Attentional Dysfunction and Recovery in Traumatic Brain Injury (TBI)

描述（由申请人提供）：最近的几项荟萃分析表明，轻度创伤性脑损伤（mTBI）的半急性期与注意力、记忆力和执行功能的轻度认知缺陷相关。然而，常规临床成像（MRI和CT）扫描通常对这些急性认知缺陷的神经元病理学以及大多数（80-90%）患者随后的恢复过程不敏感。我们目前资助的NIH工作调查了通常与mTBI相关的注意力缺陷，包括半急性（损伤后3周内）和更慢性的损伤阶段（3-5个月），使用神经心理学测试结合广泛的磁共振成像（MRI）电池。具体来说，我们正在使用功能性MRI（FMRI），扩散张量成像（DTI）和质子磁共振波谱（1H-MRS）来量化mTBI后发生的认知和神经生理变化。我们的初步数据（16例mTBI患者和16例匹配的对照组）表明，在mTBI的半急性期，存在轻微的认知缺陷、代谢异常和血流动力学紊乱。然而，我们目前的多模态成像方案缺乏神经元功能的直接测量，这将提供有关这些代谢和血管异常的潜在机制的关键信息。因此，该竞争性修订（通知号NOT-OD-09-058; NIH宣布恢复法案基金用于竞争性修订申请的可用性）寻求添加脑磁图（MEG）作为神经元集合同步放电的直接测量（即，神经元电生理学），以补充我们正在进行的NIH资助的工作。27名特征良好的轻度TBI患者和15名非颅脑创伤对照将在损伤后3周和3-5个月接受神经心理学测试和广泛的成像组合。参与者将被要求在收集FMRI（目前资助的工作）和MEG（竞争性修订）数据期间执行空间定向和静息状态任务。在所有的成像方式中，MEG和FMRI的信息组合可能是最协同的，因为每种方式都提供了更高的空间（FMRI）和时间（MEG）分辨率。将通过将新的多变量统计技术（联合独立成分分析; J-ICA）应用于所获得的数据来直接检验这一假设。J-ICA利用每个单独成像模式中存在的独特信息的效用尚未被研究，更重要的是，它也没有能力告诉mTBI后大脑内何时（MEG）和何处（FMRI）发生病理反应。本提案的影响和创新体现在几个层面。最重要的是，它解决了我们知识中的一个重要空白，即制定能够捕获mTBI后发生的动态神经变化的标准化方案。虽然神经影像学技术本身不太可能提供独立的客观诊断，但它们可能会提供对鉴别诊断和预测未来结果都很重要的增量信息。其次，MEG的加入确保我们直接测量神经元以及代谢（1H-MRS）和血管（FMRI）反应。这是至关重要的，因为坦率的神经元功能障碍可能会导致我们目前在半急性损伤的mTBI患者中观察到的代谢和血管异常。MEG提供了精确的时间分辨率，可以评估病理性神经元反应发生的时间（毫秒级）（M50 vs M100 vs M300）。到目前为止，只有少数研究利用MEG研究mTBI，并且没有在损伤的半急性阶段在脑损伤人群中进行。最后，结合这些神经影像学方式，在半急性和慢性阶段的轻度TBI的纵向研究将为TBI的人类恢复模型提供基础。虽然目前存在动物模型，但这些模型无法替代人类认知固有的复杂性。 公共卫生相关性：仅在美国，每年就有大约120万例轻度创伤性脑损伤（mTBI）病例，导致估计560亿美元的成本。mTBI的症状可以从严重的身体和精神残疾到注意力，注意力或情绪控制的微妙问题。认知困难通常出现在受伤的前几周，但通常在大多数患者（约80-90%）受伤后3-5个月缓解。理解这些认知困难的第一步是开发对神经元损伤和随后的恢复过程敏感的生物标志物，这不仅对mTBI至关重要，而且对更严重形式的TBI也至关重要。然而，在轻度TBI的急性或慢性阶段，神经病理学基础认知缺陷通常是微妙的，难以用常规成像技术检测。我们目前资助的NIH磁共振成像（MRI）技术工作提供了mTBI半急性期异常代谢和血管反应的初步证据，我们也证明了这与认知功能障碍相关。这项竞争性修订将在我们目前资助的方案中增加同步神经元放电的直接测量（脑磁图; MEG）。高分辨率空间（FMRI）和时间（MEG）信息的融合，加上随着时间的推移行为和神经心理学的措施，将提供前所未有的洞察人类mTBI恢复模型的基础。

DESCRIPTION (provided by applicant): Several recent meta-analyses suggest that the semi-acute stage of mild traumatic brain injury (mTBI) is associated with mild cognitive deficits in attention, memory and executive functioning. However, routine clinical imaging (MRI and CT) scans are usually insensitive to both the neuronal pathology underlying these acute cognitive deficits as well as to the subsequent recovery process that occurs in the majority (80-90%) of patients. Our currently funded NIH work investigates attentional deficits that are commonly associated with mTBI both semi-acutely (within 3 weeks of injury) and in the more chronic injury phase (3-5 months) using neuropsychological testing coupled with an extensive magnetic resonance imaging (MRI) battery. Specifically, we are using functional MRI (FMRI), diffusion tensor imaging (DTI) and proton magnetic resonance spectroscopy (1H-MRS) to quantify the cognitive and neurophysiological changes that occur following mTBI. Our preliminary data (16 mTBI patients and 16 matched controls) suggest subtle cognitive deficits, metabolic abnormalities and hemodynamic disturbances during the semi-acute stages of mTBI. However, our current multimodal imaging protocol lacks a direct measure of neuronal functioning, which would provide crucial information regarding potential mechanisms underlying these metabolic and vascular abnormalities. Therefore, this competitive revision (Notice Number NOT-OD-09-058; NIH Announces the Availability of Recovery Act Funds for Competitive Revision Applications) seeks to add magnetoencephalography (MEG) as a direct measure of the synchronous firing of neuronal ensembles (i.e., neuron electrophysiology) to complement our ongoing NIH funded work. Twenty-seven well- characterized mild TBI patients and 15 non-cranial trauma controls will undergo neuropsychological testing and an extensive imaging battery 3 weeks and 3-5 months post injury. Participants will be asked to perform both a spatial orienting and a resting-state task during the collection of FMRI (currently funded