Benzodiazepine Receptor in PTSD

描述(申请人提供)：作为伊拉克自由行动(OIF)的一部分，目前有超过15万名士兵部署在伊拉克，返回的OIF士兵中有12%患有创伤后应激障碍(PTSD)。389,100名士兵在越南战争中患上了慢性创伤后应激障碍，需要一生的心理健康护理，失去了工作效率，更多地利用了医疗资源。我们小组和其他人的研究表明，包括海马体、内侧前额叶皮质和杏仁核在内的功能回路发生了变化。然而，这些研究使用了对大脑功能和结构的全球测量；对大脑中调节创伤后应激障碍症状的特定神经化学系统知之甚少。苯二氮类药物系统对大脑功能有抑制作用。在动物身上的研究表明，压力会导致海马区和前额叶皮质内侧的苯二氮卓类受体结合减少。在我们所知的唯一一项关于创伤后应激障碍的神经受体研究中，我们通过单光子发射计算机断层扫描(SPECT)显示患有慢性战斗相关创伤后应激障碍的退伍军人的内侧前额叶皮质苯二氮卓类受体结合减少。我们现在拥有更高分辨率的成像(SPECT为2 mm，而SPECT为13 mm)，并由NCRR资助PI进行高分辨率研究断层扫描(HRRT)，该成像已实施两年。我们已经使用PET HRRT和[C-11]flumazenil对几名患者进行了扫描，[C-11]flumazenil是一种神经受体化合物，与苯二氮卓类受体结合，可用于成像活体人脑中的苯二氮卓类受体结合。创伤后应激障碍的神经生物学研究主要在长期和慢性创伤后应激障碍患者中进行。目前的共识是，创伤后应激障碍的早期阶段不同于慢性和长期的创伤后应激障碍，在疾病变得慢性和坚持不懈之前进行早期干预可能会提供更好的治疗机会。PI在亚特兰大退伍军人管理局的伊拉克自由行动(OIF)创伤计划中工作，每月有1000多名士兵返回佐治亚州，因此有充足的招募来源来研究早期创伤后应激障碍。这是一项先导性研究，旨在测量患有和不患有创伤后应激障碍的退伍军人的苯二氮卓类受体结合，以及在患有和不患有创伤后应激障碍的退伍军人和非战斗暴露的受试者中，用PET HRRT[C-11]氟马西尼检测非战斗暴露受试者的苯二氮卓类受体结合。我们假设与其他两组相比，创伤后应激障碍患者前额叶皮质的苯二氮卓类受体结合减少。我们还将评估苯二氮卓类药物结合预测长期结果的能力。我们预测，在评估后一年，前额叶绑定减少将与慢性创伤后应激障碍的进展相关。次要目的是评估创伤后应激障碍症状与前额叶皮质苯二氮类药物结合的关系。该项目旨在检查患有创伤后应激障碍(PTSD)的伊拉克退伍军人中苯二氮卓类受体的结合情况，并看看这一指标是否可以用于预测哪些归来的退伍军人将发展为慢性PTSD。苯二氮类药物系统在焦虑的调节中起着重要作用。了解苯二氮类药物系统的变化可能会导致对患有创伤后应激障碍的伊拉克战争退伍军人进行新的治疗；该项目还提出了一种新的方法，测试是否可以使用脑成像来预测结果，这可能为识别需要早期干预的退伍军人提供重要工具。

DESCRIPTION (provided by applicant): Over 150,000 soldiers are currently deployed in Iraq as part of Operation Iraqi Freedom (OIF), and 12% of returning OIF soldiers have posttraumatic stress disorder (PTSD). 389,100 soldiers developed chronic PTSD from the Vietnam War, requiring a life-time of mental health care, with a loss of work productivity and greater utilization of health care resources. Research from our group and others showed changes in a functional circuit including hippocampus, medial prefrontal cortex, and amygdala. However these studies used global measures of brain function and structure; little is known about specific neurochemical systems in the brain that mediate PTSD symptoms. The benzodiazepine system mediates an inhibitory effect on brain function. Studies in animals show that stress results in a decrease in benzodiazepine receptor binding in the hippocampus and medial prefrontal cortex. In the only published neuroreceptor study in PTSD to our knowledge we showed a decrease in benzodiazepine receptor binding in medial prefrontal cortex with single photon emission computed tomography (SPECT) in veterans with chronic combat-related PTSD. We now have much higher resolution imaging (2 mm versus 13 mm with SPECT) with a grant funded by the NCRR to the PI for a High Resolution Research Tomograph (HRRT), which has been in place for two years. We have scanned several patients using PET HRRT and [C-11]flumazenil, a neuroreceptor compound that binds to the benzodiazepine receptor and can be used to image benzodiazepine receptor binding in the living human brain. Studies of the neurobiology of PTSD have been primarily performed in patients with long standing and chronic PTSD. There is currently a consensus that early phases of PTSD are different than chronic and long-standing PTSD, and that early interventions before the disorder becomes chronic and unremitting may offer a better opportunity for treatment. The PI is working in the Operation Iraqi Freedom (OIF) Trauma Program at the Atlanta VA, and there over 1000 soldiers returning to the state of Georgia each month, so there are ample sources of recruitment for research on early PTSD. This is a pilot study to measure benzodiazepine receptor binding in returning OIF veterans with and without PTSD, and non combat exposed comparison subjects with PET HRRT [C-11]flumazenil in OIF combat veterans with and without PTSD and non-combat exposed subjects. We hypothesize decreased benzodiazepine receptor binding in the prefrontal cortex in PTSD compared to the other two groups. We will also assess the ability of benzodiazepine binding to predict long-term outcome. We predict decreased prefrontal binding will be associated with progression to chronic PTSD at one year post assessment. Secondary aims are to assess the relationship between PTSD symptoms and benzodiazepine binding in the prefrontal cortex. This project is designed to examine binding of the benzodiazepine receptor in Iraq combat veterans with posttraumatic stress disorder (PTSD) and to see if this measure can be used to predict which returning veterans will progress to the development of chronic PTSD. The benzodiazepine system plays an important role in the regulation of anxiety. Understanding changes in the benzodiazepine system may lead to new treatments for Iraq combat veterans with PTSD; this project also proposes a novel method of testing whether brain imaging can be used to predict outcomes, which could provide an important tool for identifying veterans in need of early intervention.