Neurodevelopmental Mechanisms Underlying the Onset of Depression among At-Risk Youth: The Role of Dysregulation in the Negative Valence System

高危青少年抑郁症发病的神经发育机制：负价系统失调的作用

• 批准号: 10658042
• 负责人: Katie L Burkhouse
• 金额: $ 68.64万
• 依托单位: RESEARCH INST NATIONWIDE CHILDREN'S HOSP
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-05-01 至 2028-02-29
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10658042
• 关键词: Address; Affect; Age; Amygdaloid structure; Area; Behavior; Behavioral; Brain; Child; Data; Depressed mood; Development; Diagnosis; Early Diagnosis; Early identification; Economic Burden; Emotional; Emotions; Event-Related Potentials; Exhibits; Female; Functional Magnetic Resonance Imaging; Functional disorder; Future; General Population; Goals; Image; Individual; Insula of Reil; Intervention; Intervention Studies; Interview; Knowledge; Link; Longitudinal Studies; Major Depressive Disorder; Measures; Mental Depression; Mentored Patient-Oriented Research Career Development Award; Modeling; Mothers; National Institute of Mental Health; Negative Valence; Onset of illness; Pathway interactions; Patient Self-Report; Performance; Physiological; Populations at Risk; Poverty; Prevention; Principal Investigator; Property; Psychophysiology; Puberty; Recording of previous events; Recurrence; Regulation; Research Personnel; Rest; Risk; Risk Marker; Role; Sample Size; Sampling; Series; Sex Differences; Specificity; Stimulus; Strategic Planning; Surveys; Symptoms; System; Telephone; Testing; Time; Work; Youth; affective neuroscience; biological sex; biomarker discovery; brain based; child depression; clinical application; cognitive control; cost effective; depression prevention; depressive symptoms; disorder prevention; disorder risk; emerging adult; emotional stimulus; high risk; imaging study; improved; indexing; innovation; maternal depression; multimodality; network dysfunction; novel; offspring; recruit; response; sex; social; statistics; support network; theories

PROJECT SUMMARY Offspring of mothers with major depressive disorder (MDD) are at substantially elevated risk for developing depression by early adulthood. Devastatingly, 60% of these high risk (HR) youth will meet criteria for MDD by age 25, versus only 16% of individuals in the general population. Recognized by the 2022 NIMH Strategic Plan, the discovery of a reliable, objective marker of MDD risk is critical for earlier detection to facilitate targeted prevention efforts for HR youth. Across studies, HR offspring exhibit maladaptive reactivity and regulatory responses to negative social-emotional stimuli. During functional magnetic resonance imaging (fMRI) tasks probing negative emotion processing (NEP), youth of depressed, versus nondepressed, mothers consistently exhibit dysfunction in brain networks responsible for adaptive NEP, including salience emotional and cognitive control networks (SEN and CCN). Critically, pilot data from the Early-Stage Principal Investigator provide compelling evidence that SEN-CCN network dysfunction during NEP may represent a brain-based marker of depression among HR youth. However, a mechanistic test of this hypothesis has yet to be evaluated in an adequately powered and demographically distributed sample of HR and low risk (LR) youth followed over a sufficient period to detect the emergence of MDD. The current R01 will employ a novel, multimodal, longitudinal study to test whether functional properties of brain networks supporting NEP predict future depression trajectories among HR and LR youth (Aim 1). In doing so, we will examine whether SEN-CCN dysfunction during NEP changes over time once depression emerges. Clarifying the question of stability is critical to determining whether SEN-CCN dysfunction during NEP is modifiable and may represent a novel MDD treatment target in HR youth (Aim 2). Prior work also shows that HR youth exhibit deficits in NEP across physiological (event-related potentials, ERPs), behavioral, and self-report indices. To determine which risk markers should be prioritized for prevention, an innovative aspect of the proposal will be to test if SEN-CCN function during NEP is superior to other cost-effective markers of risk in predicting youth depression, and whether a multi-indicator model including several units of NEP improves MDD prediction indices (Aim 3). Finally, we will explore how biological sex and puberty interact with neurodevelopmental pathways to predict depression trajectories in HR youth. To achieve these aims, we will recruit 250 youth (with and without with a maternal history of recurrent MDD). At baseline, youth (ages 9-14, 50% female) will be lifetime free of MDD to capture the emergence of depression during a period of elevated MDD risk. At baseline, 12-, and 24- months, youth will complete tasks probing negative social- emotional reactivity and regulation to generate multimodal NEP measures (fMRI, ERPs, behavior). Every 6 months, we will assess youth’s depressive symptoms and diagnoses via online surveys and phone interviews (up to 24 months). Findings will contribute to the discovery of biomarkers that are linked to the development and course of MDD among HR youth, which can be utilized in targeted MDD prevention and intervention studies.

项目摘要 患有严重抑郁症（MDD）母亲的后代有显着发展的风险 毁灭性的是，这些高风险（HR）青年中有60％符合MDD的标准 25岁，仅16％的普通人群。被2022年NIMH战略计划所认可的 发现可靠的，客观的MDD风险标记对于早期检测至关重要 人力资源青年的预防工作。在整个研究中，人力资源后代暴露了适应不良的反应性和调节性 对负面社会情感刺激的反应。在功能磁共振成像（fMRI）任务中 探测负面情绪处理（NEP），沮丧的年轻人，与不抑制的母亲一贯 在负责自适应NEP的大脑网络中显示功能障碍，包括 显着情感和认知 控制网络（SEN和CCN）。至关重要的是，早期首席研究员的试点数据提供 令人信服的证据表明，NEP期间的SEN-CCN网络功能障碍可能代表了基于大脑的标记 人力资源青年的抑郁症。但是，该假设的机理检验尚未在 足够的动力和人口统计分布的人力资源和低风险（LR）青年的样本紧随其后 足够的时间来检测MDD的出现。当前的R01将采用新颖的，多模式的纵向 研究以测试支持NEP的大脑网络的功能性能是否预测未来抑郁症 人力资源和LR青年的轨迹（AIM 1）。在此过程中，我们将检查Sen-CCN功能障碍是否在 一旦抑郁症出现，NEP会随着时间而变化。澄清稳定问题对于确定 NEP期间的SEN-CCN功能障碍是否可修改，并且可能代表新的MDD治疗靶 人力资源青年（AIM 2）。先前的工作还表明，人力资源青年暴露在生理学（与事件相关）的NEP中定义 电势，ERP），行为和自我报告指数。确定应优先考虑哪些风险标记 预防，该提案的创新方面是测试NEP期间的Sen-CCN功能是否优于 预测青年抑郁症的其他具有成本效益的风险标志，以及包括 NEP的几个单位改善了MDD预测指数（AIM 3）。最后，我们将探讨生物学性别和 青春期与神经发育途径相互作用，以预测人力资源青年的抑郁轨迹。实现 这些目标，我们将招募250名青年（有和没有重复的MDD历史）。基线， 年轻人（9-14岁，女性50％）将没有MDD的寿命，以捕获抑郁症的出现 MDD风险升高时期。在基线，12个月和24个月时，青年将完成探测负面社会的任务 - 情绪反应性和调节以产生多模式NEP测量（fMRI，ERP，行为）。每6个 几个月，我们将通过在线调查和电话访谈评估青年的抑郁症状和诊断 （长达24个月）。调查结果将有助于发现与开发相关的生物标志物和 人力资源青年中MDD的过程，可用于靶向MDD预防和干预研究。