Physical Medicine and Rehabilitation Clinics of North America
The Pathophysiology of Concussions in Youth
Section snippets
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.
References (217)
- et al.
Injury-induced alterations in N-methyl-d-aspartate receptor subunit composition contribute to prolonged 45calcium accumulation following lateral fluid percussion
Neuroscience
(2004) - et al.
Concussive brain injury is associated with a prolonged accumulation of calcium: a 45Ca autoradiographic study
Brain Res
(1993) - et al.
Dynamic changes in local cerebral glucose utilization following cerebral concussion in rats: evidence of a hyper- and subsequent hypometabolic state
Brain Res
(1991) - et al.
Lactate accumulation following concussive brain injury: the role of ionic fluxes induced by excitatory amino acids
Brain Res
(1995) Second-impact syndrome
Clin Sports Med
(1998)- et al.
Second impact syndrome: concussion and second injury brain complications
J Am Coll Surg
(2010) - et al.
Clinical considerations in the reduction of secondary brain injury
Ann Emerg Med
(1993) - et al.
Voluntary exercise following traumatic brain injury: brain-derived neurotrophic factor upregulation and recovery of function
Neuroscience
(2004) - et al.
Fluid percussion brain injury in the developing and adult rat: a comparative study of mortality, morphology, intracranial pressure and mean arterial blood pressure
Brain Res Dev Brain Res
(1996) - et al.
Heightening of the stress response during the first weeks after a mild traumatic brain injury
Neuroscience
(2011)
Long-term effects of early-life environmental manipulations in rodents and primates: potential animal models in depression research
Neurosci Biobehav Rev
Increased expression of brain-derived neurotrophic factor mRNA in rat hippocampus is associated with improved spatial memory and enriched environment
Neurosci Lett
Experience-dependent behavioral plasticity is disturbed following traumatic injury to the immature brain
Behav Brain Res
Lateral fluid percussion injury in the developing rat causes an acute, mild behavioral dysfunction in the absence of significant cell death
Brain Res
Regional changes in the expression of neurotrophic factors and their receptors following acute traumatic brain injury in the adult rat brain
Brain Res
NGF and BDNF are differentially modulated by visual experience in the developing geniculocortical pathway
Brain Res Dev Brain Res
The incidence of traumatic brain injury among children in the United States: differences by race
J Head Trauma Rehabil
Mechanoporation induced by diffuse traumatic brain injury: an irreversible or reversible response to injury?
J Neurosci
Massive increases in extracellular potassium and the indiscriminate release of glutamate following concussive brain injury
J Neurosurg
Age-dependency of 45calcium accumulation following lateral fluid percussion: acute and delayed patterns
J Neurotrauma
Cell death mechanisms following traumatic brain injury
Brain Pathol
Mitochondrial permeability transition in CNS trauma: cause or effect of neuronal cell death?
J Neurosci Res
Substrate delivery and ionic balance disturbance after severe human head injury
Acta Neurochir Suppl
Sodium channelopathy induced by mild axonal trauma worsens outcome after a repeat injury
J Neurosci Res
The role of lactic acidosis in the ischemic nerve cell injury
Acta Neuropathol Suppl
Energy dysfunction as a predictor of outcome after moderate or severe head injury: indices of oxygen, glucose, and lactate metabolism
J Cereb Blood Flow Metab
Characterization of cerebral hemodynamic phases following severe head trauma: hypoperfusion, hyperemia, and vasospasm
J Neurosurg
Cerebrovascular reactivity to CO(2) and hypotension after mild cortical impact injury
Am J Physiol
Epidemiology and pathophysiology of minor traumatic brain injury
Curr Sports Med Rep
Intracranial blood flow velocity after head injury: relationship to severity of injury, time, neurological status and outcome
J Neurol Neurosurg Psychiatry
Changes in cerebral hemodynamics assessed by transcranial Doppler ultrasonography in children after head injury
Childs Nerv Syst
Neurol Neurochir Pol
Cerebral autoregulation in pediatric traumatic brain injury
Pediatr Crit Care Med
Cerebral hemodynamic predictors of poor 6-month Glasgow Outcome Score in severe pediatric traumatic brain injury
J Neurotrauma
Temporal window of metabolic brain vulnerability to concussion: a pilot 1H-magnetic resonance spectroscopic study in concussed athletes–part III
Neurosurgery
Temporal window of metabolic brain vulnerability to concussions: oxidative and nitrosative stresses–part II
Neurosurgery
Temporal window of metabolic brain vulnerability to concussions: mitochondrial-related impairment–part I
Neurosurgery
Repeat traumatic brain injury in the juvenile rat is associated with increased axonal injury and cognitive impairments
Dev Neurosci
Repeat mild traumatic brain injury: how to adjust return to play guidelines
Curr Sports Med Rep
Return to play after concussion: principles and practice
Clin J Sport Med
Cumulative effects associated with recurrent concussion in collegiate football players: the NCAA Concussion Study
JAMA
The second impact in catastrophic contact-sports head trauma
JAMA
Second impact syndrome
Neurology
Circulating catecholamines and sympathetic activity after head injury
Neurosurgery
Monitoring of autoregulation using laser Doppler flowmetry in patients with head injury
J Neurosurg
Does second impact syndrome exist?
Clin J Sport Med
Second-impact syndrome and a small subdural hematoma: an uncommon catastrophic result of repetitive head injury with a characteristic imaging appearance
J Neurotrauma
Delayed cerebral edema and fatal coma after minor head trauma: role of the CACNA1A calcium channel subunit gene and relationship with familial hemiplegic migraine
Ann Neurol
Temporal window of vulnerability to repetitive experimental concussive brain injury
Neurosurgery
Hypothesis of the postconcussive vulnerable brain: experimental evidence of its metabolic occurrence
Neurosurgery
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2020, Physician Assistant ClinicsCitation Excerpt :These processes describe the pathophysiological process of concussion based on ionic shifts, impaired metabolism, and impaired neurotransmission. The neurometabolic cascade is characterized by an initial depolarization of neuronal membranes.4,5 An initial ion shift occurs when the biomechanical forces are applied to the brain and a large increase in excitatory amino acids, glutamate, release occurs.1
Using the Integrated Behavioral Model to Determine Sport-Related Concussion Reporting Intentions Among Collegiate Athletes
2020, Journal of Adolescent HealthThe long-term outcomes of sport-related concussion in pediatric populations
2018, International Journal of PsychophysiologyCitation Excerpt :This misunderstanding may stem from the fact that animal models indicate the acute excitotoxic cascade of concussion lasts ~7–10 days (Giza and Hovda, 2001; Giza and Hovda, 2014), a time frame which aligns with acute clinical symptomology in the majority of individuals (McCrory et al., 2017). However, the pathophysiological sequelae of concussion extends far beyond the acute neuro-metabolic cascade, with animal and human studies indicating pathological processes that endure for weeks to months following injury (Shrey et al., 2011; Bigler and Maxwell, 2012; Slobounov et al., 2012; Choe et al., 2012; Kamins et al., 2017). We are currently unaware of any study evaluating the structure, function, or connectivity of the brain that indicates that neural recovery occurs within the “acute window of clinical recovery”.
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2019, Canadian Journal of Emergency Medicine
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.