Movement Disorders: Handbook of Clinical Neurophysiology, Vol 1

Handbook of Clinical Neurophysiology Series Editors

Jasper R. Daube Managed Care Department, Mayo Clinic, 200 First Street SW; Rochester, MN 55905, USA and

Francois Mauguiere Functional Neurology and Epilepsy Department, Htipital Neurologique Pierre Wertheimer, 59 Boulevard Pinel, F-69394 Lyon Cedex 03, France

Volume 1 Movement Disorders Volume Editor

Mark Hallett Human Motor Control Section, NIH, Building 10, Room 5N226, 10 Center Drive, MSC 1428, Bethesda, MD 20892-1428, USA

2003

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First edition 2003

ISBN: 0444-50725-6 ISSN: 1567-4231 (series)

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Foreword

Clinical neurophysiology encompasses the application of a wide variety of electrophysiologic methods to the analysis of normal function and the diagnosis and treatment of diseases involving the central nervous system, peripheral nervous system and muscles. A small number of these methods are applied to a single category disease, but most are useful in multiple clinical settings. Previous editions of the Handbook of Clinical Neurophysiology have focused on categories of testing and the many ways they can be applied. The steady increase in growth of subspecialties in neurology and the study of disorders of the nervous system have led to a need for a compilation of the application of the whole range of physiologic methods used for the major categories of neurologic disease. Each volume will be designed to serve as the ultimate reference source for academic clinical neurophysiologists, and as a reference that will provide subspecialists in an area, they will need to fully understand, assess and treat disorders in their patients. As such these volumes will also serve as a major teaching text for trainees in that subspecialty. Subsequent volumes will include all of the clinical disorders served by clinical neurophysiology: the epilepsies, autonomic dysfunction, peripheral nerve disease, muscle disease, motor system disorders, somatosensory system disorders, behavioral disorders, visual and auditory system disorders, and monitoring neural function. Each will focus on the advances in one of these major areas of clinical neurophysiology. Each volume will include critical discussion of new knowledge in basic neurophysiology, approaches to characterization of disease type, localization, severity and prognosis with detailed discussion of advances in techniques to accomplish these. It is recognized that some techniques will be discussed in more than one volume, but with different focuses in each of them. Each volume will include an overview of the field, followed by a section that includes a detailed description of each of the CNP techniques used in the category of disorders, and a third section discussing specific diseases. The latter will include how to evaluate each and comparison of relative contribution of each of the methods of evaluation. A final section will discuss ongoing research studies and anticipated future advances. Selection of movement disorders as the first volume is particularly appropriate in view of the many advances in the application of clinical neurophysiology in these disorders. We are privileged to have one of the world's leaders in the clinical neurophysiology of movement disorders as the volume editor. He has done a superb job of assembling the world leaders in the description of the methods and in their application to particular categories of disease. Jasper R. Daube Francois Mauguiere

Series Editors

List of Contributors

M.Aramideh

Department of Neurology/Clinical Neurophysiology, Medical Center Alkmaar, P.O. Box 501, 1800 AM Alkmaar, The Netherlands.

C.Ardouin

INSERM 318, Joseph Fourier University, Centre Hospitalier Universitaire, Pavillon B, BP 217,38043 Grenoble Cedex 9, France.

J.U.J. Allum

Department of ORL, University Hospital, Basel, Switzerland.

P.G. Bain

Imperial College School of Medicine, Charing Cross Hospital Campus, Pulham Palace Road, London W6 8RF, UK.

A.L. Benabid

INSERM 318, Joseph Fourier University, Centre Hospitalier Universitaire, Pavillon B, BP 217,38043 Grenoble Cedex 9, France.

A. Benazzouz

INSERM 318, Joseph Fourier University, Centre Hospitalier Universitaire, Pavillon B, BP 217,38043 Grenoble Cedex 9, France.

R. Benecke

Department of Neurology, University of Rostock, Gehlsheimer Strasse 20, D-18147 Rostock, Germany.

A. Berardelli

Dipartimento di Scienze Neurologiche, Universita di Roma "La Sapienza", Viale Universita 30,00185 Rome, Italy.

B.R.Bloem

Department of Neurology, 326, University Medical Center St. Radboud, P.O. Box 9101, 6500 HB Nijmegen, The Netherlands.

C. Braun

MEG Center, Eberhard-Karls University Tubingen, Hoppe-Seyler Strasse 3, D-72076 Tubingen, Germany.

P. Brown

Sobell Department of Motor Neuroscience and Movement Disorders, Institute of Neurology, Queen Square, London WC1N 3BG, UK.

D. Burke

College of Health Sciences, The University of Sydney, Sydney, Australia.

J.N. Caviness

Department of Neurology, Mayo Clinic Scottsdale, 13400 East Shea Blvd., Scottsdale, AZ 85259, USA.

S. Chabardes

INSERM 318, Joseph Fourier University, Centre Hospitalier Universitaire, Pavillon B, BP 217,38043 Grenoble Cedex 9, France.

S. Chokroverty

Department of Neurology/Cronin 466, St. Vincents Hospital, 153 W 11th Street, New York, NY 10011, USA.

G. Croccu

Department of Neurological Sciences, University of Rome "La Sapienza", 00185 Rome, Italy.

viii

LIST OF CONTRIBUTORS

A. Curra

Istituto Neurologico Mediterraneo "Neuromed", Via Atinense 18, 86077 Pozzilli, IS, Italy.

G. Deuschl

Department of Neurology, Christian-Albrechts-Universitat Kiel, Niemannsweg 147, D-24lO5 Kiel, Germany.

C. Dohle

Department of Neurology, University Hospital Diisseldorf, Moorenstrasse 5, D-40225 Diisseldorf, Germany.

J.O. Dostrovsky

Department of Physiology, Faculty of Medicine, University of Toronto, Toronto, ON M5S lA8, Canada.

R.J. Elble

Department of Neurology, Southern Illinois University School of Medicine, P.O. Box 19643, Springfield, IL 62794-9643, USA.

U. Fietzek

Department of Neurology, Christian-Albrechts-Universitat Kiel, Niemannsweg 147, D-24lO5 Kiel, Germany.

M.K. Floeter

Electromyography Section, National Institute of Neurological Disorders and Stroke, NIH, 10 Center Drive, MSC 1404, Bethesda, MD 20892-1404, USA.

V. Fraix

INSERM 318, Joseph Fourier University, Centre Hospitalier Universitaire, Pavillon B, BP 217,38043 Grenoble Cedex 9, France.

H.-J. Freund

Department of Neurology, University Hospital Diisseldorf, Moorenstrasse 5, D-40225 Diisseldorf, Germany.

S.C. Gandevia

Spinal Injuries Research Centre, Prince of Wales Medical Research Institute, University of New South Wales, Sydney, Australia.

C. Gerloff

Cortical Physiology Research Group, Department of General Neurology, Eberhard-Karls University Tiibingen, Hoppe-Seyler Strasse 3, D-72076 Tiibingen, Germany.

J.-M. Grades

Department of Neurology, Mount Sinai Medical Center, 1 Gustave L. Levy Place, Annenberg 2/Box 1052, New York, NY 10029-6574, USA.

S.T. Grafton

Center for Cognitive Neuroscience, 6162 Moore Hall, Dartmouth College, Hanover, NH 03755, USA.

M. Hallett

Human Motor Control Section, National Institute of Neurological Disorders and Stroke, NIH, Building lO, Room 5N226, 10 Center Drive, MSC 1428, Bethesda, MD 20892-1428, USA.

M. Hayes

Department of Neurology, Concord Repatriation Hospital, Sydney, Australia.

B. Hellwig

Neurologische Universitatsklinik, Neurozentrum, Breisacher Strasse 64, D-79106 Freiburg, Germany.

W.Hening

Johns Hopkins Center for Restless Legs Syndrome, 5th Floor, Room 5B71C, Asthma & Allergy Center, 5501 Hopkins Bayview Circle, Baltimore, MD 21224, USA.

W.D. Hutchison

Department of Surgery, Division of Neurosurgery, Toronto Western HospitallMC 2-433, 399 Bathurst Street, East Wing 6-528, Toronto, ON M5T 2S8, Canada.

A. Ikeda

Department of Neurology, Kyoto University Graduate School of Medicine, Shogoin, Sakyo-ku, Kyoto 606-8507, Japan.

ix

LIST OF CONTRIBUTORS

M. Jahanshahi

Sobell Research Department of Motor Neuroscience and Movement Disorders, Institute of Neurology, Queen Square, London WCIN 3BG, UK.

R. Kaji

Department of Clinical Neuroscience, Hospital of the University of Tokushima, 2-Chome 5-1, Kuramotocho, Tokushima City, Tokushima 770-8503, Japan.

K.R. Kaufman

Biomechanics Laboratory, Charlton North L-IION, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA.

S.Klebe

Department of Neurology, Christian-Albrechts-Universitat Kiel, Niemannsweg 147, D-24105 Kiel, Germany.

A. Koudsie

INSERM 318, Joseph Fourier University, Centre Hospitalier Universitaire, Pavillon B, BP 217,38043 Grenoble Cedex 9, France.

P. Krack

INSERM 318, Joseph Fourier University, Centre Hospitalier Universitaire, Pavillon B, BP 217,38043 Grenoble Cedex 9, France.

A.M. Lozano

Department of Surgery, Division of Neurosurgery, Toronto Western HospitallMC 2-433, 399 Bathurst Street, East Wing 6-528, Toronto, ON M5T 2S8, Canada.

C.H. Liicking

Neurologische Universitatsklinik, Neurozentrum, Breisacher Strasse 64, D-79106 Freiburg, Germany.

V.G. Macefield

Spinal Injuries Research Centre, Prince of Wales Medical Research Institute, University of New South Wales, Sydney, Australia.

M.-UManto

Charge de Recherches FNRS, Neurologie, 808 Route de Lennik, 1070 Brussels, Belgium.

F. Maugulere

Department of Functional Neurology and Epileptology, Neurological Hospital, 59 Boulevard Pinel, 69330 Lyon, France.

T.Mima

Department of Brain Pathophysiology, Human Brain Research Center, Kyoto University Graduate School of Medicine, Shogoin, Sakyo-ku, Kyoto 606-8507, Japan.

T. Nagamine

Human Brain Research Center, Kyoto University Graduate School of Medicine, Shogoin, Sakyo-ku, Kyoto 606-8507, Japan.

F. Pauri

AFaR, Dip. Neuroscienze, Osdpedale Fatebenefratelli, Isola Tiberina 39, 00186 Rome, Italy.

P.Poliak

INSERM 318, Joseph Fourier University, Centre Hospitalier Universitaire, Pavillon B, BP 217, 38043 Grenoble Cedex 9, France.

B.W. Ongerboer de Visser Department of Neurology/Clinical Neurophysiology Unit, Academic Medical Center, 1105 AZ Amsterdam, The Netherlands. P.M. Rossini

Direzione Scientifica AFaR, Associazione Fatebenefratelli per la Ricerca, Lungotevere degli Anguillara 12,00186 Rome, Italy.

J.C. Rothwell

Sobell Department, Institute of Neurology, Queen Square, London WCIN 3BG, UK.

H. Shibasaki

Human Brain Research Center and Department of Neurology, Kyoto University Graduate School of Medicine, Shogoin, Sakyo-ku, Kyoto 606-8507, Japan.

x

LIST OF CONTRIBUTORS

D.M. Simpson

Clinical Neurophysiology Laboratories, Mount Sinai Medical Center, 1 Gustave L. Levy Place, New York, NY 10029, USA.

L. Sudarsky

Department of Neurology, ASB 1-2, Brigham and Women's Hospital, 75 Francis Street, Boston, MA 02115, USA.

P.O. Thompson

Department of Neurology and University Department of Medicine, Royal Adelaide Hospital and University of Adelaide, Adelaide, SA 5000, Australia.

F.Valldeoriola

Unitat d'EMG, Servei de Neurologia, Hospital Clinic, Villarroel 170, Barcelona 08036, Spain.

J. Valls·Soh~

Unitat d'EMG, Servei de Neurologia, Hospital Clinic, Villarroel 170, Barcelona 08036, Spain.

J.E. Visser

Department of Neurology, 326, University Medical Center St. Radboud, P.O. Box 9101,6500 HB Nijmegen, The Netherlands.

J. Volkmann

Department of Neurology, Christian-Albrechts-Universitat Kiel, Niemannsweg 147, D-24105 Kiel, Germany.

U. Ziemann

Clinic of Neurology, Johann Wolfgang Goethe University of Frankfurt, TheodorStem-Kai 7, D-60590 Frankfurt am Main, Germany.

Movement Disorders Handbook of Clinical Neurophysiology, Vol. I M. Hallett (Ed.) © 2003 Elsevier B.V. All rights reserved

3 CHAPTER I

Movement disorders: overview Why have a book devoted to the Clinical Neurophysiology of movement disorders? A primary consideration is the growth of the field of movement disorders. Movement disorders is a relatively new field that grew out of an original interest in Parkinson's disease. The interest in Parkinson's disease itself blossomed after the finding that it could be well treated with levodopa. The field soon expanded to other disorders involving the basal ganglia, including dystonia and Huntington's disease. Myoclonus was added shortly after the finding that many cases were treatable with 5-hydroxytryptophan. Then other disorders were included where the motor system was impaired, and the field expanded to include the ataxias, spasticity and even paresis. The field got its name from Stan Fahn and C. David Marsden who helped popularize this way of organizing neurological disorders. The field has now been codified with the formation of an international society and journal. The common theme of movement disorders is the motor system and its diseases. A good deal of emphasis in the field has been placed on pharmacology as the mainline method of treatment. Recently, genetics and cell biology have been giving insights into the nature of the disease processes that cause movement disorders. Another critical area of interest has always been in the physiology and pathophysiology of the motor system, and this is the entry point for clinical neurophysiology. How is movement normally generated? What are the abnormalities underlying manifestations such as bradykinesia, tremor, chorea, tics, and myoclonus? Not only are these questions of interest by themselves, but the answers may point toward new therapeutic options. The first intersection of clinical neurophysiology and movement disorders is this research issue about the nature of motor disturbances. Clinical neurophysiology has always been a field that has contributed to the diagnosis of neurological disorders. As has been said often, it is an extension of the neurological examination. The second intersection of clinical neurophysiology and movement disorders is diagnosis. Clinical neurophysiologists

have traditionally been trained largely in EEG and EMG, focused largely on epilepsy and neuromuscular disorders, respectively. However, it is clear that clinical neurophysiology can contribute in other areas. In addition to movement disorders, for example, clinical neurophysiology can contribute to the fields of autonomic nervous system disorders, sleep disorders, and central nervous system monitoring during operations on the brain or spine. In movement disorders that look superficially similar, it is critical to make the right diagnosis because therapies might differ. Is a quick movement a tic, a myoclonic jerk or a voluntary movement? Studies of the surface EMG and the correlative EEG can give a definitive answer. Small differences in timing, easily measured with simple techniques, can be impossible to tell by eye. What is the burst duration of EMG underlying an involuntary movement? For example, is a myoclonic jerk due to a fragment of epilepsy or a fragment of a basal ganglia movement disorder? The EMG burst length is shorter in the former than the latter. What is the latency of a muscle jerk after a stimulus? Is it shorter than possible reaction time? If so, it cannot be voluntary or psychogenic. What is the frequency of tremor and how does it change with an intervention? Exaggerated physiological tremor should reduce in frequency with weighting of the limb by 1 or 2 Hz. This cannot be appreciated by visual inspection. Might there be two components of a tremor? Again, only physiological measurements will reveal this finding. Quantification of movement disorders is often useful for monitoring change over time including assessment of therapy. There are clinical scales that can be useful, but these are largely subjective and subtle changes over months or years might be missed. Physiological techniques can be valuable in this regard and can be used, for example, to monitor the amplitude of tremor or the magnitude of spastic tone. A new intersection of movement disorders and clinical neurophysiology is therapy. EMG guidance

4

improves the delivery of botulinum toxin to muscles with unwanted spasms. Neurophysiological monitoring is valuable in locating targets for deep brain stimulation. Transcranial magnetic stimulation is being explored for its utility in several movement disorders. This should be a valuable text for clinical neurophysiologists. The topic of movement disorders is usually treated superficially in even large textbooks of clinical neurophysiology. Useful clinical methods and research techniques are covered extensively. The book anticipates that the reader will have some basic knowledge of clinical neurophysiology, but then can be useful for the novice who wants an introduction and by the expert who is looking for details.

M. HALLETT

The book is arranged in two main parts. The first part deals with techniques. Here is where the reader can find exactly how to do a specific test and how to interpret the results. The application of the techniques to movement disorders is only briefly discussed. In the second part, individual movement disorders are the topics. Each chapter describes the disorder and its physiology, concentrating on the research and clinical methods that can be useful. It might be necessary when reading these chapters to refer back to the detailed technique in the first part of the book. At the end, there is a short look to the future with some guesses as to the direction of the field. Mark Hallett Bethesda, MD, USA June 2003

Movement Disorders Handbook of Clinical Neurophysiology, Vol. 1 M. Hallett (Ed.) © 2003 Elsevier B.V. All rights reserved

7 CHAPTER 2

Electromyography Mark Hallett* Human Motor Control Section. National Institute of Neurological Disorders and Stroke, NIH, Bethesda, MD 20892-/428. USA

Electromyography (EMG) is an important tool for the analysis of movement disorders (Hallett, 1999, 2000). Muscles are responsible for movements, and EMG is a direct measurement of the activity of muscle and a fairly direct measure of alpha motoneuron activity. EMG is most commonly used in clinical neurophysiology for the analysis of peripheral neuromuscular disease, answering the questions of whether there is a neuropathy, myopathy or neuromuscular junction disorder. In general, when dealing with movement disorders, it is assumed that all those aspects are normal, and the questions are different. In this context the questions asked include what muscles are active and what is the pattern of activation. The term kinesiological EMG is sometimes applied, and it is often apt, since the issue is what is the EMG responsible for the movement. Since numerous muscles act on any joint, it is typically necessary to record from at least two muscles with antagonist actions. The main information that can be extracted is the amplitude and the timing. EMG data can be measured with surface, needle, or wire electrodes (Hallett et al., 1994). Surface electrodes have the advantages that they are not painful and they record from a relatively large volume of muscle producing a good average of its activity. For these reasons, pairs of surface electrodes are ordinarily used for the analysis of movement disorders. The two surface electrodes are typically placed near the middle of the muscle belly about 2 or 3 em apart. Belly-tendon recording is often not optimal since recording volume would be too extensive and pickup would include unintended

* Dr. Mark Hallett, M.D., Human Motor Control Section, NIH, Building 10, Room 5N226, 10 Center Dr., MSC 1428, Bethesda, MD 20892-1428, USA. E-mail address: [email protected] Tel.: 3011496-9526; fax: 3011480-2286.

nearby muscles. Needle electrodes have the advantage that they are more selective, sometimes a necessity when recording from small or deep muscles. Traditional needle electrodes are stiff, however, and it is best to use them when recording from muscles during movements that are close to isometric. If there is substantial movement, needles will be very painful, in part because of the relative movement of the skin and muscle belly. Pairs of fine wire electrodes have the advantage of selectivity similar to that of needle electrodes and are flexible, permitting free movement with only minimal pain. There is slight movement of the wires with movement, but they do provide a reasonably stable recording. Regardless of the electrodes used, it is important to avoid movement artifact, which can contaminate the EMG signal. Wire movement should be limited. Low-frequency content of the EMG signal can be restricted with filtering, and this can remove much of the movement artifact. Movement artifact is largely in the range of DC to 10 or 20 Hz. Surface EMG has significant power in this range as well, but the peak power is at about 100 Hz, so the filtering of power below 20 Hz still leaves most of the EMG power. When surface electrodes are used, their impedance should be reduced to 10 kO or less. This will reduce electrogenesis at the electrode-skin interface caused by slight movements. In order to reduce the impedance sufficiently, it is usually necessary to abrade the skin (Fig. 1). If there is a question about the possible peripheral origin of the movement disorder, then needle EMG may be very helpful. For peripheral disorders, typically there are characteristic findings. For example, there might be fasciculations, myokymia, neuromyotonia or other high frequency bursts. The amplitude of EMG conveys information about the magnitude of the central nervous system output. For this purpose it is generally not useful to

M.HALLETT

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Fig. 1. Surface EMG recordings in a normal volunteer simulating a tremor. Muscles, from top down, are biceps, triceps, flexor carpi radialis and extensor carpi radialis. (A) The recordings are contaminated with movement artifact because the surface electrodes had high impedance. (B) The recordings here are much better after the skin was abraded and the impedance was reduced to less than 10 kD.

note the magnitude in mV. Since the electrodes are not in a "standard" position and there will be varying relationships between the skin surface and the muscle belly, the absolute measurement has ambiguous meaning. There are two ways of standardizing the measurements. One is in relation to maximal voluntary EMG output, and the other is with respect to a maximum compound muscle action potential (CMAP) produced by nerve stimulation. The former is more commonly used, and in many circumstances nerve stimulation would not be easy to do anyway.

EMG is occasionally used as a measure of force, but this should only be considered approximate since the relationship between EMG amplitude and force is not exact, may change in different circumstances and is often not linear (Perry and Bekey, 1981; Solomonow et al., 1986; Hof, 1997). In processing the EMG for amplitude it is often useful to rectify and smooth the recording (Fig. 2). This process yields an "envelope" of the EMG signal. The amplitude of the envelope can be used as the magnitude of the EMG, and for a burst of EMG,

ELECTROMYOGRAPHY

9

B

8

Off

Fig. 1. Continued.

the integrated area of the envelope is a good measure. If a tremor is being recorded, then the successive envelopes of EMG form a curve like a sinusoid, and the record can be subjected to frequency analysis to get information about the frequency content of the signals driving the tremor. The EMG patterns underlying voluntary movement are characteristic and vary with the speed of movement (Berardelli et al., 1996; Hallett, 1999, 2000) (Fig. 3). A slow, smooth movement is characterized chiefly by continuous activity in the agonist. A movement made as rapidly as possible, a so-called ballistic movement, has a triphasic pattern with a burst of activity in the agonist lasting 50-100

ms, a burst of activity in the antagonist lasting 50-100 ms, and return of activity in the agonist often in the form of a burst. In different disorders of voluntary movement, there are characteristic abnormalities. With cerebellar lesions, there is prolongation of the first agonist and/or antagonist EMG bursts. The prolongations can be marked, and there is a good correlation of the acceleration time of the movement with the duration of the first agonist burst. Unwanted prolongation of acceleration time should predispose to hypermetria. The antagonist burst can be delayed as well. With parkinsonian bradykinesia, there is abnormal patterning, with multiple bursts having the

10

M.HALLETT

A

500

IJ-V

Amp 2

B

100 IJ-V

Fig. 2. Surface EMG recordings in a normal volunteer simulating a tremor. (A) The top trace is the raw EMG from biceps and the bottom is the same trace rectified. (B) This is a record similar to that in (A), but the EMG has been smoothed as well as rectified.

Table I EMG appearance in different types of involuntary movements. Disorder

EMGpattem Reflex

Myoclonus

x

Examples/comment Ballistic

x

x

Tic Dystonia Chorea

X

X

(Modified from Hallett, 1999, with pennission.)

Tonic

x

Epileptic myoclonus Ballistic movement overflow myoclonus Dystonic myoclonus

x

Not fully involuntary

X

Also athetosis

X

Also dyskinesia, ballism

ELECTROMYOGRAPHY

A

BICEPS

TRIClPS

ARM

STEP POSITION

B BICEPS

TRICEPS

SUP

II

different types of movements. Specification of duration in the range of 30-300 ms merely by clinical inspection is virtually impossible due to the relative slowness of the mechanical events compared with the electrical events. Finally, antagonist muscle relationships can be specified as synchronous or asynchronous (reciprocal) by inspection of the EMG signal. In a tremor, asynchronous activity would be described as alternating (Fig. 4). There are three EMG patterns that may underlie involuntary movements (Figs. 5 and 6) (Hallett et al., 1987, 1994; Hallett, 1997, 1999,2000). One pattern, which can be called "reflex", resembles the burst occurring in many reflexes, including H-reflexes and stretch reflexes. The EMG burst duration is 10-30 ms, and EMG activity in the antagonist muscle is virtually always synchronous. Another pattern, which can be called "ballistic", resembles voluntary ballistic movements with a triphasic pattern; there is

AIlM POSITION

Fig. 3. EMG activity in biceps and triceps during (A) fast flexion of the elbow and (B) slow, smooth flexion. STEP indicates the target to be tracked and ARM POSITION is the actual elbow angle; reaction time and movement time information can be obtained from these records. The vertical calibration line corresponds to 500 mV for A and 20 mV for B. Modified from Hallett et al., 1975, with permission.

appearance of repetitrve cycles of the triphasic pattern to complete the movement. With dystonia and athetosis, there is excessive activity, including cocontraction activity, in the antagonist. Excessive activity also overflows into muscles not needed for the action. EMG burst length can be prolonged. In athetosis particularly, there are a variety of abnormal patterns of antagonist activity that appear to block the movement from occurring. Inspection of the EMG signal of an involuntary movement reveals, first, whether the movement is regular (usually a tremor) or irregular. There are sometimes surprises in such an analysis. Rhythmic EMG activity can appear irregular clinically if the amplitude varies; irregular EMG activity will sometimes appear rhythmic clinically if it is rapid. The duration of the EMG burst associated with an involuntary movement can also be measured; specific ranges of duration are associated with

A

EXT INn

B TIB ANT

GASTROC

Fig. 4. Recordings from pairs of antagonist muscles in different tremors. (A) Needle EMG recordings from the first lumbrical and the extensor indicis in a patient with essential tremor showing synchronous activation. (B) Surface EMG recordings in a patient with Parkinson's disease showing alternating activity in tibialis anteriorand gastrocnemius. From Sabra and Hallett, 1984, with permission.

12

Fig. 5. Comparison of (A) "reflex" and (B) "ballistic" EMG appearance underlying different types of myoclonus. Part A is from a patient with reticular reflex myoclonus, and part B is from a patient with ballistic movement overflow myoclonus. Vertical calibration is 1 mV for part A and 0.5 mV for part B. From Chadwick et al., 1977, with permission.

a burst of activity in the agonist muscle lasting 50-100 ms, a burst of activity in the antagonist muscle lasting 50-100 ms, and then return of activity in the agonist, often in the form of another burst. The third pattern, which can be called "tonic", resembles slow voluntary movements and is characterized by continuous or almost continuous EMG activity lasting for the duration of the movement, from 200-1000 ms or longer. Activity can be solely in the agonist muscle, or there can be some cocontraction of the antagonist muscle with the agonist.

M.HALLETT

Different types of myoclonus show one of the three types of patterns, and the EMG can be very helpful in making a diagnosis. Dystonia and athetosis show largely tonic patterns. Chorea is characterized by a wide variation of EMG burst durations encompassing all three patterns. In tic, there can be ballistic or tonic patterns. These data are summarized in Table 1. There can also be a brief lapse in tonic innervation that is clinically called asterixis or negative myoclonus (Shibasaki, 1995). Clinically, it appears as an involuntary jerk superimposed on a postural or intentional movement. Careful observation often reveals that the jerk is in the direction of gravity, but this can be difficult since the lapse is frequently followed by a quick compensatory antigravity movement to restore limb position. The involuntary movement is usually irregular, but when asterixis comes rapidly there may be the appearance of tremor. EMG analysis shows characteristic synchronous pauses in antagonist muscles (Fig. 7). In clinical practice, it is of course valuable to couple EMG studies with either kinesiologic or EEG observations or both. Nevertheless, the simple application of EMG can be extremely helpful as a first step.

Acknowledgment This review includes sections updated from earlier chapters (Hallett, 1999, 2000). Work of the U.S. government, it has no copyright.

Fig. 6. EMG recordings from a patient with focal hand dystonia when attempting hand writing. Recordings are from 4 muscles in the right arm during motor performance. From Cohen and Hallett, 1988, with permission.

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Fig. 7. EMG and accelerometric recording of asterixis. EMG is from flexors and extensors of the wrist and accelerometer was on the dorsum of the hand. From Hallett, 1999, with permission.

References Berardelli, A, Hallett, M, Rothwell, JC, Agostino, R, Manfredi, M and Thompson, PD et al. (1996) Review Article. Single-joint rapid arm movements in normal subjects and in patients with motor disorders. Brain, 119: 661-674. Chadwick, D, Hallett, M, Harris, R, Jenner, P, Reynolds, EH and Marsden, CD (1977) Clinical, biochemical, and physiological features distinguishing myoclonus responsive to 5-hydroxytryptophan, tryptophan with a monoamine oxidase inhibitor, and clonazepam. Brain, 100: 455-487. Cohen, LG and Hallett, M (1988) Hand cramps: clinical features and electromyographic patterns in a focal dystonia. Neurology, 38: 1005-1012. Hallett, M (1997) Myoclonus and myoclonic syndromes. In: JJ Engel and TA Pedley (Eds.), Epilepsy: A Comprehensive Textbook. Lippincott-Raven, Philadelphia, pp. 2717-2723. Hallett, M (1999) Electrophysiologic evaluation of movement disorders. In: MJ Arninoff (Ed.), Electrodiagnosis in Clinical Neurology. Churchill Livingstone, New York,pp.365-380. Hallett, M (2000) Electrodiagnosis in movement disorders. In: KH Levin and HO Liiders (Eds.), Comprehensive Clinical Neurophysiology. W.B. Saunders Company, Philadelphia, pp. 281-294.

Hallett, M, Shahani, BT and Young, RR (1975) EMG analysis of stereotyped voluntary movements in man. J. Neurol. Neurosurg. Psychiatry, 38: 1154-1162. Hallett, M, Marsden, CD and Fahn, S (1987) Myoclonus (Chapter 37). In: PJ Vinken, GW Bruyn and HL Klawans (Eds.), Handbook of Clinical Neurology. Elsevier Science Publishers, Amsterdam, pp. 609-625. Hallett, M, Berardelli, A, Delwaide, P, Freund, H-J, Kimura, J and Lucking, C et al. (1994) Central EMG and tests of motor control. Report of an IFCN Committee. Electroencephalogr. Clin. Neurophysiol., 90, 404-432. Hof, AL (1997) The relationship between electromyogram and muscle force. Sportverletz Sportschaden, 11, 79-86. Perry, J and Bekey, GA (1981) EMG-force relationships in skeletal muscle. Crit. Rev. Biomed. Eng., 7: 1-22. Sabra, AF and Hallett, M (1984) Action tremor with alternating activity in antagonist muscles. Neurology, 34: 151-156. Shibasaki, H (1995) Pathophysiology of negative myoclonus and asterixis. In: S Fahn, M Hallett, HO Luders and CD Marsden (Eds.), Negative Motor Phenomena. Lippincott-Raven Publishers, Philadelphia, pp. 199209. Solomonow, M, Baratta, R, Zhou, BH, Shoji, H and D'Ambrosia, R (1986) Historical update and new developments on the EMG-force relationships of skeletal muscles. Orthopedics, 9: 1541-1543.

Movement Disorders Handbook of Clinical Neurophysiology, Vol. I

M. Hallett (Ed.) © ZOO3 Elsevier B.V. All rights reserved

15 CHAPTER 3

EEG (MEG)/EMG correlation Hiroshi Shibasaki'=

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10 ms Fig. 3. Paired-pulse inhibition and facilitation at short interstimulus-intervals (PPI, PPF). MEPs by a supra-threshold magnetic cortical test stimulus in relaxed first dorsal interosseous muscle are inhibited by a prior, sub-threshold conditioning stimulus at short inter-stimulus intervals of 1-5 ms (PPI) and facilitated at longer intervals of 10--15 ms (PPF). The left panel shows examples of EMG data from one healthy subject. The first trace shows absence of any MEP to the conditioning stimulus alone. The lower two records have two superimposed traces, the MEP to the test stimulus given alone, and the MEP to the test stimulus when given 3 (middle traces) or 2 ms (lower traces) after the conditioning stimulus. The larger MEP (dotted line) is the response to the test stimulus alone. It is dramatically suppressed at these two inter-stimulus intervals. Each trace is the average of 10 trials. The right panel shows the averaged group data of 6 subjects (means ±SD). The conditioned MEP is given as a percentage of the test MEP (y-axis) and expressed as a function of the inter-stimulus interval (x-axis) (with kind permission, from Kujirai et al., 1993a).

physiologically distinct from PPI and not merely a rebound facilitation (Ziemann et aI., 1996b; Strafella and Paus, 2001). PPI and PPF are tested at muscle rest, as both measures are suppressed by even slight voluntary contraction (Ridding et aI., 1995). PPI and PPF are studied predominantly in hand muscles but can be obtained similarly in many other muscles (Chen et aI., 1998b). PPI but not PPF decreases with age (Peinemann et aI., 2001) and may be affected by personal trait, such as the level of neuroticism (Wassermann et aI., 2001) and by the menstrual cycle (Smith et aI., 1999). GABA-A receptor agonists, N-methyl-o-aspartate (NMDA) receptor blockers, dopamine receptor agonists and serotonin result in PPI increase and/or PPF decrease (for review, Ziemann and Hallett (2000». Dopamine (D2) receptor antagonists, muscarinic receptor antagonists, GABA-B auto-receptor activation and norepinephrine agonists decrease PPI and/or increase PPF (Ziemann and Hallett, 2000; Bor-

oojerdi et aI., 2001; Liepert et aI., 2001; Plewnia et aI., 2001). Recent findings indicate that the PPI consists of at least two distinct phases of inhibition with different physiological properties, one at interstimulus intervals of about I ms, and the other at intervals of around 2.5 ms (Fisher et aI., 2002). Futhermore, PPI may in fact be a net inhibition, consisting of strong inhibitory and weaker facilitatory effects (see l-wave facilitation below). In summary, it is currently believed that PPI and PPF test the integrity and excitability of inhibitory and excitatory neuronal circuits in the motor cortex which are under the control of various neurotransmitter systems and in tum control the excitability of corticospinal neurons. 8.3.6.2. Applications (for reviews, Ziemann et al., 1998a; Ziemann, 1999; Cantello et al., 2002) Epilepsy, cerebral stroke, Parkinson's disease, Huntington's disease and other dyskinetic syn-

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dromes, dystonia, cerebellar ataxia, ALS, autosomaldominant spastic paraplegia, stiff-person syndrome, restless legs syndrome, migraine, limb amputees, Alzheimer's disease, tic and other neuro-psychiatric disorders. Most of these diseases show a decrease in PPI and/or an increase in PPF. Therefore, while suggestive of a good sensitivity for the detection of abnormalities of motor cortex excitability, PPI and PPF at present do not differentiate between even very different pathological conditions. This weakness may be overcome by refined paired-pulse stimulation techniques (Fisher et al., 2002). 8.3.7. I-wave facilitation 8.3.7.1. Techniques and principles I-wave facilitation refers to the facilitatory effects of a sub-threshold second pulse on the amplitude of a test MEP elicited by a supra-threshold first stimulus given through the same stimulation coil 0.5-6.0 IDS earlier (Ziemann et al., 1998b). Alternatively, two pulses close to MT can be used (Tokimura et al., 1996). I-wave facilitation occurs at discrete inter-stimulus intervals of 1.1-1.5 ms, 2.3-2.9 ms and 4.1-4.5 ms with much less effect at intermediary intervals (Tokimura et al., 1996; Ziemann et al., 1998b). I-wave facilitation originates through mechanisms at the level of the motor cortex (Tokimura et al., 1996; Ziemann et al., 1998b; Di Lazzaro et al., 1999c; Hanajima et al., 2002). The inter-peak latency between the three facilitatory MEP peaks is approximately 1.5 ms, comparable to the succession of I-waves (see above). I-wave facilitation is reduced by GABAergic drugs (Ziemann et al., 1998c; Wischer et al., 2001). In summary, the available evidence suggests that this paired pulse technique probes the excitability of motor cortical circuits that are responsible for the generation ofl-waves. 8.3.7.2. Applications Patients with multiple sclerosis may show a reduction of l-wave facilitation or even a complete disorganization of the MEP facilitatory peaks (Ho et ai., 1999).

8.4. Motor cortex connectivity As a general principle, motor cortex connectivity is assessed by testing the effects of a conditioning

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stimulus on the amplitude of a test MEP elicited by stimulation of the motor cortex. Another possibility is to stimulate the motor cortex and assess the activation of distant target structures by functional imaging (PET, fMRI) or electrophysiological methods (EEG, SEP, MRP). 8.4.1. Connectivity between different motor representations within motor cortex 8.4.1.1. Techniques and principles Focal conditioning stimulation of the leg area of the motor cortex inhibits a test MEP elicited by a supra-threshold pulse given a few milliseconds (1-5 ms) later over the hand area, and vice versa (Kujirai et al., 1993a). This suggests that within motor cortex connectivity is largely inhibitory. 8.4.1.2. Applications Lateral spread into motor representations of the proximal arm can occur during high-frequency repetitive TMS of the hand area of the motor cortex suggesting stimulation-induced break-down of cortico-cortical inhibitory mechanisms (Pascual-Leone et al., 1994c). Similarly, propagation of epileptic activity, such as the Jacksonian march, or an overflow of movement associated with an intended focal voluntary movement, such as in dystonia, may originate from deficient cortico-cortical inhibition between different motor representations, although this has not yet been tested. 8.4.2. Connectivity ofpremotor cortex and SMA with motor cortex 8.4.2.1. Techniques and principles Conditioning focal stimulation 3-5 em anterior to the hand area of the motor cortex, or 6 em anterior to the vertex inhibits the test MEP elicited by suprathreshold stimulation over the hand area of the motor cortex (Civardi et al., 2001). This effect is maximal at sub-threshold intensity (90% of active MT) and at an inter-stimulus interval of 6 IDS. It is thought that these conditioning sites correspond to the premotor cortex and the pre-SMA or SMA proper, and that their connections to the hand area of the motor cortex are largely inhibitory (Civardi et al., 2001; Gerschlager et al., 2001).

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8.4.2.2. Applications No data available yet. Potentially useful in neurological diseases with a presumed abnormal connectivity between the pre-motor cortex or SMA and the primary motor cortex, in particular movement disorders. 8.4.3. Inter-hemispheric connectivity between the two motor cortexes 8.4.3.1. Techniques and principles The hand areas of the two motor cortexes are connected, although sparsely, by callosal fibers (Gould et al., 1986; Rouiller et al., 1994). This transcallosal connection can be tested by the ipsilateral silent period (ISP) (Wassermann et al., 1991; Ferbert et al., 1992b; Meyer et al., 1995; Meyer et al., 1998) and inter-hemispheric inhibition and facilitation measured with a paired stimulation protocol (Ferbert et al., 1992b; Ugawa et al., 1993; Netz et al., 1995; Gerloff et al., 1998; Di Lazzaro et al., 1999a; Hanajima et al., 200la). The ISP refers to the interruption of voluntary tonic EMG activity caused by TMS of the motor cortex ipsilateral to the target muscle. In hand muscles, the ISP onset is 10-15 ms later than the onset latency of the contralateral MEP. This difference corresponds to the estimated conduction time through the corpus callosum (Cracco et al., 1989). ISP duration in hand muscles is about 30 ms (Wassermann et al., 1991; Ferbert et al., 1992b; Meyer et al., 1995; Meyer et al., 1998). Children up to the age of 6 years do not show an ISP (Heinen et al., 1998), suggesting maturation of inter-hemispheric connections between the two motor cortexes later in life. Paired stimulation applies a conditioning stimulus over one motor cortex followed by a test stimulus over the other motor cortex. Inhibition of the test MEP occurs at inter-stimulus intervals of around 10 ms, if the intensities of both stimuli are clearly above MT (Ferbert et al., 1992b; Netz et al., 1995). Interhemispheric facilitation results at inter-stimulus intervals of 4-5 or 8 ms, if the intensity of the conditioning stimulus is close to MT (Ugawa, 1993 #1067; Hanajima et al., 200la ). Very likely, these inter-hemispheric interactions are mediated by transcallosal fibers (Di Lazzaro et al., 1999a), but some data point toward the contribution of other pathways

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at the subcortical or even spinal level (Gerloff et al., 1998).

8.4.3.2. Applications ISP: Surgical lesions or agenesis of the trunk of the corpus callosum (Meyer et al., 1995; Meyer et al., 1998), multiple sclerosis (Boroojerdi et al., 1998; Hoppner et al., 1999; Schmierer et al., 2000), dystonia (Niehaus et al., 2001b), hydrocephalus (Roricht et al., 1998), schizophrenia (Hoppner et al., 2001). Inter-hemispheric facilitation/inhibition in the paired TMS protocol: Cortical myoclonus (Brown et al., 1996; Hanajima et al., 2001b), cortical-subcortical cerebral stroke (Boroojerdi et al., 1996), congenital mirror movements (Mayston et al., 1999), professional musicians (Ridding et al., 2000), schizophrenia (Daskalakis et al., 2002). 8.4.4. Connectivity from cerebellum to contralateral motor cortex 8.4.4.1. Techniques and principles The cerebellar hemispheres can be activated with percutaneous electrical (Ugawa et al., 1991a) or magnetic stimulation (Saito et al., 1995; Ugawa et al., 1995b; Werhahn et al., 1996). This leads to, on average, 50% inhibition of a test MEP elicited from the motor cortex contralateral to cerebellar stimulation at inter-stimulus intervals of 5-7 ms (Ugawa et al., 1995b; Werhahn et al., 1996). It is thought that this inhibition results from activation of the cerebello-dentato-thalamo-cortical pathway. An inhibition starting at slightly longer inter-stimulus intervals of 7-8 ms is probably caused by activation of peripheral nerve afferents at the level of the brachial plexus (Werhahn et al., 1996). 8.4.4.2. Applications The inhibitory interaction between cerebellum and motor cortex is reduced or absent in patients with lesions along the cerebello-dentato-thalamocortical pathway (Di Lazzaro et al., 1994; Ugawa et al., 1994a; Ugawa et al., 1997; Matsunaga et al., 2001). 8.4.5. Connectivity from motor cortex to ipsilateral spinal alpha-motoneurons

8.4.5./. Techniques and principles Ipsilateral corticospinal projections withdraw in an activity-dependent process during the first years

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of life (Miiller et al., 1997; Eyre et aI., 2001). In adults, ipsilateral MEP in hand muscles are elicited only in a fraction of subjects, and only if strong voluntary contraction of the target muscle and high stimulus intensity are used (Wassermann et aI., 1991; Wassermann et aI., 1994; Ziemann et aI., 1999). Compared to contralateral MEP, ipsilateral MEP are much smaller, delayed by 5-10 ms, and the optimal stimulation site is slightly more lateral and anterior (Wassermann et aI., 1991; Wassermann et aI., 1994; Ziemann et aI., 1999). The ipsilateral MEP is either mediated by a weak residual uncrossed corticospinal tract (Eyre et aI., 2001) or an oligosynaptic cortico-reticulospinal projection (Ziemann et aI., 1999). 8.4.5.2. Applications Congenital/persistent mirror movements (e.g. Farmer et aI., 1990; Cohen et aI., 1991c), cerebral palsy (e.g. Farmer et aI., 1991; Carr et aI., 1993; Cincotta et al., 2000), adult cerebral stroke: ipsilateral MEP from the affected motor cortex (Fries et aI., 1991;Alagona et aI., 2001), adult cerebral stroke: ipsilateral MEP from the unaffected motor cortex (Turton et al., 1996; Netz et aI., 1997; Caramia et aI., 2000; Trompetto et aI., 2000), corticobasal ganglionic degeneration (Valls-Sole et aI., 2001). 8.4.6. Connectivity from cutaneous and muscle afferents to motor cortex 8.4.6.1. Techniques and principles Cutaneous and proprioceptive afferent information from the body can influence motor cortex excitability at short latencies. In upper limb muscles, electrical stimulation of a mixed nerve below or at motor threshold (resulting primarily in activation of Ia fibers) and muscle stretch produce MEP facilitation in the stimulated or stretched muscle at inter-stimulus intervals around 20-30 ms, usually followed by MEP inhibition at longer intervals (Troni et aI., 1988; Day et aI., 1991; Deuschl et aI., 1991; Mariorenzi et aI., 1991; Rossini et aI., 1991; Palmer and Ashby, 1992b; Baldissera and Leocani, 1995). The short-latency MEP facilitation after mixed nerve stimulation may be preceded by a shortlatency and short-lasting MEP inhibition at inter-stimulus intervals of 19-21 ms (Tokimura et al., 2000). Blockade of muscarinic receptors leads to a reduction of this inhibition (Di Lazzaro et aI.,

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2000). Non-painful conditioning stimulation of digital cutaneous nerves produce predominantly short-latency inhibition in muscle adjacent to the stimulated finger, consistent with the It inhibitory period but merging also into the E2 excitatory period of the cutaneous reflex (Troni et aI., 1988; Mariorenzi et aI., 1991; Maertens de Noordhout et aI., 1992b; Clouston et aI., 1995; Manganotti et aI., 1997; Classen et al., 2000; Kofler et aI., 2001; Tamburin et aI., 2001). Short-latency MEP inhibition after median nerve stimulation occurs in antagonistic muscles (wrist extensors) supplied by the radial nerve, suggesting that the classical reciprocal inhibition at the spinal cord level might be assisted by a similar reciprocal inhibition at the level of motor cortex (Bertolasi et al., 1998). MEP modulation by afferent input from the hand is somatotopically organized (Terao et aI., 1995; Kofler et aI., 2001; Tamburin et al., 2001). All reported modulating effects of cutaneous and proprioceptive inputs on MEP amplitude occur largely or exclusively through mechanisms at the level of motor cortex because MEP evoked by TES and spinal alpha-motoneuron excitability as tested with H-reflexes and F waves are significantly less affected. 8.4.6.2. Applications Patients with lesions of the central somatosensory pathways lack a short-latency MEP modulation after conditioning stimulation of peripheral nerves (Bertolasi et al., 1998; Terao et aI., 1999). In contrast, patients with certain forms of epilepsy, such as progressive myoclonic epilepsy (Reutens et aI., 1993b; Cantello et aI., 1997) and patients with Creutzfeldt-Jacob disease (Yokotaet aI., 1994) show markedly increased short-latency MEP facilitation, indicating enhanced motor cortex excitability timelocked to the afferent input. 8.4.7. Other inputs to motor cortex (photic, auditory, nociceptive) 8.4.7.1. Techniques and principles MEPs in hand muscles are inhibited 55-70 ms after the unexpected presentation of a flash light (Cantello et al., 2000), or 30-60 ms after an unexpected loud sound (>80 dB, >50 ms duration) (Furubayashi et al., 2000). The latter effect habituates rapidly, and therefore, may transmit through the same system as the startle response. Nociceptive

TRANSCRANIAL MAGNETIC STIMULATION

electrical stimulation of digital nerves results in MEP inhibition of hand muscles but MEP facilitation of the biceps muscle (Kofler et aI., 1998; Kofler et aI., 2001). This MEP modulation occurs irrespective of whether the test MEP is elicited by TMS or TES, and is therefore best explained by a spinal withdrawal reflex. However, if nociceptive stimulation of the hand is produced by a COz laser, this results in MEP inhibition of hand muscles and the biceps if MEP are elicited by TMS (Valeriani et aI., 2001). MEP elicited by TES remain unaffected, suggesting a global inhibition of motor cortex following nociceptive input. 8.4.7.2. Applications No data available yet. MEP modulation by photic input may be useful in photic cortical reflex myoclonus. MEP modulation by auditory input may be useful in startle disease. 8.4.8. Motor cortex output in distant target structures tested by PET, fMRI. EEG. SEP, MRP 8.4.8.1. Techniques and principles Positron emission tomography (PET) can be used to detect metabolic change in brain areas distant from the cortex stimulated by repetitive TMS (rTMS). rTMS of the human frontal eye field results in visual cortex and superior parietal and medial parieto-occipital cortex network activation (Paus et aI., 1997). rTMS of motor cortex results in variable results depending on rTMS frequency, intensity and number of stimuli, and on the PET method ('8FDG, HzI50 ) (Fox et al., 1997; Paus et aI., 1998; Siebner et aI., 1998, 2000a, b, 2001). Most studies show a network activation, including the stimulated sensory-motor cortex, SMA and motor cortex of the opposite hemisphere. The combination of rTMS with functional magnetic resonance imaging (fMRI) is technically more difficult to achieve because the TMS pulses have to be interleaved with MR image acquisition. The first available studies demonstrate local activation of the stimulated motor cortex, both in block and singletrial designs (Bohning et aI., 1998; Bohning et aI., 1999; Bohning et aI., 2000). The combination of TMS and electroencephalography (EEG) allows assessment of TMS induced changes in electrical brain activity with high temporal resolution. Transcallosal responses appear

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8.8-12.2 ms after TMS of one motor cortex at EEG electrodes over homologous areas of the opposite hemisphere (Cracco et aI., 1989). High-resolution multi-channel EEG and inversion algorithms show that TMS of the sensori-motor cortex elicits an immediate response at the stimulated site that spreads to adjacent ipsilateral motor areas within 5-10 ms and to homologous areas in the opposite hemisphere within 20 ms (Ilmoniemi et aI., 1997; Ilmoniemi et aI., 1999; Komssi et aI., 2002). Highfrequency rTMS of frontal cortex results in an increase in directed EEG coherence between the stimulated cortex and other electrode sites, mainly within the same hemisphere (ling and Takigawa, 2000). The P25 component of the median nerve somatosensory evoked potentials (SEP) is increased when conditioned by TMS over the motor cortex contralateral to median nerve stimulation (Kujirai et al., 1993b; Seyal et aI., 1993; Schiirmann et aI., 2001). This effect is maximal when TMS precedes the median nerve stimulus by 30-70 ms (Seyal et aI., 1993), by 10 ms (Kujirai et aI., 1993b), or is given simultaneously (Schiirmann et aI., 2001). This modulation of cortical components of the SEP may underlie the TMS induced degradation of sensory stimulus detection (Cohen et al., 1991b). Low-frequency (l Hz) rTMS of motor cortex given at 110% MT over a period of 15 min leads to a significant reduction in movement related potential (Bereitschaftspotential) amplitude (Rossi et aI., 2000), suggesting that rTMS interferes with movement-related brain activity, probably through influence on cortical inhibitory networks.

