Investigating altered limbic reward system in Huntington's Disease: Implications for apathy

Huntington's disease (HD) is an inherited neurodegenerative condition characterized by motor, cognitive, and behavioral impairments. Apathy, marked by reduced motivation and goal-directed behavior, is the most prevalent psychiatric symptom in HD, impacting both patients and caregivers. Traditionally linked to executive dysfunction within the dorsolateral prefrontal cortex (dlPFC)-dorsal striatum loop in HD, the role of limbic regions in the basal ganglia and their impact on reward processing deficits remains poorly understood. This study sought to dissociate the functional correlates that are altered in reward valuation and may underlie apathy in HD. We aimed to tease apart whether apathy is associated with insensitivity to processing rewards, hypersensitivity to losses, or both, leading to the observed lack of motivation in apathetic individuals. Thirty-nine HD gene-expansion carriers (HDGEC) and 26 non-apathetic control participants underwent functional magnetic resonance imaging during a gambling task. The goal was to identify disrupted reward-related regions in HDGEC and their association with apathetic symptoms. Whole-brain analysis of gains and losses separately showed a significant reduction in activity, when HD group was compered to controls, within the left ventral striatum (VS), including the nucleus accumbens. The effect observed in the VS remained when clinically apathetic HDGEC were compared with controls. Conversely, non-apathetic HDGEC did not show any significant differences from controls. Interestingly, these group differences appeared exclusively during the processing of the reward. Additionally, higher levels of apathy were associated with especially decreased activity related with the processing of gains in this region. Our findings highlight the vulnerability of the left VS in HD and its association with the altered processing of gains, particularly in apathetic individuals, while preserving the valuation of losses. This suggests that reward insensitivity associated with VS dysfunction may be an important component of apathy in HD. Understanding the underlying mechanisms of reward processing and apathy in HD may help elucidate the implications of limbic regions as opposed to frontal executive dysfunction in apathy. ### Competing Interest Statement The authors have declared no competing interest.