Neuromodulatory mechanism of repetitive transcranial magnetic stimulation for freezing of gait in Parkinson’s disease

Primary motor cortex (M1) is vital in the pathophysiology of freezing of gait (FOG) in Parkinson’s disease (PD). Repetitive transcranial magnetic stimulation (rTMS) targeting M1 may remodel locomotor circuits and alleviate FOG. This study aimed to evaluate the therapeutic efficacy of rTMS and to explore its underlying neuromodulatory mechanisms. Initially, we enrolled 37 PD-FOG patients, 66 PD without FOG and 32 healthy controls. All participants underwent baseline (T0) assessments using TMS paradigms and multimodal magnetic resonance imaging (MRI) to identify FOG-associated neurophysiological features. Subsequently, the PD-FOG cohort received ten add-on rTMS sessions (10 Hz, 90% resting motor threshold) targeting the lower limb of M1. Efficacy and neuromodulatory mechanisms were evaluated one day post-intervention (T1) via objective gait measurements, TMS paradigms and multimodal MRI. A one-month follow-up (T2) was conducted to assess sustained efficacy. Compared to PD-NFOG and HCs, PD-FOG exhibited decreased short-interval intracortical inhibition (SICI), excessive cortico-cortical coupling and reduced fractional anisotropy (FA) in extensive white matter (WM) bundles at baseline. Following rTMS, significant improvements in gait indicators were observed at both T1 and T2 compared to T0. Furthermore, post-intervention assessments revealed increased SICI, decreased M1-occipital functional connectivity, reduced left precentral gyrus perfusion, and elevated FA in the superior longitudinal fasciculus. PD-FOG was characterized by aberrant cortical excitability, dysfunctional cortico-cortical couplings and compromised WM integrity. rTMS targeting M1 was associated with improvements in FOG symptoms, accompanied by partial modulation of the identified abnormalities, including enhanced cortical inhibition, modulation M1-occipital loop, reduced cerebral perfusion and remodeling of WM microstructural pathways.