The Neurometabolic Cascade of Concussion

Abstract

OBJECTIVE: 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. DATA SOURCES: Over 100 articles from both basic science and clinical medical literature selected for relevance to concussive brain injury, postinjury pathophysiology, and recovery of function. DATA SYNTHESIS: The primary elements of the pathophysiologic cascade following concussive brain injury include abrupt neuronal depolarization, release of excitatory neurotransmitters, ionic shifts, changes in glucose metabolism, altered cerebral blood flow, and impaired axonal function. These alterations can be correlated with periods of postconcussion vulnerability and with neurobehavioral abnormalities. While the time course of these changes is well understood in experimental animal models, it is only beginning to be characterized following human concussion. CONCLUSIONS/RECOMMENDATIONS: Following concussion, cerebral pathophysiology can be adversely affected for days in animals and weeks in humans. Significant changes in cerebral glucose metabolism can exist even in head-injured patients with normal Glasgow Coma Scores, underscoring the need for in-depth clinical assessment in an effort to uncover neurocognitive correlates of altered cerebral physiology. Improved guidelines for clinical management of concussion may be formulated as the functional significance and duration of these postinjury neurometabolic derangements are better delineated.

Figure 1

Neurometabolic cascade following experimental concussion. K⁺, potassium; Ca²⁺, calcium; CMRgluc, oxidative glucose metabolism; CBF, cerebral blood flow. (Reprinted with permission. Giza CC, Hovda DA. Ionic and metabolic consequences of concussion. In: Cantu RC, Cantu RI. Neurologic Athletic and Spine Injuries. St Louis, MO: WB Saunders Co; 2000:80–100.).

Figure 2

Neurometabolic cascade following traumatic injury. (1) Nonspecific depolarization and initiation of action potentials. (2) Release of excitatory neurotransmitters (EAAs). (3) Massive efflux of potassium. (4) Increased activity of membrane ionic pumps to restore homeostasis. (5) Hyperglycolysis to generate more adenosine triphosphate (ATP). (6) Lactate accumulation. (7) Calcium influx and sequestration in mitochondria leading to impaired oxidative metabolism. (8) Decreased energy (ATP) production. (9) Calpain activation and initiation of apoptosis. A, Axolemmal disruption and calcium influx. B, Neurofilament compaction via phosphorylation or sidearm cleavage. C, Microtubule disassembly and accumulation of axonally transported organelles. D, Axonal swelling and eventual axotomy. K⁺, potassium; Na⁺, sodium; Glut, glutamate; Mg²⁺, magnesium; Ca²⁺, calcium; NMDA, N-methyl-D-aspartate; AMPA, d-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid.