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Mechanisms of Traumatic Brain Injury

Derek Bauer, MD1

Monica L. Tung, BA2

Jack W. Tsao, MD, DPhil1,2,3,4

1 Department of Neurology, University of Tennessee Health Science

Center, Memphis, Tennessee

2 Department of Physical Medicine and Rehabilitation, Uniformed
Services University, Bethesda, Maryland
3 Department of Neurology, Uniformed Services University of the
Health Sciences, Bethesda, Maryland
4 US Navy Bureau of Medicine and Surgery, Washington, DC

Address for correspondence Jack W. Tsao, MD, DPhil, Department of

Neurology, Uniformed Services University of the Health Sciences, 4301
Jones Bridge Road, Room A1036, Bethesda, MD 20814-4799
(e-mail: jack.tsao@usuhs.edu).

Abstract
Keywords

traumatic brain injury

closed head injury
penetrating traumatic
brain injury
blast traumatic
brain injury

The authors describe the mechanisms of traumatic brain injury (TBI), examining in
depth the characteristics of closed head, penetrating, and blast-related TBI. Events on a
structural as well as cellular level are reviewed. Blast-related brain injury, in particular,
affects military service members preferentially, but is also relevant in cases of industrial
accidents as well as terrorist events.

The current understanding of the biomechanics of traumatic

brain injury (TBI) comes from a range of study types: animal
models, cadaveric and human skull studies, computational
models, and in situ investigation of strain on brain structures
during mild acceleration using magnetic resonance imaging
(MRI). There are inherent limitations to each type of study
that should be mentioned. Animal studies give insight into TBI
biomechanics mainly through accessibility; however, animal
brains and skulls are vastly different both in structure and
complexity in comparison to humans. Cadaveric and gelatin
studies using emptied skulls improves upon this issue, but the
supportive structures and uids (i.e., the meninges, dura, and
cerebrospinal uid [CSF]) have different dynamics after
death; in many instances, these structures have been removed entirely prior to studies being performed. Computational models offer promise into the study of human TBI that
would otherwise be inaccessible due to ethical concerns. The
data in most instances, though, may be difcult to verify due
to theoretical nature of the models. Lastly, MRI investigations
offer insight into the movements of the brain in situ. Generally, the forces applied to the volunteers in these studies are
far below those seen in actual closed head injury. Although
currently there is no optimal model for the evaluation of the
biomechanics of TBI, the additive understanding from these

Issue Theme Traumatic Brain Injury;

Guest Editor, Geoffrey Ling, MD, PhD,
FAAN, FANA

various study types has greatly furthered the understanding

of the mechanisms underlying TBI.

Closed Head Traumatic Brain Injury

Two broad mechanisms of TBI exist: impact, in which the
immediate force makes contact with the skull and leads to
injury; and impulse, in which a force causes head movement
without directly acting upon the head.1 Regardless of the
mechanism, acceleration of the head ensues and is brought
about by linear and rotational force. Linear force is governed
by the equation: force mass  acceleration. Rotational
force is dened as torque moment of inertia  angular
acceleration. Head trauma in normal daily life typically
involves both forces concomitantly. This is due to the relationship between a force and the center of gravity of the
object (i.e., the head) that the force is acting upon. For
example, the sum of the force vectors acting upon the head
run through the heads center of gravity, the head will display
mainly linear movement in the direction of the blow. However, this rarely occurs in isolation, as it is uncommon for a
force to act directly upon the heads center of gravity. As a
force acts upon the head further away from the center of
gravity, the degree of rotational movement increases.2

Copyright 2015 by Thieme Medical

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DOI http://dx.doi.org/
10.1055/s-0035-1549095.
ISSN 0271-8235.

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Semin Neurol 2015;35:e14e22.

