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Vet Pathol 39:679-689 (2002)
© 2002 American College of Veterinary Pathologists
ANIMAL MODELS

Traumatic Brain Injury

J. W. Finnie and P. C. Blumbergs

Veterinary Services Division, Institute of Medical & Veterinary Science (JWF), Division of Tissue Pathology, Institute of Medical & Veterinary Science (PCB), and Department of Pathology, University of Adelaide, Australia (JWF, PCB)


   Abstract
Top
 Abstract
Types of Animal Models
 Types of TBI
 Conclusion
 References
 
Animal models have played a critical role in elucidating the complex pathogenesis of traumatic brain injury, the major cause of death and disability in young adults in Western countries. This review discusses how different types of animal models are useful for the study of neuropathologic processes in traumatic, blunt, nonmissile head injury.

Key words: Animal models; neuropathology; pathogenesis; traumatic brain injury.

There are two main reasons for conducting research on traumatic, blunt, nonmissile brain injury. First, traumatic brain injury (TBI) is the leading cause of death and severe disability in people under 45 years of age in Western industrialized countries, affecting the young and adults in the most productive years of their lives and predominantly caused by motor vehicle accidents. For every fatality, there are many survivors with severe brain damage and many more with moderate or mild injury.30,51,63 Although TBI is a problem of major medical and socioeconomic significance, its pathogenesis is incompletely understood, and it is often difficult to reconstruct the events leading to the primary and secondary lesions of varying severity and regional distribution that constitute TBI.11,50 In contrast, the mechanical input in animal models is quantifiable and subject to manipulation, and head injuries are produced under controlled experimental conditions. Second, although a host of potential neuroprotective agents have been studied, the few that have shown promise under experimental conditions have failed to provide consistent and significant improvement in human clinical trials.14,16,29,108 Testing the efficacy of new drugs in animal models will therefore continue to be an essential precursor to their use in humans.

TBI is also frequently encountered in veterinary practice as a result of automobile accidents, falls, assaults, bites, and crushing injuries.19,110 But head injury in animals has generally received scant attention in the veterinary literature, and most of our knowledge is derived from their use as experimental models of human TBI.34 This review highlights the contribution of different types of animal models to our understanding of the neuropathology of head injury.


   Types of Animal Models
Top
 Abstract
 Types of Animal Models
Types of TBI
 Conclusion
 References
 
TBI may be produced by the head impacting or coming into contact with an object (contact phenomena) or acceleration/deceleration forces producing vigorous movement of the brain (acceleration/deceleration or inertial phenomena), or varying combinations of these mechanical forces.11,34,50,51,91

In most models, the mechanical input is controlled and results in injury that is reproducible, quantifiable, and clinically relevant. No single animal model can reliably replicate the full spectrum of human TBI.40,42,67,68,87,88,90

Animal models of TBI can be broadly classified as

Impact acceleration models involve direct head impacts using a piston, humane stunner or captive bolt pistol, calibrated pendulum, or weight drop onto the skull. This focal mechanical loading causes deformation of the brain which, being almost incompressible, is particularly vulnerable to strain injury. These models resemble closed head injury in motor vehicle accidents or falls where there is rapid acceleration/deceleration of the head after impact to an intact skull, but they sometimes fail to produce a highly repeatable injury. Impact acceleration models have been used in primates,54,62,81,83,84,101 sheep,32,33,35,36,64 cats,113 rats,8,71,102 and rabbits.55

Head impact models in primates were pioneered by Denny-Brown and Russell who showed that brain damage was more likely to be produced in a freely mobile head than in one that is constrained.20,21 Head impact models have reproduced several important features of TBI in primates, cats, and sheep, including contusions, subarachnoid hemorrhage, and widespread axonal injury (AI) and, in contrast to inertial acceleration models, skull fractures are commonly found. Diffuse brain injury was also produced in an impact-acceleration rat model,37,71 whereas previous impact models in rats had been largely unsuccessful because the high acceleration levels required to produce brain damage resulted in a slender margin between injury and death.40

Inertial acceleration models involve acceleration of the head without impact, unlike most human motor vehicle accident situations.78 Inertial acceleration devices generate a repeatable pathologic response, especially when the direction and distance of head movement is constrained. Angular acceleration, especially in the coronal plane, has been shown to be particularly injurious in nonhuman primates,43,44,47,81,82,83,85,86 pigs,98 and cats.80 In these models, the acceleration required to produce injury experimentally is found only in human TBI when head impact occurs.67

Inertial injury models were first developed in primates by Ommaya and Gennarelli, and subsequent modifications by Gennarelli and colleagues succeeded in reproducing many features of human TBI.38,41,43,44,46,47,83,86 By sudden deceleration of a moving frame to which the primate body was firmly attached, coma was produced by the whiplash motion of a freely mobile head. In these studies, coma was more readily produced by angular acceleration in the coronal plane and was associated with diffuse axonal injury (DAI) in the subcortical white matter.3,4,41,44,59 Angular or translational acceleration could be generated in these primates and, by controlling head motion, acute subdural hematoma, brief unconsciousness or prolonged coma, and DAI were induced.

Direct brain deformation models include both fluid percussion and rigid indentation types and use either a fluid pulse or mechanically driven piston, respectively, to rapidly compress the exposed dura or cortex through a craniotomy site.58,70,100 These models produce well-controlled levels of localized injury rather than diffuse damage. Brain deformation models have been used primarily in rats18,23–25,48,66,76,77,111 and also in cats15,56,57,89 and ferrets.65

In fluid percussion models, contusions of varying size can be produced; these being smaller and less frequent with a central (midline) impact compared with a lateral impact. In centrally directed models, scattered AI is principally found in the brainstem with modest involvement of cortical and subcortical areas.23,89,92,106,112 A lateral approach tends to produce hippocampal injury with less brainstem damage, and unilateral AI occurs in the central white matter. Contusions are also produced with central and lateral rigid indentation models, but AI is more localized than diffuse.77,99

An optic nerve stretch model has also been developed in guinea pigs, enabling AI to be studied under very controlled conditions.39,72,74

Thus, although no single animal model of nonmissile head injury produced by mechanical energy can express the great diversity of neural damage constituting human TBI, multiple animal models are nevertheless capable of replicating specific features of TBI that can be analyzed.


