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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.
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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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

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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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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

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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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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

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Received August 9, 2001. Revised November 6, 2001. Accepted 10 November, 2001