Interrogating basal ganglia reinforcement with deep brain stimulation in Parkinson’s disease.

Dopamine and the basal ganglia have been conserved over more than 500 million years of evolution. They are fundamental to animal and human behaviour. Parkinsons disease (PD) is associated with loss of dopaminergic innervation to the basal ganglia. Over 6 million people suffer from the debilitating symptoms of PD that span disturbance of emotion, cognition and movement. There is a pressing need to understand the pathogenesis of these symptoms, but an integrated account of dopamine and basal ganglia function is lacking. This constitutes a significant roadblock to scientific and therapeutic advances. To overcome this roadblock, ReinforceBG poses the novel unconventional hypothesis that loss of dopamine in PD does not impair movement per se but leads to chronic negative reinforcement of neural population dynamics. Conversely, in the healthy state, transient dopamine signals may stabilize cortexbasal ganglia activity to facilitate reentry and refinement of cortical output. To address this hypothesis, ReinforceBG will combine invasive electrocorticography and local field potential recordings with closed-loop deep brain stimulation in PD patients. Aim 1 will investigate how basal ganglia pathways coordinate neuromuscular adaptation. Aim 2 will shed light on basal ganglia reinforcement in multiple behavioural domains, including movement, gait, speech, and spatial navigation in virtual reality. Aim 3 will develop a neuroprosthetic brain-computer interface that aims to modulate basal ganglia reinforcement. ReinforceBG deviates from outdated models on pro- vs. antikinetic Go and NoGo pathways and promises a holistic-reinforcement centred view of basal ganglia function. It will leverage the unprecedented spatiotemporal precision of neuromodulation for the development of an innovative brain circuit intervention that modulates neural reinforcement in real time. This opens new horizons for the interdisciplinary treatment of brain disorders affecting the dopaminergic system.