Mild traumatic brain injury

Mild traumatic brain injury

Mild TBI, often called “concussion,” is defined by a GCS of 14 to 15 and accounts for over 80% of TBI 1).

see Mild traumatic brain injury definition.


The initial ionic flux and glutamate release result in significant energy demands and a period of metabolic crisis for the injured brain. These physiological perturbations can now be linked to clinical characteristics of concussion, including migrainous symptoms, vulnerability to repeat injury, and cognitive impairment. Furthermore, advanced neuroimaging now allows a research window to monitor postconcussion pathophysiology in humans noninvasively. There is also increasing concern about the risk for chronic or even progressive neurobehavioral impairment after concussion/mild traumatic brain injury. Critical studies are underway to better link the acute pathobiology of concussion with potential mechanisms of chronic cell death, dysfunction, and neurodegeneration 2).

Glutamate release and ionic disequilibrium

As a result of mechanical trauma, neuronal cell membranes and axons undergo disruptive stretching, leading to temporary ionic disequilibrium 3).

As a result, levels of extracellular potassium increase drastically, and indiscriminate glutamate release occurs 4).

Glutamate release activates N-methyl-D-aspartate receptors, which leads to accumulation of intracellular calcium 5) 6) 7) , causing mitochondrial respiration dysfunction, protease activation, and often initiating apoptosis 8) 9). Elevated glutamate levels were also found to be significantly correlated with derangements in lactatepotassium, brain tissue pH, and brain tissue CO2 levels in human studies 10). Additionally, sodium channel upregulation, fueled by ATPase proteins depending on glucose for energy, is observed following axonal stretch injuries 11).

Energy crisis and mitochondrial dysfunction

In combination, the cellular response to the above-mentioned ionic shifts and the downstream effects of the neurotransmitter release lead to an acute energy crisis. This occurs when, to restore ionic equilibrium, adenosine-triphosphate (ATP) -dependent sodium-potassium ion transporter pump activity increases, which augments local cerebral glucose demand 12).

Further metabolic demand is incurred by ATP-dependent sodium channel upregulation. This occurs in the face of mitochondrial dysfunction, leading cells to primarily utilize glycolytic pathways instead of aerobic metabolism for energy, and causing extracellular lactate accumulation as a byproduct 13). This acidosis, caused by hyperglycolysis, has been shown to worsen membrane permeability, ionic disequilibrium, and cerebral edema 14).

Some evidence shows that the lactate produced by this process may eventually be utilized as a source of energy by the neurons once mitochondrial oxidative respiration normalizes; in fact, one study showed that in moderate to severe TBI the incidence of abnormally high levels of lactate uptake were seen in 28% of subjects 15). The same study showed that patients exhibiting a higher rate of brain lactate uptake relative to arterial lactate levels tended to have more favorable outcomes compared to others with lower relative lactate uptake.

Alterations in cerebral blood flow

Some studies have shown that cerebral blood flow decreases immediately following the insult, and the amount of time it remains lowered seems to depend on the severity of the injury 16) 17).

Other studies, however, show no significant differences in CBF following mild TBI in subjects over 30 years of age 18). In pediatric studies, CBF has been seen to increase during the first day following mild TBI, followed by decreased CBF for many days after 19) 20). Data comparing cerebral blood flow in pediatric TBI patients has shown impaired autoregulation in 42% of moderate and severe and 17% of mild injuries 21).

Histopathologic changes

The underlying histopathologic changes that occur are relatively unknown. In order to improve understanding of acute injury mechanisms, appropriately designed pre-clinical models must be utilized.

The clinical relevance of compression wave injury models revolves around the ability to produce consistent histopathologic deficits. Mild traumatic brain injuries activate similar neuroinflammatory cascades, cell death markers and increases in amyloid precursor protein in both humans and rodents. Humans, however, infrequently succumb to mild traumatic brain injuries and, therefore, the intensity and magnitude of impacts must be inferred. Understanding compression wave properties and mechanical loading could help link the histopathologic deficits seen in rodents to what might be happening in human brains following concussions 22).


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