Brain (2002), 125, 895±903
Abnormal cortical mechanisms of voluntary muscle
relaxation in patients with writer's cramp: an fMRI
study
T. Oga,1 M. Honda,1,4 K. Toma,1 N. Murase,3 T. Okada,3,4 T. Hanakawa,1 N. Sawamoto,1
T. Nagamine,1 J. Konishi,3 H. Fukuyama,1 R. Kaji5 and H. Shibasaki1,2
Departments of 1Brain Pathophysiology, Human Brain
Research Center, 2Neurology and 3Nuclear Medicine,
Kyoto University Graduate School of Medicine, Kyoto,
4Laboratory of Cerebral Integration, National Institute for
Physiological Sciences, Myodaiji, Okazaki, and
5Department of Neurology, Tokushima University School of
Medicine, Tokushima, Japan
Summary
Although it is hypothesized that there is abnormal
motor inhibition in patients with dystonia, the question
remains as to whether the mechanism related to motor
inhibition is speci®cally impaired. The objective of the
present study was to clarify the possible abnormalities
of the mechanisms underlying voluntary muscle relaxation during motor preparation and execution in
patients with writer's cramp, using event-related functional MRI. Eight patients with writer's cramp and 12
age-matched control subjects participated in the study.
Two motor tasks were employed as an experimental
paradigm. In the relaxation task, subjects were asked to
hold their right wrist in the horizontal plane by maintaining moderate contraction of wrist extensor muscles
in the premotor phase; they relaxed those muscles
Correspondence to: Hiroshi Shibasaki, MD, PhD,
Department of Brain Pathophysiology, Human Brain
Research Center, Kyoto University Graduate School of
Medicine, 54 Kawahara-cho, Shogoin, Sakyo-ku, Kyoto,
606±8507 Japan
E-mail; [email protected]
voluntarily just once during each fMRI scanning session. In the contraction task, subjects extended the right
wrist voluntarily from the same premotor state as for
the relaxation task. Five axial images covering the primary sensorimotor cortex (SMC) and supplementary
motor area (SMA) were obtained once every second.
Activated volumes in the left SMC and the SMA were
signi®cantly reduced in patients for both muscle relaxation and contraction tasks. These data suggest that
there is impaired activation in both SMC and SMA in
voluntary muscle relaxation and contraction in patients
with writer's cramp. This implies that abnormalities of
both inhibitory and excitatory mechanisms in motor
cortices might play a role in the pathophysiology of
focal dystonia.
Keywords: writer's cramp; voluntary muscle relaxation; central motor control; inhibitory motor system; event-related
functional MRI
Abbreviations: fMRI = functional MRI; MRCP = movement-related cortical potential; ROI = region of interest;
SMA = supplementary motor area; SMC = sensorimotor cortex
Introduction
Dystonia is characterized by the appearance of involuntary
muscle contraction, which frequently causes twisting and
repetitive movements or abnormal postures (Fahn, 1988).
Exaggerated co-contractions of agonist and antagonist
muscles in the affected portion make it dif®cult for dystonia
patients to relax these muscles. A number of studies have
recently demonstrated abnormalities of the cortical motor
system in idiopathic dystonia (for a review, see Berardelli
et al., 1998; Hallett, 1998).
ã Guarantors of Brain 2002
Electrophysiological studies have shown that the amplitude
of the movement-related cortical potential (MRCP) in
association with voluntary muscle contraction of the affected
hand decreased in focal hand dystonia (FeÁve et al., 1994;
Deuschl et al., 1995). In our laboratory, Yazawa et al. (1999)
reported abnormal MRCP in patients with focal hand dystonia
prior to voluntary muscle relaxation. Studies with transcranial
magnetic stimulation (TMS), which enable us to evaluate
both excitatory and inhibitory functions of the corticospinal
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T. Oga et al.
system (Barker et al., 1987; Mills, 1988; Kujirai et al., 1993;
Wassermann et al., 1993), have shown breakdown of the
inhibitory mechanisms in the motor cortex in dystonia
(Ridding et al., 1995; Ikoma et al., 1996; Chen et al.,
1997). These ®ndings suggest that not only muscle contraction, but also muscle relaxation might be associated with
abnormal underactivation of the motor-related cortices in
focal hand dystonia, although the low spatial resolution of
these techniques does not allow us to identify precise location
of the abnormality.
