Identifying Positive Valence System Neural Deficits in Adolescent Depression

项目摘要 严重抑郁障碍(MDD)是世界范围内导致残疾的主要原因，并有一个发病高峰期 在青春期。大多数患有MDD的人在他们的一生中会经历多次发作，与 造成不良后果、自杀风险以及沉重的个人和公共健康负担。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)中的缺陷，特别是与奖励相关的缺陷 以及依赖于多巴胺(DA)大脑系统的动机改变。虽然已经检查了DA的功能 在使用正电子发射断层扫描(PET)的成年人中，放射性同位素示踪剂的使用使PET具有侵袭性和 对儿科研究来说是站不住脚的。作为另一种选择，目前的研究利用了一种新颖、快速和非侵入性的 对神经黑色素(NM)敏感的MRI获取以探讨缓解期MDD患者的中脑DA功能。 此外，我们预计中脑DA在抑郁症中破坏的关键PVS区域的改变中起作用。 具体地说，目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。在动物工作中显示出努力折扣依赖于中脑DA 并在人类核磁共振研究中激活纹状体区域。努力折扣方面的不足，这是激励的关键部分， 可能会导致抑郁症的非享乐性症状。尽管成年MDD患者有改变，但神经 对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，利用最近的一项研究 资助R01(MH119771-01A1)，用于招募和临床评估。首先，目标一号将首次测试， 无论患有MDD的青少年在关键的中脑区域是否表现出假想的DA功能下降， 黑质和腹侧被盖区，如NM-MRI所示。此外，我们将研究是否 患有MDD的青少年在腹侧纹状体表现出对努力折扣的迟钝神经编码，通过fMRI和 将探索中脑NM是否调节这些差异。第二，目标2将测试这些神经 使用一款创新的智能手机应用程序，标志物可以提高这些青少年在现实世界中的功能预测 用于深度的数字表型。这将包括对日常体力活动的不显眼的被动感知，作为 激励能力指数，以及积极情感和非享乐症状的重复自我报告 在日常运作过程中，通过生态瞬间评估。最后，目标3将测试这些神经的能力 在6个月的随访中预测抑郁和非享乐症状恶化的标志物。总而言之， 该项目承诺识别导致抑郁症的DA和PVS缺陷，最终将 导致创新的生物风险标记物和干预目标的临床翻译。

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.