Closed-head concussive injury is one of the most common causes of traumatic brain injury (TBI). Isolated concussions frequently produce acute neurological impairments, and individuals typically recover spontaneously within a short time frame. In contrast, brain injuries resulting from multiple concussions can result in cumulative damage and elevated risk of developing chronic brain pathologies. Increased attention has focused on identification of diagnostic markers that can prognostically serve as indices of brain health after injury, revealing the temporal profile of vulnerability to a second insult. Such markers may demarcate adequate recovery periods before concussed patients can return to required activities. We developed a noninvasive closed-head impact model that captures the hallmark symptoms of concussion in the absence of gross tissue damage. Animals were subjected to single or repeated concussive impact and examined using a battery of neurological, vestibular, sensorimotor, and molecular metrics. A single concussion induced transient, but marked, acute neurological impairment, gait alterations, neuronal death, and increased glial fibrillary acidic protein (GFAP) expression in brain tissue. As expected, repeated concussions exacerbated sensorimotor dysfunction, prolonged gait abnormalities, induced neuroinflammation, and upregulated GFAP and tau. These animals also exhibited chronic functional neurological impairments with sustained astrogliosis and white matter thinning. Acute changes in molecular signatures correlated with behavioral impairments, whereas increased times to regaining consciousness and balance impairments were associated with higher GFAP and neuroinflammation. Overall, behavioral consequences of either single or repeated concussive impact injuries appeared to resolve more quickly than the underlying molecular, metabolic, and neuropathological abnormalities. This observation, which is supported by similar studies in other mTBI models, underscores the critical need to develop more objective prognostic measures for guiding return-to-play decisions.
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References
1.
MarinJ.R., WeaverM.D., YealyD.M., and MannixR.C. (2014). Trends in visits for traumatic brain injury to emergency departments in the United States. JAMA, 311, 1917–1919.
2.
HogeC.W., McGurkD., ThomasJ.L., CoxA.L., EngelC.C., and CastroC.A. (2008). Mild traumatic brain injury in U.S. Soldiers returning from Iraq. N. Engl. J. Med., 358, 453–463.
3.
TerrioH., BrennerL.A., IvinsB.J., ChoJ.M., HelmickK., SchwabK., ScallyK., BretthauerR., and WardenD. (2009). Traumatic brain injury screening: preliminary findings in a US Army Brigade Combat Team. J. Head Trauma Rehabil., 24, 14–23.
4.
HanK., Mac DonaldC.L., JohnsonA.M., BarnesY., WierzechowskiL., ZoniesD., OhJ., FlahertyS., FangR., RaichleM.E., and BrodyD.L. (2014). Disrupted modular organization of resting-state cortical functional connectivity in U.S. military personnel following concussive 'mild' blast-related traumatic brain injury. NeuroImage, 84, 76–96.
5.
DashnawM.L., PetragliaA.L., and BailesJ.E. (2012). An overview of the basic science of concussion and subconcussion: where we are and where we are going. Neurosurg. Focus, 33, E5: 1–9.
6.
DumaS.M., ManoogianS.J., BussoneW.R., BrolinsonP.G., GoforthM.W., DonnenwerthJ.J., GreenwaldR.M., ChuJ.J., and CriscoJ.J. (2005). Analysis of real-time head accelerations in collegiate football players. Clin. J. Sport Med., 15, 3–8.
7.
BailesJ.E., PetragliaA.L., OmaluB.I., Nauman, E. and TalavageT. (2013). Role of subconcussion in repetitive mild traumatic brain injury. J. Neurosurg., 119, 1235–1245.
8.
FischerH. (2014). A Guide to U.S. Military Causalty Statistics: Operation New Dawn, Operation Iraqi Freedom, and Operation Enduring Freedom: CRS Report for Congress. 1–9.
9.
DaneshvarD.H., NowinskiC.J., McKeeA.C., and CantuR.C. (2011). The epidemiology of sport-related concussion. Clin. Sports Med., 30, 1–17, vii.
10.
DompierT.P., KerrZ.Y., MarshallS.W., HainlineB., SnookE.M., HaydenR., and SimonJ.E. (2015). Incidence of concussion during practice and games in youth, high school, and collegiate American football players. JAMA Pediatr. 169, 659–665.
11.
GizaC.C., KutcherJ.S., AshwalS., BarthJ., GetchiusT.S., GioiaG.A., GronsethG.S., GuskiewiczK., MandelS., ManleyG., McKeagD.B., ThurmanD.J., and ZafonteR. (2013). Summary of evidence-based guideline update: evaluation and management of concussion in sports: report of the Guideline Development Subcommittee of the American Academy of Neurology. Neurology, 80, 2250–2257.
12.