Previous PET studies in patients with dystonia revealed
hypometabolism of glucose in the basal ganglia, thalamus and
prefrontal association cortices (Karbe et al., 1992) and
hyporeactivity of regional cerebral blood ¯ow in the primary
sensorimotor cortex (SMC) and supplementary motor area
(SMA) to various sensorimotor tasks (Ceballos-Baumann
et al., 1995, 1997; IbaÂnÄez et al., 1999). These neuroimaging
®ndings generally suggest decreased baseline activity and/or
poor reactivity to motor tasks in the motor-related areas in
dystonia. It is important to note that the conventional
neuroimaging techniques employed in these studies presupposed a steady state change in regional cerebral blood ¯ow
during repetitive execution of the same tasks over a period of
several tens of seconds to a few minutes (Roland et al., 1980;
Shibasaki et al., 1993). The neuronal activities associated
with both muscle contraction and relaxation were therefore
mixed together in the data obtained from these previous
studies. It has yet to be elucidated whether the abnormality of
the motor cortex in these patients is associated with either
muscle contraction or relaxation alone, or with both of them.
Our group approached this complex problem by using
event-related functional MRI (fMRI), which has a better
temporal resolution. Toma et al. (1999) have successfully
demonstrated the neural activities associated with voluntary
muscle contraction and relaxation in normal healthy volunteers. In the present study, which adopted the same motor task
as in the previous study, we investigated cortical activity
associated with voluntary muscle contraction and relaxation
`separately' in patients with writer's cramp.
Material and methods
We studied eight patients with writer's cramp (three females
and ®ve males). The mean age was 35 years (range 22±
58 years) and the mean duration of illness was 4.6 years
(range 2±11 years). All patients were the right-hand dominant
users and complained of dif®culty in writing. According to
the classi®cation of Sheehy and Marsden (1982), ®ve patients
had simple and three patients had complex writer's cramp. At
the time of this experiment, the symptoms appeared only
during writing in ®ve of the eight patients and, in the
remaining three patients, symptoms occurred both on writing
and other hand tasks. No patients had other neurological
disorders. Six patients had been treated with muscle afferent
block for their symptoms (Kaji et al., 1995a), but not later
than 1 month before the experiment. Twelve healthy subjects
[10 males and two females; mean age 31 years (range 23±42
years)] were studied as normal controls. Data from eight
subjects from the control group were previously reported for a
different purpose (Toma et al., 1999) and they were
reanalysed with some modi®cation for the present experiment. All patients and control subjects gave informed consent
before the experiment after the purpose and procedure of
this study was explained. The study was approved by The
Committee of Medical Ethics, Graduate School of Medicine,
Kyoto University.
Behavioural paradigm
Two motor tasks, muscle relaxation and muscle contraction,
were employed as described previously by Toma et al.
(1999). Both tasks were performed with the subject's right
hand.
Each trial of the muscle relaxation task started with a
premotor phase in which the subject held the right wrist in the
horizontal plane with the palm down by maintaining
moderate contraction of the wrist extensor muscles
(Fig. 1A). The subject then relaxed those muscles as quickly
as possible in a self-initiated manner, causing abrupt wrist
drop after the gravity (motor phase). The subject kept the
relaxed position until the end of each trial by avoiding any
additional movement (postmotor phase).
In the muscle contraction task, after holding the horizontal
position of the right wrist just like in the relaxation task, the
subject extended the right wrist as quickly as possible up to
~60° from the horizontal plane (motor phase) and kept the
extended position until the end of the trial (postmotor phase).
Before the image acquisition, the subject was trained to
perform all of the tasks satisfactorily with the aid of surface
EMGs, until they could keep the EMG activities of other
irrelevant muscles completely silent. Especially in the
relaxation task, the subject was well trained to relax the
extensor carpi radialis (ECR) muscle without concomitant
contraction of the antagonist muscles [e.g. ¯exor carpi ulnaris
muscle (FCU)] in association with the muscle relaxation. The
subject was also trained to control the amount of EMG
activity of the premotor phase so as to be nearly identical in
the muscle relaxation and contraction tasks.
Data acquisition
Functional imaging was conducted with a whole body 1.5
tesla MRI scanner (Horizon; General Electric Medical
Systems, Milwaukee, Wis., USA). Images were obtained
using a single-shot, blipped, gradient-echo echoplanar pulse
sequence using the following parameters: TR (repetition
time) = 1000 ms, TE (echo time) = 43 ms, FA (¯ip
angle) = 60°, slice thickness = 5 mm, slice gap = 1 mm,
imaging matrix = 64 3 64, FOV (®eld of view) = 24 3 24 cm.
Based on the ®ndings of our previous study (Toma et al.,
1999), we focused on the activity in the SMC and SMA, both
of which might play a role in motor inhibition; ®ve axial
Event-related fMRI in writer's cramp
Fig. 1 Experimental conditions (A) and surface EMG records in
the MRI scanner (B). (A) Photographs showing muscle relaxation
(upper panel) and contraction (lower panel) tasks. In the
relaxation task, the subject held the right wrist in a horizontal
plane with the palm down by maintaining moderate contraction of
the wrist extensor muscles. The subject then relaxed these muscles
as quickly as possible, causing abrupt wrist drop under the
in¯uence of gravity, and kept the relaxed position until the end of
the trial. In the contraction task, the subject was instructed to
perform the task in a similar manner to the relaxation task. Note
that maintaining moderate contraction of the wrist extensor
muscles is also required during the premotor phase in the
contraction task. (B) An example of surface EMGs recorded from
bilateral forearm muscles during fMRI scanning in the relaxation
task. Despite the conspicuous signals caused by radio frequency
pulses on the record, the EMG offset can be identi®ed; this
happens to coincide with the 30th scan in this particular trial.
