Linking Injury Severity to Brainstem White Matter Integrity: A Tractography Study

尽管绝大多数头部损伤被归类为轻到中度，但许多患者报告说 持续的神经精神症状，尽管临床神经成像正常。一般来说，创伤性脑损伤 (TBI)很难检测和诊断，而且问题的范围大大复杂化，因为我们 对神经损伤的神经病理学和后遗症知之甚少。从历史上看，脑干一直是 在TBI的背景下，这是一个特别脆弱的结构。然而，不幸的是，据我们所知， 目前还没有与伤害严重程度变量(例如，意识丧失[LOC]~创伤后)相关的数据 健忘症[PTA]~冲击波的数量和频率)以及通常经历的脑震荡后 症状(PCS~例如，睡眠困难、平衡/协调问题、头晕、耳鸣)到实际病理 在人脑中，这可能与无法将微小的关键白质束可视化直接相关 在脑干内，一个对呼吸功能至关重要的重要结构，心血管 规则，以及睡眠和警觉。尽管弥散张量成像(DTI)被认为可以帮助 常规影像技术在评价颅脑损伤患者时存在的不足 关注脑干白质完整性和损伤严重程度的全面、多学科的脑外伤研究 标记物，而对这一群体的研究极其有限。例如，到目前为止，全脑 人类的DTI数据是使用成像有限的多层切片采集技术收集的 决议用非常薄的切片进行测量，禁止研究小白质束和 颅内深层结构(即脑干)。事实上，脑干DTI在脑损伤中的研究很少，而且还没有 评估了重要的损伤严重程度变量和持久的神经精神症状之间的关系 构成了创伤后综合症。 尽管在脑损伤方面的DTI研究很少，但动物和临床研究以及 我们自己的试验数据支持这项建议-为DTI作为潜在的 颅脑损伤相关脑白质损伤的生物标志物。因此，我们建议使用一种新开发的方法(Hardi~ 在建议书的方法部分中描述的)与高空间分辨率的解剖图像相结合 以帮助识别和可视化可能代表脑外伤解剖基础的重要脑干束。 使用这种方法，毫米切片和概率脑束造影术允许更薄的脑干束 已识别，特别是在低各向异性地区。因此，在190名退伍军人和战斗控制组(轻度到中度)中 TBI：120~战斗和非战斗暴露NC：70)，我们将在一本小说的背景下使用DTI跟踪技术， 尖端成像序列和解析方法，以充分分割和适当地可视化关键 脑干白质束及其与重要损伤严重程度变量和PCS的关系 各种损伤机制的症状(冲击伤与钝力伤)。主要目标还将检查是否 以及其他重要的损伤变量(例如，爆炸次数和邻近程度)如何改变 在这个脆弱的人群中，白质完整性和PCS症状。据我们所知，我们的建议 代表了第一个完全分割并正确可视化关键脑干白质束的人，检查 脑干白质完整性与神经损伤机制的关系及其与重要损伤的关系 严重性和PCS变量。我们期望这一发现将提高我们对弥散张量成像临床应用的认识。 确定轻到中度脑损伤的特定脑干白质改变，将提供新的 关于不同损伤机制对组织中已显示的脑区的影响的信息 研究特别容易受到脑损伤的影响。显然，损伤严重程度特征和 持续的PCS症状，典型地与神经解剖学的植物精神起源的体征有关 底物将对这个相对较新的领域产生非常重要的影响。

Although the vast majority of all head injuries are classified as mild to moderate, many patients report persistent neuropsychiatric symptoms, despite normal clinical neuroimaging. Generally, traumatic brain injury (TBI) is difficult to detect and diagnose, and the scope of the problem is compounded significantly given that we know very little about the neuropathology and sequelae of neurotrauma. Historically, the brainstem has been implicated as a particularly vulnerable structure in the context of TBI. However, unfortunately, to our knowledge, there are no existing data relating injury severity variables (e.g., loss of consciousness [LOC]~ post-traumatic amnesia [PTA]~ number and frequency of blasts) as well as commonly experienced post-concussive symptoms (PCS~ e.g., sleep difficulties, balance/coordination problems, dizziness, tinnitus) to actual pathology in the human brain, and this could be directly related to the inability to visualize small, critical white matter tracts within the brainstem, a vital structure that is critically important for respiratory function, cardiovascular regulation, and sleep and alertness. Although it is thought that diffusion tensor imaging (DTI) can help address the shortcomings of conventional imaging techniques in the evaluation of patients with TBI, there is a lack of comprehensive, multidisciplinary TBI studies focusing on brainstem white matter integrity and injury severity markers, and research examining this population has been extremely limited. For example, to date, whole-brain DTI data in humans have been collected using multislice acquisition techniques that have limited imaging resolution to perform measurements with very thin slices, prohibiting the study of small white matter tracts and deep intracranial structures (i.e., brainstem). Indeed, there are very few brainstem DTI studies in TBI, and none have assessed associations to important injury severity variables and enduring neuropsychiatric symptoms comprising the posttraumatic syndrome. Despite a paucity of DTI studies in TBI, promising findings from animal and clinical studies-as well as our own pilot data in support of this proposal-provide preliminary support for the potential use of DTI as a biomarker of TBI-related white matter injury. We thus propose to use a newly developed methodology (HARDI~ described in the Methods section of the proposal) coupled with high spatial-resolution anatomic images in order to help identify and visualize important brainstem tracts that may represent the anatomical substrates of TBI. Using this approach, millimetric slices and probabilistic tractography allow thinner brainstem tracts to be identified, especially within low anisotropic areas. Thus, in 190 veterans and combat controls (mild to moderate TBI: 120~ combat and non-combat exposed NC: 70), we will employ DTI tractography in the context of a novel, cutting edge imaging sequence and analytic approach in order to fully segment and properly visualize critical brainstem white matter tracts and relate white matter integrity to important injury severity variables and PCS symptoms across mechanism of injury (blast versus blunt force TBI). Primary aims will also examine whether and how other important injury variables (e.g., number and proximity of blasts) modify the relationship between white matter integrity and PCS symptoms in this vulnerable population. To our knowledge, our proposal represents the first to fully segment and properly visualize critical brainstem white matter tracts, examine brainstem white matter integrity by mechanism of neurotrauma, and relate DTI indices to important injury severity and PCS variables. We expect that findings will advance our knowledge of the clinical utility of DTI in identifying specific brainstem white matter changes in mild to moderate TBI, and they will provide novel information about the effects of differing mechanisms of injury on brain regions that have been shown in tissue studies to be particularly vulnerable to the effects of TBI. Clearly, linkages of injury severity characteristics and enduring PCS symptoms typically associated with vegetative signs of psychiatric origin to a neuroanatomic substrate would have very important implications for this relatively new field.