By Douglas Labar, MD, PhD

Professor of Neurology, Weill Cornell Medical College

Dr. Labar reports no financial relationships relevant to this field of study.

Synopsis: In several randomized, sham-controlled trials, repetitive transcranial magnetic stimulation was shown to be effective in reducing the motor manifestations of Parkinson’s disease, with minimal side effects.

Source: Chou Y, et al. Effects of repetitive transcranial magnetic stimulation on motor symptoms in Parkinson’s disease. A systematic review and meta-analysis. JAMA Neurol 2015;72:432-440.

Parkinson’s disease (PD) prevalence is increasing with our aging population. Medical therapy typically is beneficial, but side effects, such as dyskinesias, may develop, and medication efficacy may be lost. Deep brain stimulation (DBS) may help, but there are associated brain surgery risks. Increasingly, recent attention has been directed toward non-invasive brain stimulation as an alternative treatment. This includes repetitive transcranial magnetic stimulation (rTMS).

Chou et al carried out a meta-analysis of studies on rTMS for PD. Trials were considered for inclusion if there was a population of idiopathic PD, if there was a sham control, and if the Unified Parkinson’s Disease Rating Scale-III (UPDRS-III) motor score was reported as an outcome measure. Furthermore, adequate data on medication states during assessment, timing of outcome measures, and rTMS protocol details (such as stimulation site) were required. A multiple database search on the terms “Parkinson’s disease” and “repetitive transcranial stimulation” or “rTMS” or “repetitive TMS” retrieved 2203 studies, of which 20 studies met all inclusion criteria. In total, 470 participants were included in the meta-analysis.

The mean improvement on the UPDRS-III was -6.42; there was a medium effect size favoring active over sham treatments. Motor outcomes from high-frequency stimulation applied over primary motor cortex (M1), and low-frequency stimulation applied over other frontal areas, were superior to sham. In contrast, low-frequency stimulation applied over M1, and high-frequency stimulation applied over other frontal areas, did not change motor function significantly.

There was no difference between motor outcomes measured up to 1 day after rTMS vs measured 1-12 weeks after rTMS. A greater number of rTMS pulses was a predictor of a greater effect. Adverse events were extremely rare and none were serious. For example, Shirota et al was cited as reporting only headaches in 2/102 subjects.1 Similarly, in a separate review on safety and tolerability or rTMS in 1137 PD patients, VonLoh et al noted adverse events in 4%, and none were serious.2

Thus, rTMS may represent an effective and safe non-medical, non-surgical treatment for motor symptoms in PD. However, a practical matter not assessed in the reviewed studies was patient compliance. With medications and DBS, after the initial prescription or surgery, by default PD patients are on “continuing therapy” at home. In contrast, with rTMS, the patients must come to the doctor’s office or hospital for every therapy session (although after a course of treatments, improvements may last months, as noted above).

Commentary

The number of rTMS visits optimal for a PD response is yet to be determined. But as a point of reference, for treating depression with rTMS (the only U.S. FDA-cleared indication), a common schedule is daily therapy for each working day for 6 weeks.3 As an alternative, might patients self-deliver rTMS at home to improve accessibility, convenience, and compliance? While an at-home technology for PD seems unlikely in the near future, there are developments in this area.

Self-administered single-pulse TMS for migraine with aura has been shown to reduce pain more than sham stimulation,4 with no discernible evidence of harm to humans.5 A single-pulse TMS system (Spring TMS, eNeura, USA) now is FDA-cleared for migraine patient home use. No home rTMS devices are available.

A different helmet-shaped device with seven distributed magnetic coils to induce low-level pulsed electromagnetic fields (PEMF) in the brain also is under development (Re5 ApS, Denmark). The applied magnetic fields are orders of magnitude less than rTMS. Among many other reported tissue changes, PEMF recently have been said to induce neurite outgrowth in a dopaminergic cell culture line.6 A clinical trial of transcranial PEMF (T-PEMF) for PD is underway (ClinicalTrials.gov Identifier NCT02125032; Odense University Hospital, Funen, Denmark). Patients receive 30 minutes per day of active or sham T-PEMF daily for 8 weeks. A change in UPDRS from baseline is the primary outcome measure. Thus, direct comparisons of these T-PEMF results with the rTMS results reviewed in the Chou et al meta-analysis will be possible, and will be of considerable interest.

References

  1. Shirota Y, et al. Supplementary motor area stimulation for PD: A randomized controlled study. Neurol 2013;80:1400-1405.
  2. VonLoh M, et al. Safety of TMS in PD: A review of the literature. Parkinsonism Rel Dis 2013;19:573-585.
  3. Janicak P, et al. Durability of clinical benefit with TMS in the treatment of pharmacoresistant major depression: Assessment of relapse during a 6-month, multisite, open-label study. Brain Stim 2010:3:187-199.
  4. Lipton R, et al. Single-pulse TMS for acute treatment of migraine with aura: A randomized, double-blind, parallel-group, sham-controlled trial. Lancet Neurol 2010;4:373-380.
  5. Dodick D, et al. TMS for migraine: A safety review. Headache 2010;50:1153-1163.
  6. Lekhraj R, et al. PEMF potentiate neurite outgrowth in the dopaminergic MN9D cell line. J Neurosci Res 2014;92:761-771.