models of TBI, but clinical trials have failed to reproduce the benefit seen in those studies (Faden, 2002; Marklund et al., 2006). The failure to translate to success in human TBI may reflect both limitations of the experimental model and differences in the design of the animal studies (Faden, 2002; Faden and Stoica, 2007) and has led to consideration of developing a model that would be more relevant to human TBI (Morales et al., 2005). It has been suggested that no single animal model can accurately reproduce the complex, heterogeneous human TBI (Morales et al., 2005). It is also possible that the current models should be refined to involve a more comprehensive experimental design that includes dose–response studies in concert with measures of both behavior and pathology; incorporates secondary insults, such as hypotension, hypovolemia, and hypoxia, that are seen in human TBI; addresses the consequences of repeated brain injuries; considers age and sex as variables in the experimental design; and provides monitoring of measures (cerebral perfusion pressure, ICP, blood pressure, and blood gases) that would parallel those used in the management of human TBI (Statler et al., 2001; Faden, 2002; Morales et al., 2005; Thompson et al., 2005). Finally, with the recommendation to develop a classification for human TBI based on pathoanatomic measures (Saatman et al., 2008), future efforts to develop and/or refine animal models will need to consider the findings that emerge from this clinical effort.

SUMMARY OF PATHOBIOLOGY OF TRAUMATIC BRAIN INJURY

The pathobiology of TBI can be summarized as follows:

  • The traditional classifications of TBI have been based on the type of injury (focal vs. diffuse) and on the biomechanics of the primary injury (closed and missile injuries). The primary insults damage both gray and white matter and initiate secondary pathogenic events at the cellular, biochemical, and molecular levels that collectively mediate widespread damage.

  • The final common pathways for TBI are similar despite differences in the initiating event. For example, calcium-mediated activation of neurotoxic factors, production of free radicals, and mitochondrial dysfunction are general features of TBI. However, regional patterns of vulnerability and the magnitude and kinetics of those downstream events are governed by the initiating event.

  • Unlike animal models that are designed to reproduce a particular characteristic of TBI, human TBI is characteristically heterogeneous, particularly after a severe injury, with features of both focal and diffuse brain damage. The diversity of clinical outcomes reflects that heterogeneity at least in part.

Although this chapter is focusing on TBIs that are typically seen in civilians, an emerging field of research addresses brain injuries related to the military. This research includes missile-related and blast-induced brain injuries. What is clear from the effort to date is that the pathobiology of military TBIs, particularly blast injuries, has characteristics not seen in other types of brain injury, despite similar secondary injury cascades.



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