P a t h o p h y s i o l o g y of

Tr a u m a t i c Br a i n I n j u r y
Melissa J. McGinn, PhD, John T. Povlishock, PhD*

KEYWORDS
 Focal and diffuse damage  Diffuse axonal injury  Neuronal circuit disruption
 Altered neuronal and vascular responses  Influence of comorbid factors

KEY POINTS
 Traumatic brain injury (TBI) remains one of the most complex diseases in the most complex of all
organs in the body.
 The causes of TBI are many and varied and include penetrating and nonpenetrating injuries that,
based on their overall level of severity, can evoke different degrees of morbidity, typically framed
within the context of the Glasgow Coma Scale (GCS) score.
 In considering the pathobiology of TBI across the spectrum of the disease ranging from mild
through severe, it is common to discuss this disease within the context of focal versus diffuse
change, with the inference that these events typically occur in isolation, with each following a
unique footprint of pathophysiologic change.

Traumatic brain injury (TBI) remains one of the patients groups.2 In considering the pathobiology
most complex diseases known in the most com- of TBI across the spectrum of the disease ranging
plex of all organs in the body. The causes of TBI from mild through severe, it is common to discuss
are many and varied and include penetrating and this disease within the context of focal versus
nonpenetrating injuries that, based on their overall diffuse change, with the inference that these
level of severity, can evoke different degrees of events typically occur in isolation, with each
morbidity, typically framed within the context of following a unique footprint of pathophysiologic
the Glasgow Coma Scale (GCS) score.1 Although change. Although this premise is overly simplistic
imperfect, the GCS helps, together with other bio- and dismisses that most severe and moderate
logic factors, to frame the degree of injury evoked forms of injury involve combinations of focal and
by the traumatic event, thereby providing informa- diffuse injury, this categorization does help frame
tion of diagnostic and prognostic value. Although key concepts regarding brain injury.3 Accordingly,
historically it was assumed that all patients with a its usage is maintained in the current text. Addi-
similar GCS had sustained comparable forms of tionally, for simplification this consideration of
central nervous system (CNS) injury, more recent pathobiology of injury is confined to nonpenetrat-
studies and consensus conferences have illus- ing TBIs.
trated the inaccuracy of such assumptions,
explaining in part why overreliance of the GCS FOCAL TRAUMATIC BRAIN INJURY
has confounded many clinical studies and related
trials.2 In light of this, more recent studies have Focal injuries are consistent features of most
focused on patient pathoanatomic features to forms of severe and moderate injury following
neurosurgery.theclinics.com

allow for more meaningful comparisons between change within the intra-axial and extra-axial

The authors declare that they have no conflict of interest.

Department of Anatomy and Neurobiology, Medical College of Virginia Campus of Virginia Commonwealth
University, 1101 East Marshall Street, Room 12-048, Richmond, VA 23298-0709, USA
* Corresponding author.
E-mail address: [email protected]

Neurosurg Clin N Am - (2016) -–-

http://dx.doi.org/10.1016/j.nec.2016.06.002
1042-3680/16/$ – see front matter Ó 2016 Elsevier Inc. All rights reserved.
2 McGinn & Povlishock

