Exploring Brain Functional Anatomy with Positron Tomography - Symposium No. 163

EXPLORING BRAIN FUNCTIONAL ANATOMY WITH POSITRON TOMOGRAPHY

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Ciba Foundation Symposium 163

EXPLORING BRAIN FUNCTIONAL ANATOMY WITH POSITRON TOMOGRAPHY A Wiley-Interscience Publication

1991

JOHN WlLEY & SONS Chichester

. New York

. Brisbane

. Toronto . Singapore

OCiba Foundation 1991 Published in 1991 by John Wiley & Sons Ltd. Baffins Lane, Chichester West Sussex PO19 IUD,England All rights reserved. No part of this book may be reproduced by any means, or transmitted, or translated into a machine language without the written permission of the publisher.

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Library of Congress Cataloging-in-PublicationData Exploring brain functional anatomy with positron tomography. p. cm.-(Ciba Foundation symposium; 163) Editors: Derek J. Chadwick (organizer) and Julie Whelan. “Symposium on Exploring Brain Functional Anatomy with Positron Tomography, held at the Ciba Foundation, London, 12-14 March 1991”Contents p. “A Wiley-Interscience Publication.” Includes bibliographical references and indexes. ISBN 0 471 92970 0 1. Brain-Tomography-Congresses. 2. Brain-MetabolismCongresses. 3. Cerebral circulation-Congresses. 1. Chadwick, Derek. 11. Whelan, Julie. 111. Symposium on Exploring Brain Functional Anatomy with Positron Tomography (1991: Ciba Foundation) IV. Series. 1DNLM: 1. Brain-metabolism-congresses. 2. Brain-radionuclide imaging-congresses. 3. Tomography, Emission-Computed-congresses. W3 C161F v. 163/WL 141 E96] QP376.E93 1991 612.8 ’ 2-dc20 DNLM/DLC 91-40214 for Library of Congress ClP British Library Cataloguing in Publication Duta A catalogue record for this book is available from the British Library ISBN 0 471 92970 0 Phototypeset by Dobbie Typesetting Limited, Tavistock, Devon. Printed and bound in Great Britain by Biddles Ltd., Guildford.

Contents Symposium on Exploring Brain Functional Anatomy with Positron Tomography, held at the Ciba Foundation, London 12-14 March 1991 The topic of the symposium was proposed by Professor Richard Frackowiak Editors: Derek J. Chadwick (Organizer) and Julie Whelan R. Porter Introduction

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R. C. Collins* Basic aspects of functional brain metabolism Discussion 16

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H. Iida, I. Kanno and S. Miura Rapid measurement of cerebral blood flow with positron emission tomography 23 Discussion 37 General discussion Brain energy metabolism: cell body or synapse? Oxidative metabolism in brain 5 1

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D. W. Townsend Optimization of signal in positron emission tomography scans: present and future developments 57 Discussion 69 K. J. Friston, P. M. Grasby, C. D. Frith, C. J. Bench, R. J. Dolan, P. J. Cowen, P. F. Liddle and R. S. J. Frackowiak The neurotransmitter basis of cognition: psychopharmacological activation studies 76 Discussion 87 J. C. Mazziotta, D. Valentino, S. Grafton, F. Bookktein, C. Pelizzari, G. Chen and A. W. Toga Relating structure to function in vivo with tomographic imaging 93 Discussion 101 *In Professor Collins’ unavoidable absence his paper was presented by Professor John Mazziotta. V

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P. E. Roland and R. J. Seitz Positron emission tomography studies of the somatosensory system in man 113 Discussion 120 P. T. Fox and J. V. Pardo Does inter-subject variability in cortical functional organization increase with neural ‘distance’ from the periphery? 125 Discussion 140

S. Zeki A thought experiment with positron emission tomography 145 Discussion 154 M. Corbetta, F. M. Miezin, G. L. Shulman and S. E. Petersen Selective attention modulates extrastriate visual regions in humans during visual feature discrimination and recognition 165 Discussion 175 C. D. Frith Positron emission tomography studies of frontal lobe function: relevance to psychiatric disease 181 Discussion 191 M. E. Raichle Memory mechanisms in the processing of words and wordlike symbols 198 Discussion 204

R. J. Wise, U. Hadar, D. Howard and K. Patterson Language activation studies with positron emission tomography 218 Discussion 228

R. S. J. Frackowiak, C. Weiller and F. Chollet The functional anatomy of recovery from brain injury 235 Discussion 244

J. C. Baron Testing cerebral function: will it help the understanding or diagnosis of central nervous system disease? 250 Discussion 26 1

Final general discussion 265

R. Porter Summing-up 275 Index of contributors 278 Subject index 280

Participants J. C. Baron Centre Cyceron, INSERM U. 320, BP 5027, Bd Henri Becquerel, F-14021 Caen Cedex, France S. F. Cappa Clinica Neurologica, Universita di Brescia, Neurologia I1 Spedali Civili, Piazzale Ospedale 1, 1-25125 Brescia, Italy

F. Chollet Department of Neurology, HBpital Purpan, F-31059 Toulouse, France R. C. Collins* UCLA Department of Neurology, Reed Neurological Research Center, 710 Westwood Plaza, Los Angeles, CA 90024-1769, USA M. Corbetta Department o f Neurology & Neurological Surgery, Washington University School of Medicine, Box 81 11, 660 South Euclid Avenue, St Louis, MO 63110, USA

A. C. Evans Positron Imaging Laboratories, McConnell Brain Imaging Centre, Montreal Neurological Hospital & Institute, 3801 University Street, Montreal, Quebec, Canada H3A 2B4

P. T. Fox Research Imaging Center, The University of Texas Health

Science Center, 7703 Floyd Curl Drive, San Antonio, TX 78284-7800, USA

R. S. J. Frackowiak MRC Cyclotron Unit, Hammersmith Hospital, Ducane Road, London W12 OHS, UK K. J. Friston** MRC Cyclotron Unit, Hammersmith Hospital, Ducane Road, London W12 OHS, UK *Professor Collins was unable to attend the symposium. His paper was presented by Professor Mazziotta. **Present address: Neurosciences Institute, 1230 York Avenue, New York, NY 100021, USA. vii

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Participants

C. D. Frith Division of Psychiatry, Clinical Research Centre, Watford Road, Harrow, Middlesex, HA1 3UJ, UK B. Gulyas Department of Clinical Neurophysiology, Karolinska Hospital, Box 60500, S-104 01 Stockholm 60, Sweden

H. Iida Research Institute of Brain & Blood Vessels, Senshu-KubotaMachi, Akita City 010, Japan M. Jeannerod Vision et Motricitt, INSERM U. 94, 16 Avenue du Doyen LCpine, F-69500 Bron, France

