Pharmacological and pupillary evidence for the noradrenergic contribution to reinforcement learning in Parkinson's disease

Abstract Noradrenaline plays an integral role in learning, by optimising behavioural strategies and facilitating choice execution. Testing the noradrenergic framework of learning in the context of human diseases offers a test bed for current normative neuroscience theories and may also indicate therapeutic potential. Parkinson's disease is often considered as a model of dopamine deficits, including dopamine’s role in reinforcement learning. However, noradrenergic function is also severely impaired by Parkinson's disease, contributing to cognitive deficits. Using a single dose of the noradrenaline reuptake inhibitor atomoxetine, in people with Parkinson's disease (n=19, randomised double-blind placebo-controlled crossover design), we show improvements in learning compared to placebo. Computational modelling confirmed a substantial shift in the decision noise parameter, indicative of more exploitative choices. This response pattern closely resembled that of age-matched controls (n=26) and simulations of optimal response strategies. Pupillometry revealed increased baseline pupil diameter under atomoxetine, which correlated with behavioural improvements, and a heightened phasic pupillary response to feedback. Our findings confirm the noradrenergic contribution to reinforcement learning, and in doing so they challenge the simple interpretation of tonic-phasic locus coeruleus firing patterns based on pupillometry. Noradrenergic modulation is a potential treatment strategy for cognitive symptoms in Parkinson's disease and related disorders.