Clinical Neurophysiology 117 (2006) 1917–1921 www.elsevier.com/locate/clinph
Low frequency rTMS of the SMA transiently ameliorates peak-dose LID in Parkinson’s disease Livia Brusa a
a,b
, Viviana Versace a,c, Giacomo Koch a,c,*, Cesare Iani b, Paolo Stanzione Giorgio Bernardi a,c, Diego Centonze a,c
a,c
,
Clinica Neurologica, Dipartimento di Neuroscienze, Universita` di Roma Tor Vergata, Via Montpellier 1, 00133 Rome, Italy b UOC Neurologia, Ospedale S Eugenio, Rome, Italy c Fondazione Santa Lucia IRCCS, Rome, Italy Accepted 8 March 2006
Abstract Objective: To determine whether low-frequency repetitive transcranial magnetic stimulation (rTMS) may modulate L-DOPA-induced dyskinesia (LID) in dyskinetic Parkinson’s disease (PD) patients. LID is a severe motor complication in advanced PD patients. The neural mechanisms involved in LID are not clear, and it is apparent that both an excessive decrease in internal pallidus firing and a modification and overactivation of cortical motor and premotor areas are involved in its pathogenesis. Methods: Using low frequency 1 Hz repetitive rTMS we investigated whether decrease of excitability of the supplementary motor area (SMA) may result in modification of LID in PD patients. Furthermore we tested whether it was possible to enhance and/or prolong the beneficial effects of the treatment with repeated sessions of stimulation. Results: We observed that 1 Hz rTMS induced a transient reduction of dyskinesias. A single session of rTMS improved LID, while repeated sessions of stimulation failed to enhance and/or prolong the beneficial effects of the procedure, without causing motor deterioration or other adverse effects. Conclusions: These results suggest that LID may depend on an increased excitability of the SMA. Significance: SMA rTMS is effective in reducing transiently LID, although cannot yet be considered clinically useful. Ó 2006 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved. Keywords: rTMS; Transcranial magnetic stimulation; Parkinson disease; L-DOPA, Dyskinesia; Involuntary movements
1. Introduction L-DOPA is still the golden standard in Parkinson’s disease (PD) therapy, although motor complications usually occur during chronic treatment. One of the most debilitating class of motor complications is known as L-DOPA-induced dyskinesia (LID), a condition that afflicts up to 80% PD patients treated with L-DOPA for years (Blanchet et al., 1996; Fahn, 2000; Rascol et al., 2000).
*
Corresponding author. Tel.: +39 065150 1469. E-mail address:
[email protected] (G. Koch).
The neural mechanisms that underlie LID in PD are far from clear, although important advances have been made in recent years. Dyskinesia has been associated with a sequence of events that include pulsatile stimulation of dopamine receptors, downstream changes in proteins and genes, and abnormalities in non-dopamine transmitter systems. All these events combine to produce alterations in the firing patterns that signal between the basal ganglia and the cortex (Obeso et al., 2000; Bezard et al., 2001). Although changes in neural activity in the basal ganglia have been extensively studied in the untreated, experimental models of PD, few studies have focused on the electrophysiological and/or metabolic modifications that
1388-2457/$32.00 Ó 2006 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.clinph.2006.03.033
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L. Brusa et al. / Clinical Neurophysiology 117 (2006) 1917–1921
accompany LID. Filion et al. (1991) proposed that in monkeys with MPTP-induced parkinsonism LID is associated with marked decreases in firing frequency of the internal pallidus (Gpi) and similar findings were reported recently in PD patients (Lozano et al., 2000). The net effect of these imbalances would be reduced inhibition of thalamocortical neurons and overactivation of cortical motor and premotor areas (Bezard et al., 2001). Neuroimaging studies outlined the role of overactive supplementary motor area (SMA) in the development of LID (Brooks et al., 2000) and a study examining the synaptic alterations at the basis of LID reported that in this condition corticostriatal synapses are refractory to depotentiation after the induction of longterm potentiation (LTP) (Picconi et al., 2003). Based on these findings, we have hypothesized that lowfrequency (1 Hz) rTMS over the SMA may alleviate dyskinesia in PD patients. Analogies, in fact, exist between the inhibitory effect of low-frequency rTMS and the phenomenon of synaptic depotentiation, in which stimulation at frequencies in the 1 Hz range is able to reverse a previously induced LTP (Hoffman and Cavus, 2002). In a previous work we demonstrated that 1 Hz rTMS over the SMA transiently reduces dyskinesias produced by over-optimal continuous apomorphine infusion, while no significant modification was induced by high frequency 5 Hz rTMS (Koch et al., 2005). In the present study, therefore, we tested the effects of this procedure on LID caused by standard doses of L-DOPA in advanced dyskinetic PD patients. We hypothesised that a single application of 1 Hz rTMS may also transiently improved LID; furthermore we tested whether it was possible to enhance and/or prolong the beneficial effects of the treatment with repeated sessions of stimulation. 