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

毫无疑问，发育中的大脑的脆弱性和恢复的潜力是 儿童轻度创伤性脑损伤（pmTBI）是一个主要的公共卫生问题， 每年新增40万例。尽管pmTBI的神经行为症状在文献中有很好的记载， 在受伤后的最初几天到几周，很少有精心设计的研究检查了受伤的长期后果。 关于脑震荡后症状（PCS）表达的神经病理学基础更是知之甚少 以及对临床结果的影响。因此，临床医生目前不了解儿童通常如何恢复 从临床或神经生理学角度来看，在受伤的第一年。当前应用程序 通过收集纵向数据（伤后1周、4个月和1年）来解决这一关键的知识差距 神经影像学和临床数据的pmTBI患者（N = 150）和健康对照（N = 125）的大队列。 我们的初步数据显示弥漫性白色损伤，深部灰质血流动力学异常， 在相对较小的样本中，在损伤后4个月出现皮质萎缩的迹象。与动物一致 这些数据表明，需要在多个时间点进行多项成像测量，以了解 pmTBI对神经生理学和潜在的贡献因素（例如，脑血流， 脑血管反应性）。目前的研究将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，并确定个体的“恢复 选择的生物标志物的“时间过程”。PCS的评级是从孩子和家长一起收集的 通过计算机化认知测试、生活质量测量和病前功能评估。一 多壳层高角分辨率扩散成像序列提供了关于潜在的独特信息， 基本作用机制（水分）。功能活动是在空间注意力 任务和通过连通性分析。静息脑血流量的额外定量测量 并且脑血管反应性将区分血液动力学和神经元功能障碍。这些独立 测量还将提供关于深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靶点参与机制。生长曲线建模 提供了两种临床治疗的不同恢复轨迹（完全与部分恢复）的初步分析 和成像数据。目前申请的公共卫生意义是多方面的。第一，童年晚期， 青春期是大脑发育的关键时期， pmTBI可能会干扰随后的学术成就和人际关系， 受伤后的几年其次，开发跟踪损伤进展的客观生物标志物将有助于诊断 伤害的严重程度，并提供经验基础，以确定什么时候是真正安全的儿童返回 学习/体力活动。最后，了解损伤的机制是关键的第一步， 开发靶向神经病理学（即靶向参与）而不是症状缓解的新疗法， 所有pmTBI治疗的当前方法。

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.