Brain Advance Access originally published online on July 1, 2004
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Brain, Vol. 127, No. 8, 1899-1908,
August 2004
© 2004 Guarantors of Brain
doi: 10.1093/brain/awh213
Globus pallidus internus stimulation in primary generalized dystonia: a H215O PET study
1 Department of Biological and Clinical Neurosciences, Grenoble University Hospital and INSERM U318, Joseph Fourier University, Grenoble, 2 Department of Neurology, Pierre Wertheimer Neurological Hospital and INSERM U534, Lyon, 3 Cyclotron Unit (CERMEP), Pierre Wertheimer Neurological Hospital, Lyon and 4 Department of Neurology, Saint Antoine Hospital and INSERM U289, Paris, France
Correspondence to: Dr Laurent Vercueil, Neurologie, CHU Grenoble, 38043 Grenoble, Cedex 9, France E-mail: Lvercueil{at}chu-grenoble.fr
Received January 11, 2004. Revised April 7, 2004. Accepted April 9, 2004.
 |
Summary |
|---|
 Top Summary IntroductionMaterial and methodsResultsDiscussionReferences |
|---|
Globus pallidus internus (GPi) deep brain stimulation (DBS) increasingly shows promising efficacy in the treatment of severe primary generalized dystonia. Functional imaging studies have shown previously that dystonia could be related to abnormal cortical activation during voluntary movement. In the present study, the effects of GPi DBS on regional cerebral blood flow (rCBF) during a motor task were studied in patients with primary generalized dystonia. rCBF was measured using H215O and PET in eight control subjects and six patients with dystonia treated with bilateral GPi DBS. Subjects were scanned at rest and while performing joystick movements. Dystonic patients were tested in two conditions: ‘OFF’ (stimulator bilaterally switched off) and ‘ON’ (unilateral stimulation). In the ‘OFF’ condition, compared with rest, motor activation of the most dystonic hand was associated with overactivity in the contralateral dorsolateral prefrontal cortex, gyrus frontalis medialis, superior frontal gyrus (area 10), frontoorbital cortex and thalamus. In the ‘ON’ condition, GPi DBS contralaterally to the most dystonic hand induced a decrease of the overactivation in the same areas, as well as the putamen. According to the present study, generalized dystonia is associated with prefrontal overactivation which can be reversed by effective GPi DBS.
Key Words: dystonia; globus pallidus; deep brain stimulation; PET
Abbreviations: BA = Brodmann area; BFMS = Burke–Fahn–Marsden scale; DBS = deep brain stimulation; DLPFC = dorsolateral prefrontal cortex; DSS = dystonia severity score; GPi = globus pallidus internus; rCBF = regional cerebral blood flow; SMA = supplementary motor area; SPM = statistical parametric mapping.
|
Introduction |
|---|
|
TopSummaryIntroductionMaterial and methodsResultsDiscussionReferences |
|---|
Dystonia is defined as a syndrome of sustained muscle contractions, frequently causing twisting and repetitive movements, and/or abnormal postures (Fahn et al., 1998
). Primary generalized dystonia describes patients in whom dystonia is the sole phenotypic manifestation and involves a combination of segmental crural dystonia which spreads to any other segment (Fahn, 1988; Fahn et al., 1998). Most cases of early-onset primary generalized dystonia are related to DYT1 mutations located on chromosome 9q34.1. The DYT1 gene (also known as torsin A gene) is transmitted as an autosomal dominant trait with a penetrance of 30–40% (Kramer et al., 1994; Lenz et al., 1999).
Primary dystonia classically appears in middle to late childhood and progresses to generalized dystonia in a few years, leading to debilitating states (Bressman et al., 2000). Because medical treatment efficacy is limited, functional brain surgery has been considered as a potentially effective alternative treatment (Krack and Vercueil, 2001). Historically, brain surgery for dystonia followed the development of surgery for idiopathic Parkinson's disease and the observation of an improvement of dystonic symptoms in parkinsonian subjects (Krack and Vercueil, 2001). Initially, ablative procedures, especially thalamotomy, were used for generalized dystonia and produced a substantial benefit (Cooper, 1976; Andrew et al., 1983; Tasker et al., 1988; Cardoso et al., 1995). More recently, with the renewal of posteroventral pallidotomy in Parkinson's disease (Lozano et al., 1995; Lang et al., 1997; Fine et al., 2000), pallidotomy was rediscovered as a treatment for generalized dystonia and provided a substantial improvement in dystonic movements and motor function (Lozano et al., 1997; Ondo et al., 1998; Lin et al., 1999). Deep brain stimulation (DBS) has been investigated more recently, and, unlike ablative surgery, DBS is reversible and adjustable. The globus pallidus internus (GPi) is now the commonly preferred target for DBS in generalized dystonia (Coubes et al., 1999, 2000, 2002; Krack et al., 1999; Tronnier et al., 2000; Vercueil et al., 2001). In primary dystonia, no degenerative or structural neuropathological abnormalities are elicited, and several reviews suggest that there is a functional disturbance within the basal ganglia system (Brooks, 1995; Berardelli et al., 1998; Nemeth, 2002). Accordingly, a highly irregular activity within the GPi with grouped discharges separated by periods of pauses has been recorded intraoperatively (Vitek et al., 1999).
