Brain Advance Access originally published online on November 9, 2005
Brain 2006 129(1):36-46; doi:10.1093/brain/awh665
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Silent event-related fMRI reveals deficient motor and enhanced somatosensory activation in orofacial dystonia
Departments of 1 Neurology, 2 Radiology and 3 Nuclear Medicine, Klinikum rechts der Isar Muenchen, 4 Neurologisches Krankenhaus Muenchen, Germany
Correspondence to: Christian Dresel, MD, Klinikum rechts der Isar, Department of Neurology, Technische Universitaet Muenchen, Moehlstrasse 28, D-81675 Munich, Germany E-mail: dresel{at}lrz.tu-muenchen.de
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Summary |
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Previous studies showed cortical dysfunction and impaired sensorimotor integration in primary generalized and focal hand dystonia. We used a whistling task and silent event-related fMRI to investigate functional changes in patients with blepharospasm and patients with a combination of blepharospasm and oromandibular dystonia (Meige's syndrome). Whistling served as a model for a skilful orofacial movement with a high demand on sensorimotor integration. It allowed us to study the oromandibular motor system that is clinically affected in Meige's syndrome but not in isolated blepharospasm. In Meige's syndrome, functional MRI revealed deficient activation of the primary motor and ventral premotor cortex within the mouth representation area during whistling. Compared with healthy controls, both forms of orofacial dystonia had increased activation of bilateral somatosensory areas and the caudal supplementary motor area (SMA) in common. While overactivity of somatosensory areas and caudal SMA in Meige patients was partly reversed by botulinum toxin treatment, impaired motor activation was not. We conclude that impaired motor activation appears to be specific for the clinically affected oromandibular motor system in Meige's syndrome while enhanced somatosensory activation is a common abnormality in both forms of orofacial dystonia independent of the affected motor system. Somatosensory overactivity indicates an altered somatosensory representation in orofacial dystonia while impaired motor activation may be a functional correlate of reduced cortical inhibition during oromandibular motor execution in Meige's syndrome.
Key Words: fMRI; functional reorganization; orofacial movements; focal dystonia; blepharospasm
Abbreviations: BA = Brodmann area; BLEPH = patients with blepharospasm; BTX = botulinum toxin; CONTR = healthy control subjects; MEIGE = patients with Meige's syndrome; postBTX = after botulinum toxin therapy; preBTX = before botulinum toxin therapy; RMS = root mean square; SMA = supplementary motor area; S1 = primary somatosensory cortex; TMS = transcranial magnetic stimulation; UDRS = Unified Dystonia Rating Scale
Received June 9, 2005. Revised August 18, 2005. Accepted September 20, 2005.
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Introduction |
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Idiopathic or essential blepharospasm is an adult-onset focal dystonia that causes involuntary blinking and eyelid spasms (Berardelli et al., 1998
; Hallett, 2002). A combination of blepharospasm and oromandibular dystonia is called Meige's syndrome. Some patients with blepharospasm may develop Meige's syndrome with time (Defazio et al., 1999). The aetiology and pathophysiology of these and other primary focal dystonias and the progression of symptoms are not well understood.
Previous reports favour the hypothesis that a combination of environmental trigger and genetic predisposition leads to plastic changes in the brain and reduced cortical inhibition (Hallett, 2002).
Positron emission tomography (PET) and functional MRI (fMRI) provide non-invasive tools to investigate functional reorganization in patients with primary dystonia. Activation studies with H215O-PET or blood oxygen level dependent (BOLD)-contrast fMRI discovered cortical and subcortical dysfunction in dystonic patients during various motor tasks. Ceballos-Baumann et al. (1995) found underactivity of the sensorimotor cortex and caudal supplementary motor area (SMA) as well as overactivity of the lentiform nucleus and rostral SMA (preSMA) during paced joystick movements in patients with primary generalized torsion dystonia. Impaired activation of the primary motor and premotor cortex and the caudal SMA was revealed in patients with writer's cramp during writing (Ceballos-Baumann et al., 1997; Ibanez et al., 1999). Passive sensory stimulation yielded deficient activation of the sensorimotor cortex in patients with idiopathic or focal hand dystonia (Tempel and Perlmutter, 1990, 1993).
Deficient sensorimotor activation was not found consistently across different studies. For instance, guitar-induced hand dystonia led to extended activation of the primary motor cortex in patients with musician's cramp (Pujol et al., 2000), and activity in the sensorimotor and premotor cortex increased with prolonged writing in a group of patients with writer's cramp (Odergren et al., 1998). Different tasks and a varying degree of dystonia during motor execution may account for at least some of the observed differences in activation.
Compared with focal hand dystonia, few neuroimaging data are available on orofacial dystonia. Conventional neuroradiologic methods including structural MRI do not show any abnormalities. An 18F-deoxyglucose-PET study found abnormal metabolic rates in pons, cerebellum and frontal eye fields of patients with blepharospasm (Hutchinson et al., 2000). Passively stimulating the hand and mouth in patients with orofacial dystonia resulted in reduced activation of the sensorimotor cortex compared with normal subjects (Feiwell et al., 1999). Functional MRI revealed that episodes of involuntary eyelid spasms correlated with increased striatal activation in patients with blepharospasm (Schmidt et al., 2003).
The aim of this study was to investigate functional changes in patients with blepharospasm and patients with a combination of blepharospasm and oromandibular dystonia (Meige's syndrome) during the execution of a skilled orofacial movement with a high demand on sensorimotor control, i.e. whistling. The whistling task allowed us to study the oromandibular motor system that is clinically affected in Meige's syndrome and asymptomatic in isolated blepharospasm. While previous imaging studies focused on the affected motor system, we also examined patients with isolated blepharospasm to search for subclinical abnormalities without confounding oromandibular dystonic movements. We hypothesized that whistling yields abnormal sensorimotor activation in patients with orofacial dystonia as was found for other forms of focal dystonia (Ceballos-Baumann et al., 1995, 1997; Ibanez et al., 1999; Pujol et al., 2000). We were interested in how the amount of dysfunction would vary between the two patient groups. We assumed that changes of activation due to botulinum toxin (BTX) treatment would be a functional correlate of symptomatic improvement in patients while such treatment should hardly have any influence on areas affected by the primary pathology of dystonia.