8.5. Repetitive transcranial magnetic stimulation 8.5.1.1. Techniques and principles RTMS refers to repeated TMS delivered to a single scalp site (Wassermann, 1998) and requires specially designed magnetic stimulators. RTMS is divided into low-frequency (~1 Hz) and highfrequency stimulation (> 1 Hz). This division is based on the different physiological effects and degrees of risk. Low-frequency rTMS results in a long-lasting depression of the excitability of the stimulated or connected cortex (Chen et aI., 1997a; Boroojerdi et aI., 2000; Maeda et al., 2000; Muellbacher et aI., 2000; Enomoto et aI., 2001;

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110

Gerschlager et al., 2001; Touge et al., 2001; Tsuji and Rothwell, 2002) and has a low risk for adverse effects (Wassermann, 1998). In contrast, highfrequency rTMS leads to an increase in the excitability of the stimulated cortex (Pascual-Leone et al., 1994c; Maeda et al., 2000; Peinemann et al., 2000; Wu et al., 2000) and is associated with a higher risk for adverse effects (Wassermann, 1998). The parameters of stimulation are: (1) frequency; (2) intensity; (3) train length; (4) inter-train interval; and (5) total number of pulses. High-intensity and highfrequency rTMS bears the risk for spread of stimulus effects and induction of EMG discharge beyond the duration of stimulation (Pascual-Leone et al., 1993; Pascual-Leone et al., 1994c). This may result from a breakdown of cortico-cortical inhibition, and the generation of local epileptic activity. Accidental seizures were induced in altogether six healthy subjects by this form of high-intensity and -frequency rTMS (Wassermann, 1998). As a consequence, a table of the maximum safe duration of an rTMS train at a given combination of frequency and intensity was published, based on the NINDS experience (Wassermann, 1998). This table has two shortcomings as it does not include frequencies below 1 Hz and intensities below resting MT. Knowledge about the safety of the inter-train interval is limited but it was noted that two of the accidental seizures were induced at particularly short inter-train intervals ~ 1 s (Wassermann et al., I 996a; Chen et al., 1997d). Several safety studies did not find significant acute or short-term adverse effects toward motor, neuropychological, vegetative or neuro-hormonal function (Pascual-Leone et al., 1993; Wassermann et al., 1996b; Foerster et al., 1997; Jahanshahi et al., 1997; Niehaus et al., 1998; Evers et al., 2001; Niehaus et al., 2001a). It is currently unknown whether there exists an increased risk for any long-term adverse effects, in particular in those subjects who have received a large number of stimuli.

8.5.1.2. Applications Generally, rTMS is applied for two reasons, investigation of cortex function or therapy. Investigation of cortex function relies on the idea that rTMS can temporarily inactivate the stimulated cortex or neuronal network in the sense of a transient and fully reversible 'lesion', thus interfering with sensori-motor or cognitive tasks (for reviews,

Pascual-Leone et al., 1999; Walsh and Cowey, 2000). Therefore, in conjunction with PET and fMRI, rTMS can be used to determine the functional significance of metabolic activation that were demonstrated with functional neuro-imaging during sensori-motor or cognitive tasks (Cohen et al., 1997; Rossi et al., 2001). One application of particular relevance is interference of rTMS with language and speech that potentially might be used in the future as a non-invasive means for pre-surgical determination of language laterality (Pascual-Leone et al., 1991; Jennum et al., 1994; Michelucci et al., 1994; Epstein et al., 1996, 1999; Stewart et al., 2001). The most extensively investigated application of rTMS is as a therapeutic tool in major depression (for recent critical review, Lisanby and Sackheim, 2000). Other fields of potential therapeutic application are central pain following thalamic or brainstern stroke (Lefaucheur et al., 2001a, b), epilepsy (Tergau et al., 1999; Menkes and Gruenthal, 2000), Parkinson's disease (Pascual-Leone et al., 1994b; Siebner et al., 1999a; Siebner et al., 2000b), or writer's cramp (Siebner et al., 1999b). Although this appears to be an extremely important clinical avenue of rTMS, it should be noted that all of the quoted reports have not yet been rigorously replicated, and therefore have to be considered experimental work. Blinded and sham-controlled trials on large populations of patients are needed (Wassermann and Lisanby, 2001). Furthermore, recipes need to be developed for which parameters of rTMS to use for which therapeutic application. Finally, therapeutic rTMS sometimes makes things worse rather than better (Boylan et al., 2001), as may happen with any therapeutic application.

References Ahonen, JP, Jehkonen, M, Dastidar, P, Molnar, G and Hakkinen, V (1998) Cortical silent period evoked by transcranial magnetic stimulation in ischemic stroke. Electroencephalogr. Clin. Neurophysiol., 109: 224229. Alagona, G, Delvaux, V, Gerard, P, De Pasqua, V, Pennisi, G, Delwaide, PI, Nicoletti, F and Maertens de Noordhout, A (2001) Ipsilateral motor responses to focal transcranial magnetic stimulation in healthy subjects and acute-stroke patients. Stroke, 32: 13041309. Amadio S, Panizza M, Pisano F, Madema L, MiscioC, Nilsson, J, Volonte, MA, Comi, G and Galardi, G

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Walsh, V and Cowey, A (2000) Transcranial magnetic stimulation and cognitive neurosciences. Nature Rev., I: 73-79. Wang, B, Toro, C, Zeffiro, TA and Hallett, M (1994) Head surface digitization and registration: a method for mapping positions on the head onto magnetic resonance images. Brain Topogr., 6: 185-192. Warren, JD, Kimber, TE and Thompson, PD (1999) The silent period after magnetic brain stimulation in generalized tetanus. Muse. Nerve, 22: 1590-1592. Wassermann, EM (1998) Risk and safety of repetitive transcranial magnetic stimulation: Report and recommendations from the international workshop on the safety of repetitive transcranial magnetic stimulation June 5-7, 1996. Electroencephalogr. Clin. Neurophysiol., 108: 1-16. Wassermannm, EM and Lisanby, SH (2001) Therapeutic application of repetitive transcranial magnetic stimulation: a review. Clin. Neurophysiol., 112: 1367-1377. Wassermann, EM, Fuhr, P, Cohen, LG and Hallett, M (1991) Effects of transcranial magnetic stimulation on ipsilateral muscles. Neurology, 41: 1795-1799. Wassermann, EM, McShane, LM, Hallett, M and Cohen, LG (1992) Noninvasive mapping of muscle representations in human motor cortex. Electroencephalogr. Clin. Neurophysiol., 85: 1-8. Wassermann, EM, Pascual-Leone, A and Hallett, M (1994) Cortical motor representation of the ipsilateral hand and arm. Exp. Brain Res., 100: 121-132. Wassermann, EM, Cohen, LG, Flitman, SS, Chen, Rand Hallett, M (1996a) Seizures in healthy people with repeated "safe" trains of transcranial magnetic stimuli (letter). Lancet, 347: 825-826. Wassermann, EM, Grafrnan, J, Berry, C, Hollnagel, C, Wild, K, Clark, K and Hallett, M (1996b) Use and safety of a new repetitive transcranial magnetic stimulator. Electroencephalogr. Clin. Neurophysiol., 101: 412-417. Wassermann, EM, Wang, B, Zeffiro, TA, Sadato, N, Pascual-Leone, A, Toro, C and Hallett, M (1996c) Locating the motor cortex on the MRI with transcranial magnetic stimulation and PET. Neuroimage, 3: 1-9. Wassermann, EM, Greenberg, BD, Nguyen, MB and Murphy, DL (2001) Motor cortex excitability correlates with an anxiety-related personality trait. Biol. Psychiatry, 50: 377-382. Weber, M, Eisen, A and Nakajima, M (2000) Corticomotoneuronal activity in ALS: changes in the peristimulus time histogram over time. Clin. Neurophysiol., Ill: 169-177. Werhahn, KJ, Fong, JK, Meyer, BU, Priori, A, Rothwell, JC, Day, BL and Thompson, PD (1994) The effect of magnetic coil orientation on the latency of surface EMG and single motor unit responses in the first dorsal

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Movement Disorders Handbook of Clinical Neurophysiology, Vol. I M. Hallett (Ed.) © 2003 Elsevier B.V. All rights reserved

127 CHAPTER 9

Movement disorders surgery: microelectrode recording from deep brain nuclei W.D. Hutchison'v", J.O. Dostrovsky" and A.M. Lozano'" a

Department of Surgery, Division of Neurosurgery, Toronto Western Hospital, 399 Bathurst St., Toronto, ON M5T 2S8, Canada b Department of Physiology, Faculty of Medicine, University of Toronto, Toronto, ON M5S IA8, Canada

9.1. Introduction The development of imaging techniques in stereotactic brain surgery has greatly enhanced the capabilities of direct targeting of subcortical structures, but there is still a need for functional confirmation and optimization of the target. Microelectrode recordings provide the most definitive and accurate method of localization. The use of microelectrode recording for localizing subcortical targets for stereotactic brain surgery began in the 1950s with Albe-Fessard and Guiot (Guiot et aI., 1962) who used the technique to precisely delineate the motor and sensory thalamic nuclei. Microelectrode recording involves the measurement of electrical activity of brain cells with a high spatial and temporal resolution with thin probes that produce minimal mechanical disturbance of the neuropil. For this reason the technique has long remained a principal method for the analysis of the function of neurons and nuclei in the brain. Indeed, important insights into the pathophysiology of various movement disorders can be gained by investigation of the individual properties and population characteristics of neurons in the globus pallidus, thalamus and subthalamic nucleus. Microelectrode techniques are also continuing to evolve to examine simultaneous recordings from neuron pairs (Hurtado et aI., 1999; Levy et aI., 2000) and neuronal assemblies in the same and different nuclei (Nicolelis et aI., 1998).

* Correspondence to: Dr. W.D. Hutchison, Div. of Neurosurgery, Toronto Western Hospital West Wing 4-433, 399 Bathurst St., East Wing 6-528, Toronto, ON M5T 2S8, Canada. E-mail address: [email protected] or [email protected] Tel.: (416)-603-5800, ext. 2226; fax: (416)-603-5298.

Several reports of microelectrode recording techniques have been published with a focus on thalamus (Lenz et aI., 1988; Tasker et al., 1998), globus pallidus (Sterio et al., 1994; Lozano et aI., 1996; Hutchison 1998; Vitek et aI., 1998), and subthalamic nucleus (Hutchison et al., 1998a) and general articles on the techniques of extracellular recording in laboratory animals and humans (Millar 1992; Dostrovsky 1999; Lalley et al., 1999). The purpose ofthe present chapter is to review the current techniques used in our operating room and briefly outline the major neurophysiological landmarks that need to be identified for target determination in each case.

9.2. Microelectrode assembly Some detail is required in a discussion of microelectrodes, since most problems with recording are due to faulty or damaged electrodes rather than the electronic instrumentation used to amplify, filter and display the signals. In particular the fine tip of the electrode is susceptible to damage by mechanical or electrical forces. Electrodes with thicker shanks and blunter tips are less susceptible to bending and tip damage but produce more tissue damage and yield poorer multi-unit recordings. Completed electrodes with extensions allowing them to be used in a stereotactic guide tube are commercially available, but some may prefer to assemble their own. The main advantages of local manufacture are substantial cost savings and avoidance of the common problem of bending or curling of the fine tip during transport which may not be visible unless inspected under a microscope or loupes. Shank skewing may be less problematic as far as recording of good spikes is concerned but the electrode may track obliquely to the desired course. We fabricate our own electrodes from commercially available

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components. Microelectrode tips (Microprobe, Potomac, MD) are mounted on Kapton (polyimide, MicroML, College Point, NY, 23 gauge) insulated stainless steel tubing (Small Parts, Miami Lakes, FL) to extend the length for use in the stereotactic guide tube. Tungsten has the desirable properties of high tensile strength and stiffness as thin wire. Platinum is relatively malleable so unsuited to thin electrode construction on its own but when present in an alloy with iridium becomes suitably stiff as thin wire. Platinum itself is desirable as an electrode material since it reacts with free chloride in the tissue and forms a Pt-PtCI or platinum black tip interface which is non-polarizable and irreversible. This means it can convert excess hydrogen ions into hydrogen and hydroxyl ions instead of reducing the metal and physically eroding the tip during microstimulation. However, most medical electrical stimulators use biphasic pulses, so there is no net charge transfer to the patient. Tungsten microelectrodes can be plated with platinum to confer these desirable properties (see below). Tip exposures in the range of 15-25 urn are the most useful and give mostly single and occasionally multi-unit recordings. Larger tip sizes record from many more neurons making single unit discrimination more difficult whereas smaller tip sizes may record cells only in the immediate vicinity of the tip. The Parylene-C insulation on the portion of the electrode to be inserted into the extender tube is removed by mechanical stripping with fine emery paper or burning off by passing through a flame and the shank is crimped and inserted into 25 gauge stainless steel tubing so it is orthogonal with the extender tube. The 22 gauge Kapton tubing insulation fits over the extender and epoxy glue is used to make a continuous seal between the two insulators. The insulation can be tested by inserting just the electrode tip and then the rest of the shank into saline while observing the impedance reading, which should remain constant if there is no breech. Another method is to apply 3-10 V DC to the electrode in saline to watch electrolytic bubble formation, which should only occur at the tip. The thin coating of Parylene-C on the electrode tip is particularly sensitive to scratching so caution needs to be exercised during handling. Electrodes are plated using platinum and gold solutions of the free metal cations and cathodal current to attract those ions (Millar, 1992). The purpose of the prior gold plating is to aid in

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formation of a good bonding of the platinum on the tungsten. This is best carried out under microscopic control to monitor the amount of plating deposited, at least in the initial stages. The advantage of plating is to reduce the impedance and increase the signalto-noise but an added advantage is that it will protect the tungsten tip from oxidizing which occurs after prolonged storage (months). If electrodes are not plated they can be conditioned as described above in the bubble test to remove the tungsten oxides. Electrodes are best protected from damage by backloading them into 19 gauge shield tubing and securing them with adhesive tape. The shield tubing should be short enough and wide enough that the ethylene oxide will penetrate and sterilize the whole length of the electrode. Sometimes the tip can become curled during use and it will be noticeable that only vague small units are picked up in the background or there is background injury discharge before good single units can be seen. As a general rule, if there are no units recorded after about 5 mm of tracking down with the electrode, then probably the electrode is bad, since most targets are in cell dense areas, and even white matter regions show the occasional unit. With most commercially available recording systems, the impedance of the electrode can be measured in situ during a brief pause in the recording. Unplated 15-25 urn tip tungsten electrodes have impedances about 0.8-1.2 Mil. and the platinum-plated electrodes our group uses are typically 0.2-0.6 MO. Low values indicate a break in the insulation, and high values indicate that the tip may have been eroded by repeated high intensity stimulation. 9.3. Extracellular recording of spikes The term 'single unit' refers to extracellularly recorded potentials arising from action potentials generated by a single neuron. Typically, if the potential arises from the somatodendritic region of the cell the waveform is usually biphasic and of 1-2 ms duration with an after-potential, and this is referred to variously as a cell, spike or neuron. If the waveform of the potential is mono-phasic and short duration < I ms with no after-potential this usually means that its source is an axonal action potential. Multi-unit recording refers to a combination of potentials from many cells recorded simultaneously. While this allows several units to be sampled

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simultaneously, which may expedite the identification of movement-related activity, the firing rate of individual cells cannot be determined with any accuracy. Electrodes with smaller tip sizes will record mostly single units and the occasional axon especially in white matter regions such as the internal capsule. With larger tipped electrodes, more potentials are recorded at a further distance from the tip, so that in addition to the multi-units, the background noise in the recording is larger when in cell-dense regions.

9.4. Amplification and filtering of signals The relatively small bioelectric potentials (- 100 J..L V) must be amplified several thousand times (usually -5,000-50,000) for passing the signal to audio monitors and driving oscilloscopes and data display systems of computers. Typically, differential amplification is employed, so that what is amplified is the difference in signal intensity on the positive and negative leads so any large electromagnetic induction producing an interference will be common to the two leads and subtracted from the signal of interest - usually termed common mode rejection. Filtering of the signal is used to remove unwanted frequencies in the very low «200 Hz) range to provide a stable DC baseline for spike discrimination. Most often noise occurs from interference from AC mains (60 Hz in North America, 50 Hz in some other countries) due to additional equipment in the operating room that is in the vicinity of the electrode leads. This can be due to electric patient beds, monitoring equipment, overhead fluorescent lights or projection equipment. With most recording systems commercially available, sufficient shielding for dealing with this stray capacitance has been incorporated into the low noise features of the amplifier design, so again, the noise is often due to a faulty electrode with a very high impedance or a poor ground connection. Very high frequencies (> 10 kHz) need to be removed to allow individual spike waveforms to be discriminated. One source of high frequency noise in the operating room is due to cautery equipment which still produces interference with the noise reduction features of new amplifiers. Some recording systems use digital filtering of signals, the theory of which is complex and beyond the scope of this review, but one advantage is the original signal is retained and

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filtering can be changed by changing the software settings if other aspects are desired such as low frequencies of field potential oscillations.

9.5. Commercially available recording systems Several companies provide electronic equipment for recording extracellular action potentials during deep brain recording. The Axon Instruments Guideline System 3000 has been recently reviewed (Starr, 1999) and further information is available on their website (http://www.axon.com).This intraoperative system includes a "Clinical Micropositioner" that is mounted on either a Crossman-Roberts-Wells (CRW) or Leksell frame and allows movement in the X (anteroposterior) and Y (mediolateral) positions, without further adjustment of the frame settings. The recording system includes an ultra low-noise amplifier, combined with an electrical stimulation unit and a touch sensitive monitor which displays the spike waveforms as they occur on a millisecond time base as well as a more conventional oscilloscope-like tracing on a time base of 1-2 s. The level crossings viewed on the spike waveform window are displayed in a frequency histogram with 0.1-1 s bins "spike ratemeter" and the firing rate in Hz is displayed and refreshed every second. A useful feature of the Axon system is a hand-held module with controls for setting the intensity for stimulation through the tip of the electrode as well as changing the intensity of stimulation and measuring the impedance of the electrode with a 1 kHz sine wave. The stimulation parameters can be modified with pulse widths settings from 0.05 to 1 ms and the frequency range is from I to 300 Hz, and intensities range from 0-100 J..LA. A zero setting may be used as a control "null-stimulation" procedure to verify patient reports of non-motor effects such as phosphenes or tingling. Conventional parameters for microstimulation are 1-100 J..LA, a 1 s train of pulses at 300 Hz and pulse widths of 200 J..LS. These parameters are useful in determining visual and motor responses for the identification of optic tract and internal capsule respectively during pallidal procedures, internal capsule and medial lemniscus during STN and thalamic procedures as well as tremor arrest or reduction. In cases of mild tremor reduction often a longer train length of 5 s or 10 s can be carried out while visually inspecting the tremor to clarify any longer-lasting effects on tremor. In practice, stimula-

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tion above 100 tJ-A is not recommended since the high impedance of the electrode (l Mil) dictates high voltages in excess of safety requirements (> 100 V) (and most stimulators will not be able to deliver voltages greater than this). Train durations can be given manually for stimulation as long as the switch is depressed or fixed durations from 0.5 to 20 s. The recording amplifier is blocked briefly while the stimulation pulses are delivered to the electrode so the leads, once attached to the sterile electrode shaft or connector of the drive holding it, do not need to be switched. Radionics (www.radionics.com) has a Neuroplan system including an Accudrive and Taha-Burchiel Recording Electrode Kit for use with the CRW frame system. The electrode drive in this system has a cable instead of hydraulics, which obviates possible fluid leakage or suction of air into the hydraulic drive upon retractions. The entire drive is lightweight and can be autoclaved. Further features allow integrated use with DBS implantation and the system is primarily designed for use with the CRW stereotactic frame. The system is fairly compact with all operations in desktop style computer system. Further details are available on their website. AlphaOmega (http://www.alphaomega-eng.com) makes the Neurotrek system which has the capability to record up to 5 channels of data from the 5 electrode configuration used by Benabid's group. The system also includes a stepper-motor microdrive with computer based settings, that can be also controlled via a hand-held remote and depth data logging features. It has microstimulation, macrostimulation and impedance measuring capabilities on any of the 5 possible electrodes and will also record EMG data on up to 7 additional channels. The high powered and high capacity computer provides online template matching algorithms and tagging features to identify specific traces as the trajectory progresses. The template matching is supported by alphaSort (Matlab) and provides comparison of spike shapes as well as spike clusters. Temporal features are included in a post-processing software package that should meet most high level research needs with plots such as interval time histograms and cross-correlogram displays of the various channels. Additional software will plot and print out the results of specific trajectories along with recognized or "tagged" traces of sample recordings and print out a color hard-copy of the full stereotactic map. Other independent

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workers have developed shareware programs (Interspike) that have processing features specifically designed for detection of spikes trains with temporal properties (bursting and pauses) found in pallidal structures (Favre et al., 1999). At the time of writing, Medtronic (www.medtronic.com) is also in the process of developing a Lead Point recording system for use with the CRW or else frame system. 9.6. Surgical technique Standard stereotactic technique is used to calculate the target from the AC and PC co-ordinates on MRI. More detailed descriptions of the surgical technique are available (Burchiel et al., 1997) as are complete monographs on the subject (Krauss, 1996; Germano, 1998; Lozano, 2000) and it will only be briefly reviewed here for the sake of completeness. A Leksell model G stereotactic frame is applied to the head with screw-pins inserted under local anesthetic, and a fiducial box containing channels filled with radio-opaque copper sulphate is placed over the frame to obtain three dimensional reference points (X - mediolateral; Y - anterior/posterior, Z inferior/superior) for the various MRI sections. Various techniques can be used to target the structure of interest, including direct calculation of the coordinates from the visualized structure on MRI scans, or indirect targeting by localization of wellvisualized landmarks such as the anterior and posterior commissures (AC, PC) and use of a standard stereotactic atlas (Schaltenbrand and Wahren, 1977) to infer the target location. In the former method, it has been noted that some significant distortion of images occurs with direct targeting. In the latter method, co-ordinates of AC and PC are obtained from the MRI console software (GE-Signa 1.5 Tesla magnet), and these are entered into a computer program that modifies the standard sagittal maps to obtain a customized stereotactic map for each patient. 9.7. Recordings in electrode trajectories targeting globus pallidus Several groups have described their methods for localizing the globus pallidus and surrounding structures (Hutchison et al., 1994a; Sterio et al., 1994; Lozano et al., 1996; Taha et al., 1996; Burchiel

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et aI., 1997; Vitek et aI., 1998) and each uses slightly different techniques and places varying time and emphasis on the recording session. What follows is a description of our method. For pallidal procedures the target is generally considered to be in the ventral and lateral portion of GPi (Laitinen, 1990; Laitinen et aI., 1992), 20 mm lateral to the midline, 3-6 mm inferior to the AC-PC line and 2-3 mm anterior to the mid-commissural point. Recording starts about 15 mm from the target in an anterosuperior position, which corresponds to cells of GPe if initial targeting is correct. The objectives in localizing the target in globus pallidus are to identify: (1) characteristic cell types in GPe and GPi, and movement related activity of these cells; (2) the white matter lamina between these structures as well as border cells in the region; (3) optic tract ventral to the GPi; and (4) internal capsule posterior to GPi. The firing rates and patterns of basal ganglia neurons recorded in non-human primates are remarkably similar to those found in humans, so the terminology originally used in these studies is adopted here for the description of the cell types shown in Fig. 1. GPe cells have been described as occurring in two major types based on differences in firing rate and pattern as recorded in normal monkeys (DeLong, 1971; Filion et aI., 1988; Filion and Tremblay, 1991). These are the slow frequency discharge with pauses (SFD-P), and the low-frequency discharge with bursts (LFD-B). LFD-B neurons are not very common in GPe but are thought to be a characteristic feature of the region. The spontaneous ongoing activity is only about 5-10 Hz and the short bursts can reach about 300-500 Hz and occur at irregular time intervals. The known projection of GPe to thalamic reticular formation (Parent and Hazrati, 1995) and the high similarity in burst firing pattern between these cells suggests that LFB neurons are potential basal ganglia output neurons. SFD-P neurons have a higher spontaneous firing rate around 20-50 Hz which is sporadically interrupted by pauses in firing of duration about 150-300 ms (see Fig. 1). There are also cells in GPe with higher firing rates 50-70 Hz and these may be termed HFDP to follow the convention. Active and passive movements of limbs may modulate the firing rate of cells in GPe. Between GPe and GPi is a white matter lamina that is detectable by the absence of recorded units and relative quiet in background noise on the

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recordings. Border cells are frequently encountered at its margins with a wider spike (due to a longer after-hyperpolarization) than pallidal cells, which imparts a regular firing pattern due to the longer

Fig. 1. Examples of well-isolated single units found in typical electrode trajectories penetrating the segments of globus pallidus during microelectrode exploration. All traces are 2 s in duration except bottom trace which is 3 s. Top trace shows the low firing rate of a striatal neuron, typically 1-5 Hz. Next two traces down are typical cells of the external segment of globus pallidus (GPe). Low frequency discharge with bursts (LFD-B); slow frequency discharge with pauses (SFD-P). At the margins of the pallidal segments and the medullary laminae are found border cells (Bor). Lowest two traces show high frequency discharge neurons (HFD), and a tremor cell (TC) with the accelerometer output from the back of the contralateral hand indicated below. GPi,i - internal segment of the globus pallidus internus.

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relative refractory period (see Fig. 1). These electrophysiological characteristics indicate that the cells may be cholinergic and project to the cortical mantle (Carpenter, 1991). A sample of 17 border cells was found to have a mean firing rate of 35 Hz (Hutchison et aI., 1994a). After advancement of the electrode tip into GPi there is often an increase in background noise and multiunit recordings. Cells in GPi have relatively large amplitude spikes, irregular discharge patterns and the highest firing rates of all pallidal cells. The firing rates of GPi neurons are in the range of 60-80 Hz and the modal intervals for GPi neurons in the range of 5-7 ms. Some GPi neurons may show excitatory or inhibitory responses to passive and voluntary movements of limbs and orofacial structures. In some preliminary analyses of the data, there was no clear topographical organization of the body within GPi, as depicted in early studies by Hassler et al. (1979). In patients that have tremor, cells can be found with periodic oscillations in firing rate at the same frequency as the tremor (Hutchison et al., 1994b; Hutchison et al., 1997). These tremor cells show periods of coherent oscillation with limb tremor and appear to be located in ventral and lateral portions of the GPi (Hutchison et al., 1998b). Although each of the segments of GP has identified " signature" cell types that aid localization, there should be no misconception that a region can be immediately identified based on the firing rates and patterns of a few cells. Each pallidal segment has a range of firing rates and patterns and the population means of firing rates or pattern indices may show significant differences between segments. Normally a region is identified only after the track is completed and many well-isolated spikes have been recorded so that a comparison of all the firing rates and patterns can be integrated with the surmized position of the track based on the stereotactic anatomical map (Fig. 2). Below the GPi the cellular activity becomes sparse and background noise decreases. Upon entering the optic tract there may be some discernible increase in high frequency noise again due to axonal activity in the optic nerve. Stimulation at this site normally evokes phosphenes in the contralateral visual field at low current intensities (1-10 fLA). Patients frequently report white or yellow flashes of light, stars, sparkles or lightning-like patterns (see "Vi" in Fig. 2). This can be in a wedge-shaped

w.o. HUTCHISON ET AL. portion of the visual field which can sometimes be observed to move more ventral as one stimulates more dorsal in the optic tract, consistent with the rotation of the fibers in the tract at this level. In rare cases when patients do not report stimulation-evoked visual sensation, it is worthwhile to also carry out strobe-light evoked potentials by opening up the high pass filter and recording the slow-wave average (about 30-40 ms at this site) (see "VEP" in Fig. 2). If all of these features have been identified on the first trajectory through the pallidum, then the second trajectory is placed 3 rom posterior to attempt to identify the internal capsule. Recording again begins at 15 mm above the target and cells are usually again found at the top of the tract. In posteriorly located trajectories, cells may only be found at the initial part of the track indicating the posterior aspect of the GPi and the tip of the electrode will pass into the internal capsule. In the capsule, the recordings are usually quiet but the occasional unit or fiber is encountered. Passing electric current through the tip of the electrode, termed here microstimulation (up to 100 fLA, 0.2 ms pulse width, 300 Hz, 1 s train) will produce tetanic contraction of the contralateral body part or reduction or arrest of tremor (see "M" in Fig. 2). In a typical case, two or three electrode trajectories are required to complete a physiologic map and this includes unequivocal identification of the optic tract and internal capsule. If the targeting based on MRI co-ordinates is accurate, the physiological data should show a reasonably good spatial relation to the corresponding anatomical map. Macrostimulation using a large tipped (2-3 mm) electrode is used by some surgeons to locate the optic tract and internal capsule since the larger tip will allow a greater spread of electrical current. If no motor or visual effects are seen/reported at about 2 V, then the target can be considered safe from producing permanent adverse side effects.

9.8. Recording in electrode trajectories targeting the subthalamic nucleus (STN) In order to identify the STN with microelectrode recording the major features and landmarks to identify are: (1) anterior thalamus with bursting cells; (2) superior and inferior borders of STN; (3) dorsal border of SNr, and if possible; (4) the anterior and posterior borders of STN. Microelectrode

133

RECORDING IN MOVEMENT DISORDERS SURGERY

3

1

2\ #2048

GPe mel

Target

Fig. 2. Completed functional map of globus pallidus showing the location of identified neuronal types as described in Fig. 1. A total of three separate passes through the pallidum were made with the electrode in the order shown at the top of each track. Data from the mapping session is plotted on top of the customized sagittal section from the Schaltenbrand and Wahren stereotactic atlas 20 rom from the midline. Abbreviations of cell types as in Fig. 1; AC, PC - anterior and posterior commissures; mel - mid-commissural line; MEA - movement-evoked activity, "Target" refers to the tentative location chosen from the results of MRI scans, which was at the base of the pallidum but in this case would be too close to the optic tract (OT) indicated by the visual responses of the patient to microstimulation (Vi) and internal capsule (lC) indicated by motor or tetanic responses to microstimulation (M).

recording methods for the identification of STN have been described in detail already (Hutchison et al., 1998a). The target is in the center of the nucleus at about 10-12 rom lateral to the midline, I rom posterior to the mid-commissural point and 5 rom below the AC-PC line. Recording in microelectrode tracks targeting the STN starts 10 -15 rom above target. Depending on the trajectory angle in the sagittal plane, and given that the MRI-determined tentative target is reasonably accurate, recording will usually start in

thalamic reticular nucleus or in the anterior part of the ventral tier subnuclei of the thalamus (see Fig. 3). In this region and particularly in the thalamic reticular formation there are cells with spontaneous burst discharges, which have been reported previously (Raeva et al., 1991; Raeva and Lukashev, 1993) and can be considered characteristic for the region. The identification of the ventral portion of the thalamus is a useful landmark in determining the relative anterior and posterior position of the trajectory. Also the distance between the ventral border of

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W.D. HUTCHISON ET AL.

Fig. 3. Right panel shows typical examples of spike recordings during microelectrode exploration of subthalamic nucleus. Left panel shows location of the electrode track on the customized Schaltenbrand and Wahren map at 12 mm from the midline. Hpth - hypothalamus, Rt - thalamic reticular nucleus, Voa - ventralis oralis anterior, Vop - ventralis oraIis posterior, Vim - ventralis intermedius, ZI - zona incerta, H2 - H2 fields of Forel, STN - subthalamic nucleus, SNr substantia nigra pars reticulata, other abbreviations as in Fig. I.

thalamus and the dorsal border of STN may give some indication of laterality since the anteromedial portion of the STN is pitched more ventral than the dorsolateral pole. Below the thalamus the electrode tip passes into a white matter region which is "quieter" in background electrical noise, corresponding to the thalamic and lenticular fasciculi with the zona incerta in-between. The zona incerta may have sparse cells that are bursting since it is continuous with the thalamic reticular nucleus at its lateral border. Others have reported cells in zona incerta with properties similar to subthalamic nucleus neurons i.e. responses to eye movements (Ma, 1996) as well as reaching movements (Crutcher et aI., 1980) so this should be borne in mind when determining the dorsal border of the subthalamic nucleus. The entry into the subthalamic nucleus is apparent when the level of background noise in the recordings increase and high amplitude spikes with firing rates of 25-45 Hz are found (25 and 75 percentiles). A

large number of STN neurons show clear modulation in firing rate with active and passive movements of the limbs and one sample revealed 80% of the neurons had excitatory responses. Ipsilateral as well as contralateral movements could elicit responses. In patients with tremor at rest, tremor cells have also been identified in the human STN with oscillations in firing rate both at the frequency of tremor and also at high frequency around 15-25 Hz (Levy et aI., 2000). This higher frequency component imparts a "chatter" or "flutter"-like sound to the background noise on the audio monitor that appears to be characteristic for the STN and has proven a useful feature for localization, at least in those patients with tremor. STN neurons may only be recorded over a short distance if the electrode does not track through the center of the nucleus, and trajectories to be selected as sites of implantation should have a 4-5 mm segment populated by cells with STN-like properties. A tracing of a typical STN neuron is shown in Fig. 3.

RECORDING IN MOVEMENT DISORDERS SURGERY

Below the STN is the substantia nigra, which is divided into the dopaminergic pars compacta (SNpc) and the basal ganglia output portion called the pars reticulata (SNpr). The division between the two structures is not clear and one expects that there is degeneration of the SNpc in these PD cases. Based on monkey recordings where histological confirmation is possible, there is known to be differences in the firing rates of the two groups. Putative dopaminergic pars compacta cells have very low firing rates 1-5 Hz and have inflections on the initial phase of the action potential (Schultz, 1986), but are expected to be rarely encountered in PD patients. In contrast, the characteristic features of SNpr or reticulata neurons are a high (60-90 Hz) and regular firing rate but there may be another group that have lower rates around 20-30 Hz, possibly reflecting functional differences (DeLong et aI., 1983, 1985). The different firing rates in SNpr may depend on the portion of the reticulata that is explored, since motor regions are more laterally located in this nucleus (about 15 mm from the midline). In the human, SNpr neurons frequently display cardiac-induced fluctuations in spike amplitude that can make spike discrimination problematic. Microstimulation (up to 100 j.LA, 300 Hz, 1 s train, 0.3 ms p.w.) during STN cases is not as useful as with pallidal or thalamic target localization, but stimulation-induced tremor arrest or reduction from within STN has been observed. Paresthesias have been encountered in more ventral and posterior positions and may be due to current spread to medial lemniscus or pre-Iemniscal radiation. 9.9. Recording and microstimulation in the motor and sensory thalamus Movement disorders surgery may also involve targets in the ventrointermediate (V.i.m.) nucleus of the ventral tier thalamus where input from proprioceptive primary afferents (joint capsules, Golgi tendon organs and muscle spindles) as well as cerebellar afferents converge. The thalamic target in V.i.m. is 14.5 mm lateral to the midline, 2-4 mm above the AC-PC line and 6-7 mm behind the midcommissural point (see Fig. 4). Frequently the ventrocaudal nucleus (V,c.) located more posteriorly is targeted for the first trajectory since the somatotopy of Vc is an important landmark for orientation

135

and also to avoid inadvertent damage to this structure that might lead to permanent sensory loss. Thalamic subnuclei cannot be visualized directly with MRI placing increased emphasis on functional identification of the various ventral tier nuclei with microelectrodes. The objectives in the thalamic procedures are to identify: (1) kinesthetic zone; (2) deep tactile zone; (3) cutaneous tactile zone; and (4) ventral border of the tactile region. Recordings at the top of trajectories pass thorough the "motor thalamus", comprised of the ventralis oralis anterior and posterior subnuclei (V.o.a, V.o.p.) and V.i.m. and have cells somewhat similar to those already described in thalamic areas slightly more medial. Bursting cells are frequently encountered as well as non-bursting cells. Movement-related activity (kinesthetic responses) may be present and cells may be found that respond to deep pressure or deep tactile stimuli. In patients with tremor, tremor cells may be recorded in this region (* in Fig. 4), and microstimulation will produce tremor arrest (TA in Fig. 4) or reduction in tremor. Passing the electrode further ventral, the spontaneous activity will usually increase with entry into the thalamic tactile relay of Vc. Cells in this region will respond to light stroke with a brush or cotton swab. The well-known somatotopic organization within Vc may help to guide the laterality of the procedure and the best place for the lesion is just anterior to the face and thumb region of the tactile core. Laterality in Vim, therefore, is largely determined with reference to Vc somatotopy, leg indicating a more lateral location than face and hand. Microstimulation within Vc produces focal paresthesia that shows a somatotopic organization roughly corresponding to that obtained by recording the cellular responses to touch. Microstimulation in ventral Vc and below Vc in V.c.p.c (parvocellularis) may elicit painful sensation. Ventral to Vc, microstimulation may also elicit hemibody paresthesias due to lemniscal fiber stimulation and activation of large numbers of neurons in the tactile core ofVc. Usually several trajectories are made to define the anterior border of Vc and map a large enough segment of the motor thalamus to find the focus and extent of sites of effective tremor suppression from microstimulation. The target lies 2-3 mm anterior to the Vc/Vim border in regions occupied by cells with kinesthetic responses and tremor reduction or arrest from microstimulation (see Fig. 4).

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Fig. 4. Functional localization of thalamic nuclei for movement disorders surgery. Findings from 3 microelectrode trajectories are overlaid on a Schaltenbrand and Wahren sagittal map 14.5 mm from the midline. The AC-PC line is shown intersecting Pc. Thalamic nuclei are labeled as follows Vo.a., ventralis oralis anterior, V.o.p., ventralis oralis posterior, V.i.m., ventralis intermedius, v.c., ventralis caudalis.

9.10. Summary Microelectrode recording is useful to accurately delineate deep brain structures and sub-nuclei for various stereotactic targets. In addition, it yields much information on the cellular pathophysiology of movement disorders and the rational development of surgical therapy for the treatment of movement disorders.

Acknowledgements The support of both Parkinson Society of Canada and the Canadian Institute for Health ResearchINIH is gratefully acknowledged.

References Burchiel, KJ, Taha, JM and Favre, J (1997) Posteroventral pallidotomy for Parkinson's disease patients. In: 55

Rengachary and RH Wilkins (Eds.), AANS Publications Committee. Park Ridge, Illinois, pp. 13-26. Carpenter, MB (1991) Corpus striatum and related nuclei. In: TS Satterfield (Ed.). Williams and Wilkins, Baltimore, pp. 325-360. Crutcher, MD, Branch, MR, DeLong, MR and Georgopoulos, AP (1980) Activity of zona incerta neurons in the behaving primate. Soc. Neurosci. Abstr., 6: 676. DeLong, MR (1971) Activity of pallidal neurons during movement. J. Neurophysiol., 34: 414-427. DeLong, MR, Crutcher, MD and Georgopoulos, AP (1983) Relations between movement and single cell discharge in the substantia nigra of the behaving monkey. J. Neuroscience, 3: 1599-606. DeLong, MR, Crutcher, MD and Georgopoulos, AP (1985) Primate globus pallidus and subthalamic nucleus: functional organization. J. Neurophysiol., 53: 530-543. Dostrovsky, JO (1999) Invasive techniques in humans: microelectrode recordings and microstimulation. In: U Windhorst and H Johansson (Eds.), Modem Techniques in Neuroscience Research. Springer Verlag, Berlin, pp.1199-1209.

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Favre, J, Taha, JM, Baumann, T and Burchiel, KJ (1999) Computer analysis of the tonic, phasic, and kinesthetic activity of pallidal discharges in Parkinson patients. Surg. Neurol., 51: 665-672. Filion, M and Tremblay, L (1991) Abnormal spontaneous activity of globus pallidus neurons in monkeys with MPTP-induced parkinsonism. Brain Res., 547: 142151. Filion, M, Tremblay, L and Bedard, PJ (1988) Abnormal influences of passive limb movement on the activity of globus pallidus neurons in parkinsonian monkeys. Brain Res., 444: 165-176. Germano, 1M (1998) Neurosurgical treatment of movement disorders. AANS Publications Committee, Park Ridge, Illinois, 275 pp. Guiot, G, Hardy, J and Albe-Fessard, D (1962) Delimitation precise des structures sous-corticales et identification de noyaux thalamiques chez l'homme par l' electrophysiologie stereotaxique. Neurochirurgia (Stutt.), 51: 1-18. Hassler, R, Mundinger, F and Riechert, T (1979) Stereotaxis in Parkinson syndrome. Springer Verlag, Berlin, Hurtado, JM, Gray, CM, Tamas, LB and Sigvardt, KA (1999) Dynamics of tremor-related oscillations in the human globus pallidus: A single case study. Proc. Natl. Acad. Sci. USA, 96: 1674-1679. Hutchison, WD (1998) Microelectrode techniques and findings of globus pallidus. In: JK Krauss, RG Grossman and J Jankovic (Eds.). Lippincott-Raven, Philadelphia, pp. 135-152. Hutchison, WD, Lozano, CA, Davis, KD, Saint-Cyr, JA, Lang, AE and Dostrovsky, JO (1994a) Differential neuronal activity in segments of globus pallidus in Parkinson's disease patients. Neuroreport, 5: 15331537. Hutchison, WD, Lozano, AM, Kiss, ZHT, Davis, KD, Lang, AE, Tasker, RR and Dostrovsky, 10 (1994b) Tremor-related activity (TRA) in globus pallidus of Parkinson's disease (PD) patients. Soc. Neurosci. Abstr., 20: 783. Hutchison, WD, Lozano, AM, Tasker, RR, Lang, AE and Dostrovsky, JO (1997) Identification and characterisation of neurons with tremor-frequency activity in human globus pallidus. Exp. Brain Res., 113: 557563. Hutchison, WD, Allan, RJ, Opitz, H, Levy, R, Dostrovsky, JO, Lang, AE and Lozano, AM (1998a) Neurophysiological identification of the subthalamic nucleus in surgery for Parkinson's disease. Ann. Neurol., 44: 622-628. Hutchison, WD, Benko, R, Dostrovsky, JO, Lang, AE, and Lozano, AM (1998b) Coherent relation of rest tremor

and pallidal tremor cells in Parkinson's disease patients. Mov. Dis., 13 (Suppl. 2): 204. Krauss, JK, Grossman, RG and Jankovic, J (1998) Pallidal surgery for the treatment of Parkinson's disease and movement disorders. Lippincott-Raven, Philadelphia, 324 pp. Laitinen, LV (1990) Ventroposteromedial pallidotomy in Parkinsons disease. Stereotact. Funet. Neurosurg., 54+55. Laitinen, LV, Bergenheim, AT and Hariz, MI (1992) Leksell's posteroventral pallidotomy in the treatment of Parkinson's disease. J. Neurosurg., 76: 53-61. Lalley, PM, Moschovakis, AK and Windhorst, U (1999) Electrical activity of individual neurons in situ: extraand intracellular recording. In: U Windhorst and H Johansson (Eds.), Modem Techniques in Neuroscience Research. Springer, Berlin, pp. 127-172. Lenz, FA, Dostrovsky, JO, Kwan, HC, Tasker, RR, Yamashiro, K and Murphy, JT (1988) Methods for microstimulation and recording of single neurons and evoked potentials in the human central nervous system. J. Neurosurg., 68: 630-634. Levy, R, Hutchison, WD, Lozano, AM and Dostrovsky, JO (2000) High-frequency synchronization of neuronal activity in the subthalamic nucleus of parkinsonian patients with limb tremor. J. Neurosci., 20: 77667775. Lozano, AM (2000) Movement Disorder Surgery. Karger, Basel, 404 pp. Lozano, AM, Hutchison, WD, Kiss, ZHT, Davis, KD and Dostrovsky, JO (1996) Methods for microelectrodeguided posteroventral pallidotomy. J. Neurosurg., 84: 194-202. Ma, T (1996) Saccade-related omnivectoral pause neurons in the primate zona incerta. NeuroReport, 7: 27132716. Millar, J (1992) Extracellular single and multiple unit recording with microelectrodes. In: JA Stamford (Ed.), IRL Press at Oxford. New York, pp. 1-27. Nicolelis, MA, Stambaugh, CR, Brisben, A and Laubach, M (1998) Methods for simultaneous multi site neural ensemble recordings in behaving primates. In: MA Nicolelis (Ed.). CRC Press LLC, Boca Raton FLA, pp. 121-156. Parent, A and Hazrati, LN (1995) Functional anatomy of the basal ganglia. I. The cortico-basal ganglia-thalamocortical loop. Brain Res. Brain Res. Rev., 20: 91-127. Raeva, SN and Lukashev, A (1993) Unit activity in human thalamic reticularis neurons. II. Activity evoked by significant and non-significant verbal or sensory stimuli. Electroencephalogr. Clin. Neurophysiol., 86:

lID-I 22. Raeva, SN, Lukashev, A and Lashin, A (1991) Unit activity in human thalamic reticular nucleusI Spon-

138 taneous activity. Electroencephalogr. Clin. Neurophysiol.,79: 133-140. Schaltenbrand, G and Wahren, W (1977) Atlas for Stereotaxy of the Human Brain. Georg Thieme, Stuttgart, 69 plates. Schultz, W (1986) Responses of midbrain dopamine neurons to behavioural trigger stimuli in the monkey. J. Neurophysiol., 56: 1439-1461. Starr, P (1999) Instrumentation, technique, and technology. Axon Guideline System 3000. Neurosurgery, 44: 1354-1356. Sterio, D, Beric, A, Dogali, M, Fazzini, E, Alfaro, G and Devinsky, 0 (1994) Neurophysiological properties of pallidal neurons in Parkinson's disease. Ann. Neurol., 35: 586-591.

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Taha, JM, Favre, J, Baumann, TK and Burchiel, KJ (1996) Characteristics and somatotopic organization of kinesthetic cells in the globus pallidus of patients with Parkinson's disease. J. Neurosurg., 85: 1005-1012. Tasker, RR, Davis, KD, Hutchison, WD and Dostrovsky, 10 (1998) Subcortical and thalamic mapping in functional neurosurgery. In: PL Gildenberg and RR Tasker (Eds.). McGraw-Hill, New York, pp. 945-94-31. Vitek, JL, Bakay, RA, Hashimoto, T, Kaneoke, Y, Mewes, K, Zhang, JY, Rye, D, Starr, P, Baron, M, Turner, Rand DeLong, MR (1998) Microelectrode-guided pallidotomy: technical approach and its application in medically intractable Parkinson's disease. J. Neurosurg., 88: 1027-1043.

