Use of Novel Neuroimaging, Neuropsychological Methods, and Retrograde Memory Test to Detect Cognitive and Cerebral Disruption in Veterans with Mild Traumatic Brain Injury

基于神经影像的轻度神经损伤敏感标志物和神经心理学标志物的鉴定 认知障碍对于解决大量退伍军人的复杂治疗需求至关重要 有轻度创伤性脑损伤(MTBI)史。虽然神经成像方法，特别是在 弥散成像(DMRI)继续显示出良好的前景，传统的弥散成像存在明显的局限性 基于张量成像(DTI)的脑白质成像方法。具体地说，WM的高度异质性 轴突方向和来自体素内不同组织类型的采样导致对 组织属性。标准和广泛使用的DTI方法固有的这些限制可能会削弱DTI 在检测轻微形式的神经损伤方面的敏感性，特别是在关键的、复杂的WM区域 对结核分枝杆菌感染最敏感。同样，在mTBI中的认知研究结果也是喜忧参半，报告相互矛盾 以及不清楚的认知结果，可能会影响和混淆临床决策。TBI的异质性， 受伤特征的差异和受影响退伍军人之间不一致的认知特征可能是原因之一 在利用传统方法的研究中表现出的敏感性和不一致性的降低- 基于对传统神经心理测试分数的比较。事实上，mTBI的指标往往不一致 有mTBI病史的退伍军人报告的影像表现、认知报告和功能结果。 在拟议的研究中，我们将应用新的工具和方法，以便更敏感地检查WM 60例轻度颅脑损伤退伍军人和60例无脑外伤病史的退伍军人的精神障碍和神经心理表现 TBI。参与者将完成一项广泛的神经认知评估，包括一项新的逆行记忆测试 以获取新闻事实，并将接受dMRI扫描。我们建议利用一种新的神经成像方法-一 这对标准DTI协议中固有的限制是强大的-将使近端WM的调查成为可能 在考虑到切变效应的情况下，所有原因的mTBI被认为造成最大损害的沟槽深度 灰质-白质边界。我们将使用dMRI采集和分析方法，将单一和 基于联合估计扩散成像新技术的双脉冲梯度dMRI采集 (绝地)在体素和亚体素水平上整合扩散信息。均衡概率(EP)，A 对交叉纤维的复杂性和部分体积效应更稳健的各向异性度量将是 用绝地武士计算的。特别是，我们将询问驻留在脑沟灰质-白色处的体素的EP 额叶的物质边界。模拟和组织病理学研究表明，这些区域是最 易受轻度神经创伤的急性和远端影响，尤其是剪力作用 由于灰白色边缘的组织密度不同而造成的损害。第二，鉴于我们最近的工作显示 新的认知方法对检测轻度颅脑损伤患者神经心理缺陷的敏感性 认知困难，我们将研究内个性化认知表现变异性(IIV)作为 与传统的认知障碍相比，退伍军人的认知障碍可以增强脑行为的关联性 分组平均数的比较。我们还将管理一个新的认知工具，逆行记忆新闻事件 测试(RM-Net)以确定其对退伍军人的认知缺陷和脑外伤特征是否敏感 慢性颅脑损伤。综上所述，这项拟议的研究提供了一个调查WM中断的机会 使用一种新的神经成像方法(绝地)，进一步评估了一个有希望的 认知概念(IIV)和新的认知测试(RM-Net)可能会改善临床结果的评估 在mTBI后，并检查患有mTBI的退伍军人中IIV和WM中断之间的潜在关联。是这样的 尖端工作可以为进一步了解脑血管疾病的神经生物学基础奠定基础。 有神经创伤的退伍军人的MTBI和持续性脑震荡后症状，并可识别神经影像 生物标志物和认知能力有助于在未来的临床试验中评估治疗反应。

Identification of neuroimaging-based markers sensitive to mild neurotrauma and neuropsychological markers of cognitive disruption is vital toward addressing the complex treatment needs of the large number of Veterans with histories of mild traumatic brain injury (mTBI). Although neuroimaging methods, particularly in the area of diffusion imaging (dMRI) continue to show promise, there are significant limitations in the traditional, diffusion tensor imaging (DTI) based approach in white matter (WM). Specifically, a high degree of heterogeneity of WM axon orientations and sampling from disparate tissue types within a voxel contribute to inaccurate estimates of tissue properties. These limitations, inherent in standard and widely used DTI methods, likely attenuate DTI sensitivity in the detection of mild forms of neurotrauma, particularly in key, complex WM regions shown to be most susceptible to mTBI. Likewise, cognitive research findings in mTBI have been mixed, with conflicting reports and unclear cognitive outcomes that likely cloud and confuse clinical decision-making. The heterogeneity of TBI, differences in injury characteristics, and a non-uniform cognitive profile among affected Veterans likely contribute to the decreased sensitivity and inconsistency shown across studies that have leveraged traditional means- based comparisons of traditional neuropsychological test scores. Indeed, indicators of mTBI often fail to align with imaging findings, cognitive reports, and functional outcomes reported by Veterans with histories of mTBI. In the proposed study, we will apply new tools and methods in order to more sensitively examine WM disruption and neuropsychological performance in 60 Veterans with mTBI and 60 Veterans without a history of TBI. Participants will complete a broad neurocognitive assessment, including a novel test of retrograde memory for news facts, and will undergo a dMRI scan. We propose that leveraging a novel neuroimaging approach—one that is robust to the limitations inherent in standard DTI protocols—will enable investigation of WM proximal to the sulcal depths where all-cause mTBI is thought to inflict the greatest damage given shearing effects at the gray matter-white matter border. We will use dMRI acquisition and analysis methods which combine single and double pulsed field gradient dMRI acquisitions via a novel technique called Joint Estimation Diffusion Imaging (JEDI) to integrate diffusion information at the voxel and subvoxel level. Equilibrium probability (EP), an anisotropy measure that is more robust to the complexities of crossing fibers and partial voluming effects, will be calculated using JEDI. In particular, we will interrogate EP of voxels residing in the sulci at the gray matter-white matter border in the frontal lobe. Simulation and histopathological studies show these regions to be most susceptible to acute and distal effects of mild neurotrauma given the shearing effects that are particularly damaging because of differing tissue densities of the gray-white border. Second, given our recent work showing the sensitivity of newer cognitive methods to detect neuropsychological deficits in mTBI and others with mild cognitive difficulties, we will investigate intra-individuation cognitive performance variability (IIV) as a marker of cognitive disruption in order to enhance brain-behavior associations in Veterans compared to traditional comparison of group means. We will also administer a new cognitive tool, the retrograde memory news events test (RM-NET) to determine if it is sensitive to the cognitive deficits and TBI characteristics in Veterans with chronic mTBI. Taken together, the proposed study presents an opportunity to investigate WM disruption within brain regions vulnerable to mTBI using a novel neuroimaging approach (JEDI), further assess a promising cognitive concept (IIV) and new cognitive test (RM-NET), which may improve the evaluation of clinical outcomes following mTBI, and examine potential associations between IIV and WM disruption in Veterans with mTBI. Such cutting-edge work can lay the foundation for enhanced understanding of the neurobiological underpinnings of mTBI and persisting postconcussive symptoms in Veterans with neurotrauma and may identify neuroimaging biomarkers and cognitive abilities useful to evaluate treatment response in future clinical trials.