Identifying Positive Valence System Neural Deficits in Adolescent Depression

识别青少年抑郁症的正价系统神经缺陷

• 批准号: 10303951
• 负责人: David Pagliaccio
• 金额: $ 24.12万
• 依托单位: NEW YORK STATE PSYCHIATRIC INSTITUTE DBA RESEARCH FOUNDATION FOR MENTAL HYGIENE, INC
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-06-01 至 2023-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10303951
• 关键词: 17 year old; Accelerometer; Address; Adolescence; Adolescent; Adult; Affect; Affective; Anhedonia; Animals; Autopsy; Behavior; Behavioral; Biological; Brain; Cell Nucleus; Cellular Phone; Characteristics; Clinical; Clinical assessments; Corpus striatum structure; Costs and Benefits; Data; Disease; Dopamine; Ecological momentary assessment; Elderly; Exhibits; Expenditure; Food; Functional Magnetic Resonance Imaging; Funding; Health; Human; Individual; Intervention; Lead; Life Cycle Stages; Link; Magnetic Resonance Imaging; Major Depressive Disorder; Measures; Mediating; Mental Depression; Metabolism; Midbrain structure; Modality; Monitor; Motivation; Outcome; Parkinson Disease; Patient Self-Report; Pediatric Research; Phenotype; Physical Efforts; Physical activity; Positioning Attribute; Positive Valence; Predictive Factor; Process; Public Health; Radioisotopes; Recurrence; Research; Research Domain Criteria; Research Infrastructure; Rewards; Risk Marker; Schizophrenia; Severities; Signal Transduction; Substantia nigra structure; Symptoms; System; Testing; Time; Tissues; Tracer; Treatment outcome; Ventral Striatum; Ventral Tegmental Area; Work; Youth; child depression; clinical translation; critical period; depressive symptoms; digital; disability; discounting; dopamine transporter; experience; follow-up; functional MRI scan; hedonic; imaging study; improved; indexing; innovation; longitudinal course; neurodevelopment; neuromelanin; novel; pars compacta; prospective; real time monitoring; recruit; relating to nervous system; response; sensor; smartphone Application; smartphone based assessment; suicidal risk; tomography; trait; transmission process; willingness

Project Summary Major depressive disorder (MDD) is a leading cause of disability worldwide and has a peak period of onset during adolescence. Most individuals with MDD will experience multiple episodes over their life course, relating to poor outcomes, suicide risk, and large personal and public health burden. Thus, identifying mechanisms of MDD illness and course is critical to identify novel intervention targets. MDD is characterized by deficits within the RDoC Positive Valence System (PVS), particularly reward-related and motivational alterations that rely on dopamine (DA) brain systems. While DA functioning has been examined in adults using Position Emission Tomography (PET), the use of radioisotope tracers makes PET invasive and untenable for pediatric research. As an alternative, the current study leverages a novel, fast, and non-invasive MRI acquisition sensitive to neuromelanin (NM) to probe midbrain DA function in youth with remitted MDD. Further, we expect midbrain DA to contribute to alterations in key PVS domains disrupted in depression. Specifically, the current study examines effort discounting–the process by which individuals calculate the cost- benefit of expending effort to achieve reward. Effort discounting is shown in animal work to rely on midbrain DA and to activate striatal regions in human MRI studies. Deficits in effort discounting, a critical part of motivation, likely contributes to anhedonic symptoms in depression. Although alterations are noted in adult MDD, the neural encoding of effort discounting has yet to be tested in adolescents with depression. The current R21 aims to address several critical gaps by probing the PVS across multiple units of analysis in 14-17-year-olds with depression (MDD = 30) and matched healthy controls (HC = 30), capitalizing on a recently funded R01 (MH119771-01A1) for recruitment and clinical assessment. First, Aim 1 will test, for the first time, whether adolescents with MDD exhibit hypothesized reductions in DA functioning in key midbrain regions, the substantia nigra and ventral tegmental area, as indexed by NM-MRI. Further, we will examine whether adolescents with MDD exhibit blunted neural encoding of effort discounting in the ventral striatum via fMRI and will explore whether midbrain NM mediates these differences. Second, Aim 2 will test whether these neural markers improve prediction of real-world functioning in these adolescents using an innovative smartphone app for deep, digital phenotyping. This will include both unobtrusive, passive sensing of daily physical activity, as an index for motivational capacity, as well as repeated self-report of positive affective and anhedonic symptoms during everyday functioning via ecological momentary assessment. Last, Aim 3 will test the ability of these neural markers to predict the worsening of depressive and anhedonic symptoms over a 6-month follow-up. In summary, this project has the promise to identify DA and PVS deficits that contribute to depression, which, ultimately, will lead to clinical translation for innovative biological risk markers and intervention targets.

项目概要 重度抑郁症（MDD）是全球范围内导致残疾的主要原因，并且有发病高峰期 青春期期间。大多数患有 MDD 的人在其一生中都会经历多次发作，这与 导致不良结果、自杀风险以及巨大的个人和公共健康负担。因此，识别机制 MDD 疾病和病程对于确定新的干预目标至关重要。 MDD 的特点是 RDoC 正价系统 (PVS) 内的缺陷，特别是与奖励相关的缺陷 以及依赖多巴胺（DA）大脑系统的动机改变。虽然 DA 功能已经过检查 在使用正电子发射断层扫描 (PET) 的成人中，放射性同位素示踪剂的使用使得 PET 具有侵入性和 对于儿科研究来说是站不住脚的。作为替代方案，当前的研究利用了一种新颖、快速且非侵入性的方法 MRI 采集对神经黑色素 (NM) 敏感，可探测 MDD 缓解青年的中脑 DA 功能。 此外，我们预计中脑 DA 有助于改变因抑郁症而中断的关键 PVS 域。 具体来说，当前的研究考察了努力贴现——个人计算成本的过程—— 付出努力以获得回报的好处。动物工作中的努力折扣表现在依赖中脑DA 并在人类 MRI 研究中激活纹状体区域。努力折扣的不足，这是动机的关键部分， 可能会导致抑郁症的快感缺失症状。尽管成人 MDD 发生了改变，但神经 努力折扣的编码尚未在患有抑郁症的青少年中进行测试。 当前的 R21 旨在通过跨多个分析单元探索 PVS 来解决几个关键差距 在 14-17 岁抑郁症患者 (MDD = 30) 和匹配的健康对照者 (HC = 30) 中，利用最近的 资助R01（MH119771-01A1）用于招募和临床评估。首先，目标 1 将首次测试， 患有 MDD 的青少年是否表现出假设的关键中脑区域 DA 功能的减少， 黑质和腹侧被盖区，由 NM-MRI 索引。进一步，我们将检查是否 患有 MDD 的青少年通过功能磁共振成像 (fMRI) 表现出腹侧纹状体中努力折扣的神经编码迟钝， 将探讨中脑 NM 是否介导这些差异。其次，Aim 2 将测试这些神经网络是否 标记物使用创新的智能手机应用程序改进了对这些青少年现实世界功能的预测 用于深入的数字表型分析。这将包括对日常身体活动的不引人注目的被动感知，作为 动机能力指数，以及积极情感和快感缺乏症状的重复自我报告 在日常运作中通过生态瞬时评估。最后，Aim 3将测试这些神经元的能力 预测 6 个月随访期间抑郁和快感缺乏症状恶化的标记。总之， 该项目有望识别导致抑郁症的 DA 和 PVS 缺陷，最终将 导致创新生物风险标记和干预目标的临床转化。