   Types of TBI
Top
 Abstract
 Types of Animal Models
 Types of TBI
Conclusion
 References
 
Primary traumatic brain damage

This type of TBI is the result of mechanical forces producing tissue deformation at the moment of injury. These deformations may directly damage the blood vessels, axons, neurons, and glia in a focal, multifocal, or diffuse pattern of involvement and initiate dynamic and evolving processes that differ for each component part and result in complex cellular, inflammatory, neurochemical, and metabolic alterations.11,51 Primary TBI is summarized in Table 1.


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  		Table 1. Classification of traumatic brain injury.

 
Secondary traumatic brain damage

This type of TBI occurs as a complication of the different types of primary brain damage and includes ischemic and hypoxic damage and cerebral swelling, the consequences of raised intracranial pressure, hydrocephalus, and infection.11,51 These events are summarized in Table 1.

Experimental models of TBI have been devised using a variety of techniques and species, with the aim of producing repeatable lesions resembling those found in head-injured man. Although primary damage produced by mechanical forces operating at the moment of impact is largely refractory to treatment and relies on preventive measures, most brain injury evolves as a progressive cascade of events that is potentially reversible with adequate treatment. The recognition of the therapeutic window created by these delayed, secondary complications of the initial injury has led to attempts to pharmacologically manipulate some of the putative factors involved.52

Traumatic AI

Complete transection or avulsion of neural tissue produces instantaneous complete axotomy of all the nerve fibers (primary axotomy), as well as disruption of blood vessels and glial cells. The AI in less severe mechanical insults is termed secondary axotomy, and in most cases the process takes many hours or even days to be completed,73 creating a potential window for therapeutic intervention.51,92,94

The detection of AI in human TBI patients and animal models has been greatly enhanced by the introduction of immunocytochemical techniques using antibodies to axonally transported proteins, such as amyloid precursor protein (APP), neurofilament protein, and synaptophysin.51 APP immunostaining (Figs. 1–3) is the most sensitive marker of AI,105 identifying axonal swellings within 30 minutes postimpact and with minimal background interference because uninjured axons do not stain with this technique.33,36,64,114,115 But APP immunoreactive axons can still be identified many months after head injury.17



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  		Figs. 1, 2. Sheep. APP-positive axonal swellings, with most axons running longitudinally in the same direction. Some axons are irregularly beaded (arrows). Avidin–biotin–peroxidase method, hematoxylin counterstain. Bar = 40, 80 µm.
Fig. 3. Sheep. APP-positive axonal swellings cut in transverse section (arrows); uninjured axons are not stained with this immunohistochemical technique. Bar = 72 µm.

 
The total burden of AI in a given brain has been underestimated using traditional, less sensitive staining methods such as hematoxylin and eosin and silver impregnation.105 But focal nontraumatic AI around hematomas, infarcts, and abscesses cannot be distinguished from AI due to mechanical deformation of the brain, and thus APP accumulation in axons is not confined to head-injured patients and is not a specific marker for head injury.11,12,51,105

Animal models have defined the early changes after traumatic AI. Mechanical deformation and cell membrane depolarization by shearing forces lead to a marked calcium influx into cells, which may be receptor-mediated, voltage-dependent, or via transient defects in the plasmalemma (mechanoporation). As a result of this traumatic calcium overload, enzyme and gene activation occur. Proteases damage the cytoskeletal architecture leading to interruption of axonal transport and accumulation of cytoskeletal components and membranous organelles over 3–6 hours, which is manifest as axonal swellings. Axotomy becomes apparent 6–12 hours after injury, and the distal segment undergoes Wallerian degeneration.94,95 This temporal progression of axonal reaction is also variable and species-dependent, occurring more rapidly in rodents than higher order animals.88 Axons that change direction during their course appear to be more vulnerable to injury, and it is not uncommon to find APP-positive axons in one tract and few or none in an adjacent tract with a different orientation. AI is followed by widespread and intense microglial reaction.

DAI is defined as widely distributed AI in the cerebral hemispheres, corpus callosum, brainstem, and cerebellum and is an important determinant of clinical outcome after human TBI.2 It spans a clinical spectrum from concussion to severe disability, permanent unconsciousness, or the vegetative state. In severe human DAI, there may also be hemorrhage associated with tears in the corpus callosum and dorsolateral quadrants of the rostral brainstem, which serve as useful markers for the postmortem and radiologic diagnosis of DAI; no macroscopic abnormalities may be found in milder forms.9–12,51 These focal hemorrhages are rarely reported in animal models, but brainstem and cerebellar hemorrhage observed in an ovine head impact model may have been due, in part at least, to impact against the well-developed tentorium cerebelli,33,35,36,64 which closely embraces the brainstem in animals.60

The total amount of AI in a given brain may be a combination of mechanical deformation and ischemic injury, especially because ischemia-hypoxia due to failure of cerebral perfusion is one of the major secondary insults after head injury. But the current histologic methods for detecting AI are unable to distinguish between these types of AI.12 Continuous physiologic monitoring is thus mandatory when modeling AI to ensure that no complicating hypoxic episodes supervene. Injured axons also seem to be much more vulnerable to ischemia than normal axons.31

In general, widely distributed AI has been produced with some fidelity by inertial and impact acceleration models, whereas AI after direct brain deformation tends to be unilateral and localized to the impact site and subjacent white matter. Modification of the lateral rigid percussion model by opening the contralateral cranium sometimes extends AI across the midline in subcortical areas.45