The exact mechanism of DBS remains unclear, and the pathophysiological basis of dystonia is still poorly understood. Using PET and [18F]fluorodeoxyglucose (FDG), Eidelberg et al. (1998) observed an increased metabolic activity in the lentiform nuclei, cerebellum and supplementary motor areas (SMAs) in DYT1 dystonia. They also showed, in an analysis of affected gene carriers with sustained contractions at rest, an increased metabolic activity in the midbrain, cerebellum and thalamus. Few studies have examined the modifications of regional cerebral blood flow (rCBF) in generalized dystonia with PET and H215O. Vibrotactile stimulation of the hand showed an attenuation of the rCBF increase in the contralateral sensorimotor cortex (Tempel and Perlmutter, 1990, 1993) and in the SMA (Tempel and Perlmutter, 1993) in comparison with control subjects. During freely selected joystick movements, three studies reported enhanced activation (increase of rCBF) of the premotor cortex, dorsolateral prefrontal cortex (DLPFC) (Ceballos-Baumann et al., 1995a,b; Playford et al., 1998), SMA (Ceballos-Baumann et al., 1995a; Playford et al., 1998), lenticulate nucleus (Ceballos-Baumann et al., 1995a) or putamen and cerebellum (Playford et al., 1998). Concerning the primary sensorimotor cortex, one of these studies reported increased activation during the motor task in acquired hemidystonia (Ceballos-Baumann et al., 1995b), while two reported a reduced activation (Ceballos-Baumann et al., 1995a; Playford et al., 1998). At rest, Ceballos-Baumann et al. (1995b), studying patients with acquired hemidystonia, observed an increased activation in the frontoorbital cortex, thalamus and lenticulate nucleus.
Only one H215O PET study assessed the effects of GPi DBS in a single patient suffering from generalized dystonia (Kumar et al., 1999). This study showed that, during freely selected joystick movements, GPi stimulation reduced activation in the primary sensorimotor cortex, lateral premotor, SMA and prefrontal cortex, including DLPFC, corresponding to Brodmann areas (BAs) 9 and 46.
In an attempt to extend and clarify the results of the previous studies, we studied dystonic patients treated with GPi DBS using H215O PET performing freely selected joystick movements. The aim of the present study was to analyse the functional effects of GPi stimulation on rCBF during this motor task in primary generalized dystonia and to compare the activation profile in dystonic patients with those of control subjects.
|
Material and methods |
|---|
|
TopSummaryIntroductionMaterial and methodsResultsDiscussionReferences |
|---|
Subjects
We studied six patients with primary generalized dystonia treated with bilateral high-frequency GPi DBS (three women and three men; mean age = 26 years; range = 18–36) and eight control subjects (eight men; seven right-handed, one left-handed; mean age = 25 years; range = 21–28). All control subjects were healthy without neurological or psychiatric disorders and without medical treatment. Out of a series of 25 consecutive patients treated by GPi DBS for primary dystonia, six patients were included according to the following criteria: (i) dystonia without additional neurological abnormalities (Fahn, 1988
; Fahn et al., 1998); (ii) generalized dystonia requiring surgery by stimulation of the GPi because of a vital risk or a severe disability; (iii) failure of medical treatment; (iv) clinical improvement superior to 30% on the Burke–Fahn–Marsden scale (BFMS) after 3 months of bilateral GPi DBS; (v) tolerable recurrence of dystonia in the tested hand when the stimulator is switched off; and (vi) minimal cervical dystonia compatible with head immobilization required for the PET procedure. All patients were taking their regular medication during the study (anticholinergics, three patients; benzodiazepines, two patients; tetrabenazine, one patient). The three women were taking oral contraceptives. Five of the six patients had a mutation of the DYT1 gene. The patients' general characteristics and stimulation parameters for GPi DBS are shown in Table 1.
|
The quadripolar electrodes (Model 3389; Medtronic, Minneapolis, MN) were inserted in the postero-lateral GPi under stereotactic guidance and connected to a telemetrically controllable pulse generator (Kinetra; Medtronic) placed in the subclavicular area. The accuracy of electrode placement was checked by imaging techniques and intraoperative electrophysiology as previously described for stimulation in Parkinson's disease (Limousin et al., 1998
) and dystonia (Vercueil et al., 2001). The target (postero-lateral GPi) was visualized by preoperative stereotactic MRI, then drawn on the intraoperative teleradiographs. The superimposition of the tip of the electrode and the target position was checked at the end of surgery and the precise location was confirmed, after surgery, by MRI. All patients underwent surgery in Grenoble. Written informed consent was obtained from each subject according to the Declaration of Helsinki. The present study was approved by the Lyon University Hospital Ethics Committee.
