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

项目总结 患有重度抑郁障碍(MDD)的母亲的后代患抑郁症的风险大大增加 成年初期的抑郁症。毁灭性的是，这些高危(HR)青年中有60%将达到MDD的标准 25岁，而普通人群中只有16%的人。2022年NIMH战略计划确认， 发现可靠、客观的MDD风险标记物对于早期发现MDD风险是至关重要的，以促进靶向 针对HR青年的预防工作。在所有研究中，HR后代表现出适应不良的反应和调节 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 探索负性情绪加工(NEP)，抑郁的青年母亲与非抑郁的母亲 表现出负责适应性NEP的大脑网络功能障碍，包括 情绪和认知的突显 控制网络(SEN和CCN)。至关重要的是，来自早期首席调查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着 HR青年中的抑郁。然而，对这一假设的机械测试还有待于在 对人力资源和低风险(LR)青年进行了为期一年的跟踪调查 有足够的时间来检测MDD的出现。目前的R01将采用新的、多模式的、纵向的 测试支持NEP的大脑网络的功能特性是否预测未来抑郁症的研究 HR和LR青年之间的轨迹(目标1)。在此过程中，我们将检查SEN-CCN功能障碍在 一旦出现抑郁，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SEN-CCN功能障碍是否是可修改的，并可能代表MDD治疗的新靶点 青年人力资源(目标2)。先前的研究还表明，HR年轻人在生理(与事件相关)方面表现出NEP缺陷 电位、事件相关电位)、行为和自我报告指数。确定应优先处理哪些风险标记 预防，该提案的一个创新方面将是测试在NEP期间SEN-CCN功能是否优于 预测青少年抑郁的其他经济有效的风险标志，以及包括 NEP的几个单位改进了MDD预测指数(目标3)。最后，我们将探索生物性行为和 青春期与神经发育途径相互作用，以预测HR青年的抑郁轨迹。要实现 为了实现这些目标，我们将招募250名青年(有或没有反复出现MDD的母亲病史)。在基线上， 年轻人(9-14岁，50%为女性)将终身不患MDD，以捕捉在 MDD风险高发期。在基线、12个月和24个月时，年轻人将完成探索负面社会- 情绪反应和调节，以产生多模式NEP测量(功能磁共振、事件相关电位、行为)。每隔6天 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 (最多24个月)。这些发现将有助于发现与疾病发生和发展有关的生物标志物 人力资源青年的MDD病程，可用于有针对性的MDD预防和干预研究。

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.