Brain acceleration of the type that produces human DAI seems to be largely confined to animal models that have a relatively large, gyrencephalic brain such as nonhuman primates (whose ratio of brain mass to head mass is similar to man), sheep, and pigs, in part because shearing forces and inertial loading are related to brain mass.34 DAI is rarely produced by inertial loading in small animals, such as cats, ferrets, and rats.42 Gyrencephalic brains have a complex, species-specific pattern of surface convolutions resembling man,13 in contrast to the almost lissencephalic rodent brains that can tolerate much greater acceleration/deceleration forces than nonhuman primates and man. In quadrupeds, the long axes of the brain and spinal cord are parallel, whereas in man and nonhuman primates they are almost at right angles. This almost linear neuraxis in lower species may impede rotational shearing after head injury and render them less vulnerable to traumatic injury.40,90,88

Traumatic loss of consciousness

This was reliably reproduced in acceleration and percussion concussion primate models by Denny-Brown and Russell at the beginning of the modern era of neurotrauma research at Oxford in the early 1940s.20,21 These studies also demonstrated the importance of head acceleration in TBI, for impact to a freely mobile head was much more likely to produce loss of consciousness than to one constrained. Head acceleration may be either translational (linear) when the impact force passes through the center of gravity of the head or angular (rotational) when it does not. Ommaya, Gennarelli, and colleagues in Philadelphia found that angular (rotational) acceleration of the head of primates, especially in the coronal plane, produced coma more readily.1,43,44,81,85

The Philadelphia primate studies highlighted the critical importance of acceleration/deceleration in TBI, for the head does not need to strike or be struck by an object to produce widespread AI. In these studies, the greater the number of reactive axons, the more persistent the neurologic abnormalities and the duration of unconsciousness after head impact correlated with the degree of DAI. Loss of consciousness persists for seconds to minutes with mild DAI but days to weeks with more severe DAI. Ommaya and Gennarelli found that acceleration in the primate model over longer time periods (20–25 ms) as may occur in motor vehicle accidents produced prolonged traumatic coma and DAI, whereas a short acceleration time (5–10 ms) resembling that in falls caused subdural hematoma.51

Contusions

Contusions (Figs. 4–6) are regular features of TBI, and their presence confirms that a head injury has occurred. They have been observed to varying degrees in most animal models of TBI, although some brain deformation models produce hemorrhage at the gray-white matter interface rather than in the cortical mantle.18,23,77 Contusions are focal surface injuries resulting from damage to small blood vessels (Figs. 7, 8), with hemorrhages often disposed at right angles to the cortical surface. Contusions typically affect gyral crests and frequently progress to a wedge-shaped necrotic area involving the subjacent white matter, the initial focal lesion expanding due to continuing hemorrhage, ischemic necrosis, and vasogenic edema. They often occur beneath the impact site (coup contusions) and because contusions are mainly impact-related phenomena, they are often associated with skull fractures (fracture contusions) in impact acceleration models of closed head injury. Contrecoup contusions may also be found more or less opposite the impact site (Fig. 6), whereas herniation contusions occur in the margins of brain hernias. But contusions may be minimal or absent with fatal diffuse brain injuries. Laceration results when there is physical disruption of the neural parenchyma, and laceration-contusion are part of a continuous spectrum of damage at the surface of the brain.11,51



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  		Fig. 4. Sheep (clockwise from top left); lateral cerebral hemisphere impact contusion (C), with subarachnoid hemorrhage around the brainstem (bar = 11 cm); ventral aspect of the brain showing abundant subarachnoid hemorrhage (bar = 12.5 cm); focal hemorrhage in the lateral pons (arrow) (bar = 7.5 cm); left lateral hemisphere impact contusion, with contusions on the inferior aspect of the pyriform lobes (arrows) (bar = 4 cm).

 


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  		Fig. 5. Sheep. Large lateral hemisphere impact contusion (C). Bar = 4 cm.
Fig. 6. Sheep. Left lateral hemisphere impact contusion, with contrecoup contusion directly opposite. Bar = 7 cm.
Fig. 7. Sheep. Coronal section of brain showing left lateral hemisphere impact contusion and laceration (arrow), extending into the basal ganglia. HE. Bar = 5 cm.
Fig. 8. Sheep. Higher power view of the contusion in Fig. 4, showing numerous perivascular hemorrhages. HE. Bar = 2 cm.

 
Traumatic brain hemorrhage

Traumatic brain hemorrhage (Figs. 9–11) generally results from tearing of blood vessels at the moment of head impact. But gradually expanding, delayed posttraumatic hematomas may not be manifest clinically until hours or days after the initial injury when they cause elevated intracranial pressure and herniation. Bleeding into the subarachnoid space (subarachnoid hemorrhage) is the most common form of vascular injury (Fig. 4) after head trauma and is found in many types of animal models. It is usually minor but may evolve into a significant space-occupying lesion. Subdural hematoma is produced in inertial acceleration models,44 where bridging veins are ruptured by rapid angular acceleration forces and the hemorrhage may extend over an entire hemisphere. Subdural hematoma may also form adjacent to contusions in, for example, a rigid indentation model.65 Because the skull is not fractured in most animal models, epidural hematomas with progressive separation of the dura from the skull after tearing of meningeal blood vessels are not observed. But skull fractures do occur with many impact acceleration models, unless the skull is protected by a metal plate or molded cap. Intraventricular hemorrhage is a frequent complication after human and animal head impact, and hematomas may also develop in the brain substance (intracerebral hematomas). Intraparenchymal hemorrhage is often distributed throughout the central white matter and basal ganglia in inertial models and principally in the brainstem in percussion models. In human patients who die within minutes after head impact, there may be numerous petechial hemorrhages scattered throughout the brain (diffuse vascular injury), but there appears to be no animal model counterpart.11,51



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  		Fig. 9. Sheep. Extensive traumatic midbrain hemorrhage. Bar = 7 cm.
Fig. 10. Sheep. Severe traumatic thalamic hemorrhage, with midline shift and distortion of the brain. Bar = 8.5 cm.
Fig. 11. Sheep. Focal traumatic hemorrhage in the lateral pons. Bar = 4 cm.

