of the subject. (Reprinted from Crutch et al. (2001), with permission from Elsevier.)

482

A. LIU AND B.L. MILLER

visuospatial testing performance and other drawings made at the time. In Fig. 24.6A, for example, a line drawing of a man reveals the awkward placement of two arms from behind the neck. It is of interest is that the subject recognized a problem with the sketch, but could not identify what it was. Stylistically, the subject’s brushwork becomes coarser and simplified through the course of his illness. As a result, his latest portrait Fig. 24.5E, is abstract, consistent with the style of paintings he was creating simultaneously (see Fig. 24.6B). Indeed, the last portrait has virtually no distinctive features helping the viewer to recognize his identity. While the trajectory of his work demonstrates a decline, color remains vivid in his late paintings. Crutch and colleagues also note the remarkable expressiveness of the portraits and the poignant depiction of emotions such as anger, sadness, and resignation (Crutch et al., 2001). Correlating changes in artistic expression with the mood change, agitation, and late psychosis characteristic of the course of the disease (Cummings, 2004)

would represent another illuminating avenue of research. Cummings and Zarit (1987) also report the course of an artist with AD over a 30-month period. Similar to Utermohlen, the patient’s work became more simplified and primitive. His color palette became increasingly restricted and techniques such as shading and perspective lost. In summary, as these case studies suggest, disintegrating spatial relationships, regression, distortion, and stereotypy characterize the art of progressive AD (Maurer and Prvulovic, 2004). However, there has been one documented example to this rule. Danae Chambers, a British Columbian artist, demonstrated a remarkable preservation of her capacity to paint until very late in the course of her disease. A professional portraitist, she maintained her ability to paint people until eight months before her institutionalization, or when her MMSE score dropped to 8 points. Her preservation of visual working memory, recall, and perception suggest a relative preservation of the right temporoparietal

Fig. 24.6. A selection of Utermohlen’s nonportrait paintings confirm his increasing difficulty with proper spatial relationships and progression toward abstraction. (Reprinted from Crutch et al. (2001), with permission from Elsevier.)

VISUAL ART AND THE BRAIN lobes, suggesting a highly asymmetric form of AD with relative sparing of the right hemisphere, or the possibility of frontotemporal dementia (Fornazzari, 2005). 24.6.2. Frontotemporal lobar degeneration The anatomic subtypes of frontotemporal lobar degeneration (FTLD) provide a window into investigating the neurological basis of the artistic process. Previous case studies of left temporal-variant (semantic dementia) FTLD patients reveal a new preoccupation with art, greater attention to visual stimuli, and increased visual creativity during the early stages of their dementia. In contrast, patients with AD, which typically first affects the posterior parietal and medial temporal areas, show decreased visuoconstructive ability (Miller, et al., 1998; Miller and Hou, 2004). Of interest, creativity in FTLD has been observed in visual art, music, and visual invention, but not in writing or poetry (Miller et al., 2000; Mendez, 2004). In one series of case studies, left-temporal variant FTLD patients exhibited a newfound interest in art and preferred making representational drawings of landscapes, animals, and people. Abstract or symbolic art was notably absent (Miller et al., 1998; Miller et al., 2000). In another account of a 57-year-old right-handed female artist, her left-sided frontal and temporal atrophy correlated with deteriorating language and social skills

483

but increased creativity in her art-making. Unlike the prior case series, her painting evolved from more traditional landscapes and representational art to freer, more expressive, and abstract forms with the progression of her dementia. (Mell et al., 2003). Finally, a 56-yearold right-handed businessman with no previous interest in art begins painting for the first time with the onset of FTLD. He displayed heightened visual awareness to his environment, especially light and sound, even as his language and behavior deteriorated (Miller et al., 1996). One of our FTLD patients, a man presenting with behavioral change and memory, language, and executive deficits, developed a newfound preoccupation in making art (Liu et al., in press). His artwork is characterized by the bizarre representation of faces and the resulting sense of disconnection between the subjects in his work (Fig. 24.7). A sense of disinhibition pervades his painting, either through the wild dress of his subject matter (Fig. 24.7A), suggestion of sexual relationships (Fig. 24.7B), or use of profanity in his artwork (not shown). His preoccupation with faces was associated with profound deficits in the ability to recognize emotions in faces and diminished empathy for people and animals. This patient parallels a cohort described by Mendez and Perryman (2003) in whom the face became gradually distorted and ‘alien’ in association with degeneration of the right temporal lobe. These patients with predominant involvement of the right anterior

Fig. 24.7. The figures in many of one of our FTD patient’s drawings often display odd expressions on their faces, many with teeth showing. His characters often appear disinhibited (e.g., sexually provocative). A is a portrait of the patient’s cousin made in 2001. He is portrayed as a wildly costumed “Goofy Man” twisted into an impossible pose. His dialogue balloons say “I can’t hear you,” and “Bloop, bloop.”

484

A. LIU AND B.L. MILLER

temporal lobe and distortions of faces and facial emotions in their work demonstrate how the artists’ perceptions of the face translate into their work. Given these remarkable stories, it should be noted that diminished creativity is more typical of patients with FTLD, suggesting that these case studies are the exception rather than the rule (Miller et al., 1998). Selective involvement of the temporal regions, with relative sparing of the frontal regions, may provide the anatomic rationale for this subset of patients (Miller et al., 2000). The concept of paradoxical functional facilitation, a term coined by Kapur, explains how dysfunction in one sphere may allow the development of ability in another sphere (Kapur, 1996). For right-handed FTLD patients, the declining influence of the language center, increasing social disinhibition, and relative sparing of the visual systems may permit increased visual creativity (Miller et al., 1998; Mendez, 2004) Furthermore, the compulsive behaviors commonly seen in FTLD may also play an important role in artistic production, causing patients to obsessively practice and even hone their artistic techniques (Miller et al., 2000). Our patient’s compulsive nature appears to have contributed to his artistic process. Indeed, he manifested compulsive behaviors in other realms, including water intake, eating rituals, and coin collecting. Especially in the later years, he repeatedly painted the same geometric designs on store-bought sculptures and objects twenty to thirty times. Arguably, his increasing compulsion, while causing him to be more prolific, limited the creativity of his artwork (Liu et al., in press). 24.6.3. Hallucinatory states: migraine headaches and dementia with lewy bodies Migraineurs have used associated hallucinatory experiences as an inspiration for creative output. Fuller and Gale originally proposed that migraine auras served as the inspiration for the Italian surrealistic painter Georges de Chirico (1888–1978) (Fuller and Gale, 1988; Emery, 2004). Indeed, de Chirico’s compositions combine multiple places, reference several periods of history, and are filled with unrelated objects (Bogousslavsky, 2003). In a review of de Chirico’s autobiographical writings, Nicola and Podoll (2003; Podoll and Nicola, 2004) have found the artist’s experiences to be consistent with a history of migraines. While the artist reports that his hallucinations have directly influenced his painting, Blake and Landis (2003) argue that these altered states were caused by temporal lobe epilepsy, not migraines. Other painters reported to have suffered from migraines include Georgia O’Keefe (1887–1986) and Salvador Dali (1904–1989). Robinson and Podoll evaluated 562 migraneur paintings for body schema disturbances with migraine aura,

either macrosomatognosia (enlarging) or microsomatognosia (shrinking) (Robinson and Podoll, 2000). Macrosomatognosia occurred more frequently and tended to affect segments of the body, particularly the head and upper extremities. Microsomatognosia was less common and tended to involve the whole body. Based on these patterns, the authors argue for the existence of an integrative neuronal network mediating whole body perception. Similarly, hallucinations are a core feature of patients with dementia with Lewy bodies (DLB). There are scattered reports regarding the attempts of patients with DLB to capture the internal state on the canvas (Ebersbach, 2003), including Mervyn Peake (1911– 1968), an English artist and writer (Sahlas, 2003). These studies emphasize that artists’ internal experiences are generated through a brain system that is organized to perceive and interpret the world. Release of these internal systems can provide the basis for artistic activity. 24.6.4. Artistic savants In the 1970s and 1980s, psychologist Lorna Self searched widely for examples of extraordinary visual artistry. She discovered eleven children who demonstrated exceptional ability to render objects in a realistic manner from an early age. Most were mentally handicapped in some way, diagnosed as either autistic or autistic spectrum, and displayed stunted social and language development. One of her savant subjects, Nadia, drew with an extraordinarily sophisticated sense of perspective and manner of mark-making. In addition, while Nadia’s drawings were based on pictures, they were not reproduced in their exact form and could be drawn from memory. Self noticed that the autistic children start drawing objects realistically from a young age. They also called upon a wider range of subjects, tended to exclude humans as subjects, and were obsessive in their choice of subject matter (Howe, 1989). In contrast to the drawings made by savant children, those by normal children were schematic, rigid, and contained mistakes. Because the ordinary child’s world is structured through language, their drawings are infused with conceptual knowledge. As Edwards claims, ‘The child is dominated not by what he sees but the relationship he or she knows’ (Edwards, 1988). The resulting drawings are more stereotyped. For example, a table drawn with four legs of equal length betrays an understanding of the furniture’s identity, but not its relationship to real space. Conversely, the social isolation that autistic children experience may nurture a direct connection with physical reality that permits them to represent their environment more veridically.

VISUAL ART AND THE BRAIN Savants’ focal strengths—in memory, drawing or music—have been emphasized by a few researchers (Treffert and Wallace, 2002; Hou et al., 2000). While still a rare occurrence, savants with artistic skill display exceptional visual memory, coordination, and copying ability. They exhibit a strong preference for a single art medium. Often, they restrict themselves to a narrow range of subjects; i.e., animals or insects but rarely human faces. Snyder and colleagues have attempted to induce savant-like ability by applying transcranial magnetic stimulation to the left frontotemporal brain region. In four of eleven subjects, artistic skills increased following this procedure (Snyder et al., 2003).

24.7. Principles of artistic aesthetics V.S. Ramachandran has suggested that there are three key visual/physiological principles that drive the human artistic effort (Ramachandran and Hirstein, 1999). The first he calls the peak shift principle which represents the artist’s attempt to capture the visual essence of an object or principle through amplification. As an example he describes the exaggeration of the female form, poise and grace seen in many ancient and contemporary pictures of women. Similarly, the cartoonist will exaggerate unique facial features, thereby capturing more of the essence of the face than an exact copy would. The second principle relates to grouping or binding. Here Ramachandran describes the excitement and pleasure associated with linking disparate colors or shapes into a coherent whole. Here he notes the pleasure of seeing something novel emerge such as a Dalmatian dog initially seen as series of dots. In contrast, the third principle emphasizes using visual attention to isolate a single visual module. Here he emphasizes that a sketch using a few lines can be more aesthetically pleasing than a complete picture that captures every detail of a face or scene. The excessive details would distract from the key visual components, making less more. The principles elucidated by Ramachandran represent an imaginative attempt to apply the rules of brain organization toward an understanding of art esthetics. In recent years, a field of art criticism has emerged that focuses upon relationships between neuroanatomy, neurophysiology, and artistic production and appreciation. It is evident that Raphael’s madonnas, perfect reproductions of the face and body, activate very different parts of the brain than the sheets of color in a painting by Mark Rothko. Interpretation of facial expression involves an inferior temporal system that projects to the amygdala in the anterior temporal lobe, while color recognition occurs in a posterior cortical

485

visual system. In the case of facial and facial emotion recognition, the right hemisphere is dominant. Conversely, the Dada artist Duchamp intentionally engages the viewer to self-reflect, using strategies that are typical of the dominant hemisphere. He states, ‘All in all, the creative act is not performed by the artist alone; the spectator brings the work in contact with the external world by deciphering and interpreting its inner qualifications and thus adds his contribution to the creative act’ (Harth, 1999). In addition to the way that the audience perceives an artistic work, there is much to be learned about the way that an artist approaches the creative act. The artist Jackson Pollock produced some of his greatest works in a physical fury, splashing paint onto a canvas while dancing around the canvas. Pollock’s pieces achieved success in part because of his extraordinary athleticism. It is tempting to speculate that Pollock’s motor systems, including his basal ganglia, played a major role in his artistic successes. A surrealistic artist employs images from dreams (or possibly migraines), while a portrait painter like Vermeer translates a static image onto the canvas. Analysis of the artistic process offers insights into the artist and the brain. Largely neglected by the field of neurology, there has been a recent surge of interest in art and visual creativity. This has occurred along with a renaissance in neuroscience related to visual physiology. Indeed, the field of art and the brain is still in its infancy.

References Alajouanine T (1948). Aphasia and artistic realization. Brain 71: 17–41. Arenberg IK, Countryman LF, Bernstein LH, et al. (1991). Van Gogh had Meniere’s disease and not epilepsy. JAMA 265: 722–724. Bartolomeo P, Bachoud-Levi AC, De Gelder B, et al. (1998). Multiple-domain dissociation between impaired visual perception and preserved mental imagery in a patient with bilateral extrastriate lesions. Neuropsychologia 36: 239–249. Bartolomeo P, Bachoud-Levi AC, Denes G (1997). Preserved imagery for colours in a patient with cerebral achromatopsia. Cortex 33: 369–378. Bartolomeo P, Chokron S (2002). Orienting of attention in left unilateral neglect. Neurosci Biobehav Rev 26: 217–234. Bartolomeo P, D’Erme P, Gainotti G (1994). The relationship between visuospatial and representational neglect. Neurology 9: 1710–1714. Barton JJS (2004). Visual dysfunction. In M Rizzo, PJ Eslinger (Eds.), Principles and Practice of Behavioral Neurology and Neuropsychology. Philadelphia, PA. Elsevier, p. 267. Bay E (1962). Aphasia and non-verbal disorders of language. Brain 85: 411–426.

486

A. LIU AND B.L. MILLER

Bhattacharya J, Petsche H (2005). Drawing on mind’s canvas: Differences in cortical integration patterns between artists and non-artists. Hum Brain Mapp 26: 1–14. Bisiach E, Luzzatti C (1978). Unilateral neglect of representational space. Cortex 14: 129–133. Blake O, Landis T (2003). The metaphysical art of Giorgio de Chirico: Migraine or epilepsy? European neurology 50: 191–194. Blumer D (2002). The illness of Vincent van Gogh. Am J Psychiatry 159: 519–526. Bogousslavsky J (2003). The neurology of art—the example of Georgio de Chirico. European neurology 50: 189–190. Boller F (2005). Alajouanine’s painter: Paul-Elie Gernez. In J Bogousslavsky, F Boller (Eds.), Neurological Disorders In Famous Artists. Karger, Basel, pp. 92–100. Cantagallo A, Della Sala S (1998). Preserved insight in an artist with extrapersonal spatial neglect. Cortex 34: 163–189. Chatterjee A (1994). Picturing unilateral spatial neglect: Viewer versus object centered reference frames. J Neurol Neurosurg Psychiatry 57: 1236–1240. Chatterjee A (2004). The neuropsychology of visual artistic production. Neuropsychologia 42: 1568–1583. Crutch S, Isaacs R, Rossor MN (2001). Some workmen can blame their tools: Artistic change in an individual with Alzheimer’s disease. Lancet 357: 2129–2133. Cummings JL (2004). Alzheimer’s disease. N Engl J Med 351: 56–67. Cummings JL, Zarit JM (1987). Probable Alzheimer’s disease in an artist. JAMA 258: 2731–2734. De Renzi E, Spinnler H (1967). Impaired performance on colour tasks in patients with hemispheric damage. Cortex 3: 194–217. Ebersbach G (2003). An artist’s view of drug-induced hallucinosis. Mov Disord 18: 833–834. Edwards B (1988). The use of drawing as language. Lecture Outline from Symposium on Art and the Brain Art Institute of Chicago. Emery AEH (2004). Art and neurology: How neurological disease can affect an artist’s work. Pract Neurol 4: 366–371. Espinel CH (1996). De Kooning’s late colours and forms: Dementia, creativity, and the healing power of art. Lancet 347: 1096–1098. Fornazzari LR (2005). Preserved painting creativity in an artist with Alzheimer’s disease. Eur J Neurol 12: 419–424. Fuller IN, Gale MV (1988). Migraine aura as artistic inspiration. BMJ 297: 1670–1672. Gainotti G, Silveri MC, Villa G, et al. (1983). Drawing objects from memory in aphasia. Brain 106: 613–622. Gardner H (1975). Artistry following aphasia, Paper presented at the Academy of Aphasia, Victoria, British Columbia. Gardner H (1982). Artistry after brain damage. Art, Mind, and Brain: A Cognitive Approach to Creativity. Basic Books, New York, pp. 318–335.

Geschwind DH, Miller BL, DeCarli C, et al. (2002). Heritability of lobar brain volumes supports theories of brain laterality and handedness. Proc Nat Acad Sci 99: 3176–3181. Goldenberg G (1992). Loss of visual imagery and loss of visual knowledge—a case study. Neuropsychologia 30: 1081–1099. Goldenberg G, Hartmann K, Schlott I (2003). Defective pantomime of object use in left brain damage: Apraxia or asymbolia? Neuropsychologia 41: 1565–1573. Goldenberg G, Mullbacher W, Nowak A (1995). Imagery without perception—a case study of anosognosia for cortical blindness. Neuropsychologia 33: 1373–1382. Goldenberg G, Podreka I, Steiner M, et al. (1991). Contributions of occipital and temporal brain regions to visual and acoustic imagery—a spect study. Neuropsychologia 29: 695–702. Goodale MA (1993). Visual pathways supporting perception and action in the primate cerebral cortex. Curr Opin Neurobiol 3: 578–585. Goodale MA, Westwood DA (2004). An evolving view of duplex vision: Separate but interacting cortical pathways for perception and action. Curr Opin Neurobiol 14: 203–211. Guariglia C, Padovani A, Pantano P, et al. (1993). Unilateral neglect restricted to visual imagery. Nature 364: 235–237. Halligan P, Fink G, Marshall J, et al. (2003). Spatial cognition: Evidence from visual neglect. Trends Cogn Sci 7: 125–133. Halligan PW, Marshall JC (1997). The art of visual neglect. Lancet 350: 139–140. Harth E (1999). The emergence of art and language in the human brain. J Consciousness Studies 6: 97–115. Heller W (1994). Cognitive and emotional organization of the brain: Influences on the creation and perception of art. In D Zaidel (Ed.), Neuropsychology. New York Press, New York, pp. 271–292. Henderson VW, Mack W, Williams BW (1989). Spatial disorientation if Alzheimer’s disease. Arch Neurol 46: 391–394. Hou C, Miller BL, Cummings J, et al. (2000). Artistic savants. Neuropsychiatry Neuropsychol Behav Neurol 13: 29–38. Howe MJA (1989). Fragments of Genius: The Strange Feats of Idiots Savants. Chapman and Hall, Routledge, New York, pp. 134–149. Janson HW, Janson AF (1997). History of Art, 5th edn, 16–25. Jung R (1974). Neuropsychologie und neurophysiologie des konturund formsehens in zeichnerei und malerei. In H Weick (Ed.), Pyschopathologie Mususcher Gestaltungen. Stuttgart, FK Shattauer, pp. 27–88. Kaplan E (1980). Presidential address. International Neuropsychology Society. San Diego, California. Kaplan JA, Gardner H (1989). Artistry after unilateral brain disease. In: F Boller, J Grafman (Eds.), Handbook of Neuropsychology, Vol. 2. Elsevier, Amsterdam, pp. 141–155.

VISUAL ART AND THE BRAIN Kapur N (1996). Paradoxical facilitated function in brain– behaviour research. A critical review. Brain 119: 1775–1790. Karnath HO, Ferber S, Himmelbach H (2001). Spatial awareness is a function of the temporal not the posterior parietal lobe. Nature 411: 960–963. Kirk A, Kertesz A (1991). On drawing impairment in Alzheimer’s disease. Arch Neurol 48: 73–77. Liu A, Rankin KP, Werner K, et al. (in press). A case study of an emerging visual artist with frontotemporal lobar degeneration and amyotrophic lateral sclerosis. Neurocase. Marr D (1982). Vision: A Computational Investigation into the Human Representation and Processing of Visual Information. WH Freeman, San Francisco, California. Marsh GG, Philwin B (1978). Unilateral neglect and constructional apraxia in a right-handed artist with a left posterior lesion. Cortex 23: 149–155. Marshall JC, Halligan PW (1993). Imagine only the half of it. Nature 364: 193–194. Maurer K, Prvulovic D (2004). Paintings of an artist with Alzheimer’s disease: Visuoconstructural deficits during dementia. J Neural Transm 111: 235–245. Mell JC, Howard SM, Miller BL (2003). Art and the brain: The influence of frontotemporal dementia on an accomplished artist. Neurology 60: 1707–1710. Mendez MF (2004). Dementia as a window into the neurology of art. Med Hypotheses 63: 1–7. Mendez MF, Mendez MA, Martin R, et al. (1990). Complex visual disturbances in Alzheimer’s Disease. Neurology 40: 439–443. Mendez M, Perryman KM (2003). Disrupted facial empathy in drawings from artists with frontotemporal dementia. Neurocase 9: 44–50. Merigan W, Freeman A, Meyers SP (1997). Parallel processing streams in human visual cortex. Neuroreport 8: 3985–3991. Miller BL, Boone K, Cummerings JL, et al. (2000). Functional correlates of musical and visual ability in frontotemporal dementia. Br J Psychiatry 176: 458–463. Miller BL, Cummings J, Mishkin F, et al. (1998). Emergence of artistic talent in frontotemporal dementia. Neurology 51: 978–981. Miller BL, Hou CE (2004). Portraits of artists: Emergence of visual creativity in dementia. Arch Neurol 61: 842–844. Miller BL, Ponton M, Benson DF, et al. (1996). Enhanced artistic creativity with temporal lobe degeneration. Lancet 348: 1744. Morrant JCA (1993). The wing of madness: The illness of Vincent van Gogh. Can J Psychiatry 38: 480–484. Nicola U, Podoll K (2003). L’Aura di Giorgio de Chirico: Arte Emicranica e Pittura Metafisica. Mimesis, Milano. Ota H, Fujii T, Suzuki K, et al. (2001). Dissociation of bodycentered and stimulus-centered representations in unilateral neglect. Neurology 57: 2064–2069. Peru A, Pinna G (1997). Right personal neglect following a left hemisphere stroke. Cortex 33: 585–590.

487

Peterson JM (1979). Left-handedness: Differences between student artists and scientists. Percept Mot Skills 48: 961–962. Podoll K, Nicola U (2004). The illness of Giorgio de Chirico—migraine or epilepsy? European neurology 51: 186. Ramachandran VS, Hirstein W (1999). The science of art. A neurological theory of artistic experience. J Consciousness Studies 6: 15–51. Rizzo M, Robin DA (1990). Simultanagnosia: A defect of sustained attention yields insights on visual information processing. Neurology 40: 447–455. Rizzo M, Smith V, Pokorny J, et al. (1993). Color perception profiles in central achromatopsia. Neurology 43: 995–1001. Roberson IH, Marshall JC (1993). Unilateral Neglect: Clinical and Experimental Studies. Lawrence Erlbaum, Hove. Robinson D, Podoll K (2000). Macrosomatognosia and microsomatognosia in migraine art. Acta Neurol Scand 101: 413–416. Sacks O (1995). The case of the colorblind painter. In O Sacks, An Anthropologit on Mars: Seven Paradoxical Tales. Knopf, New York, pp. 3–41. Sahlas DJ (2003). Dementia with Lewy bodies and the neurobehavioral decline of Mervyn Peake. Arch Neurol 60: 889–892. Schnider A, Regard M, Benson DF, et al. (1993). Effects of a right-hemisphere stroke on an artist’s performance. Neuropsychiatry Neuropsychol Behav Neurol 6: 249–255. Servos P, Goodale MA (1995). Preserved visual imagery in visual form agnosia. Neuropsychology 33: 1383–1394. Servos P, Goodale MA, Humphrey GK (1993). The drawing of objects by a visual form agnostic: Contribution of surface properties and memorial representations. Neuropsychologia 31: 251–259. Shuren JE, Brott TG, Schefft BK, et al. (1996). Preserved color imagery in an achromatopsic. Neuropsychologia 34: 485–489. Smith WS, Mindelzun RE, Miller BL (2003). Simultanagnosia through the eyes of an artist. Neurology 60: 1832–1834. Snyder AW, Mulcahy E, Taylor JL, et al. (2003). Savant-like skills exposed in normal people by suppressing the left fronto-temporal lobe. J Integr Neurosci 2: 149–158. Snyder AW, Thomas M (1997). Autistic artists give clues to cognition. Perception 26: 93–96. Swindell CS, Holland AL, Fromm D, et al. (1988). Characteristics of recovery of drawing ability in left and right brain damaged patients. Brain Cogn 7: 16–30. Treffert DA, Wallace GL (2002). Islands of genius. Artistic brilliance and a dazzling memory can sometimes accompany autism and other developmental disorders. Sci Am 286: 76–85. Ungerleider LG, Mishkin M (1982). Two cortical visual systems. In: DJ Ingle, MA Goodale, RJ Mansfield (Eds.), The Analysis of Visual Behavior. MIT Press, Cambridge, Massachusetts, pp. 549–586.

488

A. LIU AND B.L. MILLER

Vallar G (1993). The anatomical basis of spatial hemineglect in humans. In: IH Robertson, JC Marshall (Eds.), Unilateral Neglect: Clinical and Experimental Studies. Lawrence Erlbaum, Hove, UK, pp. 27–59. Wapner W, Judd T, Gardner H (1978). Visual agnosia in an artist. Cortex 14: 343–364.

Watson JD, Myers R, Frackowiak RS, et al. (1993). Area V5 of the human brain: Evidence from a combined study using positron emission tomography and magnetic resonance imaging. Cereb Cortex 3: 79–94. Zeki SM (1990). A century of cerebral achromatopsia. Brain 113: 1721–1177.

Handbook of Clinical Neurology, Vol. 88 (3rd series) Neuropsychology and behavioral neurology G. Goldenberg, B.L. Miller, Editors # 2008 Elsevier B.V. All rights reserved

Chapter 25

Laboratory testing of emotion and frontal cortex ROBERT W. LEVENSON*, ELIZABETH ASCHER, MADELEINE GOODKIND, MEGAN McCARTHY, VIRGINIA STURM, AND KELLY WERNER Department of Psychology, University of California, Berkeley, CA, USA

25.1. Introduction Modern neuropsychological testing is based on a highly differentiated model of cognitive functioning in which deficits can appear in any of a number of processes (e.g., memory, executive function, computation, attention). Moreover, many of these processes can be further broken down into subprocesses that can also be assessed (e.g., short-term, long-term, and working memory). The state of affairs is much less advanced for testing emotional functioning. As with cognition, there are compelling theoretical, empirical, and anatomical reasons to consider the emotion system as consisting of a number of different processes and subprocesses. However, there are relatively few tests available for assessing emotional functioning and, among those, the relationship with specific emotion processes is often not well articulated. In fact, in many neuropsychological batteries, only a single emotion process is tested (e.g., the ability to recognize the emotion being expressed in a photo of a facial expression). In our view, extrapolations about overall emotional functioning based on testing a single emotional process can be very misleading. This chapter begins with a discussion of what we consider most critical for a comprehensive assessment of emotional functioning and then describes the assessment procedures we use. Because our work is primarily conducted in the laboratory, our procedures are designed for that environment. In recent years we have used these procedures with hundreds of patients with neurodegenerative diseases (frontotemporal lobar degeneration, Alzheimer’s, amyotrophic lateral sclerosis), congenital neurological diseases (Moebius syndrome), and focal lesions (orbitofrontal), as well as with neurologically *

normal controls. We consider the laboratory to be an excellent test bed for developing, refining, and evaluating assessment techniques. Those techniques that prove most useful can then be translated into forms more appropriate for use in the clinic and at the bedside.

25.2. Emotion Definitions of emotions vary in terms of their emphasis on biological features, cognitive features, appraisal processes, motor action patterns, expressive behavior, language, and coping. The way that emotion is defined significantly influences the design of the assessment battery necessary to assess emotional functioning. The definition we have proposed emphasizes the adaptive, organizing function of emotion: ‘Emotions are shortlived psychological–physiological phenomena that represent efficient modes of adaptation to changing environmental demands.’ (Levenson, 1994, p. 123). For us, emotion serves a number of functions, altering attention, adjusting behaviors upward and downward in response hierarchies, and activating relevant associative networks in memory. An important function of emotion is to organize numerous biological systems (including facial expression, somatic muscles, voice tone, autonomic nervous system, endocrine system) into a bodily milieu that is optimal for effective response. Emotions serve important social functions, moving us toward certain people and away from others. Reflecting this view, our laboratory assessment of emotional functioning focuses on brief emotional phenomena (not on longer moods) and on the activation of multiple response systems (not on a single system such as verbal report of emotional experience). Moreover, it includes assessment of emotion in interpersonal contexts.

Correspondence to: Robert W. Levenson, PhD, Department of Psychology, 3210 Tolman Hall #1650, University of California, Berkeley, CA 94720–1650, USA. E-mail: [email protected].

490

R.W. LEVENSON ET AL.

25.3. Emotion processes We believe that three emotional processes should be included in any comprehensive assessment of emotional functioning: (a) emotional reactivity, (b) emotional regulation, and (c) emotional understanding. Emotional reactivity refers to the type, magnitude, and duration of response that occurs in reaction to changes in the internal and external environment that have significance for our goals and wellbeing. Emotional regulation refers to the adjustments in type, magnitude, and duration of emotional response that are made to meet personal goals and situational demands. Emotional understanding refers to the recognition of emotions in self and others, and to the understanding of why these emotions have occurred and what their consequences may be. We believe that each of these processes is subserved by different neural circuitry, and thus can be differentially impacted by injury and disease.

Perhaps because the term ‘emotional regulation’ is so closely associated with reining in emotions, it is easy to think of emotional regulation as being limited to emotional inhibition or suppression. However, it is clear that emotional regulatory competence also involves the ability to amplify or exaggerate emotion in situations where the emotional signal to conspecifics must be clear and unambiguous. Often emotional reactivity and regulation are difficult to separate. Take, for example, a situation in which a patient exhibits a very small behavioral response to a highly stressful film. Is this patient showing a low level of emotional reactivity or a high level of emotional regulation? The difficulty of making this distinction underscores the value of assessing the individual’s capacity to regulate emotion when instructed to do so. This capacity to regulate on demand can be determined with some certainty, whereas assessing the emotional regulation that occurs spontaneously will always be difficult to separate completely from emotional reactivity.

25.3.1. Emotional reactivity Emotional reactivity is usually operationalized in terms of the type, magnitude, and duration of response. In the laboratory, emotional reactivity is typically assessed by presenting the individual with a standardized stimulus thought to elicit emotion in most people (e.g., viewing a film of a child mourning the death of his father) or a personally meaningful stimulus (e.g., remembering the death of one’s own parent) and then measuring the reaction in one or more emotional response systems (see below). It is our belief that emotional reactivity can only be assessed accurately in vivo, that is, as emotions are actually produced. Procedures in which individuals are asked to indicate the emotional responses they think they would have or have had in particular situations measure different processes (e.g., emotional selfknowledge, knowledge of normative responses) and are prone to biased and erroneous reports. 25.3.2. Emotional regulation Gross (1998, p. 275) defines emotional regulation as: . . .the processes by which individuals influence which emotions they have, when they have them, and how they experience and express these emotions. Emotion regulatory processes may be automatic or controlled, conscious or unconscious, and may have their effects at one or more points in the emotion generative process.

25.3.3. Emotional understanding Emotional knowledge takes a number of forms, ranging from the relatively simple (e.g., knowledge about whether or not we or others are experiencing emotion), to the more differentiated (e.g., knowledge about the particular emotion and intensity of emotion being experienced), to the highly complex (e.g., theories of emotion and emotional regulation, metacognitions about emotion, beliefs about the relationships between emotions and other aspects of the human condition such as health, wellbeing, and relationship stability). We consider the basic building block of emotional understanding to be empathic accuracy—the ability to know what another person is feeling. This can be assessed in its simplest form by having people identify which particular emotion is shown in a photograph. Two common tests of this sort are the Florida Affect Battery (Bowers, 1992) and the Facial Expressions of Emotion (Young et al. 2002). The Florida Affect Battery also has sections in which emotions are identified from tone of voice (prosody). More complex, and arguably more ecologically valid assessments of emotional understanding involve using dynamic stimuli in which the emotional content unfolds over time and is embedded in a meaningful social context. Examples of these more dynamic stimuli include films (Gross and Levenson, 1995) and observed social interactions (Levenson and Ruef, 1992).

LABORATORY TESTING OF EMOTION AND FRONTAL CORTEX

25.4. Emotion types There are three broad categories of emotion that should be considered when assessing emotional functioning: (a) negative emotions, (b) positive emotions, and (c) self-referential emotions. Most contemporary emotion researchers and theorists do not view emotion as a monolith. Thus, it is no longer tenable to assume that what holds for one type of emotion holds for all types of emotions. 25.4.1. Negative emotions Negative emotions prepare the organism for dealing with conditions of threat, challenge, and opportunity. Basic negative emotions such as anger, disgust, fear, and sadness are characterized as having different associated patterns of facial expression, motor action, and physiological activation that have been selected through evolution as being most likely to deal successfully with the eliciting condition most of the time (Levenson, 2003). Early theorizing and laboratory studies of emotion often focused almost exclusively on negative emotions, emphasizing such adaptive patterns as ‘flight’ and ‘fight’ and their associated patterns of psychological activation. 25.4.2. Positive emotions Positive emotions were relatively understudied and their functions less well documented until recently. In our work, the role that positive emotions play in calming, soothing, and ‘undoing’ the physiological effects of negative emotions has been emphasized (Fredrickson and Levenson, 1998; Levenson, 1988). Others have focused on the role positive emotions play in broadening perspectives, increasing flexibility of response, and increasing group cohesion (Fredrickson, 1998; Isen, 1999). 25.4.3. Self-referential emotions Self-referential emotions involve evaluation of the self with respect to social norms. They can be negatively (e.g., shame, guilt, embarrassment) or positively toned (e.g., pride). These emotions, which require some degree of self-consciousness and self-awareness, appear relatively late in ontogeny and phylogeny.

491

experience, (b) emotional expressive behavior, (c) peripheral physiology, and (d) emotional language. 25.5.1. Self-reported emotional experience Self-reported emotional experience can be obtained in a number of different ways. In our laboratory, we ask participants to provide ratings of the intensity of their subjective experience for a list of discrete emotions (e.g., fear, anger, amusement) and dimensions (e.g., pleasantness, arousal) after an emotion-eliciting event. Additionally, we sometimes have participants use a rating dial to indicate how they are feeling (positive– neutral–negative) continuously throughout an emotional experience (Mauss et al., 2005). 25.5.2. Emotional expressive behavior Emotional expressive behavior is typically quantified by applying objective coding systems to videotapes of participants’ emotional behavior. In our laboratory, we use coding systems based either exclusively on facial muscle activity (facial action coding system [FACS]; Ekman and Friesen, 1978) or on multiple indicators including facial expression, tone of voice, and content of speech (Gottman, 1989; Gross and Levenson, 1993). FACS is the most exacting and laborious of these systems, allowing the coder to decompose any observed facial expressions into its component facial muscle actions based on repeated, slow-motion viewing of video recordings. 25.5.3. Peripheral physiology Peripheral physiology is usually quantified in terms of selected measures of cardiovascular, electrodermal, respiratory, and somatic activity. Timing of measurement is quite important because these systems are often only under the influence of emotion for brief periods before they return to the service of other functions (e.g., homeostasis). In our laboratory, we precede each emotion elicitation with a resting baseline period and then obtain measures continuously throughout the elicitation and during a post-elicitation ‘cooling down’ period. Analyses focus either on the times during which we attempted to stimulate emotion (e.g., while the participant watches a film) or when we have independent evidence that an emotion has occurred (e.g., when an emotional facial expression appears during an interaction between a patient and caregiver).

25.5. Emotion response systems 25.5.4. Emotional language A comprehensive assessment of emotion should sample from the various systems that constitute the emotional response including: (a) self-reported emotional

Emotional language is often quantified by determining the frequency or proportion of words used in different

492

R.W. LEVENSON ET AL.

categories (e.g., all emotion words, negative emotion words, fear words). A number of computer-assisted approaches can be used that facilitate this kind of text analysis (Mergenthaler, 1985). A multi-system assessment of emotional functioning has a number of advantages, especially when working with patients for whom measurement of one or more systems may be unreliable (e.g., self-report of subjective experience in aphasic patients). Multi-system assessment is also important when the pathology is thought to affect the organization or coherence among response systems (Mauss et al., 2005).

25.6. Laboratory tests of emotion 25.6.1. Acoustic startle reflex The acoustic startle reflex is a primitive, defensive response to the threat posed by a sudden loud noise (Sokolov, 1963). It consists of a stereotyped pattern of somatic and facial muscle actions (Ekman et al., 1985) and attendant activation of autonomic nervous system response (Soto et al., 2005). We use a 115 db, 100 ms burst of white noise administered through loudspeakers behind the patient (roughly commensurate with a close proximity gunshot). We administer the startle under three conditions, which enable us to probe different aspects of emotional functioning. In the unanticipated condition, the startle occurs without warning. This provides a good measure of emotional reactivity to a simple aversive stimulus. In the anticipated condition, the startle is preceded by a 20 s countdown. Because the person knows exactly when it will occur, it provides an opportunity for preparation and thus allows us to assess spontaneous emotional regulation strategies. In the inhibited condition, the startle is preceded by a 20 s countdown and instructions are given to hide reactions; this assesses the capacity to regulate emotion on demand. An exaggerated condition in which instructions are given to increase the visibility of reactions can also be included. The startle response exists on the boundary between reflex and emotion (Ekman et al., 1985). Although the initial response (typically occurring in the first 500 ms) is quite stereotypical, it is often followed by a secondary response that is a ‘response to having been startled,’ which varies greatly across individuals. As the person takes stock of what has happened (including his or her reaction to the loud noise) the secondary response can take any of several forms, including amusement, embarrassment, anger, or fear. We have found this secondary response to be quite vulnerable to certain types of brain injury (e.g., dramatically reduced in frontotemporal lobar degeneration; Sturm et al., 2006).

Intact autonomic responding to non-emotional stimuli has been found in the context of frontal lobe injury (Damasio et al., 1990). However, there is evidence that patients with frontal lobe damage (i.e., orbitofrontal damage) show disrupted autonomic responding to emotional and social stimuli (Damasio et al., 1990; Roberts et al., 2004) in spite of normal reactivity to an unanticipated startle stimulus (Roberts et al., 2004). Injury to the frontal lobes (e.g., from head injury or neurodegenerative disease) is likely to also damage the pathways that connect regions of the frontal lobes (e.g., anterior insula) with subcortical structures (e.g., hypothalamus). Although these pathways are thought to be involved in autonomic responding to emotional stimuli, it is unclear if their disruption affects the kind of low-level autonomic reactivity embodied in the startle response (Chu et al., 1997). 25.6.2. Startle eye-blink modulation The acoustic stimulus used to elicit the startle response described in the previous section is sufficiently loud to activate an intense defensive, whole-body reflex (Sokolov, 1963). An acoustic stimulus of considerably lower amplitude (typically ranging from 95–100 db) will activate a smaller startle reflex (Lang et al., 1990) that can be quantified by electromyographic measurement of the intensity of the associated eye blink. To put this in perspective, a 115 db acoustic stimulus is more than 30 times more powerful than a 100 db stimulus. Unlike the high amplitude startle, the lower amplitude startle does not disrupt ongoing activity and thus can be used as a repeated background ‘probe’ stimulus while the person is engaged in other activities. The amplitude of the startle eye blink is an indicator of higher cortical functioning such as attentional and emotional processing. In particular it reflects affective valence-positive/approach states attenuate the amplitude of the eye blink and negative/avoidance states have a potentiating effect. Startle eye-blink modulation tests can provide useful information about underlying attentional and emotional state processes without being subject to demand characteristics or voluntary reporting biases (e.g., Bradley and Vrana, 1993). These qualities make them particularly appealing for use with patient populations where self-report might be difficult or unreliable. Startle eye-blink modulation can be considered in terms of valence match or mismatch. Researchers have proposed that stimuli that elicit positive emotion engage the approach motivational system, while stimuli that elicit negative emotion engage the withdrawal motivational system (Lang, 1994). If a startle probe, an aversive stimulus, is presented while a participant is

LABORATORY TESTING OF EMOTION AND FRONTAL CORTEX experiencing a positive stimulus, there is a valence mismatch between the engaged motivational system and the startle probe, thus the ensuing startle response is attenuated. However, if a negative emotional state is engaged and the startle probe is then presented, the startle response will be augmented. Vrana et al. (1988) found a significant linear relationship between stimulus valence and startle eye-blink amplitude, as evidenced by attenuated startle amplitude when viewing emotionally positive relative to neutral slides, and potentiated startle amplitude when viewing emotionally negative relative to neutral slides. Studies of the temporal course of modulation reveal that the eye-blink amplitude continues to be modulated even after the emotion-eliciting stimulus has been removed (Larson et al., 1998). 25.6.3. Films Carefully selected excerpts from commercial and other films can be used to elicit emotions. Real-life emotions are often induced by dynamic, external visual and auditory stimuli that unfold over time, thus films have a relatively high degree of ecological validity. Films have been used in laboratory studies for years, going back to their early use to induce diffuse ‘stress’ responses (e.g., Lazarus et al., 1962). Gross and Levenson (1995) identified a set of films that elicit the emotions of amusement, anger, contentment, disgust, fear, sadness, and surprise as well as a neutral emotional state. Based on this work, it appears that anger is the most difficult emotion to elicit reliably using short film excerpts. Films have also been found to be useful for producing general positive and negative valenced states (Hubert and de Jong-Meyer, 1990). Film clips lend themselves to the assessment of emotional reactivity (by having participants simply watch the film), emotional regulation (by instructing participants to alter emotional responses), and emotional understanding (by having participants indicate the emotion being experienced by characters in the film). It is important to consider possible cognitive and language deficits when using films with patients. Thematic complexity of films varies greatly, thus it is important to match films with the cognitive capabilities of the population being assessed. We have found that, even with highly impaired patients, it is possible to elicit emotion with carefully selected, thematically simple film stimuli. 25.6.4. Slides The International Affective Picture System (Lang et al., 1988) consists of over 700 colored images of situations that are selected because of their properties

493

of evoking emotion and being internationally understandable. These pictures have been used in a large number of studies of emotional, cognitive, social, and biobehavioral functioning. Normative ratings of pleasure and arousal for each picture are available, which help in stimuli selection and comparing findings across laboratories. An attempt has been made to find stimuli that fill all quadrants of the pleasure/arousal affective space, including the difficult quadrant comprised of stimuli that are unpleasant, but minimally arousing. The pictures utilize real-world settings in order to induce the automatic perception of emotion. Although in theory the full array of specific emotions could be represented, there are clear biases (e.g., pictures of contamination and mutilation in the high unpleasant/high arousal quadrant that typically elicit the emotion of disgust). The IAPS slides are primarily useful for assessing emotional reactivity. Slides that portray emotional facial expressions could also be used to assess that aspect of emotional understanding. Because these pictures are static, cognitively simple, and do not require language processing, they can be very useful when working with impaired patients. 25.6.5. Relived emotions Recalling memories of emotionally significant events can be a powerful elicitor of emotion. Long-term memories of emotional events may be stored in particularly strong forms due to the interaction of the adrenergic system (which is active during strong emotions) and the amygdala (Cahill, 1996; 1999). Emotional memories may be relatively spared in individuals suffering from retrograde amnesia that affects more neutral or semantic autobiographical memories (Daum et al., 1996; Hamann et al., 1997). A growing body of research suggests that autobiographical memory is mediated by complex networks of frontal, temporal, and occipital areas that differ as a function of type of knowledge, emotional valence, and temporal remoteness (Fink et al., 1996; Conway et al., 2001; Markowitsch, 1999; Peifke et al., 2003). We use emotional memories of two kinds: personally relevant, autobiographical emotional memories (e.g., recalling one’s saddest or happiest moment), and memories of shared historic or group events (‘flashbulb’ memories such as recalling the events of September 11, 2001). Autobiographical memories can elicit intense emotion, but their idiosyncratic nature leads to differences in the characteristics of memories across individuals. Flashbulb memories provide much better comparability of the memory per se across

494

R.W. LEVENSON ET AL.

individuals but can vary greatly in terms of personal salience and capacity to elicit emotion. To identify personally relevant autobiographical memories, we use a semi-structured interview format to prompt participants to retrieve memories of specific events that elicited a specific emotion (Ekman et al., 1983). Subsequently, participants are asked to relive those memories as strongly as possible. Emotional responses (self-reported subjective experience, expressive behavior, physiology, language) are assessed during both the retrieval and reliving periods. We consider relived memories to be most useful for assessing emotional reactivity, less so for assessing emotional regulation (it is difficult to both recall/relive a memory and control it at the same time), and least useful for assessing emotional understanding. Because memory is involved, these tasks need to be used judiciously with patients who have memory impairments. 25.6.6. Singing Among the self-referential emotions, we have focused on embarrassment in our laboratory studies. We use a singing task in which participants unwittingly become an object of attention and evaluation. Participants are seated in front of a television monitor while their expressive behavior is recorded and peripheral physiology monitored continuously. After sitting quietly through a baseline period, they are asked to sing a familiar song— we have been using ‘My Girl’ by The Temptations, which works well with patients in their 50s and 60s. The instrumental background music is played through headphones, and the lyrics are presented on the television monitor. Upon completion of the song, the experimenter removes the headphones and instructs participants simply to watch the television for the next task. Without warning, they are shown a recording of their just-completed singing performance. In our laboratory, participants are typically alone while watching themselves sing, but it would be possible to have an ‘audience’ present (Shearn et al., 1990). Singing tasks of this sort are effective elicitors of embarrassment or other signs of self-consciousness (e.g., amusement). Other methods that have been used for this purpose include posing complex facial expressions (Keltner, 1995) or having participants disclose personal, emotional experiences (Beer et al., 2003). Self-conscious emotions have been associated with regions of the frontal lobes (e.g., medial prefrontal cortex; Takahashi et al., 2004), and are therefore important to assess in individuals who might have frontal lobe damage. Self-conscious emotions serve to regulate social behavior, and when disrupted, can be associated with behavioral disinhibition and violation of social

norms (Keltner et al., 1995; Keltner and Buswell, 1997). Corroborative empirical evidence finds that patients with orbitofrontal damage (marked clinically by such behavioral disinhibition) have dysregulated self-conscious emotions (Beer et al., 2003). The singing task is thematically and instructionally simple and is suitable for use with even quite impaired patients (if patients have trouble reading lyrics, childhood songs like ‘Twinkle Twinkle Little Star’ can be used). The singing task is less suitable for patients with language and vocal impairments. 25.6.7. Interpersonal interaction Emotional displays are thought to serve important interpersonal functions, such as facilitating social bonds (e.g., joy during play; Fredrickson, 1998; Panksepp, 2000) and eliciting help from others (e.g., crying as a distress signal; Bowlby, 1969). Exhibiting these displays appropriately, as well as successfully reading and responding to the emotions of others, are critical skills for adaptive emotional functioning. We assess socioemotional functioning in the laboratory by using an interpersonal interaction task that we originally developed to study the interactions of husbands and wives (Levenson and Gottman, 1983). This task allows us to sample naturalistic interpersonal interaction between patients and their spouses, partners, or caregivers. It provides a ‘real world’ assessment of emotional reactivity (generating emotional responses during the interaction), emotional regulation (modulating emotions appropriately for the situation), and emotional understanding (recognizing and responding to the emotions of the other person). In this task, the patient and interaction partner sit in chairs facing each other and engage in 15-minute conversations preceded by a 5-minute silent resting period; during this 20-minute task behavior is videotaped and physiology is monitored continuously from both patient and partner. We have found the most powerful elicitor of emotion is having the dyad discuss an area of conflict in their relationship. We also use neutral topics (e.g., discussing the events of the day), positive topics (e.g., discussing things they enjoy doing together), or disease-specific topics (e.g., discussing the way the illness has changed their relationship). Before each conversation, a facilitator helps the dyad decide on the topic for discussion. Interpersonal interactions provide an additional way of assessing emotional understanding. After the conclusion of each conversation, we have participants view the video recording and use a rating dial to report continuously on the valence (negative–neutral– positive) of their own emotions during the interaction

Table 25.1 Laboratory tests of emotional processing

Emotion types

Acoustic Startle Reflex

Reactivity Regulation (instructed and spontaneous)

Subjective Behavioral Physiological

Startle Eye-blink Modulation

Reactivity

Negative Positive and Selfreferential in secondary reaction Negative Positive

Films

Reactivity Regulation (instructed) Understanding (identify or track emotions of target) Reactivity Regulation (instructed)

Negative (anger difficult) Positive Self-referential

Subjective Behavioral Physiological

Require cognitive processing Difficult to elicit anger

Negative (anger difficult) Positive

Subjective Behavioral Physiological

Slides presented via laptop or portable video device

Relived emotions

Reactivity

Negative Positive Self-referential

Singing

Reactivity

Self-referential

Task needs to be simplified for very impaired patients

Dyadic Interaction

Reactivity Regulation (instructed and spontaneous) Understanding

Negative Positive Self-referential

Subjective Behavioral Physiological Language Subjective Behavioral Physiological Subjective Behavioral Physiological Language

Minimal cognitive and language demands Biased toward eliciting disgust, amusement, sexual arousal Makes high demands on memory Idiosyncratic stimuli—not standardized

Music presented via tape or laptop; camcorder for playback of singing No additional instrumentation needed

Slides

Behavioral

Advantages and disadvantages

For bedside use

Requires little cognitive processing Produces a general defensive response rather than specific emotions Requires little cognitive processing Unobtrusive and continuous

Acoustic startle presented via recording and headphones

Produces highly naturalistic sample of emotional functioning Responses influenced by both members of dyad

Acoustic startle presented via recording and headphones; simple electromyographic device Films presented via laptop or portable video device

No additional instrumentation needed

LABORATORY TESTING OF EMOTION AND FRONTAL CORTEX

Emotion response systems

Emotion processes

495

496

R.W. LEVENSON ET AL.

(Gottman and Levenson, 1985). This can be followed by a second viewing in which each participant rates his or her partner’s emotional state. Comparing the two sets of ratings gives an objective indicator of the ability of partners to understand each other’s emotions. The neural correlates of emotional understanding, particularly in dynamic or social contexts, have not been extensively studied. Using more static stimuli in less interpersonal contexts, both lesion and imaging studies implicate a wide range of brain areas associated with the recognition of negative emotions, including the amygdala, thalamus, insula, anterior cingulate, right somatosensory and parietal cortices, anterior temporal cortex, and frontal and prefrontal areas, especially in the orbitofrontal and medial areas (e.g., Reiman et al., 1997; Sprengelmeyer et al., 1999; Calder et al., 2000; Adolphs et al., 2000; 2002; Wicker et al., 2003). Difficulties comprehending emotional prosody have been associated with right-hemisphere lesions involving basal ganglia and temporoparietal cortex and atrophy in frontal and diencephalic areas in acute stroke patients (Starkstein et al., 1994). Although static emotional stimuli are quite convenient, interpersonal interaction provides a powerful and natural way to study most aspects of emotional functioning. Even with quite impaired patients, interpersonal interaction can provide a vivid snapshot of emotional strengths and deficits, including important nuances (e.g., mutual gaze patterns, listening behaviors) that may not be revealed using other methods. 25.6.8. Control tasks When working with frontal lobe patients, we typically have access to a fairly complete clinical examination and neuropsychological workup. This information is extremely helpful in identifying problems with attention, memory, language, etc., that could influence our assessment of emotional functioning. Furthermore, additional simple testing of particular systems relevant to emotional functioning is helpful in interpreting results. For this purpose, we typically assess: (a) understanding of emotion terms—a test in which terms such as ‘anger’ and ‘fear’ are matched with a list of definitions; (b) knowledge of the content of the emotioneliciting stimuli—to ensure that the stimuli we present to the patient are processed appropriately; (c) autonomic functioning—we use an isometric handgrip task and sometimes a valsalva maneuver to ensure that autonomic responding is intact; and (d) facial muscle movement—a simple test of the ability to make simple facial muscle movements (e.g., lowering the eyebrows) and emotional facial expressions (e.g., happy) is helpful to identify any abnormalities.

25.7. Laboratory and bedside testing In Table 25.1 we summarize the various laboratory tests of emotional processing in terms of the emotion processes, types, and response systems they sample; their advantages and disadvantages; and their suitability for use at the bedside. Despite the fact that much of our laboratory testing of emotional functioning makes use of considerable computing, physiological monitoring, and audiovisual resources, most of the tests can be simplified for bedside use. Audio and video stimulus presentation can be accomplished via laptop computer; self-report responses can be entered in a laptop or recorded on paper; expressive behavior can be recorded via small camcorders or ‘coded’ in real time; and peripheral physiology can be monitored manually, via portable devices, or using analog-to-digital interfaces that connect to the laptop.

25.8. Conclusion In this chapter we have provided an overview of a more differentiated view of emotional functioning in neurological patients than has been typical in the clinical and research literatures. It is our belief that comprehensive testing of emotional functioning should consider key emotion processes (reactivity, regulation, understanding), types (negative, positive, self-referential), and response systems (self-reported experience, expressive behavior, peripheral physiology, language). We believe that this kind of assessment will not only help inform and improve diagnosis and treatment of those neurological disorders that exact a toll on emotional functioning, but also increase our understanding of the neural substrates of emotion. We have also described a number of tests that can be used in the laboratory to obtain this kind of differentiated, comprehensive assessment of emotional functioning. It is our hope that as data accumulate using these methods on normal and neurological populations, those tests that prove most useful and that provide unique diagnostic information can be migrated relatively rapidly for use at the bedside.

References Adolphs R, Damasio H, Tranel D (2002). Neural systems for recognition of emotional prosody: A 3-D lesion study. Emotion 2: 23–51. Adolphs R, Damasio H, Tranel D, et al. (2000). A role for somatosensory cortices in the visual recognition of emotion as revealed by three-dimensional lesion mapping. J Neurosci 20: 2683–2690.

LABORATORY TESTING OF EMOTION AND FRONTAL CORTEX Beer JS, Heerey EA, Keltner D, et al. (2003). The regulatory function of self-conscious emotion: Insights from patients with orbitofrontal damage. J Pers Soc Psychol 85: 594–604. Bradley MM, Vrana SR (1993). The startle probe in the study of emotion and emotional disorders. In: N Birbaumer, A Ohman (Eds.), The Structure of Emotion. Hogrete & Huber, Seattle, WA, pp. 270–287. Bowers D, Blonder L, Heilman K (1992). The Florida Affect Battery. Center for Neuropsychological Studies, Cognitive Neuroscience Laboratory, Gainesville, FL. Bowlby J (1969). Disruption of affectional bonds and its effects on behavior. Can Ment Health 59: 12. Cahill L (1996). Neurobiology of memory for emotional events: Converging evidence from infra-human and human studies. Cold Spring Harb Symp Quant Biol 61: 259–264. Cahill L (1999). A neurobiological perspective on emotionally influenced, long-term memory. Semin Clin Neuropsychiatry 4: 266–273. Calder AJ, Keane J, Manes F, Antoun N, Young AW (2000). Impaired recognition and experience of disgust following brain injury. Nat Neurosci 3: 1077–1078. Conway MA, Pleydell-Pearce CW, Whitecross SE (2001). The neuroanatomy of autobiographical memory: A slow cortical potential study of autobiographical memory retrieval. J Mem Lang 45: 493–524. Chu C-C, Tranel D, Damasio AR, et al. (1997). The autonomic-related cortex: Pathology in Alzheimer’s disease. Cereb Cortex 7: 86–95. Damasio AR, Tranel D, Damasio H (1990). Individuals with sociopathic behavior caused by frontal damage fail to respond autonomically to social stimuli. Behav Brain Res 41:81–94. Daum I, Flor H, Brodbeck S, et al. (1996). Autobiographical memory for emotional events in amnesia. Behav Neurol 9:57–67. Ekman P, Friesen WV (1978). Facial Action Coding System. Palo Alto, CA, Consulting Psychologists Press. Ekman P, Friesen WV, Simons RC (1985). Is the startle reaction an emotion? J Pers Soc Psychol 49: 1416– 1426. Ekman P, Levenson RW, Friesen WV (1983). Autonomic nervous system activity distinguishes among emotions. Science 221:1208–1210. Fink GR, Markowitsch HJ, Reinkemeier M, et al. (1996). Cerebral representation of one’s own past: Neural networks involved in autobiographical memory. J Neurosci 16: 4275–4282. Fredrickson BL (1998). What good are positive emotions? Rev Gen Psychol 2:300–319. Fredrickson BL, Levenson RW (1998). Positive emotions speed recovery from the cardiovascular sequelae of negative emotions. Cogn Emott 12: 191–220. Gottman JM (1989). The specific affect coding system (SPAFF). Unpublished research manual, University of Washington. Gottman JM, Levenson RW (1985). A valid procedure for obtaining self-report of affect in marital interaction. J Consult Clin Psychol 53:151–160.

497

Gross JJ (1998). The emerging field of emotion regulation: An integrative review. Rev Gen Psychol 2: 271–299. Gross JJ, Levenson RW (1993). Emotional suppression: Physiology, self-report, and expressive behavior. J Pers Soc Psychol 64:970–986. Gross JJ, Levenson RW (1995). Emotion elicitation using films. Cogn Emot 9: 87–108. Hamann SB, Cahill L, McGaugh JL, et al. (1997). Intact enhancement of declarative memory for emotional material in amnesia. Learn Mem 4: 301–309. Hubert W, de Jong-Meyer R (1990). Psychophysiological response patterns to positive and negative film stimuli. Biol Psychol 31: 73–93. Isen AM (1999). Positive Affect. New York, NY, John Wiley & Sons Ltd. Keltner D (1995). Signs of appeasement: Evidence for the distinct displays of embarrassment, amusement, and shame. J Pers Soc Psychol 68: 441–454. Keltner D, Buswell BN (1997). Embarrassment: Its distinct form and appeasement functions. Psychol Bull 122: 250–270. Keltner D, Moffitt TE, Stouthamer-Loeber M (1995). Facial expressions of emotion and pscyhopathology in adolescent boys. J Abnorm Psychol 104: 644–652. Lang PJ (1994). The motivational organization of emotion: Affect-reflex connections. In: SHM van Goozen, NE van de Poll, JA Seargeant (Eds.), Emotions: Essays on Emotion Theory. Lawrence Erlbaum Associates, Hillsdale, NJ, pp. 61–93. Lang PJ, Bradley MM, Cuthbert BN (1990). Emotion, attention, and the startle reflex. Psychol Rev 97: 377–395. Lang PJ, Greenwald MK, Bradley MM (1988). The International Affective Picture System (IAPS) standardization procedure and initial group results for affective judgments (Technical reports 1A-1D). Center for the Study of Emotion and Attention, University of Florida. Larson CL, Sutton SK, Davidson RJ (1998). Affective style, frontal EEG asymmetry, and the time-course of the emotion-modulated startle response. Poster presented at the 38th annual meeting of the Society for Psychophysiological Research, Denver, Colorado. Lazarus R, Speisman J, Mordkoff A, Davidson L (1962). A laboratory study of psychological stress produced by a motion picture film. Psychol Monogr 76 (whole number 553). Levenson RW (1988). Emotion and the autonomic nervous system: A prospectus for research on autonomic specificity. In: HL Wagner (Ed.), Social Psychophysiology and Emotion: Theory and Clinical Applications. John Wiley & Sons, Chichester, UK, pp. 17–42. Levenson RW (1994). Human emotion: A functional view. In: P Ekman, RJ Davidson (Eds.), The Nature of Emotion: Fundamental Questions. Oxford, New York, pp. 123–126. Levenson RW (2003). Autonomic specificity and emotion. In: RJ Davidson, KR Scherer, HH Goldsmith (Eds.), Handbook of Affective Sciences. Oxford University Press, New York, pp. 212–224. Levenson RW, Gottman JM (1983). Marital interaction: Physiological linkage and affective exchange. J Pers Soc Psychol 45: 587–597.