T. Jones PET Methods Section, MRC Cyclotron Unit, Hammersmith Hospital, Ducane Road, London W12 OHS, UK N. A. Lassen Department of Clinical PhysiologicaVNuclear Medicine, Bispebjerg Hospital, Bispebjerg Bakke 23, DK-2400 Copenhagen NV, Denmark E. T. MacKenzie Centre Cyceron. INSERM U. 320, BP 5027, Bd Henri Becquerel, F- 14021 Caen Cedex, France

J. C. Mazziotta Department of Neurology, UCLA School of Medicine, University of California, Los Angeles, CA 90024-1769, USA R. E. Passingham Department of Experimental Psychology, University of Oxford, South Parks Road, Oxford OX1 3UD, UK F. Plum Department of Neurology, The New York Hospital-Cornell Medical Center, 525 East 68th Street, New York, NY 10021, USA R. Porter (Chairman) Faculty of Medicine, Monash University, Clayton, Melbourne, Victoria 3168, Australia

M. E. Raichle Division of Radiation Sciences, Edward Mallinckrodt Institute of Radiology, Washington University School of Medicine, St Louis, MO 63110, USA P. E. Roland Department of Clinical Neurophysiology, Karolinska Hospital, Box 60500, S-104 01 Stockholm 60, Sweden L. Sokoloff Laboratory for Cerebral Metabolism, National Institute of Mental Health, Building 36, Room lAO5, National Institutes of Health, Bethesda, MD 20892, USA

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D. W. Townsend Division of Nuclear Medicine, HBpital Cantonal, University of Geneva, CH-1211 Geneva 4, Switzerland E. K. Warrington Department of Clinical Neuropsychology, The National Hospital, Queen Square, London WClN 3BG, UK R. J. Wise PET Clinical Group, Westminster & Charing Cross Hospital, Reynolds Building, St Dunstan’s Road, London W6 8RP, UK S. Zeki Department of Anatomy and Developmental Biology, University College London, Gower Street, London WClE 6BT, UK

Introduction Robert Porter Faculty of Medicine, Monash University, Clayton, Melbourne, Victoria 3 168, Australia

Historically, the exploration of brain functional anatomy has used the methods of clinicopathological correlation. Enormous difficulties and great uncertainty surround the interpretation of the signs and symptoms which seem t o be associated with damage or disease of localized brain regions. Broca’s contribution established the fact of anatomical localization of function within the cerebral cortex in 1861, even though, as Marie later demonstrated, his description of the extent of the lesion in his aphasic patient was incomplete. Hughlings Jackson’s studies of patients with partial epileptic seizures led him to draw conclusions about the structural organization of motor functions within the cerebral cortex which were soon shown to exist in the living, normal brain, when electrical stimulation of the cerebral cortex revealed the ordered nature of the functional representation of movement. Foerster, already a respected clinical neurologist, began to perform neurosurgical operations in the early 1920s. In the process of providing treatment for his patients, he seems to have regarded each operation as a n opportunity to conduct a physiological experiment and to study functional anatomy. Many of his observations on the interpretation of these experiments and his conclusions about the functions of different regions of the cerebral cortex in movement performance, deduced from both stimulation and ablation experiments, are summarized in his Hughlings Jackson lecture in 1935. From this work and from the observations of Penfield and his co-workers, who utilized the opportunity provided by operative excision of cerebral tumours, vascular malformations, or epileptic foci, to stimulate the exposed surface of the cerebral cortex electrically in conscious patients and to record the resulting effects in elaborate detail, have come most of our general views of human brain functional anatomy (Fig. 1). Almost all of this information relates to surface topography: the surface of the brain has been the only part accessible both to the surgeon’s scalpel and to his stimulating electrode. Moreover, and creating a problem for those developing theories of functional anatomy, some influence of the fact that the subjects were all suffering disorders which required surgical intervention could have distorted the findings towards those created by pathology rather than to observations about normal physiology. Even the earlier methods of study of regional cerebral blood flow, which could be applied to normal human subjects, 1

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FIG. 1. Schematic diagram of the functional anatomy of the human brain, as depicted in summarizing the observations of Penfield & Boldrey (1937). (Reproduced with permission of Macmillan Publishing Company from The cerebral cortex of man by Penfield & Rasmussen. Copyright 1950 Macmillan Publishing Company; copyright renewed 01978 Theodore Rasmussen.)

allowed information about the flow through only the most superficial structures to be used as a gauge of increased or decreased local metabolism, resulting from more, or less, functional neuronal and synaptic activity in the region. Positron emission tomography (PET), whether used to study regional cerebral blood flow or to examine directly the regional metabolism or transmitter turnover of the brain, can, by its very nature, allow deep as well as superficial regions of the brain to be examined. Methods of illustrating blood flow or metabolism in these deep structures have been developed which allow tomographic sections to be constructed by computer and to reveal functional activities in deep, previously hidden regions. Yet we shall still need to validate the precise relationships between oxygen consumption, glucose metabolism, blood flow changes and neuronal interactions which describe these phenomena quantitatively (Fig. 2).

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NERVE SIGNAL TRANSMISSION

FIG. 2. This schematic diagram illustrates the deductive steps that are involved in interpreting changes in glucose metabolism or blood flow as modifications of neuronal activity which must have occurred in regions of the brain. Although oxygen consumption and blood flow are linked, the temporal relationships between changes in these following alterations in nerve signal transmission are poorly understood, and the precise neurophysiologicalcauses of the energy debt, and such things as the quantitative metabolic costs of excitation and inhibition at synapses, are still debated.

How has the evidence obtained with these new techniques, in normal human subjects and in those with disordered brain function, advanced our knowledge of the functional anatomy of the human brain? Which aspects of any global neuronal function, that can be separately described, are in fact localized, where are these localized, and what are the biochemical mechanisms used for that localization? That is what we are here to discuss. However, we shall also have to attempt to evaluate the techniques themselves, to examine the influence of the methods used on the functional anatomical information that they make available to us. Have we significantly advanced our knowledge beyond that

