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

基本信息

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
项目类别：
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

项目摘要

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.

项目摘要重度抑郁症（MDD）是全球残疾的主要原因，并具有高峰时期在青少年期间。大多数具有MDD的人会在他们的人生课程中体验多集，与结果不佳，自杀风险以及庞大的个人和公共卫生伯恩。那是确定的机制 MDD疾病和课程对于确定新颖的干预目标至关重要。 MDD的特征是在RDOC正价系统（PVS）中定义，特别是与奖励有关的以及依赖多巴胺（DA）脑系统的动机变化。虽然DA功能已被检查在使用位置排放层析成像（PET）的成年人中，放射性同位素示踪剂的使用使宠物侵入性和对小儿研究站不住脚。作为替代方案，当前的研究利用了一种新颖，快速和无创的 MRI获取对神经苯胺敏感（NM）探测禁止MDD的年轻人中的中脑DA功能。此外，我们预计中脑DA会导致抑郁症中断的关键PVS域的改变。具体而言，当前的研究考试努力打折 - 个人计算成本的过程 - 花费努力获得奖励的好处。在动物工作中显示折扣的努力折现以依靠中脑DA 并激活人类MRI研究中的纹状体区域。努力打折的赤字，动机的关键部分，也许会导致抑郁症的鼻症状。在抑郁症的青少年中，编码努力打折的编码尚待测试。当前的R21旨在通过多个分析单位探测PV来解决几个关键差距在14-17岁的抑郁症（MDD = 30）和匹配的健康对照（HC = 30）中，资助R01（MH119771-01A1）用于招募和临床评估。首先，AIM 1将首次测试 MDD的青少年是否暴露了主要中脑区域DA功能的假设减少， NM-MRI索引，黑质尼格拉和腹侧对段区域。此外，我们将研究是否 MDD的青少年通过fMRI和将探索中脑NM是否介导了这些差异。其次，AIM 2将测试这些中立是否标记使用创新的智能手机应用程序改善了这些青少年中现实世界功能的预测用于深度，数字表型。这将包括每日体育锻炼的不引人注目的被动敏感性，作为一个动机能力的索引，以及重复的积极情感和鼻音症状的自我报告每天通过生态瞬间评估运作。最后，AIM 3将测试这些中性的能力在6个月的随访中预测抑郁症和无鼻涕符号的标记。总之，该项目有望识别DA和PVS定义有助于抑郁症，最终将导致创新生物风险标志物和干预靶标的临床翻译。