Movement Disorders Handbook of Clinical Neurophysiology, Vol. 1 M. Hallett (Ed.) © 2003 Elsevier B.V. All rights reserved

139 CHAPTER 10

Polysomnography and related procedures s. Chokroverty* Department of Neurology/Cronin 466, St. Vincents Hospital, New York, NY 10011, USA

Scientific progress in the laboratory evaluation of sleep and its disorders has been rather slow but great advances have been made in the last century. The driving forces in this understanding have been the discovery of the human electroencephalogram (EEG) by Berger (1929) and rapid eye movements (REMs) during sleep by Aserinsky and Kleitman (1953). Polysomnography (PSG) has come to be viewed as the single most important laboratory technique for assessment of sleep and its disorders as well as for diagnosis and differential diagnosis of abnormal movements during sleep at night. PSG refers to recordings of multiple physiological characteristics during sleep whereas polygraphy denotes recordings of similar characteristics during any time of the day. The first polygraphic study to record motor activities during sleep was probably reported by Oswald in 1959 under the title of "sudden bodily jerks on falling asleep". In this chapter I briefly outline PSG recording techniques, indications for PSG, simultaneous video-PSG, and pertinent PSG findings in selected sleep disorders, computerized PSG, recording artifacts and related laboratory procedures for assessment of patients with movement disorders with or without complex behavior during sleep including multiple sleep latency test (MSLT), maintenance of wakefulness test (MWT) and actigraphy.

determine the patient's perception of quality of sleep and the actual test results. In order to assess chronic daytime sleepiness, the patient is asked to fill out the Epworth Sleepiness Scale (ESS) (Johns, 1991), which contains questions relating to the likelihood of dozing off in situations such as riding as a passenger in a car and watching television (Table 1). PSG allows assessment of sleep stages and wakefulness, respiration, cardiocirculatory functions and body movements (Keenan, 1999). EEG, electrooculogram (EOG) and electromyogram (EMG) of the chin muscle are recorded to study and score sleep staging (Rechtschaffen and Kales, 1968). Respiratory recording includes measurement of airflow and respiratory effort (Parisi, 1999; Kryger, 2000). PSG Table I Epworth sleepiness scale. Eight situations

Scores*

1. Sitting and reading 2. Watching television 3. Sitting in a public place (e.g., a theater or a meeting) 4. Sitting in a car as a passenger for an hour without a break 5. Lying down to rest in the afternoon

10.1. Techniques of PSG recording

PSG records multiple simultaneous physiological characteristics during sleep at night (Keenan, 1999). A pre- and post-study sleep questionnaire helps * Correspondence to: Prof. S. Chokroverty, Dept. of Neurology/Cronin 466, St. Vincents Hospital, 153 W l lth Street, New York, NY 10011, USA. E-mail address:[email protected] Fax: + 1 (212) 604-1555.

6. Sitting and talking to someone 7. Sitting quietly after a lunch without alcohol 8. In a car, while stopped for a few minutes in traffic

* Scale to determine total scores: 0= would never doze; I = slight chance of dozing; 2=moderate chance of dozing; 3=high chance of dozing. Source: Adapted from M.W. Johns. A new method for measuring daytime sleepiness: the Epworth Sleepiness Scale. Sleep 1991; 14: 540-545.

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S. CHOKROVERTY

also records electrocardiogram (EKG), finger oxymetry, limb muscle activity, particularly EMG of the tibialis anterior muscles bilaterally, snoring and body positions. Special techniques not used routinely include measurements of intraesophageal pressure, esophageal pH and measurements of penile tumescence for assessing patients with erectile dysfunction. Equipment for recoding PSG contains AC and DC amplifiers. The AC amplifiers are used to record physiological characteristics showing high frequencies such as EEG, EOG, EMG, and EKG. A DC amplifier is typically used to record potentials with slow frequency such as for recording the output from the oxymeter, pH meter or CPAP titration pressure changes and recording of intraesophageal pressure. AC or DC amplifiers may be used to record respiratory flow and effort. Sensitivity and filter settings vary according to the physiological characteristics recorded (Table 2). The standard speed for recording traditional PSG is 10 mm1s, so that each monitor screen or page is a 30-s epoch. In patients with suspected nocturnal seizures, however, a 30 mm/s recording speed (a lO-s epoch) is used for easy identification of epileptiform activity. Analog recording using paper is currently being replaced in most of the laboratories by digital system recordings. It is important to have facility for simultaneous video recording to monitor the behavior during sleep. It is advantageous to use two cameras for sleep screen viewing covering the entire body. A low light level camera should be used to obtain good quality video in the dark and an infrared light source should be available after turning the laboratory lights

off. The monitoring station should have a remote control, which can zoom, tilt or pan the camera for adequate viewing. The camera should be mounted on the wall across from the head end of the bed. An intercom from a microphone near the patient should be available.

10.2. Technique of recording of multiple physiological characteristics 10.2.1. Electroencephalography Most laboratories using international 10-20 electrode placement system recorded from at least 4 channels (C3-A2, C4-Al, Ol-Al and 02-A2) to clearly document the onset of sleep. Some laboratories use 8-10 channels to cover the parasagittal and the temporal areas of the brain to record possible focal or diffuse EEG abnormalities as well as for epileptiform activities. Both bipolar montage and referential montage connecting the electrodes between an active and a relatively inactive site (e.g. AI, A2, Cz, pz) are recommended. The importance of multiple channel EEG recordings is to document focal or diffuse slow waves and particularly epileptiform discharges. Many patients are referred to the PSG laboratory for a possible diagnosis of nocturnal seizures. The standard recommended EEG recordings of 1-2 channels or even 4 channels of recordings will miss most of the epileptiform discharges during all night recording. Therefore, in patients suspected of nocturnal seizures, polysomnographic study should include multiple channels of EEG covering temporal and parasagittal regions and simultaneous video record-

Table 2 Filter and sensitivity settings for polysomnographic studies. Time constant (s)

Lowfrequency filter (Hz)

Sensitivity

70 or 35

0.4

0.3

5-7 u.V/mm

70 or 35

0.4

0.3

5-7 u.V/mm

90

0.04

5.0

2-3 fLV/mm

15

0.12

1.0

1 mV/cm to start; adjust

0.1

5-7 fLV/mm; adjust

Characteristics

Highfrequency filter (Hz)

Electroencephalogram Electro-oculogram Electromyogram Electrocardiogram Airflow and effort

15

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POLYSOMNOGRAPHY AND RELATED PROCEDURES

ing (video-PSG study) for correlation of the electrical activity with the actual behavior of the patients. In computerized (digital) PSG recordings that are now performed in most laboratories it is easy to change the recording speed from the standard 10 mm/s of the usual sleep recording to 30 mm/s of the standard EEG recording for proper identification of the epileptiform discharges. Special seizure montages with full complement of standard electrodes and special electrode placements (e.g. T1 and T2 electrodes) should be used. The value of videoPSG for the diagnosis of seizure disorders and parasomnias has been clearly documented by Aldrich and Jahnke (Aldrich and Jahnke, 1991). 10.2.2. Electro-oculography (EDG)

EOG records corneoretina1 (relative positivity at the cornea and a relative negativity at the retina) potential difference (Walczak and Chokroverty, 1999). A typical electrode placement is one em superior and lateral to the outer canthus of one eye with a second electrode placed 1 em inferior and lateral to the outer canthus of the opposite eye. Both these electrodes are then connected to a single reference electrode, either the same ear or the mastoid process of the temporal bone. Therefore, right outer canthus (ROC) and left outer canthus (LaC) electrodes are referred to either A1 or A2. In this arrangement, conjugate eye movements produce out-of-phase deflections in the two channels whereas the EEG slow activities contaminating the eye electrodes are in-phase. Both conjugate horizontal and vertical eye movements are detected by this placement scheme. The sensitivity and filter settings for EOG are similar to those used for EEG (see Table 2).

10.2.3. EMG recordings during standard PSG

EMG activity is an important physiological characteristic that needs to be recorded for sleep staging as well as for diagnosis and classification of a variety of sleep disorders. In a standard PSG recording, EMGs are recorded from mentalis or submental and right and left tibialis anterior muscles. Mental or submental EMG activity is monitored to record axial muscle tone, which is significantly decreased during REM sleep, and, therefore, an important physiological characteristic for identifying REM sleep. Additional electrodes over the masseter muscles

may be needed in patients with bruxism (tooth grinding) to document bursts of EMG activities associated with bruxism. For recording from tibialis anterior muscles, surface electrodes are used and the distance between the two electrodes is 2-2.5 em. Bilateral tibialis anterior EMG is important to record in patients suspected of restless legs syndrome (RLS) because the periodic limb movements in sleep (PLMS), which are noted in 80% of such patients, may alternate between the two legs. Ideally, the recording should also include one or two EMG channels from the upper limbs in patients with RLS as occasionally PLMS are noted in the upper limbs. For patients with suspected REM behavior disorder, multiple EMGs from all four limbs are essential as there is often a dissociation of the activities between upper and lower limb muscles in such patients. If the upper limb EMGs are not included in patients suspected of REM behavior disorder, REM sleep without atonia may be missed in some cases. In patients presenting with abnormal movements such as dystonic, choreoathetoid or ballismic movements as noted in patients with nocturnal paroxysmal dystonia (a type of frontal lobe seizure disorder), multiple muscle surface EMG recordings in addition to video-PSG recordings may be obtained to document such activities. Other EMG recordings include intercostal and diaphragmatic EMG to record respiratory muscle activities. EMG shows progressively decreasing tone from wakefulness through stages I-IV of NREM sleep. In REM sleep the EMG is markedly diminished or absent. In REM behavior disorder, a characteristic finding is absence of muscle atonia during REM sleep in the EMG recording and the presence of phasic muscle bursts repeatedly during REM sleep. 10.2.4. Electrocardiography

A single channel of EKG is sufficient during PSG recording by placing one electrode over the sternum and the other electrode at a lateral chest location. Gold cup surface electrodes are used to record the EKG. Table 2 lists the filter settings and sensitivities for such recording. 10.2.5. Respiratory monitoring technique

PSG recording must routinely include methods to monitor airflow and respiratory effort adequately to

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correctly classify and diagnose sleep disordered breathing (SDB). Respiratory effort can be measured by mercury-filled or piezoelectric strain gauges, inductive plethysmography, impedance pneumography, respiratory magnetometers and respiratory muscle EMG (Kryger, 20(0). Most commonly Piezoelectric strain gauges and inductive plethysmography are used to monitor respiratory effort. Airflow can be measured by thermistors, thermocouples or a nasal cannula-pressure transducer recording nasal pressure (Kryger, 2000). The best way to detect arterial O2 content (Pa02) is by invasive method using an arterial cannula. This is not viable from the practical standpoint and in any case intermittent sampling of blood through the cannula may not reflect the severity of hypoxemia during a particular disordered breathing event. Therefore, noninvasive method by finger pulse oximetry is routinely used to monitor arterial oxygen saturation (Sa02) or arterial oxyhemoglobin saturation, which reflects the percentage of hemoglobin that is oxygenated (Kryger, 2000). 10.2.6. Body position monitoring

Body position is monitored by placing sensors over one shoulder and using a DC channel. Snoring and apneas are generally worse in the supine position and therefore, CPAP titration must include observing patients in the supine position for evaluating optimal pressure for titration. 10.2.7. Snoring

This can be monitored by placing a miniature microphone on the patient's neck. There is no general accepted standardized technique to record quantitatively the intensity of snoring. 10.2.8. Beginning and ending the PSG

All important information including "lights out" and "lights on" as well as any unusual behavior and motor events should be clearly documented by the technologist before and during the recording. This must include the patient's name, age, date of study, the identification number, purpose of the recording (before referring the patient to the laboratory for PSG study, sleep clinicians should have performed complete history and physical examination formulat-

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ing a provisional diagnosis) and the name of the technician. When awakened in the morning (either spontaneously or at a set time), the patient is asked to fill out a post-study questionnaire which includes estimation of time to fall asleep, total sleep time, number of awakenings and the quality of sleep

10.3. Sleep stage scoring technique The gold standard for scoring a particular sleep stage is still that recommended in the manual by Rechtschaffen and Kales (R-K) in 1968 (Rechtschaffen and Kales, 1968) following recommendations by an ad hoc committee. This was originally devised for sleep scoring in normal adults. There are, however, serious limitations using the R-K manual for scoring sleep stages in pathological states and many investigators recommend a computerized rather than the manual scoring technique. However, computerized techniques have many pitfalls and have not been accepted as a gold standard yet. In the future, with more sophisticated development of computer technology, a computer scoring technique most likely will supercede the manual scoring technique. Sleep stage scoring is based on three physiologic criteria: EEG, EOG and EMG. For R-K scoring an EEG recorded at C3/A2 or C4/Al should be used, especially for the purpose of amplitude criteria. The recommendation is for an epoch by epoch scoring and the most commonly used epoch is 30 s. 10.3.1. Scoring ofperiodic limb movements in sleep

Periodic limb movements in sleep are involuntary movements periodically recurring during sleep and are counted from the right and left tibialis anterior EMG recordings. The scoring criteria for PLMS can be summarized as follows (Atlas Task Force of the American Sleep Disorders Association, 1993): the movements must occur as part of 4 consecutive movements; the duration of each EMG burst should be 0.5 to 5 s; the interval between bursts should be 4-90 s; the amplitude of the EMG bursts, although variable, should be more than 25% of the EMG bursts recorded during the pre-sleep calibration recording. PLMS (Fig. 1) mayor may not be associated with arousals, and they should be scored separately. To score PLMS associated with arousal

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Fig. 1. A portion of polysomnographic fragment showing periodic limb movements in sleep (PLMS). Left (LT) and right (RT) tibialis anterior (TIB) electromyography (EMG). The top 4 channels show EEG (international nomenclature). LOC: Left oculogram; ROC: Right oculogram. CHIN: Chin EMG. EKG: Electrocardiogram. ABD: Abdomen. S.02: Oxygen saturation in percent by finger oxymetry.

the arousal must occur within 3 s of onset of PLMS. PLMS is expressed as an index consisting of number of PLMS per hour of sleep. To be of pathologic significance PLMS index should be 5 or more. Leg movements may be noted occurring periodically associated with resumption of breathing following recurrent episodes of apneas or hypopneas. These respiratory related leg movements should not be counted as PLMS. PLMS are generally seen during NREM sleep but they can occur rarely during REM sleep. In patients with restless legs syndrome, however, periodic limb movements may occur during wakefulness when they are termed period limb movements in wakefulness (PLMW). 10.3.2. Indications for PSG and video-PSG

In addition to the standard indications for PSG as published in the guidelines (Indications for Poly-

somnography Task Force, 1997) by the American Academy of Sleep Medicine (e.g. suspected SDB, patients with excessive daytime sleepiness (EDS), CPAP titration in patients with obstructive sleep apnea syndrome (OSAS), prior to surgical procedures or dental appliances in patients with OSAS, suspected narcolepsy-cataplexy syndrome and atypical or violent parasomnias), video-PSG combining PSG with multiple EEG channels and simultaneous video recording is very useful in patients with abnormal movements and behavior during sleep at night. If these motor activities during sleep occur frequently, the changes of capturing these events in the video-PSG are much better than if these had been occurring infrequently. The video recording can include multiplex analog signal captured on a tape but currently many commercially available systems include digital video directly synchronizing and time-locking the abnormal behavior to the PSG

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144 Table 3

Table 3

Classification of abnormal motor activities during sleep.

Continued.

Motor parasomnias

Drug-induced nocturnal dyskinesias

1. Sleep-wake transition disorders a. Rhythmic movement disorder b. Sleep talking (somniloquy) c. Nocturnal leg cramps d. Propriospinal myoclonus at the transition from wakefulness to drowsiness 2. NREM sleep parasomnias a. Confusional arousals b. Sleepwalking c. Sleep terror 3. REM sleep parasomnias a. Nightmares b. REM sleep behavior disorder 4. Diffuse parasomnias (no stage preference) a. Bruxism b. Neonatal sleep myoclonus

1. Levodopa-induced myoclonus in Parkinson's disease 2. Medication-induced (e.g. tricyclic antidepressants, levodopa, lithium) periodic limb movements in sleep (PLMS)

Restless legs syndrome (RLS) - Periodic limb movements A. Nocturnal jerks and body movements in obstructive sleep apnea syndrome B. Excessive fragmentary myoclonus seen in a variety of sleep disorders C. Sleep-related panic attacks D. Dissociative disorders E. Fatal familial insomnia F. Post-traumatic stress disorder G. Narcolepsy-cataplexy-sleep paralysis syndrome

Nocturnal seizures 1. True nocturnal seizures a. Tonic seizure b. Benign rolandic seizure c. Autosomal dominant nocturnal frontal lobe seizure d. Nocturnal frontal lobe epilepsy (Nocturnal paroxysmal dystonia) e. Paroxysmal arousals and awakenings f. Episodic nocturnal wanderings g. Electrical status epilepticus in sleep 2. True nocturnal and diurnal seizures (diffuse seizures) a. Generalized tonic-clonic seizure b. Myoclonic seizure c. Infantile spasms (West's syndrome) d. Partial complex seizure e. Frontal lobe seizure f. Epilepsia partialis continua 3. Pseudoseizure (psychogenic non-epileptic seizure)

Involuntary movement disorder 1. Always persisting during sleep: a. Palatal myoclonus or palatal tremor 2. Frequently persisting during sleep a. Spinal and propriospinal myoclonus b. Tics in Tourette's syndrome c. Hemifacial spasms d. Hyperekplexia or exaggerated startle syndrome 3. Sometimes persisting during sleep a. Tremor b. Chorea c. Dystonia d. Hemiballisms

signals. Depending on the availability of the channels and the electrode inputs in the equipment multiple channels of EEGs (e.g. for suspected nocturnal seizure disorder) and EMGs to include additional muscles (e.g. to record from forearm flexor and extension muscles, masseter and other muscles for patients with suspected rapid eye movement behavior disorder (RBD) and bruxism) are recommended. Video-PSG may help characterize the movements, differentiate one jerk from another, identify a specific entity and most importantly differentiate abnormal motor activities from nocturnal seizures. Video-PSG may aid in the diagnosis of other co-existing sleep disorder, e.g. OSAS, RBD, narcolepsy. Video-PSG thus helps us classify abnormal motor activities during sleep into several identifiable entities (Table 3), e.g. motor parasomnias, noctural seizures, involuntary diurnal movements persisting during sleep, PLMS, excessive fragmentary myoclonus seen in a variety of sleep disorders, dissociative disorders, nocturnal jerks and body movements seen in patients with OSAS. Many parasomnias (defined as abnormal movements and behavior introducing into sleep without necessarily disrupting sleep architecture) may be mistaken for nocturnal seizures. For example, confusional arousals, sleep walking, sleep terror, sleep talking, bruxism, rhythmic movement disorder, RBD, nightmares and dissociative

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Table 4 Indications for video PSG. • Unusual and complex arousal disorders • Complex behaviors suspicious of RBD but not absolutely certain based on the history • Behavior and motor events at night suggesting possible nocturnal seizure disorder • EDS in patients with epilepsy to determine if excessive sleepiness is due to repeated nocturnal seizures, an undesirable side effect of antiepiieptic medications or due to an associated sleep disorder (e.g. sleep apnea) • Suspected psychogenic dissociative disorder • Other motor parasomnias (e.g. rhythmic movement disorder, bruxism) which may be mistaken for nocturnal seizures • Involuntary diurnal movement disorder persisting during sleep • Coexisting second sleep disorder (e.g. narcolepsy and RBD, OSAS and sleep walking, narcolepsy and sleep apnea) • For medicolegal purpose when the patient presents with violent behavior during sleep, video-PSG studies are mandatory to evaluate such patients for correct diagnosis of parasomnias or seizure disorders

disorders may be mistaken for seizures. RBD and nightmares occur during REM sleep. These conditions can be diagnosed and differentiated from one another based on characteristic clinical features combined with EEG and video-PSG findings. Table 4 lists indications for video-PSG. There is some controversy regarding the diagnosis of periodic limb movement disorder (PLMD) causing sleep fragmentation, arousals and excessive daytime sleepiness. Periodic limb movements in sleep (PLMS) have been noted in a number of sleep disorders as well as in normal individuals, particularly in patients over 60-65. Although the specificity of PLMS is not defined, at least 80% of patients with RLS show PLMS on PSG recordings. Therefore to document PLMS in RLS, PSG may be indicated. However, the diagnosis of RLS is a clinical one and has been based on international study group criteria (Allen et aI., 2003). PLMS as well as a sleep disturbance are not part of the essential criteria for the diagnosis of RLS. PSG indications, therefore, for RLS-PLMS remain somewhat dubious and contentious. Some investigators do not believe in the existence of PLMD as a

separate sleep disorder causing sleep dysfunction and EDS (Mahowald, 2002). The indications for pure PLMS or PLMD currently remain undetermined and further investigations including outcome studies are needed to document that PLMS or PLMD may cause sleep disturbance and EDS. Usually if one spends sufficient time in history taking and examining the patient it is possible to make a clinical diagnosis. However, even in clinically obvious cases it is important to confirm the clinical diagnosis by laboratory tests before instituting therapy because inappropriate or incorrect treatment may cause adverse side effects without necessarily helping the patient. On many occasions, however, the spells are atypical, unusual and often violent requiring video-PSG confirmation of the events. Correlation of the events with the time of the night and a particular sleep staging is important for correct diagnosis. For example, arousal disorder occurs during slow wave sleep in the first third of the night and RBD occurs during REM sleep usually in the last half to last third of the night. Rhythmic movement disorder (head banging, head rolling, body rocking) occurs during sleep stage transition from any stage of sleep whereas during psychogenic dissociated disorder EEG shows a wakeful pattern. The distinct disadvantage of video-PSG is additional expense and technologist time to place additional electrodes for extended EEG montage for suspected nocturnal seizure disorder and extended EMG montage to record multiple additional muscles for suspected RBD and bruxism. 10.4. Characteristic PSG findings in nocturnal movement disorders

There are no distinctive PSG patterns noted in most nocturnal movement disorders except characteristic epileptiform EEG patterns in nocturnal seizures. PSG findings are diagnostically nonspecific but video-PSG findings may help in the diagnosis, differential diagnosis, and in understanding pathophysiology. 1004.1. PSG findings in RLS-PLMS

These patients may show delayed sleep onset, fragmented sleep with repeated arousals and PLMS, which are noted in at least 80% of RLS patients. PLMS index (number of PLMS per hour of sleep)

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below 5 is considered normal. Based on the PLMS index the severity of PLMS may be classified into mild (index of 5-25), moderate (index of more than 25-50) and severe (index of more than 50). 10.4.2. PSG findings in parasomnias and dissociative disorders

In NREM parasomnias (e.g. sleep walking, sleep terror and confusional arousals), spells arise out of slow wave sleep and are not stereotyped but are prolonged lasting for minutes and may be up to 10 min in contrast to patients with seizure disorders who may show stereotyped behavior lasting for a few seconds to a minute or two. Furthermore, EEG shows no evolving pattern in the arousal disorders, thus, differentiating from ictal EEG with rhythmically evolving pattern of slow waves, sharp waves or

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spikes. High voltage delta waves, non-reactive alpha, stage I sleep and movement artifacts in the EEG are the other features found in patients with arousal disorders. In patients with REM behavior disorder (RBD) the behavior occurs out of REM sleep and, therefore, the EEG shows the characteristic REM sleep pattern of desynchronized EEG containing a mixture of alpha, beta and theta activities often associated with characteristic "saw-tooth" waves and rapid eye movements. The EMG shows absence of muscle atonia, phasic muscle bursts and the video may document excessive limb movements, which may be rhythmic or arrhythmic. Figure 2 is a representative sample from a patient with RBD. Psychogenic dissociative disorders may present with a variety of abnormal movements resembling those noted in frontal lobe seizures. However, in

Fig. 2. A fragment of polysomnographic tracing from a patient REM sleep behavior disorder. Note sustained muscle tone and phasic EMG bursts in the electromyograms from chin, left (L) and right (R) arms, left and right tibialis anterior muscles during REM sleep. EDGs (top two channels) show rapid eye movements and EEG (channels 3-6 from the top) is in stage 1 with a mixture of theta, alpha and beta rhythms. (Reproduced with permission from Drs. Carlos Schenck and Mark Mahowald.)

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dissociative disorders the movements are nonstereotyped and the EEG shows wakeful patterns both during and after the spells. Rhythmic movement disorder can arise during sleep-wake state transition or rarely during sleep stage transition. This condition may mimic the behavior pattern of partial complex seizure but EEG shows no ictal pattern, thus, differentiating rhythmic movement disorder from patients with partial complex seizure. Orofacial movements in patients with bruxism sometimes resemble orofacial automatisms of partial complex seizure. However, EEG in bruxism shows no ictal pattern in contrast to patients with partial complex seizure. EMG in bruxism shows characteristic rhythmic bursts in the masseter muscles and these myeogenic artifacts are also reflected in the EEG electrodes.

10.4.3. PSG findings in diurnal movement disorders There has been a growing awareness amongst both movement disorder and sleep specialists about an interaction between sleep and the movement disorders. There is increasing understanding about the effects of diurnal movements on sleep and the effect of sleep on a variety of diurnal movement disorders, and how sleep-wake states modulate the daytime and night-time abnormal movements. A case in point is the recent controversy about "sleep attacks" in Parkinson's disease (PD) patients on newer dopamine agonists. Whether these agents or the disease itself are responsible for excessive sleepiness or unpredictable "sleep attacks" remain controversial but this controversy has re-emphasized the presence of sleep dysfunction which may be seen in up to 70% to 90% of PD patients. Overnight PSG findings in PD include decreased slow wave and REM sleep, reduced sleep spindles, decreased sleep efficiency, disruption of NREM-REM sleep cycling, rapid blinking at sleep onset, sleep fragmentation, and REM-onset blepharospasm. In those presenting with RBD the EMG shows absence of muscle atonia and increased phasic EMG bursts during REM sleep. In addition, some PD patients may document SDB and PLMS. Parkinsonian tremor may persist during NREM stages I and II, is absent in slow wave and REM sleep but may reappear during sleep stage transition.

PSG findings in progressive supranuclear palsy include increased sleep latency, repeated arousals and awakenings, decreased NREM stage I and REM sleep, decreased sleep spindles, in some patients, reduced REM latency and occasionally sleep apnea. In Tourette's syndrome, PSG recordings shows increased body movements and motor tics during all stages of sleep. An increased number of awakenings and mild reduction of REM sleep may also be seen. There is an increased prevalence of sleep walking and sleep terror in these patients. PSG findings in Huntington's chorea include sleep fragmentation with progressive deterioration as the disease progresses. Other findings include decreased sleep efficiency in 48%-80% of cases and a mild reduction of REM sleep. Persistence of the involuntary movements in NREM stages I and II and reemergence during REM sleep may also be seen. Sleep spindles are increased in amplified and density. PSG findings in torsion dystonia consist of prolonged sleep latency, repeated awakenings, reduced sleep efficiency and decreased REM sleep. Dystonic movements decrease during NREM stages I and II, and are absent during slow wave and REM sleep.

10.4.4. Computerized PSG The advantages of computerized PSG include easy data acquisition, display and storage (Hirshkowitz and Moore, 1994; Hasan, 1996; Kubicki and Hermann, 1996; Hirshkowitz and Moore, 1999; Penzel and Conradt, 2000; Agarwal and Gotman, 2002). It is easy to review the record on-line (i.e, the ability to look back at early tracing during progression of recording). The other advantages include the ability to manipulate large quantity of data for review and storage for permanent record keeping. It is also easy to review using a variety of filter settings, sensitivities, monitor speeds and reformatted montages (i.e, new montages may be created retrospectively from the electrode derivations used during actual recording). In a particular segment with a question of potential epileptiform event (e.g. spikes, sharp waves, spike and waves and sharp and slow waves) the standard PSG speed of 10 mm/s can be quickly changed to the usual EEG speed of 30 mm/s for recognizing the evolving pattern of activation for a correct diagnosis. These capabilities help

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identify an abnormal EEG pattern and distinguish artifacts from true cerebral events. Computerized PSG makes it easy to document all events, to edit and report. The computerized PSG can store the raw data on relatively inexpensive CD-ROM or other suitable media making it easy to keep database and access raw data. European data format (EDF) is the most common format for exchange of digital PSGs between different laboratories in different countries. Simultaneous video monitoring during PSG recording is essential to obtain patient's behavior and motor manifestations, particularly in patients with parasomnias and nocturnal seizures. Recently introduced digital video incorporated into the computerized PSG system is an important advance over the traditional video tape recording. Digital video recordings, however, use a lot of space on the hard disk and one way to handle this problem is to save only small segments of digital video. The latest digital versatile disk (DVD) may solve the storage problems in the future. In order to overcome the limitations and fallacies of the R-K system and to reduce the time for scoring, automatic computer-assisted scoring techniques have been proposed (Hasan, 1996; Kubicki and Hermann, 1996; Hirshkowitz and Moore, 1999; Penzel and Conradt, 2000) and are commercially available. Some of the later methods are still evolving but none of the techniques have received wide popularity because of serious limitations in obtaining an acceptable scoring and because of lack of standardization, validation and precision in the methods. Some of the problems in computer-assisted scoring include artifact recognition, differentiating stage I NREM sleep from REM sleep, discriminating different sleep stages, inability to differentiate eye movements from high amplitude delta waves and failure to detect upper airway resistance. Attempts have also been made to develop computer methods to identify obstructive, central and mixed apneas and hypopneas as well as arousals and PLMS but the methods remain ambiguous, imprecise, and variable resulting in lack of universal acceptance yet. Computerized scoring has no real gold standard to compare the data. Another disadvantage of computer scoring is that there is no standardized procedure for scoring of various physiological characteristics. Furthermore, for comparison between visual and computerized scoring sampling remains a problem.

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R-K manual scoring still remains today the gold standard in clinical practice.

10.5. Artifacts during PSG recording Artifacts refer to extraneous electrical activities not recorded from the regions of interest (e.g. the brain, muscles, eyes and heart). These extraneous electrical activities may obscure the biological signals of interest and, therefore, recognition and correction of these artifacts is an important task for the polysomnographic technologist. The artifacts can be divided into three categories: physiological, environmental and instrumental (Keenan, 1999; Walczak and Chokroverty, 1999). 10.5.1. Physiological artifacts

These include myogenic potentials, artifacts resulting from movements of the head, eyes, tongue, mouth and other body parts, sweating, pulse and EKG artifacts as well as rhythmic tremorogenic artifacts. 10.5.2. Environmental sources of electrical signals

These may simulate electrocerebral activity or may obscure the EEG activities and include 60 Hz (or 50 Hz), artifacts resulting from the telephone or the pager systems. Electrostatic artifacts result from movements of the subjects in the environment. Most important is keeping the impedance of recording electrodes below 5 K. 10.5.3. Instrumental artifacts

These arise from faulty electrodes, electrode wires, switches and the polygraph machine itself. A very common artifact is electrode "pops" which are transient sharp waves or slow waves limited to one electrode. These artifacts result from faulty electrode placement or insufficient electrode gel causing abrupt changes in impedance. The electrode should be reset and gel applied. If this persists then electrodes need to be changed. Other sources of artifacts are the electrode wires, cables and the switches. In the PSG machine random fluctuations of charges result in some instrumental noise artifacts. If the sensitivity is greater than 2 microvolts per mm, which are not generally used in PSG recordings, then these instrument artifacts may

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interfere with the recording. Loose contacts in switches or wires may also cause sudden changes in voltage or loss of signal. 10.6. Pitfalls of PSG

Polysomnography is the single most important laboratory test for assessment of sleep disorders, particularly in patients presenting with excessive daytime somnolence and those suspected of nocturnal seizures, parasomnias or other abnormal motor activities. However, PSG has considerable limitations (Hinmanen and Hasan, 2000; Hirshkowitz, 2000). There is no standardized uniform protocol used in all sleep laboratories and this may make the comparison of the data from one laboratory to another somewhat misleading. The most serious limitation is that the ovemight in-laboratory PSG is labor intensive, time consuming and expensive. A single night's PSG may miss the diagnosis of mild OSAS, PLMS, parasomnias or nocturnal seizures. PSG data and patient's clinical findings may not be concordant. PSG data may be confounded by the first night effects (e.g. increased wakefulness and stage I NREM sleep and decreased slow wave and REM sleep). 10.7. Multiple sleep latency test

The most common indication for referring a patient for multiple sleep latency test (MSLT) is excessive daytime sleepiness (EDS), although sleep onset and sleep maintenance insomnia is the most common complaint in the general population. The initial step in assessment of the patient with EDS is a detailed sleep history and other history and physical examination. For assessment of persistent sleepiness the Epworth Sleepiness Scale (ESS) (Johns, 1991) is often used to assess a general level of sleepiness. This is a subjective propensity to sleepiness assessed by the patient under eight situations on a scale of 0-3, with three indicating a situation when chances of dozing off are highest. The maximum score is 24 and a score of 10 suggests the presence of EDS. This test has been weakly correlated with MSLT scores. The ESS and MSLT, however, test different types of sleepiness. MSLT tests the propensity to sleepiness objectively, and ESS the general feeling of sleepiness or subjective propensity to sleepiness. The Stanford Sleepiness

Scale (SSS) (Keenan, 1999) is a 7 point scale to measure subjective sleepiness but it does not measure persistent sleepiness. Visual Analog Scale (Keenan, 1999) is the other scale used to assess alertness and wellbeing in which subjects indicate their feelings of alertness at an arbitrary point on a line of 0-100 mm scale with 100 being the maximum sleepiness and 0 being the most alertness. 10.7.1. Technique of MSLT

The MSLT has been standardized and includes several general and specific procedures (Carskadon et al., 1986; Cherbin, 2003). The test is preceded by an overnight polysomnographic study and is scheduled about 2-3 hours after the conclusion of the overnight PSG study. The actual test consists of 4-5 opportunities for napping at 2 hour intervals and each recording session lasts for a maximum of 20 min. Between tests subjects must remain awake. The measurements include average sleep onset latency and the presence of sleep onset rapid eye movements (SOREMs). If no sleep occurs then the test is concluded 20 min after lights out. Fifteen minutes after the first 30-s epoch of any stage of sleep the test is terminated. If the finding is indefinite then it is better to continue the test than to end it prematurely. Mean sleep latency is calculated as the average of the latencies to sleep onset for each of the 4-5 naps. Mean sleep latency of less than 5 min is consistent with pathologic sleepiness. A mean sleep latency of 10-15 min is considered normal; and a mean sleep latency of up to 5-10 min is consistent with mild sleepiness. The occurrence of REM sleep within 15 min of sleep onset is defined as SOREMs. 10.7.2. Indications for MSLT

Narcolepsy is the single most important indication for performing the MSLT (Thorpy, 1992). A mean sleep latency of less than 5 min combined with SOREMs in 2 or more of the 4-5 recordings during MSLT is strongly suggestive of narcolepsy, although REM sleep dysregulation and circadian rhythm sleep disorders may also lead to such findings. In patients with upper airway obstructive sleep apnea syndrome (OSAS) the MSLT is indicated to assess the degree of severity of daytime sleepiness. Sometimes the patients underestimate the presence

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of sleepiness and often deny daytime symptoms. In such patients it is important to assess the daytime sleepiness so that the appropriate advice regarding the driving and avoidance of dangerous situations during the daytime can be given to the patient to prevent disastrous consequences. Patients with excessive daytime sleepiness with no easily ascertainable cause should also have an MSLT to document objectively EDS and findings suggesting REM sleep dysregulation. In idiopathic hypersomnia the MSLT findings will be consistent with pathologic sleepiness without SOREMs.

10.7.3. Reliability, validity and limitation of the MSLT The sensitivity and specificity of the MSLT in detecting sleepiness have not been clearly determined (Cherbin, 2003). The test-retest reliability of the MSLT, however, has been documented in both normal subjects and patients with narcolepsy. In subjects with sleepiness caused by circadian rhythm sleep disorders, sleep deprivation and ingestion of hypnotics and alcohol pathologic sleepiness has been validated by MSLT. However, there is poor correlation between the MSLT and ESS. The patient's psychological and behavioral state also interferes with the MSLT results. MSLT objectively measures tendency to sleep rather than the likelihood of falling asleep. If the patient suffers from severe anxiety or psychological disturbances causing behavioral stimulation, MSLT may not show sleepiness even in a patient complaining of EDS.

10.8. Maintenance of wakefulness test The MWT is a variant of the MSLT to measure a patient's ability to stay awake (Doghramji et al., 1997). Sleep latency is defined as in MSLT from lights out to the first epoch of any stage of sleep. It has generally been accepted that if the mean sleep latency is less than 11 min there is impairment of wake tendency. The MWT is useful in differentiating groups with normal daytime alertness from those with EDS. The MWT is more sensitive than MSLT in assessing the effects of treatments (e.g. CPAP titration in OSAS and the stimulant treatment for narcolepsy). It is less useful and less sensitive than the MSLT as a diagnostic test for narcolepsy. The MSLT and the MWT do have separate functions: the MSLT

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unmasks physiologic sleepiness, which depends on both circadian and homeostatic factors whereas the MWT is a reflection of the individual's capability to resist sleep and is influenced by physiologic sleepiness.

10.8.1. Actigraphy Monitoring of body movements and other activities can be performed continuously for days, weeks or even months by using an actigraph, also known as actometer or actimeter (Standards of Practice Committee of the American Sleep Disorders Association, 1995). This can be worn on the wrist or alternatively on the ankle for recording arm, leg and body movements. The actigraph uses piezoelectric sensors, which function as accelerometers to record acceleration or deceleration of movements rather than the actual movement. The principle of analysis is based on the fact that increased movements are seen during wakefulness in contrast to markedly decreased movements or no movements during sleep. Several actigraph models are in developing stage to carefully regulate the sampling frequencies and duration, filters, sensitivities and the dynamic range in order to detect and quantify PLMS but no generally accepted standardized technique of quantifying and identifying PLMS discriminating from other movements (e.g. those resulting from parasomnias, nocturnal seizures and other dyskinesias) is currently available. Currently the role of actigraphy in detecting, quantifying and differientiating abnormal motor activities remains controversial but there is immense potential in the future for such applications with the development of sophisticated models and techniques.

10.9. Conclusion Patients presenting with abnormal movements during sleep constitute a group of the most challenging sleep disorders. Many such patients remain undiagnosed or misdiagnosed for years and are often subjected to inappropriate treatment. We must make an effort to correctly diagnose and classify such disorders. In this chapter, I briefly summarized an important laboratory procedure (e.g. PSG) which might be helpful in assessment of patients presenting with abnormal motor activities during sleep. I must, however, emphasize that any laboratory procedure

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must act as facilitator and be subservient to the clinical approach to such patients. References Agarwal, Rand Gotman, J (2002) Digital tools in polysomnography. J. Clin. Neurophysiol., 19: 136143. Aldrich, M and Jahnke, B (1991) Diagnostic value of video-EEG polysomnography. Neurology, 41: 1060. Allen, RP, Piechietti, D and Hening, WA et al., and the International Restless Legs Syndrome Study Group (2003) Restless Legs Syndrome: diagnostic criteria, special considerations and epidemiology. Sleep Med., 4(2): 101-119. Aserinsky, E and Kleitman, N (1953) Regularly occurring periods of eye motility and concomitant phenomena during sleep. Science, 118: 273. Atlas Task Force of the American Sleep Disorders Association (1993) Recording and scoring leg movements. Sleep, 16: 748. Berger, H (1929) Uber das Elektroencephalogramm des Menschen. Arch. Psychiatr. Nervenkr., 87: 527-570. Carskadon, MA, Dement, WC and Mitler, M et al. (1986) Guidelines for the Multiple Sleep Latency Test (MSLT): a standard measure of sleepiness. Sleep, 9: 519. Cherbin, R (2003) Assessment of sleepiness. In: S Chokroverty, WA Hening and AS Walters (Eds.), Sleep and Movement Disorders. Butterworth-Heinemann; Boston. Doghramji, K, Mitler, M and Sangal, RB et al. (1997) A normative study of the maintenance of wakefulness test (MWT). Electroencephalogr. Clin. Neurophysiol., 103: 554. Hasan, J (1996) Past and future of computer-assisted sleep analysis and drowsiness assessment. J. Clin. Neurophysiol., 13: 295-313. Hirshkowitz, M (2000) Standing on the shoulders of giants: The standardized sleep manual after 30 years. Commentary. Sleep Med. Rev., 4: 169-179. Hirshkowitz, M and Moore, CA (1994) Issues in computerized polysomnography. Sleep, 17: 105. Hirshkowitz, M and Moore, CA (1999) Computerized and portable sleep recording. In: S Chokroverty (Ed.), Sleep Disorders Medicine. Butterworth-Heinemann: Boston, pp. 237-244.

151 Hinmanen, S-L and Hasan, J (2000) Limitations of Rechtschaffen and Kales. Sleep Med. Rev., 4: 149-167. Indications for Polysomnography Task Force, American Sleep Disorders Association Standards of Practice Committee (1997) Practice parameters for the indications for polysomnography and related procedures. Sleep, 20: 406-422. Johns, MW (1991) A new method for measuring daytime sleepiness: the Epworth Sleepiness Scale. Sleep, 14: 540. Keenan, SA (1999) Polysomnographic technique: An overview: In: S Chokroverty (Ed.), Sleep Disorders Medicine. Butterworth-Heinemann: Boston, pp. 151174. Kryger, MH (2000) Monitoring respiratory and cardiac function. In: MH Kryger, T Roth and WC Dement (Eds.), Principles and Practice of Sleep Medicine. WB Saunders Company: Philadelphia, pp. 1217-1230. Kubicki, S and Hermann, WM (1996) The future of computer-assisted investigation of the polysomnogram: Sleep microstructure. J. Clin. Neurophysiol., 13: 285294. Mahowald, M (2002) Hope for the PLMS quagmire: Editorial. Sleep Med., 3: 463-464. Oswald, I (1959) Sudden body jerks on falling asleep. Brain, 82: 92. Parisi, RA (1999) Respiration and respiratory function: Technique of recording and evaluation. In: S Chokroverty (Ed.). Butterworth-Heinemann: Boston, pp. 215221. Penzel, T and Conradt, R (2000) Computer based sleep recording and analysis. Sleep Med. Rev., 4: 131-J48. Rechtschaffen, A and Kales, A (1968) A Manual of Standardized Terminology, Techniques and Scoring System for Sleep Stages of Human Subjects. Washington, D.C.: U.S. Govemment Prinitng Office. Standards of Practice Committee of the American Sleep Disorders Association (1995) Practice parameters for the use of actigraphy in the clinical assessment of sleep disorders. Sleep, 18: 285-228. Thorpy, M (1992) The clinical use of the multiple sleep latency test. Sleep, 15: 268-276. Walczak, T and Chokroverty, S (1999) Electroencephalography, electromyography, and electro-oculography: General principles and basic technology. In: S Chokroverty (Ed.), Sleep Disorders Medicine. Butterworth-Heinemann: Boston, pp. 175-203.

Movement Disorders Handbook of Clinical Neurophysiology, Vol. 1 M. Hallett (Ed.) © 2003 Elsevier B.Y. All rights reserved

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CHAPTER II

Microneurography and motor disorders David Burke?", Simon C. Gandevia'' and Vaughan G. Macefield" "College of Health Sciences, The University of Sydney and h Spinal Injuries Research Centre, Prince of Wales Medical Research Institute, University of New South Wales, Sydney, Australia

The technique of microneurography was developed by Vallbo and Hagbarth (1968) and Hagbarth and Vallbo (1968), and has since been used to shed light on motor control mechanisms, cutaneous tactile sensations, pain and disturbances to sympathetic efferent function. This chapter addresses the technique and some of the contributions made using it to understanding the role of the 'Y efferent system in the control of movement and motor disorders.

11.1. Technique In microneurography, the experimenter inserts a sterilized microelectrode manually through the skin into an underlying nerve trunk and then guides the electrode tip into the desired nerve fascicle. The electrodes are usually monopolar tungsten electrodes with a shaft diameter of - 200 urn, tapered to a tip of 1-5 p.m and insulated to the tip (Fig. 1). To obtain good single unit recordings from large myelinated axons, the electrode impedance measured at 1 kHz is usually of the order of 100-300 kil. A special concentric needle electrode has also been used by some investigators (Hallin and Wiesenfeld, 1981). Different authorities use or eschew stimulation through the microelectrode to guide insertion, but all rely on auditory feedback when close to or within a fascicle. Figure 1 illustrates the recording technique, but there is a size distortion that belies the fact that the microelectrode is much larger (shaft 200 urn) than the largest axons «20 urn), Nevertheless, manipulating the position of recording tip within the fascicle is relatively easy for experienced experi-

* Correspondence to: David Burke, MD, DSc, College of Health Sciences, Medical Foundation Building - K25, University of Sydney, NSW 2006, Australia. E-mail address:[email protected]

Tel.: lnt +61.2.9036.3091; fax: lnt +61.2.9036.3092.

menters, and it is possible to focus on different types of activity - multi-unit activity, single unit activity and the activity in unmyelinated axons, afferent or efferent. Axons with background activity are preferentially detected, merely because their discharge can be heard and the recording can be focused on this activity. Single unit recordings are those in which the activity of a single unit stands out from background activity and noise, with a sufficiently large spike that it can be heard and seen reliably, and are usually from the largest axons because the amplitude of the action potential is a function of the square of axon diameter.

11.2. Fusimotor involvement in control of reflex function, muscle tone and voluntary movement Traditionally, muscle spindle afferents have held pride of place among muscle afferents, largely because their discharge can be directly modulated by 'Y efferent (fusimotor) drive, an unusual property for a sensory receptor. Recordings from muscle spindle endings have been used as measures of 'Y efferent activity. However, this practice is safe only if all other influences on spindle discharge are measured and controlled, and this is rarely possible in human experiments. Accordingly, there are conflicting data and conclusions in the literature and, inevitably, this review reflects the experience and biases of the authors.