 
There is widespread breakdown of the blood-brain barrier to circulating proteins very early after TBI in many animal models,18,76,93,100,109 often attended by brain swelling. Brain swelling encompasses both edema and congestion and, together with hematomas, is the major contributor to increased intracranial pressure. It may eventually lead to distortion, shift, and herniation of the brain. Edematous swelling often occurs around contusions and intracerebral hemorrhages in humans and animal models, whereas swelling of one hemisphere in man may result from a combination of congestion and edema. Diffuse swelling of the entire brain due to hyperemia occurs in young children, even after an apparently trivial injury, but is uncommon in adults. Generalized brain swelling produces gyral flattening, sulcal narrowing, and ventricular collapse.11,51

Reactive microglia also influence clinical outcome after TBI because they are the principal immune effector elements of the brain, are the major source of central nervous system–derived proinflammatory cytokines, assist wound healing in neural tissues, and produce many neurotoxic agents.53 Excitotoxicity may be a further important mediator of TBI. Traumatic brain deformation in animal models results in massive impact depolarization and excessive release of excitatory amino acid neurotransmitters, especially glutamate, into the extracellular fluid.28,61 Although the storage, transmission, and uptake of glutamate is normally finely regulated, a marked rise in extracellular glutamate after TBI is highly toxic to neurons.96

Chronic brain injury

The long-term effects of TBI depend on a combination of the different types of primary and secondary damage sustained and their relative severity, but modeling of chronic brain injury has rarely been attempted.40,88 But in a fluid percussion model eliciting AI, reorganization of the axonal cytoskeleton occurred over a 28-day period with a spontaneous regenerative attempt.15

TBI is a major risk factor for Alzheimer's disease (AD),75 and diffuse ß-amyloid deposits have been reported to occur between 4 hours and 2.5 years in human TBI.97 Transgenic mice engineered to overexpress human APP twofold (APP-YAC mice) failed to produce amyloid plaques or cognitive change after injury,79 whereas transgenic mice overexpressing human APP 10-fold (PD-APP mice) showed hippocampal neuronal loss and decreased cognitive function.107 The use of genetically engineered mice to study the link between TBI and neurodegenerative diseases, and the pathogenesis of TBI more generally, has recently been reviewed.69

Pediatric TBI modeling

Although there are important age-related differences in the response of the brain to TBI, there have been few animal models using an immature brain, and differences in the stage of maturity of the brain at birth between species are important.7 Species can be categorized as prenatal (sheep and guinea pigs) or postnatal (rat, rabbit, pig, and man) brain developers in relation to the growth spurt, the period when brain growth is most rapid.26 The pig may be suitable as a model of human pediatric TBI because its brain development closely parallels that of humans, and both species have a peak in brain growth at the time of birth.22 In man, the long postnatal growth period of the brain renders it particularly vulnerable to traumatic injury and recovery is more complicated because it is superimposed on continuing developmental events. Moreover, although the sequence of brain development is well characterized, the effect of trauma on these immensely intricate developmental processes and the resumption of the orderly progression after injury is unknown.49,103,116

Models of pediatric TBI have produced contusional injury in the juvenile rat and pig by controlled cortical impact,6,27 and a model of subdural hematoma has also been reported in piglets.104 Impact-acceleration brain damage has been produced in young rats and lambs.5,33,36 In the rat model, AI was largely confined to the brainstem,5 whereas in the lamb model there was early and widespread AI,36 the severity of which was substantially influenced by the region of the head impacted.35


   Conclusion
Top
 Abstract
 Types of Animal Models
 Types of TBI
 Conclusion
References
 
The complexity and diversity of TBI pathology will ensure a continuing role for animal models to define more accurately the cascade of morphologic and biochemical events occurring after a traumatic insult. One of the most important insights into the pathogenesis of TBI provided by animal models has been the realization that many structural changes, particularly AI, are not immediate and irreversible but often time-dependent evolving processes that may be amenable to therapeutic intervention. Animal models will be essential to evaluate potential neuroprotective agents.


   References
Top
 Abstract
 Types of Animal Models
 Types of TBI
 Conclusion
 References
 