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available from the results of electrical stimulation or other studies? What are the limitations of the techniques? What is the spatial resolution of the method of measurement and does this vary with the different positron emitters that are used to probe different metabolic events? How could spatial resolution be improved? A major problem for the study of analysable function has been the temporal resolution of all our methods of studying the human brain, apart from the realtime measures of electrical or magnetic changes produced by the nervous tissue itself during the performance of that function. Can the real-time evaluation of function be analysed, using modifications of PET, and what are the approaches that could be adopted to relate changing metabolic events directly, and temporally, to functional states, even while these are occurring? A part of the programme of this symposium must deal with the technique itself and with the sophisticated computer manipulation of measures of the coincidence of events. But the several brain functions, to the study of which the method is applied, also need our consideration. Some of those functions are ones in which there is an opportunity to control the stimulus and to analyse the details of the response. Human vision is a case in point. Already we know a great deal about the functional anatomy and the psychophysics of vision. In relation to other aspects of human brain function we have less ability to control the physiological events whose underlying regional metabolic changes we wish to analyse. Learning and memory and language are cases in point. It is surely to address these more complex questions that we need to apply new research tools, and we should not be daunted by the difficulties of interpreting the results of our studies. Finally, is there a clinical role for these investigations in the understanding of disorder in the human brain, and what is the role of PET in diagnosis? Are there examples, other than the localization of a difficult-to-detect epileptic focus, of the application of PET in patient management? We shall hear about the role of PET in following recovery from brain injury and in assessing frontal lobe function with relevance to psychiatric illness. Is this an indication that the routine monitoring of brain status in some clinical conditions may employ these methods in the future? As a neurophysiologist, I shall be interested to learn whether we have evidence of changes in regional function during development, as learned patterns of behaviour are established; or as the nervous system ages and the functional capacities of the human brain decline. Where do these changes during development or during ageing manifest themselves, and what is their biochemical basis? At this exciting stage of the development of this technique and its applications, the questions that can be raised outnumber the answers that have yet been provided. At this symposium, however, we have the opportunity to exchange views on the latest evidence that is available, to speculate on its meaning, and to project our thinking into the future and into the unknown.

Introduction

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References Penfield W, Boldrey E 1937 Somatic motor and sensory representation in the cerebral cortex of man as studied by electrical stimulation. Brain 60:389-443 Penfield W, Rasmussen AT 1950 The cerebral cortex of man. A clinical study of localisation of function. Macmillan, New York

Basic aspects of functional brain metabolism Robert C. Collins

Department of Neurologyp Reed Neurological Research Center, UCLA School of Medicine, Los Angeles, CA 90024, USA

Abstract. Brain energy metabolism and blood flow are greatest in neuropil where there is a high density of oxidative enzymes and capillaries. Here fluctuations in synaptic potentials cause the greatest demand on metabolism through the continuous need to pump ions to maintain membrane charge. A transient increase in functional activity within a pathway causes an increase in energy metabolism followed by an increase in blood flow. The vascular response is biphasic, with an initial increase followed by a plateau phase. The site and magnitude of the response reflect the quality and intensity of the stimulus. Prolonged changes in functional activity within a pathway cause a reorganization of energy metabolizing

enzymes and vascular architecture.

1991 Exploring brain functional anatomy with positron tomography. Wiley, Chichester (Ciba Foundation Symposium 163) p 6-22

The last several years have witnessed important advances in the use of positron emission tomography for the study of functional anatomy in humans. New techniques and experimental strategies can now provide partial localization of simple and complex sensory processing (Fox et a1 1987a,b, Lueck et a1 1989), aspects of language (Petersen et a1 1988, 1990) and selected cognitive functions (Posner et a1 1988, Pardo et a1 1991). This progress has largely come from improvement in temporal resolution, which means that it is now possible to study blood flow changes in brain functional activity in time windows of 40 seconds (Raichle et a1 1983). In addition, improvements in tomographic design now permit studies of glucose utilization in small zones and structures in brain, such as the superior colliculus and the cerebellar dentate nucleus (Spinks et a1 1988). Finally, advances in image analysis have allowed subtraction of one image from another-permitting the subtraction of different behavioural states from each other (Fox et a1 1988). This has allowed the separation of experimental states from control conditions, as well as the localization of more complex brain functions either ‘parallel’ to simple functions, or in a hierarchical relation to them. The studies underlying these advances are the subject of this symposium. 6

Functional brain metabolism

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TABLE 1 Experimental approaches to functional anatomy ~

Technique

Species

Lesion analysis

Humans and Loss of behaviour after damage to a site animals indicates its contribution to the missing

The epileptic focus

The stimulating electrode The recording electrode

Metabolic mapping

Function

behaviour Focal seizures crudely evoke the functional properties of a site and its circuits Animals The evoked behaviour reveals the functional properties of the stimulated site and its circuits (primarily motor system) Changes in neuronal firing, linked to Animals receptive field stimuli or movement, localize sites and patterns of functional organization Humans and Regional changes in blood flow and energy metabolism localize sites of animals physiological activation Humans

Definitions of functional anatomy are highly dependent on the method of analysis (Table 1). Ultimately there must be some congruence between the various approaches to determining the brain sites and systems activated during selected behaviours. Congruence is high for simple behaviours; for example, all methods agree on the localization of primary visual cortex. The identification of distributed systems underlying complex behaviours will require comparison of results obtained using many different procedures. It is important to define how each method is limited by the sensitivity and capacity of its measurements, if we are to identify false negatives and positives. In order to understand these issues for metabolic mapping it is necessary to appreciate basic aspects of the anatomy, physiology and biochemistry that underlie functional brain changes.

Functional architecture of brain The distribution of blood vessels throughout the brain follows a few common principles of design (Bar 1980). For laminated structures like cerebral cortex, hippocampus and the olfactory bulb, surface arteries break up into arterioles that penetrate at right-angles into the brain. The distribution of penetrating arterioles is non-random on cerebral cortex and reflects functional organization, such as the whisker fields in the rodent’s somatosensory cortex (Pate1 1983). Feeding capillaries branch off from the penetrating arterioles to supply capillary networks within horizontal laminae. The penetrating arterioles lie in register with the vertical orientation of ascending cortical dendrites, whereas capillary

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networks become differentially distributed to supply functional subspecializations along or within horizontal laminae. The variation in capillary density throughout brain shows a high correlation ( r = 0.88, P 0.001 has been excluded). To the right of the SPM projections the results have also been displayed on drawings of the medial (upper two of four) and lateral (lower two of four) aspects of each hemisphere.

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St Louis group acknowledge in a later publication (Petersen et al 1990), and therefore if left PSTG is part of the semantic system it may not be revealed in a comparison of two tasks that both involve the semantic system. There is also the question of what influence articulation has on the subject’s own auditory cortex. The St Louis study gives some intriguing information on this point. In one comparison, silent inspection of a list of words was compared with reading the list aloud. Reading aloud activated output structures, such as SMA and primary sensorimotor cortex, but apparently there was no significant increase of rCBF in auditory cortex-despite the fact that when reading aloud the subjects were hearing their own voices at the brisk rate of 60 words per minute. This suggests an attentional mechanism whereby the response of the auditory cortex, at least in terms of increased rCBF, is present when the speech input is ‘other’ and absent when the voice is ‘own’. The signal from a PET study is the net change in rCBF in response to a task. An interaction in a region whereby one aspect of the task, such as comprehending a spoken word, increases rCBF while another, such as turning the attention of the auditory cortex away from one’s own voice, suppresses rCBF in a closely related region may result in an apparent lack of activation, although in reality there is a complex interplay of different neural influences. We have observed selective activation of left PSTG in other tasks. Reading aloud lists of concrete and abstract words was compared with the control state of seeing nonsense font and saying the same word in response to each stimulus. Although the subjects were reading different words in the active state and simply saying the same word over and over again in the control state, the neural networks responsible for articulation were similarly activated, and there were no significant differences between task and control in anterior structures. The only significant difference in posterior structures was activation of left PSTG in response to reading aloud real words. A very similar result was seen when the subjects repeated aloud concrete and abstract words that they heard, compared to hearing reversed words. Our results suggest a central role for left PSTG in single-word tasks. If we refer to a simple model of single-word comprehension and production (Fig. 2), is it possible to identify this process? In doing so, we shall have to explain why the St Louis group did not activate the left PSTG in many of their single-word tasks. Both groups have used reading and repeating words aloud as activation tasks, but with different ends in mind, and this is reflected in the difference in the control states. Neural networks associated with articulation were identified in the St Louis design; reading and repeating aloud real words were compared to seeing and hearing real words without the subjects speaking. However, the obvious difference between task and control in our study was that the stimuli were meaningful in the activation tasks compared to the controls (reading and repeating real words compared with seeing nonsense font and hearing reversed words, with vocalization during the control states). If we combine these results

