Driving motor cortex oscillations restores plasticity and improves bradykinesia features in Parkinson's disease

In Parkinson's disease (PD), impaired plasticity of the primary motor cortex (M1) contributes to bradykinesia. Enhancing cortical γ oscillations through transcranial alternating current stimulation (tACS) restores M1 plasticity, but whether this translates into bradykinesia improvement remains unclear. We conducted a double-blind, sham-controlled study to determine whether M1 γ-tACS improves intermittent theta burst stimulation (iTBS)-induced plasticity and alleviates bradykinesia in PD. Forty participants (20 patients and 20 healthy controls - HCs) underwent two randomized sessions: iTBS-γ tACS and iTBS-sham tACS. We assessed corticospinal excitability and GABA-A-ergic-related intracortical inhibition using transcranial magnetic stimulation, and bradykinesia features through finger-tapping kinematic analysis before and 5, 15, and 30 min after iTBS-tACS. iTBS-sham tACS failed to induce M1 plasticity in PD, whereas iTBS-γ tACS elicited M1 plasticity (p = 0.006) and improved SICI (p = 0.004). These neurophysiological changes in PD were paralleled by improvement in bradykinesia features, i.e., faster and wider movements (all ps < 0.001). No changes were observed following iTBS-sham tACS or in HCs. SICI γ-tACS-induced changes correlated with the clinical score in patients (r = 0.68, p < 0.001), and plasticity changes correlated with velocity improvement (r = 0.61, p = 0.003). γ entrainment restores M1 plasticity and GABA-A activity, alleviating bradykinesia in PD with effects persisting beyond stimulation. These findings have translational relevance and offer insights into bradykinesia pathophysiology (ClinicalTrials.gov Identifier: NCT06297538, registration date March 7, 2024).