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Subjects
We studied three different groups: 13 patients with blepharospasm (BLEPH), three of them BTX-naïve, 13 patients with Meige's syndrome (MEIGE), two of them BTX-naïve and 13 healthy control subjects (CONTR). The mean age was 61.6 (range: 49–71) years in the BLEPH group, 62.4 (range: 46–69) years in the MEIGE group and 54.8 (range: 42–66) years in the CONTR group. Patients with blepharospasm on average had symptoms for 6.3 ± 4.9 (SD) years and received a mean dose of 155 ± 49 units of BTX (Dysport®) while patients with Meige's syndrome had symptoms for 9.5 ± 6.5 years and a mean dose of 181 ± 49 units of BTX. Out of the 13 patients with Meige's syndrome, 12 initially presented with blepharospasm for at least several months before they developed oromandibular dystonia.
Patients were prospectively recruited from our movement disorder clinics. Inclusion criteria were: (i) idiopathic blepharospasm or Meige's syndrome, (ii) no previous neuroleptic medication, (iii) no other neurologic or psychiatric disease, (iv) normal MRI brain scan, (v) right-handedness according to the Edinburgh handedness inventory (Oldfield, 1971) and (vi) ability to whistle for >3 s without interrupting dystonic movements. All except BTX-naïve patients received regular periorbital injections of BTX at intervals of 
3 months. Among the 13 patients with Meige's syndrome, three had additional injections into the platysma, one had additional injections into the masseter and another one had additional injections into the platysma and the masseter prior to the study. One patient had received injections into the M. orbicularis oris. All participants gave their written informed consent according to the Declaration of Helsinki, and the study protocol was approved by the ethics board of the Klinikum rechts der Isar, Technische Universitaet Muenchen.
Patients had two fMRI appointments: 4 weeks (postBTX) and 3 months (preBTX) after the last BTX injection. The dates of the preBTX and postBTX measurements were randomized and balanced within the groups. Patients were videotaped on these days according to a videoprotocol of the Dystonia Study Group (Comella et al., 2003), and a clinical status was obtained using two different clinical scales: the Fahn–Marsden scale (Burke et al., 1985) and the Unified Dystonia Rating Scale (UDRS; Comella et al., 2003). To obtain the Fahn–Marsden scale, a provoking factor (0–4), a severity factor (0–4) and a weighting factor (0.5–1) are multiplied and subsequently added for nine different body areas. To calculate the UDRS, the duration and severity of dystonia are rated from 0 (no dystonia) to 4 (75% of time/maximal inability) and added for 14 different body areas. A training session before the fMRI experiment ensured that patients and control subjects performed the task adequately.
Silent event-related fMRI and tasks
To minimize task-related imaging artefacts during the execution of orofacial movements, a silent event-related fMRI paradigm (Amaro et al., 2002) was used where intervals of image acquisition (EPI: 2.63 s) alternated with silent periods (8.47 s) for performance of the task (Fig. 1). The task onset was jittered within the silent interval in order to avoid effects of anticipation and habituation. The time of image acquisition was synchronized with the maximum of the haemodynamic response function.
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Whistling (WH: 3 s) is a well-defined orofacial motor task with a high demand on sensorimotor integration and motor precision and was used to investigate the oromandibular motor system. Task performance during functional MRI was monitored by recording the generated whistle sounds using a home-built MR-compatible microphone. Voluntary breathing (BR: 3 s) was chosen as an appropriate control condition to cancel out respiratory-related activations (Fink et al., 1996
; McKay et al., 2003). During the breathing condition, subjects had to breath out through their nostrils and listened to their own prerecorded whistle sound via MR-compatible headphones (Siemens, Erlangen, Germany). Each task was preceded by a preparatory interval (PREP: 1.72 s) where subjects were visually instructed to take a breath by an exclamation mark visible on a translucent screen (Fig. 1). The task symbols (WH or BR) were presented immediately after the preparatory interval. After completing the task, the subjects were instructed to relax for the next image acquisition (DELAY: 1.95 s).
The head was fixed with foam pads to minimize head movements. T2*-weighted whole brain echo planar images were acquired on a 1.5 T Siemens Symphony MRT (TR/TE/TA = 11 100 ms/50 ms/2630 ms, 
= 90°, FoV = 224 mm, 64 x 64, 28 slices à 4.5 mm, 10% slice gap). Four runs yielded 72 images per condition. A T1-weighted anatomical dataset was obtained from each subject using a magnetization prepared rapid acquisition gradient echo-sequence (TR/TE/TI = 1540 ms/3.93 ms/800 ms, = 12°, FoV = 256 mm, 160 slices, voxel size 1 x 1 x 1 mm3). Anatomical MR images were rated normal by an experienced neuroradiologist who was blinded to the diagnosis.
fMRI data analysis
Functional imaging data were analysed using the statistical parametric mapping software SPM2 (Wellcome Insititute of Imaging Neuroscience, London, http:/www.fil.ion.ucl.ac.uk/spm/) and MATLAB (The Mathworks Inc., Natick, USA). After discarding the first three images to allow for magnetization effects to settle, functional images of all four runs were realigned to the first image and normalized to the Montreal Neurological Institute (MNI) template (Friston et al., 1995a). Normalized images were smoothed with an isotropic Gaussian kernel of 8 mm full width at half maximum before entering the statistical analysis (Friston et al., 1995b). To reduce the effect of low-frequency drifts arising from respiratory motion or scanner equipment, global normalization to the grand mean was used. First level contrast images for the contrast whistling versus breathing (WH > BR) were created for each subject using a subtraction model where the baseline images were subtracted from active task-images. In a second level (random effects) analysis, t-tests were applied to these contrast images in order to draw population-based inferences about statistically significant differences within and between groups (Holmes and Friston, 1998). Since we expected to find activation of a sensorimotor network including sensorimotor and premotor cortex, SMA, cingulate gyrus, thalamus, insula, basal ganglia and cerebellum in the within-group and between-group comparisons (Frackowiak et al., 1998), the threshold of significance for activation in these areas was set at P < 0.001 uncorrected.
