Modulating inhibitory synaptic plasticity to restore basal ganglia dynamics in Parkinson's disease

Parkinson's disease is characterized, in part, by hypoactivity of 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). In people with Parkinson's disease (n = 32), we explored the potential use of intracranial stimulation for eliciting long-term potentiation (LTP) of these underactive pathways to produce improvement of symptoms that persist beyond stimulation cessation. During GPi deep brain stimulation (DBS) surgery, we found strong evidence (P < 0.05; BF10 > 10) of increased amplitudes of hand movements and striato-GPi evoked potentials before versus after high-frequency microstimulation. In a small sample of outpatients with sensing-enabled GPi-DBS, we found anecdotal evidence (P < 0.10; BF10 > 1) of improved hand movements and attenuated beta frequency oscillations. In STN, enduring behavioural effects, potentiation of GPe-STN projections (intraoperative), and decreases to beta oscillations (extraoperative) were not observed. Our findings support that LTP-like effects in GPi may produce motor improvements that extend beyond stimulation cessation, while the lack of effects in STN suggests the need for optimizing stimulation paradigms for effective LTP induction. These findings nevertheless highlight the potential of LTP-based strategies for sustained therapeutic benefits, which may be useful for mitigating DBS side-effects and optimizing battery usage.