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1 Department of Neurology, University of Tennessee Health Science Address for correspondence Jack W. Tsao, MD, DPhil, Department of
Center, Memphis, Tennessee Neurology, Uniformed Services University of the Health Sciences, 4301
2 Department of Physical Medicine and Rehabilitation, Uniformed Jones Bridge Road, Room A1036, Bethesda, MD 20814-4799
Services University, Bethesda, Maryland (e-mail: jack.tsao@usuhs.edu).
3 Department of Neurology, Uniformed Services University of the
Health Sciences, Bethesda, Maryland
4 US Navy Bureau of Medicine and Surgery, Washington, DC
Abstract The authors describe the mechanisms of traumatic brain injury (TBI), examining in
Keywords depth the characteristics of closed head, penetrating, and blast-related TBI. Events on a
traumatic brain injury structural as well as cellular level are reviewed. Blast-related brain injury, in particular,
The current understanding of the biomechanics of traumatic various study types has greatly furthered the understanding
brain injury (TBI) comes from a range of study types: animal of the mechanisms underlying TBI.
models, cadaveric and human skull studies, computational
models, and in situ investigation of strain on brain structures
Closed Head Traumatic Brain Injury
during mild acceleration using magnetic resonance imaging
(MRI). There are inherent limitations to each type of study Two broad mechanisms of TBI exist: impact, in which the
that should be mentioned. Animal studies give insight into TBI immediate force makes contact with the skull and leads to
biomechanics mainly through accessibility; however, animal injury; and impulse, in which a force causes head movement
brains and skulls are vastly different both in structure and without directly acting upon the head.1 Regardless of the
complexity in comparison to humans. Cadaveric and gelatin mechanism, acceleration of the head ensues and is brought
studies using emptied skulls improves upon this issue, but the about by linear and rotational force. Linear force is governed
supportive structures and uids (i.e., the meninges, dura, and by the equation: force mass acceleration. Rotational
cerebrospinal uid [CSF]) have different dynamics after force is dened as torque moment of inertia angular
death; in many instances, these structures have been re- acceleration. Head trauma in normal daily life typically
moved entirely prior to studies being performed. Computa- involves both forces concomitantly. This is due to the rela-
tional models offer promise into the study of human TBI that tionship between a force and the center of gravity of the
would otherwise be inaccessible due to ethical concerns. The object (i.e., the head) that the force is acting upon. For
data in most instances, though, may be difcult to verify due example, the sum of the force vectors acting upon the head
to theoretical nature of the models. Lastly, MRI investigations run through the heads center of gravity, the head will display
offer insight into the movements of the brain in situ. Gener- mainly linear movement in the direction of the blow. How-
ally, the forces applied to the volunteers in these studies are ever, this rarely occurs in isolation, as it is uncommon for a
far below those seen in actual closed head injury. Although force to act directly upon the heads center of gravity. As a
currently there is no optimal model for the evaluation of the force acts upon the head further away from the center of
biomechanics of TBI, the additive understanding from these gravity, the degree of rotational movement increases.2
Issue Theme Traumatic Brain Injury; Copyright 2015 by Thieme Medical DOI http://dx.doi.org/
Guest Editor, Geoffrey Ling, MD, PhD, Publishers, Inc., 333 Seventh Avenue, 10.1055/s-0035-1549095.
FAAN, FANA New York, NY 10001, USA. ISSN 0271-8235.
Tel: +1(212) 584-4662.