work) and MEG (competitive revision) data. Amongst all of the imaging modalities, the combination of information from MEG and FMRI is likely to be the most synergistic due to the increased spatial (FMRI) and temporal (MEG) resolution that each modality provides. This hypothesis will be directly tested by applying novel multivariate statistical techniques (joint independent component analyses; J-ICA) to the acquired data. The utility of J-ICA to capitalize on the unique information present in each individual imaging modality has not been studied, and, more importantly, neither has its ability to tell both when (MEG) and where (FMRI) pathological responses are occurring within the brain following mTBI. The impact and innovation of the current proposal lies on several levels. Foremost, it addresses an important gap in our knowledge regarding the development of standardized protocols that are capable of capturing the dynamic neurological changes that occur after mTBI. While it is unlikely that neuroimaging techniques alone will ever be able to provide an independent objective diagnosis, it is likely that they will provide incremental information important for both differential diagnosis and predictions about future outcome. Second, the addition of MEG ensures we are directly measuring neuronal as well as metabolic (1H-MRS) and vascular (FMRI) responses. This is critical given that frank neuronal dysfunction could potentially drive both the metabolic and vascular abnormalities that we are currently observing in our semi-acutely injured mTBI patients. MEG provides exquisite temporal resolution that will permit an evaluation of when (on the millisecond level) the pathological neuronal response is occurring (M50 versus M100 versus M300). To date, there have only been a few studies that have utilized MEG to study mTBI and none have been conducted during the semi-acute stage of injury in an unselected population. Finally, a longitudinal study of mild TBI during both the semi-acute and chronic phase that combines these neuroimaging modalities will provide the foundation for a human recovery model in TBI. Although current animal models exist, these are a poor substitute for the complexities inherent in human cognition. PUBLIC HEALTH RELEVANCE: In the United States alone, there are approximately 1.2 million mild traumatic brain injury (mTBI) cases per year that result in an estimated cost of $56 billion dollars. The symptoms of mTBI can range from severe physical and mental disability to subtle problems with attention, concentration, or emotional control. Cognitive difficulties are often present in the first few weeks of injury, but typically remit 3-5 months post injury in the majority (approximately 80-90%) of patients. The first step for understanding these cognitive difficulties is to develop biomarkers that are sensitive to neuronal injury and the subsequent recovery process, which will be critical not only for mTBI, but also for more severe forms of TBI. However, the neuropathology underlying cognitive deficits in the acute or chronic phases of mild TBI is often subtle and difficult to detect with conventional imaging techniques. Our currently funded NIH work with magnetic resonance imaging (MRI) techniques provide preliminary evidence of abnormal metabolic and vascular responses in the semi-acute phase of mTBI, which we have also shown to correlate with cognitive dysfunction. This competitive revision will add a direct measurement of synchronous neuronal firing (magnetoencephalography; MEG) to our currently funded protocol. The fusion of high-resolution spatial (FMRI) and temporal (MEG) information, coupled with behavioral and neuropsychological measures over time, will provide unprecedented insight into the foundation of a mTBI recovery model in humans.