Multifocal repetitive TMS for motor and mood symptoms of Parkinson disease: A randomized trial

Abstract

Objective: To assess whether multifocal, high-frequency repetitive transcranial magnetic stimulation (rTMS) of motor and prefrontal cortex benefits motor and mood symptoms in patients with Parkinson disease (PD).

Methods: Patients with PD and depression were enrolled in this multicenter, double-blind, sham-controlled, parallel-group study of real or realistic (electric) sham rTMS. Patients were randomized to 1 of 4 groups: bilateral M1 ( + sham dorsolateral prefrontal cortex [DLPFC]), DLPFC ( + sham M1), M1 + DLPFC, or double sham. The TMS course consisted of 10 daily sessions of 2,000 stimuli for the left DLPFC and 1,000 stimuli for each M1 (50 × 4-second trains of 40 stimuli at 10 Hz). Patients were evaluated at baseline, at 1 week, and at 1, 3, and 6 months after treatment. Primary endpoints were changes in motor function assessed with the Unified Parkinson's Disease Rating Scale-III and in mood with the Hamilton Depression Rating Scale at 1 month.

Results: Of the 160 patients planned for recruitment, 85 were screened, 61 were randomized, and 50 completed all study visits. Real M1 rTMS resulted in greater improvement in motor function than sham at the primary endpoint (p < 0.05). There was no improvement in mood in the DLPFC group compared to the double-sham group, as well as no benefit to combining M1 and DLPFC stimulation for either motor or mood symptoms.

Conclusions: In patients with PD with depression, M1 rTMS is an effective treatment of motor symptoms, while mood benefit after 2 weeks of DLPFC rTMS is not better than sham. Targeting both M1 and DLPFC in each rTMS session showed no evidence of synergistic effects.

Clinicaltrialsgov identifier: NCT01080794.

Classification of evidence: This study provides Class I evidence that in patients with PD with depression, M1 rTMS leads to improvement in motor function while DLPFC rTMS does not lead to improvement in depression compared to sham rTMS.

© 2016 American Academy of Neurology.

Figures

Figure 1. Repetitive Transcranial Magnetic Stimulation (rTMS) for Motor and Mood Symptoms of Parkinson's Disease (MASTER-PD) study flow diagram

*The analysis included all participants who completed the primary study end point visit and were not excluded from analysis. DLPFC = dorsolateral prefrontal cortex.

Figure 2. Hamilton Depression Rating Scale (HAM-D) scores at study time points in dorsolateral prefrontal cortex (DLPFC) repetitive transcranial magnetic stimulation (rTMS) group and Unified Parkinson’s Disease Rating Scale (UPDRS) part III scores at study time points in M1 rTMS group compared to double-sham group

(A and B) Improvement in motor symptoms after rTMS to primary motor cortex vs sham. Consistent with prior studies, there was a significant improvement in motor scores after M1 rTMS compared to double sham at the primary endpoint (A) that returned to baseline by 3 months (B). (C and D) Lack of improvement in mood symptoms after rTMS to DLPFC vs sham. In contrast to prior reports, rTMS to left DLPFC resulted in less antidepressant response at the primary 1-month endpoint than double sham (C). This difference was specific to this single time point (D) and driven in part by a single outlier (see text). *p < 0.05, **p < 0.001.

Figure 3. Time course of Unified Parkinson’s Disease Rating Scale (UPDRS) part III and Hamilton Depression Rating Scale (HAM-D) scores by treatment group

Lack of improvement in motor or mood symptoms after combined M1 + DLPFC rTMS vs sham. There was no significant improvement in motor (A and B) or mood (C and D) symptoms after combined M1 + dorsolateral prefrontal cortex (DLPFC)repetitive transcranial magnetic stimulation (rTMS) vs sham. There was also no added benefit of M1 + DLPFC stimulation on motor symptoms compared to M1 stimulation alone (A and B) or mood benefit compared to DLPFC alone (C and D).