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Disturbed surround inhibition in focal hand dystonia.

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Disturbed Surround
Inhibition in Focal
Hand Dystonia
Young H. Sohn, MD1,2 and Mark Hallett, MD1
Disturbances in surround inhibition could account for
various movement disorders. Here we test the functional
operation of surround inhibition in focal hand dystonia.
Transcranial magnetic stimulation was set to be triggered
by self-initiated voluntary flexion of the index finger.
During this movement, motor-evoked potential amplitudes from the little finger muscle were significantly suppressed in healthy subjects but enhanced in dystonia patients. This result supports the idea that disturbed
surround inhibition is a principal pathophysiological
mechanism of dystonia.
Ann Neurol 2004;56:595–599
Surround inhibition, suppression of excitability in an
area surrounding an activated neural network, is a
physiological mechanism to focus neuronal activity and
to select appropriate neuronal responses. It is proposed
to be an essential mechanism in the motor system,
where it could aid the selective execution of desired
movements.1 Disturbances in surround inhibition may
account for various movement disorders, including dystonia,1–3 but this association remains to be demonstrated.
Recently, we demonstrated the functional existence
of surround inhibition in the human motor cortex, using transcranial magnetic stimulation (TMS).4 Motorevoked potential (MEP) amplitudes of the little finger
muscle were significantly suppressed during voluntary
flexion of the index finger, despite an increase in spinal
excitability.4 Using a similar experimental setting, we
evaluated surround inhibition in the motor cortex of
the patients with focal hand dystonia.
From the 1Human Motor Control Section, National Institute of
Neurological Disorders and Stroke, National Institutes of Health,
Bethesda, MD; and 2Department of Neurology and Brain Research
Institute, Brain Korea 21 Project for Medical Science, Yonsei University College of Medicine, Seoul, Korea.
Received Apr 13, 2004, and in revised form Jul 19. Accepted for
publication Jul 19, 2004.
Published online Sep 30, 2004, in Wiley InterScience
( DOI: 10.1002/ana.20270
Address correspondence to Dr Hallett, Human Motor Control Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Building 10, Room 5N226, 10 Center
Drive, Bethesda, MD 20892. E-mail:
© 2004 American Neurological Association
Published by Wiley-Liss, Inc., through Wiley Subscription Services
Subjects and Methods
Seven patients with focal hand dystonia (four men and three
women; mean age, 52 years; range, 42– 67 years) and seven
age-matched, right-handed healthy subjects (five men and
two women; mean age, 51 years; range, 39 – 67 years) participated in this study after giving their written informed
consent. The patients’ clinical characteristics are shown in
the Table. This study was approved by the local ethics committee.
Transcranial Magnetic Stimulation
Surface electromyography (EMG) activity was recorded
(bandpass, 10 –2000Hz) from the abductor digiti minimi
(ADM), extensor indicis proprius (EIP), first dorsal interosseus (FDI), and flexor digitorum superficialis (FDS) muscles
of the affected arm in patients and the right arm in healthy
subjects, using a conventional EMG machine (Counterpoint,
Skovlunde, Denmark). The signal was digitized at a frequency of 5kHz and fed into a laboratory computer for further offline analysis. A figure-eight–shaped coil (each loop
measured 70mm in diameter) connected to a Magstim 200
magnetic stimulator (Magstim, Dyfed, United Kingdom)
was placed flat on the scalp over the left motor cortex at the
optimal site for eliciting maximal amplitude MEPs in ADM.
The individual resting motor threshold was determined to
the nearest 1% of the maximum stimulator output and was
defined as the minimal stimulus intensity required to produce MEPs of greater than 50␮V in at least 5 of 10 consecutive trials.
