Neurochemical Cascade of Concussion

Brain Injury
ISSN: 0269-9052 (Print) 1362-301X (Online) Journal homepage: http://www.tandfonline.com/loi/ibij20
Neurochemical cascade of concussion

Matthew P. MacFarlane & Thomas C. Glenn
To cite this article: Matthew P. MacFarlane & Thomas C. Glenn (2015) Neurochemical cascade
of concussion, Brain Injury, 29:2, 139-153, DOI: 10.3109/02699052.2014.965208
To link to this article: http://dx.doi.org/10.3109/02699052.2014.965208
Published online: 14 Jan 2015.
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Date: 01 October 2016, At: 23:12
http://informahealthcare.com/bij
ISSN: 0269-9052 (print), 1362-301X (electronic)
Brain Inj, 2015; 29(2): 139153
! 2015 Informa UK Ltd. DOI: 10.3109/02699052.2014.965208
REVIEW

Matthew P. MacFarlane1,2 & Thomas C. Glenn1,2
1
UCLA Cerebral Blood Flow Laboratory, Los Angeles, CA, USA and 2Department of Neurosurgery, David Geffen School of Medicine at UCLA,
Los Angeles, CA, USA
Abstract
Keywords
Primary objective: The aim of this literature review was to systematically describe the sequential
metabolic changes that occur following concussive injury, as well as identify and characterize
the major concepts associated with the neurochemical cascade.
Research design: Narrative literature review.
Conclusions: Concussive injury initiates a complex cascade of pathophysiological changes that
include hyper-acute ionic flux, indiscriminant excitatory neurotransmitter release, acute
hyperglycolysis and sub-acute metabolic depression. Additionally, these metabolic changes
can subsequently lead to impaired neurotransmission, alternate fuel usage and modifications in
synaptic plasticity and protein expression. The combination of these metabolic alterations has
been proposed to cause the transient and prolonged neurological deficits that typically
characterize concussion. Consequently, understanding the implications of the neurochemical
cascade may lead to treatment and return-to-play guidelines that can minimize the chronic
effects of concussive injury.
Concussion, concussion pathophysiology,

metabolism, mild traumatic brain injury,
physiology
Introduction
In the scientific and clinical communities, a consensus has yet
to emerge for the clinical definition and pathophysiological
requirements of a concussion. However, the most encompassing and agreed upon definition for a concussive event is
any biomechanical injury, not necessarily to the head, that
causes transient neurological dysfunction [1]. Concussion is
also recognized as a mechanical injury that leads to cerebral
dysfunction without significant cell death [2].
It has been proposed that concussion and mild traumatic
brain injury (mTBI) be used interchangeably since much of
the clinical symptomology overlaps and as many as 80% of
concussions are diagnosed as mTBI [2]. Neither mTBI nor
concussive injuries show gross abnormalities on neuroimaging and most patients recover without permanent damage [2,
3]. For these reasons, much of the literature uses these
two terms interchangeably [3] and many of the pathophysiological models of concussion are based on animal models
of mTBI. Despite much of the literature parallelling
mTBI and concussion, it should be noted that some have
proposed that the two injuries be considered distinct clinical
diagnoses.
As evidence of the lasting impacts of concussion
compounds, another clinical event has emerged, called
Correspondence: Thomas Glenn, Department of Neurosurgery, David
Geffen School of Medicine at UCLA, PO Box 956901, 300 Stein Plaza,
Room 533, Los Angeles, CA, 90095-6901, USA. Tel: 310-206-0626.
E-mail: tglenn@mednet.ucla.edu
History
Received 3 December 2013
Revised 15 April 2014
Accepted 17 April 2014
Published online 13 January 2015
post-concussive syndrome, to encompass chronic, prolonged

effects. Although the symptoms of concussion are characterized by the transient neuronal changes and dysfunction,
many patients have persistent complaints of headache,
fatigue, emotional lability and cognitive problems [3].
Post-concussive syndrome is characterized by the aforementioned neurological symptoms and between 4080% of
patients display these in some form, with 1015% experiencing them after 1 year [3]. The factors that influence the
severity and duration of these symptoms are the timing or
number of repeat concussions, genetics and other clinical
components [4].
The neurochemical cascade of concussion is the metabolic
and pathophysiological changes that begin immediately at the
time of biomechanical injury and continue for an extended
period of time, based on various clinical factors and is a topic
of undergoing research. The neurochemical changes of the
cascade are causally related, but vary in the duration and
extent of change [5]. Concussion and traumatic brain injury
are characterized by behavioural and neurological changes
[5]. However, understanding the metabolic changes will help
to determine the course of clinical care, the extent of damage
and the treatment options [5]. Evidence of this lies in the
notion that significant metabolic changes can occur despite a
normal Glasgow Coma Score (GCS) and overt clinical
recovery can occur even with prolonged metabolic changes
[6, 7]. In addition, the metabolic alterations of concussion
have been correlated with behavioural abnormalities and postconcussion vulnerability [1, 5].
140
M. P. MacFarlane & T. C. Glenn
Brain Inj, 2015; 29(2): 139153
Table I. Metabolic data from trauma patients and normal controls.

Predictor
CBF
CMRO2
CMRglc
CMRlac
AVDO2
AVDglc
AVDlac
Art glucose
Art lactate
Metabolic Ratio
Jugo2Sat
Arto2Sat
Age
Gender
Units
1
ml/100 g min
ml/100 g min1
mg/100 g min1
mg/100 g min1
ml dl1
mg dl1
mg dl1
mg dl1
mg dl1
%
%
years
% Male
Trauma* (n 49)
Normal (n 31)
p Value
40.17 13.2
1.4 0.43
3.43 2.32
0.0355 0.41
3.76 1.37
8.94 6.57
0.0464 0.94
122.7 33.8
14.05 8.2
4.11 2.11
72.9 8.6
98.5 1.5
35.7
73%
46.2 10.5
3.10 0.56
4.46 1.16
0.18 0.21
6.89 1.35
9.89 2.92
0.40 0.48
82.2 8.3
6.7 2.1
5.83 1.41
61.7 5.9
97.5 1.2
33.3 8.3
74%
0.01
0.0001
0.0002
0.0001
0.0001
0.002
0.0002
0.0001
0.0001
0.0001
0.0001
0.0001
0.4
1
*The trauma cohort consists of patients with moderate or severe TBI who had an initial GCS less than or
equal to 8.
CBF, cerebral blood flow; CMR, cerebral metabolic rate; AVD, arteriovenous difference.
Original source: Glenn et al. [8].
Metabolic study of cerebral metabolism

