Improvement of motor performance and modulation of cortical excitability by repetitive transcranial magnetic stimulation of the motor cortex in Parkinson's disease
Introduction
Progressive degeneration of mesencephalic dopaminergic nuclei leads to various motor disturbances in Parkinson's disease (PD). Initially, drugs like l-dopa or dopaminergic agonists are able to control these symptoms, but with the progress of the disease, these drugs disclose some shortcomings, i.e. insufficient efficacy or adverse effects. Therefore new therapeutic strategies have been developed, like chronic electrical stimulation of deep brain structures, particularly the subthalamic nucleus (Limousin et al., 1995, Limousin et al., 1998). According to the basal ganglia–thalamocortical circuit model (Alexander et al., 1990), the degeneration of dopaminergic nigrostriatal pathways would result in functional deafferentation of the frontal cortex, including the primary motor cortex, that could contribute to the pathophysiology of motor disturbances in patients with PD. Therefore, the motor cortex is an appealing target for neuromodulation therapy in PD.
Cortical activity can be transiently modified by the application of repetitive transcranial magnetic stimulation (rTMS). Shortening of reaction time and movement time during 5 Hz rTMS applied over the motor cortex was first shown in patients with PD in 1994 (Pascual-Leone et al., 1994). Since this first study, several rTMS trials have been reported in PD, based on various experimental designs: (i) focal stimulation using a figure-of-eight coil or non-focal stimulation using a circular coil; (ii) low-frequency stimulation (from 0.2 to 1 Hz) or high-frequency stimulation (5, 10 or 20 Hz); (iii) subthreshold stimulation, i.e. at intensity lower than motor threshold, or suprathreshold stimulation, i.e. at intensity above motor threshold; (iv) clinical assessment by motor task speed measurement or by motor performance scoring, e.g. using the Unified Parkinson's Disease Rating Scale (UPDRS). Then, the results of all the previous rTMS studies performed in patients with PD are puzzling owing to their methodological differences. Only one study assessed the effects of focal primary motor cortex stimulation on UPDRS score (Siebner et al., 2000b) and showed a significant improvement of the UPDRS score after a 20 min session of subthreshold 5 Hz rTMS.
Beside rTMS protocols, single- or paired-pulse TMS paradigms allow to study some excitatory and inhibitory nervous pathways involved in motor control, and provide various parameters of cortical excitability, e.g. motor threshold, silent period, intracortical inhibition or facilitation. Studies of cortical excitability determinants in PD disclosed mainly a reduction of motor inhibitory control, which could be restored following various anti-parkinsonian medication or neurosurgical therapies (reviewed in Cantello et al. (2002)), whereas the influence of rTMS remains unknown.
In the present series of 12 patients with PD, we have tested the effects of motor cortex rTMS on motor performance assessed by UPDRS scoring and timed motor tasks, and on motor cortex excitability assessed by single- and paired-pulse TMS techniques. Sessions of rTMS were applied at two frequencies, 0.5 and 10 Hz, compared to sham stimulation (negative control) and to l-dopa administration (positive control).
Section snippets
Patients
Twelve patients (5 women and 7 men) aged from 51 to 76 years (mean±SEM: 64±2) were included in this study. All these patients fulfilled the UK Parkinson's Disease Brain Bank criteria for idiopathic PD (Gibbs and Lees, 1988) and suffered from a bilateral akinetic-rigid syndrome. Patients with permanent rest tremor were excluded from the study because of their impossibility to maintain a complete relaxation of hand muscles, precluding a reliable determination of the rest motor threshold. Other
Results
No adverse effect of rTMS was observed. The results of the 4 interventions (l-dopa intake, 0.5 Hz rTMS, 10 Hz rTMS or sham rTMS) are shown by Fig. 1, Fig. 2 for clinical scores and by Fig. 3 for motor cortex excitability parameters. Due to the limited number of patients, it was impossible to define subgroups and to determine statistically the influence of the age of the patient, of the stage or the duration of the disease, or of the dose of l-dopa intake on these results.
Discussion
The present study showed that primary motor cortex stimulation could improve motor performance in patients with PD, concomitantly with cortical excitability changes. The mean reduction of UPDRS motor score resulting from 0.5 or 10 Hz rTMS (−19.5 or −17.1%) was equal to 28–32% of the l-dopa effect (−61.2%). Because it was not ethical to keep patients unmedicated for several days, we were not able to appraise the duration of rTMS effects, as it was reported for patients with writer's cramp (
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