Clinical assessment
The patients and control subjects were videotaped during the scanning procedure to check the accuracy of the task execution and rest, and the appearance of dystonic postures. Based on these videotape recordings, we evaluated the six patients' severity of dystonia in the tested hand by using a dystonia severity score (DSS) developed by our group to score off-period dystonia in Parkinson's disease patients (Krack et al., 1999) and already used in another clinical study with dystonic patients (Detante et al., 2004): 0, no dystonia; 1, minimal dystonia or abnormal posture; 2, moderate dystonia; 3, severe dystonia with a moderate interference with movement; and 4, severe dystonia with an intense interference with movement. Moreover, the patients were videotaped before and after each scan and scored with the BFMS (Burke et al., 1985).
Activation tasks
PET scanning was performed at the CERMEP medical cyclotron in Lyon.
Subjects were scanned while executing a motor task with the dominant hand for control subjects and with the more dystonic hand for patients (Table 1). Subjects lay down with their eyes closed.
The conditions were the following: (i) for control subjects, rest (Rest control) and execution of a motor task (Exe control); and (ii) for patients, rest without stimulation (Rest OFF), execution of a motor task without stimulation (Exe OFF), rest with unilateral effective GPi DBS (Rest ON) and execution with unilateral effective GPi DBS (Exe ON). Each condition was carried out in triplicate, lasted for 90 s and began a few seconds before H215O injection. The motor task conditions were randomized.
During the rest condition, subjects were asked to relax their arms and hands keeping the joystick in a central position. They heard tones every 3 s (30 tones) and were instructed to not react. During the free selection task, subjects had to move a joystick after each tone in a single direction (either left, right, forward or back). Subjects freely chose one direction. They were asked to move the joystick as randomly as possible and to avoid repetitive sequences. The completion of the joystick movement was recorded for each subject and the errors were counted automatically when the subject failed to complete the movement because of a reduced amplitude or an absence of movement.
The control subjects underwent six scans (1.5 h): three at rest and three during movement execution. The patients underwent six scans in the OFF stimulation condition and six in the ON condition. In the OFF stimulation condition, the stimulator was bilaterally switched off (OFF/OFF) with a recurrence of dystonia in the tested hand. In the ON stimulation condition, only the stimulator contralateral to the tested hand was switched on (ON/OFF) with a maximal clinical benefit on the hand tested. Unilateral stimulation was chosen as the ON condition to not confound ipsilateral and contralateral effects of this stimulation. The stimulator had been switched on or off for 3.40 h (range = 0.25–6.50) on average before the PET scanning, depending on the tolerable recurrence of dystonia. Because of the latency between turning on the stimulator and the clinically induced effects, PET scans in the ON stimulation condition were performed on one day and PET scans in the OFF stimulation condition another day within the same week. The order of stimulation conditions for each patient was randomized.
Scanning procedure
Subjects' heads were maintained in a fixed position using a thermoformed mask. Confirmation of head position throughout the examination was made by laser alignment along with reference points on Reid's line before and after each session. PET scans were acquired using a Siemens CTi HR+ tomograph (CTi/Siemens, Knoxville, TN) in three-dimensional mode. Transmission data were acquired using rotating sources filled with 68Ge/68Ga. Images were reconstructed by 3D back-filtered projection (Hanning filter; cut-off frequency, 0.5 cycles/pixel), giving a transaxial resolution of 6.5 mm full width at half maximum, and displayed in a 128x128 pixel format with 63 planes creating 2 mm cubic voxels. rCBF was estimated by recording the distribution of radioactivity following an intravenous injection of 370 MBq of H215O through a forearm catheter placed into the brachial vein. The integrated counts were collected for 90 s. For data analysis, we only considered the 60 s corresponding to the maximum radioactivity. The interval between successive H215O administrations was 10 min to allow for adequate radioactivity decay.
Statistical analysis and PET data
For clinical data, we compared the BFMS scores and DSS obtained in the OFF and ON stimulation conditions with a Wilcoxon signed rank test. A P value <0.05 was considered significant. We also compared the number of errors made by control subjects and patients in the ON and OFF stimulation conditions with a Mann–Whitney U test. A P value <0.05 was considered significant.
Image and statistical analyses were performed using MATLAB 5.3 (MathWorks, Natick, MA) for statistical parametric mapping (SPM 99, Wellcome Department of Cognitive Neurology, MRC Cyclotron Unit, London). First, the images corresponding to one control subject and the two patients who used their left hand to perform the tasks were inverted along the x-axis, making it appear that all subjects had performed the task using their right hand. Briefly, series of scans were aligned to the first scan with an automated algorithm for head movement correction and then normalized into a standard stereotactic space. The images were smoothed with an isotropic Gaussian filter of 10 x 10 x 10 mm to allow for interindividual gyral variation and to improve the signal to noise ratio. Global differences in rCBF were covaried out for all voxels, and comparisons across conditions were made using t statistics with appropriate linear contrasts, and then converted to Z-scores. Coordinates of the activated foci obtained from SPM 99 were then converted into Talairach coordinates (Talairach and Tournoux, 1988). Only regional activation significant at P < 0.001 at each pixel, uncorrected for multiple comparisons, and with Z-scores >3.30 were retained. Uncorrected P values were accepted because of an a priori strong hypothesis on the primary and prefrontal cortex.