498

R.W. LEVENSON ET AL.

Levenson RW, Ruef AM (1992). Empathy: A physiological substrate. J Pers Soc Psychol 63: 234–246. Markowitsch HJ, Calabrese P, Neufeld H, Gehlen W, Durwen HF (1999). Retrograde amnesia for world knowledge and preserved memory for autobiographic events. A case report. Cortex 35: 243–252. Mauss IB, Levenson RW, McCarter L, et al. (2005). The tie that binds? Coherence among emotion experience, behavior, and physiology. Emotion 5: 175–190. Mergenthaler E (1985). Textbank Systems: Computer Science Applied in the Field of Psychoanalysis. Springer, Heidelberg. Panksepp J (2000). The riddle of laughter: Neural and psychoevolutionary underpinnings of joy. Curr Dir Psychol Sci 9: 183–186. Piefke M, Weiss PH, Zilles K, Markowitsch HJ, Fink GR (2003). Differential remoteness and emotional tone modulate the neural correlates of autobiographical memory. Brain 126: 650–668. Reiman EM, Lane RD, Ahern GL, Schwartz GE, Davidson RJ, Friston KJ, et al. (1997). Neuroanatomical correlates of externally and internally generated emotion. Am J Psychiatry 154: 918–925. Roberts NA, Beer JS, Werner KH, et al. (2004). The impact of orbital prefrontal damage on emotional activation to unanticipated and anticipated acoustic startle stimuli. Cogn Affect Behav Neurosci 4: 307–316. Shearn D, Bergman E, Hill K, Abel A, Hinds L (1990). Facial coloration and temperature responses in blushing. Psychophysiology 27: 687–693.

Sokolov EN (1963). Higher nervous functions: The orienting reflex. Annu Rev Physiol 25: 545–580. Soto JA, Levenson RW, Ebling R (2005). Cultures of moderation and expression: Emotional experience, behavior, and physiology in Chinese Americans and Mexican Americans. Emotion 5: 154–165. Starkstein SE, Federoff JP, Price TR, et al. (1994). Neuropsychological and neuroradiologic correlates of emotional prosody comprehension. Neurology 44: 515–522. Sturm VE, Rosen HJ, Allison S, et al. (2006). Self-conscious emotion deficits in frontotemporal lobar degeneration. Brain 129: 2508–2516. Sprengelmeyer R, Young AW, Schroeder U, et al. (1999). Knowing no fear. Proc R Soc Lond B Biol Sci 266: 2451–2456. Takahashi H, Yahata N, Koeda M, et al. (2004). Brain activation associated with evaluative processes of guilt and embarrassment: An fMRI study. Neuroimage 23: 967–974. Vrana SR, Spence EL, Lang PJ (1988). The startle probe response: A new measure of emotion? J Abnorm Psychol 97: 487–491. Wicker B, Keysers C, Plailly J, et al. (2003). Both of us disgusted in my insula: The common basis of seeing and feeling disgust. Neuron 40: 655–664. Young A, Perrett D, Calder A, et al. (2002). Facial Expressions of Emotion: Stimuli and Tests. Thames Valley Test Company, Bury St. Edmunds, UK.

Handbook of Clinical Neurology, Vol. 88 (3rd series) Neuropsychology and behavioral neurology G. Goldenberg, B.L. Miller, Editors # 2008 Elsevier B.V. All rights reserved

Chapter 26

Neuropsychological characterization of mild cognitive impairment SELAM NEGASH, YONAS ENDALE GEDA, AND RONALD C. PETERSEN* Alzheimer’s Disease Research Center, Mayo Clinic College of Medicine, Rochester, MN, USA

26.1. Introduction With the increasing of the population of older adults, there is a growing interest in improving quality of life in old age and in early detection and prevention of cognitive decline. One important aspect of this endeavor is to identify individuals at an earlier point in the cognitive decline such that therapeutic interventions can be aimed at this juncture. Mild cognitive impairment (MCI) has been proposed as a condition of intermediate symptomology between the cognitive changes of aging and fully developed symptoms of dementia such as those seen in Alzheimer’s disease (AD). The rationale for the study of MCI is derived from the assumption that the sooner one intervenes in a degenerative process, the more likely the damage done to the central nervous system can be prevented. Hence the construct has been developed to represent a transitional stage between the cognitive changes of aging and very early dementia.

26.2. History The concept of MCI has evolved considerably over the years. The first attempt to characterize cognitive changes at the normal tail-end of the continuum dates back to 1962, where VA Kral used the term benign senescent forgetfulness to describe very early memory concerns with aging (Kral, 1962). This was followed by a National Institute of Mental Health workgroup in 1986 that proposed the term age-associated memory impairment (AAMI) to refer to memory changes that were felt to be variant of normal aging (Crook et al., 1986). Shortcomings of AAMI included restriction of *

impairment to memory domain only and comparison of memory function in older adults to performance of young adults. As such, AAMI was unable to delineate individuals at risk of developing pathological conditions from those undergoing the processes of normal aging. The international psychogeriatric association coined the term age associated cognitive decline (AACD) in an effort to bypass many of the shortcomings recognized in AAMI (Levy, 1994). The operational criteria for AACD referenced a variety of cognitive domains presumed to decline in normal aging and included ageand education-adjusted normative values. Alternatively, the Canadian Study of Health and Aging coined the term cognitive impairment–no dementia (CIND) to identify individuals with impaired cognitive function but not of sufficient severity to constitute dementia (Graham et al., 1997). In many respects these ‘in-between’ persons resemble MCI subjects but the CIND label actually includes a broader subset of the population. The construct of CIND encompasses individuals with lifelong cognitive impairment, static encephalopathy, and learning disability. Recently, some investigators have defined subsets of persons with CIND who more closely resemble MCI subjects (Fisk et al., 2003). The term MCI was initially used in the late 1980s by Reisberg and colleagues to describe individuals with a Global Deterioration Scale (GDS) of 3 (Reisberg et al., 1982; 1988; Flicker et al., 1991). Another classification has used the Clinical Dementia Rating Scale (CDR) to identify individuals with CDR 0.5 stage of ‘questionable dementia.’ (Morris, 1993; Morris et al., 2001) While both GDS and CDR are useful scales for classification of individuals along the continuum of severity of cognitive impairment, they do not necessarily correspond to

Correspondence to: Ronald C. Petersen, PhD, MD, Professor of Neurology, Cora Kanow Professor of Alzheimer’s Disease Research, Director, Alzheimer’s Disease Research Center, Mayo Clinic College of Medicine, Rochester, MN 55905, USA.

500

S. NEGASH ET AL.

specific diagnoses; in fact, individuals with GDS 3 or CDR 0.5 may either meet the criteria for MCI or mild dementia or AD. That is, the level of severity alone does not determine a specific diagnosis. In recent years, MCI has emerged to represent a stage of impairment beyond what is considered normal for age, but not of sufficient magnitude as to warrant the diagnosis of dementia or AD (Petersen, 2003b).

26.3. Diagnosis The operational criteria for MCI have followed similar evolution. The first major study focusing on the clinical characterization and outcome of MCI was published in 1999, and this study demonstrated the feasibility of using MCI to identify individuals as high risk for further cognitive decline and progression to dementia of the Alzheimer-type. The results of this and other studies focusing on the use of MCI as a research tool led to the adoption of the American Academy of Neurology practice parameter on early detection of dementia in 2001 (Petersen et al. 2001). The original criteria for MCI are outlined in Table 26.1. This construct was Table 26.1 Mild cognitive impairment original criteria 1. Memory complaint, preferably qualified by an informant. 2. Memory impairment for age. 3. Preserved general cognitive function. 4. Intact activities of daily living. 5. Not demented.

essentially believed to be a clinical description of persons who have impairment in the cognitive domain of memory and were destined to develop AD (Petersen et al., 1999). More recently, the construct has been expanded to include impairments in other cognitive domains that may progress to non-AD dementias. At the Symposia of the International Working Group on Mild Cognitive Impairment, held in Stockholm in 2003, the criteria for MCI were expanded (Winblad et al., 2004; Petersen, 2004). Essentially, two subtypes emerged: amnestic (including memory impairment) and non-amnestic (other non-memory cognitive domains impaired). This nomenclature is currently being using by the National Institute on Aging sponsored Alzheimer’s Disease Centers Program through their Uniform Data Set and by the Alzheimer’s Disease Neuroimaging Initiative (Mueller et al., 2005). Fig. 26.1 depicts the diagnostic algorithm that can be used to arrive at a diagnosis of a particular subtype of MCI. This diagnostic process usually begins with a person, or an informant who knows the person well, expressing some complaint about the person’s cognitive function. When presented with these complaints, the clinician should first establish whether this constitutes normal cognition or suspected dementia. This can be done by taking a history and performing a mental status exam, possibly complemented with neuropsychological testing (Daly et al., 2000). If the clinician determines that the patient is neither normal for age nor demented, but has experienced a cognitive decline by history with functional activities largely preserved, then the patient can be described as having MCI.

Fig. 26.1. Current algorithm for diagnosing MCI and its subtypes. (Reprinted from Petersen, 2004.)

NEUROPSYCHOLOGICAL CHARACTERIZATION OF MILD COGNITIVE IMPAIRMENT Once the diagnosis of MCI is established, the next task is to identify the clinical subtype. Here, the clinician should first determine whether memory is impaired, since memory impairment strongly predisposes the individual towards AD. This can be determined by office memory tests, usually involving an instrument with a delayed recall component or by more detailed neuropsychological testing. If memory is determined to be impaired for age and education, the clinician can assume that this is an amnestic subtype of MCI. If, on the other hand, memory is found to be relatively spared, but the person has impairment in other non-memory cognitive domains such as language, executive function, or visuospatial skills, this constitutes a non-amnestic subtype of MCI. Finally, the clinician should determine whether other cognitive domains are also impaired. This can also be addressed using neuropsychological testing or other relatively brief office instruments. A diagnosis of amnestic MCI—single domain is assumed if the impairment involves only memory domain, whereas amnestic MCI—multiple domain pertains to impairments in the memory domain plus at least one other cognitive domain, such as language, executive function, or visuospatial skills. Likewise, a diagnosis of non-amnestic MCI—single domain is assumed if there is impairment in a single non-memory domain, whereas non-amnestic MCI—multiple domain refers to impairments in multiple non-memory domains. This exercise is typically what is done in clinical practice to determine the clinical phenotypes of diseases. After the clinical characterization of the patient’s symptoms has been determined, the next step involves determining the etiology of the symptoms. This is typically done based on the history from the patient and

501

informant, laboratory testing for other causes of cognitive impairment and neuroimaging studies. Following these evaluations, the clinician then determines if the likely cause of the MCI syndrome is degenerative (gradual onset, insidious progression), vascular (abrupt onset, vascular risk factors, history of strokes, TIAs), psychiatric (history of depression, depressed mood, or anxiety) or secondary to concomitant medical disorders (congestive heart failure, diabetes mellitus, systemic cancer). As Fig. 26.2 depicts, the single- and multiple-domain amnestic MCI subtypes with presumed degenerative etiology likely represent a prodromal form of AD (Petersen, 2004). The non-amnestic subtypes that emphasize impairments in the non-memory domains may have a higher likelihood of progressing to non-AD dementias, such as frontotemporal dementia and dementia with Lewy bodies (Boeve et al., 2004). Therefore, combining the clinical syndrome with putative etiologies can be useful in predicting the ultimate type of dementia to which these diseases will evolve.

26.4. Neuropsychology While the diagnosis of MCI is ultimately a clinical judgment, neuropsychological testing can be useful along several steps of the decision process. When a patient presents with a cognitive complaint, neuropsychological tests, used in conjunction with patient history and mental status exam, could be useful in determining whether the complaint constitutes normal cognition or suspected dementia. Measures of global cognitive function, such as adult intelligence tests, can be used here; these measures indicate that while MCI patients do not perform as well as healthy controls, they still function

Fig. 26.2. Outcome of clinical phenotypes of MCI according to presumed etiology. (Adapted from Petersen, 2003b.)

502

S. NEGASH ET AL.

in the normal range, and they are not demented (Petersen et al., 1999). In addition to helping differentiate MCI from normal aging and dementia, neuropsychological testing could also be useful in the differential diagnosis of MCI. That is, if one follows the algorithm in Fig. 26.1, the neuropsychological profile of a patient could be useful in determining whether (i) memory is impaired, and (ii) other cognitive domains are also involved. This process can be illustrated using an approach taken by the Mayo Clinic Alzheimer’s Disease Patient Registry (ADPR), which is a prospective populationbased cohort established to study the incidence, prevalence, and risk factors for the development of MCI. In this study, participants undergo neurological examinations that include a detailed history from the patient and an informant, and also complete a variety of rating scales, including the Short Test of Mental Status (Kokmen et al., 1987), Hachinski Ischemic Scale (Rosen et al., 1980), and Geriatric Depression Scale (Sheikh and Yesavage, 1986; Yesavage, 1988). As shown in Table 26.2, neuropsychological evaluation is performed, which consists of two or three measures in each of the following cognitive domains: memory, executive function, language, and visuospatial skills. Each component test of each domain generates a raw score and this score is converted to a Mayo’s Older American Normative Studies (MOANS) value that corrects for age and transforms the raw scores to comparably scaled scores (Ivnik et al., 1992). The MOANS scores on each measure are then combined within a domain to

Table 26.2 Neuropsychological screening battery in the mayo ADPR Cognitive domain

Subtests

Memory

Logical Memory II, delayed recall (Wechsler, 1987) Visual Reproduction II, delayed recall (Wechsler, 1987) Auditory Verbal Learning Test (Rey, 1964) Trail Making Test B (Reitan, 1958) Digit Symbol Substitution (Wechsler, 1981) Boston Naming Test (Kaplan et al., 1983) Controlled Oral Word Association Test (Benton and Hamsher, 1989) Block Design (Wechsler, 1981) Object Assembly (Wechsler, 1981)

Attention/executive function Language

Visuospatial

yield a domain score which is tantamount to a z-score for that domain. To further describe this procedure, the following clinical scenario can be useful. It is important to note here, however, the above approach is described for illustrative purposes and that no particular test or cutoff score is specified. Rather, this was left to the judgment of the clinician in the appropriate clinical context. As such, while neuropsychological testing is useful, it is not used as an absolute

Case Study 26.1 A 68-year-old right-handed woman with 12 years of education presented with forgetfulness for recent events and future engagements. For the past year, she had been aware of lapses of recall of items she previously would have remembered easily. Family members and close friends also noticed these changes. Otherwise, she was living independently and had no difficulty carrying out activities of daily living, such as handling her own finances, cooking, and driving. She had difficulty identifying the onset of these symptoms but felt that they had gradually become worse in recent months. She denied depression, stress, or other complicating medical issues. She requested an appointment with a physician in order to determine if this memory problem should be pursued further. The clinical evaluation was suggestive of cognitive impairment but not severe enough to warrant

the diagnosis of dementia. Neuropsychological testing showed the following domain scores: Memory:
1.6, Attention/Executive Function: 1.0, Language:
0.5, and Visuospatial: 0.2. Comment This person probably has amnestic MCI. She is becoming slightly more forgetful, and this is noticeable to her family and friends. The most salient feature of the history concerns forgetfulness of insidious onset that gradually progressed in recent months. Consistent with this, neuropsychological testing revealed that the domain score for memory was 1.6 standard deviations below the mean. Otherwise, all other domains were within normal range for her age.

NEUROPSYCHOLOGICAL CHARACTERIZATION OF MILD COGNITIVE IMPAIRMENT determinant in the diagnosis. The clinician should determine what constitutes sufficient cognitive decline from a premorbid level of cognitive function. The clinician may be challenged by persons who are of either high intellect whose performance is now in the statistically ‘normal’ range, but this level of performance represents a change for that person, or by persons with low education level whose lower cognitive performance may not represent a change from baseline. The preferable approach to this challenge is to assimilate all the available data and make a clinical judgment. A precise history from the patient and an informant coupled with neuropsychological testing can be invaluable. It should also be noted that neuropsychological assessments can be confounded by test–retest variability. This is especially true of memory-based tasks. While population-based or group means show stability over time on test–retest assessments (Ivnik et al., 1995), individual variability can be profound. One approach to limit variability on test–retest measures is the use of composite z-scores based on multiple test measures grouped by cognitive domain. Such composite scores would be expected to average variability across multiple test measures, essentially smoothing out the performance profile that might otherwise be seen with individual test measures. MCI subtypes with a prominent deficit in the memory domain likely progress to AD (Petersen et al., 1999; Grundman et al., 2004). Pure amnestic MCI, however, is relatively rare (Alladi et al., 2006; Ganguli, 2006), and individuals show additional impairments in other cognitive domains, including, attention, language, and visuospatial ability (Albert et al., 2001; Bennett et al., 2002; Rabin et al., 2006). The risk of dementia is increased in patients with multiple domain impairment (Bozoki et al., 2001). Less is known as to which domain becomes affected following memory as one progresses from amnestic MCI to AD; some studies suggest attention/executive function is the next domain to be impaired, as neurodegenerative changes involving medial temporal lobe structures have impact on the closely related prefrontal network which mediates attentional functions (Tierney et al., 1996b; Albert et al., 2001; Negash et al., 2006). Several longitudinal and cross-sectional studies have also examined the utility of neuropsychological tests in predicting conversion from MCI to AD (Hanninen et al., 1995; Tierney et al., 1996b; Rubin et al., 1998; Petersen et al., 1999; Chen et al., 2000; Ritchie et al., 2001). One of the consistent findings from these studies is that episodic memory performance is among the most salient predictors of conversion to AD (Flicker et al., 1991; Tierney et al., 1996b; Small et al., 1997; Kluger

503

et al., 1999; Petersen et al., 1999). Further, evidence from neuroimaging studies indicates that hippocampal atrophy correlates with memory decline in amnestic MCI (Grundman et al., 2003), and also predicts conversion to AD (Jack et al., 1999). Some studies have also found that memory tests can be combined with apolipoprotein E4 carrier status to improve ability to predict progression to AD (Tierney et al., 1996a). As such, a combination of clinical features, neuropsychological testing, biomarkers and neuroimaging can be useful in improving diagnostic accuracy of MCI and ability to predict dementia. As most research on MCI has focused on amnestic MCI, relatively less is known with regards to the nonmemory domains of MCI. If one follows further the algorithm in Fig. 26.1, questions pertaining to whether or not other cognitive domains are involved can be addressed by assessing cognitive functions in nonmemory domains, such as attention/executive function, language, and visuospatial skills. MCI subtypes that emphasize impairment in attention and visuospatial domains likely progress to dementia with Lewy bodies (DLB) (Boeve et al., 2004). Consistently, patients with DLB have marked impairment on tests of attention and executive function (Salmon et al., 1996; McKeith et al., 1996). They also have impairment in visuospatial functioning, such as perceiving and drawing complex images. Compared to AD, they perform significantly worse on tasks of attention, visuoperceptual organization and letter fluency; by contrast, AD patients perform poorly on tests of verbal memory and confrontational naming (Ferman et al., 1999). As such, this disproportional relationship between attention and memory domains may help differentiate DLB from AD, and identifying these subtle differences while patients are in the transitional stage of MCI can prove useful from a therapeutic standpoint. MCI subtypes with a prominent language deficit may progress to frontotemporal dementia (FTD). One FTD subtype that is characterized by impairment in the language domain, such as reduced speech output, loss of word meaning, and impaired comprehension (Neary et al., 1998), typically has preferential involvement of the left temporal lobe. Patients with FTD can also perform poorly on tests of memory; however, these impairments are not amnestic, but reflective of failures in sustained and selective attention. Consequently, FTD patients show greater benefits from cues than do AD patients. As such, MCI patients of the non-amnestic subtype who present with prominent language impairment could represent a prodrome for FTD. MCI subtypes that likely progress to vascular dementia (VaD) could also show memory deficits.

504

S. NEGASH ET AL.

Case Study 26.2 A 74-year-old right-handed male patient presented with complaints of confusion and difficulties in reasoning and decision making. Additionally, his family members noted that he got lost while driving and had difficulty navigating familiar places. Neurological examination including a mental status exam showed impairments in attention and construction. His symptoms caused him great concern but did not significantly affect activities of daily living. Laboratory testing and CT of the head were unrevealing. His neurological evaluation was negative for stroke or any other significant neurological condition. Neuropsychological testing was notable for impairments in visuospatial and attention/executive function

MCI patients with vascular etiology tend to exhibit mixed features, where impairments can occur in amnestic or non-amnestic domains. These patients can show deficits on tests of category fluency, visuospatial skills, or executive function, in the presence or absence of a memory deficit (Ingles et al., 2002; Loewenstein et al., 2006). As such, it is difficult to differentiate between MCI subtypes that progress to AD and VaD solely on the basis of neuropsychological testing, and other information such as laboratory testing and patient history are required. As can be apparent, the diagnosis of MCI or dementia cannot be made by neuropsychological testing alone, and clinical judgment is required. Neuropsychological measures cannot fully distinguish among different types of dementia, because there is substantial overlap in neuropsychological profiles. Further, performance on neuropsychological tests is affected by many factors, including education, age, cultural background, and other comorbidities. The usefulness of any battery for identifying MCI will depend on its composition, size, and supporting data. A brief battery, including measures of delayed recall, new learning, attention, executive function, and visuospatial ability, could provide valuable information for screening and diagnosis if interpreted correctly.

26.5. Outcome and predictors Several population- and community-based studies have estimated the progression rate of MCI to dementia. Some variability exists in these estimates, which is

domains. Language and memory domains were within normal limit for age and educational level (Memory:
0.5, Attention/Executive Function:
1.2, Language: 0.8, and Visuospatial:
1.4). Comment This patient probably has non-amnestic MCI, with impairments in multiple domains of visuospatial and attention/executive function. He experienced geographic disorientation, and also had attentional impairments. He did not, however, show memory deficits, and his language domain score was also within normal range.

perhaps most reflective of variability in diagnostic criteria (Ritchie et al., 2001; Larrieu et al., 2002; Ganguli et al., 2004). The typical rate at which amnestic MCI patients progress to AD is 10–15% per year (Petersen et al., 1999; Gauthier et al., 2006). Researchers from Harvard University have reported a lower conversion rate of 6% per year. This lower rate, however, may have been due to recruitment strategy and selection of instrument, as participants in this study were recruited through media advertisement, and Clinical Dementia Rating (CDR) was the sole instrument for evaluation. The ‘stability’ of the MCI construct has also been examined by some studies. The PAQUID study in France reported a reversion rate of 40% over 2–3 years follow-up (Larrieu et al., 2002). This high rate of reversion to normal cognition may be due at least in part to the use of the Benton Visual Retention Test as the sole memory measure included in the diagnostic criteria for MCI. Thus, while some variability exists, possibly arising from variant diagnostic criteria, the consistent finding across these studies is that individuals with MCI develop dementia at a higher rate than the general population. Recently, the role of neuroimaging in predicting progression to AD has gained a great deal of attention (Killiany et al., 2000; Fox et al., 2001; Jack, 2003). Jack and colleagues have pioneered this effort and have shown that atrophy of the hippocampal formation predicts the rate of progression from amnestic MCI to AD (Jack et al., 1999). Additional measures, such as whole brain volume and ventricular volumes, have also been shown to predict progression to AD, indicating that

NEUROPSYCHOLOGICAL CHARACTERIZATION OF MILD COGNITIVE IMPAIRMENT structural MRI is useful (Jack et al., 2005). The role of FDG-PET in predicting progression has also been documented by some studies (Small et al., 1995; Reiman et al., 1996; Drzezga et al., 2005). Molecular imaging techniques that allow investigators to ‘visualize’ the development of the pathologic process have also gained interest in recent years (Klunk et al., 2004; Small et al., 2006). The Pittsburgh Compound B (PiB) is the most popular agent and labels fibrillar amyloid plaques. A second compound, developed at UCLA, is FDDNP and labels multiple neuritic elements including neuritic plaques and neurofibrillary tangles. These tracers, although in their infancy, are exciting new imaging techniques. The possible utility of CSF biomarkers in predicting rapid progression to AD has also gained attention. A recent large study indicated that low CSF Ab and high tau levels might predict which MCI subjects are likely to progress to AD more rapidly than others (Hansson et al., 2006). Ultimately, amnestic MCI subjects may be subclassified on ApoE4 carrier status, hippocampal volumes, FDG-PET markers, CSF tau and Ab levels and possibly molecular imaging tracers to identify a pure group of individuals who are highly likely to progress to AD.

26.6. Treatments As the focus of dementia research moves toward prevention, numerous clinical trials on MCI are being undertaken. Currently, there are no FDA approved treatments for MCI. While one would not expect an overall treatment for MCI due to the heterogeneity of the construct, treatments for amnestic MCI (aMCI) of a degenerative etiology that is likely progress to AD might be more feasible (Geda and Petersen, 2001; Petersen, 2003; Gauthier, 2004; Gauthier et al., 2006). Table 26.3 outlines the clinical trials on amnestic MCI that have been recently completed. Over 5,000

505

subjects have been studied worldwide largely using therapies which have been proposed for AD or were under consideration. A few trials were done to assess the impact on symptoms while most have been designed to have an impact on the rate of progression from MCI to AD (Petersen, 2003a). The most promising trial was conducted by the Alzheimer’s Disease Cooperative Study, which is a consortium of AD research centers in the USA and Canada (Petersen et al., 2005). A total of 769 subjects with amnestic MCI were randomly assigned to receive either donepezil, vitamin E, or placebo. Subjects were followed for three years; the primary endpoint was the clinical diagnosis of AD and secondary endpoints included a variety of cognitive measures, quality of life indices, and pharmoeconomic measurements. The amnestic MCI subjects progressed to AD at a rate of 16% per year. Over the three years of the study, there were no significant differences in the probability of progression to AD among the three treatment groups. However, since assumptions of the primary-analysis model were not met, prespecified group comparisons were carried out at each of the six-month evaluations. This analysis demonstrated that the donepezil group had a reduced risk of developing AD for the first 12 months of the study. Subsequent analyses showed that the treatment effect was more prominent among ApoE4 carriers, with a reduction in risk apparent throughout the 36 months of the study. The results of the secondary analysis of cognitive and global measures supported the primary outcome results. This was the first study to show that donepezil treatment may delay the clinical diagnosis of AD in MCI, and also demonstrated the feasibility of carrying out such large scale studies in MCI. Other trials have investigated the cholinesterase inhibitors, galantamine and rivastigmine, in MCI. Johnson and Johnson performed two international randomized, double-blind, placebo-controlled trials using their AD

Table 26.3 MCI clinical trials Sponsor

Compound

Duration

Endpoint

Outcome

ADCS Merck Novartis Janssen Pfizer UCB Cortex

Donepezil Vitamin E Rofecoxib Rivastigmine Galantamine Donepezil Piracetam Ampakine

3 yr 2–3 yr 3–4 yr 2 yr 6 mo 1 yr 4 wks

AD AD AD AD Symptoms Symptoms Symptoms

Partial donepezil effect Negative Negative Negative Partial symptom effect Negative Negative

506

S. NEGASH ET AL.

compound, galantamine (Gold et al., 2004). The studies assessed the ability of galantamine to slow the progression from amnestic MCI (as measured by a CDR of 0.5) to AD (as measured by a CDR of 1). There were a total of 2,048 subjects in both trials with a mean age of around 70 years. In neither trial did galantamine slow the progression of subjects from CDR 0.5 to 1 by 24 months. There was a trend for a reduction in the rate of progression in both trials in favor of galantamine (13% galantamine vs. 18% on placebo in one trial and 17% galantamine vs. 21% placebo in the other trial), but the trials did not reach statistical significance. Another large trial was conducted by Novartis using its acetylcholinesterase inhibitor, rivastigmine (Feldman et al., 2004). This study involved 1,018 subjects and was designed to assess the rate of progression from aMCI to AD over the course of two years. However, due to an unexpectedly slow conversion rate, the study was extended to four years. Over that time frame, 17.3% of the rivastigmine subjects progressed while 21.4% of the placebo subjects progressed, a difference which was not significant. There were essentially no changes over this time frame in the composite cognitive battery. The other large trial of aMCI was conducted by Merck with their COX 2 inhibitor, rofecoxib (Thal et al., 2005). This was a randomized, placebo-controlled, double-blind study involving 1,457 subjects with amnestic MCI and also assessed the rate of progression to AD over two years. However, as in the rivastigmine trial, the progression rate was lower than expected and the trial had to be extended to four years. The annual conversion rate to AD was 6.4% for the rofecoxib subjects and 4.5% for the placebo subjects and this treatment effect was statistically significant (p¼0.011) in favor of placebo, but the secondary cognitive measures did not corroborate this primary outcome. Hence, the investigators believed that this treatment difference was not clinically meaningful. Several factors led to a greater rate of progression to AD including a lower Mini-Mental State Exam score, Apo E4 carrier status, age, female gender, and prior use of ginkgo biloba. When these factors were used to analyze the primary outcome, the treatment effect in favor of placebo was no longer present. Thus, while there are several clinical trials being conducted globally, currently, there are no pharmacological interventions demonstrated to be efficacious in MCI. Nonetheless, as MCI is a rapidly evolving area of investigation, more effective treatment options are likely to be forthcoming.

26.7. Future directions While the construct of MCI is a useful clinical entity, further refinements of the criteria and the prediction

techniques may be necessary for prognosticating the outcomes. Further specificity of the criteria may result if certain biomarkers prove to be predictive of the ultimate outcome. For example, given the literature on the utility of volumetric MRI measures to predict the outcome of amnestic MCI subjects, volumetric measurements of the whole brain and hippocampal formations may lead to further refinement (Jack et al., 2005). Several studies have indicated that ApoE4 carrier status further enhances the predictability of MCI subjects to progress to AD (Petersen et al., 1995). There are limited data indicating that FDG-PET may increase the sensitivity and the specificity of progressing to AD (Drzezga et al., 2005). Finally, recent studies on the possibility of the use of Pittsburgh Compound B (PiB), amyloid imaging, or FDDNP as a means of imaging the underlying pathologic process involved in evolving AD may be useful (Klunk et al., 2004; Small et al., 2006). Ultimately, it may take a combination of factors to enhance the predictive outcome of aMCI. One large multi-center trial, the Alzheimer’s Disease Neuroimaging Initiative (ADNI) is currently underway to assess the utility of some of these markers (Mueller et al., 2005). ADNI is funded by the National Institute on Aging and industry in conjunction with the Alzheimer’s Association and is enrolling 200 normal subjects, 400 subjects with aMCI and 200 subjects with mild AD. All of the individuals will be scanned with an MRI at 1.5tesla and 25% will be scanned with a 3tesla MRI. In addition, 50% of the cohort will receive FDGpET and CSF for biomarkers will be obtained in at least 20–50% of the cohort. Blood and urine biomarkers will be obtained on all subjects and the participants will be clinically evaluated approximately every six months for the normal and MCI groups and will be followed for three years while the mild AD subjects will be followed for two years. The study will be completed around 2010. In summary, the construct of MCI is becoming an increasingly important clinical entity. The American Academy of Neurology has recently performed an evidenced-based medicine review of the literature and concluded that MCI is a useful clinical construct and that persons with MCI should be identified and monitored because of their increased likelihood of progressing to dementia (Cooper et al., 1991). On the research side, the concept of MCI has influenced virtually all aspects of research on aging and dementia including clinical aspects, neuropsychology, epidemiology, neuroimaging, neuropathology, mechanisms of disease, and clinical trials. As such, the amnestic MCI subtype as a precursor of clinically AD is being considered for an inclusion in diagnostic coding manuals such as the DSM V since it meets many of the diagnostic criteria for consideration; however, much discussion needs to ensue (Petersen and O’Brien, 2006).

NEUROPSYCHOLOGICAL CHARACTERIZATION OF MILD COGNITIVE IMPAIRMENT

References Albert MS, Moss MB, Tanzi R, et al. (2001). Preclinical prediction of AD using neuropsychological tests. J Int Neuropsychol Soc 7: 631–639. Alladi S, Arnold R, Mitchell J, et al. (2006). Mild cognitive impairment: Applicability of research criteria in a memory clinic and characterization of cognitive profile. Psychol Med 36: 507–515. Bennett DA, Wilson RS, Schneider JA, et al. (2002). Natural history of mild cognitive impairment in older persons. Neurology 59: 198–205. Benton AL, Hamsher K (1989). Multilingual Aphasia Examination. AJA Associates, Iowa City, IA. Boeve B, Ferman TJ, Smith GE, et al. (2004). Mild Cognitive Impairment preceding dementia with Lewy Bodies. Neurology 62: A86. Bozoki A, Giordani B, Heidebrink JL, et al. (2001). Mild cognitive impairments predict dementia in nondemented elderly patients with memory loss. Arch Neurol 58: 411–416. Chen P, Ratcliff G, Phil D, et al. (2000). Cognitive tests that best discriminate between presymptomatic AD and those who remain nondemented. Neurology 55: 1847–1853. Cooper JK, Mungas D, Verma M, et al. (1991). Psychotic symptoms in Alzheimer’s disease. Int J Geriatr Psychiatry 6: 721–726. Crook T, Bartus RT, Ferris SH, et al. (1986). Age-associated memory impairment: Proposed diagnostic criteria and measures of clinical change—report of a National Institute of Mental Health Work Group. Dev Neuropsychol 2: 261–276. Daly E, Zaitchik D, Copeland M, et al. (2000). Predicting conversion to Alzheimer disease using standardized clinical information. Arch Neurol 57: 675–680. Drzezga A, Grimmer T, Riemenschneider M, et al. (2005). Prediction of individual clinical outcome in MCI by means of genetic assessment and (18)F-FDG PET. J Nucl Med 46: 1625–1632. Feldman H, Scheltens P, Scarpini E, et al. (2004). Behavioral symptoms in mild cognitive impairment. Neurology 62: 1199–1201. Ferman TJ, Boeve BF, Smith GE, et al. (1999). REM sleep behavior disorder and dementia: Cognitive differences when compared with AD. Neurology 52: 951–957. Fisk JD, Merry HR, Rockwood K (2003). Variations in case definition affect prevalence but not outcomes of mild cognitive impairment. Neurology 61: 1179–1184. Flicker C, Ferris SH, Reisberg B (1991). Mild cognitive impairment in the elderly: Predictors of dementia. Neurology 41: 1006–1009. Fox NC, Crum WR, Scahill RI, et al. (2001). Imaging of onset and progression of Alzheimer’s disease with voxelcompression mapping of serial magnetic resonance images. Lancet 358: 201–205. Ganguli M (2006). Mild cognitive impairment and the 7 uses of epidemiology. Alzheimer Dis Assoc Disord 20: S52–S57. Ganguli M, Dodge HH, Shen C, et al. (2004). Mild cognitive impairment, amnestic type: An epidemiologic study. Neurology 63: 115–121.

507

Gauthier S (2004). Pharmacotherapy of mild cognitive impairment. Dialogues Clin Neurosci 6: 391–395. Gauthier S, Reisberg B, Zaudig M, et al. (2006). Mild cognitive impairment. Lancet 367: 1262–1270. Geda YE, Petersen RC (2001). Clinical trials in mild cognitive impairment. In: S Gauthier, JL Cummings (Eds.), Alzheimer’s Disease and Related Disorders Annual. Martin Dunitz, London, pp. 69–83. Gold M, Francke S, Nye JS, et al. (2004). Impact of APOE genotype on the efficacy of galantamine for the treatment of mild cognitive impairment. Neurobiol Aging 25: S521. Graham JE, Rockwood K, Beattie BL, et al. Prevalence and severity of cognitive impairment with and without dementia in an elderly population. Lancet 349: 1793–1796. Grundman M, Jack CR, Jr., Petersen RC, et al. (2003). Hippocampal volume is associated with memory but not nonmemory cognitive performance in patients with mild cognitive impairment. J Mol Neurosci 20: 241–248. Grundman M, Petersen RC, Ferris SH, et al. (2004). Mild cognitive impairment can be distinguished from Alzheimer disease and normal aging for clinical trials. Arch Neurol 61: 59–66. Hanninen T, Hallikainen M, Koivisto K, et al. (1995). A follow-up study of age-associated memory impairment: Neuropsychological predictors of dementia. J Am Geriatr Soc 43: 1007–1015. Hansson O, Zetterberg H, Buchhave P, et al. (2006). Association between CSF biomarkers and incipient Alzheimer’s disease in patients with mild cognitive impairment: A follow-up study. Lancet Neurol 5: 228–234. Ingles JL, Wentzel C, Fisk JD, et al. (2002). Neuropsychological predictors of incident dementia in patients with vascular cognitive impairment, without dementia. Stroke 33: 1999–2002. Ivnik RJ, Malec JF, Smith GE, et al. (1992). Mayo’s Older Americans Normative Studies: WAIS-R, WMS-R and AVLT norms for ages 56 through 97. Clin Neuropsychol 6: 1–104. Ivnik RJ, Smith GE, Malec JF, et al. (1995). Long-term stability and intercorrelations of cognitive abilities in older persons. Psychol Assess 7: 155–161. Jack CR Jr (2003). Magnetic resonance imaging. In: RC Petersen, (Ed.), Mild Cognitive Impairment: Aging to Alzheimer’s Disease. Oxford University Press, New York, pp. 105–132. Jack CR Jr, Petersen RC, Xu Y-C, et al. (1999). Prediction of AD with MRI-based hippocampal volume in mild cognitive impairment. Neurology 52: 1397–1403. Jack CR Jr, Shiung MM, Weigand SD, et al. (2005). Brain atrophy rates predict subsequent clinical conversion in normal elderly and amnestic MCI. Neurology 65: 1227–1231. Kaplan EF, Goodglass H, Weintraub S (1983). The Boston Naming Test, 2nd edn. Lea & Febiger, Philadelphia. Killiany RJ, Gomez-Isla T, Moss M, et al. (2000). Use of structural magnetic resonance imaging to predict who will get Alzheimer’s disease. Ann Neurol 47: 430–439. Kluger A, Ferris SH, Golomb J, et al. (1999). Neuropsychological prediction of decline to dementia in nondemented elderly. J Geriatr Psychiatry Neurol 12: 168–179.

508

S. NEGASH ET AL.

Klunk WE, Engler H, Nordberg A, et al. (2004). Imaging brain amyloid in Alzheimer’s disease with Pittsburgh Compound-B. Ann Neurol 55: 303–305. Kokmen E, Naessens JM, Offord KP (1987). A short test of mental status: description and preliminary results. Mayo Clin Proc 62: 281–288. Kral VA (1962). Senescent forgetfulness: Benign and malignant. Can Med Assoc J 86: 257–260. Larrieu S, Letenneur L, Orgogozo JM, et al. (2002). Incidence and outcome of mild cognitive impairment in a populationbased prospective cohort. Neurology 59: 1594–1599. Levy R (1994). Aging-associated cognitive decline. Int Psychogeriatr 6: 63–68. Loewenstein DA, Acevedo A, Agron J, et al. (2006). Cognitive profiles in Alzheimer’s disease and in mild cognitive impairment of different etiologies. Dement Geriatr Cogn Disord 21: 309–315. McKeith IG, Galasko D, Kosaka K, et al. (1996). Consensus guidelines for the clinical and pathologic diagnosis of dementia with Lewy bodies (DLB): Report of the consortium on DLB international workshop. Neurology 47: 1113–1124. Morris JC (1993). The Clinical Dementia Rating (CDR): Current version and scoring rules. Neurology 43: 2412–2414. Morris JC, Storandt M, Miller JP, et al. (2001). Mild cognitive impairment represents early-stage Alzheimer disease. Arch Neurol 58: 397–405. Mueller SG, Weiner MW, Thal LJ, et al. (2005). The Alzheimer’s Disease Neuroimaging Initiative. In: JR Pettrella, PM Doraiswamy (Eds.), Neuroimaging Clinics of North America: Alzheimer’s Disease: 100 years of Progress, Vol. 15. Elsevier Saunders, Philadelphia, pp. 869–877. Neary D, Snowden JS, Gustafson L, et al. (1998). Frontotemporal lobar degeneration: A consensus on clinical diagnostic criteria. Neurology 51: 1546–1554. Negash S, Geda YE, Pankratz VS, et al. (2006). Progression of cognitive impairments in mild cognitive impairment: What is the next domain to be impaired after memory? International Congress of Alzheimer’s Disease [Abstract]. Petersen R (2003a). Mild cognitive impairment clinical trials. Nat Rev Drug Discov 2: 646–653. Petersen RC (2003b). Conceptual overview. In: RC Petersen (Ed.), Mild Cognitive Impairment: Aging to Alzheimer’s Disease. Oxford University Press, New York, pp. 1–14. Petersen RC (2004). Mild cognitive impairment as a diagnostic entity. J Intern Med 256: 183–194. Petersen RC, O’Brien J (2006). Mild cognitive impairment should be considered for DSM-V. J Geriatr Psychiatry Neurol 19: 147–154. Petersen RC, Smith GE, Ivnik RJ, et al. (1995). Apolipoprotein E status as a predictor of the development of Alzheimer’s disease in memory-impaired individuals. JAMA 273: 1274–1278. Petersen RC, Smith GE, Waring SC, et al. (1999). Mild cognitive impairment: Clinical characterization and outcome. Arch Neurol 56: 303–308. Petersen RC, Stevens JC, Ganguli M, et al. (2001). Practice parameter: Early detection of dementia: Mild cognitive

impairment (an evidence-based review). Neurology 56: 1133–1142. Petersen RC, Thomas RG, Grundman M, et al. (2005). Donepezil and vitamin E in the treatment of mild cognitive impairment. N Engl J Med 352: 2379–2388. Rabin LA, Roth RM, Isquith PK, et al. (2006). Self- and informant reports of executive function on the BRIEF-A in MCI and older adults with cognitive complaints. Arch Clin Neuropsychol: . Reiman EM, Caselli RJ, Yun LS, et al. (1996). Preclinical evidence of Alzheimer’s disease in persons homozygous for the E4 allele for apolipoprotein E. N Engl J Med 334: 752–758. Reisberg B, Ferris SH, de Leon MJ, et al. (1982). The Global Deterioration Scale for assessment of primary degenerative dementia. Am J Psychiatry 139: 1136–1139. Reisberg B, Ferris SH, de Leon MJ, et al. (1988). Stagespecific behavioral, cognitive, and in vivo changes in community residing subjects with age-associated memory impairment and primary degenerative dementia of the Alzheimer’s type. Drug Dev Res 15: 101–114. Reitan RM (1958). Validity of the Trail Making Test as an indicator of organic brain damage. Percept Mot Skills 8: 271–276. Rey A (1964). L’Examen Clinique en Psychologie. Presses Universitaires de France, Paris. Ritchie K, Artero S, Touchon J (2001). Classification criteria for mild cognitive impairment: A population-based validation study. Neurology 56: 37–42. Rosen WG, Terry RD, Fuld PA, et al. (1980). Pathological verification of ischemic score in differentiation of dementias. Ann Neurol 7: 486–488. Rubin DH, Storandt M, Miller JP, et al. (1998). A prospective study of cognitive function and onset of dementia in cognitively health elders. Arch Neurol 55: 395–401. Salmon DP, Galasko D, Hansen LA, et al. (1996). Neuropsychological deficits associated with diffuse Lewy body disease. Brain Cogn 31: 148–165. Sheikh JI, Yesavage JA (1986). Geriatric Depression Scale (GDS): Recent evidence and development of a shorter version. In: TL Brink (Ed.), Clinical Gerontology: A Guide to Assessment and Intervention. Haworth Press, New York, pp. 165–173. Small BJ, Herlitz A, Fratiglioni L, et al. (1997). Cognitive predictors of incident Alzheimer’s disease: A prospective longitudinal study. Neuropsychology 11: 413–420. Small GW, Kepe V, Ercoli LM, et al. (2006). FDDNP-PET binding differentiates MCI from dementia and increases with clinical progression. Alzheimers Dement 2: 5318–5319. Small GW, Mazziotta JC, Collins MT, et al. (1995). Apolipoprotein E Type 4 allele and cerebral glucose metabolism in relatives at risk for familial Alzheimer disease. JAMA 273: 942–947. Thal LJ, Ferris SH, Kirby L, et al. (2005). A randomized, double-blind, study of rofecoxib in patients with mild cognitive impairment. Neuropsychopharmacology 30: 1204–1215.

NEUROPSYCHOLOGICAL CHARACTERIZATION OF MILD COGNITIVE IMPAIRMENT Tierney MC, Szalai JP, Snow WG, et al. (1996a). A prospective study of the clinical utility of ApoE genotype in the prediction of outcome in patients with memory impairment. Neurology 46: 149–154. Tierney MC, Szalai JP, Snow WG, et al. (1996b). Prediction of probable Alzheimer’s disease in memory-impaired patients: A prospective longitudinal study. Neurology 46: 661–665. Wechsler DA (1981). Wechsler Adult Intelligence ScaleRevised. Psychological Corporation, New York.

509

Wechsler DA (1987). Wechsler Memory Scale-Revised. Psychological Corporation, New York. Winblad B, Palmer K, Kivipelto M, et al. (2004). Mild cognitive impairment—beyond controversies, towards a consensus. J Intern Med 256: 240–246. Yesavage JA (1988). Geriatric Depression Scale. Psychopharmacol Bull 24: 709–711.

Handbook of Clinical Neurology, Vol. 88 (3rd series) Neuropsychology and behavioral neurology G. Goldenberg, B.L. Miller, Editors # 2008 Elsevier B.V. All rights reserved

Chapter 27

Neuropsychology of Alzheimer’s disease MARILYN ALBERT* Department of Neurology, Johns Hopkins University, Baltimore, MD, USA

27.1. Introduction Dementia, particularly Alzheimer’s disease (AD), was first emphasized as a major public health problem over 30 years ago (Katzman, 1976). This led to increased research efforts to understand the clinical presentation and diagnosis, the pathobiology and underlying cause, treatments for established disease and, more recently, an emphasis on early diagnosis and treatment. It is fortunate that there is considerable consensus with regard to the clinical phenotype of AD. This has led to the development of widely accepted clinical criteria for use in both clinical and research settings (McKhann et al., 1984; American Psychiatric Association, 1994). Many subsequent studies have demonstrated that these criteria can be reliably applied across sites and that accuracy of diagnosis in comparison with pathological findings is high (e.g., Blacker et al., 1994). Agreement about clinical criteria also permitted the conduct of a large number of clinical trials, ultimately leading to approval of five medications for AD, four cholinesterase inhibitors and Memantine (an NMDA receptor antagonist). These medications offer symptomatic relief, but do not alter the rate at which patients decline over time. This has increased the urgency of finding better treatments for AD, as the demographic shift in the population toward greater life expectancy suggests geometrically increasing numbers of AD patients in the coming decades unless more effective treatments can be developed. An improved understanding of the neurobiology of AD has led to optimism that disease-modifying treatments may be on the horizon (Selkoe, 2005). There is, however, concern that if disease is too far advanced, response to these treatments may be muted. This, in turn, has led a focus on identifying patients as early as possible in the course of disease. *

Since AD was first described, it has been clear that the symptoms develop gradually over many years (Alzheimer, 1907). Thus, it would seem that, by definition, there must be a prodromal phase of disease during which symptoms are evolving but the individual does not yet meet criteria for dementia. Various terms have been used to describe this prodromal phase, but the term mild cognitive impairment (MCI) has gained the widest recognition (Flicker et al., 1991; Petersen et al., 1999). There has been divergence, however, in how the criteria for MCI have been applied, leading to widely varying estimates of its prevalence in the population (e.g., Ritchie et al., 2001; Larrieu et al., 2002) and controversy regarding its utility as a clinical syndrome (Gauthier and Touchon, 2005). The current review will focus on the neuropsychology of AD and MCI, delineating where broad areas of consensus exist and, where there is disagreement, outlining the primary issues to be resolved. Since the cognitive deficits in AD and MCI are the result of selective alterations in the brain, the relationship between neuropsychological deficits and neuropathological or brain imaging findings will also be discussed, where relevant.

27.2. Typical clinical presentation of AD 27.2.1. Clinical issues 27.2.1.1. Cognitive presentation This clinical presentation typifies the vast majority of patients with AD. It is a disorder whose initial feature is gradually progressive difficulty with learning and retention of new information. This difficulty with episodic memory is evident in day-to-day activities where retention over a delay is needed (such as remembering conversations and appointments), and on memory tasks that require an individual to learn something

Correspondence to: Marilyn S. Albert, PhD, Johns Hopkins University, Department of Neurology, 720 Rutland Avenue, Baltimore, MD 21205–2196. E-mail: [email protected], Tel:þ1-(410)-614-3040.

512

M. ALBERT

Case Study 27.1 A 75-year old female, married for almost 50 years, began showing gradual cognitive decline. She had increasing difficulty in remembering recent events. For example, from one week to the next she might forget a conversation she had with her daughter over the phone, she was increasingly likely to forget appointments with friends, and might forget to buy some of the items at the store when shopping. Over time, the memory problems became more pronounced, so that she might forget conversations from one day to the next, rather than one week to the next, and began asking the same questions repeatedly within a short period of time. She could, however, still remember important personal and political events from the past. In addition, multi-stepped tasks, such as cooking or balancing the checkbook, became problematic. For example, she had been an excellent cook, and on occasion would forget an essential ingredient in a recipe she knew well, or overcook one item in a meal, while another was underdone. In casual social situations she seemed unchanged, but she seemed less interested in spending time with family and friends and, when at community events, was less likely to be actively engaged. As these problems became gradually worse, her family realized that something was wrong and brought her for evaluation. Her neurological examination was unremarkable. She had a snout reflex and decreased ankle jerks, but no focal signs or symptoms. On mental status testing, she received a score of 25 on the Mini Mental State Exam (MMSE), losing 2/3 points on recall of the three items, losing 2 points on orientation, and 1 point on spelling WORLD backwards. Formal neuropsychological testing showed impaired recall of a story after a delay, and impaired list learning and retention. She was impaired on Trails B of the Trail Making Test (which requires one to

new (e.g., a story or a word list) and then retain it over a delay (Welsh et al., 1991). Once the disease is well established, impairments are evident on episodic memory tasks that assess both verbal and nonverbal information (Storandt and Hill, 1989). Problems with executive function are also common in most patients early in the course of disease. Multi-step tasks that require switching from one aspect of task to

alternately connect numbers and letters in sequence); she took much longer than normal to complete the task, and made two errors. Her verbal fluency was decreased both for generation of words based on letters (e.g., F, A, S) and categories (e.g., animals). Her confrontation naming ability, as assessed by the Boston Naming Test, was slightly low. Trails A of the Trail Making Task (which only requires one to connect numbers in sequence) was, however, within normal limits, as was digit span forward (the ability to repeat a series of numbers in the order they were given). A magnetic resonance imaging (MRI) scan showed atrophy, but no evidence of strokes or other structural lesion. Laboratory tests performed to examine potential metabolic problems were within normal limits. She was taking medication for hypertension and hypercholesterolemia, both of which appeared to be well treated. Over the course of the next 6 years, the cognitive problems became progressively worse. Her memory impairment was so severe that she no longer remembered getting married or recognized her children or grandchildren. She developed progressive difficulty with language; over time she had more and more difficulty finding words in conversation; she was able to read but comprehension was gradually impaired. Her social interaction was limited, as she was increasingly fearful outside the home and became agitated in group situations with a lot of activity. On postmortem, she received a diagnosis of definite AD. She had widespread neuronal loss, and evidence of neuritic plaques and neurofibrillary tangles throughout the temporal, parietal, and frontal lobes. She also had a couple of lacunar infarcts and other evidence of small vessel disease.

another, such as preparing a meal, are particularly prone to difficulty. Neuropsychological tasks that emphasize set formation and set switching are, likewise, most sensitive impairments in the early phase of disease. The Trail Making test is a good example of this, particularly because it requires the individual to switch from one over-learned series to another (i.e., switching from numbers to letters, both of which must be connected in order).

NEUROPSYCHOLOGY OF ALZHEIMER’S DISEASE The typical AD patient then develops problems with language. There are subtle problems with naming and verbal fluency early in disease. Some investigators have argued that this is because of an underlying problem with semantic networks (Chan et al., 1993), an issue that is discussed further below. During the middle phase of disease, it is the language problems that become progressively worse. The patient has increasing difficulty finding the words to express themselves and understanding complex ideas or sentences. Interestingly, reading is generally preserved till late in the disease, but this is often accomplished with little understanding of what is being read. Spatial abilities also experience the greatest decline in the middle stages of disease in patients with a typical presentation. As a consequence, tasks that involve copying two-dimensional figures are generally preserved in mildly impaired patients. It has been reported that tasks that involve a spatial component are impaired in mild AD, but this is usually because they make other types of cognitive demands as well. For example, clock copying is generally preserved in mildly impaired patients, whereas clock drawing to command, which requires planning and organization, as well as spatial ability, is not (Rouleau et al., 1996). Sustained attention is well preserved in mild-tomoderately impaired AD patients. If a task is simple enough that the patient can keep the instructions in mind (e.g., as in digit span where one is asked to repeat a series of numbers in order), then it is generally performed within the normal range. This finding is so consistent, that impairments in attention in an otherwise mildly impaired patient is used as a marker that the patient has a disorder other than AD, such as dementia with Lewy bodies (McKeith, 2006) or delirium (Kramer and Reifler, 1992). 27.2.1.2. Cognitive history While cognitive testing is important in confirming the diagnosis of AD, a good cognitive history is essential. Since the patient’s self-report may be unreliable, it is important to obtain a cognitive history from one or more family members (or equivalent caregivers). The history needs to elicit information about three issues: (1) the initial symptoms, (2) the time of onset, (3) the nature of progression. Determining the initial symptoms will provide essential information regarding the diagnosis. For example, an early symptom of frontotemporal dementia (FTD) is often a change in personality (e.g., inappropriate behavior), while the most common early symptom of Alzheimer’s disease is a gradually progressive decline in the ability to learn new information. Several years after the disease has begun, which is

513

when most patients’ conditions are actually diagnosed, the cognitive symptoms of the two disorders may be very similar, so that information regarding the initial symptoms may be critical to accurate diagnosis. Establishing the time of onset will provide important clues regarding the nature of the disorder, because some diseases are well known for their particularly rapid rate of decline (e.g., Creutzfeldt–Jakob disease). It will also enable the clinician to give the family some tentative feedback regarding the course of the illness. If the point at which the disorder began is known, the rate of decline can be determined by seeing how long it has taken the patient to reach the present level of function. While estimates of the rate of progression can be only roughly approximated, it is extremely helpful for the family to have an estimate in making plans for the future. Determining whether the initial symptoms came on suddenly or gradually also aids in diagnosis. If the onset of illness is gradual and insidious, as in Alzheimer’s disease, it is often only in retrospect that the family realizes that a decline has occurred. In contrast, a series of small strokes, even if not evident on MRI, generally produce a history of sudden onset and stepwise progression. There may, for example, be an incident (e.g., a fall or a period of confusion) that marks the beginning of the disorder. Delirium generally has an acute onset as well, although if they are the result of a condition such as drug toxicity, this may not be the case. The manner in which the symptoms have progressed over time also provides important diagnostic information. A stepwise deterioration, characterized by sudden exacerbations of symptoms, is most typical of multi-infarct dementia. However, a physical illness in a patient with AD (e.g., pneumonia, a hip fracture, etc.) can cause a rapid decline in cognitive function. The sudden worsening of symptoms in a psychiatric patient (e.g., depression) also can produce an abrupt decrease in mental status. Careful questioning is therefore necessary to determine the underlying cause of a stepwise decline in function. 27.2.1.3. Neurological examination, laboratory and imaging findings The neurological examination is generally unremarkable in the early stage of AD. Thus it is most useful for identifying whether signs and symptoms of disorders other than AD are present (e.g., Parkinson’s disease, Creutzfeldt– Jakob disease, Huntington’s disease, etc.). Laboratory findings are also used to identify causes of cognitive decline that are unrelated to a neurodegenerative process (e.g., thyroid, liver, or kidney disease, B12 deficiency, etc.). Likewise, in the clinical setting, imaging findings are generally used to determine whether other diseases,

514

M. ALBERT

beside AD, are the cause of the patient’s cognitive decline (e.g., strokes, tumors, etc.). In the USA, positron emission tomography (PET) is approved for reimbursement only for the differential diagnosis of AD vs. FTD. Thus, physicians are only supposed to request reimbursement from Medicare for a PET scan if FTD is suspected.

that similar patient populations are likely to be included in studies regardless of their location around the world.