Linear acceleration has been associated with pulses of

increased intracranial pressure as well as intracranial pressure gradients.3 This pressure has been associated with strain
at the level of the brainstem.4 However, the degree of strain,
as well as the severity of injury, is less in experimental models
of linear acceleration as compared with rotational acceleration. Primate studies have shown an inability to produce loss
of consciousness without rotational acceleration.5 This is
corroborated by computational models that have estimated
up to 90% of the strain occurring on the human brain occurs
via rotational acceleration.6 Thus, from both animal and
human studies, rotational acceleration is posited as the
primary determinant of injury in closed head injury.
The direction from which a force acts upon the head
determines the degree of rotational movement of the head
as well as the injury severity. Primate models of experimental
TBI show forces acting in the coronal plane are associated
with more severe neuropathological changes, as well as a
worse clinical outcome.7 Computational models also suggest
larger amplitude skull deection as well as increased shear
stress with lateral impact.8 Retrospective human studies
show that lateral head injuries are more likely to be severe.9
It should be noted in the retrospective human studies that it is
unclear if the lateral blow is causative or merely correlative
due to confounding issues such as lateral injury being associated with a lack of bracing for a blow that cannot be accounted
for in the mechanism of injury.
After the physical injury a complex series of events occurs
at the cellular level, the sequence of which is still not
completely understood. The most robust fund of information
about the biochemistry of TBI is in animal models, but with
many aspects of this research having been validated in human
studies. Injury to the brain parenchyma causes both immediate mechanical damage as well as a longer lasting biochemical
cascade.10 This sequence of biochemical events is associated
with multiple electrolyte imbalances, oxidative metabolism
dysfunction, and alterations in glucose metabolism.
Mechanical injury results in unregulated neuronal membrane depolarization and ring.11 This indiscriminate depolarization leads to a rapid, marked release of the excitatory
amino acid glutamate into the extracellular space, which in
turn leads to potassium release through activation of kainate,
NMDA, and AMPA receptors.12 This increase in extracellular
potassium leads to an imbalance in the potassium intracellular : extracellular potassium gradient, which is the primary
determinant of the neuronal resting membrane potential. As
the resting membrane potential becomes less negative (normal: -70 mV) it approaches the threshold potential (normal:
-55mV); this leads to an increased likelihood of spontaneous
neuronal depolarization. This unregulated neuronal ring
causes further release of excitatory amino acids, which leads
to even greater extracellular potassium imbalance.
Astrocytes surrounding healthy neurons offer the rst
compensatory mechanism for this increased extracellular
potassium.13 However, following injury, glial compensation
is not sufcient to correct the ion imbalance and neuronal
membrane transporters, particularly as the Na/K-ATPase
becomes overactivated. This antiporter is the primary deter-

Bauer et al.

minant of resting neuronal membrane potential and requires

one unit of ATP for the transport of three ions of sodium
extracellularly and two ions of potassium intracellularly. In
rat models following traumatic injury, Na/K-ATPase activity
increases to compensate for the excessive extracellular potassium and loss of normal ion balance. This increase in
enzyme activity is associated with a marked increase in
energy expenditure,14 which appears to occur immediately
after injury.15 The degree of increase in metabolic demand is
unclear in humans, but current estimates suggest that this
enzyme is responsible for approximately 20% of all neuronal
energy expenditure in the human cerebral cortex during
basal conditions.16
Following potassium ion shifts, intracellular calcium increases following traumatic injury due to pore formation
from activated NMDA receptors.17,18 This increase may endure for 48 hours or more due to alterations in NMDA
receptor subunit composition.19 Intramitochondrial calcium
subsequently increases concomitantly with intracellular calcium increase, and is associated with mitochondrial swelling
and impaired oxidative metabolism.2022 Increased extracellular calcium has also been implicated as an integral step in
neuronal cell death, although the exact mechanism through
which this may occur is still unclear.23
Intracellular magnesium is depleted following traumatic
injury in experimental models, and early posttrauma intervention with magnesium supplementation has shown some
promise of neuroprotection in animals.24,25 Experimental
models have shown that early magnesium supplementation
may reduce cellular apoptosis through reduction in p53
enzyme activity. However, a recent double-blind placebocontrolled trial in moderate-to-severe TBI in humans revealed no therapeutic effects of magnesium and suggested
the possibility of deleterious outcomes associated with magnesium intervention administered at the time of presentation.26 To date, the importance of cellular magnesium shifts
after TBI in humans is unclear.
As discussed above, neurons attempt to compensate for
these various ion disturbances. In the face of this increase in
cellular energy demand, metabolic derangement occurs primarily through decreased cerebral blood ow and mitochondrial dysfunction. Under normal conditions, there is a tightly
regulated relationship between neuronal metabolic demand
and cerebral blood ow, often referred to as neurovascular
coupling. When TBI occurs, this relationship is lost. Lateralized damage sustained from uid percussion injury in rats
produces moderate to severe injury and is associated with
localized as well as diffuse (bilateral hemispheric) reduction
in cerebral blood ow. This decrease is signicantly present
up to 4 hours postinjury and is associated with up to a 50%
reduction in ow.27,28 Investigations in humans have also
shown decreased cerebral blood ow, particularly when focal
lesions secondary to trauma are present.29 In this setting,
much needed oxygen and glucose delivery to the brain is
impaired in a period of critically increased demand.
The neurons ability to produce energy is also decreased
following traumatic injury. Oxidative metabolism, as evidenced through decreased mitochondrial cytochrome
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Bauer et al.