compartments. Subdural and epidural hematomas recent biomarker discovery has shown the utility
are the result of mechanical deformation and for blood biomarkers, such as glial fibrillary acidic
different forms of vascular disruption that can protein, and its breakdown products in recog-
exert morbidity by ensuing brain compression, nizing ultraearly, the presence of contusion even
with recent literature suggesting that subdural he- in injury of relatively minor severity.6–8 The
matomas can also exert damaging local re- assumption is that the contusion also evokes glial
sponses related to focal ischemia, reperfusion cell damage and the subsequent release of glial
injury, vasogenic edema, and reduced cerebral fibrillary specific protein, which is detected in the
blood flow.4 Contusional changes most commonly systemic circulation. Although such biomarkers
involve the frontal and temporal lobes, although do not replace the need for routine imaging, they
other loci can be involved via the generation of may be of ultimate value in prescreening patients
coup, directly beneath the site of impact, versus sustaining milder forms of injury, which may
countercoup, directly opposite the site of impact, require more advanced imaging to detect modest
lesions. Contusions are typically hemorrhagic le- contusional damage that would negatively impact
sions that began within the cortex and are most outcome.9
common at the crests of the cerebral gyri, and
advance into the subcortical white matter in the DIFFUSE TRAUMATIC BRAIN INJURY
more severe forms of injury. Despite this primary
cortical predilection, in some cases contusions By definition, diffuse injury is more scattered, and
can develop at the grey/white interface with sub- is not linked to a specific focus of destructive tis-
sequent expansion into the overlying grey matter. sue damage. Rather, it shows a more widespread
The presence of hemorrhage within the contusion distribution wherein damaged structures are scat-
gives rise to local edema and ischemic change, tered among other intact/unaltered neuronal and
which leads to tissue destruction, neuronal necro- vascular components. To date, in animals and
sis, and ultimately cavitation with surrounding humans, diffuse injuries have been shown to
reactive gliosis. In some cases, continued hemor- potentially involve diffuse neuronal damage,
rhagic progression or expansion of the contusion microvascular change, and axonal perturbation
in the pericontusional zones has been observed. and disconnection.10,11 The understanding of the
Although historically this hemorrhagic progres- pathogenesis of neuronal and microvascular
sion was postulated to occur secondary to coagul- change, however, is somewhat limited and fo-
opathy, other contemporary studies suggest that cuses on the potential that the mechanical forces
other causative factors are at work. Recently, of injury elicit various forms of membrane change
Kurland and colleagues5 have shown that the ce- leading to ionic dysregulation and/or altered
rebral vasculature is mechanosensitive, with the permeability that in turn evokes lethal and suble-
likelihood that mechanosensitive endothelial cells thal damage. In the context of diffuse and focal
are activated in the penumbra, which does not neuronal cell death, multiple cell death pathways
experience the destructive forces occurring within have been identified12; however, their overall prev-
the contusional core itself. In this scenario, the alence in the context of diffuse TBI and their overall
contusional penumbra experiences endothelial implications for morbidity remain a matter of
mechanosensitive activation of two transcription controversy.
factors, specificity protein 1 and nuclear factor- In contrast to the incomplete appreciation clini-
B.5 These factors play a key role in the regulation cians have of the pathophysiology of diffuse
of sulfonylurea receptor 1, which forms the regula- neuronal and microvascular change, understand-
tory subunit of the NCCa-ATP channel. This subunit ing of scattered axonal injury is much more com-
has been implicated in vascular dysfunction and/ plete and its implications for animal and patient
or damage, leading to endothelial necrosis.5 morbidity are better understood. Since the
Irrespective of the contusion’s origin and expan- groundbreaking work of Adams and others in the
sion, the morbidity associated with these collec- postmortem examination of brain-injured humans,
tive contusional changes is a direct function of it is now appreciated that scattered or diffuse
their location, size, depth, and potential for bilat- axonal injury (DAI) is a consistent component of
eral brain involvement. Thus, large bilateral lesions most forms of TBI and a key contributor to TBI-
exert considerably more morbidity than seen in induced morbidity.13,14 Although first described
isolated lesions, which unless involving homolo- in the corpus callosum, subcortical white matter,
gous cortical domains may exert little to no fornix, and varied brainstem white matter systems,
morbidity.3 Because of their bloody constituents, it is now well recognized that DAI may occur at
focal lesions are readily identified with routine im- numerous brain sites involving white and grey mat-
aging, such as computed tomography, although ter. Based on early pathologic analysis using silver
 Pathophysiology of Traumatic Brain Injury 3