ECR = extensor carpi radialis muscle; FCU = ¯exor carpi ulnaris
muscle; Rt = right; Lt = left.
slices were obtained to cover these areas. Each imaging
session consisted of 60 time point dynamic scans (i.e. 60 s)
and contained a single experimental trial. Before the functional imaging, a high resolution T1-weighted image of the
whole brain was collected (TR = 10.8 ms, TE = 1.8 ms,
inversion time = 300 ms, FA = 15°, slice thickness = 1.5 mm,
no slice gap, imaging matrix = 256 3 256 and
FOV = 24 3 24 cm). Additional anatomic T1-weighted
images corresponding to the echoplanar images of ®ve slices
897
were also obtained to identify the activation area precisely
(TR = 600 ms, TE = 17 ms, FA = 30°, slice thickness = 5 mm,
slice gap = 1 mm, imaging matrix = 256 3 256 and
FOV = 24 3 24 cm).
Subjects were laid supine on a scanner bed and their head
was immobilized with a forehead strap and urethane foam
pads. Noise was partially masked by earplugs throughout the
experiment. Several seconds before the beginning of each
imaging session, the subject was instructed to take up the
premotor position. For both tasks, the subject performed a
single motor event (i.e. muscle relaxation or contraction) in a
self-initiated manner at ~25±30 s after the beginning of each
session. The subject was instructed to avoid counting the
timing verbally. Ten sessions were performed successively
for each task. The order of motor tasks was counterbalanced
across the patients and across the control subjects.
To identify the timing of the motor event, the surface EMG
signals were recorded from the bilateral ECR and FCU during
each functional scanning using a digital EEG±EMG recording system (EEG 2100; Nihonkohden, Tokyo, Japan). A pair
of carbon electrodes (BRS-150E; NEC Medical Systems,
Tokyo, Japan) was placed over each muscle belly, 2 cm apart
from each other. The EMG signals were ®ltered with 30±
120 Hz pass-band (±3 dB), digitized at 500 Hz and stored on a
magneto-optical disk for the subsequent analysis. During
image acquisition, radio frequency pulses arising from the
MRI scanner produced electric signal on the EMG record at a
regular pace. By referring to these signals, the timing of the
motor event was identi®ed as an abrupt decrease and increase
of EMG discharges for the muscle relaxation and contraction,
respectively (Fig. 1B). Additionally, two of the authors
visually monitored the timing of the motor event as well as
the task performance throughout the image acquisition. After
the experiment, the subject was asked to report verbally on
the subjective dif®culty of each task.
Data analysis
Images were analysed using SPM96 software (Wellcome
Department of Cognitive Neurology, London, UK) with inhouse modi®cation (Toma et al., 1999). Calculations and
image matrix manipulations were performed in Matlab
(Mathworks, Sherborn, Mass., USA) on a Sun Sparc Ultra 2
workstation (Sun Microsystems, Mountain View, Calif.,
USA). The initial nine scans of each session were excluded
from the analysis to exclude non-equilibrium state of
magnetization. The effect of head motion across scans was
corrected by realigning all the scans to the ®rst one, using a
least sum of squares method with a 3D sinc interpolation
(Friston et al., 1994). Because each motor event was
performed in a self-initiated manner, the onset of motor
event was variable between the trials with respect to the
scanning time. Thus, all the series of dynamic scans were
realigned time-locked to the motor event. As a result, either
the ®rst or the last few scans were not included in the analysis
depending on the session. Global normalization was per-
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T. Oga et al.
formed by scaling the activity in each pixel linearly with
respect to global activity. Data were smoothed in the spatial
domain using an isotropic Gaussian kernel (full-width at halfmaximum = 7 mm) to improve the signal-to-noise ratio.
fMRI time series data were analysed using a general linear
model (Friston et al., 1995a). The analysis was performed on
an individual subject basis according to our previous study
(Toma et al., 1999). Three box-car functions were constructed to model each of the premotor, motor and postmotor
phases. For each function, the value `1' was given for the
phase of interest and `0' for the remaining phases. In terms of
the box-car function for the motor phase, three scans (one
coinciding with the event onset and the others its two
preceding scans) were assigned to 1. Each box-car function
was convolved with a Gaussian-shaped haemodynamic
response function (delay 6 s, dispersion 8 s) (Friston 1995b;
Worsley and Friston 1995) to produce three regressors of
interest used in the analysis. Systematic difference across
trials was modelled as a confounding effect. The general
linear model calculated a weighting coef®cient for each
regressor. To focus on a transient signal change associated
with motor event, we calculated t deviates at each voxel by
using a linear contrast (±1, 2, ±1) for (premotor, motor,
postmotor) and, after transforming into Z scores with the unit
normal distribution, created SPM{Z} maps consisting of the
voxels with Z > 3.09 with no correction. For the sake of
convenience in this article, we use the term `activation' to
represent the transient signal increase disclosed by the above
analysis.
