The Neurometabolic Cascade of Concussion.
To review the underlying pathophysiologic processes of concussive brain injury and relate these neurometabolic changes to clinical sports-related issues such as injury to the developing brain, overuse injury, and repeated concussion.
An Overview of Concussion Pathophysiology.
Immediately after biomechanical injury to the brain, abrupt, indiscriminant release of neurotransmitters and unchecked ionic fluxes occur. The binding of excitatory transmitters, such as glutamate, to the N-methyl-D-aspartate (NMDA) receptor leads to further neuronal depolarization with efflux of potassium and influx of calcium. These ionic shifts lead to acute and subacute changes in cellular physiology.
Acutely, in an effort to restore the neuronal membrane potential, the sodium-potassium (Na+-K+) pump works overtime. The Na+-K+ pump requires increasing amounts of adenosine triphosphate (ATP), triggering a dramatic jump in glucose metabolism. This “hypermetabolism” occurs in the setting of diminished cerebral blood flow, and the disparity between glucose supply and demand triggers a cellular energy crisis. The resulting energy crisis is a likely mechanism for postconcussive vulnerability, making the brain less able to respond adequately to a second injury and potentially leading to longer-lasting deficits.
Following the initial period of accelerated glucose utilization, the concussed brain goes into a period of depressed metabolism. Persistent increases in calcium may impair mitochondrial oxidative metabolism and worsen the energy crisis. Unchecked calcium accumulation can also directly activate pathways leading to cell death. Intra-axonal calcium flux has been shown to disrupt neurofilaments and microtubules, impairing posttraumatic neural connectivity.
This overview represents a simplified framework of the neurometabolic cascade. Other important components of posttraumatic cerebral pathophysiology include, but are not limited to, generation of lactic acid, decreased intracellular magnesium, free radical production, inflammatory responses, and altered neurotransmission. We will now discuss some of the pertinent details of postconcussive pathophysiology in both experimental animal models and in humans…
Reductions in Magnesium
Intracellular magnesium levels are also immediately reduced after Traumatic Brain Injury (TBI) and remain low for up to 4 days. This reduction in magnesium has been correlated with postinjury neurologic deficits, and pretreatment to restore magnesium levels results in improved motor performance in experimental animals. Decreased magnesium levels may lead to neuronal dysfunction via multiple mechanisms. Both glycolytic and oxidative generation of ATP are impaired when magnesium levels are low. Magnesium is necessary for maintaining the cellular membrane potential and initiating protein synthesis. Finally, low levels of magnesium may effectively unblock the NMDA receptor channel more easily, leading to greater influx of Ca2+ and its potentially deleterious intracellular consequences.
In this study the researchers showed that magnesium is reduced in the brain cells after a concussion-type injury potentially worsening damage and dysfunction in the nerve cells. This occurred due to the impairment in ATP or energy production in the low magnesium environment and due to the low magnesium level’s allowing Calcium to flood the cells. When the researchers restored magnesium levels in experimental animals the subjects’ motor performance, (the ability of the nerves to stimulate the muscles to function), improved. Unfortunately, nutritional deficiency is on the rise in the United States due to the trend for “convenience” foods. Magnesium is an important and often overlooked mineral and supplementation can improve health conditions currently affecting many Americans.
Michael A. Visconti, ND, AP
Christopher C. Gizacorresponding author and David A. Hovda. “The Neurometabolic Cascade of Concussion” J Athl Train. 2001 Jul-Sep; 36(3): 228–235.