Delineating the Reward Circuitry of Anhedonia

描述快感缺乏的奖励回路

基本信息

批准号：
9312118
负责人：
Benjamin Adam Ely
金额：
$ 4.12万
依托单位：
ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-06-11 至 2019-06-10
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9312118
关键词：
Address Adolescence Adolescent Adopted Adult Age Amygdaloid structure Anatomy Anhedonia Anterior Area Behavior Biology Brain Cause of Death Clinical Clinical Psychology Contralateral Data Development Diagnostic Dimensions Disease Etiology Evaluation Exhibits Fellowship Functional Magnetic Resonance Imaging Future Gambling Goals Habenula Heterogeneity Human Hyperactive behavior Image Individual Differences Insula of Reil Intervention Laboratories Magnetic Resonance Imaging Major Depressive Disorder Measures Medial Mental Depression Mental disorders Methodology Modeling Morbidity - disease rate National Institute of Mental Health Nature Neurobiology Nucleus Accumbens Outcome Pattern Pharmaceutical Preparations Phenotype Play Population Pre-Clinical Model Prefrontal Cortex Procedures Process Public Health Recurrence Reporting Research Research Personnel Research Training Resolution Rest Rewards Role Severities Signal Transduction Strategic Planning Suicide Symptoms Techniques Testing Therapeutic Time Training Translational Research Treatment Failure Ventral Tegmental Area Work age group cingulate cortex connectome critical developmental period experience human data imaging approach improved in vivo mortality multimodality neural circuit neuroimaging novel outcome forecast phenomenological models pleasure pre-clinical pre-doctoral response reward anticipation reward circuitry reward expectancy reward processing subclinical depression success symptom cluster training opportunity young adult

项目摘要

PROJECT SUMMARY/ABSTRACT Major depressive disorder (MDD) is a major public health concern associated with significant morbidity and mortality. Although MDD often emerges in adolescence, research in this age group remains scarce. The heterogeneity of adolescent MDD has further hampered identification of the disorder’s neurobiological underpinnings. To address these challenges, this research training fellowship utilizes a dimensional approach focusing on the core MDD symptom of anhedonia—the reduced capacity to experience pleasure. Anhedonia severity is highly variable in adolescent MDD, with increased severity predicting poor prognosis and suicide. Our research aims to delineate reward circuitry deficits associated with anhedonia. Converging preclinical data suggest that hyperactivity of the habenula (Hb), a small limbic hub, may underlie such deficits by excessively inhibiting reward signaling by the Ventral Tegmental Area (VTA) and downstream Nucleus Accumbens (NAc). Characterizing and even visualizing these regions in vivo has been a challenge in humans, however, due to technical constraints in magnetic resonance imaging (MRI). The propose research aims to comprehensively examines these critical reward regions using high resolution functional MRI approaches spearheaded by the Human Connectome Project (HCP) and high-fidelity analysis techniques. The project is supported by substantial data from our laboratory documenting a wide range of anhedonia severity in adolescent MDD, as well as relationships between anhedonia severity and intrinsic functional connectivity (iFC) of the NAc with the Anterior Cingulate Cortex (ACC). More recently, we reported iFC of the Hb with targets including the VTA and ACC in healthy HCP subjects; moreover, subjects with high vs. low subclinical depression scores exhibited distinct iFC patterns with regions associated with MDD, including the amygdala and insula. This study therefore proposes to examine the role of the Hb and VTA, as well as the NAc and cortical regions, in human reward circuitry and test the overall hypothesis that alterations in this circuitry are associated with MDD and anhedonia. We will examine high resolution resting-state and reward task fMRI data from (Aim 1) healthy young adult HCP subjects and (Aim 2) 35 psychotropic-medication free adolescents with MDD and 20 matched controls (ages 12-18, Tanner stage ≥ 4). Study procedures for adolescents will include diagnostic evaluations, dimensional measures of anhedonia, and an MRI session. Analyses will focus on the Hb, VTA, NAc, and cortical reward regions, examining iFC, activation during specific reward processes, group differences, and associations with anhedonia severity. SIGNIFICANCE: The proposed research addresses the heterogeneous nature of adolescent MDD by focusing on a narrow phenotype of anhedonia to examine the role of critical reward circuitry. The proposed multimodal training will provide experience in both clinical translational research and advanced imaging methodologies. This line of work has the potential to inform etiological models, improve diagnostics, and facilitate the development of targeted interventions.

项目概要/摘要重度抑郁症（MDD）是一个重大的公共卫生问题，与显着的发病率和尽管 MDD 经常出现在青春期，但对该年龄段的研究仍然很少。青少年 MDD 的异质性进一步阻碍了对该疾病神经生物学的识别为了应对这些挑战，该研究培训奖学金采用了维度方法。关注快感缺失的核心 MDD 症状——体验快乐的能力降低。青少年 MDD 的严重程度差异很大，严重程度增加预示预后不良和自杀。我们的研究旨在描述与快感缺乏相关的奖励回路缺陷。表明缰核（Hb）（一个小的边缘中枢）的过度活跃可能是由于过度过度活动而导致这种缺陷的原因抑制腹侧被盖区 (VTA) 和下游伏隔核 (NAc) 的奖赏信号传导。然而，在体内表征甚至可视化这些区域对人类来说一直是一个挑战，因为本研究旨在全面解决磁共振成像 (MRI) 的技术限制。使用高分辨率功能性 MRI 方法检查这些关键奖励区域人类连接组计划（HCP）和高保真分析技术该项目得到了支持。我们实验室的大量数据记录了青少年 MDD 的快感缺乏严重程度，如以及快感缺失严重程度和 NAc 与神经元的内在功能连接 (iFC) 之间的关系最近，我们报道了 Hb 的 iFC，其目标包括 VTA 和此外，健康 HCP 受试者中的 ACC 表现出高与低亚临床抑郁症评分本研究中，与 MDD 相关的区域（包括杏仁核和岛叶）具有不同的 iFC 模式。因此建议研究 Hb 和 VTA 以及 NAc 和皮质区域在人类中的作用奖励电路并测试该电路的改变与 MDD 相关的总体假设我们将检查来自（目标 1）健康的高分辨率静息态和奖励任务功能磁共振成像数据。年轻成年 HCP 受试者和（目标 2）35 名患有 MDD 且未服用精神药物的青少年和 20 名匹配的青少年对照（12-18 岁，Tanner 阶段 ≥ 4）。青少年的研究程序将包括诊断评估，快感缺乏的维度测量，以及 MRI 分析将重点关注 Hb、VTA、NAc 和皮质奖励区域，检查 iFC、特定奖励过程中的激活、群体差异和与快感缺乏严重程度的关联意义：拟议的研究解决了异质性问题。通过关注快感缺乏的狭隘表型来检查关键性的作用，从而了解青少年MDD的本质拟议的多模式培训将提供临床转化研究的经验。和先进的成像方法有可能为病因模型提供信息，改进。诊断，并促进有针对性的干预措施的制定。