Performance analysis
Reaction time (RT), execution time (ET), fundamental frequency (FF) and root mean square (RMS) amplitude of each whistle sound are acoustic measures for the motor performance and control during whistling and were extracted from each participant's audio files using a MATLAB-based algorithm. The RMS amplitude served as a parameter for the loudness of the sound signal as no measurement of absolute sound pressure levels was possible within the magnetic environment of the scanner. For each subject, the intra-subject mean values 
, 
, 
and 
and SDs RTV, ETV, FFV and RMSV that provide a measure for the intra-subject variability of these parameters were calculated. Lower amplitudes and higher variabilities of , or amplitude indicate deficits in motor control and performance during whistling and suggest difficulties in repeatedly producing a constant whistle sound. For group comparisons, we computed the intra-group mean values and SDs thereof. We performed multiple two-sided t-tests with a significance threshold of P < 0.05, corrected for multiple comparisons, to test for significant differences of mean parameters between the groups.
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Task performance
The quantitative analysis of acoustic recordings confirmed that patients and control subjects performed the task accurately with similar motor performance and no errors (Table 1). No significant difference in key performance parameters was found between the groups. Patients with Meige's syndrome had slightly lower mean RMS amplitudes compared with controls and blepharospasm patients, which indicates that Meige patients had difficulties with the precise motor control during whistling. This finding reflects the longer duration and the more widespread manifestation of dystonia in these patients compared with patients with blepharospasm. The videotapes showed no increase of dystonic symptoms during whistling outside the scanner room. BTX treatment was effective in all patients according to the clinical assessment and the evaluation of the clinical scores. The Fahn–Marsden scale for the group BLEPH preBTX was 2.9 ± 1.3 (SD) and improved by 1.9 ± 1.3 postBTX while the UDRS preBTX was 3.8 ± 0.8 and improved by 1.8 ± 1.2 postBTX. In the MEIGE group, the Fahn–Marsden scale preBTX was 5.4 ± 3.7 and improved by 2.5 ± 2.8 postBTX while the UDRS preBTX was 7.8 ± 2.7 and improved by 2.8 ± 1.3 postBTX.
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Within-group comparisons
CONTR
The whistling task activated a symmetrically represented sensorimotor network including the following areas compared with voluntary breathing: the mouth representation area of the sensorimotor and ventral premotor cortex, bilateral thalamus, right globus pallidus, left putamen, bilateral rostral paravermal cerebellum, brainstem and the occipital cortex (Table 2; Fig. 2A).
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BLEPH
Whistling activated the following areas bilaterally in patients with blepharospasm preBTX: sensorimotor and ventral premotor cortex, caudal SMA, insula (Brodmann area; BA 13), putamen, rostral paravermal cerebellum, brainstem and occipital cortex. Unilateral activations were found in the left anterior cingulate cortex, left globus pallidus and right thalamus. A similar network without significant activation of the insula was observed postBTX.
MEIGE
In patients with Meige's syndrome preBTX, whistling activated the sensorimotor and ventral premotor cortex, the rostral paravermal cerebellum and the occipital cortex bilaterally, and the globus pallidus and pons on the left side. A similar network except activation of the left globus pallidus was found postBTX.
Between-group comparisons
BLEPH preBTX versus CONTR
Patients with blepharospasm preBTX showed overactivity of the post-central gyrus (BA 2/40) and caudal SMA bilaterally, the left dorsolateral prefrontal cortex (DLPFC, BA 44) and the left paravermal cerebellum during whistling compared with healthy controls (Table 3; Fig. 3A). Deficient activation was found in the left cerebellum and the left fusiform gyrus.
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MEIGE preBTX versus CONTR
Patients with Meige's syndrome preBTX had deficient bilateral activation of the motor and ventral premotor cortex, particularly of the right ventral premotor cortex, in the mouth representation area during whistling compared with normal controls (Fig. 2B). Similar to patients with isolated blepharospasm preBTX, relative overactivity of the post-central gyrus and, at a lower threshold of significance (P < 0.01 uncorrected, extent threshold 25 voxels), of the left caudal SMA was found (Fig. 3B).
MEIGE preBTX versus BLEPH preBTX
Deficient bilateral activation of the motor and ventral premotor cortex was also found when patients with Meige's syndrome preBTX were compared to patients with blepharospasm preBTX (Fig. 2C).
BLEPH preBTX versus postBTX
There was no significant difference of activation in patients with blepharospasm preBTX and postBTX.
MEIGE preBTX versus postBOTX
PostBTX, overactivity in the right post-central gyrus and inferior parietal cortex (BA 40) as well as the left caudal SMA found in the contrast MEIGE preBTX versus CONTR was significantly reduced (Fig. 3C).
