Neurobiology of PTSD During REM Sleep

描述(申请人提供)：创伤后应激障碍(PTSD)是一种衰弱的、通常是慢性的精神障碍，在军事部署期间和之后对白天的功能和睡眠产生不利影响。创伤暴露后早期出现的睡眠抱怨的主观报告和快速眼动(REM)睡眠中断的客观指标在后续评估中与创伤后应激障碍的风险增加相关。噩梦和失眠是创伤后应激障碍的核心特征，独立地导致不良的临床结果，并且往往对心理和药物一线干预具有抵抗力。这些观察表明，白天的创伤后应激障碍症状可能部分是由REM睡眠特有的机制介导的，而这些REM睡眠特有的机制并没有被推荐的一线治疗正常化。然而，快速眼动睡眠期间创伤后应激障碍的神经生物学相关性仍未被探索。创伤后应激障碍的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反应性和/或内侧前额叶皮质对杏仁核的自上而下的抑制是创伤后应激障碍的特征。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，它们通过与脑干基础前脑的促进觉醒区域以及参与REM睡眠产生的促进睡眠区域和脑干区域相互联系。因此，在创伤后应激障碍中报道的杏仁核和内侧前额叶皮质神经元活动的变化可能对参与快速眼动睡眠产生的脑区的神经元活动产生深远的影响。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)来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非药物治疗的军人，他们符合DSM-IV创伤后应激障碍诊断标准，年龄在21岁到45岁之间，将参与这项研究。他们将根据经过验证的程序，在早晨清醒和快速眼动期间同时完成多导睡眠监测(睡眠)和正电子发射断层扫描(PET)研究。10名年龄匹配、暴露在战斗中、没有任何精神障碍的退伍军人将接受同样的评估和PET手术。此外，在创伤后应激障碍受试者中收集的数据将与年龄匹配的重度抑郁症患者的档案数据进行比较，以探索快速眼动睡眠期间创伤后应激障碍特有的大脑代谢变化。这项探索性研究的结果将为快速眼动睡眠中创伤后应激障碍的神经生物学相关性提供新的见解，并将为随后的假设驱动的R01提案提供关于创伤后应激障碍的睡眠神经生物学相关性的信息。阐明快速眼动睡眠中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，以确定睡眠障碍抵抗创伤后应激障碍和其他应激障碍一线治疗的潜在机制。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)患者中经常受到干扰。这项研究建议通过在伊拉克自由行动和患有创伤后应激障碍的持久自由军事归来的军人样本中使用有效的睡眠神经成像方法来探索快速眼动睡眠期间创伤后应激障碍与清醒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观察到的变化模式进行比较。这项拟议研究的发现将提供新的见解，即在清醒和睡眠期间创伤后应激障碍的神经生物学关联。

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.