2. Patients and methods The study was approved by our local ethics committee. Ten advanced PD patients suffering from disabling peak-dose dyskinesias following L-DOPA ingestion were enrolled (6 male; 4 female; mean age (yrs) 61 ± 8.04; mean disease duration (yrs) 16.4 ± 5.4; mean L-DOPA therapy duration (yrs) 12.4 ± 3.02; mean L-DOPA daily dose (mg) 1345 ± 276). Diagnosis of idiopathic PD was made according with Brain Bank Criteria (Hughes et al., 1992). Antiparkinsonian medications producing the best control of PD and LID symptoms were fixed for at least 1 month prior and during the study. Experts of movement disorders (L.B. and P.S.) diagnosed peak dose dyskinesia PD patients clinically. A MagStim Rapid magnetic stimulator (Magstim, Whitland, UK), connected with a figure-of-eight coil with a diameter of 70 mm was used to deliver rTMS over the scalp 3 cm anterior to Cz (to stimulate simultaneously the SMA of both hemispheres) or at a control parietal site corresponding to Pz of the 10–20 EEG system in the sagittal midline (Koch et al., 2004, 2005). For each subject, the precise position to stimulate was selected to be sufficiently
anterior so that the current spread to the primary motor cortex would not elicit muscle twitch in shoulder, trunk or lower limb muscle. The target sites were marked on a tightly fitting Lycra cap worn by the subject, and the coil was maintained in that position for the duration of the experiment. The coil was applied with the handle pointing posteriorly in order to induce a posterior–anterior (PA) directed current in the underlying cortex possibly affecting both SMA at the same time. Although we did not use neuronavigation systems and therefore we were not able to control for the precise site of stimulation in each patient, in our previous study (Koch et al., 2005) we found that SMA rTMS induced symmetrical effects on apomorphine induced dyskinesias in both hemisomas, suggesting that stimulation presumably involved cortical areas of both hemisphere. Individual resting motor excitability threshold (RMT) was calculated according to international standards. With Nine hundred pulses of 1 Hz rTMS (90% RMT, 15 min duration) were applied. For sham SMA stimulation, the coil was angled away so that no current was induced in the brain. Two sets of experiments were conducted. 2.1. Experiment A All patients were fastened and in withdrawal of therapy from the night before. Four video-recorded sessions were performed in four consecutive days. The assessment in each session consisted of a complete Unified Parkinson’s Disease Rating Scale motor Section 3 (UPDRS III) (Fahn and Elton, 1987) executed in off-therapy condition (CAPIT) (Langston et al., 1992) in the morning. L-DOPA/carbidopa dispersible formulation 200/50 mg was administered and UPDRS III and Abnormal Involuntary Movement Scale (AIMs) (May et al., 1983) were calculated every 15 min for 1 h (t0, t15, t30, t45, t60). A complete evaluation lasted approximately 3–4 min at t0. Immediately after L-DOPA administration, no stimulation trial was performed during session S1, sham SMA rTMS was administered in S2 session, and 1 Hz rTMS over SMA, and 1 Hz rTMS over Pz were applied during session S3 and S4 respectively. The order of the sessions was pseudo-randomized across patients (Fig. 1). 2.2. Experiment B One week later, PD patients were submitted to five consecutive days of 1 Hz SMA rTMS. During the first four days of stimulation and the week before, antiparkinsonian medications were maintained stable. The fifth day an identical session as S3 (S5) was performed. Patients completed an hourly on-dyskinesia-off diary during the all protocol period (1 week + 5 days) to calculate the percentage of the 24 h day spent on with dyskinesia (Melamed et al., 1999). Two blinded raters expert in the field of movement disorders rated videotapes independently to provide AIMs
L. Brusa et al. / Clinical Neurophysiology 117 (2006) 1917–1921
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Fig. 1. Schematic representation of experimental procedure. In each session rTMS was applied in different conditions immediately after L-DOPA ingestion. The assessment in each session consisted of a complete Unified Parkinson’s Disease Rating Scale motor Section 3 (UPDRS III) and Abnormal Involuntary Movement Scale (AIMs) calculated every 15 min for 1 h (t0, t15, t30, t45, and t60) after L-DOPA ingestion.