  1. Adams JH, Doyle D, Ford I, Gennarelli TA, Graham DI, McLellan DR: Diffuse axonal injury in head injury: definition, diagnosis, and grading. Histopathology 15:49-59, 1989[Medline]
  2. Adams JH, Graham DI, Gennarelli TA: Acceleration induced head injury in the monkey. II. Neuropathology. Acta Neuropathol (Berl) 7: (Suppl) 26, 1981
  3. Adams JH, Graham DI, Gennarelli TA: Neuropathology of acceleration-induced head injury in the subhuman primate. In: Head Injury: Basic and Clinical Aspects, ed. Grossman RG, Gildenberg PL, pp 141-150, Raven Press, New York, NY 1982
  4. Adams JH, Graham DI, Gennarelli TA: Head injury in man and experimental animals—neuropathology. Acta Neurochir Suppl 32:15-30, 1983[Medline]
  5. Adelson PD: Animal models of traumatic brain injury in the immature: a review. Exp Toxicol Pathol 51:130-136, 1999[Medline]
  6. Adelson PD, Jenkins LW, Hamilton RL, Robichaud P, Tran MP, Kochanek PM: Histopathologic response of the immature rat to diffuse traumatic brain injury. J Neurotrauma 18:967-976, 2001[CrossRef][Medline]
  7. Adelson PD, Robichaud P, Hamilton RL, Kochanek PM: A model of diffuse traumatic brain injury in the immature rat. J Neurosurg 85:877-884, 1996[Medline]
  8. Bakay L, Lee JC, Lee GC, Peng J-R: Experimental cerebral concussion. I. An electron microscopic study. J Neurosurg 47:525-531, 1977[Medline]
  9. Blumbergs PC: Pathology. In: Head Injury. Pathophysiology and Management of Severe Closed Injury, ed. Reilly P, Bullock R, pp 39-70, Chapman and Hall Medical, London, UK 1997
  10. Blumbergs PC: Changing concepts of diffuse axonal injury. J Clin Neurosci 5:123-124, 1998
  11. Blumbergs PC, Jones NR, North JB: Diffuse axonal injury in head trauma. J Neurol Neurosurg Psychiatry 52:838-841, 1989[Abstract/Free Full Text]
  12. Blumbergs PC, Scott G, Manavis J, Wainwright H, Simpson DA, McLean AJ: Staining of amyloid precursor protein to study axonal damage in mild head injury. Lancet 344:1055-1056, 1994[CrossRef][Medline]
  13. Bolon B: Comparative and correlative neuroanatomy for the toxicological pathologist. Toxicol Pathol 28:6-27, 2000[Abstract/Free Full Text]
  14. Bullock MR, Lyeth BG, Muizelaar JP: Current status of neuroprotection trials for traumatic brain injury: lessons from animal models and clinical studies. Neurosurgery 45:207-217, 1999[CrossRef][Medline]
  15. Christman CW, Salvant JB, Walker SA, Povlishock JT: Characterization of a prolonged regenerative attempt by diffusely injured axons following traumatic brain injury in adult cat: a light and electron microscopic immunocytochemical study. Acta Neuropathol (Berl) 94:329-337, 1997[CrossRef][Medline]
  16. Cohadon F: Brain protection. Adv Tech Stand Neurosurg 21:77-152, 1994[Medline]
  17. Cornish R, Blumbergs PC, Manavis J, Scott G, Jones NR, Reilly PL: Topography and severity of axonal injury in human spinal cord trauma using amyloid precursor protein as a marker of axonal injury. Spine 25:1227-1233, 2000[CrossRef][Medline]
  18. Cortez SC, McIntosh TK, Noble LJ: Experimental fluid-percussion brain injury: vascular disruption and neuronal and glial alterations. Brain Res 482:271-282, 1989[CrossRef][Medline]
  19. de Lahunta A: Veterinary Neuroanatomy and Clinical Neurology. 2nd ed., pp 356-364, Saunders, Philadelphia, PA 1983
  20. Denny-Brown D, Russell WR: Experimental cerebral concussion. Brain 64:93-164, 1941[Free Full Text]
  21. Denny-Brown D: Cerebral concussion. Physiol Rev 25:296-325, 1945[Free Full Text]
  22. Dickerson JWT, Dobbing J: Prenatal and postnatal growth and development of the central nervous system of the pig. Proc R Soc Lond 166:384-395, 1967[Abstract/Free Full Text]
  23. Dixon CE, Clifton CL, Lighthall JW, Yaghmai AA, Hayes RL: A controlled cortical impact model of traumatic brain injury in the rat. J Neurosci Methods 39:253-262, 1991[CrossRef][Medline]
  24. Dixon CE, Lighthall JW, Anderson TE: Physiologic, histopathologic, and cineradiographic characterization of a new fluid-percussion model of experimental brain injury in the rat. J Neurotrauma 5:91-104, 1988[Medline]
  25. Dixon CE, Lyeth BG, Povlishock JT, Findling RL, Hamm RJ, Marmarou A, Young HF, Hayes RL: A fluid-percussion model of experimental brain injury in the rat. J Neurosurg 67:110-119, 1987[Medline]
  26. Dobbing J: The late development of the brain and its vulnerability. In: Scientific Foundations of Pediatrics, ed. Davis JA, Dobbing J, 2nd ed., pp 745-748, Heinemann Medical, London, UK 1981
  27. Duhaime A-C, Margulies SS, Durham SR, O'Rourke MM, Golden JA, Marwaha S, Raghupathi R: Maturation-dependent response of the piglet brain to scaled cortical impact. J Neurosurg 93:455-462, 2000[Medline]
  28. Faden AI: Neuroprotection and traumatic brain injury: the search continues. Arch Neurol 58:1553-1555, 2001[Free Full Text]
  29. Faden AI, Demediuk P, Panter S, Vink R: The role of excitatory amino acids and NMDA receptors in traumatic brain injury. Science 244:798-800, 1990
  30. Fearnside MR, Simpson DA: Epidemiology. In: Head Injury. Pathophysiology and Management of Severe Closed Injury, ed. Reilly P, Bullock R, pp 3-24, Chapman and Hall Medical, London, UK 1997
  31. Fehlings MG, Tator CH, Linden RD: The relationships among the severity of spinal cord injury, motor and somatosensory evoked potentials and spinal cord blood flow. EEG Clin Neurophysiol 74:241-259, 1989[CrossRef][Medline]
  32. Finnie JW: Animal models of traumatic brain injury: a review. Aust Vet J 79:628-633, 2001[Medline]
