Animal models of closed and penetrating types of TBI have been created to facilitate the development of diagnostic tools and medical interventions. Validation of the models requires comparison to human data in order to demonstrate that they reproduce one or more relevant features of the human injury. For both closed and penetrating TBI, seminal posttraumatic autopsy studies34, 35
provided a foundation for validation of animal models. Less is known about the neuropathology associated with TBI of milder severity because most of these injuries are non-fatal.
Based on what is known about the neuropathology and neurological consequences of more severe clinical injuries, animal models have been developed for closed and penetrating TBI. Two of the most commonly used closed TBI models, the fluid percussion injury model and the controlled cortical impact model, both involve opening the skull and exposing the dura of the brain to a transient pressure wave36, 37
. Although opening the skull would seem to be counterintuitive for producing a “closed” head injury, these models have been validated for reproducing relevant neuropathology and behavioral deficits associated with human TBI. Similarly, the inertial acceleration model of closed TBI produces DAI without any actual impact to the head. This too may seem counterintuitive since most clinical injuries involve a combination of impact and inertial forces. However, the utility of this model is its ability to reproduce and characterize the pathophysiology of a purely diffuse injury38
. It is also important to note that the inertial acceleration model is only applicable for use with larger animals, such as swine. This is because the acceleration required to reproduce clinically relevant neuropathology is inversely proportional to brain mass, and thus exceeds the device’s capabilities for smaller animals, e.g. rodents. Additional differences in morphology, such as the brain surface, geometry, and white/gray matter ratios are also important considerations when designing clinically relevant models of TBI39
. Thus, the animal models of closed TBI do not
use devices to create known mechanical or physical parameters associated with human TBI, but rather to create whatever physical parameters or conditions are necessary to replicate the known clinical neuropathology.
Despite the caveats of developing animal models based on physical conditions or insult parameters associated with human injury, this has been a necessary approach for bTBI because of the limited knowledge of human neuropathology. Some of the more common models make use of blast tubes or structures that produce systematic and calibrated blast wave transients with peak pressure levels of approximately 20 to 350 kPa7, 40, 41, 42, 43
. Open and contained field models have also been developed7
to recreate more naturalistic blast environments. The field models are more complex and can potentially simulate all four types of blast injury (primary, secondary, tertiary, and quaternary). Alternatively, the blast tube models may be able to solely characterize the brain’s response to the primary injury, the direct response to the blast pressure wave. However, what is unknown is the extent which the brain experiences deformation in response to the primary blast. During the Workshop, Dr. Philip Bayly (Washington University, Saint Louis, MO) presented data on the use of dynamic, tagged magnetic resonance imaging (MRI), to enable real time measurements of brain movement which may help address this question. His data demonstrated that even very mild linear and angular accelerations of the head create movement and shear strains in the brain.
Although it is virtually impossible to rigorously validate the bTBI models without more precise human data, these models appear to reproduce many of the overt neuropathological and behavioral deficits that have been described following human exposures (). For example, vasospasm, edema, contusion, axonal injury, and hemorrhage have all been described following blast injury in civilians or military populations22, 23, 24
and have also been demonstrated in rodent and/or pig models7, 20
. Transient alterations in electroencephalograms44
and tympanic membrane perforations are associated with blast injury45
and are also reproduced in some of the animal models7, 46
. Cognitive deficits, a common and often major neurological consequence of human bTBI, have also been demonstrated with animal models13, 23
. Human bTBI is often associated with other injuries, such as burns, limb amputations, hemorrhagic shock, etc., and in fact, there are very few clinical cases of individuals who have experienced only primary blast injury47
. This observation has driven interest in the generation of an animal model of polytrauma to capture some of the added complexities of the injury48
. However, PTSD and depression, which are strongly associated with human bTBI, have not been evaluated in the animal models. Seizures and posttraumatic epilepsy are well-known sequelae of all types of TBI, but especially penetrating injuries49
. Reproducing post-traumatic seizures in an animal model of bTBI may require development of a polytrauma model that combines exposure to blast overpressure with a penetrating injury model50
Neuropathology and neurological consequences associated with bTBI by reference number.
The animal models have also provided some insights into the cellular and molecular pathophysiology of bTBI. Most, if not all of the pathophysiology described following experimental bTBI has also been observed in animal models of closed TBI51, 52
. Neuronal, axonal and glial injuries have all been observed following bTBI7, 41
. White matter seems to be more vulnerable in some studies7
. Both apoptotic and necrotic pathways appear to contribute to neuronal death51, 53
. The axonal injury may be attributable to the impairment of axonal transport and consequent accumulation of phosphorylated neurofilament proteins in neuronal cell bodies after blast exposure, similar to what has been observed in DAI40
. Exposure to a nonlethal blast wave revealed widespread activation of microglia in the white and gray matter of the rat brain54
, consistent with activation of inflammatory processes. These neuroinflammatory responses have been observed within a day after exposure54
, and may be partially attributable to disruption of the blood brain barrier55
. Oxidative damage is believed to mediate many of these processes7, 51
. Inducible nitric oxide synthase (iNOS), an important modulator of cerebral blood flow, is elevated after blast exposure41
. It has been suggested that iNOS may be a therapeutic target because administration of a specific inhibitor of iNOS attenuated the neurobehavioral deficits following bTBI in rats42
. However, the beneficial versus detrimental effects of iNOS following TBI remain unclear and further experiments are warranted56, 57
. Taken together, the pathophysiology of bTBI appears to be similar to that of closed TBI. Whether distinct differences and a signature profile will emerge for bTBI following comprehensive and systematic comparisons to closed and penetrating TBI, or whether the response to injury is truly similar remains to be determined.