salts, the occurrence of DAI was confirmed in Of further interest, in the context of DAI, is that it
humans by the finding of axonal spheroids, with can be identified in humans and animals across
the belief that the axons were immediately severed the spectrum of TBI, ranging from mild to severe.
at the time of injury leading to retraction and expul- Although overall numbers and anatomic loci
sion of a ball of axoplasm.13,15 More contemporary involved are reduced in the milder forms of injury,
studies exploring these issues in animals and this does not imply that this axonal injury is innoc-
humans suggested that this is not the case. uous and without biologic consequence. Rather,
Rather, they demonstrated that the course of injury recent findings in animals and humans suggest
focally perturbed the axonal membrane leading to that such limited injury in the grey and white matter
a cascade of calcium-mediated events that impair can trigger an imbalance of the brain’s excitatory
axonal transport resulting in progressive focal and inhibitory networks thereby leading to
axonal swelling and disconnection.16–20 With dysfunction.28–32 Thus, in a sense TBI is a disease
disconnection the distal, detached axonal projec- of brain network/circuit dysfunction where
tions then undergo target deafferentation and syn- increasing injury severity leads to increasing circuit
aptic loss, together with generalized wallerian disruption followed by increased morbidity.
degeneration.21,22 From this perspective, DAI is
conceptualized as a disease of disconnection, FUNCTIONAL CHANGES EVOKED BY
which has led many to consider TBI as a disorder TRAUMATIC BRAIN INJURY
of diffuse circuit disruption, disrupting excitatory
and inhibitory networks (discussed later). There is a growing appreciation that the pathobio-
Although traditionally, the identification of DAI logic response to injury is also characterized by
has relied on postmortem examination to confirm widespread functional changes involving the intact
the presence of axonal spheroids either through cerebral microcirculation and intact neuronal cir-
the use of silver salts or antibodies to amyloid pre- cuitry. Although these functional changes have
cursor protein, the last decade has witnessed an been best described in the milder forms of TBI,
explosive growth in the ability of advanced imaging there is compelling evidence that suggests that
techniques to identify this pathology. Specifically, they also occur with injuries of increased severity.
use of MRI, incorporating diffusion-weighted imag- On the vascular front, it is well recognized that
ing and/or susceptibility-weighted imaging has more severe forms of head injury are associated
allowed clinicians to better appreciate the potential with a loss of cerebrovascular autoregulation
for the occurrence of DAI and its distribution in an where cerebral blood flow becomes directly pres-
injured brain.9,23–25 Although these techniques sure passive dependent on the systemic blood
have not been fully characterized and controversy pressure to elicit either hyperperfusion or hypoper-
persists regarding their overall ability to recognize fusion.33,34 Importantly, these disturbances in
specific features of DAI, they do represent impor- autoregulation occur in the absence of overt struc-
tant noninvasive diagnostic approaches. tural damage in the cerebral conductance vessels
Although the previous discussion suggests that and thus reflect a direct functional response to the
all DAI is characterized by a progression of traumatic episode.
changes that ultimately lead to axonal swelling In addition to these autoregulatory disturbances,
and disconnection, it is also important to note other more subtle vascular changes can occur and
that other recent studies have shown that the these have been identified across the spectrum of
forces of injury can also evoke damage to other injury ranging from mild through severe.35,36 Multi-
axonal populations that show no evidence of ple experimental and more limited clinical studies
swelling but rather, show evidence of cytoskeletal have confirmed that although intact, many
collapse and rapid destructive and degradative arterioles and arteries exhibit impaired vaso-
processes.26 This finding suggests that reliance reactivity to normal physiologic challenges
on markers of axonal swelling alone underesti- involving endothelial-dependent and smooth mus-
mates the overall burden of axonal injury. Further- cle–dependent processes.37–40 Such abnormal
more, it was also initially assumed that these vascular responses to normal endothelial-
axonal events occurred exclusively in large tract dependent pathways and smooth muscle respon-
myelinated axons; however, it is now well recog- sivity have been described in the acute phases
nized that unmyelinated axons are preferentially postinjury and in the more chronic phases at which
vulnerable to the forces of injury and thus, may be time substantial neurologic recovery occurs. The
more important players in the pathobiology and biologic implications of such impaired vascular
morbidity of injury.27 Collectively, these findings reactivity are not well appreciated. However, it is
illustrate the importance of DAI while also speaking postulated that these impaired responses could
to its heterogeneity and biologic complexity. contribute to continued morbidity, should the
4 McGinn & Povlishock

