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: 10414992
• 负责人: David Pagliaccio
• 金额: $ 19.05万
• 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 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10414992
• 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.

项目摘要 重性抑郁障碍（MDD）是世界范围内导致残疾的主要原因，并且具有发病高峰期 在青春期。大多数MDD患者在其生命过程中会经历多次发作， 结果不佳，自杀风险，以及巨大的个人和公共卫生负担。因此，确定 MDD疾病和病程对于确定新的干预目标至关重要。 MDD的特征是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。虽然已经检查了DA功能， 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， 不适合儿科研究作为替代方案，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，以探测MDD缓解青年的中脑DA功能。 此外，我们预计中脑DA有助于改变关键PVS域破坏抑郁症。 具体来说，目前的研究探讨了努力折扣-个人计算成本的过程- 付出努力获得回报的好处。在动物实验中，努力折扣依赖于中脑DA 并在人类MRI研究中激活纹状体区域。努力折扣的缺陷，激励的关键部分， 很可能会导致抑郁症的快感缺失症状虽然在成人MDD中注意到了改变，但神经系统 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测PVS来解决几个关键差距 在14-17岁的抑郁症患者（MDD = 30）和匹配的健康对照组（HC = 30）中，利用最近的 资助R 01（MH 119771 - 01 A1）用于招募和临床评估。首先，目标1将首次测试， 是否患有MDD的青少年在关键的中脑区域表现出假设的DA功能降低， 黑质和腹侧被盖区，如NM-MRI所示。此外，我们将研究是否 通过fMRI，患有MDD的青少年在腹侧纹状体表现出对努力折扣的神经编码钝化， 将探讨是否中脑NM介导这些差异。其次，Aim 2将测试这些神经元是否 使用创新的智能手机应用程序，标记物改善了对这些青少年真实世界功能的预测 进行深度的数字表型分析这将包括日常身体活动的不显眼的被动感测， 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，目标3将测试这些神经元的能力， 在6个月的随访中预测抑郁和快感缺失症状恶化的标志物。总的来说， 这个项目有希望确定导致抑郁症的DA和PVS缺陷，最终将 导致创新的生物风险标志物和干预目标的临床转化。