Title (72 Characters) Insensitivity to Loss is Associated with Apathy in Huntington’s Disease. Running Head (21 Characters) Loss and Apathy in HD Key Words Apathy, Huntington’s disease, Neuropsychology, Neurodegeneration Authors and Affiliations

Background Apathy is a deficit in goal-directed behavior that significantly affects quality of life and function. It is common in Huntington’s disease (HD) and other disorders affecting cortico-striatal pathways. Deficits in processing of reward, altered effort and executive dysfunction are associated with apathy in other disorders, but the cognitive processes leading to apathy in HD remain largely unknown. A previously reported deficit in learning from losses in HD raises the possibility of a hitherto unrecognized mechanism leading to apathy. This study’s objective was to delineate the cognitive processes associated with apathy in HD. Methods We tested 51 HD participants and 26 controls on a battery of novel and established measures to assess the contribution to apathy in HD of executive function, reward value, reward-effort calculations, instrumental learning and response to reward and loss. Results HD participants had deficits in instrumental learning with impaired response to loss, but no evidence to suggest altered reward-related behavior or effort. We also saw an executive dysfunction contribution to apathy in HD. Discussion We report the novel finding that apathy in HD is associated with blunted responses to losses and impaired instrumental learning. This association is consistent with the known early degeneration of the indirect pathway and amygdala involvement in apathy in HD, but is previously unreported in any disorder. In keeping with the comparative preservation of the ventral striatum and orbito-frontal cortex in HD, reward valuation and reward-effort calculations did not contribute to apathy. Background Apathy, a deficit in goal-directed behavior, is common in neurological diseases affecting frontal cortex, white matter and basal ganglia. Apathy severely impairs function and quality of life for patients and carers. A number of cognitive processes are hypothesized to contribute to goal-directed behavior: initiation; including option generation and selection (reward valuation and reward-effort calculations), planning (executive function), and outcome evaluation (learning from loss and reward). Deficits in reward valuation, reward-effort calculations, learning from reward and executive function leading to apathy have been demonstrated across disorders. However, one important aspect of goal-directed behavior: avoiding aversive stimuli and stopping deleterious actions, has so far not been directly linked to clinical apathy. Apathy occurs in up to 80% of patients with Huntington’s disease (HD; an inherited neurodegenerative disorder focused on the striatum, affecting the indirect pathway earliest, before involving the direct pathway, cortex (progressing occipito-frontally), and white matter). Apathy is a core feature of HD: showing progression with disease course, occurring before motor onset and occurring at higher rates in HD gene carriers compared to non-gene carriers blinded to their genetic status. Despite apathy’s impact on HD patients and central status to the disease, knowledge of the cognitive processes underpinning apathy in HD is limited. Apathy in HD has been correlated with executive dysfunction, but none of the other potentially contributory processes have been probed. Although apathy is common in diseases affecting cortico-striatal circuits, the distribution of neuropathology differs across diseases. This suggests that the mechanisms leading to apathy may also differ. Without knowing the relative contribution of different processes to apathetic behavior, targeted treatments cannot be developed. Since a selective deficit in learning from loss, but not reward has been previously reported in HD, it may be that apathy in HD is associated with impaired sensitivity to loss. This is in keeping with the known preferential degeneration of the indirect pathway in HD. We explored this concept using a battery of cognitive tasks measuring reward-value, reward-effort calculation, response to failure, and instrumental learning from loss and reward, to delineate the cognitive processes leading to apathy in HD.