injured brain sustain a posttraumatic, secondary there is a marked suppression of compound action
insult involving hypotension, hypoxia, and/or other potentials in the myelinated and unmyelinated fi-
vascular response factors. ber populations within the corpus callosum.
In addition to the recognition of widespread Although in the animal model assessed there
functional vascular change following TBI, there is was evidence of limited structural change within
now compelling evidence of a series of complex the callosal myelinated and unmyelinated fiber
neuronal functional changes that impact posttrau- populations, the overall degree of this damage
matic neurologic function and subsequent recov- did not significantly complicate data analysis. In
ery.41,42 These changes seem to be more subtle these studies, Reeves and colleagues27 showed
and reversible in the milder forms of injury wherein in the early posttraumatic period a significant sup-
little overt structural damage is observed within pression of myelinated and unmyelinated fiber
the brain parenchyma. Comparably, although compound action potential generation. Over time
more pronounced in the more severe forms of postinjury, however, the compound action poten-
injury wherein overt structural damage is identi- tials showed a virtually complete recovery in the
fied, these functional changes may also be signif- assumed nonaxotomized myelinated fiber popula-
icant players in the ensuing continued brain tion, whereas the unmyelinated fibers exhibited
dysfunction/morbidity. persistent and enduring compound action poten-
Although the understanding of the electrophysi- tial suppression.
ologic responses of the brain to various forms of Collectively, these findings reinforce the
injury is in its infancy, there is now compelling ev- concept of electrophysiologic change following
idence that the traumatic episode can, at multiple injury, showing in some cases there is significant
levels, trigger changes in excitation and inhibition recovery, whereas in others there is enduring
involving glutaminergic and GABAergic function.42 change. How all of these findings relate to those
This elicits an imbalance of the normal excitation events occurring in humans with TBI remains to
and inhibition needed to control brain function be determined, yet their very occurrence and char-
and support cognition.32 In animal mild TBI, there acterization suggests a complex series of func-
is compelling evidence that many intact, undam- tional changes involving neocortical, cortical, and
aged neurons within the neocortex become hyper- intercortical circuitry that can contribute to a multi-
excitable within days postinjury, contributing to level platform of circuit disruption.
brain dysfunction. Similarly, within the hippocam-
pal domains, a large number of electrophysiologic EXCITOTOXICITY AND IONIC FLUX
studies using slice preparations have shown com-
parable posttraumatic changes in hippocampal Occurring in concert with and contributing to the
circuits where, once again, TBI can affect excit- evolution of the previously described focal and
atory and inhibitory synaptic transmission, giving diffuse abnormalities is a host of generalized
rise to dysfunctional hippocampal circuits.43 changes that serve to further perpetuate the pro-
Although there is some variance in the general gression of TBI pathophysiology. Such perturba-
physiologic findings across studies, with some tions, which include widespread neuroexcitation,
showing posttraumatic decrease in excitability in ionic flux, and neurometabolic change, among
the hippocampal area CA1, others have shown in other sequelae, are diverse and as with all other
in vivo preparations increased excitability, which features of TBI, are influenced by the nature and
may be a function of in vivo versus in vitro differ- severity of the injury. Excessive excitatory amino
ences and other technical confounds.44 Neverthe- acid signaling is recognized as a key factor in the
less, there is compelling evidence that these cascade of pathophysiologic events that follow
parameters do change over time postinjury. TBI. A rapid, transient increase in extracellular
Collectively these data suggest that the imbalance glutamate has been described within minutes
of excitation and inhibition can contribute to following insult to the brain, the magnitude and
disequilibrium with catastrophic consequences duration of which have been shown to correlate
for CNS circuits that underlie cognitive function to injury severity.45–50 This acute increase in extra-
and other high level cortical activities.42 Although cellular glutamate levels in the injured brain has
most of these observations have been made with been attributed to the excessive release of gluta-
hippocampal slices and neocortical whole cell mate from presynaptic nerve terminals of depolar-
patch clamp analyses, other more direct physio- ized neurons, leakage of glutamate from neuronal
logic assessments have also shown evidence of and glial (mainly astrocytic) cells exhibiting
functional change, which directly relates to initial damaged/perturbed membranes, or the extrava-
morbidity and potential recovery. Reeves and col- sation of glutamate through a disrupted blood-
leagues27 have recently shown that following TBI, brain barrier (BBB).51,52 Also contributing to
 Pathophysiology of Traumatic Brain Injury 5

