Mechanisms underlying vulnerabilities after repeat mild traumatic brain injuries

Traumatic brain injury (TBI) has drawn national attention for its high incidence and mechanistic complexity. The majority of TBI cases are "mild" in nature including concussions and mild TBI (mTBI). Concussions are a distinct form of mTBI where diagnosis is difficult, quantification of the incidence is challenging and there is greater risk for subsequent injuries. While concussions occur in the general population, it has become a hallmark injury consistently observed among adolescent and young adult athletes and the risks for repeat TBI (rTBI) is significant. Clinical and experimental evidence shows that the magnitude and duration of deficits is dependent on the number and the interval between injuries. Several studies suggest that metabolic vulnerabilities after injury may contribute to the window for cerebral vulnerability from rTBI. In addition to metabolism, this review addresses how age, sex and hormones also play an important role in the response to repeat concussions. Understanding how these factors collectively contribute to concussion and rTBI recovery is critically important in establishing age/sex appropriate return to play guidelines, injury prevention, therapeutic interventions and mitigation of long-term consequences of rTBI.