We carried out statistical analyses both within groups and between groups. For the within-group analysis, we calculated statistical parametric mappings (SPM) comparing the motor task with rest in control subjects (Exe control versus Rest control), in patients without stimulation (Exe OFF versus Rest OFF) and in patients using unilateral GPi stimulation (Exe ON versus Rest ON). We also compared the ON and OFF stimulation conditions to evaluate the effect of GPi DBS at rest (Rest OFF versus Rest ON) and during the motor task [(Exe OFF versus Rest OFF) – (Exe ON versus Rest ON) and (Exe ON versus Rest ON) – (Exe OFF versus Rest OFF)].
For the between-group analysis, we calculated SPM during resting and active conditions. The following comparisons were made for the motor task: (i) control subjects versus patients in the OFF stimulation condition to evaluate rCBF changes due to primary generalized dystonia [(Exe OFF versus Rest OFF) – (Exe control versus Rest control)]; and (ii) control subjects versus patients in the ON stimulation condition to appreciate the effects of GPi DBS [(Exe ON versus Rest ON) – (Exe control versus Rest control)].
|
Results |
|---|
|
TopSummaryIntroductionMaterial and methodsResultsDiscussionReferences |
|---|
Task performance
At the time of PET scanning, all patients had dystonia in the task-performing hand during the OFF stimulation condition. The ON stimulation condition improved dystonia in the performing hand during the motor task, and two patients (2 and 6) had complete amelioration of dystonia (Table 2). Dystonia severity in the performing hand was significantly higher (P < 0.05) during the OFF stimulation condition (mean DSS = 2.7; range = 2.0–4.0) than during the ON stimulation condition (mean DSS = 1.2; range = 0–3.0). Moreover, the mean value of the BFMS was 44.6 (range = 24.5–77.0) in the OFF stimulation condition, and 34.4 (range = 17.5–69.5) in ON stimulation condition (Table 2). This improvement of 23% on BFMS by acute unilateral GPi DBS was significant (P = 0.002).
|
During the OFF stimulation condition, we recorded 25 (range = 12–43) errors per 90 movements on average and 27 (range = 15–45) errors during the ON stimulation condition. Control subjects made 17 (range = 11–22) errors on average. Thus, patients made more errors in both conditions compared with controls. However, regardless of the stimulation condition, the difference between patients and controls did not reach statistical significance (in the ON and OFF stimulation condition P = 0.06 and P = 0.14, respectively).
PET results
Within-group comparison: control subjects (Table 3)
When motor execution of the right hand was compared with rest (Exe control versus Rest control), we observed significant activations in the left primary motor cortex, left and right premotor cortex (lateral BA 6), left thalamus and cerebellar hemispheres. The right parietal cortex (BA 7) was also activated by the motor task. No significant activation was observed in the DLPFC.
|
Within-group comparison: patients
Motor task without GPi DBS (OFF stimulation condition) (Table 4). When the motor task was compared with rest (Exe OFF versus Rest OFF), we observed significant activations in the left primary sensorimotor cortex, right and left caudal SMA, left DLPFC (BA 9), left parietal (BA 7 and 40), right anterior cingulate cortex (BA 24), in the left thalamus, vermis and cerebellar hemispheres. Contrary to that observed in the control group, activation was not elicited in the premotor cortex.
|
Motor task with effective unilateral GPi DBS (ON stimulation condition) (Table 5). When the motor task was compared with rest (Exe ON versus Rest ON), there was significant activation in the left primary sensorimotor cortex, left caudal SMA, left parietal cortex (BA 40), cerebellar vermis and right cerebellar hemisphere. Contrary to the results obtained in the OFF stimulation condition, we did not observe rCBF changes in the thalamus, DLPFC or right SMA.
|
Modifications of rCBF induced by effective unilateral GPi DBS at rest (Table 6; Fig 1). Left GPi stimulation during the rest condition in dystonic patients was associated with increased activation (Rest ON versus Rest OFF) in the right DLPFC (BA 9), right inferior frontal gyrus (BA 47), left gyrus frontalis medius (BA 11), parietal cortex bilaterally (right BA 7, 40 and left BA 31), right temporal cortex (BA 38), left cingulate cortex (BA 23) and in the right cerebellar hemisphere. Increased activation in the right caudate nucleus, left thalamus and left GPi (site of stimulation) was also noted. Moreover, left GPi DBS decreased activation (Rest OFF versus Rest ON) of the left primary motor cortex at rest.
