Neurobiology of PTSD During REM Sleep

描述（由申请人提供）：创伤后应激障碍（PTSD）是一种使人衰弱的慢性精神障碍，在军事部署期间和之后对白天功能和睡眠产生不利影响。在随访评估中，创伤暴露后早期发生的主观睡眠抱怨和客观快速眼动（REM）睡眠中断指数与PTSD风险增加有关。噩梦和失眠是创伤后应激障碍的核心特征，独立导致临床结果不佳，并且往往对心理和药物一线干预具有抗性。这些观察结果表明，白天PTSD症状可能部分由REM睡眠特异性机制介导，而这些REM睡眠特异性机制并没有被推荐的一线治疗正常化。然而，快速眼动睡眠期间PTSD的神经生物学相关性仍未被探索。使用激活范式的PTSD清醒神经成像研究表明，杏仁核对恐惧和威胁相关刺激的高度反应，和/或内侧前额皮质对杏仁核自上而下的抑制受损是PTSD的特征。动物研究表明，杏仁核和内侧前额叶皮层是重要的睡眠调节器，通过它们与脑干基底前脑的唤醒促进区，以及与睡眠促进区和参与产生快速眼动睡眠的脑干区域的相互联系。因此，创伤后应激障碍中杏仁核和内侧前额叶皮层神经元活动的变化可能对参与快速眼动睡眠产生的大脑区域的神经元活动产生深远影响。本探索性/发展性研究资助奖（R21）的目标是通过使用最先进的睡眠神经成像[18F]-氟-2-脱氧-d -葡萄糖（FDG）正电子发射断层扫描（PET），探索快速眼动睡眠期间创伤后应激障碍的神经生物学相关性。10名从“伊拉克自由行动”和“持久自由行动”中返回的无药物治疗的军人，符合DSM-IV的PTSD诊断标准，年龄在21 - 45岁之间，参加本研究。他们将在早晨清醒和快速眼动期间根据验证的程序同时完成多导睡眠图（睡眠）和PET研究。10名没有任何精神疾病的年龄匹配的战斗暴露退伍军人将接受同样的评估和PET程序。此外，将收集的PTSD受试者数据与年龄匹配的重度抑郁症患者的档案数据进行比较，以探索PTSD在快速眼动睡眠期间特异性的脑代谢变化。这项探索性研究的发现将为快速眼动睡眠期间PTSD的神经生物学相关性提供新的见解，并将为后续关于PTSD睡眠神经生物学相关性的假设驱动R01建议提供信息。阐明快速眼动睡眠期间PTSD的神经生物学相关性也可能指导未来的努力，以确定睡眠障碍对PTSD和其他应激障碍一线治疗的潜在抵抗机制。公共卫生相关性：快速眼动（REM）睡眠是动物恐惧条件反射的敏感指标，在创伤后应激障碍（PTSD）患者中经常中断。本研究拟通过对从伊拉克自由行动和持久自由行动中返回的创伤后应激障碍军人样本，采用经过验证的睡眠神经成像方法，探讨快速眼动睡眠期间创伤后应激障碍的神经生物学相关性。并比较患有创伤后应激障碍的退伍军人从清醒到快速眼动睡眠的大脑代谢活动变化模式，与年龄匹配的没有创伤后应激障碍的战斗暴露退伍军人和目前患有严重抑郁症的患者的变化模式。这项研究的发现将为创伤后应激障碍在清醒和睡眠期间的神经生物学相关性提供新的见解。

DESCRIPTION (provided by applicant): Posttraumatic stress disorder (PTSD) is a debilitating and often chronic mental disorder that adversely affects daytime functioning and sleep during and after military deployment. Subjective reports of sleep complaints and objective indices of rapid-eye movement (REM) sleep disruption occurring early after trauma exposure are associated with increased risk of PTSD at follow-up assessments. Nightmares and insomnia are core features of PTSD, independently contribute to poor clinical outcomes, and are often resistant to psychological and pharmacological first-line interventions. These observations suggest that daytime PTSD symptoms may be partially mediated by REM sleep-specific mechanisms, and that these REM sleep-specific mechanisms are not normalized by recommended first-line treatments. However, the neurobiological correlates of PTSD during REM sleep remain unexplored. Waking neuroimaging studies in PTSD that used activation paradigms indicate that hyper-responsiveness of the amygdala to fear and threat-related stimuli, and /or impaired top-down inhibition of the amygdala by the medial prefrontal cortex characterize PTSD. Animal studies have shown that the amygdala and the medial prefrontal cortex are important modulators of sleep, via their interconnections with arousal-promoting regions of the brainstem basal forebrain, as well as with sleep-promoting regions and brainstem regions involved in the generation of REM sleep. Thus, changes in neuronal activity of the amygdala and medial prefrontal cortex reported in PTSD may have profound impact on neuronal activity of brain regions involved in REM sleep generation. The goal of this Exploratory/Developmental Research Grant Award (R21) is to explore the neurobiological correlates of PTSD during REM sleep by using state-of-the science sleep neuroimaging [18F]-fluoro-2-deoxy-D-glucose (FDG) positron emission tomography (PET). Ten non-medicated military returnees from Operation Iraqi Freedom and Operation Enduring Freedom, who meet DSM-IV diagnostic criteria for PTSD, and who are between the ages of 21 and 45 years old will participate in this study. They will complete simultaneous polysomnographic (sleep) and PET studies during morning wakefulness and REM according to validated procedures. Ten age-matched combat-exposed military veterans without any psychiatric disorders will undergo the same assessments and PET procedures. In addition, data collected in PTSD subjects will be compared to archival data from age-matched patients with major depression to explore PTSD-specific cerebral metabolic changes during REM sleep. Findings derived from this exploratory study will provide new insights into the neurobiological correlates of PTSD during REM sleep, and will inform a subsequent, hypothesis-driven R01 proposal on the sleep neurobiological correlates of PTSD. Elucidating the neurobiological correlates of PTSD during REM sleep may also guide future efforts to identify the mechanisms underlying resistance of sleep disturbances to first-line treatments of PTSD and of other stress disorders. PUBLIC HEALTH RELEVANCE: Rapid-eye movement (REM) sleep is sensitive index of fear conditioning in animals, and is often disrupted in patients with posttraumatic stress disorder (PTSD). This study proposes to explore the neurobiological correlates of PTSD during REM sleep relative to wakefulness by using validated sleep neuroimaging methods in a sample of military returnees from Operation Iraqi Freedom and Operation Enduring Freedom with PTSD, and to compare patterns of changes in brain metabolic activity from wakefulness to REM sleep in veterans with PTSD to patterns of changes observed in age-matched combat- exposed veterans without PTSD and with patients with current major depression. Findings from the proposed study will provide new insights the neurobiological correlates of PTSD during both wakefulness and sleep.