  33. Finnie JW, Blumbergs PC, Manavis J, Summersides GE, Davies RA: Evaluation of brain damage resulting from penetrating and non-penetrating captive bolt stunning using lambs. Aust Vet J 78:775-778, 2000[Medline]
  34. Finnie JW, Lewis SB, Manavis J, Blumbergs PC, Van den Heuvel C, Jones NR: Traumatic axonal injury in lambs: a model for pediatric axonal damage. J Clin Neurosci 6:38-42, 1999[CrossRef][Medline]
  35. Finnie JW, Manavis J, Blumbergs PC, Summersides GE: Brain damage in sheep from penetrating captive bolt stunning. Aust Vet J 80:67-69, 2002[Medline]
  36. Finnie JW, Van den Heuvel C, Gebski V, Manavis J, Summersides GE, Blumbergs PC: Effect of impact on different regions of the head of lambs. J Comp Pathol 124:159-164, 2001[CrossRef][Medline]
  37. Foda MA, Marmarou A: A new animal model of diffuse brain injury in rats. Part II. Morphological characterization. J Neurosurg 80:301-313, 1994[Medline]
  38. Gennarelli TA: Head injury in man and experimental animals: clinical aspects. Acta Neurochirurg 32: (Suppl) 1-13, 1983
  39. Gennarelli TA: Animate models of human head injury. J Neurotrauma 11:357-368, 1994[Medline]
  40. Gennarelli TA, Adams JH, Graham DI: Acceleration induced head injury in the monkey. I. The model, its mechanical and physiological correlates. Acta Neuropathol (Berl) 7: (Suppl) 23, 1981
  41. Gennarelli TA, Thibault LE: Experimental production of prolonged traumatic coma in the primate. In: Advances in Neurotraumatology, ed. Villiani R, pp 53-58, Excerpta Medica, Amsterdam, Netherlands 1982
  42. Gennarelli TA, Thibault LE: Experimental production of prolonged traumatic coma in the primate. In: Advances in Neurotraumatology, ed. Villiani R, pp 31-33, Excerpta Medica, Amsterdam, the Netherlands 1983
  43. Gennarelli TA, Thibault LE: Biological models of head injury. In: Central Nervous System Trauma Status Report, ed. Povlishock JT, Becker T, pp 392-405, National Institute of Neurological and Communicative Disorders and Strokes, National Institutes of Health, Bethesda, MD 1985
  44. Gennarelli TA, Thibault LE, Adams JH, Graham DI, Thompson CJ, Marcincin RP: Diffuse axonal injury and traumatic coma in the primate. Ann Neurol 12:564-574, 1982[CrossRef][Medline]
  45. Gennarelli TA, Thibault LE, Goldstein D: Axonal injury in the rat cerebral cortex in a modified rigid indenter cortical impact model. J Neurotrauma 9:60, 1992
  46. Gennarelli TA, Thibault LE, Ommaya AK: Pathophysiologic responses to rotational and translational acceleration of the head. In: 16th Stapp Car Crash Conference Proceedings, pp 296-308, SAE, New York, NY 1972
  47. Gennarelli TA, Thibault LE, Ross DT, Meaney D: Enhancement of axonal damage in the forebrain during contralateral cranectomy during controlled cortical impact injury in the rat. Proceedings of the Society for Neuroscience 15:1990
  48. Gennarelli TA, Thibault LE, Tipperman R, Tomei G, Sergot R, Brown M, Maxwell WL, Graham DI, Adams JH, Irvine A: Axonal injury in the optic nerve: a model simulating diffuse axonal injuries in the brain. J Neurosurg 71:244-253, 1989[Medline]
  49. Graham DI: Neuropathology of head injury. In: Neurotrauma, ed. Narayan RK, Wilberger JE, Povlishock JT, pp 43-60, McGraw-Hill, New York, NY 1996
  50. Graham DI, Ford I, Adams JH, Doyle D, Lawrence AE, McLellan DR, Ng NK: Fatal head injury in children. J Clin Pathol 42:18-22, 1989[Abstract/Free Full Text]
  51. Graham DI, Gennarelli TA: Trauma. In: Greenfield's Neuropathology ed. Graham DI, Lantos PL, 6th ed vol. 1: pp 197-262, Arnold, London, UK, 1997
  52. Graham DI, McIntosh TK, Maxwell WL, Nicoll JAC: Recent advances in neurotrauma. J Neuropath Exp Neurol 59:641-651, 2000[Medline]
  53. Giulian D: Microglia and tissue damage in the central nervous system. Neurol Neurobiol 55:379-389, 1990
  54. Gurdjian ES, Roberts VL, Thomas LM: Tolerance curves of acceleration and intracranial pressure and protective index in experimental head injury. J Trauma 6:600-604, 1966[Medline]
  55. Gutierrez E, Huang Y, Haglid K, Bao F, Hansson HA, Hamberger A, Viano D: A new model for diffuse brain injury by rotational acceleration. I. Model, gross appearance, and astrocytosis. J Neurotrauma 18:247-257, 2001[CrossRef][Medline]
  56. Hayes RL, Katayama Y, Young HF, Dunbar JG: Coma associated with flaccidity produced by fluid-percussion concussion in the cat. I. Is it due to depression of activity within the brainstem reticular formation? Brain Inj 2:31-49, 1988[Medline]
  57. Hayes RL, Stalhammar D, Povlishock JT, Allen AM, Galinat BJ, Becker DP, Stonnington HH: A new model of concussive brain injury in the cat produced by extradural fluid volume loading. II. Physiological and neuropathological observations. Brain Inj 1:93-112, 1987[Medline]
  58. Hicks RR, Baldwin SA, Scheff SW: Serum extravasation and cytoskeletal alterations following traumatic brain injury in rats. Comparison of lateral fluid percussion and cortical impact models. Mol Chem Neuropathol 32:1-16, 1997[Medline]
  59. Jane JA, Steward O, Gennarelli TA: Axonal degeneration induced by experimental noninvasive minor head injury. J Neurosurg 62:96-100, 1985[Medline]
  60. Jubb KVF, Huxtable CR: The nervous system. In: Pathology of Domestic Animals ed. Jubb KVF, Kennedy PC, Palmer N, 4th ed vol. 1: p 323, Academic Press, San Diego, CA 1993
  61. Katayama Y, Becker DP, Tamura T, Hovda DA: Massive increases in extracellular potassium and the indiscriminate release of glutamate following concussive brain injury. J Neurosurg 73:889-900, 1990[Medline]
