Attentional Dysfunction and Recovery in Traumatic Brain Injury (TBI)

描述（由申请人提供）：最近一项涉及1463例轻度创伤性脑损伤（TBI）病例（39项不同研究）的荟萃分析表明，认知功能障碍通常存在于损伤的半急性期（效应量d = .54），但在损伤后3个月未观察到神经心理学缺陷。在轻度TBI后的所有认知缺陷中，注意力和注意力分散困难是最常见的报道和观察到的症状之一。然而，神经病理学基础的注意力障碍，在最初几周的伤害和随后的恢复过程中，目前正在研究使用新的神经影像技术。本申请提出使用神经心理学测试和两种实验室测量（定向和选择性注意任务）来量化这种注意力缺陷，并且使用功能磁共振成像（FMRI）、扩散张量成像（DTI）和磁共振波谱（MRS）来量化在轻度TBI中作为时间的函数发生的潜在神经元变化。具体而言，27名轻度TBI患者和15名非颅脑创伤对照将在受伤后3周和3-5个月进行神经心理学测试和广泛的成像电池。在功能磁共振成像会议期间，参与者将被要求执行一个空间定向任务和一个任务，要求他们处理来自两种感觉模态（数字Stroop）的冲突信息。迄今为止，绝大多数TBI神经影像学研究仅采用单一成像方式（MRS或FMRI或DTI），选择的患者未控制损伤后时间或损伤严重程度，也未对患者进行纵向研究。因此，本提案的影响和创新体现在几个层面。最重要的是，它解决了我们目前知识中的一个重要空白，即开发能够捕获轻度TBI后发生的动态神经变化的标准化方案。常规临床成像方式（MRI和CT扫描）通常对大多数（80-90%）患者发生的急性认知缺陷的神经元病理学以及随后的恢复过程不敏感。第二，所选择的成像模态中的每一个包含关于不同类别的神经元组织的功能的不同信息（即，FMRI =灰质功能和血管系统的间接测量; DTI =白色物质完整性的测量; MRS =神经元和轴突健康的直接测量）。来自这三种不同成像技术的信息的组合可能是协同的，并且超过单独的每种单独的模态的总和。我们将直接测试这一假设，通过应用新的多元统计技术（联合独立成分分析; J-ICA）的采集成像数据。最后，在半急性和慢性阶段使用这些神经成像方式的轻度TBI的纵向研究将提供TBI的人类恢复模型的基础。虽然单靠神经影像学技术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。重要的是，实现上述目标对于最终确定少数有发生未来并发症风险的轻度TBI患者至关重要，以便在有更好的成功机会时立即进行干预。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（TBI）病例，估计造成560亿美元的费用。轻度TBI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。这不仅对轻度TBI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的急性或慢性阶段中识别潜在的认知缺陷的病理学通常是微妙的，并且难以用常规成像技术如CT或MRI检测。这表明，更多的研究为基础的神经成像技术，如功能磁共振成像（FMRI），扩散张量成像（DTI）和磁共振波谱（MRS）的诊断效用和预测有效性需要探索。多种神经成像技术的使用是至关重要的，因为不同的模态测量不同的信号（例如，血液动力学的、代谢的或电生理学的），其来源于脑中的不同组织源（例如，白色与灰质），这对于识别头部创伤后可能发生的弥漫性损伤将是重要的。潜在的急性病理学可能是多方面的，涉及白色和灰质，这表明对神经元完整性的几个不同领域进行采样是理解急性认知缺陷以及随后的正常恢复过程的必要的第一步。此外，这些生物标志物可能有助于区分小部分轻度TBI患者，这些患者由于损伤而继续存在认知问题。

DESCRIPTION (provided by applicant): A recent meta-analysis involving 1463 cases (39 different studies) of mild traumatic brain injury (TBI) indicated that cognitive dysfunction was typically present in the semi-acute phase of injury (effect size d = .54) but that no neuropsychological deficits were observable at three months post-injury. Of all cognitive deficits following mild TBI, difficulties with attention and distractibility are one of the most commonly reported, and observed, symptoms. However, the neuropathology underlying attentional dysfunction in the first few weeks of injury and the subsequent recovery process are currently understudied using newer neuroimaging techniques. The current application proposes to use neuropsychological testing and two laboratory measures (orienting and selective attention tasks) to quantify this attentional deficit, and functional magnetic resonance imaging (FMRI), diffusion tensor imaging (DTI) and magnetic resonance spectroscopy (MRS) to quantify the underlying neuronal changes that occur as a function of time in mild TBI. Specifically, 27 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. During the FMRI session, participants will be asked to perform a spatial orienting task and a task that requires them to process conflicting information from two sensory modalities (Numeric Stroop). To date, the vast majority of TBI neuroimaging studies have employed only a single imaging modality (MRS or FMRI or DTI), have selected patients without controlling for time post-injury or severity of injury, and have not studied patients longitudinally. Thus, the impact and innovation of the current proposal therefore lies on several levels. Foremost, it addresses an important gap in our current knowledge regarding the development of standardized protocols that are capable of capturing the dynamic neurological changes that occur after a mild TBI. Routine clinical imaging modalities (MRI and CT scans) are usually insensitive to both the neuronal pathology underlying acute cognitive deficits as well as to the subsequent recovery process that occurs in the majority (80-90%) of patients. Second, each of the selected imaging modalities contains different information about the functioning of different classes of neuronal tissues (i.e., FMRI = indirect measure of gray matter functioning and vasculature; DTI = measure of white matter integrity; MRS = direct measure of neuronal and axonal health). The combination of information from these three different imaging techniques is likely to be synergistic and exceed the sum of each individual modality alone. We will directly test this hypothesis by applying novel multivariate statistical techniques (joint independent component analyses; J-ICA) to the acquired imaging data. Finally, a longitudinal study of mild TBI during both the semi-acute and chronic phase using these neuroimaging modalities will provide the foundation for a human recovery model in TBI. 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 that will be important for both differential diagnosis and predictions about future outcome. Importantly, the realization of the above will be critical for eventually identifying the minority of mild TBI patients at risk for developing future complications so that intervention can occur acutely, when there is a better chance of success. PUBLIC HEALTH RELEVANCE: In the United States alone, there are approximately 1.2 million mild traumatic brain injury (TBI) cases per year that result in an estimated cost of $56 billion dollars. The symptoms of mild TBI 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. This will be critical not only for mild TBI, but also for more severe forms of TBI as well. However, the identification of the pathology underlying cognitive deficits in the acute or chronic phases of mild TBI is often subtle, and hard to detect with conventional imaging techniques such as CT or MRI. This suggests that the diagnostic utility and predictive validity of more research-based neuroimaging techniques, such as functional magnetic resonance imaging (FMRI), diffusion tensor imaging (DTI) and magnetic resonance spectroscopy (MRS) needs to be explored. The use of multiple neuroimaging techniques is crucial because different modalities measure different signals (e.g., hemodynamic, metabolic or electrophysiological) that originate from different tissue sources in the brain (e.g., white versus gray matter), which will be important for identifying the diffuse injuries that may occur following head trauma. It is likely that the underlying acute pathology is multifaceted and involves both white and gray matter, suggesting that sampling several different domains of neuronal integrity is a necessary first step to understanding the acute cognitive deficits as well as the subsequent normal recovery process. Moreover, these bio- markers may be useful for distinguishing the small percentage of mild TBI patients who continue to have cognitive problems due to the injury.