Vet Pathol 39:679–689 (2002)

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. 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, trau-
matic 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 ac-
cidents. For every fatality, there are many survivors
with severe brain damage and many more with mod-
erate 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 of-
ten difficult to reconstruct the events leading to the
primary and secondary lesions of varying severity and
regional distribution that constitute TBI.11,50 In con-
trast, the mechanical input in animal models is quan-
tifiable and subject to manipulation, and head injuries
are produced under controlled experimental condi-
tions. Second, although a host of potential neuropro-
tective agents have been studied, the few that have
shown promise under experimental conditions have
failed to provide consistent and significant improve-
ment in human clinical trials.14,16,29,108 Testing the effi-
cacy 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, as-
saults, 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 de-
rived from their use as experimental models of human
TBI.34 This review highlights the contribution of dif-
ferent types of animal models to our understanding of
the neuropathology of head injury.
679
Types of Animal Models
TBI may be produced by the head impacting or
coming into contact with an object (contact phenom-
ena) or acceleration/deceleration forces producing vig-
orous 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
● inertial (nonimpact) acceleration models
● direct brain deformation models.
Impact acceleration models involve direct head im-
pacts using a piston, humane stunner or captive bolt
pistol, calibrated pendulum, or weight drop onto the
skull. This focal mechanical loading causes deforma-
tion of the brain which, being almost incompressible,
is particularly vulnerable to strain injury. These mod-
els resemble closed head injury in motor vehicle ac-
cidents or falls where there is rapid acceleration/de-
celeration 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 fea-
680 Finnie and Blumbergs Vet Pathol 39:6, 2002

tures of TBI in primates, cats, and sheep, including Table 1. Classification of traumatic brain injury.
contusions, subarachnoid hemorrhage, and widespread
axonal injury (AI) and, in contrast to inertial acceler- Primary traumatic brain damage (neural or vascular [or
both])
ation models, skull fractures are commonly found. Dif-
fuse brain injury was also produced in an impact-ac- Diffuse
celeration rat model,37,71 whereas previous impact Diffuse axonal injury (DAI)
models in rats had been largely unsuccessful because Diffuse vascular injury (DVI)
the high acceleration levels required to produce brain Focal
damage resulted in a slender margin between injury Vascular injury resulting in
and death.40 Intracerebral hemorrhage
Inertial acceleration models involve acceleration of Subdural hemorrhage
the head without impact, unlike most human motor Extradural (epidural) hemorrhage
vehicle accident situations.78 Inertial acceleration de- Axonal injury
vices generate a repeatable pathologic response, es- Contusion
pecially when the direction and distance of head move- Laceration
ment is constrained. Angular acceleration, especially Secondary traumatic brain damage
in the coronal plane, has been shown to be particularly Diffuse
injurious in nonhuman primates,43,44,47,81,82,83,85,86 pigs,98 Diffuse hypoxic-ischemic damage
and cats.80 In these models, the acceleration required Diffuse brain swelling
to produce injury experimentally is found only in hu-
Focal
man TBI when head impact occurs.67
Inertial injury models were first developed in pri- Focal hypoxic-ischemic injury
Focal brain swelling
mates by Ommaya and Gennarelli, and subsequent
modifications by Gennarelli and colleagues succeed-
ed in reproducing many features of human
TBI.38,41,43,44,46,47,83,86 By sudden deceleration of a mov- indentation models, but AI is more localized than dif-
ing frame to which the primate body was firmly at- fuse.77,99
tached, coma was produced by the whiplash motion of An optic nerve stretch model has also been devel-
a freely mobile head. In these studies, coma was more oped in guinea pigs, enabling AI to be studied under
readily produced by angular acceleration in the coronal very controlled conditions.39,72,74
plane and was associated with diffuse axonal injury Thus, although no single animal model of nonmis-
(DAI) in the subcortical white matter.3,4,41,44,59 Angular sile head injury produced by mechanical energy can
or translational acceleration could be generated in express the great diversity of neural damage constitut-
these primates and, by controlling head motion, acute ing human TBI, multiple animal models are neverthe-
subdural hematoma, brief unconsciousness or pro- less capable of replicating specific features of TBI that
longed coma, and DAI were induced. can be analyzed.
Direct brain deformation models include both fluid
percussion and rigid indentation types and use either Types of TBI
a fluid pulse or mechanically driven piston, respec- Primary traumatic brain damage
tively, to rapidly compress the exposed dura or cortex
through a craniotomy site.58,70,100 These models pro- This type of TBI is the result of mechanical forces
duce well-controlled levels of localized injury rather producing tissue deformation at the moment of injury.
than diffuse damage. Brain deformation models have These deformations may directly damage the blood
been used primarily in rats18,23–25,48,66,76,77,111 and also in vessels, axons, neurons, and glia in a focal, multifocal,
cats15,56,57,89 and ferrets.65 or diffuse pattern of involvement and initiate dynamic
In fluid percussion models, contusions of varying and evolving processes that differ for each component
size can be produced; these being smaller and less fre- part and result in complex cellular, inflammatory, neu-
quent with a central (midline) impact compared with rochemical, and metabolic alterations.11,51 Primary TBI
a lateral impact. In centrally directed models, scattered is summarized in Table 1.
AI is principally found in the brainstem with modest
Secondary traumatic brain damage
involvement of cortical and subcortical are-
as.23,89,92,106,112 A lateral approach tends to produce hip- This type of TBI occurs as a complication of the
pocampal injury with less brainstem damage, and uni- different types of primary brain damage and includes
lateral AI occurs in the central white matter. Contu- ischemic and hypoxic damage and cerebral swelling,
sions are also produced with central and lateral rigid the consequences of raised intracranial pressure, hy-
Vet Pathol 39:6, 2002 Traumatic Brain Injury Models 681

