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Gulf War and Health, Volume 7: Long-Term Consequences of Traumatic Brain Injury 2 BIOLOGY OF TRAUMATIC BRAIN INJURY This chapter presents a general overview of the pathobiology of traumatic brain injury (TBI) and describes two traditional classifications of TBI that are based on findings in animal models and in brain-injured patients. It also addresses the emerging field of blast-induced neurotrauma (BINT) with an emphasis on the biomechanics and physics of injury, pathobiology, and their implications in the context of medical treatment. PATHOBIOLOGY OF TRAUMATIC BRAIN INJURY Damage to the traumatized brain is a consequence of the initial mechanical insult and the subsequent activation of secondary pathogenic cascades that collectively influence the temporal progression of the primary insult (McIntosh, 1994; Werner and Engelhard, 2007). It is important to emphasize that human TBI is a heterogeneous disorder in which pathogenic factors may have variable magnitude and occur in various combinations (Graham et al., 2000; Faden, 2002). Single isolated lesions are relatively uncommon in human TBI (Graham et al., 2000). The more common presentation is one of multiple lesions—an outcome that probably reflects injury severity (Graham et al., 2000). A more generalized picture has emerged from studies of the injured human brain and in animal models of TBI in which the pathobiology of TBI is considered in the context of four phases (described below) (Graham et al., 2002). That categorization has provided a context for better understanding the relationship between the primary insult and secondary pathogenic events. However, the temporal sequence of events may overlap substantially (Moppett, 2007). Phase 1 represents the initial mechanical damage that results in rupture of cellular and vascular membranes, release of intracellular contents, and cessation of blood flow (McIntosh, 1994; Werner and Engelhard, 2007). Impairment of cerebral blood flow and metabolism leads to anaerobic glycolysis and accumulation of lactic acid (Werner and Engelhard, 2007). Energy-dependent membrane ion pumps fail as adenosine triphosphate (ATP) stores become depleted (Werner and Engelhard, 2007). This phase is governed by the nature of the injury and the profile of the host (Graham et al., 2002). The location and magnitude of brain damage reflect the characteristics of the primary insult; for example, gunshot wounds and vehicular collisions produce different patterns of injury. Specifics of the host—including age, health, sex, and genetics—influence the outcome of the primary insult (Moppett, 2007).
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Gulf War and Health, Volume 7: Long-Term Consequences of Traumatic Brain Injury Phase 2 involves the progressive deterioration of the neural axis that arises from biochemical and molecular events that collectively promote necrotic and apoptotic cell death (Graham et al., 2002; Thompson et al., 2005). The events include release of the excitatory amino acid neurotransmitters, such as glutamate and aspartate; activation of glutamate receptors; influx of calcium into cells and release of calcium from intracellular stores; free-radical generation; and inflammation (Graham et al., 2002; Thompson et al., 2005; Werner and Engelhard, 2007). In both animal and human studies, TBI results in increased extracellular glutamate concentrations (Schouten, 2007). The increase has been attributed to disruption of the blood–brain barrier and exposure of the brain to humoral-derived glutamate, excessive synaptic release, and decreased glutamate transporter (Yi and Hazell, 2006). Glutamate is the most abundant excitatory neurotransmitter in the brain. In the setting of TBI, an increase in glutamate results in overstimulation of ion-channel–linked and G-protein–linked glutamate receptors. Excessive activation of those ion channels results in prolonged depolarization and ionic imbalance, depletion of ATP stores, and increases in intracellular free calcium that potentially activate numerous pathogenic cascades (Yi and Hazell, 2006). Intracellular calcium increases rapidly after TBI. That is attributed to an increased influx of Ca2+ from the extracellular compartment and a release of Ca2+ from intracellular stores, including mitochondria. The increase in intracellular Ca2+ leads to activation of intracellular proteases, including calcium-activated neutral proteases (calpains), phospholipases, and endonucleases. Those downstream events mediate cytoskeletal damage, increase intracellular concentrations of free fatty acids, promote free-radical generation, and lead to cell injury and death (Marklund et al., 2006; Werner and Engelhard, 2007). An important component of the secondary injury cascade results from the generation of reactive oxygen species (ROSs) that include superoxides, hydrogen peroxide, hydroxyl radicals, nitric oxide, and peroxynitrite. Each ROS has an unpaired electron in its outer electron shell and thus is highly reactive and unstable (Calabrese et al., 2008). The excessive production of ROSs is due in part to excitotoxicity, free iron, and interactions between ROSs (Potts et al., 2006). Glutamate-mediated excitotoxicity leads to an increase in intracellular calcium and the subsequent induction of enzymes, such as nitric oxide synthase and xanthine oxidase, that produce free radicals. Mitochondria, when exposed to increased intracellular calcium, become sources of ROSs (Sullivan et al., 2005; Bayir and Kagan, 2008). Accumulation of free iron, resulting from the degradation of heme, catalyzes the formation of superoxide from free oxygen and of the hydroxyl radical from hydrogen peroxide. It is important to note that free radicals such as superoxide and nitric oxide interact with one another to produce other free radicals, including peroxynitrite. Under physiologic conditions, endogenous antioxidants—including superoxide dismutase, glutathione peroxidase, and catalase—prevent oxidative damage (Potts et al., 2006). Superoxide dismutase catalyzes the conversion of superoxide to hydrogen peroxide, which is further degraded by glutathione peroxidase and catalase to molecular oxygen and water. Low-molecular-weight antioxidants—including glutathione, melatonin, and uric acid—and dietary sources of tocopherols, ascorbic acid and lipoic acid, are also available in the brain. A group of genes, referred to as vitagenes, function to preserve cellular homeostasis during stress. This family consists of the heat-shock proteins HO-1 and Hsp32. HO-1 confers protection by degrading the pro-oxidant heme and producing biliverdin, the precursor of the
