microvasculature, including the formation of vasogenic edema (Hall 1996; Kontos and Povlishock 1986; Siesjo and Wieloch 1985).
cellular changes herald expression of cytokines and other markers of injury, including heat shock protein and im-mediate early genes. There is also a rapid and florid astro-cytic response that defines the margins of the contusion with the establishment of a glial limitans.
In many of the models, there is also evidence of more widely distributed pathology. Such changes include tissue tears in the dentate gyrus of the hemisphere and evidence of axonal swellings and bulb formation in the white mat-ter of both the ipsi- and contralamat-teral hemispheres.
Reference was made in the section Classification and Mechanisms of Brain Damage to the concept of primary and secondary brain damage, with the implication that the latter is not restricted to head injury but is the conse-quence of a further insult to an already damaged brain.
Additional evidence for this concept is the identification of changes in various neuronal populations that are re-mote from the site of contusion. There are a number of mechanisms that might account for these lesions, and their importance has been demonstrated by the finding that lesions in the CA-3 subfield and hilus of the dentate gyrus correlate with the severity of posttraumatic mem-ory dysfunction (Smith et al. 1995).
Models of Diffuse TBI
Typically, models of diffuse traumatic brain injury attempt to replicate the human clinicopathological entity of TAI, in which there is widespread microscopical evidence of dam-age to the axons. Damdam-age to axons under these conditions has been shown to be produced primarily by high-strain rotational or angular acceleration, not necessarily associ-ated with impact. Until relatively recently there was only one animal model that replicated all of the clinical features of TAI. This was the Penn-2 Hyge model using nonhuman primates, in which it was possible to induce a pattern and type of damage that paralleled the features seen in humans (Adams et al. 1982; Gennarelli et al. 1982). Nonhuman pri-mates were originally chosen for this experimental model due to their large brain mass, which allows the develop-ment of high strain between regions of tissue. As the brain size decreases, the forces necessary to induce similar strains increase exponentially. To exemplify this point, the Penn-2 device is capable of producing 18,000 kg of thrust, just enough to generate sufficient forces to cause TAI in a 50-to 75-g nonhuman primate brain. In this model, it was pos-sible to induce a spectrum of pathology, the exact nature of which depended on the biomechanical profile of the injury.
For example, rapid rotation acceleration in the sagittal plane produced SDHs, whereas a slower acceleration in the coronal plane produced DAI (Gennarelli and Thibault 1982).
More recently, a porcine model of rotational acceler-ation brain injury has been developed using young adult miniature swine that have a brain mass of approximately 60–70 g (Meaney et al. 1993). To date, although axonal injury has been produced in subcortical white matter in the porcine model, it has not been possible to induce tis-sue tears or gliding contusions, and axonal injury is asso-ciated with only brief loss of consciousness (Smith et al.
1997b).
A model of impact acceleration brain injury in rats has been shown to produce widely distributed axonal damage.
In this model, a weight is dropped onto a plate fixed to the cranium of a rat (Marmarou et al. 1994). Unlike most brain injury models, the head is not fixed in place and is allowed to rotate downward. It has been suggested that it is this motion, in combination with impact, which results in the overt widespread damage to axons.
Models have also been developed to mimic closed head injury in infants and children. These include the use of immature rats (Adelson et al. 1996) and juvenile pigs (Duhaime et al. 2000; Madsen and Rejke-Nielsen 1987).
A more recent study using the Hyge apparatus in the im-mature pig has demonstrated that nonimpact, inertial brain trauma induced SDH and TAI, with a characteristic distribution (Raghupathi and Margulies 2002).
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