Comprehensive Physiology Wiley Online Library

Role of Microvascular Disruption in Brain Damage from Traumatic Brain Injury

Full Article on Wiley Online Library



ABSTRACT

Traumatic brain injury (TBI) is acquired from an external force, which can inflict devastating effects to the brain vasculature and neighboring neuronal cells. Disruption of vasculature is a primary effect that can lead to a host of secondary injury cascades. The primary effects of TBI are rapidly occurring while secondary effects can be activated at later time points and may be more amenable to targeting. Primary effects of TBI include diffuse axonal shearing, changes in blood‐brain barrier (BBB) permeability, and brain contusions. These mechanical events, especially changes to the BBB, can induce calcium perturbations within brain cells producing secondary effects, which include cellular stress, inflammation, and apoptosis. These secondary effects can be potentially targeted to preserve the tissue surviving the initial impact of TBI. In the past, TBI research had focused on neurons without any regard for glial cells and the cerebrovasculature. Now a greater emphasis is being placed on the vasculature and the neurovascular unit following TBI. A paradigm shift in the importance of the vascular response to injury has opened new avenues of drug‐treatment strategies for TBI. However, a connection between the vascular response to TBI and the development of chronic disease has yet to be elucidated. Long‐term cognitive deficits are common amongst those sustaining severe or multiple mild TBIs. Understanding the mechanisms of cellular responses following TBI is important to prevent the development of neuropsychiatric symptoms. With appropriate intervention following TBI, the vascular network can perhaps be maintained and the cellular repair process possibly improved to aid in the recovery of cellular homeostasis. © 2015 American Physiological Society. Compr Physiol 5:1147‐1160, 2015.

Comprehensive Physiology offers downloadable PowerPoint presentations of figures for non-profit, educational use, provided the content is not modified and full credit is given to the author and publication.

Download a PowerPoint presentation of all images


Figure 1. Figure 1. Pathophysiology of neuronal cell death following traumatic brain injury. An intracranial pressure spike, axonal shearing, and brain contusion contribute to secondary mechanisms that lead to an increase in Ca2+ channel opening. The generation of reactive oxygen species can ultimately contribute to cell death.
Figure 2. Figure 2. Depiction of a vasospasm resulting from traumatic brain injury. Vasospasm can be triggered by subarachnoid hemorrhage or blood pressure spikes. Pericytes near vessels release endothelin‐1, which triggers vasoconstriction.
Figure 3. Figure 3. The effects of traumatic brain injury on the blood‐brain barrier. TBI can cause disruptions of tight junction proteins connecting endothelial cells. Astrocytes can undergo astrogliosis and the basement membrane can become disrupted. Ultimately, these changes increase the likelihood of red blood cell extravasations.
Figure 4. Figure 4. Complex interplay of secondary mechanisms following traumatic brain injury. Secondary mechanisms of injury have multiple known effects. A few included are cellular necrosis, apoptosis, neurodegeneration, and tauopathy. Timing of activation and pathway connections are still being teased out with preclinical models of TBI.
Figure 5. Figure 5. The chronic effects of traumatic brain injury. Some individuals experiencing TBI are more susceptible to chronic effects than others. Environmental and genetic factors play a role. Pathologic changes that may develop include neurofibrillary tangles, axonal shearing, and amyloid plaques. Neuropsychiatric symptoms may also develop such as depression, impulsivity, cognitive decline, and confusion. These chronic effects following TBI remains a topic of growing importance receiving renewed research focus and funding.


Figure 1. Pathophysiology of neuronal cell death following traumatic brain injury. An intracranial pressure spike, axonal shearing, and brain contusion contribute to secondary mechanisms that lead to an increase in Ca2+ channel opening. The generation of reactive oxygen species can ultimately contribute to cell death.


Figure 2. Depiction of a vasospasm resulting from traumatic brain injury. Vasospasm can be triggered by subarachnoid hemorrhage or blood pressure spikes. Pericytes near vessels release endothelin‐1, which triggers vasoconstriction.


Figure 3. The effects of traumatic brain injury on the blood‐brain barrier. TBI can cause disruptions of tight junction proteins connecting endothelial cells. Astrocytes can undergo astrogliosis and the basement membrane can become disrupted. Ultimately, these changes increase the likelihood of red blood cell extravasations.