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Discussion |
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In this study we used silent event-related fMRI to investigate functional changes in patients with blepharospasm and patients with a combination of blepharospasm and oromandibular dystonia (Meige's syndrome) during whistling. Whistling allowed us to study the oromandibular motor system that is clinically affected in Meige's syndrome and adjacent to the affected periorbital motor system in isolated blepharospasm. The whistling task activated a common distributed network including the sensorimotor and ventral premotor cortex, basal ganglia and rostral paravermal cerebellum in all groups. Patients with Meige's syndrome showed deficient activation of the primary motor and ventral premotor cortex in the mouth representation area when compared with normal subjects and patients with isolated blepharospasm. Compared with controls, both forms of orofacial dystonia had relative overactivity of the bilateral post-central gyrus and the caudal SMA in common. BTX therapy partly reversed the overactivity of post-central gyrus and caudal SMA in Meige's syndrome.
Impaired activation of primary motor and premotor areas in Meige's syndrome
Deficient activation of the primary motor and ventral premotor cortex during whistling appears to be a specific finding for the clinically affected oromandibular motor system in Meige's syndrome as it was not found in isolated blepharospasm. This impaired motor activation was not reversed by BTX therapy despite clinical improvement. It is, therefore, considered as being related to the primary pathology of orofacial dystonia.
Analogous to the current findings in Meige's syndrome, a number of studies that focused on the clinically affected motor system have reported deficient motor activation in other forms of primary dystonia, e.g. during writing in patients with writer's cramp (Ceballos-Baumann et al., 1997; Ibanez et al., 1999) or during joystick movements in patients with idiopathic torsion dystonia (Ceballos-Baumann et al., 1995). The tasks in these studies induced some degree of dystonia during motor execution and, similar to our findings, the observed impairment of motor activation was not reversed by the peripheral motor de-efferentiation due to BTX injections (Ceballos-Baumann et al., 1997). Other imaging studies described extended activation within the primary sensorimotor cortex compared with controls suggesting enhanced primary motor activity, e.g. during full expression of guitar-induced hand dystonia in patients with musician's cramp (Pujol et al., 2000) or during writing in patients with writer's cramp (Preibisch et al., 2001). In contrast to blepharospasm and oromandibular dystonia, musician's cramp and writer's cramp are task-specific dystonias. To date, it is not clear whether task-specific dystonias are particular manifestations of a focal dystonia or whether they are completely different conditions with a distinct pathophysiology (Berardelli et al., 1998). It would, therefore, not be surprising to find different cerebral activation patterns for diverse forms of dystonia. Furthermore, the observed activation patterns in studies of the affected motor system may be confounded by the task used in the individual study and the onset and severity of dystonia during motor execution.
A confounding effect of dystonia during motor execution was observed in patients with simple writer's cramp where initially diminished activation of the sensorimotor and premotor cortex increased with prolonged writing and progression of symptoms (Odergren et al., 1998). Further support for an influence of dystonia on activation patterns comes from another study on simple writer's cramp (Ibanez et al., 1999). These patients remained free of symptoms during a contraction task of the affected hand but developed a varying degree of dystonia during writing. The centre of deficient activation was located in the contralateral sensorimotor cortex during the contraction task and in the premotor cortex during writing. In our study, patients with Meige's syndrome disclosed impaired activation of both areas. Writing and whistling are skilled movements with a high demand on sensorimotor integration and movement control. Studies on finely controlled finger movements (Ehrsson et al., 2000; Sadato et al., 1996) have observed a function of the premotor cortex in sensorimotor integration and control of limb movements. The finding of impaired premotor activation in writer's cramp and Meige's syndrome may indicate a common deficit of sensorimotor integration in these patients since previous reports have already suggested disturbed sensorimotor integration in patients with dystonia (Abbruzzese and Berardelli, 2003). For instance, patients who are affected by focal hand dystonia had problems to correctly programme the grip-lift force interaction during a precision grip task while the trajectory of movement was intact (Odergren et al., 1996).
The asymptomatic hand contraction task in the study by Ibanez et al. (1999) did not require the same amount of sensorimotor integration as the writing task. The authors argued that deficient activation of the primary motor cortex during this task not confounded by dystonic motor activity is a subclinical abnormality of the affected hand in writer's cramp and may be related to the underlying pathology of focal dystonia. In our study, we extended these findings by investigating patients with isolated blepharospasm where the oromandibular motor system is not affected by dystonia. But although neurophysiological and imaging studies had previously detected subclinical abnormalities in asymptomatic or distant body parts of patients with orofacial (Curra et al., 2000; Feiwell et al., 1999) or other forms of dystonia (Tempel and Perlmutter, 1990, 1993; Pauletti et al., 1993; Byrnes et al., 1998; Thickbroom et al., 2003), we did not find dysfunctional motor activation in blepharospasm as expected. As stated above, we conclude that impaired motor and premotor activation appears to be a rather specific finding for the clinically affected motor system in Meige's syndrome.
While patients with a focal dystonia such as writer's cramp or Meige's syndrome revealed reduced premotor activation during motor execution, patients with primary generalized torsion dystonia showed enhanced activation of the lateral premotor cortex and the rostral SMA during joystick movements in freely chosen directions (Ceballos-Baumann et al., 1995). This difference in activation may reflect a different pathophysiology of focal and generalized dystonias as well as task-related effects. Externally triggered movements such as our whistling task predominantly activate the lateral premotor cortex while movement selection as in the joystick task is mainly associated with activity in the rostral SMA (Jahanshahi et al., 1995; Deiber et al., 1999). Moreover, one-dimensional joystick movements do not require the same high amount of coordination and sensorimotor control like writing or whistling, an aspect that may contribute to the observed differences in activation.
The cause of the observed functional changes in the motor and premotor cortex of patients with dystonia is unknown. A hypothesis favoured by many researchers is a task-related reduction of inhibitory activity compared with healthy controls (Ceballos-Baumann et al., 1997; Ibanez et al., 1999; Hallett, 2002). As the fMRI-BOLD signal does not distinguish between excitatory or inhibitory activity, reduced local inhibitory activity would yield a decrease in regional haemodynamic response (Logothetis and Pfeuffer, 2004). Alternatively, impaired motor activation could be due to decreased activation of cortical excitatory interneurons. However, electrophysiological data and animal research provide a stronger support for the hypothesis of a loss of inhibition than for a lack of intracortical excitation in the primary motor cortex. Clinically, deficient activation of excitatory interneurons does not explain very well the increase and overflow of peripheral muscular activity observed in dystonia.
