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

Abstract:

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.