drocephalus, and infection.11,51 These events are sum-

marized in Table 1.
Experimental models of TBI have been devised us-
ing 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 mo-
ment of impact is largely refractory to treatment and
relies on preventive measures, most brain injury
evolves as a progressive cascade of events that is po-
tentially reversible with adequate treatment. The rec-
ognition 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 an-
imal models has been greatly enhanced by the intro-
duction of immunocytochemical techniques using an-
tibodies to axonally transported proteins, such as am-
yloid precursor protein (APP), neurofilament protein,
and synaptophysin.51 APP immunostaining (Figs. 1–3)
is the most sensitive marker of AI,105 identifying ax-
onal 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
The total burden of AI in a given brain has been
underestimated using traditional, less sensitive staining Figs. 1, 2. Sheep. APP-positive axonal swellings, with
most axons running longitudinally in the same direction.
methods such as hematoxylin and eosin and silver im-
Some axons are irregularly beaded (arrows). Avidin–biotin–
pregnation.105 But focal nontraumatic AI around he- peroxidase method, hematoxylin counterstain. Bar 5 40, 80
matomas, infarcts, and abscesses cannot be distin- mm.
guished from AI due to mechanical deformation of the Fig. 3. Sheep. APP-positive axonal swellings cut in
brain, and thus APP accumulation in axons is not con- transverse section (arrows); uninjured axons are not stained
fined to head-injured patients and is not a specific with this immunohistochemical technique. Bar 5 72 mm.
marker for head injury.11,12,51,105
Animal models have defined the early changes after
traumatic AI. Mechanical deformation and cell mem- port and accumulation of cytoskeletal components and
brane depolarization by shearing forces lead to a membranous organelles over 3–6 hours, which is man-
marked calcium influx into cells, which may be recep- ifest as axonal swellings. Axotomy becomes apparent
tor-mediated, voltage-dependent, or via transient de- 6–12 hours after injury, and the distal segment under-
fects in the plasmalemma (mechanoporation). As a re- goes Wallerian degeneration.94,95 This temporal pro-
sult of this traumatic calcium overload, enzyme and gression of axonal reaction is also variable and spe-
gene activation occur. Proteases damage the cytoskel- cies-dependent, occurring more rapidly in rodents than
etal architecture leading to interruption of axonal trans- higher order animals.88 Axons that change direction
682 Finnie and Blumbergs
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 wide-
spread and intense microglial reaction.
DAI is defined as widely distributed AI in the ce-
rebral 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 un-
consciousness, 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 re-
ported 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 sec-
ondary insults after head injury. But the current his-
tologic methods for detecting AI are unable to distin-
guish between these types of AI.12 Continuous physi-
ologic 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/de-
celeration forces than nonhuman primates and man. In
quadrupeds, the long axes of the brain and spinal cord
Vet Pathol 39:6, 2002
are parallel, whereas in man and nonhuman primates
they are almost at right angles. This almost linear neur-
axis 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 impor-
tance of head acceleration in TBI, for impact to a free-
ly mobile head was much more likely to produce loss
of consciousness than to one constrained. Head accel-
eration 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. Om-
maya, 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 persis-
tent the neurologic abnormalities and the duration of
unconsciousness after head impact correlated with the
degree of DAI. Loss of consciousness persists for sec-
onds 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 pe-
riods (20–25 ms) as may occur in motor vehicle ac-
cidents produced prolonged traumatic coma and DAI,
whereas a short acceleration time (5–10 ms) resem-
bling 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 oc-
curred. 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 man-
tle.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 cor-
tical 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 phenom-
Vet Pathol 39:6, 2002 Traumatic Brain Injury Models 683