Mechanisms of TBI Bauer et al. e15
Linear acceleration has been associated with pulses of minant of resting neuronal membrane potential and requires
increased intracranial pressure as well as intracranial pres- one unit of ATP for the transport of three ions of sodium
sure gradients.3 This pressure has been associated with strain extracellularly and two ions of potassium intracellularly. In
at the level of the brainstem.4 However, the degree of strain, rat models following traumatic injury, Na/K-ATPase activity
as well as the severity of injury, is less in experimental models increases to compensate for the excessive extracellular po-
of linear acceleration as compared with rotational accelera- tassium and loss of normal ion balance. This increase in
tion. Primate studies have shown an inability to produce loss enzyme activity is associated with a marked increase in
of consciousness without rotational acceleration.5 This is energy expenditure,14 which appears to occur immediately
corroborated by computational models that have estimated after injury.15 The degree of increase in metabolic demand is
up to 90% of the strain occurring on the human brain occurs unclear in humans, but current estimates suggest that this
via rotational acceleration.6 Thus, from both animal and enzyme is responsible for approximately 20% of all neuronal
human studies, rotational acceleration is posited as the energy expenditure in the human cerebral cortex during
primary determinant of injury in closed head injury. basal conditions.16
The direction from which a force acts upon the head Following potassium ion shifts, intracellular calcium in-
determines the degree of rotational movement of the head creases following traumatic injury due to pore formation
as well as the injury severity. Primate models of experimental from activated NMDA receptors.17,18 This increase may en-
TBI show forces acting in the coronal plane are associated dure for 48 hours or more due to alterations in NMDA
with more severe neuropathological changes, as well as a receptor subunit composition.19 Intramitochondrial calcium
worse clinical outcome.7 Computational models also suggest subsequently increases concomitantly with intracellular cal-
oxidase activity, is markedly reduced following injury.30 the ability to evaluate dynamic hyperacute changes in
Several mechanisms contribute to this mitochondrial dys- clinical practice.
function, including structural damage, as evidenced through Despite these limitations, many electrographic changes
loss of cristae membranes,31 increased mitochondrial calci- occurring after TBI have been elucidated. Blunt force injury to
um,22 and increased reactive oxygen species.32 Subsequent rats using weight drops from up to 2 m has been associated
human studies have also clearly delineated mitochondrial with paroxysmal epileptiform discharges for 30 to 60 seconds
dysfunction after TBI.33 following injury.42 These abnormal electrographic discharges
Mitochondrial impairment severely limits ATP synthesis in appear to occur in the setting of elevated levels of excitatory
neurons, which rely heavily on oxidative metabolism, leading amino acids.43 Electroencephalographic evaluation in hu-
to neurons shifting to glycolysis for ATP synthesis. Research in mans has been done as early as 15 minutes after TBI in
animal models15 and human studies34 shows increased gly- industrial dockworkers, but no epileptiform or fast activity
colysis as one of the early changes following TBI. This com- was seen. The majority of EEGs were normal, and the few that
pensatory mechanism is inefcient. Glycolysis in the absence were abnormal showed slowing in the theta- to delta-fre-
of oxidative metabolism nets merely 4 ATP per glucose quency range.44 Despite the relative lack of data showing
molecule compared with the 34 to 38 generated through hyperacute epileptiform activity in humans, EEG changes
glycolysis with oxidative metabolism in healthy neurons. have been characterized in other studies. Most notably, subtle
Glycolysis is also unable to generate sufcient energy to slowing has been shown in the background frequency in EEG
keep up with cellular demand. As much as a 51% drop in in humans following TBI. This slowing may take weeks to a
ATP levels has been documented in rat models in the imme- few months to return to preinjury frequency.1,45
Secondary injuries are caused by objects propelled by the exposures correlate to the severity of TBI.60 If the source of the
force of the explosion; tertiary injuries are caused if the body explosion is an enhanced-blast device, the primary blast
is thrown back by the blast wind; and quaternary injury is ignites secondary explosions, resulting in a longer and
characterized by burns or toxic exposures (e.g., napalm) more intense period of overpressure.54 Reection of the blast
resulting from the explosion.5052 Closed explosions often wave on surrounding surfaces can multiply the peak over-
cause building collapse, shattered windows, and ying debris, pressure by 2 to 8 times the incident pressure and increase
which increases the risk for penetrating or blunt injuries.48 the number of peaks as well as the total duration of the
Quinary injuries have been dened as exposure to biological positive-pressure phase (Fig. 1B).56,57 Furthermore, the
or radioactive elements packed into the bomb48 that can reected waves often strike the individual from different
result in the individual falling into a hyperinammatory state directions.57 Unsurprisingly, exposure to blasts in a closed
with hyperpyrexia, sweating, low central venous pressure, space is associated with more severe injuries and higher
and positive uid balance.53 Others have classied exacer- mortality.56 However, the vast majority of explosions in
bations or complications of pre-existing conditions as qua- Operation Enduring Freedom (OEF) and Operation Iraqi Free-
ternary injury.54 Signicantly, blast noise and transportation dom (OIF) occur in the open eld.48 An explosive incident
alone can produce neurobehavioral and biochemical changes adjacent to, but not inside of, a vehicle causes a pressure wave
in rats in the absence of injury.55 These effects may contribute that is mostly reected off and not transmitted inside the
to or exacerbate the underlying neuropathology in those who vehicle. Pressure loading on the vehicle itself may cause
sustain head injury in combat.55 accelerationdeceleration that results in blunt TBI similar
The biophysics of primary injuries is distinct from the to what might occur from a motor vehicle accident (MVA).