Cerebral metabolic studies are employed to determine the
extent of fuel consumption, uptake and delivery [5]. In
general, these studies look at changes in the production of
lactate and carbon dioxide, the consumption of glucose and
oxygen, cerebral blood flow (CBF) and pH [5]. Injuries to the
central nervous system (CNS) cause a deviation from the
steady state metabolic activity of the normal CNS and, thus,
an alteration in one metabolite cannot be used to infer a
change in another [5]. Under normal physiological conditions,
cerebral blood flow is tightly coupled to glucose metabolism
and neuronal activity in a process called cerebral autoregulation [1] (p. 229). Table I shows the average global cerebral
metabolic values determined by the Kety-Schmidt technique,
including CBF and cerebral metabolic rate of glucose
(CMRglc), from a 2003 study that included 31 normal
patients [8]. Since morphological damage is not a suitable
predictor of outcome in concussion, metabolic studies will
help to determine the cellular pathophysiology, delineate
impacted regions of the brain and predict outcome by
reflecting cellular integrity and functionality [5].
Overview of neurochemical cascade and

pathophysiology
Upon biomechanical injury, there is an abrupt disruption of
cellular homeostasis that initiates intertwined and causally
related biochemical alterations in the brain [5]. The shearing
and stretching forces of the biomechanical event cause a
disruption of cellular membranes, referred to as mechanoporation, that cause an efflux of intracellular K+ [9]. The
initial depolarization triggers an indiscriminant release of
excitatory neurotransmitters resulting in a massive excitation
that opens ligand-gated channels [5]. This causes a feed-back
loop of depolarization and the proceeding influx of extracellular Ca2+, which is then sequestered into mitochondria [2].
The ATP-dependent Na+-K+ membrane pump, responsible
for maintaining resting membrane potential, works in
overdrive to restore the disrupted ionic gradient [1]. This

causes a massive consumption of cellular ATP and an
increasing energy demand, producing a state of hyperglycolysis to satisfy this energy deficit [5, 10, 11]. During this
period of hypermetabolism, there is a simultaneous uncoupling of autoregulation resulting in a decrease in CBF [1].
This scenario of hypermetabolism with a decreased energy
supply potentially leads to an energy crisis [1]. The surge of
extracellular Ca+2 is sequestered into mitochondria, which
subsequently inhibits oxidative metabolism and can also
impair axonal function [2]. These acute metabolic disruptions
can cause prolonged neuronal dysfunction and lead to various
metabolic changes in the brain.
Biomechanics and animal models of

concussive injury
Biomechanics of brain injury
The two major categories of traumatic brain injury which are
based on impact biomechanics are diffuse and focal injuries.
Focal injuries result from a severe impact event that leads to
cortical and sub-cortical contusions and lacerations as well as
intracranial bleeding [3] These clinical findings are generally
present only in severe TBI [3] and, hence, are useful in
distinguishing concussion from a more serious injury. Diffuse
injury is characterized by acceleration and deceleration forces
that cause stretching and tearing of fragile brain tissue [3].
Therefore, a direct injury is not a requirement of a mild
traumatic event [3]. Concussion is a form of diffuse injury
caused by significant mechanical stresses, despite a lack of
resulting overt morphological damage [3, 5]. The biomechanical forces theorized to inflict the majority of tissue damage
are rotational or angular accelerationdeceleration forces
rather than the linear counterparts [12, 13]. It is believed these
rotational forces acting on the midbrain and thalamus can
cause a transient disruption of the reticular activating system,
resulting in the loss of consciousness often associated with
concussion [12, 14].
DOI: 10.3109/02699052.2014.965208
Overview of animal models of traumatic brain injury

Most of the pathophysiological research on traumatic brain
injury has been conducted through experimental animal
models, with the cortical contusion model and fluid percussion model being the two prevailing methods [6]. The cortical
contusion model entails the removal of part of the skull and
directly inflicting injury to nave brain tissue [3]. However,
this model produces bleeding and contusions to the animal
brain (clinical consequences generally not seen in concussion)
and, thus, makes this method questionable for the study
of concussive injury [3, 15]. The fluid percussion model
is theorized to produce sub-lethal ionic fluxes and metabolic
disruption at the cellular level, while causing a lesser effect on
the cell body and myelin sheaths of neurons [5, 16].
Mild fluid percussion pathophysiology and symptomology
align with that of clinical studies and the belief that the
biomechanical model of concussive injury is based on
the stretching and disruption of neuronal and axonal membranes [3].
Hyperacute and acute neurometabolic changes

Initial K+ efflux and abrupt neuronal depolarization
Immediately following the initiating mechanical event,
stretching and shearing forces cause disruption of cellular
membranes, axonal stretching and the opening of voltagegated channels which lead to an efflux of intracellular K+ [1,
10, 17]. The biomechanical injury causes this indiscriminant
flux of intracellular K+ through deregulated channels and
transient membrane defects [9]. This notion has been
confirmed by research showing that tetrodotoxin administered
through microdialysis can prevent some of the K+ flux after
concussive injury [10]. Consequently, the abrupt ionic flux is
significant enough to cause aberrant neuronal depolarization
and firing [1, 5, 18].
Further increases in the extracellular concentration of K+
are thought to be due to the opening of voltage-gated channels
caused by the abnormal neuronal firing [5]. A feedback loop
is introduced by the initial depolarization that causes a cycle
of depolarization, opening of voltage-gated channels, greater
efflux of K+ and subsequent release of excitatory neurotransmitters [5].
141
K+ is not the only ionic gradient disturbed, since

EAAs act on a number of receptors and channels
including kainite, N-methyl-D-aspartate (NMDA) and
D-amino-3-hydroxy-5-methyl-4-isoxazole-propionic
acid
(AMPA) receptors [1, 3, 6]. Glutamate binds to NMDA
receptors, opening a channel in which K+ and Ca2+ can flow
down their respective gradients [1, 6]. This stage of the ionic
perturbation has shown to be predominantly caused by
NMDA receptors (NMDARs), because these fluxes are
resistant to tetrodotoxin, a NMDAR agonist, but not to
kynurenic acid [6, 10]. Much of the literature implicates
NMDAR as the main receptor responsible for these
unchecked ionic fluxes, but some research has noted the
AMPA receptor to play a nearly equivalent role [1].
The indiscriminant release of EAAs results in massive
excitation and depolarization as well as an excessive intracellular accumulation of Ca2+ [12]. In animal models, this
excitation phase and simultaneous period of hyperglycolysis
can last from several minutes to 2 hours (see Figure 1 and
Figure 2 material below) [1, 22]. This period of excitation has
been associated with the initiation and spread of seizure
activity [23]. Following excitation, glial cells and neurons enter
into a phase of metabolic suppression, resulting in widespread
depression [12, 24].
Spreading depression
Following massive excitation the brain enters a state of
spreading depression, also referred to as neuronal depression
[1, 6, 12]. This post-TBI depression differs from classic
spreading depression in that TBI depression occurs concurrently in diffuse areas of the brain [1, 24, 25]. The significant
depolarization seen post-concussion has been implicated as the
major factor responsible for this wide-spread depression,
although other studies have speculated changes in cerebral
perfusion, neuronal degradation, anatomic re-organization and
imbalance of excitation and inhibition could play a role [1, 5 p.
1469]. In addition, the depletion of cellular ATP may intensify
this depression [1, 12]. The combination of these causative
factors is hypothesized to be responsible for the immediate
neurological deficits experienced post-injury, including loss of
consciousness, amnesia and other cognitive dysfunction [1, 5,
12]. It should be noted that this initial spreading depression
differs in aetiology from the subsequent metabolic depression.
Release of excitatory neurotransmitters

