Sports-related concussions are particularly common during adolescence, a time when even mild brain injuries may disrupt ongoing brain maturation and result in long-term complications. A recent focus on the consequences of repetitive concussions among professional athletes has prompted the development of several new experimental models in rodents, as well as the revision of guidelines for best management of sports concussions. Here, we consider the utility of rodent models to understand the functional consequences and pathobiology of concussions in the developing brain, identifying the unique behavioral and pathological signatures of concussive brain injuries. The impact of repetitive concussions on behavioral consequences and injury progression is also addressed. In particular, we focus on the epidemiological, clinical, and experimental evidence underlying current recommendations for physical and cognitive rest after concussion, and highlight key areas in which further research is needed. Lastly, we consider how best to promote recovery after injury, recognizing that optimally timed, activity-based rehabilitative strategies may hold promise for the adolescent athlete who has sustained single or repetitive concussions. The purpose of this review is to inform the clinical research community as it strives to develop and optimize evidence-based guidelines for the concussed adolescent, in terms of both acute and long-term management.

Recent evidence supports the hypothesis that repetitive mild traumatic brain injuries (rmTBIs) culminate in neurological impairments and chronic neurodegeneration, which have wide-ranging implications for patient management and return-to-play decisions for athletes. Adolescents show a high prevalence of sports-related head injuries and may be particularly vulnerable to rmTBIs due to ongoing brain maturation. However, it remains unclear whether rmTBIs, below the threshold for acute neuronal injury or symptomology, influence long-term outcomes. To address this issue, we first defined a very mild injury in adolescent mice (postnatal day 35) as evidenced by an increase in Iba-1- labeled microglia in white matter in the acutely injured brain, in the absence of indices of cell death, axonal injury, and vasogenic edema. Using this level of injury severity and Avertin (2,2,2-tribromoethanol) as the anesthetic, we compared mice subjected to either a single mTBI or 2 rmTBIs, each separated by 48 h. Neurobehavioral assessments were conducted at 1 week and at 1 and 3 months postimpact. Mice subjected to rmTBIs showed transient anxiety and persistent and pronounced hypoactivity compared to sham control mice, alongside normal sensorimotor, cognitive, social, and emotional function. As isoflurane is more commonly used than Avertin in animal models of TBI, we next examined long-term outcomes after rmTBIs in mice that were anesthetized with this agent. However, there was no evidence of abnormal behaviors even with the addition of a third rmTBI. To determine whether isoflurane may be neuroprotective, we compared the acute pathology after a single mTBI in mice anesthetized with either Avertin or isoflurane. Pathological findings were more pronounced in the group exposed to Avertin compared to the isoflurane group. These collective findings reveal distinct behavioral phenotypes (transient anxiety and prolonged hypoactivity) that emerge in response to rmTBIs. Our findings further suggest that selected anesthetics may confer early neuroprotection after rmTBIs, and as such mask long-term abnormal phenotypes that may otherwise emerge as a consequence of acute pathogenesis.

Due to a high incidence of traumatic brain injury (TBI) in children and adolescents, age-specific studies are necessary to fully understand the long-term consequences of injuries to the immature brain. Preclinical and translational research can help elucidate the vulnerabilities of the developing brain to insult, and provide model systems to formulate and evaluate potential treatments aimed at minimizing the adverse effects of TBI. Several experimental TBI models have therefore been scaled down from adult rodents for use in juvenile animals. The following chapter discusses these adapted models for pediatric TBI, and the importance of age equivalence across species during model development and interpretation. Many neurodevelopmental processes are ongoing throughout childhood and adolescence, such that neuropathological mechanisms secondary to a brain insult, including oxidative stress, metabolic dysfunction and inflammation, may be influenced by the age at the time of insult. The long-term evaluation of clinically relevant functional outcomes is imperative to better understand the persistence and evolution of behavioral deficits over time after injury to the developing brain. Strategies to modify or protect against the chronic consequences of pediatric TBI, by supporting the trajectory of normal brain development, have the potential to improve quality of life for brain-injured children.