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

描述（由申请人提供）：快感缺失长期以来被认为是重度抑郁症（MDD）的核心症状。基于努力的决策的临床前动物模型为快感缺乏的神经和神经药理学底物的假设提供了强有力的基础。这些模型表明，中脑边缘多巴胺的预测的重要性，以获得奖励，在克服反应成本，以获得奖励，以及前扣带在评估反应成本的重要性，在丘脑核。从表面上看，多巴胺耗竭动物表现出的行为似乎类似于缺乏快感型MDD的动机缺陷。然而，很难将这些临床前模型与MDD的临床研究相结合，因为：1）临床文献中未能区分享乐（快乐）和动机的缺陷，2）缺乏人类动机缺陷的客观实验测量，以及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失的动机因素。奖励的努力支出任务（EEfRT）测量了个体在为给定的金钱奖励水平付出努力的意愿方面的差异。EEfRT仔细改编的努力为基础的决策范式中使用的动物研究的中脑边缘多巴胺系统和前扣带。在人类中，已显示对EEfRT的peptide预测健康对照中的特质快感缺失和多巴胺功能的个体差异。本研究的目的是：（1）利用事件相关功能磁共振成像技术（event-relatedfMRI）研究24例健康对照者基于努力的决策行为的神经机制，并验证腹侧纹状体和前扣带回在预测基于努力的决策行为中的作用：（2）验证EEfRT检测24例抑郁症患者行为缺陷和自我报告动机缺陷的敏感性;以及（3）检验患有MDD和自我报告的动机缺陷的患者在进行EEfRT期间将显示异常的腹侧纹状体和前扣带回激活的假设。如果成功的话，拟议的研究将显着提高我们的能力，以确定特定的行为缺陷的快感缺失症状的MDD，以及他们的神经生物学底物，并提供基础，为未来的研究效用的EEfRT和功能磁共振成像作为一个行为或生物标志物的临床和临床结果的研究。 公共卫生相关性：预计到2020年，MDD将成为美国死亡和残疾的第二大原因，而快感缺失仍然是MDD中最难治疗的症状之一。该提案提供了临床前模型的独特翻译，试图了解快感缺失的神经基质，并开发一种客观的生物标志物，可用于开发专门针对解决MDD动机缺陷的治疗方法。

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.