Using a LabVIEW program (National Instrument, Austin,
TX) and a Schmidt discriminator, TMS was set to be triggered by EMG activity of the FDS (self-triggered TMS). The
sensitivity of the Schmidt discriminator was set at a level sufficient to correctly detect the onset of EMG activity and not
to produce triggering while resting (usually 100␮V peak-topeak EMG amplitude). “Go” signals were given at random
intervals between 5 and 9 seconds. Subjects were asked to
flex their right index finger after the “go” signal with a selfpaced delay (there was instruction not to react immediately).
Before the experiment, subjects practiced making a brief (duration, approximately 100 milliseconds) and selective movement with monitoring their own EMG activity. Seven sessions of self-triggered TMS were applied in a random order
at various intervals (3, 15, 40, 80, 200, 500, and 1,000 mil-
liseconds) between EMG onset and TMS trigger. Two control sessions without self-triggering were given before and after self-triggered sessions. MEP size was determined by
averaging peak-to-peak amplitudes over 18 trials for each session at stimulus intensity of 140% of individual resting motor threshold. Average MEP amplitudes obtained at selftriggered TMS were compared with the average MEPs of
control TMS and expressed as a percentage.
Peripheral Nerve Stimulation
With supramaximal electrical stimulation of the ulnar nerve
at the wrist, peak-to-peak amplitude and persistence of F
waves (average, 18 trials) of ADM were determined in both
control and self-triggered sessions at 10-millisecond intervals
between EMG onset and stimulation. Compound muscle action potentials (maximum, six trials) of ADM was also determined in both control and self-triggered sessions at 10millisecond intervals.
Statistical Analysis
Data were expressed as means ⫾ standard errors of the
means. The percentage changes in MEP amplitudes of patients at different intervals of self-triggered TMS sessions
were compared with those of healthy subjects by using
repetitive-measures analysis of variance. The values at each
interval, and changes in both F waves and compound muscle
action potentials were compared between patients and
healthy subjects by using the nonparametric Mann–Whitney
U test. Those p values less than 0.05 were considered statistically significant.
All subjects performed index finger flexion selectively
and briefly; average EMG duration of FDS was 132
milliseconds (range, 102–175 milliseconds) in patients
and 126 milliseconds (range, 76 –176 milliseconds) in
healthy subjects. Offline analysis of EMG recordings
showing that index finger movement–related muscles
(FDS, FDI, and EIP) were active during the movement
(average EMG amplitudes, 420, 563, and 251␮V in
patients and 424, 747, and 201␮V in healthy subjects,
respectively), but that ADM was usually quiet or with
small and brief EMG (average, 86␮V in patients and
73␮V in healthy subjects), supports our assumption
Table. Patients’ Characteristics
Affected Hand
Writer’s cramp
Musician’s cramp
Writer’s cramp
Writer’s cramp
Writer’s cramp
Hand dystonia
Writer’s cramp
BTX ⫽ botulinum toxin.
Annals of Neurology
Vol 56
No 4
October 2004
Main Dystonic Movement
Extension of the index finger
Flexion of the middle finger
Extension of the index finger
Wrist flexion
Extension of the fingers (II–V)
Flexion of the wrist and all fingers
Flexion of the wrist and middle finger
(mo from
last injection)
BTX (3)
BTX (12)
BTX (3)
BTX (5)
that abduction of the little finger and flexion of the
index finger were not synergistic. Despite dystonia in
the tested hand, no patient showed overt movement of
the little finger during the index finger flexion.
Resting motor threshold was comparable between
patients (46 ⫾ 2.2%) and healthy subjects (45 ⫾
1.8%). During index finger flexion, MEP amplitudes
of ADM were significantly suppressed in healthy subjects but enhanced up to 270% of those at rest in patients (Fig 1A). The MEP changes of ADM in patients
were significantly different from those in healthy subjects at intervals of 3, 15, 40, and 80 milliseconds.
MEP amplitudes of muscles related to index finger
movements, FDS (flexion), EIP (extension), and FDI
(abduction) were significantly enhanced up to three
times larger than those at rest. MEP changes in these
muscles were comparable between patients and healthy
subjects (see Figs 1B–D).
