White Matter Damage in Subconcussive Blast Exposure

描述（由申请人提供）：最近在伊拉克和阿富汗冲突中的军事人员暴露于炸弹和其他装置产生的爆炸力（初爆）是常见的。临床医生和专家已经建立了诊断轻度创伤性脑损伤的最低症状标准，包括感觉改变（例如感到眩晕和困惑）、意识丧失（LOC）和暴露于爆炸或撞击后的失忆症。弥散张量成像（DTI）证实这些症状与白质损伤有关。然而，对无症状暴露于重复爆炸后白质的研究很少。与此相关，最近的几项研究报告了优秀运动员在没有脑震荡症状的情况下反复撞击后的白质损伤。我们的目的是评估近期未出现TBI（次震荡爆炸暴露）临床症状的初级爆炸暴露军人的脑白质损伤和认知功能障碍。爆炸动物模型支持白质损伤的系统机制，如神经炎症和神经毒性过程，这些过程可能导致弥漫性和广泛的组织损伤，在受影响个体中具有空间异质性。我们将使用量化白质损伤的空间异质性损伤的方法，这些方法比传统的体向或感兴趣区域方法更敏感。我们预计，在次震荡爆炸暴露组和轻度脑外伤组中，白质损伤将明显大于未爆炸暴露的受试者。我们将使用机器学习方法来推广关于轻度TBI临床病例中白质大小的知识。然后，我们将测试这些知识（验证），以对新病例做出诊断预测，特别是对缺乏TBI临床诊断的爆炸暴露个体。我们将评估白质空间分布损伤与其他指标之间的关系，包括灰质体积、静息状态功能连通性、认知表现以及创伤后应激障碍和抑郁症的症状。如果我们证实了我们的关键预测，即组织损伤、认知障碍和生活功能质量的改变是由次震荡冲击波暴露引起的，那么我们就有理由用基于神经影像学的诊断标准来增强基于临床症状的轻度TBI诊断方法。结果进一步表明，在没有对创伤性脑损伤进行急性临床诊断的情况下，许多有慢性症状（如情绪症状、疲劳、注意力不集中）的爆炸暴露个体被错误地诊断为其他疾病（如抑郁症、创伤后应激障碍）。大规模验证我们的方法，包括将其转化为平民的次震荡暴露（例如体育运动），将证明在临床环境中实施先进的扩散成像和分析技术。

DESCRIPTION (provided by applicant): Exposure to explosive forces (primary blast) emanating from bombs and other devices is common in recent military personnel from the conflicts in Iraq and Afghanistan. Clinicians and experts have established minimum symptom criteria for diagnosis of mild TBI including altered sensorium (e.g. feeling dazed and confused), loss of consciousness (LOC), and amnesia following exposure to blast or impact. Diffusion Tensor Imaging (DTI) has demonstrated that these symptoms are associated with white matter damage. However, little attention has been given to investigating white matter following asymptomatic exposure to repetitive blast. Relatedly, several recent studies report white matter damage in elite athletes following repetitive impacts despite the absence of concussive symptoms. Our goal is to assess damage to white matter and impairments in cognitive performance in recent military personnel with primary blast exposure without clinical symptoms of TBI (subconcussive blast exposure). Animal models of blast support systemic mechanisms of white matter damage such as neuroinflammatory and neurotoxic processes that are likely to result in diffuse and widespread tissue injury that is spatially heterogeneous among affected individuals. We will use methods for quantifying spatially heterogeneous damage to white matter damage that are more sensitive than conventional voxelwise or region-of-interest approaches. We anticipate comparable white matter damage in a subconcussive blast exposed group and a mild TBI group that will be significantly greater than in blast- unexposed subjects. We will use a machine learning approach to generalize knowledge about the magnitude of white matter in clinically established cases of mild TBI. We will then test this knowledge (validation) to make diagnostic predictions for new cases, particularly blast-exposed individuals, who lack a clinical diagnosis of TBI. We will assess the association between spatially distributed injury to white matter and other measures including, gray matter volume, resting-state functional connectivity, cognitive performance, and symptoms of PTSD and depression. If we confirm our key predictions that tissue damage, cognitive impairment, and functional quality of life changes result from subconcussive blast exposure, it would argue for an augmentation of the established approach for making clinical symptom-based diagnoses of mild TBI with neuroimaging-based diagnostic criteria. The results would further imply that many blast-exposed individuals with chronic symptoms (e.g. mood symptoms, fatigue, inattention) are being incorrectly diagnosed with other conditions (e.g. depression, PTSD) in the absence of acute clinical diagnosis of TBI. Validation of our approach on a large scale including translation to civilian subconcussive exposure (e.g. sports), would argue for implementing advanced diffusion imaging and analytic techniques in the clinical setting.