Basal Ganglia Stimulation Ameliorates Schizophrenia Exploration Anomalies

Abstract

Any learning agent must balance between exploiting its knowledge and exploring new alternatives. Schizophrenia patients are known to have maladaptive exploration-exploitation (E-E) balance1,2 and are impaired at reversal learning tasks as early as their first psychotic episode. The cortico-basal ganglia (BG)-dorsolateral prefrontal cortex (DLPFC) network plays a significant role in learning processes3,4. However, how this network maintains the E-E balance and what alters the balance in schizophrenia remains elusive. Using a combination of extracellular recordings, pharmacological manipulations, macro-stimulation techniques, and an adaptive reinforcement learning model, we show that in the non-human primate (NHP), the external segment of the globus pallidus (GPe, the central nucleus of the BG network) maintain this balance. Furthermore, whereas the chronic, low-dose administration of N-methyl-D-aspartate (NMDA) receptor (NMDA-R) antagonist, phencyclidine (PCP) leads to E-E imbalance, low-frequency GPe macro-stimulation restores it. E-E balance provides a holistic framework to resolve some of the apparent paradoxes that have emerged within schizophrenia research2. Our findings suggest that Schizophrenia symptoms may reflect abnormal DLPFC-BG E-E balance, and GPe stimulation may be advantageous for these patients.