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

抑郁症的快感缺乏和基于努力的决策的神经基础

• 批准号: 8031006
• 负责人: DAVID HAROLD ZALD
• 金额: $ 19.11万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-12-10 至 2012-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8031006
• 关键词: Address; Age; Amygdaloid structure; Anhedonia; Animal Model; Animals; Anterior; Behavior; Behavioral; Behavioral Paradigm; Biological Markers; Biological Markers; Cause of Death; Clinical; Clinical Research; Corpus striatum structure; Data; Decision Making; Depressed mood; Diagnosis; Dopamine; Dorsal; Elements; Event; Expenditure; Failure; Functional Magnetic Resonance Imaging; Future; Gender; Human; Individual; Individual Differences; Link; Literature; Major Depressive Disorder; Measures; Mediating; Mental Depression; Modeling; Motivation; Neurobiology; Nucleus Accumbens; Outcomes Research; Patient Self-Report; Patients; Performance; Pre-Clinical Model; Prevalence; Probability; Process; Productivity; Psychological reinforcement; Recruitment Activity; Research; Rewards; Role; Scanning; Speed; Surface; Symptoms; Task Performances; Testing; Translating; Translations; United States; Ventral Striatum; Work; base; behavior measurement; cost; disability; hedonic; high reward; instrument; mesolimbic system; neurobiological mechanism; neuromechanism; novel; pleasure; pre-clinical; preference; relating to nervous system; response; reward processing; sex; trait; willingness

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.

描述（由申请人提供）：长期以来，Anhedonia一直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Anhedonia的神经和神经药物底物提供了有力的基础。这样的模型表明，中左右多巴胺投影对伏隔核的重要性在克服响应成本方面以获得奖励，以及前依赖在评估响应成本中的重要性。从表面上看，多巴胺耗尽的动物表现出的行为似乎类似于表征Anhedonic MDD的动机缺陷。但是，很难将这些临床前模型与MDD的临床研究相结合，因为：1）未能区分享乐主义（愉悦）和临床文献中的动机缺陷，2）缺乏客观的实验性测量人类动机缺陷的实验度量，以及3）专门针对动机或耐药性的研究的研究。为了解决这个问题，我们已经开发了并验证了一种新型的行为范式，以探索人类的阿尼多尼亚动机元素。奖励任务（EEFRT）的努力支出衡量了在给定水平的货币奖励的愿望的意愿上的个体差异。 EEFRT仔细地改编自中氧甲贝胺系统和前扣带回的动物研究中使用的基于努力的决策范例。在人类中，已经证明对EEFRT的同性恋可以预测健康对照中特征性Anhedonia和多巴胺功能的个体差异。本提案试图：1）使用与事件相关的fMRI阐明健康对照中基于努力的决策的神经相关性（n = 24），以及关于腹侧纹状体和前扣带的特定作用的假设在预测基于努力的决策中的特定作用； （2）验证EEFRT对MDD和自我报告的动机缺陷个体的行为缺陷的敏感性（n = 24）； （3）检验以下假设：MDD和自我报告的动机缺陷患者将在EEFRT表现过程中显示出异常的腹侧纹状体和前扣带回激活。如果成功的话，拟议的研究将显着增强我们确定MDD及其神经生物学底物的特定行为缺陷的能力，并为将来的EEFRT和FMRI实用性研究提供了基础，以作为行为或生物标志物的临床和临床结果研究。 公共卫生相关性：预计到2020年，MDD将成为美国的第二大死亡和残疾原因，而Anhedonia仍然是MDD治疗的最困难症状之一。该提案提供了临床前模型的独特翻译，以尝试了解Anhedonia的神经底物并开发客观的生物标志物，该标志物可用于开发专门针对MDD中的动机缺陷量身定制的治疗方法。