Neurobiology of Self-Referential Processing in Posttraumatic Stress Disorder Dysfunction and Recovery

项目摘要 创伤后应激障碍（PTSD）是一种与自杀风险增加有关的衰弱性疾病， 辍学，失业，关系不稳定，以及其他精神疾病的发展 紊乱据估计，每年有30亿美元的劳动生产力损失在这种疾病上。的 在美国，大多数人在一生中都会经历创伤性事件，但并不是所有人都会患上PTSD。 有证据表明，遗传和表观遗传因素占这些个体差异的30 - 70%，但 他们发挥这种影响的机制还不很清楚。从长远来看，理解 这些机制将极大地告知如何识别那些处于某些创伤后应激障碍症状群风险中的人， 以及如何为最佳康复效果定制个性化治疗。 以前的研究已经确定了情绪和认知的负面变化，特别是负面的 自我认知的改变（例如，羞耻感，感觉到的无知，无能）作为一个强有力的预测， PTSD风险、状态和严重程度。消极的自我处理与神经相关物的改变有关 自我参照处理（例如，中线皮质结构）和自传体记忆系统（例如， 内侧颞叶结构（MTL）。消极的自我认知也与压力改变有关 下丘脑-垂体-肾上腺（HPA）轴系统的反应生理学。以前的研究在 培训实验室已经确定了一个候选基因，FKBP 5，它参与HPA轴功能的调节， MTL内存系统。FKBP 5的多态性也与PTSD的风险增加有关。 此外，参与HPA轴调节的启动子的DNA甲基化状态，包括HPA轴和HPA轴的启动子。 已知FKBP 5和糖皮质激素受体基因NR 3C 1与PTSD治疗结果相关 和回应。 利用功能磁共振成像方法，本研究旨在检查 创伤经历与消极自我参照加工的神经机制之间的关系， 并确定这种关系在PTSD消退过程中如何变化。此外，这项建议旨在更好地 了解FKBP 5和NR 3C 1的表观遗传特征如何预测，也许会改变， 从创伤后应激障碍（和消极的自我认知）中恢复沿着其神经相关因素。这种理解将 帮助识别对特定的基于经验的PTSD治疗反应最佳的个体， 认知加工疗法，同时进一步将风险的遗传生物标志物与神经中介 PTSD病理学的潜在表型

Project Summary Posttraumatic Stress Disorder (PTSD) is a debilitating disorder associated with increased suicide risk, educational dropout, unemployment, relationship instability, and the development of other psychiatric disorders. An estimated 3 billion dollars are lost in workforce productivity each year to this disorder. The majority of individuals in the US will experience a traumatic event in their lifetime, yet not all develop PTSD. There is evidence that genetic and epigenetic factors account for 30 – 70% of these individual differences, but the mechanisms by which they exert this influence are not well understood. In the long run, understanding these mechanisms will greatly inform both how to identify those at risk for certain clusters of PTSD symptoms, and how to tailor individual treatments for the best recovery outcomes. Previous research has identified negative alterations in mood and cognition, specifically negative alterations in self-cognitions (e.g., shame, perceived worthlessness, incompetence) as a strong predictor of PTSD risk, status, and severity. Negative self-processing is associated with alterations in the neural correlates of self-referential processing (e.g., midline cortical structures) and autobiographical memory systems (e.g., medial temporal lobe structures, MTL). Negative self-cognitions are also associated with altered stress response physiology in the hypothalamic–pituitary–adrenal (HPA) axis system. Previous research in the training lab has identified a candidate gene, FKBP5, that is involved in the modulation of HPA axis function and MTL memory systems. Polymorphisms in FKBP5 are also associated with increased risk for PTSD. Additionally, the DNA methylation status of promoters involved in HPA axis regulation, including those for both FKBP5 and the glucocorticoid receptor gene, NR3C1, is known to be associated with PTSD treatment outcome and response. Using functional magnetic resonance imaging approaches, the present research aims to examine the relationship between traumatic experience and the neural mechanisms of negative self-referential processing, and determine how this relationship changes during PTSD extinction. Also, this proposal aims to better understand how the epigenetic profile of both FKBP5 and NR3C1 predicts, and perhaps changes, in response to recovery from PTSD (and negative self-cognitions) along with its neural correlates. This understanding will help identify individuals who will respond most optimally to a specific empirically based PTSD treatment, Cognitive Processing Therapy, while further connecting genetic biomarkers of risk with neural intermediate phenotypes underlying PTSD symptomatology.