Studies using transcranial magnetic stimulation (TMS) showed reduced inhibition and increased excitability of the motor cortex in focal dystonia compared with normal subjects (Ridding et al., 1995; Ikoma et al., 1996; Chen et al., 1997; Curra et al., 2000). Low-frequency repetitive TMS of the motor cortex yielded a temporary normalization of such deficient intracortical inhibition and a beneficial effect on handwriting in patients with writer's cramp (Siebner et al., 1999). Similarly, administration of BTX transiently normalized reduced intracortical inhibition of the primary motor cortex in idiopathic torsion cervical dystonia (Kanovsky et al., 2005) and in a mixed group of patients with generalized, segmental and task-specific dystonia (Gilio et al., 2000). The authors of the latter study proposed that these cortical changes most likely originate from peripheral BTX-mediated mechanisms of action, including a reduced input from muscle spindle afferents (Gilio et al., 2000; Hallett, 2000b). This proposal was substantiated by a subsequent TMS study that found reduced muscular M-responses during peripheral stimulation but failed to obtain significant differences of cortical excitability in a group of patients with writer's cramp (Boroojerdi et al., 2003). Earlier, Byrnes and colleagues had shown that the changes in corticomotor representations of hand and forearm muscles in patients with writer's cramp were temporarily reversed after injection of BTX (Byrnes et al., 1998). Regarding a long-term effect of BTX therapy, the study on idiopathic torsion cervical dystonia suggested that such treatment may have a permanent impact on cortical excitability and may contribute to the long-lasting treatment-induced remission in these patients (Kanovsky et al., 2005). Motor activation studies including our own study have so far not shown a significant effect of BTX treatment on activation of the primary motor cortex (Ceballos-Baumann et al., 1997).
A decrease in cortical negativity over the contralateral motor cortex prior to the onset of voluntary finger movements also indicated loss of inhibitory cortical activity in patients with writer's cramp (Deuschl et al., 1995) or primary generalized dystonia (Van der Kamp et al., 1995). In primates, dystonia-like movement patterns with co-contractions of agonist and antagonist muscles were induced when GABAergic function of inhibitory neurons in the primary motor cortex was interrupted by the GABA antagonist bicuculline (Matsumura et al., 1992). Evidence for a GABAergic deficit in human dystonia comes from an MR spectroscopic study that found reduced inhibitory GABA levels in the sensorimotor cortex and lentiform nuclei of patients with writer's cramp (Levy and Hallett, 2002).
A more diffuse, i.e. a less focused activation of primary motor and premotor areas may be an alternative explanation for the impaired motor activation observed in patients with Meige's syndrome or other forms of focal dystonia (Ceballos-Baumann et al., 1995, 1997; Ibanez et al., 1999). Areas that are more diffusely activated in the analysis of a single subject may achieve a greater spatial extent but a lower statistical significance in the within-group analysis. These areas may, therefore, appear as being deficiently activated in the between-group comparisons. Such diffused activations may well be due to the above-mentioned defective cortical inhibition, or they might be caused by a reorganization of corticomotor representations as was found in patients with writer's cramp applying TMS (Byrnes et al., 1998). Along with a potentially different pathophysiological mechanism of task-specific dystonias, the hypothesis of more diffused activations in dystonic patients would fit previous findings, which showed a greater spatial extent of sensorimotor cortex activation within a group (Preibisch et al., 2001) or single patients (Pujol et al., 2000) with task-specific hand dystonia.
Enhanced activation of mesiocaudal premotor and superior parietal areas in orofacial dystonia
Both patient groups had overactivity of the mesiocaudal premotor cortex, i.e. the caudal SMA, and bilateral superior parietal cortex during whistling in common. Overactivity of the caudal SMA contrasts underactivity of primary motor and ventral premotor areas in patients with Meige's syndrome and possibly indicates a rearrangement of activitation in executive motor areas. Such a rearrangement of activitation may be due to changes in movement strategy or a compensation for abnormal movement preparation in orofacial dystonia. Electrophysiological measurements that have found alterations of contingent negative variation and movement-related cortical potentials over lateral and midline motor areas (Deuschl et al., 1995; Kaji et al., 1995; Hamano et al., 1999) have pointed to an abnormality of movement preparation in patients with dystonia (Hallett, 2000a). These electrophysiological data primarily suggested reduced motor and premotor activation, which have been found in our patients with Meige's syndrome or in previous imaging studies of patients with other forms of dystonia as discussed above. The overactivity detected in the very caudal part of the SMA could be a compensation for this impaired motor activation.
Post-central overactivity during orofacial motor execution suggests that the somatosensory system is involved in the development of orofacial dystonia. Such a hypothesis is underlined by the clinical observation that some patients with orofacial dystonia use a sensory trick, a so-called geste antagonistique such as touching or stroking the face periorbitally, to alleviate their symptoms (Hallett, 2002). In our study, four patients with blepharospasm and seven patients with Meige's syndrome described such a manoeuvre to be effective. The sensory trick can even transiently modulate the blink reflex circuitry in patients with blepharospasm (Gomez-Wong et al., 1998).
