Exploring sex differences in the neural correlates of PTSD: Impact of oxytocin

描述（由申请人提供）：创伤后应激障碍（PTSD）是一种慢性和致残障碍，可能在暴露于创伤性事件后发生。虐待儿童是导致PTSD的主要原因之一。回避、过度觉醒和对事件的侵入性回忆的症状会持续到成年。尽管女性患PTSD的可能性是男性的两倍多，但人们对PTSD风险和复原力的性别差异背后的神经生物学因素知之甚少。杏仁核是大脑边缘区域，在评估社会心理刺激的显著性方面起着关键作用。使用血氧水平依赖（BOLD）功能磁共振成像（fMRI）的研究发现，PTSD患者对恐惧面孔的图片表现出夸张的杏仁核反应。催产素（OT）是一种神经肽，能促进社会联系、信任和冷静。鼻内注射OT可减少杏仁核对恐惧面孔的反应。值得注意的是，在杏仁核和OT系统之间的相互作用中发现了性别二态性。此外，还发现了性别对早期生活经历的敏感性差异，这表明OT可能是一个关键的神经生物学因素，强调了PTSD风险和恢复力的性别差异。本研究的长期目标是提供初步数据，以指导R01应用程序探索1)神经肽和边缘脑活动之间的相互作用如何参与PTSD的病理生理；2)边缘脑活动的神经肽能调节的性别差异；3)这些差异如何赋予PTSD的风险和恢复能力。为了实现这些目标，我们提出了三个具体目标。具体目标1：比较儿童期创伤相关PTSD患者男性（n=15）和女性（n=15）的杏仁核对恐惧面孔的反应；经历过童年创伤的无创伤后应激障碍（无其他主要I轴障碍）的适应力强的男性（n=15）和女性（n=15）。具体目标2：比较四个研究组中鼻内OT与安慰剂对杏仁核对恐惧面孔的反应。具体目的3：探讨血浆催产素水平与四个研究组之间杏仁核反应之间的相互作用。所有受试者将在儿童创伤问卷中获得中等到严重的分数，并有符合创伤后应激障碍诊断统计手册iv标准a的儿童创伤史。杏仁核反应将使用BOLD功能磁共振成像进行测量，所有女性将在月经周期的卵泡早期到中期进行扫描。鼻内OT或安慰剂将采用双盲交叉设计，在两次扫描之前进行。血浆OT样本将在给药前收集。对男性和女性PTSD患者的比较将有助于深入了解PTSD风险相关神经生物学的性别差异。对有和没有创伤后应激障碍的儿童虐待史的男性和女性进行比较，将提供有关心理弹性神经基质性别差异的关键信息。

DESCRIPTION (provided by applicant): Posttraumatic stress disorder (PTSD) is a chronic and disabling disorder that can occur following exposure to a traumatic event. Child abuse is one of the leading causes of PTSD. Symptoms of avoidance, hyperarousal, and intrusive recollections of the event can persist into adulthood. Although, women are more than twice as likely as men to develop PTSD, little is known about the neurobiological factors that underlie sex differences in risk and resilience to PTSD. The amygdala is a limbic brain region that plays a critical role in evaluating the salience of psychosocial stimuli. Studies using blood oxygen level dependent (BOLD) functional magnetic resonance imaging (fMRI) have found that individuals with PTSD show exaggerated amygdala responses to pictures of fearful faces. Oxytocin (OT) is a neuropeptide that promotes social bonding, trust and calmness. Intranasal administration of OT reduces amygdala responding to fearful faces. Of note, sexual dimorphisms in the interaction between the amygdala and the OT system have been found. In addition, sex differences in the sensitivity of the OT system to early life experiences have also been found and suggest that OT may be a critical neurobiological factor that underscores sex differences in risk and resilience to PTSD. The broad and long-term objectives of this proposal are to provide preliminary data that will guide an R01 application exploring 1) how interactions between neuropeptides and limbic brain activity are involved in the pathophysiology of PTSD 2) sex differences in neuropeptidergic regulation of limbic brain activity and 3) how these differences confer risk and resilience to PTSD. To meet these objectives we have proposed three specific aims. Specific Aim 1: To compare amygdala responding to fearful faces between men (n=15) and women (n=15) with PTSD related to childhood trauma; and resilient men (n=15) and women (n=15) without PTSD (free of other major Axis I disorders) who have experienced childhood trauma. Specific Aim 2: To compare intranasal OT versus placebo on amygdala responding to fearful faces between the four study groups. Specific Aim 3: To explore the interaction between plasma levels of oxytocin and amygdala responding between the four study groups. All subjects will have moderate to severe scores on the Childhood Trauma Questionnaire and a history of a childhood trauma that meets the Diagnostic Statistical Manual-IV Criterion A of PTSD. Amygdala responding will be measured using BOLD fMRI and all of the women will be scanned during the early to mid-follicular phase of their menstrual cycle. Intranasal OT or placebo will be administered in a double-blind, crossover design before each of two scanning sessions. Plasma OT samples will be collected prior to medication administration. Comparisons between men and women with PTSD will provide insight into sex differences in the neurobiologic correlates of risk in PTSD. Comparisons between men and women with a history of child abuse with and without PTSD will provide critical information regarding sex differences in the neural substrates of resilience.