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I I I I I I I

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FIG. 2. A simple model of single-word processing adapted from Ellis & Young (1988). After early acoustic analysis of a heard word the appropriate information is passed to the auditory input lexicon, the site of encoded entries for familiar words (the visual input lexicon performs the same function for read words). Subsequent activation of the appropriate entry in the semantic system makes the meaning of the word apparent to the subject. The speech output lexicon is the word-form store for familiar spoken words, and it may not be separable from the auditory input lexicon (indicated by the enclosing box). Although there are three routes by which either a heard or read word can be spoken (a route for direct grapheme-to-phoneme conversion is not depicted in the diagram), we consider that the evidence in the neuropsychological literature supports the notion that hearing or reading a familiar word will normally automatically activate its entry in the semantic system. The study of Petersen et a1 (1988) suggests that monitoring of one's own speech after articulation (dashed line) does not normally occur.

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with the involvement of left PSTG during silent verb retrieval, and the lack of involvement of regions outside the STG in the category judgement tasks, can we assume that left PSTG is part of the neural network which makes up the semantic system? There are a number of reasons for thinking that this has not been established on the data available. This region could be acting as the speech output lexicon (the word-form system for speech output) in a number of the tasks (including silent verb generation, because, as previously discussed, networks involved in speech output are activated by this task). In Fig. 2, the auditory input and speech output lexicons are depicted as separate processors, but some consider that these are a single entity (Allport & Funnel1 1981), and therefore one possibility is that left PSTG acts as the input lexicon when hearing words and as the output lexicon during preparation for articulation. One argument against this is that because left PSTG was not activated in the comparison of reading aloud versus reading silently in the St Louis study, the speech output lexicon must be in one of the anterior regions that were activated in this comparison (although we have already alluded to the possible masking influence that ‘own’ voice may have on rCBF in the PSTG, and such an effect will have to be excluded in a future study before we can rule out left PSTG as the site of the speech output lexicon). A further explanation for the number of tasks that have elicited a left PSTG response in our series of studies is the activation of verbal short-term memory. Paying attention to any single-word task will automatically involve short-term memory. Patients with impairment of auditory verbal short-term memory have lesions involving the left superior temporal region (Warrington et a1 1971). Although the memory trace may only last a few seconds, there is the implication that this trace represents continuous neural activity over this time period, with renewal of activity each time a new stimulus is presented. Whether the neural pathways responsible for verbal short-term memory are separable from those involved with auditory or visual encodement of phonemes or graphemes is another issue, one that cannot be revealed by a PET study because the memory trace is dependent on the subject perceiving a spoken or written word. Studies on single patients We have only very limited information from patient studies to date, although we are hopeful that these will give insight into the functional recovery of language after focal cerebral injury, such as infarction. Ideally, each range of activation tasks should be tailored to a particular patient’s deficits, but this raises a major practical problem. If we are to see which regions, outside the site of injury, are being activated abnormally, the patient has to be compared to a group of normals: after anatomical standardization and normalization of global CBF across patient and subjects, each pixel of patient data is compared with the scatter of values from the same pixel in normals, and the results are displayed as the

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regions where rCBF in the patient is significantly different from the normal range. The power of such a test clearly increases with the number of normal subjects studied, which raises the spectre of gathering data on about one dozen normal subjects for each patient studied. Currently, we are pursuing two possible solutions. The first is to study a number of aphasic patients, with a range of deficits that have recovered to a variable degree with time after the onset of symptoms, with ‘off-the-peg’ activation tasks on which we already have normal data. This approach is based on the knowledge that our range of tasks covers a large number of anterior and posterior regions that are known to be the common sites of lesions in aphasic patients. So, for instance, we can look at verb generation in a patient with a left posterior frontal infarct; we know that left DLPFC is normally used in the task, therefore we can investigate when abnormal activation patterns, possibly compensatory, occur in the patient. This might be termed the neurological approach. The alternative has been to identify a particular group of patients with a well-defined aphasic or alexic syndrome and collect normal data for that group. We still do not group the patient data in analysis, because no two patients are exactly alike in terms of the details of their behavioural deficits, and we have no apriori evidence for thinking that the attempts by the patients to overcome their deficits rely on the same neural networks. This is a more neuropsychological approach. We are beginning to see results. As an example, we have studied one patient with deep dyslexia in whom the whole of the left middle cerebral artery territory had become infarcted (flow 410 m1/100 ml per min). Deep dyslexia is an acquired disorder, with a number of features which include semantic errors during reading, e.g. reading ‘street’ as ‘avenue’, a wrong word with similar meaning, and a relatively preserved ability to read concrete words, e.g. ‘comb’ or ‘train’, compared to abstract words, e.g. ‘faith or charity’ (see Shallice 1988). Our activation tasks were designed to investigate the dissociation between this patient’s reading of concrete and abstract words. In the three tasks of seeing nonsense font, reading abstract words and reading concrete words, the patient showed increased blood rCBF in right extrastriate cortex and right inferior temporal gyrus compared to twelve normal subjects. This presumably reflects the greater degree of early visual processing of the letter or letter-like strings in the right hemisphere as a result of the devastation of most of the left hemisphere. There were no additional right hemisphere regions activated by reading abstract words compared to ‘reading’ nonsense font, but reading concrete words produced additional activation in right thalamus and right frontal cortex. Analysis on the data from further patients with deep dyslexia is currently being undertaken to see whether this result is found in other patients. Concluding remarks

