The Pathophysiology of Concussions in Youth

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Glutamate Release and Ionic Disequilibrium

The postconcussive metabolic cascade has been well studied and characterized, both in animal models and in humans. As a result of mechanical trauma, neuronal cell membranes and axons undergo disruptive stretching, leading to temporary ionic disequilibrium.2 As a result, levels of extracellular potassium increase drastically, and indiscriminate glutamate release occurs.3 Glutamate release activates N-methyl-d-aspartate receptors, which leads to accumulation of intracellular calcium,4, 5, 6

Vulnerability to second injury and second impact syndrome

Postconcussive physiologic changes have been shown to increase the vulnerability of the brain to further injury, particularly in cases in which a second concussive injury is sustained within days of the first. This phenomenon can lead to more severe and permanent deficits. Numerous studies, both in animal models and in humans, support the concept of postconcussive vulnerability, prompting the development of many sets of return-to-play guidelines.23, 24, 25, 26, 27, 28 Research has shown that

Experimental

Experimental brain injury models have indicated that brain activation is altered for several weeks after TBI. Changes in excitability and circuit function have not only been observed in more severe brain injury but also after mild TBI.45, 46 Anatomic changes after trauma along with subtle changes in neuronal properties influence neuronal excitability. These postinjury changes in brain activation have an array of consequences ranging from alterations in synaptic plasticity,46 axonal sprouting47

Experimental

Brain injury leads to alterations in molecular substrates of synaptic plasticity. Of particular interest are the effects on proteins such as BDNF and the NMDAR, which are strongly linked with synaptic strengthening and play a significant role in experience-dependent plasticity.86, 87 Because the young brain is undergoing developmental changes, injury-induced alterations of molecular markers of plasticity may not only affect injury outcome, as it has been shown in adults, but also deviate

Timing of return to activity

As discussed earlier, there is substantial evidence that neural activation and plasticity are altered after developmental TBI. It is also known that physiologic neural activation can promote recovery, whereas excessive activation may exacerbate cellular damage. These neurobiological principles, then, underlie the clinically relevant determination of the optimal timing for return to activity after TBI/concussion.

Experimental

It is well known that biomechanical forces applied to neural tissue result in dysfunction and damage to axons.170, 171, 172 Changes in axonal integrity and function have been described in experimental models of mild TBI,39 including a recently described model of repeat concussive injury in the juvenile rat.26 In this juvenile model, the degree of axonal damage and glial reactivity was amplified when 2 closed head injuries were experienced 1 day apart. Behaviorally, a single mild TBI caused a

Chronic traumatic encephalopathy and late risk of dementia

Chronic traumatic encephalopathy is a progressive neurodegenerative disease found in some individuals subjected to repetitive mild TBI. Neuropathologically, it can be described as a tauopathy of the brain manifesting as neurofibrillary tangles throughout most of the brain with a relative paucity of β-amyloid deposition.186

Summary

Our understanding of the phenomenon of concussion has been shaped significantly by experimental work in animal models, as well as extrapolation of physiologic measurements from humans with more severe TBI. This review covers 3 main postconcussive periods: (1) the acute neurometabolic cascade, (2) the subacute phase of altered neural activation and axonal disconnection, and (3) the chronic accumulation of insults that may lead to permanent impairments. The acute neurometabolic cascade involves

Acknowledgments

NS27544, NS057420, NS06190, the Child Neurology Foundation/Winokur Family Foundation, the Today's and Tomorrow's Children Fund, and UCLA Brain Injury Research Center.

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    This work was supported by: NS27544, NS057420, NS06190, the Child Neurology Foundation/ Winokur Family Foundation, the Today's and Tomorrow's Children Fund, and the UCLA Brain Injury Research Center.

    The authors have nothing to disclose.

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