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Gulf War and Health, Volume 7: Long-Term Consequences of Traumatic Brain Injury antioxidant bilirubin. Hsp70 inhibits NF-κB signaling and intrinsic apoptotic pathways (Calabrese et al., 2008). In the setting of TBI, each of those neuroprotective systems in the brain becomes overwhelmed, and cell damage arises from free-radical–mediated lipid peroxidation. protein and DNA oxidation, and inhibition of the mitochondrial electron-transport chain. In general, an inflammatory response in the brain differs from that in other organs. It is exemplified by a more modest and delayed recruitment of leukocytes into the brain than into peripheral organs (Lucas et al., 2006). Brain microglia, in contrast, are activated and release inflammatory mediators beginning within minutes to hours after TBI (Lucas et al., 2006). The mediators often express neurotoxic and neuroprotective properties (Morganti-Kossmann et al., 2007). For example, cytokines may either promote damage or support recovery processes; in some cases, cytokines, such as interleukin-6, may perform both functions (Morganti-Kossmann et al., 2007). Collectively, the pathogenic cascade of events described in the preceding paragraphs culminates in death of neurons and glia and white matter degeneration. Distinct anatomic patterns of cell death that accompany TBI are evident in neuronal and glial populations and reflect both apoptosis and necrosis (Raghupathi, 2004; Bramlett and Dietrich, 2007). Necrotic death and apoptotic cell death of neurons and glia have been identified in contused areas, the tissue bordering a contusion, and subcortical regions, including the hippocampus, cerebellum, and thalamus (Raghupathi et al., 2000; Raghupathi, 2004; Yakovlev and Faden, 2004). In the case of the contused cortex, gross loss of neurons culminates in a distinct lesion, enlarges with time postinjury, and coincides with progressive atrophy of gray and white matter (Bramlett and Dietrich, 2007). The vulnerability of astrocytes to TBI has also been recently reconsidered (Floyd and Lyeth, 2007). Historically, the dogma has been that astrocytes are more resistant to injury than neurons (Lukaszevicz et al., 2002). Beyond the characteristic swelling that is seen (Castejon, 1998), those cells show an early injury response that coincides with regional patterns of neuronal vulnerability. Kinetic studies suggest that loss of astrocytes precedes neuronal injury suggesting that early impairment of astrocytes contributes to neuronal death (Floyd and Lyeth, 2007). Astrocytes play time-dependent diverse roles in TBI (Chen and Swanson, 2003); here we consider their involvement in the acutely injured brain (modulation of extracellular glutamate and K+ concentrations, scavenging of ROSs, and inflammation) and during wound healing (glial scar formation, restoration of the blood–brain barrier, and growth factor production) (Chen and Swanson, 2003). Neurons depend on astrocytes for their survival in an acutely injured brain (Chen and Swanson, 2003). After brain injury, glutamate is cleared from the extracellular space by Na+-dependent glutamate transporters that are localized on astrocytes. Thus, astrocytes are thought to play a critical role in maintaining extracellular glutamate concentrations below toxic levels. Glutamate transport occurs across a steep concentration gradient with much higher concentrations (1–10 mM) in neurons and glia and lower concentrations (less than 10 mM) in the extracellular compartment. That gradient is overcome by the coupling of the intracellular influx of glutamate ions to the inward movement of 3 Na+ ions and 1 H+ ion and the outward movement of 1 K+, a process that shifts energy expenditure from neurons to astrocytes. Glutamate transporters can move substrate both inward and outward.
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Gulf War and Health, Volume 7: Long-Term Consequences of Traumatic Brain Injury Astrocytes can scavenge ROSs, limiting the rise in extracellular K+, and are active participants in the proinflammatory response (Chen and Swanson, 2003). Astrocytes express higher levels of the antioxidant glutathione than neurons and thus may support neuronal survival. As brain tissue becomes ischemic, extracellular K+ increases, and this leads to cell swelling and glutamate release. Astrocytes can also limit the increase in intracellular K+ both indirectly and directly. The former occurs by passive movement of K+ from the extracellular space into astrocytes that is facilitated by electric coupling between glia. With more K+, K+ is actively taken up by the action of astrocyte Na+/K+ ATPase. Finally, there are parallels between the astrocyte response to injury and the proinflammatory response seen in tissues outside the central nervous system. Astrocytes are sources of inducible nitric oxidase synthase and produce cytokines, interleukins, and interferons. The consequences of production of those factors are not completely understood, in part because of their cross-talk with one another and the context of their involvement, which is probably cell-specific. In the more chronically injured brain, astrocytes are integral to both adverse and beneficial wound-healing events (Chen and Swanson, 2003). They form a glial scar that represents both physical and chemical barriers to axonal regeneration. Counter to that adverse role, reactive astrocytes also participate in the re-establishment of the blood–brain barrier and release trophic factors that may foster plasticity. Damage to white matter fiber tracts is also a hallmark of TBI. White matter injury is evidenced in part by axonal degeneration, oligodendrocyte death, and demyelination. White matter damage in relative isolation (“pure” diffuse axonal injury) is sufficient to result in severe and persistent morbidity. White matter damage is also often found in combination with other injuries, such as contusion (as produced in many experimental models). With the advent of imaging, including diffusion-tensor imaging (DTI), evolving white matter damage can be measured in detail and validated against more conventional anatomic outcomes. This approach is exemplified in a recent study that used DTI to assess axonal injury over time (MacDonald et al., 2007). Pericontusional white matter damage was evident in both the acute and subacute periods after experimental TBI. DTI revealed the stereotypic response of early axonal injury followed by demyelination and edema at later periods postinjury. Those findings provide a foundation for translation to the clinical setting where findings in the animal model can be tested for their predictability in human TBI. Diffuse axonal injury is triggered by acceleration–deceleration forces (Buki and Povlishock, 2006). Although instantaneous direct damage to axons may result from shear and tensile forces, the more common presentation is one whereby axons undergo an evolving process (Maxwell et al., 1997) that begins with focal axolemmal permeability, which permits influx of calcium that is normally excluded by the axon (Buki and Povlishock, 2006) . In vitro studies of fine, unmyelinated fibers also suggest that deformation of axons induces sodium influx via Na+ channels, which triggers an increase in intra-axonal calcium via the opening of voltage-gated calcium channels and reversal of the Na+–Ca2+ exchanger (Wolf et al., 2001). Calcium-induced proteolytic pathways are key components of evolving axonal pathogenesis (Buki and Povlishock, 2006). Calcium-induced activation of the cysteine protease calpain results in degradation of spectrin, a major constituent of the subaxonal cytoskeleton. Calcium-mediated spectrin proteolysis is evident on the surface of mitochondria, and it is
