The structural concomitants of mild brain injury havebeen the subject of some discussion. The alteration inlevel of consciousness, even if brief, suggests widespreadneuronal dysfunction (Gennarelli 1987; Peerless andNewcastle 1967). There is evidence that structural neuronaldamage can accompany even very mild brain injury.Animal models of brain injury using the fluid percussionmodel in cats (Povlishock and Coburn 1989) and controlledangular acceleration devices in nonhuman primates(Jane et al. 1985) strongly suggest that mild braininjury is often associated with evidence of axonal injury.Although axotomy may occur at the time of injury,delayed axotomy also contributes significantly to the neuropathologicaloutcome. Delayed axotomy is believed tooccur subsequent to initial changes in the permeability ofthe axolemma (axonal membrane) and disruption of certainelements of the cytoskeleton, particularly axonal neurofilaments.This in turn can lead to axonal distortion,disruption of axoplasmic transport (see Povlishock andChristman 1995 for review), and eventual separation ofthe proximal and distal portion of the axon even in theabsence of an overt tear at the time of injury. Walleriandegeneration (with beadlike swelling and eventual degenerationof the distal axon and its terminals) can occur. Secondarydeafferentation (structural changes and sometimesneuronal death due to loss of synaptic input) intarget areas of the afflicted axon can follow (Povlishockand Christman 1995; Povlishock and Coburn 1989).These changes in axon structure evolve over a 12- to 24-hour period in the cat model and can be seen in theabsence of structural damage to neighboring supportiveor vascular tissue. The wallerian changes take place overthe subsequent 2–60 days (Povlishock and Coburn 1989).Identification of the molecular mechanisms involved mayeventually suggest interventions to block or reduce neuronaldamage (see Chapter 2, Neuropathology, andChapter 39, Pharmacotherapy of Prevention). Regenerativeactivity (including sprouting and enlarged axonalareas at the tip of growing axons) over a period of weeksto several months subsequent to the trauma can be seen,perhaps mirroring the recovery process observed inhumans (Povlishock and Christman 1995; Povlishock andCoburn 1989). Povlishock and Christman (1995) suggestedthat the success or functional outcome of suchregenerative activity may depend on the severity of injury.There is evidence that MTBI results in neuropathologicalchanges in humans similar to those described inanimal models. For example, Oppenheimer (1968) reporteddestruction of myelin, axonal retraction bulbs(beadlike structures at the proximal end of a rupturedaxon), and aggregates of small reactive glial cells (indicatingrecent tissue injury) in a variety of brain regions in fivepatients with minor or trivial injuries. One such patienthad been knocked down by a motor scooter and had noLOC but was described as “stunned.” PTA lasted approximately

20 minutes. Using immunostaining for amyloidprecursor protein as a marker for axonal injury, Blumbergset al. (1994) reported multifocal axonal injury in fiveindividuals who had sustained very mild injuries with periodsof unconsciousness as brief as 1 minute.In addition to the microscopic structural changes describedabove, both animal models and human studiessuggest that MTBI can result in at least temporary alterationof the normal balance between cellular energy demandand energy supply. Under normal circumstances,energy consumption roughly matches energy supply atthe neuronal level, and alterations in energy demand (i.e.,increased neuronal metabolic activity) can be accommodatedby utilization of intracellular stores, and subsequentlyby increased blood flow to facilitate the supply ofoxygen and glucose. However, even MTBI can result insignificant changes in intracellular and extracellular concentrationsof ions such as potassium, sodium, calcium,and magnesium. Restoration of the normal intracellularand extracellular milieu requires a significant increase inenergy expenditure that is initially met by hyperglycolysis.However, ongoing energy demands require an increasein blood flow, and this normal coupling of increasedenergy demand to increased energy supply can bedisrupted after MTBI (Bergsneider et al. 2000; Giza and