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

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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.