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(39项不同研究)轻度创伤性脑损伤(TBI)的荟萃分析表明，认知功能障碍通常出现在损伤的半急性阶段(效应大小d=.54)，但在损伤后3个月没有观察到神经心理障碍。在轻度脑外伤后的所有认知障碍中，注意力障碍和注意力分散是最常见的报道和观察到的症状之一。然而，目前使用较新的神经成像技术对损伤后最初几周内潜在的注意功能障碍和随后的恢复过程的神经病理学研究不足。目前的应用建议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)来量化这种注意缺陷，并使用功能磁共振成像(FMRI)、扩散张量成像(DTI)和磁共振波谱(MRS)来量化轻度脑损伤中发生的潜在神经元变化。具体来说，27名轻度颅脑损伤患者和15名非颅脑损伤对照组将在受伤后3周和3-5个月接受神经心理测试和广泛的成像组检查。在功能磁共振成像过程中，参与者将被要求完成一项空间定向任务，以及一项要求他们处理来自两种感觉通道的相互冲突的信息的任务(数字Stroop)。到目前为止，绝大多数的脑外伤神经成像研究只采用了单一的成像方式(MRS或fMRI或DTI)，选择的患者没有控制损伤后的时间或损伤的严重程度，也没有纵向研究患者。因此，当前提案的影响和创新在于几个层面。最重要的是，它解决了我们目前关于标准化方案开发的一个重要空白，该方案能够捕捉轻微脑外伤后发生的动态神经变化。常规的临床影像检查(MRI和CT扫描)通常对大多数患者(80%-90%)的急性认知障碍背后的神经元病理以及随后的康复过程都不敏感。其次，每种选定的成像方式都包含关于不同类别神经组织功能的不同信息(即，fMRI=灰质功能和血管系统的间接测量；DTI=脑白质完整性的测量；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很可能是协同的，并且超过了每一种单独的成像技术的总和。我们将通过将新的多变量统计技术(联合独立分量分析；J-ICA)应用于获取的成像数据来直接检验这一假设。最后，使用这些神经成像方法对半急性和慢性期的轻度脑损伤进行纵向研究，将为脑损伤的人类康复模型奠定基础。虽然仅靠神经成像技术不太可能提供独立的客观诊断，但它们很可能会提供对鉴别诊断和对未来结果的预测都很重要的增量信息。重要的是，认识到上述情况对于最终确定少数有可能发展为未来并发症的轻度脑损伤患者至关重要，以便在有更好的成功机会时能够迅速地进行干预。与公共卫生相关：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560亿美元的损失。轻度脑外伤的症状可以从严重的身体和精神残疾到注意力、注意力集中或情绪控制的轻微问题。认知障碍通常出现在损伤的最初几周，但在大多数(约80%-90%)患者中，通常在损伤后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记物。这不仅对轻微的脑损伤至关重要，对更严重的脑损伤也是如此。然而，在轻度脑损伤的急性期或慢性期，认知障碍的病理基础往往是微妙的，很难用传统的成像技术如CT或MRI检测出来。这表明，需要探索更多以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)的诊断实用性和预测有效性。多种神经成像技术的使用是至关重要的，因为不同的模式测量来自大脑不同组织来源(例如，白质和灰质)的不同信号(例如，血流动力学、代谢或电生理)，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。其潜在的急性病理可能是多方面的，涉及白质和灰质，这表明采样几个不同的神经元完整性区域是理解急性认知障碍以及随后的正常恢复过程的必要的第一步。此外，这些生物标记物可能有助于区分因损伤而继续存在认知问题的一小部分轻度脑损伤患者。

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.