To obtain standardized anatomical information of activated
foci, SPM{Z} was transformed into the standardized space in
Talairach coordinates (Talairach and Tournoux, 1988) by
applying the parameters obtained from the anatomical
normalization of the 3D anatomic image after coregistering
it with ®ve-slice functional and anatomical images. The x, y
and z coordinates of the voxels with maximum Z score in each
region were analysed statistically between the two tasks using
MANOVA (multivariate analysis of variance).
The region of interest (ROI) was set up on the left SMC and
bilateral SMA, based on the results of our previous fMRI
study (Toma et al., 1999). First, the pre- and postcentral gyri
and the precentral hand knob (Yousry et al., 1997) were
identi®ed on the anatomical axial images. The activated area
around the hand knob was accepted as the SMC. Then,
adopting the mean location of the peak activation in the SMC
of the two tasks as a centre for each subject, a 3D rectangular
ROI with a ®xed size (20 mm 3 20 mm 3 24 mm) was
de®ned so as to cover the SMC activation of all the subjects.
As for SMA, the clusters of activated voxels along the
interhemispheric ®ssure anterior to the bilateral central sulci
were identi®ed in both tasks in all subjects. The centre of the
ROI was de®ned as the mean location of the peak activation
in the SMA of the two tasks in each subject. A 3D rectangular
ROI with a ®xed size (30 mm 3 50 mm 3 24 mm) covering
the activated clusters of the SMA was de®ned for all the
subjects. The volume of the activated voxels in each ROI was
statistically examined by ANOVA (analysis of variance) with
a post hoc test, with the factors of TASK (relaxation versus
contraction) and GROUP (patient versus control).
Results
Task performance
Both the patient and control groups performed all the tasks
satisfactorily. In the patient group, no dystonic postures were
seen during either task. Some control subjects and patients
reported that they felt the contraction task more dif®cult to
perform than the relaxation task. The mean onset time of
motor event with respect to the beginning of each session did
not differ between the groups or between the tasks (patient
29.1 6 2.3 s for relaxation and 29.9 6 2.3 s for contraction;
control 29.5 6 2.0 s for relaxation and 29.7 6 2.0 s for
contraction).
Imaging data
In Fig. 2A, activated areas associated with the muscle
contraction and relaxation tasks in one representative subject
from each group are superimposed on the subject's own
anatomical MRI. The robust activation was observed in the
left SMC and the SMA during both tasks. The left dorsal
premotor area was also activated in both groups and in
both tasks. In Fig. 2B, the mean signal change across 10
sessions in the SMA for the relaxation task from the same
patient as shown in Fig. 2A is shown. It is noteworthy that the
signal change was evident even in a single trial, which is
shown by dots representing each single value at each
sampling point.
The brain regions showing the signi®cant activation for
each task are shown in Table 1, along with the maximal Z
scores and the number of subjects who showed activation in
each region. The volume of voxels that showed signi®cant
activation within each ROI was evaluated statistically. The
two-factor ANOVA revealed that, for both tasks, the mean
activated volume was signi®cantly greater in the control
group than in the dystonia group both in the left SMC [F(1,
36) = 11.4, P < 0.005] and in the SMA [F(1, 36) = 5.6,
P < 0.05] (Fig. 3). For both the patient and control groups, the
activated volume in the SMA was signi®cantly larger in the
relaxation task than in the contraction task [F(1, 36) = 4.32,
P < 0.05], but no difference was found in the left SMC [F(1,
36) = 0.14, P = 0.71). There was no signi®cant
TASK 3 GROUP interaction in either area [SMC F(1,
36) = 0.37, P = 0.55; SMA F(1, 36) = 0.18, P = 0.67]. The
mean coordinates of the peak activation in the left SMC and
the SMA are shown for each task in each group in Table 2.
The MANOVA showed no signi®cant difference in the site
of activation in the left SMC (Wilk's lambda = 0.96, P = 0.72)
or in the SMA (Wilk's lambda = 0.90, P = 0.32) between the
groups or between the tasks.