scores. Both video-raters were blinded to rTMS and the scores were generated after a consensus was reached comparing the individual scores. Furthermore, in each session dyskinesia latency after L-DOPA ingestion was calculated (in minutes). Dyskinesia latency was defined as the time interval between L-DOPA ingestion and appearance of dyskinetic movements (both choreic or dystonic) at least in one body segment (i.e., head, upper arm, leg, and foot). Non-parametric Friedman ANOVAs for repeated measures with Time main effect was applied on mean AIMs and UPDRS Section 3 scores for each session and to compare dyskinesia latency in each session. On-dyskinesia-off diary results were analyzed utilizing a further non-parametric Friedman ANOVA. Wilcoxon test was performed as a post hoc comparison.
all the sessions (Table 1). By contrast, AIMs score raised from t15 in S1, S2, and S4. In S3 and S5, in which real SMA rTMS was administered, a higher AIMs score was observed only from t30. At t45 and t60 no significant difference was found between all sessions (Table 2 and Fig. 2). When comparing S3 and S5, no significant UPDRS and AIMs score changes were found at any time of evaluation. Analysis of dyskinesia onset latency showed a significant increase at session S3 vs. S1 (40 ± 56 min vs. 18 ± 14 min; p < 0.05; v2 = 3.5), and at session S5 vs. S1 (41 ± 52 min vs. 18 ± 12 min; p < 0.05; v2 = 3.5). No differences were found by comparing dyskinesia time to onset at S3 vs. S5, nor comparing S1 vs. S2 vs. S4, indicating that the same effect was induced by rTMS in a single session before and after 5 days of repeated sessions. Patient diaries showed that 5 days SMA rTMS failed to affect the 24 daily hours percentage spent on with dyskinesia (53 ± 16% vs. 51 ± 14%, n.s.; v2 = 0.42).
3. Results Mean subjects’ motor threshold was 54 ± 5.2%. The procedure was well tolerated by patients and no adverse effect was reported. In each session, a significant change of AIMs and UPDRS scores was observed over the times following L-DOPA. UPDRS improved from t15 to t60 in
4. Discussion In the present study we have shown that 1 Hz rTMS over the SMA is safe and transiently effective against
Table 1 PD patients mean UPDRS Section 3 scores (± S.D.) in the different sessions t0 Basal (S1) Sham rTMS (S2) 1 Hz SMA rTMS (S3) 1 Hz Pz rTMS (S4) 1 Hz SMA rTMS (S5-Experiment B) Friedman ANOVA (times in S1 vs. S0 vs. S1 vs. S2 vs. S3)
36.5 37.5 38.0 36.0 36.0 n.s.
t15 (5.60) (5.1) (4.3) (5.0) (4.3)
25.7 25.1 25.0 25.2 26.1 n.s.
t30 (7.0)* (6.1)* (6.2)* (8.2)* (5.0)*
17.3 16.1 18.6 16.6 19.1 n.s.
t45 (2.9)* (2.6)* (3.1)* (3.4)* (2.5)*
16.1 16.2 17.6 16.0 18.3 n.s.
t60 (2.9)* (2.6)* (2.3)* ( 2.1)* (3.9)*
17.1 16.7 18.1 17.2 12.1 n.s.