The initial ionic perturbation causes an indiscriminant release
of neurotransmitters, mainly excitatory amino acids (EAA)
[19, 20]. Extracellular concentrations of glutamate drastically
increase, having been shown to increase up to 50-fold [10].
The non-specific neurotransmitter release, predominately
glutamate, is responsible for stimulating EAA receptors,
inducing ligand-gated K+ channels and causing further efflux
of K+ [10, 21]. It has been shown that kynurenic acid, an
EAA inhibitor, can greatly reduce the K+ efflux in rats with
fluid percussion brain injury, providing evidence that the
main causative factors of the K+ surge are EAAs [5, 10]. In
addition, extracellular K+ and glutamate levels can be
effectively monitored in vivo through mircodialysis, a technique that has confirmed the dramatic increase of these two
metabolites [4].
Cellular management of K+ flux

The CNS utilizes certain cellular mechanisms that attempt
to minimize the ionic flux effects and to return neurons to ionic
homeostasis. Glial cells possess the ability to uptake excessive
K+ in order to restore extracellular K+ concentrations to
normal physiological levels [10, 26, 27]. This system is
effective enough to modulate extracellular K+ levels below a
limit ranging of 610 mM [5 p. 1460, 28]. The extracellular
concentration of K+ following a very mild concussion
likely does not cross the threshold of this regulatory system,
but a more serious concussive event can overwhelm
the system, allowing for an unregulated rise in extracellular
K+ [5, 10]. In vivo measurements through microdialysis in
human patients have confirmed this drastic rise in extracellular
K+ [4, 29].
142
Brain Inj, 2015; 29(2): 139153
Figure 1. Representation of the time course

for the ionic and metabolic alterations
following experimental concussion. K+,
potassium ion; Ca2+, calcium ion; CMR,
cerebral metabolic rate; gluc, glucose; CBF,
cerebral blood flow. Original source: Giza
and Hovda [134].
The ATP-dependent Na+-K+ pump, another mechanism

for regulating extracellular K+ concentrations, works in
overdrive to restore ionic balance [6]. High levels of active
transport quickly utilize cellular ATP reserves and energy
availability becomes a critical issue for neurons [6]. To meet
the energetic demands of the Na+-K+ pump, the cell upregulates rapid yet ineffective glycolysis for a period that may
last between 30 minutes and 4 hours [6, 22].
Increased glucose utilization and period of
hyperglycolysis
In order to satisfy the energetic demands of pump activation,
ATP production via glycolysis is selectively activated and
accelerated (Figure 2) [1, 30]. The energetic link to the K+
efflux has been shown in a handful of experiments that
correlate the K+ efflux time course with that of up-regulated
glucose metabolism [5]. Immediately following fluid percussion injury in rats, the rate of glucose metabolism increases and
continues for up to 30 minutes post-injury in the ipsilateral
cortex and hippocampus [22]. Another study involving rats that
underwent fluid percussion injury showed increases in glucose
utilization for up to 4 hours in areas distant from the contusion
core [1 p. 229, 31]. Fluid percussion injury experiments
calculate the rate of glucose metabolism within the first 30
minutes post-injury to be 3046% greater in injured rats than in
controls [11, 22, 32]. Positron emission tomography (PET)
scanning is a neuroimaging technique that can measure
cerebral glucose metabolic rates in humans and PET studies
have confirmed a period of hyperglycolysis in humans with
mild and severe TBI [4, 33, 34].
Under normal physiological conditions, cerebral oxidative
metabolism runs near maximum capacity and, therefore, any
increase in energetic demand from concussion is managed by
the up-regulation of glycolysis [1, 31]. Additionally, oxidative
metabolism becomes inhibited by Ca2+ sequestration into
mitochondria, causing glycolysis to meet these energetic
deficits as well [35, 36].
Sub-acute metabolic changes

Although the metabolic changes of concussion present
themselves in a continuum, the following changes are
considered to be part of the prolonged sub-acute response.
Lactate accumulation and acidosis
As glycolysis becomes a dominant form of producing ATP,
intracellular concentrations of lactate rise. Previous literature
shows a definitive increase in lactate concentrations in both
brain tissue and cerebrospinal fluid following experimental
fluid percussion injury [37, 38]. More recent studies using
magnetic resonance spectroscopy (MRS), a form of MRI that
can calculate concentrations of neurometabolites, show an
increase in the lactate pyruvate ratio (LPR) and in lactate
concentrations [12, 39]. In normal physiological states, lactate
cannot be reasonably detected by MRS [39].
Likely confirmation of a direct link of the massive K+ flux
to lactate accumulation came from an experiment that
followed lactate concentrations with microdialysis after
fluid percussion injury. When kynurenic acid, an EAA
antagonist, was administered prior to injury, the rise in
lactate concentration was attenuated [40]. EAAs are responsible for the massive depolarization, K+ efflux and the
subsequent up-regulation of glycolysis to re-establish ionic
gradients.
Hyperglycolysis is responsible for the initial increase in
lactic acid, but its continued accumulation is due to disruption
of the TCA cycle [1, 5]. Inhibition of oxidative metabolism
prevents excessive lactate from being shuttled for breakdown
in the TCA cycle [1]. However, once oxidative metabolism
resumes, the excess lactate can be used as a fuel source [12].
Rises in intracellular and extracellular concentrations of
lactate can eventually lead to acidosis [12]. The consequences
of acidosis encompass cell membrane damage and increased
permeability, altered or inhibited cellular function, partial breakdown of the bloodbrain barrier (BBB) and
widespread cerebral oedema [1, 5, 12]. Consequently, lactate
DOI: 10.3109/02699052.2014.965208
143
Figure 2. Graphical representation of the neurochemical cascade. Metabolic changes: (1) Initial wave of depolarization and K+ efflux. (2)
Indiscriminant release of excitatory neurotransmitters, predominantly glutamate. (3) Massive K+ efflux. (4) Activation and hyperactivity of ATPdependent Na+-K+ pump. (5) Increased glucose uptake and hyperglycolysis. (6) Lactate production and accumulation. (7) Ca2+ influx and
sequestration and subsequent inhibition of oxidative metabolism. (8) Initiation of depressed metabolic state. (9) Potential activation of apoptotic
pathways. Axonal alterations: (A) Axolemmal membrane disruption and Ca2+ influx. (B) Neurofilament compaction. (C) Decreased microtubule
stability and microtubule disassembly. (D) Dysfunctional axonal transport, organelle accumulation, blebbing and axotomy. Original source: Giza and
Hovda ([1], p 230).
accumulation and acidosis is believed to account for some of

the sub-acute neurologic deficits and vulnerability [5].
Apparent paradoxical effects of lactate
A study performed in 2003 investigated the cerebral metabolic rates (CMRs) of glucose, lactate and oxygen in TBI
patients to determine if there is a correlation between
abnormalities in these CMRs and neurological outcome (see
Table I) [8]. Abnormal cerebral uptake of lactate was
observed in 28% of patients studied, whereas only 2%
showed abnormal lactate production [8]. Additionally, the
study observed a positive correlation between a higher rate of
lactate uptake relative to arterial lactate level and a better
neurological outcome [8]. However, a lower absolute level
of arterial lactate was associated with a positive outcome
and a higher level was associated with a worse outcome [8].
New evidence shows that the abnormal uptake of lactate in