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Gulf War and Health, Volume 7: Long-Term Consequences of Traumatic Brain Injury possible this proteolysis mediates mitochondrial damage. Mitochondrial damage can lead to energy failure and thus disrupt ionic homeostasis, activation of the caspase death cascade, and ultimately structural proteolysis and axonal disconnection. Cell death is the downstream consequence of perturbations that begin within minutes after injury and extend over a period of days and in some cases months. The kinetics of cell death varies according to cell type, location, nature of the initial insult, and the collective profile of secondary pathogenic events. The mechanisms of cell death, necrosis and apoptosis, have been studied in detail. Necrotic cell death involves membrane failure, disruption of ion homeostasis, and rapid degradation of the cytoskeleton (Povlishock and Katz, 2005). In classical light microscopy, neurons initially appear swollen with pyknotic nuclei (Povlishock and Katz, 2005) and show an affinity for histochemical markers of cell injury, including acid fuchsin (Cortez et al., 1989) and fluorojade (Hallam et al., 2004). The nucleus and cytoplasmic organelles, including mitochondria, are swollen; there is cytoplasmic vacuolation; and the integrity of the plasma membrane is compromised (Dietrich et al., 1994; Raghupathi et al., 2000). The pathobiology of apoptotic cell death has yet to be clearly elucidated. In contrast with necrosis, apoptosis is not linked to disruption of the cell membrane. Rather, the classic picture of an apoptotic neuron includes an intact membrane with internucleosomal DNA strand breaks, nuclear shrinkage, chromatin compaction, and cytoplasmic condensation and disintegration. The end stage of apoptosis is characterized by blebbing of the cell membrane and the emergence of spherical bodies. In contrast with the rapid death seen in necrosis, apoptotic cell death occurs over a longer period. Data also show that apoptosis is associated with a shift in the balance between proapoptotic and antiapoptotic factors (Raghupathi, 2004). Apoptosis has been linked to the excitatory amino acid cascade, increased intracellular calcium, and free radicals (Raghupathi, 2004). Data also show that apoptosis is associated with a shift in the balance between proapoptotic and antiapoptotic factors (Raghupathi, 2004). Neuronal apoptosis occurs by two pathways: one involves the activation of caspases, and a second is caspase-independent and involves the release of apoptotic factors from mitochondria (Zhang et al., 2005a). Proteolytic cleavage of substrates by caspases, whether by an extrinsic or intrinsic pathway, produces the characteristic phenotype of apoptosis. Some mitochondrial proteins, such as apoptosis-inducing factor (AIF), can induce apoptosis in the absence of activation of caspases. AIF-mediated cell death has been demonstrated in an experimental model of TBI (Zhang et al., 2005a). The secondary mechanisms occurring during phase 2 are potential targets for therapeutic intervention because of their kinetic profiles (Marklund et al., 2006). They are typically delayed in onset and may extend for hours or months after TBI (Graham et al., 2002; Thompson et al., 2005; Marklund et al., 2006). A key challenge, however, is to translate findings from animal models of TBI to the head-injured patient. Animal models are designed to produce a relatively homogeneous type of injury whereas a key feature of human TBI is heterogeneity. That distinction may partially account for differences in the kinetics of secondary pathogenic events when one compares findings in the animal model with the human condition. For example, with few exceptions, increased extracellular glutamate returns to control values within the first several hours after experimental TBI (Marklund et al., 2006). In contrast, microdialysis data from human TBI have demonstrated an increase in glutamate that is sustained for up to 9 days after injury (Bullock et al., 1998; Vespa et al., 1998; Marklund et al., 2006). A recent review addressed the
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Gulf War and Health, Volume 7: Long-Term Consequences of Traumatic Brain Injury failure of large, multicenter phase II clinical trial to produce an improvement in outcome in TBI patients (Marklund et al., 2006) and raised concern about the ability to translate from bench to bedside. (For detailed discussion of why therapies shown to be efficacious in animals failed to translate to human TBI, see recent reviews: Statler et al., 2001; Cernak, 2005; Morales et al., 2005; Thompson et al., 2005; Marklund et al., 2006; Kokiko and Hamm, 2007.) In phase 3, secondary events—such as hypoxia, hypotension, ischemia, increased intracranial pressure (ICP) and brain swelling, and metabolic failure—perturb brain function further and augment cell injury (Statler et al., 2001; Graham et al., 2002; Marklund et al., 2006). As in phase 2, those secondary insults occur over an extended period of time postinjury and so are suitable targets for therapeutic intervention. In human TBI, hypoxia and hypotension occur in one-third of patients with TBI (Statler et al., 2001; Morganti-Kossmann et al., 2007). Hypotension is a principal predictor of poor outcome after TBI: a single episode of systolic blood pressure of less than 90 mm Hg is associated with a 150% increase in mortality (Statler et al., 2001). In a recent prospective multicenter study, about 40% of patients with TBI sustained a secondary insult before reaching the hospital (Chi et al., 2006). Of those patients, 65% had episodes of hypoxia, 11% were hypotensive, and 24% showed a combination of those two secondary insults. Episodes of hypoxia were particularly notable in that they were independently predictive of death. Moreover, the episodes occurred despite aggressive medical management, including endotracheal intubation. Posttraumatic ischemia has been demonstrated in both animal models and humans after TBI and is associated with poor neurologic outcome. The factors mediating posttraumatic ischemia include mechanical damage to blood vessels, hypotension in concert with autoregulatory failure, and lack of available endogenous vasomodulators, such as nitric oxide and prostaglandins (Werner and Engelhard, 2007). Injury severity is a determinant of the magnitude of increase in ICP (Thompson et al., 2005). Increased ICP is usually a consequence of brain swelling that occurs in response to disruption of the blood–brain barrier and the later evolution of cerebral edema (Pasternak and Lanier, 2007). Edema has a profound effect on the brain because of the restrictions imposed by the bony calvarium, which limit further expansion of the edematous brain and lead to an increase in ICP. Metabolic failure arises from mitochondrial dysfunction, reduced availability of the nicotinic coenzyme pool, and intramitochondrial overload (Werner and Engelhard, 2007). Outcome is worsened in accordance with the degree of metabolic failure (Werner and Engelhard, 2007). An alternative finding has been hypermetabolism of glucose, which reflects an uncoupling of cerebral blood flow and metabolism. It is a scenario whereby massive transmembrane ionic fluxes and neuroexcitation are not adequately met by increases in cerebral blood flow (Werner and Engelhard, 2007). Phase 4, representing recovery and functional outcome, is influenced by primary and secondary injury responses and by wound-healing events, including phagocytic removal of cellular debris, glial scar formation, and plastic changes in neural networks. Recovery of function after brain injury is described in three phases (Wieloch and Nikolich, 2006). Phase 1 involves reversal of inhibition of function and initiation of cell repair, phase 2 entails a change in the properties of existing pathways, and phase 3 involves the formation of new connections