PowellJ.W., and Barber–FossK.D. (1999). Traumatic brain injury in high school athletes. JAMA, 282, 958–963.
13.
WassermanE.B., KerrZ.Y., ZuckermanS.L., and CovassinT. (2016). Epidemiology of sports-related concussions in National Collegiate Athletic Association Athletes From 2009–2010 to 2013–2014: symptom prevalence, symptom resolution time, and return-to-play time. Am. J. Sports Med., 44, 226–233.
14.
ZuckermanS.L., MorganC.D., BurksS., ForbesJ.A., ChamblessL.B., SolomonG.S., and SillsA.K. (2015). Functional and structural traumatic brain injury in equestrian sports: a review of the literature. World Neurosurg. 83, 1098–1113.
15.
UnderwoodE. (2013). Neuroscience. NFL kicks off brain injury research effort. Science, 339, 1367.
16.
WeinsteinE., TurnerM., KuzmaB.B., and FeuerH. (2013). Second impact syndrome in football: new imaging and insights into a rare and devastating condition. Journal of neurosurgery. Pediatrics, 11, 331–334.
17.
GuskiewiczK.M., McCreaM., MarshallS.W., CantuR.C., RandolphC., BarrW., OnateJ.A., and KellyJ.P. (2003). Cumulative effects associated with recurrent concussion in collegiate football players: the NCAA Concussion Study. JAMA, 290, 2549–2555.
18.
WebbeF.M., and BarthJ.T. (2003). Short-term and long-term outcome of athletic closed head injuries. Clinics Sports Med. 22, 577–592.
19.
ArciniegasD.B., AndersonC.A., TopkoffJ., and McAllisterT.W. (2005). Mild traumatic brain injury: a neuropsychiatric approach to diagnosis, evaluation, and treatment. Neuropsychiatr. Dis.Treat., 1, 311–327.
20.
PellmanE.J. (2003). Background on the National Football League's research on concussion in professional football. Neurosurgery, 53, 797–798.
21.
PellmanE.J., VianoD.C., TuckerA.M., CassonI.R., and WaeckerleJ.F. (2003). Concussion in professional football: reconstruction of game impacts and injuries. Neurosurgery, 53, 799–812.
22.
BeyT., and OstickB. (2009). Second impact syndrome. West. J. Emerg. Med., 10, 6–10.
23.
IversonD., LewisK.L., CaputiP., and KnospeS. (2010). The cumulative impact and associated costs of multiple health conditions on employee productivity. J. Occup. Environ. Med., 52, 1206–1211.
24.
PrinsM.L., AlexanderD., GizaC.C., and HovdaD.A. (2013). Repeated mild traumatic brain injury: mechanisms of cerebral vulnerability. J. Neurotrauma, 30, 30–38.
25.
EisenbergM.A., AndreaJ., MeehanW., and MannixR. (2013). Time interval between concussions and symptom duration. Pediatrics, 132, 8–17.
26.
WeilZ.M., GaierK.R., and KarelinaK. (2014). Injury timing alters metabolic, inflammatory and functional outcomes following repeated mild traumatic brain injury. Neurobiol. Dis., 70, 108–116.
27.
MacGregorA.J., DoughertyA.L., MorrisonR.H., QuinnK.H., and GalarneauM.R. (2011). Repeated concussion among U.S. military personnel during Operation Iraqi Freedom. J. Rehabil. Res. Dev., 48, 1269–1278.
McKeeA.C., SternR.A., NowinskiC.J., SteinT.D., AlvarezV.E., DaneshvarD.H., LeeH.S., WojtowiczS.M., HallG., BaughC.M., RileyD.O., KubilusC.A., CormierK.A., JacobsM.A., MartinB.R., AbrahamC.R., IkezuT., ReichardR.R., WolozinB.L., BudsonA.E., GoldsteinL.E., KowallN.W., and CantuR.C. (2013). The spectrum of disease in chronic traumatic encephalopathy. Brain, 136, 43–64.
30.
BelangerH.G., VanderploegR.D. and McAllisterT. (2016). Subconcussive blows to the head: a formative review of short-term clinical outcomes. J. Head Trauma Rehabil., 31, 159–166.
31.
LaurerH.L., BareyreF.M., LeeV.M., TrojanowskiJ.Q., LonghiL., HooverR., SaatmanK.E., RaghupathiR., HoshinoS., GradyM.S., and McIntoshT.K. (2001). Mild head injury increasing the brain's vulnerability to a second concussive impact. J. Neurosurg., 95, 859–870.
32.
UryuK., LaurerH., McIntoshT., PraticoD., MartinezD., LeightS., LeeV.M., and TrojanowskiJ.Q. (2002). Repetitive mild brain trauma accelerates Abeta deposition, lipid peroxidation, and cognitive impairment in a transgenic mouse model of Alzheimer amyloidosis. J. Neurosci., 22, 446–454.