|
|
Modifications of rCBF induced by effective unilateral GPi DBS during the motor task (Table 7). During freely selected joystick movements of the right hand, unilateral GPi stimulation did not increase cerebral activation. Instead, left GPi stimulation produced a decrease in activation of the left superior frontal gyrus (BA 10), right temporal cortex (BA 38), left putamen and left thalamus.
|
Between-group comparison
In the OFF stimulation condition (Fig. 2). During freely selected movements, there was significantly greater activation during the OFF stimulation state for dystonic patients in the left superior frontal gyrus (BA 10), right inferior frontal gyrus, left gyrus orbitale (BA 11), a large part of the left DLPFC (BA 8, 46), gyrus frontalis medialis (BA 9, 10) and parietal cortex (BA 40). No lesser degree of activation was seen in dystonic patients during the OFF stimulation condition compared with control subjects.
|
In the ON stimulation condition (Fig. 3). For freely selected movements, we observed significantly increased activation of a small segment of the left DLPFC (BA 8/9, 46) (Fig. 3), left gyrus rectus (BA 11), left premotor cortex and left temporal cortex (BA 37). Contrary to that observed when comparing the control group with patients during the OFF stimulation state (Fig. 2), no differences in rCBF were noted in the left orbital gyrus and left middle frontal gyrus (BA 45). No lesser degree of activation was seen in dystonic patients in the ON stimulation condition compared with control subjects.
|
|
Discussion |
|---|
|
TopSummaryIntroductionMaterial and methodsResultsDiscussionReferences |
|---|
The three main results of this study involving a homogeneous population of dystonic patients (five out of six DYT1 carriers) are: (i) hand movements hampered by dystonia in primary generalized dystonia are characterized by prefrontal overactivation including the DLPFC and frontoorbital cortex; (ii) in contrast to the pattern displayed by the control group, caudal SMA activation, but no lateral premotor activation, was observed during task performance in dystonic patients; and (iii) GPi DBS decreases the overactivation in the contralateral thalamus, putamen, DLPFC and frontoorbital cortex, thus restoring a more physiological activation pattern.
Of particular interest is the pattern of activation at rest in dystonic patients receiving unilateral GPi DBS. Contralateral to the side of stimulation, a significant increase of rCBF is seen in the prefrontal cortex including the DLPFC, inferior frontal gyrus, parietal cortex, posterior cingulate cortex and caudate nucleus. Ipsilateral to the side of stimulation, a similar augmentation of activity is seen in the GPi and thalamus. Moreover, unilateral GPi DBS reduces activation in the primary motor cortex on the ipsilateral side at rest.
Clinical improvement of dystonia by GPi stimulation during the PET study
The stimulator was switched on or off for an average of 3.40 h (0.25–6.50 h) prior to PET scan acquisition. For each patient, we assessed the time between the stimulation onset and the appearance of clinical effects with a preliminary study of tolerance. Acute clinical effects normally began after a few minutes and this remained stable for hours (notably during the duration of the PET scan). As a result, it was possible to analyse a true recurrence of hand dystonia in the OFF condition, and subsequently demonstrate a real improvement of dystonia in the ON condition for each patient prior to the PET scan. Thus, we were able to elicit a tolerable recurrence of hand-tested dystonia in the OFF stimulation condition.
On PET scan, unilateral GPi DBS produced a 23% improvement in BFMS for all body parts and a 56% reduction in DSS for dystonia in each tested limb. However, these findings cannot be extrapolated to the long-term effects of bilateral GPi stimulation as the stimulator was switched on or off only for several hours before scoring and the stimulation was unilateral. Additionally, the present study demonstrated that GPi DBS is a fully reversible treatment providing a clear clinical benefit in generalized dystonia, notably in patients carrying the DYT1 mutation (Coubes et al., 1999, 2000, 2002; Tronnier et al., 2000; Vercueil et al., 2001).
OFF stimulation: abnormal cerebral activation pattern of dystonia during hand movements
Dystonic patients during the OFF stimulation periods can be considered representative of primary generalized dystonia patients without treatment. Assuming this hypothesis is true, it is possible to evaluate modifications of cerebral activation during a motor task in primary generalized dystonia. The contralateral primary sensory cortex, DLPFC and parietal cortex (BA 40) are activated in dystonic patients but not in healthy subjects (Table 4). In contrast to control subjects, the premotor cortex was not activated during task execution in dystonic patients. Whereas the caudal SMA was bilaterally activated in dystonic patients, it was not activated in the control group. This pattern of prefrontal overactivation was confirmed by the between-group comparisons (Fig. 2). The rCBF in the contralateral prefrontal cortex of dystonic patients was higher than that found in control subjects during task execution compared with the resting state. These overactivated prefrontal areas included the DLPFC, frontoorbital cortex and the middle frontal gyrus. The overactivation of the parietal cortex, primary sensory cortex or caudal SMA was not confirmed by the between-group comparison.