11.2.1. Effects of immediate history on spindle discharge It is now well documented that the discharge of muscle spindle endings is affected by previous stretch (Edin and Vallbo, 1988) and by previous fusimotor activation (Ribot-Ciscar et al., 1991; Proske et al., 1993; Wilson et al., 1995), such that, for example, the discharge of muscle spindle endings

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Fig. 1. Unitary recording from a human muscle spindle. For the recording on the right, the tungsten rnicroelectrode was inserted percutaneously into a motor fascicle of the ulnar nerve at the wrist and the target muscle identified by the responses to intraneural electrical stimulation and the responses to passive and active movements of the digits. The recording was made from a spontaneously-active (presumed secondary) spindle ending in the 4th dorsal interosseous. The spindle ending increased its discharge during extension (right panel) and passive abduction (not shown) at the 4th metacarpophalangeal joint, the responses to stretch and shortening being essentially static. A sketch of the technique is on the left. The rnicroelectrode is introduced manually and, when in situ, it is supported without rigid fixation at one end by its connecting lead and at the other by the skin and subcutaneous tissue. Its position is adjusted within the nerve until the tip penetrates the desired nerve fascicle. Minor adjustments are made to bring the desired neural activity into focus. Note that the rnicroelectrode has a shaft diameter of - 200 urn and that the largest axons have a diameter of - 20 urn,

may remain elevated for long after a voluntary contraction, as in Fig. 2 (Macefield et al., 1991; Wilson et al., 1995). This is not due to on-going fusimotor drive but to the persistence of actinmyosin bonds formed in intrafusal fibers by 'Y efferent -activity that accompanied the contraction but ceased with it. The resulting distortions of spindle responsiveness could account for some of the discrepancies between different studies. The effects of intrafusal thixotropy can be quite prominent, sufficient to produce changes in reflex function and distortions of proprioceptive sensations which depend on perception of muscle spindle discharge (e.g. Wise et al., 1998). 11.2.2. 'Y drive to resting muscle

In human subjects who are at rest, there is a very low, possibly negligible level of fusimotor drive, particularly in static 'Y efferents (Vallbo et al., 1979; Burke, 1981; Gandevia and Burke, 1992), such that

muscle spindle discharge and the response to stretch do not change appreciably following complete nerve block (Burke et al., 1976, 1981a). There may be some activity in dynamic 'Y efferents, and this may be altered by the reflex action of cutaneous afferents (Aniss et al., 1990; Gandevia et al., 1994) and, possibly, by reinforcement maneuvers (see below, Ribot-Ciscar et al., 2000). In normal subjects who are at rest, muscle tone and the tendon jerk are therefore not dependent on the level of fusimotor drive, and hypotonia and hyporeflexia cannot be due to the withdrawal of background v activity (for reviews, see Burke, 1983, 1988). 11.2.3. Reflex reinforcement

The potentiation of spinal reflexes by reinforcement maneuvers (such as the Jendrassik maneuver) is largely due to effects on reflex transmission within

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Fig. 2. Activation of a muscle spindle ending in tibialis anterior (TA) during a 60 s contraction. Panel A shows the first 20 s of the contraction, and panel B the last 10 s, the traces being the nerve recording, ankle dorsiflexion force and integrated EMG of TA. The axon had no background discharge at rest but was activated during the contraction, discharging at - 12 Hz. On cessation of the contraction, there was a high-frequency burst of impulses from the afferent as the spindle was stretched, but the discharge then continued despite the complete subsidence of EMG and force. Panel C shows the "twitch test" used to identify the afferent as of spindle origin (upper trace: discharge of the afferent in five supramaximal trials; second trace: corresponding twitch contractions). The lowest trace shows superimposed action potentials of the afferent. From Macefield et al. (1991), with permission.

the spinal cord, not to activation of the 'Y efferent system. It was believed that selective activation of dynamic 'Y efferents would potentiate the muscle spindle response to percussion sufficiently to enhance the tendon jerk (Paillard, 1955), but some authorities question whether dynamic 'Y activation could do so (Morgan et al., 1984; Wood et al., 1994), and there is evidence that it does not (Gregory et al., 2001). Some studies using microneurography have demonstrated that effective reinforcement maneuvers produce no enhancement of the background discharge or the response to stretch of muscle spindle afferents in EMG-silent muscles at constant length (Vallbo and Hagbarth, 1966; Hagbarth et al., 1975c; Burke, 1981; Burke et al., 1981b; Ribot et al., 1986), or their ease of activation in voluntary contractions (Burke et aI., 1980a). Others have reported that reinforcement maneuvers produce an increased background spindle discharge (Burg et al., 1974; Szumski et al., 1974; Ribot-Ciscar et aI., 2000), or an increased discharge of presumed dynamic 'Y efferent axons though, parodoxically, without an increase in group Ia activity (Ribot et al.,

1986). However, these maneuvers may also increase the discharge of at least some (X motoneurons (Ribot et al., 1986), raising questions about the selectivity claimed for the 'Y activation (Hagbarth et aI., 1975c; see also Ribot-Ciscar et al., 2000). If reinforcement increased the background spindle discharge, this should depress reflex transmission from the active afferents (through the mechanism known as "homosynaptic" depression). This would depress rather than enhance the tendon jerk and the H-reflex (Hultbom et al., 1996; Wood et aI., 1996), unless the spindle response to percussion could be enhanced sufficiently to overcome the "homosynaptic" depression due to increased background spindle activity. The available evidence suggests that it cannot (Gregory et al., 2001). If reflex reinforcement occurs within spinal cord circuitry, as is suggested by Fig. 3, one would expect the H-reflex to be potentiated, as indeed it is (Landau and Clare, 1964; Bussel et al., 1978; Burke et al., 1981b; Dowman and Wolpaw, 1988; Zehr and Stein, 1999; Gregory et al., 2001). Potentiation of the H-reflex is difficult to explain on a fusimotor mechanism. Similarly, when subjects are warned of the need to contract a muscle (anticipation), train on a task or mentally rehearse a movement, there is no evidence for selective activation of 'Y motoneurons although, in each instance, spinal reflex excitability is increased (Burke et al., 1980b; Gandevia and Burke, 1985; Gandevia et al., 1997). In addition, fusimotor drive does not contribute to the reflex enhancement accompanying a motor adaptation task (Al-Falahe et al., 1990). These studies indicate that there are effective mechanisms for controlling reflex "gain" independent of the fusimotor system. 11.2.4. Voluntary contractions

During a nerve block that affects (X motor axons preferentially, the effort to contract the paralyzed muscle increases the discharge of spindle endings, presumably because it activates 'Y efferents directed to the paralyzed muscle (Burke et aI., 1979a). This finding provided support for the view that, when normal subjects contract a muscle voluntarily (or unintentionally), static 'Y motoneurons innervating the contracting muscle (but not its inactive synergists) are activated (Vallbo and Hagbarth, 1966; Vallbo, 1971, 1974; Vallbo et al., 1979). When the contraction is isometric, the 'Y activation is usually

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Fig. 3. Effects of the Jendrassik maneuver. Panel A shows the relationship between the intensity of tendon percussion to the Achilles tendon (in arbitrary units) and the amplitude of the integrated multi-unit afferent response from the nerve fascicle innervating soleus (in arbitrary units) for one subject. Circles: subject relaxed. Triangles: subject performing the Jendrassik maneuver. Filled symbols: percussion that produced a tendon jerk. Open symbols: no reflex response. The "threshold" for the tendon jerk was equivalent to 15 units of afferent activity (or 12 units of percussion) when relaxed but 9 units of afferent activity (4-5 units of percussion) when performing the Jendrassik maneuver. Panel B shows for the same data, using the same symbols, the relationship between the afferent volley and the reflex EMG. During the Jendrassik maneuver (triangles), the same afferent volley produced a significantly greater reflex response than at rest (circles). From Burke et aI. (l98Ib), with permission.

sufficient to enhance the background discharge of spindle endings (Fig. 2), increase their discharge variability, increase their static response to stretch, and diminish the pause in discharge that occurs on muscle shortening (Vallbo, 1971, 1973, 1974; Burke et al., 1979b). There is evidence that voluntary effort also activates dynamic 'Y efferents (Kakuda and Nagaoka, 1998), and that f3 (skeletofusimotor) efferents can be activated by both voluntary effort (Aniss et al., 1988; Kakuda et al., 1998) and transcranial stimulation of the motor cortex (Rothwell et aI., 1990). When voluntary contractions produce muscle shortening, the enhanced fusimotor drive can be sufficient to maintain or even increase spindle discharge (Vallbo, 1973), but this occurs only if the movement is slow or the muscle is contracting against a load (Burke et al., 1978a, b; Hulliger et al., 1985). The increase in spindle discharge usually occurs after the onset of EMG activity in the contracting muscle, at some 20-50 ms when the contractions are rapid and phasic (Vallbo, 1971; Hagbarth et al., 1975a). However, while there has been clear evidence of a-'Y co-activation in all

voluntary acts so far tested, the balance between the a and 'Y drives can be varied (Burke et al., 1980a;

Vallbo and Hulliger, 1981; Wessberg and Vallbo, 1995). This would be expected given that different descending pathways have quantitatively different effects on a and 'Y motoneurons, and that many peripheral afferent inputs have different reflex effects on a and 'Y motoneurons (Aniss et al., 1990; Gandevia et al., 1994). Nevertheless, the evidence for disproportionate activation of 'Y motoneurons during motor learning and precision finger movements is, at best, quite modest (Vallbo and AI-Falahe, 1990; Wessberg and Vallbo, 1995; Kakuda et al., 1996). In fatiguing submaximal isometric contractions the enhancement of muscle spindle discharge is maximal initially and then decreases by about onethird (Macefield et al., 1991), a finding that implies that feedback support to the contraction is maximal initially but subsequently wanes. A further implication is that, contrary to classical views (Merton, 1953), the 'Y efferent system is not mobilized to compensate for fatigue, at least under isometric conditions. When a motor nerve is blocked distal to

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MICRONEUROGRAPHY AND MOTOR DISORDERS

the recording site, recordings can be made from the axons of ex motoneurons deprived of feedback support from endings in the now-paralyzed muscle (Gandevia et aI., 1990, 1993; Macefield et aI., 1993). The discharge rates of motor axons reach only about two-thirds of those of normally intact motor units, a finding that suggests significant feedback support to the contracting motoneuron pool. It is more difficult to maintain motor unit firing in the absence of this feedback, but subjects can still recruit and de-recruit motoneurons and modulate motoneuron firing rates, given only knowledge of the effort that they are sending to the muscle. 11.4. Cutaneous atTerents and motor control

The traditional view that cutaneous afferents play little role in motor control is just as fallacious as the view that muscle afferents play no role in sensation. In the control of hand function, cutaneous afferents are at least as important as muscle spindle afferents and, for some motor acts, they are arguably more important sources of afferent feedback, capable of reflexly modifying the command for movement at multiple levels - segmental, suprasegmental and cerebral. There are extensive data on the response patterns of different cutaneous mechanoreceptors to tactile stimuli, to skin stretch and to passive movement of the hand (for review see Macefield, 1998), yet there has been relatively little work on the roles of tactile afferents in motor control. Most of this work has dealt with the sensorimotor specializations of the hand which, given its high density of tactile afferents (particularly in the finger pads), is perhaps not surprising. At the very least, receptors in the skin provide facilitation of the motoneuron pool: electrical or mechanical stimulation of cutaneous afferents causes short-latency (spinal) and long-latency increases in the EMG of muscles acting on the digits (Darton et aI., 1982; Evans et aI., 1986; Macefield et aI., 1996b) and, in the absence of muscle afferent feedback (anesthetic block ofthe ulnar nerve), tactile afferents traveling in the median nerve have been shown to increase the size of a volitionaIly generated motor output (Gandevia et aI., 1990). Moreover, the input from a single cutaneous afferent is sufficiently strong that it can modulate the ongoing EMG of muscles acting on the receptor-bearing digit, at

spinal latencies (McNulty et aI., 1999); conversely, the synaptic input of a single muscle spindle afferent is weak, at least for muscle spindles in the leg (Gandevia et aI., 1986). However, more than this simple facilitation of motoneurons, tactile afferents are actively engaged in fine motor control of the hand. Because of their location at the skin/object interface, cutaneous mechanoreceptors are ideally placed to monitor the loads applied by or to the finger pads during manipulation of a gripped object. Indeed, anesthesia of the digits seriously compromises the capacity to perform a precision grip and to adjust the grip force automatically as a function of the load and surface conditions (Johansson et aI., 1992c; Hager-Ross and Johansson, 1996). Tactile afferents also provide information on the frictional conditions of the object, information that is incorporated automatically into grading the grip force required to hold an object (Cole and Johansson, 1993). Unpredictable pulling forces applied to an object held between finger and thumb evoke automatic increases in grip force that serve to prevent escape of the object from the grasp (Cole and Abbs, 1988; Johansson et al., 1992a, b, c; Macefield et aI., 1996a; Macefield and Johansson, 1996), and rnicroneurographic studies have shown that tactile afferents in the glabrous skin of the digits are the only receptors capable of triggering these increases in grip force (Macefield et aI., 1996a); muscle and joint afferents respond only during the resultant increases in grip force (Macefield and Johansson, 1996). 11.5. Studies in patients

11.5.1. Spasticity There are relatively few reports of muscle spindle activity in spastic patients (Hagbarth et aI., 1973, 1975b; Szumski et aI., 1974; Wilson et aI., 1999).All are from hemiplegic patients; there are no published studies from patients with spinal cord injury. The studies of Szumski et al. (1974) and Hagbarth et al. (1975b) involved discharge patterns during clonus (described below with Parkinsonian tremor). Hagbarth et aI. (1973) reported that the responses to controlled stretch of 9 endings in triceps surae of hemiplegic patients were not greater than those of 12 spindle endings in normal subjects. Wilson et al.

D. BURKEET AL.

158

Instantaneous frequency

Fig. 4. Muscle spindle afferent innervating extensor carpi radialis (ECR) during deliberate isometric wrist extension in a patient suffering from hemiplegic spasticity (extensor strength 68% of that of the contralateral side). The afferent did not maintain a background discharge when truly at rest. During voluntary efforts to contract the muscle ("Extension"), the spindle ending was activated together with the EMG of ECR. Between the deliberate contractions, the ending was activated unintentionally during inadvertent contractions, but again with EMG. The ending in ECR was not activated during an unintentional contraction of the forearm flexors that occurred when the patient was told to relax ECR. The insert (top right) shows action potential morphology (multiple superimposed discharges). From Wilson et a1. (1999), with permission.

(1999) documented the properties of 26 endings in the forearm extensors. Background spindle discharge rates were the same as in healthy volunteers, reinforcement and other maneuvers did not enhance spindle discharge selectively, cutaneo-fusimotor reflexes could not be demonstrated, and spindles in the paretic muscles were no more difficult to activate in voluntary attempts to contract the weak muscles than in normal subjects (Fig. 4). These studies lead to the conclusion that there is no primary defect of fusirnotor function in hemiplegic spasticity - the hyper-reflexia is not due to enhanced 'Y efferent drive, and the loss of dexterity is not due to inability to activate 'Y motoneurons appropriately for the degree of a activation. Whether the same holds true for patients with spinal spasticity remains to be demonstrated. It is not unreasonable to speculate that cutaneo-fusimotor reflexes could be disinhibited in spinal patients, much as are cutaneomuscular reflexes, and it is conceivable that "normal" peripheral afferent inputs from skin, joints,

etc. may produce a background discharge in 'Y efferents. 11.5.2. Parkinson's disease The only published data from parkinsonian patients are those of Hagbarth et a1. (1975b) on parkinsonian tremor and of Wallin et al. (1973) on multi-unit muscle afferent responses to muscle stretch, together with a re-analysis of some of these data (Burke et al., 1977). In parkinsonian tremor muscle spindle endings tended to discharge twice, during the shortening phase of the test muscle (with the EMG of that muscle) and during the lengthening phase (which would subject muscle spindles to stretch). There was a similar biphasic pattern in healthy subjects who made rapid alternating movements to mimic tremor (Hagbarth et al., 1975a) whereas, in the reflex-sustained movements of clonus in spastic patients, spindle discharge occurred only during the stretching phase of the oscillating

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MICRONEUROGRAPHY AND MOTOR DISORDERS

movement (Szumski et al., 1973; Hagbarth et al., 1975b). In multi-unit recordings, it was noted that spontaneous or evoked fluctuations in rigidity involved parallel fluctuations in afferent activity and EMG and that there was more background afferent activity in rigid muscles than in normal subjects who were relaxed. The shortening reaction is a phenomenon characteristic of Parkinson's disease and other basal ganglia disturbances, but may also occur in normal human subjects. There is one recording of a shortening reaction in a normal subject: passive dorsiflexion produced an involuntary contraction of tibialis anterior, and this was associated with a muscle spindle discharge, much as was recorded when the subject made a voluntary dorsiflexion movement (Burke et aI., 1978b). The above data suggest that there is no primary defect of fusimotor function in parkinsonian rigidity. Parkinsonian rigidity seems to behave more as if there were a defect of supraspinal drives onto relatively normal spinal mechanisms, those drives affecting a and 'Y motoneurons much as would volitional drives. However, these conclusions are based on qualitative impressions rather than quantitative recordings, and more extensive studies are required before the views can be accepted as definitive. 11.5.3. Dystonia There have been no published microneurographic studies in dystonia, but there is literature suggesting that different forms of dystonia are due to or associated with a disturbance of sensory processing, affecting particularly the input from muscle spindle endings (Kaji et al., 1995; Grunewald et aI., 1997; Yoshida et al., 1998). In addition, some of the beneficial effects of botulinum toxin in dystonic syndromes may be due to effects on the neuromuscular junction of 'Y efferents on intrafusal fibers. 11.6. Clinical value

With microneurography, the findings depend on the site of the microelectrode within a fascicle. A recording from a single afferent axon is rarely representative of the population response, whether the afferent is of cutaneous or muscle origin. Multiunit recordings can provide a representative picture

of large-fiber activity within the fascicle, but are difficult to quantify. Accordingly, when one considers the data for an individual patient, microneurography currently has no place as a diagnostic procedure, even if insights into pathophysiology come when the data from a number of patients are pooled. Evoked compound action potentials to electrical stimulation have been recorded using microneurography, and the full range of afferent axons from large-myelinated to unmyelinated can be discriminated. However, the diagnostic value of such recordings is debatable, and similar data can be obtained with near-nerve needle electrodes. The clinical value of microneurography comes from the unique insights that it can provide into pathophysiology. References Al-Falahe, NA, Nagaoka, M and Vallbo, AB (1990) Lack of fusimotor modulation in a motor adaptation task. Acta Physiol. Scand., 140: 23-30. Aniss, AM, Gandevia, SC and Burke, D (1988) Reflex changes in muscle spindle discharge during a voluntary contraction. J. Neurophysiol., 59: 908-921. Aniss, AM, Diener, H-C, Hore, J, Burke, D and Gandevia, SC (1990) Reflex activation of muscle spindles in human pretibial muscles during standing. J. Neurophysiol., 64: 671-679. Burg, D, Szumski, AJ, Struppler, A and Velho, F (1974) Assessment of fusimotor contribution to reflex reinforcement in humans. J. Neurol. Neurosurg. Psychiatry, 37: 1012-1021. Burke, D (1981) The activity of human muscle spindle endings in normal motor behavior. In: R Porter (Ed.), International Review of Physiology, Vol. 25, Neurophysiology IV. University Park Press, Baltimore, pp.91-126. Burke, D (1983) Critical examination of the case for or against fusimotor involvement in disorders of muscle tone. In: JE Desmedt (Ed.), Motor Control Mechanisms in Health and Disease, Advances in Neurology, Vol. 39. Raven Press, New York, pp. 133-150. Burke, D (1988) Spasticity as an adaptation to pyramidal tract injury. In: SG Waxman (Ed.) Functional Recovery in Neurological Disease, Advances in Neurology, Vol. 47. Raven Press, New York, pp. 401-423. Burke, D, Hagbarth, K-E, Lofstedt, L and Wallin, BG (1976) The responses of human muscle spindle endings to vibration during isometric contraction. J. Physiol. (Lond.), 261: 695-711.

160 Burke, D, Hagbarth, K-E and Wallin, BG (1977) Reflex mechanisms in Parkinsonian rigidity. Scand. J. Rehab. Med., 9: 15-23. Burke, D, Hagbarth, K-E and Lofstedt, L (1978a) Muscle spindle responses in man to changes in load during accurate position maintenance. J. Physiol. (Lond.), 276: 159-164. Burke, D, Hagbarth, K-E and Lofstedt, L (1978b) Muscle spindle activity in man during shortening and lengthening contractions. J. Physiol. (Lond.), 277: 131-142. Burke, D, Hagbarth, K-E and Skuse, NF (1979a) Voluntary activation of spindle endings in human muscles temporarily paralysed by nerve pressure. J. Physiol. (Lond.), 287: 329-336. Burke, D, Skuse, NF and Stuart, DG (1979b) The regularity of muscle spindle discharge in man. J. Physiol. (Lond.), 291: 277-290. Burke, D, McKeon, B and Westerman, RA (1980a) Induced changes in the thresholds for voluntary activation of human spindle endings. J. Physiol. (Lond.),302: 171-181. Burke, D, McKeon, B, Skuse, NF and Westerman, RA (1980b) Anticipation and fusimotor activity in preparation for a voluntary contraction. J. Physiol. (Lond.), 306: 337-348. Burke, D, McKeon, B and Skuse, NF (198Ia) The irrelevance of fusimotor activity to the Achilles tendon jerk of relaxed humans. Ann. Neurol., 10: 547-550. Burke, D, McKeon, B and Skuse, NF (1981 b) Dependence of the Achilles tendon reflex on the excitability of spinal reflex pathways. Ann. Neurol., 10: 551-556. Bussel, B, Morin, C and Pierrot-Deseilligny, E (1978) Mechanism of monosynaptic reflex reinforcement during Jendrassik maneuver in man. J. Neurol. Neurosurg. Psychiatry, 41: 40-44. Cole, KJ and Abbs, JH (1988) Grip force adjustments evoked by load force perturbations of a grasped object. J. Neurophysiol., 60: 1513-1522. Cole, KJ and Johansson, RS (1993) Friction at the digitobject interface scales the sensorimotor transformation for grip responses to pulling loads. Exp. Brain Res., 95: 523-532. Darton, K, Lippold, OC, Shahani, M and Shahani, U (1985) Long-latency spinal reflexes in humans. J. Neurophysiol., 53: 1604-1618. Edin, BB and Vallbo, AB (1988) Stretch sensitization of human muscle spindles. J. Physiol. (Lond.), 400: 101-111. Evans, AL, Harrison, LM and Stephens, JA (1989) Taskdependent changes in cutaneous reflexes recorded from various muscles controlling finger movement in man. J. Physiol. (Lond.), 418: 1-12.

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Gandevia, SC and Burke, D (1985) Effect of training on voluntary activation of human fusimotor neurons. J. Neurophysiol., 54: 1422-1429. Gandevia, SC and Burke, D (1992) Does the nervous system depend on kinesthetic information to control natural limb movements? Behav. Brain Sci., 15: 614632. Gandevia, SC, Burke, D and McKeon, B (1986) Coupling between human muscle spindle endings and motor units assessed using spike-triggered averaging. Neurosci. Lett., 71: 181-186. Gandevia, SC, Macefield, G, Burke, D and McKenzie, DK (1990) Voluntary activation of human motor axons in the absence of muscle afferent feedback. The control of the deafferented hand. J. Physiol. (Lond.), 113: 15631581. Gandevia, SC, Macefield, VG, Bigland-Ritchie, B, Gorman, RB and Burke, D (1993) Motoneuronal output and gradation of effort in attempts to contract acutely paralysed leg muscles in man. J. Physiol. (Lond.), 471: 411-427. Gandevia, SC, Wilson, L, Cordo, PJ and Burke, D (1994) Fusimotor reflexes in relaxed forearm muscles produced by cutaneous afferents from the human hand. J. Physiol. (Lond.), 479: 499-508. Gandevia, SC, Wilson, LR, Inglis, JT and Burke, D (1997) Mental rehearsal of motor tasks recruits alpha-motoneurons but fails to recruit human fusimotor neurons selectively. J. Physiol. (Lond.), 505: 259-266. Gregory, JE, Wood, SA and Proske, U (2001) An investigation into mechanisms of reflex reinforcement by the Jendrassik maneuver. Exp. Brain Res., 138: 366-374. Grunewald, RA, Yoneda, Y, Shipman, JM and Sagar, HJ (1997) Idiopathic focal dystonia: a disorder of muscle spindle afferent processing? Brain, 120: 2179-2185. Hagbarth, K-E and Vallbo, AB (1968) Discharge characteristics of human muscle afferents during muscle stretch and contraction. Exp. Neurol., 22: 674-694. Hagbarth, K-E, Wallin, G and Lofstedt, L (1973) Muscle spindle responses to stretch in normal and spastic subjects. Scand. J. Rehab. Med., 5: 156-159. Hagbarth, K-E, Wallin, G and Lofstedt, L (1975a) Muscle spindle activity in man during voluntary fast alternating movements. J. Neurol. Neurosurg. Psychiatry, 38: 625635. Hagbarth, K-E, Wallin, G, Lofstedt, L and Aquiionius, SM (1975b) Muscle spindle activity in alternating tremor of Parkinsonism and in clonus. J. Neurol. Neurosurg. Psychiatry, 38: 636-641. Hagbarth, K-E, Wallin, G, Burke, D and Lofstedt, L (1975c) Effects of the Jendrassik maneuver on muscle spindle activity in man. J. Neurol. Neurosurg. Psychiatry, 38: 1143-1153.

MICRONEUROGRAPHY AND MOTOR DISORDERS

Hager-Ross, C and Johansson, RS (1996) Non-digital afferent input in reactive control of fingertip forces during precision grip. Exp. Brain Res., 110: 131-141. Hallin, RG and Wiesenfeld, Z (1981) A standardized electrode for percutaneous recording of A and C fiber units in conscious man. Acta Physiol. Scand., 113: 561-563 Hulliger, M, Nordh, E and Vallbo, AB (1985) Discharge in muscle spindle afferents related to direction of slow precision movements in man. J. Physiol. (Lond.), 362: 437-453. Hultborn, H, Illert, M, Nielsen, J, Paul, A, Ballegaard, M and Wiese, H (1996) On the mechanism of the postactivation depression of the H-reflex in human subjects. Exp. Brain Res., 108: 450-462. Johansson, RS, Riso, R, Hager, C and Backstrom, L (1992a) Somatosensory control of precision grip during unpredictable pulling loads. I. Changes in load force amplitude. Exp. Brain Res., 89: 181-191. Johansson, RS, Hager, C and Riso, R (1992b) Somatosensory control of precision grip during unpredictable pulling loads. II. Changes in load force rate. Exp. Brain Res., 89: 192-203. Johansson, RS, Hager, C and Backstrom, L (1992c) Somatosensory control of precision grip during unpredictable pulling loads. III. Impairments during digital anesthesia. Exp. Brain Res., 89: 204-213. Kaji, R, Rothwell, JC, Katayama, M, Ikeda, T, Kubori, T, Kohara, N, Mezaki, T, Shibasaki, H and Kimura, J (1995) Tonic vibration reflex and muscle afferent block in writer's cramp. Ann. Neurol., 38: 155-162. Kakuda, N, Vallbo, AB and Wessberg, J (1996) Fusimotor and skeletomotor activities are increased with precision finger movement in man. J. Physiol. (Lond.), 492: 921-929. Kakuda, N, Miwa, T and Nagaoka, M (1998) Coupling between single muscle spindle afferent and EMG in human wrist extensor muscles: physiological evidence of skeletofusimotor (beta) innervation. Electroencephalogr. Clin. Neurophysiol., 109: 360-363. Kakuda, N and Nagaoka, M (1998) Dynamic response of human muscle spindle afferents to stretch during voluntary contraction. J. Physiol. (Lond.), 513: 621628. Landau, WM and Clare, MH (1964) Fusimotor function. Part IV. Reinforcement of the H-reflex in normal subjects. Arch. Neurol., 10: 117-122. Macefield, VG (1998) The signalling of touch, finger movements and manipulation forces by mechanoreceptors in human skin. In: JW Morley (Ed.), Neural Aspects of Tactile Sensation. Elsevier, Amsterdam, pp 89-130. Macefield, VG, Rothwell, JC and Day, BL (1996b) The contribution of transcortical pathways to long-latency

161 stretch and tactile reflexes in human hand muscles. Exp. Brain Res., 108: 172-184. Macefield, G, Hagbarth, K-E, Gorman, R, Gandevia, SC and Burke, D (1991) Decline in spindle support to alpha-motoneurons during sustained voluntary efforts. J. Physiol. (Lond.), 440: 497-512. Macefield, VG, Gandevia, SC, Bigland-Ritchie, B, Gorman, RB and Burke, D (1993) The firing rates of human motoneurons voluntarily activated in the absence of muscle afferent feedback. J. Physiol. (Lond.), 471: 429-443. Macefield, VG, Hager-Ross, C and Johansson, RS (1996a) Control of grip force during restraint of an object held between finger and thumb: responses of cutaneous afferents from the digits. Exp. Brain Res., 108: 155171. Macefield, VG and Johansson, RS (1996) Control of grip force during restraint of an object held between finger and thumb: responses of muscle and joint afferents from the digits. Exp. Brain Res., 108: 172-184. Merton, PA (1953) Speculations on the servo control of movement. In: JL Malcolm and JAB Gray (Eds.), The Spinal Cord. Ciba Foundation Symposium, Churchill, London, pp. 84-91. McNulty, PA, Tnrker, KS and Macefield, VG (1999) Evidence for strong synaptic coupling between single tactile afferents and motoneurons supplying the human hand. J. Physiol. (Lond.), 518: 883-893. Morgan, DL, Prochazka, A and Proske, U (1984) Can fusimotor activity potentiate the responses of muscle spindles to a tendon tap? Neurosci. Lett., 50: 209-215. Paillard, J (1955) Reflexes et Regulations d'Origine Proprioceptive Chez l'Homme. Arnette, Paris. Proske, U, Morgan, DL and Gregory, IE (1993) Thixotropy in skeletal muscle and in muscle spindles: a review. Prog. Neurobiol., 41: 705-721. Ribot, E, Roll, JP and Vedel, JP (1986) Efferent discharges recorded from single skeletomotor and fusimotor fibers in man. J. Physiol. (Lond.), 375: 2251-2268. Ribot-Ciscar, E, Tardy-Gervet, MF, Vedel, JP and Roll, JP (1991) Post-contraction changes in human muscle spindle resting discharge and stretch sensitivity. Exp. Brain Res., 86: 673-678. Ribot-Ciscar, E, Rossi-Durand, C and Roll, JP (2000) Increased muscle spindle sensitivity to movement during reinforcement maneuvers in relaxed human subjects. J. Physiol. (Lond.), 523: 271-282. Rothwell, JC, Gandevia, SC and Burke, D (1990) Activation of fusimotor neurons by motor cortical stimulation in human subjects. J. Physiol. (Lond.), 431: 743-756. Szumski, AJ, Burg, D, Struppler, A and Velho, F (1974) Activity of muscle spindles during muscle twitch and

162 clonus in normal and spastic human subjects. Electroencephalogr. Clin. Neurophysiol., 37: 589-597. Vallbo, AB (1971) Muscle spindle response at the onset of isometric voluntary contractions in man. Time difference between fusimotor and skeletornotor effects. J. Physiol. (Lond.), 218: 405-431. Vallbo, AB (1973) Muscle spindle afferent discharge from resting and contracting muscles in nonnal human subjects. In: JE Desmedt (Ed.), New Developments in Electromyography and Clinical Neurophysiology, Vol. 3. Karger, Basel, pp. 251-262. Vallbo, AB (1974) Human muscle spindle discharge during isometric voluntary contractions. Amplitude relations between spindle frequency and torque. Acta Physiol. Scand., 90: 319-336. Vallbo, AB and Hagbarth, K-E (1968) Activity from skin mechanoreceptors recorded percutaneously in awake human subjects. Exp. Neurol., 21: 270-289. Vallbo, AB and Hulliger, M (1981) Independence of skeletomotor and fusimotor activity in man? Brain Res., 223: 176-180. Vallbo, AB and Al-Falahe, NA (1990) Human muscle spindle response in a motor learning task. J. Physiol. (Lond.), 421: 553-568. Vallbo, AB, Hagbarth, K-E, Torebjork, HE and Wallin, BG (1979) Somatosensory, proprioceptive, and sympathetic activity in human peripheral nerves. Physiol. Rev., 59: 919-957. Wallin, BG, Hongell, A and Hagbarth, K-E (1973) Recordings from muscle afferents in Parkinsonian

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rigidity. In: JE Desmedt (Ed.), New Developments in Electromyography and Clinical Neurophysiology, Vol. 3. Karger, Basel, pp. 263-272. Wessberg, J and Vallbo, AB (1995) Human muscle spindle afferent activity in relation to visual control in precision finger movements. J. Physiol. (Lond.), 482: 225-233. Wilson, LR, Gandevia, SC and Burke, D (1995) Increased resting discharge of human spindle afferents following voluntary contractions. J. Physiol. (Lond.), 488: 833840. Wilson, LR, Gandevia, SC, Inglis, IT, Gracies, J-M and Burke, D (1999) Muscle spindle activity in the affected upper limb after a unilateral stroke. Brain, 122: 20792088. Wise, AK, Gregory, JE and Proske, U (1998) Detection of movements of the human forearm during and after cocontraction of muscles acting at the elbow joint. J. Physiol. (Lond.), 508: 325-330. Wood, SA, Morgan, DL, Gregory, JE and Proske, U (1994) Fusimotor activity and the tendon jerk in the anaesthetized cat. Exp. Brain Res., 98: 101-109. Wood, SA, Gregory, JE and Proske, U (1996) The influence of muscle spindle discharge on the human Hreflex and the monosynaptic reflex in the cat. J. Physiol. (Lond.), 497: 279-290. Yoshida, K, Kaji, R, Kubori, T, Kohara, N, Iizuka, T and Kimura, J (1998) Muscle afferent block for the treatment of oromandibular dystonia. Movement Dis., 13: 699-705.

Movement Disorders Handbook of Clinical Neurophysiology, Vol. 1 M. Hallett (Ed.) © 200] Elsevier B.V. All rights reserved

163 CHAPTER 12

Imaging Scott T. Grafton * Center for Cognitive Neuroscience, Dartmouth College, Hanover; NH 03755, USA

12.1. Introduction Brain imaging plays an important role in the evaluation of patients with movement disorders. Anatomic imaging is essential for ruling out structurallesions in subcortical nuclei and cortex, and for identifying regional atrophic changes. Imaging of brain metabolism and neurotransmitter function is an important adjunct to the clinical examination in patients with atypical akinetic-rigid syndromes that might not be secondary to idiopathic Parkinson's disease. Functional activation studies provide unique insight into normal motor control as well as the pathophysiologic basis of abnormal motor control. These imaging methods encompass techniques based on conventional x-rays, magnetic resonance and radionuclide tomography. In this chapter these techniques are reviewed and related to clinical applications, basic research and assessment of pharmacological and surgical therapy for movement disorders.

12.2. Structural imaging Although conventional x-rays of the skull are no longer used diagnostically in movement disorders, they are important historically for lesion localization and premorbid clinical-radiological correlation. In a classic 1917 study of injured soldiers, Holmes used conventional x-rays to relate the location of bullets lodged in the cerebellar hemispheres to cardinal signs of cerebellar damage including unilateral ataxia, hypotonia and dysiadochokinesia (Holmes,

* Correspondence to: Dr. Scott T. Grafton, M.D., Director, Dartmouth Brain Imaging Center, Center for Cognitive Neuroscience, 6162 Moore Hall, Dartmouth College, Hanover, NH 03755, USA. E-mail address: [email protected] Tel.: + I (603) 646-0038; fax: + I (603) 646-1181.

1917). With the development of computer assisted tomographic imaging (CT) in the 1970s it became possible to identify supratentorial structural lesions that could cause secondary movement disorders. This early imaging work revealed that the most common structural lesion leading to parkinsonian symptoms was a large cortical or glial tumor with deformation of the basal ganglia. It is extremely rare for tumors located directly within the basal ganglia to cause parkinsonism (Waters, 1993). Other lesions, occasionally associated with parkinsonism are listed in Table 1. The advent of CT also brought attention to the incidental finding of basal ganglia calcification, i.e. Fahr's disease. The incidence of basal ganglia calcification in a general adult population is approximately 0.7%. Of these persons, less than 7% have any motor symptoms (Murphy, 1979; Brannan et aI., 1980). However, if the patient presents with hypoparathyroidism there is a 70% chance of basal ganglia calcification. This increases to almost 100% for patients with pseudohypoparathyroidism. The likelihood of motor symptoms also increases (Muenter and Whisnant, 1968; Sachs et aI., 1982; Illum and Dupont, 1985). With CT it also became possible to identify white matter changes consistent with subTable I Structura11esions associated with an akinesis or rigidity. Cortical tumors Glioma Meningioma Other Subdural hematoma Striatal abscess Midbrain tuberculoma Ventriculomegally Posterior fossa cyst Normal pressure hyodrocephalus Vascular parkinsonism

164

cortical infarction and associated arteriosclerotic parkinsonism (Critchley, 1929), i.e. subcortical arteriosclerotic encephalopathy (Binswanger's disease) (Thompson and Marsden, 1987; Bennett et al., 1990). CT was the first method to generate reliable volumetric measurements of brain anatomy in vivo. Striatal atrophy in advanced Huntington's disease was readily measured and it became possible to correlate clinical severity with tissue loss in the head of the caudate nucleus (Grafton et aI., 1992). With the introduction of magnetic resonance imaging in the early 1980s, image resolution and tissue contrast improved dramatically. The primary use of anatomic MR imaging in movement disorders is to exclude vascular disease or neoplasm causing symptoms that could mimic a neurodegenerative disease (Waters, 1993). Infratentoriallesions such as cerebellar atrophy in the hereditary ataxias can also be screened reliably. MRI changes in the basal ganglia can be seen in a variety of systemic diseases, as listed in Table 2. Most of these can be readily diagnosed clinically. Structural imaging with MRI allows for unprecedented accuracy in volumetric measurements of complete nuclei, such as the putamen or caudate. Large databases of normal and pathologic brain anatomy are currently being generated for probabilistic assessment of structure, form and volume (Mazziotta et al., 2001; Toga and Thompson, 2001). These measures can be correlated with clinical progression in Huntington's disease and possibly used to detect presymptomatic gene-positive persons at risk for the disease (Aylward et aI., 2000). Using special acquisition parameters, it may be possible to identify subtle changes in other neurodegenerative disorders including Parkinson's disease (Hu et aI., 2001).

12.3. Functional imaging 12.3.1. Radionuclide imaging The advent of single photon emission tomographic (SPECT) imaging provided early measurements of brain cerebral blood flow. With this method patients are injected with a radioactive agent that binds to cerebral tissue in proportion to local cerebral blood flow, a receptor or some other biologic marker (Podreka et aI., 1987). Injections and images are acquired with the subject at rest. Gamma-ray energy is detected with a set of

S.T. GRAFTON

Table 2 Diseases with MRI signal changes in basal ganglia. Hypointensity Wilson's diease Leigh's disease CO intoxication Anoxia Hallervorden-Spatz disease Cyanide poisoning Methanol intoxication GM2-gangliosidosis Hemolytic uremic disease Hyperintensity Wilson's disease Creutzfeldt-Jakob disease Manganese toxicity Hepatic encephalopathy AIDS Normal aging Calcified basal ganglia Hypo- and pseudohypoparathyroidism Fahrs syndrome CO intoxication Birth anoxia Tuberous sclerosis Mitochondrial encephalopathies Radiation and methotrexate therapy AIDS Congenital folate deficiency, dihydropteridine reductase deficiency Japanese B encephalitis, herpes simplex encephalitis Down syndrome Cockayne's syndrome MRI, magnetic resonance imaging; CO, carbon monoxide; AIDS, acquired immune deficiency syndrome.

collimated detectors rotating slowly around the head. Images are of low resolution (> 1.5 em) and nonuniform. Deep brain structures such as basal ganglia are of low image intensity due to attenuation of the radioactive emitter by overlying tissue. SPECT studies using blood flow tracers provided early evidence for changes in basal ganglia with Huntington's disease and temporo-parietal hypoperfusion in Alzheimer's disease. More recently, the cocaine analog 213-carbomethoxy-313-4-iodophenyl-tropane (beta-CIT) labeled with 1231 and related compounds have played an essential role in the assessment of the presynaptic striatal dopamine transporter uptake site (Brucke et al., 1993).

IMAGING

Development of positron emission tomography (PET) imaging in the early 1980s resolved many of the technical limitations of SPECT (better resolution, no attenuation artifacts) (Phelps et al., 1975). The range of biologic radiotracers that could be created with cyclotron produced radioisotopes was greatly expanded. Dominating these new compounds was "F-fluorodeoxyglucose (FDG) (Reivich et aI., 1979). The tracer is trapped within cells in proportion to glucose transport and utilization. Imaging of regional radioactivity within the brain provided a direct, simple assessment of relative glucose metabolism. Glucose metabolism is strongly correlated with local neuronal activity (Jueptner and Weiller, 1995). In particular, lesions and physiologic studies in rodents and non-human primates have established that regional metabolism reflects both excitatory and inhibitory neuronal activity and this activity is predominantly a reflection of pre-synaptic function (Nudo and Masterton, 1986). Under pathologic conditions glucose metabolism is altered when there is a change of neuronal density. Importantly, this measure was observed to be highly sensitive to underlying pathologic conditions and more reliable than other imaging methods such as blood flow imaging with SPECT or PET agents. Early clinical studies identified marked metabolic changes in temporoparietal cortex in both early and advanced Alzheimer's disease and mesial temporal hypometabolism in complex partial epilepsies. Thus, one might hope to identify subtle alterations of function circuits in movement disorders using metabolic rather than structural imaging. However, glucose metabolism also shows large changes in association with normal neuronal activation (Sokoloff, 1977). Thus, the behavioral state of the human or animal during the 20-30 min uptake period of FDG after intravenous injection will have a strong impact on the regional metabolism measured by PET imaging. In disorders with involuntary movement neural systems associated with movement production could have increased metabolic activity (Colebatch et aI., 1990; Brooks et aI., 1992b). This can potentially blur the distinction between metabolic abnormalities due to a disease (trait) with those due to a symptom (state).

12.3.1.1. Hypokinetic movement disorders A variety of cortical and subcortical metabolic changes are observed in the hypokinetic movement

165

disorders, i.e, disorders where there is a reduction of volitional movement. In Parkinson's disease the characteristic finding on PET imaging is elevated glucose metabolism in the striatum and mild to moderate reductions of cortical metabolism (Kuhl et aI., 1984; Eidelberg et aI., 1994). The hyperactivity in striatum is consistent with autoradiographic studies of non-human primates with parkinsonian symptoms secondary to the neurotoxin N-methyl-4-phenyl-l,2,3,6-tetrahydropyridine (MPTP) (Crossman et aI., 1985). Using this pattern of striatal hypermetabolism of PD as a benchmark, it was apparent that atypical parkinsonian syndromes, including multiple systems atrophy, striatonigral degeneration and olivopontocerebellar atrophy had different metabolic signatures as listed in Table 3 (Rosenthal et aI., 1988; De VoIder et aI., 1989; Fulham et aI., 1991; Otsuka et aI., 1991; Eidelberg et aI., 1993; Gilman et al., 1994; Otsuka et aI., 1994). An important generality is that all of the atypical syndromes are likely demonstrate striatal hypometabolism with variable involvement of cortical or cerebellar hypometabolism. Large clinical series have not yet been performed to establish the sensitivity and specificity of PET imaging. Nevertheless, the available evidence from smaller studies supports the utility of PET glucose metabolic imaging as an adjunct for diagnosing patients with clinically atypical akinetic-rigid movement disorders. Approximately 15% of PD patients will develop a significant dementia. With dementia there is a reduction of temporal-parietal cortical metabolism in the same areas as seen in Alzheimer's disease (Kuhl et aI., 1985). Whether this dementia and metabolic finding represents PD+AD, a special form of PD, or diffuse Lewy body disease with dementia is unknown. The neuropharmacology of movement disorders can be evaluated with PET radioisotopes that reflect presynaptic doparninergic function C8F-DOPA), post-synaptic DIID2 dopamine receptor binding (Spiperone, Raclopride) and non-specific opiod receptor binding (Garnett et aI., 1983). In Parkinson's disease there is an approximately 30% loss of F-DOPA uptake in striatum compared to normal subjects at symptom onset, progressing to a 60% reduction with advanced disease (Garnett et aI., 1984; Leenders et al., 1984; Leenders et aI., 1986; Martin et aI., 1987). There is a greater loss of FDOPA in the putamen than the caudate, whereas in

166

S.T. GRAFTON

Table 3 Imaging in hypokinetic movement disorders.

Metabolism

PD

PD-Dementia

Atypical PD

PSP

CBGD

Inc striatum

Inc striatum

Dec striatum

Dec frontal

Mild dec frontal

Mild dec frontal

Dec frontal

Dec striatum, cerebellum, thalamus

Dec thalamus, parietal, temporal Asymmetric!

Dec Dec cerebellar (ataxic) temperoparietal Presynaptic dopamine Postsynaptic D2

Dec putamen

Dec putamen

Dec putament

Dec putamen

Dec putamen

Mild dec caudate

Mild dec caudate

Dec caudate

Dec caudate

Dec caudate

Dec striatum

Dec striatum

Dec striatum

Dec striatum

Dec striatum

Nl-mild inc striatum (untreated) Nl-mild dec striatum (treated)

Opioid receptors Normal PMRS

Normal striatum?

Normal striatum?

Dec NANcreatine Dec NANcreatine Dec NANcreatine

Pl): Parkinson's disease; PSP: Progressive supranuclear palsy; CBGO: Corticobasal ganglionic degeneration; Atypical PO includes striatonigral degeneration, olivopontocerebellar degeneration, and multiple systems atrophy; PMRS: Proton magnetic resonance spectroscopy.

the atypical parkinsonian syndromes both caudate and putamen are typically involved (Table 3) (Brooks et aI., 1990a, b; Laihinen et al., 1995; Brucke et aI., 1997). The reliability of using these findings for radiologic diagnosis in an individual patient depends on the experience of the imaging center performing F-DOPA imaging. Individual subject diagnosis requires the study of a large normative population with low measurement variability that patient data can be compared to. Post-synaptic dopamine receptors are normal or mildly increased in untreated early Parkinson's disease, suggestive for receptor upregulation (Rinne et al., 1990a, b). With long standing treatment with L-DOPA the postsynaptic binding is normal or reduced, consistent with mild receptor down regulation (Brooks et aI., 1992a; Turjanski et al., 1997). 12.3.1.2. Hyperkinetic movement disorders The prototypic hyperkinetic movement disorder is Huntington's disease (HD), in which the loss of

medium aspiny neurons in the striatum is accompanied by profound hypometabolism and reductions of dopaminergic, opioid and GABA associated benzodiazepine binding. All of these changes can be observed in vivo with PET imaging (Myers et al., 1988; Kuwert et aI., 1990). Reductions of metabolism likely precede clinical onset and then parallel disease progression (Mazziotta et aI., 1985b; Young et al., 1986; Mazziotta et al., 1987; Young et aI., 1987; Grafton et al., 1990; Grafton et aI., 1992). The development of a direct genetic test for Huntington's disease obviates the use of functional brain imaging as a diagnostic aid for this disease (Gusella et aI., 1983, 1993). It is interesting to note that different causes of chorea can have opposing changes of striatal metabolism as listed in Table 4. There is a common pattern of striatal hypometabolism in HD, benign familial chorea and neuroacanthocytosis (Suchowersky et aI., 1986; Hosokawa et aI., 1987; Dubinsky et aI., 1989). Hypermetabolism is observed in Sydenham's chorea, lupus and tardive

167

IMAGING

NL

PO

F-OOPA

FECNT

Fig. 1. Functional neurochemistry of the basal ganglia. Integrity of pre-synaptic dopamine synthesis can be assessed with fluoro-dopa (F-DOPA). In Parkinson's disease (PD) there is a marked reduction of uptake and decarboxylation of this compound compared to normal controls (NL), particularly in the putamen. Integrity of presynaptic dopamine terminals can also be assessed by labeling the dopamine transporter protein with compounds such as 213-carbomethoxy-313-(4-chlorophenyl)8-(2-C HF)fluoroethyl)nortropane (FECNT). This proteinis normally involved in reuptake of synaptic dopamine and is a marker of dopamine terminal density. Note the marked reduction in Parkinson's disease. Images provided by Mark Goodman and Margaret Davisof Emory University, AtlantaGA. dyskinesia (Guttman et al., 1987; Weind1 et al., 1993; Pahl et al., 1995). No changes in post-synaptic dopamine receptor function have been observed in TD, suggesting the clinical symptoms may be a result of GABA related disinhibition of motor circuits rather than upregulation of the dopaminergic pathways (Blin et al., 1989; Andersson et al., 1990). The other important set of hyperkinetic movement disorders are the dystonias. The etiology of focal, segmental, hemi- or generalized dystonia, irrespective of the distribution of symptoms is remarkably diverse. MRI has been useful in identifying focal lesions within the spine, brainstem, striatum, thalamus and white matter resulting in acquired dystonia (Grafton et al., 1988; Gille et al., 1996; Kostic et al., 1996; Lehericy et al., 1996; Karsidag et al., 1998; Kurita et al., 1998). This diversity of lesion location makes it difficult to generate a unifying pathophysio-

logic model that predicts the occurrence of dystonic movements. Functional imaging is an important alternative approach for characterizing the pathophysiology of dystonia. By definition, there is forceful and prolonged simultaneous co-contraction of agonist and antagonist muscles which distort the affected extremities into stereotypic postures (Oppenheim, 1911). Thus, imaging studies examining neural substrates of the dystonias can potentially be complicated by movement related activation. Using fluorodeoxyglucose (FDG), brain glucose metabolism has been measured in both focal and generalized dystonia (Stoessl et al., 1986; Martin et al., 1988; Karbe et al., 1992; Hirato et al., 1993; Eidelberg et al., 1995; Galardi et al., 1996; Dethy et al., 1998; Mazziotta et al., 1998). Experimental strategies to avoid movement-related activation include scanning subjects in their sleep or scanning presymptomatic subjects who test positive for the dystonia gene DYTl (Eidelberg et al., 1998; Mazziotta et al., 1998). The main finding in DYTl patients was an increased covariance of metabolism within the lentiform nucleus, cerebellum and supplementary motor area, suggesting disregulated control between cortical and subcortical motor areas.

12.3.2. Proton magnetic resonance spectroscopy Given appropriate technical modifications, conventional MRI scanners can be used to perform proton magnetic resonance spectroscopy (PMRS) of brain metabolites. The most commonly detected signals are related to N-acetylaspartate (NAA) a relative marker of neuronal density, choline-containing compounds (Cho) and creatine-phosphocreatine (Cr). Absolute quantification is difficult and most studies investigate altered ratios of these metabolites with each other. Comparative studies of PD, MSA, PSP and CBGD have been performed (Federico et al., 1999; Abe et al., 2000). Single volume assays, localized to the lentiform nucleus as well as frontal cortex assays, usually demonstrate reductions of the NAA/Cho and NANCr peak ratio in all of the atypical parkinsonian syndrome patients compared to controls. Reductions of NAA/Cho or NAA/Cr are less dramatic and inconsistently observed in the frontal lobe or striatum of PD, in part due to measurement error secondary to inorganic paramagnetic substances within the basal ganglia (Clarke and Lowry, 2000). When a reduction is observed it

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S.T. GRAFTON

Table 4 Imaging in hyperkinetic movement disorders. Huntington's disease

Neuroacanthocystosis

Benign familial chorea

DRPLA

SLE

Sydenham's chorea

Tardive dyskinesia

Metabolism

Dec dorsal striatum Dec frontal (advanced)

Dec dorsal striatum

Dec dorsal striatum

Dec dorsal striatum

Inc striatum

Inc striatum

Inc striatum

Postsynaptic D2

Dec striatum

Dec striatum

()pioidreceptors

Dec striatum

Central benzodiazepine

Dec striatum

Normal

Normal

DRPLA: Dentatorubropallidoluysian atrophy SLE: Systemic lupus erythematosis PMRS: Proton magnetic resonance spectroscopy

can correlate with disease severity (Abe et al., 2000). Recent studies show reductions of NANCr ratios in both motor cortex and temporo-parietal cortex compared to healthy controls, suggesting alterations of thalamocortical projection areas in PD (Lucetti et al., 2001). Animal models of Parkinson's disease reveal an increase of striatal glutamate activity. However, several proton magnetic resonance spectroscopy studies of striatal glutamate + glutamine relative to Cr have been normal in PD patients who are dyskinetic, non-dyskinetic and there has been no change with acute dopaminergic treatment by apomorphine (Clarke et al., 1997; Taylor-Robinson et al., 1999). This suggests the changes observed in animal models are currently too subtle to be detected byPMRS.

such as PET as well as magnetic resonance imaging (Mazziotta et al., 1985a; Belliveau et al., 1991).