F-wave amplitudes of ADM were remarkably enhanced during index finger flexion both in patients and
healthy subjects (Fig 2). This enhancement appeared
more prominent in patients than healthy subjects, albeit not statistically different. F-wave persistence was
also enhanced during index finger flexion (from 74.8
to 96.2% in patients and from 82.3 to 94.2% in
healthy subjects), albeit statistically insignificantly.
Compound muscle action potentials of ADM were not
changed during the movement in either patients or
healthy subjects.
Surround inhibition must come from dynamic functional interactions, since different muscle synergies are
active in different tasks.5,6 Abduction of the little finger should be in the inhibitory surround of index finger flexion, because these movements cannot be per-
Fig 1. Changes in motor-evoked potential (MEP) amplitude of tested muscles in self-triggered transcranial magnetic stimulation
(TMS) at each interval (3, 15, 40, 80, 200, 500, and 1,000 milliseconds) from electromyography (EMG) onset of flexor digitorum
superficialis (FDSs) to TMS, compared with the resting state. (asterisk) Significant difference between patients and healthy subjects
(p ⬍ 0.05). (A) MEP amplitudes of abductor digiti minimi (ADM) are significantly suppressed in healthy subjects but are enhanced in patients during voluntary flexion of the index finger. (B–D) MEP amplitudes of first dorsal interosseus (FDI), extensor
indicis proprius (EIP), and FDS were significantly enhanced both in patients and healthy subjects, during and immediately after
voluntary flexion of the index finger.
Sohn and Hallett: Surround Inhibition in Dystonia
Fig 2. F-wave amplitudes are significantly enhanced during
self-triggered sessions compared with those in resting condition
in both patients (unshaded bars) and healthy subjects (shaded
bars). (asterisk) Significant difference between the two conditions (p ⬍ 0.05).
formed simultaneously without special practice. As
shown in a previous study,4 MEP amplitudes of ADM
were significantly suppressed during voluntary flexion
of the index finger in healthy subjects, a finding that
supports the existence of surround inhibition in the
human motor cortex. In contrast, patients with focal
hand dystonia showed significantly enhanced ADM
MEPs, suggesting that the operation of surround inhibition is impaired in these patients. Although spinal
excitability was enhanced in the patients, disturbed surround inhibition appears to occur mainly at the supraspinal level, because enhanced spinal excitability was
also observed in healthy subjects. Offline analysis of
EMG recordings, which showed comparable EMG activity (for both duration and amplitude) in ADM between the patients and healthy subjects, could sufficiently exclude the presence of abnormally increased
cocontraction of ADM during the index finger movement. None of our patients took medications for their
dystonia, a fact that excludes any medication effect.
Four patients received multiple Clostridium botulinum
toxin injections that might have affected their motor
excitability.7 However, this effect should be minimal,
because the last injections were done 3 months ago or
longer, and any effect should have fully worn off by
this time of the experiment.
In the basal ganglia, the activity of the direct and
indirect pathways modulates thalamic excitatory output
to the motor cortex in the opposite way.1 This arrangement of the basal ganglia–thalamocortical output could
regulate neural networks in the motor cortex, resulting
in a recruitment of groups of cells related to a desired
movement and a concurrent suppression of cells related
to other unwanted movements, that is, surround inhibition. Disturbances in this circuitry could produce enhanced excitability of surrounding muscles, resulting in
cocontraction and therefore dystonia.1,2 Although actual contraction of ADM did not occur in our patients
Annals of Neurology
Vol 56
No 4
October 2004
during the index finger movements, enhanced excitability of surround muscles would foster the development of cocontraction and produce dystonia. Evidence
for a role of the basal ganglia–thalamic circuit in the
pathogenesis of dystonia is provided from clinicopathological studies in patients with dystonia.8,9 Intracerebral recordings in patients with dystonia showed altered patterns of neuronal activity in the palladum and
thalamus,3 suggesting that these structures play a role
in its development.
