Chapter 50A Trauma of the Nervous System
Basic Neuroscience of Neurotrauma
Experimental Models of Traumatic Brain Injury
Severe closed-head injury produces a range of cerebral lesions that may be divided into four general categories: (1) diffuse axonal injury, (2) vascular lesions including subdural hematoma, (3) contusion, and (4) neuronal degeneration in selectively vulnerable regions. In a recent review of animal models of head injury, Cernak (2005) classified models of head injury according to the biomechanics of the injury. Fluid percussion and controlled cortical impact models are characterized as a constrained direct brain deformation injury model, whereas inertial injury models and impact acceleration models are considered unconstrained in head movement and more closely mimic human TBI. Other models have specifically targeted brain trauma that occurs in combat situations. These include high-velocity penetrating and blast injury. In an attempt to investigate the effects of mechanical deformation on specific cell types, in vitro models of stretch-induced injury have also been developed.
Acceleration Concussion
Human head injury is never as pure as an experimental model, and the total human injury condition may not be addressed adequately with a single animal model. Therefore, the use of complicated models in assessing pathomechanisms after TBI can provide valuable data (Statler et al., 2001). Many of these studies have added secondary insults such as hypotension (shock), hypoxia, or hyperthermia after the primary injury to more adequately mimic human head trauma. However, this added component to the model can result in complex data interpretation. Thus, once a particular feature of human brain injury is produced in an experimental model, the pathogenesis of the injury can be critically investigated.
Military Models
The incidence of brain injury is currently estimated to be as high as 40% to 70% of combat casualties. Advancements in protective body armor have limited the number of high-velocity impact injuries to the brain, but the use of improvised explosive devices has caused blast injury to become more prevalent. Military-relevant models have only recently been developed, and much work is needed to fully explore pathomechanisms induced by these models. Two models of significance are the penetrating ballistic brain injury model and a blast injury model using a metal tube with a small amount of plastic explosives at one end. The penetrating brain injury (PBI) model mimics a bullet wound by expanding and contracting a balloon that has been inserted into the brain (Williams et al., 2005). Injury severity and placement of the probe can be varied so that different types of bullet injuries can be studied. PBI produces robust histopathological damage and increases in intracranial pressure (ICP) and hemorrhage. In addition, sensorimotor deficits are observed in this model, along with seizure activity. Blast injury models have been developed that can mimic whole-body blast or local blast injury (Cernak and Noble-Haeusslein, 2010). This type of trauma produces cognitive deficits, with ultrastructural and oxidative damage to the hippocampus. Axonal damage is also present, as indicated by increases in phosphorylated neurofilament proteins. These military-relevant injury models have the potential to provide valuable information for managing and treating combat casualties.
In Vitro Models
Using these approaches, investigators have found that trauma induces a wide range of primary cellular alterations. Astrocytic responses include hyperplasia, hypertrophy, and increased glial fibrillary acidic protein content. Increases in intracellular calcium occur, which are blocked by specific receptor antagonists. Traumatized astrocytes also produce interleukins and neurotrophic factors. Neonatal cortical neurons that are stretched undergo delayed depolarization that depends on the activation of specific receptor populations. Combined mechanical trauma and metabolic impairment in vivo also induces N-methyl-d-aspartate receptor–dependent neuronal cell death and caspase-3–dependent apoptosis. In vitro experimental approaches provide novel data concerning intracellular signaling cascades, mechanisms underlying cellular responses to trauma, and the role of specific cell types in the pathophysiology of brain trauma (Chen et al., 2009; LaPlaca et al., 2009).
Neuronal Damage After Traumatic Brain Injury
Temporal Patterns of Neuronal Death
The neuropathological sequelae of experimental and human TBI have been well described (Bramlett and Dietrich, 2004; Povlishock and Katz, 2005). In experimental TBI, temporal patterns of neuronal damage have also been characterized. As early as 6 hours after cortical contusion injury, the contused tissue appears edematous, and pyknotic neurons are apparent at the injury site. By 8 days, a cortical cavity has developed that is surrounded by a border containing necrotic tissue, a glial scar, or both. The temporal profile of neuronal damage after parasagittal FP brain injury has also been assessed with light and electron microscopy. As early as 1 hour after impact, dark shrunken neurons indicative of irreversible damage are seen in cortical layers overlying the gliding contusion that displays BBB breakdown to protein tracers. Ultrastructural studies demonstrate that early BBB dysfunction results from mechanical damage of small venules in vulnerable regions including the external capsule. In some brain regions, focal sites of acute neuronal damage are associated with extravasated protein, whereas neuronal damage in other regions appears to occur without overt BBB breakdown. Astrocytic swelling is observed early after injury, with increased glial fibrillary acidic protein immunoreactivity apparent at later times in areas, demonstrating histopathological damage (Fig. 50A.1). In terms of neuroprotection, the acuteness of this damage limits the potential for therapeutic interventions directed against the early neuronal and glial response to TBI.
More subacute patterns of neuronal injury have been documented in various TBI models. At 3 days after moderate parasagittal FP brain injury, scattered necrotic neurons are present throughout the frontoparietal cerebral cortex remote from the impact site (Fig. 50A.2). In addition, selective neuronal damage is seen in the CA3 and CA4 hippocampal subsectors, the dentate hilus, and lateral thalamus ipsilateral to the trauma. These patterns of selective neuronal damage are associated with a well-demarcated contusion overlying the lateral external capsule. Ultrastructural changes consistent with apoptosis have been described after TBI, so delayed patterns of neuronal cell death may involve necrotic and programmed cell death processes.
Progressive Damage
Only recently has the progressive nature of the histopathological consequences of TBI been appreciated (Bramlett and Dietrich, 2007). At 2 months after moderate parasagittal FP injury, significant atrophy of the cerebral cortex, hippocampus, and thalamus is apparent in histological sections (Fig. 50A.3, A). Progressive tissue loss in the cortex and hippocampus at various times up to 1 year after lateral FP injury have been reported. Similar findings have been found in a model of controlled cortical impact injury. At 3 weeks and 1 year after injury, analysis demonstrated a significant hemispheric volume loss and expansion of the ipsilateral lateral ventricle. Thus atrophy of gray matter structures is associated with significant enlargement of the lateral ventricle.
Ventricular expansion not associated with hydrocephalus or increased ICP is felt to be a sensitive indicator of structural damage and an indirect measure of white matter atrophy. Indeed, ventricular size has been correlated with memory disturbances; patients with the highest ventricular volumes demonstrated significantly lower memory scores. Recent findings provide direct evidence of progressive white matter damage after FP brain injury (Bramlett and Dietrich, 2007). At 1 year after TBI, severe atrophy of specific tracts including the external capsule and cerebral peduncle was documented (see Fig. 50A.3, B). The importance of a progressive injury cascade after TBI in terms of other neurological conditions merits consideration. For example, if mild head trauma leads to a progressive reduction in neuronal reserve, would the person who sustained such trauma be more susceptible than others to neurodegenerative processes associated with aging? Some epidemiologic studies have indeed indicated that a history of brain trauma is a risk factor for Alzheimer disease.