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.

项目概要 患有重度抑郁症 (MDD) 的母亲的后代患抑郁症的风险显着升高 成年早期抑郁症。令人震惊的是，这些高风险 (HR) 青少年中 60% 将在以下时间达到 MDD 标准： 25 岁左右，而一般人群中这一比例仅为 16%。得到 2022 年 NIMH 战略计划的认可， 发现 MDD 风险的可靠、客观标记对于早期检测以促进有针对性的治疗至关重要 人力资源青年的预防工作。跨研究，HR 后代表现出适应不良反应和调节 对负面社会情绪刺激的反应。在功能磁共振成像 (fMRI) 任务期间 探究消极情绪处理（NEP）、抑郁症青年与非抑郁症母亲的一致 表现出负责适应性 NEP 的大脑网络功能障碍，包括 情感和认知的显着性 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基于大脑的标记 人力资源青年的抑郁症。然而，这一假设的机械检验尚未得到评估 对 HR 和低风险 (LR) 青年进行了充分的权力和人口统计分布样本跟踪 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纵向 研究测试支持 NEP 的大脑网络的功能特性是否可以预测未来的抑郁症 HR 和 LR 青年的发展轨迹（目标 1）。在此过程中，我们将检查 SEN-CCN 是否在 一旦抑郁症出现，NEP 就会随着时间而变化。明确稳定性问题对于确定稳定性至关重要 NEP 期间的 SEN-CCN 功能障碍是否可以改变，并且可能代表 MDD 的新治疗目标 人力资源青年（目标 2）。之前的工作还表明，人力资源青年在跨生理（事件相关）的 NEP 方面表现出缺陷 潜力、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 期间的 SEN-CCN 功能是否优于 预测青少年抑郁症的其他具有成本效益的风险标记，以及多指标模型是否包括 NEP 的几个单元改进了 MDD 预测指数（目标 3）。最后，我们将探讨生物性别和 青春期与神经发育途径相互作用，可预测 HR 青少年的抑郁轨迹。达到 为了实现这些目标，我们将招募 250 名青少年（有或没有母亲复发性 MDD 病史）。在基线处， 青少年（9-14 岁，50% 为女性）将终生免受抑郁症的困扰 MDD 风险升高的时期。在基线、12 个月和 24 个月时，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式 NEP 测量（fMRI、ERP、行为）。每 6 几个月后，我们将通过在线调查和电话采访来评估青少年的抑郁症状和诊断 （最长 24 个月）。研究结果将有助于发现与发育和发育相关的生物标志物。 人力资源青年MDD课程，可用于有针对性的MDD预防和干预研究。