33.
LuoJ., NguyenA., VilledaS., ZhangH., DingZ., LindseyD., BieriG., CastellanoJ.M., BeaupreG.S., and Wyss–CorayT. (2014). Long-term cognitive impairments and pathological alterations in a mouse model of repetitive mild traumatic brain injury. Front. Neurol., 5, 12.
34.
YuF., ShuklaD.K., ArmstrongR.C., MarionC.M., RadomskiK.L., SelwynR.G., and DardzinskiB.J. (2016). Repetitive model of mild traumatic brain injury produces cortical abnormalities detectable by magnetic resonance diffusion imaging (DTI/DKI), histopathology, and behavior. J. Neurotrauma, 34, 1364–1381.
35.
PetragliaA.L., PlogB.A., DayawansaS., ChenM., DashnawM.L., CzernieckaK., WalkerC.T., ViteriseT., HyrienO., IliffJ.J., DeaneR., NedergaardM., and HuangJ.H. (2014). The spectrum of neurobehavioral sequelae after repetitive mild traumatic brain injury: a novel mouse model of chronic traumatic encephalopathy. J. Neurotrauma, 31, 1211–1224.
36.
BrodyD.L., Mac DonaldC., KessensC.C., YuedeC., ParsadanianM., SpinnerM., KimE., SchwetyeK.E., HoltzmanD.M., and BaylyP.V. (2007). Electromagnetic controlled cortical impact device for precise, graded experimental traumatic brain injury. J. Neurotrauma, 24, 657–673.
37.
MouzonB., ChaytowH., CrynenG., BachmeierC., StewartJ., MullanM., StewartW., and CrawfordF. (2012). Repetitive mild traumatic brain injury in a mouse model produces learning and memory deficits accompanied by histological changes. J. Neurotrauma, 29, 2761–2773.
38.
MiyauchiT., WeiE.P., and PovlishockJ.T. (2014). Evidence for the therapeutic efficacy of either mild hypothermia or oxygen radical scavengers after repetitive mild traumatic brain injury. J. Neurotrauma, 31, 773–781.
39.
KhalinI., JamariN.L., RazakN.B., HasainZ.B., NorM.A., ZainudinM.H., OmarA.B., and AlyautdinR. (2016). A mouse model of weight-drop closed head injury: emphasis on cognitive and neurological deficiency. Neural Regen. Res., 11, 630–635.
40.
KaneM.J., Angoa–PerezM., BriggsD.I., VianoD.C., KreipkeC.W., and KuhnD.M. (2012). A mouse model of human repetitive mild traumatic brain injury. J. Neurosci. Methods, 203, 41–49.
41.
XuL., NguyenJ.V., LeharM., MenonA., RhaE., ArenaJ., RyuJ., Marsh–ArmstrongN., MarmarouC.R., and KoliatsosV.E. (2016). Repetitive mild traumatic brain injury with impact acceleration in the mouse: multifocal axonopathy, neuroinflammation, and neurodegeneration in the visual system. Exp. Neurol., 275, Pt. 3, 436–449.
42.
ShultzS.R., BaoF., OmanaV., ChiuC., BrownA., and CainD.P. (2012). Repeated mild lateral fluid percussion brain injury in the rat causes cumulative long-term behavioral impairments, neuroinflammation, and cortical loss in an animal model of repeated concussion. J. Neurotrauma, 29, 281–294.
43.
KoliatsosV.E., CernakI., XuL., SongY., SavonenkoA., CrainB.J., EberhartC.G., FrangakisC.E., MelnikovaT., KimH., and LeeD. (2011). A mouse model of blast injury to brain: initial pathological, neuropathological, and behavioral characterization. J. Neuropathol. Exp. Neurol., 70, 399–416.
44.
CernakI., MerkleA.C., KoliatsosV.E., BilikJ.M., LuongQ.T., MahotaT.M., XuL., SlackN., WindleD., and AhmedF.A. (2011). The pathobiology of blast injuries and blast-induced neurotrauma as identified using a new experimental model of injury in mice. Neurobiol. Dis., 41, 538–551.
45.
ColeJ.T., YarnellA., KeanW.S., GoldE., LewisB., RenM., McMullenD.C., JacobowitzD.M., PollardH.B., O'NeillJ.T., GrunbergN.E., DalgardC.L., FrankJ.A., and WatsonW.D. (2011). Craniotomy: true sham for traumatic brain injury, or a sham of a sham?. J. Neurotrauma, 28, 359–369.
46.
