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：
9185679
负责人：
Andrew Robert Mayer
金额：
$ 69.87万
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 2021-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9185679
关键词：
18 year old Academic achievement Accident and Emergency department Accounting 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 Gray unit of radiation dose 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 Phase Physical activity Play Post-Concussion Syndrome Problem behavior Prognostic Marker Public Health Quality of life Recovery Recruitment Activity Research Design Resolution Rest Risk Role Sample Size Sampling Severities Social Functioning Staging Structure Symptoms Techniques Thalamic structure Therapeutic Trials Time Trauma Unconscious State Water Work X-Ray Computed Tomography Youth cerebral atrophy cerebrovascular cingulate gyrus clinically significant cognitive function cognitive testing cohort computerized diagnosis standard evidence base experience follow-up gray matter hemodynamics imaging modality mild traumatic brain injury nerve injury neuroimaging neuropathology neurophysiology neuropsychiatry new therapeutic target processing speed symptomatology therapeutic target therapy development tool traumatic event 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特的，或者小儿轻度创伤性脑损伤（pmTBI）代表了一个主要的公共卫生问题尽管 PMTBI 的神经行为症状在医学界已有详细记录，但每年约有 400,000 例新病例。在受伤后的最初几天到几周内，很少有精心设计的研究来检验受伤的长期后果。对于脑震荡后症状（PCS）表达背后的神经病理学知之甚少因此，目前尚不清楚儿童通常如何康复。从临床或神经生理学角度来看，在受伤的第一年。通过收集纵向数据（受伤后 1 周、4 个月和 1 年）来解决这一关键的知识差距大量 pmTBI 患者 (N = 150) 和健康对照 (N = 125) 的神经影像和临床数据。我们的初步数据表明弥漫性白质损伤、深部灰质血流动力学异常、损伤后 4 个月的皮质萎缩迹象与动物的情况一致。模型，这些数据表明需要在多个时间点进行多次成像测量才能理解 pmTBI 对神经生理学和潜在影响因素（例如脑血流量、当前的研究将这些发现扩展到早期慢性损伤。阶段，确定这些弥漫性损伤与临床结果的关系，并确定个人的“恢复情况” 选定的生物标志物的“时间进程”是从儿童和家长处收集的。包括计算机化认知测试、生活质量测量和病前功能评估。多壳高角分辨率扩散成像序列提供了有关潜力的独特信息潜在的作用机制（水分数）是在空间注意力期间测量的。任务并通过静息脑血流量的额外定量测量。脑血管反应性将消除血流动力学与神经元功能障碍的歧义。措施还将提供有关深层灰质结构中的脉管系统如何受到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。提供对临床和临床两种不同恢复轨迹（完全恢复与部分恢复）的初步分析当前应用的公共卫生意义是多方面的。青春期是大脑发育的关键时期，神经行为症状持续存在遵循 pmTBI 可能会干扰后续的学业成就和人际关系其次，开发跟踪损伤进展的客观生物标志物将有助于诊断。伤害严重程度，并为确定儿童何时真正安全返回提供经验基础最后，了解伤害机制是关键的第一步。开发针对神经病理学（即目标参与）而不是缓解症状的新疗法，目前所有 pmTBI 疗法的方法。