TBI patients is observed in the early stages post-injury and
occurs most frequently in the first 5 days after insult [41].
A number of possibilities have been speculated as to why
there is this apparently paradoxical effect of lactate on the
brain after TBI. One potential explanation is based on the
degree of disruption to oxidative metabolism after injury. The
mildly injured brain has a higher degree of intact oxidative
metabolism and, thus, lactate could be taken up by the brain
and be shuttled to the TCA cycle, after being converted to
pyruvate [8]. On the other hand, the severely injured brain has
a more depressed CMR02 and, hence, lactate may not be used
as effectively for oxidative metabolism, leading to accumulation [8]. Another explanation for the advantage of lactate as
a fuel source in an ATP-scarce cellular environment is that
glycolysis requires an initial investment of two molecules of
ATP, whereas lactate can be readily converted to pyruvate
144
without ATP [8]. It has also been hypothesized that lactate,

instead of entering the TCA cycle, could act as a free radical
scavenger during this time of oxidative stress [8].
Accumulation and sequestration of Ca2+
The initial indiscriminant release of EAAs activates NMDA
receptors which form pores that allow the efflux of Ca2+ ions
and lead to a dramatic rise in intracellular Ca2+ concentrations [1]. Additionally, cells have the ability to manage drastic
increases in intracellular Ca2+ through buffering mechanisms
and, when these mechanisms are exposed to the extracellular
space following injury, these cells act as a calcium sink [5,
42]. The drawing in of Ca2+ from surrounding tissues leads to
an extracellular and intracellular rise in Ca2+ levels [5, 42].
Another reason for the high intracellular and intraxonnal
concentrations of Ca2+ is due to stretching and shearing
forces causing transient membrane disruption and subsequent
ionic flux [2, 43, 44]. To restore cytosolic levels, Ca2+ is
sequestered into mitochondria where it can cause dysfunction
to oxidative metabolism [2].
After fluid percussion injury (FPI) to animals, Ca2+
accumulation in the ipsilateral cerebral cortex, dorsal hippocampus and striatum continued until post-injury day (PID)
23 and returned back to control levels by PID 4 [5, 45].
However, if morphological damage was sustained, Ca2+ levels
did not resolve by PID 4 [5, 45]. Other FPI models show the
increase beginning as soon as within 1 hour post-injury and
accumulation persisting for as long as 24 days [46, 47].
High intracellular levels of Ca2+ have a number of
deleterious effects on cellular and metabolic function and
can ultimately lead to cell death [5]. Ca2+ accumulation
triggers the over-activation of phospholipases [48], plasmalogenase [49, 50], calpains [49, 50], protein kinases [51],
nitric oxide synthase [1] and endonucleases [1 p. 231]. These
metabolic alternations can lead to over-production of free
radicals [52], cytoskeletal re-organization [53] and activation
of apoptotic signals [54]. Eventually, these changes lead to
mitochondrial damage and can result in cell death [1].
Although apoptosis is induced in more severe TBI, Ca2+
accumulation in mTBI generally does not produce cell death,
despite altered metabolic function [1].
Impaired oxidative metabolism due to Ca2+ sequestration
can be measured by cytochrome C oxidase histochemistry
[55]. Cytochrome C shows a biphasic reduction in the
ipsilateral cortex [55]. A mild reduction occurs on PID 1 that
recovers by PID 2 [55]. Another more significant reduction
begins on PID 3, bottoms out on PID 5 and recovers by PID
10 [55]. Similar biphasic reductions of cytochrome C occur in
the ipsilateral hippocampus, although it is more prolonged,
with decreases persisting past PID 10 [55].
Reduced magnesium levels
Magnesium plays a critical role in glycolysis and oxidative
metabolism, is necessary for proper membrane potential and
is an integral ion in protein synthesis initiation [1, 5]. One
study found that intracellular levels of magnesium following
experimental TBI were decreased for up to 24 hours when
measured by nuclear magnetic resonance (NMR) spectroscopy [45, 46]. Other research conducted in both rats and
Brain Inj, 2015; 29(2): 139153
humans indicates that magnesium levels decrease immediately following injury and this reduction can persist for up to
4 days [1, 56, 57]. Low levels of magnesium have been
shown to disrupt glycolytic and oxidative ATP production
[1]. In addition, the reduction timeline correlates well
with neurological deficits and is supported by data showing
that pre-treatment of animals with magnesium resulted
in improved motor performance [1, 58]. Another hypothesis
for why this reduction is detrimental to cellular functionality is that low levels of magnesium may unblock
NMDA channels and, hence, allow for a greater influx of
Ca2+ [1].
Recent literature and clinical trials challenge earlier animal
studies that indicate an increase in magnesium levels can be
neuroprotective. Studies involving the administration of
magnesium to patients with TBI have shown various results
along the multiple stages of clinical trials [59]. The successes
of pre-clinical trials have yet to translate to an overall
advantageous outcome [59]. One possibility is that overconcentration of magnesium can induce a number of disease
pathways including renal failure [59]. Other clinical studies
have noted that magnesium blood levels cannot be used to
predict CSF magnesium concentration [60]. Future clinical
studies of the administration of magnesium will need to
balance potential neuroprotective properties with side-effects
as well as find an effective means to administer magnesium
into the brain [59].
Changes in cerebral blood flow
Under normal physiological conditions, CBF is highly
coupled to cerebral glucose metabolism and uncoupling of
this regulatory system can lead to a damaging metabolic crisis
[1]. The changes in CBF induced by severe TBI are dynamic
and well characterized as triphasic in nature [6]. On PID 0,
there is cerebral hypoperfusion with an average CBF of
32.3 mL/100 g min1 that leads to cerebral hyperemia with an
average CBF of 46.8 mL/100 g min1 on PID 13 [6, 61].
Beginning on PID 4, there is a period of cerebral vasospasm
with decreased CBF of 35.7 mL/100 g min1 and elevated
cerebral artery velocities (96.7 cm s1) that continues
through PID 15 [6, 61 p. 12]. This model has not been
highly investigated in patients with mTBI, but a similar
triphasic response may occur after less severe injury [6].
Evidence from FPI models indicates a reduction in CBF of
up to 50% [1, 62, 63]. Additionally, studies of adult and
paediatric patients with mTBI or severe TBI show CBF is
decreased and remains low for an extended duration depending on the severity of the injury [2]. It is hypothesized that
changes in autoregulation, vasospasm and/or regional perfusion differences are responsible for the observed changes
in CBF [1, 2]. Interestingly, local alterations to brain tissue
can cause simultaneous excess and inadequate perfusion in
different regions of the brain [2].
Rodent studies have indicated that decreases in CBF may
be responsible for the period of vulnerability to a second
injury following concussion and TBI [2, 64]. This vulnerability is believed to exist because any additional energy
demand or reduction in energy supply could exacerbate injury
and lead to permanent damage [1].
DOI: 10.3109/02699052.2014.965208
Prolonged metabolic depression and hypometabolism