Functional changes in the post-central gyrus during motor tasks are not specific for patients with orofacial dystonia but were also discovered in other forms of focal dystonia (Ceballos-Baumann et al., 1997; Braun et al., 2003; Lerner et al., 2004). Interestingly, somatosensory overactivity was found in patients with isolated blepharospasm as well indicating a subclinical abnormality in these patients. Findings of enhanced somatosensory activation during motor execution raised the question about whether dystonia could be a disorder of the somatosensory system (Hallett, 1995), although no deficits in peripheral sensory perception have yet been described in literature. As we will discuss further below, such somatosensory overactivation is unlikely to be secondary to abnormal motor action owing to the particular task in this study, at least for the blepharospasm group. Additionally, somatosensory overactivity was not reversed by BTX treatment despite clinical improvement in blepharospasm. It may, therefore, be a crucial precondition for developing this disorder. Such an interpretation is supported by the observation that almost all patients with Meige's syndrome presented initally with blepharospasm several months before they developed oromandibular dystonia and now show the same pattern of somatosensory overactivation as patients with isolated blepharospasm.
Over the last years, there is growing evidence that structural as well as functional changes in the sensory cortex of patients with primary dystonia play a pivotal role in the pathophysiology of this disorder. Abnormal central processing of passive sensory stimulation in idiopathic dystonia and writer's cramp was first described by Tempel and Perlmutter (1990, 1993) using regional cerebral blood flow measurements by H215O-PET. The authors applied vibrotactile stimulation to the hand and lip and found a contralateral decrease in cortical activation during stimulation of the affected and the unaffected side compared with healthy subjects. A similar pattern of reduced sensorimotor activation during passive sensory stimulation was demonstrated in patients with blepharospasm and Meige's syndrome (Feiwell et al., 1999). Magnetencephalography revealed that the distance between cortical somatosensory representations of different fingers during tactile stimulation (Bara-Jimenez et al., 1998) or different motor tasks (Elbert et al., 1998; Braun et al., 2003) is decreased in patients with focal hand dystonia. A similar degraded topography was documented using fMRI (Butterworth et al., 2003). Patients with writer's cramp showed an altered interaction of simultaneously applied peripheral stimuli to fingers of the affected hand (Sanger et al., 2002). The severity of dystonia was correlated with the amount of overacitivity in the primary somatosensory cortex (SI) during dystonic writing in patients with writer's cramp (Lerner et al., 2004). Voxel-based morphometry disclosed an increase of grey matter indicating structural remodelling in primary somatosensory areas of patients with focal hand dystonia (Garraux et al., 2004).
These results indicate an alteration of central receptive fields with a loss of distinction and an overlap of individual finger representations. Similar findings in primates where ongoing somatosensory stimulation during repetitive overuse of the hand yielded an enlargement and overlap of cortical digital representations in S1 corroborate the significance of this functional reorganization in somatosensory representations (Byl et al., 1996). Increased bilateral post-central overactivity during whistling may be a functional correlate of such an altered somatosensory representation in patients with orofacial dystonia. It is unlikely that enhanced S1 activation in our study was due to discomfort or pain during whistling since none of our patients reported any such sensation during the experiment. Even though increased proprioceptive input due to potential task-induced dystonia cannot be fully excluded in the Meige group, such afferent input seems unlikely to be causal for S1 overactivity in the blepharospasm group where the oromandibular motor system that is tested during whistling is asymptomatic. The finding of subclinical somatosensory overactivity in blepharospasm is an important result of this study, which extends previous knowledge about dystonia-related abnormalities in clinically asymptomatic body parts (Tempel and Perlmutter, 1990, 1993; Pauletti et al., 1993; Byrnes et al., 1998; Feiwell et al., 1999; Curra et al., 2000; Thickbroom et al., 2003).
BTX-induced functional changes
Administration of BTX partly reversed the overactivity observed in the somatosensory cortex and caudal SMA of patients with Meige's syndrome akin to patients with writer's cramp (Ceballos-Baumann et al., 1997). An effect of BTX therapy in the blepharospasm group could only be identified at a reduced statistical threshold of P < 0.05 uncorrected and was, therefore, not significant. The latter result suggests that the effect of treatment may be small and difficult to detect when a clinically asymptomatic motor system is investigated as in the blepharospasm group.
BTX injections can decrease cortical somatosensory activity by reduced kinaesthetic input following peripheral motor denervation or by reducing the amount of dystonia during motor execution (Hallett, 2000b). A reduction of S1 overactivity similar to that of BTX therapy in orofacial dystonia was found when a sensory trick manoeuvre was applied in patients with cervical dystonia (Naumann et al., 2000). This type of peripheral sensory stimulation not only modulated the clinical symptoms of focal dystonia but also normalized pathologic regional cerebral blood flow patterns in affected patients. Together with the peripheral muscle weakness, BTX treatment may, therefore, contribute to the clinical improvement observed in Meige patients by partly normalizing deranged somatosensory activation patterns during motor execution. This interpretation would be consistent with findings in writer's cramp patients where the severity of dystonia correlated with the amount of overactivity in S1 (Lerner et al., 2004).
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TopSummaryIntroductionMethodsResultsDiscussionConclusionReferences |
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Functional MRI revealed deficient activation of the primary motor and ventral premotor cortex in patients with Meige's syndrome where the whistling task investigated the clinically affected oromandibular motor system. As this impaired motor activation was not modulated by BTX therapy, it is considered to be related to the primary pathology of orofacial dystonia. It might be a functional correlate of reduced cortical inhibition in motor and premotor areas during oromandibular motor execution in Meige's syndrome. Enhanced somatosensory activation during the execution of an orofacial motor task indicates an altered somatosensory representation in both forms of orofacial dystonia. This functional reorganization might be a crucial precondition for developing blepharospasm. Partial normalization of this enhanced somatosensory activation after BTX therapy was observed in a subgroup of patients and may contribute to the beneficial effect of such therapy.
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Acknowledgements |
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This study was supported by the Deutsche Forschungsgemeinschaft (Grant: Ce 33/4.2) and the Kommission Klinische Forschung (KKF) of the Klinikum rechts der Isar, Technische Universitaet Muenchen. We are grateful to Dr M. Messner and Dr R. Ilg at the Department of Neurology for their help in recruiting patients and to the technical staff at the Department of Radiology for their assistance.