Alterations in various cortical inhibitory mechanisms
were demonstrated in patients with dystonia.10 –15
However, the changes in these cortical inhibitory
mechanisms may not represent the changes in basal
ganglia function specifically related to dystonia but
may rather be nonspecific in that they are also observed
in various other neurological problems, of both peripheral and central origin.16,17 The method we used in
this study could be more appropriate to evaluate surround inhibition regulated by the basal ganglia–
thlamocortical circuit than other methods, and it may
be a useful tool to help us evaluate the mechanism of
various movement disorders. In conclusion, these results provide evidence that disturbed surround inhibition is a principal mechanism of dystonia.
We thank D. Schoenberg for skillful editing.
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3. Vitek JL. Pathophysiology of dystonia: a neuronal model. Mov
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4. Sohn YH, Hallett M. Surround inhibition in human motor
cortex. Exp Brain Res (in press).
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9. Lee MS, Marsden CD. Movement disorders following lesions
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balance between motor cortical excitation and inhibition in focal, task specific dystonia. J Neurol Neurosurg Psychiatry 1995;
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Neurology 1997;49:1054 –1059.
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cortical inhibition in writer’s cramp as revealed by changes in
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Rapid Eye Movement Sleep
Behavior Disorder In
Parkinsonism with PARKIN
Hatice Kumru, MD, Joan Santamaria, MD,
Eduardo Tolosa, MD, Francesc Valldeoriola, MD,
Esteban Muñoz, MD, Maria J. Marti, MD,
and Alex Iranzo, MD
Rapid eye movement sleep behavior disorder (RBD) in
the setting of parkinsonism or dementia often reflects an
underlying synucleinopathy. Lewy bodies, intraneuronal
aggregates containing abnormal ␣-synuclein, are absent
in most cases of parkinsonism with parkin mutations
(Park2). We performed clinical history and videopolysomnography in 10 Park2 patients (seven men; age,
51.2 ⴞ 11.6 years; parkinsonism duration, 18.3 ⴞ 11.2
years) and found RBD in 6. In all instances, RBD followed the onset of motor symptoms by several years. Our
study shows that RBD is frequent in Park2, suggesting
that mechanisms other than synuclein deposition can
cause RBD in neurodegenerative disorders.
Ann Neurol 2004;56:599 – 603
Rapid eye movement (REM) sleep behavior disorder
(RBD) is a parasomnia characterized by vigorous behaviors during REM sleep, usually associated with unpleasant
dreams.1 It has been reported in several neurodegenerative
disorders, with a disproportionately greater frequency in
diseases associated with abnormal deposition of
␣-synuclein, such as Parkinson’s disease (PD), multiplesystem atrophy, or dementia with Lewy bodies.2 In the
setting of parkinsonism or degenerative dementia, RBD
often reflects an underlying synucleinopathy.2
Juvenile-onset parkinsonism with parkin gene mutations (Park2) is characterized by early onset, L-dopa–responsive parkinsonism, foot dystonia, and slow progression of disease.3 Freezing, falls, and behavioral and
autonomic disturbances have also been reported.4 Lewy
bodies, intraneuronal aggregates containing abnormal
From the Neurology Service, Hospital Clı́nic de Barcelona and Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS),
Barcelona, Spain.
Received Apr 26, 2004, and in revised form Jul 19. Accepted for
publication Jul 19, 2004.
Published online Sep 30, 2004, in Wiley InterScience
( DOI: 10.1002/ana.20272
Address correspondence to Dr Santamaria, Neurology Service, Hospital Clinic de Barcelona, c/ Villarroel, 170, Barcelona 08036,
Spain. E-mail:
© 2004 American Neurological Association
Published by Wiley-Liss, Inc., through Wiley Subscription Services
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