Introduction

Over the past 20 years, our appreciation of the pathobiology of traumatic brain injury has increased significantly. Prior to that time, it was unknown whether the morbidity associated with traumatic brain injury was a direct result of traumatically induced vascular failure or alternatively the direct disruption of brain parenchyma and its neural connections. We now appreciate that the traumatic episode involves a progression and possible interaction of brain parenchymal and vascular changes across the full spectrum of traumatic brain injury, ranging from mild through severe. In relation to the brain parenchyma, it is now understood that brain injuries of varying severity are capable of releasing a surge of neurotransmitters that participate in abnormal agonist–receptor interactions causing altered postsynaptic signal transduction correlated with behavioral abnormalities (Hayes et al., 1988, 1992; Mclntosh et al., 1989a; Katayama et al., 1990). Importantly, these same neuroexcitatory surges have also been linked to post-traumatic glucose hypermetabolism (Hayes et al., 1984; Yoshino et al., 1991; Hovda, 1996) that can have catastrophic consequences if an uncoupling of flow and metabolism occurs. In addition to these neuroexcitatory-mediated changes, it is known that the shear and tensile forces of injury also stretch axons throughout the neuraxis, resulting in focal alterations of axoplasmic transport that lead to axonal swelling and detachment (Povlishock et al., 1983; Povlishock, 1992; Povlishock and Jenkins, 1995).