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|---|
|
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|---|
Abbruzzese G, Berardelli A. Sensorimotor integration in movement disorders. Mov Disord 2003; 18: 231–40.[CrossRef][Web of Science][Medline]
Amaro E Jr, Williams SC, Shergill SS, Fu CH, MacSweeney M, Picchioni MM, et al. Acoustic noise and functional magnetic resonance imaging: current strategies and future prospects. J Magn Reson Imaging 2002; 16: 497–510.[CrossRef][Web of Science][Medline]
Bara-Jimenez W, Catalan MJ, Hallett M, Gerloff C. Abnormal somatosensory homunculus in dystonia of the hand. Ann Neurol 1998; 44: 828–31.[CrossRef][Web of Science][Medline]
Berardelli A, Rothwell JC, Hallett M, Thompson PD, Manfredi M, Marsden CD. The pathophysiology of primary dystonia. Brain 1998; 121: 1195–212.
Boroojerdi B, Cohen LG, Hallett M. Effects of botulinum toxin on motor system excitability in patients with writer's cramp. Neurology 2003; 61: 1546–50.
Braun C, Schweizer R, Heinz U, Wiech K, Birbaumer N, Topka H. Task-specific plasticity of somatosensory cortex in patients with writer's cramp. Neuroimage 2003; 20: 1329–38.[CrossRef][Web of Science][Medline]
Burke RE, Fahn S, Marsden CD, Bressman SB, Moskowitz C, Friedman J. Validity and reliability of a rating scale for the primary torsion dystonias. Neurology 1985; 35: 73–7.
Butterworth S, Francis S, Kelly E, McGlone F, Bowtell R, Sawle GV. Abnormal cortical sensory activation in dystonia: an fMRI study. Mov Disord 2003; 18: 673–82.[CrossRef][Web of Science][Medline]
Byl NN, Merzenich MM, Jenkins WM. A primate genesis model of focal dystonia and repetitive strain injury: I. Learning-induced dedifferentiation of the representation of the hand in the primary somatosensory cortex in adult monkeys. Neurology 1996; 47: 508–20.
Byrnes ML, Thickbroom GW, Wilson SA, Sacco P, Shipman JM, Stell R, et al. The corticomotor representation of upper limb muscles in writer's cramp and changes following botulinum toxin injection. Brain 1998; 121: 977–88.
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.[CrossRef][Web of Science][Medline]
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.
Comella CL, Leurgans S, Wuu J, Stebbins GT, Chmura T. Rating scales for dystonia: a multicenter assessment. Mov Disord 2003; 18: 303–12.[CrossRef][Web of Science][Medline]
Curra A, Romaniello A, Berardelli A, Cruccu G, Manfredi M. Shortened cortical silent period in facial muscles of patients with cranial dystonia. Neurology 2000; 54: 130–5.
Defazio G, Berardelli A, Abbruzzese G, Coviello V, Carella F, De Berardinis MT, et al. Risk factors for spread of primary adult onset blepharospasm: a multicentre investigation of the Italian movement disorders study group. J Neurol Neurosurg Psychiatry 1999; 67: 613–9.
Deiber MP, Honda M, Ibanez V, Sadato N, Hallett M. Mesial motor areas in self-initiated versus externally triggered movements examined with fMRI: effect of movement type and rate. J Neurophysiol 1999; 81: 3065–77.
Deuschl G, Toro C, Matsumoto J, Hallett M. Movement-related cortical potentials in writer's cramp. Ann Neurol 1995; 38: 862–8.[CrossRef][Web of Science][Medline]
Ehrsson HH, Fagergren A, Jonsson T, Westling G, Johansson RS, Forssberg H. Cortical activity in precision-versus power-grip tasks: an fMRI study. J Neurophysiol 2000; 83: 528–36.
Elbert T, Candia V, Altenmuller E, Rau H, Sterr A, Rockstroh B, et al. Alteration of digital representations in somatosensory cortex in focal hand dystonia. Neuroreport 1998; 9: 3571–5.[Web of Science][Medline]
Feiwell RJ, Black KJ, McGee-Minnich LA, Snyder AZ, MacLeod AM, Perlmutter JS. Diminished regional cerebral blood flow response to vibration in patients with blepharospasm. Neurology 1999; 52: 291–7.
Fink GR, Corfield DR, Murphy K, Kobayashi I, Dettmers C, Adams L, et al. Human cerebral activity with increasing inspiratory force: a study using positron emission tomography. J Appl Physiol 1996; 81: 1295–305.
Frackowiak RS, Friston KJ, Frith CD, Dolan RJ, Mazziotta JC. Human brain function, 1st edn. London: Academic Press; 1998.
Friston KJ, Ashburner J, Frith CD, Poline JB, Heather JD, Frackowiak RSJ. Spatial registration and normalization of images. Hum Brain Mapp 1995a: 165–89.
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 1995b: 189–210.
Garraux G, Bauer A, Hanakawa T, Wu T, Kansaku K, Hallett M. Changes in brain anatomy in focal hand dystonia. Ann Neurol 2004; 55: 736–9.[CrossRef][Web of Science][Medline]
Gilio F, Curra A, Lorenzano C, Modugno N, Manfredi M, Berardelli A. Effects of botulinum toxin type A on intracortical inhibition in patients with dystonia. Ann Neurol 2000; 48: 20–6.[CrossRef][Web of Science][Medline]
Gomez-Wong E, Marti MJ, Cossu G, Fabregat N, Tolosa ES, Valls-Sole J. The ‘geste antagonistique’ induces transient modulation of the blink reflex in human patients with blepharospasm. Neurosci Lett 1998; 251: 125–8.[CrossRef][Web of Science][Medline]
Hallett M. Is dystonia a sensory disorder? Ann Neurol 1995; 38: 139–40.[CrossRef][Web of Science][Medline]
Hallett M. Disorder of movement preparation in dystonia. Brain 2000a; 123: 1765–6.