Our findings confirm previous studies showing an abnormal pattern of cerebral activation during hand movements in primary generalized dystonia (Ceballos-Baumann et al., 1995a, b; Playford et al., 1998). This pattern is characterized by an enhanced activation (increase of rCBF) mainly in the DLPFC and SMA. Contrary to other studies, we noted no overactivation in the lenticulate nucleus, cerebellum or premotor cortex (Ceballos-Baumann, 1995a; Playford et al., 1998).
This abnormal pattern in dystonia involves the lateral prefrontal areas implicated in movement preparation. This is consistent with the idea that there is a disorder of movement preparation and selection in dystonia. During our simple externally cued task, patients used prefrontal areas normally involved in more complex motor tasks, notably in self-initiated tasks used by Jenkins et al. (2000). This enhanced activity of the prefrontal cortex, including the DLPFC, may be a result of overactivity of the basal ganglia via increased output through the thalamo-cortical pathway.
It is interesting to note that our findings in primary dystonia contrast with those reported in patients with Parkinson's disease undertaking the same task in which the activity of the SMA and DLPFC is decreased (Playford et al., 1992; Samuel et al., 1997).
ON stimulation: GPi stimulation corrects the abnormal activation pattern of dystonia during hand movements
The present study provides important insights into the effects of GPi DBS in primary generalized dystonia. Contrary to the OFF stimulation condition (Table 4), during the ON stimulation state (Table 5), no rCBF increase is displayed in the DLPFC and thalamus during the motor task. Moreover, unilateral GPi DBS reduces activation in the ipsilateral superior frontal gyrus (BA 10), thalamus and putamen (Table 7). No increase of cerebral activation was induced by the GPi stimulation during hand movements. When comparing patients in the ON stimulation condition with controls, we showed that GPi DBS reduces the prefrontal overactivation (Fig. 3), thus restoring a more physiological activation pattern. Thus, GPi DBS corrects the abnormal prefrontal overactivation in primary dystonia, as suggested in a previous study of one patient. However, we did not observe an activation of the primary cortex by GPi stimulation (Kumar et al., 1999).
In contrast to Ceballos-Baumann et al. (1997) who found that botulinum toxin does not reverse the cortical dysfunction associated with writer's cramp (focal dystonia), we observe in our study that modifications of basal ganglia dysfunction with GPi stimulation in generalized dystonia can reverse the abnormal activation pattern. This finding supports the view that the primary pathophysiological disorder in dystonia is associated with abnormal neuronal activity in the basal ganglia system and possibly in the GPi.
GPi DBS effects at rest
At rest, GPi DBS increases activation in the contralateral DLPFC and the ipsilateral thalamus and GPi (Table 6; Fig. 1). This finding is another argument to consider that GPi DBS modifies basal ganglia function.
However, contrary to the motor task condition, the results at rest show a paradoxical effect with an increased rCBF within several cortical and subcortical areas which seems to aggravate the abnormal dystonic activity pattern. A similar paradoxical effect at rest was also observed in other imaging studies addressing the effects of DBS in Parkinson's disease (Limousin et al., 1997; Ceballos-Baumann et al., 1999).
More generally, this finding raises the question of the DBS proper effect which remains unclear. Emerging data (Garcia et al., 2003; Hashimoto et al., 2003) suggest that stimulation feeds thalamo-cortical pathways with high frequencies. The abnormal neuronal activity pattern would be masked by this high-frequency feeding. This might explain the overactivity at rest of the GPi, thalamus and cortical projections, especially prefrontal cortex. This is in keeping with the anatomical projection from the somatomotor GPi to cortical areas other than the primary motor cortex via the thalamus (Hoover and Strick, 1999).
This apparent paradoxical effect of GPi DBS at rest does not preclude that, during movement, GPi stimulation restores, at least in part, the regular cortex function. During a motor task, high-frequency stimulation of the postero-lateral GPi seems to improve the abnormal dystonic activity pattern (Ceballos-Baumann et al., 1995a; Playford et al., 1998). Therefore, the effect of GPi stimulation seems to be task dependent as suggested in other functional imaging studies using DBS (Limousin et al., 1997; Ceballos-Baumann et al., 1999).
Such a hypothesis accounts for the GPi DBS-induced clinical improvement of primary dystonia both at rest and during voluntary movement.
|
Acknowledgements |
|---|
We wish to thank Peter Dominey (ISC, Lyon, France) for his software creativity, Bradley Wallace for his helpful comments, and the nurses of the CERMEP for technical support. O.D. was supported by the ‘Fondation pour la Recherche Médicale’ (FRM). The study was funded by the Clinical Research Department of Grenoble University Hospital and was a part of a research project (PHRC AOM 98 030) with the Clinical Research Department of Paris Hospital (AP-HP).
|
References |
|---|
|
TopSummaryIntroductionMaterial and methodsResultsDiscussionReferences |
|---|
Andrew J, Fowler CJ, Harrison MJ. Stereotaxic thalamotomy in 55 cases of dystonia. Brain 1983; 106: 981–1000.