Figure 4. Complex interplay of secondary mechanisms following traumatic brain injury. Secondary mechanisms of injury have multiple known effects. A few included are cellular necrosis, apoptosis, neurodegeneration, and tauopathy. Timing of activation and pathway connections are still being teased out with preclinical models of TBI.


Figure 5. The chronic effects of traumatic brain injury. Some individuals experiencing TBI are more susceptible to chronic effects than others. Environmental and genetic factors play a role. Pathologic changes that may develop include neurofibrillary tangles, axonal shearing, and amyloid plaques. Neuropsychiatric symptoms may also develop such as depression, impulsivity, cognitive decline, and confusion. These chronic effects following TBI remains a topic of growing importance receiving renewed research focus and funding.
References
 1.Abdul‐Muneer PM, Chandra N, Haorah J. Interactions of oxidative stress and neurovascular inflammation in the pathogenesis of traumatic brain injury. Mol Neurobiol, 2014 [Epub ahead of print].
 2.Abdul‐Muneer PM, Schuetz H, Wang F, Skotak M, Jones J, Gorantla S, Zimmerman MC, Chandra N, Haorah J. Induction of oxidative and nitrosative damage leads to cerebrovascular inflammation in an animal model of mild traumatic brain injury induced by primary blast. Free Radic Biol Med 60: 282‐291, 2013.
 3.Adalbert R, Nogradi A, Babetto E, Janeckova L, Walker SA, Kerschensteiner M, Misgeld T, Coleman MP. Severely dystrophic axons at amyloid plaques remain continuous and connected to viable cell bodies. Brain 132: 402‐416, 2009.
 4.Adibhatla RM, Hatcher JF. Lipid oxidation and peroxidation in CNS health and disease: From molecular mechanisms to therapeutic opportunities. Antioxid Redox Signal 12: 125‐169, 2010.
 5.Albert‐Weissenberger C, Siren AL. Experimental traumatic brain injury. Exp Transl Stroke Med 2: 16, 2010.
 6.Alford PW, Dabiri BE, Goss JA, Hemphill MA, Brigham MD, Parker KK. Blast‐induced phenotypic switching in cerebral vasospasm. Proc Nat Acad Sci U S A 108: 12705‐12710, 2011.
 7.Alves JL. Blood‐brain barrier and traumatic brain injury. J Neurosci Res 92: 141‐147, 2014.
 8.Amantini A, Carrai R, Lori S, Peris A, Amadori A, Pinto F, Grippo A. Neurophysiological monitoring in adult and pediatric intensive care. Minerva Anestesiol 78: 1067‐1075, 2012.
 9.Angoa‐Perez M, Kane MJ, Briggs DI, Herrera‐Mundo N, Viano DC, Kuhn DM. Animal models of sports‐related head injury: Bridging the gap between pre‐clinical research and clinical reality. J Neurochem 129: 916‐931, 2014.
 10.Arun P, Abu‐Taleb R, Oguntayo S, Tanaka M, Wang Y, Valiyaveettil M, Long JB, Zhang Y, Nambiar MP. Distinct patterns of expression of traumatic brain injury biomarkers after blast exposure: Role of compromised cell membrane integrity. Neurosci Lett 552: 87‐91, 2013.
 11.Asakuno K, Ishida A. Intraarterial vasodilator therapy immediately rescued pure cortical deafness due to bilateral cerebral vasospasm. Surg Neurol Int 5: 61, 2014.
 12.Asl SZ, Khaksari M, Khachki AS, Shahrokhi N, Nourizade S. Contribution of estrogen receptors alpha and beta in the brain response to traumatic brain injury. J Neurosurg 119: 353‐361, 2013.
 13.Baalman KL, Cotton RJ, Rasband SN, Rasband MN. Blast wave exposure impairs memory and decreases axon initial segment length. J Neurotrauma 30: 741‐751, 2013.
 14.Badaut J, Bix GJ. Vascular neural network phenotypic transformation after traumatic injury: Potential role in long‐term sequelae. Transl Stroke Res 5: 394‐406, 2014.
