Abstract
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 subserve 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 hypothesized 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 Unified Parkinson's Disease Rating Scale part three motor score. The primary outcome variable was choice (accept/decline offer) analysed using a hierarchical generalized 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 characterized 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 incentivization 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 characterizes 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.
Highlights
Deciding if an action, or sequence of actions, is ‘worth it’ is a cognitive process lying at the core of motivated goal-directed behaviour (Mogenson et al, 1980; Balleine and O’Doherty, 2010; Salamone et al, 2016)
This study demonstrates that altered effort-based decisionmaking is associated with the clinical phenotype of apathy in patients with Parkinson’s disease
The effect is not a generalized reduction in willingness to engage in effort, but rather is predominantly driven by reduced responding to low reward outcomes, suggesting apathy is associated with reduced incentivization by reward, rather than increased sensitivity to action costs
Summary
Sequence of actions, is ‘worth it’ is a cognitive process lying at the core of motivated goal-directed behaviour (Mogenson et al, 1980; Balleine and O’Doherty, 2010; Salamone et al, 2016). In Parkinson’s disease, apathy is associated in particular with reduced metabolism within ventral striatum, medial frontal cortex including dorsal anterior cingulate cortex and ventral midbrain (Lawrence et al, 2011; Huang et al, 2013; Robert et al, 2014), reduced grey matter volume of ventral striatum (Carriere et al, 2014), and reduced functional connectivity between these brain regions (Baggio et al, 2015) These are the same brain areas demonstrated to underlie effort-based decision-making in healthy humans (Croxson et al, 2009; Prevost et al, 2010; Klein-Flugge et al, 2016; Hauser et al, 2017; Le Heron et al, 2017). In experimental animal models, disruption of homologues of these regions induces a seemingly apathetic state, in which animals are no longer as willing to invest effort for reward (Walton et al, 2002; Hauber and Sommer, 2009)
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