Friedman ANOVA (t0 vs. t15vs. t30 vs. t45 vs. t60) (3.2)* (3.2)* (2.3)* (3.4)* (2.1)*
v2 = 28.3 v2 = 27.0 v2 = 23.6 v2 = 27.4 v2 = 23.5
p < 0.0001; p < 0.0001; p < 0.0001; p < 0.0001; p < 0.0001;
post post post post post
hoc: hoc: hoc: hoc: hoc:
*vs.
t0 t0 *vs. t0 *vs. t0 *vs. t0 *vs.
p < 0.01, p < 0.01, p < 0.01, p < 0.01, p < 0.01,
vs. vs. vs. vs. vs.
t15 t15 t15 t15 t15
p < 0.01 p < 0.01 p < 0.01 p < 0.01 p < 0.01
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L. Brusa et al. / Clinical Neurophysiology 117 (2006) 1917–1921
Table 2 PD patients mean AIMs scores (± S.D.) in the different sessions t0
t30
t45
t60
Friedman ANOVA (t0 vs. t15vs. t30 vs. t45 vs. t60)
0.0 (0.0) 6.25 (1.6)* 0.0 (0.0) 6.62 (1.0)*
7.62 (1.3)* 7.87 (1.24)*
7.12 (1.5)* 7.12 (1.4)*
3.00 (0.9)* 2.87 (0.8)*
1 Hz SMA rTMS (S3) 0.0 (0.0) 1.37 (1.5)§
4.25 (2.8)*§
5.75 (3.3)*
3.37 (2.3)*
8.00 (0.9)*
7.02 (1.3)*
2.79 (1.3)*
v2 = 28.0 p < 0.001; post hoc: *vs. t0 p < 0.01 v2 = 28.1 p < 0.001; post hoc: *vs. t0 p < 0.01 v2 = 23.4 p < 0.001; post hoc: *vs. t0 p < 0.01, vs. t15 p < 0.01 v2 = 28.2 p < 0.001; post hoc: *vs. t0 p < 0.01 v2 = 25.8 p < 0.001; post hoc: *vs. t0 p < 0.01, vs. t15 p < 0.01
Basal (S1) Sham rTMS (S2)
1 Hz Pz rTMS (S4)
t15
0.0 (0.0) 6.24 (1.4)*
1 Hz SMA rTMS 0.0 (0.0) 1.45 (1.4)§ 3.50 (1.7)*§ 6.12 (2.7)* 4.87 (2.7)* (S5-Experiment B) Friedman ANOVA n.s. v2 = 23.3 p < 0.0001 v2 = 17.6 p < 0.0001 v2 = 0.39 n.s. v2 = 4.42 n.s. (times in S-1 vs S0 vs S1 vs S2 vs S3) § § Post hoc Wilcoxon test vs. S1 p < 0.01 vs. S1 p < 0.01
LID in advanced PD patients. These results are consistent with the idea that SMA plays a central role in the development of LID in PD patients, and extend a previous observation in apomorphine-induced dyskinesias (Koch et al., 2005). The effect of low-frequency rTMS was time-dependent and lasted 15 min after the end of stimulation. This finding is in agreement with previous studies demonstrating that the reduction of cortical excitability induced by 1 Hz rTMS outlast the period of stimulation in a range from minutes to hours, depending on the duration of the trains (Chen et al., 1997; Munchau et al., 2002). The beneficial effects of SMA rTMS cannot be potentiated with repeated sessions of stimulation, suggesting that the plastic neuronal changes induced by treatment vanish with the disappearance of the clinical effects. This was unexpected in the light of others investigations. Previous studies clearly demonstrated that cumulative plastic changes can be produced by premotor rTMS and premotor rTMS can have long lasting effects on motor cortical excitability both in healthy controls and PD patients. Ba¨umer et al. (2003) reported on healthy subjects that excitability changes following 1 Hz premotor rTMS on the second day of stimulation lasted significantly longer than the ones
observed on day 1, implying that cumulative changes in premotor–motor circuits were induced by the first rTMS session. More importantly, 1 Hz premotor rTMS lasted significantly longer in de novo PD patients as compared to healthy controls (up to a week) even after a single rTMS session (Buhmann et al., 2004). In our opinion it is possible that distinct cortical areas of the motor system (i.e. SMA vs premotor) may have dissimilar properties of excitability and being susceptible by different long-lasting modulation induced by repeated session of rTMS. On the other hand it is also possible that de novo PD may be more susceptible to rTMS cumulative changes (Buhmann et al., 2004) than the advanced dyskinetic PD sample recruited in our study. Finally our PD patients were treated during 1 week, while longer periods of repeated sessions have been adopted by some authors reporting potentially beneficial and specific rTMS effects on bradikinesia and psychomotor speed in PD patients following high frequency (>5 Hz) stimulation of the motor cortex (Mally and Stone, 1999; Wassermann and Lisanby, 2001; Cantello et al., 2002; Tsuji and Akamatsu, 2003). Thus further studies with longer protocols of stimulation may determine if longer sessions may lead to some long-lasting beneficial effects for LID.