oxidase activity, is markedly reduced following injury.30

Several mechanisms contribute to this mitochondrial dysfunction, including structural damage, as evidenced through
loss of cristae membranes,31 increased mitochondrial calcium,22 and increased reactive oxygen species.32 Subsequent
human studies have also clearly delineated mitochondrial
dysfunction after TBI.33
Mitochondrial impairment severely limits ATP synthesis in
neurons, which rely heavily on oxidative metabolism, leading
to neurons shifting to glycolysis for ATP synthesis. Research in
animal models15 and human studies34 shows increased glycolysis as one of the early changes following TBI. This compensatory mechanism is inefcient. Glycolysis in the absence
of oxidative metabolism nets merely 4 ATP per glucose
molecule compared with the 34 to 38 generated through
glycolysis with oxidative metabolism in healthy neurons.
Glycolysis is also unable to generate sufcient energy to
keep up with cellular demand. As much as a 51% drop in
ATP levels has been documented in rat models in the immediate postinjury period.35 Within 6 hours in experimental
models, there is a transition from a hypermetabolic to a
hypometabolic state.15 The exact mechanism for this metabolic transition is unclear, but there is some suggestion that
trauma leads to a decrease in enzymatic activity essential for
glucose metabolism.36 In addition, glucose hypometabolism
in the rst few days after moderate TBI is correlated with
injury severity in human studies.37 Furthermore, one study
has also shown that a selective decrease in gray matter
glucose metabolism within the rst 8 days of moderate-tosevere injury is correlated with a worse neurologic outcome
at 12 months as quantied by the Glasgow Coma and
Outcome Scales.38
It is in this setting of lost neurovascular coupling, impaired
oxidative metabolism, and inadequate compensatory mechanisms that a so-called metabolic crisis arises, in which
cellular metabolic demands are in a state of great ux with
tenuous energy supply.39 This period may be of paramount
clinical signicance. Experimental models show that secondary injury during the hypometabolic state after initial TBI is
associated with a signicant worsening of the metabolic
situation.40 This sequence of events may provide insight
into the clinical phenomenon known as second impact syndrome, in which innocuous trauma after initial head injury is
associated with potentially fatal consequences.41 This clinical
event is associated with adolescent and young adult men,
generally under the age of 24, who develop severe diffuse
cerebral edema after a second episode of head trauma
(usually within hours to 4 days of the rst incidence of
trauma).
The immediate post-TBI period has also been studied
extensively electrographically. However, there are multiple
inherent limitations in electroencephalographic (EEG)
evaluation in experimental or clinical studies. In experimental models, animals are anesthetized for humane reasons, which may suppress spontaneous neuronal ring
after mechanical injury. In human studies, the time delay
between injury to presentation is often delayed, and the
time to EEG is often much longer. This delay severely limits
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the ability to evaluate dynamic hyperacute changes in

