Impaired value-based decision-making in Parkinson's Disease Apathy

Abstract

Apathy is a common and disabling complication of Parkinsons disease characterised by reduced goal-directed behaviour. Several studies have reported dysfunction within pre-frontal cortical regions and projections from brainstem nuclei whose neuromodulators include dopamine, serotonin and noradrenaline. Work in animal and human neuroscience have confirmed contributions of these neuromodulators on aspects of motivated decision making. Specifically, non-dopaminergic neuromodulators, influence decisions to explore alternative courses of action or persist in an existing strategy to achieve a rewarding goal. Building upon this work, we hypothesised that Apathy in Parkinsons disease should be associated with a failure to adequately monitor and make adaptive choices when the rewarding outcome of decisions are uncertain. Using a 4-armed restless bandit reinforcement learning task, we studied decision making in 75 volunteers; 53 patients with Parkinsons disease, with and without clinical apathy, and 22 age matched healthy controls. Patients with Apathy exhibited impaired ability to choose the highest value bandit. Task performance predicted an individual patients apathy severity measured using the Lille Apathy Rating scale (R = -0.46, p<0.001). Computational modelling of the patients choices confirmed the apathy group made decisions that that were indifferent to the learnt value of the options, consistent with previous reports of reward insensitivity. Further analysis demonstrated a shift away from exploiting the highest value option and a reduction in perseveration which also correlated with apathy scores (R = -0.5, p<0.001). We went on to acquire fMRI in 59 volunteers; a group of 19 patients with and 20 without apathy and 20 age matched controls performing the restless bandit task. Analysis of the fMRI signal at the point of reward feedback confirmed diminished signal within ventromedial prefrontal cortex in Parkinsons disease, which was more marked in Apathy, but not predictive of their individual Apathy severity. Using a model-based categorisation of choice type, decisions to explore lower value bandits in the apathy group activated pre-frontal cortex to a similar degree to the age-matched controls. In contrast, Parkinsons patients without apathy demonstrated significantly increased activation across a distributed thalamo-cortical network. Enhanced activity in the thalamus predicted individual apathy severity across both patient groups and exhibited functional connectivity with dorsal anterior cingulate cortex and anterior insula. Given that task performance in patients without apathy was no different to the age-matched controls, we interpret the recruitment of this network as a possible compensatory mechanism, which compensates against symptomatic manifestation of apathy in Parkinsons disease.