27.2.1.4. Diagnostic criteria for AD

27.3.1.1. Cognitive presentation

The clinical diagnostic criteria for AD encapsulate the description above. They require that the patients have a gradually progressive decline in two or more domains of cognition (with memory predominant), of sufficient severity to impair social and occupational function. As noted above, these criteria (McKhann et al., 1984; American Psychiatric Association, 1994) have been widely accepted for a number of decades. This uniformity of approach has greatly helped research into the underlying cause of the disease because it has meant

This clinical presentation typifies a very rare and unusual group of patients with AD. Like the typical patients, the symptoms are gradually progressive but the initial symptom is in the area of spatial ability. Any task that requires spatial skill will be impaired. In the example above, the Trail Making Test was impaired because it involved spatial skill, not because set formation and set shifting was affected. There is difficulty with episodic memory but in the early stage of disease there tends to be less loss of information over a delay than retention over a delay than

27.3. Spatial presentation of AD 27.3.1. Clinical issues

Case Study 27.2 A 53-year-old male, married for about 20 years, began having evidence of a change in function. At first, he complained that he was having trouble seeing. He went to the optometrist who checked his eye-glasses and concluded the prescription was appropriate. He had a few minor automobile accidents, primarily related to problems judging distance between his car and another object. He was an avid golfer, and his golf game deteriorated. He had the sense that going down stairs was more difficult and walked more slowly and carefully when he did. He then began having trouble remembering recent events and started keeping a calendar in order to keep track of things. His job performance as a business executive began to suffer, secondary to these difficulties, and he was urged to have an evaluation. His neurological examination was within normal limits, with the exception of visual fields. It was clear that he had trouble tracking a moving object in space (such as pencil or a finger). On mental status testing, he received a score of 28 on the MMSE, losing 1/3 points on recall of the three items, and 1/1 point on figure copying. Formal neuropsychological testing showed mild impairments both on recall of a story after a delay, and impaired list learning and retention. He was impaired on both Trails A and Trails B of the Trail

Making Test; it took him a very long period of time to scan the page and figure out where to draw each line. His confrontation naming ability was impaired because he misidentified the objects (e.g., he called the ‘harmonica’ a ‘bus’). His verbal fluency was normal for both letters and categories. An MRI scan showed atrophy, but no evidence of focal abnormality. All laboratory tests were within normal limits. He was taking no medications. Over the course of the next 12 years, the cognitive problems became progressively worse. His visual problems became progressively worse to the point where he became almost functionally blind. He had increasing problems with depth perception and would misreach for objects and could not judge the depth of the tread on the stairs. He had trouble discriminating objects of similar colors, for example, he couldn’t see mashed potatoes on a white plate. His memory problems also gradually worsened but until very late in the disease course were never as severe as his spatial difficulty. He eventually developed difficulty with language and attention, but this was many years after the diagnosis. On postmortem, he received a diagnosis of definite AD. He had widespread neuronal loss, and evidence of neuritic plaques and neurofibrillary tangles in visual association pathways as well as in the temporal and parietal lobes.

NEUROPSYCHOLOGY OF ALZHEIMER’S DISEASE

515

is the case in the typical patient (Albert et al., 1990), leading to a lesser memory impairment in daily life. The age of onset of the patient described above is also characteristic of this presentation of disease. As a group, the patients tend to be younger, often under the age of 65, though older autopsy confirmed patients with this presentation have been described. It should be noted that, since these patients are rare, and typically have an early onset of disease, the majority of neuropsychological findings concerning AD pertain to patients with the typical presentation described above.

patients have been reported who even appear to have a visual field cut. On postmortem, AD pathology is commonly seen in visual association pathways in the occipitoparietotemporal junction, as well as in more widespread areas of the temporal and parietal lobes; there is generally less pathology than would be expected in the prefrontal cortex (Hof et al., 1997). The imaging findings are particularly helpful in making the diagnosis because an MRI will rule out the presence of a stroke or tumor that could explain the striking difficulty with visual perception.

27.3.1.2. Cognitive history

27.3.1.4. Diagnostic criteria for AD

The cognitive history is important in establishing the diagnosis, as it is with the AD patient with the typical presentation. The initial symptoms are gradually progressive but in the spatial domain, rather than the domain of memory. As a group the patients tend to have more insight than the typical patients. Since their memory is only mildly impaired early in the course of disease, they are often good historians, describing their sense that they were not seeing normally and their ineffective efforts to ‘correct’ their vision.

The clinical diagnostic criteria for AD tend to be appropriate for these patients, as most have a memory deficit as well as a spatial deficit by the time they come to clinical attention.

27.3.1.3. Neurological examination, laboratory and imaging findings The neurological examination is generally unremarkable, with the exception of visual field testing. Some

27.4. Language presentation of AD 27.4.1. Clinical issues 27.4.1.1. Cognitive presentation This clinical presentation typifies another group of very rare patients with AD. Like the typical patients, the symptoms are gradually progressive but the initial symptom is in the area of language ability. Any task that requires language skill will be impaired. In the example above, word list learning was impaired because it

Case Study 27.3 A 68-year-old woman, married for over 30 years, began showing gradual cognitive decline. She had increasing difficulty with speech. She was hesitant in her speech and experienced increasing trouble with word finding. She paused frequently, searching for words, and occasionally made errors in pronunciation. Over time she began to have trouble with reading and comprehension. She gradually developed difficulty handling complex tasks, such as planning a meal. Her neurological examination was unremarkable. On mental status testing, she received a score of 25 on the MMSE, losing 4 points on spelling WORLD backwards and 1 point on repeating the phrase ‘no ifs, ands, or buts.’ She had difficulty repeating the 3 words to be remembered, but was able to recall them after a delay. Formal neuropsychological testing showed impairments in almost all aspects of language, including confrontation naming, reading, writing, and comprehension. Verbal fluency for both letters and categories

was impaired. She was slow on Trails B of the Trail Making Test; and made 1 error. Memory testing that used spatial stimuli (such as figure recall) was within normal limits. However, memory testing that involved word list learning was impaired. An MRI scan showed atrophy, but no evidence of focal abnormality. All laboratory tests were within normal limits. She was taking medicine for thyroid disease and hypertension. Over time, problems with memory developed, but this was many years after the onset of her language problems. By the time her memory problems developed, she was using gesture to supplement her speech because of her difficulty communicating by normal means. On postmortem, she received a diagnosis of definite AD. She had neuronal loss, and evidence of neuritic plaques and neurofibrillary tangles throughout the temporal, parietal, and frontal lobes.

516

M. ALBERT

involved language skill, not because memory was affected. It is unclear whether problems with executive function appear early in the course of disease, as they did with this patient, as case reports of such patients are limited. The age of onset of the patient described above is also characteristic of this presentation of disease. As a group, the patients tend to be slightly younger than those with the typical presentation of AD. 27.4.1.2. Cognitive history The cognitive history is important in establishing the gradual onset of the symptoms, but clinical presentation and cognitive history overlaps that seen in a form of FTD known as progressive aphasia (PPA). Thus, when seen early in the course of disease it is exceedingly difficult to determine whether the patient will have AD or FTD on autopsy. 27.4.1.3. Neurological examination, laboratory and imaging findings The neurological examination is generally unremarkable. As with the spatial presentation of AD, the imaging findings are helpful in ruling out the presence of a tumor or series of strokes that could explain the progressive difficulty with language. Little is known about the utility of PET scans in differentiating the language presentation of AD from PPA. 27.4.1.4. Diagnostic criteria for AD The clinical diagnostic criteria for AD tend not to identify these patients early in the course of disease unless memory problems are an early manifestation. Most patients with the language presentation of AD, in fact, meet criteria for PPA. It has even been argued that since the pathology of PPA is often nonspecific, the patients who have come to autopsy have had both disorders but the latter one was unrecognized. In clinical settings it is, unfortunately, necessary to tell the patient and family that while the patient clearly has a neurodegenerative disorder, the specific diagnosis is unclear.

27.5. Prodromal AD There is considerable evidence to support the argument that there is a transitional phase between normal function and AD dementia. The feasibility of studying this transitional phase is based on the fact that the clinical hallmark of AD is a progressive decline in cognitive function. A number of research groups therefore recruited nondemented individuals with mild cognitive impairments and followed them over time, with the goal of

examining the nature of the cognitive changes that occurred during the transitional phase between normality and frank dementia. Neuropsychological studies of individuals defined as neither normal nor demented, demonstrate progressive declines in cognition over time, which are particularly striking in the area of episodic memory, as discussed further below. Other domains appear to be affected as well, however, consistent with the fact that the clinical criteria for dementia require impairment in two or more cognitive domains. Pathological findings in nondemented cognitively impaired individuals are particularly important in this context. Given the difficulty of obtaining brain tissue at a time that individuals are not demented, it is not surprising few published results are available. The largest sample comes from the Religious Order Study and included 37 individuals with a clinical diagnosis of mild cognitive impairment (MCI), 60 normal controls, and 83 cases of AD (Bennett et al., 2005). Of the 37 MCI cases, 40% had a low likelihood of AD based on NIA–Reagan criteria, with 60% demonstrating an intermediate or high likelihood of AD. This was in contrast to the normals, where these proportions were reversed (60% vs. 40%, respectively). Only 10% of the cases with clinically diagnosed AD had a low likelihood of AD based on pathological criteria. A report from the Mayo Clinic included 15 people who died with a clinical diagnosis of MCI, 28 normal controls and 23 cases of AD (Petersen et al., 2006). Most patients with MCI did not meet neuropathologic criteria for AD; the authors argued that the pathological features represented a transitional state of evolving AD. These reports contrast with the findings from Washington University where almost all of the cases met pathological criteria for AD (Morris et al., 2001). This suggests that there is likely variation in the clinical criteria used to define the cases during life. It is evident that in some sets of cognitively impaired nondemented cases, the proportion of those with a high likelihood of AD based on pathological criteria is much less than among individuals who meet clinical criteria for AD; however, a substantial number of nondemented cognitively impaired individuals do meet pathological criteria for AD. It is also important to note that many of the cases, regardless of clinical diagnosis, had evidence of vascular disease (Bennett et al., 2005; Petersen et al., 2006). Taken together, these findings indicate that it is possible to identify individuals in a transitional state between normal function and AD dementia, and that such individuals have cognitive and brain changes that are consistent with a transitional phase of disease. For research purposes, it seems important to retain the

NEUROPSYCHOLOGY OF ALZHEIMER’S DISEASE distinctiveness of this phase of disease so that the characteristics of this phase and the effectiveness of interventions can be carefully studied. In clinical settings, distinguishing a transitional phase of disease also seems very important in order to provide appropriate feedback to patients. Recent research studies indicate that there is considerable variation in the clinical outcome of individuals who are said to be cognitively impaired but nondemented by whatever criteria. As prediction of outcome remains challenging, even in research settings, it seems important to communicate this lack of certainty when providing a clinical diagnosis to individual patients.

27.6. Heterogeneity of MCI A review of the literature suggests that much of the controversy surrounding the term MCI derives largely from the fact that the criteria have been implemented in a variety of ways in research settings, while at the same time the syndrome is more heterogeneous than originally suggested. The clinical criteria have changed over time in recognition of this heterogeneity. However, a number of important issues remain to be clarified. The MCI criteria elucidated by Petersen and colleagues in 1999 implied that cases of MCI represented a fairly uniform group of individuals (Petersen et al., 1999). These criteria were as follows: (i) memory complaint, corroborated by an informant if possible, (ii) objective memory impairment for age, (iii) relatively preserved general cognition for age, (iv) intact basic activities of daily living, (v) not demented. Following studies demonstrating that MCI cases defined in this manner had a more variable outcome than had been previously suggested, the criteria were modified to permit clinical subtypes with variable outcomes, based on the presumed etiology of underlying the disorder. Two primary subtypes were delineated, based on whether a predominant memory disorder was present or absent, called amnestic and non-amnestic MCI (Petersen, 2004). The revised criteria also acknowledged the possibility that more than one cognitive domain might be impaired within each of these subtypes (e.g., amnestic MCI, single or multiple domain impaired). These revised criteria are conceptually similar to the term cognitive impairment no dementia (CIND) introduced by the Canadian Study of Health and Aging (Davis and Rockwood, 2004) in that they encompass a broad range of cognitive deficits caused by multiple etiologies. In this context, the original clinical criteria for MCI were clearly focused on amnestic MCI, and Petersen and colleagues were clearly attempting to focus on individuals likely to be in the prodromal phase of

517

AD. Their work and that of numerous other groups has since demonstrated that amnestic MCI subjects (single or multiple domain impaired) are at increased risk of progressing to a diagnosis of AD over time. What was also unrecognized in the original reports was the importance of the source of subjects as a factor in both the severity and the nature of the population under study. In retrospect it now seems clear that the broader one casts the net of inclusion in a study, the more likely one is to include individuals with less severe underlying disease. It is therefore not surprising that studies emerging from memory clinics in tertiary care settings report the highest proportion of individuals who progress to meet criteria for AD over time (e.g., Rubin et al., 1989). Whereas, studies that recruit broadly from the community (e.g., via the media) are likely to have much lower rates of ‘conversion’ to AD on follow-up (e.g., Daly et al., 2000). This does not necessarily mean that the underlying disease process is different but rather that the investigators have captured a different range of disease severity within their study population. An additional source of variation is introduced when studies are conducted in epidemiological settings as opposed to clinical settings. In epidemiological settings it is virtually impossible to require that each subject have an informant (as is usually the case in clinic-based studies), as epidemiological studies seek to represent the entire range of individuals in the population. Therefore it is necessary to rely more heavily on neuropsychological testing as the marker of cognitive decline. This increases the importance of the particular cognitive tests that have been selected; the reliability and validity of each of the tests is critical, as well as the range of cognitive domains included in the test battery. For example, if tests are selected that have a ceiling effect, it is likely that fewer individuals with impairments will be found. Likewise, if a particular cognitive domain is not included in a test battery (e.g., executive function), it would not be possible to determine whether the subjects would have been impaired in that domain. In order to maximize enrollment and followup it is also necessary to reduce the length of the evaluation in an epidemiological setting, as opposed to a clinical setting, resulting in less detailed information than is optimal. These restrictions, if applied equally to all participants, most likely influence the absolute numbers of individuals identified in a particular category (as sensitivity will vary depending on the procedures employed), but they should not alter the relative proportion of individuals meeting criteria or the proportion of individuals who change status over time. As studies of nondemented cognitively impaired individuals expanded to broader settings, it also became

518

M. ALBERT

clear that there were substantial numbers of individuals whose memory impairment was the predominant but not sole cognitive problem that could be seen. Many individuals with prodromal AD were slightly impaired in other domains (e.g., language or executive function) in addition to memory. Likewise, individuals were seen whose primary cognitive impairment was in domains other than memory (e.g., attention or spatial skill). The recent revision of the MCI criteria (Petersen, 2004) recognizes these findings and appropriately acknowledges that multiple clinical syndromes must, by definition, have a transitional phase during which cognitive impairments are in evolution. The revised criteria now describe criteria for amnestic MCI (single and multiple domains impaired), which is thought to represent the majority of individuals who will progress to a diagnosis of AD over time. Those with non-amnestic MCI (single and multiple domains impaired) are thought to pertain to the transitional phase of other dementias (e.g., frontotemporal dementia, vascular dementia) as well as psychiatric disorders (e.g., depression), though in practice these distinctions can be blurred (e.g., Fisk et al., 2003). It is therefore necessary to evaluate an MCI case who comes for clinical evaluation with the same rigor one would bring to the diagnosis of a patient with dementia. That is, to consider all potential medical, psychiatric or neurologic causes of cognitive impairment before making a diagnosis. The number of non-amnestic MCI cases that have been followed to a diagnosis of dementia is limited. It is therefore difficult to provide much information about which specific MCI criteria they fit the best, and the numbers of subjects with various non-AD dementias or psychiatric disorders one is likely to see within a group of MCI cases, defined broadly. There is, however, sufficient evidence to indicate that cases of depression will be included in this group. Moreover, cases of amnestic MCI who progress to AD are also likely to have neuropsychiatric symptoms (particularly dysphoria and irritability), thus making the diagnostic process challenging (Copeland et al., 2003; Hwang et al., 2004).

27.7. Neuropsychological testing in AD and MCI 27.7.1. Episodic memory Difficulty with the acquisition of new information is generally the first and most salient symptom to emerge in patients with AD, as noted above. When clinical neuropsychological tests are used to evaluate memory in AD patients, it is clear that recall and recognition

performance are impaired in both the verbal and nonverbal domain (Wilson et al., 1983; Storandt and Hill, 1989). Experimental studies have examined AD patients to determine whether the manner in which information is lost over brief delays is unique in any way to this patient group. A comparison of AD patients to amnestic patients with Korsakoff’s syndrome (KS) and demented patients with Huntington’s disease (HD) demonstrated that AD patients recalled significantly fewer words over a two-minute delay than either of the other two patient groups (Moss et al., 1986). Whereas the KS, HD, and normal control subjects lost an average of 10% to 15% of the verbal information between the 15-second and two-minute delay intervals, patients with AD lost an average of 75% of the material. Numerous studies have compared AD patients to controls and confirmed that the patients consistently showed a rapid loss of information over brief delays (e.g., Butters et al., 1988; Hart et al., 1988). A comparison of AD patients and patients with FTD (Moss and Albert, 1988) and with progressive supranuclear palsy (PSP) patients (Milberg and Albert, 1989) demonstrated the severe recall deficits of the AD patients in comparison to patients with FTD and PSP. Consistent with the findings above, a comparison of a range of memory measures in a national study involving mildly impaired AD patients and controls (the CERAD study), concluded that measures of delayed recall (in the form of a saving score where measures adjusted for the information originally acquired) are best at discriminating AD patients from controls (Welsh et al., 1991; 1992). Measures of episodic memory are, however, not particularly useful in staging AD patients across levels of severity, primarily because memory is so impaired early in the course of disease. An analysis of the CERAD study data found that a combination of measures that included fluency, visuospatial ability, and recognition memory best differentiated mildly impaired patients from those with either moderate or severe levels of impairment (Welsh et al., 1992). These findings support the conclusion that in most patients with AD memory impairments precede impairments in language and spatial function. As noted above, recently numerous research groups have recruited nondemented individuals with MCI and followed them over time to determine the nature of the cognitive changes that occurred during prodromal AD. Among these studies there is considerable consensus that tests of memory are significantly different among nondemented individuals with mild memory deficits who receive a diagnosis of AD on follow-up, as compared with those who also have memory problems but do not progress to AD within a few years time (Tuokko

NEUROPSYCHOLOGY OF ALZHEIMER’S DISEASE et al., 1991; Bondi et al., 1994; Petersen et al., 1994; Newmann et al., 1994; Small et al., 1995; Jacobs et al., 1995; Tierney et al., 1996; Rubin et al., 1998; Kluger et al., 1999; Chen et al., 2000; Albert et al., 2001; Howieson et al., 2003). There is also widespread agreement concerning the underlying cause of these memory changes in AD. Synaptic dysfunction, neuronal loss, and AD pathology first occur in medial temporal lobe regions (Hyman et al., 1984; Selkoe, 2005). This is particularly evident in the entorhinal cortex and CA1 region of the hippocampus (Gomez-Isla et al., 1996), brain regions critical for normal memory (Squire and Zola, 1996). This conclusion is supported by in vivo neuroimaging studies showing significant atrophy of these brain regions in MCI cases (for reviews see Atiya et al., 2003; Kantarci and Jack, 2003).

27.7.2. Executive function In addition to memory problems, mildly impaired AD patients are substantially impaired in a set of abilities collectively referred to as ‘executive functions.’ This was not recognized initially, as early studies did not include sensitive tests of executive function. Once investigators began to evaluate mildly impaired AD patients with sensitive tests of executive function, these impairments became apparent. For example, mildly impaired patients were shown to be impaired a task that involved coordinating two concurrent tasks (Baddeley et al., 1986) as well as tasks requiring shifting between stimulus dimensions (Sahakian et al., 1990; Filoteo et al., 1992). Mild-to-moderately impaired patients also demonstrate executive function deficits (Becker, 1988; Morris and Baddeley, 1988; Lafleche et al, 1990; Nestor et al., 1991; Bondi et al., 2002). In order to determine whether an impairment in executive function precedes or coexists with significant deficits in spatial and language function, a number of studies have compared very mildly impaired AD patients to controls on tasks assessing a range of cognitive domains. Grady et al. (1988) reported that deficits on tasks of memory and executive function preceded impairments in language. Lafleche and Albert (1995) attempted to characterize the specific aspect of executive function that was impaired in very mildly impaired AD patients. They assessed a broad range of executive function tests. It was found that those requiring set shifting, sequencing and self-monitoring were particularly impaired, whereas those that required abstraction and concept formation were only marginally affected in very mild AD patients. Likewise, performance on the tests of confrontation naming, figure copying, and

519

sustained attention were not impaired. Taken together, these findings suggest that selected aspects of executive function, particularly those involving set shifting and self-monitoring, are affected very early in the course of disease. There is, however, a lack of consensus regarding whether executive function deficits are prominent during prodromal AD. The discrepancies among studies are due, at least in part, to the fact that few studies have examined a wide variety of cognitive domains, thus limiting the types of associations that can be found. A number of studies have reported that executive function abnormalities are evident in the prodromal stage of AD (Grady et al., 1988; Sahakian et al., 1990; Tierney et al., 1996; Albert et al., 2001; Chen et al., 2000; 2001; Albert et al., 2007). Others have reported that declines in confrontation naming are more likely to be impaired among those destined to develop AD (e.g., Saxton et al., 2004). The reasons for these discrepancies remain to be resolved. The brain abnormalities responsible for the executive function deficits seen among individuals destined to develop AD are less clear. At least two potential neurobiological explanations have been suggested. Findings from functional imaging indicate that during prodromal AD there is dysfunction within a brain network that involves the dorsolateral prefrontal cortex and the anterior cingulate (Milham et al., 2002). Alterations in these brain regions have been associated with impairments in executive function (Bush et al., 2002). An alternative possibility is that the disruption of the cortico-cortical connections that are seen in AD (Morrison et al., 2002) may be responsible for executive dysfunction during prodromal AD. 27.7.3. Language Mild-to-moderately impaired AD patients have impairments in confrontation naming and verbal fluency. Some investigators have argued that these deficits are the result of a broader impairment in semantic memory, defined as ‘that system which processes, stores and retrieves information about the meaning of words, concepts and facts’ (Warrington, 1975). Semantic memory abnormalities in patients with AD have been documented using a range of tasks that include category fluency (Martin and Fedio, 1983; Troster et al., 1989; Hodges et al., 1992; Chan et al., 1993), category membership (Grossman et al., 1998), confrontation naming (Martin and Fedio, 1983; Hodges et al., 1992; Grossman et al., 1998), and similarity judgments (Chan et al, 1993; 1995; 1997). In addition, several studies of word priming (Salmon et al., 1988; Glosser et al., 1998; Milberg et al., 1999) have reported

520

M. ALBERT

significant deficits in AD patients, though other studies failed to find this effect (Nebes and Brady, 1988). Studies of semantic memory in AD patients suggest that some conceptual domains may be more impaired than others, in particular that patients with AD have a specific impairment in the conceptual domain of ‘living things.’ For example, in studies assessing confrontation naming (Silveri et al., 1991; Grossman et al., 1998) and picture recognition (Silveri et al., 1991), mild to moderate AD patients performed significantly worse on living things than nonliving things. Other studies have, however, failed to reveal such category-specific differences, using a variety of tasks including recognition naming (Tippett et al., 1996), category-naming fluency and drawing fluency (Mickanin et al., 1994), and category membership judgments (Grossman et al., 1998). It has been suggested that discrepant findings regarding category-specific semantic loss in AD patients is related to the fact that some brain regions are more critical for category-specific judgments than others, and the appearance of a deficit depends on the anatomic distribution of disease in the specific patients examined (Grossman, 1998). These issues remain unresolved. 27.7.4. Visuospatial function Visuospatial function is impaired in the course of AD. On simple copying tasks, such as drawing a clock or a triangle, mild AD patients do not differ from normal controls (Rouleau et al., 1992; Karrasch et al., 2005). However, visuospatial impairments are common among mild-to-moderately impaired patients. (Kurylo et al., 1994; Rouleau et al., 1996). When subjects are asked to draw a figure to command, such as a clock, impairments are evident among mildly impaired AD patients. However, these appear to be the result of conceptual errors, rather than visuospatial errors. Mildly impaired AD patients tend to make perseverative errors and ‘stimulus-bound responses’ but graphic difficulties are extremely uncommon at this stage of disease (Rouleau et al., 1992). Evaluations of patients at differing levels of severity (Heinik et al., 2002) as well as longitudinal data collected from the same individuals (Rouleau et al., 1996) indicates that performance on clock drawing to command gets progressively worse over time, and that conceptual errors were particularly sensitive to overall change in dementia severity. The sensitivity of clock drawing to command in mild AD patients led investigators to determine whether this task might be sensitive to individuals in the prodromal phase of AD. However, a number of studies indicate that clock drawing to command is not

useful for the identification of MCI cases (Powlishta et al., 2002; Seigerschmidt et al., 2002). It should be noted that some aspects of spatial skill are very well retained early in the course of AD. Mirror-tracing skill, which involves tracing a pattern (e.g., a 4- or 6-pointed star) seen only in a mirrorreversed view), has been the best studied. While mildto-moderately AD patients have poor recall or recognition of their mirror-tracing experience, they acquire and retain mirror-tracing skill and generalize it to another object as well as normal subjects (Gabrieli et al., 1993; Rouleau et al., 2002). This is comparable to the findings reported in the amnestic patient H.M. (Gabrieli et al., 1993). The brain abnormalities responsible for visuospatial difficulty of AD patients with a typical presentation has been studied in small numbers of individuals. The findings suggest that constructional difficulties are related to neurofibrillary tangle pathology in the superior parietal lobe, the posterior cingulate, and the occipital cortex (Giannakopoulos et al., 1998). 27.7.5. Attention Mild AD patients do not have impairments on a simple test of sustained attention that makes few demands on memory, such as digit span forward. However, mildly impaired patients demonstrate selective impairments on attentional tasks that are more complex. Tests of choice reaction time and cued choice reaction time are impaired in mild AD (Levinoff et al., 2005). Dual task performance is also impaired in mild AD patients, particularly when one or both of the tasks are not relatively automatized (Crossley et al., 2004; FernandezDuque and Black, 2006).

27.8. Additional approaches 27.8.1. Inference of emotion and beliefs Successful social interaction depends at least in part on the ability to make inferences about the emotions and beliefs of others (Fodor, 1987). The ability to infer what another person is feeling has been studied for many years in patients with acute brain damage, such as a stroke; the data suggest that impairments in emotion perception are related to difficulty with social interactions. The ability to infer what another person believes to be true (often known as the individual’s ‘theory of mind’) has also been studied for many years, initially in children with developmental disabilities; these data also suggest that impairments in inference of belief are related to difficulty with social interaction.

NEUROPSYCHOLOGY OF ALZHEIMER’S DISEASE Studies investigating emotion processing in patients with AD have focused primarily on the ability to identify emotions (either perceptually or by inference). Results of these studies suggest that AD patients are not impaired in processing emotional information conveyed in facial expression, vocal intonation, or gesture, but that they are impaired on tasks that require interpretation of situational information portrayed in scenes and stories (Allender and Kaszniak, 1989; Albert et al., 1991; Cadieux and Greve, 1997; Koff et al., 1999). The ability to infer beliefs in others has also been examined in several studies involving AD patients. One of these studies included both first-order tasks (where participants are asked to infer the beliefs of others) and second-order tasks (where participants are asked to infer someone’s belief about someone else’s belief). In this study, performance of AD patients on the first-order tasks was no different from that of healthy controls, but AD patients were impaired relative to controls on the second-order tasks (Gregory et al., 2002). One study examining only first-order tasks (Zaitchik et al., 2004) and another examining only second-order tasks (Garcia-Cuerva et al., 2001) reported similar findings. A recent study has directly compared the ability to infer emotions with the ability to infer beliefs in patients with mild-to-moderate AD (Zaitchik et al., in press). Parallel procedures are used to assess inference of beliefs and inference of emotion in both first-order and second-order tasks. Each task included a control condition to determine whether any impairments of the subjects are due to the mental state inference in particular (i.e., inference about an emotion or a belief), as compared with inferences about information unrelated to a mental state (e.g., inference about an object, such as a picture). Results showed that the ability to infer emotions and beliefs in first-order tasks remains largely intact in mild-to-moderate AD patients. Patients were able to utilize mental states in the prediction, explanation, and moral evaluation of behavior. Impairment on second-order tasks involving inference of mental states was equivalent to impairment on control tasks, suggesting that patients’ difficulty is secondary to their cognitive impairments. 27.8.2. Screening tests The most widely used tests are the Mini-Mental State Exam (Folstein et al., 1975), the Blessed Dementia Scale (Blessed et al., 1968), the Short Portable Mental Status Questionnaire (Pfeiffer, 1975), the Clock Drawing Test (CDT) (Watson et al., 1993) and the 7-Minute Screen (Solomon et al., 1998). These tests all take

521

approximately 10 minutes to administer and have high test–retest reliability. Of these, the MMSE has most commonly been used in clinical settings. Its strength is that it assesses a broad range of cognitive abilities (i.e., memory, language, spatial ability, set shifting) in a simple and straightforward manner. In addition, the wide use of the MMSE in epidemiologic studies has yielded cutoff scores that facilitate the identification of patients with cognitive dysfunction. The other screening tests have been used in a variety of experimental settings, but epidemiologic data are limited. Finally, the extensive use of the MMSE has produced widespread familiarity with its scoring system, facilitating communication among clinicians. Each of these tests is imperfect as a screening tool, in that they are not sensitive to early stages of disease and are impacted by the age, education, and racial background of the individual (Manly et al., 1999). As a result, there is a continuing debate about whether screening for dementia is beneficial, particularly in primary care settings. The most recent consensus statement from the US Preventive Services Task Force did not recommend screening for dementia (Boustani et al., 2003). They found good evidence that some screening tests have good sensitivity but only fair specificity in detecting cognitive impairment and dementia. In the absence of effective treatments for AD, they could not recommend screening, particularly because the feasibility of screening and treatment in routine clinical practice and the potential harms of screening (i.e., labeling the patient) are unknown. When disease-modifying agents for AD are available, the risk–benefit ratio for screening will change. The consensus recommendations may then change as well. 27.8.3. Neuropsychological evaluation in clinical trials All randomized controlled clinical trials in the USA of medications aimed at treating patients with AD have used neuropsychological tests as one of the two primary markers of drug efficacy (the other measure is a global clinical rating). The most widely used test in these clinical trials is the Alzheimer’s Disease Assessment Scale—Cognitive Subscale (ADAS-Cog; see Mohs, 1996 for a review). The primary reason the ADAS-Cog has been so widely accepted is that it was shown to be not only a valid and reliable measure of cognition in AD patients, but to also change reliably with disease severity over time. Although the FDA has not mandated its use, the inclusion in early trials accepted by the FDA resulted in the concern that use of any other test would be problematic.

522

M. ALBERT

Several recent clinical trials have attempted to broaden the way in which cognition is evaluated in patients with AD and MCI. The Alzheimer’s Disease Cooperative Study group evaluated five types of tasks that might extend the cognitive domains assessed by the ADAS-Cog as well as the range of symptom severity covered. These tasks included: a word list learning test with delayed free recall, a recognition memory test for faces, a series of letter and digit cancellation tests, tests of praxis, and a series of maze completion tests. The test that proved to be sensitive to broad range of dementia was the digit cancellation (Mohs et al., 1997). The word list learning test and a subset of mazes tasks were impaired in very mild AD cases. These were therefore recommended for inclusion in future trials. An alternative approach is best represented by the test battery used by Elan in the trial of AN-1792 (the first immunotherapy trial for AD) (Gilman et al., 2005). A broad neuropsychological battery was included as an adjunct to the ADAS-Cog and clinical global rating. No significant differences were found between the antibody responder and placebo groups for the ADAS-Cog or the clinical global rating of change. However, analyses of a composite score from the neuropsychological battery demonstrated improvement in the antibody responders. This finding was used to support the continuation of the development of the immunization approach to AD. The Alzheimer’s Disease Neuroimaging Initiative (ADNI), a multi-center national effort designed as natural history clinical trial, is focused on developing imaging measures for inclusion in clinical trials of cases with AD and MCI (Mueller et al., 2005). However, a broad range of neuropsychological measures have been included in the study and data will therefore be available on the relationship between both the cognitive and imaging measures as markers of disease progression. As a result of these efforts, it is likely that future clinical trials will include a broader array of neuropsychological tasks than have been used in the past. This will be particularly important when trials are routinely extended to cases of MCI.

References Albert M, Blacker D, Moss M, et al. (2007). Longitudinal change in cognitive performance among individuals with mild cognitive impairment. Neuropsychology 21: 168–169. Albert M, Cohen C, Koff E (1991). Perception of affect in patients with dementia of the Alzheimer type. Arch Neurol 48: 791–795. Albert M, Duffy F, McAnulty G (1990). Electrophysiological comparisons between two groups of patients with Alzheimer’s disease. Arch Neurol 47: 857–863.

Albert M, Moss M, Tanzi R, et al. (2001). Preclinical prediction of AD using neuropsychological tests. J Int Neuropsychol Soc 7: 631–639. Allender J, Kaszniak AW (1989). Processing of emotional cues in patients with dementia of the Alzheimer’s type. Int J Neurosci 46: 147–155. Alzheimer A (1907). Uber eine eigenartige Erkrankugn der Hirnrinde. Allg Z Psychiatr Psych-Gerichtl Med 64: 146–148. American Psychiatric Association (1994). Diagnostic and Statistical Manual, 4th edn. American Psychiatric Association, Washington. Atiya M, Hyman BT, Albert M, et al. (2003). Structural magnetic resonance imaging in established and prodromal Alzheimer’s disease: A review. Alzheimer Dis Assoc Disord 17: 177–195. Baddeley A, Logie R, Bressi S, et al. (1986). Dementia and working memory. Q J Exp Psychol 38: 603–618. Becker JT (1988). Working memory and secondary memory deficits in Alzheimer’s disease. J Clin Exp Neuropsychol 10: 739–753. Bennett D, Schneider J, Bienias J, et al. (2005). Mild cognitive impairment is related to Alzheimer pathology and cerebral infarctions. Neurology 64: 834–841. Blacker D, Albert M, Bassett S, et al. (1994). Reliability and validity of NINCDS-ADRA criteria for Alzheimer’s disease. The National Institute of Mental Health Genetics Initiative. Arch Neurol 51: 1198–1204. Blessed G, Tomlinson BE, Roth M (1968). The association between quantitative measures of dementia and of senile changes in the cerebral gray matter of elderly subjects. Br J Psychiatry 114: 797–811. Bondi M, Monsch A, Galasko D, et al. (1994). Preclinical cognitive markers of dementia of the Alzheimer type. Neuropsychology 8: 374–384. Bondi M, Serody A, Chan A, et al. (2002). Cognitive and neuropathologic correlates of Stroop Color-Word Test performance in Alzheimer’s disease. Neuropsychology 16: 335–343. Boustani M, Peterson B, Hanson L, et al. (2003). Screening for dementia in primary care: A summary of the evidence for the U.S. Preventive Services Task Force. Ann Intern Med 138: 927–937. Bush G, Vogt BA, Holmes J, et al. (2002). Dorsal anterior cingulate cortex: A role in reward-based decision making. Proc Nat Acad Sci 99: 523–528. Butters N, Salmon D, Heindel W, et al. (1988). Episodic, semantic and procedural memory: Some comparisons of Alzheimer and Huntington disease patients. In: RD Terry (Ed.), Aging and the Brain. Raven Press, New York, pp. 63–87. Cadieux N, Greve K (1997). Emotion processing in Alzheimer’s disease. Int J Neuropsychiatry 3: 411–419. Chan AS, Butters N, Paulsen JS, et al. (1993). An assessment of the semantic network in patients with AD. J Cogn Neurosci 5: 254–261. Chan AS, Butters N, Salmon DP (1997). The deterioration of semantic networks in patients with Alzheimer’s disease: A cross-sectional study. Neuropsychologia 35: 241–248.

NEUROPSYCHOLOGY OF ALZHEIMER’S DISEASE Chan AS, Butters N, Salmon DP, et al. (1995). Comparison of the semantic networks in patients with dementia and amnesia. Neuropsychology 9: 177–186. Chen P, Ratcliff G, Belle S, et al. (2000). Cognitive tests that best discriminate between presymptomatic AD and those who remain nondemented. Neurology 55: 1847–1853. Chen P, Ratcliff G, Belle S, et al. (2001). Patterns of cognitive decline in presymptomatic Alzheimer disease: A prospective community study. Arch Gen Psychiatry 58: 853–858. Copeland M, Daly E, Hines V, et al. (2003). Psychiatric symptomology and prodromal AD. Alzheimer Dis Assoc Disord 17: 1–8. Crossley M, Hiscock M, Foreman J (2004). Dual-task performance in early stage dementia: Differential effects of automatic and effortful processing. J Clin Exp Neuropsychol 26: 332–346. Daly E, Zaitchik D, Copeland M, et al. (2000). Predicting ‘conversion’ to AD using standardized clinical information. Arch Neurol 57: 675–680. Davis H, Rockwood K (2004). Conceptualization of mild cognitive impairment: A review. Int J Geriatr Psychiatry 19: 313–319. Fernandez-Duque D, Black S (2006). Attentional networks in normal aging and Alzheimer’s disease. Neuropsychology 20: 133–143. Filoteo J, Delis D, Massman P, et al. (1992). Directed and divided attention in Alzheimer’s disease: Impairment in shifting attention to global and local stimuli. J Clin Exp Neuropsychol 14: 871–883. Fisk J, Merry H, Rockwood K (2003). Variations in case definition affect prevalence but not outcomes of mild cognitive impairment. Neurology 61: 1179–1184. Flicker C, Ferris S, Reisberg B (1991). Mild cognitive impairment in the elderly: Predictors of dementia. Neurology 41: 1006–1009. Fodor J (1987). Psychosemantics: The Problem of Meaning in the Philosophy of Mind. Bradford Books/MIT Press, Cambridge, MA. Folstein M, Folstein S, McHugh P (1975). ‘Mini-Mental State.’ A practical method for grading the cognitive state of patients for the clinician. J Psychiatr Res 12: 189–198. Gabrieli J, Corkin S, Mickel S, et al. (1993). Intact acquisition and long-term retention of mirror tracking skill in Alzheimer’s disease and global amnesia. Behav Neurosci 107: 899–910. Garcia-Cuerva A, Sabe L, Kuzis G, et al. (2001). Theory of mind and pragmatic abilities in dementia. Neuropsychiatry Neuropsychol Behav Neurol 14: 153–158. Gauthier S, Touchon J (2005). Mild cognitive impairment is not a clinical entity and should not be treated. Arch Neurol 62: 1164–1166. Giannakopoulos P, Duc M, Gold G, et al. (1998). Pathological correlates of apraxia in Alzheimer’s disease. Arch Neurol 55: 689–695. Gilman S, Koller M, Black R, et al. (2005). Clinical effects of Abeta immunization (AN1792) in patients with AD in an interrupted trial. Neurology 64: 1553–1562.

523

Glosser G, Grugan PK, Friedman RB, et al. (1998). Lexical, semantic, and associative priming in Alzheimer’s disease. Neuropsychology 2: 218–224. Gomez-Isla T, Price JL, McKeel DW, et al. (1996). Profound loss of layer II entorhinal cortex neurons occurs in very mild Alzheimer’s disease. J Neurosci 16: 4491–4500. Grady CL, Haxby JV, Horwitz B, et al. (1988). Longitudinal study of the early neuropsychological and cerebral metabolic changes in dementia of the Alzheimer type. J Clin Exp Neuropsychol 10: 576–596. Gregory C, Lough S, Stone V, et al. (2002). Theory of mind in patients with frontal variant frontotemporal dementia and Alzheimer’s disease: Theoretical and practical implications. Brain 125: 752–764. Grossman M, Robinson K, Biassou N, et al. (1998). Semantic memory in AD: Representativeness, ontologic category, and material. Neuropsychology 12: 34–42. Hart RP, Kwentus JA, Harkins SW, et al. (1988). Rate of forgetting in mild Alzheimer’s type dementia. Brain Cogn 7: 31–38. Heinik J, Solomesh I, Shein V, et al. (2002). Clock drawing test in mild and moderate dementia of the Alzheimer’s type: A comparative and correlation study. J Geriatr Psychiatry 17: 480–485. Hodges J, Salmon D, Butters N (1992). Semantic memory impairment in AD: Failure of access or degraded knowledge? Neuropsychologia 30: 301–314. Hof P, Vogt B, Bouras C, et al. (1997). Atypical form of Alzheimer’s disease with prominent posterior cortical atrophy: A review of lesion distribution and circuit disconnection in cortical visual pathways. Vision Res 37: 3609–3625. Howieson D, Camicioli R, Quinn J, et al. (2003). Natural history of cognitive decline in the oldest old. Neurology 60: 1489–1494. Hwang T, Masterman D, Ortiz F, et al. (2004). Mild cognitive impairment is associated with characteristic neuropsychiatric symptoms. Alzheimer Dis Assoc Disord 18: 17–21. Hyman BT, VanHoesen G, Damasio A, et al. (1984). Alzheimer’s disease: Cell specific pathology isolates the hippocampal formation. Science 225: 1168–1170. Jacobs D, Sano M, Dooneief G, et al. (1995). Neuropsychological detection and characterization of preclinical Alzheimer’s disease. Neurology 45: 957–962. Kantarci K, Jack CR (2003). Neuroimaging in Alzheimer disease: An evidence-based review. Neuroimaging Clin N Am 13: 197–209. Karrasch M, Sinerva E, Granholm P, et al. (2005). CERAD test performance in amnestic mild cognitive impairment and Alzheimer’s disease. Acta Neurol Scand 111: 172–179. Katzman R (1976). The prevalence and malignancy of Alzheimer disease. A major killer. Arch Neurol 33: 217–218. Kluger A, Ferris S, Golomb J, et al. (1999). Neuropsychological performance of decline in dementia in non-demented elderly. J Geriatr Psychiatry Neurol 12: 168–179. Koff E, Zaitchik D, Montepare J, et al. (1999). Processing of emotion through the visual and auditory domains by patients with Alzheimer’s disease. J Int Neuropsychol Soc 5: 32–40.

524

M. ALBERT

Kramer S, Reifler B (1992). Depression, dementia and reversible dementia. Clin Geriatr Med 8: 289–297. Kurylo D, Corkin S, Growdon J (1994). Perceptual organization in Alzheimer’s disease. Psychol Aging 9: 562–567. Lafleche G, Albert M (1995). Executive function deficits in mild Alzheimer’s disease. Neuropsychology 9: 313–320. Lafleche GC, Stuss DT, Nelson RF, et al. (1990). Memory scanning and structured learning in Alzheimer’s disease and Parkinson’s disease. Can J Aging 9: 120–134. Larrieu S, Letenneur L, Orgogozo J, et al. (2002). Incidence and outcome of mild cognitive impairment: A populationbased prospective cohort. Neurology 59: 1594–1599. Levinoff E, Saumier D, Chertkow H (2005). Focused attention deficits in patients Alzheimer’s disease and mild cognitive impairment. Brain Cogn 57: 127–130. Manly J, Jacobs D, Sano M, et al. (1999). Effect of literacy on neuropsychological test performance in nondemented, education-matched elders. J Int Neuropsychol Soc 5: 191–202. Martin A, Fedio P (1983). Word production and comprehension in Alzheimer’s disease: The breakdown of semantic knowledge. Brain Lang 19: 124–141. McKeith I (2006). Consensus guidelines for the clinical and pathologic diagnosis of dementia with Lewy bodies (DLB): Report of the consortium on DLB International Workshop. J Alzheimers Dis 9: 417–423. McKhann G, Drachman D, Folstein MF, et al. (1984). Clinical diagnosis of Alzheimer’s disease: Report of the NINCDSADRDA work group under the auspices of Department of Health and Human Services Task Force. Neurology 34: 939–944. Mickanin J, Grossman M, Onishi K, et al. (1994). Verbal and nonverbal fluency in patients with probable Alzheimer’s disease. Neuropsychology 8: 385–394. Milberg W, Albert M (1989). Cognitive differences between patients with PSP and Alzheimer’s Disease. J Clin Exp Neuropsychol 11: 605–614. Milberg WP, McGlinchey-Berroth R, Duncan KM, et al. (1999). Alterations in the dynamics of semantic activation in Alzheimer’s disease: Evidence for the Gain/Decay hypothesis of a disorder of semantic memory. J Int Neuropsychol Soc 5: 641–658. Milham MP, Erickson K, Banich MT, et al. (2002). Attentional control in the aging brain: Insights from an fMRI study of the Stroop task. Brain Cogn 49: 277–296. Mohs R (1996). The Alzheimer’s Disease Assessment Scale. Int Psychogeriatr 8: 195–203. Mohs R, Knopman D, Petersen R, et al. (1997). Development of cognitive instruments for use in clinical trials of antidementia drugs. Additions to the Alzheimer’s Disease Assessment Scale that broaden its scope. Alzheimer Dis Assoc Disord 11: S13–S21. Morris J, Storandt M, Miller J, et al. (2001). Mild cognitive impairment represents early-stage Alzheimer’s disease. Arch Neurol 58: 397–405. Morris RG, Baddeley AD (1988). Primary and working memory functioning in Alzheimer-type dementia. J Clin Exp Neuropsychol 10: 276–279. Morrison J, Hof P (2002). Selective vulnerability of corticocortical and hippocampal circuits in aging and Alzheimer’s disease. Prog Brain Res 136: 467–486.

Moss MB, Albert MS (1988). Alzheimer’s disease and other dementing disorders. In: MS Albert, MB Moss (Eds.), Geriatric Neuropsychology. Guilford, New York, pp. 145–178. Moss MB, Albert MS, Butters N, et al. (1986). Differential patterns of memory loss among patients with Alzheimer’s disease, Huntington’s disease and Alcoholic Korsakoff’s Syndrome. Arch Neurol 43: 239–246. Mueller S, Weiner M, Thal L, et al. (2005). The Alzheimer’s Disease Neuroimaging Initiative. Neuroimaging Clin N Am 15: 869–877. Nebes RD, Brady CB (1988). Integrity of semantic fields in Alzheimer’s disease. Cortex 24: 291–299. Nestor PG, Parasuraman R, and Haxby JV. Speed of information processing and attention in early Alzheimer’s dementia. Dev Neuropsychol 7: 243–236. Newmann S, Warrington E, Kennedy A, et al. (1994). The earliest cognitive change in a person with familial Alzheimer’s disease: Presymptomatic neuropsychological features in a pedigree with familial Alzheimer’s disease confirmed at necropsy. J Neurol Neurosurg Psychiatry 57: 967–972. Petersen R (2004). Mild cognitive impairment. J Intern Med 256: 183–194. Petersen R, Parisi J, Dickson D, et al. (2006). Neuropathologic features of amnestic mild cognitive impairment. Arch Neurol 63: 665–672. Petersen R, Smith G, Ivnik R, et al. (1994). Memory function in very early Alzheimer’s disease. Neurology 44: 867–872. Petersen R, Smith G, Waring S, et al. (1999). Mild cognitive impairment: Clinical characterization and outcome. Arch Neurol 56: 303–308. Pfeiffer E (1975). A short portable mental status questionnaire for the assessment of organic brain deficit in elderly patients. J Am Geriatr Soc 23: 433–441. Powlishta K, Von Dras D, Stamford A, et al. (2002). The clock drawing test is a poor screen for very mild dementia. Neurology 59: 898–903. Ritchie K, Artero S, Touchon J (2001). Classification criteria for mild cognitive impairment: A population-based validation study. Neurology 56: 37–42. Rouleau I, Salmon D, Butters N (1996). Longitudinal analysis of clock drawing in Alzheimer’s disease patients. Brain Cogn 31: 17–34. Rouleau I, Salmon D, Butters N, et al. (1992). Quantitative and qualitative analyses of clock drawings in Alzheimer’s and Huntington’s disease. Brain Cogn 18: 70–87. Rouleau I, Salmon D, Virbancic M (2002). Learning, retention and generalization of mirror tracking skill in Alzheimer’s disease. J Clin Exp Neuropsychol 24: 239–250. Rubin E, Morris J, Grant E, et al. (1989). Very mild senile dementia of the Alzheimer type. I. Clinical assessment. Arch Neurol 46: 379–382. Rubin E, Storandt M, Miller JP, et al. (1998). A prospective study of cognitive function and onset of dementia in cognitively healthy elders. Arch Neurol 55: 395–401. Sahakian B, Downes J, Eagger S, et al. (1990). Sparing of attentional relative to mnemonic function in a subgroup of patients with dementia of the Alzheimer type. Neuropsychologia 28: 1197–1213.

NEUROPSYCHOLOGY OF ALZHEIMER’S DISEASE Salmon DP, Shimamura AP, Butters N, et al. (1988). Lexical and semantic priming deficits in patients with Alzheimer’s disease. J Clin Exp Neuropsychol 10: 477–494. Saxton J, Lopez O, Ratcliff G, et al. (2004). Preclinical Alzheimer’s disease: Neuropsychological test performance 1.5 to 8 years prior to onset. Neurology 63: 2341–2347. Selkoe D (2005). Defining molecular targets to prevent Alzheimer disease. Arch Neurol 62: 192–195. Seigerschmidt E, Mosch E, Siemen M, et al. (2002). The clock drawing test and questionable dementia: Reliability and validity. Int J Geriatr Psychiatry 17: 1048–1054. Silveri MC, Daniele A, Giustolisi L, et al. (1991). Dissociation between living and nonliving things in dementia of the Alzheimer type. Neurology 41: 545–546. Small G, LaRue A, Komo S, et al. (1995). Predictors of cognitive change in middle-aged and older adults with memory loss. Am J Psychiatry 152: 1757–1764. Solomon P, Hirschoff A, Kelly B, et al. (1998). A 7-minute neurocognitive screening battery highly sensitive to Alzheimer’s disease. Arch Neurol 55: 349–355. Squire LR, Zola SM (1996). Structure and function of declarative and nondeclarative memory systems. Proc Nat Acad Sci 93: 13515–13522. Storandt M, Hill RD (1989). Very mild senile dementia of the Alzheimer type. II. Psychometric test performance. Arch Neurol 46: 383–386. Tierney M, Szalai J, Snow W, et al. (1996). Prediction of probable Alzheimer’s disease in memory-impaired patients: A prospective longitudinal study. Neurology 46: 661–665.

525

Tippett LJ, Grossman M, Farah MJ (1996). The semantic memory impairment of Alzheimer’s disease: Category specific? Cortex 32: 143–153. Troster A, Salmon D, McCullough D, et al. (1989). A comparison of the category fluency deficits associated with Alzheimer’s and Huntington’s disease. Brain Lang 37: 500–513. Tuokko H, Vernon-Wilkinson J, Weir J, et al. (1991). Cued recall and early identification of dementia. J Clin Exp Neuropsychol 13: 871–879. Warrington EK (1975). The selective impairment of semantic memory. Q J Exp Psychol 27: 635–657. Watson Y, Arfken C, Birge S (1993). Clock completion: An objective screening test for dementia. J Am Geriatr Soc 41: 1235–1240. Welsh K, Butters N, Hughes J, et al. (1991). Detection of abnormal memory decline in mild cases of Alzheimer’s disease using CERAD neuropsychological measures. Arch Neurol 48: 278–281. Welsh K, Butters N, Hughes J, et al. (1992). Detection and staging in Alzheimer’s disease: Use of the neuropsychological measures developed for the Consortium to Establish a Registry for Alzheimer’s Disease. Arch Neurol 49: 448–452. Wilson R, Bacon L, Fox P, et al. (1983). Primary memory and secondary memory in dementia of the Alzheimer type. J Clin Neuropsychol 5: 337–344. Zaitchik D, Koff E, Brownell H, et al. (2004). Inference of mental states in patients with Alzheimer’s disease. Cognit Neuropsychiatry 9: 301–313. Zaitchik D, Koff E, Brownell H, et al. (2006). Inference of belief and emotions in patients with Alzheimer’s disease. Neuropsychol 20: 11–20.

Handbook of Clinical Neurology, Vol. 88 (3rd series) Neuropsychology and behavioral neurology G. Goldenberg, B.L. Miller, Editors # 2008 Elsevier B.V. All rights reserved

Chapter 28

Neuropsychology of frontotemporal dementia C.M. KIPPS, J.A. KNIBB, K. PATTERSON, AND J.R. HODGES* MRC Cognition and Brain Sciences Unit, Cambridge, UK

28.1. Introduction The current understanding of frontotemporal lobar degeneration (FTLD) owes no small part to the original observations and descriptions of Arnold Pick over a century ago (Pick, 1892; 1901; 1904). Current classifications recognize the heterogeneity within the disorder, and three main variants are commonly described (Lund and Manchester Groups, 1994; Neary et al., 1998; Hodges et al., 1999; McKhann et al., 2001). Frontotemporal dementia (FTD), also known as frontal variant (fv-FTD) or behavioral variant (bv-FTD), typically presents with disturbed behavior and is the most common of the three syndromes. Two language variants are also described: semantic dementia (SD), known also as temporal variant FTD (tv-FTD) and a progressive nonfluent aphasic syndrome (PNFA). The clinical phenotype in FTLD has an inconsistent association with the underlying pathology. Clinical presentations are seldom pure, and several symptoms are shared across the different variants, with further overlap on both a anatomical and pathological level. In this regard, although FTD has been typically associated with frontal lobe disturbance, it is frequently accompanied by temporal lobe disease. The situation is mirrored in SD, and to a lesser extent in PNFA. It is helpful to view these disorders as individually reflecting the local extent of a widespread pathological process affecting frontal and temporal lobe networks. In clinical practice, diagnosis is based on the predominant symptom, which is probably most useful in categorizing the types of impairment that patients are likely to manifest. Although bv-FTD is defined by its behavioral presentation, patients with language variants of FTD often also exhibit behavioral disturbance. Conversely, a mild degree of language impairment frequently accompanies the behavioral syndrome. *

28.2. Behavioral variant FTD 28.2.1. Clinical features The disorder presented in Case Study 28.1 presents as a behavioral syndrome with an insidious onset. There is early decline in social conduct, both personal and interpersonal, with emotional blunting and loss of insight (Neary et al., 1998; Bozeat et al., 2000; McKhann et al., 2001; Table 28.1). However, only a minority of patients display all of these core features on initial presentation (Mendez and Perryman, 2002). As descriptive criteria, many features remain difficult to quantify although efforts are being made to operationalize them (Rankin et al. 2005b). Several further deficits may be observed, and comprise the supportive clinical features for diagnosis: decline in self-care, mental rigidity, distractibility, hyperorality, perseverative and stereotyped behavior and several language features such as altered speech output, echolalia, speech stereotypies or mutism. Imaging abnormalities are not essential for the diagnosis, but when present predominantly involve the frontal and temporal lobes. When abnormal, neuropsychological testing should demonstrate impairment on frontal lobe tests in the absence of severe amnesia, aphasia or perceptuospatial disorder. More recent clinically targeted criteria have broadened the diagnostic scope, and simply require an early and progressive alteration in personality, with abnormal behavioral modulation resulting in responses or activities which are inappropriate enough to disrupt social or occupational functioning (McKhann et al. 2001). Diagnosis is usually easy when many abnormal clinical features are present, but can be particularly tricky in the early stages of disease. It is important to establish that symptom onset is indeed gradual, and that this represents

Correspondence to: John Hodges, MRC Cognition and Brain Sciences Unit, 15 Chaucer Rd, Cambridge CB2 2EF, UK. E-mail: [email protected], Tel þ44-(0)1223-355294 Ext 690, Fax: þ44-(0)1223-359062.

528

C.M. KIPPS ET AL.

Case Study 28.1 A 66-year-old man, married for 35 years, who at the time of presentation ran a guest house, had developed progressive and dramatic alteration in his personality over 7 years. Previously gregarious, he became rather withdrawn, and ceased conversation with his wife. He lacked empathy, and was quite disinhibited with friends and family, often making sexually suggestive comments, despite a complete lack of libido. He was profoundly unmotivated, and extremely repetitive. He overate to a gross degree, and was quite suspicious of those around him. His memory had also declined somewhat, and there was a suggestion of mild difficulty with naming objects. There was no insight into any of these problems, yet he was able to give a fluent and accurate account of his earlier life. He had a pout and a grasp reflex, was slightly unsteady on his feet, and had depressed ankle jerks, but no other focal neurological signs. On cognitive evaluation he was well oriented, and achieved 28 out of 30 on the Mini Mental State Examination (MMSE). On the Addenbrooke’s Cognitive Examination (ACE), he scored 90 out a possible 100 points, with marked impairment only on verbal fluency.

Table 28.1 Clinical features of bv-FTD (not all present in every case) Clinical features social–behavioral changes

eating behavior changes insight relatively unimpaired imaging

disinhibition apathy lack of empathy mental rigidity or inflexibility stereotypic behaviors decline in personal care inability to regulate intake preference for sweet foods lost or markedly impaired episodic memory (usually) visuospatial function language (variable) predominantly frontal and/or right temporal atrophy

Formal neuropsychological assessment showed intact story recall, with information retained after a delay. There was very mild impairment of backwards digit span consistent with some impairment of working memory. Language and visuospatial functions were well preserved, but there were marked deficits on tests of frontal function, particularly on the Wisconsin Card Sorting and Trails tests. There was symmetrical frontal and temporopolar atrophy on an MRI scan, and there was marked frontotemporal hypoperfusion on an 18FDG-PET scan. There was a marked deterioration over the subsequent 12 months, and he became increasingly impulsive and unpredictable. His MMSE dropped to 6 over this time. At postmortem there was a moderate degree of cerebral atrophy, particularly of the anterior frontal and temporal lobes, with generalized enlargement of the ventricles. Microscopic examination showed frontotemporal lamina II vacuolation with the presence of ubiquinated inclusions in the inferior olivary nucleus, consistent with a diagnosis of frontotemporal dementia.

a distinct change from premorbid functioning. Apathy, manifesting as passivity, inertia, or social withdrawal is perhaps the most common problem, and may result in significant impairment in activities of daily living (ADL) (Kertesz et al., 1997; Gregory, 1999; Mendez and Perryman, 2002; Pijnenburg et al., 2004). Lack of insight is usual in bv-FTD, and stands in marked contrast to patients with predominant language impairment, who commonly recognize their deficits. Most FTD patients do not believe they are unwell, and in fact up to a third have no complaint at all when assessed (Pijnenburg et al., 2004). This can make the consultational challenging, but often these patients have minor somatic complaints or forgetfulness which are less confrontational about discuss, and may be a way of engaging their co-operation (Pijnenburg et al., 2004). It is important to interview caregivers separately, as there are often sensitive issues to consider which are difficult to broach during a joint discussion. It is often easier to mention specific behavioral issues to the patient after the full extent of the problem has been ascertained from the caregiver in private.

