Testing a Diathesis-Stress Model of Adolescent Suicide: Dopaminergic, Social, and Inhibitory Mechanisms

项目摘要 自杀是一项重大的公共卫生危机，目前是10-24人中的第二大死因- 一岁的孩子。自杀想法和行为(STB)在青春期急剧增加，尤其是 在抑郁的青少年中很常见。然而，确定哪些抑郁的青少年 自杀行为的高危人群尚未形成。创新、多模式研究探索 生物学和社会情感机制可能阐明改善青少年自杀预测的潜在靶点 并减少不必要的生命损失。 目前STB的素质-应激模型假设了易患远端疾病之间的相互作用 个人对STB和最近的压力源，特别是社会拒绝和人际损失。最近的评论 强调STB的潜在神经疾病，但发现有限，特别是对高危青少年。 目前的项目针对三种远端神经机制--多巴胺能、社会性和抑制性缺陷--在一个 14-17岁青少年样本：抑郁青少年有自杀念头(n=55)或最近自杀 尝试(n=55)和人口统计学匹配的健康对照组(n=35)。首先，尸检结果表明 成人自杀中的多巴胺能缺陷，但检测体内的多巴胺功能对了解 青春期STB的前瞻性风险。因此，我们将利用一种新的磁共振成像(MRI) 在关键的中脑投射区域对神经黑色素作为多巴胺的非侵入性替代物的获得性敏感。 鉴于多巴胺对奖赏的贡献以及抑郁症中的非享乐性缺陷，我们假设 多巴胺能减少在青少年STB中将是突出的，特别是在尝试者中。第二，自杀 尝试者比理想者经历更多的人际压力，因此，拟议的项目将澄清 社交处理神经回路的改变增加了自杀行为的风险。我们假设 在一个生态有效的聊天室核磁共振任务中，受试者将表现出迟钝的纹状体反应 与Ideator相比，对同龄同龄人的拒绝接受和更多的脑岛反应。第三，负面的 紧迫感，一种在负面情绪后冲动行事的倾向，与青少年自杀有关 行为。我们假设，受试者将表现出额叶、纹状体和岛叶抑制缺陷。 情绪去/不去核磁共振范式，遵循社会评估应激源诱导负面情绪状态。 将从儿科急诊科招募青少年理想者和尝试者，并遵循 在高危的3个月期间，10%的青少年会在出院后90天内试图自杀。 人际压力将通过前瞻性的生态瞬时评估和随访来表征 深入的回顾访谈。总而言之，这些新颖的多模式磁共振成像和压力测量具有很大的优势 承诺阐明青少年自杀行为的途径，这是NIMH研究的关键优先事项。

Project Summary Suicide is a major public health crisis and, currently, is the second leading cause of death among 10-24- year-olds. Suicidal thoughts and behaviors (STB) increase drastically during adolescence and are particularly common among depressed adolescents. However, definitive markers to identify which depressed adolescents are most at-risk for suicidal behaviors have not been developed. Innovative, multimodal studies probing biological and socioemotional mechanisms may elucidate potential targets to improve prediction of youth suicide and reduce the needless loss of life. Current diathesis-stress models of STB posit interactions between distal diatheses that predispose individuals to STB and proximal stressors, particularly social rejection and interpersonal loss. Recent reviews highlight potential neural diatheses for STB, yet findings are limited, particularly for high-risk adolescents. The current project targets three distal neural mechanisms–dopaminergic, social, and inhibitory deficits–in a sample of 14-17-year-old adolescents: depressed adolescents either suicidal ideation (n=55) or a recent suicide attempt (n=55) and demographically matched healthy controls (n=35). First, post-mortem work has implicated dopaminergic deficits in adult suicide, but examining dopamine function in vivo is critical to understand prospective risk for adolescent STB. Thus, we will leverage a novel Magnetic Resonance Imaging (MRI) acquisition sensitive to neuromelanin as a non-invasive proxy for dopamine in key midbrain projection regions. Given the contribution of dopamine to reward and anhedonic deficits in depression, we hypothesize that dopaminergic reductions will be prominent in adolescent STB, particularly among attempters. Second, suicide attempters experience more interpersonal stress than ideators, and thus, the proposed project will clarify whether alterations in social processing neural circuitry confer heightened risk for suicidal behaviors. We hypothesize that, during an ecologically valid Chatroom MRI task, attempters will exhibit blunted striatal response to acceptance and increased insula response to rejection by same-age peers relative to ideators. Third, negative urgency, the tendency to act impulsively following negative emotions, is implicated in adolescent suicidal behaviors. We hypothesize that attempters will exhibit frontal, striatal, and insular inhibition deficits during an emotional Go/No-Go MRI paradigm, following a social-evaluative stressor to induce a negative mood state. Adolescent ideators and attempters will be recruited from a pediatric emergency department and followed for a high-risk 3-month period, as 10% of adolescents will attempt suicide within 90 days of hospital discharge. Interpersonal stress will be characterized over follow-up via prospective ecological momentary assessment and in-depth retrospective interviews. Collectively, these novel multimodal MRI and stress measures hold great promise to elucidate the pathway to adolescent suicidal behaviors, a key NIMH research priority.