Structural and functional neural alterations in suicidality among Veterans with PTSD

项目摘要/摘要 研究：美军退伍军人自杀率是平民自杀率的两到六倍 对口单位。自杀意念(SI)和自杀未遂(SA)是自杀死亡的主要前兆，发生在 比死亡频率高得多，造成巨大的个人和社会负担，但相对 人们对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中的标志性伤势。两者的高共患率和夸大的患病率 退伍军人中的自杀和创伤后应激障碍，突出了促进对共同和 区分这两者之间的神经机制。与创伤和应激相关的突触丢失和 大脑区域内固有连接网络的大规模变化与情绪、认知和 行为在SI/SA和创伤后应激障碍文献中都存在。然而，实地工作的一个主要障碍是缺乏 创伤后应激障碍队列中SI/SA的神经生物学研究。初步数据支持这样一种观点，即 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。具体地说，患有创伤后应激障碍的退伍军人似乎支持SI 有突触改变的神经特征，不同于创伤后应激障碍症状的严重程度、抑郁和年龄。 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是 对96名退伍军人进行了3组研究(n=32/组)：单纯创伤后应激障碍；创伤后应激障碍+SI；创伤后应激障碍+SA。健壮， 将使用(A)证明突触改变的独特模式和位置的补充证据 全脑顶端结构磁共振成像(MRI)测量皮质厚度，(B) 静息状态功能连通性磁共振成像(RS-fcMRI)，用于测量全球大脑连通性(GBC)，以及(C) 弥散磁共振成像测量弥散GBC(DGBC)，这是微结构架构和连通性的测量。 退伍军人将在年龄、性别、创伤后应激障碍症状严重程度和创伤性脑损伤病史方面进行匹配。本研究 可在退伍军人自杀和退伍军人事务部的两个操作优先领域确定治疗目标的生物标记物 创伤后应激障碍，告知新药开发有效的药理干预措施，并最终促进 为缓解数百万人--老兵和平民--的痛苦而让路 自杀。 候选人：埃弗里尔博士表现出了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，长达十多年。短期目标包括收到 CDA-2通过严格的培训目标提高她的专业知识(重点是 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 国家创伤后应激障碍中心-临床神经科学部(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调查， 诊断、确定SI/SA风险和恢复能力的生物标记物，以及治疗选择。 环境：基础设施、导师的质量、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以退伍军人为重点的研究环境 分部和耶鲁是无与伦比的。这提供了独特的机会来支持Averill博士过渡到 通过特殊的有针对性的培训/指导独立，并进行低成本/高收益的研究 具有推动这一领域的巨大潜力，为退伍军人带来更好的结果，并为 以退伍军人管理局为中心的成功职业生涯。

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.