Bilateral intermittent theta burst stimulation over the primary motor cortex improves motor and affective symptoms via thalamic network reintegration in mid-stage Parkinson's disease

Bilateral intermittent theta burst stimulation (iTBS) targeting the primary motor cortex (M1) has emerged as a promising neuromodulatory approach for Parkinson's disease (PD), although evidence supporting its clinical efficacy as an adjunctive treatment remains limited. This randomized, double-blind, sham-controlled crossover study examined the therapeutic potential of bilateral M1-iTBS in fifteen patients with mid-stage PD in the on-medication state. Motor, neuropsychiatric, and cognitive outcomes were assessed through standardized clinical scales following five iTBS sessions, alongside voxelwise resting-state functional magnetic resonance imaging, to identify neural-related mechanisms. Real iTBS induced a maximum improvement of nine points on the Movement Disorder Society-Unified PD Rating Scale part III, with clinical responders (≥20% improvement) demonstrating an eleven-point enhancement. Responders exhibited strengthened cerebello-thalamic and thalamo-cortical connectivity, suggesting partial thalamic functional reintegration with associative cortices and compensatory functional reorganization, which correlated significantly with reduced bradykinesia. Additionally, real iTBS produced clinically meaningful improvement in affective symptomatology in depression and anxiety responder patients, accompanied by modulation of top-down and bottom-up emotion regulation circuits and normalization of cerebellar activity. These findings support bilateral M1-iTBS as an effective adjunctive intervention for managing motor and nonmotor manifestations in patients with mid-stage PD, with mechanistic insights provided by symptom-related functional connectivity changes.