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）是一种慢性和致残性疾病，可在暴露于创伤事件后发生。虐待儿童是PTSD的主要原因之一。回避、过度觉醒和侵入性回忆事件的症状可以持续到成年。虽然女性患PTSD的可能性是男性的两倍多，但人们对PTSD风险和恢复力性别差异的神经生物学因素知之甚少。杏仁核是大脑边缘系统的一个区域，在评估心理社会刺激的显著性方面起着关键作用。使用血氧水平依赖（BOLD）功能性磁共振成像（fMRI）的研究发现，PTSD患者对恐惧面孔的照片表现出夸大的杏仁核反应。催产素（OT）是一种神经肽，可以促进社会联系，信任和平静。鼻内给药OT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，OT系统对早期生活经历的敏感性也存在性别差异，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。本提案的广泛和长期目标是提供初步数据，指导R 01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的病理生理学，2）边缘脑活动神经肽能调节的性别差异，以及3）这些差异如何赋予PTSD的风险和恢复力。为了实现这些目标，我们提出了三个具体目标。具体目标1：比较杏仁核对与儿童创伤相关的PTSD男性（n=15）和女性（n=15）之间可怕面孔的反应;以及经历过儿童创伤的无PTSD（无其他主要轴I障碍）的弹性男性（n=15）和女性（n=15）。具体目标2：比较鼻内OT与安慰剂对四个研究组之间杏仁核对恐惧面孔的反应。具体目标3：探讨血浆催产素水平和杏仁核反应之间的相互作用。所有受试者的儿童期创伤问卷评分为中度至重度，且儿童期创伤史符合PTSD诊断统计手册-IV标准A。杏仁核反应将使用BOLD功能磁共振成像测量，所有女性将在月经周期的早期到中期卵泡期进行扫描。鼻内OT或安慰剂将在两次扫描前以双盲、交叉设计给药。将在给药前采集血浆OT样本。男性和女性PTSD患者之间的比较将提供对PTSD风险的神经生物学相关性的性别差异的深入了解。有和没有PTSD的虐待儿童史的男性和女性之间的比较将提供关于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.