Fig. 4. Sheep (clockwise from top left); lateral cerebral hemisphere impact contusion (C), with subarachnoid hemorrhage
around the brainstem (bar 5 11 cm); ventral aspect of the brain showing abundant subarachnoid hemorrhage (bar 5 12.5
cm); focal hemorrhage in the lateral pons (arrow) (bar 5 7.5 cm); left lateral hemisphere impact contusion, with contusions
on the inferior aspect of the pyriform lobes (arrows) (bar 5 4 cm).

ena, 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 re-
sults 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
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 post-
traumatic 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. Sub-
dural 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 ob-
served. But skull fractures do occur with many impact
acceleration models, unless the skull is protected by a
metal plate or molded cap. Intraventricular hemor-
rhage is a frequent complication after human and an-
imal head impact, and hematomas may also develop
in the brain substance (intracerebral hematomas). In-
traparenchymal 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 pe-
techial hemorrhages scattered throughout the brain
(diffuse vascular injury), but there appears to be no
animal model counterpart.11,51
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 ede-
ma and congestion and, together with hematomas, is
the major contributor to increased intracranial pres-
sure. It may eventually lead to distortion, shift, and
herniation of the brain. Edematous swelling often oc-
curs around contusions and intracerebral hemorrhages
684 Finnie and Blumbergs Vet Pathol 39:6, 2002

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

in humans and animal models, whereas swelling of Chronic brain injury

one hemisphere in man may result from a combination
of congestion and edema. Diffuse swelling of the en-
tire brain due to hyperemia occurs in young children,
even after an apparently trivial injury, but is uncom-
mon in adults. Generalized brain swelling produces
gyral flattening, sulcal narrowing, and ventricular col-
lapse.11,51
Reactive microglia also influence clinical outcome
after TBI because they are the principal immune ef-
fector elements of the brain, are the major source of
central nervous system–derived proinflammatory cy-
tokines, 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 excit-
atory amino acid neurotransmitters, especially gluta-
mate, into the extracellular fluid.28,61 Although the stor-
age, transmission, and uptake of glutamate is normally
finely regulated, a marked rise in extracellular gluta-
mate after TBI is highly toxic to neurons.96
The long-term effects of TBI depend on a combi-
nation of the different types of primary and secondary
damage sustained and their relative severity, but mod-
eling of chronic brain injury has rarely been attempt-
ed.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 b-amyloid deposits have been re-
ported to occur between 4 hours and 2.5 years in hu-
man TBI.97 Transgenic mice engineered to overexpress
human APP twofold (APP-YAC mice) failed to pro-
duce amyloid plaques or cognitive change after inju-
ry,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
Vet Pathol 39:6, 2002 Traumatic Brain Injury Models 685

model of human pediatric TBI because its brain de-

velopment 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 in-
jury 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 im-
mensely intricate developmental processes and the re-
sumption of the orderly progression after injury is un-
known.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 im-
pacted.35

Conclusion
The complexity and diversity of TBI pathology will
ensure a continuing role for animal models to define
more accurately the cascade of morphologic and bio-
chemical events occurring after a traumatic insult. One
of the most important insights into the pathogenesis of
TBI provided by animal models has been the realiza-
tion that many structural changes, particularly AI, are
not immediate and irreversible but often time-depen-
dent evolving processes that may be amenable to ther-
apeutic intervention. Animal models will be essential
to evaluate potential neuroprotective agents.

Fig. 9. Sheep. Extensive traumatic midbrain hemor-
rhage. Bar 5 7 cm.
Fig. 10. Sheep. Severe traumatic thalamic hemorrhage,
with midline shift and distortion of the brain. Bar 5 8.5 cm.
Fig. 11. Sheep. Focal traumatic hemorrhage in the lat-
eral pons. Bar 5 4 cm.
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 dif-
ferences in the stage of maturity of the brain at birth
between species are important.7 Species can be cate-
gorized as prenatal (sheep and guinea pigs) or post-
natal (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
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