12.3.3. Functional brain mapping

12.3.3.1. PET CBF The PET blood flow method requires injections of radioactive water or inhalation of radioactive CO 2 (which is converted to water in the lungs by carbonic anhydrase). The amount of radioactivity appearing in the brain is proportional to local blood flow. The temporal resolution is limited to the time it takes to acquire sufficient radioactive counts, typically on the order of 45-90 s. Spatial resolution is nominally 5 mm and more realistically 10-15 mm after image processing. Only 10-15 scans are acquired per subject due to limits on human exposure to radioactivity. Subject motion leads to image blurring, rather than signal dropout, thus the technique can be useful in patients with abnormal movements.

Over a century ago Sherrington and Roy noticed the relationship of brain blood flow and regional activity (Roy and Sherrington, 1890). It is a remarkable fact that increases of neuronal activity, down to the columnar level of spatial resolution will lead to corresponding changes of local blood flow across a slightly larger volume of tissue and with a delay of approximately 4 s (Malonek and Grinvald, 1996; Logothetis et al., 2001). This change of blood flow can be measured with radionuclide techniques

12.3.3.2. FMR1 BOLD imaging The most commonly used functional magnetic resonance imaging technique is the blood oxygen level dependent method (BOLD) (Ogawa et al., 1990). The method detects change in the contrast of T2* weighted images by varying levels of oxygen saturation. As blood flow to an area increases, so does the delivery of oxygenated blood. The method is enhanced with MRI gradients that are capable of

IMAGING

rapid acquisition using echo planar imaging (EPI) techniques (Cohen and Weisskoff, 1991). A typical commercial 1.5 Tesla scanner is capable of acquiring 10-12 slices per second with EPI imaging. Signal detection is improved with surface coils, stronger magnetic fields and acquisition at lower sampling densities (64 x 64 matrix). The method is very sensitive to head movement (signal dropout rather than signal blurring), artifacts from motion in the magnetic field (from eye or limb movements) and susceptibility artifacts maximal at air tissue interfaces such as near the sinuses. Run to run and across session variance in tMRI can be significant and create challenges for across session experimental designs (Aguirre et aI., 1998; Glover, 1999; Waldvogel et al., 2000). The tight confines of an MRI scanner have also set limits on the types of movements and behavior that can be examined in this restrictive environment. Nevertheless, tMRI has replaced PET as the most commonly used method for investigating functional anatomy in normal subjects. 12.3.3.3. Functional imaging of normal motor control Nearly two decades of experiments have mapped the functional anatomy of normal human motor behavior while subjects performed a broad range of motor tasks during brain imaging. The scope of this work is beyond the capacity of this chapter. Core observations include: (l) the delineation of the somatotopic organization of motor cortex, SMA and premotor areas (Colebatch et aI., 1991; Grafton et aI., 1991; Walter et aI., 1992; Grafton et aI., 1993; Sanes et aI., 1995); (2) the identification of premotor and parietal areas for movement selection, preparation, and on-line control (Deiber et aI., 1991, 1996; Honda et aI., 1998b; Desmurget et aI., 1999); (3) the involvement of cerebellum in movement timing and coordinated motor control (Jueptner et aI., 1996; Jueptner and Weiller, 1998; Wolpert et aI., 1998; Miall et aI., 2001); (4) the involvement of motor cortex and SMA in procedural and sequential learning (Jenkins et aI., 1994; Grafton et aI., 1995a; Karni et aI., 1995; Sadato et aI., 1996; Doyon et aI., 1997; Hazeltine et aI., 1997; Boecker et aI., 1998; Honda et aI., 1998a; Toni et aI., 1998; Grafton et aI., 2001); (5) modulation of activity in motor cortex and cerebellum as a function of force and velocity (Dettmers et aI., 1995, 1996a, b; Turner et aI., 1998).

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These experiments form a critical background for interpreting changes of functional circuits in patients with movement disorders. 12.3.3.4. Functional brain mapping of movement disorders Functional brain imaging has been used most intensively to understanding the pathophysiologic basis of Parkinson's disease. This work forms an essential benchmark for interpreting future investigations of the functional topography of other movement disorders. The goal in PD imaging research has been to determine how altered basal ganglia (BG) information processing due to dopamine deficiency leads to altered control of movements at both the cortical and subcortical levels. A key advance was developing reliable methods that could detect movement-related activity throughout cortical and subcortical circuits. For example, PET and tMRI studies of simple movement can detect activation in almost all of the nuclei of the cortico-subcortical motor circuit (Bucher et aI., 1995; Winstein et aI., 1997; Turner et aI., 1998). A related goal asks if patterns of activity observed by imaging studies correspond to specific parkinsonian signs such as bradykinesia or akinesia. Most published imaging studies of PD have focused on the hypothesis that SMA underactivity is a cause of akinesia. In this model BG dysfunction culminates in an inadequate recruitment of SMA neurons resulting in impaired movement initiation. In principal, this is a reasonable approach as the SMA is one of the main cortical receiving areas of the BG motor circuit (Schell and Strick, 1984) and the SMA has been linked to a variety of motor behaviors that are impaired in PD, including, most notably, the selection and generation of internallyguided movements. Thus, tasks that require repeated internal selection and initiation of discrete movements should provide a good substrate for testing the association between parkinsonian akinesia and SMA activity. As predicted, PD patients show a smallerthan-normal increase in CBF in the SMA during movement tasks that require selection and execution of unidirectional ballistic joystick movements (Playford et al., 1992). In a critical follow-up experiment, a more carefully designed movement task was used to compare internally and externally generated movements in normal subjects and PD patients (Jahanshahi et aI., 1995). Subjects were trained to

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make simple index finger extensions every 3 s by self initiation or external triggering, yoked to the same rate. The tasks required minimal working memory or other cognitive demands. PD patients had a smaller-than-normal activation of SMA for self-initiated movements. It is noteworthy that no differences in brain activity between normal subjects and PD patients were found in this study when they performed similar movements under an externally triggered condition. When PD patients performing the internal generation task are treated with dopamine agonists (apomorphine) there is a "normalization" of the movement-related activation of SMA accompanied by a reduction in reaction times (Jahanshahi et al., 1995). A similar effect of dopamine replacement therapy was observed by Rascol et aI. in PD patients performing a sequential movement task which requires frequent initiation of self-generated discrete finger-to-thumb movements (Rasco1 et al., 1992). They showed with single photon emission tomography (SPECT), that the SMA is under-activated in PD patients during this task (i.e. that that SMA had a smaller-than-normal task-related increase in CBF) and that the SMA defect normalized with apomorphine therapy. These results provide additional evidence that SMA activation is modulated by the BG motor circuit and that dopamine replacement therapy can ameliorate the inadequate thalamocortical facilitation of the SMA. Dopamine replacement therapy, by releasing thalamocortical facilitation, restores normal SMA activation patterns and movement initiation improves. Alternative models are emerging from imaging experiments to understand the symptoms of PD. One of these models is task specific compensation. Imaging studies have detected patterns of CBF in PD patients that may reflect adaptive changes, some of which may be closely linked to the particular motor task being performed. Using SPECT, Rascol et al. (1997) found that untreated PD patients demonstrated an abnormally high activation of the cerebellum ipsilateral to the moving arm when they performed sequential finger-to-thumb movements. Coincident with the cerebellar overactivation was a smaller-than-normal activation of the SMA, as predicted by the akinesia model. The increased activity in cerebellum was not seen in a separate group of PD subjects who were studied when on their normal dopamine replacement therapy. Cer-

S.T. GRAFrON

ebellar overactivation in untreated PD patients may be part of a compensatory recruitment of alternate motor circuits in the parkinsonian brain (including the visually driven cortico-ponto-cerebellar loop (Glickstein and Stein, 1991» in an attempt to overcome impaired function of the mesial frontal cortical circuits. Other studies also provide evidence of abnormal increased cerebral activity (CBF) in PD patients and indicate, additionally, that the specific patterns of under- and over-activation hinge on what behavioral task is used. Using PET, Samuel et al. found a bilateral task-related increase in CBF in dorsolateral premotor and inferior parietal cortices in untreated PD subjects performing a sequential finger tapping task (Samuel et al., 1997a). These areas were not activated in normal subjects performing the same task. Samuel et al. also found a task-related underactivation of mesial frontal and prefrontal areas in the PD subjects. These observations have been confirmed and extended recently by Catalan et aI. (Catalan et aI., 1999) in a PET study of PD and normal subjects performing either sequential finger movements of increasing complexity or an internal generation task (similar to the internal generation task first used by Playford et al. (1992). During sequential finger movements, they found a relative overactivation (i.e. a greater task-related increase in CBF than observed in normals) of bilateral parietal cortices, lateral premotor areas, and precuneus. Interestingly, Catalan et aI. observed that mesial frontal areas (anterior SMA/cingulate cortex) were activated during motor sequence performance in both PD and normal subjects, but that CBF increased progressively with more complex sequences only in the PD subjects. In contrast, when the same PD subjects performed the internal generation task, no parietal or premotor overactivations were observed and the mesial frontal areas, including SMA, were under-active, as previous studies predicted. Although some of the results described thus far can be interpreted within the model for parkinsonian akinesia, other results call for a revised or expanded model. The contrasting results for sequential movement and internal generation tasks in the Catalan et aI. study, for instance, indicate that the specific differences in brain activity between PD and normal subjects depend critically on the nature of the behavioral task being performed. The use of tasks that accentuate different facets of parkinsonian

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motor impairment may expand our understanding of the functional substrates of parkinsonian symptoms other than akinesia. 12.4. Imaging therapy in movement disorders 12.4.1. Ablative surgical therapy

The current model of PO pathophysiology provides a clear rationale for surgical treatment of PO by stereotaxic ablation of the posteroventral GPi (pallidotomy). Both in PO patients and in primate models of PO, pallidotomy can reduce significantly the cardinal symptoms of PO while producing no overt side-effects (Laitinen et aI., 1992; Dogali et aI., 1995; Baron et al., 1996). The presumed mechanism of action for pallidotomy is an elimination of excessive pallidothalamic inhibition and a subsequent recovery of function in the previously under-excited frontal cortical areas. The efficacy of pallidotomy as a treatment for PO points clearly to the conclusion that most of the symptoms of PO arise from the impaired function of cortical motor areas secondary to excessive inhibitory outflow from the pallidum and not, as might be assumed, from impaired BG function per se (Wichmann and DeLong, 1996). Functional imaging studies of pallidotomy have provided results consistent with the akinesia model of PO pathophysiology (Ceballos-Baumann et aI., 1994; Grafton et al., 1994, 1995b; Samuel et aI., 1997b). A consistent finding across studies has been that following pallidotomy, there is a movement

related increase of activity in the SMA compared to rest conditions. 12.4.2. Deep brain stimulation

A relative drawback of surgical pallidotomy is the potential morbidity (acute and chronic) resulting from a permanent brain lesion. The introduction of high frequency deep brain stimulation (DBS) is an important alternative to ablation because the electrode can be introduced without producing significant brain damage and, by adjusting stimulation sites and parameters, the optimal response can be obtained. Reports of clinical response to DBS are promising (Siegfried and Lippitz, 1994; Limousin et aI., 1997; Krack et aI., 1998; DBS study group, 2001). The stimulating electrode can be positioned at several nodes of the subcortical motor circuit, including the GPi, subthalamic nucleus (STN) and the motor thalamus. Evidence to date in unblinded, non-randomized trials suggest similar maximal benefit for placement in the STN and pallidum, although patients with STN stimulators may require lower amounts of supplemental L-DOPA therapy (DBS study group, 2001). The mechanism by which DBS achieves therapeutic results remains speculative. PET has been used to examine the effects of therapeutic DBS on CBF. In the first report, Limousin et aI. explored the effects on cerebral blood flow of DBS in GPi and STN (Limousin et al., 1997). Clinically effective levels of stimulation in STN led to a greater task-related increase in CBF in

Fig. 2. Functional adaptation in Parkinson's disease. PET blood flow imaging was used to assess motor system activity during visually guided tracking at different velocities. Areas in white represent sites where PD patients show a greater increase of activity as movements become faster relative to controls. These sites include bilateral premotor cortex, motor cortex, globus pallidus and cerebellum. In PD these areas are recruited to a greater degree than normal subjects to achieve the same level of performance. Images provided by Robert Turner, DC San Francisco, California.

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the SMA and dorsolateral prefrontal cortex compared to ineffective stimulation. Of concern, however, clinically effective stimulation of the GPi produced no significant changes in CBF. In a second study, Davis et. al., examined the effect of GPi DBS on brain activity during a "rest" condition (Davis et al., 1997). Clinically beneficial stimulation in the GPi was associated with a CBF increase in mesial frontal cortex anterior to the SMA. This result suggests that DBS altered the inhibitory GPi output in a manner analogous to ablation and thereby disinhibited the frontal thalamocortical circuit. The authors proposed that the increased CBF in the mesial cortical areas, although observed under a "resting" condition, could be responsible for a reduction of akinesia. In a more recent study, patients were examined while they performed simple paced sequential reaching movements. Concurrent regional cerebral blood flow recordings revealed a significant enhancement of motor activation responses in the left sensorimotor cortex and bilateral supplementary motor area. Significant correlations were evident between the improvement in motor performance and the regional cerebral blood flow changes mediated by stimulation (Fukuda et al., 2001). The combined results of these different imaging studies can be taken as further evidence that surgical therapeutic interventions for PD lead to increased cerebral activity in areas that are targets from pallido-thalamic connections. 12.4.3. Fetal transplantation

Functional imaging of dopaminergic function is extremely useful for assessing the in vivo viability and growth of transplants of fetal substantia nigra tissue in patients with advanced Parkinson's disease (Lindvall et al., 1989; Lindvall et al., 1994). Fluorodopa imaging can be used as an independent measure of tissue viability (Freed et al., 1990; Lindvall et al., 1990). In a recent large randomized trial there was significant evidence for increased fluorodopa uptake in the patients treated by transplantation therapy suggesting dopamine producing fiber outgrowth of transplanted tissue (Freed et al., 2001). An interesting observation emerging from the randomized clinical trials of PD using fetal transplantation has been a potent placebo effect in the patients receiving sham surgery. A functional imaging study helps to explain this puzzling response. PD

S.T. GRAFTON

patients who were told they were to get a new medical therapy for their disease were scanned and the availability of post-synaptic dopamine receptors was assessed with PET (de la Fuente-Fernandez et al., 2001). Patients given a placebo showed reduced receptor availability, suggesting they were releasing endogenous dopamine in the setting of increased reward expectancy (a new therapy). This measurable increase of endogenous dopamine could also improve parkinsonian symptoms. This finding is consistent with recent studies in non-human primates establishing the importance of the BG for facilitating reward expectancy and learning (Schultz, 2001). Acknowledgments

Supported NS33504.

by

PHS

Grants

NS37470

and

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Movement Disorders Handbook of Clinical Neurophysiology, Vol. I M. Hallett (Ed.) © 2003 Elsevier B.V. All rights reserved

181 CHAPTER 13

Accelerometry Rodger J. Elble* Department of Neurology, Southern Illinois University School of Medicine, P.O. Box 19643, Springfield, IL 62794-9643, USA

Accelerometers are small lightweight motion transducers that are capable of measuring accelerations less than 0.02 G (G=9.807 m/s', the static acceleration of gravity). The use of accelerometers in human motion analysis is the focus of this chapter. The Internet is a rich source of additional information pertaining to basic technology and manufacturers, and Table 1 contains an incomplete list of useful sites.

13.1. Common types of accelerometers Several types of accelerometers are now commercially available, but piezoresistive, piezoelectric and capacitance accelerometers are employed most commonly in human applications. These accelerometers are based on Newton's law of mass acceleration (Force=massxacceleration) and Hooke's law of spring action (Force=spring constant x change in length of a spring). Therefore, for a known mass attached to an elastic material, one can relate acceleration to the extent that the elastic material is stretched or compressed. Piezoresistive accelerometers consist of a small mass attached to a semiconductor beam that behaves like a spring. Deflection of the beam is measured with strain gauges that are connected in a Wheatstone bridge. The output voltage of the Wheatstone bridge is proportional to acceleration. Piezoelectric accelerometers contain a mass that is attached to a piezoelectric crystal, which behaves as a spring. Deformation of the crystal produces a small voltage (- millivolts) that is proportional to acceleration. Capacitance accelerometers contain a variable

* Correspondence to: Dr. R.I. Elb1e, Department of Neurology, Southern lllinois University School of Medicine, P.O. Box 19643, Springfield, IL 62794-9643, USA. E-mail address: [email protected] Tel.: 217-524-7881 (ext. 3002); fax: 217-524-1903.

capacitor, in which the gap between the capacitor plates changes in proportion to acceleration.

13.2. Technical specifications and considerations In selecting an accelerometer, one must consider the required size, weight, durability, frequency range, linear amplitude range, sensitivity, transverse sensitivity, and resolution. These specifications for accelerometers are provided on the Internet web sites of most manufacturers (Table 1). Miniature accelerometers are now so small and lightweight that many are suitable for most human applications. Triaxial accelerometers with an approximate weight and volume of 10-20 g and 1-2 em' are common. Accelerometers ofthis size are necessary when recording from small body parts, such as the finger and when multiple accelerometers are used. Durability is specified in terms of the maximum acceleration that the device can experience without damage. Accelerometers are frequently constructed with mechanical stops that prevent damage by excessive sudden acceleration (i.e. shock), as may occur if the accelerometer is dropped or struck against a hard object. Sufficiently durable accelerometers can withstand shock accelerations of at least ±2000 G. Shock accelerations of this magnitude may be achieved when an accelerometer is dropped onto a hard surface, so these devices must be handled with care. The frequency range (i.e. frequency response) of most accelerometers is flat from approximately 0 Hz to 500 Hz or greater. The upper limit of the frequency range should be more than 4 times the highest frequency of movement that will be encountered. Most accelerometers easily satisfy this requirement for human applications, in which the frequency content of motion is 0-30 Hz. Accelerometers usually contain some form of damping to

182

R.J. ELBLE

Table I Accelerometers and gyroscopes for human motion analysis. Manufacturer

Internet web site

Entran Devices, Inc.

www.entran.com

Piezoelectric

Kistler Instrument Corp.

www.kistler.com

Piezoresistive

Endevco U.K., Ltd.

www.endevco.co.uk

Accelerometers Type

Piezoresistive

Piezoelectric Capacitance Capacitance

Analog Devices

www.analog.com

Capacitance

Silicon Designs, Inc.

www.silicondesigns.com

Piezoelectric

Cambridge Neurotechnology

www.camntech.co.uk

Piezoelectric

1M Systems

www.imsystems.net

Motus Bioengineering, Inc.

www.motusbioengineering.com

Activity monitors (accelerometers)

Gyroscopes

Gyroscope

prevent resonant oscillation at the accelerometer's natural frequency, which resides just beyond the upper limit of the frequency range. The frequency response of piezoresistive and capacitance accelerometers extends down to 0 Hz, making them sensitive to the static acceleration of gravity and providing a useful means of static calibration. The low-frequency limit of piezoelectric devices is 0.1 Hz or higher. The sensitivity (mV/G) of an accelerometer is inversely proportional to its amplitude range. Therefore, accelerometers with excessively large ranges should be avoided. The amplitude range should have a linear sensitivity ± 1%. An amplitude range of ± lOG is suitable for most human applications, and a typical sensitivity for this range is 5-10 mV/G (Verplaetse, 1996). An amplitude range of ±20 G may be needed for accelerometers mounted on the feet or ankles during walking and running (Bouten et al., 1997). The transverse axis (cross) sensitivity is the degree to which an accelerometer erroneously detects Decelerations perpendicular to the axis of sensitivity. The transverse sensitivity should be 3% or less. The resolution of an accelerometer is the lowest acceleration that can be measured. Resolution is

determined mainly by the level of transducer noise and is 0.02 G or less for most accelerometers used in human applications. Intrinsic sources of accelerometer error and noise are: (1) electronic device noise (e.g. due to fluctuations in the power source); (2) transverse axis sensitivity; and (3) thermal drift in de response (piezoresistive devices). Ambient sources of noise are: (1) electrical interference (e.g. 60 Hz noise); (2) ambient vibrations (e.g. as when riding a car or bike); (3) inadvertent bumping or jarring with another physical object (e.g. striking the accelerometer against a table or door frame); and (4) loose or faulty attachment of the accelerometer to a body part, resulting in extraneous mechanical resonance (Bouten et al., 1997). These sources of noise have a cumulative effect when acceleration is numerically integrated over long periods of time to obtain velocity and position estimates, and this problem is a major impediment to the use of accelerometers in motion analysis of complex movements such as walking and reaching.

13.3. Signal conditioning Most accelerometers require a power source, and the power source should be stable and free of noise

ACCELEROMETRY

in order to avoid power fluctuations that cause measurement error. The output of the accelerometer is filtered and amplified before being sampled into a computer with an analog-digital converter. Highpass filters and AC-coupled amplifiers do not eliminate the sensitivity of accelerometers to gravity but are useful when the DC component of acceleration is of no interest. Low-pass filters are needed to attenuate noise at frequencies greater than the maximum frequency of biological interest. The sampling frequency of the analog-digital converter should be greater than twice the cutoff frequency of the low-pass filter, in order to avoid aliasing. 13.4. Measuring motion in 3-dimensional space

The output of accelerometers must be integrated once to obtain velocity and twice to obtain position. For a sinusoidal displacement of amplitude A (onehalf peak-to-peak amplitude), the velocity and acceleration are the first and second derivatives of displacement: displacement=A sin (wt) velocity=Aw cos(wt) accelerationw-Ass' sin(wt)

where w is the frequency of oscillation in radians per second (l cycle/s= 1 Hz=2'lT radians/s) and t is time. Thus, for two oscillations (e.g. tremors) of identical displacement amplitude but different frequencies, the oscillation with the higher frequency will have a larger velocity and acceleration. A corollary to this rule is that high-frequency low-amplitude noise will be more evident in accelerometric measurements than in position measurements, as obtained with a photogrammetric motion analysis system. Another corollary is that for a sinusoidal movement like tremor, displacement and velocity can be estimated with accelerometry by dividing the measured acceleration by w2 and to, respectively. Motion of a limb or other body part rarely occurs in a single direction. In general, a body part may exhibit translational motion in any of three orthogonal (X, Y, Z) directions, and it may rotate about any of these axes. An accelerometer will record translational and rotational inertial accelerations to the extent that these acceleration vectors are in line with the accelerometer's axis of sensitivity. In addition, gravitational acceleration is recorded to the extent

183

that the axis of sensitivity is in the vertical direction of earth's gravity. Gravitational acceleration may contribute significantly to the total acceleration detected by the axis of an accelerometer and thereby limits the ability of accelerometry to reflect translational and rotational motion (i.e. inertial acceleration) of a body part. The task of separating the gravitational and inertial components of acceleration is impossible unless multiple accelerometers are used, and even with multiple accelerometers, measurement error may preclude the accurate separation of gravitational and inertial accelerations. Consider the situation in Fig. 1 in which a rodshaped body part (e.g. the index finger) rotates vertically about a fixed axis (e.g. the metacarpophalangeal joint), such that there is no translational motion. A biaxial accelerometer is attached to the body part at distance R from the axis of rotation. When the body part is perfectly horizontal, gravity is parallel to the t-axis and perpendicular to the r-axis, and the effect of gravity is reflected only in the t-axis of the accelerometer. However, the influence of gravity on the t-axis decreases as the body part rotates up and down, and the influence of gravity on the r-axis increases. The gravitational components in the t and r axes are G cos and G sin . Therefore, for fluctuations in of ± 10 degrees (20 degrees peak to peak), the gravitational component of t-axis acceleration will fluctuate between 1.0 G and 0.985 G, and the gravitational component of r-axis acceleration will be ±0.174 G. Thus, gravitational fluctuations in the r-axis of the accelerometer are substantially greater than in the t-axis, and the influence of gravity on the t-axis is nearly constant (i.e. varies less than 0.015 G). The differences in t-axis and r-axis gravitational fluctuations are significant in situations such as the one depicted in Fig. 1 because the inertial acceleration in the t-axis is much greater than the inertial acceleration in the r-axis. For example, a 6-Hz tremor producing vertical accelerometer movements of ± 1.22 em (0.0244 m peak-to-peak) produces joint rotations of ± sin:' ( 1.2217) = ±0.175 radians = ± 10 degrees, assuming the accelerometer is mounted 7 ern from the joint (i.e, R=0.07 m in Fig. 1). For sinusoidal joint rotations of this magnitude, the t-axis inertial acceleration is R times the angular acceleration, which equals ±0.07· 0.175(2'lT6)2/ 9.807=±1.77 G. These fluctuations in inertial acceleration are much larger than the 0.015 G

184

fluctuations in t-axis gravitational acceleration, so the output of the t-axis of the accelerometer will reflect the fluctuations in inertial acceleration plus the nearly constant effect of gravity, which is easily removed with a highpass filter or by numerically subtracting 1.0 G. By contrast, the r-axis inertial acceleration would fluctuate between zero and R times the angular velocity squared, which equals 0.07(0.175· 2'lT6)2/9.807 =0.311 G. These fluctuations in inertial acceleration are comparable to the ±0.174 G fluctuations r-axis gravitational acceleration, so the output of the r-axis of the accelerometer will reflect significant contributions from inertial acceleration and gravity. The gravitational component will tend to obscure the inertial component, which is the measure of body motion.

RJ. ELBLE

Angular acceleration (a=d 24>/dr) cannot be computed from a, and a, in Fig. 1 because 4> is not known, and hence the contributions of gravity to a, and a, cannot be computed. However, angular acceleration can be computed if a second accelerometer is mounted between the joint and the first accelerometer. Both accelerometers will have the same gravitational influence if they are mounted with the same orientation (i.e. their t-axes are parallel; Fig. 2), and the equations for angular acceleration are R,a=a1t+G cos(4)(t)) and R2a= a 2t+G cos(4)(t)), where the subscripts 1 and 2 refer to accelerometers 1 and 2. Subtracting these two equations gives the following equation for angular acceleration: a=(a't - a2t)/(R, - R2). This approach can be extended to 3-dimensional space using at least six uniaxial accelerometers that are strategically positioned on the body segment (Padgaonkar et al., 1975). The computed angular acceleration can be integrated to obtain angular velocity and rotation (4)), and having computed 4>, the r-axis and t-axis gravitational accelerations could be computed at any time t. Note that this approach assumes the precise strategic alignment of the pairs of accelerometers, and malalignment will produce error in computing a. This error and any noise in a, will have a cumulative effect when a is integrated to obtain 4>. Consequently, accelerometers are not suitable for measuring absolute translational position and rotation in space over extended periods of time because

a, = Rd 2c'P/dt2-Gcosc'P(t) For c'P(t) = c'P o sin(2JZji),

at = -R[ c'P o(2JZff sin(2JZ"fi)]-Gcos[c'Po sin(2JZ"fi)]

a, =-R(dc'P/dt)2-Gsin(c'P(t» For c'P(t) = c'P o sin(2JZji),

a, = -R[c'P o2JZfcos(2JZ"fi)f - Gsin(c'Po sin(2JZji» =-O.5R(c'Po2JZf)2[cos(4trft) + 1]-Gsin(c'Po sin(2trft» Fig. 1. Schematic diagram of a rigid body rotating about a fixed axis. A biaxial accelerometer (shaded box) is attached to the rigid body at a distance R from the axis of rotation. The X-Y reference axes are fixed to the axis of rotation. The t and r axes are the accelerometer axes of sensitivity. The equations for acceleration in the t and r axes (a, and a,) are given for a sinusoidally varying angle of rotation , with amplitude c'P o and frequency f (Hz). G is the acceleration of gravity.

Fig. 2. Same as Fig. I but for two biaxial accelerometers, mounted in parallel for the measurement of angular acceleration a=d 2c'P/df

185

ACCELEROMETRY

accelerometer error and noise accumulate in proportion to f. Commercially available electromagnetic and photogrammetric motion analysis systems are better suited for measuring position and rotation (Ladin et aI., 1989). Accelerometers are best suited for measuring relative motions (e.g. tremor and other involuntary movements) and short-duration changes in position and rotation. In Fig. 1, the frequency of oscillation in the inertial component of a,. is twice the frequency of sinusoidal oscillation in because of the trigonometric relationship cos 2wt= 2 cos' wt - 1. Similarly, the oscillation in the t-axis gravitational component occurs at 2w because cos( ..... v.>

d!-
a

1.E+00

C.H. LUCKING AND B. HELLWIG

1

1.5

1.E+00 1.E-Ol 1.E-02 +---,---..,--.:.....,----.---.-------, Hz

o

2

5

10

15

20

25

30

Coherence between the two EMGs

e

1

2l

0.8

c:

0.6

CIl

0.4

l!1 s: 0

o

0.2 0 0

5

10

15

20

25

30

Hz

Fig. 1. (a, b) Surface EMG recordings from the right and left quadriceps muscle in a patient with primary orthostatic tremor. (c, d) Spectra of both EMG time series showing a distinct peak at about 15 Hz. (e) Coherence between the two EMG time series showing a highly significant peak at the tremor frequency. The horizontal line indicates the level of significance

(p

.lIl: ftI

NO LOAD 0 ." 0

WITH LOAD

0

II)

,..

Normal

0 ,.. 0 0

0 0

"

0

It) l")

I

+~---

at

a.

_-

- :.- --

0

0

30

-~

"

ON OFF

60

P.O.

01

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60

Movement amplitude (deg) Fig. 2. Underscaling of movement velocity in Parkinson's disease. Subjects made rapid self-paced, self-terminated flexion movements of the wrist in their own time through 15° or 60° either without (left) or with an opposing force (right). Note how the peak velocity of movement increases with distance moved in both patients and healthy controls. However, the velocity at anyone movement amplitude is smaller in patients. Note also that treatment with L-DOPA only improves velocity mildly in the patient group for this simple task. (Data from Berardelli et al., 1986.)

conclusion is that parkinsonian patients have more difficulty in performing sequential movements that rely more on an internally determined than an externally triggered mode (Dettmers et al., 1996).

would consume more of the processing resource, and lead to difficulties in performing several tasks at once, or in switching between tasks. When required to perform more than one task at once, this would become a limiting factor.

26.1.2.1. What is the nature of the extra deficits in performance of complex movements? The problem of combining tasks or switching from one task to another is not confined to movement. It can be observed in cognitive tasks or combined cognitive and motor tasks (Brown and Marsden, 1991; Oliveira et al., 1998). Such observations are important since they indicate that the extra deficit seen in complex movements is not necessarily a purely motor problem. They raise the possibility that global processing mechanisms, perhaps involving attention, are also a factor. Brown and Marsden (1991) suggested that patients either have a limited processing "resource" that interferes with their ability to run more than one task at the same time, or that they have difficulty in switching this resource between tasks. An alternative is that the global resource is the same in patients, but that tasks are performed less automatically than normal. Effectively, patients may try to compensate for lack of basal ganglia input by devoting more resources to each single task they perform. In this case, each task

26.1.3. Sensorimotor processing The studies above have focused primarily on details of motor tasks, but recent work also suggests that there may be minor abnormalities of sensorimotor processing in patients with Parkinson's disease that could affect the preparation of instructions to move. Schneider et al. (1986) reported that two point discrimination and proprioceptive position sense was reduced, whilst Klockgether et al. (1995) in a study that tested integration of visual and kinesthetic information in an arm reaching movement found that peripheral feedback was compromized in patients. This point was taken further in a study by Demirci et al. (1997) who devized a task where patients had to match their visual and kinesthetic impressions of the position of their fingers. When kinesthesia was used to match to a visual reference, patients underestimated distance. If we assume that the patients' visual sense was normal, then this implies a "reduced" sense of kinesthetic input in Parkinson's disease. The authors

422

suggested that this may relate to the underscaling of motor output discussed above. The unexpected conclusion from the latter was that in a simple ballistic movement, patients' motor system might be able to produce a large initial burst of agonist EMG but did not do so. The result was that their movements were slower than they need have been. Demciri et al. (1997) suggest that a larger motor command was not selected because patients may not actually have perceived their movements to be slow due to the underscaling of their sensory input. 26.1.4. EEG studies: physiological mechanisms of bradykinesia 26.1.4.1. Bereitschaftspotential (BP) As described in the chapter by Shibasaki, the Bereitschaftspotential gives a measure of brain activation in the period immediately preceding a selfpaced voluntary movement. Since the latter are slow in Parkinson's disease, it is clearly of interest to investigate whether there is an accompanying abnormality in the pattern of brain activation prior to such

J.e. ROTHWELL movements. In early studies, there was some debate over whether the BP was abnormal in Parkinson's disease. Some of the controversy was resolved by Dick et al. (1987), who showed that L-DOPA could affect the amplitude of the BP both in normal subjects and in patients, and that a difference between patients with PD and normals was crucially dependent on the level of dopaminergic function. They went on to show that the BP in patients OFF therapy was reduced in the early part (BPI), whilst it was larger than normal in the later part (BP2). The net effect was that the peak BP was virtually the same in the patients as in normals (Fig. 3). They suggested that underactivity of a source in the SMA was responsible for the reduction of the early component, and that this was compensated by overactivity in lateral motor areas nearer the time of onset of movement. Recent studies have tended to confirm this idea. For example, Jabanshahi et al. (1995) noted that premovement EEG activity was normal in patients with Parkinson's disease when they performed an externally triggered task compared with the reduction that is seen in self-paced movements (Fig. 1). Cunnington et al. (1995, 1997)

Fig. 3. Grand average premovement EEG activity in eight healthy age matched subjects and eight patients with Parkinson's disease after overnight withdrawal of their normal medication. The movement was a self-paced extension of the index finger, with 50-100 trials averaged in each subject. Note that in the patients (PD), the amplitude of the early portion of the BP is smaller than in normals (N), particularly in the midline and ipsilateral leads. (Data from Dick et al., 1987.)

DISEASES AND TREATMENTS: PARKINSON'S DISEASE

proposed that underactivation of SMA in PD patients made them more reliant on external cues so that they did not use predictive models when cues were available. Premovement activity could, however, be induced in patients if they were asked to attend to the time of the next movement, and this improved task performance (Cunnington et al., 1999). The authors suggested that attentional processes allow lateral premotor systems, less impaired by basal ganglia dysfunction, to compensate for deficiencies in midline motor systems that normally are active in internally generated tasks. Inherent noise in the signal means that the BP is not a reliable measure in individual cases. However, group studies have shown that it is sensitive to the effects of treatment, being larger, particularly in the second part, in patients after pallidotomy (Limousin et al., 1999). These early studies involved subjects repeating the same movement over many trials. Later studies have required that subjects chose to make different movements (e.g. moving a joystick up, down, left or right) on each trial. In healthy subjects, the BP is much larger than when subjects make the same movement on each occasion, perhaps reflecting the additional processing necessary to choose between movements on each trial (Touge et al., 1995; Praamstra et al., 1996a, b). Praamstra et al. (1998) used dipole modeling to show that the most likely source for the extra activation was the SMA. This extra activation is lacking in patients with Parkinson's disease, consistent with the model outlined above. 26.1.4.2. Lateralized readiness potential (LRP) Normal functioning or even compensation for underactive midline motor areas by the lateral motor cortical areas is supported by LRP studies. Praamstra et al. (1998) employed a task using incompatible target and distractor elements to precue which hand was to be used for a forthcoming movement. Sometimes the precue made subjects expect that they would have to respond with the wrong hand. In these trials the reaction time was longer than if the precue biased responses to the correct hand. EEG recording of the lateralized readiness potential (the difference between motor cortical activity in the two hemispheres) showed that the distractor cue often caused early activation of the motor cortex controling the wrong response hand. This activity was

423

larger in patients, and was associated with a longer delay in producing a correct behavioral reaction. The interpretation is that external sensory stimuli in the precue can bias activity towards one or other side of the brain in expectation of a subsequent imperative stimulus. In patients with Parkinson's disease this system seems to work more efficiently than in healthy subjects, and is compatible with the idea that there is increased access of external cues to motor areas of cerebral cortex. Praamstra and Plat (2001) recorded the LRP in a task where the visual instruction to press a right or left hand key was presented to one or other side of a central fixation spot. Subjects therefore had to shift attention to one or other side before they could react. This attentional shift elicited an attention-related ERP component just preceding the movementrelated LRP, i.e. the N2pc. The N2pc was distributed broadly on the scalp from occiput to frontal areas, and the authors suggested it represented simultaneous attention-related activity in occipital and motor areas of the cortex. Interestingly, the attentionrelated activity attributed to motor areas was of significantly higher amplitude in Parkinson's disease patients compared to age-matched controls. This suggests that changes in motor excitability produced by shifts of attention are larger in patients, and this again may be one mechanism that is employed to compensate for decreased activity in basal ganglia output. 26.1.4.3. Contingent negative variation (CNV) Although the CNV and the BP share some common mechanisms, it is usually found that the CNV is more depressed in Parkinson's disease than the BP (Ikeda et al., 1997; Gerschlager et al., 1999). An important difference between the tasks may be that the S2 stimulus in the CNV paradigm acts as a stimulus for the next movement, whereas in the BP, no cue for movement is given. We might speculate that healthy subjects prepare for the forthcoming movement to the same extent in the CNV task as they do in the BP task. This yields a large amplitude potential in both situations. Patients with Parkinson's disease may prepare less effectively in the BP situation, but in the CNV, they may tend to rely on S2 as an external cue to trigger release of movement. Thus, in the CNV paradigm, there will be much more difference in the level of preparation prior to S2 in patients and normals than in the BP task. The

424

CNV improves significantly after DBS of the subthalamic nucleus (Gerschlager et al., 1999) (Fig. 4). 26.1.4.4. Event related synchronization! desynchronization (ERS/ERD) Abnormalities in cortical activation prior to and during movement have been also found with the technique of event-related desynchronization (ERD) (Defebvre et al., 1996; Magnani et al., 1998). The amount of power in the alpha (10 Hz) and beta (20 Hz) ranges of EEG activity decreases about one second before onset of movement, and remains lower than at rest while movement occurs. It has been suggested that the 10-20 Hz rhythm occurs because the activity of cortical neurons tends to become synchronized during periods of relative inactivity. If so, ERD is a measure of cortical activation that reflects uncoupling of the population activity into more discrete temporal and spatial patterns. The duration of the ERD prior to voluntary movements is shorter in patients with Parkinson's disease and the pattern of movement related attenuation of the alpha and beta rhythms during various

J.e. ROTHWELL

types of motor tasks is abnormal. Brown and Marsden (1999) found that dopaminergic stimulation in PD restores the movement-related attenuation of the alpha and beta rhythms. This effect was specific for the motor areas involved in the motor task and correlated with the improvement of bradykinesia. Similar findings were present in the study of Wang et al. (1999) on simple and complex movements. The above studies suggest that the basal ganglia have a role in releasing cortical elements from idling rhythms during voluntary movement. In a recent report, Brown et al. (2001) carried this idea one stage further by examining the effect of dopaminergic stimulation on the coherence between activity at different frequencies in different nuclei of the basal ganglia. They recorded local potentials from patients with implanted electrodes in STN and internal pallidum, and found that when OFF medication there was clear coherence between activity in the 20-30 Hz range, whereas ON medication this changed to 60-70 Hz. Interestingly, the coherence at 60-70 Hz increased during movement whereas that in the OFF state in the 20-30 Hz range decreased (Cassidy et al., 2002).

Fig. 4. Mean CNV traces for Parkinson's disease subjects with subthalamic nucleus stimulation on (thick line) compared with off (thin line) stimulation. Potentials are shown from 200 ms before the warning stimulus until 600 ms after the imperative stimulus (total duration 2.8 s). Note the clear increase in all leads during stimulation. (From Gerschlager et al., 1999.)

DISEASES AND TREATMENTS: PARKINSON'S DISEASE

26.1.4.5. Somatosensory evoked potentials Neurophysiological studies of sensory input have generally found there to be no change in the parietal components of the SEP, but a number of studies have shown that the frontal N30 may be reduced in amplitude (De Mari et aI., 1995; Garcia et aI., 1995; Onofrj et aI., 1995; Traversa et aI., 1995; Drory et aI., 1998; Bostantjopoulou et aI., 2000) Treatment with apomorphine or pallidal stimulation through chronic implanted electrodes tends to increase the amplitude (De Mari et aI., 1995; Pierantozzi et aI., 1999). If part of the N30 is related to activation in SMA, then the reduced amplitude in patients may be another sign of the underactivation of midline motor areas in Parkinson's disease. In addition, the enhancement of the N30 may be related to the enlarged long latency stretch reflexes seen in patients (Ashbridge et aI., 1997). 26.1.5. Transcranial magnetic stimulation; physiological mechanisms of bradykinesia 26.1.5.1. Thresholds, cortical inhibition and silent period Corticomotoneuronal conduction and motor threshold are both normal in Parkinson's disease (Dick et aI., 1984; Priori et aI., 1994; Valls-Sole et aI., 1994; Ridding et aI., 1995). Indeed, the fact that movements elicited by direct stimulation of the motor cortex are the same whether the stimulus is given when patients are immobile and OFF therapy or dyskinetic and ON therapy confirms that bradykinesia is not primarily the result of any deficit in the final output pathways of the motor areas of cortex. Despite the lack of change in threshold, the slope of the relationship between stimulus intensity and response size is steeper than normal when tested at rest (Valls-Sole et aI., 1994; Filippi et aI., 2001). Perhaps as a result of this, voluntary contraction facilitates responses less than in normal subjects (Valls-Sole et aI., 1994). The implication is that the distribution of cortical excitability at rest is skewed towards higher values than normal. This seems unlikely to be the result of a primary basal ganglia deficit, and may well be an attempt to compensate for slow recruitment of commands to move by making it easier to recruit activity from a resting state. There are also changes in the excitability of cortical inhibitory circuits. The silent period is

425

shorter in bradykinetic patients (Priori et aI., 1994; Deuschl, 1999), and normalized by treatment with LDOPA. Short latency inhibition as tested at rest using the double pulse paradigm of Kujirai et aI. (1993) is also smaller in patients than normal (Ridding et aI., 1995), and normalized by administration of apomorphine (Pierantozzi et aI., 2001) (Fig. 5). Kleine et al. (2001) recently suggested that this may increase the number of I wave volleys recruited by each TMS pulse and lead to a longer depolarization of spinal motoneurons than normal. It is difficult to know whether these changes contribute to bradykinesia or whether they represent some form of compensatory process. Ridding et aI. (1995) suggested that activity in cortical inhibitory circuits is normally used to reinforce spatial and temporal patterns of cortical excitability appropriate for a forthcoming or ongoing task. Even though basal ganglia projections to primary motor cortex are smaller than those to midline motor areas, such activity could still contribute to patterns of cortical inhibition. If so, the deficits in cortical inhibition might be a primary factor in bradykinesia since one source of information about the pattern of cortical excitability for a task would have been lost. An alternative explanation is that the reduced inhibition is a compensatory mechanism that makes it easier for motor commands to access cortical output. Bilateral stimulation of the subthalamic nucleus can normalize the amount of short latency paired pulse inhibition (Cunic et aI., 2002). A final type of interaction between two suprathreshold stimuli was tested by Berardelli et aI. (1996b). They performed these experiments during a slight voluntary contraction and found that the test response was inhibited more than normal at 100 and 150 ms. It may be that during contraction, PD patients lack the facilitation seen in healthy subjects. The inhibition normalized after treatment with LDOPA. 26.1.5.2. TMS before movement TMS has also been employed to examine the buildup of corticospinal excitability prior to a reaction time movement (e.g. Starr et aI., 1988). Responses to stimuli given early in the reaction period (up to 70 ms after the imperative stimulus in a simple reaction task) elicit responses with the same probability or the same amplitude as immediately before the reaction. Thereafter, the probability or

426

J.e. ROTHWELL

Fig. 5. The time course of ICI in PD patients, as tested by a conditioning-test paired-pulse TMS protocol at 1-6 ms ISIs. Motor responses were obtained from a representative PD patient recorded in off DBS (A), during bilateral GPi DBS (B), bilateral STN DBS (C) and finally, during apomorphine infusion (D). It is worth noting that both STN and GPi DBS reversed the reduced ICI observed in off DBS mimicking the apomorphine effect. In each panel, the top two traces show the response to the conditioning and the test stimuli given alone. In this figure, each trace is the average of four sweeps. TMS artefacts correspond to the vertical bars at constant and variable position, respectively. (From Pierantozzi et al., 2001.)

427

DISEASES AND TREATMENTS: PARKINSON'S DISEASE

amplitude of responses increases gradually until the onset of overt EMG activity (Pascual-Leone et al., 1992). The latter period represents build-up of excitability in the corticospinal system (motor cortex and spinal cord) that finally causes visible movement. The former is usually taken as a measure of the time taken to activate the commands to move. In bradykinetic patients with Parkinson's disease, the duration of the initial period is unchanged whereas the latter period of increasing excitability is longer than in healthy subjects (Pascual-Leone et al., 1994). According to this interpretation, commands are selected as fast as in healthy subjects, but the initial execution of the commands is slow. However, there are two other possible explanations of these results. First, programming of movement commands may continue during the initial part of the execution of a task. If this process were slower than normal then it would increase the duration of the premovement increase in corticospinal excitability. A second possibility is that two processes are involved in movement execution. One may create the increase in corticospinal excitability prior to movement, and the other may be the movement command itself. Again, the first phase could be slow in patients and delay the onset of movement. It is not clear what system could act as a modulator of excitability prior to movement. However, it is interesting to note that the excitability of the reticulospinal system, tested either by the startle response (Vidailhet et al., 1992) (see also chapter by Valls-Sole) or audiospinal facilitation of H-reflexes (Delwaide et al., 1993), is decreased in Parkinson's disease. If this were involved in setting excitability prior to movement then it could account for the slow build up of responses to TMS. 26.1.5.3. TMS interruption of movement Cunnington et al. (1996) asked patients to make a rapid sequence of finger movements from left to right along a tapping board. They gave single pulse TMS at maximum intensity through a 5 em figure eight coil over the SMA randomly with respect to the button presses. They found that if the stimuli occurred in the early part of the interval between two presses, then the next button press was slower than expected. There was no effect if the stimulus occurred in the late part of the button pressing interval, and no effect in healthy subjects. They suggested, in line with data from PET experiments

(Jenkins et al., 1992) that this indicated that the SMA function was compromized in patients and therefore easier to disrupt than in healthy subjects. 26.2. Rigidity

Meara and Cody (1992, 1993) showed that rigidity at the wrist is related to the level of stretch evoked EMG activity in wrist flexor/extensor muscles during manipulation of the wrist joint. However several pathways, from monosynaptic Ia to group II and long loop responses can potentially contribute to such reflexes, and there is evidence that Parkinson's disease may affect transmission in all of them. Clinically, the tendon jerk is usually said to be normal in Parkinson's disease, but measurements of EMG responses evoked in the FDI muscle by mechanical muscle stretch showed that the tendon jerk component of the response was small or absent compared with normal (Wenzelburger et al., 2000). Since the EMG response to electrical stimulation of muscle afferents was the same as normal, Noth et al. (1988) suggested that the muscle spindle was less sensitive to phasic muscle stretch in Parkinson's disease. They speculated that increased static gamma drive might be responsible and increase the longer latency responses due to activity in group II afferents. There is some evidence that group II reflexes are enhanced in Parkinson's disease. Berardelli et al. (1983) examined the long-latency stretch reflexes evoked in the triceps surae and tibialis anterior muscle during passive movements of the ankle. These responses were tonic, lasting as long as the stretch was applied, and the authors considered them to be of group II origin. They were larger in patients than in healthy subjects. Long loop reflexes are also enhanced in Parkinson's disease (Rothwell et al., 1983; Ashbridge et al., 1997). These reflexes, which are best seen in muscles that work on the fingers and wrist employ a transcortical pathway that operates in parallel with the spinal tendon jerk pathway. The afferents responsible are thought to be Ia fibers from primary spindle endings. In general, the degree of enhancement is not related to clinical measures of muscle stiffness, but in individual patients, pallidotomy has been shown to decrease both the long latency response and the clinical rigidity (Limousin et al., 1999; Hayashi et al., 2001) (Fig. 6).