XuL.Y., RyuJ., NguyenJ.V., ArenaJ., RhaE., VranisP., HittD., Marsh–ArmstrongN., and KoliatsosV.E. (2015). Evidence for accelerated tauopathy in the retina of transgenic P301S tau mice exposed to repetitive mild traumatic brain injury. Exp. Neurol., 273, 168–176.
47.
HuangL., CoatsJ.S., Mohd–YusofA., YinY., AssaadS., MuellnerM.J., KamperJ.E., HartmanR.E., DulcichM., DonovanV.M., OyoyoU., and ObenausA. (2013). Tissue vulnerability is increased following repetitive mild traumatic brain injury in the rat. Brain Res. 1499, 109–120.
48.
McAteerK.M., CorriganF., ThorntonE., TurnerR.J., and VinkR. (2016). Short and long term behavioral and pathological changes in a novel rodent model of repetitive mild traumatic brain injury. PloS One, 11, e0160220.
49.
OjoJ.O., MouzonB., GreenbergM.B., BachmeierC., MullanM., and CrawfordF. (2013). Repetitive mild traumatic brain injury augments tau pathology and glial activation in aged hTau mice. J. Neuropathol. Exp. Neurol., 72, 137–151.
50.
PetragliaA.L., PlogB.A., DayawansaS., DashnawM.L., CzernieckaK., WalkerC.T., ChenM., HyrienO., IliffJ.J., DeaneR., HuangJ.H., and NedergaardM. (2014). The pathophysiology underlying repetitive mild traumatic brain injury in a novel mouse model of chronic traumatic encephalopathy. Surg. Neurol. Int., 5, 184.
51.
GoddeyneC., NicholsJ., WuC., and AndersonT. (2015). Repetitive mild traumatic brain injury induces ventriculomegaly and cortical thinning in juvenile rats. J. Neurophysiol., 113, 3268–3280.
52.
LeungL.Y., LarimoreZ., HolmesL., CartagenaC., MountneyA., Deng–BryantY., SchmidK., ShearD., and TortellaF. (2014). The WRAIR projectile concussive impact model of mild traumatic brain injury: re-design, testing and preclinical validation. Ann. Biomed. Eng., 42, 1618–1630.
53.
ChenZ., LeungL.Y., MountneyA., LiaoZ., YangW., LuX.C., DaveJ., Deng–BryantY., WeiG., SchmidK., ShearD.A., and TortellaF.C. (2012). A novel animal model of closed-head concussive-induced mild traumatic brain injury: development, implementation, and characterization. J. Neurotrauma, 29, 268–280.
54.
YarnellA.M., BarryE.S., MountneyA., ShearD., Tortella, F. and GrunbergN.E. (2016). The Revised Neurobehavioral Severity Scale (NSS-R) for rodents. Curr. Protoc. Neurosci., 75, 9.52.1–9.52.16.
55.
BassoD.M., BeattieM.S., and BresnahanJ.C. (1995). A sensitive and reliable locomotor rating scale for open field testing in rats. J. Neurotrauma, 12, 1–21.
56.
MountneyA., LeungL.Y., PedersenR., ShearD., and TortellaF. (2013). Longitudinal assessment of gait abnormalities following penetrating ballistic-like brain injury in rats. J. Neurosci. Methods, 212, 1–16.
57.
MountneyA., ShearD.A., PotterB., MarcsisinS.R., SousaJ., MelendezV., TortellaF.C., and LuX.C. (2013). Ethosuximide and phenytoin dose-dependently attenuate acute nonconvulsive seizures after traumatic brain injury in rats. J. Neurotrauma, 30, 1973–1982.
58.
Deng–BryantY., LeungL.Y., CaudleK., TortellaF., and ShearD. (2016). Cognitive evaluation using Morris Water Maze in neurotrauma. Methods Mol. Biol., 1462, 539–551.
59.
SharmaA., ChandranR., BarryE.S., BhomiaM., HutchisonM.A., BalakathiresanN.S., GrunbergN.E., and MaheshwariR.K. (2014). Identification of serum microRNA signatures for diagnosis of mild traumatic brain injury in a closed head injury model. PloS One, 9, e112019.
60.
BeckwithJ.G., GreenwaldR.M., ChuJ.J., CriscoJ.J., RowsonS., DumaS.M., BroglioS.P., McAllisterT.W., GuskiewiczK.M., MihalikJ.P., AndersonS., SchnebelB., BrolinsonP.G., and CollinsM.W. (2013). Head impact exposure sustained by football players on days of diagnosed concussion. Med. Sci. Sports Exerc., 45, 737–746.
61.
DavisG.A., IversonG.L., GuskiewiczK.M., PtitoA., and JohnstonK.M. (2009). Contributions of neuroimaging, balance testing, electrophysiology and blood markers to the assessment of sport-related concussion. Br. J. Sports Med., 43, Suppl. 1, i36–45.
62.
