Neuroimaging Investigation of mTBI and its Potentiation of PTSD in Veterans

 描述(由申请人提供)： 与战斗相关的轻度创伤性脑损伤(MTBI)是导致军人、OEF/OIF/OND退伍军人和公众将军持续身体、认知、情感和行为缺陷的主要原因。最近的研究还表明，mTBI大大增加了患创伤后应激障碍(PTSD)的风险。然而，mTBI的病理生理学机制尚不完全清楚，其长期疗效也存在争议。此外，mTBI增强PTSD发展的可能性的神经机制甚至不清楚。一个重要的因素是，传统的神经成像技术，如MRI和CT，在检测mTBI或PTSD引起的生理异常或预测长期认知和行为结果方面敏感性有限。CT和MRI通常为阴性，即使在mTBI或PTSD患者中也是如此，他们经历了持续的脑震荡后症状(PCS)和/或PTSD症状。该应用程序的主要目标是开发和验证体素静息状态脑磁图(RS-MEG)源成像技术，该成像技术将识别异常并在单个对象的基础上辅助诊断患有和不患有PTSD的mTBI患者。我们还将应用rS-MEG源成像来检查不同频段的PTSD神经回路的异常，并利用rS-MEG来研究mTBI增强PTSD的神经成像基础。我们将研究四组退伍军人(每组50人)：1)被诊断为无创伤后应激障碍的退伍军人(单纯创伤后应激障碍组)；2)被诊断患有创伤后应激障碍但没有创伤后应激障碍的退伍军人(仅创伤后应激障碍组)；3)被诊断为患有创伤后应激障碍和创伤后应激障碍的退伍军人；4)健康对照(HC)退伍军人。具体目标1将开发和验证一种基于单个受试者的体素方式的脑磁慢波(增量频段，1-4赫兹)源成像方法，通过检测常规MRI/CT无法看到的神经元异常来辅助mTBI的诊断。我们将使用来自HC老兵的数据建立RS-MEG慢波成像方法的体素标准数据库，并通过交叉验证不属于数据库的HC样本中的MEG数据来评估特异性。我们将研究一种基于自举的非参数方法，以将我们的分析扩展到不满足所需高斯分布的体素。然后，我们将检查脑磁慢波源的阳性检测率(即灵敏度)和重测可靠性 单纯mTBI组和合并mTBI-PTSD组的退伍军人损伤的影像检测方法。还将在群体水平上研究异常脑磁图慢波产生的空间分布，以确定特别容易受到mTBI影响的大脑区域。《特定目标2》将使用RS-MEG源成像来检查创伤后应激障碍神经回路的异常，并研究mTBI增强创伤后应激障碍发展的神经基础。在单纯创伤后应激障碍组和合并创伤后应激障碍组中，我们将检查与情绪处理神经回路功能障碍(即杏仁核、腹内侧前额叶皮质(VmPFC)和海马体)相关的创伤后应激障碍模型是否可以解释不同频段的基于电磁的RS-MEG源成像技术检测到的异常。我们还将研究PTSD神经回路高频段异常脑磁图信号与mTBI并存的异常脑磁图慢波产生的关系。特定目标3将使用体素脑磁源成像来检查患有mTBI和/或创伤后应激障碍的退伍军人的临床症状和认知障碍的神经生理学基础。该项目的成功将极大地改进基于神经影像的技术，以有效地诊断mTBI，并促进对mTBI的神经生物学、神经心理学和神经精神病学效应之间关系的理解，这些都是本申请申请的重点。

 DESCRIPTION (provided by applicant): Combat-related mild Traumatic brain injury (mTBI) is a leading cause of sustained physical, cognitive, emotional, and behavioral deficits in military service members, OEF/OIF/OND veterans, and generals public. Recent studies have also showed that mTBI substantially increases the risk of developing post-traumatic stress disorder (PTSD). However, the pathophysiology of mTBI is not completely understood and its long-term effects are controversial. Furthermore, the neuronal mechanisms for mTBI potentiating the likelihood of PTSD development are even less clear. A significant factor has been that conventional neuroimaging techniques such as MRI and CT have limited sensitivity in detecting physiological abnormalities caused by mTBI or PTSD, or predicting long-term cognitive and behavioral outcomes. CT and MRI are generally negative even in mTBI or PTSD patients who experience persistent post-concussive symptoms (PCS) and/or PTSD symptoms. A main goal of this application is to develop and validate a voxel-wise resting-state magnetoencephalography (rs-MEG) source imaging technique that will identify abnormalities and assist in the diagnosis of mTBI patients with and without PTSD on a single-subject basis. We will also apply rs-MEG source imaging to examine the abnormality in PTSD neurocircuitry in different frequency bands, and to use rs-MEG to investigate the neuroimaging basis of mTBI's potentiation of PTSD. We will study four groups of veterans (N=50 per group): 1) veterans diagnosed with mTBI without PTSD (mTBI-only group); 2) veterans diagnosed with PTSD without mTBI (PTSD-only group); 3) veterans diagnosed with comorbid mTBI and PTSD; 4) healthy control (HC) veterans. Specific Aim 1 will develop and validate a single-subject based, voxel-wise, MEG slow-wave (delta-band, 1-4 Hz) source imaging approach for assisting in mTBI diagnosis by detecting neuronal abnormalities not visible with conventional MRI/CT. We will establish a voxel-wise normative database for the rs-MEG slow-wave imaging approach using data from HC veterans, and assess specificity by cross-validating MEG data in a sample of HCs that are not part of the database. A non-parametric method based on bootstrapping will be studied to expand our analysis to voxels that fail to meet the required Gaussian distribution. We will then examine the positive detection rate (i.e., sensitivity) and test-retest-reliability of the MEG slow-wave source imaging approach for detecting injuries in veterans from mTBI-only and comorbid mTBI-PTSD groups. The spatial distribution of the abnormal MEG slow-wave generation will also be studied at the group level to identify the brain areas that are particularly vulnerable to mTBI. Specific Aim 2 will use rs-MEG source imaging to examine abnormalities in PTSD-based neurocircuitry and to investigate the neural basis of mTBI's potentiation of PTSD development. In PTSD-only and comorbid groups, we will examine whether a model of PTSD associated with dysfunction in emotion processing neurocircuitry (i.e., amygdala, ventro-medial prefrontal cortex (vmPFC), and hippocampus), can account for abnormalities detected by electromagnetic-based rs-MEG source imaging techniques for different frequency bands. We will also study the relationship between abnormal MEG signals in high-frequency bands from PTSD neurocircuitry and co-existing abnormal MEG slow-wave generation due to mTBI. Specific Aim 3 will use voxel-wise MEG source imaging to examine the neurophysiological basis of clinical symptoms and cognitive impairments in veterans with mTBI and/or PTSD. The success of this project will significantly improve neuroimaging-based techniques for efficient diagnosis of mTBI, and advance the understanding of the relationships among neurobiological, neuropsychological, and neuropsychiatric effects of mTBI, which are the foci of this Request for Applications.