Personalized rTMS of the pre-SMA to alleviate levodopa-induced dyskinesia in Parkinson's disease: a randomized controlled cross-over trial

Background:
Most patients with Parkinson's disease (PD) develop levodopa-induced dyskinesia (LID) during long-term levodopa treatment [1]. Our own research has implicated the pre-supplementary motor area (pre-SMA) in the pathophysiology of LID [2]. We also showed that a single session of “inhibitory” 1-Hz repetitive transcranial magnetic stimulation (rTMS) of pre-SMA reduces the magnitude and delays the onset of LID provoked by subsequent levodopa intake [3]. This acute beneficial effect scaled positively with the rTMS-induced electrical field in the pre-SMA [3].

Aim:
This randomized clinical trial (RCT) will employ personalized dosing of rTMS and a novel quadruple pulse version of 1Hz rTMS, contrasting the acute anti-dyskinetic effects of 1Hz quadri-pulse stimulation (QPS) at inter-pulse intervals of 7.7 msec (130 Hz “gamma” bursts) and 50 msec (“beta” bursts).

Methods:
Patients will be randomized to 1Hz beta or gamma burst QPS of pre-SMA. On separate days,
patients will receive a real or sham QPS session in counter-balanced order before they receive a single dose of levodopa. The intensity of QPS will be individually defined to induce the same mean electrical field in the pre-SMA. Primary outcomes include time between levodopa intake and LID onset, and LID severity assessed using the MDS-Unified Dyskinesia Rating Scale (UDysRS) based on blinded video assessments.

Discussion:
The study will shed new light on the acute anti-dyskinetic effects of 1 Hz QPS targeting the pre-SMA. Results will help to optimize therapeutic outcomes and inform neurostimulation strategies for more effective LID treatment.