  62. Kobrine AI, Kempe LG: Studies in head injury. I. An experimental model of closed head injury. Surg Neurol 1:34-37, 1973[Medline]
  63. Krause JF, McArthur DL, Silverman TA, Jayaraman M: Epidemiology of brain injury. In: Neurotrauma, ed. Narayan RK, Wilberger JE, Povlishock JT, pp 13-30, McGraw-Hill, New York, NY 1996
  64. Lewis SB, Finnie JW, Blumbergs PC, Scott G, Manavis J, Brown C, Reilly PL, Jones NR, McLean AJ: A head impact model of early axonal injury in the sheep. J Neurotrauma 13:505-514, 1996[Medline]
  65. Lighthall JW: Controlled cortical impact: a new experimental brain injury model. J Neurotrauma 5:1-15, 1988[Medline]
  66. Lighthall JW, Anderson TE: In vivo models of experimental brain and spinal cord trauma. In: The Neurobiology of Central Nervous System Trauma, ed. Salzman SK, Faden AI, pp 3-11, Oxford University Press, New York, NY, 1994
  67. Lighthall JW, Dixon CE, Anderson TE: Experimental models of brain injury. J Neurotrauma 6:83-97, 1989[Medline]
  68. Lighthall JW, Goshgarian HG, Pinderski CR: Characterization of axonal injury produced by controlled cortical impact. J Neurotrauma 7:65-76, 1990[Medline]
  69. Longhi L, Saatman KE, Raghupathi R, Laurer HL, Lenzlinger PM, Riess P, Neugebauer E, Trojanowski JQ, Lee VM, Grady MS, Graham DI, McIntosh TK: A review and rationale for the use of genetically engineered animals in the study of traumatic brain injury. J Cereb Blood Flow Metab 21:1241-1258, 2001[CrossRef][Medline]
  70. Marmarou A, Montasser A, Foda A-E, Van den Brink W, Campbell J, Kita H, Demetriadou K: A new model of diffuse brain injury in rats. I. Pathophysiology and biomechanics. J Neurosurg 80:291-300, 1994[Medline]
  71. Marmarou A, Shima K: Comparative studies of edema produced by fluid percussion injury with lateral and central models of injury in cats. Adv Neurol 52:233-300, 1990[Medline]
  72. Maxwell WL, Graham DI: Loss of axonal microtubules and neurofilaments after stretch injury to guinea pig optic nerve fibres. J Neurotrauma 14:603-614, 1997[Medline]
  73. Maxwell WL, Kosanlavit R, McCreath BJ, Reid O, Graham DI: Freeze-fracture and cytochemical evidence for structural and functional alteration in the axolemma and myelin sheath of guinea pig nerve fibres after stretch injury. J Neurotrauma 16:273-284, 1999[Medline]
  74. Maxwell WL, Povlishock JT, Graham DI: A mechanistic analysis of nondisruptive axonal injury: a review. J Neurotrauma 14:419-410, 1997[Medline]
  75. Mayeux R, Ottman R, Tang MX, Noboa-Bauza L, Marder K, Gurland B, Stem Y: Genetic susceptibility and head injury as risk factors for Alzheimer's disease among community-dwelling elderly persons and their first-degree relatives. Ann Neurol 33:494-501, 1993[CrossRef][Medline]
  76. McIntosh TK, Noble L, Andrews B, Faden AI: Traumatic brain injury in the rat: characterization of a midline fluid-percussion model. Cent Nerv Syst Trauma 4:119-134, 1987[Medline]
  77. McIntosh TK, Vink R, Noble L, Yamakami I, Fernyak S, Faden A: Traumatic brain injury in the rat: characterization of a lateral fluid percussion model. Neuroscience 28:233-244, 1989[CrossRef][Medline]
  78. McLean AJ: Brain injury without head impact. In: Traumatic Brain Injury. Bioscience and Mechanics, ed. Bandak FA, Eppinger RH, Ommaya AK, pp 45-49, Ann Liebert, Larchmont, NY, 1996
  79. Murai H, Pierce JES, Raghupathi R, Smith DH, Saatman KE, Trojanowski JO, Lee VM, Loring JF, Eckman C, Younkins S, McIntosh TK: Two-fold overexpression of human ß-amyloid precursor proteins in transgenic mice does not affect the neuromotor cognitive or neurodegenerative sequelae following experimental brain injury. J Comp Neurol 392:428-438, 1998[CrossRef][Medline]
  80. Nelson LR, Auen EL, Bourke RS, Barron KD: A new head injury model for evaluation of treatment modalities. Neurosci Abst 5:516, 1979
  81. Ommaya AK: Experimental head injury in the monkey. In: Head Injury Conference Proceedings, ed. Caveness WF, Walker AE, pp 3211-3342, Lippincott, Philadelphia, PA, 1966
  82. Ommaya AK, Corrao P, Letcher FS: Head injury in the chimpanzee: biodynamics of traumatic unconsciousness. J Neurosurg 39:167-177, 1973[Medline]
  83. Ommaya AK, Gennarelli TA: Cerebral concussion and traumatic unconsciousness: correlation of experimental and clinical observations on blunt head injuries. Brain 97:633-654, 1974[Free Full Text]
  84. Ommaya AK, Gennarelli TA: Corelation between the biomechanics and pathophysiology of head injury. In: Neural Trauma, ed. Sano K, Ischii S, pp 275-289, American Elsevier, New York, NY, 1974
  85. Ommaya AK, Hirsch AE: Tolerances for cerebral concussion from head impact and whiplash in primates. J Biomech 4:13-31, 1971[CrossRef][Medline]
  86. Ommaya AK, Hirsch AE, Flamm ES, Mahone RH: Cerebral concussion in the monkey: an experimental model. Science 153:211-212, 1966[Abstract/Free Full Text]
  87. Park HK, Fernandez II, Dujovny M, Diaz FG: Experimental animal models of traumatic brain injury: medical and biomechanical mechanism. Crit Rev Neurosurg 9:44-52, 1999
  88. Povlishock JT: An overview of brain injury models. In: Neurotrauma, ed. Narayan RK, Wilberger JE, Povlishock JT, pp 1325-1336, McGraw-Hill, New York, NY 1996
  89. Povlishock JT, Becker DP, Cheng CLY, Vaughan GW: Axonal change in minor head injury. J Neuropathol Exp Neurol 42:225-242, 1983[Medline]
  90. Povlishock JT, Becker DP, Sullivan HG, Miller JD: Vascular permeability alterations to horseradish peroxidase in experimental brain injury. Brain Res 153:223-239, 1978[CrossRef][Medline]