heightened glutamate levels within the synaptic milieu following injury.45,61–63 The ionic flux that re-
cleft are alterations in astrocytic glutamate reup- sults from the dramatic, yet brief rise in extracel-
take mechanisms, either caused by the functional lular glutamate concentrations induces marked
impairment of astrocytes (resulting from mechani- increases in cerebral glucose use (and consequent
cal injury or energy depletion) or by the downregu- accumulation of extracellular lactate), presumably
lation and/or decreased activity of astrocytic to promote the re-establishment of ionic homeo-
glutamate transporters (ie, GLAST, GLT-1).53–55 stasis in the face of evolving neuropathologic
The acute interstitial glutamate surge, which has change.61,64 Following this brief period of hyper-
been observed in experimental and clinical TBI glycolysis in the acute phase (ie, first few days
settings, triggers the unregulated and excessive postinjury in humans), a global reduction in glycol-
stimulation of glutamate receptors (particularly ysis occurs, persisting until recovery, which in
N-methyl-D-aspartate receptors), leading to ionic humans can range from weeks to months postin-
dysregulation in the form of massive accumulations jury.65–69 The clinical course of recovery typically
in extracellular [K1] and the influx of Na1 and Ca21 parallels the restoration of normal brain glucose
through glutamate receptor-gated ion chan- use.
nels.45,56,57 Furthermore, the release of Ca21 from The ability to detect and monitor the ongoing
intracellular stores (ie, endoplasmic reticulum) metabolic changes associated with TBI has been
together with the activation of voltage gated calcium made possible by PET, in vivo microdialysis
channels results in the additional accumulation of (MD), and proton magnetic resonance spectros-
free intracellular Ca21. This ionic flux induces a state copy (discussed elsewhere in this issue). MD
of metabolic crisis, ultimately approaching energy monitoring of the brain interstitial fluid and PET
failure, as the brain attempts to restore ionic homeo- functional imaging studies have revealed the hy-
stasis via increased activity of ATP-dependent ion permetabolic/hypometabolic temporal sequence
pumps (discussed later). The increased intracellular described previously, characterized by acute in-
Ca21 concentrations that result from excessive creases in glucose metabolism (with a concomi-
glutamate signaling also induce cellular damage tant decline in extracellular glucose) localized
through a variety of additional mechanisms, predominantly within the contusion and pericontu-
including (1) the activation of destructive calcium- sional regions within the involved hemisphere, with
dependent proteases (ie, calpains and caspases), more global, uniform declines in (glucose and ox-
(2) the generation of damaging reactive oxygen ygen) metabolism occurring at later time points
and nitrogen species, and (3) mitochondrial impair- postinjury.65–68,70,71 A similar sequence and time
ment (caused by Ca21 overload) and mitochondrial course in the period of metabolic depression
permeability transition pore formation, leading to (approximately 2 to 4 weeks) is observed irrespec-
apoptotic events.58–60 Such processes have been tive of injury severity, which has been speculated
described in the context of the focal and diffuse so- to relate either to the duration of posttraumatic
matic, axonal, and vascular changes described pre- confusion and posttraumatic amnesia in moderate
viously, operant at varying degrees along the to severe diffusely injured patients or to the less
spectrum from mild to severe TBI. For example, in overt cognitive effects associated with a more
the context of TBI-induced cell death, it is posited mild diffuse injury.3,72 Alternatively, differences in
that more modest increases in cell intracellular glucose compartmentalization in mild versus se-
free Ca21 levels will drive the cellular machinery vere TBI may be a factor.
toward apoptosis, whereas excessive glutamate The declining levels of extracellular glucose that
receptor activation with markedly enhanced Ca21 characterize the MD pattern seen during the acute
levels promote necrotic events. hypermetabolic period following injury are often
paralleled by elevations in microdialysate lactate
METABOLIC CHANGE levels, suggesting a shift to anaerobic glycol-
ysis.73,74 Elevated brain lactate levels gradually
In concert with the previously described changes normalize after a few days in those who survive
in excitotoxicity and ionic flux, metabolic change the traumatic episode, but remain heightened 5-
occurs following TBI of all severities; with regional, to 10-fold over basal levels in fatal TBI.75 Although
multifocal, and/or global abnormalities in meta- studies have validated glucose metabolism–
bolism likely occurring as a consequence of the related microdialysate measurements against
injury-induced circuit disruption and network established indices of oxygen metabolism and ce-
destabilization described previously. A crucial rebral blood flow (ie, jugular venous oxygen satu-
event that triggers some metabolic dysfunction is ration, partial pressure of oxygen in brain tissue,
the increase in the release of excitatory amino or PET measurements) in severely injured patients
acids, particularly glutamate, into the extracellular with TBI exhibiting confirmed ischemic episodes,
6 McGinn & Povlishock