NEUROPSYCHOLOGY OF FRONTOTEMPORAL DEMENTIA Disinhibition is a common early symptom, and seems particularly prevalent in those with predominant frontal and right temporal lobe dysfunction (EdwardsLee et al., 1997; Lindau et al., 2000). Patients with FTD may act impulsively without thought for the consequences, or make tactless, inappropriate social remarks. Crude or improper sexual commentary is quite common, but does not appear to be invariably associated with hypersexuality. The use of pornography or sexual chat lines is often mentioned, sometimes with significant financial consequence, but in fact reduced libido is reported in the majority (Miller et al., 1995). Abnormal eating behavior can be profound, causing marked weight gain. Patients with bv-FTD typically become gluttonous with altered eating habits. Table manners deteriorate; food is sometimes taken from others, piled inappropriately high on the plate, or stuffed into the mouth all at once. Often there is undue haste to start eating. Changes in food preference such as refusing to eat new foods, insisting on eating particular favorites (e.g., fish and chips, or bananas and milk) for every meal, or becoming a vegetarian or fruitarian are less common in bv-FTD than in SD, although they may occur in either condition. As progressive temporal lobe pathology disrupts semantic knowledge about food, bizarre food choices may emerge: orange juice used as gravy, or the eating of partially thawed or moldy food. Stereotypic and ritualistic behaviors such as preoccupation with counting or clockwatching, consistently choosing the same leisure activity, repeatedly eating the same food and rigid adherence to routine are all more common in the FTD subgroups than in AD (Nyatsanza et al., 2003). Simple motor stereotypes involving grunting, humming, lip smacking, hand rubbing, or foot tapping are seen in up to 75% of patients with prominent apathy (Snowden et al., 2001). Repeated wandering or pacing a fixed route is quite common in bv-FTD. More complex repetitive routines such as the use of a catchphrase (verbal stereotypy), or clapping the same rhythm, are consistently seen in both bv-FTD and SD, but to a greater extent in the latter. Many patients with SD develop a particular, and obsessive, interest in puzzles and jigsaws. Neglect of self-care and impairment of other activities of daily living is common, and reflects a combination of apathy, unconcern, and poor judgment. As a consequence, these patients are far more functionally disabled than AD patients matched for Mini Mental State Examination (MMSE) scores (Rosen et al., 2004a). In the absence of a carer, the inevitable result is varying degrees of squalor which in turn may prompt conflict with neighbors or local authorities. Inability to handle financial affairs renders these patients

529

susceptible to deception by others, and liable to run up significant debt without concern for the consequences. Concern about poor memory may prompt patients or their carers to seek medical advice, but it is overshadowed by accounts of the behavioral disturbance. Often the memory problems are actually the result of apathy, inattention, or a degree of semantic impairment for words and concepts. Although true amnesic symptoms have good discriminatory value for AD, particularly in the early stages, there are several reports highlighting genuine episodic memory disturbance in FTD at presentation (Binetti et al., 2000; Caine et al., 2001; Hodges and Miller, 2001; Pasquier et al., 2001; Rosen et al., 2002b; Hodges et al., 2004; Graham et al., 2005). In practice, it is usually impaired registration and/or inefficient retrieval of information—both probably related to reduced attention or effort—that are to blame for the memory complaint (Pasquier et al., 2001). There is a distinct lack of empathy for the emotional concerns of others, which may manifest as selfishness or an insensitivity to embarrassment (Perry et al., 2001). Similarly, it appears that personal emotional expression is affected, as is the recognition of emotion in others (Lavenu et al., 1999; Snowden et al., 2001). Generalized emotional blunting becomes particularly common as the disease progresses (Mendez and Perryman, 2002). Failure to recognize and respond to anger expressed by others may partly explain some of the socially inappropriate behavior of these patients. Depression is rare in FTD, but this is not the case in SD. Irritability, aggressive behavior, and ‘cold-heartedness’ are common (Rankin et al., 2003). Dysexecutive symptoms, such as impaired organization, planning, and goal-setting are present in both FTD and AD, and are related to disease severity. As such they do not discriminate well between the two diseases (Bozeat et al., 2000), and such symptoms may be as much a consequence of apathy as poor judgment. 28.2.2. Behavioral rating scales Behavior in FTD can be quantified using a variety of rating scales: the Frontal Behavioural Inventory (FBI) (Kertesz et al., 1997; 2000b; 2003a), Frontal Behavioural Score (FBS) (Lebert et al., 1998), Neuropsychiatric Inventory (NPI) (Cummings et al., 1994), Cambridge Behavioural Inventory (CBI) (Bozeat et al., 2000) and an inventory used by the Manchester Group (Barber et al. 1995). A rating scale of stereotypical behaviors commonly found in FTD has also been reported (Shigenobu et al., 2002). Some are based on direct interview; others, such as the CBI, which is the instrument used in

530

C.M. KIPPS ET AL.

the Cambridge memory clinics, can be filled out by the carer prior to the clinical interview. Incorporating a number of memory items, as well as a functional assessment, in the inventory is useful as it often allows one to distinguish the symptom complex from that of AD, and to estimate the likely level of disability and carer burden. The FBI, applied to a mixed group of neurodegenerative disorders, was useful in discriminating FTLD from AD, PNFA and depression, but had less success when FTLD was compared with vascular dementia, as there was significant overlap. In that situation it was indifference, perseveration, and utilization behavior that helped distinguish the two disorders (Kertesz et al., 2000b). Using the FBS—in which endorsement of any item within one of four domains (self monitoring dyscontrol, self neglect, self-centered behavior, affective disorder) is scored as positive for that feature— a distinction could be made between FTD and either vascular dementia or AD (Lebert et al., 1998). These patients were defined clinically, although several had pathological confirmation. Behavioral features that are common in FTD and SD may cluster: using the CBI, abnormal stereotypic and eating behaviors, together with impaired social awareness, were useful in contrasting the profile of the FTLD variants with AD, but not each other. Other researchers have reported separate behavioral profiles for FTD and SD, and describe an apathetic (FTD-A) and disinhibited (FTD-D) form of the classic behavioral disorder. Emotional impairments and compulsive, repetitive behaviors were more common in FTD than SD, as was gluttony, and separated the groups using discriminant analysis. The FTD-D group shared characteristics from each group, and no feature had a unique association with this group. Using the NPI, disinhibition and apathy were more commonly seen in FTD than AD, with the reverse pattern seen for depression (Levy et al., 1996). The overall benefit of such rating scales undoubtedly lies more in providing a structured behavioral symptom profile than in any summated behavioral score. This profile may then be used to guide subsequent, more detailed enquiry. Interestingly, total behavioral scores appear to remain relatively stable over time in FTD (Kertesz et al., 1997; Gregory, 1999; Marczinski et al., 2004), and high scores are often present early in the disease. Relatively stable scores may well reflect adaptation by carers to the changed circumstances, as well as the effect of interventions such as psychotropic medication. High scores at presentation may also reflect a bias whereby mild behaviors, initially tolerated as being eccentric, escalate and reach crisis point around the time of diagnosis.

It is difficult to be confident that behavioral rating scales do not simply reflect biases in the predominantly clinical diagnoses that are being predicted, particularly when these scales are being used to discriminate FTD from other neurodegenerative diseases. There is the potential for a degree of circularity as the inclusion criteria for FTD involve mainly behavioral characteristics which are also incorporated into behavioral rating scales. Prospective studies with consecutive recruitment, with diagnoses defined additionally on imaging or pathological grounds, would be very useful. In a number of patients, it remains remarkably difficult to be certain about the clinical diagnosis. Such patients display the behavioral phenotype of the disorder, but seem to have a particularly good prognosis, and do not deteriorate at the same rate as other cases. In some of them it is true to say that frank dementia supervenes. A normal MRI scan at presentation, particularly if the disease onset has been relatively slow, suggests that a degree of caution is warranted when giving prognostic information, or indeed a confirmed diagnosis (Davies et al., 2005b). It is not until these patients are followed longitudinally without significant neuroradiological or behavioral deterioration that doubts about the diagnosis can be resolved. To our knowledge, well documented patients of this nature have yet to come to postmortem.

28.3. Neuropsychological tests in FTD A wide range of neuropsychological tests have been applied to patients with FTD in order to characterize their deficits, and to distinguish them from patients who have other neurodegenerative disorders. 28.3.1. Cognitive screening tests In predominantly behavioral cases, both bedside cognitive assessments and standard formal neuropsychology may be normal (Gregory and Hodges, 1996; Gregory et al., 1998). A high score on the mini-mental state examination (MMSE) (Folstein et al., 1975) does not exclude the diagnosis, as this scale focuses on memory, orientation, and a small number of language items, which can be preserved until late in the course of FTD. In a recent epidemiological study across several sites (Johnson et al., 2005), the mean initial MMSE score was 22.4 out of a maximum possible 30. The variance of this estimate was large, emphasizing that some patients may score very well on this test at presentation. The Addenbrooke’s Cognitive Examination (ACE) is a more comprehensive instrument, with a maximum score of 100, that incorporates all of the MMSE components

NEUROPSYCHOLOGY OF FRONTOTEMPORAL DEMENTIA

531

but additionally provides more assessment of language and semantic memory than the 30-item MMSE. The frontal assessment battery (FAB) combines tests of concept similarities, letter fluency, and motor sequencing with assessment of inhibitory control and frontal release signs such as the grasp reflex (Dubois et al., 2000). Performance correlates with scores on the Mattis Dementia Rating Scale (DRS) and with performance (number of categories achieved and number of perseverative errors) on the Wisconsin Card Sorting Test (WCST), but does not distinguish well between FTD and subcortical frontal syndromes such as PSP. The FAB similarities test assesses concept knowledge and the ability to express it via questions such as how a table and a chair, or a banana and an orange, are alike. This is easy to perform at the bedside and is the most discriminating subtest of the battery. Scores in AD are higher than in FTD, and the performance is independent of age (Slachevsky et al., 2004). Although the battery was also assessed on a small subgroup of patients with relatively preserved MMSE, this may not adequately match for degree of dementia severity, and it remains unclear as to what happens in more subtle situations when FTD patients score very well on the MMSE.

on the Brixton spatial anticipation task (Lough et al., 2005). Ability to inhibit prepotent responses to a sentence completion task such as the Hayling test may also be quite abnormal, even in mild FTD (Lough et al., 2005). In contrast, ability to correctly plan the minimum number of moves needed on the Tower of London task was not significantly impaired in mild FTD relative to controls, although patients were slower at it (Rahman et al., 1999b).

28.3.2. Executive function measures

28.3.5. Digit span

Poor performance on tests of executive function has been demonstrated in many studies comparing FTD with controls, but the ability of such tests to discriminate between FTD and AD remains relatively poor because the performance of both groups may be impaired (Miller et al., 1991; Frisoni et al., 1995; Pachana et al., 1996; Hodges et al., 1999; Pasquier et al., 2001). Nevertheless, they remain useful for documenting one aspect of the overall profile of the disorder, both behavioral and cognitive.

Digit span, a measure of working memory which is dependent on executive and phonological processes, is inconsistently impaired in FTD, thus limiting its usefulness as a measure of impaired attention (Gregory et al., 1997; Boone et al., 1999; Rahman et al., 1999b; Pasquier et al., 2001; Gregory et al., 2002; Rosen et al., 2002b; Graham et al., 2005). This is likely to reflect poor disease severity matching across studies. In our own experience, it is a relatively insensitive measure, particularly in early disease.

28.3.3. Trails, card sorting, Brixton, Hayling, and Tower of London tests

28.3.6. Visuospatial function

Patients with FTD do badly on the Trails test, especially the alternating letter–number task in Part B of this test. Their performance is below that of controls (Rosen et al., 2002b), but is similar to that of many patients with AD (Kramer et al., 2003). They take longer to reach the first category on the Wisconsin Card Sorting Test (WCST), achieve fewer categories overall, and make a greater number of perseverative errors relative to controls (Miller et al., 1991; Neary et al., 1998; Snowden et al., 2003; Diehl et al., 2005; Thompson et al., 2005). A similar failure to shift attentional set has been shown

28.3.4. Verbal fluency A reduction in verbal output is a common finding in FTD. Many studies report verbal fluency measures (Elfgren et al., 1993; Gregory et al., 1997; Mathuranath et al., 2000; Rosen et al., 2002b; Perri et al., 2005), probably because these are so simple to administer. Letter fluency involves the timed generation of as many words as possible beginning with a particular letter (e.g., F, A, S), while category fluency tests the ability to provide words that are semantically related (e.g., animals). In FTD there is usually a marked deterioration in letter fluency, accompanied to a lesser extent by category fluency, whereas in SD, scores are usually much lower for categories than letters.

Visuospatial function remains intact in FTD until the late stages (Brun et al., 1994; Barber et al., 1995; Varma et al., 1999) although poor organizational strategies may impair scores on some tasks such as copying of the Rey Figure. Inconsistencies can often be resolved by normal performance on visuospatial tasks such as those contained in the Visual Object and Space Perception Battery (VOSP) (Warrington and James, 1991). In tests of spatial span and spatial working memory, patients with mild FTD perform similarly to controls (Rahman et al., 1999a). Their performance on spatial and pattern recognition is normal, but they are slower than controls.

532

C.M. KIPPS ET AL.

28.3.7. Language In addition to a commonly observed degree of abnormality on the verbal fluency measures mentioned above, severe reduction in fluency without phonological, syntactic, or semantic deficits (‘dynamic aphasia’) has occasionally been documented in FTD (Snowden et al., 1996). Otherwise, language skills appear to be relatively unaffected in FTD (Thompson et al., 2005), with good comprehension and largely intact performance on tests of picture naming, word–picture matching, generation of word definitions and other semantically based tasks such as the Pyramids and Palm Trees Test (Hodges et al. 1999; Perry and Hodges, 2000; Howard and Patterson, 1992). There are, however, several reports of disproportionate impairment in comprehension of verbs (actions) relative to nouns (objects) in this patient group (Cappa et al., 1998; Rhee et al., 2001; Snowden et al., 2003). On a word–picture matching task, verb processing ability correlated with executive function performance, namely the Stroop, letter fluency, and Trails B tasks, suggesting that this skill is sensitive to executive resource demands. Similar findings have been seen in FTD associated with motor neuron disease (FTDMND). Syntactic deficits can be shown using the Test of Reception of Grammar (TROG) (Bishop, 1983; Bak et al., 2001). 28.3.8. Episodic memory Memory complaints in FTD are relatively common, but usually not specific. About 8% of pathologically confirmed cases have reported memory symptoms in the initial stages of disease (Hodges et al., 2004), and showed documented impairments on verbal memory tasks relative to controls (Rosen et al., 2002b). The predictive value of such amnesic symptoms may not be very high, given both the nonspecific way in which carers and patients describe memory complaints, and the heterogeneous manner in which they manifest. Although most patients with primary memory complaints are likely to have AD, the diagnostic criteria for this disease have poor specificity with respect to FTD (Varma et al., 1999), and impairments in memory are poorly discriminatory. Thus, absence of severe amnesia (giving a high negative predictive value) markedly increases the odds ratio for FTLD to be confirmed pathologically, but the converse is not true (Rosen et al., 2002b). In contrast to AD, patients with FTD perform better on both recognition and recall tasks (Glosser et al., 2002), and do not have the accelerated forgetting typical

of AD in delayed free recall conditions. Verbal priming improves performance on a word completion task in FTD, prompting suggestions that memory dysfunction results from inefficient retrieval strategies, rather than true amnesia (Pasquier et al., 2001). On the other hand, a study comparing forced-choice recognition and free recall for verbal and nonverbal material showed no difference in performance between AD and FTD variants, leading the authors to propose that it was encoding rather than retrieval that accounted for differences between groups (Glosser et al., 2002). They commented on the rather inefficient, serial order, stimulus-bound means of this encoding in FTD. While item detection (discriminating previously seen from novel items) is at control levels, temporal source memory (remembering that an item came from list A vs. list B) is at chance (Simons et al., 2002). Spatial source memory (memory for an item’s spatial location), by contrast, seems to be normal in FTD (A Graham, unpublished data). In AD, patients are typically impaired at both item detection and source memory, temporal or spatial. There remain, however, a number of FTD patients with true amnesic symptoms, who remain indistinguishable from AD during life notwithstanding the presence of behavioral disturbance (Caine et al., 2001). Assessing accuracy at task performance is the most commonly used means of neuropsychological evaluation, but such an approach lacks specificity; patients with either AD or FTD may perform poorly, but the reasons for this may be quite different. Analysis of the different kinds of errors typical of the two disorders has produced interesting results (Thompson et al., 2005). Concrete thought and interpretation, perseveration, confabulation, and poor organization were responsible for the profile of performance of FTD subjects across a range of neuropsychological tasks, and seem to echo their behavioral dysfunction. 28.3.9. Newer tests The relative lack of success in delineating a typical pattern of neuropsychological dysfunction in FTD has prompted investigators to explore a range of novel tasks in an attempt to quantify the social cognitive deficit in these patients. Executive function measures are believed to be sensitive to abnormalities in dorsolateral prefrontal cortex (Duncan and Owen, 2000) but the initial locus of pathology in FTD often seems to involve the orbitofrontal and superior medial frontal cortices (Broe et al., 2003; Kril and Halliday, 2004). Lesions in these regions have been associated with abnormalities of social conduct and emotion (Hornak et al., 2003).

NEUROPSYCHOLOGY OF FRONTOTEMPORAL DEMENTIA 28.3.10. Decision-making In view of the prominent impairments shown by patients with FTD in the areas of appetite and reward processing, there is surprisingly little data on learning for reward in this condition. Rahman et al. (1999a) tested decision-making using a reversal paradigm called the ID-ED shift task. Patients were specifically impaired at the reversal aspects of the task. They could not change their behavior when a previously rewarded stimulus was no longer rewarded, but had no difficulty in transferring a rule learnt on one set of exemplars to a different, but related set of stimuli. In the same study, the authors used the Cambridge Gamble task to assess risk-taking behavior. In this task, bets are placed on the likely position of yellow tokens hidden under one of two boxes on the screen. Patients with FTD showed true risk taking behavior in that they bet a larger proportion of their accumulated winnings on the outcome. They did not, however, perform less accurately than controls in this task, even though their deliberation times were significantly longer, a feature seen in other patients with orbitofrontal lesions (Rogers et al., 1999). Their risk-taking was not just a reflection of impulsive behavior, as bets had to be placed in a manner that minimized this possibility. More recent work by our group has shown that patients with FTD are significantly impaired on a task requiring concurrent visual discriminations and that, unlike controls, their performance is not enhanced by the addition of a genuine, and otherwise motivating, monetary reward (A Graham, unpublished data). 28.3.11. Theory of mind Demonstration of abnormalities in the ventromedial aspect of the frontal lobes in FTD prompted interest in the possibility that aspects of social cognition such as the Theory of Mind (ToM) might be impaired in these patients. In a comparison with normal controls, and MMSE-matched AD patients, Gregory et al. (2002), showed that in FTD both first and second order ToM was significantly worse than in controls, and that an even greater proportion of FTD patients were impaired on the faux pas task. On the faux pas task, patients made a number of errors, with false positive and false negative endorsements, as well as inappropriately inferring that a faux pas had been caused intentionally. In contrast, performance by patients with AD was compromised by memory impairment as indicated by their scores on control questions. In an interesting study, Snowden et al. (2003) showed that FTD patients were more likely than controls or Huntington’s disease patients to make errors

533

of omission, and to provide inappropriately concrete responses in a cartoon interpretation task. They also used relatively fewer verbs depicting mental states (e.g., thinking, believing) when asked to describe a mental state cartoon. This was not just an effect of poor verbal fluency, as mental state verbs were affected more than physical state verbs. When tested on a story comprehension task which involved representation of first and second order Theory of Mind, the FTD patients performed poorly, although this was for both physical and mental state stories. Verb production overall was impaired relative to controls, and is resonant with findings from studies mentioned earlier that suggest a disproportionate impairment of verbs relative to nouns in FTD (Bak et al., 2001; Cappa et al., 1998; Rhee et al., 2001). On a test of eye gaze preference, several of the patients persisted in selecting their own personal favorites as the target. In a similar vein, we have observed patients who use idiosyncratic patterns in their use of rating scales (e.g., 10, 9, 8, 7, etc. for successive items). Such eccentricity highlights one of the potential confounds in testing this particular group. The role of executive function in performing some of these tasks is controversial. In a recent study (Lough et al., 2005), performance on both the Hayling and Brixton tasks was unrelated to the performance of FTD patients on a mental state cartoon interpretation task. In fact, it appeared that executive function played a supportive role in processing of cartoons and story vignettes rather than being directly involved in mental state representation. Executive impairments, however, have the potential to mask more specific deficits in the theory of mind (Snowden et al., 2003), particularly if they are severe. Furthermore, it seems that the ability to process social rule violations is related to executive function measures; despite this, knowledge of social rules themselves is unaffected (Lough et al., 2005). The ability to judge the severity of rule violations (moral versus conventional) is compromised in FTD, with patients tending to judge all social violations equally severely. 28.3.12. Personality measures Poor recognition of emotional responses in others, and a lack of empathy, are frequently seen in FTD, and yet there are relatively few studies which attempt to quantify these aspects of impaired social functioning in this disease. On the interpersonal adjectives scale (IAS), a caregiver-based rating of interpersonal functioning, FTD patients show increased submissiveness, possibly as a function of increased apathy. Patients with semantic dementia, by contrast, were rated as more cold-hearted instead, with only a marginal decrease in social dominance (Rankin et al., 2003). Both groups maintained

534

C.M. KIPPS ET AL.

their dysfunctional personality styles more rigidly than comparable patients with Alzheimer’s disease. A subsequent study reported a correlation between the volume of right orbitofrontal cortex with ‘agreeableness’ (Rankin et al., 2004). Disintegration of the sense of self, as reflected in changes in behavior, dress, or religious ideas, was reported in six patients with right-sided frontotemporal hypoperfusion on SPECT imaging. This occurred despite the patients’ retained knowledge of their own premorbid personality traits (Miller et al., 2001). Many other socially inappropriate behaviors have been linked to right-predominant frontotemporal dysfunction in FTD patients (Mychack et al., 2001). It is worth bearing in mind, however, that whilst the disease process in FTD is often asymmetric, it is virtually never unilateral (Chan et al., 2001; Thompson et al., 2003; Seeley et al., 2005). Other research groups have attempted to use personality indices to quantify aspects of the behavioral changes in FTD such as impaired insight. On the same interpersonal adjectives questionnaire (IAS) as above, self reports of current personality in FTD actually match relatives’ accounts of premorbid personality most closely (Rankin et al., 2005a). Patients tend to exaggerate their positive qualities, whilst minimizing any negative ones, and have worst insight for areas of their personality that have undergone the most significant change. 28.3.13. Empathy Two studies have assessed the characteristic indifference to the emotional concerns of others using the interpersonal reactivity index (IRI), a four factor structure reflecting cognitive (perspective-taking and fantasy) and emotional (empathic concern and personal distress) aspects of empathy (Davis, 1980; Lough et al., 2005; Rankin et al., 2005b). In frontal or behavioral variant patients, perspective-taking (Lough et al., 2005; Rankin et al., 2005b) and empathic concern (Lough et al., 2005) were impaired relative to age-matched controls. Semantic dementia patients were impaired across all four factors, reflecting a more profound cognitive and emotional indifference to others. Interestingly, patients with AD were not impaired on these measures, suggesting a defined neural substrate for empathy, and not just brain degeneration per se as the source of its deterioration. 28.3.14. Emotional recognition and regulation The ability of patients with FTD to recognize facial emotional expressions in others is particularly impaired for anger, sadness, and disgust (Lavenu et al., 1999;

Keane et al., 2002; Lough et al., 2005). There are, however, inconsistent results when this type of test is applied longitudinally, with AD, but not FTD, patients showing deteriorating performance (Lavenu and Pasquier, 2005). In two cross-sectional studies, fear recognition was also impaired (Rosen et al., 2004b; Lough et al., 2005). A test of identifying vocal emotion yielded similar results: angry and sad voices were poorly identified, but there were additional deficits in recognizing the sounds of happiness or surprise (Keane et al., 2002).

28.4. Progressive nonfluent aphasia 28.4.1. Clinical features Traditionally, the first level of classification of aphasic syndromes has been based on whether or not a patient’s speech remains fluent, as this is one of the most salient differences between the classical fixed-lesion aphasias of Broca and Wernicke types. More recently, fluency has been used as a marker of the heterogeneity within progressive aphasia (Snowden et al., 1989; Hodges and Patterson, 1996; Mesulam, 2001), and indeed this observation is useful in distinguishing between SD and PNFA in the clinic. The distinction is not, however, as straightforward as it might seem. One problem, as we shall see, is that SD patients sometimes show dysfluency related to their word-finding impairment, and conversely that PNFA patients may at times produce at least some stretches of fluent speech. Another is that different observers use different—and not always explicit— criteria to define the terms. The description ‘non-fluent’ may refer to any or all of abnormally slow speech in terms of words per minute, an excessive length of time between utterances, disordered speech rhythm or melody, effortful articulation, hesitation due to wordfinding difficulty, or other speech abnormalities. Though each of these features is useful in describing an individual patient’s speech, none is reliably present in PNFA, and not all are reliably absent in SD. In other words, a description based on fluency alone is neither precise nor powerful enough to discriminate between the two syndromes. The most frequent initial symptom in PNFA is of word-finding difficulty, though a substantial minority of cases do not report this at the first consultation. Other possible presenting complaints include hesitant speech, difficulty constructing a sentence, or difficulty with writing (Table 28.3). Behavioral features similar to those of bv-FTD may occur (Kertesz et al., 2003b; Hodges et al., 2004), sometimes reported as a change in personality, but these typically appear later (if at all) and almost never dominate the clinical picture. The onset is gradual, and usually precedes presentation to

NEUROPSYCHOLOGY OF FRONTOTEMPORAL DEMENTIA

535

Case Study 28.2 A 75-year-old retired clerk presented to the Memory Clinic with an 18-month history of speech problems. He complained of hesitancy, word-finding difficulty, and distorted speech. There were no complaints suggestive of autobiographical or day-to-day memory impairment, and he continued to pursue hobbies such as gardening without difficulty. No personality change was reported, and he had insight into his problems. His spontaneous speech was poorly articulated, with short phrases and many phonological errors. Word-finding difficulty was obvious and led to frequent pauses; speech melody and rhythm were abnormal even on occasions when there was no particularly marked word-finding difficulty. He was frustrated by his inability to communicate, and used gesture to supplement speech where possible. He performed poorly on simple tests of naming, phonological processing, and syntactic comprehension. His digit span was reduced, as was his fluency in word production from an initial letter cue (P) as well as from a semantic category (animals). He processed written words accurately in tasks requiring nonverbal output, but he made errors in reading aloud. He showed good recall of both verbal and nonverbal material, performed well on a nonverbal semantic task, and his visuospatial abilities were preserved. Two years later, his speech had deteriorated further, and was now only partially intelligible, with very frequent phonetic errors occurring in short, telegraphic utterances. He was profoundly anomic

clinic by two or three years. Most PNFA patients present in their sixties; the diagnosis is unusual outside the ages of 50 to 75. No sex bias has been demonstrated (Westbury and Bub, 1997; Kertesz et al., 2003b; GornoTempini et al., 2004; Knibb et al., 2005), and there are no known risk factors other than age. There is sometimes a family history of early-onset dementia, but only rarely is there a clear-cut Mendelian inheritance pattern. The number of words uttered per minute is not always low in PNFA, although the length of individual sentences or utterances is almost universally reduced. Some patients fill in the gaps in their online speech using stereotyped, overlearned phrases. In others, initiating speech becomes more difficult; they prefer to listen rather than to speak, and give mostly monosyllabic answers when asked a direct question. Such a patient may appear

in spontaneous speech as well as on formal tests of naming, and often resorted to stereotyped phrases such as ‘it’s all right.’ His ability to understand complex syntax had also deteriorated. He continued to make use of nonverbal means of communication, even learning new gestures, and his semantic and visuospatial abilities were still intact. He died seven years after the onset of his symptoms. A sample of his speech is given in Table 28.2, presumed target words are italicized; line breaks indicate pauses in speech. Table 28.2 Sample of speech in PNFA patient er nides (nine days) And an air oh nd (aeroplane) have flow and er mornd bandelenz (?) and er the when we came out a coach and took ed us all round er hohdel (hotel) three days and er we er coach er two days and aspleep (asleep) and oat five days uz er uz like it’s alright

[holding up nine fingers] [points to the window]

[pointing down]

[holds up three fingers] [holds up two fingers] [holds up five fingers] [laughs, mimes sleeping] [gives ‘thumbs up’ sign]

laconic rather than dysphasic, a pattern known as ‘dynamic aphasia’ (Costello and Warrington, 1989; Esmonde et al., 1996). Other patients are closer to classical nonfluent aphasia, and show effortful, labored speech with distorted rhythm and melody. Still others show largely normal runs of speech in between prolonged word-finding pauses. Phonetic paraphasias are a characteristic, though not ubiquitous, feature of PNFA. Many patients make spontaneous speech errors which are clearly phonetically related to the target, for example ‘spoot’ for ‘spoon.’ In others, these occur more frequently in naming or repetition tasks. Patients are usually aware of their errors, and may attempt to self-correct, sometimes producing successively better approximations (conduit d’approche): ‘elective, elecrit, electry’ for ‘electricity.’ Patients only

536

C.M. KIPPS ET AL.

Table 28.3 Clinical features of PNFA (not all present in every case) Clinical features word-finding difficulty speech production difficulty phoneme substitution errors disordered grammar

nonlinguistic deficits

relatively unimpaired

imaging

in spontaneous speech in picture naming tests difficulty initiating speech disordered articulation in spontaneous speech on repetition, especially of nonwords in spontaneous speech in syntactic comprehension tests on repetition of complex sentences executive impairment upper-limb and/or orofacial apraxia word comprehension knowledge of items they cannot name left perisylvian atrophy

whose speech is distorted and nonfluent, should be assessed for other possible diagnoses, such as bulbar motor neuron disease (MND). Handwriting may also be affected nonlinguistically by the co-occurrence of upper-limb apraxia with PNFA, as in the syndrome of corticobasal degeneration (CBD) (see below).

28.5. Semantic dementia 28.5.1. Clinical features The first complaint in SD is almost always of isolated word-finding difficulty. However, this is so insidious in onset, and speech is otherwise so well preserved, that other symptoms have usually evolved by the time the patient presents to clinic. Among these are difficulty understanding spoken words, deterioration in spelling, and difficulty recognizing faces (Table 28.4). Behavioral features are commoner and occur earlier in SD than in PNFA, and include irritability, stereotyped behaviors, Table 28.4 Clinical features of SD (most present in most cases)

rarely complain of difficulty understanding speech, but testing very often uncovers problems in sentence comprehension. The deficit is in the understanding of syntax, rather than of individual words. For example, the passive construction in the sentence ‘A lion was attacked by a tiger’ may be misinterpreted as active voice, causing the patient to assign the roles of attacker and victim the wrong way round. Closed-class words such as prepositions may also be misunderstood. By contrast, frank grammatical errors in speech are a less common feature, and are less common in PNFA than in nonfluent aphasia due to fixed lesions (Graham et al., 2004). They do occur in some patients, however, and consist of omission or misuse of inflections or grammatical words, or abnormal word order: ‘She’s in the washing, er, doing the washing;’ ‘Well, woman cleaning;’ ‘Cupboard. Plate.’ Impairments of reading and writing also occur as part of the PNFA syndrome. Surface dyslexia has been reported (Watt et al., 1997), and may be commoner than previously thought (Knibb and Hodges, 2005), although it is unusual for a PNFA patient to complain of difficulty with reading. In fact, reading a passage of text aloud usually elicits speech which is more fluent and less paraphasic than when the patient speaks spontaneously, although reading text aloud is more difficult and errorprone than reading the same component words as single items (Patterson et al., 2005). Grammatical deficits are sometimes more apparent in writing than in speech. A patient who can write fluently and grammatically, but

Clinical features word-finding difficulty

word comprehension

speech errors

difficulty with uncommon irregular words other semantic impairments

behavioral changes

relatively unimpaired

imaging

in spontaneous speech in picture naming tests unable to give information about the items alienation du mot (‘what’s a hobby?’) in word-picture matching tests overuse of generic words circumlocution coordinate semantic errors in reading and writing in verb inflection on picture–picture matching tests on sound–picture matching tests face recognition bizarre food combinations or food fads stereotyped behaviors inflexibility, irritability loss of empathy syntactic comprehension speech articulation, phonology, and grammar striking anterior temporal lobe atrophy usually asymmetric, most often left worse than right

NEUROPSYCHOLOGY OF FRONTOTEMPORAL DEMENTIA

537

Case Study 28.3 A 54-year-old care assistant in a nursing home presented to the Memory Clinic with a 12-month history of ‘loss of memory for words,’ gradual in onset and progressive. She first noticed a problem when she had difficulty naming the contents of the food trolley at work. She had also noticed difficulty in remembering the names of friends and family members. There was no problem with day-to-day or autobiographical memory. Her family reported no behavioral changes, and she was functioning normally in terms of practical skills and daily living. Physical neurological examination was normal. She was fully orientated, and rapidly learned her way around the ward where she had been admitted for investigation. Her conversation was fluent and superficially normal, with intact speech rhythm and melody, accurate articulation, and correct pronunciation and grammar. However, her complaint of word-finding difficulty was borne out in her speech, which was characterized by extensive circumlocution and a tendency to use generic words such as ‘thing.’ She was severely impaired in naming tasks, and her errors were semantically related to the target (‘horse’ for ‘elephant’). When asked to generate the names of

and changes in eating behavior (Snowden et al., 2001; Thompson et al., 2003). SD and PNFA share a similar profile in terms of age, sex, and family history (see comments above.) Spontaneous speech may appear normal to the casual listener, even at quite advanced stages of the disease. Early on, however, the trained ear should notice a shift towards the use of general, high-level category terms when the context requires a specific word, for example ‘place’ instead of ‘hospital’ or ‘creature’ instead of ‘goat’; frank within-category semantic errors (‘dog’ for ‘goat’) may also be seen. Circumlocution is another common strategy—‘play music with it’ for ‘violin,’ or ‘you see them outside, it goes around’ for ‘goat.’ All of these naming errors become more noticeable on formal naming tests. Hesitation while searching for a word is less prominent in SD than in PNFA, although the anomia is much more profound, and semantic errors are typical. Impairment of single-word comprehension is often equally striking. Occasionally a patient loses familiarity

as many animals as possible, she could think of only five in a minute, but she was better at generating words from an initial letter. Her conversational comprehension was good, and she could follow complex commands easily provided that they were composed of common nouns and verbs; but her understanding of less common individual words was impaired. She could read aloud fluently, but regularized the pronunciation of words with an irregular spelling-to-sound correspondence (e.g., pint pronounced to rhyme with ‘mint,’ gauge pronounced ‘gorge,’ etc.). Her nonverbal memory was normal, but word-list learning and other measures of verbal memory were impaired. With progression of the illness, her speech became almost empty of meaningful words, dominated by ‘thing,’ ‘do,’ ‘go’ and similar words. Later still, she was only able to speak in stereotyped expressions— ‘special place,’ ‘those bits.’ She developed impairment on nonverbal tests of semantic knowledge, and became unable to demonstrate the use of household objects, although her level of function at home remained good for a long time. She died 14 years after the onset of her symptoms and had MND-type Ubiquitin pathology.

with a word to the extent of saying, ‘Hobby, hobby. . . I should know what a hobby is, but I can’t remember.’ This has been called alienation du mot (Poeck and Luzzatti, 1988), and is a very specific sign of SD. Usually, however, comprehension impairment must be specifically elicited, by saying a word to the patient and asking them to point to a picture, or to define the word in as much detail as possible. The definitions produced may be frankly inaccurate, but more typically they are vague as in ‘a big one, I’ve got one of those,’ or simply overgeneralized and lacking in specific details. The progressive loss of vocabulary leads to parallel deficits on tests of word production and word comprehension, and errors occur on corresponding items in each test (Lambon Ralph and Howard, 2000). This also applies to surface dyslexia, another core feature of the SD syndrome. The pronunciation of many English words is predictable from their spelling (e.g., ‘cord,’ ‘loot,’ or ‘mint’), while for others it is not (e.g., ‘word,’ ‘foot,’ or ‘pint’). In surface dyslexia, irregular words are pronounced as if they had a typical spelling–sound

538

C.M. KIPPS ET AL.

relationship. Similarly, although the grammatical structure of speech is preserved, over-regularization errors frequently occur when SD patients are asked to transform a sentence in present tense into the past: e.g., ‘Today I fall on the stairs’ ! ‘Yesterday I falled on the stairs.’ 28.5.2. Behavioral features The behavioral and personality changes associated with bv-FTD are common in SD, at presentation as well as later in the illness, but the emphasis is different. Impaired social functioning results from a combination of emotional withdrawal, depression, disinhibition, apathy, and irritability. Changes in eating behavior, such as the development of a sweet tooth, are common, but usually there is a restriction of food preferences, or bizarre food choices, rather than the overeating often seen in bv-FTD. Loss of physiological drives is common and includes poor appetite, weight loss, and decreased libido. New religiosity and eccentricity of dress is also reported (Edwards-Lee et al., 1997). The right temporal variant, which has only one-third the prevalence of left sided cases, seems to be more convincingly associated with behavioral disturbance than the left (Edwards-Lee et al., 1997; Perry et al., 2001; Thompson et al., 2003; Seeley et al., 2005), but cases are seldom, if ever, purely unilateral. In a recent study, after an average of three years, the symptoms that were not present initially have generally emerged, whether they be behavioral or semantic (Seeley et al., 2005). Compulsions are a prominent, but delayed feature, and reflect the predominant temporal lobe involved. This study suggested that with left-predominant SD, visual objects such as coins or buttons are likely to become the target stimulus, while in the right-sided variant, the focus is on letters, words, and symbols (e.g., word puzzles, and writing notes to doctors), although we have observed exceptions to these general rules. Clockwatching and an intense interest in jigsaws are very common (Thompson et al., 2002). Compulsions evolve approximately 5 to 7 years after the initial symptoms, and are often accompanied by disinhibition, prosopagnosia, and altered food preference. Strong visual compulsions may result in accusations of shoplifting and theft. Lack of empathy is a feature that appears to be more common as a later feature in disease, although it may be seen at presentation if this is delayed. Mental inflexibility can be extreme and provoke marked behavioral fluctuations in response to changes in the immediate environment. Deficits in person recognition frequently occur at some stage in the disease (Thompson et al., 2003). Inability to retrieve a person’s name is extremely

common, and it is important in the clinical history to distinguish this from a failure to recognize a familiar person. There seems to be a specific problem with face processing in many SD patients, a progressive prosopagnosia, and this is more common in the right-predominant variant. We have observed a right-dominant SD patient emerge from the clinic testing room out into the waiting room where (as she knew) her husband awaited her; but she went up to a stranger in the waiting room to tell him that she was ready to go home. A recent study found a number of clinical features which were associated with either left- or rightpredominant cases at the time of first presentation to the clinic (Thompson et al., 2003). The features which were significantly more common in left-predominant SD were both language-related, namely word-finding difficulty and impaired comprehension. By contrast, right-predominant cases showed a higher prevalence of person recognition problems, social awkwardness, and poor insight into their condition. Perhaps because of this, right-predominant patients were more likely to have lost their jobs before presenting to clinic.

28.6. Neuropsychological tests in SD and PNFA 28.6.1. Language 28.6.1.1. Naming Most aphasic patients, whatever the nature of their syndrome or lesion, show some impairment on tests of picture or object naming. This includes both PNFA and SD patients, but these groups differ in their error patterns. PNFA patients obtain mid-range scores, and their errors are more often phonetic approximations than failures of retrieval (Mendez et al., 2003; Weintraub et al., 1990). They can usually demonstrate knowledge of the items they cannot name (Gorno-Tempini et al., 2004), either by giving definitions or properties of the item, by miming its shape or use, or by pointing correctly to the item given a particular property (‘which one of these has a nautical connection?’). On the other hand, all but the very earliest SD patients score very poorly on simple naming tests. Their errors are often ‘don’t know’ responses; they may also make semantically related errors, either at an inappropriately generic level (‘animal’ for ‘horse’), or from within the same category (‘piano’ for ‘harp’) (Snowden et al., 1992; Hodges et al., 1995). They have much more limited knowledge about the items that they fail to name. 28.6.1.2. Noun generation Again, both PNFA and SD affect the ability to generate words, either from a specified initial letter or from a particular category. Normal subjects can produce an

NEUROPSYCHOLOGY OF FRONTOTEMPORAL DEMENTIA average of 18 animal names or 15 words beginning with ‘F’ in a minute, with 10 as a lower limit. In SD, category fluency drops dramatically, often to just a handful of words, while letter fluency (at least early in the disease) is relatively spared—this dissociation is characteristic of SD, and reflects the underlying impairment of semantic knowledge. PNFA tends to affect both varieties of fluency to a similar extent, and the words produced often continue to show a reasonably wide variation as in normal speakers; in SD, by contrast, the instances produced are restricted to the most common, high-frequency words (e.g., ‘cat,’ ‘dog,’ and ‘horse’ for animals). 28.6.1.3. Repetition Impairment at repeating spoken words back to the examiner is a reliable feature of PNFA, and errors may be observed here before they become obvious in spontaneous speech. Long words with complex or repeated sequences of consonants are particularly difficult (‘episcopal,’ ‘hippopotamus’). The phonological structure of the word is distorted by phoneme omissions, transpositions or insertions. Often the patient will make multiple false starts, coming to a halt in midword each time. Repetition of long nonwords is even more difficult, as it relies more specifically on phonological working memory, which is typically impaired in PNFA. The Children’s Test of Nonword Repetition (Gathercole and Baddeley, 1996) is useful in eliciting subtle deficits. These problems are also reflected in a low digit span, and in difficulty with repeating sentences or following a three-part command. On the other hand, SD patients mostly find word repetition easy, and show a striking dissociation between production of a word and knowledge of its meaning. 28.6.1.4. Comprehension tasks Impairments of comprehension of single words and of syntax are characteristic of SD and PNFA respectively, and each may occur in the absence of the other. Word comprehension deficits are tested by word–picture matching, or by asking the patient to define a word, as described above. Because the underlying problem in SD is a breakdown of conceptual knowledge, item consistency is seen between tests of word production (or retrieval) and comprehension. For the same reason, SD patients also show impairment on nonverbal tests of semantic association, such as the Pyramids and Palm Trees Test (Howard and Patterson, 1992); a low score here is quite specific for SD. Simple syntactic comprehension tests are also described above, but for formal testing the TROG is particularly suitable, as it uses very common words which both PNFA and SD patients are likely to understand in isolation.

539

28.6.1.5. Reading and writing The surface dyslexia of SD is elicited using reading tests with irregular words, such as the NART (National Adult Reading Test; Nelson and Willison, 1991) or the ‘Surface List’ (Patterson and Hodges, 1992). Otherwise, tests of reading and writing are of little specific diagnostic value in these conditions. 28.6.2. Memory in PNFA and SD From a clinical perspective, there is often a striking dissociation between language and everyday memory functions in both PNFA and SD. Indeed, diagnostic criteria for progressive aphasic syndromes have generally demanded relatively preserved everyday (episodic) memory (Neary et al., 1998). However, demonstrating this preservation using standard tests is fraught with difficulty. Understanding test instructions can sometimes be a problem in PNFA as well as in SD, owing to impairments of sentence and single-word comprehension respectively. More dramatically, tests requiring spoken output are likely to be affected by anomia and other production impairments. For this reason, patients may score better (relative to control ranges) on tests of recognition than recall. On a more fundamental level, a specific impairment of verbal memory is common, particularly in SD. This deficit affects performance on tests of word-list learning such as the RAVLT (Rey Auditory–Verbal Learning Test), as well as recall of a narrative. As the phonological and semantic representations of words are disordered in PNFA and SD respectively, such a deficit is not surprising, and does not necessarily imply an impairment of anterograde memory systems. Tests which use exclusively nonverbal material, such as recall of the Rey complex figure, are more useful in this regard, provided that the patient does not have an impairment of visuospatial processing, which sometimes accompanies PNFA as part of its overlap with the corticobasal syndrome (Graham et al., 2003a; Kertesz and Munoz, 2003). It is difficult to find a single ‘memory’ test which is reliably normal in all cases, and so clinical judgment is crucial: a patient who complains mainly of symptoms of anterograde episodic memory deficits is more likely to be suffering from Alzheimer’s disease, but a degree of impairment on language-dependent tests without such symptoms does not rule out a diagnosis of PNFA or SD. 28.6.3. Executive function in PNFA and SD Impaired executive function has rarely been discussed in the context of progressive aphasia, although it is

540

C.M. KIPPS ET AL.

frequently cited as a defining impairment of the bv-FTD group (Neary et al., 1998). By implication, then, it might be taken as a relative exclusion criterion for PNFA or SD, but little published work has addressed this issue. One study (Nestor et al., 2003) found that a group of 10 PNFA patients (selected on the basis of reduced and distorted speech and impaired syntactic comprehension) showed impairment on the WCST compared with controls, although a group of AD patients were almost as impaired. Our own experience is that executive impairments are commoner in PNFA than in SD, but further investigation is needed.

28.7. Interpretation of neuropsychological test performance The interpretation of neuropsychological test scores, either routine or experimental, warrants a degree of caution. Significant heterogeneity exists in the performance of FTD patients; group effects may not be representative of individual cases. There is also frequent overlap in performance with either controls or patients with other neurodegenerative disorders, particularly Alzheimer’s disease. Conflicting results are often obtained across different studies, and can be ascribed to a number of methodological issues. Matching of patients across disease categories is one significant issue. The most common method of matching uses performance on the Mini-Mental State Examination (MMSE) to control for differences in disease severity. This is not particularly satisfactory as the MMSE does not weight different cognitive domains equally. Other studies (Kramer et al., 2003; Diehl et al., 2005) have used Clinical Dementia Rating (CDR) scores to match patients, but as illustrated in one study (Rosen et al., 2004a), this measure emphasizes functional disability, which can be inflated by marked behavioral disturbance, and may not truly reflect an equivalent pathological burden across disease groups. Failure to distinguish FTD from the language variants (PNFA and SD) has

blurred the distinct cognitive profiles of these disorders, and presumably contributed in some part to the conflicting results. Furthermore, FTLD often exhibits hemispheric asymmetry, and at least one study has demonstrated differential performance in left and right predominant FTD (Boone et al., 1999). Studies with prospective assessment of consecutively enrolled subjects are rare, but should be encouraged. As this is a field that is still dynamic, it is difficult to standardize test batteries across studies, and group sizes are likely to remain small. Pathological confirmation should be obtained wherever possible to reduce any bias resulting from clinical diagnosis, and postmortem series should aim to recruit widely, and not just patients with classical clinical features (Fig. 28.1). Care should be taken to avoid circularity whereby inclusion criteria are used to discriminate the disease from others. Lastly, even the pathologists, as final arbiters, have something to learn in this evolving field (Halliday et al., 2002). Patients with FTD are often impaired on standard neuropsychological test batteries relative to controls (Binetti et al., 2000). Whilst these tests are sensitive, however, they are often not specific in discriminating between FTD and other neurodegenerative diseases. We now discuss what is known about such discrimination.

28.8. Differential diagnosis See Table 28.5 for a summary. 28.8.1. Alzheimer’s disease Since most studies in FTD compare patients to normal controls or to those who have Alzheimer’s disease, many of the issues relevant to this section have already been discussed. Age of onset in the FTD syndromes is typically a decade earlier than in AD (Hodges et al., 2003) although this may reflect an ascertainment bias with many studies using a cutoff of 65 or 70 years.

Fig. 28.1. Imaging findings associated with frontotemporal dementia syndromes (A) behavioral variant FTD with marked frontal atrophy and ventricular enlargement; (B) progressive nonfluent aphasia showing left perisylvian atrophy; and (C) semantic dementia with anterior temporal lobe pathology, worse on the left. The images are shown in radiological convention with the left side of the patient on the right side of the image.

NEUROPSYCHOLOGY OF FRONTOTEMPORAL DEMENTIA Table 28.5 Other diagnoses to consider in suspected FTD Category

Diseases

Neurodegenerative

Alzheimer’s disease Corticobasal degeneration Progressive supranuclear palsy FTD with motor neuron disease Vascular dementia Dementia with Lewy bodies Creutzfeldt–Jakob disease Huntington’s disease Adult Asperger’s syndrome Affective disorders Schizophrenia Frontal tumor Hypothyroidism Vasculitis Vitamin deficiencies

Psychiatric

Miscellaneous

The very high prevalence of Alzheimer’s disease over the age of 75 is likely to obscure the detection of FTD in patients presenting in this age group. Because AD pathology is very common in the elderly population, atypical clinical presentations are seen relatively frequently, especially in specialist clinics. Personality change, unconcern, and socially inappropriate behavior typically distinguish FTD from the anterograde memory disturbance and topographical disorientation characteristic of Alzheimer’s disease. Stereotypic behavior, changes in eating preference or hyperorality and emotional blunting also reliably separate the groups (Bozeat et al., 2000; Rosen et al., 2002a). Failure to assess behavioral characteristics results in the incorrect classification of many FTLD subjects as AD. When the presence of social conduct disorder, hyperorality and akinesia are combined with absence of amnesia and perceptual disturbance, up to 93% of the FTLD and 97% of the AD patients are correctly classified (Rosen et al., 2002b). Although apathy is more frequent in FTD, it is not a particularly helpful discriminating feature. Abnormal perception and praxis are more discriminatory for AD than amnesic symptoms. Impaired spatial perception with spatial disorientation, inability to localize objects, or failure on spatial tasks such as tracking, copying line drawings or counting dots, dramatically increases the probability of AD in an individual patient (Varma et al., 1999). Although there is substantial overlap in the performance of FTD and AD patients, assessment of the type of errors made (i.e., perseveration, or concrete interpretation of sentences) may help distinguish the two groups (Thompson et al., 2005).

541

Focal variants of AD with marked dysexecutive features have been described (Johnson et al., 1999), but these patients have a coexisting typical AD profile, with memory and visuospatial impairment. In our Cambridge experience, non-AD patients with this pattern typically evolve into other dementia syndromes such as progressive supranuclear palsy (PSP), or have vascular dementia. Similarly, patients with proven FTD pathology have occasionally been shown to have the anterograde memory disturbance usually associated with Alzheimer’s (Caine et al., 2001; Hodges et al., 2004; Graham et al., 2005). In practice, diagnostic confusion is less common than might be imagined, as in bv-FTD it is the behavioral disturbance that dominates the clinical picture. An inventory such as the CBI readily distinguishes the symptom complexes that are typical of these disorders, and highlights the memory disturbance in cases that might otherwise be diagnosed as bv-FTD. AD pathology occasionally causes PNFA. This may be indistinguishable from the syndrome caused by FTD-spectrum pathologies (Pogacar and Williams, 1984; Green et al., 1990; Kempler et al., 1990; Benson and Zaias, 1991; Karbe et al., 1993; Galton et al., 2000; Li et al., 2000; Clark et al., 2003; Godbolt et al., 2004), at least on strictly linguistic criteria. A more frequent presentation, however, is of prominent phonological impairments and/or dysfluency in the context of episodic memory impairment or other cognitive deficits, and AD may be diagnosed confidently in this situation. Care must be exercised in interpreting the results of tests of verbal memory, tests with complicated instructions, or tests which rely on spoken or written answers, as language impairment may cause falsely low scores and suggest global impairment in a purely aphasic patient. Even when the language syndrome is relatively pure, AD pathology is very likely when the onset occurs at over 70 years of age. Similar comments apply to SD, except that it is unusual for AD pathology to mimic SD precisely. Occasionally it may produce a forme fruste of SD (a fluent aphasia without the usual attendant features). Semantic memory impairment is a common component of a global AD syndrome, but this is usually easily distinguished from pure SD by the predominance of episodic memory impairment and other deficits. In a recent pathologically confirmed series of 18 patients, only 2 patients who were clinically diagnosed with SD were eventually shown to have AD (Davies et al., 2005a). 28.8.2. Corticobasal degeneration Corticobasal degeneration (CBD) was originally described as an atypical Parkinsonian syndrome, with limb apraxia, myoclonus, cortical sensory loss, and

542

C.M. KIPPS ET AL.

the alien limb phenomenon (Rebeiz et al., 1968). More recently, language impairment has been recognized as part of the syndrome, and impairments in phonological processing have been demonstrated in patients with the clinical features of CBD but no symptomatic aphasia (Graham et al., 2003b). The term ‘CBD’ refers to a set of pathological findings as well as a clinical pattern; this association has largely stood the test of time, but a number of patients who were diagnosed with unequivocal PNFA in life have had CBD pathology at postmortem (Kertesz and Munoz, 2002; Ferrer et al., 2003). Kertesz et al. (2000a) highlighted the frequency of reports of behavioral disturbance in the case reports of CBD. This consists primarily of apathy, disinhibition, perseveration, and inattention, although as usual these deficits are not present in every subject. On the Neuropsychiatric Inventory (NPI), depression was the only feature that was endorsed more frequently in CBD than in FTD (Cummings and Litvan, 2000), although apathy (40%), irritability (20%), anxiety (15%), and disinhibition (15%) were not uncommon. How these features relate to underlying depression is unclear, but it is likely to be a significant factor in their presence. Depression is fairly uncommon in bv-FTD, as mentioned earlier. A further study suggests that behavioral features are marked in FTD from the start of the illness, and their frequency does not alter significantly, whereas in CBD, they accumulate gradually (Marczinski et al., 2004). A patient with CBD may show the classical motor features, language features, behavioral disturbance, or all three (Graham et al., 2003a). Deficits may also develop sequentially. A diagnosis of CBD should therefore be considered in a case of suspected PNFA or bvFTD, especially in the presence of visuospatial impairments or apraxia (in copying either a geometric design or a meaningless hand position). The aphasia is likely to affect phonology predominantly, and naming may be relatively spared. 28.8.3. Progressive supranuclear palsy The classical features of progressive supranuclear palsy (PSP) are disruptions of motor function, including axial rigidity, postural instability with a tendency to fall backwards, bradykinesia, and a supranuclear vertical gaze palsy (Richardson et al., 1963). However, language may also be affected. Full-blown PNFA with paraphasia and dysgrammatism has been reported (Mochizuki et al., 2003), and speech apraxia may also occur (Sakai et al., 2002), but the most frequent language impairment is difficulty in initiating output. This manifests as ‘dynamic aphasia’ (Esmonde et al., 1996), with a marked and progressive reduction in speech output and shortened phrases, but otherwise normal speech and

comprehension. Bulbar features, including dysarthria, are also common, and may hamper assessment of linguistic function. These deficits may precede the onset of the motor features, but it is usual for the PSP syndrome to appear later in the illness. The possibility of PSP should be considered in a patient presenting with a progressive dynamic aphasia, and the physical signs should be sought both at presentation and at follow-up. Apathy and disinhibition are prominent in PSP (Aarsland et al., 2001), which is in keeping with the medial and dorsolateral prefrontal cortex neuronal loss seen in this disease. However, the picture is not the florid disruption in social functioning that is seen more typically in FTD. In a recent analysis (Bak, unpublished data), there was no difference in the summed behavioral scores on the Cambridge Behavioural Inventory (CBI) across different stages of disease in PSP. This implies that it is not simply the motor dysfunction that leads to a lower reporting of behavioral disruption in PSP. Conversely, a recent report demonstrated FTD pathology with ubiquitin inclusions in three cases with a distinct PSP phenotype (Paviour et al., 2004). Extrapyramidal features dominated the clinical picture, but one patient had significant disinhibition, another presented in his mid-seventies, and a third developed fasciculations suggestive of motor neuron disease. 28.8.4. Frontotemporal dementia with motor neuron disease (FTD-MND) Frontotemporal dementia with motor neuron disease (FTD-MND) usually presents in the sixth decade, and is more common in men. Behavioral and cognitive changes invariably precede motor symptoms by 6 to 12 months. Bulbar features including dysphagia and dysarthria are particularly common. The FTD-MND syndrome is unusual for the fact that delusions and indeed hallucinations have been described (Bak and Hodges, 2001). These phenomena are not part of the usual FTD spectrum, but the remainder of the behavioral and cognitive features are indistinguishable from classical FTD, with disinhibition being particularly common (Neary et al., 2000). Progressive aphasia is a common feature of this syndrome (Bak et al., 2001). The aphasia may appear before the onset of motor features, and is usually a typical PNFA. Semantic deficits appear to be less frequent (Bak and Hodges, 2001; 2004). Progression is rapid (Bak and Hodges, 2004), and prognosis is poor—the median survival of FTD-MND patients in a recent series was just 2 years from symptom onset (Hodges et al., 2003). If physical signs of MND are not present at the first presentation to clinic, they usually appear within a year.

NEUROPSYCHOLOGY OF FRONTOTEMPORAL DEMENTIA 28.8.5. Vascular dementia Although one might expect vascular dementia affecting subcortical regions to affect the frontal lobes in a similar manner to frontotemporal dementia, this does not appear to be the case. In fact, the behavioral symptoms that distinguish FTD from vascular dementia are fairly similar to those that distinguish the disorder from AD (Snowden et al., 2001). Vascular risk factors, stepwise decline and the presence of ischemic lesions are characteristic of vascular dementia (Roman et al., 1993). It has never been reported to cause progressive aphasia.

543

particularly rapid deterioration should prompt concern about prion disease. A few cases of Creutzfeldt–Jakob disease presenting with progressive aphasia have been reported (Shuttleworth et al., 1985; Yamanouchi et al., 1986; Mandell et al., 1989), though the association is controversial (Turner et al., 1996). Other cognitive and physical features developed within weeks or months of onset in these cases, and the progression of the aphasia was also very rapid. Huntington’s disease is occasionally suggested by an appropriate family history. Irritability is common in the early stages, and early cognitive changes include impaired attention and impaired executive dysfunction (Ho et al., 2003).

28.8.6. Dementia with Lewy bodies

28.11. Conclusion The presence of delusions, hallucinations, and extrapyramidal features are uncommon in bv-FTD unless it is associated with motor neuron disease. Thus, it is seldom that DLB provokes diagnostic confusion. Similarly, the presence of visuospatial impairment in FTD would make one reconsider the diagnosis. There is a single case report of progressive aphasia with cortical Lewy body disease, but this case also had dysarthria and developed rapidly into an MND syndrome. Even as part of a broader syndrome, it is unusual for language to be impaired in these disorders.

28.9. Psychiatric diagnoses Patients with bv-FTD frequently arrive via the psychiatrist’s office, but when they do not, the effects of mood disturbance, either mania or depression, should be considered. The older patient who presents with a new mood disorder in the absence of something similar in earlier years should arouse more suspicion than someone who has been chronically depressed for years. Similarly, schizophrenic presentations tend to be in a younger age-group than the 50–60 year olds most commonly affected by FTD syndromes. In taking the history, it is vital to make every attempt to verify that there is a change in functioning with regards to behavior. Imaging may be of use, although in bv-FTD there may be little or no abnormality of structural scans many years into the disease (Davies et al., 2005b). This is not the case with SD or PNFA however. One should also consider the possibility of adult Asperger’s syndrome and be aware of the potential for dysfunctional marital relationships to paint a colorful picture of behavioral disruption.