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Fig. 6. Averaged rectified EMG responses from the wrist flexors and kinematics changes obtained by 20 perturbations from one patient to displacements of the wrist joint in extensor direction. The patient was instructed not to respond to the perturbation (passive) or to oppose it (active). Dotted vertical line indicates the time at which the torque motor was turned on to initiate the displacement. Dotted horizontal line shows the initial hand position, a level at which hand velocity was zero, or an electrically silent level in the flexor muscle activity. Vertical lines indicate the onset of Ml (30 ms), M2 (60 ms), and the time at 90 ms, from left to right, respectively. Two traces in each figure were superimposed (thin trace obtained before operation, thick trace after pallidotomy which is indicated by arrowhead). From top to bottom, hand trajectory, its velocity, and the integrated EMG of wrist flexormuscles. (From Hayashi et al., 2001.)

It should be noted that increased stretch reflexes could potentially contribute to bradykinesia if they were elicited in an antagonist muscle during an active isotonic contraction of the agonist. Johnson et al. (1991) tested this hypothesis by using a torque motor to stretch muscles unexpectedly during active sinusoidal movements of the wrist. They showed that reflexes elicited in the antagonist muscle were not suppressed as much as in normal subjects, and that the degree of abnormality was related to the amount of clinical bradykinesia. The one flaw in this argument was that the amount of activity in the antagonist muscle during unperturbed flexion/extension movements was no greater than that seen in normal subjects. Thus, there was no evidence in the actual movements tested that antagonist cocontraction could have been a limiting factor. Indeed, cocontraction has never been described as an important feature even in very rapid movements where the triphasic ballistic movement EMG pattern has been analyzed in some detail. The conclusion must be that the role of rigidity in bradykinesia has yet to be proven conclusively. In addition to these changes in stretch reflex pathways, there are changes in two other spinal reflex circuits that could potentially contribute to rigidity. Delwaide et al. (1991) used H-reflex testing in calf muscles to show that the excitability of the Ib inhibitory pathway from gastrocnemius to soleus was reduced in patients with Parkinson's disease. The degree of reduction correlated with clinical estimates of ankle rigidity. The authors also drew attention to the increase in excitability of the Ia inhibitory pathway that had been described between tibialis anterior and soleus in Parkinson's disease and suggested that both were due to overactivity of the descending projections from the nucleus reticularis gigantocellularis.

26.3. Posture Three types of measure are generally applied to postural control in Parkinson's disease: balance control during quiet stance, EMG and force responses to both externally and self-initiated disturbances of balance, and assessment of initiation and maintenance of gait.

26.3.1. Quiet stance The simplest measure of stability in quiet stance is a timed balance test in which subjects have to stand

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Fig. 7. Mean 95% confidence ellipses, computed from bidimensional center of foot pressure excusions of control subjects and subjects with Parkinson's disease in the four test conditions. AP, anteroposterior; DBS, under deep brain stimulation only; DBS + DOPA, under deep brain stimulation and levodopa; DOPA, under levodopa only; ML, mediolateral; OFF, no treatment. (From Rocchi et al., 2002.)

unsupported for 30 s or so. Only in cases of severe postural instability are such tests sensitive enough to detect changes due to treatment or disease progression. Better measures can be obtained, as described in the chapter by Bloem, using a force platform to quantify motion of the center of pressure or center of gravity in particular stance conditions (e.g. feet together). These can be supplemented with 3D measures of the motion of body segments. Postural sway has been reported to be normal (Schieppati and Nardone, 1991), reduced (Horak et aI., 1992) or increased (Rocchi et aI., 2002) in patients with Parkinson's disease. The variability probably reflects both patient selection as well whether subjects were tested ON or OFF medication. In a recent study, Rocchi et aI. (2002) found that sway was larger than normal when OFF therapy, and that it increased further when patients were ON medication (Fig. 7). Part of the difference may have

been due to increased dyskinesias when ON treatment, but this was not thought to be a major factor. Instead, the authors proposed that when OFF, patients were stiffer at the ankle than when ON treatment. This led to a reduced sway path and also may have been responsible for the higher frequencies of sway seen when OFF. Interestingly, DBS of pallidum or subthalamus reduced sway, and may be one factor in the improvement of postural control seen during DBS. Some workers have emphasized that medio-lateral control is particularly compromised in Parkinson's disease (Mitchell et aI., 1995), and this would be consistent with the observation of Maki arid colleagues that increased lateral away is associated with increased risk of falling in the elderly (Maki et aI., 1994; Maki and Mcilroy, 1996). Finally, there is some evidence that patients are more reliant on visual information to stabilize their posture than

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normal. Bronstein et al. (1990) investigated the body sway that can be provoked by slow movement of the visual surround. In Parkinson's disease, the amount of sway was larger than normal and did not habituate as quickly on repeated presentations of the same stimulus. 26.3.2. Responses to perturbations External disturbances to standing posture can be applied using a moveable platform. Toe up rotations provoke a medium latency (ML) stretch reflex response in the soleus, and a later long latency (LL) response in the tibialis anterior. The former tends to destabilize balance whilst the latter is a corrective response that pulls the body forwards (see chapter by Bloem). In Parkinson's disease, the ML response is larger than normal, and the LL response is less sensitive to the amplitude of the disturbance and less influenced by anticipatory set than in healthy subjects (Beckley et al., 1993; Bloem et al., 1994, 1996). Both factors will tend to make patients less stable in the face of perturbations than normal. Treatment with L-DOPA reduces the ML response but has little effect on the LL response. The latter failure may be related to the poor response of postural instability to drug treatment. Perturbations can also be applied by pushing or pulling on other parts of the body. Traub et al. (1980) used a motor to deliver brisk pulls to the wrist in standing subjects. This evoked short latency reflex responses in leg muscles that opposed the direction of pull. Since the responses occurred before any sway of the body was evident, they were thought to be driven by input from receptors in the arm. Such responses were reduced in Parkinson's disease particularly in patients with greater clinical instability. Voluntary movement also perturbs posture, but to reduce the movement of the center of mass, all voluntary limb movements in healthy unsupported subjects are accompanied, or even preceded, by activation of postural muscles. For example, the act of raising the arms in front of the body produces activity in posterior leg and back muscles that causes the body to sway backwards and reduces the forwards displacement of the center of mass produced by the arm movement. Similarly, the act of standing onto tip toe begins initially with reduced activity of the triceps surae and activation of the tibialis anterior to move the center of mass forwards

followed by the main activation of triceps surae to plantarflex the ankle. The timing and amplitude of such responses can be measured relatively easily using EMG. Calculation of the force produced can be performed if force plate data is available. In Parkinson's disease, the timing of anticipatory activity is approximately normal or prolonged (Dick et al., 1986; Frank et al., 2000), but the magnitude of the activity is reduced (Rogers et al., 1987). Much of the latter is accounted for by the fact that the amplitude of anticipatory activity depends on the speed of the prime movement (Lee et al., 1987), and this is reduced in Parkinson's disease. 26.3.3. Gait Gait can be analyzed in a number of ways from timed walking to the biomechanics of force development during initiation of a step. The most frequently used measures are the cadence (the number of steps per minute) and the stride length during unperturbed walking in a straight line. In healthy subjects there is a linear relation between the stride length and the walking speed. The slope of this relationship is the same in patients with Parkinson's disease, but the intercept is higher. Effectively, for any given cadence the stride length is reduced (Ebersbach et al., 1999; Morris et al., 2001). Treatment with L-DOPA improves walking speed by increasing stride length (Defebvre et al., 2002) for any given cadence. Force platform and EMG measures have been used to investigate the initiation of gait. However, the general pattern of shifts in center of pressure and center of mass are normal when normalized to the gait velocity (Halliday et al., 1998), suggesting that the program to initiate gait is intact. References Agostino, R, Berardelli, A, Formica, A, Accomero, N and Manfredi, M (1992) Sequential ann movements in patients with Parkinson's disease, Huntington's disease and dystonia. Brain, 1l5: 1481-1495. Ashbridge, E, Walsh, V and Cowey, A (1997) Temporal aspects of visual search studied by transcranial magnetic stimulation. Neuropsychologia, 35: 1l21-1l31. Beckley, OJ, Bloem, BR and Remler, MP (1993) Impaired scaling of long latency postural reflexes in patients with Parkinson's disease. Electroencephalogr. Clin. Neurophysiol., 89: 22-28. Benecke, R, Rothwell, IC, Dick, JP, Day, BL and Marsden, CD (1986) Performance of simultaneous

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433 Maki, BE, Holliday, PJ and Topper, AK (1994) A prospective study of postural balance and risk of falling in an ambulatory and independent elderly population. J. Gerontol., 49: M72-M84. Meara, RJ and Cody, FW (1992) Relationship between electromyographic activity and clinically assessed rigidity studied at the wrist joint in Parkinson's disease. Brain, 115: 1167-1180. Meara, RJand Cody, FW (1993) Stretch reflexes of individual parkinsonian patients studied during changes in clinical rigidity following medication. Electroencephalogr. Clin. Neurophysiol., 89: 261-268. Mitchell, SL, Collins, JJ, De, LC, Burrows, A and Lipsitz, LA (1995) Open-loop and closed-loop postural control mechanisms in Parkinson's disease: increasedmediolateral activity during quiet standing. Neurosci. Lett., 197: 133-136. Morris, ME, Huxham, FE, McGinley, J and Iansek, R (2001) Gait disorders and gait rehabilitation in Parkinson's disease. Adv. Neurol., 87: 347-361. Muller, T, Benz, Sand Bornke, C (2001) Delay of simple reaction time after levodopa intake. Clin. Neurophysiol., 112: 2133-2137. Oliveira, RM, Gurd, JM, Nixon, P, Marshall, JC and Passingham, RE (1998) Hypometria in Parkinson's disease: automatic vs. controlled processing. Mov. Disord., 13: 422-427. Onofrj, M, Fulgente, T, Malatesta, G, Ferracci, F, Thomas, A, Curatola, L, Bollettini, F and Ragno, M (1995) The abnormality of N30 somatosensory evoked potential in idiopathic Parkinson's disease is unrelated to disease stage or clinical scores and insensitive to dopamine manipulations. Mov. Disord., 10: 71-80. Pascual-Leone, A, Valls-Sole, J, Wassermann, EM, Brasil, NJ, Cohen, LG and Hallett, M (1992) Effects of focal transcranial magnetic stimulation on simple reaction time to acoustic, visual and somatosensory stimuli. Brain, 115: 1045-1059. Pascual-Leone, A, Valls-Sole, J, Brasil-Neto, J, Cohen, LG and Hallett, M (1994) Akinesia in Parkinson's disease. I. Shortening of simple reaction time with focal, singlepulse transcranial magnetic stimulation. Neurology, 44: 884-889. Phillips, JG, Martin, KE, Bradshaw, JL and Iansek, R (1994) Could bradykinesia in Parkinson's disease simply be compensation. J. Neurol., 241: 439-447. Pierantozzi, M, Mazzone, P, Bassi, A, Rossini, PM, Peppe, A, Altibrandi, MG, Stefani, A, Bernardi, G and Stanzione, P (1999) The effect of deep brain stimulation on the frontal N30 component of somatosensory evoked potentials in advanced Parkinson's disease patients (see comments). Clin. Neurophysiol., 110: 1700-1707.

434 Pierantozzi, M, Palmieri, MG, Marciani, MG, Bernardi, G, Giacomini, P and Stanzione, P (2001) Effect of apomorphine on cortical inhibition in Parkinson's disease patients: a transcranial magnetic stimulation study. Exp. Brain Res., 141: 52-62. Praamstra, P and Plat, FM (2001) Failed suppression of direct visuomotor activation in Parkinson's disease. J. Cogn. Neurosci., 13: 31-43. Praamstra, P, Cools, AR, Stegeman, DF and Horstink, MW (1996a) Movement-related potential measures of different modes of movement selection in Parkinson's disease. J. Neurol. Sci., 140: 67-74. Praamstra, P, Meyer, AS, Cools, AR, Horstink, MW and Stegeman, DF (1996b) Movement preparation in Parkinson's disease. Time course and distribution of movement-related potentials in a movement precueing task. Brain, 119: 1689-1704. Praamstra, P, Stegeman, DF, Cools, AR and Horstink, MW (1998) Reliance on external cues for movement initiation in Parkinson's disease. Evidence from movement-related potentials. Brain, 121: 167-177. Priori, A, Berardelli, A, Inghilleri, M, Accornero, N and Manfredi, M (1994) Motor cortical inhibition and the dopaminergic system. Pharmacological changes in the silent period after transcranial brain stimulation in normal subjects, patients with Parkinson's disease and drug-induced parkinsonism. Brain, 117: 317-323. Pullman, SI, Watts, RL, Juncos, JL, Chase, TN and Sanes, IN (1988) Dopaminergic effects on simple and choice reaction time performance in Parkinson's disease. Neurology, 38: 249-254. Ridding, MC and Rothwell, JC (1999) Afferent input and cortical organisation: a study with magnetic stimulation. Exp. Brain Res., 126: 536-544. Ridding, MC, Inzelberg, R and Rothwell, JC (1995) Changes in excitability of motor cortical circuitry in patients with Parkinson's disease. Ann. Neurol., 37: 181-188. Rocchi, L, Chiari, L and Horak, FB (2002) Effects of deep brain stimulation and levodopa on postural sway in Parkinson's disease. J. Neurol. Neurosurg. Psychiatry, 73: 267-274. Rogers, MW, Kukulka, CG and Soderberg, GL (1987) Postural adjustments preceding rapid ann movements in parkinsonian subjects. Neurosci. Lett., 75: 246-251. Rothwell, JC, Obeso, JA, Traub, MM and Marsden, CD (1983) The behaviour of the long-latency stretch reflex in patients with Parkinson's disease. J. Neurol. Neurosurg. Psychiatry, 46: 35-44. Sanes, IN (1985) Information processing deficits in Parkinson's disease during movement. Neuropsychologia, 23: 381-392. Schieppati, M and Nardone, A (1991) Free and supported stance in Parkinson's disease. The effect of posture and

J.c. RafHWELL 'postural set' on leg muscle responses to perturbation, and its relation to the severity of the disease. Brain, 114: 1227-1244. Schneider, JS, Diamond, SG and Markham, CH (1986) Deficits in orofacial sensorimotor function in Parkinson's disease. Ann. Neurol., 19: 275-282. Sheppard, D, Bradshaw, JL, Phillips, JG, Iansek, R, Cunnington, R, Georgiou, N and Bradshaw, JA (1996) Cueing of movement in Parkinson's disease. Neuropsychiat. Neuropsychol. Behav. Neurol., 9: 91-98. Sheridan, MR and Flowers, KA (1990) Movement variability and bradykinesia in Parkinson's disease. Brain, 113: 1149-1161. Siebner, HR (2000) Simultaneous repetitive transcranial magnetic stimulation does not speed fine movement in PD. Neurology, 54: 272. Starr, A, Caramia, MD, Zarola, F and Rossini, PM (1988) Enhancement of motor cortical excitability in humans by non-invasive electrical stimulation appears prior to voluntary movement. Electroencephalogr. Clin. Neurophysiol., 70: 26-32. Stelmach, GE and Worringham, CJ (1988) The preparation and production of isometric force in Parkinson's disease. Neuropsychology, 26: 93-103. Stelmach, GE, Teasdale, N, Philips, J and Worringham CJ (1989) Force production characteristics in Parkinson's disease. Exp. Brain Res., 76: 165-172. Teasdale, N, Phillips, J and Stelmach, GE (1990) Temporal movement control in patients with Parkinson's disease. J. Neurol. Neurosurg. Psychiatry, 53: 862-868. Touge, T, Werhahn, KJ, Rothwell, JC and Marsden, CD (1995) Movement-related cortical potentials preceding repetitive and random-choice hand movements in Parkinson's disease. Ann. Neurol., 37: 791-799. Traub, MM, Rothwell, JC and Marsden, CD (1980) Anticipatory postural reflexes in Parkinson's disease and other akinetic-rigid syndromes and in cerebellar ataxia. Brain, 103: 393-412. Traversa, R, Pierantozzi, M, Semprini, R, Loberti, M, Cicardi, MC, Bassi, A and Stanzione, P (1995) N30 wave amplitude of somatosensory evoked potentials from median nerve in Parkinson's disease: a phannacological study. J. Neural Transm., Suppl. 45: 177-185. Valls-Sole, J, Pascual-Leone, A, Brasi1-Neto, JP, Cammarota, A, McShane, L and Hallett, M (1994) Abnormal facilitation of the response to transcranial magnetic stimulation in patients with Parkinson's disease. Neurology, 44: 735-741. Vidailhet, M, Rothwell, JC, Thompson, PD, Lees, AJ and Marsden, CD (1992) The auditory startle response in the Steele-Richardson-Olszewski syndrome and Parkinson's disease. Brain, 115: 1181-1192.

DISEASES AND TREATMENTS: PARKINSON'S DISEASE

Wang, He, Lees, AJ and Brown, P (1999) Impairment of EEG desynchronisation before and during movement and its relation to bradykinesia in Parkinson's disease. J. Neurol. Neurosurg. Psychiatry, 66: 442-446.

435 Wenzelburger, R, Raethjen, J, Loffler, K, Stolze, H, Illert, M and Deuschl, G (2000) Kinetic tremor in a reach-tograsp movement in Parkinson's disease. Mov. Disord., 15: 1084-1094.

Movement Disorders Handbook of Clinical Neurophysiology, Vol. 1 M. Hallett (Ed.) © 2003 Elsevier B.Y. All rights reserved

437 CHAPTER 27

Parkinson-plus conditions Josep Valls-Sole" and Francese Valldeoriola Unitat d'EMG, Servei de Neurologia, Departament de Medicina, Hospital Clinic, lnstitut d'lnvestigacion Biomedica August Pi i Sunyer (IDIRAPS), Universitat de Barcelona, Villarroel170, Barcelona 08036, Spain

27.1. Introduction Diseases associated with abnormal movement control have been for a long time a subject of interest for neurologists and clinical neurophysiologists. Neurophysiological examination can provide useful cues for understanding the pathophysiological mechanisms of some symptoms and signs characteristic of specific conditions. Neurologists could use some of the neurophysiological observations for reassurance in their clinical diagnosis as well as for follow-up and objective evaluation of treatment. The paradigmatic condition presenting as an hypokinetic movement disorder is parkinsonism (Table 1). The concept of parkinsonism applies to the clinical observation of rigidity and bradykinesia. However, other features such as tremor, postural instability, gait disorders, and abnormalities in facial expression, are also considered part of the syndrome). The most frequent disorder manifesting with parkinsonism is idiopathic Parkinson's disease (IPD), which is dealt with elsewhere in this book. In this chapter, we review some of the most relevant neurophysiological findings in patients with the socalled Parkinson-plus syndromes, neurodegenerative diseases featuring parkinsonism together with other symptoms and signs. Parkinsonism might result from a dysfunction in the basal ganglia, leading to a hyperactivity in the internal part of the globus pallidus (GPi). In idiopathic Parkinson's disease (IPD), pallidal hyperactivity might be responsible for reduced activation of thalamocortical projections, as well as for abnormal control of brainstem circuits, when executing a

* Correspondence to: Dr. Josep Valls-Sole, Unitat d'EMG, Servei de Neurologia, Hospital Clinic, Villarroel 170, Barcelona 08036, Spain. E.mail address: [email protected] Tel.: 34-93-2275413; fax: 34-93-2275783.

voluntary movement (Hallett and Khoshbin, 1980; Berardelli et al., 1983; Delwaide et al., 2000). However, the situation might be slightly different in Parkinson-plus conditions, in which basal ganglia pathology is accompanied by neuronal loss and atrophy in many nuclei of the brainstem and cerebellum, and dysfunctions might be present in Table 1 Neurodegenerative diseases manifesting with parkinsonism - Idiopathic Parkinson's disease - Progressive supranuclear palsy - Multiple system atrophy - Cortico-basal ganglionic degeneration - Diffuse Lewy body disease - Parkinson-Dementia complex of Guam - Atypical parkinsonism of French West Indies - Hallervorden-Spatz syndrome - Machado-Joseph's disease - Huntington's disease (Westphal's variant) - Herniparkinson-herniatrophy syndrome - Primary pallidal atrophy - Psychogenic parkinsonism Known causes of parkinsonism - pharmacological - toxic - post-encephalitic - post-vaccination - traumatic - vascular lesions - space occupying lesions - metabolic disorders - Wilson's disease - basal ganglia calcification - parathyroid metabolism abnormalities - infections - Creutzfeldt-Jakob disease - Gerstmann-Straussler-Scheinker syndrome

438

various circuits. Regardless of whether the pathophysiological mechanisms underlying parkinsonian signs are similar or not in IPD and Parkinson-plus conditions, clinical neurophysiological manifestations of parkinsonism are common to both types of disorders. In addition, in Parkinson-plus conditions, clinical neurophysiological evaluation may show a few specific symptoms and signs, distinctive of each syndrome. In the following review, we will first describe neurophysiological features that are common to various parkinsonian syndromes, and then highlight the differential aspects between Parkinsonplus disorders.

27.2. Neurophysiological observations common to parkinsonian syndromes 27.2.1. Bradykinesia and rigidity

The term bradykinesia is used to describe slowness of movement, while the term akinesia refers to absence of movement or delay in onset of a voluntary movement (Hallett and Khoshbin, 1980; Hallett, 1990; Pascual-Leone et al., 1994). Clinical manifestations related to akinesia/bradykinesia in patients with parkinsonism include facial hypoactivity, decreased spontaneous blinking rate, hypomimia, micrographia, loss of synkinetic arm movements while walking, postural instability, difficulties in rising from a chair or in turning in bed, etc. Normal blink rate depends largely on the level of the subject's attention, and the activity being performed. However, counting the blink rate can still furnish useful information in normal subjects and patients with CNS disorders. The resting blinking rate, of 24 per minute in normal controls, was found to be reduced in most patients with parkinsonism (Karson et al., 1984), but significantly more so in patients with progressive supranuclear palsy (PSP), whose mean blinking frequency was 4 blinks per minute. Karson et al. (1984) suggested that blinking rate may be an expression of the level of dopamine activity. The most universal neurophysiological method used in the assessment of bradykinesia is the reaction time task. By recording the EMG activity of forearm flexor and extensor muscles, Hallett and Khoshbin (1980) found that IPD patients were unable to appropriately scale the size of the first agonist EMG burst to the requirements of a ballistic

1. VALLS-SOLE AND F. VALLDEORIOLA

movement, and proposed that such defect represented a physiological mechanism of bradykinesia. Since then, simple and complex reaction time task paradigms have been thoroughly used in the study of patients with IPD. However, only a few studies have included such tests in the neurophysiological examination of patients with Parkinson-plus conditions (Valldeoriola et al., 1998). The term rigidity is used to describe the increased muscle tone of patients with parkinsonism (Berardelli et al., 1983). Clinical manifestations of rigidity are the increased limb stiffness and resistance to passive movements. The stooped posture, with flexion of the neck and trunk may also be a manifestation of larger rigidity in flexor than in extensor muscles, although there could also be a component or weakness in the paraspinal muscles (Djaldetti et al., 1999). Patients with parkinsonism have difficulties to completely relax their muscles, which often show some degree of tonic background EMG activity. Several neurophysiological tests have been used to assess rigidity, but direct cliniconeurophysiological correlation has proven more difficult than with bradykinesia. In IPD, rigidity has been demonstrated neurophysiologically by observations such as an increased size of the F wave (Abbruzzese et al., 1985), increased size of long loop reflex responses to stretch (Lee and Tatton, 1975; Rothwell et al., 1983) or electrical stimuli (Deuschl and Lucking, 1990), reduced inhibition in cutaneo-muscular reflexes (Fuhr et al., 1992), decreased duration of the silent period induced by transcranial magnetic stimulation (Cantello et al., 1991; Valls-Sole et al., 1994), reduced reciprocal inhibition (Bathien and Rondot, 1977; Lelli et al., 1991), and reduced autogenic inhibition of the soleus H-reflex (Delwaide et al., 1991). None of these techniques have been applied to patients with Parkinson-plus conditions, with the single exception of the examination of autogenic inhibition in patients with PSP, which interestingly showed the opposite result to patients with IPD, i.e. an enhancement of Ib inhibition (Fine et al., 1998). . Clinical manifestations of parkinsonism are rather conspicuous in patients with Parkinson-plus syndromes. Patients with PSP exhibit marked facial hypoactivity which usually combines with some dystonic features and ocular palsy to give the appearance of astonishment, typical of these patients. Their most important functional disabilities

439

PARKINSON-PLUS CONDITIONS

Table 2 Reaction time in control subjects and in patients with parkinsonism. EMG

Movement

219 (81)

256 (86)

IPD

342 (172)

400 (197)

864 (316)

PSP

443 (170)

521 (178)

1120 (443)

MSA

262 (45)

302 (48)

728 (482)

CS

Task 589 (124)

Figures are the mean, and one standard deviation in parenthesis, of the reaction time (in ms from the imperative signal). CS = control subjects; IPD=Idiopathic Parkinson's disease; PSP=Progressive supranuclear palsy, and MSA=multiple system atrophy.

are severe postural instability, loss of equilibrium and frequent falls. In our experience (Table 2), reaction time is significantly slower in PSP than in other parkinsonisms (Valldeoriola et al., 1998). In multiple system atrophy (MSA), parkinsonism might not be present at the moment of the diagnosis (i.e. in patients with predominating cerebellar dysfunction), but it develops in most patients, reaching 91% of cases in the advanced stages of the disease (Wenning et al., 1994). In Wenning's et al, series, bradykinesia and rigidity were asymmetric in 74% of patients. When compared to patients with IPD, patients with MSA became disabled at a significantly faster rate, with more than 50% of patients being markedly disabled or wheelchair bound within 5 years of onset of parkinsonism. Reaction time in patients with the rigido-akinetic type of MSA is not markedly delayed (Valldeoriola et al., 1998), and their parkinsonian features do not differ from those of patients with IPD. Response to L-DOPA therapy has been reported in up to 40% of patients with MSA (Fearnley and Lees, 1990). Therefore, differences with other parkinsonian syndromes have to be found in other clinical features such as autonomic disturbances or sphincter denervation (Quinn, 1989). In cortico-basal ganglionic degeneration (CBGD), parkinsonism may not be the first manifestation although it is present, even though sometimes at subclinical level, in 100% of patients (Rinne et al., 1994). It is usually asymmetric, and is accompanied by other more conspicuous clinical signs, such as the alien hand, myoclonus or dystonia, which are

the ones bringing the patient to the neurologist. Secondary parkinsonism (to neuroleptics or other medications, intoxications, infections, trauma, metabolic disorders or vascular lesions) is not essentially different from the parkinsonism seen in IPD. Its diagnosis is made through the analysis of the patient's history, observation of accompanying disorders, or serological determinations.

27.2.2. Disorders of brainstem reflexes and functions Short latency brainstern reflex responses (jawjerk, Rl of the blink reflex, and SPI of the masseter inhibitory reflex) are unaltered in patients with parkinsonism. This observation indicates that the afferent and efferent fibers of the reflex arc and the brain stem mono- or oligosynaptic circuits are not abnormal in these diseases. In contrast, long latency reflexes, which follow polysynaptic pathways subject to a strong suprasegmental influence, often show abnormal excitability. Kimura (1973) was first to show such abnormal excitability in patients with IPD, using the most paradigmatic brainstem reflex, the blink reflex. The basal ganglia modulate the excitability of the blink reflex through the output signals arising from the GPi and the substantia nigra pars reticulata (SNr). According to Basso et al. (1996) and Basso and Evinger (1996), the GPi/SNr complex sends inhibitory inputs to the superior colliculus (sq, which sends excitatory inputs to the nucleus raphe magnus (nRM) which, in tum, inhibits the trigeminal neurons of the spinal nucleus. In PO, there is increased GPi/SNr inhibition of the SC which, as a consequence, reduces its excitatory inputs to the nRM. The less active nRM induces less inhibition of the spinal trigeminal nucleus, which become dis-inhibited (hyperexcitable). As in bradykinesia, it is difficult to know whether the same mechanisms apply to Parkinson-plus conditions. We found similar interneuronal brainstem excitability enhancement in PSP and MSA patients, but not in patients with CBGD (Valls-Sole et al., 1997a). Figure 1 shows the graphical results obtained in examining the excitability recovery curve of patients with different parkinsonisms. Another brainstem reflex is the involuntary motor reaction to a startling stimulus. This is an interesting method to test the function of the reticulo-spinal system (Brown et al., 1991). The startle reaction has

440

AND F. VALLDEORIOLA

1. VALLS-SOLl~

100 80 ~

cv

> o 0

60

~

o Controls

'#. 40

M

IPD

• MSA

20

a +--~-=Y-----r--"---"",--",,,,-""""---r--T"" a 100 200 300

*

*

• PSP CBGD

A

500

800

Inter-stimulus interval (ms)

Fig. 1. Blink reflex excitability recovery curves in control subjects and in patients with parkinsonism. The asterisks mark the intervals with statistically significant differences between control subjects and patients with Parkinson's disease, multiple system atrophy and progressive supranuclear palsy. Patients with cortico-basal ganglionic degeneration were not different from control subjects.

been found moderately delayed in IPD (Vidailhet et aI., 1992), severely reduced or absent in PSP (Vidailhet et aI., 1992), normal or enhanced in MSA (Valldeoriola et al., 1997; Kofler et aI., 2001), and reduced and delayed in patients with Lewy-body disease (Kofler et aI., 2001). It has not been studied in patients with CBGD. 27.3. Neurophysiological observations of interest for specific Parkinson-plus conditions 27.3.1. Progressive supranuclear palsy

This is a degenerative disorder which features parkinsonism with a severe equilibrium disturbance and frequent falls, pseudobulbar palsy, dystonia, and oculomotor gaze palsy predominating in the vertical direction (Steele et aI., 1964). Clinical criteria for probable PSP include: a progressive disorder, beginning at age 40 or later, featuring vertical oculomotor palsy and instability with falls during the first year, with no evidence of other diseases that can explain the syndrome (Litvan et al., 1996). 27.3.1.1. Eye and eyelid movement disorders Some of the most striking features differentiating PSP from Parkinson's disease regard facial expression and gaze disturbances (Golbe et aI., 1988).

Spontaneous blinking rate is significantly more reduced in patients with PSP than in other patients with parkinsonism (Karson et al., 1984; Golbe et al., 1989). Clinical evidence of eye movement difficulties are not always present when other clinical features lead to the suspicion of PSP (Golbe et aI., 1989). At this time, recording of eye movements by electrooculography might be of some help (Chu et aI., 1979; Vidailhet et aI., 1994). Surface electrodes are placed in the upper, lower, nasal and temporal edges of the orbit and the subject is requested to make horizontal and vertical eye movements. Electrooculogram recordings may show characteristic abnormalities in patients with PSP, such as slowness of vertical eye movements, absent Bell's phenomenon, square wave jerks and microsaccades (Fig. 2). In the study reported by Vidailhet et aI., 9 out of 10 patients with PSP had vertical gaze paralysis with preserved reflex eye movements. Vidailhet et al. (1984) also showed slowness of horizontal eye movement and microsaccades that can be helpful in distinguishing patients with PSP from those with other parkinsonisms. Facial reflex responses to electrical stimulation of the median nerve have a distinct pattern of abnormalities in patients with PSP (Valls-Sole et aI., 1997a). Mentalis muscle responses can be elicited

441

PARKINSON-PLUS CONDITIONS A

----------~--------

L B

Fig. 2. Electrooculogram of horizontal eye movements in a healthy control (A) and in a patient with progressive supranuclear palsy (B). The upper graphs were recorded after asking the subjects to keep their gaze fixed to the center of a blank screen, located at a distance of 70 em in front of their eyes. The lower graphs show the recordings done when subjects were asked to move their eyes to the right and left sides of the screen. Note the square-wave jerks and the microsaccades in the patient's recordings. Horizontal calibration bar is 500 ms. Vertical calibration bar is 5° for the first and third traces and 15° for the 2nd and 4th traces.

with somatosensory stimuli applied to the cutaneous territory of the median nerve, as in the so-called palmomental reflex (Dehen et al., 1975). The same stimulus can generate other facial reflex responses, such as those appearing in the orbicularis oculi (Miwa et al., 1995). As part of a study of brainstern reflexes in patients with parkinsonism, we applied electrical stimuli to the median nerve and recorded facial responses simultaneously in the mentalis and orbicularis oculi muscles. The study included patients with IPD, PSP, MSA, CBGD, and healthy volunteers. Responses in the mentalis muscle were found in most patients and in 2 out of 10 normal subjects. In all of them, whenever there were responses in the mentalis muscle, there were also responses in the orbicularis oculi muscle. The exception were the patients with PSP who had no

orbicularis oculi responses even if the responses of the mentalis muscle were not different from those observed in the other groups of patients (Valls-Sole et al., 1997a). This abnormality adds to the other eye and eyelid motility disorders of patients with PSP (Golbe et al., 1989). The possibility to find a dissociation between mentalis and orbicularis oculi responses suggests that these two responses are mediated through two different circuits. The mentalis response could be conveyed through the cortico-nuclear tract, since this tract innervates predominantly lower facial motoneurons (Jenny and Saper, 1987) and a transcortical loop has been suggested because of the contiguity between thumb and chin areas in the brain sensorimotor region (Dehen et al., 1975). The orbicularis oculi response can be the result of activating the brainstem reticular formation as a kind of somatosensory startle (Gokin and Karpukhina, 1985). The selective damage of the pontine reticular formation in patients with PSP would then be responsible for the absence of the orbicularis oculi response. Enhancement of mentalis response may occur because of disinhibition of thalamo-cortical connections from their striatal control (Maertens de Noordhout and Delwaide, 1988). Table 3 summarizes the abnormalities of eye and eyelid movements reported on patients with PSP. 27.3.1.2. The startle reaction and reaction time task experiments Patients with PSP have absent or severely reduced auditory startle reactions (Vidailhet et al., 1992). From studies carried out on rats, the startle reaction is known to be generated in the nucleus reticularis pontis caudalis (nRPC), which activates the reticulospinal tract inducing muscle responses in facial and spinal motoneurons (Davis et al., 1982). In humans, the startle reaction is also thought to originate in corresponding nuclei of the brainstem, and spread caudally and rostrally to limb and facial muscles. Neuronal loss in patients with PSP involves specifically the cholinergic neurons of the lower pontine reticular formation, including those of the pedunculo-pontine tegmental nucleus and the nucleus reticularis pontis caudalis (Zweig et al., 1987; Juncos et al., 1991; Malessa et al., 1991). Therefore, it is not surprising that patients with PSP have abnormalities in the startle reaction to auditory stimuli. In the study carried out by Vidailhet et al.

442

1. VALLS-SOLl~

AND F. VALLDEORlOLA

Table 3 Eye and eyelid movement abnormalities observed in patients with PSP. Observation

Reference

Reduced spontaneous blinking

Karson (1984)

Lid retraction

Maher and Lees (1986)

Blepharospasm

Jackson et al. (1983)

Supranuclear palsy of eyelid opening

Lepore and Duvoisin (1985)

Supranuclear palsy of eyelid closing

Golbe et al. (1989)

Reduced voluntary suppression ofVOR

Golbe et al. (1989)

Eyelid retraction (Cowper's sign)

Golbe et al. (1989)

Square-wave jerks

Chu et al. (1979)

Absent eyelid responses to acoustic stimuli

Vidailhet et al. (1992)

Absent eyelid responses to median nerve stimuli

Valls-Sole et al. (1997)

(1992), the response was absent in 3 out of 8 patients, and it was small and delayed in the other 5 patients. Patients with PSP have a significantly longer simple reaction time than other patients with parkinsonism, and their reaction time does not speed up when an additional startling stimulus is given together with the 'go' signal (Valldeoriola et al., 1998). Delay in simple reaction time has been equated to akinesia, and attributed to the fact that it takes longer than normal to sufficiently energize the structures needed for the execution of the motor task, including the primary motor cortex (Hallett, 1990). Another explanation comes from the implication of subcortical motor structures in the preparation and execution of ballistic movements (Valls-Sole et aI., 1999). Reaching a certain degree of motor preparation is necessary for the execution of ballistic movements. Motor preparation might be mediated by subcortical motor structures such as the reticulospinal tract, which is probably an important part of the execution channel for a ballistic movement. Congruent with this hypothesis, external activation of the reticulospinal tract by a startling auditory stimulus causes significant acceleration of reaction time in normal human subjects (Valls-Sole et al., 1995, 1999). The significantly longer delay in the reaction time of patients with PSP with respect to other parkinsonisms could be due to faulty preparation of the execution channel as a consequence of their abnormalities in the reticular formation.

An interesting collateral observation of the startle induced shortening of the reaction time (StartReact effect) was its reduced habituation in successive trials, which can be an advantage for clinical applicability in comparison to testing the startle reaction alone. Valldeoriola et al. (1998) applied this method to the investigation of patients with parkinsonism. These authors found a significant StartReact effect in all patients except in those with PSP (Fig. 3), and suggested that this method might have clinical applicability in early differential diagnosis between IPD and PSP. More recently, Molinuevo et al. (2000) have shown that the same results (i.e. absence of reaction time shortening in PSP patients but significant shortening in PD patients) can be obtained using transcranial magnetic stimulation (TMS). Shortening of simple reaction time with subthreshold TMS has been already reported in normal subjects and IPD patients (Pascual-Leone et al., 1992, 1994).Apart from confirming the abnormalities of PSP patients in the execution of ballistic movements, the observations reported by Molinuevo et al. (2000) give some cues on the mechanisms by which TMS induces a reaction time shortening effect: Since PSP patients do not have significant motor cortical disturbances, the effect would have been present if it were dependent on the activation of the corticospinal tract. The absence of the effect points to the possibility that TMS shortens reaction time by way of activating the reticulospinal structures through various sources: The sound stim-

443

PARKINSON-PLUS CONDITIONS

A

B

VL

Movement of wrist

----;,----~/'

Task 'go' signal

lOOms

'go' signal

-+-~~~ --t---~-----/~~~ 'go' signal 'go' signal + startle

+

startle

Fig. 3. Effects of a startle on reaction time in a control subject (A), and in a representative patient with progressive supranuclear palsy (B).

ulus inevitably delivered together with the discharge of the coil, the trigeminal inputs caused by activation of scalp and jaw muscles, and the direct activation of cortico-reticular pathways (Molinuevo et aI., 2000). 27.3.2. Multiple system atrophy

Multiple system atrophy is a progressive neurodegenerative disease featuring autonomic disorders together with parkinsonism, cerebellar or pyramidal dysfunctions (Quinn, 1989). Clinical diagnosis of probable MSA requires the presence of autonomic failure (including urinary dysfunction), and either a poor levodopa responsive parkinsonism or cerebellar dysfunction (Gilman et aI., 1999). 27.3.2.1. Autonomic dysfunction Autonomic nervous system dysfunction is the key to the diagnosis in patients with MSA who present with parkinsonism or cerebellar syndromes (Quinn,

1989), and is presently a required criterion for the diagnosis of probable MSA (Gilman et aI., 1999). Autonomic nuclei of the brainstem, the intermediolateral column, and the sacral parasympathetic neurons are some of the structures related to the autonomic nervous system in which pathological examination has revealed loss of neurons and glial cytoplasmic inclusions in patients with MSA. Clinically relevant autonomic dysfunctions in these patients are orthostatic hypotension, urinary and faecal incontinence, erectile dysfunction in males, sudomotor disregulation, and abnormalities in respiratory control during sleep. Orthostatic hypotension may be due to the inability to increase sympathetic activity with standing. This can be shown as an abnormal regulation of baroreflex responses to different stimuli (Benarroch et al., 1993). Using readily available electrophysiological equipment, it is also possible to monitor heart beat frequency. Recording the R-R interval variation by means of the signal trigger and the delay line

444

unit of an electromyograph shows graphically the reduced adaptation of the heart beat rate to a postural change or to the Valsalva maneuver (Valls-Sole, 2000). The main drawback of this test is that patients with severe bradykinesia might be unable to perform adequately the maneuvers. Reduced R-R interval variation could then be due to insufficient stimulation. For this reason, we have examined the possibilities to test R-R interval variation using methods that do not require the patient's cooperation. One of these methods is based on the observation of normal startle responses in patients with MSA (Valldeoriola et aI., 1997), and on the fact that a startle accelerates heart-beat frequency in normal subjects (Roland et aI., 1999). We have examined the behavior of such an effect in normal subjects and patients with MSA (Valls-Sole et aI., 2002). In spite of having a normal motor component of the startle reaction in chest muscles, patients with MSA had significantly smaller change of the R-R interval after the acoustic stimulus (Fig. 4). The sympathetic sudomotor skin response, or SSR (Shahani et aI., 1984), may reveal dysfunctions in the autonomic control of sudomotor reflexes. Loss of sympathetic neurons of the intermediolateral column might explain the finding of frequently abnormal SSRs in patients with MSA (Bordet et aI., 1996). Other tests of sudomotor function, such as the evaluation of the amount of sweat production to direct gland stimulation with intradermal methacholine, have also demonstrated a decreased sweat response in patients with MSA (Baser et aI., 1991). Sleep disorders are frequent in patients with MSA. Some of these disorders might be related to autonomic dysfunction. Thirty-five of 39 patients with MSA had REM sleep behavior disorders (Plazzi et aI., 1993), which preceded the diagnosis in 44% of the cases. Polysomnographic studies revealed subclinical obstructive sleep apnea in six patients, laryngeal stridor in eight patients, and periodic leg movements during sleep in ten patients. Laryngeal stridor, due to vocal cord abductor paralysis during sleep, is probably caused by selective denervation atrophy of the cricoarytenoid muscle due to selective loss of neurons in the nucleus ambiguous (Bannister et aI., 1981), and may lead to choking and death in advanced stages of MSA. This can be prevented with tracheostomy or with continuous positive air pressure (lsozaki et al., 1996; Iranzo et aI., 2000).

J. VALLS-SOLJ~

AND F. VALLDEORIOLA

A

, I

B

Auditory stimulus

Fig. 4. Modulation of heart rate by an auditory startle in a control subject (A) and in a patient with multiple system atrophy (B). Note the EMG activity of the chest muscles just after the stimulus artifact, and the reduced effect on heart rate in the patient.

27.3.2.2. Sphincter EMG In MSA patients, manifestations of autonomic dysfunctions such as erectile impotence are usually

445

PARKINSON-PLUS CONDITIONS

accompanied by urinary frequency and urgency, leading soon to incontinence, associated with large residual urine volumes (Kirby et aI., 1986). The severity of urinary symptoms is one main red flag that should warn the neurologist of the possibility that the parkinsonian patient thought to have IPD is actually facing the diagnosis of probable MSA (Quinn, 1989). Urinary incontinence in MSA patients might be due to autonomic dysfunction, loss of pontine control of micturition, striatal sphincter denervation, or a combination of all of them. Striatal sphincter denervation is attributed to the selective loss of motoneurons in the nucleus of Onuff at the S2-S3 medullary segments. Needle electromyography of the external anal sphincter, therefore, is considered an important neurophysiological test in the assessment of patients with parkinsonism, as most patients with MSA show denervation-reinnervation signs (Sakuta et aI., 1978; Eardley et aI., 1989). We and others have confirmed that anal sphincter denervation is prominent in patients with MSA, although similar type of abnormalities have been found in a large proportion of patients with PSP as well as in some patients with Parkinson's disease (Valldeoriola et aI., 1995; Giladi et aI., 2000). Therefore, the utility of anal or vesical sphincter needle EMG in the diagnosis of MSA is still under debate (Rodi et aI., 1996; Libelius and Johansson, 2000). Chronic constipation, local trauma related to delivery, and other pudendal nerve longstanding lesions may give rise also to sphincter denervation (Kiff and Swash, 1984; Podnar and Vodusek, 2000), which may diminish the validity of the sign as a true marker of motoneuronal loss. Recently, a consensus statement has been published in which sphincter EMG abnormalities are considered as a supportive laboratory finding, but not a criterion, for the diagnosis of MSA (Gilman et aI., 1999). 27.3.2.3. Minipolymyoclonus Tremor has been reported in up to 74% of MSA patients (Wenning et aI., 1994). However, this figure included several types of tremor, with only a few patients exhibiting the resting tremor typical of IPD, and a large proportion of unclassifiable hands and finger 'jerky' tremors. Electrophysiological studies of these latter movements have shown that their characteristics are closer to myoclonus than to tremor (Salazar et aI., 2000). A piezoelectric accelerometer was used to record finger movements and

analyze the frequency spectrum of the signal through fast Fourier transformation. This procedure showed that movements of MSA patients were rather nonrhythmic in comparison to those of patients with other forms of tremor. Salazar et al. (2000) suggested the term minipolymyoclonus to be used to describe these small amplitude, irregular, jerk-like abnormal movements. Other forms of myoclonus have also been reported in a few MSA patients (Chen et aI., 1992; Gouider-Khouja et al., 1995), which might have their origin in a reduced inhibition of the strio-palido-thalamo-cortical circuit (Patel and Slater, 1987). 27.3.3. Cortico-basal ganglionic degeneration

Patients with CBGD characteristically present with a progressive neurodegenerative disorder, featuring asymmetric ideomotor apraxia, cortical sensory deficit or alien limb, together with a rigidakinetic syndrome and either dystonic postures or spontaneous, action or reflex myoclonus (Gibb et aI., 1989; Riley et aI., 1990; Lang, 1996). 27.3.3.1. Myoclonus Myoclonus in CBGD is thought to be of cortical origin despite of the fact that neurophysiological evidence is lacking. The expected findings of cortical myoclonus, such as giant somatosensory evoked potentials and jerk-locked EEG potentials, are typically absent in CBGD. This is attributed to the marked frontoparietal cortical atrophy and neuronal degeneration characteristic of these patients (Gibb et aI., 1989; Brunt et aI., 1995). Cortical atrophy could involve predominantly inhibitory neurons, leading to an enhanced (disinhibited) motor cortex excitability. The 'C' wave, or focal reflex myoclonus (Sutton and Mayer, 1974), is a response seen in forearm muscles after electrical stimulation of ipsilateral cutaneous nerves of the hand. This response is thought to be mediated by fast conducting afferent and efferent pathways and might have a latency as short as 43.1±3.2 ms (Thompson et al., 1994). In some patients, focal reflex myoclonus might be elicited by stimuli of an intensity below perception threshold, which suggests a direct connection from the thalamic nuclei to the motor cortex (Mauguiere et aI., 1983). The 'C' response should not be mistaken for the long latency excitatory response of the cutaneo-muscular reflexes (Caccia et aI., 1973;

446

1. VALLS-SOLl~

AND F. VALLDEORIOLA

Fig. 5. Maps of cortical representation of hand muscles in a healthy volunteer (A) and in a patient with cortico-basal ganglionic degeneration (B).

Jener and Stephens, 1982). The cutaneo-muscular reflex can be elicited during a sustained tonic voluntary contraction of the forearm muscles. The long latency excitatory component of the cutaneomuscular reflex might be abnormally enhanced in patients with IPD or MSA (Chen et al., 1992). However, the latency of such a response is longer than that of the 'C' reflex. 27.3.3.2. Alien hand sign The lack of voluntary control of limb movements, or 'alien-hand' syndrome, that is often seen in

patients with CBGD, suggests involvement of cortical motor pathways, with dysfunctions localized either at the frontal lobe (Goldberg et al., 1981) or at the corpus callosum (Feinberg et al., 1992). Accordingly, the study of corticospinal tract functions could show abnormalities in patients with CBGD exhibiting the alien hand phenomenon. A focal, figure-of-8, coil was used to activate limited regions of the motor cortex of only one hemisphere. In this way, a motor map of the area of representation of a given muscle can be constructed by applying the coil to a grid of points in the scalp separated by 1 em. Six out of 10

PARKINSON-PLUS CONDITIONS

CBGD patients with alien hand sign had bilateral responses to focal, unilateral, TMS applied to the side contralateral to the alien hand (Fig. 5). Ipsilateral responses were delayed with respect to the contralateral ones by a mean of 7.7±2.2 ms, a time allowing for conduction through the corpus callosum. Such abnormality was not found in any of 10 normal subjects, eight patients with Alzheimer's disease, or six patients with IPD presenting with predominantly unilateral rigidity. This finding points again to an enhanced motor cortex excitability in the hemisphere contralateral to the alien hand, which may be unable to inhibit transcallosal excitatory inputs from the other hemisphere.