clinical practice.
Despite these limitations, many electrographic changes
occurring after TBI have been elucidated. Blunt force injury to
rats using weight drops from up to 2 m has been associated
with paroxysmal epileptiform discharges for 30 to 60 seconds
following injury.42 These abnormal electrographic discharges
appear to occur in the setting of elevated levels of excitatory
amino acids.43 Electroencephalographic evaluation in humans has been done as early as 15 minutes after TBI in
industrial dockworkers, but no epileptiform or fast activity
was seen. The majority of EEGs were normal, and the few that
were abnormal showed slowing in the theta- to delta-frequency range.44 Despite the relative lack of data showing
hyperacute epileptiform activity in humans, EEG changes
have been characterized in other studies. Most notably, subtle
slowing has been shown in the background frequency in EEG
in humans following TBI. This slowing may take weeks to a
few months to return to preinjury frequency.1,45
Unfortunately, the continued advancement in the understanding of the biomechanics and neurophysiology of TBI has
not translated into advancements in clinical intervention. As
mentioned above, early intervention with magnesium did not
improve clinical outcome despite promising studies in animal
models.26 The Citicoline Brain Injury Treatment (COBRIT) trial
found no signicant treatment effect with citicoline (an
intermediate in the biosynthesis of proteins that are integral
neuronal membrane proteins), despite promising preclinical
efcacy trials.46 Similarly, promising data for neuroprotection
from progesterone was obtained from the Progesterone for
the Treatment of Traumatic Brain Injury (PROTECT) phase II
trials, but the phase III trial was halted early due to lack of
benet. The absence of clinical progress is not limited to
medical treatment. Early bifrontotemporoparietal craniectomy in patients with severe TBI and refractory increased
intracranial pressure resulted in an increased likelihood of
poor clinical outcome due to adverse events such as hydrocephalus and intracranial hematoma formation, despite improvement in intracranial hypertension.47

Blast-Related Traumatic Brain Injury

Traumatic brain injury due to blast exposure is particularly
common in the military due to increased risk among combat
troops for exposure to explosive blast, although public areas
in civilian settings are increasingly targeted by extremist or
terrorist groups for attacks. Although blast-related TBI (bTBI)
represents a small fraction of the total TBI in the military, the
rate of bTBI sustained by deployed troops in Operation Iraqi
Freedom and Operation Enduring Freedom may be as high as
19.5%.
The mechanisms involved in bTBI are classied as primary,
secondary, tertiary, and quaternary. Blast exposure is often
associated with multiple mechanisms of injury. Primary
injuries are caused by the blast overpressure wave. Few
deaths are attributable to primary blast injury alone, particularly when the TBI is more severe: 70% of blast-induced
moderate-to-severe TBI also involve a penetrating injury.48,49

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Secondary injuries are caused by objects propelled by the

force of the explosion; tertiary injuries are caused if the body
is thrown back by the blast wind; and quaternary injury is
characterized by burns or toxic exposures (e.g., napalm)
resulting from the explosion.5052 Closed explosions often
cause building collapse, shattered windows, and ying debris,
which increases the risk for penetrating or blunt injuries.48
Quinary injuries have been dened as exposure to biological
or radioactive elements packed into the bomb48 that can
result in the individual falling into a hyperinammatory state
with hyperpyrexia, sweating, low central venous pressure,
and positive uid balance.53 Others have classied exacerbations or complications of pre-existing conditions as quaternary injury.54 Signicantly, blast noise and transportation
alone can produce neurobehavioral and biochemical changes
in rats in the absence of injury.55 These effects may contribute
to or exacerbate the underlying neuropathology in those who
sustain head injury in combat.55
The biophysics of primary injuries is distinct from the
mechanical forces that cause blunt or penetrating head
trauma. During detonation, a solid or liquid explosive is
instantaneously transformed into a gas. The displacement
of surrounding air creates a rapidly expanding wave front of
positive pressure (2030 GPa), known as blast overpressure,
which leaves behind a wave of negative pressure or underpressure (Fig. 1A).5658 In addition to kinetic energy, explosions may also discharge light, acoustic, and thermal
energy.59 The blast wave is followed by a blast wind moving
at several hundred km/h that is responsible for the displacement of objects in its path.50,56 The blast wind is the cause of
most severe injuries.
Many factors determine the severity of the injury caused
by the blast. The wave frequency, amplitude, duration, degree
of focusing, and distance from the source determine the
magnitude of kinetic energy that is transferred to the individual.50 The intensity of blast and quantity of prior blast

