Decision cost hypersensitivity underlies Huntington's disease apathy.

The neuropsychiatric syndrome of apathy is now recognized to be a common and disabling condition in Huntington's disease. However, the mechanisms underlying it are poorly understood. One way to investigate apathy is to use a theoretical framework of normal motivated behaviour, to determine where breakdown has occurred in people with this behavioural disruption. A fundamental computation underlying motivated, goal-directed behaviour across species is weighing up the costs and rewards associated with actions. Here, we asked whether people with apathy are more sensitive to costs of actions (physical effort and time delay), less sensitive to rewarding outcomes, or both. Based on the unique anatomical substrates associated with Huntington's disease pathology, we hypothesized that a general hypersensitivity to costs would underpin Huntington's disease apathy. Genetically confirmed carriers of the expanded Huntingtin gene (premanifest to mild motor manifest disease, n = 53) were compared to healthy controls (n = 38). Participants performed a physical effort-based decision-making task (Apple Gathering Task) and a delay discounting task (Money Choice Questionnaire). Choice data was analysed using linear regression and drift diffusion models that also accounted for the time taken to make decisions. Apathetic people with Huntington's disease accepted fewer offers overall on the Apple Gathering Task, specifically driven by increased sensitivity to physical effort costs, and not explained by motor severity, mood, cognition or medication. Drift diffusion modelling provided further evidence of effort hypersensitivity, with apathy associated with a faster drift rate towards rejecting offers as a function of varying effort. Increased delay sensitivity was also associated with apathy, both when analysing raw choice and drift rate, where there was moderate evidence of Huntington's disease apathy drifting faster towards the immediately available (low-cost) option. Furthermore, the effort and delay sensitivity parameters from these tasks were positively correlated. The results demonstrate a clear mechanism for apathy in Huntington's disease, cost hypersensitivity, which manifests in both the effort and time costs associated with actions towards rewarding goals. This suggests that Huntington's disease pathology may cause a domain-general disruption of cost processing, which is distinct from apathy occurrence in other brain disorders and may require different therapeutic approaches.