WinterD.A. (1995). Human balance and posture control during standing and walking. Gait Posture, 3, 193–214.
63.
ManciniM., and HorakF.B. (2010). The relevance of clinical balance assessment tools to differentiate balance deficits. Eur. J. Phys. Rehabil. Med., 46, 239–248.
64.
GuskiewiczK.M. (2011). Balance assessment in the management of sport-related concussion. Clin. Sports Med., 30, 89–102, ix.
65.
YangS.H., GustafsonJ., GangidineM., StepienD., SchusterR., PrittsT.A., GoodmanM.D., RemickD.G., and LentschA.B. (2013). A murine model of mild traumatic brain injury exhibiting cognitive and motor deficits. J. Surg. Res., 184, 981–988.
66.
ChouL.S., KaufmanK.R., Walker–RabatinA.E., BreyR.H., and BasfordJ.R. (2004). Dynamic instability during obstacle crossing following traumatic brain injury. Gait Posture, 20, 245–254.
67.
WilliamsG., MorrisM.E., SchacheA., and McCroryP.R. (2009). Incidence of gait abnormalities after traumatic brain injury. Arch. Phys. Med. Rehabil., 90, 587–593.
68.
OchiF., EsquenaziA., HiraiB., and TalatyM. (1999). Temporal-spatial feature of gait after traumatic brain injury. J. Head Trauma Rehabil., 14, 105–115.
69.
Kuhtz–BuschbeckJ.P., HoppeB., GolgeM., DreesmannM., Damm–StunitzU., and RitzA. (2003). Sensorimotor recovery in children after traumatic brain injury: analyses of gait, gross motor, and fine motor skills. Dev. Med. Child Neurol., 45, 821–828.
70.
BenedettiM.G., AgostiniV., KnaflitzM., GasparroniV., BoschiM., and PipernoR. (2012). Self-reported gait unsteadiness in mildly impaired neurological patients: an objective assessment through statistical gait analysis. J. Neuroeng. Rehabil. 9,64.
71.
TerashimaT. (1995). Anatomy, development and lesion-induced plasticity of rodent corticospinal tract. Neurosci. Res., 22, 139–161.
72.
SwashM., ScholtzC.L., VowlesG., and IngramD.A. (1988). Selective and asymmetric vulnerability of corticospinal and spinocerebellar tracts in motor neuron disease. J. Neurol. Neurosurg. Psychiatry, 51, 785–789.
73.
AllisonL. (1999). Imbalance following traumatic brain injury in adults: causes and characteristics. Neurol. Rep., 23, 14–18.
74.
McKeeA.C., and DaneshvarD.H. (2015). The neuropathology of traumatic brain injury. Handb. Clin. Neurol., 127, 45–66.
75.
BlumbergsP.C., JonesN.R., and NorthJ.B. (1989). Diffuse axonal injury in head trauma. J. Neurol. Neurosurg. Psychiatry, 52, 838–841.
76.
GuskiewiczK.M., RossS.E., and MarshallS.W. (2001). Postural stability and neuropsychological deficits after concussion in collegiate athletes. J. Athl. Train., 36, 263–273.
77.
BoltonA.N., and SaatmanK.E. (2014). Regional neurodegeneration and gliosis are amplified by mild traumatic brain injury repeated at 24-hour intervals. J. Neuropathol. Exp. Neurol., 73, 933–947.
78.
CunninghamT.L., CartagenaC.M., LuX.C.M., KonopkoM., DaveJ.R., TortellaF.C., and ShearD.A. (2014). Correlations between blood–brain barrier disruption and neuroinflammation in an experimental model of penetrating ballistic-like brain injury. J. Neurotrauma, 31, 505–514.
79.
HollandM.A., TanA.A., SmithD.C., and HoaneM.R. (2008). Nicotinamide treatment provides acute neuroprotection and GFAP regulation following fluid percussion injury. J. Neurotrauma, 25, 140–152.
80.
Almeida–SuhettC.P., LiZ., MariniA.M., BragaM.F., and EidenL.E. (2014). Temporal course of changes in gene expression suggests a cytokine-related mechanism for long-term hippocampal alteration after controlled cortical impact. J. Neurotrauma, 31, 683–690.
81.
WoodcockT., and Morganti–KossmannM.C. (2013). The role of markers of inflammation in traumatic brain injury. Front. Neurol., 4, 18.
82.
ZetterbergH., SmithD.H., and BlennowK. (2013). Biomarkers of mild traumatic brain injury in cerebrospinal fluid and blood. Nat. Rev. Neurol., 9, 201–210.
83.