Bauer et al.

exposures correlate to the severity of TBI.60 If the source of the

explosion is an enhanced-blast device, the primary blast
ignites secondary explosions, resulting in a longer and
more intense period of overpressure.54 Reection of the blast
wave on surrounding surfaces can multiply the peak overpressure by 2 to 8 times the incident pressure and increase
the number of peaks as well as the total duration of the
positive-pressure phase (Fig. 1B).56,57 Furthermore, the
reected waves often strike the individual from different
directions.57 Unsurprisingly, exposure to blasts in a closed
space is associated with more severe injuries and higher
mortality.56 However, the vast majority of explosions in
Operation Enduring Freedom (OEF) and Operation Iraqi Freedom (OIF) occur in the open eld.48 An explosive incident
adjacent to, but not inside of, a vehicle causes a pressure wave
that is mostly reected off and not transmitted inside the
vehicle. Pressure loading on the vehicle itself may cause
accelerationdeceleration that results in blunt TBI similar
to what might occur from a motor vehicle accident (MVA).
The vehicle itself may shield passengers from 66% of the blast
impulse.48
The direct loading of the blast overpressure wave on the
head is altered by the type of helmet worn. One study found
that 80% of those with TBI were wearing helmets at the time
of injury.53 Helmets without padding leave a gap of air
surrounding the head that can amplify pressure loading.
Padded helmets link the motion of head and helmet, enhancing the transfer of mechanical forces to the head.53 Numerous
studies using animal models have demonstrated that protecting the thorax may be more critical in limiting the extent of
injury to the cerebrovasculature.50,61
When the energy of the incident blast wave meets the
head, the magnitude of the pressure decreases sharply from
the incident point to distal areas.57 Because pressure waves
pass from areas of high to low density, the blast overpressure
wave causes spallation of higher density tissues into lower

Fig. 1 Pressure diagrams demonstrate the blast overpressure wave in outdoor (A) and indoor (B) environments.56

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density tissues.56,57 After gas-containing compartments such