It is apparent that language tasks readily produce measurable changes in rCBF

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on PET images of the brain, but it is a different matter to relate these regional changes to specific subcomponents of sophisticated information-processing models of language. The design of activation and control tasks is a matter of very fine judgement, and even then the investigator may be defeated by neural networks that overlap, and by conflicting influences on rCBF within one resolvable region. There is also the considerable problem of conservative statistics. The analysis of PET activation images can be likened to looking at a range of mountains beyond a forest. The high peaks are easily seen, and the observer might suppose that these are the only mountains in the region. However, if the observer is aware that mountain peaks are frequently topped by clouds, he may guess that distant clouds visible above the tree-tops may indicate the presence of other peaks too low to be visible-trends of increase in rCBF that fail to reach statistical significance, especially when the number of subjects studied is small, may indicate other cortical regions involved in the language task under investigation. Of course, the observer will remain completely unaware of many of the lower peaks uncapped by clouds while he stays on the wrong side of the forest, but, as the forest in this analogy is the noise inherent in the technique of PET, we shall always stand behind a forest that partially obscures our view. We can only hope for new techniques that will lop some of the height off the trees, but inevitably any PET activation study is going to underestimate the distribution of neural networks engaged by a task. It is only right that we should view with scepticism any attempt, on the basis of a significant blob on a PET scan, to constrain a complex mental process to one small brain region. There is one further important caveat in relation to studies when there is cerebral pathology present. We are using an indirect marker (rCBF) of neural activity, and the ability of the resistance blood vessels to respond normally to physiological stimuli such as increased neural activity may be attenuated after brain injury. Therefore, an absence of signal, particularly in the hemisphere ipsilateral to a large, recent focal injury, does not mean that there is not increased neural activity in partially damaged or undamaged regions of that hemisphere.

Acknowledgements We wish to thank the members of the PET Methods and Radiochemistry Sections of the MRC Cyclotron Unit, without whom our studies would not have been possible.

References Allport DA, Funnel1 E 1981 Speech production and comprehension: one lexicon or two? Philos Trans R SOCLond B Biol Sci 295:397-410 Ellis AW, Young AW 1988 Human cognitive neuropsychology. Lawrence Erlbaum Associates, Hove, UK Fox PT, Perlmutter JS, Raichle ME 1985 A stereotactic method of anatomical localization for positron emission tomography. J Comput Assisted Tomogr 9:141-153 Fox PT, Mintun MA, Reiman EM, Raichle ME 1988 Enhanced detection of focal brain responses using intersubject averaging and change-distribution analysis of subtracted PET images. J Cereb Blood Flow Metab 8:642-653

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Friston KJ, Passingham RE, Nutt JC, Heather JD, Sawle GV, Frackowiak RSJ 1989 Localization in PET images: direct fitting of the intercommissural line (AC-PC) line. J Cereb Blood Flow Metab 9:690-696 Friston KJ, Frith CD, Liddle PF, Lammertsma AA, Dolan RD, Frackowiak RSJ 19YO The relationship between global and local changes in PET scans. J Cereb Blood Flow Metab 10:458-466 Friston KJ, Frith CD, Liddle PF, Frackowiak RSJ 1991 Comparing functional (PET) images: the assessment of significant change. J Cereb Blood Flow Metab 11:690-699 Goldman-Rakic PS 1988 Topography of cognition: parallel distributed networks in primate association cortex. Annu Rev Neurosci 1 I : 137- 156 Ingvar DH, Schwartz MS 1974 Bloodflow patterns induced in the dominant hemisphere by speech and reading. Brain 97:273-288 Lammertsma AA, Cunningham VJ, Deiber M-P et a1 1990 Combination of dynamic and integral methods for generating reproducible functional CBF images. J Cereb Blood Flow Metab 10:675-686 Lassen NA, Ingvar DH, Skinhoj E 1978 Brain function and blood flow. Sci Am 239 (4):50-59

Petersen SE, Fox PT, Posner MI, Mintun M, Raichle ME 1988 Positron emission tomographic studies of the cortical anatomy of a single-word processing. Nature (Lond) 331:585-589

Petersen SE, Fox PT, Posner MI, Raichle ME, Mintun MA 1989 Positron emission tomographic studies of the processing of single words. J Cognit Neurosci 1: 153-170 Petersen SE, Fox PT, Snyder AZ, Raichle ME 1990 Activation of extrastriate and frontal cortical areas by visual words and word-like stimuli. Science (Wash DC) 249:1041-1044 Raichle ME, Martin WRW,Herscovitch P, Mintun MA, Markham J 1983 Brain blood flow measured with intravenous H,I5O. 11. lmplementation and validation. J Nucl Med 24:790-798 Shallice T 1988 From neuropsychology to mental structure. Cambridge University Press, Cambridge Spinks TJ, Jones T, Gilardi MC, Heather JD 1988 Physical performance of the latest generation of commercial positron scanner. IEEE (Inst Electr Electron Eng) Trans Nucl Sci 35:721-725 Warrington EK, Logue V, Pratt RT 1971 The anatomical localisation of selective impairment of auditory verbal short-term memory. Neuropsychologia 9:377-387 Wise R, Chollet F, Hadar U, Friston K, Hoffner E, Frackowiak R 1991 Distribution of cortical neural networks involved in word comprehension and word retrieval. Brain 1 14: 1803- I8 17

DISCUSSION

Zeki: In t h e prestriate cortex, are the areas that light up always on the left? Wise: You are referring to the nonsense font response. We get bilateral extrastriate activation in response t o letter-like symbols. T h e St Louis group see a differential activation, with increased activation coming up in the left medial extrastriate when the word seen is either real, or at least obeys normal English orthographic rules. A consonant string or nonsense font won’t activate that area so strongly.

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Zeki: And the activation that appears selectively on the left is in addition to the other areas? Raichle: Yes! Zeki: Secondly, I want to know what you really mean by networking in parallel, and processing in parallel. This distinction seems to be rather subtle, but may blur interesting things, actually. Wise: By processing in parallel I mean that a number of different processes are happening at the same time; in other words, there are a number of processors that are independent but are being activated simultaneously. For example, our category judgement and verb generation tasks must have engaged short-term memory systems, particularly during the verb generation task, when the subject was holding a noun in memory and thinking of a number of different verbs to match the noun. Furthermore, the subject had to remember the verb he had just generated to avoid perseveration. Therefore, I don’t know for certain whether some of the activated regions in this task are related to short-term verbal memory or to verb retrieval. As to anatomical parallelism, the neural network that is dealing with the meaning of words may physically lie very close to the networks that deal with acoustic analysis of speech sounds. If they lie near one another, then one signal may dominate over the other. So, if we give a subject a word with meaning, and one with no meaning at all, or even a funny sound with speech-like frequency transitions but no phonemic content, they could all produce a blob in very much the some region on a PET scan. Zeki: You are implying that a single area, on the classical definition, could be subdivided into subareas, much as you might be able to divide the striate cortex into subregions, which are in fact undertaking processing in parallel. Their extensions are also undertaking parallel processing. Wise: Yes; for example, you are getting all visual information into primary visual cortex, all mixed in together, but then it separates out into different anatomical regions that process the subcomponents of complex visual information simultaneously. Zeki: No; that’s the whole point! The inputs and the outputs are not mixed together . Wise: It is mixed macroscopically, though not, I agree, at the microscopic level. You can’t pick out a specific colour signal in the primary striate cortex with a PET scan. Baron: With respect to the activation you saw in the supplementary motor area, could this be due to some kind of internal articulatory rehearsal as part of a working memory process? Wise: I think so. I suspect that when a subject was given a word like ‘apple’, the first verb he thought of may have been ‘eat’, and it was almost coming out, but not quite; he was getting ready to speak it. There’s no reason why processing should just stop at selecting the verb with the right