In parallel with reductions in CBF, the brain enters into a subacute period of prolonged hypometabolism [2]. Although this
metabolic depression can lead to permanent damage, it is
usually self-limiting and transient for a single concussive
event [6].
After introducing FPI to rats, cerebral glucose metabolism
is depressed up to 50% at 6 hours post-insult and can persist for
as long as 5 days [6]. Earlier FPI studies in rats indicate that
glucose metabolism is suppressed for up to 10 days following
insult [5, 11]. As mentioned previously, histochemical analysis
of cytochrome oxidase following TBI parallels this time course
with decreased activity extending to PID 10 [55]. PET studies
of humans with TBI have shown a global decrease in cerebral
metabolic rate of glucose for up to 24 weeks post-injury,
confirming this period of hypometabolism exists in human
patients [1, 65]. In addition, PET studies have shown that the
degree of glucose depression is nearly equivalent in mild TBI
and severe TBI [4, 65]. Consequently, in patients with
moderate and severe TBI, metabolic recovery takes between
2 weeks and several months, but analogous longitudinal studies
in patients with mTBI have yet to be reported [4, 33].
However, longitudinal metabolic studies using MRS have
studied concussive injury and demonstrate a persistent period
of cerebral metabolic depression. The metabolites investigated with MRS are believed to represent metabolic function,
more specifically that of mitochondria. N-acetylaspartate
(NAA) is believed to be indicative of reversible neuronal and/
or mitochondrial dysfunction [12]. Lactate pyruvate ratio
(LPR) is a marker of the reductive capacity of oxidative
metabolism [6]. Creatine (Cr) is generally used as an internal
control [39]. An MRS study monitoring patients with mTBI
observed a decrease in NAA, ATP/ADP ratio and NADH/
NAD+ ratio [66]. A subsequent study by the same team of
investigators, involving 13 concussed athletes, showed an
145
18.5% decrease in NAA/Cr signal at PID 3 [67]. This signal

increased somewhat by PID 15 and returned to baseline and
control values by PID 30 [67]. Microdialysis studies of
patients with severe TBI have shown a dramatic rise in LPR
following injury [6]. However, due to the invasive nature of
microdialysis, similar studies in patients with concussion are
unlikely to be conducted [6].
Various reasons have been hypothesized as the causative
agent of depressed metabolism following TBI. Dysfunctional
and disrupted neurotransmission of cholinergic, glutamatergic
and/or adrenergic systems may be responsible for the
observed hypometabolism [12]. Lending evidence to this
notion, catecholamine agonists have been shown to increase
functional and neurological outcome in both animals and
human patients [5, 68]. In animals that were administered
D-amphetamine, the rate of neurological recovery correlated
with the rate of metabolic recovery, specifically glucose
metabolism [5, 68]. Additionally, Ca2+-induced inhibition of
oxidative metabolism and the concomitant decrease in ATP
production, as discussed earlier, is thought to underlie
metabolic depression [1].
Although it is still unknown if hypometabolism is directly
responsible for neurological deficits and second injury
vulnerability, depressed metabolism correlates with neurologic recovery [2, 5, 6]. Figure 3 also shows that functional
recovery correlated closely with metabolic recovery, whether
or not a catecholamine agonist was administered [5, 68].
Experimental evidence supports the notion that neurological
recovery is linked to metabolic functionality [6]. However, a
PET study of patients with TBI found that level of
consciousness measured by GCS did not correlate with
glucose hypometabolism [65]. Another suggestion of this
research is that neurometabolic changes may persist despite a
lack of overt clinical symptoms [65]. Consequently, it seems
plausible that multiple metabolic factors contribute to
Figure 3. Comparison of neurobehavioural recovery to glucose metabolism in saline and amphetamine treated rats with lateral fluid percussion injury.
146
neurological recovery and that a measure of one metabolite or

metabolic rate cannot fully represent metabolic integrity.
Alternative fuel usage during hypometabolic state
During hypometabolism following TBI, the brain may utilize
alternate sources of fuel to meet ongoing metabolic demands,
as glucose may not be the optimal fuel for the injured brain
[6, 69]. Well-established research shows that ketone bodies
are used during times of stress and starvation [6]. Animal
studies show that rats in ketosis or on a ketogenic diet
following cortical impact have decreased glucose metabolic
rates and improved behavioural outcomes [6, 70, 71].
Additional research suggests that ketosis induced by starvation may be advantageous in the first 24 hours following a
moderate, but not severe traumatic event [72].
Lactate has been shown to be selectively up-taken by the
injured brain and may then be used as a fuel source [8].
As noted previously, brain lactate uptake relative to absolute arterial lactate levels correlates with a positive outcome
[8, 73, 74]. Accumulating evidence also indicates that
astrocytic glycolysis produces lactate that is shuttled to
adjacent neurons for use as alternative fuel [8, 75]. Studies
have found that, following TBI, the brain stops producing
lactate and begins to uptake lactate, starting as early as 1224
hours after injury and continuing through PID 45 [8, 76].
A more recent study, in which a bolus of lactate was
administered to patients with moderate or severe TBI, showed
that the injured brain simultaneously produces, uptakes and
consumes lactate [41]. It has been speculated that lactate, as a
fuel source, is thermodynamically advantageous during an
energy crisis because no initial energy investment is required
for subsequent entry into the TCA cycle [8]. An emerging
scenario based on recent research is that a positive neurological outcome is based on the brains ability to cope with
metabolic changes and consume whatever fuel is available,
including these alternate fuel sources [8].
Brain Inj, 2015; 29(2): 139153
Diffuse axonal injury

The initial impact from a concussive event or traumatic brain
injury causes a range of axonal dysfunction referred to as
diffuse axonal injury (DAI), also known as traumatic axonal
injury. Although DAI is more pronounced in severe injuries
due to greater acceleration forces, it occurs in all TBI,
regardless of severity [2, 79]. Recent research employing
mathematical modelling of impact velocity and mechanics
has provided evidence that the velocity of impact may play a
greater role in predicting axonal injury rather than impact
force alone [80]. This modelling is based on the viscoelastic
properties of tau, a microtubule (MT) stabilizing protein [80].
Consequently, this research has suggested that alterations to
axonal MTs are caused by the disruption of tau and a
reduction in its MT-binding capacity [80]. Additionally,
stretching and shearing forces of the insult lead to membrane
disruption and increased permeability, which can last for up to
6 hours post-injury [81, 82]. As discussed previously, these
changes result in an influx of Ca2+ and subsequent increase in
intra-axonal concentrations of Ca2+ [1]. While Ca2+ influx is
not the sole causative agent of DAI, it is directly linked to the
neurometabolic changes induced by injury, whereas other
factors are more biomechanical in nature.
Increased levels of Ca2+ induce a number of deleterious
changes to axonal integrity and function. Ca2+, as the primary
regulator of calpain activation, at high intra-axonal concentrations, initiates calpain-mediated proteolysis, as well as
phosphorylation of neurofilament sidearms [83, 84]. As early
as 5 minutes after injury, changes in neurofilament structure
lead to decreased stability, compaction and ultimately
neurofilament collapse [8587]. These changes can continue
to occur until 6 hours post-injury [86, 87].
Additionally, high levels of Ca2+ can cause destabilization
of microtubules from 624 hours following injury [88, 89].
Reduced integrity of microtubules can disrupt axonal transport, result in accumulation of organelles and lead to blebbing
and axotomy [82, 89, 90].
Altered brain activation

