Assessing the interaction between L-dopa and γ-transcranial alternating current stimulation effects on primary motor cortex plasticity in Parkinson's disease

L-dopa variably influences transcranial magnetic stimulation (TMS) parameters of motor cortex (M1) excitability and plasticity in Parkinson's disease (PD). In patients OFF dopaminergic medication, impaired M1 plasticity and defective GABA-A-ergic inhibition can be restored by boosting gamma (gamma) oscillations via transcranial alternating current stimulation (tACS) during intermittent theta-burst stimulation (iTBS). However, it is unknown whether L-dopa modifies the beneficial effects of iTBS-gamma-tACS on M1 in PD. In this study, a PD patients group underwent combined iTBS-gamma-tACS and iTBS-sham-tACS, each performed both OFF and ON dopaminergic therapy (four sessions in total). Motor evoked potentials (MEPs) elicited by single TMS pulses and short-interval intracortical inhibition (SICI) were assessed before and after iTBS-tACS. We also evaluated possible SICI changes during gamma-tACS delivered alone in OFF and ON conditions. The amplitude of MEP elicited by single TMS pulses and the degree of SICI inhibition significantly increased after iTBS-gamma-tACS. The amount of change produced by iTBS-gamma-tACS was similar in patients OFF and ON therapy. Finally, gamma-tACS (delivered alone) modulated SICI during stimulation and this effect did not depend on the dopaminergic condition of patients. In conclusion, boosting cortical gamma oscillatory activity via tACS during iTBS improved M1 plasticity and enhanced GABA-A-ergic transmission in PD patients to the same extent regardless of dopaminergic state. These results suggest a lack of interaction between L-dopa and gamma-tACS effects at the M1 level. The possible neural substrate underlying iTBS-gamma tACS effects, that is, gamma-resonant GABA-A-ergic interneurons activity, may explain our findings.