Event-related fMRI in writer's cramp
Fig. 2 Activated areas for the muscle relaxation and contraction tasks in a representative patient and a
normal control subject (A), and the time course of signal change in the patient's SMA (B). (A) Activated
areas, which showed a signi®cant transient increase of activity time-locked to the motor event, are
superimposed on the subject's own anatomic MRI. The right side of the brain is shown on the right side
of the image in all ®gures. Activated areas in the left SMC and the SMA were smaller in the patient than
in the normal control subject in both relaxation and contraction tasks. (B) Averaged signal change across
10 sessions at the voxel showing the maximal Z score in the SMA for the relaxation task is represented
by a solid line. The same patient as shown in A. Each dot represents data from a single trial at each
sampling point. The vertical line indicates the offset of EMG activity. Clear transient increase of activity
is observed even in a single trial.
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T. Oga et al.
Table 1 Activated foci for muscle relaxation and contraction tasks in the patients with
writer's cramp and normal control subjects
Region
Left SMC
Patient
Control
SMA
Patient
Control
Left PMd
Patient
Control
Right PMd
Patient
Control
Left LPi
Patient
Control
Right LPi
Patient
Control
Relaxation
Contraction
Maximal Z score
Number of subjects
showing activation
Maximal Z score
Number of subjects
showing activation
3.8 6 1.6
4.8 6 1.5
8
10
4.1 6 1.4
5.7 6 1.8
7
11
5.6 6 1.8
6.5 6 1.3
7
12
5.1 6 1.6
6.2 6 1.2
7
12
3.9 6 1.2
4.1 6 1.8
6
5
3.5 6 1.4
4.9 6 1.4
3
9
4.1 6 1.0
4.1 6 1.1
4
5
3.5 6 0.8
4.2 6 1.2
4
10
4.8 6 1.3
3.8 6 0.9
4
4
4.2 6 1.4
3.7 6 1.1
7
7
3.8 6 0.9
4.9 6 1.1
2
2
3.9 6 1.3
4.0 6 1.0
3
4
PMd = dorsal premotor area; LPi = inferior parietal area
Discussion
Comparison with previous PET studies using
motor task
In the present study, we evaluated the cortical activities
associated with voluntary muscle contraction and relaxation
`separately' in patients with writer's cramp using eventrelated fMRI. The impaired cortical activation of SMC and/or
SMA by various motor tasks in patients with dystonia has
been shown by previous PET studies (Ceballos-Baumann
et al., 1995, 1997; IbaÂnÄez et al., 1999). In those studies,
however, activities associated with muscle contraction and
relaxation were mixed together due to the limitation of
temporal resolution. The present results provided further
evidence of the decreased activity of SMC and SMA
associated with not only voluntary muscle contraction, but
also muscle relaxation in writer's cramp. The ®nding strongly
supports a view that an impairment of the excitatory as well as
inhibitory motor control mechanism may be an underlying
mechanism of dystonia.
By contrast, several other studies showed a signi®cantly
greater activation in the SMC contralateral to the tested hand
in dystonia patients compared with normal subjects
(Odergren et al., 1998; Pujol et al., 2000). In these studies,
however, the patients actually developed the task-induced
dystonic posture during the experimental task. Thus, the
special form of the testing condition used in the present study
may be prone to the detection of covert underactivity of
cortical inhibitory neurones, while the other studies might
have disclosed the activity over¯ow in association with
dystonic movements probably as the result of overt breakdown of the inhibitory system (Hallett, 1998).
Abnormal cortical inhibitory mechanisms
Until now, the cortical inhibitory mechanism of the human
motor system has been investigated almost exclusively by
means of transcranial magnetic simulation. As for writer's
cramp, abnormality of the cortical inhibitory motor system
was also suggested using this method. By applying the
methods for testing the intracortical inhibition developed by
Kujirai et al. (1993), Ridding et al. (1995) found that there
was diminished inhibition in the motor cortex in patients with
focal hand dystonia. Several investigators also clari®ed the
impaired cortical inhibition in primary sensorimotor cortex in
dystonic patients by using paired magnetic shocks (Chen et al.
1997) or by estimation of the silent period during sustained
muscle contraction (Inghilleri et al., 1993; Filipovic et al.,
1997; Rona et al., 1998). On the other hand, Ikoma et al.
(1996) demonstrated increased motor evoked potential area
percentage in dystonia patients. This contradictory result can
be interpreted as the result of suppression of inhibitory
mechanism in the patients.