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AND F. VALLDEORIOLA

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450 J (2000) Neurophysiological characterization of parkinsonian syndromes. Neurophysiol. CUn., 30: 352-367. Valls-Sole, J, Pascual-Leone, A, Brasil-Neto, JP, McShane, L and Hallett, M (1994) Abnormal facilitation of the response to transcranial magnetic stimulation in patients with Parkinson's disease. Neurology, 44: 735-741. Valls-Sole, J, Sole, A, Valldeoriola, F, Munoz, E, Gonzalez, LE and Tolosa, ES (1995) Reaction time and acoustic startle in normal human subjects. Neurosci. Lett., 195: 97-100. Valls-Sole, J, Valldeoriola, F, Tolosa, E and Marti, MI (1997a) Distinctive abnormalities of facial reflexes in patients with progressive supranuclear palsy. Brain, 120: 1877-1883. Valls-Sole, J, Valldeoriola, F, Tolosa, E and Nobbe, F (1997b) Habituation of the auditory startle reaction is reduced during preparation for execution of a motor task in normal human subjects. Brain Res., 751: 155-159. Valls-Sole, J, Rothwell, JC, Goulart, F, Cossu, G and Munoz, IE (1999) Patterned ballistic movements Valls-Solt~,

J. VALLS-SOLI:;: AND F. VALLDEORIOLA

triggered by a startle in healthy humans. J. Physiol., 516: 931-938. Valls-Sole, J et al. (2002) Effects of a startle on heart rate in patients with multiple system atrophy. Mov. Disord., 17: 546-549. Veciana, M, Valls-Sole, J, Valldeoriola, F, Munoz, E and Tolosa, ES (2000) Startle effects on the R-R interval in normal controls and patients with multisystem atrophy. Mov. Disord., 15: 78 (abstract). Vidailhet, M, Rothwell, IC, Thompson, PO, Lees, AJ and Marsden, CD (1991) The auditory startle response in the Steele-Richardson-Olszewsky syndrome and Parkinson's disease. Brain, 115: 1181-1192. Vidailhet, M, Rivaud, S, Gouider-Khouja, N, Pillon, B, Bonnet, AM, Gaymard, B, Agid, Y and PierrotDeseilligny, C (1994) Eye movements in parkinsonian syndromes. Ann. Neurol., 35: 420-426. Wenning, GK, Ben Shlomo, Y, Magalhaes, M, Daniel, SE and Quinn, NP (1994) Clinical features and natural history of multiple system atrophy. An analysis of 100 cases. Brain, 117: 835-845. Zweig, RM, Whitehouse, PJ, Casanova, MF, Walker, LC, Jankel, WR and Price, DL (1987) Loss of pedunculopontine neurons in progressive supranuclear palsy. Ann. Neural., 22: 18-25.

Movement Disorders Handbook of Clinical Neurophysiology, Vol. I M. Hallett (Ed.) © 2003 Elsevier B.Y. All rights reserved

451 CHAPTER 28

Dystonia Ryuji Kaji* Department of Clinical Neuroscience, Hospital of the University of Tokushima, 2-Chome 5-1, Kuramotocho, Tokushima City, Tokushima 770-8503, Japan

28.1. Introduction: diagnosis of dystonia Dystonia is defined as a syndrome of sustained muscle contractions causing twisting or repetitive movements or abnormal postures (Fahn, 1988). It is classified as focal, segmental, multifocal, generalized or herni-dystonia according to the distribution of the symptoms. Primary or idiopathic dystonia represents a condition with no known cause, and usually lacks clinical signs other than dystonic muscle contractions. Some are found clearly genetic, and rarely accompany parkinsonism and hyperreflexia (DOPA-responsive dystonia or DRD). Dystonia may be secondary to focal lesions, other neurological illnesses or prolonged use of major tranquilizers or related drugs (secondary dystonia). Although widely used, the above definition does not fully represent the salient clinical features of this disorder, and some additional points deserve mention. Writer's cramp is a focal dystonia of the hand, which typically affects only writing at its onset (Fig. 1). This task-specificity may also be seen in other forms of dystonia. Abnormal muscle contractions involve the same set of muscles in the same way (Yanagisawa and Goto, 1971) such that the movements are stereotyped; patients with cervical dystonia, for example, always present involuntary head turning to a fixed direction. This distinguishes dystonia from other involuntary movements such as seen in chorea or athetosis, which lack stereotypy.

* Correspondence to: Prof. Ryuji Kaji, Department of Clinical Neuroscience, Hospital of the University of Tokushima, 2-Chome 5-1, Kuramotocho, Tokushima City, Tokushima 770-8503, Japan. E-mail address:[email protected] or [email protected] Tel.: 81-88-633-7206; fax: 81-88-633-7208.

Another feature of dystonia is the importance of sensory input in modifying the abnormal muscle contractions. The most characteristic is the sensory trick, in which a fixed cutaneous or proprioceptive input nearby the affected region helps the patient reestablish normal posture or movement. For instance, a patient with cervical dystonia uses touching a part of the face or the skin in the neck with his or her hand as a method to correct abnormal posture. Such a phenomenon is not lirnited to the somatosensory modality. For instance, patients with blepharospasm frequently complain of excessive brightness in the sun that leads to more eye closure, and benefit from wearing dark sunglasses. For clinical evaluation of patients, surface electromyography (EMG) studies give most valuable information. These should be recorded in different motor tasks with or without sensory trick. They may

Fig. 1. Surface EMGs recorded from wrist flexor, extensor, biceps, triceps muscles during waving (left) and writing (right) in a patient with writer's cramp. Adapted from Rothwell et al. (1983).

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be repeated to see if the pattern of muscle activation is reproducible, or stereotyped. Normal phasic voluntary movement comprises reciprocal activation of local agonist and antagonist muscles. In dystonia, surface EMGs frequently show simultaneous contraction of agonist and antagonist muscles (cocontraction) or contraction of surrounding muscles (oveiflow) (Fig. 1). If abnormal phasic muscle contractions intervene, surface EMGs should tell whether they are rhythmic tremor or irregular myoclonic jerks. Serial activation of muscles appropriate for performing a task is also impaired, so that two muscles contract not sequentially but simultaneously (Rothwell et al., 1983). These features are useful in diagnosing dystonia, and suggest that dystonia is a disorder of a motor program for performing a routine act which probably utilizes sensory input for motor control (Kaji et aI., 1995d).

28.2. Historical perspective Writer's cramp was first recognized as scrivener's palsy as early as 1855, and appeared in the Encyclopaedia Britannica in 1877. During the Victorian era, the world's great commerce center in London created a large number of scriveners who were responsible for copying many papers of contract and other business documents by hand. Many of them were required to use a quill, whose thin shaft had to be gripped firmly. Some of them soon developed a strange motor disability that first affected only writing, but later involved other tasks. In 1878, Samuel Wilks wrote on scrivener's palsy under the title of "local spasms" in his textbook (Wilks, 1878). "Local spasms" included wry neck (or spasmodic torticollis), spasm of the facial muscles (currently known as blepharospasm or Meige syndrome), and spasmodic contraction of the jaw (mandibular dystonia). All these disorders are now known as focal dystonias. The first complete account of cervical dystonia was given by Destarac (1901), who clearly showed the sensory trick or geste antagoniste as the cardinal feature. DennyBrown was puzzled by this sensory phenomenon (Gilman et aI., 1999), and viewed generalized dystonia as resulting from imbalance of reflex responses to natural sensory inputs (Denny-Brown et al., 1964; Denny-Brown, 1965). Despite these early observations, it was as late as the 1980s when all these seemingly different clinical presentations of

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focal dystonias were first recognized as sharing common features (Marsden, 1976; Sheehy and Marsden, 1982). On the other hand, a hereditary form of generalized dystonia was first described as dystonia musculorum deformans by Oppenheim (Oppenheim, 1911). Genetic studies recently showed a GAG deletion in the DYTl gene in this condition, now called primary torsion dystonia or Oppenheim dystonia.

28.3. Sensory and subcortical abnormalities in dystonia The sensory phenomena in dystonia suggest that adjusting the link between sensory input and movement allows motor commands to be issued more effectively from the brain. Repetitive exposure to bright light may induce blepharospasm (Kaji et al., 1999), and as mentioned, wearing dark sunglasses often relieves symptoms of blepharospasm. Abnormal postures in focal dystonia are often maintained after botulinum toxin injections into active muscles; in patients with cervical dystonia, previously silent agonist muscles (e.g. the anterior margin of the trapezius muscle) come into action after a hyperactive muscle (e.g. the sternocleidomastoid muscle on the same side) has been weakened with botulinum toxin. This phenomenon indicates that an abnormal body image but not individual muscle hyperactivity is pre-programmed in cervical dystonia, and underscores the crucial role of proprioceptive sensory input in causing dystonia. These sensory aspects of dystonia have attracted increasing attention (Hallett, 1995). Recently, direct evidence of sensory abnormality was obtained at the cortical level. Byl and colleagues (Byl et aI., 1996) successfully produced a model of hand dystonia in the monkey, where they found a markedly disorganized representation of the digits in the primary somatosensory cortex. Interestingly, these investigators produced the model by imposing highly repetitive and demanding task of hand opening and closing (Topp and Byl, 1999), which was similar to that of a scrivener. Subsequently, Bara-Jimenez and colleagues (Bara-Jimenez et al., 1998) found analogous abnormalities of hand representation at the cortex in patients with writer's cramp using brain mapping techniques. Recently, this hand

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Dystonia

Normal

... u

"+U

IlU

IlU 151'VI

...u IlU

... u MU

... u MU

I

.hU 51'V

I

MU

51' V

Nt

5m. 5m.

Fig. 2. Median and ulnar SEPs recorded from a normal subject (left) and a patient with hand dystonia (right). Algebraic sum (M + U) and waveforms after simultaneous stimulation (MU) are shown for each recording site (from above, frontal, parietal, cervical and brachial plexus). Double-headed arrows indicate the difference between M+U and MU, which was lost in dystonia. Adapted from Tinazzi et al. (2000).

representation was found abnormal not only in the affected but also in the non-affected hand in dystonia (Meunier et al., 2001). This speaks in favor of the disorganized sensory cortex as a cause rather than a consequence of the disease. Moreover, a trauma to the affected body part, which apparently disturbs the input-output link, has been recognized as a risk factor to develop dystonia (Jankovic, 1994). These findings strengthened the case for abnormal sensorymotor integration. Clinical sensory deficits were also documented in hand dystonia. Spatial and temporal discrimination of somesthetic stimuli were found abnormal (Bara-Jimenez et al., 2000a, b). In line with these observations, temporal and spatial summation of upper-limb somatosensory evoked potentials were found excessively large in hand dystonia (Tinazzi et al., 2000; Frasson et al., 2001) (Fig. 2). The latter findings lead to the notion that "overflow" is seen in the sensory as well as in the motor domain, and surround and collateral inhibitory mechanisms in the sensory system seem deficient (Fig. 3). Murase and colleagues (Murase et al., 2000) studied the attenua-

tion (gating) of somatosensory evoked potentials (SEPs) before and during hand movements in patients with writer's cramp, and found a lack of Cortex

--

_

Excitation

c:J Inhibition

Fig. 3. A diagram to show surround and collateral inhibition at various sensory relay nuclei. In dystonia, this inhibitory mechanism seems to be deficient. Adapted from Brodal (1981).

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Fig. 4. Premovement gatingof median SEPs in a normal subject(left) and a patientwith hand dystonia(right).Frontal N30 a and b are normally attenuated prior to movement, but are unchangedin dystonia.Adapted from Muraseet al. (2000). normal gating before movements (Fig. 4). This indicates an abnormality of utilizing sensory input in preparation for a movement in dystonia.

was interpreted as reduced presynaptic inhibition of Ia terminals. This deficient presynaptic inhibition may lead to the enhanced TVR in affected muscles, whereas blocking Ia input may compensate for the

28.4. Is dystonia a reflex abnormality? As was predicted by the reflex theory of DennyBrown (1965), dystonic contractions in writer's cramp can be reproduced by stimulating group Ia afferents by high-frequency vibration (tonic vibration reflex or TVR) and are abolished by blocking them with diluted lidocaine (muscle afferent block) (Kaji et al., 1995b, c). Multiple mechanisms must underlie this phenomenon. In normal subjects, one of the effects of vibration is to increase the preexisting presynaptic inhibition of group Ia afferent terminals, while simultaneously facilitating the TVR (Fig. 5). Using H-reflex recovery curves, Nakashima and colleagues (Nakashima et aI., 1989) demonstrated the lack of reciprocal inhibition at 20 ms conditioning-test stimuli interval in writer's cramp, possibly contributing to the co-contraction in dystonia. This

lstim

(H wave)

Fig. 5. An illustration to show the spinal stretchreflex,the gamma efferentand presynaptic inhibition.

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lack of presynaptic inhibition. In this experiment, the sensory trick of applying cutaneous input to the affected hand was equally effective for abolishing abnormal TVR and dystonic symptoms. Of note is that cutaneous input is known to enhance presynaptic inhibition. An alternative hypothesis is that muscle spindle responsiveness is enhanced through abnormal activity of the gamma motor fibers, which may be effectively blocked by diluted lidocaine. Those muscles with increased gamma activity may be prone to develop a TVR because of increased spindle sensitivity. The dysfunction of presynaptic inhibitory mechanisms was also indicated by a study using tendon stimulation (Lorenzano et al., 2000). Several studies have explored the role of vibratory stimuli in dystonia. Grunewald and colleagues (Grunewald et al., 1997) found that vibratoryinduced illusion of hand motion was abnormally perceived in hand dystonia patients who showed normal position sense at rest, which suggests impaired processing of muscle spindle afferents in dystonia. Using transcranial magnetic stimulation of the primary motor cortex (M1) as a probe, Rosenkranz and colleagues (Rosenkranz et al., 2000) found the excitability of M1, which normally increases during vibratory stimulation, is unchanged in dystonia patients. This accords with the previous observation of the lack of cerebral blood flow increases during vibrotactile stimulation in hand dystonia (Tempel and Perlmutter, 1990, 1993). Serrien and colleagues (Serrien et al., 2000) examined the effect of vibratory stimulation in the affected and unaffected hand during precision grip, and found the task was impaired in dystonics but not in normals. As for other subcortical abnormalities, an abnormality in the recovery function of the blink reflex was first found in blepharospasm (Berardelli et al., 1985). The blink reflex R2 component is normally inhibited after electric conditioning pulses. This inhibition becomes much less in blepharospasm than in normals. Similar findings of abnormal recovery function were later confirmed in other types of dystonia as well as in Parkinson's disease. In normal subjects, similar but less inhibition of R2 recovery was found after photic conditioning stimuli. Patients with blepharospasm show much less effect of photic conditioning than normals (Katayama et al., 1996). This indicates that abnormal excitability of blink reflex pathways is not appropriately inhibited by

light, and this may underlie the clinically observed sensitivity to brightness in these patients.

28.5. Abnormal brain activity preceding movements in dystonia Brain potentials preceding spontaneous movements, the Bereitschaftspotential (BP) have been studied in patients. The second component, from 650 ms to 50 ms preceding the hand movement (NS' or NS2), was found decreased in writer's cramp (Deuschl et al., 1995). Using the same raw data and the event-related desynchronization technique, Toro and colleagues (Toro et al., 2000) demonstrated less reduction of 20-30 Hz EEG power preceding hand movements in dystonics than in normals. Yazawa and colleagues (Yazawa et al., 1999) recorded BP preceding muscle relaxation in hand dystonia, and found more extensive abnormality before relaxation than before initiating movement in hand dystonia. Hummel and colleagues (Hummel et al., 2002) reported that the increase in synchrony of cortical activity, reflecting inhibitory cortical control, was defective for hand movements in dystonia. These may correspond to recent observations showing defective inhibitory cortical mechanisms as discussed later. EEGs before cued movements are generally called contingent negative variation (CNV). Its late component, representing movement preparation, was abnormally decreased specifically for head turning in cervical dystonia (Kaji et al., 1995a), and for hand movement in writer's cramp (Hamano et al., 1999) (Fig. 6). These task-specific brain activities clearly point to defective motor control for specific tasks in dystonia.

28.6. Transcranial magnetic stimulation Transcranial magnetic stimulation (TMS) of the primary motor cortex allows direct assessment of the corticospinal projection. Using different stimulus intensities and facilitation levels, Ikoma and colleagues (Ikoma et al., 1996) found abnormal excitability curves for dystonia patients. Inhibition in motor cortex is also deficient in patients with hand dystonia. Ridding and colleagues (Ridding et al., 1995) studied intracortical inhibition using a "double pulse" paradigm, in which a subthreshold conditioning pulse precedes a test pulse. They found less

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Fig. 6. Contingent negative potential (CNV) prior to head rotation (upper) and finger extension (lower) in patients with cervical dystonia (left column) and hand dystonia (right column). Grand-averages are shown and thick traces are from the patients, thin ones from normal controls. 51: warning, 52: imperative signal. Recorded from Cz. Adapted from Kaji et al. (1995) and Hamano et al. (1999).

inhibition of conditioned motor evoked potentials (MEPs) at 1-5 ms intervals in dystonia than in normals. TMS can also suppress ongoing voluntary muscle activation (silent period). The duration of this silent period is another index of the cortical excitability. Chen and colleagues (Chen et al., 1997) reported this silent period was abnormally short in dystonia, again suggesting an abnormal cortical inhibitory mechanism. These abnormalities of cortical inhibition were also found in obsessive compulsive disorder (Greenberg et al., 2000), which possibly is a psychological feature of dystonia (Kubota et al., 2001). These findings are best explained by deficient GABAergic inhibitory interneurons in motor cortex, because intrathecal baclofen, a GABA agonist, prolongs silent period in generalized dystonia (Siebner et al., 1998). More direct evidence comes from MR spectroscopy. GABA levels were significantly reduced in the sensorimotor cortex and the lentiform nucleus contralateral to the dystonic hand (Levy and Hallett, 2002). Slow (l Hz) repetitive TMS (rTMS) was shown to reduce cortical excitability or to reinforce cortical inhibition. Siebner and colleagues (Siebner et al., 1999) demonstrated that rTMS could prolong silent

periods and increase intracortical inhibition in writer's cramp. This technique may therefore prove clinically useful for treating these patients. 28.7. Treatment of dystonia Anticholinergic agents such as trihexyphenidyl and GABA agonists like baclofen have been the mainstay for medical treatment of dystonia until botulinum toxin (BTX) injections revolutionized the therapy of focal dystonia. These agents are still used in conjunction with BTX injection with success. BTX injections are superior to phenol motor point injections because of their relatively selective action on muscle fibers with increased activities. For instance, twitching muscles are more sensitive to BTX than non-twitching ones in patients with hemifacial spasm, so that twitchings can be abolished without causing complete facial paralysis. This may be due to the fact that BTX is taken up more in active muscles. The precise mechanism of this selectivity is still unknown, but recent progress in the basic toxin research has revealed that type B toxin must recognize both ganglioside GTlb and synaptotagmin II for being internalized to the motor nerve ternimals (Fig. 7) (Nishiki et al., 1996; Kozaki et al.,

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A.

I

GTIb SynaplDIagmtn II

Ach

Fig. 7. An illustration to show the acceptors of botulinum toxin type B (GTI band synaptotagmin II) for internalization of the toxin. Synaptotagmin II are mainly located at the inner surface of synaptosomes.

1998). Because synaptotagmin II is normally present in the inner surface of the synaptic vesicle, BTX is selectively taken up into those terminals with active vesicle release, or those at the activated muscles. Another important mechanism of BTX in dystonia is through its effect on intrafusal as well as extrafusal muscle fibers. Rosales and colleagues (Rosales et aI., 1996) examined the effect of BTX injections into rat muscles. They compared intrafusal fibers innervated by gamma efferent to the muscle spindles with extrafusal fibers, and found that both fiber types showed atrophy to a similar extent. Hence BTX will affect muscle afferent actively. Gilio and colleagues (Gilio et aI., 2000) studied the effect of botulinum toxin type A on intracortical inhibition in patients with dystonia. They demonstrated that BTX transiently altered the excitability of the cortical motor areas possibly through its action on muscle afferents (Hallett, 2000). Likely by utilizing this phenomenon, blocking gamma efferent fibers with diluted lidocaine and ethanol has been used to block muscle afferents (muscle afferent block or MAB) to treat writer's cramp (Kaji et aI., 1995b, c), spasmodic torticollis (Kubori et aI., 2000), oromandibular dystonia (Yoshida et aI., 1998). The advantages of MAB over botulinum toxin injection are the lack of weakness because of the relative sparing of the extrafusal

fibers, and the low cost, although it requires repeated injection trials to obtain durable effects. A triaI of MAB for blepharospasm was unsuccessful, probably because of the lack of muscle spindles in the facial muscles. Another advance in the treatment of dystonia is stereotactic surgery. There is an increasing consensus that bilateral stimulation of the internal globus pallidus (GPi) with high frequencies is effective in generalized dystonia including those with DYTl gene mutation (Coubes et aI., 2000; Tronnier and Fogel, 2000; Vercueil et aI., 2001). Deep brain stimulation of GPi was also applied in treating other types of dystonia (Krauss et aI., 1999, 2002). Because the basic abnormality in dystonia is sensory-motor disintegration, it would be reasonable to use the sensory input appropriate for motor performance as a tool of training. In fact, Zeuner and colleagues (Zeuner et aI., 2002) were successful in treating patients with writer's cramp by training those patients with braille reading. Another approach is the limb immobilization with a cast for extended periods (Priori et aI., 2001). This could possibly break down abnormal sensory-motor link in hand dystonia.

28.8. Dystonia as a basal ganglia disorder There is now increasing awareness that dystonia is a basal ganglia disorder, because focal lesions in the basal ganglia or their connections produce hemidystonia including the hand on the contralateral side (Marsden et aI., 1985), and because trihexyphenidyl, an anticholinergic agent used in Parkinson's disease, is also effective in dystonia. The basal ganglia lie between the cerebral cortex and the thalamus, with which they have dense fiber connections forming 4-5 distinct circuits allowing parallel processing of information (Alexander and Crutcher, 1990). The most studied is the motor loop, which has direct and indirect pathways. The direct pathway disinhibits the powerful inhibition of GPiI substantia nigra pars reticulata upon thalamic ventrolateral nuclei (Vop) with a net facilitation on the motor cortex. By contrast, the indirect pathway exerts an inhibitory effect. This dual system provides a center (excitatory)-surround (inhibitory) mechanism to focus its effect on selected cortical neurons. Despite considerable knowledge of the chemical

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messengers in these projections, the functional role of the loop in motor control is not precisely understood. The sensory trick in dystonia highlights sensory aspects implicated in this basal ganglia disorder. Although the basal ganglia are commonly regarded as a center for motor control, its sensory role has been under-emphasized. Lenz and colleagues (Lenz et al., 1999) made intraoperative recordings in dystonia patients and showed that neurons in Vop discharge at peak EMG spectrum frequencies of dystonic contractions. They also found abnormal sensory units responding to more than one joint in Vim, the cerebellar relay nucleus of the thalamus. This enlarged receptive area in the thalamus is probably associated with the disorganized primary sensory cortex in dystonia (Bara-Jimenez et al., 1998). Lenz and colleagues also demonstrated the lack of correlation between the discharge of jointsensitive Vim neurons and EMG of its effector muscles, suggesting a mismatch between the proprioceptive input and the effector muscle to be controlled. Physiological studies in the monkey showed that numerous neurons in the supplementary motor or premotor cortex and the basal ganglia discharge in response to a sensory cue long before the movement onset (Romo et al., 1993). However, the exact pathway through which the sensory input reaches the basal ganglia remains elusive. Animal studies indicate that sensory inputs reaching the basal ganglia significantly differ from those in the lemniscal system in that they show encoding of information that appeared to be relevant for motor control (Lidsky et aI., 1985). Indeed the basal ganglia appear to 'gate' sensory inputs at various levels (Schneider et aI., 1986; Tinazzi et aI., 2000). Stimulation of the basal ganglia inhibits auditory and visual cortical evoked responses. Lemniscal and extraleminiscal components of the somatosensory system are modified by the basal ganglia. For example, the sensory responsiveness of second order neurons in the trigeminal sensory nucleus is altered by activation of the caudate nucleus or the globus pallidus. Such gating of sensory input is known to use the centersurround inhibition mechanism. All these pieces of evidence tempt us to speculate that dystonia is a disorder of a frequently used motor program or subroutine, in which motor output is matched to a fixed sensory input (Kaji et aI., 1995d).

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Probably this motor subroutine is stored as connectivities in the motor loop. If the center-surround inhibitory mechanism in the motor loop is disrupted, the lack of inhibition of antagonist or surrounding muscles causes co-contraction or overflow phenomena. 28.9. Conclusion

Lesions of the basal ganglia mostly affect automatic movements that need sensory guidance. It is therefore likely that the basal ganglia control automatic or highly trained movements in relation to relevant sensory inputs. Tasks impaired in writer's cramp or other dystonias could be among these. Indeed most of recent works in the physiology of dystonia converge upon disturbed sensory-motor integration and the lack of inhibitory motor control. If extraneous sensory input is fed back for subsequent movement, the mismatch would set up a vicious cycle causing further delapidation of motor control, resulting in dystonic movements. References Alexander, GE and Crutcher, MD (1990) Functional architecture of basal ganglia circuits: neural substrates of parallel processing. Trends Neurosci., 13(7): 266271. Bara-Jimenez, W, Catalan, MJ, Hallett, M and Gerloff, C (1998) Abnormal somatosensory homunculus in dystonia of the hand. Ann. Neurol., 44(5): 828-831. Bara-Jimenez, W, Shelton, P and Hallett, M (2000a) Spatial discrimination is abnormal in focal hand dystonia. Neurology, 55(12): 1869-1873. Bara-Jimenez, W, Shelton, P, Sanger, TD and Hallett, M (2000b) Sensory discrimination capabilities in patients with focal hand dystonia. Ann. Neurol., 47(3): 377380. Berardelli, A, Rothwell, JC, Day, BL and Marsden, CD (1985) Pathophysiology of blepharospasm and oromandibular dystonia. Brain, 108(3): 593-608. Byl, NN, Merzenich, MM and Jenkins, WM (1996) A primate genesis model of focal dystonia and repetitive strain injury: 1. Learning-induced dedifferentiation of the representation of the hand in the primary somatosensory cortex in adult monkeys. Neurology, 47(2): 508-520. Chen, R, Wassermann, EM, Canos, M and Hallett, M (1997) Impaired inhibition in writer's cramp during voluntary muscle activation. Neurology, 49(4): 1054-1059.

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Coubes, P, Roubertie, A, Vayssiere, N, Hemm, S and Echenne, B (2000) Treatment of DYTl-generalized dystonia by stimulation of the internal globus pallidus. Lancet, 355(9222): 2220--2221. Denny-Brown, D (1965) The nature of dystonia. Bull. NY Acad. Med., 41: 858-869. Denny-Brown, DE, Gilman, S and Van der Meulen, J (1964) Patterns of cortical ablations leading to dystonic postures. Trans. Am. Neurol. Assoc., 89: 117-121. Destarac (1901) Torticolis spasmodique et spasmes functionels. Rev. Neurol., 9: 591-597. Deuschl, G, Toro, C, Matsumoto, J and Hallett, M (1995) Movement-related cortical potentials in writer's cramp. Ann. Neurol., 38(6): 862-868. Fahn, S (1988) Concepts and classification of dystonia. Adv. Neurol., 50: 1-8. Frasson, E, Priori, A, Bertolasi, L, Mauguiere, F, Fiaschi, A and Tinazzi, M (2001) Somatosensory disinhibition in dystonia. Mov. Disord., 16(4): 674-682. Gilio, F, Curra, A, Lorenzano, C, Modugno, N, Manfredi, M and Berardelli, A (2000) Effects of botulinum toxin type A on intracortical inhibition in patients with dystonia. Ann. Neurol., 48(1): 20--26. Gilman, S, Vilensky, JA, Morecraft, RW and Cook, JA (1999) Denny-Brown's views on the pathophysiology of dystonia. J. Neurol. Sci., 167(2): 142-147. Greenberg, BD, Ziemann, D, Cora-Locatelli, G, Harmon, A, Murphy, DL, Keel, JC et al. (2000) Altered cortical excitability in obsessive-compulsive disorder. Neurology, 54(1): 142-147. Grunewald, RA, Yoneda, Y, Shipman, JM and Sagar, HJ (1997) Idiopathic focal dystonia: a disorder of muscle spindle afferent processing? Brain, 120(12): 21792185. Hallett, M (1995) Is dystonia a sensory disorder? Ann. Neurol., 38(2): 139-140. Hallett, M (2000) How does botulinum toxin work? Ann. Neurol., 48(1): 7-8. Hamano, T, Kaji, R, Katayama, M, Kubori, T, Ikeda, A and Shibasaki, H et al. (1999) Abnormal contingent negative variation in writer's cramp. Clin. Neurophysiol., 110(3): 508-515. Hummel, F, Andres, F, Altenmuller, E, Dichgans, J and Gerloff, C (2002) Inhibitory control of acquired motor programs in the human brain. Brain, 125(2): 404-420. Ikoma, K, Samii, A, Mercuri, B, Wassermann, EM and Hallett, M (1996) Abnormal cortical motor excitability in dystonia. Neurology, 46(5): 1371-1376. Jankovic, J (1994) Post-traumatic movement disorders: central and peripheral mechanisms. Neurology, 44(11): 2006-2014. Kaji, R, Ikeda, A, Ikeda, T, Kubori, T, Mezaki, T, Kohara, N et al. (1995a) Physiological study of

459 cervical dystonia. Task-specific abnormality in contingent negative variation. Brain, 118(2): 511-522. Kaji, R, Kohara, N, Katayama, M, Kubori, T, Mezaki, T, Shibasaki, H et al. (l995b) Muscle afferent block by intramuscular injection of lidocaine for the treatment of writer's cramp. Muscle Nerve, 18(2): 234-235. Kaji, R, Rothwell, JC, Katayama, M, Ikeda, T, Kubori, T, Kohara, N et al. (l995c) Tonic vibration reflex and muscle afferent block in writer's cramp. Ann. Neurol., 38(2): 155-162. Kaji, R, Shibasaki, H and Kimura, J (l995d) Writer's cramp: a disorder of motor subroutine? Ann. Neurol., 38(6): 837-838. Kaji, R, Katayama-Hirota, M, Kohara, N, Kojima,Y,Yang, Q and Kimura, J (1999) Blepharospasm induced by an LED flashlight. Mov. Disord., 14(6): 1045-1047. Katayama, M, Kohara, N, Kaji, R, Kojima,Y, Shibasaki, H and Kimura, J (1996) Effect of photic conditioning on blink reflex recovery function in blepharospasm. Electroencephalogr. Clin. Neurophysiol., 101(5): 446-452. Kozaki, S, Kamata, Y,Watarai, S, Nishiki, T and Mochida, S (1998) Ganglioside GTlb as a complementary receptor component for Clostridium botulinum neurotoxins. Microb. Pathog., 25(2): 91-99. Krauss, JK, Pohle, T, Weber, S, Ozdoba, C and Burgunder, 1M (1999) Bilateral stimulation of globus pallidus internus for treatment of cervical dystonia. Lancet, 354(9181): 837-838. Krauss, JK, Loher, rr. Pohle, T, Weber, S, Taub, E, Barlocher, CB et al. (2002) Pallidal deep brain stimulation in patients with cervical dystonia and severe cervical dyskinesias with cervical myelopathy. J. Neurol. Neurosurg. Psychiatry, 72(2): 249-256. Kubori, T, Kaji, R, Mezaki, T et al. (2000) Muscle afferent block for cervical dystonia:a controlled trial with botulinum toxin. Neurology, 54: 198-199. Kubota, Y, Murai, T, Okada, T, Hayashi, A, Toichi, M and Sakihama, M et al. (2001) Obsessive-compulsive characteristics in patients with writer's cramp. J. Neurol. Neurosurg. Psychiatry, 71(3): 413-414. Lenz, FA, Jaeger, CJ, Seike, MS, Lin, YC, Reich, SG, DeLong, MR et al. (1999) Thalamic single neuron activity in patients with dystonia: dystonia-related activity and somatic sensory reorganization. J. Neurophysiol., 82(5): 2372-2392. Levy, LM and Hallett, M (2002) Impaired brain GABA in focal dystonia. Ann. Neurol., 51(1): 93-101. Lidsky, TI, Manetto, C and Schneider, JS (1985) A consideration of sensory factors involved in motor functions ofthe basal ganglia. Brain Res., 356(2): 133146. Lorenzano, C, Priori, MA, Curra, A, Gilio, F, Manfredi, M and Berardelli, A (2000) Impaired EMG inhibition

460 elicited by tendon stimulation in dystonia. Neurology, 55(12): 1789-1793. Marsden, CD (1976) Blepharospasm-oromandibular dystonia syndrome (Brueghel's syndrome). A variant of adult-onset torsion dystonia? J. Neurol. Neurosurg. Psychiatry, 39(12): 1204-1209. Marsden, CD, Obeso, JA, Zarranz, JJ and Lang, AE (1985) The anatomical basis of symptomatic hemidystonia. Brain, 108(2): 463-483. Meunier, S, Garnero, L, Ducorps, A, Mazieres, L, Lehericy, S, du Montcel, ST et al. (2001) Human brain mapping in dystonia reveals both endophenotypic traits and adaptive reorganization. Ann. Neurol., 50(4): 521527. Murase, N, Kaji, R, Shimazu, H, Katayama-Hirota, M, Ikeda, A, Kohara, N et al. (2000) Abnormal premovement gating of somatosensory input in writer's cramp. Brain, 123(9): 1813-1829. Nakashima, K, Rothwell, JC, Day, BL, Thompson, PD, Shannon, K and Marsden, CD (1989) Reciprocal inhibition between forearm muscles in patients with writer's cramp and other occupational cramps, symptomatic hemidystonia and hemiparesis due to stroke. Brain, 112(3): 681-697. Nishiki, T, Tokuyama,Y, Kamata, Y, Nemoto, Y,Yoshida, A, Sato, K et al. (1996) The high-affinity binding of Clostridium botulinum type B neurotoxin to synaptotagmin II associated with gangliosides GTlb/GDla. FEBS Lett., 378(3): 253-257. Oppenheim, H (1911) Uber eine eigenartige Kampfkrankheit des kindlichen und jugendlichen Alters (Dysbasia lordotica progressiva, Dystonia musculorum deformans). Neurol. Zentbl., 30: 1090-1107. Priori, A, Pesenti, A, Cappellari, A, Scarlato, G and Barbieri, S (2001) Limb immobilization for the treatment of focal occupational dystonia. Neurology, 57(3): 405-409. Ridding, MC, Sheean, G, Rothwell, JC, Inzelberg, Rand Kujirai, T (1995) Changes in the balance between motor cortical excitation and inhibition in focal, task specific dystonia. J. Neurol. Neurosurg. Psychiatry, 59(5): 493-498. Romo, R, Ruiz, S, Crespo, P, Zainos, A and Merchant, H (1993) Representation of tactile signals in primate supplementary motor area. J. Neurophysiol., 70(6): 2690-2694. Rosales, RL, Arimura, K, Takenaga, S and Osame, M (1996) Extrafusal and intrafusal muscle effects in experimental botulinum toxin-A injection. Muscle Nerve, 19(4): 488-496. Rosenkranz, K, Altenmuller, E, Siggelkow, S and Dengler, R (2000) Alteration of sensorimotor integration in

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musician's cramp: impaired focusing of proprioception. CUn. Neurophysiol., 111(11): 2040-2045. Rothwell, J, Obeso, J, Day, B and Marsden, C (1983) Pathophysiology of dystonia. Adv. Neurol., 39: 851863. Schneider, JS, Diamond, SG and Markham, CH (1986) Deficits in orofacial sensorimotor function in Parkinson's disease. Ann. Neurol., 19(3): 275-282. Serrien, DJ, Burgunder, JM and Wiesendanger, M (2000) Disturbed sensorimotor processing during control of precision grip in patients with writer's cramp. Mov. Disord., 15(5): 965-972. Sheehy, MP and Marsden, CD (1982) Writers' cramp - a focal dystonia. Brain, 105(3): 461-480. Siebner, HR, Dressnandt, J, Auer, C and Conrad, B (1998) Continuous intrathecal baclofen infusions induced a marked increase of the transcranially evoked silent period in a patient with generalized dystonia. Muscle Nerve, 21(9): 1209-1212. Siebner, HR, Tormos, JM, Ceballos-Baumann, AO, Auer, C, Catala, MD, Conrad, B et al. (1999) Low-frequency repetitive transcranial magnetic stimulation of the motor cortex in writer's cramp. Neurology, 52(3): 529-537. Tempel, LW and Perlmutter, JS (1990) Abnormal vibration-induced cerebral blood flow responses in idiopathic dystonia. Brain, I 13(Pt 3): 691-707. Tempel, LW and Perlmutter, JS (1993) Abnormal cortical responses in patients with writer's cramp. Neurology, 43(11): 2252-2257. Tinazzi, M, Priori, A, Bertolasi, L, Frasson, E, Mauguiere, F and Fiaschi, A (2000) Abnormal central integration of a dual somatosensory input in dystonia. Evidence for sensory overflow. Brain, 123(1): 42-50. Topp, KS and Byl, NN (1999) Movement dysfunction following repetitive hand opening and closing: anatomical analysis in Owl monkeys. Mov. Disord., 14(2): 295-306. Toro, C, Deuschl, G and Hallett, M (2000) Movementrelated electroencephalographic desynchronization in patients with hand cramps: evidence for motor cortical involvement in focal dystonia. Ann. Neurol., 47(4): 456-461. Tronnier, VM and Fogel, W (2000) Pallidal stimulation for generalized dystonia. Report of three cases. J. Neurosurg., 92(3): 453-456. Vercueil, L, Pollak, P, Fraix, V, Caputo, E, Moro, E, Benazzouz, A et al. (200 I) Deep brain stimulation in the treatment of severe dystonia. J. Neurol., 248(8): 695-700. Wilks S (1878) Lectures on diseases of the nervous system. London, Churchill.

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Yanagisawa, Nand Goto, A (1971) Dystonia musculorurn deformans. Analysis with electromyography. J. Neurol. Sci., 13(1): 39-65. Yazawa, S, Ikeda, A, Kaji, R, Terada, K, Nagamine, T, Toma, K et al. (1999) Abnormal cortical processing of voluntary muscle relaxation in patients with focal hand dystonia studied by movement-related potentials. Brain, 122(7): 1357-1366.

461 Yoshida, K, Kaji, R, Kubori, T, Kohara, N, Iizuka, T and Kimura, J (1998) Muscle afferent block for the treatment of oromandibular dystonia. Mov. Disord., 13(4): 699-705. Zeuner, KE, Bara-Jimenez, W, Noguchi, PS, Goldstein, SR, Dambrosia, JM and Hallett, M (2002) Sensory training for patients with focal hand dystonia. Ann. Neurol., 51(5): 593-598.

Movement Disorders Handbook of Clinical Neurophysiology, Vol. 1 M. Hallett (Ed.) © 2003 Elsevier B.V. All rightsreserved

463 CHAPfER29

Stiffness with continuous motor unit activity P. Brown* Sobell Department of Motor Neuroscience and Movement Disorders, Institute of Neurology, London WCI N 3BG, UK

29.1. Introduction

Table 2

Stiffness is a common feature of many disorders of the motor system. However, only rarely does it persist, regardless of relaxation or change in posture, as evidenced by continuous motor unit activity (CMUA) on EMG. Although rare, causes are varied and can involve central and peripheral conditions. Table I summarizes those features helpful in separating peripheral and central causes of stiffness in the presence of CMUA.

Central causes of stiffness with CMUA. Stiff person syndrome I Stiff person plus syndromes' I. Subacute': 'Progressive encephalomyelitis with rigidity' 2. Chronic": Brainstem form - Includes the 'jerking stiff man syndrome' Spinal form 'Stiff limb syndrome' Focal lesions of the spinal cord Intrinsic neoplasms Syringomyelia Traumatic Vascular Paraneoplastic segmental myelitis

29.2. Central stiffness with CMUA

The central causes of stiffness with CMUA are summarized in Table 2.

Infective/toxic causes Acute poliomyelitis Borreliosis Encephalomyelitis lethargica Acute or chronic tetanus Strychnine

Table I Features distinguishing central and peripheral causes of stiffness with CMUA. Central

Peripheral

++ ++

+/-

See Table 3 for clinicalfeatures. See Table 4 for clinicalfeatures. 3 Death within 3 years. Long tract signs present. 4 Survive > 3 years. Long tract signs absent/few. I

Spasm painful Reflex exacerbations Clinical myokymia! fasciculations Abnormal exteroceptive reflexes EMG evidence of neuromyotonia

++ ++ ++

* Correspondence to: Dr. P. Brown, Sobell Department of Neurophysiology, Institute of Neurology, Queen Square, London WCIN 3BG, UK. E-mail address:[email protected] Tel.: 0207 829 9836; fax: 020 7278 9836.

2

29.2.1. Tetanus

Tetanus is suggested by the classical symptoms of trismus, dysphagia and muscular rigidity (Habermann, 1978). The peripheral silent period is abnormal in contrast to the stiff person syndrome. Treatment consists of wound management, neutralization of tetanus toxin by immunoglobulins, antibiotics, treatment of muscle spasm and instability of the autonomic nervous system, and supportive care. Acute tetanus may be mimicked by strychnine poisoning (Hardin and Griggs, 1971).

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29.2.2. Focal spinal cord pathology

Focal spinal cord pathology that preferentially involves the grey matter may cause stiffness, sometimes termed alpha rigidity in the literature, based on the hypothesis that it may arise from loss of inhibitory interneuronal inputs to alpha motoneurons (Gelfan and Tarlov, 1959, 1963). Intrinsic tumors (Rushworth et al., 1961; Lourie, 1968), syringomyelia (Tarlov, 1967), vascular insufficiency (Davis et al., 1987) and paraneoplastic myelitis (Roobol et al., 1987) may be associated with stiffness, postural abnormality, CMUA, and reflex and action induced spasms of the trunk and limbs (Fig. 1). There may be additional wasting, weakness, absence of tendon reflexes and signs of denervation upon EMG in the affected myotomes. The relatively selective destruction of spinal intemeurons in some of these patients has been confirmed histologically (Rushworth et al., 1961). Effective stimuli need not be restricted to somesthetic stimulation below the level of the spinal cord pathology. Paradoxically, jerks and spasms of the legs can be precipitated in patients with spinal lesions by startle inducing stimuli, including sounds (Sikes et al., 1959; Davis et al., 1987). Presumably this represents an excessive response at the segmental level to descending reticulospinal activity. 29.2.3. Stiffperson syndrome

The term stiff man or stiff person syndrome was first introduced by Moersch and Woltman in 1956 in their original description of axial rigidity and spasm, often in association with diabetes mellitus. Histology was unremarkable in the one case that came to post-mortem. Since then a number of cases have been reported, some very similar to those of Moersch and Woltman, but others atypical in that additional signs or limb involvement were found that were absent in the original report. Some of these atypical cases have had evidence of a polio encephalomyelitis at post-mortem. It is debatable whether these cases form a continuum with the classical stiff person syndrome or whether the classical axial stiff person syndrome forms a discrete entity with atypical cases resulting from other pathologies with differing features and prognosis. The limited histology available would support the latter view and this is the one taken here.

Fig. 1. Abnormal fixed posture of arms and shoulder girdle due to rigidity with CMUA in a man with a cervical astrocytoma. Reprinted with permission from Rushworth et al. (1961).

29.2.3.1. Cases without encephalomyelitis: the classical stiffperson syndrome The classical stiff person syndrome, as described by Moersch and Woltman (1956) is characterized by paraspinal and abdominal rigidity with an exaggerated lumbar lordosis, and superimposed spasms precipitated by movement, emotional upset, peripheral stimulation or auditory startle (Fig. 2). The proximal legs are involved in some cases, but this is often only apparent on walking when the patient has a stiff wooden gait. The calf and foot muscles are rarely, if ever, involved (Moersch and Woltman,

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Fig. 2. Abnormally excessive activity of the paraspinal muscles causing folding of the skin and lumbar hyperlordosis in a patient with anti-GAD antibody positive classical axial stiff person syndrome.

1956; Spehlmann and Norcross, 1979; Lorish et al., 1989). There is no weakness, sensory loss, sphincter involvement or clinical evidence of brainstem disturbance. Diagnostic criteria for the stiff person syndrome have been adapted from those of Lorish et al. (1989) and are summarized in Table 3. Cases defined in this way respond to diazepam and baclofen and have a good prognosis. For example, Lorish et al. (1989) followed up 12 patients over a mean of nine years, all of whom remained ambulant until last seen, and experience has been similar in a recent series (Barker et aI., 1998). Up to 70% of such selected patients are diabetic (Lorish et aI., 1989) and 90%

have antibodies against the GABA-synthesizing enzyme glutamic acid decarboxylase (GAD), usually in very high titer (Barker et aI., 1998); further evidence that the general criteria of Lorish et al. (1989) can identify a disease that is fairly homogenous in both clinical and immunological terms. Nevertheless, it is clear that anti-GAD antibodies are not exclusive to the stiff person syndrome, in the same way as rheumatoid factor is not exclusively seen in rheumatoid arthritis (Nemni et aI., 1994; Saiz et aI., 1997). Apart from diabetes and anti-GAD antibodies a number of other auto-immune diseases and organ specific antibodies are commonly found in the classical stiff person syndrome, such as thyroid

466 Table 3 Criteria for the diagnosis of the classical stiff person syndrome*. I. Stiffness and rigidity in axial muscles (proximal limb muscles may also be sometimes involved). 2. Abnormal axial posture (usually an exaggeration of the normal lumbar lordosis). 3. Superimposed spasms precipitated by voluntary movement, emotional upsets and unexpected auditory and somesthetic stimuli. 4. Absence of brainstem, pyramidal, extrapyramidal and lower motor neuron signs, sphincter and sensory disturbance, and cognitive involvement.** 5. CMUA in at least one axial muscle.

* Adapted from Lorish et al. (1989). They also considered a positive response to intravenous or oral diazepam a necessary prerequisite for the diagnosis of the stiff man syndrome. ** Epilepsy may occur. disease and thyroid antibodies and pernicious anemia and antibodies to intrisic factor and gastric parietal cells. The cerebrospinal fluid may contain bands of oligoclonal IgG, but the cell count is not elevated. The pathophysiology of the stiff man syndrome remains uncertain. Moersch and Woltman found no significant pathological changes at post-mortem. This finding has since been confirmed (Trethowan et aI., 1960; Martinelli et aI., 1978), with one exception, which suggested loss of GABAergic cells in the cerebellar cortex (Warich-Kirches et al., 1997). An immune etiology seems likely in view of the autoantibody profile of many of the patients (Solimena et aI., 1990). More specifically, Guilleminault et aI. (1973) have suggested a functional imbalance between descending aminergic, possibly reticulospinal, projections to the cord, facilitating flexor reflex pathways, and inhibitory GABAergic systems. This idea receives some support from the widespread enhancement of exteroceptive reflexes, including blink reflexes (Meinck et aI., 1984), and from pharmacological studies (Guilleminault et aI., 1973; Meinck et aI., 1984). The common presence of antibodies against the GABA synthetic enzyme GAD would also be consistent with this hypothesis, although the pathogenic importance of these antibodies remains unclear, as Purkinje cells, known to contain high amounts of GAD, may be unaffected (Ishzawa et aI., 1999) and high titers of the antibody

P. BROWN

are being recognized in other conditions, particularly cerebellar ataxia (Saiz et aI., 1997). 29.2.3.2. Cases with encephalomyelitis: stiffperson plus syndromes Several cases of stiff people have now been reported with a recognizable, fairly uniform, pathology, that varies in severity (Campbell and Garland, 1956; Kasperek and Zebrowski, 1971; Lhermitte et al., 1973; Whitely et aI., 1976; Howell et aI., 1979; Fenzi et aI., 1988; Batemen et aI., 1990; Meinck et al., 1994; Armon et al., 1996; Barker et aI., 1998). This consists of a subacute or chronic encephalomyelitis with prominent involvement of the gray matter (polioencephalomyelitis). The spinal cord and brainstem are most severely affected. Hemispheric structures are relatively spared, with the frequent exception of the limbic areas. The additional clinical features associated with this pathology are listed in Table 4, and can be usefully thought of as findings suggestive of the stiff man plus syndromes. Perhaps the core feature is that rigidity is not confined to the trunk, but also involves the distal limb, often exclusively. It seems likely that the pathological changes described in the stiff man plus syndromes directly account for the curious rigidity. Similar preferential involvement of the gray matter of the spinal cord is seen in dogs with experimentally induced ischemic damage to the cord. These animals develop a form of Table 4 Clinical features in stiff people with histological evidence of a polioencephalomyelitis*. I. Rigidity and abnormal posturing of one or more limbs, that includes the hand or foot 2. Myoclonus involving all four limbs 3. Brainstem signs 4. Long tract signs 5. Lower motor neuron signs 6. Cognitive changes, especially memory impairment 7. Autononic involvement 8. CSF pleocytosis

* Subacute or chronic encephalomyelitis which predominantly affects gray matter. Findings drawn from Campbell and Garland, 1956; Kasperek and Zebrowski, 1971; Lhermitte et al., 1973; Whitely et al., 1976; Howell et al., 1979; Fenzi et aI., 1988; Batemen et aI., 1990; Meinck et al., 1994; Armon et al., 1996; Barker et aI., 1998.