Fig. 1 Pressure diagrams demonstrate the blast overpressure wave in outdoor (A) and indoor (B) environments.56
density tissues.56,57 After gas-containing compartments such cerebral vasospasm is associated with the presence of pseu-
as emboli are compressed by the pressure wave, they expand, doaneurysm and poorer outcomes at discharge.49,70
damaging surrounding tissues.56 Inertial or shearing forces Gross pathology of neuronal damage in the brain is
from the rapid transfer of kinetic energy through tissue layers characterized by white matter lesions that resemble diffuse
can injure endothelial tissue.56,57 axonal injury (DAI) or cerebral contusion.56 Lesions in bTBI
Although the lungs are more susceptible to fatal injury due are distinct from other TBI etiologies in that they are focal and
to the blast wave, the impulse threshold for mild, nonfatal scattered throughout the brain, independent of the direction
brain injury may be much lower than the pulmonary lethal of blast loading.71 The number of low fractional anisotropy
magnitude.62 Cortical tissue injury can be caused by the voxels measured in diffuse tensor imaging (DTI) showed
transcranial impact of the pressure wave itself or the trans- diffuse and global damage in a heterogeneous distribution
mission of a pressure wave from the thorax through cranial across military who had sustained blast mTBI.72 However,
arteries or CSF. Because the brain is protected by the skull, the several studies have suggested that damage is concentrated in
cranial cavity is at lower relative pressure and thus quickly the cerebellum and brainstem.73,74 Neuronal damage is char-
ooded by the volumetric blood surge.63 acterized by increased perineuronal space, cytoplasmic va-
Studies using animal models provide evidence that expo- cuolization, myelin deformation, and axoplasmic shrinkage.75
sure of the thorax to the blast may contribute more to the Disrupted axonal transport causes focal axonal swelling.75
severity of brain injury, even in the absence of head protec- In addition to tissue necrosis associated with primary
tion.57 Axonal injuries and widespread ber degeneration in brain damage, signicant damage to neuronal structures
the brain, as well as functional and behavioral impairment, can be attributed to secondary injury mechanisms. The
to become progressively more severe at 2 weeks, consistent several months to years prior.85 The regenerative benets of
with diffuse axonal injury seen in TBI of mechanical etiology, REM sleep may be impaired in these individuals, leading to
and was concentrated in the deep cerebellar white matter and chronic cognitive and emotional disturbances.85
brainstem regions.73 In a murine model of isolated primary A growing body of evidence suggests that metabolic
blast, Arun et al reported GFAP in the plasma and brain changes in the brain accompanying injury predispose indi-
decreased signicantly at 6 hours then increased at 24 hours viduals to subsequent head injuries.86,87 If a second blast is
after injury, indicating that plasma membrane integrity in sustained prior to full recovery from mTBI or bTBI, the brain is
glial and neuronal cells and the BBB were disrupted.82 more susceptible to rapid cerebrovascular dysregulation.63
Elevated GFAP immunoreactivity in the ventral hippocampus,
amygdala, and prefrontal cortex of blast exposed rats com-
Penetrating Traumatic Brain Injury
pared with sham controls 24 hours after blast injury was also
supported in a study by Kamanaksh et al.55 Despite the focus of research on damage incurred by the blast
Cernak et al reported the inammatory response in the overpressure wave, penetrating brain injury is the leading
brain of blast-exposed mice, measured by myeloperoxidase cause of injury and death in civilian and military terrorist
(MPO) activity, progressively increased at 1 week, 2 weeks, attacks.54 In a study of 408 patients with head injuries
and 1 month after blast exposure.66 Cho et al found peak evaluated at the National Naval Medical Center or Walter
cerebral levels of reactive oxygen species (ROS) and the Reed Army Medical Center neurosurgery service, 56% had
proinammatory marker IFN- at 1 day following blast sustained a penetrating TBI, of which 56% were due to blast
exposure, while microglial activation, assessed by measuring and 14% were due to gunshot wounds.49 Penetrating injuries
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