To our knowledge, there has been only one EEG study
addressing abnormal cortical inhibitory mechanisms in
dystonia. Yazawa et al. (1999) showed that the amplitude
of MRCP associated with voluntary muscle relaxation was
signi®cantly reduced at the contralateral central region in
patients with focal hand dystonia. As for the muscle
contraction, although Yazawa et al. (1999) failed to show
the difference between the patient and control groups, other
previous studies in various dystonic patients disclosed an
abnormal distribution of a diminished amplitude of the
premovement potential over the central area contralateral
to the movement (FeÁve et al., 1994; Deuschl et al., 1995;
Event-related fMRI in writer's cramp
901
Table 2 Mean coordinates of the peak activation in the
left SMC and the SMA (mean 6 SD) for muscle relaxation
and contraction tasks in the patients with writer's cramp
and normal control subjects
Left SMC
Contraction
Patient
Control
Relaxation
Patient
Control
SMA
Contraction
Patient
Control
Relaxation
Patient
Control
x
y
z
±36.9 6 5.5
±36.7 6 4.5
±16.9 6 5.9
±18.5 6 5.1
58.6 6 7.6
60.7 6 6.1
±32.9 6 4.3
±33.2 6 4.4
±17.7 6 5.7
±17.3 6 4.1
57.4 6 9.7
58.8 6 7.5
±0.6 6 3.2
0.8 6 3.9
0.9 6 9.5
4.3 6 5.7
54.3 6 5.9
52.8 6 7.6
0.0 6 2.6
2.2 6 4.7
6.8 6 10.1
6.8 6 5.9
56.8 6 10.8
55.2 6 11.1
Talairach x, y, z coordinates showing the highest Z scores are
shown in the left SMC and in the SMA for each task in each
group
Fig. 3 Volume of the activated areas in the left SMC and the SMA
during the muscle relaxation and contraction tasks (mean 6 SD)
in the patient and control groups. The activated volume in the left
SMC and the SMA is signi®cantly larger in the normal control
group than in the patient group without interaction (TASK 3
GROUP). *P < 0.05 and **P < 0.005 by ANOVA. Black =
relaxation; grey = contraction.
Van der Kamp et al., 1995). The discrepancy between the
present ®nding and that by Yazawa et al. (1999) may be due
partly to the difference in the motor task employed in the two
studies. In the study by Yazawa et al. (1999), the muscles
were completely relaxed before the muscle contraction, while
in the present study the subjects maintained weak muscle
contraction during the premotor phase. The difference in
proprioceptive feedback to the sensorimotor cortices before
the motor event might have caused the discrepancy in the two
studies.
Interpretation of underactivation of motorrelated cortices in dystonia
Impaired activation in SMC and SMA as demonstrated in this
study may be considered to re¯ect dysfunction of the motor
circuit connecting basal ganglia and cortical areas. According
to a recent hypothesis, basal ganglia act broadly to inhibit the
competing motor mechanisms that would otherwise interfere
with the desired movement (Mink, 1996). Perlmutter et al.
(1997) suggested that, in patients with dystonia, impaired
striatal D2 activity might cause diminished activity of an
indirect pathway of the basal ganglia and subsequent
disfacilitation of the thalamocortical projections to the
primary motor cortex and SMA.
Alternatively, an in¯uence of the proprioceptive sensory
input has to be taken into consideration. The afferent
feedback from motor execution may cause the peri-rolandic
activation, as reported in the studies of EEG (Mima et al.,
1996) and PET (Weiller et al., 1996; Mima et al., 1999) using
passive movements as the stimulus. Abnormalities of SMC
and SMA in dystonia have been reported by the studies
applying the somatosensory paradigms (Tempel and
Perlmutter, 1993; Feiwell et al., 1999). Based on the
neurophysiological evidence (Tempel and Perlmutter, 1990;
Kaji et al., 1995b), the possibility of abnormal sensory
processing in patients with dystonia was proposed (Hallett,
1995). Recently, Murase et al. (2000) from our group
demonstrated that, in patients with writer's cramp, the N30
component of the median nerve somatosensory evoked
potential failed to be modulated selectively during the
premovement period in a task-speci®c way, while it was
suppressed (gating) in normal subjects. This result suggests
faulty central sensory processing during the movement
preparation in the patients with writer's cramp. In the present
study, the subjects were asked to keep their wrist extended
horizontally just before the motor event and to start to relax or
contract the wrist voluntarily from that position. Thus, the
effect of muscle afferent input before and during motor event
has to be considered. We envisage a possibility that the
capacity required for processing sensory afferent information
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T. Oga et al.
before the motor event might be reduced in patients with
dystonia due to abnormal sensory processing.
In conclusion, we demonstrated for the ®rst time the
abnormally reduced activation in motor-related cortical areas
in patients with writer's cramp, associated with both voluntary muscle relaxation and contraction. Future studies on the
relationship between motor inhibitory mechanisms and the
basal ganglia or somatosensory cortex may provide useful
information to explore the pathophysiology of dystonia.
Acknowledgements
The authors wish to thank Drs Hans Joachim Freund, Mark
Hallett, Ritta Hari, John C. Rothwell, Christian Gerloff and
Rudiger J. Seitz for helpful discussions and comments. The
research reported in this article was partly supported by
Grants-in-Aid for Scienti®c Research Priority Area (C)
(Advanced Brain Science) 12210012 and 13210143,
Scienti®c Research (B) 13470134 and Special Coordination
Funds for Promoting Science and Technology from the Japan
Ministry of Education, Culture, Sports, Science and
Technology, and Research for the Future Program JSPSRFTF97L00201 from The Japan Society for the Promotion of
Science.
