Neurochemical cascade of concussion.

http://informahealthcare.com/bij ISSN: 0269-9052 (print), 1362-301X (electronic) Brain Inj, 2015; 29(2): 139–153 ! 2015 Informa UK Ltd. DOI: 10.3109/02699052.2014.965208

REVIEW

Neurochemical cascade of concussion Matthew P. MacFarlane1,2 & Thomas C. Glenn1,2 UCLA Cerebral Blood Flow Laboratory, Los Angeles, CA, USA and 2Department of Neurosurgery, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA

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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: [email protected]

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 40–80% of patients display these in some form, with 10–15% 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].

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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 ¼ 49)

Normal (n ¼ 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 acceleration–deceleration 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].

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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 naı¨ve 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].

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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 6–10 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].

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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 30–46% 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 blood–brain barrier (BBB) and widespread cerebral oedema [1, 5, 12]. Consequently, lactate


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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

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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) 2–3 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 2–4 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

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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 1–3 [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].

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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 2–4 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


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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.

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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 12–24 hours after injury and continuing through PID 4–5 [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 brain’s ability to cope with metabolic changes and consume whatever fuel is available, including these alternate fuel sources [8].

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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 [85–87]. These changes can continue to occur until 6 hours post-injury [86, 87]. Additionally, high levels of Ca2+ can cause destabilization of microtubules from 6–24 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 2–4, 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].

Blood–brain 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, blood–brain 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


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has been shown to disrupt the blood–brain 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.


Blood–brain 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, Alzheimer’s 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 80–92% of repeat concussions occur during the first 7–10

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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 2–4 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 2–4 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].


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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 athlete’s 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 3–15 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 [110–112]. 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 3–5 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

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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 40–80% 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.


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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.

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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 11–15 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 brain’s 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 blood–brain barrier disruption can lead to prolonged neurologic dysfunction and pathophysiology. Human studies of severe traumatic brain injury have correlated a greater disruption of the blood–brain 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.

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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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