Enhancing gamma oscillations restores primary motor cortex plasticity in Parkinson's disease

In humans, gamma (γ) oscillations in cortical motor areas reflect asynchronous synaptic activity and contribute to plasticity processes. In Parkinson's disease (PD), γ oscillatory activity in the basal ganglia-thalamo-cortical network is altered and the long-term potentiation (LTP)-like plasticity elicited by intermittent theta burst stimulation (iTBS) is reduced in the primary motor cortex (M1). In this study, we tested whether transcranial alternating current stimulation (tACS) delivered at γ frequency promotes iTBS-induced LTP-like plasticity in M1 in PD patients. Sixteen patients ('OFF' condition) and 16 healthy subjects (HS) underwent iTBS during γ-tACS (iTBS-γ tACS) and during sham-tACS (iTBS-sham tACS) in two sessions. Motor-evoked potentials (MEPs) evoked by single-pulse TMS and short-interval intracortical inhibition (SICI) were recorded before and after the co-stimulation. A subgroup of patients also underwent iTBS during β tACS. iTBS-sham tACS facilitated single-pulse MEPs in HS, but not in patients. iTBS-γ tACS induced a larger MEPs facilitation than iTBS-sham tACS in both groups, with similar values in patients and HS. In patients, SICI improved after iTBS-γ tACS. The effect produced by iTBS-γ tACS on single-pulse MEPs correlated with disease duration, while changes in SICI correlated with UPDRS-III scores. The effect of iTBS-β tACS on both single-pulse MEPs and SICI was similar to that obtained in the iTBS-sham tACS session. Our data suggest that γ oscillations have a role in the pathophysiology of the abnormal LTP-like plasticity in PD. Entraining M1 neurons at the γ rhythm through tACS may be an effective method to restore impaired plasticity.SIGNIFICANCE STATEMENTIn Parkinson's disease, the LTP-like plasticity of the primary motor cortex is impaired, and gamma oscillations are altered in the basal ganglia-thalamo-cortical network. Using a combined TMS-tACS approach (iTBS-γ tACS co-stimulation), we demonstrate that driving gamma oscillations restores the LTP-like plasticity in patients with Parkinson's disease. The effects correlate with clinical characteristics of patients, being more evident in less affected patients and weaker in patients with longer disease duration. These findings suggest that cortical gamma oscillations play a beneficial role in modulating the LTP-like plasticity of M1 in Parkinson's disease. The iTBS-γ tACS approach may be potentially useful in rehabilitative settings in patients