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Gulf War and Health, Volume 7: Long-Term Consequences of Traumatic Brain Injury (Wieloch and Nikolich, 2006). Efforts have been made to reverse secondary pathogenesis with an emphasis on extending treatment beyond the acute injury into this recovery phase (Kokiko and Hamm, 2007). One result is the concept that enhancing neuronal activity may facilitate cognitive recovery (Kokiko and Hamm, 2007). Strategies to support recovery also include early activation of noradrenergic, dopaminergic, and cholinergic pathways to promote functional plasticity and growth factors to support plasticity; cortical stimulation and physical therapy can enhance recovery during the chronic phase (Wieloch and Nikolich, 2006). On the basis of the complex pathophysiology of TBI, there has been a concerted effort to develop biomarkers of injury that would serve as both diagnostic and prognostic measures of injury or recovery (Kochanek et al., 2008). The availability of cerebrospinal fluid, brain tissue, and interstitial fluid from both experimental models of TBI and brain-injured patients has made it possible to identify candidate biomarkers. Putative serum biomarkers of interest have included cyclic adenosine monophosphate, thought to be an indicator of depth of coma, and neuron-specific enolase, myelin basic protein, and S100B, markers of structural damage. In more recent years, proteomics and multibead technology, based on multiple enzyme immunosorbent assays, have been developed to assay multiple proteins from a relatively small sample. Those advanced technologies offer the opportunity to track the complex injury cascade that accompanies TBI and ultimately to generate a panel of biomarkers that can be applied to the brain-injured patient. TRADITIONAL CLASSIFICATIONS OF TRAUMATIC BRAIN INJURY TBI may be classified according to the extent of the pathology of the injury or according to the biomechanics of the injury. Both these classifications are discussed below. CLASSIFICATION ACCORDING TO EXTENT OF PATHOLOGY TBI has been described pathologically as focal and/or diffuse (Smith et al., 2003; Werner and Engelhard, 2007) (Figure 2.1). Focal damage is characterized by cerebral contusions resulting from forces related to impact (Povlishock and Katz, 2005). Contrecoup contusion may be apparent but is thought to be a consequence of acceleration and deceleration rather than impact (Graham et al., 2002). Diffuse injuries arise from rapid rotations of the head that result in tissue distortion or shear and typically occur in motor-vehicle collisions and less often in falls and assaults (Smith et al., 2003; Morales et al., 2005). It is important to emphasize that focal and diffuse injuries overlap (Povlishock and Katz, 2005). Human TBI, particularly severe TBI, is heterogeneous (Graham et al., 2000; Faden, 2002). It is unusual to find a single lesion and more common to find both focal and diffuse patterns of damage. Moreover, the number of lesions increases in proportion to the severity of the injury and correlates with morbidity (Graham et al., 2000). Pathologic Features of Focal Traumatic Brain Injury Focal injuries are evidenced by lacerations, contusions, and hematomas resulting from overt vascular damage (Morales et al., 2005). Localization of a hematoma depends in part on which elements of the vascular tree are injured. Rupture of meningeal vessels, bridging veins, and intrinsic vasculature leads to extradural, subdural, and intracerebral hematomas, respectively.
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Gulf War and Health, Volume 7: Long-Term Consequences of Traumatic Brain Injury Intracerebral hematomas are commonly found in the gray matter or at boundaries between gray and white matter (Povlishock and Katz, 2005). FIGURE 2.1 Pathologic classification of TBI. Disruption of the blood–brain barrier is a feature of TBI, including focal insults. Trauma produces physical damage to blood vessels, manifested in part by hemorrhage. Barrier disruption allows entry of toxic molecules while also providing an avenue for delivery of therapeutic agents into the damaged tissues (Saunders et al., 2008). It is the latter that has prompted investigators to define the window of barrier disruption better. There is evidence that the barrier to plasma-protein–size molecules is about 4 hours, whereas smaller molecules (smaller than 10 kDa) can access the brain for up to 4 days (Saunders et al., 2008). In the head-injured patient, disruption of the barrier is associated with life-threatening cerebral edema and is the basis of treatment with intravenous hyperosmolar solutions. However, the mechanism of action is not clearly understood, and there is no gold standard, on the basis of evidence from a clinical trial, of its effectiveness (Narayan et al., 2002). Neuronal injury is also a feature of focal TBI. However, the patterns of neuronal injury are not necessarily restricted to contusional and pericontusional cortical sites (Raghupathi, 2004). Neuronal loss has been reported in more remote regions, including the hippocampus (Cortez et al., 1989; Kotapka et al., 1992; Lowenstein et al., 1992; Hicks et al., 1996), thalamus (Hicks et al., 1996; Sato et al., 2001), and the cerebellum (Sato et al., 2001; Park et al., 2006; Ai et al., 2007; Igarashi et al., 2007) in experimental models of TBI. Similar findings are seen in human TBI (Adams et al., 1985; Kotapka et al., 1992; Raghupathi, 2004). At the contusional site, neuronal injury is apparent within hours after trauma. Neurons initially appear swollen and with time assume a shrunken phenotype bearing a pyknotic nucleus, swollen mitochondria, and vacuolated cytoplasm. The volume of the lesion expands coincidentally with a chronic pattern of neuronal degeneration (Colicos et al., 1996; Hicks et al., 1996; Bramlett et al., 1997; Conti et al., 1998; Raghupathi, 2004). Pathologic Features of Diffuse Traumatic Brain Injury Four pathologic conditions have been attributed to diffuse TBI: traumatic axonal injury, hypoxic brain damage, brain swelling, and vascular injury (Morales et al., 2005; Povlishock and Katz, 2005). The disabling symptoms seen in TBI can arise from widespread traumatic axonal damage (Hurley et al., 2004; Morales et al., 2005) that is evident in postmortem brains after mild, moderate, or severe injury (Morales et al., 2005).