CsukaE., Morganti–KossmannM.C., LenzlingerP.M., JollerH., TrentzO., and KossmannT. (1999). IL-10 levels in cerebrospinal fluid and serum of patients with severe traumatic brain injury: relationship to IL-6, TNF-alpha, TGF-beta1 and blood-brain barrier function. J. Neuroimmunol., 101, 211–221.
84.
KossmannT., HansV.H.J., ImhofH.G., StockerR., GrobP., TrentzO., and MorgantikossmannM.C. (1995). Intrathecal and serum interleukin-6 and the acute-phase response in patients with severe traumatic brain injuries. Shock, 4, 311–317.
85.
SempleB.D., ByeN., RancanM., ZiebellJ.M., and Morganti–KossmannM.C. (2010). Role of CCL2 (MCP-1) in traumatic brain injury (TBI): evidence from severe TBI patients and CCL2-/- mice. J. Cereb. Blood Flow Metab., 30, 769–782.
86.
PhillipsD.J., NguyenP., AdamidesA.A., ByeN., RosenfeldJ.V., KossmannT., VallanceS., MurrayL., and Morganti–KossmannM.C. (2006). Activin a release into cerebrospinal fluid in a subset of patients with severe traumatic brain injury. J. Neurotrauma, 23, 1283–1294.
87.
MaierB., LehnertM., LaurerH.L., MautesA.E., SteudelW.I., and MarziI. (2006). Delayed elevation of soluble tumor necrosis factor receptors p75 and p55 in cerebrospinal fluid and plasma after traumatic brain injury. Shock, 26, 122–127.
88.
ShiozakiT., HayakataT., TasakiO., HosotuboH., FuijitaK., MouriT., TajimaG., KajinoK., NakaeH., TanakaH., ShimazuT., and SugimotoH. (2005). Cerebrospinal fluid concentrations of anti-inflammatory mediators in early-phase severe traumatic brain injury. Shock, 23, 406–410.
89.
SinghalA., BakerA.J., HareG.M., ReindersF.X., SchlichterL.C., and MoultonR.J. (2002). Association between cerebrospinal fluid interleukin-6 concentrations and outcome after severe human traumatic brain injury. J. Neurotrauma, 19, 929–937.
90.
HinsonH.E., RowellS., and SchreiberM. (2015). Clinical evidence of inflammation driving secondary brain injury: a systematic review. J. Trauma Acute Care Surg., 78, 184–191.
91.
YamagamiS., TamuraM., HayashiM., EndoN., TanabeH., KatsuuraY., and KomoriyaK. (1999). Differential production of MCP-1 and cytokine-induced neutrophil chemoattractant in the ischemic brain after transient focal ischemia in rats. J. Leukoc. Biol., 65, 744–749.
92.
KatayamaT., TanakaH., YoshidaT., UeharaT., and MinamiM. (2009). Neuronal injury induces cytokine-induced neutrophil chemoattractant-1 (CINC-1) production in astrocytes. J. Pharmacol. Sci., 109, 88–93.
93.
AhmedF., PlantmanS., CernakI., and AgostonD.V. (2015). The temporal pattern of changes in serum biomarker levels reveals complex and dynamically changing pathologies after exposure to a single low–intensity blast in mice. Front. Neurol., 6, 114.
94.
CampbellS.J., HughesP.M., IredaleJ.P., WilcocksonD.C., WatersS., DocagneF., PerryV.H., and AnthonyD.C. (2003). CINC-1 is an acute-phase protein induced by focal brain injury causing leukocyte mobilization and liver injury. FASEB J. 17, 1168–1170.
95.
ZhengK., LiC., ShanX., LiuH., FanW., WangZ., and ZhengP. (2013). Matrix metalloproteinases and their tissue inhibitors in serum and cerebrospinal fluid of patients with moderate and severe traumatic brain injury. Neurol. India, 61, 606–609.
96.
RiveraS., OgierC., JourquinJ., TimsitS., SzklarczykA.W., MillerK., GearingA.J., KaczmarekL., and KhrestchatiskyM. (2002). Gelatinase B and TIMP-1 are regulated in a cell- and time-dependent manner in association with neuronal death and glial reactivity after global forebrain ischemia. Eur. J. Neurosci., 15, 19–32.
97.
WattsR.P., ThomO., and FraserJ.F. (2013). Inflammatory signalling associated with brain dead organ donation: from brain injury to brain stem death and posttransplant ischaemia reperfusion injury. J. Transplantation 2013,521369.
98.
JeyaseelanK., LimK.Y., and ArmugamA. (2008). MicroRNA expression in the blood and brain of rats subjected to transient focal ischemia by middle cerebral artery occlusion. Stroke, 39, 959–966.
99.
DharapA., BowenK., PlaceR., LiL.C., and VemugantiR. (2009). Transient focal ischemia induces extensive temporal changes in rat cerebral microRNAome. J. Cereb. Blood Flow Metab., 29, 675–687.