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rigidity, termed alpha rigidity, that is due to the isolation of motoneurons from the action of spinal inhibitory interneurons (Gelfan and Tarlov, 1959, 1963). The selective loss of spinal interneurons has been confirmed in progressive encephalomyelitis with rigidity (Howell et al., 1979).

encephalomyelitis with rigidity (Fenzi et aI., 1988). A comparable situation exists in other 'paraneoplastic conditions'; most cases are rapidly progressive, but occasional patients are seen that survive many years without the appearance of malignancy, raising the possibility that similar pathology may be triggered by both tumor and autoimmune diathesis (Nemni et aI., 1993). Certainly, one case of jerking stiff man syndrome has been reported in whom antiacetylcholine receptor, antinuclear, gastric parietal, thyroid microsomal, thyroglobulin and anti-GAD antibodies were positive (Bum et aI., 1991), and striking therapeutic success has been achieved with plasmapheresis and immunosuppression (Fogan, 1996). The remaining chronic cases have delayed and mild, or no signs of brainstem dysfunction, and do not develop generalized myoclonus. Instead, the clinical picture is dominated by rigidity, postural abnormality and painful spasms of the limbs, especially distally. The legs are most commonly involved and there is a relative or total sparing of the trunk. As such the condition was initially termed the stiff leg or limb syndrome (Brown et aI., 1997). Others have suggested the term focal stiff-man syndrome on the basis that some have antibodies to GAD (Saiz et aI., 1998). However, publication of reports of single cases or short series may tend to positively discriminate against cases without GAD antibodies, where the diagnosis may be seen as less certain. In a recent large series anti-GAD antibody positive patients represented only 15% of cases of stiff limb syndrome (Barker et al., 1998). Indeed, the available, but limited, histology would be more in keeping with the other stiff man plus syndromes (see below). We prefer the term stiff limb syndrome as the upper limbs may occasionally be involved (Fig. 3), and no pathological relationship with the classical stiff man syndrome is implied. The EMG activity recorded in the limb spasms has an unusual segmented appearance in three quarters of such patients (Brown et aI., 1997; Barker et aI., 1998), distinct from the normal looking interference pattern recorded in the spasms of the stiff man syndrome (Moersch and Woltman, 1956). The segmented EMG is due to the abnormally synchronous discharge of motor units (Fig. 4). To date, pathology has only been reported in one case, in whom there were striking changes in the lumbar spinal cord, consisting of perivascular cuff-

29.2.3.3. Three types of stiffperson plus syndromes The clinical features listed in Table 4 are found in three related syndromes, that vary in the severity and distribution of pathology. The first of these stiff man plus syndromes is subacute, and has generally been termed progressive encephalomyelitis with rigidity. Histologically, it may differ from more indolent cases in the presence of demyelination. The latter characteristically spares the corticospinal tracts (Kasperek and Zebrowski, 1971; Whitely et aI., 1976; Howell et al., 1979). Clinically, the condition is characterized by widespread rigidity, painful myoclonus and spasms, and long tract and brainstem signs (Campbell and Garland, 1956; Kasperek and Zebrowski, 1971; Lhermitte et al., 1973; Whitely et al., 1976; Howell et aI., 1979). Patients survive less than three years, regardless of treatment. The relentless progression and the histology suggest a paraneoplastic etiology, and this has been confirmed in occasional cases (Batemen et al., 1990). Some authors have also suggested a viral etiology, drawing parallels with the spinal form of encephalitis lethargica (Howell et al., 1979). The remaining stiff man plus syndromes are chronic and, unlike progressive encephalomyelitis with rigidity, are remarkable for the relative absence of long tract signs, despite florid rigidity. These cases are further classified according to whether or not the clinical picture is dominated by brain stem signs. The most striking of the latter is a brainstem myoclonus that involves all four limbs, and has given rise to the term jerking stiff man syndrome (Leigh et aI., 1980). The jerks may occur in paroxysms which compromise respiration and may be fatal (Fenzi et aI., 1988). Tracheostomy and assisted ventilation may be necessary before the jerks respond to clonazepam and other antimyoclonic agents (Kullmann et aI., 1996). With this proviso, patients with the jerking stiff man syndrome may survive 10 years or more (Leigh et aI., 1980). The latter makes a paraneoplastic etiology seem unlikely, despite the fact that the basic pathological findings are similar to those found in progressive

468

P. BROWN

Fig. 3. Abnormal hand posture due to rigidity with CMUA in an anti-GAD antibody negative patient with the stiff limb variant of the stiff person syndrome.

ing, dense inflammatory infiltration of the anterior horns and diffuse astrocytosis of the surrounding gray matter (Armon et al., 1996). In addition, there was a much less marked infiltrate of the anterior horns at the cervical level, and mild perivascular cuffing in the rest of the cord, brains tern, thalamus, hippocampus and amygdala. The long tracts were spared. These findings are consistent with the idea that the stiff limb syndrome is due to pathology of the gray matter concentrated at the spinal cord level rather than the brainstem (Brown et al., 1997), a contention supported by the fact that a very similar clinical picture may arise from focal lesions that involve the central cord. The duration of the stiff limb syndrome is often measured in decades, with approximately half of cases becoming wheelchair bound (Barker et aI., 1998). Three quarters have relapses and remissions, and many have auto-antibodies, raising the possibil-

ity of an autoimmune etiology (Barker et al., 1998). Nevertheless, the autoimmune profile in these patients is reasonably distinct from that in the stiff man syndrome. Diabetes mellitus is not a feature, positive rheumatoid factor is common, and antiGAD antibodies are only found in 15% (Barker et al., 1998). Occasionally, rigidity of the limbs (sometimes with later spread to the trunk) is seen in the setting of breast or small-cell lung carcinoma. Such patients often have antibodies against the presynaptic vesicle associated 128-kD protein amphiphysin, which may have a role in synaptic vesicle endocytosis and is expresssed in breast and small-cell lung cancer tissue (De Camilli et al., 1993; Folli et aI., 1993; Dropcho, 1996). More rarely patients with tumors and rigidity may have antibodies against GAD (Silverman, 1999) or gephyrin, a cytosolic protein selectively concentrated at the postsynaptic mem-

469

STIFFNESS WITH CONTINUOUS MOTOR UNIT ACTIVITY STIFF MAN SYNDROME

STIFF LIMB SYNDROME

Fig. 4. Surface EMG recordings during spontaneous spasms in the stiff person syndrome. Left: Patient with classical axial rigidity and positive anti-GAD antibodies. Note spasm EMG is indistinguishable from that recorded in voluntary contraction. Right: Patient with rigidity of the distal lower limbs who was anti-GAD antibody negative. Spasm is confined to lower limbs and in the left (L) tibialis anterior tends to segment into large, but brief discharges. ECG artefact is arrowed. Vertical calibration is 100 f.L V and 500 f.L V for the lower and upper 4 channels respectively. Reprinted with permission from Barker et al. (1998).

brane of inhibitory synapses (Butler et al., 2000). Rarely, Borrelia burgdorferi myelitis can cause stiffness with CMUA (Martin et al., 1990). 29.2.4. Treatment of central stiffness with CMUA

Treatment of the cause, be it tetanus, focal cord pathology or paraneoplastic myelitis, should be attempted whenever possible. Around half of the stiff people with anti-amphiphysin antibody improve with prednisolone and treatment of the underlying tumor (De Camilli et al., 1993; Folli et al., 1993; Dropcho, 1996). When symptomatic treatment is necessary then oral diazepam and baclofen are usually sufficient, albeit in relatively large and frequent doses. The response of those stiff person syndrome patients with distal limb involvement tends to be less satisfactory than in those with the classical axial distribution of stiffness (Barker et al., 1998). Clonazepam, valproate, vigabatrin, gabapentin and tizanidine may occasionally be helpful. Carbamazepine and phenytoin are unhelpful, in contrast to their beneficial effects in CMUA of peripheral nerve origin. Both stiff person syndrome and stiff person-plus syndromes have been successfully treated with intrathecal baclofen delivered by pump (Stayer et al., 1997). Sudden dosage reduction

through spasm-induced rupture of the catheter, catheter dislocation or pump malfunction may, however, be fatal. Only a minority of stiff person syndrome patients have refractory disease that needs immunomodulatory treatment. Steroids often in combination with plasma exchange have been reported to be beneficial in the stiff person syndrome (Fegan, 1996), although such treatment is by no means always successful (Harding et al., 1989). Many centers now use parenteral immunoglobulin therapy as the principal treatment for severe stiff person syndrome, and its use has been supported by a randomized placebo controlled trial in 16 patients with stiff person syndrome (Dalakas et al., 2001). Two single case reports have described clinical improvement with immunoglobulin in patients with progressive encephalomyelitis with rigidity (Dropcho, 1996; Molina et al., 2000) and one case report has described improvement with immunoglobulin in the stiff limb syndrome (Souza-Lima et al., 2000). 29.2.5. Differential diagnosis of central stiffness

Spasticity due to cerebral, brainstem or spinal pathology can usually be distinguished by the velocity dependence of resistance to passive stretch, and other clinical evidence of an upper motor neuron

470

syndrome. CMUA is absent, and central motor conduction times are delayed. However, diagnostic problems can arise in patients with focal cord pathology or encephalomyelitis with rigidity, in whom tone increases often consist of a combination of stiffness with CMUA and spasticity. The rigidity seen in parkinsonism is usually readily distinguished by the presence of other clinical signs, such as bradykinesia, tremor and supranuclear ophthalmoplegia. There are, however, two extrapyramidal syndromes that can cause difficulties. The first is the neuroleptic malignant syndrome, a subacute illness characterized by generalized rigidity, autonomic dysfunction that typically follows the use of major tranquilizers or sudden withdrawal of dopaminergic treatment. It is the drug history that therefore distinguishes this from a subacute encephalomyelitis with rigidity. Second is corticobasal degeneration, which can be difficult to distinguish from the distal variant of the stiff person syndrome. Corticobasal degeneration often starts as painful rigidity in the foot and may show reflex and action induced spasm and jerks. In time, however, patients develop supranuclear ophthalmoplegias and cortical phenomena such as sensory inattention, dyspraxia and alien limb behavior. Dystonia may cause stiffness and spasm, but without the reflex spasms that characterize the stiff person syndrome. Tardive dystonia, following exposure to neuroleptics and other drugs, may often involve the axial muscles, raising the posssibility of axial stiff person syndrome. However, pain is not a prominent feature, spasm resolves in the supine position or with relaxation and there is no true CMUA. On the other hand post-traumatic dystonia is often fixed and peripheral, leading to confusion with the distal variant of the stiff person syndrome. Cases with post-traumatic dystonia are often associated with complex regional pain syndromes and have no reflex spasms. Severe rigidity may be a feature of catatonia, usually in the setting of mutism and waxy flexibility. It may complicate schizophrenia, affective disorders or occur secondary to brain pathology such as central pontine and extrapontine myelinolysis. Finally, stiffness similar to that seen in the stiff person syndrome can be psychogenic. Clinical features suggestive, but not diagnostic, of a psychogenic origin are the sudden onset, the lessening of spasm and postural abnormality when distracted

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and, conversely, a dramatic increase in severity during direct observation, settling again when no longer under direct observation. More convincing is the disappearance of the movement disorder when supposedly unobserved or following suggestion and placebo. Nevertheless, the diagnosis is a notoriously difficult one. The typical indicators of a conversion disorder, such as psychological precipitants, multiple somatizations and secondary gain mayor may not be present. Psychological factors are only discovered in a third of patients with somatization in general neurological practice (Mace and Trimble, 1991), and are, of course, not limited to those with psychogenic disease. Moreover, the distinction between primary psychological factors and those secondary or consequent to illness can be difficult.

29.3. Peripheral stiffness with CMUA 29.3.1. Neuromyotonia As stressed by Thompson (1994), this area has become confusing as terms used for electromyographic descriptions are often used to refer to clinical phenomena. Perhaps this could be resolved by the use of the qualifying terms clinical and discharge. Thus, clinical myokymia consists of the wave-like rippling of muscle, whereas myokymic discharge describes the finding of regular motor unit discharges. Usually the discharge is a brief, repetitive firing of single units at 2-60 Hz for a short period, repeated in the same sequence after a few seconds or so. Doublets or triplets are typical. Less commonly, the potential recurs continuously at a fairly uniform rate (1-5 Hz). Clinical neuromyotonia is the combination of clinical myokymia with delayed muscle contraction, whereas neuromyotonic discharge consists of bursts of motor unit action potentials at high frequency for a few seconds. Although the amplitude of the response typically wanes, the frequency is maintained unlike myotonic discharges. Neuromyotonic discharges may be spontaneous or follow needle insertion, voluntary contraction or ischemia or percussion of a nerve. Clinical neuromyotonia (Isaacs' syndrome) is a rare and heterogeneous syndrome of CMUA of peripheral nerve origin (Fig. 5). It manifests as various combinations of muscle stiffness, cramps, twitching, weakness and delayed muscle relaxation (Isaacs, 1961; Isaacs and Heffron, 1974). Unlike the stiff person syndrome, sleep and general anesthesia

STIFFNESS WITH CONTINUOUS MOTOR UNIT ACTIVITY

471

Fig. 6. Distal muscle wasting in a patient with neuromyotonia and peripheral neuropathy. Reprinted with permission from Lance et al. (1979).

Fig. 5. A boy with neuromyotonia (Isaac's syndrome) showing stiff posture and excessive muscular contraction, especially evidentin trapezius. Reprinted with permission from Isaac (1961). do not abolish motor hyperactivity in neuromyotonia (although muscle activity is eliminated by neuromuscular blockade). Neuromyotonia may be seen in the setting of inherited disease, where patients may or may not have clear clinical evidence of neuropathy (Lance et al., 1979; Fig. 6). Alternatively neuromyotonia may be acquired as an immune

mediated channelopathy in which autoantibodies to voltage gated potassium channels produce the peripheral motor nerve hyperexcitability that leads to clinical neuromyotonia (Newsom Davis, 1997). Some of these cases are paraneoplastic, usually occurring in association with thymoma or oat cell carcinoma of the lung (Partanen et al., 1980; Lee et al., 1998). Others are seen in association with autoimmune neuropathies (Vasilescu et al., 1984) and penicillamine treatment (Reeback et al., 1979). Although stiffness can be distal and associated with abnormal hand and foot postures, pain is not a prominent feature, reflex spasms are absent and myokymia, as well as fasciculations, are evident clinically, distinguishing clinical neuromyotonia

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from the distal limb variant of the stiff person syndrome. Profuse sweating and tachycardia may occur. The tendon reflexes are usually absent, occluded by the continuous muscle activity, but may return after successful treatment. The presence of sensory symptoms and signs depends on the nature of the underlying neuropathy. Involvement of the face may occur and is absent in the classical stiff person syndrome and exceptional in the stiff-man plus syndromes. Neuromyotonia may also be focal rather than generalized. For example, isolated ocular myotonia may be seen after radiation therapy to the brainstem and hypothalamus. Fasciculations and the grouped discharges of myokymia are evident on EMG. Prolonged bursts of motor units of normal appearance and complex repetitive discharges (sometimes referred to as bizarre high frequency discharges) may occur during attempts to relax following voluntary contraction or after electrical stimulation of motor nerves (Figs. 7 and 8). High frequency discharges may also be unprovoked. Evidence of muscle denervation and reinnervation and abnormalities of nerve conduction may be found according to the presence of an underlying neuropathy.

29.3.2. Treatment of stiffness with CMUA Clinical neuromyotonia responds well to phenytoin or carbamazepine. Some patients with acquired neuromyotonia have responded to plasma-exchange. Diazepam is not helpful, in contrast to central conditions responsible for stiffness with CMUA. The prognosis in those without underlying neuropathy or neoplasm may be good, with reports of remission after several years (Isaacs and Heffron, 1974).

29.3.3. Differential diagnosis ofperipheral stiffness Other causes of stiffness of peripheral origin are distinguished by the absence of CMUA. They also persist after nerve or neuromuscular blockade (with the exception of some cases of Schwartz-Jampel syndrome). Clinical myotonia is the delayed relaxation after muscle contraction giving rise to stiffness and limitation of movement. It is due to hyperactivity of the muscle cell membrane, and may also be seen focally after percussion of muscle. Percussion myotonia is not a clinical feature of neuromyotonia. Stiffness is particularly evident after voluntary movements, but under these circumstances

Fig. 7. A: Flexor digitorum profundus EMG in a patient with neuromyotonia during voluntary contraction for the duration of the horizontal bar. Note that thereafter there is spontaneous activity. Upper trace: 'Integrated' EMG. Lower trace: Raw surface EMG. B: High frequency discharge of a complex motor potential recorded with a needle electrode at the point of the vertical arrow in A. Upper trace: Morphology of the spontaneously discharging potential. Time calibration 10 ms. Middle section: Instantaneous frequency plot of the potential showing high frequency but irregular rate > 30 Hz. Lower trace: discharge of the spontaneous EMG potential. Time calibration 100 ms. Reprinted with permission from Lance et al. (1979).

the exacerbations generally last less than 1 min and are much briefer than in the stiff person syndrome or its variants. Myotonic discharge consists of repetitive discharges at rates of 20-80 Hz. They may be biphasic spike potentials less than 5 ms in duration and resembling fibrillation potentials or positive waves of 5-20 ms duration resembling positive sharp waves. Both are due to independent

STIFFNESS WITH CONTINUOUS MOTOR UNIT ACTIVITY

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Fig. 8. Spontaneous EMG of flexor digitorum profundus during brief ischemia of the muscle in a patient with neuromyotonia. Note large, irregular fasiculation potential and the smaller high-frequency discharge, the amplitude of which progressively decreases. Reprinted with permission from Lance et al. (1979).

repetitive discharges of single muscle fibers and may occur after needle insertion, voluntary contraction or muscle percussion. Their most important characteristic is that the amplitude and frequency of the potentials wax and wane. This is responsible for the typical 'dive bomber' sound in the audio display of the EMG.

29.3.3.1. Schwartz-Jampel syndrome Schwartz-Jampel syndrome or chondrodystrophic myotonia is a rare autosomal recessive condition first described in 1962 (Schwartz and Jampel, 1962) and characterized by clinical myotonia and osteoarticular deformities. Patients have a short stature and a peculiar 'pinched' and fixed facial expression with narrow eyes, puckered mouth and dimpled chin caused by facial myotonia (Fig. 9). Bone dysplasias include kyphoscoliosis, platyspondyly, hip dysplasia, bowing of the leg diaphyses and irregular epiphyses. It is unclear whether these deformities are a primary defect or secondary to myotonia. The Schwartz-Jampel syndrome has three subtypes. Type 1A and B present in childhood, with osteoarticular deformities only being prominent in type lB. Type 2 is a severe and usually lethal condition with onset during pregnancy or at birth, clinically indistinguishable from the Stuve-Wiedemann syndrome. Types lA and B have been mapped to chromosome 1p35-p36.1 (Nicole et al., 1995).

It is not known at present whether the myotonia in the Schwartz-Jampe! syndrome is neurogenic or myogenic in origin, although current evidence from single fiber EMG studies (Fig. 10) suggests that most spontaneous activity is due to muscle fiber action potentials (Spaans et al., 1990; Arimura et al., 1996). The response of muscle activity to neuromuscular blockade by D-tubocurarine has been mixed. Lehmann-Hom et aI., (1990) demonstrated impaired muscle Na" channel inactivation in muscle biopsies, but the subsequent identification of the Gly1306Glu mutation in the Na" channel gene in their case established that this patient suffered from myotonia permanens rather than the SchwartzJampel syndrome. Routine nerve conduction studies are normal, but concentric needle EMG demonstrates two types of spontaneous activity. The first consists of typical myotonic high frequency discharges with increment and decrement of firing rates and amplitudes. The second type of spontaneous activity consists of high frequency discharges without variation in frequency or amplitude (Arimura et aI., 1996). The Schwartz-Jampel syndrome may respond to carbamazepine or procainamide.

29.3.3.2. Other causes ofperipheral stiffness Clinical myotonia is most commonly seen in dystrophia myotonica. This is a dominantly inherited neuromuscular disease, highly variable and multi-

474

Fig. 9. Facial appearance in a boy with Schwartz-Jampel syndrome showing blepharospasm due to myotonia when he attempts to open the eyes after forceful closure. Note also the puckered mouth and dimpled chin. Reprinted with permission from Spaans et al. (1990).

systemic, which is caused by the expansion of a CTG repeat located in the 3' untranslated region of the DMPK gene. Normal alleles show a copy number of 5-37 repeats on normal chromosomes, amplified 100100-fold on dystrophia myotonica chromosomes. Characteristic clinical features include distal atrophy, frontal balding, cataracts, testicular atrophy, diabetes and family history. More rarely myotonia is due to myotonia congenita, and distinguished by diffuse muscle hypertrophy. This can be either autosomal dominant (Thomsen's disease) or autosomal recessive (Becker form). Also rare is the cold induced myotonia of paramyotonia congenita. Creatine phosphokinase may be elevated

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and the EMG distinctive, with waxing and waning myotonic disharges after voluntary movement, percussion, cold, needle insertion and electrical stimulation of muscle. The metabolic myopathies such as McArdle's disease and phosphofructokinase deficiency, may also produce painful muscle cramps after and during exercise. These are electrically silent. Diagnosis is confirmed by an excessive rise in lactate during ischemic muscle exercise and by muscle biopsy. Hypothyroidism may cause stiffness and cramps, and Addison's disease has been associated with stiffness, although the exact mechanism is not clear from the literature. Acute hypertonia may be seen, together with pyrexia and rhabdomyolysis, in malignant hyperthermia, an autosomal dominant disorder triggered in susceptible people by volatile anesthetics and depolarizing skeletal muscle relaxants. Malignant hyperthermia susceptibility is usually diagnosed by the in vitro contracture test performed on fresh muscle biopsies exposed to caffeine and halothane, respectively. Around 50% of affected families are linked to the ryanodine receptor gene. The gene maps to chromosome 19q13.1 and encodes a protein that acts as a calcium-release channel from the sarcoplasmic reticulum. Finally, it should not be forgotten that stiffness can be purely mechanical in origin, due to myopathy associated muscle contracture, scleroderma or arthritis.

29.4. Conclusions Stiffness in the setting of CMUA can be due to a variety of causes, involving the central and peripheral nervous system. Prominent pain and the presence of reflex spasms usually distinguishes those with central causes. Worldwide the most important cause of central stiffness and spasm is tetanus. In developed countries most patients with a central cause for their stiffness with CMUA tum out to have either focal spinal cord pathology, such as tumor, or the stiff person syndrome. Several subgroups can be recognized in the latter. If care is taken to adhere to the diagnostic criteria summarized in Table 3, treatment response and prognosis in the classical axial stiff person syndrome are excellent. Such cases have axial rigidity and about 90% are found to have anti-GAD antibodies, suggesting that the stiff man

475

STIFFNESSWITH CONTINUOUS MOTOR UNIT ACTIVITY OFF

2

3 4

5

6

OFF

:

.. ~ .- -- - - -----~' .

A

.

:

J\':

..,.

7

',,--------~--------~'""'20""O

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........~V AMP 1 OFF

Fig. lO. Spontaneous single fiber activity in biceps brachii of a patient with Schwartz-Jampel syndrome. Upper trace: Raw record (10 ms per division). Lower trace: Average of 50 potentials showing a typical single fiber potential (2 ms per division). Reprinted with permission from Spaans et al. (1990).

syndrome defined in this way represents a remarkably homogenous disease. Stiff people with "plus" signs are unlikely to have the classical stiff man syndrome. Those in whom pathology becomes available usually have an encephalomyelitis with prominent involvement of the gray matter. These cases can be divided into three groups according to the aggressiveness of the pathology, and its relative distribution - encephalomyelitis with rigidity, the jerking stiff person syndrome and the stiff limb syndrome. Some tum out to have a paraneoplastic syndrome, while a non-malignant autoimmune basis seems likely in others. Stiffness and spasm with CMUA may also be peripheral in origin, due to neuromyotonia. This may be inherited or acquired and mayor may not occur in the setting of evident neuropathy. Some of those without neuropathy may have an immune mediated channelopathy with autoantibodies to voltage gated potassium channels. References Arimura, K, Takenaga, S, Nakagawa, M, Osame, M and Stalberg, E (1996) Stimulation single fiber EMG study in a patient with Schwartz-Jampel syndrome. J. Neurol. Neurosurg. Psychiatry, 61: 425-426. Armon, C, Swanson, JW, McLean, JM, Westbrook, PR, Okazaki, H, Kurtin, PJ, Kalyan-Raman, UP and Rodriguez, M (1996) Subacute encephalomyelitis presenting as stiff-person syndrome: Clinical, polygraphic and pathologic correlations. Mov. Disord., 11: 701709. Barker, RA, Revesz, T, Thom, M, Marsden, CD and Brown, P (1998) A review of 23 patients affected by the stiff man syndrome: clinical subdivision into stiff trunk (man) syndrome, stiff limb syndrome and

progressive encephalomyelitis with rigidity. J. Neurol. Neurosurg. Psychiatry, 65: 633-640. Bateman, DE, Weller, RO and Kennedy, P (1990) Stiff man syndrome: a rare paraneoplastic disorder? J. Neurol. Neurosurg. Psychiatry, 53: 695-696. Brown, P, Rothwell, JC and Marsden, CD (1997) The stiffleg syndrome. J. Neurol. Neurosurg. Psychiatry, 62: 31-37. Bum, DJ, Ball, J, Lees, AJ, Behan, PO and MorganHughes, JA (1991) A case of progressive encephalomyelitis with rigidity and positive antiglutamic acid antibodies. J. Neurol. Neurosurg. Psychiatry, 54: 449-451. Butler, MH, Hayashi, A, Ohkoshi, N, Villrnann, C, Becker, CM, Feng, G, De Camilli, P and Solimena, M (2000) Autoimmunity to gephyrin in stiff-man syndrome. Neuron., 26: 307-312. Campbell, AMG and Garland, H (1956) Subacute myoclonic spinal intemeuronitis. J. Neurol. Neurosurg. Psychiatry, 19: 268-274. Dalakas, MC, Fujii, M, Li, M, Lutfi, B, Kyhos, J and McElroy, B (2001) High-dose intravenous immune globulin for stiff-person syndrome. N. Eng. J. Med., 345: 187()....1876. Davis, SM, Murray, NMF, Diengoh, N, Galea-Debono, A and Kocen, RS (1987) Stimulus-sensitive spinal myoclonus. J. Neurol. Neurosurg. Psychiatry, 50: 628-631. De Camilli, P, Thomas, A and Cofiell, R (1993) The synaptic vesicle-associated protein amphiphysin is the l28_kD autoantigen of stiff-man syndrome with breast cancer. J. Exp. Med., 178: 2219-2223. Dropcho, EJ (1996) Antiamphiphysin antibodies with small-cell lung carcinoma and paraneoplastic encephalomyelitis. Ann. Neurol., 39: 659-667. Fenzi, F, Bongiovanni, G, Fincati, E, Pampanin, M, Tomelleri, G and Rizzuto, N (1988) Anatomical and clinical study of a case of subacute encephalomyelitis

476 with hyperekplexia syndrome. Ital. J. Neurol. Sci., 9: 505-508. Fogan, L (1996) Progressive encephalomyelitis with rigidity responsive to plasmapheresis and immunosuppression. Ann. Neurol., 40: 451-453. Folli, F, Solimena, M, Cofieli, R, Austoni, M, Tallini, G, Fasseta, G, Bates, D, Cartlidge, N,Bottazzo, GF, Piccolo, G and De Camilli, P (1993) Autoantibodies to a 128_kd synaptic protein in three women with the stiffman syndrome and breast cancer. N. Engl. J. Med., 328: 546-551. Gelfan, S and Tarlov, 1M (1959) Interneurons and rigidity of spinal origin. J. Physiol., 146: 594-617. Gelfan, Sand Tarlov, 1M (1963) Altered neuron population in L7 segment of dogs with experimental hind-limb rigidity. Am. J. Physiol., 205: 606-616. Guilleminault, C, Sigwald, J and Castaigne, P (1973) Sleep studies and therapeutic trial with L-DOPA in a case of stiff man syndrome. Eur. Neurol., 10: 89-96. Habermann, E (1978) Tetanus. In: PJ Vinken and GW Bruyn (Eds.), Handbook of Clinical Neurology (Vol 33). Elsevier, Amsterdam, pp. 491-547. Hardin, JA and Griggs, RC (1971) Diazepam in a case of strychnine poisoning. Lancet, ii: 372-373. Harding, AE, Thompson, PD, Kocen, RS, Batchelor, JR, Davey, N and Marsden, CD (1989) Plasma exchange and immunosuppression in the stiff-man syndrome. Lancet, ii: 915. Howell, DA, Lees, AJ and Toghill, PJ (1979) Spinal internuncial neurons in progressive encephalomyelitis with rigidity. J. Neural. Neurosurg. Psychiatry, 42: 773-785. Isaacs, H (1961) A syndrome of continuous muscle-fiber activity. J. Neurol. Neurosurg. Psychiatry, 24: 319325. Isaacs, H and Heffron, JJA (1974) The 'syndrome of continuous muscle-fiber activity' cured: further studies. J. Neurol. Neurosurg. Psychiatry, 37: 2131-2135. Ishizawa, K, Komori, T, Okayama, K, Qin, X, Kaneko, K, Sasaki, S and Iwata, M (1999) Large motor neuron involvement in Stiff-man syndrome: a qualitative and quantitative study. Acta. Neuropathol. (Berl.), 97: 6370. Kasperek, S and Zebrowski, S (1971) Stiff-man syndrome and encephalomyelitis: Report of a case. Arch. Neurol., 24: 22-31. Kullmann, DM, Howard, RS, Miller, DH, Hirsch, NP, Brown, P and Marsden, CD (1996) Brainstem encephalopathy with stimulus-sensitive myoclonus leading to respiratory arrest - a description of two cases and review of the literature. Mov. Disord., 11: 715-718. Lance, JW, Burke, DE and Pollard, J (1979) Hyperexcitability of motor and sensory neurons in neuromyotonia. Ann. Neurol., 5: 523-532.

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Nemni, R, Camerlingo, M, Fazio, R, Casto, L, Quattrini, A, Mamoli, D, Lorenzetti, I, Canal, N and Mamoli, A (1993) Serum antibodies to Purkinje cells and dorsal root ganglia in sensory neuronopathy without malignancy. Ann. Neurol., 34: 848-854. Nernni, R, Braghi, S, Natali-sora, MG et al. (1994) Autoantibodies to glutamic acid decarboxylase in palatal myoclonus and epilepsy. Ann. Neurol., 36: 665-667. Newsom Davis, J (1997) Autoimmune neuromyotonia (Isaacs' syndrome): an antibody-mediated potassium channelopathy. Ann. NY Acad. Sci., 835: I I 1-119. Nicole, S, Ben Hamida, C, Beighton, P, Bakouri, S, Belal, S, Romero, N, Viljoen, D, Ponsot, G, Sammoud, A, Weissenbach, J, Fardeau, M, Ben Hamida, M, Fontaine, B and Hentati, F (1995) Localization of the Schwartz-Jampel syndrome (SJS) locus to chromosome Ip34-p36.l by homozygosity mapping. Hum. Mol. Genet., 4: 1633-1636. Partanen, VSJ, Soininen, H, Saksa, M et al. (1980) Electromyographic and nerve conduction findings in a patient with neuromyotonia, normocalcemic tetany and small-cell lung cancer. Acta. Neurol. Scand., 6I: 216-226. Reeback, J, Benton, S, Swash, M et al. (1979) Penicillamine induced neuromyotonia. BMJ, I: 14641465. Roobol, TH, Kazzaz, BA and Vecht, CHJ (1987) Segmental rigidity and spinal myoclonus as a paraneoplastic syndrome. J. Neurol. Neurosurg. Psychiatry, 50: 628631. Rushworth, G, Lishman, WA, Trevor Hughes, J and Oppenheimer, DR (1961) Intense rigidity of the arms due to isolation of motomeurons by a spinal tumor. J. Neurol. Neurosurg. Psychiatry, 24: 132-142. Saiz, A, Arpa, J, Sagasta, A, Casamitjana, R, Zarranz, Jl, Tolosa, E and Graus, F (1997) Autoantibodies to glutamic acid decarboxylase in three patients with cerebellar ataxia, late-onset insulin dependent diabetes mellitus, and polyendocrine autoimmunity. Neurology, 49: 1026-1030. Saiz, A, Graus, F,Valldeoriola, F,Valls-Sole,J and Tolosa, E (1998) Stiff-leg syndrome: a focal form of the stiffman syndrome. Ann. Neurol., 43: 400-403. Schwartz, 0 and Jampel, RS (1962) Congenital blepharophimosis associated with a unique generalized myopathy. Arch. Ophthalmol., 68: 82-87.

Sikes, ZS (1959) Stiff-man syndrome. Dis. Nerv. System, 29: 254-258. Silverman, IE (1999) Paraneoplastic stiff limb syndrome. J. Neurol. Neurosurg. Psychiatry, 67: 126-127. Solimena, M, Folli, F, Aparisi, R, Pozza, G and De Camilli, P (1990) Autoantibodies to GABA-ergic neurons and pancreatic beta cells in stiff-man syndrome. N. EngLJMed., 322: 1555-1560. Souza-Lima, CPL, Ferraz, HB, Braz, CA, Araujo, AM and Manzano, GM (2000) Marked improvement in a stifflimb patient treated with intravenous immunoglobulin. Mov. Disord., 15: 358-359. Spaans, F, Theunissen, P, Reekers, AD, Smit, L and Veldman, H (1990) Schwartz-Jampel syndrome: I. Clinical, electromyographic, and histologic studies. Muscle Nerve, 13: 516-527. Spehlmann, R and Norcross, K (1979) Stiff-man syndrome. In: HL Klawans (Ed.), Clinical Neuropharmacology (Vol. 4). Raven Press, New York, pp. 109-121. Stayer, C, Tronnier, V, Dressnandt, J, Mauch, E, Marquardt, G, Rieke, K, Muller-Schwefe, G, Schumm, F and Meinck, HM (1997) Intrathecal baclofen therapy for stiff-man syndrome and progressive encephalomyelopathy with rigidity and myoclonus. Neurology, 49: 1591-1597. Tarlov, 1M (1967) Rigidity in man due to spinal interneuron loss. Arch. Neurol., 16: 536-543. Thompson, PD (1994) Stiff people. In: CD Marsden and S Fahn (Eds.), Movement Disorders 3. ButterworthHeinemann, Oxford, pp. 373-405. Trethowan, WH, Allsop, JL and Turner, B (1960) The stiff man syndrome. Arch. Neurol., 3: 448-456. Vasilescu, C, Alexianu, M and Dan, A (1984) Muscle hypertrophy and a syndrome of continuous motor unit activity in prednisolone: responsive Guillain-Barre polyneuropathy. J. Neurol., 231: 276-279. Warich-Kirches, M, Von Bossanyi, P,Treuheit, T, Kirches, E, Dietzmann, K, Feistner, H and Wittig, H (1997) Stiff-man syndrome: possible autoimmune etiology targeted against GABA-ergic cells. Clin. Neuropath., 16: 214-219. Whiteley,AM, Swash, M and Urich, H (1976) Progressive encephalomyelitis with rigidity: Its relation to 'subacute myoclonic spinal intemeuronitis' and the 'stiff man syndrome.' Brain, 99: 27-42.

Movement Disorders Handbook of Clinical Neurophysiology, Vol. 1 M. Hallett (Ed.) © 2003 Elsevier B. V. All rights reserved

479 CHAPTER 30

Hyperekplexia P. Brown* Sobel! Department of Motor Neuroscience and Movement Disorders, Institute of Neurology, London WCI N 3BG, UK

30.1. Introduction Hyperekplexia, or startle disease, is derived from the Greek word "eK-1T}.TJO'O'W" which means 'to startle excessively' (Suhren et al., 1966). The abnormal startle consists of an exaggerated response to unexpected stimuli, particularly sounds. The classification of the startle disorders has hitherto largely relied on electrophysiological criteria, and its clinical utility has therefore been limited. Table 1 gives a clinical classification of the abnormal startle. In this, patients are separated according to whether the clinical picture is dominated by brief body jerks that clinically seem to follow the stimulus almost

immediately or by spasms that are of visibly longer latency and last a second or more. Often these spasms follow a normal or exaggerated jerk to the stimulus. This chapter will focus on one cause of short latency body jerks following unexpected stimuli; hyperekplexia, which may be hereditary or sporadic. Upon examination the hallmark ofhyperekplexia is a brief body jerk of short latency following unexpected stimuli. Such stimuli may be visual, auditory or somesthetic. Somesthetic stimuli are most effective when applied to the mantle area, particularly the face, when the response that results is sometimes termed a head retraction reflex.

Table I

30.2. Hereditary hyperekplexia

Classification of the abnormal clinical startle response.

30.2.1. Clinical aspects

* Correspondence to: P. Brown, Sobel! Department of Neurophysiology, Institute of Neurology, London WCIN 3BO, UK. E-mail address:[email protected]

Hereditary hyperekplexia was first described by Kirstein and Silfverskiold in 1958. A detailed and landmark description of a large Dutch family followed in 1966 (Suhren et aI., 1966). The clinical picture is characterized by three major features. The first is generalized stiffness immediately after birth, remitting during the first years of life. The stiffness increases with handling and disappears during sleep. It is likely that the so-called "hereditary stiff-baby syndrome" (Klein et aI., 1972; Sander et aI., 1980) is the early presentation of hereditary hyperekplexia (Lingam et aI., 1981; Weaver et aI., 1982). Second, patients suffer from an excessive startle reflex, to unexpected, particularly auditory, stimuli. The severity and frequency of the excessive startle reflex can increase due to nervousness, fatigue, and the expectation of being frightened. Third, is a temporary generalized stiffness following the startle response, causing patients to fall 'as stiff as a stick' (Suhren et al., 1966). Attacks of stiffness last a few seconds (Fig. 1) and are by no means elicited by every stimulus presentation. Consciousness is preserved.

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Fig. 1. EMG record of the tonic spasm occurring after an unexpected sound in a patient with symptomatic hyperekplexia. The tonic spasm starts about 2 s after the stimulus, and is clearly separate from the very rapid and brief startle response (seen 2 s into the trace). left (L), right (R). Reprinted from Brown et al., 1991a with by permission.

Nevertheless, these spasms frequently culminate in injury. These tonic responses are distinct from the tonic spasms of multiple sclerosis, which are usually painful, unilateral and rarely stimulus sensitive. Several additional clinical features have been described in patients with hereditary hyperekplexia, although these are not obligatory for the diagnosis. Periodic limb movements in sleep and hypnagogic myoclonus are frequently reported (Kirstein and Silfverskiold, 1958; Gastaut and Villeneuve, 1967; Andermann et al., 1980; Morley et al., 1982; Kurczynski, 1983; Saenz et al., 1984; Brown et al., 1991a; Hayashi et al., 1991; Shahar et al., 1991; Matsumoto et al., 1992; Pascotto and Coppola, 1992). Other features are inguinal, umbilical or epigastric herniae (Suhren et al., 1966; Klein et al., 1972; Lingam et al., 1981), congenital dislocations of the hip (Hayashi et al., 1991), epilepsy (Suhren et al., 1966; Saenz et al., 1984), feeding and breathing problems in newborns (Shahar et al., 1991; Giacoia and Ryan, 1994), and sudden infant death (Suhren et al., 1966; Giacoia and Ryan, 1994). Most patients have normal intelligence, but some mildly retarded patients have been reported (Shahar et al., 1991; Ryan et al., 1992). On neurological examination, neonates have a markedly increased muscle tone and head retraction reflex. The baby is alert, but shows marked hypoki-

nesia (Tijssen and Brouwer, 1999). Adults with the major form of hyperekplexia often walk with a stifflegged, mildly wide-based gait without signs of ataxia (Suhren et al., 1966). Tendon reflexes and tone are normal, or slightly increased, without clear evidence of a pyramidal syndrome (Suhren et al., 1966). Tapping the nose induces an exaggerated head-retraction reflex in most patients (Suhren et al., 1966; Andermann et al., 1980; Kurczynski, 1983; Shahar et al., 1991; Matsumoto et al., 1992). This consists of a brisk, involuntary backward jerk of the head. It occurs only infrequently in normal subjects (Wartenberg, 1941). 30.2.2. Genetics of hereditary hyperekplexia

Linkage analysis has mapped a major gene for this disorder to chromosome 5q33-35 (Ryan et al., 1992). Different missense mutations in the GLRAI (glycine receptor) gene, Pr0250Thr (Saul et al., 1999), Gln266His (Milani et al., 1996), Arg271Leu (Shiang et al., 1993), Arg271Gln (Shiang et al., 1993; Rees et al., 1994; Schorderet et al., 1994; Shiang et al., 1995; Tijssen et al., 1995; Bernasconi et al., 1996; Elmslie et al., 1996), Lys276Glu (Seri et al., 1997), and Tyr279Cys (Shiang et al., 1995), have been identified in families with the autosomal dominant form of hyperekplexia. Besides the domi-

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nant form of hyperekplexia, two recessive cases, both offspring of consanguineous parents, have been described (Rees et al., 1994; Brune et al., 1996). In one patient a recessive point mutation, Ile244Asn (Rees et al., 1994), was detected while the other patient carried a homozygous deletion encompassing exon 1 to 6 of the GLRA1 gene (Brune et al., 1996). In a further family, two patients compound heterozygous for two mutations, Arg252His and Arg392His, showed the hyperekp1exia phenotype (Vergouwe et al., 1999). Glycine is an inhibitory neurotransmitter and the glycine receptor is a hetero-oligomeric ligand-gated chloride channel, mainly located in post-synaptic membranes in vertebrate brainstem and spinal cord (Betz, 1991). A high concentration of glycine receptors is found in the intemeurons; particularly Renshaw cells and Ia inhibitory intemeurons (Fyffe, 1991). The receptor consists of five subunits (30: and 213) forming a ring with a central ion-conducting pore. The glycine receptor has different isofonns, comprising different variants of the ligand-binding 0: subunits. The mutations described in hyperekplexia are located in the alpha-l subunit. This consists of a large extracellular N-terminal domain, four transmembrane segments (M1-M4) and a short extracellular C terminus (Grenningloh et al., 1990; Rajendra et al., 1995). Autosomal dominant mutations in the GLRAI gene, located within the intracellular M1-M2 loop, M2 domain or the extracellular M2-M3 loop, disrupt signal transduction. Normally, chloride influx through the channel antagonizes membrane depolarization. Decreased chloride permeability of the neuronal membrane therefore results in diminished inhibition of neuronal firing. 30.2.3. The minor form

In the original Dutch family, described in 1966, two clinical forms of the disorder were recognized (Suhren et al., 1966). These two forms have also been described in a Canadian pedigree and named the major and minor form of hyperekplexia (Andermann et al., 1980). The major form is characterized by the triad of neonatal stiffness, excessive startle and tonic spasms described above. The minor form consists of excessive startle responses without any signs of stiffness, neither in relation to the startle response, nor in the neonatal period. The occasional

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occurrence of the minor form has been confirmed in other families (Brown et al., 1991a; Pascotto and Coppola, 1992), and a large pedigree with 10 affected patients has been described, suffering from both major and minor forms of hyperekplexia, although clinical details were scanty (Saul et al., 1999). Opinion is presently divided as to whether the minor form represents a variation in expression of the same gene defect as the major form. In particular, in the Dutch pedigree described by Suhren, only family members with tonic spasms were found to carry the mutation (Tijssen et al., 1995, 1996), suggesting that in at least some families the 'minor' form may be a partial phenocopy. 30.3. Sporadic hyperekplexia Sporadic cases of hyperekplexia do not seem to have a genetic basis (Gastaut and Vileneuve, 1967; Vergouwe et al., 1997); indeed many are symptomatic and usually a consequence of brainstem pathology such as infarct, hemorrhage or encephalitis (Table 2). They too may exhibit tonic spasms and episodes of sustained myoclonic jerks which are therefore not unique to hereditary hyperekplexia (Gastaut and Vileneuve, 1967; Brown et al., 1991a). 30.4. Differential diagnosis Hyperekplexia is distinguished from the normal startle reflex by its lower threshold, greater extent and resistance to habituation (Brown et al., 1991a; Chokroverety et al., 1992; Matsumoto et al., 1992). The normal startle response rarely involves the lower limbs in a sitting subject, whereas this is almost always the case in hyperekplexia. The normal startle response habituates within 1-5 trials of auditory stimulation repeated every 20 s or so, leaving only an auditory blink reflex, whereas in hyperekplexia extensive jerks persist. The pathological differential diagnosis is as follows: 30.4.1. Excessive responses to startling stimuli without stiffness in between 30.4.1.1. Startle-induced epilepsy Startle epilepsy, as described by Alajouanine and Gastaut (1955) and reviewed by Chauvel et al.

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(1992), can readily be distinguished from hyperekplexia, although similar pathophysiological mechanisms may operate in the tonic episodes of each condition. Startle epilepsy is most often seen in the setting of early brain damage, usually perinatal anoxia. Most patients have a hemiparesis, and mental retardation is common. However, these seizures may also occur without infantile hemiplegia (Manford et al., 1996). Seizures begin in childhood or adolescence, and tend to be frequent. They consist of tonic spasms, lasting up to 30 s, with preservation of consciousness. The spasms are typically asymmetrical and predominantly involve the paretic limbs. They may be elicited by unexpected auditory, visual or somesthetic stimulation, but, in contrast to Table 2 Causes of symptomatic hyperekplexia. J. Static encephalopathies Static perinatal encephalopathy without tonic spasms (Shiamura, 1973) Post-traumatic encephalopathy (Duensing, 1952; Krauss et al., 1997) Post-anoxic encephalopathy (Brown et aI., 1991a)

2. Brainstem encephalitis Paraneoplastic (Duensing, 1952) Sarcoidosis (Brown et aI., 1991a) Jerking stiff person syndrome (Leigh et al., 1980; Brown et aI., 1991a) Viral encephalomyelitis (Fenzi et al., 1988) 3. Demyelination (Duensing, 1952; Brown et aI., 1991a) 4. Vascular lesions Occlusion of the posterior thalamic arteries (Fariello et al., 1983) Brainstem hemorrhage/infarct (Duensing, 1952; Kohara et aI., 1988; Shibasaki et al., 1988; Kimber and Thompson, 1997) 5. Structural lesions Cervico-medullar compression (Winston, 1983) 6. Gilles de la Tourette syndrome (Stell et aI., 1995) 7. Post-traumatic stress disorder (Howard and Ford, 1992)

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hyperekplexia, are also spontaneous. Other seizure types occur in about a quarter of patients (Chauvel et al., 1992). Cranial imaging is abnormal in the majority of patients, usually showing unilateral atrophy involving the lateral central and pericentral cortex. The interictal EEG is generally abnormal with localized or diffuse slow waves and spikes. Ictal scalprecorded EEG shows a fast low amplitude discharge often preceded by a high voltage spike at the vertex. Using depth electrodes the tonic seizures have been shown to originate in the motor or supplementary motor cortex (Bancaud et al., 1967; Chauvel et al., 1992). 30.4.1.2. Reflex myoclonus The clinical features distinguishing hyperekplexia from brainstem reticular reflex myoclonus are summarized in Table 3. Propriospinal myoclonus can cause reflex axial jerks but the face is always spared, and sensitivity to sound is rarely seen. Both brainstem reticular reflex and propriospinal myoclonus have frequent spontaneous jerks that also serve to distinguish them from hyperekplexia (Hallett et al., 1977; Brown et al., 1991b). 30.4.1.3. Culture-bound syndromes The "Jumping Frenchmen of Maine" (Stevens, 1965; Howard and Ford, 1992), Latah (Yap, 1951) and Myriachit (Yap, 1951) are culture-bound syndromes including excessive startle responses, echolalia, and echopraxia. Stiffness has not been described in these patients. 30.4.1.4. Gilles de la Tourette syndrome In Gilles de la Tourette syndrome excessive startling has occasionally been described (Stell et al., 1995), but more frequently a normal startle reflex induces motor tics and obsessive compulsive behavior (Lees et al., 1984; Eapen et al., 1994; Tijssen et al., 1999). 30.4.1.5. Conversion disorder Distinguishing psychogenic jerks from hyperekplexia may be difficult. The former are suggested by "la belle indifference," distractability, suggestibility and an inconsistent pattern of EMG activity in the jerks (Thompson et al., 1992). The latency of reflex responses can be very long (> 100 ms).

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Table 3 Differential diagnosis of hyperekplexia and brainstem reticular reflex myoclonus. Jerks to auditory stimuli

Hyperekplexia' Brainstem reticular reflex myoclonus

+ +

Greatest stimulus sensitivity to taps

Presence of spontaneous and action-induced jerks

Duration of individual EMG bursts'

+