Modulation of inhibitory synaptic plasticity for restoration of basal ganglia dynamics in Parkinson’s disease

Abstract Introduction Parkinson’s disease is characterized, in part, by hypoactivity of both direct pathway inhibitory projections from striatum to the globus pallidus internus (GPi) and indirect pathway inhibitory projections from globus pallidus externus (GPe) to the subthalamic nucleus (STN), giving rise to disrupted basal ganglia circuit activity. In this study, we explored the use of intracranial stimulation for eliciting long-term potentiation (LTP) of each of these pathologically underactive inhibitory projections for the restoration of basal ganglia circuit dynamics and amelioration of motor symptoms. Methods Data were collected from a total of 31 people with Parkinson’s disease (42 hemispheres). During deep brain stimulation (DBS) surgery, we assessed microelectrode stimulation-induced changes to inhibitory evoked field potentials (fEP) and hand kinematics before versus after a 40-second train of high-frequency stimulation (HFS) in the GPi (n = 7, 11 sites at 100 Hz) and STN (n = 10, 14 sites at 100 Hz; n = 4, 7 sites at 180 Hz). Additionally, we assessed changes to beta oscillations and hand kinematics in people with chronic DBS implants in the GPi (n = 6 at 125 Hz) and STN (n = 4 at 180 Hz). Results Intraoperatively, increases in fEP amplitude (p = 0.002) and improved motor performance (p = 0.003) were observed after 100 Hz HFS in the GPi; while in STN, HFS did not potentiate fEPs (p = 0.589) or improve motor performance (p = 0.460) (similar results yielded for 180 Hz in STN). Similarly, extraoperative GPi-DBS produced suppression of beta power (p=0.096) and motor improvement (p = 0.077) before versus after HFS at 125 Hz; while STN-DBS at 180 Hz did not significantly affect beta power (p = 0.267) or motor performance (p=0.850). Interpretation Our findings support that LTP-like effects in GPi may produce motor improvements that extend beyond stimulation cessation, aligning with optogenetic studies showing long-lasting motor recovery through periodic D1-striatal activation in rodents. The lack of effects in STN suggests that stimulation paradigms may require optimization for effective LTP induction. These findings nevertheless highlight the potential of LTP-based strategies for sustained therapeutic benefits in Parkinson’s disease, warranting further investigation into periodic stimulation paradigms for optimizing DBS efficacy and side effect profiles.