100.
FreilichR.W., WoodburyM.E., and IkezuT. (2013). Integrated expression profiles of mRNA and miRNA in polarized primary murine microglia. PloS One, 8, e79416.
101.
PapaL., SilvestriS., BrophyG.M., GiordanoP., FalkJ.L., BragaC.F., TanC.N., AmeliN.J., DemeryJ.A., DixitN.K., MendesM.E., HayesR.L., WangK.K., and RobertsonC.S. (2014). GFAP out-performs S100beta in detecting traumatic intracranial lesions on computed tomography in trauma patients with mild traumatic brain injury and those with extracranial lesions. J. Neurotrauma, 31, 1815–1822.
102.
PapaL., BrophyG.M., WelchR.D., LewisL.M., BragaC.F., TanC.N., AmeliN.J., LopezM.A., HaeusslerC.A., Mendez GiordanoD.I., SilvestriS., GiordanoP., WeberK.D., Hill–PryorC., and HackD.C. (2016). Time course and diagnostic accuracy of glial and neuronal blood biomarkers GFAP and UCH-L1 in a large cohort of trauma patients with and without mild traumatic brain injury. JAMA Neurol. 73, 551–560.
103.
PapaL., LewisL.M., FalkJ.L., ZhangZ., SilvestriS., GiordanoP., BrophyG.M., DemeryJ.A., DixitN.K., FergusonI., LiuM.C., MoJ., AkinyiL., SchmidK., MondelloS., RobertsonC.S., TortellaF.C., HayesR.L., and WangK.K. (2012). Elevated levels of serum glial fibrillary acidic protein breakdown products in mild and moderate traumatic brain injury are associated with intracranial lesions and neurosurgical intervention. Ann. Emerg. Med., 59, 471–483.
104.
RubensteinR., ChangB., DaviesP., WagnerA.K., RobertsonC.S., and WangK.K. (2015). A novel, ultrasensitive assay for tau: potential for assessing traumatic brain injury in tissues and biofluids. J. Neurotrauma, 32, 342–352.
105.
ZemlanF.P., JauchE.C., MulchaheyJ.J., GabbitaS.P., RosenbergW.S., SpecialeS.G., and ZuccarelloM. (2002). C-tau biomarker of neuronal damage in severe brain injured patients: association with elevated intracranial pressure and clinical outcome. Brain Res. 947, 131–139.
106.
NeseliusS., ZetterbergH., BlennowK., MarcussonJ., and BrisbyH. (2013). Increased CSF levels of phosphorylated neurofilament heavy protein following bout in amateur boxers. PloS one, 8, e81249.
107.
ShahimP., TegnerY., WilsonD.H., RandallJ., SkillbackT., PazookiD., KallbergB., BlennowK., and ZetterbergH. (2014). Blood biomarkers for brain injury in concussed professional ice hockey players. JAMA Neurol. 71, 684–692.
108.
GaoH., HanZ., BaiR., HuangS., GeX., ChenF., and LeiP. (2016). The accumulation of brain injury leads to severe neuropathological and neurobehavioral changes after repetitive mild traumatic brain injury. Brain Res. 1657, 1–8.
109.
KwonB.K., StammersA.M., BelangerL.M., BernardoA., ChanD., BishopC.M., SlobogeanG.P., ZhangH., UmedalyH., GiffinM., StreetJ., BoydM.C., PaquetteS.J., FisherC.G., and DvorakM.F. (2010). Cerebrospinal fluid inflammatory cytokines and biomarkers of injury severity in acute human spinal cord injury. J. Neurotrauma, 27, 669–682.
110.
TsaiM.C., WeiC.P., LeeD.Y., TsengY.T., TsaiM.D., ShihY.L., LeeY.H., ChangS.F., and LeuS.J. (2008). Inflammatory mediators of cerebrospinal fluid from patients with spinal cord injury. Surg. Neurol., 70, Suppl. 1, S1:19–24.
111.
LorenzlS., AlbersD.S., LeWittP.A., ChirichignoJ.W., HilgenbergS.L., CudkowiczM.E., and BealM.F. (2003). Tissue inhibitors of matrix metalloproteinases are elevated in cerebrospinal fluid of neurodegenerative diseases. J. Neurol. Sci., 207, 71–76.
112.
LeeM.A., PalaceJ., StablerG., FordJ., GearingA., and MillerK. (1999). Serum gelatinase B, TIMP-1 and TIMP-2 levels in multiple sclerosis. A longitudinal clinical and MRI study. Brain, 122 ( Pt 2), 191–197.
113.