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meaning; processing would continue up to the point of articulation. This is how I visualize it. Cuppa: I am not convinced that the best control group for the deep dyslexic patient consists of normal readers. Deep dyslexics usually have very large lesions, and therefore perhaps this patient was simply using what brain remained to him for reading. A better control situation might be another dyslexic patient with a large left hemispheric lesion, but with a different dyslexic pattern, without any effect of word concreteness. Wise: You are probably right! It is difficult to sort out which control group to use. We were trying initially to see how the right cerebral hemisphere of the deep dyslexic patient differed from the right hemisphere of normal readers. But I agree that a large hole in the left cerebral hemisphere must have all sorts of profound effects, whatever the resulting neurological deficit. We do think, though, that the right hemisphere was involved, to explain the dissociation between concrete and abstract reading. Cuppa: Yes, because there is evidence from other fields, such as auditory evoked potential studies (Papanicolaou et a1 1984), that some linguistic processes in chronically aphasic patients are carried out by the right hemisphere. Perhaps the participation of this hemisphere in reading is not specific for deep dyslexia, but can be found in any patient with an extensive left hemisphere lesion, who by definition cannot use the normal left hemisphere pathways for reading. Wise: Yes. We are planning to scan more patients with more common forms of alexia. Corbetta: I’m not convinced by the kind of subtraction that you are using, Dr Wise. You use a lot of what we call ‘complex subtractions’-that is, a subtraction between two activation tasks (for example, hearing words played backwards minus reading false fonts, or reading words minus reading false fonts). These complex subtractions may be problematic when there are functional interactions betweem the activated brain systems. For example, we have data suggesting that visual and auditory systems work in a cross-inhibitory fashion. When the visual system is engaged by a visual task, the auditory system shows blood flow reductions, and vice versa (S. E. Petersen & M.E. Raichle, personal communication). In order to assess the relative role of each task in explaining activations obtained in a complex subtraction between the two, you should compare each task with a simpler control state (e.g. a visual fixation point control). So I’m not against complex subtractions in general, but I really think they should be used along with simple subtractions. Wise: There are two schools of thought on this. I am sympathetic to your preferred approach. In fact, in our reading tasks, we had no fixation point control; they all involved seeing nonsense font or words. In our earlier work on hearing words (Wise et a1 1991), there was a rest state, better called the freewheeling brain state, when there was no activation task used. However, even if one looks at concrete reading versus fixation point control, or abstract reading

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versus fixation point control, and compares the difference, a statistician will tell you that what is important is the direct comparison between concrete and abstract reading. Frackowiak: The best control state is the ‘constrained state’, which differs from the active state only by the feature you are trying to map. To call a ‘free-wheeling’ state, or even a state where you are fixating on a cross and dreaming about anything you like, a ‘control’ state, is to my mind quite wrong. Raichle: We seem to be polarizing this issue of control states when it doesn’t need to be polarized. We in St Louis do as many complex subtractions as you do, but we have also found it useful, in evaluating the data at the outset, to compare these various states against, say, a fixation point, because it gives you the entire picture. It’s a means of gaining a perspective as you look at the data. Dr Wise, we have struggled, as you have, with the auditory system, and we seem to be thinking along the same lines. It has been very difficult to separate these things out. We think it’s possible that much of the complex anatomy of the auditory system is packaged more closely together than that of the visual system. Therefore, we have greater difficulty, given the resolution available, with the anatomical relationships of the auditory system and with pulling things apart that are so close together. We once looked for simple functional responses (induced by hand vibration) in individuals who had compromised cerebral vasculature (occluded carotid artery on one side) but no infarction of tissue (Powers et a1 1988). Their vasculature didn’t respond normally to such stimulation (Powers et a1 1988). This has always worried us in relation to studying patients with vascular lesions. I was delighted to see that you are doing this and are getting good responses. Have you thought about the fact that once the brain has been injured, the relationship between the vasculature and the neuronal elements could be distorted, and could mislead you? Wise: Yes. We know that we use an indirect marker of neural activity when we measure regional blood flow. You will see some results from Richard Frackowiak where motor activation tasks elicited local blood flow increases in stroke patients. However, if a lesion alters the reactivity of resistance blood vessels, changes in flow may not occur in response to variations in neural activity. It is a pity that regional oxygen metabolism doesn’t seem t o be a better way of looking at changes in brain activity, but, according to you, oxygen metabolism is uncoupled from blood flow during activation. Obviously, a metabolic tracer would be better than a blood flow tracer for following changes in electrical activity. Raichle: Or, possibly, if one could think of ways to couple electrical recording to your PET study, guided by where you think the response might be, to see if you get an electrical response.

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Wise: We are hoping that although the right hemisphere may have a degree of vasoparalysis after a left hemisphere stroke, the vascular reactivity returns fairly soon after the insult. So, we hope to see changes in the right hemisphere, if there are any interesting changes to see. But 1 agree that we are constrained by this problem, and it probably means that the most interesting studies, serial ones starting very early after the ictus, are going to encounter this difficulty. Frith: It seems to me that many of the questions that are raised by these interesting results could be answered with purely psychological experiments, rather than having to go into PET. Maybe for each PET experiment you should be doing ten psychological experiments first, to ensure that you have the right paradigms. For example, your finding of SMA activation is very interesting, and suggests that you should look at the effects of articulatory suppression on some of these tasks. We have done this in relation to verbal fluency. We asked people to write down as many words as they could think of in a category, while saying ‘la la la’ all the time. This interferes with the task when you are asked to give all the words you can think of beginning with, say, the letter A, but not when you have to give all the words that are, say, animals, suggesting that there is an articulation component in the phonological task but not in the semantic task. Thus we might expect the SMA to light up in phonological verbal fluency, but not in semantic verbal fluency. There are similar ways in which you could ask questions such as: is there a store for real words which is not involved in processing consonant strings? You can demonstrate the distinction psychologically, and then ask PET whether such a store can be localized. Warrington: Dr Wise, 1 think the flow diagram that you showed (Fig.2, p 224) is too simple and needs to be expanded to incorporate all the data now available. I also find the use of the word ‘semantic’ too simplistic. I liked your point that there is a lot of information available, not only in the neurological literature, but also in the cognitive neuropsychological literature; but I do not think this is sufficiently well known. The idea that ‘semantics’ are ‘in’ the frontal lobes is not secure. First, equating ‘word retrieval’-that is, pronouncing a word aloud-with semantic knowledge of that word is inappropriate. There are patients with full semantic knowledge of a word who may have grave difficulty in word retrieval tasks. Second, there is likely to be more than one procedure for retrieving a word-for example, when you are naming an object, when you are answering a question, and when you are trying to fill in the ‘slots’ in a sentence frame. You also retrieve words when you are doing a word-generating task. 1 suggest that the last is least like normal language, although this is a task that is very useful to the clinician. The question: ‘how many words can you think of beginning with the letter A?’ is, in my view, a problem-solving task and probably not a core component of spoken language. Perhaps because it is such an unfamiliar problem-solving task, we do, in fact, find frontal lobe deficits. Similarly with monitoring tasks: monitoring the events going on in the