28.10. Other differential diagnoses Hypothyroidism, vasculitis, and vitamin deficiencies, though unlikely, should be considered. Structural lesions such as a frontal lobe tumor could in principle present as a progressive Broca’s aphasia, and

Symptoms in frontotemporal lobar dementia are related to the underlying structures involved in the pathological process, and not the nature of the pathology itself. There are reliable symptom clusters which define syndromes, but there are several language and behavioral features that show significant overlap between the different variants of FTLD. Future work needs to continue to delineate the relevant neural substrates of the disturbed cognition in these patients. As the nature of the disease becomes clearer, it is likely that the disease will be recognized in more patients, particularly those over the age of 65 who have previously been given a diagnosis of Alzheimer’s disease. Despite substantial progress in delineating the features of this disease, there remains no effective treatment, either symptomatic or curative.

Acknowledgements Dr. C. Kipps is supported by the Wellcome Trust (Grant No. 073580) and Prof. J. Hodges by the UK Medical Research Council.

References Aarsland D, Litvan I, Larsen JP (2001). Neuropsychiatric symptoms of patients with progressive supranuclear palsy and Parkinson’s disease. J Neuropsychiatry Clin Neurosci 13: 42–49. Bak TH, Hodges JR (2001). Motor neurone disease, dementia and aphasia: Coincidence, co-occurrence or continuum? J Neurol 248: 260–270. Bak TH, Hodges JR (2004). The effects of motor neurone disease on language: Further evidence. Brain Lang 89: 354–361. Bak TH, O’Donovan DG, Xuereb JH, et al. (2001). Selective impairment of verb processing associated with pathological changes in Brodmann areas 44 and 45 in the motor neurone disease–dementia–aphasia syndrome. Brain 124 : 103–120. Barber R, Snowden JS, Craufurd D (1995). Frontotemporal dementia and Alzheimer’s disease: Retrospective

544

C.M. KIPPS ET AL.

differentiation using information from informants. J Neurol Neurosurg Psychiatry 59: 61–70. Benson DF, Zaias BW (1991). Progressive aphasia: A case with postmortem correlation. Neuropsychiatry Neuropsychol Behav Neurol 4: 215–223. Binetti G, Locascio JJ, Corkin S, et al. (2000). Differences between Pick disease and Alzheimer disease in clinical appearance and rate of cognitive decline. Arch Neurol 57: 225–232. Bishop DVM (1983). The Test for Reception of Grammar Age and Cognitive Performance Research Centre. University of Manchester, Manchester. Boone KB, Miller BL, Lee A, et al. (1999). Neuropsychological patterns in right versus left frontotemporal dementia. J Internat Neuropsychol Soc 5: 616–622. Bozeat S, Gregory CA, Lambon Ralph MA, et al. (2000). Which neuropsychiatric and behavioural features distinguish frontal and temporal variants of frontotemporal dementia from Alzheimer’s disease? J Neurol Neurosurg Psychiatry 69: 178–186. Broe M, Hodges JR, Schofield E, et al. (2003). Staging disease severity in pathologically confirmed cases of frontotemporal dementia. Neurology 60: 1005–1011. Brun A, Englund B, Gustafson L, et al. (1994). Clinical and neuropathological criteria for frontotemporal dementia. The Lund and Manchester Groups. J Neurol Neurosurg Psychiatry 57: 416–418. Caine D, Patterson K, Hodges JR, et al. (2001). Severe anterograde amnesia with extensive hippocampal degeneration in a case of rapidly progressive frontotemporal dementia. Neurocase 7: 57–64. Cappa SF, Binetti G, Pezzini A, et al. (1998). Object and action naming in Alzheimer’s disease and frontotemporal dementia [see comment]. Neurology 50: 351–355. Chan D, Fox NC, Scahill RI, et al. (2001). Patterns of temporal lobe atrophy in semantic dementia and Alzheimer’s disease. Ann Neurol 49: 433–442. Clark DG, Mendez MF, Farag E, et al. (2003). Clinicopathologic case report: Progressive aphasia in a 77-year-old man. J Neuropsychiatry Clin Neurosci 15: 231–238. Costello AL, Warrington EK (1989). Dynamic aphasia: The selective impairment of verbal planning. Cortex 25: 103–114. Cummings JL, Litvan I (2000). Neuropsychiatric aspects of corticobasal degeneration. Adv Neurol 82: 147–152. Cummings JL, Mega M, Gray K, et al. (1994). The Neuropsychiatric Inventory: Comprehensive assessment of psychopathology in dementia. Neurology 44: 2308–2314. Davies RR, Hodges JR, Kril JJ, et al. (2005a). The pathological basis of semantic dementia. Brain 128(9): 1984–1985. Davies RR, Kipps CM, Mitchell J, et al. (2005b). Progression in frontotemporal dementia: identifying a benign behavioural variant on MRI. Arch Neurol 63: 1627–31. Davis MH (1980). A multidimensional approach to individual differences in empathy. JSAS Catalog of Selected Documents in Psychology 10. Diehl J, Monsch AU, Aebi C, et al. (2005). Frontotemporal dementia, semantic dementia, and Alzheimer’s disease: The

contribution of standard neuropsychological tests to differential diagnosis. J Geriatr Psychiatry Neurol 18: 39–44. Dubois B, Slachevsky A, Litvan I, et al. (2000). The FAB: A Frontal Assessment Battery at bedside. Neurology 55: 1621–1626. Duncan J, Owen AM (2000). Common regions of the human frontal lobe recruited by diverse cognitive demands. Trends Neurosci 23: 475–483. Edwards-Lee T, Miller BL, Benson DF, et al. (1997). The temporal variant of frontotemporal dementia. Brain 120: 1027–1040. Elfgren C, Passant U, Risberg J (1993). Neuropsychological findings in frontal lobe dementia. Dementia 4: 214–219. Esmonde T, Giles E, Xuereb J, et al. (1996). Progressive supranuclear palsy presenting with dynamic aphasia. J Neurol Neurosurg Psychiatry 60: 403–410. Ferrer I, Hernandez I, Boada M, et al. (2003). Primary progressive aphasia as the initial manifestation of corticobasal degeneration and unusual tauopathies. Acta Neuropathol (Berl) 106: 419–435. Folstein MF, Folstein SE, McHugh PR (1975). Mini-mental state: A practical method for grading the mental state of patients for clinicians. J Psychiatr Res 12: 189–198. Frisoni GB, Pizzolato G, Geroldi C, et al. (1995). Dementia of the frontal type: Neuropsychological and [99Tc]-HMPAO SPET features. J Geriatr Psychiatry Neurol 8: 42–48. Galton CJ, Patterson K, Xuereb JH, et al. (2000). Atypical and typical presentations of Alzheimer’s disease: A clinical, neuropsychological, neuroimaging and pathological study of 13 cases. Brain 123: 484–498. Gathercole SE, Baddeley AD (1996). The Children’s Test of Nonword Repetition. Psychological Test Corporation, Harcourt Brace. Glosser G, Gallo JL, Clark CM, et al. (2002). Memory encoding and retrieval in frontotemporal dementia and Alzheimer’s disease. Neuropsychology 16: 190–196. Godbolt AK, Beck JA, Collinge J, et al. (2004). A presenilin 1 R278I mutation presenting with language impairment. Neurology 63: 1702–1704. Gorno-Tempini ML, Dronkers NF, Rankin KP, et al. (2004). Cognition and anatomy in three variants of primary progressive aphasia. Ann Neurol 55: 335–346. Graham A, Davies R, Xuereb J, et al. (2005). Pathologically proven frontotemporal dementia presenting with severe amnesia. Brain 128: 597–605. Graham NL, Bak TH, Hodges JR (2003a). Corticobasal degeneration as a cognitive disorder. Mov Disord 18: 1224–1232. Graham NL, Bak T, Patterson K, et al. (2003b). Language function and dysfunction in corticobasal degeneration. Neurology 61: 493–499. Graham N, Patterson K, Hodges J (2004). When more yields less: Speaking and writing deficits in nonfluent progressive aphasia. Neurocase 10: 141–155. Green J, Morris JC, Sandson J, et al. (1990). Progressive aphasia: A precursor of global dementia? Neurology 40: 423–429.

NEUROPSYCHOLOGY OF FRONTOTEMPORAL DEMENTIA Gregory CA (1999). Frontal variant of frontotemporal dementia: A cross-sectional and longitudinal study of neuropsychiatric features. Psychol Med 29: 1205–1217. Gregory CA, Hodges JR (1996). Frontotemporal Dementia: Use of consensus criteria and prevalence of psychiatric features. Neuropsychiatry Neuropsychol Behav Neurol 9: 145–153. Gregory C, Lough S, Stone V, et al. (2002). Theory of mind in patients with frontal variant frontotemporal dementia and Alzheimer’s disease: Theoretical and practical implications. Brain 125: 752–764. Gregory CA, McKenna PJ, Hodges JR (1998). Dementia of frontal type and simple schizophrenia: Two sides of the same coin? Neurocase 4: 1–6. Gregory CA, Orrell M, Sahakian B, et al. (1997). Can frontotemporal dementia and Alzheimer’s disease be differentiated using a brief battery of tests? Int J Geriatr Psychiatry 12: 375–383. Halliday G, Ng T, Rodriguez M, et al. (2002). Consensus neuropathological diagnosis of common dementia syndromes: Testing and standardising the use of multiple diagnostic criteria. Acta Neuropathol (Berl) 104: 72–78. Ho AK, Sahakian BJ, Brown RG, et al. (2003). Profile of cognitive progression in early Huntington’s disease. Neurology 61: 1702–1706. Hodges JR, Davies R, Xuereb J, et al. (2003). Survival in frontotemporal dementia. Neurology 61: 349–354. Hodges JR, Davies RR, Xuereb JH, et al. (2004). Clinicopathological correlates in frontotemporal dementia. Ann Neurol 56: 399–406. Hodges JR, Graham N, Patterson K (1995). Charting the progression in semantic dementia: Implications for the organisation of semantic memory. Memory 3: 463–495. Hodges JR, Miller B (2001). The neuropsychology of frontal variant frontotemporal dementia and semantic dementia. Introduction to the special topic papers: Part II. Neurocase 7: 113–121. Hodges JR, Patterson K (1996). Nonfluent progressive aphasia and semantic dementia: A comparative neuropsychological study. J Int Neuropsychol Soc 2: 511–524. Hodges JR, Patterson K, Ward R, et al. (1999). The differentiation of semantic dementia and frontal lobe dementia (temporal and frontal variants of frontotemporal dementia) from early Alzheimer’s disease: A comparative neuropsychological study. Neuropsychology 13: 31–40. Hornak J, Bramham J, Rolls ET, et al. (2003). Changes in emotion after circumscribed surgical lesions of the orbitofrontal and cingulate cortices. Brain 126: 1691–1712. Howard D, Patterson K (1992). Pyramids and Palm Trees: A Test of Semantic Access from Pictures and Words. Thames Valley Test Company, Bury St. Edmunds, Suffolk. Johnson JK, Diehl J, Mendez MF, et al. (2005). Frontotemporal lobar degeneration: Demographic characteristics of 353 patients. Arch Neurol 62: 925–930. Johnson JK, Head E, Kim R, et al. (1999). Clinical and pathological evidence for a frontal variant of Alzheimer disease. Arch Neurol 56: 1233–1239.

545

Karbe H, Kertesz A, Polk M (1993). Profiles of language impairment in primary progressive aphasia. Arch Neurol 50: 193–201. Keane J, Calder AJ, Hodges JR, et al. (2002). Face and emotion processing in frontal variant frontotemporal dementia. Neuropsychologia 40: 655–665. Kempler D, Metter EJ, Riege WH, et al. (1990). Slowly progressive aphasia: Three cases with language, memory, CT and PET data. J Neurol Neurosurg Psychiatry 53: 987–993. Kertesz A, Davidson W, Fox H (1997). Frontal behavioral inventory: Diagnostic criteria for frontal lobe dementia. Can J Neurol Sci 24: 29–36. Kertesz A, Davidson W, McCabe P, et al. (2003a). Behavioral quantitation is more sensitive than cognitive testing in frontotemporal dementia. Alzheimer Dis Assoc Disord 17: 223–229. Kertesz A, Davidson W, McCabe P, et al. (2003b). Primary progressive aphasia: Diagnosis, varieties, evolution. J Int Neuropsychol Soc 9: 710–719. Kertesz A, Martinez-Lage P, Davidson W, et al. (2000a). The corticobasal degeneration syndrome overlaps progressive aphasia and frontotemporal dementia. Neurology 55: 1368–1375. Kertesz A, Munoz DG (2002). Primary progressive aphasia: A review of the neurobiology of a common presentation of Pick complex. Am J Alzheimers Dis Other Demen 17: 30–36. Kertesz A, Munoz DG (2003). Primary progressive aphasia and Pick complex. J Neurol Sci 206: 97–107. Kertesz A, Nadkarni N, Davidson W, et al. (2000b). The Frontal Behavioral Inventory in the differential diagnosis of frontotemporal dementia. J Int Neuropsychol Soc 6: 460–468. Knibb JA, Hodges JR (2005). Semantic dementia and primary progressive aphasia: A problem of categorisation? Alzheimer Dis Assoc Disord 19 (Suppl1): S7–S14. Knibb JA, Xuereb JH, Patterson K, et al. (2005). Clinical and pathological characterisation of progressive aphasia. Ann Neurol 59(1): 156–165. Kramer JH, Jurik J, Sha SJ, et al. (2003). Distinctive neuropsychological patterns in frontotemporal dementia, semantic dementia, and Alzheimer disease. Cogn Behav Neurol 16: 211–218. Kril JJ, Halliday GM (2004). Clinicopathological staging of frontotemporal dementia severity: Correlation with regional atrophy. Dement Geriatr Cogn Disord 17: 311–315. Lambon Ralph MA, Howard D (2000). Gogi aphasia or semantic dementia? Simulating and assessing poor verbal comprehension in a case of progressive fluent aphasia. Cogn Neuropsychol 17: 437–465. Lavenu I, Pasquier F (2005). Perception of emotion on faces in frontotemporal dementia and Alzheimer’s disease: A longitudinal study. Dement Geriatr Cogn Disord 19: 37–41. Lavenu I, Pasquier F, Lebert F, et al. (1999). Perception of emotion in frontotemporal dementia and Alzheimer disease. Alzheimer Dis Assoc Disord 13: 96–101.

546

C.M. KIPPS ET AL.

Lebert F, Pasquier F, Souliez L, et al. (1998). Frontotemporal behavioral scale. Alzheimer Dis Assoc Disord 12: 335–339. Levy ML, Miller BL, Cummings JL, et al. (1996). Alzheimer disease and frontotemporal dementias. Behavioral distinctions. Arch Neurol 53: 687–690. Li F, Iseki E, Kato M, et al. (2000). An autopsy case of Alzheimer’s disease presenting with primary progressive aphasia: A clinicopathological and immunohistochemical study. Neuropathology 20: 239–245. Lindau M, Almkvist O, Kushi J, et al. (2000). First symptoms—frontotemporal dementia versus Alzheimer’s disease. Dement Geriatr Cogn Disord 11: 286–293. Lough S, Kipps C, Triess C, et al. (2005). Social reasoning, emotion and empathy in frontal variant frontotemporal dementia. Neuropsychologia 44: 950–958. Lund and Manchester Groups (1994). Clinical and neuropathological criteria for frontotemporal dementia. J Neurol Neurosurg Psychiatry 57: 416–418. Mandell AM, Alexander MP, Carpenter S (1989). Creutzfeldt–Jakob disease presenting as isolated aphasia. Neurology 39: 55–58. Marczinski CA, Davidson W, Kertesz A (2004). A longitudinal study of behavior in frontotemporal dementia and primary progressive aphasia. Cogn Behav Neurol 17: 185–190. Mathuranath PS, Nestor PJ, Berrios GE, et al. (2000). A brief cognitive test battery to differentiate Alzheimer’s disease and frontotemporal dementia. Neurology 55: 1613–1620. McKhann GM, Albert MS, Grossman M, et al. (2001). Clinical and pathological diagnosis of frontotemporal dementia: Report of the Work Group on Frontotemporal Dementia and Pick’s Disease. Arch Neurol 58: 1803–1809. Mendez MF, Clark DG, Shapira JS, et al. (2003). Speech and language in progressive nonfluent aphasia compared with early Alzheimer’s disease. Neurology 61: 1108–1113. Mendez MF, Perryman KM (2002). Neuropsychiatric features of frontotemporal dementia: Evaluation of consensus criteria and review. J Neuropsychiatry Clin Neurosci 14: 424–429. Mesulam MM (2001). Primary progressive aphasia. Ann Neurol 49: 425–432. Miller BL, Cummings JL, Villanueva-Meyer J, et al. (1991). Frontal lobe degeneration: Clinical, neuropsychological, and SPECT characteristics. Neurology 41: 1374–1382. Miller BL, Darby AL, Swartz JR, et al. (1995). Dietary changes, compulsions and sexual behavior in frontotemporal degeneration. Dementia 6: 195–199. Miller BL, Seeley WW, Mychack P, et al. (2001). Neuroanatomy of the self: Evidence from patients with frontotemporal dementia. Neurology 57: 817–821. Mochizuki A, Ueda Y, Komatsuzaki Y, et al. (2003). Progressive supranuclear palsy presenting with primary progressive aphasia—clinicopathological report of an autopsy case. Acta Neuropathol (Berl) 105: 610–614. Mychack P, Kramer JH, Boone KB, et al. (2001). The influence of right frontotemporal dysfunction on social

behavior in frontotemporal dementia. Neurology 56: S11–S15. Neary D, Snowden JS, Gustafson L, et al. (1998). Frontotemporal lobar degeneration: A consensus on clinical diagnostic criteria. Neurology 51: 1546–1554. Neary D, Snowden JS, Mann DM (2000). Cognitive change in motor neurone disease/amyotrophic lateral sclerosis (MND/ALS). J Neurol Sci 180: 15–20. Nelson HE, Willison J (1991). National Adult Reading Test, 2nd edn. NFER-Nelson Publishing Co. Ltd. Nestor PJ, Graham NL, Fryer TD, et al. (2003). Progressive non-fluent aphasia is associated with hypometabolism centred on the left anterior insula. Brain 126: 2406–2418. Nyatsanza S, Shetty T, Gregory C, et al. (2003). A study of stereotypic behaviours in Alzheimer’s disease and frontal and temporal variant frontotemporal dementia. J Neurol Neurosurg Psychiatry 74: 1398–1402. Pachana NA, Boone KB, Miller BL, et al. (1996). Comparison of neuropsychological functioning in Alzheimer’s disease and frontotemporal dementia. J Int Neuropsychol Soc 2: 505–510. Pasquier F, Grymonprez L, Lebert F, et al. (2001). Memory impairment differs in frontotemporal dementia and Alzheimer’s disease. Neurocase 7: 161–171. Patterson K, Graham N, Lambon Ralph MA, et al. (2005). Progressive non-fluent aphasia is not a progressive form of non-fluent (post-stroke) aphasia. Aphasiology 20: 1018–1034. Patterson K, Hodges JR (1992). Deterioration of word meaning: Implications for reading. Neuropsychologia 30: 1025–1040. Paviour DC, Lees AJ, Josephs KA, et al. (2004). Frontotemporal lobar degeneration with ubiquitin-only-immunoreactive neuronal changes: Broadening the clinical picture to include progressive supranuclear palsy. Brain 127: 2441–2451. Perri R, Koch G, Carlesimo GA, et al. (2005). Alzheimer’s disease and frontal variant of frontotemporal dementia. A very brief battery for cognitive and behavioural distinction. J Neurol 252: 1238–1244. Perry RJ, Hodges JR (2000). Differentiating frontal and temporal variant frontotemporal dementia from Alzheimer’s disease. Neurology 54: 2277–2284. Perry RJ, Rosen HR, Kramer JH, et al. (2001). Hemispheric dominance for emotions, empathy and social behaviour: Evidence from right and left handers with frontotemporal dementia. Neurocase 7: 145–160. ¨ ber die Beziehungen der senilen HirnatroPick A (1892). U phie zur Aphasie. Prager Medizinische Wochenschrift 17 [translated in Berrios and Girling (1994). Hist Psych 5: 542–547. Pick A (1901). Senile Hirnatrophie als Grundlage von Herderescheinungen. Wien Klin Wochenschr 14 [translated in Girling and Markova´ (1995). Hist Psych 6: 533–537. Pick A (1904). Zur Symptomatologie der linksseitigen Schla¨fenlappenatrophie. Monatsschrift fu¨r Psychiatrie und Neurologie 16: 378–388.

NEUROPSYCHOLOGY OF FRONTOTEMPORAL DEMENTIA Pijnenburg YA, Gillissen F, Jonker C, et al. (2004). Initial complaints in frontotemporal lobar degeneration. Dement Geriatr Cogn Disord 17: 302–306. Poeck K, Luzzatti C (1988). Slowly progressive aphasia in three patients. The problem of accompanying neuropsychological deficit. Brain 111: 151–168. Pogacar S, Williams RS (1984). Alzheimer’s disease presenting as slowly progressive aphasia. R I Med J 67: 181–185. Rahman S, Robbins TW, Sahakian BJ (1999a). Comparative cognitive neuropsychological studies of frontal lobe function: Implications for therapeutic strategies in frontal variant frontotemporal dementia. Dement Geriatr Cogn Disord 10: 15–28. Rahman S, Sahakian BJ, Hodges JR, et al. (1999b). Specific cognitive deficits in mild frontal variant frontotemporal dementia. Brain 122: 1469–1493. Rankin KP, Baldwin E, Pace-Savitsky C, et al. (2005a). Self awareness and personality change in dementia. J Neurol Neurosurg Psychiatry 76: 632–639. Rankin KP, Kramer JH, Miller BL (2005b). Patterns of cognitive and emotional empathy in frontotemporal lobar degeneration. Cogn Behav Neurol 18: 28–36. Rankin KP, Kramer JH, Mychack P, et al. (2003). Double dissociation of social functioning in frontotemporal dementia. Neurology 60: 266–271. Rankin KP, Rosen HJ, Kramer JH, et al. (2004). Right and left medial orbitofrontal volumes show an opposite relationship to agreeableness in FTD. Dement Geriatr Cogn Disord 17: 328–332. Rebeiz JJ, Kolodny EH, Richardson EP Jr (1968). Corticodentatonigral degeneration with neuronal achromasia. Arch Neurol 18: 20–33. Rhee J, Antiquena P, Grossman M (2001). Verb comprehension in frontotemporal degeneration: The role of grammatical, semantic and executive components. Neurocase 7: 173–184. Richardson JC, Steele J, Olszewski J (1963). Supranuclear ophthalmoplegia, pseudobulbar palsy, nuchal dystonia and dementia. A clinical report on eight cases of heterogenous system degeneration. Trans Am Neurol Assoc 88: 25–29. Rogers RD, Everitt BJ, Baldacchino A, et al. (1999). Dissociable deficits in the decision-making cognition of chronic amphetamine abusers, opiate abusers, patients with focal damage to prefrontal cortex, and tryptophan-depleted normal volunteers: Evidence for monoaminergic mechanisms. Neuropsychopharmacology 20: 322–339. Roman GC, Tatemichi TK, Erkinjuntti T, et al. (1993). Vascular dementia: Diagnostic criteria for research studies. Report of the NINDS-AIREN International Workshop. Neurology 43: 250–260. Rosen HJ, Gorno-Tempini ML, Goldman WP, et al. (2002a). Patterns of brain atrophy in frontotemporal dementia and semantic dementia. Neurology 58: 198–208. Rosen HJ, Hartikainen KM, Jagust W, et al. (2002b). Utility of clinical criteria in differentiating frontotemporal lobar degeneration (FTLD) from AD. Neurology 58: 1608–1615.

547

Rosen HJ, Narvaez JM, Hallam B, et al. (2004a). Neuropsychological and functional measures of severity in Alzheimer disease, frontotemporal dementia, and semantic dementia. Alzheimer Dis Assoc Disord 18: 202–207. Rosen HJ, Pace-Savitsky K, Perry RJ, et al. (2004b). Recognition of emotion in the frontal and temporal variants of frontotemporal dementia. Dement Geriatr Cogn Disord 17: 277–281. Sakai K, Furui E, Komai K, et al. (2002). [Acquired stuttering as an early symptom in a patient with progressive supranuclear palsy]. Rinsho Shinkeigaku 42: 178–180. Seeley WW, Bauer AM, Miller BL, et al. (2005). The natural history of temporal variant frontotemporal dementia. Neurology 64: 1384–1390. Shigenobu K, Ikeda M, Fukuhara R, et al. (2002). The Stereotypy Rating Inventory for frontotemporal lobar degeneration. Psychiatry Res 110: 175–187. Shuttleworth EC, Yates AJ, Paltan-Ortiz JD (1985). Creutzfeldt–Jakob disease presenting as progressive aphasia. J Natl Med Assoc 77: 649–50, 652, 655. Simons JS, Verfaellie M, Galton CJ, et al. (2002). Recollection-based memory in frontotemporal dementia: Implications for theories of long-term memory. Brain 125: 2523–2536. Slachevsky A, Villalpando JM, Sarazin M, et al. (2004). Frontal assessment battery and differential diagnosis of frontotemporal dementia and Alzheimer disease. Arch Neurol 61: 1104–1107. Snowden JS, Bathgate D, Varma A, et al. (2001). Distinct behavioural profiles in frontotemporal dementia and semantic dementia. J Neurol Neurosurg Psychiatry 70: 323–332. Snowden JS, Gibbons ZC, Blackshaw A, et al. (2003). Social cognition in frontotemporal dementia and Huntington’s disease. Neuropsychologia 41: 688–701. Snowden JS, Goulding PJ, Neary D (1989). Semantic dementia: A form of circumscribed cerebral atrophy. Behav Neurol 2: 167–182. Snowden JS, Griffiths HL, Neary D (1996). Progressive language disorder associated with frontal lobe degeneration. Neurocase 2: 429–440. Snowden JS, Neary D, Mann DM, et al. (1992). Progressive language disorder due to lobar atrophy. Ann Neurol 31: 174–183. Thompson JC, Stopford CL, Snowden JS, et al. (2005). Qualitative neuropsychological performance characteristics in frontotemporal dementia and Alzheimer’s disease. J Neurol Neurosurg Psychiatry 76: 920–927. Thompson SA, Graham KS, Patterson K, et al. (2002). Is knowledge of famous people disproportionately impaired in patients with early and questionable Alzheimer’s disease? Neuropsychology 16: 344–358. Thompson SA, Patterson K, Hodges JR (2003). Left/right asymmetry of atrophy in semantic dementia: Behavioral– cognitive implications. Neurology 61: 1196–1203. Turner RS, Kenyon LC, Trojanowski JQ, et al. (1996). Clinical, neuroimaging, and pathologic features of progressive nonfluent aphasia. Ann Neurol 39: 166–173.

548

C.M. KIPPS ET AL.

Varma AR, Snowden JS, Lloyd JJ, et al. (1999). Evaluation of the NINCDS-ADRDA criteria in the differentiation of Alzheimer’s disease and frontotemporal dementia. J Neurol Neurosurg Psychiatry 66: 184–188. Warrington EK, James M (1991). VOSP: The Visual Object and Space Perception Battery Thames Valley Test Company. Watt S, Jokel R, Behrmann M (1997). Surface dyslexia in nonfluent progressive aphasia. Brain Lang 56: 211–233.

Weintraub S, Rubin NP, Mesulam MM (1990). Primary progressive aphasia. Longitudinal course, neuropsychological profile, and language features. Arch Neurol 47: 1329–1335. Westbury C, Bub D (1997). Primary progressive aphasia: A review of 112 cases. Brain Lang 60: 381–406. Yamanouchi H, Budka H, Vass K Sr (1986). Unilateral Creutzfeldt–Jakob disease. Neurology 36: 1517–1520.

Handbook of Clinical Neurology, Vol. 88 (3rd series) Neuropsychology and behavioral neurology G. Goldenberg, B.L. Miller, Editors # 2008 Elsevier B.V. All rights reserved

Chapter 29

Neuropsychology of dementia with Lewy bodies ¨ STER DANIEL I. KAUFER* AND ALEXANDER I. TRO Department of Neurology, University of North Carolina School of Medicine, Chapel Hill, NC, USA

29.1. Introduction Increasing recognition of dementia syndromes associated with Lewy body pathology over the last several decades has culminated in the formal description of ‘dementia with Lewy bodies’ (DLB) as a distinctive, though controversial, neurodegenerative entity (McKeith et al., 1996). Standardized clinical diagnostic criteria have spurred intensive research efforts on a variety of fronts related to DLB, including characterizing its neuropsychological and neuropsychiatric features, their neuroimaging and pathological correlates, and burgeoning clinical therapeutic trials. More recently, such research efforts have yielded updated diagnostic criteria that expand the defining clinical characteristics and provide a more rigorous pathological definition of DLB (McKeith et al., 2005). Juxtaposed with the evolving concept of Lewy body dementias, nonmotor manifestations of Parkinson’s disease (PD) are commanding increased attention. The emerging view of PD as a multisystem disorder with variable expression of clinical features primarily reflects the distribution of Lewy bodies in motor and nonmotor areas of the brain. Other pathological features, such as amyloid plaques, a hallmark of Alzheimer’s disease (AD), commonly occur in the setting of dementia and parkinsonism. Pathological overlap between AD and PD gives rise to various clinical admixtures of dementia and parkinsonism that present a nosological challenge to existing diagnostic criteria for AD and PD. The emerging view of a neurodegenerative spectrum linking AD and PD defies the historical stereotype of these disorders as monolithic disease entities that primarily affect cognitive and motor functioning, respectively. The conceptualization of DLB as a distinctive clinicopathologic entity may be informed by its associated neuropsychological features. Further work in this area *

will facilitate differential diagnosis and foster a better understanding of the inter-relationships among PD, DLB, and AD. Accordingly, this chapter will review neuropsychological aspects of DLB emphasizing comparative features to PD and AD and underlying pathological substrates.

29.2. Historical perspective 29.2.1. Parkinson’s disease The eponymous illness of PD (paralysis agitans) was first described by James Parkinson in 1817. In his case series of six patients, Parkinson asserted that the intellect and senses were preserved, although his use of the term ‘melancholia’ suggests that he did appreciate altered mood states as an associated feature (Parkinson, 1817; see also Darvesh and Freedman, 1996). Parkinson’s formulation of PD as a cognitively neutral disease was challenged by Charcot and Vulpian (1861; 1862), and by isolated reports in the late nineteenth and early twentieth centuries. However, many outside France remained skeptical of cognitive compromise in PD, probably until the middle of the twentieth century (Goetz, 1992). Naville (1922) introduced the term ‘bradyphrenia’ to describe slowing of information processing speed and diminished attention seen in individuals with postencephalitic parkinsonism (PEP). Harkening back to Parkinson a century ago, Friedrich Lewy, whose name has been appended to the eosinophilic, neuronal inclusion bodies (corps de Lewy) in 1919 (Schiller, 2000), did not distinguish depression and dementia when he characterized PD, although one or both of these symptoms were present in the majority of subjects examined (Lewy, 1912; 1923). Furthermore, Lewy apparently did not appreciate the significance of the inclusion bodies he had identified (initially in PEP)

Correspondence to: Daniel Kaufer, MD, Department of Neurology, CB # 7025, University of North Carolina School of Medicine, 3114 Bioinformatics Building, Chapel Hill, NC 27599–7025. E-mail: [email protected], Tel: 919-966-0998.

550

¨ STER D.I. KAUFER AND A.I. TRO

for PD, which were centered in the midbrain substantia nigra, but also occurred in other brainstem nuclei and more rarely, in forebrain regions such as the substantia inominata. 29.2.2. Dementia with Lewy bodies Dementia associated with Lewy bodies was not recognized until the last 40 years of the twentieth century (Holdorff, 2002). Okazaki et al. (1961) reported two patients who exhibited clinical features of parkinsonism and dementia and observed Lewy-body like eosinophilic inclusions in various regions of cerebral cortex. Although these inclusion bodies lacked the distinctive halo that is characteristic of brainstem Lewy bodies (Fig. 29.1), he identified the similarity between these cortical inclusions and brainstem Lewy bodies, and the putative association of these cerebral inclusions with dementia. Kosaka et al. (1980) in Japan first reported a case series of patients with clinical dementia that had variable involvement of Lewy bodies in cortical and limbic regions in addition to the brainstem regions typically associated with PD. In 1990, Kosaka and two other groups of investigators independently described similar disorders of dementia in the setting of parkinsonism and Lewy body pathology. These included ‘diffuse Lewy body disease’ (Kosaka, 1990), ‘senile dementia of the Lewy body type’ (SDLT; Perry et al., 1990) and the ‘Lewy body variant of Alzheimer’s disease’ (LBV-

AD; Hansen et al., 1990). As defined, individuals with SDLT or LBV-AD subjects had cortical (and brainstem) Lewy bodies and amyloid plaques as pathological features. By contrast, DLBD was divided into subtypes based on the distribution of Lewy body pathology and whether or not amyloid plaques were also present. A brainstem-predominant distribution of Lewy bodies defined PD, whereas additional Lewy body pathology in limbic and cortical brain regions defined LBV-AD and SDLT. The variable presence of amyloid plaques formed the basis of two distinct pathological subtypes: 1) a common form, with mixed Lewy body and amyloid pathology, representing the majority of cases (about 75%), and 2) a pure form, with only Lewy body pathology (Fig. 29.2). The terminological diffusion attending Lewy body dementia syndromes was partially resolved when ‘dementia with Lewy bodies’ was adopted as a common name for Lewy body dementia syndromes at a consensus conference (McKeith et al., 1996). In addition, specific clinical and pathological criteria were identified for DLB. The consortium on DLB (CDLB) clinical criteria were formulated as a hierarchical scheme with three core features in addition to dementia: fluctuating cognition, recurrent visual hallucinations, and motor parkinsonism. The number of core features present yielded a probabilistic diagnosis of DLB, with the presence of any single core feature warranting the designation ‘possible,’ and two or more

Fig. 29.1. Brainstem Lewy body. Note halo-like appearance of eosinophilic intracytoplasmic inclusions (H & E stain). Courtesy of Dr Ronald Hamilton, University of Pittsburgh.

NEUROPSYCHOLOGY OF DEMENTIA WITH LEWY BODIES Limbic/Cortical Lewy bodies

Brainstem Lewy bodies

Amyloid Plaques

551

Neurofibrillary Tangles

Parkinson’s Disease “Pure” LBD

Lewy Body Dementia

“Common” LBD Alzheimer’s Disease

Fig. 29.2. Clinicopathological relationships among Lewy body dementia, Alzheimer’s disease, and Parkinson’s disease.

constituting ‘probable’ DLB. Several clinical features that ‘support’ the diagnosis of DLB (unexplained syncope, systematized delusions, other types of hallucinations, neuroleptic sensitivity) were also identified, but were not incorporated into this diagnostic algorithm. The CDLB criteria distinguished DLB from PD with dementia (PDD) on the basis of the relative onset of motor and cognitive or neuropsychiatric symptoms. In PDD, parkinsonian motor signs predate the appearance of cognitive symptoms by more than one year, whereas motor signs that occur within one year of the onset of dementia characterize DLB. This distinction is not supported on pathological evidence and leaves PDD as a relatively featureless dementia syndrome distinguished by DLB solely by its time of onset following motor parkinsonism (Aarsland et al., 2004). This disparity in clinical definitional criteria for DLB and PDD stands as one of the most glaring areas of needed attention. The CDLB criteria provided much needed standardization of research criteria, which were found to be very specific but poorly sensitive for diagnosing DLB. This appears to be largely attributable to cases where diffuse Lewy body pathology is accompanied by AD pathological features, based on the work of Lopez et al. (2002). After a 3rd international DLB consortium meeting convened in 2003, revised clinical and new pathological criteria for DLB have recently become available (McKeith et al., 2005). In addition to core features, several ‘suggestive’ features have been identified that conditionally rank as a core feature for determining probable DLB when another core feature is present. Additional supportive features were also identified, including the presence of REM sleep behavior disorder and neuroleptic sensitivity (Table 29.1). New pathological criteria expand

Table 29.1 Revised clinical diagnostic criteria for DLB Central feature: Progressive cognitive decline that interferes with social and occupational function. Core features: (any 2 ¼ Probable DLB, any one ¼ Possible DLB) 1. Fluctuating cognition 2. Recurrent visual hallucinations 3. Spontaneous motor parkinsonism *Suggestive features: (one or more present with a core feature ¼ Probable DLB, any one alone ¼ Possible DLB) 1. REM sleep behavior disorder 2. Severe neuroleptic sensitivity 3. Decreased tracer uptake: a) in striatum on SPECT dopamine transporter imaging, or b) on MIBG myocardial scintigraphy Supportive features: (common but lacking diagnostic specificity) 1. Repeated falls and syncope 2. Transient, unexplained loss of consciousness 3. Systematized delusions 4. Hallucinations in other modalities *5. Relative preservation of medial lobe on CT or MRI scan *6. Generalized decreased tracer uptake on SPECT or PET imaging in occipital regions *7. Prominent slow wave activity on EEG with temporal lobe transient sharp waves *New additions to criteria. Adapted from McKeith et al. (2005).

on Kosaka’s descriptive system and provide more a detailed assessment of regional Lewy body densities and require the use of immunostaining with alphasynuclein, the protein that forms the core constituent of Lewy

552

¨ STER D.I. KAUFER AND A.I. TRO

bodies. Prior to 1999, pathological assessment of Lewy bodies was performed with ubiquitin staining methods, which are less sensitive to detecting Lewy bodies, thereby underestimating the prevalence of DLB or the extent of pathologic involvement in a given individual. Another important feature of the pathological criteria for DLB is that AD pathological features, notably neurofibrillary tangles, are now accounted for in a probabilistic scheme for pathological diagnostic classification. For example, widespread Lewy body pathology and little neurofibrillary tangle pathology would warrant a high probability diagnosis of DLB; if tangles were abundant in widespread regions, then a diagnosis of AD would be more appropriate independent of Lewy body burden. In most cases, Lewy bodies and neurofibrillary tangles tend not to occur together, in contrast to amyloid plaques, which virtually always occur in AD and are present in many cases of DLB (common form).

29.3. DLB clinical diagnostic criteria 29.3.1. Dementia There is marked variability in the clinical presentation of DLB. The initial manifestations of DLB may be cognitive deficits or any of the core features of DLB, alone or in conjunction with a dementia syndrome. With respect to specific cognitive deficits, DLB patients tend to be more impaired on attentional, executive, and visuospatial tasks (Hansen et al., 1990; Sahgal et al., 1992; Calderon et al., 2001). The UCSD study (Hansen et al., 1990) was among the first to characterize robust neuropsychological differences between AD and DLB (Common form, or LBV-AD). This cohort of AD and DLB subjects matched on age, education, and level of dementia from an autopsy-based series were compared on a battery of neuropsychological tests. Whereas performance on letter fluency, WAIS-R Digit Span, and WISC-R Block design tests was more impaired in DLB compared to AD subjects, no group differences were noted in verbal episodic memory, arithmetic, confrontational naming, or category fluency. This observed pattern of greater attentional, executive, and visuospatial cognitive deficits in DLB relative to AD subjects has been a generally consistent finding in subsequent studies (Gnanalingham et al., 1997; Connor et al., 1998; Noe et al., 2004). 29.3.2. Fluctuating cognition Cognitive fluctuations in DLB may take many forms, ranging from periods of confusion interspersed with periods of lucidity, to marked decreases in level of arousal and extended periods of daytime somnolence. The time course of variability ranges from minute-to-minute

changes, or last as long as weeks at a time. Diurnal variations in behavior referred to as ‘sundowning’ are a common feature of dementia, particularly in more advanced stages, and are not specific for DLB. Cognitive fluctuations in DLB are reminiscent of delirium; the history and evaluation must carefully account for possible toxic and medical factors known to produce acute confusional states. This is particularly important, as DLB patients are typically more sensitive to drugs with anticholinergic side effects. A structured assessment for fluctuating cognition has been used successfully in research settings and may be amenable to selected practice settings (Walker et al., 2000). A recent study identified four distinguishing features of fluctuations in DLB: 1) daytime lethargy, 2) napping for 2 or more hours per day, 3) staring into space, and 4) episodes of disorganized speech (Ferman et al., 2004). Although the pathophysiological basis of fluctuating cognition in DLB is unknown, it may depend more on aberrant activity in cholinergic and monoaminergic modulatory projection neurotransmitter systems that comprise the reticular activating system (Perry et al., 1999; Dringenberg, 2000). Greater EEG background slowing and temporal slow-wave transients in DLB compared to AD subjects are suggested to reflect greater neocortical cholinergic deficits in DLB and may be putative electrophysiological correlates of fluctuating cognition in DLB (Briel et al., 1999). 29.3.3. Visual hallucinations Psychotic manifestations are common in AD and are typically reported to be even more prevalent in DLB. Visual hallucinations are most common, affecting over 60% of subjects with DLB, although delusions, misidentification syndromes, and other types of hallucinations also may occur (Ballard et al., 1999). Among the latter, delusional themes of paranoia, abandonment, and a ‘phantom boarder’ may be more common in DLB compared to AD (Simard et al., 2000). Visual hallucinations in DLB often involve children, little people, or animals, but may also involve inanimate objects. A variable degree of insight may attend the hallucinatory phenomena, ranging from passive amusement to intense fear. The recurrent nature of visual hallucinations in DLB is characteristic, and helps distinguish DLB from hallucinatory experiences that may be circumstantially provoked by dopaminergic or anticholinergic drugs. A recent study (Tiraboschi et al., 2006) identified the early appearance of visual hallucinations as one of the strongest distinguishing characteristics of DLB relative to AD. Perry et al. (1990) reported that DLB subjects that hallucinated had more severe loss of neocortical

NEUROPSYCHOLOGY OF DEMENTIA WITH LEWY BODIES choline acetyltransferase (ChAT) activity, the synthetic enzyme for acetylcholine, and relatively preserved serotonin markers compared to DLB subjects that did not hallucinate. Another study (McShane et al., 1996) observed that visual hallucinations appearing early in the course of DLB tended to be correlated with the presence of cortical Lewy bodies. 29.3.4. Parkinsonian motor signs Parkinsonian motor dysfunction is the hallmark of PD and typically includes two or more of the following: 1) limb rigidity, 2) bradykinesia (slowing of and difficulty initiating movements), 3) resting tremor, typically asymmetric, and 4) loss of postural reflexes (Gelb et al., 1999). In DLB, spontaneous parkinsonian motor features are present in a majority of affected individuals, but tend to be less severe than in PD. Rigidity and bradykinesia are the most common parkinsonian features of DLB. Compared to PD, there is often no resting tremor or asymmetry in motor signs, and rigidity may be more severe (Gnanalingham et al., 1997). Decreased facial expression (hypomimia), marked action/intention tremors, and gait disturbances are also more severe than in PD (Aarsland et al., 2001). As parkinsonian motor signs may be an adverse effect of neuroleptic drugs, or to a lesser degree, newer atypical antipsychotic drugs, it is important to clinically distinguish spontaneous from drug-induced parkinsonian features. Lewy body accumulation in the substantia nigra is a consistent, if not invariable feature of DLB, although Lewy body density is typically lower than in PD (Kosaka, 1990). Similarly, dopaminergic deficits in the midbrain and striatum are generally less severe in DLB (40–60% reduction) compared to PD (80% reduction) (Langlais et al., 1993). In vivo PET functional neuroimaging has shown reduced dopamine transporter density in DLB (Walker et al., 1999). 29.3.5. Sleep–Wake cycle disturbances Sleep–wake cycle disturbances frequently occur in AD and PD, and may be even more problematic in DLB. Although sleep disturbances in DLB have not been well-characterized, one study reported a greater burden of overall sleep disturbances, increased nocturnal motor activity, and increased daytime somnolence in DLB compared to AD subjects (Grace et al., 2000). Alterations in rapid-eye movement (REM) sleep associated with vivid dreams, nocturnal vocalizations, and combativeness (REM sleep behavior disorder or RBD) reflects the dissociation of REM sleep components (rapid, fluttering eye movements, dreaming, and skeletal muscle atonia) that manifest as acting out a dream. RBD occurs

553

in about 25% of subjects of PD subjects and may precede the onset of parkinsonian motor signs (Comella et al., 1998). Given the prominent role of brainstem cholinergic projections in regulating REM sleep, aberrant cholinergic neurotransmission is implicated as a contributing factor to the expression of RBD. Boeve et al. (1998) studied 37 subjects with dementia and RBD confirmed by polysomnography and observed that 34 subjects (92%) had one or more core features of DLB. A majority of subjects also exhibited neuropsychological test performance deficits consistent with DLB. A retrospective study by Ferman et al. (2002) identified cases of DLB that presented with dementia and RBD in the absence of hallucinations and parkinsonism, suggesting that RBD may be an early feature of DLB. 29.3.6. Neuropsychiatric symptoms Neuropsychiatric symptoms in AD and PD have been consistently reported to be a major source of distress to caregivers and are often an important factor leading to the decision to place the patient in an institutional care facility. In addition to the often florid visual hallucinations seen in patients with DLB, auditory hallucinations and misidentification delusions (e.g., Capgras syndrome) are other common neuropsychiatric manifestations. Moreover, in a prospective clinical study of DLB, Ballard et al. (1999) observed anxiety symptoms to be the most common nonpsychotic symptom, being present in 55/138 (40%) of subjects. Depressive symptoms, including anhedonia and loss of energy, have also been reported to be more frequent in DLB subjects compared to AD (Rockwell et al., 2000).

29.4. Epidemiology and genetics 29.4.1. Epidemiology Dementia prevalence rates among patients with PD vary widely (8–93%), depending upon diagnostic criteria, sampling, and case ascertainment methods used. Historically, reported prevalence rates have typically ranged between 20% and 40% (Mohr et al., 1995). Prevalence estimates of DLB and PDD are also affected by how cases are defined using clinical and/or pathological data and the study sample used. Although standard criteria for DLB have existed for a decade, there are no widely used standardized diagnostic criteria for PDD. DLB was initially reported to represent 15–25% of all dementia cases (McKeith et al., 1996), although this is probably more representative of a specialized referral center population. Drawing from a large Norwegian community sample, a longitudinal, prospective study of dementia prevalence in PD reported baseline, 4-year, and 8-year

554

¨ STER D.I. KAUFER AND A.I. TRO

point prevalence rates of 26%, 51%, and 78% (Aarsland et al., 2003). In a longitudinal sample of PD and dementia subjects followed until autopsy, 83% of PD subjects developed dementia over the study period, with male gender and core features of DLB (hallucinations, cognitive fluctuations, depression, and sleep disturbance) being associated with higher risk (Galvin et al., 2006). Although the incidence rate is a more accurate metric than prevalence due to increased mortality associated with dementia, there is comparatively little data regarding incidence rates for dementia in PD and DLB. Dementia incidence is reported to be about 3% for persons with PD younger than 60 years and 15% or less for persons with PD older than 80 years (Mayeux et al., 1990; Biggins et al., 1992; Marder et al., 1995). One study involving DLB study yielded an incidence estimate of DLB at 0.1% per year for the general population and 3.2% a year for all new dementia cases (Zaccai et al., 2005).

found that while both groups demonstrated executive dysfunction, only the sporadic PD group had memory impairments. The apoliopoprotein E e4 genotype has been linked to an increased risk of Alzheimer’s disease and decreased performance on memory tests in healthy elderly, and has also recently been observed to be a risk factor for dementia in PD (Huang et al., 2006). However, Tro¨ster and Fields (2003) did not find memory differences between nondemented PD groups with and without e4 alleles. Other genetic mutations that are of interest in the context of dementia and PD are the Iowa kindred with early dementia (PARK 4, with a locus on chromosome 4p) (Farrer et al., 1999), and the Contursi kindred (PARK 1) (Golbe et al., 1996), in which atypical clinical features include fluent aphasia and palilalia.

29.4.2. Genetics

Parkinson’s disease involves the loss of pigmented cells from the substantia nigra, particularly the ventrolateral part, and other pigmented nuclei in the brainstem. The majority (70–80%) of dopaminergic neurons in the substantia nigra must be destroyed before PD motor symptoms emerge (Bernheimer et al., 1973). The pathological hallmark of PD is the Lewy body which is composed primarily of alphasynuclein. While brainstem Lewy bodies have a filamentous and granular core, cortical Lewy bodies seen in DLB and PDD lack this ‘core and halo’ appearance. Lewy neurites are composed of filamentous aggregates of alphasynuclein and have been correlated with the severity of dementia in one study based on their accumulation in the CA2 region of the hippocampus (Churchyard and Lees, 1997). Kosaka et al. (1980) proposed a pathological classification of diffuse Lewy body disease encompassing three topographical categories: brainstem, transitional, and cortical. The brainstem category corresponds to PD, in which Lewy bodies are confined to the pigmented brainstem nuclei. The transitional category (also called the limbic category) describes the additional distribution of Lewy bodies in the limbic cortices, most prominently in the insula, cingulate, and parahippocampal gyrus. In the cortical type, Lewy bodies are abundant in the neocortex. Braak et al. (2003; 2006) have recently attempted to define the sequence of neuropathological changes in PD by developing a staging system analogous to their staging scheme for Alzheimer’s disease, which is based on the topography and extent of neurofibrillary tangle deposition. The Braak stages of PD and their core features based on the distribution of inclusion body (Lewy

Several genetic mutations and loci have recently been identified and linked to parkinsonism in a small number of families (for review see Dekker et al., 2003). The term parkinsonism is used because the constellation of clinical features and associated neuropathology is variable. Though the relevance of these findings to sporadic cases of PD and parkinsonism remains unknown, it is anticipated that these mutations will help identify molecular pathways of potential diagnostic and therapeutic relevance (Hardy et al., 2003). To date, linkage studies have identified six genetic loci (called PARK 1, PARK 3, PARK 4, PARK 5, PARK 8, and NR4A2) that co-segregate with parkinsonism in families with autosomal dominant inheritance. Four other loci have been linked to autosomal recessive forms of parkinsonism: PARK 2, PARK 6, PARK 7, and PARK 9. Only one locus, on the long arm of chromosome 1 (PARK 10), has been linked to sporadic, late-onset, non-Mendelian PD. Although the various loci have all been mapped to specific chromosomes, only five of the 10 genetic mutations have been wellcharacterized: the alphasynuclein gene on the long arm of chromosome 4 (4q) (PARK 1), the parkin gene on chromosome 6q (PARK 2), the ubiquitin C-terminal hydrolase L1 gene on the short arm of chromosome 4 (4p) (PARK 5), the DJ-1 gene on chromosome 1p (PARK 7), and the NR4A2 gene on chromosome 2q. Potential genetic contributions to the variability of neuropsychological profiles in PD and associated disorders have not received sufficient investigative attention. Dujardin et al. (2001) recently compared small groups of patients with sporadic and familial PD, and

29.5. Neuropathology and pathophysiology 29.5.1. Lewy body pathology

NEUROPSYCHOLOGY OF DEMENTIA WITH LEWY BODIES body and Lewy neurite) pathology are presented in Table 29.2 (see also Fig. 29.3). Braak stage 3 and 4 reflect the appearance of motor parkinsonism secondary to substantia nigra pathologic involvement, and the initial involvement of limbic areas, corresponding to Kosaka’s transitional category of Lewy body pathology. The role of Lewy bodies in the dementia of PD, and whether the clinical entities of DLB and PDD are neuropathologically and neuropsychologically distinct, have been ongoing areas of controversy. While dementia and overall severity of cognitive impairment have been associated with cortical Lewy body density, especially in frontal and temporal cortices (Gomez-Tortosa et al.,

555

1999; Hurtig et al., 2000), there are cases of PD with dementia that lack cortical pathology (Perry et al., 1985; Xuereb et al., 1990). Furthermore, some patients with a clinical diagnosis of PD, but meeting neuropathological criteria for DLB at necropsy, may not have a history of clinically significant cognitive impairment (Colosimo et al., 2003). Despite these limitations and contradictions, the prevailing view emerging from recent studies is that DLB and PDD, though temporally distinct with respect to the relative onset of cognitive and motor symptoms, are much more similar than not in terms of their overall clinical, neuropsychological, neuropathologic features.

Table 29.2 Braak staging of neuropathology in Parkinson’s disease Stage

Region

Loci of pathology

1 2 3 4

medulla upper medulla pontine tegmentum midbrain basal prosencephalon

5

neocortex

6

neocortex

Dorsal IX/X motor nucleus and/or immediate reticular zone Stage 1 þ caudal raphe nuclei, gigantocellular reticular nucleus and ceruleus–subceruleus complex Stage 2 þ midbrain (esp. pars compacta of substantia nigra) Stage 3 þ medial temporal-limbic (confined to transentorhinal region and CA2-plexus) Stage 4 þ high order sensory association areas of the neocortex and prefrontal cortex Stage 5 þ first order sensory association neocortical areas and premotor areas; mild changes in primary sensory areas and primary motor field (variable)

After Braak et al. (2003).

Fig. 29.3. Schematic diagram of inclusion body pathology staging of Parkinson’s disease. (A) Medial view depicting stages 1–4, and (B) lateral view depicting progressive neocortical involvement in stages 5–6. Courtesy of Dr Heiko Braak, JW Goethe University.

556

¨ STER D.I. KAUFER AND A.I. TRO

29.5.2. Neurochemical pathology 29.5.2.1. Dopamine Dopamine depletion in the striatum is generally more severe in the putamen, reflecting motor circuitry, than the caudate, which has more direct affiliation with neurobehaviorally relevant neural circuitry. Cognitive and affective changes accompanying PD and related disorders, when attributable to dopaminergic system pathology, are probably linked to mesocortical and mesolimbic dopaminergic systems that arise principally from the midbrain ventral tegmental area. Neurobehavioral changes in PD may also reflect nondopaminergic system dysfunction (Pillon et al., 2001), as cognitive deficits tend to correlate with the motor symptoms that tend to be less responsive to levodopa (e.g., gait and speech dysfunction), but not with motor symptoms responsive to levodopa (e.g., tremor and rigidity) (Pillon et al., 1989). Dopaminergic dysfunction in PD and related dementias does not appear to play a major role in cognitive alterations, although a modulatory role in cortical processing mediated through the mesocortical pathways has been implicated (Mattay et al., 2002). Conventional neuropsychological tests may not be sensitive to dopamine-related cognitive deficits in PD and related disorders, as these deficits can be subtle and highly specific. Several studies have shown that levodopa may affect only selected aspects of executive function, and even have opposing influences on different executive functions (Lange et al., 1992; Owen et al., 1995; Fournet et al., 2000). Functional neuroimaging with magnetic resonance imaging using cognitive and pharmacological activation paradigms and positron emission tomography (PET) are emerging as a powerful tools for probing the role of dopaminergic system involvement in neurobehavioral changes associated with PD and related conditions (Cools et al., 2002; Mattay et al., 2002; Mentis et al., 2002; Feigin et al., 2003). 29.5.2.2. Acetylcholine Although AD has been cast as the prototypical cholinergic deficit syndrome vis-a`-vis the ‘cholinergic hypothesis of memory dysfunction’ postulated over two decades ago, recent evidence (and reconsideration of previous data) suggest otherwise. Compared to AD, DLB patients also have a relatively greater degree of cortical cholinergic deficits, presumably reflecting selective loss of cholinergic inputs from the basal forebrain cholinergic nuclei (Langlais et al., 1993; Perry et al., 1993). Tiraboschi et al. (2000) observed that ChAT activity was similarly decreased in the midfrontal region of subjects with PD and DLB (with or without concomitant AD pathology), and was more than two

times lower than in AD subjects. Recent data from Bohnen et al. (2003) using C-11[PMP] PET ligand-receptor neuroimaging to measure in vivo acetylcholinesterase activity in subjects with PDD or DLB, PD, and AD demonstrate a similar relative profile. Moreover, recent studies in mild to moderate AD have shown no correlation between cholinergic markers and dementia severity in mild to moderate AD. By contrast, a robust correlation (r ¼ 0.67) has been observed between neocortical cholinergic deficits and dementia severity in DLB (Samuel et al., 1997). The latter findings parallels the observation that dementia in PD is typically associated with cholinergic depletion in the nucleus basalis of Meynert (nbM) of 70% or higher (Jellinger et al., 1993). 29.5.3. Frontal–subcortical circuits Cognitive and other neurobehavioral disturbances accompanying PD and related disorders can also be understood by considering the pathophysiology of striatal–thalamocortical circuits. Although the traditional model of five frontal–striatal–thalamic–frontal circuits (Alexander et al., 1986; Mega and Cummings, 1994) has been updated by recent anatomical findings (for reviews see Middleton and Strick, 2000; Saint-Cyr, 2003), the framework of segregated cortical–subcortical loops connecting different prefrontal and basal ganglionic structures that help regulate different cognitive and behavioral output remains a useful heuristic. According to this model, the frontal cortex and basal ganglia are linked by five loops (circuits) that, although anatomically and functionally segregated, retain their relative position and proximity to each other in shared anatomic structure. While the closed portion of each circuit forms a convergent loop from cortical to subcortical elements and back, open portions of the circuitry are also present that allow for mutual interaction with other cortical regions, such as medial temporal lobe limbic areas (Joel, 2001). The five circuits are named for their origin: the dorsolateral, orbitofrontal, anterior cingulate, motor, and oculomotor circuits. The first three circuits are particularly important in the regulation of cognition, affect, and motivation, respectively. The five circuits have both direct and indirect pathways linking the striatum with the substantia nigra and internal globus pallidus, with the indirect pathway involving the external globus pallidus and subthalamic nucleus. From a clinical perspective, the model of frontal–subcortical loops helps explain how lesions in subcortical structures that are affiliated with a specific zone of prefrontal cortex (e.g., dorsolateral) may produce clinical deficits that would normally be associated with a lesion in that cortical region. As an ironic historical aside, this model of cognitive and behaviorally relevant frontal–subcortical

NEUROPSYCHOLOGY OF DEMENTIA WITH LEWY BODIES loops helped bridge the dichotomy between cortical and subcortical dementia syndromes and, in doing so, rendered these otherwise clinically useful descriptive categorical terms obsolete.