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Gulf War and Health, Volume 7: Long-Term Consequences of Traumatic Brain Injury Diffuse axonal injury, an important predictor of outcome (Graham et al., 2002), evolves over hours to days and is characterized by axonal swellings and bulbs (Hurley et al., 2004). Primary axotomy, that is, the severing of an axon, is rare in human TBI and is associated with severe TBI. Diffuse axonal injury may culminate in axotomy, but this process is likely delayed in onset, beginning 12–24 hours after injury (Moppett, 2007). It was originally thought that mechanically induced damage to axons impaired axonal transport and that this impairment led to axonal swelling and ultimately axonal disconnection. Recent work, however, has shed light on the pathobiology of axonal injury (Povlishock and Katz, 2005). Although tearing of the axon may occur, it is usually limited to more severe injuries. Rather, axonal injury evolves as a consequence of focal changes in the plasmalemma, including altered permeability, which ultimately impede axonal transport. Data suggest that altered axolemmal permeability allows the influx in calcium and the subsequent activation of proteases that then disrupt the cytoskeleton. Under conditions of normal transport kinetics, focal swelling occurs as a consequence of the buildup of transported molecules and leads ultimately to disconnection of the axon. Traumatic axonal swellings are not the only indicator of axonal damage. In fact, cytoskeletal perturbations after TBI need not culminate in axonal swellings (Povlishock and Katz, 2005). Rather, there may be a switch from anterograde to retrograde transport, which prevents the buildup of transported molecules (Povlishock and Katz, 2005). The complexity of axonal injury is also evidenced by recent studies of unmyelinated fiber tracts that showed that ionic dysregulation contributes to impairment of anterograde transport (Iwata et al., 2004). There are also data that show that unmyelinated, small-caliber axons may be particularly vulnerable to TBI (Reeves et al., 2005) and may play an important role in morbidity. Hypoxia, brain swelling, and vascular injury are also seen in diffuse injuries (see above as a description of those events is provided in more detail). CLASSIFICATION ACCORDING TO BIOMECHANICS OF INJURY Human head injury is also categorized according to the type of primary injury, either closed (blunt and not caused by a missile) or penetrating injuries (Graham et al., 2002; Morales et al., 2005) (Figure 2.2). Closed Injury Closed injury includes static and dynamic loading. Static loading occurs when a gradual force is applied to the brain whereas dynamic loading is characterized by rapid acceleration and deceleration. Static loading is not common in human head injury. It may occur in victims of natural disasters, such as earthquakes and landslides, who become trapped under heavy debris. In such a scenario, the head is particularly vulnerable to injury imposed by a gradual force, greater than 200 ms (Graham et al., 2002). Dynamic loading is more common in human brain injury and is associated with rapid acceleration and deceleration of the brain (Graham et al., 2002). In contrast with static loading, the forces associated with dynamic loading occur in less than 200 ms. Outcome is governed by tissue strain, which is defined as the amount of deformation that occurs as a consequence of the force applied to the brain (Graham et al., 2002; Morales et al., 2005).