Concussion leads to long-term deficits in memory and
cognition despite a lack of morphological damage [1].
However, concussion may result in changes to cholinergic,
glutamatergic and adrenergic neurotransmission and
can lead to alterations in protein expression and synthesis
[5, 12]. A well-studied case of altered expression due to the
neurochemical cascade is changes in sub-unit regulation
of NMDA receptors. Throughout development, the NM2A
sub-unit of the tetrameric NMDA receptor becomes the
dominant sub-unit allowing for faster flux of Ca2+ ions [77].
The NM2B sub-unit is associated with slower flux of Ca2+
[77]. Following fluid percussion injury in paediatric rats,
the NM2A sub-unit is down-regulated by PID 24, with
no altered expression of NM2B [78]. This suggests the
altered expression of NMDAR sub-units is a neuroprotective
mechanism of calcium regulation [6, 78]. Furthermore,
NMDAR is associated with long-term depression and
long-term potentiation (LTP) of neural tissue [6]. LTP
has been shown to be impaired beginning on PID 2, which
parallels the time course of altered NMDAR sub-unit
expression [78].
Bloodbrain barrier disruption (BBBD) in

sub-concussive injuries
Link between sub-concussive injuries and mTBI
Biomechanical events causing direct or indirect impact to the
brain are considered to be sub-concussive if the insult does
not result in the clinically diagnosable symptoms of concussion [91]. Employing helmet accelerometers, studies have
estimated athletes participating in contact sports can sustain
hundreds of sub-concussive impacts per season [92]. Research
suggests that repetitive sub-concussive impacts can lead to
significant axonal injury, bloodbrain barrier (BBB) permeability and evidence of neuroinflammation [91 p. 1235].
A number of pathological parallels may exist between
concussive and sub-concussive injuries as they occupy the
mild end of the traumatic brain injury continuum, which
warrant inclusion in this chapter. The biomechanical forces of
a sub-concussive injury are less substantial than a concussive
event and, thus, changes directly linked to impact mechanics
may be present and heightened in concussion. As mentioned
earlier, lactate accumulation following traumatic brain injury
DOI: 10.3109/02699052.2014.965208
has been shown to disrupt the bloodbrain barrier and

increase its permeability. Thus, metabolic or cellular disruptions induced by BBB disruption (BBBD) in sub-concussive
injury may be applicable to any area of mTBI pathobiology
that increases BBB permeability. Additionally, following
mTBI, leukocytes have been shown to release inflammatory
factors that could contribute to cell death and, therefore,
neurological changes [93]. The preceding findings are likely
relevant only to those patients that are subjected to multiple
sub-concussive head-hits and/or concussive events as the
effects are cumulative.
Bloodbrain barrier disruption
BBBD is an instantaneous increase in permeability of brain
vasculature that results in immediate and delayed pathogenic
effects after insult [3, 94, 95]. The effects of BBBD have been
shown to increase in severity if accompanied by an immunological response initiated by entry of peripheral anti-CNS
autoantibodies [96, 97]. Furthermore, BBBD has been linked
to a number of neurological disorders including seizures,
Alzheimers disease, stroke and TBI [94].
Release of S100B and immunologic response
The presence of astrocytic protein S100B in serum has been
associated with BBBD and neurological disorders including
TBI [98, 99]. This biomarker is employed in some emergency
departments to diagnose or rule out mTBI [100]. A study
conducted in 2012 collected baseline, pre-game, post-game
and end-of-season serum samples from 57 football players,
none of whom suffered a concussion [101]. Blinded analysis
was performed on game films to determine the number of
sub-concussive head-hits (SHHs) each player sustained during
the season [101]. The study found the presence of S100B in
non-concussed athletes, indicating that SHHs cause a transient disruption of the BBB [102]. Additionally, the number and
severity of SHHs correlated with the level of elevation of
S100B in serum [101].
Consequently, the study showed that repetitive elevations
of S100B in serum lead to the presence and proliferation of
S100B autoantibodies [101]. There was a positive correlation
between the elevation intensity of S100B and the serum level
of S100B autoantibodies [101]. However, these autoantibodies are not pathogenic unless they penetrate through a leaky
BBB [97, 102]. The transient disruption of the BBB from
multiple SHHs and/or concussive events may allow for
passage of S100B autoantibodies, subsequent pathogenic and
immunological responses and pre-disposition to neurological
disease [101].
Cumulative and chronic effects of concussion

The neurometabolic cascade of concussion leaves the brain
more vulnerable to a second injury, which has been shown to
compound concussive symptomology in a time-dependent
manner. A study found that 50% of American National
Football League (NFL) athletes return to play (RTP) during
the same game in which a concussion was sustained [92, 101].
Additionally, a study of collegiate athletes showed that
8092% of repeat concussions occur during the first 710
147
days following injury [103, 104]. Another study, one that

monitored soccer players, found that performance in memory
and planning functions was inversely proportional to the
number of prior concussions [105 p. 973]. Therefore,
understanding the prolonged chronology of the cascade will
help dictate RTP guidelines and elucidate the potential for
chronic cumulative effects from repetitive concussion.
Period of vulnerability
Sub-acute changes following TBI, such as increased intracellular Ca2+ concentrations, impaired oxidative metabolism,
disturbances of neurotransmission, alterations of CBF and
delayed cell death are linked to a period of vulnerability to
second injury [1]. Evidence suggests that these factors act
synergistically to produce an energetic deficit and concomitant diminished response to a second insult [1, 6]. However,
each of these dysfunctional processes has a distinct chronology of recovery and, therefore, understanding the time
course of each component is critical [1].
Further Ca2+accumulation
A second insult introducing another indiscriminant flux of
Ca2+ may further impair oxidative metabolism when energetic output is already diminished [1]. Although Ca2+
accumulation is severity dependent, rat models have indicated
this period to last between 24 days post-injury [47, 106]. At
this time, additional increases in intracellular Ca2+ may be
enough to activate proteases and apoptotic pathways [1].
Diminished CBF
As noted earlier, CBF in patients with TBI is reduced in a
triphasic manner that begins on PID 0 and continues through
PID 15 [61]. This reduction likely occurs to resolve a
mismatch between CBF supply and diminished oxidative
metabolism demand [1, 6]. However, a second insult may
re-introduce metabolic crisis as CBF may be unable to
respond to a stimulus-induced increase in cerebral glucose
metabolism during this time period [1 p. 232].
Hypometabolism
Human PET studies show a decrease in cerebral glucose
metabolism for between 24 weeks following injury [65]. At
this time, oxidative metabolism is running at maximal levels
and, thus, further energetic demands from a second insult
could result in irreversible neuronal damage [1]. A single
concussive event is described by minimal cell death, but a
second insult may lead to pronounced cell death due to this
energetic crisis [1]. However, this is a controversial topic
as research has neither determined a deleterious or
neuroprotective effect of glucose hypometabolism after a
second injury [6, 107].
Impaired neurotransmission
Changes in neurotransmission are believed to play a role
in metabolic vulnerability and may also increase the chances
of sustaining a second injury. As discussed previously,
NMDA receptors are an integral component of excitatory
neurotransmission and are altered beginning on PID 2 [79].
148
These alterations have been shown to last for up to 1 week