 15.Bailes JE, Petraglia AL, Omalu BI, Nauman E, Talavage T. Role of subconcussion in repetitive mild traumatic brain injury. J Neurosurg 119: 1235‐1245, 2013.
 16.Balestreri M, Czosnyka M, Chatfield DA, Steiner LA, Schmidt EA, Smielewski P, Matta B, Pickard JD. Predictive value of Glasgow Coma Scale after brain trauma: Change in trend over the past ten years. J Neurol Neurosurg Psychiatry 75: 161‐162, 2004.
 17.Bauer AM, Rasmussen PA. Treatment of intracranial vasospasm following subarachnoid hemorrhage. Front Neurol 5: 72, 2014.
 18.Begum G, Harvey L, Dixon CE, Sun D. ER stress and effects of DHA as an ER stress inhibitor. Transl Stroke Res 4: 635‐642, 2013.
 19.Begum G, Yan HQ, Li L, Singh A, Dixon CE, Sun D. Docosahexaenoic acid reduces ER stress and abnormal protein accumulation and improves neuronal function following traumatic brain injury. J Neurosci 34: 3743‐3755, 2014.
 20.Bernales S, McDonald KL, Walter P. Autophagy counterbalances endoplasmic reticulum expansion during the unfolded protein response. PLoS Biol 4: e423, 2006.
 21.Biancardi VC, Son SJ, Ahmadi S, Filosa JA, Stern JE. Circulating angiotensin II gains access to the hypothalamus and brain stem during hypertension via breakdown of the blood‐brain barrier. Hypertension 63: 572‐579, 2014.
 22.Bor‐Seng‐Shu E, Figueiredo EG, Fonoff ET, Fujimoto Y, Panerai RB, Teixeira MJ. Decompressive craniectomy and head injury: Brain morphometry, ICP, cerebral hemodynamics, cerebral microvascular reactivity, and neurochemistry. Neurosurg Rev 36: 361‐370, 2013.
 23.Brandner S, Kellermann I, Hore N, Bozhkov Y, Buchfelder M. Clinical Course Score (CCS): A new clinical score to evaluate efficacy of neurotrauma treatment in traumatic brain injury and subarachnoid hemorrhage. J Neurosurg Anesthesiol 27: 26‐30, 2014.
 24.Bruns J, Jr., Hauser WA. The epidemiology of traumatic brain injury: A review. Epilepsia 44(Suppl 10): 2‐10, 2003.
 25.Bukovics P, Czeiter E, Amrein K, Kovacs N, Pal J, Tamas A, Bagoly T, Helyes Z, Buki A, Reglodi D. Changes of PACAP level in cerebrospinal fluid and plasma of patients with severe traumatic brain injury. Peptides 60: 18‐22, 2014.
 26.Bullock R, Zauner A, Woodward JJ, Myseros J, Choi SC, Ward JD, Marmarou A, Young HF. Factors affecting excitatory amino acid release following severe human head injury. J Neurosurg 89: 507‐518, 1998.
 27.Cernak I, Noble‐Haeusslein LJ. Traumatic brain injury: An overview of pathobiology with emphasis on military populations. J Cereb Blood Flow Metab 30: 255‐266, 2010.
 28.Chalouhi N, Whiting A, Anderson EC, Witte S, Zanaty M, Tjoumakaris S, Gonzalez LF, Hasan D, Starke RM, Hann S, Ghobrial GM, Rosenwasser R, Jabbour P. Comparison of techniques for ventriculoperitoneal shunting in 523 patients with subarachnoid hemorrhage. J Neurosurg 121: 904‐907, 2014.
 29.Chen B, Mutschler M, Yuan Y, Neugebauer E, Huang Q, Maegele M. Superimposed traumatic brain injury modulates vasomotor responses in third‐order vessels after hemorrhagic shock. Scand J Trauma Resusc Emerg Med 21: 77, 2013.
 30.Cho HJ, Sajja VS, Vandevord PJ, Lee YW. Blast induces oxidative stress, inflammation, neuronal loss and subsequent short‐term memory impairment in rats. Neuroscience 253: 9‐20, 2013.
 31.Clark RS, Chen J, Watkins SC, Kochanek PM, Chen M, Stetler RA, Loeffert JE, Graham SH. Apoptosis‐suppressor gene bcl‐2 expression after traumatic brain injury in rats. J Neurosci 17: 9172‐9182, 1997.
 32.Clark RS, Kochanek PM, Watkins SC, Chen M, Dixon CE, Seidberg NA, Melick J, Loeffert JE, Nathaniel PD, Jin KL, Graham SH. Caspase‐3 mediated neuronal death after traumatic brain injury in rats. J Neurochem 74: 740‐753, 2000.
