Structural and functional neural alterations in suicidality among Veterans with PTSD

项目总结/摘要 研究：美国退伍军人自杀率是平民的2至6倍 同行自杀意念（SI）和自杀企图（SA）是自杀死亡的主要前兆，发生在 比死亡的频率高得多，造成巨大的个人和社会负担，但相对而言， 关于它们的病理生理学知之甚少。这在创伤后应激障碍（PTSD）中尤其如此， 伊拉克和阿富汗战争的标志性伤害。合并症的高发生率和两者的高患病率 自杀和创伤后应激障碍的退伍军人，突出了促进对共享和 区分它们之间的神经机制创伤和压力相关的突触丢失的证据， 在涉及情绪，认知和大脑区域内在连接网络的大规模改变 行为存在于SI/SA和PTSD文献中。然而，该领域的一个主要障碍是缺乏 创伤后应激障碍人群中基于神经生物学的SI/SA研究。初步数据支持这一观点， 突触改变的位置和模式可能与个体和环境特征相互作用， 影响临床表现和症状严重程度。具体来说，支持SI的创伤后应激障碍退伍军人似乎 具有与PTSD症状严重程度、抑郁和年龄不同的突触改变的神经特征。 扩展这项工作，最先进的多模式神经成像和行为评估会议将 在3个研究组（n=32/组）的96名退伍军人中进行：仅PTSD; PTSD+SI; PTSD+SA。坚固耐用， 突触改变的独特模式和位置的补充证据将使用（a） 全脑顶点结构磁共振成像（MRI）以测量皮质厚度，（B） 静息状态功能连接MRI（rs-fcMRI），以测量整体脑连接（GBC），以及（c） 扩散MRI测量扩散GBC（dGBC），这是微结构架构和连通性的量度。 退伍军人将在年龄，性别，PTSD症状严重程度和创伤性脑损伤史上进行匹配。本研究 可以在VA的两个操作优先领域中识别治疗目标的生物标志物-自杀和 创伤后应激障碍，通知有效的药理学干预新药开发，并最终推进 为减轻数百万人的痛苦开辟了道路-退伍军人和平民都一样-与 自杀倾向 候选人：Averill博士表现出对改善退伍军人心理健康的坚定承诺 护理，重点是创伤后应激障碍和自杀预防超过十年。短期目标包括： CDA-2通过严格的培训目标（专注于神经生物学， SI/SA，多模式神经成像和统计学），并为未来的资金提供数据，因为她建立了一个 国家创伤后应激障碍临床神经科学中心（NCPTSD-CND）的利基研究计划。 长期目标包括成为退伍军人自杀预防和创伤后应激障碍领域的思想领袖 通过旨在为新药开发和改进预防提供信息的实证研究， 诊断，识别SI/SA中的风险和恢复力的生物标志物，以及治疗方案。 环境：基础设施、导师的素质、补充资金支持、技术和 国家创伤后应激障碍临床神经科学中心提供的退伍军人为重点的研究环境 组织和耶鲁是无与伦比的。这提供了一个独特的机会，以支持博士Averill在她的过渡， 通过特殊的有针对性的培训/指导，并进行低成本/高收益的研究， 具有推动该领域发展的巨大潜力，为退伍军人带来更好的结果，并为 成功的职业生涯。

PROJECT SUMMARY/ABSTRACT Research: Veterans of the U.S. military die by suicide at a rate of two to six times that of their civilian counterparts. Suicidal ideation (SI) and suicide attempts (SA), cardinal precursors to death by suicide, occur at significantly greater frequency than death and cause immense individual and societal burden, yet relatively little is known about their pathophysiology. This is especially so in posttraumatic stress disorder (PTSD), a signature injury of the wars in Iraq and Afghanistan. High rates of comorbidity and inflated prevalence of both suicidality and PTSD in Veterans, highlights the urgency of advancing understanding of the shared and distinguishing neural mechanisms between these. Evidence of trauma- and stress-related synaptic loss and large-scale alterations in intrinsic connectivity networks in brain regions implicated in mood, cognition, and behavior exists in both SI/SA and PTSD literature. However, a major obstacle in field is the scarcity of neurobiologically-based studies of SI/SA in PTSD cohorts. Preliminary data supports the notion that the location and pattern of synaptic alterations may interact with individual and environmental characteristics to affect clinical presentation and symptom severity. Specifically, Veterans with PTSD endorsing SI appear to have a neural signature of synaptic alterations distinct from PTSD symptom severity, depression, and age. Extending this work, state-of-the-art multimodal neuroimaging and behavioral assessment sessions will be conducted in 96 Veterans across 3 study groups (n=32/group): PTSD only; PTSD+SI; PTSD+SA. Robust, complimentary evidence of a unique pattern and location of synaptic alterations will be demonstrated using (a) whole-brain vertex-wise structural magnetic resonance imaging (MRI) to measure cortical thickness, (b) resting-state functional connectivity MRI (rs-fcMRI) to measure global brain connectivity (GBC), and (c) diffusion MRI to measure diffusion GBC (dGBC), a measure of microstructural architecture and connectivity. Veterans will be matched on age, sex, PTSD symptom severity, and history of traumatic brain injury. This study may identify biomarkers of treatment targets in two of the operational priority areas for the VA – suicide and PTSD, inform novel drug development of efficacious pharmacologic interventions, and ultimately advance the field making way to alleviate suffering of millions of individuals – Veteran and civilian alike - struggling with suicidality. Candidate: Dr. Averill has demonstrated an unwavering commitment to improving Veterans’ mental health care, with emphasis on PTSD and suicide prevention for well over a decade. Short-term goals include receipt of the CDA-2 to both advance her expertise through rigorous training objectives (focused on the neurobiology of SI/SA, multimodal neuroimaging, and statistics) and to provide data for future funding as she establishes a niche program of research in the National Center for PTSD-Clinical Neurosciences Division (NCPTSD-CND). Long-term goals include becoming a thought leader in the areas of suicide prevention and PTSD in Veterans through empirical investigations aimed at informing novel drug development and improved prevention, diagnostics, identification of biomarkers of risk and resilience in SI/SA, and treatment options. Environment: The infrastructure, quality of mentors, supplementary funding support, technology, and Veteran-focused research environment available at the National Center for PTSD-Clinical Neurosciences Division and Yale are unparalleled. This offers unique opportunity to support Dr. Averill in her transition to independence though exceptional targeted training/mentorship and to conduct a low cost/high yield study with great potential to advance the field, lead to improved outcomes for Veterans, and set a foundation for a successful VA-centric career.