557

and agnosia) are generally absent in PD, and if present prior to or within the first year of onset of motor (extrapyramidal) signs, should raise concern for DLB. 29.6.2. Attention

29.6. Cognitive domains 29.6.1. Overview A growing number of studies have investigated the neuropsychological differentiation of DLB, PDD, and AD. Perhaps because the majority of DLB cases involve pathological changes of AD (McKeith et al., 2003) rather than pure cases (also called diffuse Lewy body disease), the emphasis has been on comparing neuropsychological performance in AD and DLB. In general, these studies converge in finding that AD is characterized by more prominent declarative memory impairment, whereas DLB is associated with more pronounced visuoperceptual, attentional, and verbal fluency impairments (Hansen et al., 1990; Sahgal et al., 1992; Salmon et al., 1996; Salmon and Galasko, 1996; Galasko et al., 1996; Gnanalingham et al., 1997; Walker et al., 1997; Connor et al., 1998; Shimomura et al., 1998; Simard et al., 2000; Aarsland et al., 2003; Collerton et al., 2003). Most studies to date have focused on differences between AD and DLB compared to each other and normal elderly controls, with PD and PDD groups less often represented. The use of different diagnostic criteria for DLB (before the 1996 McKeith criteria, in particular), heterogeneity within DLB samples (e.g., common vs. pure form), and whether or not there is pathological confirmation of diagnosis are important limitations surrounding the data accumulated to date. Nevertheless, a systematic review of domain-specific cognitive deficits in DLB offers insight into the fundamental differences between AD and DLB, and the relationship between DLB and PD. In PD, detailed neuropsychological testing often reveals subtle cognitive alterations that, while of academic interest, may lack clinical significance. Such cognitive deficits typically reflect a prefrontal–subcortical syndrome characterized by slowness of thought, inefficient learning and recall, diminished working memory capacity, and mild executive dysfunction (Bondi and Tro¨ster, 1997; Pillon et al., 2001). Though deficits are most apparent on tasks requiring spontaneous development and deployment of efficient information processing strategies (Taylor and Saint-Cyr, 1995), and such difficulty can account for many early test performance decrements (Bondi et al., 1993), executive deficits cannot account for the full range of cognitive deficits described in PD (Tro¨ster and Fields, 1995). Hallmarks of cortical dysfunction (e.g., apraxia, amnesia, aphasia,

Performance on simple attention tasks such as digit span and spatial span is preserved in PD (Huber et al., 1986b; Pillon et al., 1986; Sullivan and Sagar, 1989). However, on tasks requiring divided or selective attention (or the self-allocation of attention), patients with PD are likely to demonstrate difficulty, though impairments may be task dependent (Gauntlett-Gilbert et al., 1999; Lee et al., 1999). Both limited attentional resources and/or attentional set shifting may contribute to PD subjects’ poor performance on Stroop-like tasks that require naming of the color of the ink in which a word (the name of an incongruent color) is printed, thus necessitating selective attention and inhibition of the prepotent verbal response (Dujardin et al., 1999; Woodward et al., 2002). As the disease progresses, patients may demonstrate impairments even on attention tasks that provide external cues (Yamada et al., 1990). The finding of greater impairment of attention in DLB compared to AD is intriguing because fluctuating cognition, a putative hallmark of DLB, has been linked to attention impairment (Walker et al., 2000). Performance on simple attentional tasks such as digit span have been reported to be more impaired in DLB compared to AD (Hansen et al., 1990), but this difference has not been consistent (Salmon et al., 1996; Gnanalingham et al., 1997; Walker et al., 1997; Connor et al., 1998). However, DLB subjects typically have been reported to be more impaired than AD patients on more demanding attentional tasks, such as MMSE mental control tasks (Ala et al., 2001) visual search and set shifting (Saghal et al., 2004) and the WAIS Digit Symbol test (Shimomura et al., 1998). DLB subjects have also been reported to have selective deficits in visual vs. auditory selective attention compared to AD, as well as more difficulty on a test of sustained attention and the Stroop test (Calderon et al., 2001). Noe et al. (2004) reported significantly worse performance on visual and auditory cancellation tasks by both DLB and PDD compared to AD subjects who were matched by age and dementia severity, whereas no differences were observed on any tests between the DLB and PDD subjects. Using computerized simple and choice reaction time and vigilance tasks, Ballard et al. (2002) demonstrated a similar profile between PDD and DLB subjects, who both showed much greater variability in reaction times across a number of tasks compared to AD subjects. More recently, Bradshaw et al. (2006) demonstrated similar findings of greater

558

¨ STER D.I. KAUFER AND A.I. TRO

attentional impairment and variability in reaction times in DLB compared to AD subjects, but also showed that the degree of relative differences noted between AD and DLB subjects varied by the degree of executive and visuospatial demands imposed by the task at hand. Such data reinforce the primary attentional impairment seen in DLB subjects and provide a means for investigating the neural underpinnings of fluctuating cognition in DLB. Although some studies (Downes et al., 1998) have found DLB to demonstrate more severe impairments than PDD on tasks involving attention and working memory (WAIS-R Arithmetic, Stroop), and verbal fluency (letter, category, and alternating fluency tasks, the majority of studies to date, including a recent large prospective longitudinal cohort study, suggest that deficits in attention and other cognitive domains in DLB and PDD share a common basis (Aarsland et al., 2004, Galvin et al., 2006). Further support for convergence between DLB and PDD comes from similarly robust improvements reported on simple and complex reaction time tasks in response to the cholinesterase-inhibitor treatment rivastigmine during placebo-controlled trials involving either DLB (Wesnes et al., 2002) or PDD subjects (Wesnes et al., 2005). 29.6.3. Executive functions Executive functions comprise a variety of cognitive operations (planning, abstraction, conceptualization, mental flexibility, insight, judgment, self-monitoring, and regulation) that are critical to adaptive, goal-directed behavior. By their nature, executive cognitive functions as noted above are modeled by tests designed to assay one or more of these functions, but doing so typically imposes structure and constraints on task performance that may limit the ecological validity of such findings to real-world contingencies. Poor performance on various tests of executive (or ‘frontal lobe’) function may be an early indicator of subsequent dementia in PD (Jacobs et al., 1995; Mahieux et al., 1998; Piccirilli et al., 1989; Woods and Tro¨ster, 2003). Working memory spans attentional, executive, and mnemonic processes, and is a limited-capacity, multicomponent system that permits temporary, online manipulation and storage of information to guide and control action. In PD, impairments in working memory have been related to both reduced capacity of the system (Gabrieli et al., 1996) and difficulty inhibiting responses (Kensinger et al., 2003; Rieger et al., 2003). Deficits in working memory are important to discern as they will generally impose significant limitations on neuropsychological performance across a variety of tests. Another issue of particular importance to neuropsychological evaluation in the context of self-monitoring

is whether awareness of deficits is compromised, which in turn might limit the validity of information obtained on interview and self-report measures. While cognitive impairment in PD might be associated with reduced awareness of deficits, metacognition in DLB and PDD, in contrast to AD, appears to be relatively preserved (Starkstein et al., 1996; Seltzer et al., 2001). Executive cognitive functions have generally been reported to be more impaired in DLB and PDD compared to AD (Simard et al., 2000; Collerton et al., 2003). Aarsland et al. (2003) reported decreased performance of similar magnitude in PDD and DLB subjects compared to AD subjects on the Mattis DRS initiation/ perseveration subscale. These findings are congruent with previous qualitative work showing that DLB subjects were more susceptible on neuropsychological testing to distraction, difficulty engaging a task and shifting from one task to another, confabulation, and perseveration (Doubleday et al., 2002). One study (Calderon et al., 2001) showed DLB subjects to be more impaired on the Stroop test and on letter fluency than AD subjects, although another study (Noe et al., 2004) found no difference on letter or category fluency. Discrepancies noted likely reflect differences in subject characteristics across studies and differences in the batteries used to assess executive cognitive functions. Insight into the pathophysiology of executive cognitive dysfunction in DLB and PDD comes from a recent study by Bohnen et al. (2006). In this study comparing 11 PDD (including 4 DLB) and 13 non-demented PD subjects to 14 normal elderly controls, global cortical acetylcholinesterase (AChE) activity measured by PET PMP imaging showed a greater reduction in PDD (21%) compared to nondemented PD (13%) subjects. Overall cortical AChE activity showed the strongest correlation to performance on the WAIS-III Digit Span (r ¼ 0.57), implicating working memory as being strongly influenced by cholinergic activity. Other executive cognitive tests, the Stroop Color–Word test (r ¼ 0.46), Trails B-A condition (r ¼ 0.44), and the Benton Judgement of Line Orientation test (r ¼ 0.43), were also significantly correlated to global cortical AChE activity. Interestingly, no correlation between cortical AChE and performance on a word list memory test (CVLT) was observed. These data directly implicate cholinergic dysfunction in playing a role in attentional and executive cognitive deficits associated with PD and related dementias. 29.6.4. Visuoperceptual and spatial functions The nature of visuoperceptual and spatial deficits in PD is controversial. Although some have argued that visuospatial deficits are among the earliest and most

NEUROPSYCHOLOGY OF DEMENTIA WITH LEWY BODIES readily observable neurobehavioral deficits in PD (Passafiume et al., 1986), others suggest that such deficits are not primarily visuoperceptual in nature, but rather, might be secondary to impaired saccadic eye movements (Bodis-Wollner, 2003) or limited information processing resources and their strategic allocation (Brown and Marsden, 1986). Thus, the observation that patients with PD might perform poorly in assembling blocks to match a pattern or drawing, tracing, or copying complex figures (Pirozzolo et al., 1982; Stern et al., 1984) may relate to motor demands of the tasks. However, impairments on visuoperceptual and spatial tasks are also observed when motor demands of tasks are minimized (Boller et al., 1984; Lee et al., 1998; Levin et al., 1991). Early studies noted greater difficulties in DLB compared to AD subjects in performing a variety of visuospatial and constructional tasks (Hansen et al., 1990; Simard et al., 2000; Collerton et al., 2003). More recently, pentagon-copying from the MMSE has been reported to be more impaired in DLB compared to AD subjects (Ala et al., 2001) or DLB and PDD compared to AD subjects (Cormack et al., 2004). In the latter study, copying performance in DLB and PDD subjects was selectively related to disturbances in praxis and perceptual processing, whereas in AD subjects performance of the figure copy task was related to overall dementia severity. DLB subjects in this study were also compared to AD subjects in a visual search task and were impaired in both the automatic visual search (pop-out effect) and serial search conditions of the task, with the latter being under attentional control. Together, these findings implicate a pre-attentive perceptual locus of impairment. Noe et al. (2004) also reported greater deficits in DLB and PDD subjects on the Benton Visual Retention task and the Rosen Drawing test compared to AD subjects. Several studies have identified elementary visual perceptual deficits in DLB to be associated with visual hallucinations. Mori et al. (2000) evaluated matched AD and DLB subjects and noted the latter to be more impaired across a battery of visuospatial tasks. DLB subjects with misidentification of television figures being present (5/24 total) performed much worse on tasks involving size discrimination, form discrimination, and visual counting compared to DLB subjects without that misidentification syndrome. Moreover, DLB subjects with visual hallucinations (18/24 total) performed significantly worse on a task of identifying overlapping figures. Using the Visual Object and Space Perception test, object and spatial perceptual abilities were more impaired in DLB compared to AD subjects (Calderon et al., 2001). Another study (Cahn-Weiner et al., 2003) observed no overall differences on

559

clock-drawing between AD and DLB subjects, but noted more planning and conceptual errors in the latter group. Mosimann et al. (2004) reported similar findings in subjects with PDD, as well as DLB. In comparison to AD subjects, both DLB and PDD subjects performed significantly worse on tasks involving object–form perception and space–motion perception. Among DLB and PDD subjects, those with visual hallucinations (36/44 total) performed significantly worse on tasks of object–form and space–motion discrimination, and a task of angle discrimination compared to non-hallucinating DLB and PDD subjects. Together these findings implicate elementary visual perceptual disturbances as a predisposing factor to visual hallucinations in DLB and PDD and implicate a common mechanistic neural substrate. That visual perceptual disturbances in DLB and PDD may be a predisposing factor to visual hallucinations has several important consequences. First, the recent finding that visual hallucinations are among the strongest clinical predictors of DLB and PDD (Tiraboschi et al., 2006; Galvin et al., 2006) suggests that corresponding visual perceptual deficits would be important to screen for and assess more comprehensively as part of a neuropsychological test battery. Second, functional imaging methods have implicated occipital lobe involvement as a distinguishing feature of DLB in comparison to the temporal and parietal lobe abnormalities typically seen in AD. The presence of occipital lobe hypoperfusion on SPECT functional imaging has been reported to distinguish DLB from AD subjects with a sensitivity of 65% and specificity of 87% (Lobotesis et al., 2000). A recent PET study of autopsy-confirmed AD and DLB subjects demonstrated that occipital hypometabolism distinguished DLB from AD with a sensitivity of 90% and specificity of 87% (Minoshima et al., 2001). In some cases, occipital hypometabolism preceded the clinical appearance of symptoms that distinguished DLB from AD, which supports its potential utility as a sensitive differential diagnostic marker. Third, the apparent mechanistic convergence of visual hallucinations and visuospatial deficits in DLB suggest a potential common therapeutic pathway based on cholinergic mechanisms. Secondary analyses from a large placebo-controlled trial of rivastigmine suggests that PDD subjects with hallucinations decline more rapidly and may be more therapeutically responsive to treatment (Burn et al., 2006). 29.6.5. Learning and memory Several taxonomies of memory exist, but one of the most common distinguishes between declarative and nondeclarative memory. Declarative memory refers to

560

¨ STER D.I. KAUFER AND A.I. TRO

facts and data acquired via learning processes that are accessible to conscious recollection. Nondeclarative memory, in contrast, refers to ‘knowing how’ and is expressed only via the performance of task operations. Thus, the content of nondeclarative memory is not available to conscious recollection. Declarative memory impairments are circumscribed in PD in the absence of dementia. Although this is not an invariant finding, the learning of new information may be slowed in PD (Faglioni et al., 2000), and while free recall is impaired, recognition is relatively preserved (Beatty and Monson, 1989). As patients develop more global cognitive impairments or dementia, both recall and recognition are compromised (Beatty et al., 1989), and impairments, particularly in delayed recall, become evident with longer disease duration (Zakzanis and Freedman, 1999). There is also evidence that patients with PD and dementia have impairments in remote memory (Freedman et al., 1984; Huber et al., 1986a; Leplow et al., 1997). However, unlike in AD, in which the impairment is often characterized by a temporal gradient (revealing of more dramatic impairment of recent than remote information), the impairment in PD is equally severe for information across past decades. In general, DLB subjects perform better on tests of declarative (episodic) memory than do AD patients, although this may be selective for verbal material (Salmon et al., 1996; Simard et al., 2000; Collerton et al., 2003). On the Mattis Memory subscale, DLB subjects performed at a similar level as PDD subjects, and both showed relatively preserved memory performance compared to AD subjects (Aarsland et al., 2003). Noe and colleagues (Noe et al., 2004) also reported a similar level of performance in PDD and DLB subjects on both the recall and recognition portions of the Selective Reminding Test, which was significantly better than AD subjects. On the CVLT, however, Hamilton et al. (2004) noted similar performance in a cohort of autopsy-confirmed AD and DLB subjects on immediate and delayed recall, but poorer recognition performance by AD subjects. Simard et al. (2002) noted similar findings of more severely impaired delayed and cued recall in AD compared to DLB subjects. These findings are consistent with data from the majority of previous studies (Simard et al., 2000; Collerton et al., 2003) showing a relative preservation of recognition memory for verbal material in DLB compared to AD subjects, who have primary deficits in encoding and storage. Taken together, these findings suggest that impaired or inefficient retrieval contributes significantly to the memory deficits in DLB. Comparing AD and DLB subject performance on the WMS-R Logical Memory test, DLB subjects performed

at a significantly higher level on both immediate recall and delayed recall (Calderon et al., 2001). However, on the Recognition Memory Test for faces and words, both AD and DLB subjects performed significantly worse than elderly controls. Moreover, on the Benton Visual Retention test, DLB and PDD subjects both performed worse on recognition than did AD subjects (Noe et al., 2004), suggesting a dissociation between verbal and nonverbal memory processing in DLB and PDD. Further investigation is needed to determine to what degree elementary visual perceptual dysfunction may be contributing to visual memory impairment in DLB. The major pathological substrate of more severe amnestic deficits in AD relative to DLB and PDD likely reflects the burden of neurofibrillary tangles in the entorhinal cortex and surrounding medial temporal lobe regions (Braak stage I for AD). Even with concomitant AD pathology associated with LBV-AD (Hamilton et al., 2004), DLB subjects appear to be less affected with respect to consolidation and storage of verbal material than AD subjects. Although medial temporal lobe atrophy has been reported in DLB (Tam et al., 2005), it is generally not as severe as in AD. Furthermore, among neocortical and paralimbic regions assayed for AChE activity by PET, Bohnen et al. (2003) noted that the hippocampal region was the only one where the degree of decreased AChE activity was more severe in AD compared to DLB and PDD subjects. Together, the combination of lesser degrees of neuropathological involvement and cholinergic deficit in the medial temporal regions underlie the relatively preserved mnemonic functioning in DLB compared to AD. 29.6.6. Language Overall language dysfunction in DLB appears to be similar to that of AD (Simard et al., 2000; Collerton et al., 2003), with early mild, and progressively more severe impairment in confrontational naming and verbal fluency. Although some studies (Noe et al., 2004) have reported similar degrees of performance on letter and category fluency tasks, others (Lambon-Ralph et al., 2001) show DLB patients to have greater impairment on phonemic or letter fluency tasks compared to AD subjects. Different underlying mechanisms have been inferred from these findings, with AD subjects thought to have a selective deficit in processing within semantic networks, whereas DLB subjects are thought to have a more generalized attentional/executive deficit that contributes to difficulty in retrieving material that is linked either semantically or phonetically. Two qualitative indices of fluency performance have been devised that may illuminate the mechanisms underlying fluency deficits in DLB, switching and

NEUROPSYCHOLOGY OF DEMENTIA WITH LEWY BODIES clustering (Troyer et al., 1997). Switching refers to disengaging from one subcategory of words and moving onto another category that are related either semantically or phonemically. Clustering refers to the production of consecutive items from the same semantic or phonemic subcategory. The most efficient strategy likely involves retrieval of highly related words within one subcategory, followed by a switch to another subcategory where other highly related words may be accessed. Switching impairments are more common in patients with PDD than in AD, while deficits in clustering are more pronounced in AD than PDD (Tro¨ster et al., 1998; Troyer et al., 1998). Even when verbal fluency output is diminished in PD patients without dementia, clustering appears to be preserved (Heiss et al., 2001). These findings suggest that switching may be more dependent on intact executive or frontal–subcortical functions, which tend to be more compromised in PDD than in AD. Qualitative analysis of errors has also been applied to confrontational naming deficits in PDD. Tro¨ster et al. (1996) utilized the error categorization system for the Boston Naming Test described by Hodges et al. (1991) and compared the performances of a normal control group to those of AD and PDD groups equated for overall severity of cognitive impairment. Both AD and PDD subjects named fewer items than the control group, but AD subjects were more severely impaired than PDD subjects. The type of errors committed also differentiated the two dementia groups. The AD group made more phonemic errors, such as mispronunciations or distortions of the target, but sharing at least one syllable with it, and ‘don’t know’ responses than the control and PDD groups, which did not differ in the number of these errors. Both PDD and AD subjects made more semantic errors than the control group, but the PDD group made more semantic errors that were associative in nature. That is, PDD subjects tended to produce responses that were clearly related to the target, such as describing an associated action or function, a physical attribute, a contextual associate, or a subordinate or proper noun example of the target. These findings were interpreted to indicate that category knowledge in PDD is accessible to a limited extent, but insufficient to generate item names. By contrast, category knowledge is often unavailable in AD, consistent with the notion that AD involves degradation of semantic networks. Fields et al. (1996) compared errors on the Boston Naming Test between PD and PDD groups and had similar findings. Semantic errors made by normal control group were largely within-category errors, representing the same semantic category as the target, but being visually dissimilar (e.g., ‘spinach’ for ‘asparagus’). By contrast, semantic errors by PDD subjects

561

were generally associative errors, while the PD group did not differ significantly from either the control or the PDD groups in the proportion of semantic errors that were associative in nature. These data suggest that retrieval difficulty, rather than a degradation of semantic networks per se, attend naming difficulties in PDD.

29.7. Conclusions Over the last decade substantial progress has been made in defining and characterizing clinical syndromes lying at the intersection of dementia and parkinsonism. Whereas DLB as initially cast had more in common with AD vis-a`-vis the term Lewy body variant of AD, DLB is now more directly linked to PD and PDD by the common thread of alphasynuclein pathology. Recently revised diagnostic criteria for DLB detail specific signs and symptoms (visual hallucinations, RBD, etc.) although specific cognitive profiling is remarkably absent from the diagnostic criteria. Further work in this area is needed and will likely contribute to more precise clinical definitions of DLB and PD with late-onset dementia, which appear to have similar clinical features except at the time of symptomatic onset. Treatments that increase cholinergic transmission were developed based on the role of acetylcholine in learning and memory, but have proven to be useful in treating attentional and other noncognitive symptoms associated with DLB and PDD. These findings are consistent with recent evidence that both disorders have greater central cholinergic deficits than AD, and that attentional and executive cognitive disturbances have been directly linked to decreased cortical cholinergic activity with in vivo PET imaging (Bohnen et al., 2003). To fully take advantage of technological advances in functional neuroimaging, and in conjunction with more refined molecular genetic analyses, among the greatest challenges ahead is to more accurately characterize the clinical phenotypic expression of DLB and PDD.

References Aarsland D, Ballard CG, Halliday G (2004). Are Parkinson’s disease with dementia and dementia with Lewy bodies the same entity? J Geriatr Psychiatry Neurol 17: 137–145. Aarsland D, Ballard C, McKeith I, et al. (2001). Comparison of extrapyramidal signs in dementia with Lewy bodies and Parkinson’s disease. J Neuropsychiatry Clin Neurosci 13: 374–379. Aarsland D, Litvan I, Salmon D, et al. (2003). Performance on the Dementia Rating Scale in Parkinson’s disease with dementia and dementia with Lewy bodies: Comparison with progressive supranuclear palsy and Alzheimer’s disease. J Neurol Neurosurg Psychiatry 74: 1215–1220.

562

¨ STER D.I. KAUFER AND A.I. TRO

Alexander GE, DeLong MR, Strick PL (1986). Parallel organization of functionally segregated circuits linking basal ganglia and cortex. Annu Rev Neurosci 9: 357–381. Ballard CG, Aarsland D, McKeith I, et al. (2002). Fluctuations in attention: PD dementia vs DLB with parkinsonism. Neurology 59: 1714–1720. Ballard C, Holmes C, McKeith I, et al. (1999). Psychiatric morbidity in dementia with Lewy bodies: A prospective clinical and neuropathological comparative study with Alzheimer’s disease. Am J Psychiatry 156: 1039–1045. Beatty WW, Monson N (1989). Lexical processing in Parkinson’s disease and multiple sclerosis. J Geriatr Psychiatry Neurol 2: 145–152. Bernheimer H, Birkmayer W, Hornykiewicz O, et al. (1973). Brain dopamine and the syndromes of Parkinson and Huntington. J Neurol Sci 20: 415–455. Biggins CA, Boyd JL, Harrop FM, et al. (1992). A controlled, longitudinal study of dementia in Parkinson’s disease. J Neurol Neurosurg Psychiatry 55: 566–571.. Bodis-Wollner I (2003). Neuropsychological and perceptual defects in Parkinson’s disease. Parkinsonism Relat Disord 9: S83–S89. Boeve BF, Silber MH, Ferman TJ, et al. (1998). REM sleep behavior disorder and degenerative dementia; an association likely reflecting Lewy body disease. Neurology 51: 363–370. Bohnen NI, Kaufer DI, Hendrickson R, et al. (2006). Cognitive correlates of cortical cholinergic denervation in Parkinson’s disease and parkinsonian dementia. J Neurol 253: 242–247. Bohnen NI, Kaufer DI, Ivanco LS, et al. (2003). Cortical cholinergic function is more severely affected in parkinsonian dementia than in Alzheimer disease: An in vivo positron emission tomographic study. Arch Neurol 60: 1745–1748. Boller F, Passafiume D, Keefe NC, et al. (1984). Visuospatial impairment in Parkinson’s disease: Role of perceptual and motor factors. Arch Neurol 41: 485–490. Bondi MW, Kaszniak AW, Bayles KA, et al. (1993). Contributions of frontal system dysfunction to memory and perceptual abilities in Parkinson’s disease. Neuropsychology 7: 89–102. Bondi MW, Tro¨ster AI (1997). Parkinson’s disease: Neurobehavioral consequences of basal ganglia dysfunction. In PD Nussbaum (Ed.), Handbook of Neuropsychology and Aging. Plenum, New York, pp. 216–245. Braak H, Bohl JR, Muller CM, et al. (2006). Stanley Fahn Lecture 2005: The staging procedure for the inclusion body pathology associated with sporadic Parkinson’s disease reconsidered. Mov Disord 21: 2042–2051. Braak H, Tredici KD, Ru¨b U, et al. (2003). Staging of brain pathology related to sporadic Parkinson’s disease. Neurobiol Aging 24: 197–211. Bradshaw JM, Saling M, Anderson V, et al. (2006). Higher cortical deficits influence attentional processing in

dementia with Lewy bodies relative to patients with dementia of the Alzheimer’s type and controls. J Neurol Neurosurg Psychiatry 77: 1129–1135. Briel RC, McKeith IG, Barker WA, et al. (1999). EEG findings in dementia with Lewy bodies and Alzheimer’s disease. J Neurol Neurosurg Psychiatry 66: 401–403. Burn D, Emre M, McKeith I, et al. (2006). Effects of rivastigmine in patients with and without visual hallucinations in dementia associated with Parkinson’s disease. Mov Disord 21: 1899–1907. Cahn-Weiner DA, Williams K, Grace J, et al. (2003). Discrimination of dementia with Lewy bodies from Alzheimer’s disease and Parkinson disease using the clock drawing test. Cogn Behav Neurol 16: 85–92. Calderon J, Perry RJ, Erzinclioglu SW, et al. (2001). Perception, attention, and memory are disproportionately impaired in dementia with Lewy bodies compared with Alzheimer’s disease. J Neurol Neurosurg Psychiatry 70: 157–164. Charcot JM, Vulpian A (1861). De la paralysie agitante. Gazette Hebdomadaire Med Chir 8: 765–767. Charcot JM, Vulpian A (1862). De la paralysie agitante. Gazette Hebdomadaire Med Chir 9: 54–59. Churchyard A, Lees AJ (1997). The relationship between dementia and direct involvement of the hippocampus and amygdala in Parkinson’s disease. Neurology 49: 1570–1576. Collerton D, Burn D, McKeith I, et al. (2003). Systematic review and meta-analysis show that dementia with Lewy bodies is a visual-perceptual and attentional-executive dementia. Dement Geriatr Cogn Disord 16: 229–237. Colosimo C, Hughes AJ, Kilford L, et al. (2003). Lewy body cortical involvement may not always predict dementia in Parkinson’s disease. J Neurol Neurosurg Psychiatry 74: 852–856. Comella CL, Nardine TM, Diederich NJ, et al. (1998). Sleeprelated violence, injury, and REM sleep behavior disorder in Parkinson’s disease. Neurology 51: 526–529. Connor DJ, Salmon DP, Sandy TJ, et al. (1998). Cognitive profiles of autopsy-confirmed Lewy body variant vs pure Alzheimer disease. Arch Neurol 55: 994–1000. Cools R, Stefanova E, Barker RA, et al. (2002). Dopaminergic modulation of high-level cognition in Parkinson’s disease: The role of the prefrontal cortex revealed by PET. Brain 125: 584–594. Cormack F, Aarsland D, Ballard C, et al. (2004). Pentagon drawing and neuropsychological performance in Dementia with Lewy bodies, Alzheimer’s disease, and Parkinson’s disease with dementia. Int J Geriatr Psychiatry 19: 371–377. Darvesh S, Freedman M (1996). Subcortical dementia: A neurobehavioral approach. Brain Cogn 31: 230–249. Dekker MCJ, Bonifati V, van Duijn CM (2003). Parkinson’s disease: Piecing together a genetic jigsaw. Brain 126: 1722–1733. Doubleday EK, Snowden JS, Varma AR, et al. (2002). Qualitative performance characteristics differentiate dementia

NEUROPSYCHOLOGY OF DEMENTIA WITH LEWY BODIES with Lewy bodies and Alzheimer’s disease. J Neurol Neurosurg Psychiatry 72: 602–607. Downes JJ, Priestley NM, Doran M, et al. (1998). Intellectual, mnemonic, and frontal functions in dementia with Lewy bodies: A comparison with early and advanced Parkinson’s disease. Behav Neurol 11: 173–183. Dringenberg HC (2000). Alzheimer’s disease: More than a ‘cholinergic disorder’—evidence that cholinergic-monoaminergic interactions contribute to EEG slowing and dementia. Behav Brain Res 115: 235–249. Dujardin K, Defebvre L, Grunberg C, et al. (2001). Memory and executive function in sporadic and familial Parkinson’s disease. Brain 124: 389–398. Dujardin K, Degreef JF, Rogelet P, et al. (1999). Impairment of the supervisory attentional system in early untreated patients with Parkinson’s disease. J Neurol 246: 783–788. Faglioni P, Saetti MC, Botti C (2000). Verbal learning strategies in Parkinson’s disease. Neuropsychology 14: 456–470. Farrer M, Gwinn-Hardy K, Muenter M, et al. (1999). A chromosome 4p haplotype segregating with Parkinson’s disease and postural tremor. Hum Mol Genet 8: 81–85. Feigin A, Ghilardi MF, Carbon M, et al. (2003). Effects of levodopa on motor sequence learning in Parkinson’s disease. Neurology 60: 1744–1749. Ferman TJ, Boeve BF, Smith GE, et al. (2002). Dementia with Lewy bodies may present as dementia and REM sleep behavior disorder without parkinsonism or hallucinations. J Int Neuropsychol Soc 8: 907–914. Ferman TJ, Smith GE, Boeve BF, et al. (2004). DLB fluctuations: Specific features that reliably differentiate DLB from AD and normal aging. Neurology 62: 181–187. Fields JA, Paolo AM, Tro¨ster AI (1996). Visual confrontation naming in Parkinson’s disease with and without dementia [abstract]. Clin Neuropsychol 10: 321–322. Fournet N, Moreaud O, Roulin JL, et al. (2000). Working memory functioning in medicated Parkinson’s disease patients and the effect of withdrawal of dopaminergic medication. Neuropsychology 14: 247–253. Freedman M, Rivoira P, Butters N, et al. (1984). Retrograde amnesia in Parkinson’s disease. Can J Neurol Sci 11: 297–301. Gabrieli JDE, Singh J, Stebbins G, et al. (1996). Reduced working memory span in Parkinson’s disease: Evidence for the role of a frontostriatal system in working and strategic memory. Neuropsychology 10: 322–332. Galasko D, Katzman R, Salmon DP, et al. (1996). Clinical and neuropathological findings in Lewy body dementias. Brain Cogn 31: 166–175. Galvin JE, Pollack J, Morris JC (2006). Clinical phenotype of Parkinson dementia. Neurology 67: 61605–61611. Gauntlett-Gilbert J, Roberts RC, Brown VJ (1999). Mechanisms underlying attentional set-shifting in Parkinson’s disease. Neuropsychologia 37: 605–616. Gelb DJ, Oliver E, Gilman S (1999). Diagnostic criteria for Parkinson disease. Arch Neurol 56: 33–39.

563

Gnanalingham KK, Byrne EJ, Thornton A, et al. (1997). Motor and cognitive function in Lewy body dementia: Comparison with Alzheimer’s and Parkinson’s diseases. J Neurol Neurosurg Psychiatry 62: 243–252. Goetz CG (1992). The historical background of behavioral studies in Parkinson’s disease. In SJ Huber, JL Cummings (Eds.), Parkinson’s Disease: Neurobehavioral Aspects. Oxford University Press, New York, pp. 3–9. Golbe LI, Di Iorio G, Sanges G, et al. (1996). Clinical genetic analysis of Parkinson’s disease in the Contursi kindred. Ann Neurol 40: 767–775. Gomez-Tortosa E, Newell K, Irizarry MC, et al. (1999). Clinical and quantitative pathologic correlates of dementia with Lewy bodies. Neurology 53: 1284–1291. Grace JB, Walker MP, McKeith IG (2000). A comparison of sleep profiles in patients with dementia with Lewy bodies and Alzheimer’s disease. Int J Geriatr Psychiatry 11: 1028–1033. Hamilton JM, Salmon DP, Galasko D, et al. (2004). A comparison of episodic memory deficits in neuropathologically confirmed Dementia with Lewy bodies. J Int Neuropsychol Soc 10: 689–697. Hansen L, Salmon D, Galasko D, et al. (1990). The Lewy body variant of Alzheimer’s disease: A clinical and pathological entity. Neurology 40: 1–8. Hardy J, Cookson MR, Singleton A (2003). Genes and parkinsonism. Lancet Neurol 2: 221–228. Heiss C, Kalbe E, Kessler J (2001). Quantitative und qualitative Analysen von verbalen Flu¨ssigkeitsaufgaben bei Parkinsonpatienten. Z Neuropsychol 12: 188–199. Hodges JR, Salmon DP, Butters N (1991). The nature of the naming deficit in Alzheimer’s and Huntington’s disease. Brain 114: 1547–1558. Holdorff B (2002). Friedrich Heinrich Lewy (1885–1950) and his work. J Hist Neurosci 11: 19–28. Huang X, Chen PC, Kaufer DI, et al. (2006). Apolipoprotein E role in dementia in Parkinson’s disease: A meta-analysis. Neurology 63: 189–193. Huber SJ, Shuttleworth EC, Paulson GW (1986a). Dementia in Parkinson’s disease. Arch Neurol 43: 987–990. Huber SJ, Shuttleworth EC, Paulson GW, et al. (1986b). Cortical vs subcortical dementia. Neuropsychological differences. Arch Neurol 43: 392–394. Hurtig HI, Trojanowski JQ, Galvin J, et al. (2000). Alphasynuclein cortical Lewy bodies correlate with dementia in Parkinson’s disease. Neurology 54: 1916–1921. Jacobs DM, Marder K, Cote LJ, et al. (1995). Neuropsychological characteristics of preclinical dementia in Parkinson’s disease. Neurology 45: 1691–1696. Jellinger K, Bancher C, Fischer P (1993). Neuropathological correlates of mental dysfunction in Parkinson’s disease. In C Wolters, E Scheltens (Eds.), Mental Dysfunction in Parkinson’s Disease. Amsterdam, Vrije Universiteit, pp. 141–161. Joel D (2001). Open interconnected model of basal gangliathalamocortical circuitry and its relevance to the clinical syndrome of Huntington’s disease. Mov Disord 16: 407–423.

564

¨ STER D.I. KAUFER AND A.I. TRO

Kensinger EA, Shearer DK, Locascio JJ, et al. (2003). Working memory in mild Alzheimer’s disease and early Parkinson’s disease. Neuropsychology 17: 230–239. Kosaka K (1990). Diffuse Lewy body disease in Japan. J Neurol 237: 197–204. Kosaka K, Matsushita M, Oyanagi S, et al. (1980). A clinicopathological study of the ‘Lewy body disease.’ Seishin Shinkeigaku Zasshi 82: 292–311. Lambon-Ralph MA, Powell J, Howard D, et al. (2001). Semantic memory is impaired in both dementia with Lewy bodies and dementia of the Alzheimer’s type: A comparative neuropsychological study and literature review. J Neurol Neurosurg Psychiatry 70: 149–156. Lange KW, Robbins TW, Marsden CD, et al. (1992). L-dopa withdrawal in Parkinson’s disease selectively impairs cognitive performance in tests sensitive to frontal lobe dysfunction. Psychopharmacology (Berl) 107: 394–404. Langlais PJ, Thal LJ, Hansen L, et al. (1993). Neurotransmitters in basal ganglia and cortex of Alzheimer’s disease with and without Lewy bodies. Neurology 43: 1927–1934. Lee AC, Harris JP, Calvert JE (1998). Impairments of mental rotation in Parkinson’s disease. Neuropsychologia 36: 109–114. Lee SS, Wild K, Hollnagel C, et al. (1999). Selective visual attention in patients with frontal lobe lesions or Parkinson’s disease. Neuropsychologia 37: 595–604. Leplow B, Dierks C, Herrmann P, et al. (1997). Remote memory in Parkinson’s disease and senile dementia. Neuropsychologia 35: 547–557. Levin BE, Llabre MM, Reisman S, et al. (1991). Visuospatial impairment in Parkinson’s disease. Neurology 41: 365–369. Lewy FH (1912). Paralysis agitans I Pathologische Anatomie. In M Lewandowsky (ED.), Handbuch der Neurologie, Band 3. Springer Verlag, Berlin, pp. 920–933. Lewy FH (1923). Die Lehre vom Tonus und der Bewegung. Zugleich Systmatische Untersuchungen zur Klinik, Physiologie, Pathologie und Pathogenese der Paralysis Agitans. Julius Springer, Berlin. Lobotesis K, Fenwick JD, Phipps A, et al. (2000). Occipital hypoperfusion on SPECT in dementia with Lewy bodies but not AD. Neurology 56: 643–649. Lopez OL, Becker JT, Kaufer DI, et al. (2002). Research evaluation and prospective diagnosis of dementia with Lewy bodies. Arch Neurol 59: 43–46. Mahieux F, Fenelon G, Flahault A, et al. (1998). Neuropsychological prediction of dementia in Parkinson’s disease. J Neurol Neurosurg Psychiatry 64: 178–183. Marder K, Tang MX, Cote L, et al. (1995). The frequency and associated risk factors for dementia in patients with Parkinson’s disease. Arch Neurol 52: 695–701. Mattay VS, Tessitore A, Callicott JH, et al. (2002). Dopaminergic modulation of cortical function in patients with Parkinson’s disease. Ann Neurol 51: 156–164. Mayeux R, Chen J, Mirabello E, et al. (1990). An estimate of the incidence of dementia in idiopathic Parkinson’s disease. Neurology 40: 1513–1517.

McKeith IG, Burn DJ, Ballard CG, et al. (2003). Dementia with Lewy bodies. Semin Clin Neuropsychiatry 8: 46–57. McKeith IG, Dickson DW, Lowe J, et al. (2005). Dementia with Lewy bodies: Diagnosis and management. Third report of the DLB consortium. Neurology 65: 1863–1872. McKeith IG, Galasko D, Kosaka K, et al. (1996). Consensus guidelines for the clinical and pathological diagnosis of Dementia with Lewy bodies (DLB): Report on the consortium on DLB international workshop. Neurology 47: 1113–1124. McShane R, Keene J, Gedling K, et al. (1996). Hallucinations, cortical Lewy body pathology, cognitive function, and neuroleptic use in dementia. In RH Perry, IG McKeith, EK Perry (Eds.), Dementia with Lewy Bodies: Clinical, Pathological, and Treatment Issues. Cambridge University Press, New York, pp. 85–98. Mega MS, Cummings JL (1994). Frontal–subcortical circuits and neuropsychiatric disorders. J Neuropsychiatry Clin Neurosci 6: 358–370. Mentis MJ, McIntosh AR, Perrine K, et al. (2002). Relationships among the metabolic patterns that correlate with mnemonic, visuospatial, and mood symptoms in Parkinson’s disease. Am J Psychiatry 159: 746–754. Middleton FA, Strick PL (2000). Basal ganglia output and cognition: Evidence from anatomical, behavioral, and clinical studies. Brain Cogn 42: 183–200. Minoshima S, Foster NL, Sima AAF, et al. (2001). Alzheimer’s disease versus dementia with Lewy bodies: Cerebral metabolic distinction with autopsy confirmation. Ann Neurol 50: 358–365. Mohr E, Mendis T, Grimes JD (1995). Late cognitive changes in Parkinson’s disease with an emphasis on dementia. Adv Neurol 65: 97–113. Mori E, Shimomura T, Tatsuo T, et al. (2000). Visuoperceptual impairment in dementia with Lewy bodies. Arch Neurol 57: 489–493. Mosimann UP, Mather G, Wesnes KA, et al. (2004). Visual perception in Parkinson disease dementia and dementia with Lewy bodies. Neurology 63: 2091–2096. Naville F (1922). Les complications et let sequelles mentales de l’encephalite epidemique. Encephale 17: 369–375423– 436. Noe E, Marder K, Bell KL, et al. (2004). Comparison of dementia with Lewy bodies to Alzheimer’s disease and Parkinson’s disease with dementia. Mov Disord 19: 60–67. Okazaki H, Lipkin LE, Aronson SM (1961). Diffuse intracytoplasmic ganglionic inclusions (Lewy type) associated with progressive dementia and quadraparesis in flexion. J Neuropathol Exp Neurol 20: 237–244. Owen AM, Sahakian BJ, Hodges JR, et al. (1995). Dopamine-dependent fronto-striatal planning deficits in early Parkinson’s disease. Neuropsychology 9: 126–140. Parkinson J (1817). An Essay on the Shaking Palsy Sherwood, Neely & Jones, London.

NEUROPSYCHOLOGY OF DEMENTIA WITH LEWY BODIES Passafiume D, Boller F, Keefe MC (1986). Neuropsychological impairment in patients with Parkinson’s disease. In I Grant, KM Adams (Eds.), Neuropsychological Assessment of Neuropsychiatric Disorders. Oxford University Press, New York, pp. 374–383. Perry EK, Curtis M, Dick DJ, et al. (1985). Cholinergic correlates of cognitive impairment in Parkinson’s disease: Comparisons with Alzheimer’s disease. J Neurol Neurosurg Psychiatry 48: 413–421. Perry EK, Irving D, Kerwin JM, et al. (1993). Cholinergic transmitter and neurotrophic activities in Lewy body dementia: Similarity to Parkinson’s and distinction from Alzheimer disease. Alzheimer Dis Assoc Disord 7: 69–79. Perry EK, Marshall E, Kerwin JM, et al. (1990). Evidence of a monoaminergic:cholinergic imbalance related to visual hallucinations in Lewy body dementia. J Neurochem 55: 1454–1456. Perry E, Walker M, Grace J, et al. (1999). Acetylcholine in mind: a neurotransmitter correlate of consciousness? Trends Neurosci 22: 273–280. Perry R, Irving D, Blessed G, et al. (1990). Senile dementia of the Lewy body type: A clinically and neuropathologically distinct form of dementia in the elderly. J Neurol Sci 95: 119–139. Piccirilli M, D’Alessandro P, Finali G, et al. (1989). Frontal lobe dysfunction in Parkinson’s disease: Prognostic value for dementia? European neurology 29: 71–76. Pillon B, Boller F, Levy R, et al. (2001). Cognitive deficits and dementia in Parkinson’s disease. In F Boller, SF Cappa (Eds.), Handbook of Neuropsychology, 2nd edn, Vol. 6. Elsevier, Amsterdam, pp. 311–371. Pillon B, Dubois B, Cusimano G, et al. (1989). Does cognitive impairment in Parkinson’s disease result from nondopaminergic lesions? J Neurol Neurosurg Psychiatry 52: 201–206. Pillon B, Dubois B, Lhermitte F, et al. (1986). Heterogeneity of cognitive impairment in progressive supranuclear palsy, Parkinson’s disease, and Alzheimer’s disease. Neurology 36: 1179–1185. Pirozzolo FJ, Hansch EC, Mortimer JA, et al. (1982). Dementia in Parkinson disease: A neuropsychological analysis. Brain Cogn 1: 71–83. Rieger M, Gauggel S, Burmeister K (2003). Inhibition of ongoing responses following frontal, nonfrontal, and basal ganglia lesions. Neuropsychology 17: 272–282. Rockwell E, Choure J, Galsasko D, et al. (2000). Psychopathology at initial diagnosis in dementia with Lewy bodies versus Alzheimer disease; comparison of matched groups with autopsy-confirmed diagnoses. Int J Geriatr Psychiatry 15: 819–823. Sahgal A, Galloway PH, McKeith IG, et al. (1992). Matching-to-sample deficits in patients with senile dementias of the Alzheimer and Lewy body types. Arch Neurol 49: 1043–1046. Saint-Cyr JA (2003). Frontal-striatal circuit functions: Context, sequence, and consequence. J Int Neuropsychol Soc 9: 103–127.

565

Salmon DP, Galasko D (1996). Neuropsychological aspects of Lewy body dementia. In R Perry, I McKeith, E Perry (Eds.), Dementia with Lewy Bodies: Clinical, Pathological, and Treatment Issues. Cambridge University Press, Cambridge, UK, pp. 99–113. Salmon DP, Galasko D, Hansen LA, et al. (1996). Neuropsychological deficits associated with diffuse Lewy body disease. Brain Cogn 31: 148–165.. Samuel W, Alford M, Hofstetter CR, et al. (1997). Dementia with Lewy bodies versus pure Alzheimer’s disease: Differences in cognition, neuropathology, cholinergic dysfunction, and synapse density. J Neuropathol Exp Neurol 56: 499–508. Schiller F (2000). Fritz Lewy and his bodies. J Hist Neurosci 9: 148–151. Seltzer B, Vasterling JJ, Mathias CW, et al. (2001). Clinical and neuropsychological correlates of impaired awareness of deficits in Alzheimer disease and Parkinson disease: A comparative study. Neuropsychiatry Neuropsychol Behav Neurol 14: 122–129. Shimomura T, Mori E, Yamashita H, et al. (1998). Cognitive loss in dementia with Lewy bodies and Alzheimer disease. Arch Neurol 55: 1547–1552. Simard M, van Reekum R, Cohen T (2000). A review of cognitive and behavioral symptoms in dementia with Lewy bodies. J Neuropsychiatry Clin Neurosci 12: 425–450. Simard M, van Reekum R, Myran D, et al. (2002). Differential memory impairment in dementia with Lewy bodies and Alzheimer’s disease. Brain Cogn 49: 244–249. Starkstein SE, Sabe L, Petracca G, et al. (1996). Neuropsychological and psychiatric differences between Alzheimer’s disease and Parkinson’s disease with dementia. J Neurol Neurosurg Psychiatry 61: 381–387. Stern Y, Mayeux R, Rosen J (1984). Contribution of perceptual motor dysfunction to construction and tracing disturbances in Parkinson’s disease. J Neurol Neurosurg Psychiatry 47: 983–989. Sullivan EV, Sagar HJ (1989). Nonverbal recognition and recency discrimination deficits in Parkinson’s disease and Alzheimer’s disease. Brain 112: 1503–1517. Tam CW, Burton EJ, McKeith EJ, et al. (2005). Temporal lobe atrophy on MRI in Parkinson disease with dementia and dementia with Lewy bodies. Neurology 64: 861–865. Taylor AE, Saint-Cyr JA (1995). The neuropsychology of Parkinson’s disease. Brain Cogn 28: 281–296. Tiraboschi P, Hansen LA, Alford M, et al. (2000). Cholinergic dysfunction in diseases with Lewy bodies. Neurology 54: 407–411. Tiraboschi P, Salmon DP, Hansen LA, et al. (2006). What best differentiates Lewy body from Alzheimer’s disease in early-stage dementia? Brain 129: 729–735. Tro¨ster AI, Fields JA (1995). Frontal cognitive function and memory in Parkinson’s disease: Toward a distinction between prospective and declarative memory impairments? Behav Neurol 8: 59–74. Tro¨ster AI, Fields JA (2003). Apolipoprotein E genotype and memory in healthy elderly and Parkinson’s disease [abstract]. J Int Neuropsychol Soc 9: 525.

566

¨ STER D.I. KAUFER AND A.I. TRO

Tro¨ster AI, Fields JA, Paolo AM, et al. (1996). Visual confrontation naming in Alzheimer’s disease and Parkinson’s disease with dementia [abstract]. Neurology 46: A292–A293. Tro¨ster AI, Fields JA, Testa JA, et al. (1998). Cortical and subcortical influences on clustering and switching in the performance of verbal fluency tasks. Neuropsychologia 36: 295–304. Troyer AK, Moscovitch M, Winocur G (1997). Clustering and switching as two components of verbal fluency: Evidence from younger and older healthy adults. Neuropsychology 11: 138–146. Troyer AK, Moscovitch M, Winocur G, et al. (1998). Clustering and switching on verbal fluency tests in Alzheimer’s and Parkinson’s disease. J Int Neuropsychol Soc 4: 137–143. Walker MP, Ayre GA, Perry EK, et al. (2000). Quantification and characterisation of fluctuating cognition in dementia with Lewy bodies and Alzheimer’s disease. Dement Geriatr Cogn Disord 11: 327–335. Walker Z, Allen RL, Shergill S, et al. (1997). Neuropsychological performance in Lewy body dementia and Alzheimer’s disease. Br J Psychiatry 170: 156–158. Walker Z, Costa DC, Ince P, et al. (1999). In-vivo demonstration of dopaminergic degeneration in dementia with Lewy bodies. Lancet: 646–647. Wesnes KA, McKeith I, Edgar C, et al. (2005). Benefits of rivastigmine on attention in dementia associated with Parkinson disease. Neurology 65: 1654–1656.

Wesnes KA, McKeith IG, Ferrara R, et al. (2002). Effects of rivastigmine on cognitive function in dementia with Lewy bodies: A randomised placebo-controlled international study using the cognitive drug research computerised assessment system. Dement Geriatr Cogn Disord 13: 183–192. Woods SP, Tro¨ster AI (2003). Prodromal frontal/executive dysfunction predicts incident dementia in Parkinson’s disease. J Int Neuropsychol Soc 9: 17–24. Woodward TS, Bub DN, Hunter MA (2002). Task switching deficits associated with Parkinson’s disease reflect depleted attentional resources. Neuropsychologia 40: 1948–1955. Xuereb JH, Tomlinson BE, Irving D, et al. (1990). Cortical and subcortical pathology in Parkinson’s disease: Relationship to parkinsonian dementia. Adv Neurol 53: 35–40. Yamada T, Izyuuinn M, Schulzer M, et al. (1990). Covert orienting attention in Parkinson’s disease. J Neurol Neurosurg Psychiatry 53: 593–596. Zaccai J, McCracken C, Brayne C (2005). A systematic review of prevalence and incidence studies of dementia with Lewy bodies. Age Ageing 34: 561–566. Zakzanis KK, Freedman M (1999). A neuropsychological comparison of demented and nondemented patients with Parkinson’s disease. Appl Neuropsychol 6: 129–146.

Handbook of Clinical Neurology, Vol. 88 (3rd series) Neuropsychology and behavioral neurology G. Goldenberg, B.L. Miller, Editors # 2008 Elsevier B.V. All rights reserved

Chapter 30

The neuropsychology of vascular dementia MARGARET E. WETZEL AND JOEL H. KRAMER* Department of Neurology, University of California, San Francisco, CA, USA

30.1. Introduction Vascular dementia is considered one of the most common types of dementia in the elderly (Rabinstein et al., 2004). Beyond this somewhat general concept, however, there is much less agreement about the frequency with which vascular dementia occurs and the mechanisms by which cerebrovascular disease produces a dementia syndrome (Erkinjuntti, 2002; O’Brien et al., 2003; Black, 2005). In fact, given the heterogeneity of cerebrovascular disorders, it is not surprising that no clear consensus has emerged regarding causal factors, underlying neuropathology, clinical symptoms, characteristic neuropsychological profiles, and developmental course. In this chapter, we will review several features of vascular dementia, including diagnostic criteria, prevalence, underlying mechanisms and subtypes, comorbidity with other disorders, and neuropsychological and neurobehavioral characteristics.

30.2. Prevalence Cerebrovascular disease is fairly common in the general population By the age of 70, 70% of the population has white matter lesions on MRI brain scans (O’Brien et al., 2003), and it is estimated that 11 million Americans may have a silent stroke every year without showing symptoms (de la Torre, 2002). According to population-based studies, silent lacunes are found in 11–24% of the population, with white matter lesions appearing in 62–95% of the elderly on imaging (Roman et al., 2002). Age is the single strongest risk factor for cerebrovascular disease and strokes (Gorelick, 2004; Roman, 2005). Other known risk factors include male gender and AfricanAmerican ethnicity (Sacco et al., 1991). Chinese or Japanese background may also be a risk factor. *

Potentially modifiable risk factors, such as atrial fibrillation, hypertension, cardiac disease, diabetes mellitus, smoking, alcoholism, and hyperlipidemia (Schoenberg and Shulte 1988; Tell et al., 1988; Wolf et al., 1991; Sacco, 1994) have been identified as well and should be monitored by a physician. Hyperlipidemia and smoking primarily accelerate atherosclerosis of the larger arteries, while hypertension also increases arteriolosclerosis in small vessels. Risk of vascular dementia is almost doubled if the patient has a history of arterial hypertension (Lindsay et al., 1997). Diabetes mellitus enhances atherogenesis in both large and small arteries (Caplan et al., 1990), and cardiac emboli associated with atrial fibrillation tend to lodge in the early branches of the larger arteries (Wolf et al., 1978; Feinberg et al., 1990). While cerebrovascular disease is found quite frequently in the community, the prevalence of vascular dementia is much harder to assess and is a function not only of the diagnostic criteria used, but also of how the study samples are collected. Study samples can be autopsy series, community surveys, dementia clinics, or general medical clinics. The prevalence of vascular dementia at autopsy varies from 0.03% to 58%, with a mean of 5–15% (Jellinger, 2005), demonstrating the difficulties in assessing validity of both diagnosis and pathology due to the source of subject recruitment for these studies. Holmes et al. (1999) evaluated 80 consecutive dementia cases brought to autopsy and illustrated the challenges associated with making a clinical diagnosis of vascular dementia. When the NINDS-AIREN criteria were used for making in vivo diagnoses, 8.8% of the sample met criteria for probable vascular dementia; 1.3% had possible vascular dementia, and 5% had mixed diagnoses (vascular dementia with either Alzheimer’s disease or Lewy body dementia). On autopsy, of the 7 cases who met criteria for probable vascular

Correspondence to: Joel H. Kramer, PsyD, Department of Neurology, University of California, San Francisco, Box 1207, San Francisco, CA 94143–1207. E-mail: [email protected], Tel: 415-476-7561, Fax: 415-476-4800.

568

M.E. WETZEL AND J.H. KRAMER

dementia, only 3 had infarctions alone, and 4 had infarctions concurrent with other pathology. Infarctions were found in 16 of the remaining 73 cases who were not thought to have a vascular dementia based on clinical considerations. The NINDS-AIREN criteria appear to have high specificity but low sensitivity and often a diagnosis of vascular dementia is made without looking at confounding vascular risk factors. In an autopsy case of 78 patients with dementia in China, vascular dementia alone was found in 38.5%, while Alzheimer’s dementia accounted for 14% (Wang et al., 2003). In Japan, pure vascular dementia is seen in 22–35% of patients at autopsy, as compared to 7–10% in the west (Jellinger, 2002). Knopman et al. (2003) studied 89 subjects with varying dementia diagnoses. AD was pathologically determined in 51%, with mixed vascular dementia in 12% and pure vascular dementia in 11%. They concluded that the DSM-IV had a sensitivity of 75% with a specificity of 81%. In another recent study, Reed et al. (2004) found that of 9 subjects diagnosed with AD, 3 had mixed AD and vascular dementia, while one had vascular dementia alone. In a series of 50 autopsied cases of dementia, Tomlinson et al., (1970) observed that ‘at least one third of all patients with dementia have a significant vascular component,’ and Knopman et al. (2001) noted that between 30–40% of dementia cases have a degree of CVD pathology at autopsy. Among the first 106 autopsies of patients enrolled in the Consortium to Establish a Registry for Alzheimer Disease (CERAD) with a clinical diagnosis of AD, 87% showed histological changes confirming a diagnosis of AD (Gearing et al., 1995). However, vascular lesions of varying nature and size were also present in 21%. The proportion of cases with mixed vascular and primary neuronal pathologies has been noted to increase with age. Vascular dementia was diagnosed in 15% of patients dying younger than age 70 years, and in 22.5% of patients dying older than age 70 years (Katzman et al. 1988). Thus, data from hospital autopsy series indicates that vascular disease contributes to dementia in approximately one quarter to one third of cases. The ratio of Alzheimer’s disease to vascular dementia is approximately 5:1 in hospital-based dementia clinics. A review of 7 clinical series of patients with dementia (n ¼ 689) showed the most common diagnosis by far to be primary degenerative dementia (47%); a diagnosis of vascular dementia was made in only 9% (Chui, 1989). This ratio is significantly higher than found in community-based surveys. Lindsay et al., (1997) reported prevalence rates of 7 per 1000 in the community and 115 per 1000 in institutions. Referral bias represents the most likely explanation for the

discrepancy in prevalence rates between clinics and hospitals; patients with strokes tend to go to stroke, rather than dementia, clinics. Computations of prevalence rates are somewhat complicated, however, since they do not directly assess whether there is a causal relationship between dementia and stroke, or in which direction the causal relationship runs. Ferrucci et al., (1996), for example, reported that patients with dementia are at greater risk of suffering a stroke than are cognitively normal elderly, and patients with severe cognitive impairment are twice as likely to suffer stroke than patients with only moderate cognitive impairment. Indeed, de la Torre (2002) reports that 30% of Alzheimer disease brains at autopsy also show some form of cerebrovascular pathology. Another way of assessing the relationship between dementia and cerebrovascular disease is to evaluate the prevalence of dementia in patients with known history of stroke. The prevalence of dementia among patients hospitalized with stroke tends to be high. Based on performance on WAIS (Wechsler Adult Intelligence Scale), for example, 56.3% of 71 patients hospitalized with stroke were diagnosed with dementia (Ladurner et al., 1982). Tatemichi et al. (1990) examined 726 patients with acute ischemic stroke and judged 15.9% to be demented. In a separate series of 251 stroke patients studied 3 months after acute infarction, Tatemichi et al. (1992a) diagnosed dementia in 26.8% based on modified DSM-III R criteria. Similarly, Suzuki et al. (1991) found dementia in 27.2% of 136 patients, and Pohjasvaara et al. (1997) found dementia in 20% of 486 patients hospitalized with stroke. Dementia is clearly common after stroke, occurring in one quarter to one third of cases.