References
Barker AT, Freeston IL, Jalinous R, Jarratt JA. Magnetic
stimulation of the human brain and peripheral nervous system: an
introduction and the results of an initial clinical evaluation.
Neurosurgery 1987; 20: 100±9.
Berardelli A, Rothwell JC, Hallett M, Thompson PD, Manfredi M,
Marsden CD. The pathophysiology of primary dystonia. [Review].
Brain 1998; 121: 1195±212.
Ceballos-Baumann AO, Passingham RE, Warner T, Playford ED,
Marsden CD, Brooks DJ. Overactive prefrontal and underactive
motor cortical areas in idiopathic dystonia. Ann Neurol 1995; 37:
363±72.
Ceballos-Baumann AO, Sheean G, Passingham RE, Marsden CD,
Brooks DJ. Botulinum toxin does not reverse the cortical
dysfunction associated with writer's cramp. A PET study. Brain
1997; 120: 571±82.
Chen R, Wassermann EM, Canos M, Hallett M. Impaired inhibition
in writer's cramp during voluntary muscle activation. Neurology
1997; 49: 1054±9.
Deuschl G, Toro C, Matsumoto J, Hallett M. Movement-related
cortical potentials in writer's cramp. Ann Neurol 1995; 38: 862±8.
Fahn S. Concept and classi®cation of dystonia. [Review]. Adv
Neurol 1988; 50: 1±8.
Feiwell RJ, Black KJ, McGee-Minnich LA, Snyder AZ, MacLeod
AM, Perlmutter JS. Diminished regional cerebral blood ¯ow
response to vibration in patients with blepharospasm. Neurology
1999; 52: 291±7.
FeÁve A, Bathien N, Rondot P. Abnormal movement related
potentials in patients with lesions of basal ganglia and anterior
thalamus. J Neurol Neurosurg Psychiatry 1994; 57: 100±4.
Filipovic SR, Ljubisavljevic M, Svetel M, Milanovic S, Kacar A,
Kostic VS. Impairment of cortical inhibition in writer's cramp as
revealed by changes in electromyographic silent period after
transcranial magnetic stimulation. Neurosci Lett 1997; 222:
167±70.
Friston KJ, Jezzard P, Turner R. Analysis of functional MRI timeseries. Hum Brain Mapp 1994; 1: 153±71.
Friston KJ, Holmes AP, Worsley KJ, Poline JB, Frith CD,
Frackowiak RSJ. Statistical parametric maps in functional
imaging: a general linear approach. Hum Brain Mapp 1995a; 2:
189±210.
Friston KJ, Holmes AP, Poline JB, Grasby PJ, Williams SC,
Frackowiak RS, et al. Analysis of fMRI time-series revisited.
Neuroimage 1995b; 2: 45±53.
Hallett M. Is dystonia a sensory disorder? Ann Neurol 1995; 38:
139±40.
Hallett M. The neurophysiology of dystonia. [Review]. Arch Neurol
1998; 55: 601±3.
IbaÂnÄez V, Sadato N, Karp B, Deiber MP, Hallett M. De®cient
activation of the motor cortical network in patients with writer's
cramp. Neurology 1999; 53: 96±105.
Ikoma K, Samii A, Mercuri B, Wassermann EM, Hallett M.
Abnormal cortical motor excitability in dystonia. Neurology 1996;
46: 1371±6.
Inghilleri M, Berardelli A, Cruccu G, Manfredi M. Silent period
evoked by transcranial stimulation of the human cortex and
cervicomedullary junction. J Physiol (Lond) 1993; 466: 521±34.
Kaji R, Kohara N, Katayama M, Kubori T, Mezaki T, Shibasaki H,
et al. Muscle afferent block by intramuscular injection of lidocaine
for the treatment of writer's cramp. Muscle Nerve 1995a; 18: 234±
5.
Kaji R, Rothwell JC, Katayama M, Ikeda T, Kubori T, Kohara N,
et al. Tonic vibration re¯ex and muscle afferent block in writer's
cramp. Ann Neurol 1995b; 38: 155±62.
Karbe H, Holthoff VA, Rudolf J, Herholz K, Heiss WD. Positron
emission tomography demonstrates frontal cortex and basal ganglia
hypometabolism in dystonia. Neurology 1992; 42: 1540±4.
Kujirai T, Caramia MD, Rothwell JC, Day BL, Thompson PD,
Ferbert A, et al. Corticocortical inhibition in human motor cortex. J
Physiol (Lond) 1993; 471: 501±19.