as emboli are compressed by the pressure wave, they expand,
damaging surrounding tissues.56 Inertial or shearing forces
from the rapid transfer of kinetic energy through tissue layers
can injure endothelial tissue.56,57
Although the lungs are more susceptible to fatal injury due
to the blast wave, the impulse threshold for mild, nonfatal
brain injury may be much lower than the pulmonary lethal
magnitude.62 Cortical tissue injury can be caused by the
transcranial impact of the pressure wave itself or the transmission of a pressure wave from the thorax through cranial
arteries or CSF. Because the brain is protected by the skull, the
cranial cavity is at lower relative pressure and thus quickly
ooded by the volumetric blood surge.63
Studies using animal models provide evidence that exposure of the thorax to the blast may contribute more to the
severity of brain injury, even in the absence of head protection.57 Axonal injuries and widespread ber degeneration in
the brain, as well as functional and behavioral impairment,
was also less severe in blast-exposed animals who wore chest
protection, whether or not head protection was worn.61 Even
a subconcussive blast can damage white matter integrity in
the brain.64 Rafaels et al used chest protection in the absence
of head protection in a ferret model to show that the
threshold to produce a nonfatal brain injury could be crossed
at lower blast intensities than those required to cause a fatal
pulmonary injury.65
Pulmonary injuries result in insufcient gas exchange or
blockage of vessels by emboli that can cause brain damage.
Implosion forces cause the air in the lungs to contract then
hyperinate, which can trigger the vago-vagal reex and
subsequently the Bezold-Jarish reex, resulting in apnea,
tachypnea, dyspnea, bradycardia, and hypotension.50,63,66
Sudden changes in air pressure can tear blood vessels, form
arterial air emboli, and damage alveolar structures, leading to
pneumothorax, emphysema, and pneumomediastinum.48
Insufcient gas exchange can lead to arterial oxygen desaturation and venous acidosis.67 Release of emboli and ischemia
increase the risk for stroke, myocardial infarction, and spinal
cord and bowel infarction.56 Ischemia in the brain stimulates
the release of neurotransmitters in the extracellular space.68
The buildup of neurotransmitters is responsible for neuronal
cell death by calcium-mediated mechanisms.58,68 Blastrelated TBI may also make an individual more susceptible to
minor hemodynamic changes by impairing vascular autoregulation in response to changes in arterial pressure, O2, and CO2.69
Cerebrovascular changes in bTBI include hyperemia, subarachnoid hemorrhage (SAH), rapid brain swelling, increased
intracranial pressure (ICP), pseudoaneurysm, and vasospasm.50,58,59,68 Cerebrovascular damage does not occur
preferentially in any brain location, but tends to affect smaller
structures, suggesting that the natural brain geometry, and
not blast loading, may determine which areas are injured.63
Cerebral vasospasm, characterized by hypercontraction of
endothelial smooth muscle and sustained vasoconstriction,
occurs in nearly half of bTBI survivors. Presentation typically
occurs several days after injury, and lasts up to 2 weeks
following blast exposure.57,70 The incidence of traumatic
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cerebral vasospasm is associated with the presence of pseudoaneurysm and poorer outcomes at discharge.49,70
Gross pathology of neuronal damage in the brain is
characterized by white matter lesions that resemble diffuse
axonal injury (DAI) or cerebral contusion.56 Lesions in bTBI
are distinct from other TBI etiologies in that they are focal and
scattered throughout the brain, independent of the direction
of blast loading.71 The number of low fractional anisotropy
voxels measured in diffuse tensor imaging (DTI) showed
diffuse and global damage in a heterogeneous distribution
across military who had sustained blast mTBI.72 However,
several studies have suggested that damage is concentrated in
the cerebellum and brainstem.73,74 Neuronal damage is characterized by increased perineuronal space, cytoplasmic vacuolization, myelin deformation, and axoplasmic shrinkage.75
Disrupted axonal transport causes focal axonal swelling.75
In addition to tissue necrosis associated with primary
brain damage, signicant damage to neuronal structures
can be attributed to secondary injury mechanisms. The
brains reaction to these injuries involves activation of multiple pathways that damage cells through oxidative stress, the
inammatory response, and metabolic dysfunction.
Free-radical generation promotes apoptosis in neurons
and endothelial cells through calcium-mediated pathways.58,68 Activation of inducible nitric oxide synthase
(iNOS) contributes to oxidative damage.75 Elevated NO can
react with superoxide anions to form peroxynitrite, a highly
reactive species that harms the endothelium and affects
vascular reactivity.69
Gene expression array studies that have found robust
changes in gene expression in brain tissue of animals exposed
to blast, including upregulation of genes involved in neuronal
proliferation and differentiation, neuronal NOS, and several
metabolic pathways.76 A separate study analyzing gene expression 24 hours after blast exposure reported increased
genes in inammatory pathways, including glial brillary
acidic protein (GFAP) and complement component 1.77 Comparing gene expression in rats exposed to blast at 1, 4, and
7 days after injury found that most signicant changes in gene
expression occurred 1 and 4 days after injury, suggesting
normalization at day 7.78
Cytokine assays provide evidence that an immune response is mounted following bTBI. Opening of the blood
brain barrier (BBB) results from the loosening of tight junctions due to severe edema secondary to Na/K ATPase
dysfunction, high intracranial pressure and matrix metalloproteinase activation.53,58,79 Unlike what is seen in blunt
TBI, the opening of the BBB occurs immediately following
blast injury, and is not delayed.71 Subsequent activation of the
microglia initiates cellular injury and repair mechanisms by
complement-mediated apoptosis and phagocytosis.58,68,80,81
Quantication of proinammatory markers and other
cytokines in the brain following blast injury in animals has
not produced consistent results on the timing of this response
following injury. Garman et al reported opening of the BBB
(measured by IgG reactivity) at 24 hours post injury and
occurring in regions distal to axonal injury.73 IgG reactivity
was no longer found at 3 days; however, axonal injury seemed

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several months to years prior.85 The regenerative benets of