30.3. Mechanisms and subtypes of vascular dementia In a very broad sense, cerebrovascular disease can be either hemorrhagic or ischemic. Hemorrhage most often refers to a rupture of small arteries that are damaged from hypertension. Though not as common as ischemia, hemorrhage can have both profound and subtle affects on cognition, and makes up roughly 20% of all strokes. A hemorrhage is an excess amount of blood flow into surrounding tissues due to a burst blood vessel, and can be classified as intraparenchymal (ICH), subarachnoid (SAH), epidural, and subdural. Epidural and subdural stroke are typically caused by trauma, while an ICH stroke is primarily due to chronic hypertension which weakens blood vessel walls and results in blood flow directly to the parenchymal region of the brain. SAH, on the other hand, is predominantly an aneurysm, which causes a ballooning of a weak part

THE NEUROPSYCHOLOGY OF VASCULAR DEMENTIA of a vessel wall due to increased pressure. As this continues, the vessel may rupture, causing bleeding into the spaces between the inner and middle layers of tissue covering the brain. Neuropsychological deficits resulting from an aneurysm may or may not be correlated with the particular site of the brain in which the aneurysm occurred (Richardson, 1991; Irle et al., 1992; Bjeljac et al., 2002), but impaired cognition including memory domains and frontal lobe functions are often present. In addition, the time lapse after aneurysm rupture is important in determining possible underlying mechanisms as well as the neuropsychological profile of a patient (D’Esposito et al., 1996); Hutter et al. (1999) also argue that the bleeding pattern at the time of the hemorrhage can have an impact on the pattern of cognitive dysfunction. The pattern of neuropsychological deficits following an SAH are dependent on the extent of the bleeding pattern (Hutter et al., 1999), the time following aneurysm (D’Esposito et al., 1996), and location and size of the resulting lesion(s) (D’Esposito et al., 1996; Jimbo et al., 2000; Bjeljac et al., 2002). Following an SAH, most patients suffer from memory loss and mood changes, in addition to decreased frontal lobe function and language difficulties, decreased pattern recognition, concentration and attention. However, in one study, up to 30% of 63 patients did not suffer any cognitive deficits (Bjeljac et al., 2002). It is necessary when evaluating hemorrhagic stroke and its functional outcomes to assess both time post-onset and location of hemorrhage. More common than hemorrhage, however, is ischemia, or occlusion of the blood vessels, which results in decreased blood flow. Consequently, there will not be adequate blood flow to provide the essential substrates (e.g., oxygen and glucose) to support cell metabolism to particular areas of the brain. The relationship between cerebral blood flow and cell dysfunction is not a simple one, however, and is determined by the specific oxygen and glucose requirements of individual cells, local cerebral blood flow, and duration of hypoperfusion. Local cerebral blood flow is lowest in the periventricular and deep white matter, and this can be of particular relevance for vascular dementia. These regions are perfused by long, small, penetrating end-arterioles with no collaterals (Moody et al., 1990). Thus, the deep white matter is most susceptible to ischemia when there is either a systemic drop in blood pressure (acute hypotension) or widespread small vessel arteriopathy (e.g., arteriosclerosis associated with chronic hypertension (Schmidt et al., 2004)). When blood flow drops to approximately 17 ml/min/100 gm, neuronal membranes depolarize and clinical dysfunction appears (Sharbrough et al., 1973). If blood flow is promptly restored, normal brain function may be restored, and the clinical diagnosis is

569

a transient ischemic attack (TIA) if symptoms persist for less than 24 hours. When blood flow diminishes below approximately 10 ml/min/100 gm for greater than 30 minutes, neuronal membranes degenerate irreversibly, causing neuronal death and cerebral infarction (Heiss, 1983). Clinically, a completed stroke or cerebrovascular accident (CVA) has occurred. Occlusion of a single blood vessel results in focal ischemia. More global ischemia follows systemic disturbances in circulation (e.g., cardiac arrest, hypovolemic shock). In these instances, the most vulnerable brain areas are the border zones located at the far reaches of the major cerebral arteries and the periventricular deep white matter where the long-penetrating arterioles end (O’Brien et al., 2003; Kalaria et al., 2004). Ischemic stroke makes up roughly 80% of the population that suffers from stroke, and this includes multiple infarcts, strategic infarction, subcortical ischemia and Binswanger’s disease (Cummings, 1993; Loeb and Meyer, 1996). Neuropsychologists need to be aware of the differences between these syndromes, since they present with different patterns of cognitive impairment. Multi-infarct dementia (MID) is a term that was previously used quite broadly to refer to all types of vascular dementia, though it now refers more specifically to large vessel disease, usually occlusions of main branches of the anterior, middle, and posterior cerebral arteries that produce cortical lesions. These infarcts are typically caused by either atherosclerotic plaques within the arterial walls or from emboli of cardiac origin. Neurobehavioral symptoms vary greatly as a function of where and how large the cortical lesions are, but can include aphasia, apraxia, agnosia, and inattention syndromes. In an autopsy series of 175 cases of dementia, MID made up roughly 15% of all vascular dementia cases (Brun, 1994). MID is more characteristically associated with step-wise progression and does not occur in concordance with AD as often as other ischemic dementias. The sudden onset and step-wise progression traditionally thought to be associated with cerebrovascular disease is probably specific to multi-infarct dementia, and is less characteristic of the other vascular syndromes. In 1894, Otto Binswanger described 8 patients with slowly progressive mental deterioration and pronounced white matter changes, with secondary dilatation of the ventricles. In Binswanger’s disease, also known as subcortical arteriosclerotic encephalopathy, there is typically a history of persistent hypertension or systemic vascular disease. While relatively uncommon, its clinical course may be insidious, with long plateaus and the accumulation of focal neurologic signs (Babikan and Ropper, 1987; Roman, 1987). Slowly progressive dementia is common with a decidedly prefrontal flavor,

570

M.E. WETZEL AND J.H. KRAMER

including apathy, lack of drive, mild depression, and alterations of mood (Loeb, 2000; Libon et al., 2004). Neuropathological features include extensive demyelination and destruction of subcortical white matter, with relative sparing of the cortical U fibers. Pathology is typically more pronounced in the temporal and occipital lobes. Criteria for clinical diagnosis have been offered by Caplan and Schoene (1978) and include the presence of vascular risk factors, focal ischemic lacunar lesions in the white matter that are confluent on neuroimaging, age of onset between 55 and 75, subacute onset of focal neurological signs, and extensive white matter attenuation on T1 and hyperintensity on T2 weighted MR images. A strategically placed infarct, typically in the thalamus, frontal white matter, basal ganglia, or angular gyrus can result in dementia when it produces enough cognitive disturbance to cause functional decline. For example, in some individuals, a single paramedian branch supplies both anteromedial thalamic regions. Occlusion of the paramedian artery in these cases will lead to bilateral infarction of the dorsomedial nucleus and the mammillothalamic tracts (Bogousslavsky et al., 1988), disconnecting the prefrontal executive and limbic–diencephalic memory systems. Similarly, an infarct in the inferior genu of the internal capsule may strategically disrupt the inferior and medial thalamic peduncles carrying thalamocortical fibers related to cognition and memory (Tatemichi et al., 1992b; 1993). Kooistra and Heilman (1988) also reported on a lacune in the posterior limb of the left internal capsule resulting in a persistent verbal memory disorder. A cerebrovascular syndrome that is receiving increasing attention in the last decade as a cause of dementia is subcortical ischemic vascular disease, which accounts for up to 50% of vascular dementia syndromes. This condition is typically the result of occlusions of the deep penetrating arterioles and arteries that feed the basal ganglia, thalamus, white matter, and internal capsule. The lesions are small, and often referred to as lacunes or lacunar infarcts; the syndrome is sometimes known as lacunar state dementia or etat lacunaire. Lacunes average 2 mm in volume, but can range from 0.2 to 15 mm (Cummings, 1995; Capizzano et al., 2000). While subcortical ischemic vascular disease (SIVD) is typically associated with age and hypertension, there is also a variant of SIVD called cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). CADASIL is a genetic disorder linked to a mutation in the Notch 3 gene of chromosome 19 (Davous, 1998; Markus et al., 2002). Although patients are typically free of classical vascular risk factors like hypertension and diabetes, the disorder affects the small vessels of the brain and results in extensive subcortical infarcts and leukoencephalopathy and

can affect cognition. Moreover, it has been suggested (Peters et al., 2005; Charlton et al., 2006) that CADASIL may offer insight into a ‘pure’ cognitive profile for subjects with vascular dementia, as patients with CADASIL tend to display cognitive decline at an early age, thereby ruling out the likelihood of a concomitant neurodegenerative dementia process. A strategically placed infarct may cause dementia if it is in a functionally important region of the brain. This disease is limited to a few, or, in some cases, a single infarct, which, due to its location, produces a change in cognition. Strategic sites may include the caudate nucleus, key white matter areas, or a thalamic infarct, and the angular gyrus or basal forebrain, and resulting cognitive decline is dependent on the location of the infarct.

30.4. Diagnostic criteria The importance of understanding vascular dementia is undermined by the difficulties in its diagnosis. Several different diagnostic criteria for vascular dementia have been proposed over the years and are summarized in Table 30.1. The DSM-IV is one of the most widely used nosologies, requiring the presence of multiple cognitive deficits, and at minimum includes memory impairment and either aphasia, apraxia, agnosia, or executive impairment. Deficits must be severe enough to cause impairment in occupational or social functioning. The emphasis on memory and cortical dementia symptoms like aphasia and apraxia clearly reflect the Alzheimer’s bias in these diagnostic criteria and may not work as well for subcortical syndromes. A diagnosis based on symptoms associated with Alzheimer’s dementia may fail to recognize many patients who have not fully progressed to dementia, but have impaired cognitive function due to vascular disease. For a diagnosis of vascular dementia, DSM-IV requires that there be either focal neurological signs and symptoms or laboratory evidence indicative of cerebrovascular disease. Clinicians must judge the cerebrovascular disease to be etiologically related to the dementia, however, which may be difficult in cases where the infarcts are small and localized in subcortical regions. The International Classification of Diseases 10th revision [ICD-10] (WHO, 1993) uses different criteria, and low rates of agreement between the two nosologies for dementia have been reported (Erkinjuntti, 1997). Introduced in 1993, the ICD-10 allows classification for different vascular dementia subtypes and requires at minimum an unequal distribution of deficits in higher cognitive functions, clinical evidence of focal brain damage, and significant cerebrovascular disease. Relatively new, these criteria have not been widely used and have been criticized for their low accuracy

THE NEUROPSYCHOLOGY OF VASCULAR DEMENTIA

571

Table 30.1 Diagnostic criteria for vascular dementia MIS Modified HIS ICD-10

DSM-IV

NINDS-AIREN

ADDTC VCI

VCD

Abrupt onset; history of strokes; focal symptoms; focal signs; focal (single or multiple) CT—low density areas Abrupt onset; stepwise deterioration; somatic complaints; emotional incontinence; history of hypertension; history of stroke; focal neurologic symptoms; focal neurologic signs Unequal distribution of higher cognitive functions Decline in memory Decline in social functioning Evidence of focal brain damage Evidence of cerebrovascular disease Focal neurological signs Evidence and symptoms of cerebrovascular disease Decreased executive functioning Temporal relationship of stroke and dementia Relevant cerebrovascular disease on brain imaging Focal neurological signs Temporal relationship between cerebrovascular disease and onset of dementia or abrupt cognitive decline and stepwise progression Evidence of two or more ischemic strokes by history, neurological signs, and/or neuroimaging studies OR a single stroke with a clearly documented temporal relationship to the onset of dementia Subjects do not meet criteria for memory impairment and functional deficits Cognitive impairment is assessed to have an underlying vascular cause Cognitive impairment is such that it causes functional deficits Cognitive impairment resulting from a cerebrovascular etiology Explicitly excludes disabling isolated sequelae of stroke, i.e., severe aphasia

HIS ¼ Hachinski Ischemia Score; ICD-10 ¼ International Classification of Diseases, 10th revision; DSM-IV ¼ Diagnostic and Statistical Manual of Mental Disorders—Fourth Edition; NINDS-AIREN ¼ National Institute of Neurological Disorders and Stroke—Association Internationale pour la Recherche et l’Enseignement en Neurosciences; ADDTC ¼ Alzheimer’s Disease Diagnostic and Treatment Centers; VCI ¼ vascular cognitive impairment; VCD ¼ vascular cognitive disorder.

in diagnosing vascular dementia (Wetterling et al., 1993; Cosentino et al., 2004). Two other sets of diagnostic criteria for vascular dementia have been proposed. The National Institute of Neurological Disorders and Stroke, in conjunction with the Association Internationale pour la Recherche et l’Enseignement en Neurosciences, published the NINDS-AIREN consensus criteria in 1993 (Roman et al., 1993). In the NINDS-AIREN system, dementia is defined by cognitive decline manifested by impairment of memory and of two or more cognitive domains. Cerebrovascular disease is defined by the presence of focal signs on neurological examination and evidence of relevant cerebrovascular disease on neuroimaging. The cerebrovascular disease can be a large cortical infarct, a single strategically placed infarct, or multiple subcortical or white matter lesions. The relationship between the dementia syndrome and the cerebrovascular disease is more sharply defined than in the DSMIV, and is inferred by the dementia occurring within three months of a stroke, abrupt onset of cognitive impairment, or fluctuating, stepwise progression.

NINDS-AIREN further establishes criteria for probable vascular dementia and possible vascular dementia that is confirmed using postmortem neuropathological criteria. Chui et al. (1992) proposed a different diagnostic system based on the experience of the State of California Alzheimer’s Disease Diagnostic and Treatment Centers (ADDTC). The ADDTC criteria focus on ischemic vascular dementia. This system is somewhat unique in that memory impairment is not necessary for a diagnosis of dementia to be made. The key criterion for dementia is a deterioration from prior levels in two or more areas of intellectual functioning sufficient to interfere with the patient’s customary affairs of life. A diagnosis of probable vascular dementia is made when there is evidence of two or more ischemic strokes by history, neurological signs, and/or neuroimaging studies; or a single stroke with a clearly documented temporal relationship to the onset of dementia. In order to assess the role vascular risk factors may have in a dementia syndrome, Hachinski et al. (1975) implemented the Hachinski Ischemia Score (HIS) in 1975. The HIS is structured as a one and two point checklist, including focal

572

M.E. WETZEL AND J.H. KRAMER

neurological signs, depression, and history of stroke and hypertension. The HIS was introduced before modern imaging techniques like CT and MRI were available, and several modified ischemia scales have since been established. The most widely used include the Rosen Modified Hachinski Ischemia Score (Rosen et al., 1980) and Loeb and Gandolfo’s Modified Ischemic Score (Loeb and Gandolfo, 1983). Loeb and Gandolfo’s criteria, in particular, have provided a more useful modified scale which incorporates focal abnormality on CT imaging. While these do not serve as diagnostic criteria, they can aid in the diagnosis of a vascular syndrome. In 2000, Chui et al. (2000) performed a multicenter study to compare four of these five criteria (DSM-IV, HIS, NINDS-AIREN, and ADDTC) to determine inter-rater reliability and prevalence of diagnosis. The most frequently diagnosed vascular dementia cases came from using modified HIS or DSM-IV criteria, while the NINDS-AIREN criteria resulted in the smallest amount of cases. The original HIS and ADDTC diagnosed at a moderate frequency. Inter-rater reliability was highest for the HIS and lowest for a diagnosis of probable vascular dementia with the ADDTC. The NINDS-AIREN, while high in sensitivity, can be low in specificity due to the requirement of a time correlation between stroke and onset of dementia. Clearly, the clinical criteria for a diagnosis of vascular dementia are not interchangeable. In a recent population-based autopsy study, Knopman et al. (2003) concluded that the best predictor of pure vascular disease, as determined at autopsy, was a temporal relationship between stroke and onset of dementia, though it did not have perfect sensitivity. One of the largest challenges in diagnosing antemortem vascular dementia, according to the study, are patients not suffering from overt clinical strokes. In another autopsy-defined study, Reed et al. (2004) found the Hachinski Ischemia Scale was not a good predictor of cerebrovascular pathology unless a patient had a high score (> 6). Moreover, they discovered little correlation between clinical signs and cerebrovascular pathology, noting that ‘Less than half of the high CVD [pathology] cases had focal neurological signs or symptoms.’ In addition to these diagnostic criteria proposed in the 1990s, several clinicians have begun to implement a diagnosis of vascular cognitive impairment or vascular cognitive disorder (VCD). The term VCD was first used by Sachdev (1999), and Roman et al., (2004) have recently deemed this a new global diagnostic category to serve for all vascular related types of cognitive impairment, ranging from vascular cognitive impairment to vascular dementia. This category stems from a diagnosis of vascular cognitive impairment (VCI),

a term originally proposed by Hachinski (1994) in order to describe patients across an entire spectrum of cognitive impairment related to cerebrovascular disease. This spectrum ranges from patients at high risk for cognitive impairment who do not yet display any deficits (‘brainat-risk’ stage) to patients with severe vascular dementia. VCI focuses more on standard neuropsychological measures that are related to vascular disease in order to provide treatment for patients who may not yet be showing overt symptoms. There are no widely accepted criteria for this condition, but the Canadian Study on Health and Aging proposed that VCI include subjects whose cognitive impairment did not meet the DSMIII-R criteria for dementia and had cognitive impairment of a vascular origin, with cognitive impairment causing functional deficits. Today, this term generally excludes patients with severe vascular dementia. VCD, on the other hand, has been proposed to update both VCI and vascular dementia and their implications. It would include VCI, vascular dementia, and mixed Alzheimer’s and CVD. Roman et al. (2004) argue the need for a definition of impaired cognition due to CVD that is not primarily based on memory impairment, but, instead, on executive dysfunction and functional loss. VCI, in contrast, focuses on memory impairment as the primary deficit and excludes subjects with stroke who, according to the ICD classification, are categorized as such. The use of neuroimaging has also become commonly applied to determine a diagnosis of vascular origin, and is a key criterion to both the NINDS-AIREN and ADDTC criteria. We now recognize that the NINDS-AIREN criteria are the most widely used and most specific of these criteria for diagnosing vascular dementia (Pohjasvaara et al., 2000), though they may be less sensitive than HIS or DSM-IV. The concomitant use of NINDSAIREN, DSM-IV and ICD-10 criteria in selected series have shown that they overlap in < 50% of the cases (Wetterling et al., 1996). Among this abundance of conflicting criteria, researchers are becoming increasingly aware of the ‘blurred’ lines between vascular risk factors, cognitive impairment, and vascular dementia. As we become more familiar with this disease and struggle to understand its heterogeneity, it is necessary to keep in mind that it is often clinically seen in conjunction with Alzheimer’s disease. Assessing the presence or absence of an Alzheimer’s disease profile is critical when applying a diagnosis of vascular dementia. We must also keep in mind that depressive disorder is often present in patients with cerebrovascular disease. It is easy to mistake depression for the beginning signs of cognitive impairment due to vascular disease, and this is

THE NEUROPSYCHOLOGY OF VASCULAR DEMENTIA something clinicians must consider when making a diagnosis (Holmes et al., 1999; Black, 2005).

30.5. Subcortical ischemic vascular disease Subcortical ischemic vascular disease is the most common type of vascular dementia, and the neuropsychology and behavior of this disease will be the primary focus of the rest of the chapter. Marie (1901) and Ferrand (1902) first described the syndrome of dementia associated with multiple lacunar infarcts in 50 residents of a chronic care facility. Clinical features included sudden hemiparesis, dementia, dysarthia, pseudobulbar palsy and affect, crying, small-stepped gait, and urinary incontinence. Aphasia and heminopsia never occurred. Similar clinical features were confirmed by Fisher (1965). More recently, Cummings (1995) described several of the neuropsychological, neuropsychiatric, and motor features associated with SIVD and highlighted ways in which SIVD resembles the dementia associated with other subcortical syndromes. According to Cummings (1995), anywhere between 13 and 51% of patients with vascular dementia have subcortical lacunes, while Fein et al. (2000) reported that SIVD accounts for 36 to 50% of all vascular dementias. Advances in neuroimaging during the past two decades have enabled researchers and clinicians to more accurately and reliably determine when subcortical ischemic vascular disease is present. Several issues continue to be debated, however. Key questions that we will address in the remainder of this chapter include: 1) the relationship between subcortical lacunes and dementia; 2) differentiation between SIVD and Alzheimer’s disease; and 3) mechanisms by which SIVD impairs cognition. SIVD is a complex and multifaceted disorder, and the ways in which it produces a dementia syndrome are only just beginning to be understood. Several different components of SIVD could potentially disrupt cognition. These include the specific nature of the subcortical pathology, disruption to subcortical–cortical circuits, and more diffuse brain dysfunction that extends beyond the specific regions of infarction. In addition, whenever a patient with SIVD presents, the possibility of comorbidity, particularly with AD, always exists. Several studies have linked specific parameters of subcortical pathology to the severity of nature of the dementia. Lafosse et al. (1997), for example, were interested in discovering whether certain features such as number of infarcts and extent of white-matter changes were related to SIVD patients’ neuropsychological functioning. Consistent with a subcortical–

573

frontal disconnection model, greater white-matter change in an SIVD population was associated with reduced fluency and poorer spontaneous recall, whereas increasing number of infarcts was associated with poorer recognition memory. Furthermore, ventricular enlargement was related to poorer delayed cued recall. Libon et al., (1998) differentiated AD and SIVD groups on the basis of MRI indices of white matter alterations and size of the hippocampal formation. The body of the hippocampal formation and parahippocampal gyrus were consistently smaller in the AD group, and the size of the hippocampal formation was positively correlated with performance on the CVLT recognition discriminability index. In addition, subjects with SIVD exhibited greater white matter alterations than subjects with AD. If the subcortical pathology has direct bearing on cognitive impairment, three possible factors should be considered: the number or volume of lesions, the location of the lesions, and the extent of white matter signal hyperintensities. Tomlinson et al., (1970) initially proposed that dementia followed with volumes of infarctions greater than 100 ml, and Loeb and Meyer illustrate in one autopsy neuroimaging study that dementia can occur with only 20–30 ml of infarcted brain tissue (Loeb and Meyer, 1996). Strong correlations between lacunar volume and cognitive functioning have not been routinely found, however, though the location of a lesion can play a role. It is well established that strategically located lesions in the thalamus and frontal white matter can produce significant cognitive impairment (Erkinjuntti et al., 1996). What is less clear is the clinical significance of most small infarcts in the basal ganglia and internal capsule. The severity of white matter lesions have been correlated with the Verbal Output Disturbance and Anxiety/Depression factors of the Neurobehavioural Rating Scale (Sultzer et al., 1995), as well as executive functioning (Kramer et al., 2002). Side of lesion may also be important, evidenced by Caplan et al. (1990) when they reviewed ten left- and eight right-sided lesions involving the head of the caudate in the distribution of Heubner’s artery. With the more extensive lesions, neurological signs included temporary motor weakness, decreased spontaneous and associative movements, and dysarthria. Contralateral neglect was noted with right-sided lesions, while speech and memory deficits were noted with left-sided ones. Interestingly, Mungas et al. (2001) correlated white matter changes, not lacunes, as defined on MRI, with selected neuropsychology measures. Functional imaging studies tend to show that brain regions surrounding or even remote from the infarction are hypometabolic, indicating that brain dysfunction

574

M.E. WETZEL AND J.H. KRAMER

in SIVD is more widespread. These remote effects are thought to be related to disconnections within subcortical–cortical circuits. In light of the neuropsychological evidence supporting a subcortical–frontal model of dysfunction, it would be reasonable to hypothesize that the frontal lobes are particularly vulnerable to these disconnections. Using positron emission tomography (PET), Sultzer et al. (1995) found the metabolic rate in the frontal cortex was lower in patients with a lacunar infarct of the basal ganglia or thalamus than in those without. Both Tullberg et al. (2004) and Kwan et al. (1999) also showed that SIVD patients had lower whole brain regional cerebral metabolic rates of glucose than controls or cognitively normal subjects with lacunes. Structural imaging studies have also described widespread cortical changes in SIVD. Cortical gray matter is reduced in cognitively impaired and demented patients with lacunes compared to controls (Fein et al. 2000). The extent of cortical gray matter reduction in SIVD patients was similar to AD patients, although the SIVD patients had greater ventricular size and more white matter lesions. Eight subjects with pathological confirmed absence of AD pathology indicate that comorbidity cannot explain cortical gray matter reductions. Lafosse et al. (1997) reported that cortical atrophy in their SIVD subjects was related to poorer performance on most of the neuropsychological measures. They argued that the pattern of correlations with cortical atrophy and their findings of greater cortical atrophy in the SIVD group than AD group suggest that a degenerative cortical process may be involved as well. These researchers concluded that characteristic deficits in SIVD may result from a combination of diminished executive functions based on direct ischemic damage to subcortical–frontal circuits and diffuse cortical dysfunction based on trans-synaptic degeneration. Alternately, the diffuse cortical atrophy may be associated with microvascular ischemic changes in the cortex. Hippocampal volume loss may also be present in SIVD, even with no AD pathology present at autopsy (Pantoni et al. 1996; Fein et al., 2000). Du and colleagues reported that hippocampal volumes in SIVD were 18% less than normal controls (Du et al., 2002). Atrophic changes in mesial temporal regions may be less in SIVD than AD, however, and several studies have reported smaller hippocampi in AD versus SIVD (Libon et al., 1998; Fein et al., 2000; Du et al., 2002). In one particular study, Mungas et al. (2001) noted that while white matter changes correlated with selected neuropsychology measures, the decline in cognitive functioning in SIVD was most strongly linked to associate hippocampal and gray matter changes. Hippocampal volume was one of the most effective

tools in differentiating normals from cognitively impaired subjects, while cortical gray matter helped distinguish impaired and demented subjects. Fein et al.’s work (2000) supports this idea, concluding that the hippocampal and cortical changes associated with SIVD are responsible for cognitive impairment. The main difficulty we are faced with when looking at these numerous studies is determining the extent to which cerebrovascular disease has an affect on cognition. Reed et al. (2004) summarize this in their autopsy-defined study: ‘The crux of the issue is that there is presently no means by which cerebrovascular pathology, defined at autopsy, can be confidently related to cognitive impairment during life.’ Kramer et al. (2004) echo this concern; it is imperative that we come closer to defining neuropsychological and clinical measures to determine the role cerebrovascular pathology has in affecting cognition.

30.6. Comorbidities The fact that a cognitively impaired patient has neuroimaging evidence for cerebrovascular disease does not necessarily imply a causal relationship between the cerebrovascular disease and the cognitive deficits. Several studies have suggested that a high proportion of well functioning community dwelling elderly have had a lacunar infarct without obvious clinical impact. The Cardiovascular Health Study (Price et al., 1997; Longstreth et al., 1998) evaluated a large population-based sample 65 years and older (n ¼ 3660) with brain MRI. Infarcts (lesions > 3 mm) were found in 28% of the 3397 participants with no known history of stroke, and 20% of the entire study population had suffered ‘silent’ strokes. Older subjects and those with history of migraine were more likely to have had a silent stroke. Shintani et al. (1998) also found age to be a risk factor for silent strokes, along with systolic hypertension and duration of hypertension. Kobayashi et al. (1997) scanned 933 neurologically normal adults covering a broader (and younger) age range, and reported subcortical lacunes (also > 3 mm) in only 10.6% of the sample. In addition to age and hypertension, diabetes and alcohol habits were risk factors. In the more recent Rotterdam study (Vermeer et al., 2003), 54% of 1077 elderly subjects had one or more silent infarcts (also > 3 mm), and these subjects were at five times greater risk of suffering a future stroke. Autopsy studies have also demonstrated that silent infarcts can be found in over 10% of elderly subjects (Shinkawa et al., 1995). Are silent infarcts necessarily associated with changes in cognition? Unfortunately, most studies that scan large numbers of seemingly normal elderly do not extensively evaluate neuropsychological functioning.

THE NEUROPSYCHOLOGY OF VASCULAR DEMENTIA Bornstein et al. (1996) concluded that silent brain infarctions were not predictive of later dementia, but their study was restricted to patients who later on suffered a clinical ischemic stroke. In one particularly relevant study, Kramer et al. (2002) performed neuropsychological testing on normal elderly with and without subcortical lacunes who were well matched in age, education and Mattis DRS score (mean 137.3 for the lacune group and 139.9 for the control group). The presence of a subcortical lacune was established by MRI. Subjects with subcortical lacunes did not perform as well as normal elderly with visual memory or executive functioning, including lower Stroop Interference and California Card Sorting scores, but no differences were observed for spatial ability, verbal memory, or language. No group differences were found on measures of recent verbal memory, recent spatial memory, language, or spatial ability. On the Stroop Interference Test, there were no group differences on the color naming or word reading conditions. On the interference condition, however, regression analyses indicated that the presence of a subcortical lacune predicted slower performance. Results indicate that subcortical ischemic vascular disease is associated with subtle declines in executive functioning, even in nondemented patients. They concluded that nondemented elderly with subcortical lacunes may display subtle cognitive deficits, but are able to function at a normal level within their communities. Nondemented patients with CADASIL have also been reported to have subtle declines in executive functioning as measured by the Wisconsin Card Sort and the Trail-Making Test (Taillia et al., 1998). Baum et al. (1996) correlated white matter abnormalities with subtle cognitive impairment in normally functioning subjects, ages 45–65, and these changes can also be related to depressive symptoms (de Groot et al., 2000). It is clear that subcortical ischemic vascular disease leads to changes in cognition, but there is no direct correlate between lacunar volume and cognitive performance (Mungas et al., 2001), and Mungas et al. (2001) assert that white matter lesions may serve as a better predictor of vascular cognitive decline due to SIVD. There are a number of emerging studies that support this claim (Matsubayashi et al., 1992; Baum et al., 1996; Gunning-Dixon and Raz, 2000). Of possible relevance is a study designed to assess cognitive sequelae of transient ischemic attacks (TIA) using a brief neuropsychological test battery. Nichelli et al. (1986) failed to find an association between TIAs and later dementia. In contrast, Price et al. (1997) reported that silent subcortical lacunes were strongly associated with lower scores on a digit-symbol substitution test and more abnormalities on neurological examination.

575

Despite the evidence for an association between subcortical infarcts and cognitive impairment, some investigators still argue that lacunes do not cause dementia. Nolan et al., (1998), for example, studied 87 consecutive dementia patients at autopsy and concluded that dementia could not be attributed to the effects of cerebrovascular disease alone. The bulk of evidence does offer a clear link between small vessel disease and dementia, however, although the patient’s functional deficits may not be concurrent with the stroke. Loeb et al. (1992) reported that 23% of patients who initially presented with a single lacunar infarct who were followed for four years ultimately developed dementia, indicating that silent lacunes pose a risk factor for development of dementia. DeCarli et al. (2004) studied 52 patients with mild cognitive impairment and concluded that while vascular risk factors, including lacunes and white matter disease, can cause cognitive decline, they are not predictive of a progression to dementia. They argue that white matter and infarcts do not affect the course of a dementia disease. Interestingly, Scheid et al. (2006) observed that while neuroimaging is important for a diagnosis of the disease, it does not correlate with severity of cognitive impairment or decline. In another large population based study, Solfrizzi et al. (2004) studied a sample of 2,963 individuals between the ages of 65 and 84 years old. The prevalence rate of mild cognitive impairment (MCI) was 3.2%, and statistical analysis suggested that coronary artery disease, age, and hypertension were all risk factors for MCI, further supporting the idea that vascular risk factors do create the potential for development of dementia.

30.7. Differentiation between SIVD and Alzheimer’s disease Differentiating SIVD from Alzheimer’s disease is often difficult clinically because the two diseases can present so similarly, and this is our single greatest challenge when diagnosing vascular dementia. Both disorders are diseases of the elderly, with increasing prevalence with increasing age. Because small subcortical lacunes are so often ‘silent,’ SIVD, like AD, can begin quite insidiously. Progression in SIVD can also be slow. The classic way of differentiating vascular dementia from AD relies on the presence of rapid onset, stepwise progression, high Hachinski scores, and vascular risk factors. These clinical signs are typically more appropriate for large vessel disease, and have only limited applications to SIVD. Even traditional neuroimaging may not assist with differential diagnosis because of comorbidity. Many patients with AD have lacunes and vascular risk factors; some studies, in fact,

576

M.E. WETZEL AND J.H. KRAMER

have even suggested that AD patients may be at greater risk for cerebrovascular disease than their nondemented age peers. If presented with a moderately demented patient with a single, small infarct in the internal capsule, many clinicians will assume that the lacune is not a primary contributor to the dementia. The assumption that the lacune is only incidental is supported by the fact that a relatively large percentage of normal elderly has lacunes. Consequently, it may not be possible to know with certainty what role the lacunes are playing in the patient’s cognitive dysfunction. One might expect that the patterns of neuropsychological deficits in SIVD and AD would be different as a function of difference in their underlying neuropathology (Mendez and Ashla-Mendez, 1991). AD involves neurofibrillary tangles and neuritic plaques in temporal limbic structures and posterior association cortex, and commonly presents with impairment in memory, language and conceptual abilities. In SIVD, the presence of multiple subcortical lacunes and white matter hyperintensities are thought to affect subcortical–frontal circuits. Cummings (1995) described three subcortical–frontal circuits that mediate cognitive, motivational, and emotional processes. The dorsolateral prefrontal circuit includes the lateral convexity of the frontal lobe, dorsolateral caudate, portions of the globus pallidus and substantia nigra, and ventral anterior and dorsomedial thalamic nuclei. The dorsolateral circuit plays a prominent role mediating executive functioning, including response inhibition, fluency, working memory, and retrieval from long-term memory. Shallice and Burgess (1991) identify the dorsolateral prefrontal cortex as an essential component of a supervisory attentional system that regulates selection among competing choices. They postulate that this supervisory or executive system is normally required for planning and decision-making, error correction or troubleshooting, in novel situations, or in overcoming strong habitual or tempting responses. It would appear that the dorsolateral frontal network creates a work area for assembling, analyzing, and manipulating multiple actual as well as imagined contingencies over time and space. Cummings (1995) also proposed an orbitofrontal circuit and a medial frontal circuit. The orbitofrontal circuit projects from the orbitofrontal cortex to ventral portions of the caudate, which in turn is connected with the amygdalae, midbrain nuclei, ventrolateral and dorsomedial thalamus, and the temporal lobe. The orbitofrontal circuit mediates the modulation of social behavior; lesions can produce tactlessness, indifference to others and impulsive behavior. Obsessive–compulsive behaviors may also occur. The medial frontal circuit incorporates the anterior cingulate, nucleus accumbens, the amygdalae, dorsomedial thalamus and midbrain structures. The

medial frontal circuit is thought to mediate motivation; lesions here are associated with apathy and disinterest. Each subcortical loop is vulnerable to pathology in different vascular systems. For example, the basal ganglia and thalamus are perfused by small penetrating arteries that arise from or near the Circle of Willis. In the basal ganglia, the ‘limbic’ and lateral orbital circuits, which subserve attention and emotion, are positioned in the ventral–medial caudate and receive their blood supply primarily from perforating branches of the anterior communicating artery. The dorsolateral frontal–subcortical circuits are positioned more laterally and are fed predominantly from the lenticulostriate arteries taking origin from the M1 segment of the middle cerebral artery, as well as deep penetrating arteries, including the anterior choroidal artery and arteries near the posterior Circle of Willis. A subcortical–frontal deficit model for SIVD predicts that executive functioning and motor programming abnormalities would be disproportionately affected in SIVD, while memory and language would be disproportionately affected in AD. In their neuropsychological examination of vascular dementia, Kertesz and Clydesdale (1994) found that patients with SIVD performed worse on tests that are influenced by frontal and subcortical mechanisms. For example, SIVD patients had greater difficulty on the MDRS-derived scale of Motor Performance, which measures motor perseveration and bimanual coordination deficits associated with frontal lobe dysfunction. SIVD patients also showed greater impairment on the WAIS-R Picture Arrangement subtest. This speeded task requires the sequential ordering of cards depicting various person–object and interpersonal interaction and is sensitive to frontal lobe disease. In comparison to the SIVD group, patients with AD were found to perform poorly on measures of memory (WMS-R immediate story recall) and language (Western Aphasia Battery repetition subtest). Kemenoff et al. (1999) compared 27 patients with SIVD to 34 patients without lacunes on a broad range of neuropsychological measures. All SIVD patients met ADDTC criteria for vascular dementia and had MRI evidence for one or more subcortical lacunes (Chui et al., 1992). No group differences were found on age, education and total Mattis DRS score. SIVD patients performed relatively better on the Memory versus the Conceptualization subscale of the DRS, while AD patients demonstrated the opposite pattern. SIVD patients showed greater impairment on phonemic fluency relative to category fluency, while AD patients provided more intrusions and exhibited poorer visual memory. After entering the discriminating neuropsychological variables into a logistic regression, SIVD

THE NEUROPSYCHOLOGY OF VASCULAR DEMENTIA and AD patients were categorized with 84% accuracy. Results support the view that a subcortical–frontal pattern of neuropsychological performance is present in SIVD and may be useful for clinical diagnosis. Lending further support for a subcortical–frontal deficit model, Wolfe et al. (1990) tested the hypothesis that patients with multiple subcortical lacunes were selectively impaired on neuropsychological tests susceptible to frontal lobe impairment. Executive abilities, including verbal fluency, semantic clustering, shifting of mental set, and response inhibition were all compromised in patients with multiple subcortical lacunes on CT. Tei et al. (1997) found that patients with early-stage AD had significantly lower scores on a test of visuospatial memory, while patients with multiple subcortical infarction with mild cognitive impairment demonstrated significantly worse performance on an executive function test sensitive to frontal lobe dysfunction (Wisconsin Card Sorting Test). Padovani et al. (1995) also explored the relationship between vascular dementia and frontal lobe systems impairment. Patients with multi-infarct dementia were found to be more impaired on measures of frontal lobe functioning such as Controlled Oral Word Association and Wisconsin Card Sorting Test perseverative errors. AD patients were more impaired on measures of memory functioning (e.g., CVLT-Total Recall and Delayed Recall, Spatial Recall Test) and on a measure of language comprehension. Lafosse et al. (1997) used well matched and well defined samples of SIVD and AD patients, comparing them on select language and verbal memory tests. On the basis of the different patterns of neuropathological involvement in SIVD and AD, these researchers hypothesized that patients with SIVD would demonstrate better confrontation naming, worse verbal fluency (COWAT) and better memory performance. While notable differences in confrontation naming were not found, SIVD patients had poorer verbal fluency, but better free recall, fewer intrusions, and better recognition memory than AD patients. Based on their marked relative impairment in verbal fluency, Lafosse et al. (1997) suggested that the unifying feature of the SIVD patients’ neuropsychological deficits was related to a failure of executive functions mediated by the frontal lobes. The pattern of deficit on verbal fluency tasks may also have utility in differential diagnosis. Carew et al. (1997) reported that SIVD patients and normal elderly controls performed better on category than letter fluency tasks, whereas the opposite was observed among AD patients. In addition, SIVD patients produced fewer responses than AD participants on letter fluency tasks, but there was no difference between AD and SIVD patients on category fluency.

577

Other studies have emphasized differences in memory functioning in AD and SIVD. Erker et al. (1995) compared Alzheimer’s and vascular dementia patients on both global and specific indices of cognitive and neuropsychological functioning. The AD and vascular dementia patients were equivalent in their global level of neuropsychological impairment. However, a significant interaction was found between IQ vs. Wechsler Memory Scale Memory Quotient (MQ) and Alzheimer’s vs. multi-infarct diagnosis. Compared to the AD group, vascular dementia patients showed relative preservation of memory in the context of deterioration in global cognitive functioning. Hassing and Backman (1997) also found greater memory impairment among Alzheimer’s vs. vascular dementia patients. They compared the two dementia groups on a series of episodic memory tasks, assessing face recognition, word recall, and object recall. While no group differences were found on face recognition and object recall, vascular dementia patients showed an advantage over Alzheimer’s patients in word recall. Hassing and Backman suggest that this selective word recall deficit may also be interpreted in terms of greater impairment of language related functions in AD compared with vascular dementia. Libon et al. (1998) demonstrated that patients with AD and SIVD can be dissociated on the basis of differing patterns of impairment on tests of declarative and procedural memory. The California Verbal Learning Test (CVLT) was used to measure declarative memory, while a pursuit rotor learning task was used as a measure of procedural memory. The SIVD group performed as poorly as the AD group on the CVLT list A immediate free recall test trials. By contrast, patients with SIVD showed a greater capacity to retain information, as evidenced by their significantly higher score on the CVLT recognition discriminability index. An opposite pattern of performance was demonstrated on the pursuit rotor task, with AD subjects exhibiting greater learning than SIVD subjects. These results are consistent with other reports of subcortical dementia patients (e.g., Huntington’s disease) exhibiting deficits in procedural memory (Knopman and Nissen, 1991). Five years later, Kramer et al.’s (2004) work supported this finding when they studied neuropsychological measures with a sample of 56 neurological normal controls and patients with AD (n ¼ 27) or SIVD (n ¼ 35) well matched for age, education, and total DRS score. Subjects were administered the MAS Verbal Learning Test (MAS) which contains several learning trials, delayed free recall and recognition memory trials. With recognition memory, both patient groups performed significantly below the control group. For the MAS, post-hoc comparison between the SIVD

578

M.E. WETZEL AND J.H. KRAMER

and AD groups only approached significance, with the SIVD group performing better than the AD group. More marked differences between SIVD and AD were found when rates of learning and forgetting were analyzed. During the six learning trials on the MAS, there were no differences between the two demented groups in overall recall or rate of learning across trials. The AD patients had a significantly steeper decline in recall over a 30-minute delay than did the SIVD patients. The SIVD patients maintained information over the delay as well as the controls. Kramer and colleagues argue if a patient with SIVD, as evidenced by imaging, exhibits a swift decline of forgetting after a delay, clinicians may be suspect of concomitant AD. Models of subcortical dementia also posit disproportionate difficulty with processing speed, concentration, and mental control. In support of this, mildly demented patients with subcortical ischemic vascular disease (lacunes or extensive white matter lesions) who were comparable to AD patients on memory and abstract thinking tasks were disproportionately impaired on tests of attention (Matsuda et al., 1998). Similarly, in an investigation of sustained attention, vascular dementia patients were slower in stimulus categorization time and made more omission and commission errors on a continuous performance task (Mendez et al., 1997). Gainotti et al. (1992) found that AD and vascular dementia patients differed in their qualitative approaches to visuospatial tasks. Both groups were compared on a measure of visual reasoning (Raven’s Colored Matrices) and on measures of constructional ability (Simple Copy and Copy with Landmarks). Compared to vascular dementia patients, AD patients were more likely to show stimulus boundedness, or the ‘closing in phenomenon’ in their copies of geometric figures. This difference was found despite equivalent performances in their overall scores on copying tasks. AD patients were also more likely to provide globalistic responses on the Raven’s as compared to vascular dementia patients. In a study of clock drawing performances, Alzheimer’s patients were more likely than vascular dementia patients to make errors in drawing a clock within a pre-drawn circle (Meier, 1995). In addition, 50% of the incorrect drawings by vascular dementia patients were characterized by a segmentation strategy. The segmentation approach involves first dividing the circle into segments with any number of radial lines. Only 25% of the incorrect drawings by AD patients were characterized by this copying abnormality. Despite these findings, it is important to keep in mind that neuropsychological differences between AD and SIVD may not always be so obvious. Reed et al.,

(2004) found that neuropsychological measures were inadequate in determining presence of pure, pathologically defined, SIVD and emphasize the importance of looking instead for multiple vascular risk factors in patients with AD. Neuropsychology measures are important in determining the overlap between SIVD and AD and should be closely examined when ruling out a diagnosis of vascular dementia. Several recent studies have emphasized the parallel between CADASIL and small vessel disease; this unique disease offers the opportunity to study what cognitive domains subcortical disease may affect, independent of AD. Charlton et al. (2006) compared 34 patients with CADASIL to 54 subjects with small vessel disease presenting with lacunar stroke and white matter disease on imaging with 25 normal controls. Patients with CADASIL and small vessel disease performed worse than controls on Trails switching task and verbal fluency. In summary, a review of the literature suggests that SIVD and AD patients differ in their pattern of performance on specific measures of cognitive functioning. Neuropsychological comparisons have generally reported relative deficits in SIVD compared to AD in subcortical–frontal executive functions, such as verbal fluency, attention, sequencing, and problem solving (Rosenstein, 1998). Relative advantages in SIVD compared to AD have included better memory performance, fewer intrusions, better comprehension, and confrontation naming (Lukatela et al., 1998). Differences, however, can be extremely subtle, and it is important to closely examine a patient’s performance, imaging, and clinical symptoms in order to provide an accurate diagnosis.

30.8. Areas for future research We remain on the forefront of understanding subcortical ischemic vascular disease. Mild subcortical ischemic vascular disease affects a large proportion of nondemented elderly, and more severe forms of the disorder comprise the second most common cause of dementia. A great deal of basic and applied research is clearly needed. We propose three areas where additional clinical research is sorely needed: diagnosis, neuropsychiatric symptoms, and treatment. Our current base of knowledge about SIVD is hindered by the lack of uniformity in how SIVD is defined. In reviewing behavioral literature on SIVD, we are struck by the several different ways in which study groups are defined. In some instances, vascular dementia groups are defined on the basis of Hachinski scores and vascular risk factors without reliance on neuroimaging findings. Altogether too many studies lump

THE NEUROPSYCHOLOGY OF VASCULAR DEMENTIA all vascular dementia patients into a single group, paying little heed to the tremendous differences between multi-infarct dementia, SIVD and Binswanger’s disease. Even when a study is restricted to SIVD, there is wide variability in diagnostic criteria. CT scans may be less sensitive to white matter disease, for example, and some researchers do not distinguish between lacunes and extensive white matter signal intensities. There remains a lack of consensus on what constitutes a lacune, whether T1 or T2 MRI images are most reliable, or how large a lesion must be before it can be called a lacune. There is considerable need for a consensus conference on diagnostic criteria for SIVD, and a willingness on the part of researchers to use a common diagnostic standard. Much of the clinical research on SIVD has focused on neuropsychological changes. While this research continues to be relevant, the emphasis going forward needs to be on pathology proven cases. We know from studies of depression that psychiatric symptoms are associated with subcortical hyperintensities, particularly in the elderly (Simpson et al., 1997; Tupler et al., 2002; Firbank et al., 2004). Anxiety, depression, and the overall severity of neuropsychiatric symptoms in vascular dementia patients have also been associated with the extent of white matter ischemia (Sultzer et al., 1995). Greater awareness of the neuropsychiatric features of SIVD can simultaneously improve patient care and guide our understanding of brain–behavior relationships. In order for us to best assess the role neuropsychology may play in SIVD, it is imperative we increase our base of autopsy defined cases so that we may rule out any potential comorbidities, especially Alzheimer’s disease. Concomitant AD is our greatest challenge in assessing the role vascular disease may be playing in cognitive impairment, and without autopsy defined cases we will not be able to rule out AD as a contributing factor to a dementia syndrome. Finally, treatment aimed at primary prevention, secondary prevention, and tertiary care is needed. Primary intervention should dovetail with efforts aimed at reducing the prevalence of vascular disease in general. However, there are a large number of normal elderly with so-called silent lacunes who are at greater risk than their peers for developing a dementia. For those patients with SIVD, more clinical trials are needed to assess the viability of anticholinesterases and other medications that may improve cognitive functioning in other dementing disorders.

References Babikan V, Ropper AH (1987). Binswanger’s disease: A review. Stroke 18: 2–12.

579

Baum KA, Schulte C, Girke W, et al. (1996). Incidental whitematter foci on MRI in ‘healthy’ subjects: Evidence of subtle cognitive dysfunction. Neuroradiology 38: 755–760. Bjeljac M, Keller E, Regard M, et al. (2002). Neurological and neuropsychological outcome after SAH. Acta Neurochir Suppl 82: 83–85. Black SE (2005). Vascular dementia. Stroke risk and sequelae define therapeutic approaches. Postgrad Med 117: 15–16, 19–25. Bogousslavsky J, Regli F, Uske A (1988). Thalamic infarcts: Clinical syndromes, etiology, and prognosis. Neurology 38: 837–848. Bornstein NM, Gur AY, Treves TA, et al. (1996). Do silent brain infarctions predict the development of dementia after first ischemic stroke? Stroke 27: 904–905. Brun A (1994). Pathology and pathophysiology of cerebrovascular dementia: Pure subgroups of obstructive and hypoperfusive etiology. Dementia 5: 145–147. Capizzano AA, Schuff N, Amend DL, et al. (2000). Subcortical ischemic vascular dementia: Assessment with quantitative MR imaging and 1H MR spectroscopy. AJNR Am J Neuroradiol 21: 621–630. Caplan LR, Schmahmann JD, Kase CS, et al. (1990). Caudate infarcts. Arch Neurol 47: 133–143. Caplan LR, Schoene WC (1978). Clinical features of subcortical arteriosclerotic encephalopathy (Binswanger disease). Neurology 28: 1206–1215. Carew TG, Lamar M, Cloud BS, et al. (1997). Impairment in category fluency in ischemic vascular dementia. Neuropsychology 11: 400–412. Charlton RA, Morris RG, Nitkunan A, et al. (2006). The cognitive profiles of CADASIL and sporadic small vessel disease. Neurology 66: 1523–1526. Chui HC (1989). Dementia. A review emphasizing clinicopathologic correlation and brain–behavior relationships. Arch Neurol 46: 806–814. Chui HC, Mack W, Jackson JE, et al. (2000). Clinical criteria for the diagnosis of vascular dementia: A multicenter study of comparability and interrater reliability. Arch Neurol 57: 191–196. Chui HC, Victoroff JI, Margolin D, et al. (1992). Criteria for the diagnosis of ischemic vascular dementia proposed by the State of California Alzheimer’s Disease Diagnostic and Treatment Centers. Neurology 42: 473–480. Cosentino SA, Jefferson AL, Carey M, et al. (2004). The clinical diagnosis of vascular dementia: A comparison among four classification systems and a proposal for a new paradigm. Clin Neuropsychol 18: 6–21. Cummings J (1993). Frontal–subcortical circuits and human behavior. Arch Neurol 50: 73–80. Cummings JL (1995). Anatomic and behavioral aspects of frontal–subcortical circuits. Ann NY Acad Sci 769: 1–13. Davous P (1998). CADASIL: a review with proposed diagnostic criteria. Eur J Neurol 5: 219–233. DeCarli C, Mungas D, Harvey D, et al. (2004). Memory impairment, but not cerebrovascular disease, predicts progression of MCI to dementia. Neurology 63: 220–227.

580

M.E. WETZEL AND J.H. KRAMER

de Groot JC, de Leeuw FE, Oudkerk M, et al. (2000). Cerebral white matter lesions and depressive symptoms in elderly adults. Arch Gen Psychiatry 57: 1071–1076. de la Torre JC (2002). Alzheimer disease as a vascular disorder: Nosological evidence. Stroke 33: 1152–1162. D’Esposito M, Alexander MP, Fischer R, et al. (1996). Recovery of memory and executive function following anterior communicating artery aneurysm rupture. J Int Neuropsychol Soc 2: 565–570. Du AT, Schuff N, Laakso MP, et al. (2002). Effects of subcortical ischemic vascular dementia and AD on entorhinal cortex and hippocampus. Neurology 58: 1635–1641. Erker GJ, Searight HR, Peterson P (1995). Patterns of neuropsychological functioning among patients with multi-infarct and Alzheimer’s dementia: A comparative analysis. Int Psychogeriatr 7: 393–406. Erkinjuntti T (1997). Vascular dementia: Challenge of clinical diagnosis. Int Psychogeriatr 9: 51–58 discussion 77–83. Erkinjuntti T (2002). Diagnosis and management of vascular cognitive impairment and dementia. J Neural Transm Suppl(63): 91–109. Erkinjuntti T, Benavente O, Eliasziw M, et al. (1996). Diffuse vacuolization (spongiosis) and arteriolosclerosis in the frontal white matter occurs in vascular dementia. Arch Neurol 53: 325–332. Fein G, Di Sclafani V, Tanabe J, et al. (2000). Hippocampal and cortical atrophy predict dementia in subcortical ischemic vascular disease. Neurology 55: 1626–1635. Feinberg WM, Seeger JF, Carmody RF, et al. (1990). Epidemiologic features of asymptomatic cerebral infarction in patients with nonvalvular atrial fibrillation. Arch Intern Med 150: 2340–2344. Ferrand J (1902). Essai sur l’hemiplegie des vieillards: Les lacunes de disintegration cerebrale. These, Paris. Ferrucci L, Guralnik JM, Salive ME, et al. (1996). Cognitive impairment and risk of stroke in the older population. J Am Geriatr Soc 44: 237–241. Firbank MJ, Lloyd AJ, Ferrier N, et al. (2004). A volumetric study of MRI signal hyperintensities in late-life depression. Am J Geriatr Psychiatry 12: 606–612. Fisher CM (1965). Lacunes: Small, deep cerebral infarcts. Neurology 15: 774–784. Gainotti G, Parlato V, Monteleone D, et al. (1992). Neuropsychological markers of dementia on visual–spatial tasks: A comparison between Alzheimer’s type and vascular forms of dementia. J Clin Exp Neuropsychol 14: 239–252. Gearing M, Mirra SS, Hedreen JC, et al. (1995). The Consortium to Establish a Registry for Alzheimer’s Disease (CERAD). Part X. Neuropathology confirmation of the clinical diagnosis of Alzheimer’s disease. Neurology 45: 461–466. Gorelick PB (2004). Risk factors for vascular dementia and Alzheimer disease. Stroke 35: 2620–2622. Gunning-Dixon FM, Raz N (2000). The cognitive correlates of white matter abnormalities in normal aging: A quantitative review. Neuropsychology 14: 224–232. Hachinski V (1994). Vascular dementia: A radical redefinition. Dementia 5: 130–132.

Hachinski VC, Illiff LD, Zilhka E, et al. (1975). Cerebral blood flow in dementia. Arch Neurol 32: 632–637. Hassing L, Backman L (1997). Episodic memory functioning in population-based samples of very old adults with Alzheimer’s disease and vascular dementia. Dement Geriatr Cogn Disord 8: 376–383. Heiss WD (1983). Flow thresholds of functional and morphological damage of brain tissue. Stroke 14: 329–331. Holmes C, Cairns N, Lantos P, et al. (1999). Validity of current clinical criteria for Alzheimer’s disease, vascular dementia, and dementia with Lewy bodies. Br J Psychiatry 174: 45–51. Hutter BO, Kreitschmann-Andermahr I, Mayfrank L, et al. (1999). Functional outcome after aneurysmal subarachnoid hemorrhage. Acta Neurochir Suppl 72: 157–174. Irle E, Wowra B, Kunert HJ, et al. (1992). Memory disturbances following anterior communicating artery rupture. Ann Neurol 31: 473–480. Jellinger KA (2002). The pathology of ischemic-vascular dementia: An update. J Neurol Sci 203–204: 153–157. Jellinger KA (2005). Understanding the pathology of vascular cognitive impairment. J Neurol Sci 229–230: 57–63. Jimbo H, Hanakawa K, Ozawa H, et al. (2000). Neuropsychological changes after surgery for anterior communicating artery aneurysm. Neurol Med Chir (Tokyo) 40: 83–86; discussion 86–87. Kalaria RN, Kenny RA, Ballard CG, et al. (2004). Towards defining the neuropathological substrates of vascular dementia. J Neurol Sci 226: 75–80. Katzman R, Lasker B, Bernstein N (1988). Advances in the diagnosis of dementia: Accuracy of diagnosis and consequences of misdiagnosis of disorders causing dementia. In: Aging and Dementia, Raven. New York pp. 17–62. Kemenoff LA, Kramer JH, Mungas D, et al. (1999). Neuropsychological differentiation of vascular and Alzheimer’s dementia. Poster session presented at the 107th Annual Convention of the American Psychological Association, Boston. Kertesz A, Clydesdale S (1994). Neuropsychological deficits in vascular dementia vs Alzheimer’s disease: Frontal lobe deficits prominent in vascular dementia. Arch Neurol 51: 1226–1231. Knopman DS, DeKosky ST, Cummings JL, et al. (2001). Practice parameter: Diagnosis of dementia (an evidencebased review). Report of the Quality Standards Subcommittee of the American Academy of Neurology. Neurology 56: 1143–1153. Knopman DS, Nissen MJ (1991). Procedural learning is impaired in Huntington’s disease: Evidence from the serial reaction time task. Neuropsychologia 29: 245–254. Knopman DS, Parisi JE, Boeve BF, et al. (2003). Vascular dementia in a population-based autopsy study. Arch Neurol 60: 569–575. Kobayashi S, Okada K, Koide H, et al. (1997). Subcortical silent brain infarction as a risk factor for clinical stroke. Stroke 28: 1932–1939. Kooistra CA, Heilman KM (1988). Memory loss from a subcortical white matter infarct. J Neurol Neurosurg Psychiatry 51: 866–869.

THE NEUROPSYCHOLOGY OF VASCULAR DEMENTIA Kramer JH, Mungas D, Reed BR, et al. (2004). Forgetting in dementia with and without subcortical lacunes. Clin Neuropsychol 18: 32–40. Kramer JH, Reed BR, Mungas D, et al. (2002). Executive dysfunction in subcortical ischaemic vascular disease. J Neurol Neurosurg Psychiatry 72: 217–220. Kwan LT, Reed BR, Eberling JL, et al. (1999). Effects of subcortical cerebral infarction on cortical glucose metabolism and cognitive function. Arch Neurol 56: 809–814. Ladurner G, Iliff LD, Lechner H (1982). Clinical factors associated with dementia in ischaemic stroke. J Neurol Neurosurg Psychiatry 45: 97–101. Lafosse JM, Reed BR, Mungas D, et al. (1997). Fluency and memory differences between ischemic vascular dementia and Alzheimer’s disease. Neuropsychology 11: 514–522. Libon DJ, Bogdanoff B, Cloud BS, et al. (1998). Declarative and procedural learning, quantitative measures of the hippocampus, and subcortical white alterations in Alzheimer’s disease and ischaemic vascular dementia. J Clin Exp Neuropsychol 20: 30–41. Libon DJ, Price CC, Davis Garrett K, et al. (2004). From Binswanger’s disease to leuokoaraiosis: What we have learned about subcortical vascular dementia. Clin Neuropsychol 18: 83–100. Lindsay J, Hebert R, Rockwood K (1997). The Canadian Study of Health and Aging: risk factors for vascular dementia. Stroke 28: 526–530. Loeb C (2000). Binswanger’s disease is not a single entity. Neurol Sci 21: 343–348. Loeb C, Gandolfo C (1983). Diagnostic evaluation of degenerative and vascular dementia. Stroke 14: 399–401. Loeb C, Gandolfo C, Croce R, et al. (1992). Dementia associated with lacunar infarction. Stroke 23: 1225–1229. Loeb C, Meyer JS (1996). Vascular dementia: Still a debatable entity? J Neurol Sci 143: 31–40. Longstreth WT Jr, Bernick C, Manolio TA, et al. (1998). Lacunar infarcts defined by magnetic resonance imaging of 3660 elderly people: The Cardiovascular Health Study. Arch Neurol 55: 1217–1225. Lukatela K, Malloy P, Jenkins M, et al. (1998). The naming deficit in early Alzheimer’s and vascular dementia. Neuropsychology 12: 565–572. Marie P (1901). Des foyers lacunaires de desintegration et de differents autres etats cavitaires du cerveau. Rev Med (Mex) 21: 281–298. Markus HS, Martin RJ, Simpson MA, et al. (2002). Diagnostic strategies in CADASIL. Neurology 59: 1134–1138. Matsubayashi K, Shimada K, Kawamoto A, et al. (1992). Incidental brain lesions on magnetic resonance imaging and neurobehavioral functions in the apparently healthy elderly. Stroke 23: 175–180. Matsuda O, Saito M, Sugishita M (1998). Cognitive deficits of mild dementia: A comparison between dementia of the Alzheimer’s type and vascular dementia. Psychiatry Clin Neurosci 52: 87–91. Meier D (1995). The segmented clock: A typical pattern in vascular dementia. J Am Geriatr Soc 43: 1071–1073.

