Distinct effects of apathy and dopamine on effort-based decision making in Parkinson’s disease

Effort-based decision making is a cognitive process crucial to normal motivated behaviour. Apathy is a common and disabling complication of Parkinson’s disease, but its aetiology remains unclear. Intriguingly, the neural substrates associated with apathy also sub-serve effort-based decision making in animal models and humans. Furthermore, the dopaminergic system plays a core role in motivating effortful behaviour for reward, and its dysfunction has been proposed to play a crucial role in the aetiology of apathy in Parkinson’s disease. We hypothesised that disrupted effort-based decision making underlies the syndrome of apathy in Parkinson’s disease, and that this disruption may be modulated by the dopaminergic system. An effort-based decision making task was administered to 39 patients with Parkinson’s disease, with and without clinical apathy, ON and OFF their normal dopaminergic medications across two separate sessions, as well as 32 healthy age- and gender-matched controls. On a trial-by-trial basis participants decided whether to accept or reject offers of monetary reward in return for exerting different levels of physical effort via handheld, individually calibrated dynamometers. Effort and reward were manipulated independently, such that offers spanned the full range of effort/reward combinations. Apathy was assessed using the Lille apathy rating scale. Motor effects of the dopamine manipulation were assessed using the UPDRS part three motor score. The primary outcome variable was choice (accept/decline offer). analysed using a hierarchical generalised linear mixed effects model, and the vigour of squeeze (Newtons exerted above required force). Both apathy and dopamine depletion were associated with reduced acceptance of offers. However, these effects were driven by dissociable patterns of responding. While apathy was characterised by increased rejection of predominantly low reward offers, dopamine increased responding to high effort, high reward offers, irrespective of underlying motivational state. Dopamine also exerted a main effect on motor vigour, increasing force production independently of reward offered, while apathy did not affect this measure. The findings demonstrate that disrupted effort based decision making underlies Parkinson’s disease apathy, but in a manner distinct to that caused by dopamine depletion. Apathy is associated with reduced incentivisation by the rewarding outcomes of actions. In contrast, dopamine has a general effect in motivating behaviour for high effort, high reward options without altering the response pattern that characterises the apathetic state. Thus the motivational deficit observed in Parkinson’s disease appears not to be simply secondary to dopaminergic depletion of mesocorticolimbic pathways, suggesting non-dopaminergic therapeutic strategies for apathy may be important future targets.