The neuropsychiatric syndrome of apathy is now recognized to be a common and disabling condition in Huntington’s disease (HD). However, the mechanisms underlying it are poorly understood. One way to investigate apathy is to utilise 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 HD pathology, we hypothesised that a general hypersensitivity to costs would underpin HD 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 HD 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 also drift rate, where there was moderate evidence of HD 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 HD, cost hypersensitivity, which manifests in both the effort and time costs associated with actions towards rewarding goals. This suggests that HD pathology may cause a domain-general disruption of cost processing, which is distinct to apathy occurrence in other brain disorders, and may require different therapeutic approaches.

中文翻译：

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决策成本超敏反应是亨廷顿病情感淡漠的基础


冷漠的神经精神综合症现在被认为是亨廷顿舞蹈症 （HD） 中常见的致残性疾病。然而，人们对其背后的机制知之甚少。调查冷漠的一种方法是利用正常动机行为的理论框架，来确定具有这种行为中断的人发生崩溃的位置。跨物种的动机、目标导向行为的基本计算是权衡与行动相关的成本和回报。在这里，我们询问了冷漠的人是否对行动成本（体力劳动和时间延迟）更敏感，对奖励结果不太敏感，或者两者兼而有之。根据与HD病理学相关的独特解剖基质，我们假设对成本的普遍超敏反应是HD冷漠的基础。将经基因证实的扩增亨廷顿基因携带者（从显前到轻度运动表现性疾病 （n=53））与健康对照 （n=38） 进行比较。参与者执行了一项基于体力劳动的决策任务（Apple Gathering Task）和一项延迟贴现任务（Money Choice Questionnaire）。使用线性回归和漂移扩散模型分析选择数据，这些模型也考虑了做出决策所花费的时间。冷漠的 HD 患者在 Apple Gathering Task 中接受的报价总体上较少，特别是由于对体力劳动成本的敏感性增加，而不是用运动严重程度、情绪、认知或药物来解释。漂移扩散模型提供了努力超敏反应的进一步证据，冷漠与拒绝录取的更快漂移率相关，这是不同努力的函数。 延迟敏感性的增加也与冷漠有关，无论是在分析原始选择时还是在漂移率时，都有中等证据表明 HD 冷漠更快地向立即可用（低成本）选项漂移。此外，这些任务的工作量和延迟敏感性参数呈正相关。结果证明了 HD 中冷漠、成本超敏反应的明确机制，这表现在与实现奖励目标的行动相关的努力和时间成本上。这表明HD病理学可能导致成本处理的领域一般中断，这与其他脑部疾病中的冷漠不同，可能需要不同的治疗方法。