following injury in the developing rat [79]. A second insult
can compound dysfunctional transmission and lead to further
cognitive impairment [1]. Long-term potentiation (LTP) is
speculated to be involved in memory, cognition and attention
[1]. Animal models have shown changes in LTP can last for
up to 8 weeks and, therefore, may increase an athletes
susceptibility of sustaining a second injury.
Additionally, alterations to inhibitory transmission have
been shown in animal models following experimental TBI
[108, 109]. During this period in which inhibitory mechanisms are altered, EAA release and depolarization from a
second insult may increase susceptibility to aberrant excitatory transmission and seizure activity [1]. It should also be
noted that axonal damage as well as impaired axonal transport
in human brain tissue has been shown to continue for weeks
after trauma and may contribute to cognitive deficits and
dysfunctional neurotransmission [1].
Metabolic evidence from MRS and NMR
Multiple studies have reported that MRS abnormalities persist
much longer than the reported recovery of symptoms,
indicating that a clinical recovery may not signify a complete
metabolic recovery [2]. The previously mentioned study of 13
concussed athletes that showed an 18.5% decrease in NAA/Cr
for a single concussive event also monitored three players
who sustained a second injury [67]. The second concussive
events occurred between 315 days post-injury [67]. Whereas
athletes with a single concussion had an increase in their
NAA/Cr by PID 15 and full return to baseline by PID 30,
these three players had continued reduction at PID 15 and did
not return to baseline values until PID 45 [67]. These results
have been confirmed by similar findings of multi-centre
analyses [2, 6]. However, others groups have found that NAA
levels may persist in a reduced state for between one to
several months and up to 1 year [110112].
Animal models of repetitive concussive injury have
elucidated a more comprehensive perspective of the acute
and sub-acute window of vulnerability. Rats subjected to a
single concussion via weight drop injury show a decrease in
NAA, as well as ATP [66]. A separation of 5 days between
insults showed no difference between singly and doubly
concussed rats [66]. However, a separation of 3 days resulted
in a compounded decrease in NAA and ATP, signifying
amplification of oxidative metabolism disruption [113].
A related study of repeat concussion in mice found that if a
second injury was sustained between 35 days post-injury,
cognitive impairment developed, whereas a second
injury inflicted at day 7 showed no development of cognitive
deficits [114].
Second impact syndrome
Although much of the pathophysiology and underlying
susceptibility of second impact syndrome (SIS) was presented
in the previous section, SIS encompasses the severe clinical
consequences of a second injury. Due to the potential deadly
effects, SIS is one of the major stipulations of RTP guidelines
[6, 115]. When an initial insult has yet to resolve pathologically, a seemingly minor second head trauma can result in
Brain Inj, 2015; 29(2): 139153
severe neurological deficits, coma and death [116]. SIS

initially manifests with general concussive symptoms before
escalating to catastrophic cerebral oedema within a few days
of the subsequent insult [6, 116].
Extensive cerebral oedema without haematoma is the
signature post-mortem pathological finding of SIS [116]. It
has been proposed that the observed dysfunction of
cerebrovascular autoregulation following mTBI cannot
adjust to the dramatic rise in blood pressure that occurs
after catecholamine surge from a second injury [12, 116].
The resulting rise in intracranial pressure causes vascular
engorgement of the brain with subsequent oedema and
herniation [6, 116].
Post-concussion syndrome
Although post-concussive syndrome (PCS) is merely a
clinical diagnosis for prolonged symptoms and mostly falls
outside of the scope of this chapter, it is important to note that
PCS encompasses the chronic manifestations of concussion.
Many of the signs and symptoms of concussion, as defined by
the 4-week interval following insult, are the same as PCS [12,
14, 15]. As many as 4080% of patients with concussion
experience some form of PCS, highlighting the need for
continued study of chronic metabolic changes [3]. In accordance with this idea, MRS studies have noted prolonged
metabolic changes initiated by a single concussive event and
compounded alterations by repetitive insults [6].
Chronic implications of neurochemical cascade
Repetitive concussions have been shown to induce neuronal
proteopathy or alterations in protein homeostasis that can lead
to delayed chronic neuropsychiatric and cognitive impairments referred to as chronic traumatic encephalopathy (CTE)
[12]. Although CTE has no clinically accepted guidelines, a
significant pathological finding of CTE includes neurofibrillary tangles due to tau pathology [2, 12]. Tau is a normal
cytosolic protein that promotes microtubule stability and
polymerization [3]. Given that tau-induced neurofibrillary
tangles are speculated to be caused by the loss of cellular
homeostasis [117] and, as previously discussed, changes in
microtubule stability occur immediately after axonal injury, it
seems reasonable that a link between these chronic and
acute pathologies exist. However, a biochemical link has
yet to implicate a direct causal relationship between the
two [3, 9].
Additionally, the neurometabolic cascade is believed to upregulate the expression of Apolipoprotein E (ApoE), a protein
that plays an integral role in neuronal and glial lipid
re-distribution as well as other critical neuronal maintenance
functions [12, 118, 119]. ApoE-"4, an allelic polymorphism
of the ApoE gene, has been shown to produce an isoform
more susceptible to misconfiguration and, thus, degradation
via proteolysis [118]. The breakdown of misconfigured ApoE
has been shown to produce bioactive toxic fragments that can
disrupt cellular function [118]. This may indicate that
repetitive up-regulation of ApoE via repeat concussions
combined with a pre-disposition to produce a misconfigured
ApoE protein could result in an increased risk of developing
neurodegenerative diseases.
DOI: 10.3109/02699052.2014.965208
Paediatric-specific concerns
Given that sport-related concussion occurs most frequently in
paediatric and young adult patients, understanding the
consequences of concussion on the developing brain is
critical [4]. Current research is conflicting about whether or
not the immature brain is more resilient or vulnerable to
injury.
149
environment will show an increase in cortical thickness, larger

neurons, proliferation of dendritic branching and improved
cognition [129, 130]. Following moderate fluid percussive
injury, rats reared in an enriched environment fail to develop
the aforementioned indicators of increased plasticity [129,
130]. Consequently, there may be a period following a
concussive event in which the developing brain is less
responsive to external stimuli [4, 129].
Earlier resolution of metabolic dysfunction
Paediatric second impact syndrome
Models of developing animals indicate the immature brain