JohnsonD., BoutteA., SchnudK., ShearD.A., DaveI., TortellaF., CartagenaC. (2015). Investigation of putative acute serum diagnotic biomarkers in a projectile concussive impact injury. Abstracts from The 33rd Annual National Neurotrauma Symposium June 28–July 1, 2015 Santa Fe, New Mexico. J. Neurotrauma, 32, A5–A19.
114.
MadathilS.K., NelsonP.T., SaatmanK.E., and WilfredB.R. (2011). MicroRNAs in CNS injury: potential roles and therapeutic implications. BioEssays, 33, 21–26.
115.
JiaL., HaoF., WangW., and QuY. (2015). Circulating miR-145 is associated with plasma high-sensitivity C-reactive protein in acute ischemic stroke patients. Cell Biochem. Funct., 33, 314–319.
116.
TanL., YuJ.T., TanM.S., LiuQ.Y., WangH.F., ZhangW., JiangT., and TanL. (2014). Genome-wide serum microRNA expression profiling identifies serum biomarkers for Alzheimer's disease. J. Alzheimers Dis., 40, 1017–1027.
LuX.C., HartingsJ.A., SiY., BalbirA., CaoY., and TortellaF.C. (2011). Electrocortical pathology in a rat model of penetrating ballistic-like brain injury. J. Neurotrauma, 28, 71–83.
119.
TebanoM.T., CameroniM., GallozziG., LoizzoA., PalazzinoG., PezziniG., and RicciG.F. (1988). EEG spectral analysis after minor head injury in man. Electroencephalogr. Clin. Neurophysiol., 70, 185–189.
120.
NuwerM.R., HovdaD.A., SchraderL.M., and VespaP.M. (2005). Routine and quantitative EEG in mild traumatic brain injury. Clin. Neurophysiol., 116, 2001–2025.
121.
GosselinN., LassondeM., PetitD., LeclercS., MongrainV., CollieA., and MontplaisirJ. (2009). Sleep following sport-related concussions. Sleep Med. 10, 35–46.
122.
DunkleyB.T., DaCosta, L., BethuneA., JetlyR., PangE.W., TaylorM.J., and DoesburgS.M. (2015). Low-frequency connectivity is associated with mild traumatic brain injury. NeuroImage Clin. 7, 611–621.
123.
ThompsonJ., SebastianelliW., and SlobounovS. (2005). EEG and postural correlates of mild traumatic brain injury in athletes. Neurosci. Lett., 377, 158–163.
124.
ModarresM., KuzmaN.N., KretzmerT., PackA.I., and LimM.M. (2016). EEG slow waves in traumatic brain injury: convergent findings in mouse and man. Neurobiol. Sleep Circadian Rhythms, 1, pii: S2451994416300025.
125.
ThatcherR.W., BiverC., McAlasterR. and SalazarA. (1998). Biophysical linkage between MRI and EEG coherence in closed head injury. NeuroImage, 8, 307–326.
126.
VyazovskiyV.V., OlceseU., HanlonE.C., NirY., CirelliC., and TononiG. (2011). Local sleep in awake rats. Nature, 472, 443–447.
127.
TononiG., and CirelliC. (2006). Sleep function and synaptic homeostasis. Sleep Med. Rev., 10, 49–62.
128.
McCreaM., GuskiewiczK.M., MarshallS.W., BarrW., RandolphC., CantuR.C., OnateJ.A., YangJ., and KellyJ.P. (2003). Acute effects and recovery time following concussion in collegiate football players: the NCAA Concussion Study. JAMA, 290, 2556–2563.
129.
WillerB., and LeddyJ.J. (2006). Management of concussion and post-concussion syndrome. Curr. Treat Options Neurol., 8, 415–426.
130.
LeddyJ.J., BakerJ.G., KozlowskiK., BissonL., and WillerB. (2011). Reliability of a graded exercise test for assessing recovery from concussion. Clin. J. Sport Med., 21, 89–94.
131.
KozlowskiK.F., GrahamJ., LeddyJ.J., Devinney–BoymelL., and WillerB.S. (2013). Exercise intolerance in individuals with postconcussion syndrome. J. Athl. Train., 48, 627–635.
132.
MannixR., BerglassJ., BerknerJ., MoleusP., QiuJ., AndrewsN., GunnerG., BerglassL., JantzieL.L., RobinsonS., and MeehanW.P.3rd (2014). Chronic gliosis and behavioral deficits in mice following repetitive mild traumatic brain injury. J. Neurosurg., 121, 1342–1350.
133.
McKeeA.C., CantuR.C., NowinskiC.J., Hedley–WhyteE.T., GavettB.E., BudsonA.E., SantiniV.E., LeeH.S., KubilusC.A., and SternR.A. (2009). Chronic traumatic encephalopathy in athletes: progressive tauopathy after repetitive head injury. J. Neuropathol. Exp. Neurol., 68, 709–735.
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