Abstract
INTRODUCTION: Cortico-subcortical dysfunction from dopaminergic depletion is a hallmark of Parkinson's disease (PD). Modulating primary motor cortex (M1) excitability with intermittent theta burst stimulation (iTBS) may restore network integrity in PD by targeting neurobiological changes at excitatory, structural, and serological levels. This study aimed to demonstrate the clinical and neurobiological effects of bilateral M1 iTBS in patients with PD. METHODS: Seventeen patients with Hoehn-Yahr stage II-III PD in the on-medication state underwent daily bilateral M1 iTBS sessions for 5 consecutive days in a randomized, double-blind, placebo-controlled, crossover design. The primary clinical outcomes were the relative change from baseline at four follow-up points after the final iTBS session, measured by the Movement Disorder Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS) Parts II, III, and IV. Changes in corticospinal excitability, structural brain imaging, and serum biomarkers of neurodegeneration, astrocytic activation, and neuroplasticity were also assessed. RESULTS: Real iTBS induced a significant improvement in MDS-UPDRS Part III scores, yielding more than twice the therapeutic benefit observed with sham stimulation. Responders (> 20% improvement) showed a mean 9-point improvement. Similarly, real iTBS stimulation resulted in an increase in corticospinal excitability of the clinically most affected hemisphere. In responders, serum brain-derived neurotrophic factor levels increased along with an increase in left ventral diencephalon volume, which was the strongest predictor of clinical response. CONCLUSION: Bilateral M1 iTBS may represent a valuable adjunctive therapeutic option for pharmacological treatment of motor symptoms in patients with PD by promoting structural brain changes and enhancing synaptic plasticity in intermediate disease stages. CLINICAL TRIAL REGISTRATION: https://clinicaltrials.gov/ : NCT06840145, retrospectively registered on September 9, 2023.