Fig. 2. The graph shows that, when compared to the other sessions, 1 Hz rTMS over the SMA significantly ameliorates abnormal involuntary movement score 15 and 30 min after the ingestion of L-DOPA.
L. Brusa et al. / Clinical Neurophysiology 117 (2006) 1917–1921
In PD patients with LID, overactivation of SMA has been postulated on the basis of neuroimaging studies. Brooks et al. using [H1515O]-positron emission tomography (PET) found in dyskinetic PD patients a relative overactivation of SMA, motor cortical areas and the basal ganglia, the degree of which correlated with the severity of dyskinesia, indicating that dyskinesias are associated with inappropriate overactivity of striato-frontal projections both at rest and during volitional actions. Indeed, a relative overactivity of motor and premotor areas of the cortex, including the supplementary motor area (SMA), has been reported when comparing non-dyskinetic and dyskinetic patients with a SPECT study (Rascol et al., 1998). Our findings are in keeping with the hypothesis that overactivation of the SMA observed in neuroimaging studies reflects a state of altered cortical excitability in dyskinetic PD patients, as we have observed a marked reduction of LID following 1 Hz rTMS, a procedure commonly believed to induce transient inhibition of the stimulated region. rTMS of cortical sensorimotor areas might modify the strength of synaptic connectivity also in subcortical areas, and namely in the striatum. In experimental parkinsonism, LID is associated with abnormal persistence of synaptic potentiation at corticostriatal synapses (Picconi et al., 2003), a result which is in good agreement with the idea that low-frequency rTMS promotes depotentation at cortical and subcortical synapses (Hoffman and Cavus, 2002); furthermore rTMS of the premotor cortex modulates dopamine levels within the striatum (Strafella et al., 2001) indicating that the observed effects against dyskinesia may rely on the interference of the stimulation with the dopamine-sensitive abnormal corticostriatal circuit. In conclusion, 1 Hz rTMS stimulation over the SMA determines a marked although transient improvement of LID in PD patients. The favorable effect is ephemeral and limits so far the value of rTMS as a practical means for modifying LIDs and being of some clinical use. However the positive effects against dyskinesia of rTMS are of considerable pathophysiological interest. Reduction of LIDs might rely on the transient depression of synaptic excitability at the cortical level, and/or on the promotion of depontentiation at corticostriatal inputs from the SMA to the putamen. References Ba¨umer T, Lange R, Liepert J, et al. Repeated premotor rTMS lead to cumulative changes of motor cortex excitability in humans. Neuroimage 2003;20:550–60. Bezard E, Brotchie JM, Gross CE. Pathophysiology of levodopa-induced dyskinesia: potential for new therapies. Nat Rev Neurosci 2001;8:577–88. Blanchet PJ, Allard P, Gregoire L, Tardif F, Bedard PJ. Risk factors for peak dose dyskinesia in 100 levodopa-treated parkinsonian patients. Can J Neurol Sci 1996;23(3):189–93. Brooks DJ, Piccini P, Turjanski N, Samuel M. Neuroimaging of dyskinesia. Ann Neurol 2000;47(4 Suppl. 1):S154–8. Buhmann C, Gorsler A, Ba¨umer T, et al. Abnormal excitability of premotor–motor connections in de novo Parkinson’s disease. Brain 2004;127:2732–46.
