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 患有重度抑郁症（MDD）的母亲的后代患上抑郁症的风险大大增加。 抑郁症早期成年。令人震惊的是，这些高风险（HR）青年中的60%将符合MDD的标准， 25岁，而在一般人群中只有16%。在2022年NIMH战略计划中， 发现可靠、客观的MDD风险标志物对于早期检测至关重要， 为青年人权作出预防努力。在所有研究中，HR后代表现出适应不良的反应性和调节性。 对负面社会情绪刺激的反应。在功能性磁共振成像（fMRI）任务中， 探讨消极情绪处理（NEP），青年抑郁症，与非抑郁症，母亲一致 表现出负责适应性NEP的大脑网络功能障碍，包括 情绪和认知的显著性 控制网络（SEN和CCN）。重要的是，来自早期主要研究者的试点数据提供了 令人信服的证据表明，NEP期间SEN-CCN网络功能障碍可能代表了一种基于大脑的标记物， HR青年抑郁症然而，对这一假设的机械检验还有待于在 充分把握和人口统计学分布的HR和低风险（LR）青年样本， 有足够的时间来检测MDD的出现。目前的R 01将采用一种新型的，多模态，纵向 一项旨在测试支持NEP的大脑网络功能特性是否能预测未来的抑郁症的研究 高风险和低风险青年的发展轨迹（目标1）。在这样做的时候，我们将检查是否SEN-CCN功能障碍， 一旦出现抑郁症，NEP就会随着时间的推移而变化。澄清稳定性问题对于确定 NEP期间的SEN-CCN功能障碍是否是可改变的，并可能代表一种新的MDD治疗靶点， 青年人力资源（目标2）。先前的研究还表明，HR青年在生理（事件相关）方面表现出NEP的缺陷。 电位，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，该提案的一个创新方面将是测试NEP期间SEN-CCN功能是否优于上级 预测青年抑郁症的其他具有成本效益的风险标志物，以及多指标模型是否包括 几个单位的NEP改善了MDD预测指数（目标3）。最后，我们将探讨生物性别和 青春期与神经发育通路相互作用，以预测HR青年的抑郁轨迹。实现 为了实现这些目标，我们将招募250名青年（有或没有复发性MDD的母亲病史）。在基线时， 青少年（9-14岁，50%女性）将终身无MDD，以捕捉抑郁症的出现， MDD风险升高的时期。在基线、12个月和24个月大的时候，青少年将完成探索负面社会影响的任务。 情绪反应和调节，以产生多模态NEP测量（fMRI，ERP，行为）。每6 我们将通过在线调查和电话访谈评估青少年的抑郁症状和诊断， (up 24个月）。研究结果将有助于发现与发展相关的生物标志物， 抑郁症的过程中人力资源青年，可用于有针对性的抑郁症预防和干预研究。