enters a hyper-acute period of glucose metabolism and
subsequent state of hypometabolism, parallelling that of the
developed brain [22]. However, unlike adult rats which
experience prolonged metabolic depression, pre-weaning rats
(post-natal day 17) show an earlier resolution of hypometabolism, indicating some metabolic alterations may recover
quicker in the developing brain [2, 120]. Additional studies of
concussion on immature rats have found a similar early
resolution of the calcium flux and the absence of neurological
or pathological dysfunction following fluid percussive injury
[4, 121, 122]. Another recent study has shown that, after
introducing closed head injury, only those injuries with a high
mortality rate of 75% cause deficits [123].
Human studies employing magnetic resonance imaging
have indicated that recovery of certain metabolic parameters
may be age-dependent. A study of 12 paediatric patients with
an age range of 1115 years showed no changes in MRI and
MRS following concussive injury [124]. However, a multicentre study of 40 young adults reported a 15-day reduction in
NAA/Cr, an interval aligning with that seen in adult patients
with concussion [67, 125].
The malignant and fatal cerebral oedema of second impact

syndrome described previously occurs most often in children
and adolescents [131, 132]. It is believed that paediatric
patients, while recovering from an initial injury, have an
impaired ability to cope with the catecholamine surge of a
second impact [116]. Additionally, paediatric patients have an
increased mismatch of cerebrovascular autoregulation following a second concussive event [116, 133].
However, it should be noted that some researchers are
skeptical of SIS as a clinical diagnosis. A review of SIS noted
that none of the 17 published case reports of SIS at the time of
authorship had met the four prognostic criteria [131]. In
addition, case reports have been published on children who
experienced delayed cerebral oedema resulting in death
without a distinguishing prior injury [132]. Despite this
potential discrepancy, malignant and fatal cerebral oedema is
pronounced and occurs most frequently in the paediatric
population [131, 132].
Increased neurologic vulnerability

In contrast to the observed decrease in metabolic recovery
time, experimental research has elucidated a perceived
increase in neurological vulnerability to concussion in
paediatric patients. A closed head injury study in mice
found that action potentials of myelinated callosal fibres
remained intact following injury, whereas unmyelinated fibres
experienced conduction deficits for up to 14 days post-injury
[126]. Additional experimental research shows that unmyelinated white matter fibres appear to be more susceptible to
traumatic brain injury [127]. Myelination is an ongoing
process throughout adolescence and young adulthood, especially in the frontal lobes which are the neuropsychological
substrate for complex cognitive tasks such as working
memory, attention, and executive functions [4 p. 49, 128].
Interestingly, these are the cognitive deficits observed in
patients after TBI [4]. Based on these findings, it seems
reasonable to conclude that paediatric patients are more
vulnerable to the neurological effects of concussion in an agedependent manner.
Consistent with evidence of neurological impairment in
paediatric patients with TBI, animal studies have found a
likely decrease in synaptic plasticity following concussion [1].
Experience-dependent plasticity is a measure of the brains
ability to manipulate its structure and function based on
environmental stimulation [4]. Rats reared in an enriched
Conclusion
Concussive injury initiates a complex cascade of pathological
metabolic and ionic changes in the brain that lead to acute and
chronic consequences. Phases along the continuum of injury
pathology, such as hyperacute ionic flux, acute hyperglycolysis and sub-acute metabolic depression, have been linked to
neurological alterations and deficits that are typically
experienced following concussion. Chronic changes including
post-concussive syndrome and chronic traumatic encephalopathy continue to be studied by novel imaging techniques
that allow for non-invasive metabolic analysis of the brain.
Additionally, a milder form of traumatic brain injury, subconcussive head-hits, has provided insight into how metabolic
and bloodbrain barrier disruption can lead to prolonged
neurologic dysfunction and pathophysiology.
Human studies of severe traumatic brain injury have
correlated a greater disruption of the bloodbrain barrier,
higher systemic lactate concentrations and a lower CMRO2
with poor recovery [8]. Similarly, MRS metabolic studies of
patients with concussion have shown an association between
prolonged metabolic alterations and the window of neurologic
dysfunction. Evidence indicates that the severity of metabolic
changes initiated by a concussive event are directly related to
the length and degree of neurological recovery. In addition,
these changes have been implicated to cause a window of
vulnerability following injury that should dictate return-toplay guidelines. These guidelines must also consider a
growing pool of evidence that suggests metabolic changes
as well as length of recovery following mTBI are agedependent.
150
Declaration of interest
The authors report no conflicts of interest. This work was
supported in part by the UCLA Brain Injury Research Center
and award PO1NS058489 from the National Institute of
Neurological Disorders and Stroke (NINDS).
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Neurochemical Cascade of Concussion

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What is the neurochemical cascade of concussion?

What is the neurochemical cascade of concussion?

What are some of the metabolic changes that occur following a concussive injury?

What are some of the metabolic changes that occur following a concussive injury?

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Neurochemical cascade of concussion

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Date: 01 October 2016, At: 23:12

Neurochemical cascade of concussion

Concussion, concussion pathophysiology,

post-concussive syndrome, to encompass chronic, prolonged

M. P. MacFarlane & T. C. Glenn

Brain Inj, 2015; 29(2): 139153

Table I. Metabolic data from trauma patients and normal controls.

Metabolic study of cerebral metabolism

Overview of neurochemical cascade and

overdrive to restore the disrupted ionic gradient [1]. This

Biomechanics and animal models of

Overview of animal models of traumatic brain injury

Hyperacute and acute neurometabolic changes

Neurochemical cascade of concussion

K+ is not the only ionic gradient disturbed, since

Release of excitatory neurotransmitters

Cellular management of K+ flux

M. P. MacFarlane & T. C. Glenn

Brain Inj, 2015; 29(2): 139153

Figure 1. Representation of the time course

The ATP-dependent Na+-K+ pump, another mechanism

Sub-acute metabolic changes

Neurochemical cascade of concussion

accumulation and acidosis is believed to account for some of

New evidence shows that the abnormal uptake of lactate in

M. P. MacFarlane & T. C. Glenn

without ATP [8]. It has also been hypothesized that lactate,

Brain Inj, 2015; 29(2): 139153

Prolonged metabolic depression and hypometabolism

Neurochemical cascade of concussion

18.5% decrease in NAA/Cr signal at PID 3 [67]. This signal

M. P. MacFarlane & T. C. Glenn

neurological recovery and that a measure of one metabolite or

Brain Inj, 2015; 29(2): 139153

Diffuse axonal injury

Altered brain activation

Bloodbrain barrier disruption (BBBD) in

Neurochemical cascade of concussion

has been shown to disrupt the bloodbrain barrier and

Cumulative and chronic effects of concussion

days following injury [103, 104]. Another study, one that

M. P. MacFarlane & T. C. Glenn

These alterations have been shown to last for up to 1 week

Brain Inj, 2015; 29(2): 139153

severe neurological deficits, coma and death [116]. SIS

Neurochemical cascade of concussion