581

Mendez MF, Ashla-Mendez M (1991). Differences between multi-infarct dementia and Alzheimer’s disease on unstructured neuropsychological tasks. J Clin Exp Neuropsychol 13: 923–932. Mendez MF, Cherrier MM, Perryman KM (1997). Differences between Alzheimer’s disease and vascular dementia on information processing measures. Brain Cogn 34: 301–310. Moody DM, Bell MA, Challa VR (1990). Features of the cerebral vascular pattern that predict vulnerability to perfusion or oxygenation deficiency: an anatomic study. AJNR Am J Neuroradiol 11: 431–439. Mungas D, Jagust WJ, Reed BR, et al. (2001). MRI predictors of cognition in subcortical ischemic vascular disease and Alzheimer’s disease. Neurology 57: 2229–2235. Nichelli P, Bonito V, Candelise L, et al. (1986). Three-year neuropsychological follow-up of patients with reversible ischemic attacks. Ital J Neurol Sci 7: 443–446. Nolan KA, Lino MM, Seligmann AW, et al. (1998). Absence of vascular dementia in an autopsy series from a dementia clinic. J Am Geriatr Soc 46: 597–604. O’Brien JT, Erkinjuntti T, Reisberg B, et al. (2003). Vascular cognitive impairment. Lancet Neurol 2: 89–98. Padovani A, Di Piero V, Bragoni M, et al. (1995). Patterns of neuropsychological impairment in mild dementia: A comparison between Alzheimer’s disease and multi-infarct dementia. Acta Neurol Scand 92: 433–442. Pantoni L, Garcia JH, Brown GG (1996). Vascular pathology in three cases of progressive cognitive deterioration. J Neurol Sci 135: 131–139. Peters N, Opherk C, Danek A, et al. (2005). The pattern of cognitive performance in CADASIL: A monogenic condition leading to subcortical ischemic vascular dementia. Am J Psychiatry 162: 2078–2085. Pohjasvaara T, Erkinjuntti T, Vataja R, et al. (1997). Dementia three months after stroke. Baseline frequency and effect of different definitions of dementia in the Helsinki Stroke Aging Memory Study (SAM) cohort. Stroke 28: 785–792. Pohjasvaara T, Mantyla R, Ylikoski R, et al. (2000). Comparison of different clinical criteria (DSM-III, ADDTC, ICD10, NINDS-AIREN, DSM-IV) for the diagnosis of vascular dementia. National Institute of Neurological Disorders and Stroke—Association Internationale pour la Recherche et l’Enseignement en Neurosciences. Stroke 31: 2952–2957. Price TR, Manolio TA, Kronmal RA, et al. (1997). Silent brain infarction on magnetic resonance imaging and neurological abnormalities in community-dwelling older adults. The Cardiovascular Health Study. CHS Collaborative Research Group. Stroke 28: 1158–1164. Rabinstein AA, Romano JG, Forteza AM, et al. (2004). Rapidly progressive dementia due to bilateral internal carotid artery occlusion with infarction of the total length of the corpus callosum. J Neuroimaging 14: 176–179. Reed BR, Mungas DM, Kramer JH, et al. (2004). Clinical and neuropsychological features in autopsy-defined vascular dementia. Clin Neuropsychol 18: 63–74.

582

M.E. WETZEL AND J.H. KRAMER

Richardson JT (1991). Cognitive performance following rupture and repair of intracranial aneurysm. Acta Neurol Scand 83: 110–122. Roman GC (1987). Senile dementia of the Binswanger type. A vascular form of dementia in the elderly. JAMA 258: 1782–1788. Roman GC (2005). Vascular dementia prevention: A risk factor analysis. Cerebrovasc Dis 20: 91–100. Roman GC, Erkinjuntti T, Wallin A, et al. (2002). Subcortical ischaemic vascular dementia. Lancet Neurol 1: 426–436. Roman GC, Sachdev P, Royall DR, et al. (2004). Vascular cognitive disorder: A new diagnostic category updating vascular cognitive impairment and vascular dementia. J Neurol Sci 226: 81–87. Roman GC, Tatemichi TK, Erkinjuntii T (1993). Vascular Dementia: Diagnostic criteria for research studies. Neurology 43: 250–260. Rosen WG, Terry RD, Fuld PA, et al. (1980). Pathological verification of ischaemic score in differentiation of the dementias. Ann Neurol 7: 486–488. Rosenstein LD (1998). Differential diagnosis of the major progressive dementias and depression in middle and late adulthood: A summary of the literature of the early 1990s. Neuropsychol Rev 8: 109–167. Sacco RL (1994). Ischemic stroke. In: PB Gorelick, M Alter (Eds.), Handbook of Neuroepidemiology. Marcel Decker, New York, pp. 77–119. Sacco RL, Hauser WA, Mohr JP (1991). Hospitalized stroke in blacks and Hispanics in northern Manhattan. Stroke 22: 1491–1496. Sachdev P (1999). Vascular cognitive disorder. Int J Geriatr Psychiatry 14: 402–403. Scheid R, Preul C, Lincke T, et al. (2006). Correlation of cognitive status, MRI- and SPECT-imaging in CADASIL patients. Eur J Neurol 13: 363–370. Schmidt R, Scheltens P, Erkinjuntti T, et al. (2004). White matter lesion progression: A surrogate endpoint for trials in cerebral small-vessel disease. Neurology 63: 139–144. Schoenberg BS, Shulte BPM (1988). Cerebrovascular disease: Epidemiology and geopathology. In: PJ Vinkin, GW Bruyn, HL Klawans (Eds.), Handbook of Clinical Neurology, Vascular Diseases, Vol. 53. Elsevier Science, Amsterdam, pp. 1–26. Shallice T, Burgess P (1991). Higher order cognitive impairments and frontal lobe lesions in man. In: HS Levin, HM Eisenberg, AL Benton (Eds.), Frontal Lobe Function and Dysfunction. Oxford University Press, Oxford, pp. 125–138. Sharbrough FW, Messick JM Jr, Sundt TM Jr (1973). Correlation of continuous electroencephalograms with cerebral blood flow measurements during carotid endarterectomy. Stroke 4: 674–683. Shinkawa A, Ueda K, Kiyohara Y, et al. (1995). Silent cerebral infarction in a community-based autopsy series in Japan. The Hisayama Study. Stroke 26: 380–385.

Shintani S, Shiigai T, Arinami T (1998). Silent lacunar infarction on magnetic resonance imaging (MRI): Risk factors. J Neurol Sci 160: 82–86. Simpson SW, Jackson A, Baldwin RC, et al. (1997). 1997 IPA/Bayer Research Awards in Psychogeriatrics. Subcortical hyperintensities in late-life depression: Acute response to treatment and neuropsychological impairment. Int Psychogeriatr 9: 257–275. Solfrizzi V, Panza F, Colacicco AM, et al. (2004). Vascular risk factors, incidence of MCI, and rates of progression to dementia. Neurology 63: 1882–1891. Sultzer DL, Mahler ME, Cummings JL, et al. (1995). Cortical abnormalities associated with subcortical lesions in vascular dementia. Clinical and position emission tomographic findings. Arch Neurol 52: 773–780. Suzuki K, Kutsuzawa T, Nakajima K, et al. (1991). Epidemiology of vascular dementia and stroke in Akita, Japan. In: WKA Hartmann, S Hoyer (Eds.), Cerebral Ischemia and Dementia. Springer-Verlag, New York, pp. 16–24. Taillia H, Chabriat H, Kurtz A, et al. (1998). Cognitive alterations in non-demented CADASIL patients. Cerebrovasc Dis 8: 97–101. Tatemichi TK, Desmond DW, Mayeux R, et al. (1992a). Dementia after stroke: Baseline frequency, risks, and clinical features in a hospitalized cohort. Neurology 42: 1185–1193. Tatemichi TK, Desmond DW, Prohovnik I, et al. (1992b). Confusion and memory loss from capsular genu infarction: A thalamocortical disconnection syndrome? Neurology 42: 1966–1979. Tatemichi TK, Foulkes MA, Mohr JP, et al. (1990). Dementia in stroke survivors in the Stroke Data Bank cohort. Prevalence, incidence, risk factors, and computed tomographic findings. Stroke 21: 858–866. Tei H, Miyazaki A, Iwata M, et al. (1997). Early-stage Alzheimer’s disease and multiple subcortical infarction with mild cognitive impairment: Neuropsychological comparison using an easily applicable test battery. Dement Geriatr Cogn Disord 8: 355–358. Tell GS, Crouse JR, Furberg CD (1988). Relation between blood lipids, lipoproteins, and cerebrovascular atherosclerosis. A review. Stroke 19: 423–430. Tomlinson BE, Blessed G, Roth M (1970). Observations on the brains of demented old people. J Neurol Sci 11: 205–242. Tullberg M, Fletcher E, DeCarli C, et al. (2004). White matter lesions impair frontal lobe function regardless of their location. Neurology 63: 246–253. Tupler LA, Krishnan KR, McDonald WM, et al. (2002). Anatomic location and laterality of MRI signal hyperintensities in late-life depression. J Psychosom Res 53: 665–676. Vermeer SE, Hollander M, van Dijk EJ, et al. (2003). Silent brain infarcts and white matter lesions increase stroke risk in the general population: The Rotterdam Scan Study. Stroke 34: 1126–1129. Wang LN, Zhu MW, Gui QP, et al. (2003). [An analysis of the causes of dementia in 383 elderly autopsied cases]. Zhonghua Nei Ke Za Zhi 42: 789–792.

THE NEUROPSYCHOLOGY OF VASCULAR DEMENTIA Wetterling T, Kanitz RD, Borgis KJ (1993). Clinical evaluation of the ICD-10 criteria for vascular dementia. Eur Arch Psychiatry Clin Neurosci 243: 33–40. Wetterling T, Kanitz RD, Borgis KJ (1996). Comparison of different diagnostic criteria for vascular dementia. (ADDTC, DSM-IV, ICD-10, NINDS-AIREN). Stroke 27: 30–36. WHO (1993). The ICD-10 classification of mental and behavioural disorders: Diagnostic criteria for research. Geneva, WHO.

583

Wolf PA, D’Agostino RB, Belanger AJ, et al. (1991). Probability of stroke: A risk profile from the Framingham Study. Stroke 22: 312–318. Wolf PA, Dawber TR, Thomas HE Jr, et al. (1978). Epidemiologic assessment of chronic atrial fibrillation and risk of stroke: The Framingham study. Neurology 28: 973–977. Wolfe N, Linn R, Babikian VL, et al. (1990). Frontal systems impairment following multiple lacunar infarcts. Arch Neurol 47: 129–132.

Index Page numbers in italics, e.g. 198, refer to figures. Page numbers in bold, e.g. 198, denote tables. A abstraction, 52, 142, 146, 259–60 abulia, 54, 87, 291 acalculia, 144 clinical presentation, 339, 342–5 definition, 139, 144, 339 diagnosis and assessment, 351–2 identification of digit strings in, 343 model-oriented study of, 350 pathophysiology, 348–50 production of number words in, 344 rehabilitation for, 352–3 transcoding in, 342–4 acetylcholine 1, 4, 19, 31, 35, 37, 94, 115, 243, 261–2, 304, 553, 561. See also cholinergic neuron(s) acetylcholinesterase (AChE), 2, 6, 14–16, 19–22, 558, 560 acetylcholinesterase inhibitors (AChEIs), 10, 12–21 achromatopsia, 43, 418, 420, 423, 478–9 acquired neurogenic stuttering (ANS), 276–7 activation brain, 6–8, 12–13, 66, 71–2, 79, 79, 90, 98, 195, 230 neurodegenerative disorders and, 89 reasoning tasks and, 79 addiction, 34, 245 adrenaline, 31. See also norepinehprine affect regulation, 250, 250–1 aging Alzheimer’s disease and, 76, 113, 116–17, 121 learning, 120–1 memory and, 119–21, 499 mild cognitive impairment with, 75–7 models of cognitive decline, 113 normal neurologic change in, 76–7, 81, 113–14, 116–17, 117–18, 499, 502 agnosia associative, 139, 148 auditory, 45, 450 color, 149 topographanosia and, 139, 147, 150 visual (See visual agnosia)

agraphia, 139, 292, 317 akinesis, 256 akinetic mutism, 54, 138, 163, 256, 275 alcoholism, 567 alexia, 55, 139–40, 144, 288, 291–3, 298, 311, 314, 316, 318, 339, 343, 350, 381, 398, 432, 449, 461 allochiria, 376, 384–5 Alzheimer’s disease age-corrected z-scores in, 121 amyloid plaques in, 549 anomia in, 301 aphasia in, 291 apraxia in, 56, 381 art and, 479–83 attention in, 520 characterization, 113 clinical trials, 521–2 cognition in, 115, 119, 499, 513–15, 519 cortical degeneration in, 167 dementia in, 120, 126–7, 146, 190 diagnosis, 114–17, 117–18, 118–19, 513–16, 540, 573, 575–8 emotions in, 520–1 entorhinal dysfunction and, 49 examination for, 513–14, 518–20 functional neuroimaging of, 81–5 history, 511 language in, 513, 515–16 Lewy body dementia and, 551 memory and, 74, 114, 167, 186, 211, 512, 559–60 metabolism in, 82, 83–4 music and, 466 naming impairment in, 64, 126 Parkinson’s disease and, 551 pathology, 1–2, 13, 33, 207 presentation, 511–14 priming in, 228–9 problem solving tests in, 115 prodromal, 76, 516–17 progression rate, 82 reading and writing in, 311 receiver operating charcteristic (ROC) curves, 117 retrograde amnesia in, 123

Alzheimer’s disease (Continued ) screening tests for 521 (See also specific screening test) semantic disorders in, 212–13 symptoms, 82, 479, 513–15, 541 treatment, 13–15, 20, 262 vascular dementia and, 568 visuospatial function in, 479, 520, 481–2 Alzheimer’s Disease Assessment Scale – Cognitive Subscale (ADASCS), 521–2 Alzheimer’s Disease Cooperative Study, 505, 522 Alzheimer’s Disease Diagnostic and Treatment Centers (ADDTC), 571, 572, 576 Alzheimer’s Disease Neuroimaging Initiative (ADNI), 506, 522 Alzheimer’s Disease Patient Registry (ADPR), 502, 502 aminergic transmitter systems, 31, 36 amnesia anterograde, 49, 139, 150–2, 155, 157, 158, 162–9, 185, 187, 192 /mnestic block syndrome, 171 psychogenic, 172 retrograde (RA), 49, 74, 122–3, 140, 150–1, 155, 157, 162, 165–6, 169, 185–9, 192–3, 195–7, 493 surgically induced, 169 transient epileptic (TEA), 194 transient global (TGA), 169–70, 189 amnesic mild cognitive impairment (aMCI), 84, 85, 86, 505–6 amphetamine, 53, 98, 243, 277, 303–4 amygdala basolateral, 3 conditioned behavior and, 52–3 dopaminergic cells and, 21 emotional processing, 49, 52–3, 75, 168, 493, 496 executive function, 80 genes, cognition and, 98 hypometabolism in, 87

586 amygdala (Continued ) memory and, 52, 96, 161, 172, 421, 485 neural connections, 4, 32, 53, 87, 162, 243, 253, 256, 465 neuroadrenergic neurons and, 33 opiod receptors in, 95 serotonin (5-HT) receptors in, 35–6 Urbach–Wiethe disease and, 168 amyloid plaques, 3, 14, 82, 505, 549–50, 552 aneurysms, 54, 258 anomia, 55, 120, 125, 148, 203, 209, 213, 288, 291–3, 298, 301, 344, 419, 537, 539 anomic aphasia, 291, 298 anosognosia, 44, 139, 147, 257, 289, 294, 359, 362, 445–6 anterior cingulate cortex (ACC) activation and arousal, 8, 96 Alzheimer’s disease and, 119, 519 cholinergic fibers, 3 cognitive functions, 19, 47, 75, 77, 256, 496, 556 neural connections, 4, 21, 53, 120, 239, 243, 252–3, 255–6, 576 neuroimaging, 9 performance monitoring of, 255 anterior temporal neocortex, 53 antidepressant drugs, 33 antipsychotics, 33, 36, 37 apathy, 17, 19, 37, 54, 86–7, 120, 257, 259, 262, 528, 542, 570, 576 aphasia alexia and, 292 assessment, 287–9 art and, 473 Broca’s, 55, 269, 276, 289, 292–3, 295, 297–8, 304, 318, 345, 347–8, 543 conduction, 290, 298 doubles and 436 (See also doubles) fluent, 86, 88, 208–9, 216, 424, 541, 554 global, 55, 276, 291–2, 296, 298, 348 hearing, 293 history, 287 non-fluent, 208, 209 post stroke, 18 presentation, 55, 295–7 reading and, 293 semantic disorders in, 203–11, 208 subcortical, 293 syndromes, 55–6 transcortical, 297 treatment and recovery, 73–4, 302–4 apraxia callosal, 332–3 conceptual, 56 conduction, 56

INDEX apraxia (Continued ) constructional (CA), 120, 145, 360, 373, 375, 376, 378, 380, 380–1, 385, 421 definition of, 56, 323–4 face, 333 handedness and, 332–3 history of, 323–4 ideational, 139, 145, 293, 331–2 ideomotor, 56, 144–5, 269, 288–9, 331–2, 375 imitation of gestures in, 324 limb kinetic, 56 neuroanatomy of, 56 ocular motor, 396 oral–facial, 277 of speech (See apraxia of speech) apraxia of speech definition of, 270 developmental (DAS), 277 diagnosis, 275–7 etiology of, 271–2 history of, 269–70 inner speech in, 280–1 left inferior motor cortex in, 273 lenticular zone in, 273 localization, 272–5 models, 279–80 motor control in, 277–9 mutism in, 270, 275 phonetic vs. phonemic errors in, 272 subcortical white matter in, 272–3 symptoms, 270, 271 treatment, 277 arousal, 1, 4, 13, 21, 33, 37, 47, 96, 98, 138, 255–6, 261, 275, 465, 491, 493, 495, 552 art and artistry aesthetics of, 485 in Alzheimer’s disease, 479–83 brain research and, 471–2 details vs. form in, 473 frontotemporal lobar degeneration and, 483 hemispheric contributions to, 472–5 history and role of, 471 migraine and, 484 neural and cognitive basis of, 382–4 in savants, 484–5 symbolic, 473 artists vs. non-artists, 472 ascending reticular activating system, 137–8 asomatognosia, 443, 445, 451–3 Asperger’s syndrome, 258, 541, 543 associative agnosia, 139, 148 atrial fibrillation, 567 atropine, 4

attention in Alzheimer’s disease, 557–8 cerebral cortex and, 47 in dementia, 126, 557–8 executive functions and, 126–7 orientation and, 140–1 neuroanatomy and neurophysiology, 47–8 in Parkinson’s disease, 557–8 perception and, 396–9 working memory and, 126–7 attention deficit hyperactivity disorder (ADHD), 91, 245, 255, 258, 261–2 Attention/Concentration Index, 115, 126 attentional processing, 13, 47, 126 auditory agnosia, 45, 450 auditory comprehension, 288 auditory cortex, 10, 44, 45, 45–6, 293, 299, 461, 462, 463 auditory doubles, 429, 448–50 auditory hallucinations, 436, 448 auditory neglect, 362 auditory pathway, 460 auditory processing, 44–5, 460 autism, 18, 91, 258 autoscopic phenomena. See autoscopy; doubles; hallucination: autoscopic; heautoscopy; out-of-body experience autoscopy anatomy of, 436–8 clinical presentation, 435–6 etiology, 436 lesion locations in, 437 phenomenology of, 433 B basal forebrain, 2, 4, 13–14, 20–1, 137, 139, 143, 162, 163, 165–6, 171, 243, 261, 556, 570 basal ganglia, 363 apraxia of speech and, 273 cholinergic neurons, 4 circulation, 576 dopamine and, 96 emotion and, 52, 496 executive functions, 252, 257–8 infarct, 570, 573–4 language and, 71 learning and, 231–3 memory and, 75, 165 metabolism, 82, 88 motor skills and, 232 neural connections, 2, 21, 41, 165, 556 Parkinson’s disease and, 120 role in ANS, 276 serotonin (5-HT) receptor binding, 35

INDEX basolateral limbic circuit, 161, 162, 165 Battery for Visuospatial Abilities (BVA), 373 bedside neurological tests, 140–1, 152, 259, 362, 496 Behavioral Assessment of Dysexecutive Syndrome (BADS), 259 behavioral economists, 80 bilateral optic ataxia, 404 bilingualism 71–3 See also language binding potential (BP), 93, 94–6 bipolar disorder, 18, 258 Birmingham Object Recognition Battery (BORB), 426 Blessed Dementia Scale, 521 blindness, 42, 43, 148, 293, 424, 477 Blint’s syndrome, 44, 148, 374, 393–4, 397, 399, 402, 409–11, 479 Block Design Test, 115–16, 117 Blood Oxygenation Level Dependent (BOLD), 65–7, 79, 98–9, 318–19, 349 Boston Diagnostic Aphasia Test, 426 Boston Naming Test, 425, 502, 512, 561 bradykinesia, 120, 128, 304, 542, 553 bradyphrenia, 128, 549 brain abnormal metabolism detection in, 82 activation, 6–8, 12–13, 66, 71–2, 79, 79, 90, 98, 195, 230 blood flow (See regional cerebral blood flow) development, 97 dopaminergic neurons, 34 dorsal stream, 479 functional organization, 67 imaging 21, 36, 64, 78, 94, 97, 99, 281, 511 See also (neuroimaging) infarct lesions, 574 injury, (See brain injury) ischemic penumbra of, 295 language areas, 352 metabolism, 63–4, 74, 81–2, 84–6, 87, 88–9, 94, 167, 170–1, 172, 297, 559 hypometabolism, 64, 74, 81–2, 85, 87, 89, 167, 170–1, 297, 559 normal aging of, 81 receptors, 33 serotonin (5-HT) neuron function, 36 tumors, 54, 166, 258, 311 ventral stream 43, 210, 216, 313, 375, 383, 400, 401, 406, 477 See also specific brain structures

brain injury acquired neurogenic stuttering (ANS) from, 276 alexia from, 311 amnesia from, 185 aphasia from, 55, 295 apraxia of speech from, 272 artistic abilities following, 472 color deficits following, 473 dysexecutive functions, 257–8 emotion and, 492 executive functions and, 251, 257–8 focal, 376 infection and, 257 left brain, 326, 376–80, 384, 473 mathematical abilities following, 353 memory and, 48, 75, 122, 156, 160–2, 169, 185 motor behavior and, 56 plasticity, 71 reading and, 311 recovery from, 49, 262 right brain damage, 53, 360, 376–7, 377, 378–9, 379, 380, 384, 386, 473, 475, 553, 561 social skills following, 54 treatment and recovery, 18, 49, 262, 474 brainstem, 12, 20, 41, 44, 52, 120, 137, 243, 256, 258, 272, 401, 461, 553–4 Lewy bodies, 550, 550 nuclei, 161, 550, 554 Broca, Paul, 55, 61, 69, 74, 269, 323 Broca’s aphasia. See aphasia: Broca’s Broca’s area, 70, 73, 272, 274, 280 Brodmann’s areas, 45, 45–6, 241, 437, 477, 479 butyrylcholinesterase (BuChE), 2, 14–16, 22 C calbindin, 3 calculation 346. See also number California Verbal Learning Test (CVLT), 116, 117–18, 120, 121, 121–2, 558, 560, 573, 577 cancellation task, 147, 360–2, 386 [11C]carfentanil, 95, 98 [11C]diprenorphine, 95 [11C]raclopride, 64, 94–7 caregivers, 258, 263, 494, 513, 528, 553 category fluency, 116, 117–18 caudate nucleus, 4, 70, 95–6, 289, 570 cerebellum, 36, 81–2, 88–9, 94, 258, 302, 304, 383, 399, 462, 464 cerebral asymmetry, 44–7 cerebral atrophy, 82

587 cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), 570, 574, 578 cerebral cortex Alzheimer’s disease and, 15 audition and, 44 classification, 42 cognitive function, 47, 50, 97, 258 dementia syndromes of, 120, 550 desynchronization, 4 development and, 91–2 fatal familial insomnia (FFI), 89 functional divisions, 41 higher cognitive functions of, 47 memory and, 158–9 motor function, 331 neural connections, 41, 46–7, 165, 243 organization, 239 reorganization, 89, 444 serotonin (5-HT) neurons in, 35 specialization, 41 vison and 41, 421–3 See also orbitofrontal cortex cerebral blood flow, 9, 10, 16, 35, 61, 63–5, 67, 89, 274, 295, 478, 569 cerebral hemisphere functions, 473–4 cerebral injury and lesions, 41–2, 48, 55–6 cerebral metabolism, 82, 88–9 cerebral neocortex, 42 cerebral visuospatial cognition, 44–7 cerebrovascular accident. See stroke choline acetyltransferase (ChAT), 1, 13, 16, 553, 556 cholinergic neuron(s) projections, 4 receptors, 4–6, 13 regulation of frontal cortex by, 4 cholinergic therapies, 18–19 cholinesterase inhibitors, 14, 262, 303–4 Classification and Regression Tree (CART) model in Alzheimer’s disease, 118 Clinical Dementia Rating (CDR), 503, 540 Clock Drawing Test (CDT), 521 cochlea, 44, 460, 461 cognition challenge, 94–5 cholinergic therapies, 13–19 challenge to, 95–6 developmental disorders and, 91 dysfunctions 138 (See also specific diseases and syndromes) flexibility, 142 genes and, 97–9

588 cognition (Continued ) high-order, 62, 82 improvements in, 8, 12, 21 inheritability, 97 learning skills of, 232–3 oculomotor symptoms and, 397–8 processes 1, 13, 34, 36, 51, 67, 78 (See also specific cognitive process) models, 78, 113 neural substrate, 256 neurochemistry, 92–7 numerical 340–2, 346–9, 354 (See also acalculia) reading and writing (See reading) reasoning, 79, 113, 259 sensory processing and, 41–7 social, 79, 90 spatial, 373, 381, 533 speech (See speech) unified modular model of, 78 cognitive skill learning, 232–3 color imagery neuroanatomy of, 477–8 perception of, 473 color agnosia, 149 computerized tomography (CT), 61 conceptual priming, 227 Consortium to Establish a Registry for Alzheimer Disease’s (CERAD), 518, 568 constructional apraxia (CA). See apraxia: constructional constructional disturbances. See visuoconstrucitonal disturbances; visuospatial disorders constructional tasks, 375, 380, 382, 384–5, 559 context-appropriate behavior, 250–1 corpus callosum, 55–6, 76, 148, 258, 277, 293, 314, 332–3, 343, 424, 461, 464 cortical dementia syndrome of Alzheimer’s disease, 120, 126–7 corticobasal degeneration (CBD), 56, 260, 382, 536, 541, 541–2 Cotard syndrome, 441–2 Creutzfeldt-Jakob disease (CJD), 88, 167, 541 Crovitz test, 185, 187, 193 cytochrome oxidase, 43, 82 D decision making, 78–81, 504 Deficit Hyperactivity Disorder, 255 de´ja` ve´cu, 447 Delis–Kaplan Executive Function System (DKEFS), 259 delusional misidentifications syndromes, 447

INDEX dementia cortical, 120, 126–7 diagnosis, 82, 571, 572 frontal type (See frontotemporal dementia) funtional neuroimaging in, 81 hallucination in 484 and HIV, 123 in Parkinson’s disease, 16, 86, 120 prevalence, 17 semantic (See semantic dementia) thalamic, 163, 167 treatment, 21 vascular (See vascular dementia) with Lewy bodies (See dementia with Lewy bodies) dementia with Lewy bodies (DLB) clinical presenation, 86, 550, 551, 552–3, 556 cognition in, 552 diagnosis, 16, 86, 541, 543, 550–2, 556 epidemiology, 553 functional neuroimaging of, 86 hallucinations in, 484, 552–3 history, 550–2 memory in, 559–60 neuroanatomy of, 554 neurochemical pathology, 2, 86, 556–7 Parkinsonian motor signs in, 553 prevalence, 554 sleep-wake cycle disturbances in, 553 treatment, 17, 20 visual processing and 382. See also dementia depersonalization, 440, 450–1, 453 depression, 12, 53–4, 94, 120, 289, 530, 542–3, 549, 572 developmental apraxia of speech (DAS) 277. See also apraxia of speech developmental dyscalculia 340. See also alcalculia developmental dyslexia, 91–2, 92, 99, 316 diabetes, 170, 501, 567, 570, 574 diaschisis, 73, 88, 294, 363, 364 diencephalon, 163–4, 164, 165 diffuse Lewy body disease, 550, 554, 557 diffusion tensor imaging (DTI), 70, 76, 92, 464 digit span test, 115, 127, 140–2, 238, 290, 300, 345, 512–13, 520, 528, 531, 539, 557 donepezil, 8, 11–19, 262, 505

dopamine (DA) anxiety and, 97 binding, 94 dementia with Lewy bodies and, 556 executive processes and, 19, 34–5, 97–8 memory and, 34–5, 96, 242–4 receptors, 33, 64, 86, 94, 97–8, 242, 244, 261–2, 368 regulation, 37, 95, 97, 465 synaptic concentration, 93–6 transporter, 551, 553 dorsal stream, simultanagnosia and, 479 dorsal striatum, 34, 81, 293 doubles 429–30, 438–40, 442–3, 446–53. See also heautoscopy Down syndrome (DS), 2, 18–19, 21, 97 DSM-IV criteria, 119, 211, 453, 568, 570, 571, 572 dysarthria, 120, 269, 270, 273, 275, 290, 292, 299, 542–3, 573 dyschromatopsia, 478–9 dysexecutive syndromes, 80 definition, 249 diagnosis, 259–61 management, 261–2 neurodevelopmental conditions and, 258 neuropathology, 252, 258 pharmacological management, 261–2 surgery as cause for 258. See also executive functions dyslexia, 72, 91–2, 314, 537, 466, 536, 539 E electrodermal skin conductance response, 256 electroencephalogram (EEG), 4, 18, 54, 61–2, 89, 100, 239, 449, 452, 461–3, 465, 472, 552 emotion anatomy and physiology of, 52–3 definition, 489–90 embarrassment and, 491–2, 494, 529 and episodic memory, 49 and expressive behavior, 491 language and, 491–2 negative, 491 neural correlates of, 496 peripheral physiology and, 491 positive, 491 processing, 52, 53, 490–2, 496 reactivity, 490 response systems, 491–2 right hemisphere and, 53–4 self-referential, 491 self-reported experience and, 491 social functions and, 52–4 testing, 492–4, 495 understanding, 490

INDEX epinephrine 31. See also norepinephrine epilepsy, 95, 167, 187, 297, 429, 436 episodic memory. See memory: episodic error analysis, 384 evoked related potentials (ERPs), 61 Executive Control Battery (ECB), 260 executive functions, 253 Alzheimer’s disease and, 115 clinical assessment, 258–61 definition, 77, 249–51 impairment, 77, 80 monitoring, 250, 255 neural basis for, 252–6 neurodegenerative diseases and, 558 organization, 250–1 reasoning, 77–80, 90, 113, 165, 237 schema, 250 second order, 250 theoretical perspectives on, 251–2 trust and reciprocity, 80 eye movement disorder, 397 F facial action coding system (FACS), 491 Facial Recognition Test, 425 fatal familial insomnia (FFI), 88–9, 167 feeling of a presence, 442–3, 445 Fellini’s cartoons, 475 5-HT, 31, 35–7, 97–8, 243, 553 [18F]fluorodopa, 96–7 foreign accent syndrome (FAS), 142, 276 Frontal Assessment Battery (FAB), 259, 260, 531 frontal lobe abstraction and 52 (See also abstraction) ACh fibers in, 3 activation, 77 alternating tasks, inhibition and, 51 Alzheimer’s disease and, 19, 126, 515 apraxia and, 56 cerebral vascular disease and, 88 cholinergic system and, 2, 5, 14, 18 cognition and, 16, 51, 76, 113, 119, 533 damage, 51, 80, 142, 187, 191, 253, 256, 258, 259, 492, 494 depression, 54 diffusion abnormality, 296 dopaminergic systems and, 12 dysfunction, 141 executive functions, 50, 51, 494, 558, 577 hypometabolism, 88 language and, 210

frontal lobe (Continued ) memory and, 165, 171, 186, 188, 188, 193, 239, 243, 527, 569 neglect syndromes, 363, 365–6 neural connections, 1, 48, 50, 120, 139, 252–3, 254, 401, 576 nicotinic receptors in, 21 retrograde amnesia and, 186 speech and, 299, 316 visual tasks and, 52 See also frontotemporal dementia frontal operculum, 70 frontotemporal dementia (FTD) art and, 483, 483 behavioral rating scales for, 529–30 behavioral variant, 527, 528, 528–30 cognitive screening tests for, 530–1 diagnosis, 86–8, 533, 540, 541, 542–3 emotion and, 534 episodic memory in, 532 executive functions and, 80, 531 imaging, 86–8, 382 mild cognitive impairment and, 504 personality measures, 533–4 syndromes, 540 Theory of Mind and, 533 verbal fluency in, 531 frontotemporal dementia with motor neuron disease (FTD-MND) 542. See also frontotemporal lobar dementia frontotemporal lobar dementia (FTLD) art and, 483–4 compulsive behaviors and, 484 diagnosis, 527, 530 history, 527 priming in, 229 variants, 530 functional magnetic resonance imaging (fMRI) 6–7, 10, 12–13, 52–3, 61–3, 65–7, 73, 76, 78, 90–1, 92, 99–100, 171, 350, 461, 465. See also magnetic resonance imaging functional neuroimaging. See neuroimaging G Gage, Phineas, 54, 257 galantamine, 8, 12, 14, 16, 19, 262, 421, 505, 505 galvanic skin response (GSR), 256 gamma-aminobutyric acid (GABA), 3 gene therapy, 14, 20 genes and cognitive processes, 97–9 Geriatric Depression Scale, 502 Gerstmann syndrome, 145, 339, 352 globus pallidus, 4, 120, 240, 556, 576 glutamate, 19, 31, 35, 37 G-protein coupled receptors, 5

589 gyrus angular, 315, 363 fusiform, 7, 10, 75, 315–16, 319, 349, 422–3 midfrontal, 9, 10 supramarginal (SMG), 363 temporal, 42, 45, 68, 128, 289, 297–9, 313, 316, 350, 363, 441, 445, 449, 460 H Hachinski Ischemia Scale (HIS), 571, 572 hallucination auditory, 436, 448 autoscopic (AH), 429–30, 432–3, 433–8, 441, 443–4, 452 in dementia with Lewy bodies, 484 migraine headaches and, 484 and pseudohallucinations, 435, 447 visual, 44, 86, 434, 436–8, 446, 449, 550, 551, 552–3, 559, 561 vestibular, 436, 443 Halstead–Reitan Battery, 425 hearing. See auditory processing hearing of a presence, 449 heautoscopy (HAS), 9, 42, 429, 433, 433–5, 438–42, 451, 453 hemiachromatopsia, 478 hemianopia, 140, 144, 293, 345, 359–61, 363, 421, 434, 436–8, 443–6, 474 hemiparesis, 273, 289–91, 324, 367, 380, 443, 461, 573 hemispatial neglect, 139, 144, 146–7, 294, 313, 359–63, 366–8 hemispheric asymmetry reduction in old adults (HAROLD), 76 herpes simplex encephalitis (HSE), 49, 50, 187, 190–2, 211–19, 257 hippocampal–diencephalic memory system, 122–3 hippocampus acetylcholine effects upon, 10 activation, 8, 8, 10, 75 Alzheimer’s disease and, 49, 84, 212 atrophy, 84 cognition and, 49, 52, 74 formation, 48, 161, 162, 165, 167, 505, 573 hypometabolism in, 87 memory and, 48, 49, 50, 52, 75, 96, 139, 168, 194, 195, 196, 225, 519 neural connections, 32–3, 48–9, 87, 243, 261, 364, 401 neuroimaging, 9 Parkinson’s disease and, 554 serotonin (5-HT) receptors in, 35, 36 histamine, 37 HIV/AIDS, 123, 167, 257, 258

590 Huntington’s disease, 18, 75, 97, 120, 121, 123, 231, 257, 518, 533, 541, 543, 577 hyperlipidemia, 170, 567 hypermetamorphosis, 52 hypertension, 15, 73, 567–70, 571, 572, 574 hypoesthesia, 442, 446, 451 hypothalamus, 32–3, 52, 139, 262, 465, 492 hypothyroidism, 541, 543 I imitation of gestures, 324–7 inferior parietal lobe (IPL), 363 inhibition, 51–2, 249, 250, 255–6 initiation, 250, 250, 256 insomnia, 61, 88, 447 International Classification of Diseases (ICD), 10, 570–2 intraparietal sulcus (IPS), 363 IQ, 90, 156, 170, 193, 197, 577 ischemic penumbra, 73 J jargonaphasia, 204, 289 judgment of line orientation test (JLOT), 373, 376–7, 381, 383 K Kissing and Dancing test, 209–10, 210 Korsakoff syndrome (KS), 49, 162–3, 186, 186, 518 L language acquisition, 72 Alzheimer’s disease and, 560–1 aphasic language disorders and, 55 areas, 67–8, 71, 73–4, 91, 343, 349 -associated disorders, 143–5 bilingualism, 71–3 brain regions and, 55 combinatorial procedures of, 301–2 dementia with Lewy bodies and, 560–1 invariance, 71 and lexical–semantic representations, 300–1 neuroanatomy of, 55, 68, 71, 209–11, 298–301 neuroimaging, 67–74 organization, 279 Parkinson’s disease and, 560–1 perception, 299 phonological representations of, 299–300 plasticity, 71 processing, 69, 73 production, 299 semantic knowledge and, 125–6 sentence comprehension, 71 laterodorsal nuclei, 3–4

INDEX learning algorithms, 35, 60 associative, 6, 8, 353 categories, 125, 131, 232–4 emotional, 52 habit, 150, 232–3 memory and, 120–2 motor, 124, 231–2, 273–4, 277 neurodegenerative diseases and, 559–60 new semantic, 191 procedural, 140 reversal, 36 semantic, 191–2 verbal, 116–17, 120, 121, 577 word list, 151, 515, 522, 537, 539 Lewy bodies 120, 124, 382, 501, 549–50, 550, 551–5 See also dementia with Lewy bodies lexical semantics, 316–17 limbic system, 33, 35–6, 52, 158, 160–1, 161 locus coeruleus (LC), 32, 47 Logical Memory Test, 116, 118 Luria’s hand sequences, 141, 152 Luria’s loops, 143, 145, 151 M magnetic resonance imaging (MRI) 61, 63, 71, 86, 156, 158, 164, 296. See also functional magnetic resonance imaging magnetic resonance perfusion weighted imaging (PWI), 295 magnetoencephalography (MEG), 61–2, 67, 100, 239, 274, 461–2, 464 mammillary bodies, 48–9, 52, 162, 169 mammillothalamic memory system, 49–50 Mattis Dementia Rating Scale, 116, 126, 531 Mayo Clinic Alzheimer’s Disease Patient Registry (ADPR), 502 medulla, 32, 46, 555 Melodic Intonation Therapy (MIT), 73, 303 memory Alzheimer’s disease and, 74, 114, 167, 186, 211, 512, 559–60 anterograde 163, 167, 186, 541 (See also amnesia: anterograde) artistic, 474, 484 autobiographical, 95, 151, 159, 171, 185–97, 195, 493–4, 537 brain regions for, 62 brief vs. extensive loss of, 189 classification, 48–52, 238 color, 479 consolidation, 196

memory (Continued ) declarative 48, 150, 341 (See also memory: episodic; memory: explicit) declining, 76 degenerative diseases and (See specific disorders) emotion processing structures and, 161 episodic, 48–52, 74–7, 84, 88, 99, 114, 119–24, 128, 151, 159, 160, 168, 185, 191, 203, 225, 229, 290, 344, 381, 503, 512, 514, 516–19, 528, 529, 532, 539, 541–2, 560, 577 explicit, 124, 225, 227–8, 231–2 functional imaging of 194–5 (See also neuroimaging) immediate, 144, 150 impairment (See specific disease) implicit, 75, 81, 123, 124, 128, 163, 192, 225–6, 228, 230, 233, 466 infectious processes and, 166–7 long-term, 89, 325 models, 48, 74–5 non-declarative, 48, 150, 151 perceptual memory, 159 primary, 114, 532 procedural, 159, 164, 225, 231–2, 383, 577 processing, 9, 99, 161–2, 165, 168–9, 171–2, 256 recognition, 165, 573, 577 rehabilitation, 353 remote, 49–50, 113, 123, 186, 190–3, 195, 560 retrograde, 189, 197 secondary, 114 semantic, 48–50, 70, 74–5, 115, 120, 122, 125–6, 128, 143, 148, 150–1, 159, 160, 168, 185, 189–92, 213–14, 219, 225, 230, 330–1, 381, 425, 519–20, 531, 541 short term 50, 72, 75, 126, 157, 166, 238, 398 (See also memory: working) spatial, 168, 365–6, 398, 574 systems, 49–50, 75, 159–60, 160, 226, 424 testing, 150 verbal, 49, 62, 140, 274, 347, 433, 504, 539, 560 visual, 151, 410, 424, 474, 477, 574, 576–7 working (WM), 11, 19, 21, 35, 50–1, 69, 72, 75–6, 81, 89–90, 96–9,

INDEX working (WM) (Continued) 113, 115, 120, 126–7, 138, 144, 150, 166, 171, 238–41, 243, 249–50, 250, 251–2, 253, 254–62, 281, 301, 312, 341–2, 346, 349, 351–2, 365, 368, 482, 528, 531, 539, 557–8, 576 mental examination, 140–52 mental retardation, 18, 97 migraine, 170, 276, 429, 436, 443, 479, 484, 574 migraine auras, 484 mild cognitive impairment (MCI) in Alzheimer’s disease, 503, 517–18 amnestic, 500, 501–3, 505 clinical phenotypes of, 501 definition, 85 diagnosis, 500, 500–1, 504, 517–18 functional neuroimaging of, 8–9, 76, 85 history of, 499–500 metabolism, 84 neurological testing in, 89, 518–20 neuropsychology, 11–13, 501–3 non-amnestic, 501, 504 risk factors, 502–6 treatments, 505, 505–6 Mini-Mental State Exam (MMSE), 17, 82, 116, 126, 146, 260, 482, 506, 512, 514–5, 521, 528–31, 533, 540, 557, 559 mixed transcortical aphasia (MTA), 291 Money Road Map Test, 116, 127 monitoring, 250, 251, 255 Montreal Battery of Evaluation of Amusia (MBEA), 462 motivation, 4, 34–5, 41, 53–4, 56, 164, 250, 255–6, 261–2, 556, 576 motor aphasia. See apraxia of speech motor cortex, 46 motor deficits, 365–6 motor learning neuroimaging studies, 232 motor neglect, 359, 361–3 motor perseveration, 143 motor procedural memory, 384 multiple sclerosis (MS), 7, 12, 18, 167, 258, 276, 311 muscarinic receptors, 4–6, 12, 14–15, 17, 21, 99 music absolute pitch and, 464 cognitive models for, 461, 463 emotion and, 464–6 musicians vs. non-musicians and, 464 neurological basis for, 459 perception, 459–64 pitch and melody, 462 reward circuitry and, 465 rhythm and meter, 463–4

music (Continued ) scale and harmony, 462–3 syntax, 463 timbre, 463 musician’s dystonia, 464 myoclonus, 88, 541 N neglect anatomy of, 363–4 auditory, 362 dyslexia, 313, 367 mechanisms, 364–6 nonspatial deficits in, 366 personal, 361–2 representational, 362 right hemisphere and, 361, 363 syndrome, 363–4 tests for, 147 unilateral spatial (USN), 385–6 visual, 359–62, 445, 451, 474–7 nerve growth factor (NGF), 20 nervous system. See specific component Neurobehavioural Rating Scale, 573 neuroeconomics, 80–1 neuroimaging 6–7, 12, 47, 49, 61–2, 67–8, 70, 73–8, 81, 91, 98–9, 171, 194, 230, 232–3, 239, 241, 242, 255, 257, 295, 316, 317, 319, 383, 501, 503, 519, 556. See also diffusion tensor imaging functional magnetic resonance imaging, magnetic resonance imaging, positron emission tomography, single positron emission computed tomography neuromodulators, 13, 94, 98 neurotransmitters, 31, 32 nerve growth factor (NGF), 20 nicotine, 5, 10, 19, 33 nicotinic receptors, 4–6, 10, 12, 14–16, 19, 21 NINDS-AIREN criteria for dementia, 567–8, 571, 572 noradrenaline (NA) 31–3, 36. See also norephinephrine norepinephrine, 19, 31, 35, 37, 98, 243, 261, 262, 304, 466 nucleus accumbens, 4, 32–4, 36, 53–4, 87, 95, 165, 465, 576 nucleus basalis of Meynert (NBM), 2–4, 10, 21, 165, 183, 556 nucleus reticularis, 3, 4, 21 number calculation, 341 form, 342, 350 input/output, 341 mental representations, 341

591 number (Continued ) perseveration, rotation, and closing-in, 386 spatial representation, 342 transcoding, 341 Number Processing and Calculation Battery (NPC), 351–2 O occipital lobes, 48, 139, 477, 479, 570 oculocentric reference frame, 408 olfactory tubercle, 4 optic ataxia (OA) in Balint’s syndrome, 44, 148, 374 definition, 479 movement disorders and, 400, 409 neural basis for, 375, 395, 402–6, 406 parietal lobe function and, 400 perceptual vs. motor deficit in, 409 visual agnosia and, 405, 406 visuoattentional disorders and, 396 visuospatial, 374, 381, 396–7, 403, 404, 408–9 optic chiasm, 42 optic tracts, 42, 477 orbitofrontal cortex (OFC), 3–4, 19, 36, 52–4, 68, 81, 139, 211, 256, 258, 465, 534, 576 organization, 250–1 organ of corti, 44 orthography-to-phonology conversion (OPC), 314–16 out-of-body experience (OBE), 429–30, 431, 433, 434, 435, 438 P Pacinian corpuscles, 46 Papez circuit, 74, 161 parahippocampal cortex, 49, 240 paralexia, 144, 292 paralytic mutism, 275 paraphasia, 300 definition, 55 formal verbal, 288, 300–1, 354 phonemic, 55, 204, 270, 271–2, 288–90, 292, 300–1 semantic, 144, 204–6, 288, 290, 297, 301 parietal lobes, 45, 48, 56, 316, 325, 328, 383, 398–9, 424, 514–15 parkinsonism, 16–17, 86, 549, 550–5 Parkinson’s disease (PD) Alzheimer’s disease and, 551 ANS in, 276 Braak staging, 555, 555 characteristics, 95, 120, 257, 554 cholinergic systems and, 2, 17, 21 cognition and, 120 dementia in, 16, 120, 551

592 Parkinson’s disease (PD) (Continued ) dopamine in, 34, 243 frontal–subcortical circuits in, 556–7 genetics, 97 history, 549–50 learning in, 232 memory and, 167, 121 motor responses, 124, 325 prevalence, 17 treatment, 20, 262 visuoperceptual and spatial functions in, 558 Parkinson’s disease dementia (PDD), 86 pathways from the retina to the striate, 42 pedunculopontine, 3–4, 21 perceptual categorization deficit, 421 perceptual priming, 226–1 performance monitoring, 62, 78, 255 perfusion weighted imaging (PWI), 295, 317, 319 permanent amnesic syndrome, 74 perseverance, 250 personality traits, 96–7, 105–6 phantom limbs, 430, 441, 444 phonemes, 69, 270–1, 276, 279–80, 299, 300–1 phonemic error, 270 phonetic distortion, 270, 271 phonetic encoding, 270, 279, 279–81 phonetic impairment, 270, 275–6, 280–1 phonology-to-orthography conversion (POC), 314–16, 317, 318 physostigmine, 7, 9, 10, 14–15 planning action, 141, 210–11, 216–17, 219 dysfunction, 141–2 as executive function, 250 higher, 138 motor, 51, 68, 269, 281, 312, 365, 375 polymorphism, 13, 97–9, 244 pons, 32, 45, 47, 292 positron emission tomography (PET) 6, 21, 61–7, 76, 80–2, 84–5, 88, 93–4, 96, 99, 100, 462, 505, 506, 514, 556. See also single positron emission computed tomography prefrontal cortex (PFC) activation, 10–12, 76, 79 aging, 113 Alzheimer’s disease and, 519 cognitive function, 36, 54, 76–8, 81, 138, 242–4, 255–6, 472, 494, 532, 576 language and, 69

INDEX prefrontal cortex (PFC) (Continued ) lateral, 78, 240 memory and, 74–6, 96, 191, 239–42, 252, 254–5 neural connections, 4, 35, 239–40, 243, 252–3, 256, 401, 465 organization, 241 in Parkinson’s disease, 555 pharmacology, 3, 34, 37, 62, 98, 243–4, 261 in progressive supranuclear palsy, 542 regulation, 32, 255 in speech, 302 priming completion, 123–4 conceptual, 227–31 dementia and, 229–30 impaired, 124, 231 implicit, 123 neural basis of, 230–1 perceptual, 226–31 semantic, 208, 212–13 verbal, 532 prion diseases, 88–9 progressive nonfluent aphasic syndrome (PNFA), 535–6, 539 progressive supranuclear palsy (PSP), 126, 257, 518, 541–2 Promoting Aphasics Communication Effectiveness (PACE), 303 prosopagnosia, 43, 139, 149–50, 213, 420, 421, 424, 425 pseudobulbar palsy, 573 psychopaths, 54, 80 putamen, 4, 75, 86, 95–6, 120, 289, 292, 556 Pyramids and Palm Trees Test, 209, 210, 214, 219, 426, 532, 539 Q quantitative magnitude representation impairment, 345–6 R radiotracer chemistry, 92, 94 reading cognition and, 312, 312 functional imaging studies of, 314 modality-specific representations for, 316–18 models, 313 neural substrate, 313–18 spelling and, 319 See also language reasoning, 79, 113, 259 Receiver Operating Characteristic (ROC), 116–17, 117 regional cerebral blood flow (rCBF), 9, 10, 19, 65, 73, 86 Remote Memory battery, 123

remote memory curves, 186 repetitive transcranial magnetic stimulation (rTMS), 95 resistance to interference, 250, 250 retina, 42–3, 365, 477 reversal-learning paradigm, 36 reward circuitry, 465 Rey complex figure, 146, 379, 386 Rey-Osterreith Complex Figure (ROCF), 376, 380–2, 384 rivastigmine, 7, 12, 14–19, 262, 505–6, 558–9 S schizophrenia, 13, 18, 34–7, 94, 162, 245, 258, 429, 443, 446–7, 541 scopolamine, 4, 6, 7–9, 94 semantic dementia Alzheimer’s disease and, 301 brain blood flow in, 87 clinical features, 536, 536–8 cognition in, 86, 229–30, 342, 472 diagnosis, 211, 218 frontotemporal dementia and, 257 (See also frontotemporal dementia) frontotemporal lobar dementia and 229, 527 (See also frontotemporal dementia) imaging, 540 memory in, 50, 190–2, 196, 203, 210 neural basis for, 50, 88, 190, 213, 219 personality in, 533–4 symptoms, 229 semantic–lexical disturbances, 74, 115, 204, 205–7, 217–18, 218 semantic network, 126, 214 sensory processing and cognition, 41–7 septohippocampus, 10, 13, 48–50 serial 7s test, 141 serotonin (5-HT), 31, 35–7, 97–8, 243, 553 set-shifting, 250–1 7-Minute Screen, 521 Short Test of Mental Status, 502 simple logical sequences test, 142 simultanagnosia, 374, 381, 479 single positron emission computed tomography (SPECT) 61–4, 82, 85–7, 94, 99, 164. See also positron emission tomography sleep behavior disorder, 18, 551, 553 small vessel disease, 258, 512, 574, 578 sociopathic behavior, 80 somatic sensory information processing, 46

INDEX somatoparaphrenia, 443–8 somatosensory cortex, 46–7 somatosensory processing, 46–7 Spatial Numerical Association of Response Codes, 342 speech acquired neurogenic stuttering in (ANS), 276 communicative gestures in, 327 disorders, 143, 151 localization, 328 motor programming, 280 processing, 461 spelling and, 318. See also language spinal cord, 20, 41 somatosensory cortex (SSC), 46–7 statistical parametric mapping (SPM), 64–5, 65, 82, 86–7, 92–3, 96, 98 stroke acute, 173, 221, 295, 297, 315–18, 359 chronic, 295, 297, 314–16 circle of Willis and, 576 cognitive impairment and, 574 dementia and, 568–9 hemisphere, 271, 314, 350, 473–4, 475, 476 medial cerebral artery (MCA), 274, 363 parietal stroke, 365 silent, 574 subcortical, 573–4 temporoparietal, 146 thalmic, 165, 297, 570, 574 Stroop paradigm, 142 subcortical ischemic vascular disease (SIVD), 570, 573–8 substantia nigra, 4, 21, 33, 120, 240, 257, 550, 553–6, 576 superior parietal lobe (SPL), 363 supervisory attentional system (SAS), 252 systemic lupus erythematosus (SLE), 258 systemic vascular disease, 569 T tacrine, 14, 17–18 tau protein, 85, 88 tegmentum, 2, 3, 555 temporal lobe lesions, 187–8, 198 thalamus anterior, 162 aphasia and, 293 circulation, 576 cognitive functions, 88 damage, 137 dementia, 163, 167

thalamus (Continued ) executive functions and, 52, 98, 252, 496 genes and, 98 infarcts, 165, 297, 570, 574 lesions, 573 mediodorsal, 3–4, 21, 34, 159, 165 memory and, 48, 49, 161, 166 metabolism, 82, 87, 89, 171 neglect and, 363 neural connections, 2–4, 32–3, 41–2, 44–7, 120, 139, 240, 254, 256, 576 opiod receptors, 95 role in ANS, 276 sound perception and, 461 Theory of Mind (ToM), 533 tool and object use, 329 topographagnosia, 139, 147, 150 Trail Making Test, 116, 502, 512, 514–15 transcoding, 353–4 transcortical motor aphasia (TCMA), 203–4, 206, 290–1, 293, 297, 302 transcortical sensory aphasia (TCSA), 290–1, 293–4, 304 transcranial magnetic stimulation (TMS), 62 U ultimatum game, 81 Unilateral Spatial Neglect (USN), 385–6 Urbach–Wiethe disease, 168, 168 V vascular aphasia, 73 vascular cognitive disorder (VCD), 571, 571–2 vascular cognitive impairment (VCI), 571, 572 vascular dementia (VaD) cholinergic system in, 2, 15, 21 classification, 15–16, 572 cognition in, 387 comorbidities, 574–5 diagnosis, 541, 543, 570–1, 571, 572–3, 578 frontal lobe system impairment and, 577 functional neuroimaging of, 88 gene therapy for, 20 ischemic, 571 mechanisms, 568–70 memory and, 504 mixed, 568 neuroimaging, 88 prevalence, 567–8, 570 progression from MCI, 504

593 vascular dementia (VaD) (Continued ) subcortical ischemic vascular disease and, 573–4 subtypes, 568–70 ventral pallidum, 4, 164 ventral stream, 43, 210, 216, 313, 375, 383, 400, 405–6, 477–9 ventral striatum, 4, 21, 34, 36, 53, 87, 96, 465 ventral tegmental area (VTA), 33, 261, 465 verbal fluency, 17, 87, 113, 115, 125–6, 142, 144, 259, 381, 512–14, 519, 528, 531–2, 533, 557–8, 560–1, 577–8 vestibular processing, 431, 436, 438, 441 visual agnosia apperceptive, 139, 148, 421 classification, 417 clinical assessment, 418–19, 424–6, 374, 478 definition, 43 neuropathology of, 423, 423–4 object, 291 optic ataxia and, 405 ventral stream and 400, 477, See also perceptual categorization deficit; prosopagnosia; simultanagnosia visual cortex, 4, 7, 9–10, 42, 42, 86, 239, 401, 421, 422, 477 visual extinction, 362 visual imagery, 147, 191–2, 383–4, 477–9 visual neglect, 359–61 Visual Object and Space Perception Battery (VOSP), 373, 375, 381, 426, 531, 531 visual processing, 41–4, 53, 86, 128, 210, 216–19, 254, 313, 345, 364, 374, 396–7, 400, 402, 417, 421, 435, 438, 478 visual recognition disorders, 148, 149 Visual Reproduction Test, 116, 118 visual-to-motor network, 401 visuoconstructional disturbances, 375–6 visuospatial assessment, 373 visuospatial disorders, 127, 139, 145–8, 359–61, 373–5, 377, 381, 445, 451, 474–7, 558, 376–80 W Wechsler Memory Scale-Revised, 115, 126, 425, 560, 576 Wernicke, Carl 55, 69 Wernicke’s aphasia, 55, 204, 275, 289–90, 292, 295, 297–8, 345, 347–8 Wernicke’s area, 45, 70, 73, 296–8, 316

594 white matter aging and, 113, 567 apraxia of speech and, 272–3 dementia and, 88, 91, 575 development, 90 diffusion abnormality in, 296 diseases and, 258

INDEX white matter (Continued ) executive dysfunction and, 258, 575 ischemia, 569, 579 lesions, 88, 258, 273, 386, 423, 424, 567, 570–1, 573–5, 578 metabolic rate, 81

white matter (Continued ) tracts, 113, 257–8, 464 Williams syndrome, 97, 459 Wisconsin Card Sorting Test (WCST), 115, 127, 255, 531, 577