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日间功能和睡眠产生不利影响。创伤暴露后早期发生的睡眠主诉的主观报告和快速眼动（REM）睡眠中断的客观指数与后续评估中PTSD的风险增加相关。夜惊和失眠是PTSD的核心特征，独立地导致不良的临床结果，并且通常对心理和药理学一线干预具有抵抗力。这些观察结果表明，白天的PTSD症状可能部分介导的REM睡眠特异性机制，这些REM睡眠特异性机制没有正常化的建议一线治疗。然而，快速眼动睡眠期间创伤后应激障碍的神经生物学相关性仍未得到探讨。使用激活范式的PTSD清醒神经影像学研究表明，杏仁核对恐惧和威胁相关刺激的高反应性，和/或内侧前额叶皮层对杏仁核的自上而下抑制受损是PTSD的特征。动物研究表明，杏仁核和内侧前额叶皮质是睡眠的重要调节器，通过它们与脑干基底前脑的唤醒促进区域以及与睡眠促进区域和参与REM睡眠产生的脑干区域的相互连接。因此，PTSD中杏仁核和内侧前额叶皮质神经元活动的变化可能对REM睡眠产生相关脑区的神经元活动产生深远影响。这项探索性/发展性研究资助奖（R21）的目标是通过使用科学睡眠神经成像[18 F]-氟-2-脱氧-D-葡萄糖（FDG）正电子发射断层扫描（PET）来探索REM睡眠期间PTSD的神经生物学相关性。从伊拉克自由行动和持久自由行动返回的10名未接受药物治疗的军人将参加本研究，他们符合DSM-IV创伤后应激障碍的诊断标准，年龄在21至45岁之间。他们将根据经验证的程序在早晨清醒和REM期间完成同步多导睡眠图（睡眠）和PET研究。10名年龄匹配的没有任何精神疾病的战斗暴露退伍军人将接受相同的评估和PET程序。此外，将从PTSD受试者中收集的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REM睡眠期间PTSD特异性脑代谢变化。这项探索性研究的结果将为REM睡眠期间PTSD的神经生物学相关性提供新的见解，并将为随后的关于PTSD睡眠神经生物学相关性的假设驱动的R 01提案提供信息。阐明快速眼动睡眠期间创伤后应激障碍的神经生物学相关性也可能指导未来的努力，以确定睡眠障碍对创伤后应激障碍和其他应激障碍一线治疗的抵抗机制。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，并且经常在创伤后应激障碍（PTSD）患者中受到干扰。本研究旨在通过使用经验证的睡眠神经成像方法，对从伊拉克自由行动和持久自由行动返回的患有创伤后应激障碍的军人样本进行研究，以探讨REM睡眠期间与觉醒相关的创伤后应激障碍的神经生物学相关性。并将患有创伤后应激障碍的退伍军人从觉醒到REM睡眠的大脑代谢活动变化模式与年龄匹配的战斗中观察到的变化模式进行比较，没有创伤后应激障碍的退伍军人和目前患有严重抑郁症的患者。这项研究的发现将为清醒和睡眠期间PTSD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.