Berardelli A, Rothwell JC, Hallett M, Thompson PD, Manfredi M, Marsden CD. The pathophysiology of primary dystonia. Brain 1998; 121: 1195–212.
Bressman SB, Sabatti C, Raymond D, de Leon D, Klein C, Kramer PL, et al. The DYT1 phenotype and guidelines for diagnostic testing. Neurology 2000; 54: 1746–52.
Brooks DJ. The role of the basal ganglia in motor control: contributions from PET. J Neurol Sci 1995; 128: 1–13.[CrossRef][ISI][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.
Cardoso F, Jankovic J, Grossman RG, Hamilton W. Outcome after stereotactic thalamotomy for dystonia and hemiballismus. Neurosurgery 1995; 36: 501–8.[ISI][Medline]
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 1995a; 37: 363–72.[CrossRef][ISI][Medline]
Ceballos-Baumann AO, Passingham RE, Marsden CD, Brooks DJ. Motor reorganization in acquired hemidystonia. Ann Neurol 1995b; 37: 746–57.[CrossRef][ISI][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.
Ceballos-Baumann AO, Boecker H, Bartenstein P, von Falkenhayn I, Riescher H, Conrad B, et al. A positron emission tomographic study of subthalamic nucleus stimulation in Parkinson disease: enhanced movement-related activity of motor-association cortex and decreased motor cortex resting activity. Arch Neurol 1999; 56: 997–1003.
Cooper IS. 20-year followup study of the neurosurgical treatment of dystonia musculorum deformans. Adv Neurol 1976; 14: 423–52.[Medline]
Coubes P, Echenne B, Roubertie A, Vayssière N, Tuffery S, Humbertclaude V, et al. Treatment of early-onset generalized dystonia by chronic bilateral stimulation of the internal globus pallidus. A propos of a case. [French]. Neurochirurgie 1999; 45: 139–44.[ISI][Medline]
Coubes P, Roubertie A, Vayssière N, Hemm S, Echenne B. Treatment of DYT1-generalised dystonia by stimulation of the internal globus pallidus. Lancet 2000; 355: 2220–1.[CrossRef][ISI][Medline]
Coubes P, Cif L, Azais M, Roubertie A, Hemm S, Diakonoya N, et al. Treatment of dystonia syndrome by chronic electric stimulation of the internal globus pallidus. [French]. Arch Pediatr 2002; 9 Suppl 2: 84s–6s.[Medline]
Detante O, Vercueil L, Krack P, Chabardes S, Benabid AL, Pollak P. Off-period dystonia in Parkinson's disease but not generalized dystonia is improved by high-frequency stimulation of the subthalamic nucleus. Adv Neurol 2004; 94: 309–14.[Medline]
Eidelberg D, Moeller JR, Antonini A, Kazumata K, Nakamura T, Dhawan V, et al. Functional brain networks in DYT1 dystonia. Ann Neurol 1998; 44: 303–12.[CrossRef][ISI][Medline]
Fahn S. Concept and classification of dystonia. Adv Neurol 1988; 50: 1–8.[Medline]
Fahn S, Bressman SB, Marsden CD. Classification of dystonia. Adv Neurol 1998; 78: 1–10.[Medline]
Fine J, Duff J, Chen R, Chir B, Hutchison W, Lozano AM, et al. Long-term follow-up of unilateral pallidotomy in advanced Parkinson's disease. N Engl J Med 2000; 342: 1708–14.
Garcia L, Audin J, D'Alessandro G, Bioulac B, Hammond C. Dual effect of high-frequency stimulation on subthalamic neuron activity. J Neurosci 2003; 23: 8743–51.
Hashimoto T, Elder CM, Okun MS, Patrick SK, Vitek JL. Stimulation of the subthalamic nucleus changes the firing pattern of pallidal neurons. J Neurosci 2003; 23: 1916–23.
Hoover JE, Strick PL. The organization of cerebellar and basal ganglia outputs to primary motor cortex as revealed by retrograde transneuronal transport of herpes simplex virus type 1. J Neurosci 1999; 19: 1446–63.
Jenkins IH, Jahanshahi M, Jueptner M, Passingham RE, Brooks DJ. Self-initiated versus externally triggered movements. Brain 2000; 123: 1216–28.
Krack P, Vercueil L. Review of the functional surgical treatment of dystonia. Eur J Neurol 2001; 8: 389–99.[CrossRef][ISI][Medline]
Krack P, Pollak P, Limousin P, Benazzouz A, Deuschl G, Benabid AL. From off-period dystonia to peak-dose chorea: the clinical spectrum of varying subthalamic nucleus activity. Brain 1999; 122: 1133–46.