REM sleep may be impaired in these individuals, leading to
chronic cognitive and emotional disturbances.85
A growing body of evidence suggests that metabolic
changes in the brain accompanying injury predispose individuals to subsequent head injuries.86,87 If a second blast is
sustained prior to full recovery from mTBI or bTBI, the brain is
more susceptible to rapid cerebrovascular dysregulation.63

Penetrating Traumatic Brain Injury

Despite the focus of research on damage incurred by the blast
overpressure wave, penetrating brain injury is the leading
cause of injury and death in civilian and military terrorist
attacks.54 In a study of 408 patients with head injuries
evaluated at the National Naval Medical Center or Walter
Reed Army Medical Center neurosurgery service, 56% had
sustained a penetrating TBI, of which 56% were due to blast
and 14% were due to gunshot wounds.49 Penetrating injuries
were associated with a higher frequency of vascular injuries
such as posttraumatic vasospasm, traumatic aneurysm, arteriovenous occlusion, as well as higher admission injury
severity scores and a longer stay in the intensive care unit.49
Many improvised explosives are constructed with shaped
charges or packed with smaller metal objects that increase
risk of this type of injury.56 Penetrating TBI is dened by the
intrusion of a foreign object such as a bullet, shrapnel, packed
charges, or other debris into the cranium.
Although the equation KE mv2 is typically used to
describe the energy transfer in penetrating injuries, this is
also an oversimplication of other variables including impact
velocity, energy release rate, tumbling, shape and design of
projectile, cavitation, and ballistic coefcient.88 Initial contact
with the skull generates a brief shock wave, followed by rapid
transfer of a large magnitude of kinetic energy to incident
tissues, slicing through neurons, glial cells, and the cerebrovasculature.53,89 Additional forces include lacerating and
crushing forces, shock waves and cavitation.53 An impending
projectile will depress the surrounding medium directly in
front of it, and the transfer of energy causes waves of
compression. A cavity is formed along the track of the
projectile; this tunnel is widened through cycles of stretching
and collapse of the surrounding tissue that dampen as energy
dissipates.53
In the acute stage, penetrating brain injury (PBI) is characterized by mechanical tearing and rupture of blood vessels,
resulting in subdural or intracranial hematomas and brain
edema.57,58,89 Immediate mechanical damage to cells and
tissue structures, including rupture of the BBB, is followed by
further injury due to secondary mechanisms.89,90 Hemorrhage and necrosis result in release of cytotoxic metabolites
that exacerbate the injury and cause cerebral edema.91 The
buildup of uid in the brain increases intracranial pressure,
resulting in cerebral ischemia.91
Neuronal degeneration due to secondary mechanisms was
seen in a rat model of penetrating ballistic-like brain injury
(PBBI) as early as 2 hours after injury, and began to decrease
from day 3 to day 7.92 In a rat model of PBBI, Zoltewicz et al
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to become progressively more severe at 2 weeks, consistent