  91. Povlishock JT, Christman CW: The pathobiology of traumatic brain injury. In: The Neurobiology of Central Nervous System Trauma, ed. Salzman SK, Faden AI, pp 109-120, Oxford University Press, New York, NY, 1994
  92. Povlishock JT, Christman CW: The pathobiology of traumatically induced axonal injury in animals and humans: a review of current thoughts. J Neurotrauma 12:555-564, 1995[Medline]
  93. Povlishock JT, Erb DE, Astruc J: Axonal response to traumatic brain injury. Reactive axonal change, deafferentation, and neuroplasticity. J Neurotrauma 9:S189, 1992
  94. Povlishock JT, Hayes RL, Michel ME, McIntosh TK: Workshop on animal models of traumatic brain injury. J Neurotrauma 11:723-732, 1994[Medline]
  95. Povlishock JT, Marmarou A, McIntosh T, Trojanovski JQ, Moroi J: Impact acceleration injury in the rat: evidence for focal axolemmal change and related neurofilament sidearm alteration. J Neuropathol Exp Neurol 56:347-359, 1997[Medline]
  96. Regan RF, Choi DW: Excitotoxicity and central nervous system trauma. In: The Neurobiology of Central Nervous System Trauma, ed. Salzman SK, Faden AI, pp 173-181, Oxford University Press, New York, NY, 1994
  97. Roberts GW, Gentleman SM, Lynch A, Murray L, Landon M, Graham DI: ß-amyloid protein deposition in the brain after severe head injury implications for the pathogenesis of Alzheimer's disease. J Neurol Neurosurg Psychiatry 57:419-425, 1994[Abstract/Free Full Text]
  98. Ross DT, Brasko J, Graham DI: Axonal injury produced by moderate lateral fluid percussion in adult rats. I. Comparison of silver staining and neurofilament labelling patterns of damaged axons. J Neurotrauma 11:124, 1994 [Abstract]
  99. Ross DT, Meaney DF, Sabol M, Smith DH, Gennarelli TA: Distribution of diffuse axonal injury following inertial closed head injury in miniature swine. Exp Neurol 126:1-10, 1994[CrossRef][Medline]
  100. Schmidt RH, Grady MS: Regional patterns of blood-brain barrier breakdown following central and lateral fluid percussion injury in rodents. J Neurotrauma 10:415-430, 1993[Medline]
  101. Sekino H, Nakamura N, Kanda R, Yasue M, Masuzawa H, Aoyagi N, Mii K, Kohno H, Sugimori T, Sugiura M, Kikuchi A, Ono K: Experimental head injury in monkeys using rotational acceleration impact. Neurol Med Chir (Tokyo) 20:127-136, 1979
  102. Shapira Y, Shohami E, Sidi A: Experimental closed head injury in rats: mechanical pathophysiologic and neurologic properties. Crit Care Med 16:258-265, 1988[Medline]
  103. Shapiro K, Smith LP: Special considerations for the pediatric age group. In: Head Injury, ed. Cooper PR, 3rd ed., pp 427-458, Williams and Wilkins, Baltimore, MD 1993
  104. Shaver EG, Duhaime A-C, Curtis M, Gennarelli TA, Barrett R: Experimental acute subdural hematoma in infant piglets. Pediatr Neurosurg 25:123-129, 1996[Medline]
  105. Sherriff FE, Bridges LR, Gentleman SM, Sivaloganathan S, Wilson S: Markers of axonal injury in post mortem human brain. Acta Neuropath 88:433-439, 1994
  106. Shima K, Marmarou A: Evaluation of brainstem dysfunction following severe fluid percussion head injury to the cat. J Neurosurg 74:270-277, 1991[Medline]
  107. Smith DH, Nakamura M, McIntosh TK, Wang J, Rodriguez A, Chen XH, Raghupathi R, Saatman KE, Clemens J, Schmidt ML, Lee VM: Brain trauma induces massive hippocampal neuron death linked to a surge in ß-amyloid levels in mice overexpressing mutant amyloid precursor protein. Am J Pathol 153:1005-1010, 1998[Abstract/Free Full Text]
  108. Statler KD, Jenkins LW, Dixon CE, Clark RS, Marion DW, Kochanek PM: The simple model versus the super model: translating experimental traumatic brain injury research to the bedside. J Neurotrauma 18:1195-1206, 2001[CrossRef][Medline]
  109. Sullivan HG, Martinez J, Becker DP, Miller JD, Griffith R, Wist AO: Fluid percussion model of mechanical brain injury in the cat. J Neurosurg 45:520-534, 1976
  110. Summers BA, Cummings JF, deLahunta A: Veterinary Neuropathology. p 15, Mosby, St Louis, MO, 1995
  111. Tanno H, Nockels RP, Pitts LH, Noble LJ: Breakdown of the blood-brain barrier after fluid percussive brain injury in the rat. I. Distribution and time course of protein extravasation. J Neurotrauma 9:21-32, 1992[Medline]
  112. Thibault LE, Meaney DF, Anderson BJ, Marmarou A: Biomechanical aspects of a fluid percussion model of brain injury. J Neurotrauma 9:311-322, 1992[Medline]
  113. Tornheim PA, Linwnicz DH, Hirsch CS, Brown DL, McLaurin RL: Acute responses to blunt head trauma. Experimental model and gross pathology. J Neurosurg 59:431-438, 1983[Medline]
  114. Van den Heuvel C, Blumbergs PC, Finnie JW, Manavis J, Jones NR, Reilly PL, Pereira R: Upregulation of amyloid precursor protein messenger RNA in response to traumatic brain injury: an ovine head impact model. Exp Neurol 159:441-450, 1999[CrossRef][Medline]
  115. Van den Heuvel C, Blumbergs PC, Finnie JW, Manavis J, Lewis SB, Jones NR, Reilly PL, Pereira R: Upregulation of amyloid precursor protein and its mRNA in an experimental model of pediatric head injury. J Clin Neurosci 7:140-145, 2000[CrossRef][Medline]
  116. Ward JD: Pediatric head injury. In: Neurotrauma, ed. Narayan RK, Wilberger JE, Povlishock JT, pp 859-867, McGraw-Hill, New York, NY 1996
Request reprints from Prof. P. C. Blumbergs, Neuropathology, Institute of Medical & Veterinary Science, Frome Road, Adelaide 5000 (Australia). E-mail: peter.blumbergs{at}imvs.sa.gov.au.


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