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outside world is known to be impaired in patients with ‘frontal’ lobe lesions rather than in those with semantic deficits. Semantic deficits are more appropriately examined using quite different testing procedures. These two kinds of task, both purporting to access semantic knowledge, may be impaired in patients in whom semantic knowledge may be demonstrated to be entirely intact. Wise: I depicted only one ‘black box’ for the semantic system, and this is clearly inadequate. We have to start somewhere, however. I am sure there will be considerablerefinement of the type of activation tasks we use in future studies. We are really dependent on advice from cognitive neuropsychologists. Roland: Dr Wise, you showed us very beautiful dissections of language processing by your activations; you also showed this block diagram, to which Professor Warrington referred. But how do you commit your block diagram to the activations you see, and how do those activations modify your block diagram of the processing? You may say that this diagram is just an aid to thinking about these processes, but I don’t think that’s sufficient as an answer. If you believe that processing is going on, as is indicated in this diagram, you must be able to identify the stations in the diagram by looking at the activations. If a block diagram is to be useful, then you have to be able to define, within that diagram, what you are talking about, anatomically and physiologically. If not, you could just move your boxes around so that they fit whatever hypothesis you might like to test. Wise: I see your point; we have a major conflict of interest here. The Ellis & Young (1988) ‘black box and arrow’ diagram is simple, but I used it because the PET scanner is a simple machine compared to the brain, and if you include say 40 black boxes, you will never match then with the results from PET studies. One must remember that all these ‘black boxes’ were derived from behavioural studies on normal subjects or patients, with no reference to anatomy at all. Many cognitive neuropsychologists do not mind where those ‘black boxes’ are, but are concerned that they can be demonstrated to exist as processing subcomponents of language, using observations on symptom dissociations in patients. I am trying to put the ‘black boxes’ on the brain; and you are also saying that we should do this, because the processors of a neuropsychological model must exist as neural networks. However, a particular network may be localized to one small region or be widely distributed, either diffusely or as a number of discrete subcomponents. We may not be able to identify distributed networks on a PET scan, if there is only a small, diffuse increase in flow in response to an activation task.

References Ellis AW, Young AW 1988 Human cognitive neuropsychology. Lawrence Erlbaum Associates, Hove, UK

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Papanicolaou AC, Levin HS, Eisenberg HM 1984 Evoked potential correlates of recovery from aphasia after focal left hemisphere injury in adults. Neurosurgery 14:412-415 Powers WJ, Fox PT, Raichle ME 1988 The effect of carotid artery disease on the cerebrovascular response to physiologic stimulation. Neurology 38: 1475- 1478 Wise R , Chollet F, Hadar U , Friston K , Hoffner E, Frackowiak R 1991 Distribution of cortical neural networks involved in word comprehension and word retrieval. Brain 1 14:1803- 1817

The functional anatomy of recovery from brain injury R. S. J. Frackowiak, C.Weiller and F. Chollet

MRC Cyclotron Unit, Hammersmith Hospital, Ducane Road, London W12 OHS, UK

Abstract. The functional neuroanatomical basis for recovery from ischaemic brain injury is not known. We have used positron emission tomography (PET) to study changes in the functional organization of the brain in patients recovering from striatocapsular motor strokes. Significant changes in regional cerebral blood flow (rCBF) were found during repetitive sequential opposition movements of the fingers in normal subjects and in patients with recovery from motor deficits. There was a difference in the pattern of cerebral activation when patients performed the motor task with the unaffected hand (when the activation was lateralized to contralateral sensorimotor and premotor cortex and ipsilateral cerebellum) and when the task was performed with the recovered, previously plegic hand (when the activation was bilateral and involved novel areas of cortex, especially area 40). Comparisons of rCBF maps at rest in the patient group and in normal subjects showed areas with significantly decreased rCBF in the patients (contralateral to the plegic hand in the basal ganglia, thalamus, insular cortex, brainstem and ipsilateral cerebellum), which reflected the distribution of dysfunction caused by the ischaemic lesions. A significantly increased activation over and above that in normal subjects was found in patients during movement of the recovered fingers in ipsilateral premotor cortex and bilateral frontal operculadinsular regions and area 40, the ipsilateral basal ganglia (the ischaemic lesion lying contralaterally) and the contralateral cerebellum. We postulate that these findings may be explained by the generation of movements by pathways that are different from those that normal subjects use to perform what are ordinarily fairly simple, automated tasks. We suggest that this is a direct demonstration of cerebral plasticity resulting in the resolution of acquired motor deficits. 1991 Exploring brain functional anatomy with positron tomography. Wiley, Chichester (Ciba Foundation Symposium 163) p 235-249

Clinical recovery of neurological function is often observed after acute ischaemic brain injury (Twitchell 1951). A number of mechanisms have been proposed t o account for such recovery. Among these are redundancy i n the neural representation of function, sprouting and reinforcement of existing, though normally secondary or alternative neuronal circuits, a n d the formation of new polysynaptic connections (Merill & Wall 1978, Wall 1977). Clinical observations further indicate that a degree of bilateral cerebral control of motor function may persist into adulthood. Hence there may be a role f o r ipsilateral cortical

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efferent pathways in subserving movement after contralateral cerebral injury. This hypothesis is most dramatically supported by the motor recovery observed in children after surgical hemispherectomy (Gardner 1933). Conversely, it is also clear that unilateral hemispheric lesions can induce bilateral motor deficits (Jones et a1 1989, Colebatch & Gandevia 1989). Positron emission tomography (PET) can be used to detect significant regional changes in cerebral blood flow (rCBF) which are an indirect measure of local neuronal activity (Raichle 1987). Focal rCBF changes can be elicited by behavioural, physiological or other stimuli and can be detected, in vivo, from the whole brain simultaneously. The site of focal CBF change gives information on the cerebral structures associated with, or underlying, the activity under study. We have chosen ischaemic stroke in man as a natural model of brain injury. Lesions are produced which can be clearly defined anatomically by appropriate computed tomography (CT) or magnetic resonance imaging (MRI). The model is inconvenient in that the site and extent of the lesion are not controllable, because every human stroke is different and significant distortions of normal anatomy may be induced. There may also be remote functional effects that are reflected in rCBF changes that are not necessarily predictable from the site of the infarct and which may themselves have an influence on recovery (Feeney & Baron 1986). We have developed methods that allow comparison of patterns of change in local neural activity (reflected by significant changes in rCBF) in both patients and normal subjects. In this way we have sought to find evidence for plastic changes of functional neural connectivity in man. This chapter describes work on the functional anatomy of recovery in the motor system. To this end we have used a finger opposition task which we know from previous studies gives a large, reproducible lateralized increase of rCBF (Colebatch et a1 1991). We chose to investigate recovery of motor function because it can be measured relatively simply by clinical observation and there is considerable knowledge of the normal anatomy of finger movements. Clinical material

