Improvement of motor performance and modulation of cortical excitability by repetitive transcranial magnetic stimulation of the motor cortex in Parkinson's disease

Abstract

Objective: To assess the effects of focal motor cortex stimulation on motor performance and cortical excitability in patients with Parkinson's disease (PD).

Methods: Repetitive transcranial magnetic stimulation (rTMS) was performed on the left motor cortical area corresponding to the right hand in 12 ‘off-drug’ patients with PD. The effects of subthreshold rTMS applied at 0.5 Hz (600 pulses) or at 10 Hz (2000 pulses) using a ‘real’ or a ‘sham’ coil were compared to those obtained by a single dose of l-dopa. The assessment included a clinical evaluation by the Unified Parkinson's Disease Rating Scale and timed motor tasks, and a neurophysiological evaluation of cortical excitability by single- and paired-pulse TMS techniques.

Results: ‘Real’ rTMS at 10 or 0.5 Hz, but not ‘sham’ stimulation, improved motor performance. High-frequency rTMS decreased rigidity and bradykinesia in the upper limb contralateral to the stimulation, while low-frequency rTMS reduced upper limb rigidity bilaterally and improved walking. Concomitantly, 10 Hz rTMS increased intracortical facilitation, while 0.5 Hz rTMS restored intracortical inhibition.

Conclusions: Low- and high-frequency rTMS of the primary motor cortex lead to significant but differential changes in patients with PD both on clinical and electrophysiological grounds. The effects on cortical excitability were opposite to previous observations made in healthy subjects, suggesting a reversed balance of cortical excitability in patients with PD compared to normals. However, the underlying mechanisms of these changes remain to determine, as well as the relationship with clinical presentation and response to l-dopa therapy.

Significance: The present study gives some clues to appraise the role of the primary motor cortex in PD. Clinical improvement induced by rTMS was too short-lasting to consider therapeutic application, but these results support the perspective of the primary motor cortex as a possible target for neuromodulation in PD.

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).