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Gulf War and Health, Volume 7: Long-Term Consequences of Traumatic Brain Injury Tolerance of deformation varies with the type of tissue: bone is the strongest, and neural and vascular elements are the most vulnerable (Graham et al., 2002). Tensile strain and shear strain are the two types that most commonly cause damage to the vasculature and brain (Graham et al., 2002). Dynamic loading is categorized as either impulsive or impact loading. Impulsive loading occurs when the head is stopped or set into motion by an indirect impact, such as a blow to the thorax. Head injury results from the inertia produced by the movement of the head. Impact loading, the more common form of dynamic loading, results when a blunt object strikes the head. Inertia and contact occur in combination. An example would be deceleration of the head when a moving automobile strikes a tree and then the driver’s head strikes the steering wheel. FIGURE 2.2 Classification of TBI based on primary insult. Penetrating and Perforating Injuries Missile injuries, such as gunshot wounds, are a common cause of TBI. These injuries are classified as either penetrating or perforating depending on how the missile traverses the head (Graham et al., 2002). In penetrating injuries, the object enters and lodges within the cranial cavity. Perforating injuries occur when the object traverses the cranial cavity and leaves through an exit wound. The extent of damage is governed by features of the missile (shape and mass) and by its direction and velocity (Morales et al., 2005). Damage is also related to the amount of energy that is released in passage through the brain (Graham et al., 2002). Although brain damage is often severe, there are instances when the bullet bypasses critical centers and the person maintains consciousness (Graham et al., 2002). THERAPEUTICS AND TRAUMATIC BRAIN INJURY A number of recent reviews have addressed pharmacologic strategies of treatment for TBI (Faden, 2002; Morales et al., 2005; Thompson et al., 2005; Marklund et al., 2006; Schouten, 2007). The strategies have targeted secondary injury cascades, including those related to excitotoxicity, calcium channels, oxidative stress, inflammation, cell-death pathways, calpains, endocrine-related abnormalities, altered neurotransmission, and growth factors (Marklund et al., 2006). Pharmacologic blockade targeting those pathways has improved the outcome in animal
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Gulf War and Health, Volume 7: Long-Term Consequences of Traumatic Brain Injury 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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Gulf War and Health, Volume 7: Long-Term Consequences of Traumatic Brain Injury Cernak, I., Z. Malicevic, V. Prokic, G. Zunic, D. Djurdjevic, S. Ilic, and J. Savic. 1997. Indirect neurotrauma caused by pulmonary blast injury: Development and prognosis. International Review of the Armed Forces Medical Services 52:114–120. Cernak, I., J. Savic, D. Ignjatovic, and M. Jevtic. 1999a. Blast injury from explosive munitions. Journal of Trauma-Injury Infection and Critical Care 47(1):96–103. Cernak, I., J. Savic, Z. Malicevic, G. Zunic, P. Radosevic, and I. Ivanovic. 1996a. Leukotrienes in the pathogenesis of pulmonary blast injury. Journal of Trauma-Injury Infection and Critical Care 40(3 Suppl):S148–S151. Cernak, I., J. Savic, Z. Malicevic, G. Zunic, P. Radosevic, I. Ivanovic, and L. Davidovic. 1996b. Involvement of the central nervous system in the general response to pulmonary blast injury. Journal of Trauma-Injury Infection and Critical Care 40(3 Suppl):S100–S104. Cernak, I., J. Savic, G. Zunic, N. Pejnovic, O. Jovanikic, and V. Stepic. 1999b. Recognizing, scoring, and predicting blast injuries. World Journal of Surgery 23(1):44–53. Cernak, I., V. J. Savic, J. Kotur, V. Prokic, M. Veljovic, and D. Grbovic. 2000. Characterization of plasma magnesium concentration and oxidative stress following graded traumatic brain injury in humans. Journal of Neurotrauma 17(1):53–68. Cernak, I., V. J. Savic, A. Lazarov, M. Joksimovic, and S. Markovic. 1999c. Neuroendocrine responses following graded traumatic brain injury in male adults. Brain Injury 13(12):1005–1015. Cernak, I., Z. Wang, J. Jiang, X. Bian, and J. Savic. 2001a. Cognitive deficits following blast injury-induced neurotrauma: Possible involvement of nitric oxide. Brain Injury 15(7):593–612. ———. 2001b. Ultrastructural and functional characteristics of blast injury-induced neurotrauma. Journal of Trauma-Injury Infection and Critical Care 50(4):695–706. Chavko, M., W. A. Koller, W. K. Prusaczyk, and R. M. McCarron. 2007. Measurement of blast wave by a miniature fiber optic pressure transducer in the rat brain. Journal of Neuroscience Methods 159(2):277–281. Chen, Y., and R. A. Swanson. 2003. Astrocytes and brain injury. Journal of Cerebral Blood Flow and Metabolism 23(2):137–149. Chi, J. H., M. M. Knudson, M. J. Vassar, M. C. McCarthy, M. B. Shapiro, S. Mallet, J. J. Holcroft, H. Moncrief, J. Noble, D. Wisner, K. L. Kaups, L. D. Bennick, and G. T. Manley. 2006. Prehospital hypoxia affects outcome in patients with traumatic brain injury: A prospective multicenter study. Journal of Trauma-Injury Infection and Critical Care 61(5):1134–1141. Chiffelle, T. L. 1966. Pathology of direct air-blast injury. In Technical Progress Report DA-49-146-XY-055. Washington, DC: Defense Atomic Support Agency, Department of Defense. Clemedson, C. J. 1956. Blast injury. Physiological Reviews 36(3):336–354. Clemedson, C. J., L. Frankenberg, A. Jonsson, H. Pettersson, and A. B. Sundqvist. 1969. Dynamic response of thorax and abdomen of rabbits in partial and whole-body blast exposure. American Journal of Physiology 216(3):615–620. Colicos, M. A., C. E. Dixon, and P. K. Dash. 1996. Delayed, selective neuronal death following experimental cortical impact injury in rats: Possible role in memory deficits. Brain Research 739(1–2):111–119.