Hallett M. How does botulinum toxin work? Ann Neurol 2000b; 48:7–8.[CrossRef][Web of Science][Medline]
Hallett M. Blepharospasm: recent advances. Neurology 2002; 59: 1306–12.
Hamano T, Kaji R, Katayama M, Kubori T, Ikeda A, Shibasaki H, et al. Abnormal contingent negative variation in writer's cramp. Clin Neurophysiol 1999; 110: 508–15.[CrossRef][Web of Science][Medline]
Holmes AP, Friston KJ. Generalisability, random effects and population inference. Neuroimage 1998; 7: S754.
Hutchinson M, Nakamura T, Moeller JR, Antonini A, Belakhlef A, Dhawan V, et al. The metabolic topography of essential blepharospasm: a focal dystonia with general implications. Neurology 2000; 55: 673–7.
Ibanez V, Sadato N, Karp B, Deiber MP, Hallett M. Deficient 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.
Jahanshahi M, Jenkins IH, Brown RG, Marsden CD, Passingham RE, Brooks DJ. Self-initiated versus externally triggered movements. I. An investigation using measurement of regional cerebral blood flow with PET and movement-related potentials in normal and Parkinson's disease subjects. Brain 1995; 118: 913–33.
Kaji R, Ikeda A, Ikeda T, Kubori T, Mezaki T, Kohara N, et al. Physiological study of cervical dystonia. Task-specific abnormality in contingent negative variation. Brain 1995; 118: 511–22.
Kanovsky P, Bares M, Streitova H, Klajblova H, Daniel P, Rektor I. The disorder of cortical excitability and cortical inhibition in focal dystonia is normalised following successful botulinum toxin treatment: an evidence from somatosensory evoked potentials and transcranial magnetic stimulation recordings. Neurology 2005; 64 (Suppl. 1): A381.
Lerner A, Shill H, Hanakawa T, Bushara K, Goldfine A, Hallett M. Regional cerebral blood flow correlates of the severity of writer's cramp symptoms. Neuroimage 2004; 21: 904–13.[CrossRef][Web of Science][Medline]
Levy LM, Hallett M. Impaired brain GABA in focal dystonia. Ann Neurol 2002; 51: 93–101.[CrossRef][Web of Science][Medline]
Logothetis NK, Pfeuffer J. On the nature of the BOLD fMRI contrast mechanism. Magn Reson Imaging 2004; 22: 1517–31.[CrossRef][Web of Science][Medline]
Matsumura M, Sawaguchi T, Kubota K. GABAergic inhibition of neuronal activity in the primate motor and premotor cortex during voluntary movement. J Neurophysiol 1992; 68: 692–702.
McKay LC, Evans KC, Frackowiak RS, Corfield DR. Neural correlates of voluntary breathing in humans. J Appl Physiol 2003; 95: 1170–8.
Naumann M, Magyar-Lehmann S, Reiners K, Erbguth F, Leenders KL. Sensory tricks in cervical dystonia: perceptual dysbalance of parietal cortex modulates frontal motor programming. Ann Neurol 2000; 47: 322–8.[CrossRef][Web of Science][Medline]
Odergren T, Iwasaki N, Borg J, Forssberg H. Impaired sensory-motor integration during grasping in writer's cramp. Brain 1996; 119: 569–83.
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.[CrossRef][Web of Science][Medline]
Oldfield RC. The assessment and analysis of handedness: the Edinburgh inventory. Neuropsychologia 1971; 9: 97–113.[CrossRef][Web of Science][Medline]
Pauletti G, Berardelli A, Cruccu G, Agostino R, Manfredi M. Blink reflex and the masseter inhibitory reflex in patients with dystonia. Mov Disord 1993; 8: 495–500.[CrossRef][Web of Science][Medline]
Preibisch C, Berg D, Hofmann E, Solymosi L, Naumann M. Cerebral activation patterns in patients with writer's cramp: a functional magnetic resonance imaging study. J Neurol 2001; 248: 10–7.[CrossRef][Web of Science][Medline]
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.[CrossRef][Web of Science][Medline]
Ridding MC, Sheean G, Rothwell JC, Inzelberg R, Kujirai T. Changes in the balance between motor cortical excitation and inhibition in focal, task specific dystonia. J Neurol Neurosurg Psychiatry 1995; 59: 493–8.
Sadato N, Campbell G, Ibanez V, Deiber M, Hallett M. Complexity affects regional cerebral blood flow change during sequential finger movements. J Neurosci 1996; 16: 2691–700.[Abstract]
Sanger TD, Pascual-Leone A, Tarsy D, Schlaug G. Nonlinear sensory cortex response to simultaneous tactile stimuli in writer's cramp. Mov Disord 2002; 17: 105–11.[CrossRef][Web of Science][Medline]
Schmidt KE, Linden DE, Goebel R, Zanella FE, Lanfermann H, Zubcov AA. Striatal activation during blepharospasm revealed by fMRI. Neurology 2003; 60: 1738–43.
Siebner HR, Tormos JM, Ceballos-Baumann AO, Auer C, Catala MD, Conrad B, et al. Low-frequency repetitive transcranial magnetic stimulation of the motor cortex in writer's cramp. Neurology 1999; 52: 529–37.
Tempel LW, Perlmutter JS. Abnormal vibration-induced cerebral blood flow 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.
Thickbroom GW, Byrnes ML, Stell R, Mastaglia FL. Reversible reorganisation of the motor cortical representation of the hand in cervical dystonia. Mov Disord 2003; 18: 395–402.[CrossRef][Web of Science][Medline]
Van der Kamp 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.[CrossRef][Web of Science][Medline]
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