Kramer PL, Heiman GA, Gasser T, Ozelius LJ, de Leon D, Brin MF, et al. The DYT1 gene on 9q34 is responsible for most cases of early limb-onset idiopathic torsion dystonia in non-Jews. Am J Hum Genet 1994; 55: 468–75.[ISI][Medline]
Kumar R, Dagher A, Hutchison WD, Lang AE, Lozano AM. Globus pallidus deep brain stimulation for generalized dystonia: clinical and PET investigation. Neurology 1999; 53: 871–4.
Lang AE, Lozano AM, Montgomery EB, Duff J, Tasker R, Hutchison W. Posteroventral medial pallidotomy in advanced Parkinson's disease. N Engl J Med 1997; 337: 1036–42.
Lenz FA, Jaeger CJ, Seike MS, Lin YC, Reich SG, DeLong MR, et al. Thalamic single neuron activity in patients with dystonia: dystonia-related activity and somatic sensory reorganization. J Neurophysiol 1999; 82: 2372–92.
Limousin P, Greene J, Pollak P, Rothwell J, Benabid AL, Frackowiak R. Changes in cerebral activity pattern due to subthalamic nucleus or internal pallidum stimulation in Parkinson's disease. Ann Neurol 1997; 42: 283–91.[CrossRef][ISI][Medline]
Limousin P, Krack P, Pollak P, Benazzouz A, Ardouin C, Hoffmann D, et al. Electrical stimulation of the subthalamic nucleus in advanced Parkinson's disease. N Engl J Med 1998; 339: 1105–11.
Lin JJ, Lin GY, Shih C, Lin SZ, Chang DC, Lee CC. Benefit of bilateral pallidotomy in the treatment of generalized dystonia. Case report. J Neurosurg 1999; 90: 974–6.[ISI][Medline]
Lozano AM, Lang AE, Galvez-Jimenez N, Miyasaki J, Duff J, Hutchinson WD, et al. Effect of GPi pallidotomy on motor function in Parkinson's disease. Lancet 1995; 346: 1383–7.[CrossRef][ISI][Medline]
Lozano AM, Kumar R, Gross RE, Giladi N, Hutchison WD, Dostrovsky JO, et al. Globus pallidus internus pallidotomy for generalized dystonia. Mov Disord 1997; 12: 865–70.[CrossRef][ISI][Medline]
Nemeth AH. The genetics of primary dystonias and related disorders. Brain 2002; 125: 695–721.
Ondo WG, Desaloms M, Jankovic J, Grossman RG. Pallidotomy for generalized dystonia. Mov Disord 1998; 13: 693–8.[CrossRef][ISI][Medline]
Playford ED, Jenkins IH, Passingham RE, Nutt J, Frackowiak RS, Brooks DJ. Impaired mesial frontal and putamen activation in Parkinson's disease: a positron emission tomography study. Ann Neurol 1992; 32: 151–61.[CrossRef][ISI][Medline]
Playford ED, Passingham RE, Marsden CD, Brooks DJ. Increased activation of frontal areas during arm movement in idiopathic torsion dystonia. Mov Disord 1998; 309–18.
Samuel M, Ceballos-Baumann AO, Blin J, Uema T, Boecker H, Passingham RE, et al. Evidence for lateral premotor and parietal overactivity in Parkinson's disease during sequential and bimanual movements: a PET study. Brain 1997; 120: 963–76.
Talairach J, Tournoux P. Co-planar stereotaxic atlas of the human brain: (3-dimensional proportional system: an approach to cerebral imaging). Stuttgart: Thieme; 1988.
Tasker RR, Doorly T, Yamashiro K. Thalamotomy in generalized dystonia. Adv Neurol 1988; 50: 615–31.[Medline]
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.
Tronnier VM, Fogel W. Pallidal stimulation for generalized dystonia. J Neurosurg 2000; 92: 453–6.[ISI][Medline]
Vercueil L, Pollak P, Fraix V, Caputo E, Moro E, Benazzouz A, et al. Deep brain stimulation in the treatment of severe dystonia. J Neurol 2001; 248: 695–700.[CrossRef][ISI][Medline]
Vitek JL, Chockkan V, Zhang JY, Kaneoke Y, Evatt M, DeLong MR, et al. Neuronal activity in the basal ganglia in patients with generalized dystonia and hemiballismus. Ann Neurol 1999; 46: 22–35.[CrossRef][ISI][Medline]
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  I. U. Isaias, R. L. Alterman, and M. Tagliati Outcome predictors of pallidal stimulation in patients with primary dystonia: the role of disease duration Brain, July 1, 2008; 131(7): 1895 - 1902. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Tisch, P. Limousin, J. C. Rothwell, P. Asselman, L. Zrinzo, M. Jahanshahi, K. P. Bhatia, and M. I. Hariz Changes in forearm reciprocal inhibition following pallidal stimulation for dystonia Neurology, April 11, 2006; 66(7): 1091 - 1093. [Abstract] [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||