with diffuse axonal injury seen in TBI of mechanical etiology,
and was concentrated in the deep cerebellar white matter and
brainstem regions.73 In a murine model of isolated primary
blast, Arun et al reported GFAP in the plasma and brain
decreased signicantly at 6 hours then increased at 24 hours
after injury, indicating that plasma membrane integrity in
glial and neuronal cells and the BBB were disrupted.82
Elevated GFAP immunoreactivity in the ventral hippocampus,
amygdala, and prefrontal cortex of blast exposed rats compared with sham controls 24 hours after blast injury was also
supported in a study by Kamanaksh et al.55
Cernak et al reported the inammatory response in the
brain of blast-exposed mice, measured by myeloperoxidase
(MPO) activity, progressively increased at 1 week, 2 weeks,
and 1 month after blast exposure.66 Cho et al found peak
cerebral levels of reactive oxygen species (ROS) and the
proinammatory marker IFN- at 1 day following blast
exposure, while microglial activation, assessed by measuring
MCP-1 levels, remained high at 2 weeks.83 The observation of
an increase in both ROS and proinammatory markers at
1 day following injury leaves a causal relationship between
these mechanisms unclear.83 Cytokine assays in rat brain
tissue following blast suggests a unique inammatory prole
including increased IL-1, IL-6, and IL-12p70 at 2 hours
postinjury that later decreases to normal levels at 24 hours,
while levels of MIP-1 increased and remained elevated.77
The nding of glutathione and low-molecular-weight thiols
in the hippocampus suggests synapse or terminal degeneration, despite the absence of cell death observed in this
region.77 Platelet activation, including integrin expression
associated with prothrombotic activity and serotonin release
into plasma, was observed at 4 hours postinjury in mice
exposed to three blasts in quick succession.84 Changes in
platelet phenotype were accompanied by release of MPO by
polymorphonuclear neutrophils into the serum, signaling
activation of the inammatory response.84 These changes
tended to normalize by 72 hours after injury.84
Metabolic dysfunction is characteristic of hypotension and
contributes to an environment of low energy availability in a
situation of high demand required for cerebral repair.50,69,83
Cerebral metabolic dysfunction, including reduced glucose
metabolism consistent with energy crisis, has been wellcharacterized in animal models and supported in human
clinical studies.12
Reduced glucose metabolism may last months to years
after blast injury. Studying chronic metabolic change using
brain uorodeoxyglucose positron emission tomography
(FDG-PET) in veterans who had sustained multiple blast
exposures within the past 5 years, Peskind et al reported
reduced cerebral metabolic rates of glucose differences with
respect to control subjects, most notably in the left and right
medial temporal lobes and regions in the cerebellum.74 The
involvement of the cerebellum could support the increased
susceptibility of this structure to injury by blast.74 Similarly, a
reduction in brain glucose metabolism was found during
rapid-eye-movement (REM) sleep in addition to wakefulness
in OEF/OIF veterans who had sustained blast and/or mTBI

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Mechanisms of TBI

Bauer et al.

described the immediate increase in UCH-L1 and other

biomarkers of cellular debris in the serum, which differs
from both blunt TBI and bTBI, where these molecules are
not observed until hours or days later.90 The rapid appearance
of these biomarkers in the blood and CSF indicate the protein
efux through the ruptured BBB, which remains permeable
for 7 days after injury.90 This cell death is likely mediated by
the calpain rather than the caspase apoptotic pathway.90
The immune response, including activation of microglia
and astrogliosis, migration of macrophages, and release of
proinammatory cytokines, occurs as a secondary response
to tissue injury.89,92 At 72 hours following PBI, dissection of
rat brains showed regions of necrotic tissue were also densely
populated with inammatory cells such as macrophages and
neutrophils.92 Histopathological analysis by Williams et al at
72 hours showed positive GFAP and OX-42 staining, indicating astrogliosis and microgliosis, respectively.92 In contrast,
Zoltewicz et al did not nd GFAP levels in the cortex to be
elevated until 7 days after injury.90
Axonal degeneration, indicated by silver staining, was not
observed until 72 hours following injury, increasing through
day 7.92 This is also the result of a neuroinammatory
response. With the opening of the BBB, complement proteins
form C5b-9/MAC complexes on neurons and contribute to
neurodegeneration 3 days following injury in rats.93
Similar to PBBI, PBI caused by knife injury produced a longlasting and widespread neuroinammatory response in rats,
which was indicated by increased translocator protein (TPSO)
density and corresponding NMDA receptor decrease.94 Regions of increased sensitivity to proinammatory signals,
such as the neocortex and hippocampus, were associated
with greater TPSO density and reduced NMDAR at 7 days
postinjury, whereas the opposite was true in the striatum.94
This result supports a prolonged inammatory response and
also suggests greater vulnerability to secondary damage in
these regions.

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Conclusions
Traumatic brain injury is a prominent injury occurring in
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many common features in the potentiation of injury through
secondary injury mechanisms and physical and neuropsychological outcome. However, as indicated by the biophysics
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Animal model experiments have contributed greatly to resolving what these differences are and the impact they have
on neuronal cell survival, but further research is warranted.

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Disclaimer

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The opinions or assertions contained herein are the private

views of the authors and are not to be construed as ofcial or
as reecting the views of the Department of the Navy or the
Department of Defense.

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