Neurobiological markers of risk and resilience for psychopathology in youth at familial risk for mood disorders

在年轻人中，重度抑郁症（MDD）和双相情感障碍（BD）是十大原因中的两个 残疾和自杀的风险增加。由于BD通常最初表现为MDD发作， BD经常被误诊，因此得不到有效的治疗。情绪障碍的家族史是 是早发性MDD和BD以及其他精神疾病的可靠预测因子。先前的研究已经确定 BD或MDD高家族风险的健康青年相对于低家族风险的神经生物学差异， 一项研究已经确定了BD与MDD家族高危青年之间的神经回路差异。 与此相关的是，有初步证据表明，神经标记物可以预测精神病理学的后期发作， BD和MDD家族高危青年。这些研究表明，有一些脆弱性的标志， 可以在症状发作前在大脑中检测到，这可能会进一步增加精神健康状况不佳的风险 在这些敏感的年轻人中。然而，现有的研究一直受到样本量小的限制 以及随着时间的推移缺乏多个纵向症状测量，这阻碍了 一个强有力的生物标志物，区分风险概况之间的青年与家族史的BD与MDD。的 在青年中识别BD和MDD风险的基于大脑的特征将促进对BD和MDD风险的理解。 脆弱性加剧的潜在机制，这可能最终为更早和更广泛地 准确识别这些疾病。本研究的目的是揭示独特的神经生物学概况， 健康青年中BD和MDD的高家族风险，并研究这些生物标志物是否预测了 随后的发病和整个青春期精神病理学的纵向过程。本研究将包括 MDD（HR-MDD，n = 1，564）或BD（HR-BD，n=407）低（LR，n= 3，915）或高家族风险的健康青年， 长达3年的纵向数据，来自具有里程碑意义的青少年大脑认知发展（ABCD） Study.目的1将研究情绪- 健康HR-BD、HR-MDD和LR青年之间基线时的奖励相关网络，使用全脑种子- 以杏仁核、腹侧纹状体和背侧纹状体作为感兴趣的种子区域的体素方法。目的2 将确定3年内青少年期维度精神症状的纵向轨迹， 使用基于群体的轨迹建模的高家族风险青年。目标3将调查是否改变 情绪和奖励相关网络中的基线FC预测了后期临床诊断的存在。 青春期和/或青春期更严重的维度症状纵向过程。这 研究将揭示关键的洞察机制，有助于风险与弹性在脆弱的 青年有可能成为干预措施的关键生物目标。这些知识也可能潜在地告知 早期发现和干预计划，这将有助于减轻BD和MDD的巨大负担。

Among youth, major depressive disorder (MDD) and bipolar disorder (BD) represent two of the top ten causes of disability and confer heightened risk of suicide. Since BD often initially presents as a MDD episode, youth with BD are frequently misdiagnosed and thus receive ineffective treatment. Family history of mood disorders is a robust predictor of early-onset MDD and BD as well as other psychiatric disorders. Prior studies have identified neurobiological differences between healthy youth at high familial risk for BD or MDD relative to low familial risk, and one study has identified neural circuit differences between youth at high familial risk for BD versus MDD. Relatedly, there is preliminary evidence for neural markers that predict later onset of psychopathology among youth at high familial risk for BD and MDD. These studies suggest that there are markers of vulnerability that can be detected in the brain, prior to symptom onset, which may further increase risk for poor mental health outcomes among these susceptible youth. However, extant research has been limited by small sample sizes and a lack of multiple longitudinal symptom measurements over time, which have hindered the identification of robust biomarkers that distinguish risk profiles among youth with a family history of BD versus MDD. The identification of brain-based signatures of BD and MDD risk in youth would advance understanding of distinct mechanisms underlying heightened vulnerability, which may ultimately inform approaches for earlier and more accurate identification of these disorders. The present study aims to uncover unique neurobiological profiles of high familial risk for BD and MDD among healthy youth, and to investigate whether these biomarkers predict the subsequent onset and longitudinal course of psychopathology across adolescence. This study will include healthy youth at low (LR, n=3,915) or high familial risk for MDD (HR-MDD, n=1,564) or BD (HR-BD, n=407) with longitudinal data up to 3 years, derived from the landmark Adolescent Brain Cognitive Development (ABCD) Study. Aim 1 will examine dissociable patterns of resting-state functional connectivity (FC) in emotion- and reward-related networks at baseline between healthy HR-BD, HR-MDD, and LR youth, using a whole-brain seed- to-voxel approach with the amygdala, ventral striatum, and dorsal striatum as seed regions of interest. Aim 2 will ascertain longitudinal trajectories of dimensional psychiatric symptoms across adolescence over 3 years in high familial risk youth using group-based trajectory modeling. Aim 3 will investigate whether alterations in baseline FC within emotion- and reward-related networks predicts the presence of a clinical diagnosis in later adolescence and/or a more severe longitudinal course of dimensional symptoms across adolescence. This research will reveal critical insight into the mechanisms that contribute to risk versus resilience in vulnerable youth, potentially serving as key biological targets for interventions. This knowledge may also potentially inform early detection and intervention programs, which will help to alleviate the immense burden of BD and MDD.