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Gulf War and Health, Volume 7: Long-Term Consequences of Traumatic Brain Injury Faden, A. I. 2002. Neuroprotection and traumatic brain injury: Theoretical option or realistic proposition. Current Opinion in Neurology 15(6):707–712. Faden, A. I., and B. Stoica. 2007. Neuroprotection: Challenges and opportunities. Archives of Neurology 64(6):794–800. Finnie, J. W. 1993. Pathology of experimental traumatic craniocerebral missile injury. Journal of Comparative Pathology 108(1):93–101. Fischer, J., and C. Mathieson. 2001. The history of the Glasgow Coma Scale: Implications for practice. Critical Care Nursing Quarterly 23(4):52–58. Floyd, C. L., and B. G. Lyeth. 2007. Astroglia: Important mediators of traumatic brain injury. Progress in Brain Research 161:61–79. Garai, O. 1944. Blast injury: Non-fatal case with neurological signs. Lancet 788–789. Gennarelli, T. A., and E. Wodzin. 2006. AIS 2005: A contemporary injury scale. Injury 37(12):1083–1091. Graham, D. I., T. Gennarelli, and T. K. McIntosh. 2002. Trauma. In Greenfields’s Neuropathology. New York: Arnold. Pp. 823–882. Graham, D. I., T. K. McIntosh, W. L. Maxwell, and J. A. Nicoll. 2000. Recent advances in neurotrauma. Journal of Neuropathology and Experimental Neurology 59(8):641–651. Guy, R. J., E. Kirkman, P. E. Watkins, and G. J. Cooper. 1998. Physiologic responses to primary blast. Journal of Trauma-Injury Infection and Critical Care 45(6):983–987. Hallam, T. M., C. L. Floyd, M. M. Folkerts, L. L. Lee, Q. Z. Gong, B. G. Lyeth, J. P. Muizelaar, and R. F. Berman. 2004. Comparison of behavioral deficits and acute neuronal degeneration in rat lateral fluid percussion and weight-drop brain injury models. Journal of Neurotrauma 21(5):521–539. Harmon, J. W., and M. Haluszka. 1983. Care of blast-injured casualties with gastrointestinal injuries. Military Medicine 148(7):586–588. Harmon, J. W., J. A. Sampson, G. M. Graeber, Y. Phillips, and D. Richmond. 1988. Readily available serum chemical markers fail to aid in diagnosis of blast injury. Journal of Trauma-Injury Infection and Critical Care 28(1 Suppl):S153–S159. Hicks, R., H. Soares, D. Smith, and T. McIntosh. 1996. Temporal and spatial characterization of neuronal injury following lateral fluid-percussion brain injury in the rat. Acta Neuropathology 91(3):236–246. Hirshberg, B., A. Oppenheim-Eden, R. Pizov, M. Sklair-Levi, A. Rivkin, E. Bardach, M. Bublil, C. Sprung, and M. R. Kramer. 1999. Recovery from blast lung injury: One-year follow-up. Chest 116(6):1683–1688. Huang, J. Z., Z. Yang, Z. Wang, and H. Leng. 1996. Study on characteristics of blast-fragment combined injury in dogs. Journal of Trauma-Injury Infection and Critical Care 40(3 Suppl):S63–S67. Huller, T., and Y. Bazini. 1970. Blast injuries of the chest and abdomen. Archives of Surgery 100(1):24–30. Hurley, R. A., J. C. McGowan, K. Arfanakis, and K. H. Taber. 2004. Traumatic axonal injury: Novel insights into evolution and identification. Journal of Neuropsychiatry and Clinical Neurosciences 16(1):1–7.
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Gulf War and Health, Volume 7: Long-Term Consequences of Traumatic Brain Injury Igarashi, T., M. B. Potts, and L. J. Noble-Haeusslein. 2007. Injury severity determines purkinje cell loss and microglial activation in the cerebellum after cortical contusion injury. Experimental Neurology 203(1):258–268. Irwin, R. J., M. R. Lerner, J. F. Bealer, P. C. Mantor, D. J. Brackett, and D. W. Tuggle. 1999. Shock after blast wave injury is caused by a vagally mediated reflex. Journal of Trauma-Injury Infection and Critical Care 47(1):105–110. Iwata, A., P. K. Stys, J. A. Wolf, X. H. Chen, A. G. Taylor, D. F. Meaney, and D. H. Smith. 2004. Traumatic axonal injury induces proteolytic cleavage of the voltage-gated sodium channels modulated by tetrodotoxin and protease inhibitors. Journal of Neuroscience 24(19):4605–4613. Jaffin, J. H., L. McKinney, R. C. Kinney, J. A. Cunningham, D. M. Moritz, J. M. Kraimer, G. M. Graeber, J. B. Moe, J. M. Salander, and J. W. Harmon. 1987. A laboratory model for studying blast overpressure injury. Journal of Trauma-Injury Infection and Critical Care 27(4):349–356. Jones, E., N. T. Fear, and S. Wessely. 2007. Shell shock and mild traumatic brain injury: A historical review. American Journal of Psychiatry 164(11):1641–1645. Khil'ko, V. A., V. R. Gofman, A. T. Grechko, L. A. Glaznikov, and A. Shulev Iu. 1997. [The early diagnosis of the severity of blast trauma to the brain and auditory system]. Zhurnal voprosy neǐrokhirurgii imeni N. N. Burdenko (3):35–37. Khil'ko, V. A., A. Shulev Iu, A. A. Starchenko, N. V. Zgoda, A. N. Khlunovskii, S. A. Komarets, and V. V. Blinov. 1995a. [The immunological and biochemical reactions of the cerebrospinal fluid in victims of blast injuries of the skull and brain]. Vestnik khirurgii imeni I. I. Grekova 154(4–6):54–55. Khil'ko, V. A., A. Shulev Iu, N. V. Zgoda, A. A. Starchenko, A. N. Khlunovskii, S. A. Komarets, and V. N. Bikmullin. 1995b. [Cellular immune reactions in the victims of explosive injuries to the skull and brain]. Vestnik khirurgii imeni I. I. Grekova 154(1):64–66. Kochanek, P. M., R. P. Berger, H. Bayir, A. K. Wagner, L. W. Jenkins, and R. S. Clark. 2008. Biomarkers of primary and evolving damage in traumatic and ischemic brain injury: Diagnosis, prognosis, probing mechanisms, and therapeutic decision making. Current Opinions in Critical Care 14(2):135–141. Kokiko, O. N., and R. J. Hamm. 2007. A review of pharmacological treatments used in experimental models of traumatic brain injury. Brain Injury 21(3):259–274. Kotapka, M. J., D. I. Graham, J. H. Adams, and T. A. Gennarelli. 1992. Hippocampal pathology in fatal non-missile human head injury. Acta Neuropathology 83(5):530–534. Lavery, G. G., and K. G. Lowry. 2004. Management of blast injuries and shock lung. Current Opinions in Anesthesiology 17(2):151–157. Levin, H. S. 1990. Memory deficit after closed head injury. Journal of Clinical and Experimental Neuropsychology: Official Journal of the International Neuropsychological Society 12(1):129–153. ———. 1995. Prediction of recovery from traumatic brain injury. Journal of Neurotrauma 12(5):913–922.
