Novel Neuroimaging and Neuropsychological Methods Sensitive to 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记物的鉴定及神经心理学标记物 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 MTBI的历史。尽管神经成像方法，特别是扩散成像(DMRI)领域的方法仍在继续 为了显示希望，传统的基于扩散张量成像(DTI)的方法有很大的局限性 在白质(WM)中，WM轴突方向和采样的高度异质性 体素内不同的组织类型导致对组织属性的不准确估计。这些限制， 标准和广泛使用的DTI方法所固有的，可能会降低检测轻度形式的DTI敏感性 神经创伤，特别是在关键的、复杂的西医区域，显示出最容易受到mTBI的影响。同样， 认知研究的结果好坏参半，相互矛盾的报告和不清楚的认知结果很可能 云和困惑的临床决策。颅脑损伤的异质性，损伤特征的差异，以及 受影响的退伍军人中认知特征不统一可能是导致敏感度降低和 在通常利用传统手段的可用研究中显示出不一致 神经心理测验分数的比较。事实上，mTBI的指标往往与影像表现不一致， 以及有mTBI病史的退伍军人报告的认知和功能结果。 在拟议的研究中，我们试图应用新的工具和方法来更敏感地检查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。参与者将完成广泛的神经认知评估，并将接受dMRI扫描。我们建议 利用一种新的神经成像方法-一种对标准DTI固有的限制具有健壮性的方法 协议-将能够对脑沟深度附近的WM进行调查，在那里，各种原因的mTBI被认为造成了 在灰白质交界区，考虑到剪切效应，损伤最大。我们将使用dMRI采集 以及将单脉冲和双脉冲梯度dMRI采集通过新的 一种名为联合估计扩散成像(JEDI)的技术，用于整合体素和 亚体素级别。平衡概率(EP)，一种各向异性度量，对复杂的 交叉纤维和部分体积效应，将使用绝地来计算。特别是，我们将审问EP的 体素位于前额沟深度内的灰色和白质之间的边界内。模拟和 组织病理学研究表明，这些区域最容易受到轻微的急性和远端影响 神经创伤所产生的剪切效应是特别有害的，因为不同的组织密度 灰白色边框。其次，鉴于我们最近的工作显示了较新的认知方法对检测的敏感性 的神经心理缺陷，我们将研究内个性化认知表现变异性(IIV)。 作为认知障碍的标志，以增强退伍军人的大脑行为关联 传统的分组比较法。综上所述，拟议的研究提供了一个机会 用一种新的神经成像方法研究易受mTBI影响的脑区白质破坏 (绝地)，进一步评估一个有前途的认知概念(IIV)，它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 在未来的试验中对评估治疗反应有用的生物标志物。

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 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), where 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 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 available studies that have typically leveraged traditional means-based comparisons of neuropsychological test scores. Indeed, indicators of mTBI often fail to align with imaging findings, as well the cognitive and functional outcomes reported by Veterans with histories of mTBI. In the proposed study, we seek to 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 and will undergo an 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 in the gray-white matter border zone. 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 within the border between the gray and WM within frontal the sulcal depths. Simulation and histopathological studies show these regions to be most susceptible to acute and distal effects of mild neurotrauma given 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, 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. Taken together, the proposed study presents an opportunity to investigate white matter disruption within brain regions vulnerable to mTBI using a novel neuroimaging approach (JEDI), further assess a promising cognitive concept (IIV) 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 useful to evaluate treatment response in future trials.