The Impact of Diffuse Mild Brain Injury on Clinical Outcomes in Children

弥漫性轻度脑损伤对儿童临床结果的影响

基本信息

批准号：
9685257
负责人：
Andrew Robert Mayer
金额：
$ 148.48万
依托单位：
THE MIND RESEARCH NETWORK
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-07-01 至 2022-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9685257
关键词：
18 year old Academic achievement Accident and Emergency department Acute Address Adolescence Affect Animal Model Animals Attention Biological Markers Blood Vessels Brain Brain Injuries Cerebrovascular Circulation Child Childhood Chronic Clinical Clinical Data Clinical Trials Cognitive Confidence Intervals Consensus Corpus striatum structure Data Development Diagnosis Diffuse Diffuse Brain Injury Diffusion Edema Emotional Exhibits Foundations Future Goals Gold Growth Image Impaired cognition Impairment Individual Injury Intelligence Interpersonal Relations Intervention Knowledge Lateral Learning Lesion Literature Measurement Measures Modeling Neurobehavioral Manifestations Neurobiology Neurologic Neuronal Dysfunction Outcome Parents Parietal Pathology Patient Self-Report Patients Pediatric cohort Phase Physical activity Play Post-Concussion Syndrome Problem behavior Prognostic Marker Public Health Quality of life Recovery Research Design Resolution Rest Risk Role Sample Size Sampling Severities Social Functioning Structure Symptoms TBI treatment Techniques Thalamic structure Therapeutic Trials Time Trauma Unconscious State Water X-Ray Computed Tomography Youth cerebral atrophy cerebrovascular cingulate gyrus clinical predictors clinically significant cognitive function cognitive recovery cognitive testing computerized diagnosis standard evidence base experience follow-up gray matter hemodynamics imaging modality mild traumatic brain injury nerve injury neurodevelopmental effect neuroimaging neuropathology neurophysiology neuropsychiatry new therapeutic target processing speed prospective recruit symptomatology therapeutic biomarker therapeutic target therapy development tool traumatic event vascular injury white matter white matter injury

项目摘要

There is no question that the vulnerabilities of the developing brain and the potential for recovery are unique, or that pediatric mild traumatic brain injury (pmTBI) represents a major public health concern with ≈400,000 new cases annually. Although the neurobehavioral symptoms of pmTBI are well-documented in the first days to weeks post-injury, few well-designed studies have examined the long-term consequences of injury. Even less is known about the neuropathology underlying the expression of post-concussive symptoms (PCS) and the impact on clinical outcomes. Thus, clinicians currently do not understand how children typically recover in the first year of injury from either a clinical or neurophysiologic perspective. The current application addresses this critical knowledge gap by collecting longitudinal (1 week, 4 months and 1 year post-injury) neuroimaging and clinical data on a large cohort of pmTBI patients (N = 150) and healthy controls (N = 125). Our preliminary data suggests diffuse white matter injuries, hemodynamic abnormalities in deep gray matter, and signs of cortical atrophy at 4 months post-injury in a relatively small sample. Consistent with animal models, these data indicate that multiple imaging measures at multiple time-points are needed to understand the dynamic effects of pmTBI on neurophysiology and underlying contributory factors (e.g., cerebral blood flow, cerebral vascular reactivity). The current study will extend these findings to the early chronic and chronic injury stages, determine how these diffuse injuries relate to clinical outcomes, and determine the individual “recovery time-courses” of selected biomarkers. Ratings of PCS are collected from both child and parent in conjunction with computerized cognitive testing, quality of life measures, and assessments of pre-morbid functioning. A multi-shell high angular resolution diffusion imaging sequence provides unique information on potential underlying mechanisms of action (water fractions). Functional activity is measured during a spatial attention task and through connectivity analyses. Additional quantitative measurements of resting cerebral blood flow and cerebral vascular reactivity will disambiguate hemodynamic from neuronal dysfunction. These independent measures will also provide critical information on how the vasculature in deep gray matter structures is affected by trauma, providing mechanisms of target engagement for future therapeutic trials. Growth curve modeling provides preliminary analyses of different recovery trajectories (fully versus partially recovered) for both clinical and imaging data. The public health significance of the current application is multifold. First, late childhood and adolescence constitutes a critical time for brain development, and persistent neurobehavioral symptoms following pmTBI can interfere with subsequent academic achievements and interpersonal relationships for years post-injury. Second, developing objective biomarkers that track injury progression will aid in diagnosis of injury severity and provide an empirical foundation for determining when it is truly safe for children to return to learn/physical activity. Finally, understanding the mechanisms of injury represents a critical first step for developing novel therapies that target neuropathology (i.e. target engagement) rather than symptom mitigation, the current approach for all pmTBI therapies.

毫无疑问，发育中的大脑的脆弱性和恢复的潜力是独一每年约400,000个新案件。尽管PMTBI的神经行为症状已在受伤后的第一天到几周，很少有精心设计的研究检查了伤害的长期后果。关于神经病理学的众所周知，脑震荡后症状（PC）的表达的知之甚少。以及对临床结果的影响。这是临床医生目前不了解儿童通常如何康复从临床或神经生理学的角度来看，在受伤的第一年。当前的应用程序通过收集纵向来解决这个关键的知识差距（伤害后1周，4个月和1年）大量PMTBI患者（n = 150）和健康对照组（n = 125）的神经影像学和临床数据。我们的初步数据表明弥漫性白质损伤，深灰质中的血液动力学异常，并在相对较小的样本中受伤后4个月的皮质萎缩迹象。与动物一致模型，这些数据表明需要多个时间点的多个成像度量来理解 PMTBI对神经生理学和潜在因素的动态影响（例如，脑血流，脑血管反应性）。当前的研究将把这些发现扩展到早期慢性和慢性损伤阶段，确定这些弥漫性损伤与临床结果的关系，并确定个体“恢复选定的生物标志物的时间场景。通过计算机认知测试，生活质量测量以及对疗程前功能的评估。一个多壳高角度分辨率扩散成像序列提供了有关电势的独特信息基本的作用机理（水分分数）。在空间注意力期间测量功能活动任务和连接分析。静息脑血流的其他定量测量脑血管反应性将使血液动力学与神经元功能障碍抗衡。这些独立措施还将提供有关深灰质结构中脉管系统如何影响的关键信息通过创伤，为未来的治疗试验提供目标参与机制。生长曲线建模为这两个临床提供了不同恢复轨迹（完全相对于部分恢复）的初步分析和成像数据。当前申请的公共卫生意义是多重的。首先，童年晚期和青少年构成了大脑发育的关键时刻，持续的神经行为症状遵循PMTBI可以干扰随后的学术成就和人际关系伤害后。第二，开发目标生物标志物以跟踪损伤进展将有助于诊断伤害严重程度，并为确定儿童真正安全返回的经验基础学习/体育锻炼。最后，理解伤害的机制代表了关键的第一步开发针对神经病理学（即靶向参与）而不是缓解症状的新型疗法，所有PMTBI疗法的当前方法。