Patients were selected with first-time ischaemic events, clearly characterized by a single, appropriately sited lesion on structural imaging, with no other antecedent neurological or significant general medical history. The primary criterion for inclusion was the presence of a hemiparesis of acute onset affecting one upper limb (at least), followed by substantial recovery of power and dexterity, sufficient to allow the performance of a rapid (three movements per two seconds), sequential finger-to-thumb opposition task. The 10 selected patients had a variety of anatomically sited lesions but all involved at least the striatocapsular region and spared the primary motor cortex. For analytical purposes, the ‘normal’ hand was always located to the left (indeed, all but two infarcts were on the left) and the recovered hand to the right, by flipping

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the images of the two patients with right hemisphere infarcts about the vertical axis. Mapping cerebral blood flow changes Regional cerebral blood flow (rCBF) was measured with a dynamichtegral technique with P O z as the flow tracer (Lammertsma et a1 1990), which was administered by inhalation for two minutes. Twenty-one successive PET images were collected for 0.5 min before tracer delivery (background scan) and for 3 min after the beginning of tracer administration. Patients and normal subjects performed the motor task repetitively in a controlled manner throughout the scanning period. The task consisted of sequential finger-to-thumb opposition movements which were not forceful but brisk, precise and of large amplitude, with the tip of the thumb touching each of the four fingers in turn at a rate of three oppositions in two seconds. Six blood flow scans were performed in each session, with two at rest, two while moving the fingers of the left, unaffected hand, and two while moving the fingers of the right, recovered hand. The ordering of tasks was balanced to avoid habituation effects. The PET brain images of individuals were transformed to conform to a standard anatomical space by identification and reference to the intercommissural line (AC-PC line), as described previously (Friston et a1 1989). Each image was smoothed to account for variation in normal functional anatomy. The confounding effect of global differences in CBF between subjects was removed using an analysis of covariance (Friston et a1 1990). All image analysis was then performed on a pixel-by-pixel basis to generate mean CBF maps for each activated state across all subjects. This averaging procedure resulted in improvement of signal-to-noise ratios and an estimate of error variance for each pixel in the maps. The comparisons between brain states were then performed in a planned manner using standard statistical techniques from which were generated statistical parametric maps (SPM) of significant stateassociated changes in rCBF. Comparisons were made between (a) the resting distribution of blood flow in patients and normal subjects; (b) the pattern of activation elicited by movements of each hand in patients; and (c) the magnitude of the activation elicited in patients on movement of each hand and that obtained in normal subjects. Functional disconnections We analysed the functional disconnections caused by the infarct by comparing cortical and subcortical distributions of rCBF in the group of ten patients at rest with the distribution of blood flow in a group of ten age-matched normal subjects. The 10 patients were aged 21-62 years (mean: 41 years) and all had ischaemic striatocapsular infarcts. No other focal abnormality was seen on

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structural imaging. The extracranial and intracranial large vessels were normal on Doppler examination. The 10 healthy volunteers were aged 28-69 years (mean: 47 years), had no significant antecedent neurological history, and were neurologically normal and functioning at work and socially without detectable impairment, Some generalizations can be made from the results of this study because of the relatively homogeneous siting of the lesions in the striatocapsular region. At rest, there was significantly decreased rCBF in the brains of patients in the left striatum and internal capsule, corresponding to the site of the lesion. In addition, there were significant decreases in the left insular, primary sensorimotor and lateral prefrontal cortices, thalamus, midbrainlcerebral peduncle and in the contralateral cerebellum (Fig. 1) (see colour plate). None of these areas was infarcted on structural imaging. These areas of significant hypometabolism at rest can be considered as direct, functional remote consequences of the focal infarcts. It is however, possible that parts of the areas of hypoperfusion immediately surrounding the infarcts are caused by partial neuronal attrition, short of frank infarction; but this cannot be true for the more distant areas and those lying outside the territory of the feeding artery. These areas also constitute components of the motor system-in particular the primary motor and prefrontal cortices, and the striatum, thalamus and cerebellum. On the other hand, other components, such as the premotor cortex on the side of the lesion, are conspicuous in their lack of any change in rCBF, while the insular cortex has a much less clearly defined relationship to this system. The striatocapsular lesions result in a complex pattern of chronic deactivation which includes motor and neighbouring association areas. The hypoperfusion in the midbrain/ peduncular region can be interpreted as a result of degeneration of the pyramidal tract, a major constituent of this anatomical region. There were other areas in which rCBF at rest was higher in patients than in normal subjects, namely the right striatum (putamen and caudate nucleus) and premotor cortex, and left posterior cingulate. The findings in contralateral premotor cortex and its subcortical projection area, the striatum, are of particular interest, given the changes in activity in the supplementary motor areas (SMA) and in both premotor cortices with repetitive tasks of the upper limb that we have observed in normal subjects (Colebatch et al 1991). The chronic increase in rCBF due to a remote ischaemic lesion may therefore constitute the result of functional disinhibition of motor areas in a single network by a contralateral lesion in a constituent part of the same system. The disinhibition of the contralateral ‘motor hemisphere’ may form an integral part of the recovery process. The recovered hand

The pattern of rCBF changes seen in response to movement of the ‘normal’ hand was compared to that elicited by the same movement carried out by the

FIG. 1 (Fruckowiuk et ul) Comparison of rCBF at rest between 10 patients with striatocapsular infarcts and 10 normal subjects. Areas with decreased rCBF in patients are shown. The upper row represents features averaged from the 10 patients into Talairach space. Below, coronal, sagittal and transverse projections of the statistical parametric maps (SPMs) obtained by a comparison between patients and normal controls are displayed. All areas with significant decreases in rCBF in the patients are shown. The grid is the standard, proportional, stereotactic grid of Talairach & Tournoux (1988) which defines the three-dimensional space into which all the brains have been normalized. The line drawings are of the horizontal brain contours at the level of the AC-PC line (intercommissural line) (below), in the midsagittal plane (upper lefr), and at the midpoint of the AC-PC line in the coronal plane (upper right). The display permits rapid inspection and localization of all the data. The ‘hot’ end of the rainbow scale (distributed over 255 levels) shows areas of maximally significant rCBF difference and the ‘cold’ end the threshold of P