1921
Cantello R, Tarletti R, Civardi C. Transcranial magnetic stimulation and Parkinson’s disease. Brain Res Rev 2002;38(3):309–27. Chen R, Classen J, Gerloff C, et al. Depression of motor cortex excitability by low-frequency transcranial magnetic stimulation. Neurology 1997;48:1398–403. Fahn S. The spectrum of levodopa-induced dyskinesias. Ann Neurol 2000;47(4 Suppl. 1):S2–9, Discussion S9–S11. Fahn S, Elton RL. UPDRS Development Committee. Unified Parkinson’s Disease Rating Scale. In: Fahn S, Marsden CD, Calne D, Golstein M, editors. Recent developments in Parkinson’s disease, vol. 2. Florham Park, NY: MacMillan Healthcare Information; 1987. p. 153–63, 293– 304. Filion M, Tremblay L, Bedard PJ. Effects of dopamine agonists on the spontaneous activity of globus pallidus neurons in monkeys with MPTP-induced parkinsonism. Brain Res 1991;547(1):152–61. Hoffman RE, Cavus I. Slow transcranial magnetic stimulation, long-term depotentiation, and brain hyperexcitability disorders. Am J Psychiatry 2002;159:1093–102. Hughes AJ, Daniel SE, Kilford L, Lees AJ. Accuracy of clinical diagnosis of idiopathic Parkinson’s disease: a clinico-pathological study of 100 cases. J Neurol Neurosurg Psychiatry 1992;55(3):181–4. Koch G, Oliveri M, Brusa L, Stanzione P, Torriero S, Caltagirone C. High-frequency rTMS improves time perception in Parkinson disease. Neurology 2004;63(12):2405–6. Koch G, Brusa L, Caltagirone C, Peppe A, Oliveri M, Stanzione P, Centonze D. rTMS of supplementary motor area modulates therapyinduced dyskinesias in Parkinson disease. Neurology 2005;65(4):623–5. Langston JW, Widner H, Goetz CG, et al. Core assessment program for intracerebral transplantations (CAPIT). Mov Disord 1992;7:2–13. Lozano AM, Lang AE, Levy R, Hutchison W, Dostrovsky J. Neuronal recordings in Parkinson’s disease patients with dyskinesias induced by apomorphine. Ann Neurol 2000;47(4 Suppl. 1):S141–6. Mally J, Stone TW. Improvement in Parkinsonian symptoms after repetitive transcranial magnetic stimulation. J Neurol Sci 1999;162(2):179–84. May PR, Lee MA, Bacon RC. Quantitative assessment of neurolepticinduced extrapyramidal symptoms: clinical and nonclinical approaches. Clin Neuropharmacol 1983;6:S35–51. Melamed E, Olanow CW, Nutt JG, Lang AE. Dyskinesias assessment workshop: reports from the working group. Mov Disord 1999;14(Suppl. 1):69–73. Munchau A, Bloem BR, Irlbacher K, Trimble MR, Rothwell JC. Functional connectivity of human premotor and motor cortex explored with repetitive transcranial magnetic stimulation. J Neurosci 2002;22(2):554–61. Obeso JA, Rodriguez-Oroz MC, Rodriguez M, DeLong MR, Olanow CW. Pathophysiology of levodopa-induced dyskinesias in Parkinson’s disease: problems with the current model. Ann Neurol 2000;47(4 Suppl.s 1):S22–32, Discussion S32–S34. Picconi B, Centonze D, Hakansson K, Bernardi G, Greengard P, Fisone G, et al. Loss of bidirectional striatal synaptic plasticity in L-DOPAinduced dyskinesia. Nat Neurosci 2003;6(5):501–6. Rascol O, Sabatini U, Brefel C, Fabre N, Rai S, Senard JM, et al. Cortical motor overactivation in parkinsonian patients with L-DOPAinduced peak-dose dyskinesia. Brain 1998;121(Pt 3):527–33. Rascol O, Brooks DJ, Korczyn AD, De Deyn PP, Clarke CE, Lang AE. A five-year study of the incidence of dyskinesia in patients with early Parkinson’s disease who were treated with ropinirole or levodopa. 056 Study Group. N Engl J Med 2000;342(20):1484–91. Strafella AP, Paus T, Barret J, Dagher A. Repetitive transcranial magnetic stimulation of the human premotor cortex induces dopamine release in the caudate nucleus. J Neurosci 2001;21:1–4. Tsuji S, Akamatsu N. Does transcranial magnetic stimulation improve the motor symptoms of Parkinson disease? J Neurol 2003;250(Suppl. III):47–50. Wassermann EM, Lisanby SH. Therapeutic application of repetitive transcranial magnetic stimulation: a review. Clin Neurophysiol 2001;112(8):1367–77.