several recent MD studies have suggested that occurs.87–89 In addition to the scavenging and
ischemia may be a less common phenomenon in phagocytosis of cellular debris, these resident im-
TBI than previously assumed and that increased mune surveillance cells also mediate inflammation
lactate/pyruvate ratios seen in patients with TBI through the production of various inflammatory cy-
may alternatively indicate either limited glucose tokines, proteases, and reactive free radical spe-
supply or impairment of the glycolytic pathway cies.90–92 Over and above this acute microglial
machinery (ie, mitochondrial damage) as opposed response to injury, several recent studies have
to an overt lack of oxygen.76–79 In patients with se- shown that microglia can maintain a primed, or
vere TBI, the previously described nonischemic proinflammatory profile for weeks to months after
excitotoxicity and metabolic crisis are associated the acute effects of injury have dissipated.93 It is
with spreading depolarizations (cortical spreading surmised that this primed and possibly hyperreac-
depressions), which are pathologic waves of tive microglial phenotype can potentially set the
depolarization of neurons and astrocytes that stage for more progressive degenerative change
propagate through the cerebral gray matter, sup- and chronic patient morbidity, along with an
pressing synaptic activity as they do so.80 increased vulnerability to subsequent insult.
Spreading depolarizations have been recently Concomitant with the local microglial inflamma-
described following experimental and clinical tory response is the cerebral infiltration and accu-
TBI, where they are thought to contribute to mulation of peripheral immune cells via their
ongoing ionic dysregulation and energy crisis, extravasation across a BBB exhibiting increased
and have been linked to poor outcome.81–83 permeability caused by mechanical disruption or
vascular dilatation and leakage mediated by vaso-
NEUROINFLAMMATION active inflammatory molecules.94–97 The recruit-
ment of peripheral immune cells to the injured
Although traditionally considered a site of “immu- brain is further promoted by vascular endothelial
nologic privilege” because of the lack of a changes (ie, the cytokine-induced upregulation of
lymphatic system and the presence of a relatively adhesion molecules, such as intercellular adhe-
impermeable BBB to activated immune/inflamma- sion molecule-1) and the release of chemokines
tory cells, it is now recognized that the CNS does by resident CNS cells.98–100 The infiltrating periph-
not constitute an immunoprivileged system but eral immune cells most associated with TBI-
rather, that the brain exhibits the classic hallmarks induced inflammation include neutrophils and
of inflammation following TBI.84 The inflammatory macrophages/monocytes, both of which have
response of the brain to traumatic insult is multi- been shown to mediate early inflammatory events
factorial, encompassing the activation of resident via the release of various inflammatory cytokines,
CNS immune cells and the cerebral infiltration of proteases, free radicals, and other inflammatory
peripheral immune cells (by way of an altered mediators (leukotrienes and prostaglandins) in
BBB), both of which mediate inflammatory pro- addition to phagocytosing cellular and/or
cesses through a variety inflammatory cytokines, axotomy-related debris. The sequence of events
chemokines, adhesion molecules, reactive oxygen associated with the cerebral infiltration of periph-
and nitrogen species, and complement factors, eral immune cells in response to a focal/contusive
among others. Occurring concurrently and as a TBI involves early neutrophilic recruitment within
consequence of these inflammatory events is the the first 24 hours postinjury followed by the
formation of cerebral edema, subsequent brain delayed recruitment of macrophages between 36
swelling, and increased intracranial pressure, all and 48 hours postinjury.94,101 The absence of an
of which contribute to unfavorable outcome early neutrophilic infiltration in the diffusely injured
following TBI. brain is thought to be a reflection of the less overt
Although inflammatory events are evoked in tissue disruption and only mild/moderate BBB
response to focal and diffuse TBI, the sequelae compromise associated with this form of brain
of posttraumatic inflammation has predominately injury.
been characterized in the context of focal insult. Experimental and clinical TBI investigations
The primary tissue damage (somatic and axonal) have implicated numerous factors in the inflamma-
induced by mechanical insult to the brain triggers tory response to TBI. Notably, alterations in
inflammation through the release of intracellular regional, intrathecal, and systemic concentrations
and intra-axonal contents, extravasated blood of several inflammatory cytokines (interleukin-1,
products, and increased free radical production/ -1b, -6, -8, -10, -12, and tumor necrosis factor)
oxidative stress, among other factors.85,86 In have been observed in the acute (and some cases
response to these perturbations in tissue homeo- chronic) posttraumatic period following human
stasis, the local activation of CNS microglia and experimental TBI.102–107 These cytokines
 Pathophysiology of Traumatic Brain Injury 7

(and related chemokines) mediate inflammation by 4. Fujisawa H, Maxwell WL, Graham DI, et al. Focal
promoting excitotoxicity, recruiting peripheral im- microvascular occlusion after acute subdural hae-
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