Mills KR. Excitatory and inhibitory effects on human spinal
motoneurones from magnetic brain stimulation. Neurosci Lett 1988;
94: 297±302.
Mima T, Terada K, Maekawa M, Nagamine T, Ikeda A, Shibasaki
H. Somatosensory evoked potentials following proprioceptive
stimulation of ®nger in man. Exp Brain Res 1996; 111: 233±45.
Mima T, Sadato N, Yazawa S, Hanakawa T, Fukuyama H,
Yonekura Y, et al. Brain structures related to active and passive
®nger movements in man. Brain 1999; 122: 1989±97.
Mink JW. The basal ganglia: focused selection and inhibition of
Event-related fMRI in writer's cramp
competing motor programs. [Review]. Prog Neurobiol 1996; 50:
381±425.
Murase N, Kaji R, Shimazu H, Katayama-Hirota M, Ikeda A,
Kohara N, et al. Abnormal premovement gating of somatosensory
input in writer's cramp. Brain 2000; 123: 1813±29.
Odergren T, Stone-Elander S, Ingvar M. Cerebral and cerebellar
activation in correlation to the action-induced dystonia in writer's
cramp. Mov Disord 1998; 13: 497±508.
Perlmutter JS, Tempel LW, Black KJ, Parkinson D, Todd RD.
MPTP induces dystonia and parkinsonism. Clues to the
pathophysiology of dystonia. Neurology 1997; 49: 1432±8.
Pujol J, Roset-Llobet J, Rosines-Cubells D, Deus J, Narberhaus B,
Valls-Sole J, et al. Brain cortical activation during guitar-induced
hand dystonia studied by functional MRI. Neuroimage 2000; 12:
257±67.
Ridding MC, Sheean G, Rothwell JC, Inzelberg R, Kujirai T.
Changes in the balance between motor cortical excitation and
inhibition in focal, task speci®c dystonia. J Neurol Neurosurg
Psychiatry 1995; 59: 493±8.
Roland PE, Larsen B, Lassen NA, Skinhoj E. Supplementary motor
area and other cortical areas in organization of voluntary
movements in man. J Neurophysiol 1980; 43: 118±36.
Rona S, Berardelli A, Vacca L, Inghilleri M, Manfredi M.
Alterations of motor cortical inhibition in patients with dystonia.
Mov Disord 1998; 13: 118±24.
Sheehy MP, Marsden CD. Writers' crampÐa focal dystonia. Brain
1982; 105: 461±80.
903
Tempel LW, Perlmutter JS. Abnormal vibration-induced cerebral
blood ¯ow responses in idiopathic dystonia. Brain 1990; 113: 691±
707.
Tempel LW, Perlmutter JS. Abnormal cortical responses in patients
with writer's cramp. Neurology 1993; 43: 2252±7.
Toma K, Honda M, Hanakawa T, Okada T, Fukuyama H, Ikeda A,
et al. Activities of the primary and supplementary motor areas
increase in preparation and execution of voluntary muscle
relaxation: an event- related fMRI study. J Neurosci 1999; 19:
3527±34.
VanderKamp W, Rothwell JC, Thompson PD, Day BL, Marsden
CD. The movement-related cortical potential is abnormal in
patients with idiopathic torsion dystonia. Mov Disord 1995; 10:
630±3.
Wassermann EM, Pascual-Leone A, Valls-Sole J, Toro C, Cohen
LG, Hallett M. Topography of the inhibitory and excitatory
responses to transcranial magnetic stimulation in a hand muscle.
Electroencephalogr Clin Neurophysiol 1993; 89: 424±33.
Weiller C, Juptner M, Fellows S, Rijntjes M, Leonhardt G, Kiebel
S, et al. Brain representation of active and passive movements.
Neuroimage 1996; 4: 105±110.
Worsley KJ, Friston KJ Analysis of fMRI time-series revisitedÐ
again [letter]. Neuroimage 1995; 2: 173±181.
Yazawa S, Ikeda A, Kaji R, Terada K, Nagamine T, Toma K, et al.
Abnormal cortical processing of voluntary muscle relaxation in
patients with focal hand dystonia studied by movement-related
potentials. Brain 1999; 122: 1357±66.
Shibasaki H, Sadato N, Lyshkow H, Yonekura Y, Honda M,
Nagamine T, et al. Both primary motor cortex and supplementary
motor area play an important role in complex ®nger movement.
Brain 1993; 116: 1387±98.
Yousry TA, Schmid UD, Alkadhi H, Schmidt D, Peraud A, Buettner
A, et al. Localization of the motor hand area to a knob on the
precentral gyrus. A new landmark. Brain 1997; 120: 141±57.
Talairach J, Tournoux P. Co-planar sterotaxic atlas of the human
brain. Stuttgart: Thieme; 1988.
Received August 9, 2001. Revised November 6, 2001.
Accepted 10 November, 2001