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Gulf War and Health, Volume 7: Long-Term Consequences of Traumatic Brain Injury Moochhala, S. M., S. Md, J. Lu, C. H. Teng, and C. Greengrass. 2004. Neuroprotective role of aminoguanidine in behavioral changes after blast injury. Journal of Trauma-Injury Infection and Critical Care 56(2):393–403. Moppett, I. K. 2007. Traumatic brain injury: Assessment, resuscitation and early management. British Journal of Anaesthesia 99(1):18–31. Morales, D. M., N. Marklund, D. Lebold, H. J. Thompson, A. Pitkanen, W. L. Maxwell, L. Longhi, H. Laurer, M. Maegele, E. Neugebauer, D. I. Graham, N. Stocchetti, and T. K. McIntosh. 2005. Experimental models of traumatic brain injury: Do we really need to build a better mousetrap? Neuroscience 136(4):971–989. Morganti-Kossmann, M. C., L. Satgunaseelan, N. Bye, and T. Kossmann. 2007. Modulation of immune response by head injury. Injury 38(12):1392–1400. Mundie, T. G., K. T. Dodd, M. S. Lagutchik, J. R. Morris, and D. Martin. 2000. Effects of blast exposure on exercise performance in sheep. Journal of Trauma-Injury Infection and Critical Care 48(6):1115–1121. Narayan, R. K., M. E. Michel, B. Ansell, A. Baethmann, A. Biegon, M. B. Bracken, M. R. Bullock, S. C. Choi, G. L. Clifton, C. F. Contant, W. M. Coplin, W. D. Dietrich, J. Ghajar, S. M. Grady, R. G. Grossman, E. D. Hall, W. Heetderks, D. A. Hovda, J. Jallo, R. L. Katz, N. Knoller, P. M. Kochanek, A. I. Maas, J. Majde, D. W. Marion, A. Marmarou, L. F. Marshall, T. K. McIntosh, E. Miller, N. Mohberg, J. P. Muizelaar, L. H. Pitts, P. Quinn, G. Riesenfeld, C. S. Robertson, K. I. Strauss, G. Teasdale, N. Temkin, R. Tuma, C. Wade, M. D. Walker, M. Weinrich, J. Whyte, J. Wilberger, A. B. Young, and L. Yurkewicz. 2002. Clinical trials in head injury. Journal of Neurotrauma 19(5):503–557. Nishida, M. 2001. Shock tubes and tunnels: Facilities, instrumentation, and techniques. Shock tubes. In Handbook of Shock Waves. Vol. 1, edited by C. Ben-Dor, O. Igra, and T. Elperin. San Diego, CA: Academic Press. Pp. 553–585. No Author. 2001a. Part 1: Guidelines for the management of penetrating brain injury. Introduction and methodology. Journal of Trauma-Injury Infection and Critical Care 51(2 Suppl):S3–S6. No Author. 2001b. Surgical management of penetrating brain injury. Journal of Trauma-Injury Infection and Critical Care 51(2 Suppl):S16–S25. Ohnishi, M., E. Kirkman, R. J. Guy, and P. E. Watkins. 2001. Reflex nature of the cardiorespiratory response to primary thoracic blast injury in the anaesthetised rat. Experimental Physiology 86(3):357–364. Ommaya, A. K., and T. A. Gennarelli. 1974. Cerebral concussion and traumatic unconsciousness. Correlation of experimental and clinical observations of blunt head injuries. Brain 97(4):633–654. Owen-Smith, M. S. 1981. Explosive blast injury. Medical Bulletin of the US Army Europe 38:36–43. Pabuscu, Y., N. Bulakbasi, M. Kocaoglu, B. Ustunsoz, and C. Tayfun. 2003. A different approach to missile induced head injuries. Computerized Medical Imaging and Graphics 27(5):397–409. Park, E., S. McKnight, J. Ai, and A. J. Baker. 2006. Purkinje cell vulnerability to mild and severe forebrain head trauma. Journal of Neuropathology and Experimental Neurology 65(3):226–234.
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Gulf War and Health, Volume 7: Long-Term Consequences of Traumatic Brain Injury Williams, A. J., G. S. Ling, and F. C. Tortella. 2006b. Severity level and injury track determine outcome following a penetrating ballistic-like brain injury in the rat. Neuroscience Letters 408(3):183–188. Williams, A. J., H. H. Wei, J. R. Dave, and F. C. Tortella. 2007. Acute and delayed neuroinflammatory response following experimental penetrating ballistic brain injury in the rat. Journal of Neuroinflammation 4:17. Wolf, J. A., P. K. Stys, T. Lusardi, D. Meaney, and D. H. Smith. 2001. Traumatic axonal injury induces calcium influx modulated by tetrodotoxin-sensitive sodium channels. Journal of Neuroscience 21(6):1923–1930. Yakovlev, A. G., and A. I. Faden. 2004. Mechanisms of neural cell death: Implications for development of neuroprotective treatment strategies. NeuroRx 1(1):5–16. Yang, Z., Z. Wang, C. Tang, and Y. Ying. 1996. Biological effects of weak blast waves and safety limits for internal organ injury in the human body. Journal of Trauma-Injury Infection and Critical Care 40(3 Suppl):S81–S84. Yehuda, R. 1999. Linking the neuroendocrinology of post-traumatic stress disorder with recent neuroanatomic findings. Seminars in Clinical Neuropsychiatry 4(4):256–265. Yelverton, J. T. 1996. Pathology scoring system for blast injuries. Journal of Trauma-Injury Infection and Critical Care 40:S111–S115. Yi, J. H., and A. S. Hazell. 2006. Excitotoxic mechanisms and the role of astrocytic glutamate transporters in traumatic brain injury. Neurochemistry International 48(5):394–403. Yoganandan, N., F. A. Pintar, S. Kumaresan, D. J. Maiman, and S. W. Hargarten. 1997. Dynamic analysis of penetrating trauma. Journal of Trauma-Injury Infection and Critical Care 42(2):266–272. Zhang, J., N. Yoganandan, F. A. Pintar, and T. A. Gennarelli. 2005b. Temporal cavity and pressure distribution in a brain simulant following ballistic penetration. Journal of Neurotrauma 22(11):1335–1347. Zhang, X., Y. Chen, L. W. Jenkins, P. M. Kochanek, and R. S. Clark. 2005a. Bench-to-bedside review: Apoptosis/programmed cell death triggered by traumatic brain injury. Critical care 9(1):66–75.
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