Anhedonia and the neural basis of effort-based decision-making in depression

描述(申请人提供)：快感缺乏长期以来一直被认为是严重抑郁障碍(MDD)的核心症状。基于努力的决策的临床前动物模型为有关快感缺失的神经和神经药理学基础的假说提供了强有力的基础。这些模型表明，中脑边缘多巴胺投射到伏隔核在克服反应成本以获得奖励方面的重要性，以及前扣带回在评估反应成本方面的重要性。从表面上看，多巴胺缺乏的动物表现出的行为似乎与缺乏快乐性MDD的动机缺陷相似。然而，将这些临床前模型与MDD的临床研究相结合一直是困难的，原因是：1)临床文献中未能区分快感(愉悦)和动机缺陷，2)缺乏对人类动机缺陷的客观实验测量，3)缺乏专门针对动机或享乐缺陷患者的研究。为了解决这个问题，我们开发并验证了一种新的行为范式，用于探索人类快感缺乏症的动机因素。奖励任务的努力支出(EEFRT)衡量了个体在为给定的金钱奖励水平而付出努力的意愿上的差异。EEFRT是从基于努力的决策范式中精心改编而来的，该范式用于动物研究中的中脑边缘多巴胺系统和前扣带回。在人类中，EEFRT的表现已被证明可以预测健康对照组中快感缺乏症和多巴胺功能的个体差异。目前的建议旨在：1)使用事件相关功能磁共振成像来阐明健康对照组(n=24)基于努力的决策的神经关联，并测试关于腹侧纹状体和前扣带回在预测基于努力的决策中的具体作用的假设；(2)验证EEfRT在检测MDD和自我报告的动机缺陷个体的行为缺陷方面的敏感性(n=24)；以及(3)检验这样的假设，即MDD和自我报告的动机缺陷的患者在EEfRT执行期间将显示异常的腹侧纹状体和前扣带回激活。如果成功，这项拟议的研究将显著提高我们识别MDD缺乏享乐症状的特定行为缺陷及其神经生物学底物的能力，并为未来研究EEfRT和fMRI作为临床和临床结果研究的行为或生物标记物的效用提供基础。 与公共卫生相关：MDD预计到2020年将成为美国第二大致死和致残原因，快感缺乏仍然是MDD最难治疗的症状之一。该提案提供了一种独特的临床前模型翻译，试图既了解快感缺乏症的神经基础，又开发一种客观的生物标记物，可用于开发专门为解决MDD动机缺陷而量身定做的治疗方法。

DESCRIPTION (provided by applicant): Anhedonia has long been recognized as a core symptom of major depressive disorder (MDD). Preclinical animal models of effort-based decision-making provide a strong basis for hypotheses regarding the neural and neuropharmacological substrates of anhedonia. Such models indicate the importance of mesolimbic dopamine projections to the nucleus accumbens in overcoming response costs in order to obtain rewards, and the importance of the anterior cingulate in evaluating response costs. On the surface, the behaviors displayed by dopamine depleted animals appear similar to the motivational deficits that characterize anhedonic MDD. However, it has been difficult to integrate these preclinical models with clinical studies of MDD, because of: 1) a failure to distinguish between deficits in hedonics (pleasure) and motivation in the clinical literature, 2) the lack of objective experimental measures of motivational deficits in humans, and 3) the dearth of studies specifically targeting patients with motivational or hedonic deficits. To address this issue, we have developed and validated a novel behavioral paradigm for exploration of motivational elements of anhedonia in humans. The Effort Expenditure for Rewards Task (EEfRT) measures individual differences in the willingness to expend effort for a given level of monetary reward. The EEfRT was carefully adapted from effort-based decision-making paradigms used in animal studies of the mesolimbic dopamine system and anterior cingulate. In humans, peformance on the EEfRT has been shown to predict individual differences in trait anhedonia and dopamine function in healthy controls. The present proposal seeks to:1) use event-related fMRI to elucidate the neural correlates of effort-based decisions in healthy controls (n =24), and test hypotheses regarding the specific roles of the ventral striatum and anterior cingulate in predicting effort-based decisions; (2) validate the sensitivity of the EEfRT for detecting behavioral deficits in individuals with MDD and self-reported motivational deficits (n=24); and (3) test the hypothesis that patients with MDD and self-reported motivational deficits will show abnormal ventral striatal and anterior cingulate activations during performance of the EEfRT. If successful, the proposed research will significantly enhance our ability to identify specific behavioral deficits of anhedonic symptoms in MDD, as well as their neurobiological substrates, and provide the basis for future studies on the utility of the EEfRT and fMRI to serve as a behavioral or biomarker for clinical and clinical outcome research. PUBLIC HEALTH RELEVANCE: MDD is predicted to become the second leading cause of death and disability in the United States by the year 2020, and anhedonia remains among the most difficult symptoms to treat in MDD. This proposal provides a unique translation of preclinical models to attempt to both understand the neural substrates of anhedonia and to develop an objective biomarker that could be used to develop treatments particularly tailored for addressing motivational deficits in MDD.