 33.Covey DC, Born CT. Blast injuries: Mechanics and wounding patterns. J Surg Orthop Adv 19: 8‐12, 2010.
 34.Creed JA, DiLeonardi AM, Fox DP, Tessler AR, Raghupathi R. Concussive brain trauma in the mouse results in acute cognitive deficits and sustained impairment of axonal function. J Neurotrauma 28: 547‐563, 2011.
 35.Cui T, Zhu G. Ulinastatin attenuates brain edema after traumatic brain injury in rats. Cell Biochem Biophys, 2014 [Epub ahead of print].
 36.Cullen DK, Vernekar VN, LaPlaca MC. Trauma‐induced plasmalemma disruptions in three‐dimensional neural cultures are dependent on strain modality and rate. J Neurotrauma 28: 2219‐2233, 2011.
 37.Cullen NK, Crescini C, Bayley MT. Rehabilitation outcomes after anoxic brain injury: A case‐controlled comparison with traumatic brain injury. PM R 1: 1069‐1076, 2009.
 38.Dagher JH, Habra N, Lamoureux J, De Guise E, Feyz M. Global outcome in acute phase of treatment following moderate‐to‐severe traumatic brain injury from motor vehicle collisions vs assaults. Brain Inj 24: 1389‐1398, 2010.
 39.Dapul HR, Park J, Zhang J, Lee C, DanEshmand A, Lok J, Ayata C, Gray T, Scalzo A, Qiu J, Lo EH, Whalen MJ. Concussive injury before or after controlled cortical impact exacerbates histopathology and functional outcome in a mixed traumatic brain injury model in mice. J Neurotrauma 30: 382‐391, 2013.
 40.Deniaud A, Sharaf el dein O, Maillier E, Poncet D, Kroemer G, Lemaire C, Brenner C. Endoplasmic reticulum stress induces calcium‐dependent permeability transition, mitochondrial outer membrane permeabilization and apoptosis. Oncogene 27: 285‐299, 2008.
 41.Dennis AM, Haselkorn ML, Vagni VA, Garman RH, Janesko‐Feldman K, Bayir H, Clark RS, Jenkins LW, Dixon CE, Kochanek PM. Hemorrhagic shock after experimental traumatic brain injury in mice: Effect on neuronal death. J Neurotrauma 26: 889‐899, 2009.
 42.Depreitere B, Guiza F, Van den Berghe G, Schuhmann MU, Maier G, Piper I, Meyfroidt G. Pressure autoregulation monitoring and cerebral perfusion pressure target recommendation in patients with severe traumatic brain injury based on minute‐by‐minute monitoring data. J Neurosurg 120: 1451‐1457, 2014.
 43.DeWitt DS, Prough DS. Blast‐induced brain injury and posttraumatic hypotension and hypoxemia. J Neurotrauma 26: 877‐887, 2009.
 44.DiLeonardi AM, Huh JW, Raghupathi R. Impaired axonal transport and neurofilament compaction occur in separate populations of injured axons following diffuse brain injury in the immature rat. Brain Res 1263: 174‐182, 2009.
 45.Dileonardi AM, Huh JW, Raghupathi R. Differential effects of FK506 on structural and functional axonal deficits after diffuse brain injury in the immature rat. J Neuropathol Exp Neurol 71: 959‐972, 2012.
 46.Dore‐Duffy P, Wang S, Mehedi A, Katyshev V, Cleary K, Tapper A, Reynolds C, Ding Y, Zhan P, Rafols J, Kreipke CW. Pericyte‐mediated vasoconstriction underlies TBI‐induced hypoperfusion. Neurol Res 33: 176‐186, 2011.
 47.Engel DC, Mies G, Terpolilli NA, Trabold R, Loch A, De Zeeuw CI, Weber JT, Maas AI, Plesnila N. Changes of cerebral blood flow during the secondary expansion of a cortical contusion assessed by 14C‐iodoantipyrine autoradiography in mice using a non‐invasive protocol. J Neurotrauma 25: 739‐753, 2008.
 48.Ewing‐Cobbs L, Prasad M, Kramer L, Louis PT, Baumgartner J, Fletcher JM, Alpert B. Acute neuroradiologic findings in young children with inflicted or noninflicted traumatic brain injury. Child Nerv Syst 16: 25‐33; discussion 34, 2000.
 49.Faden AI, Demediuk P, Panter SS, Vink R. The role of excitatory amino acids and NMDA receptors in traumatic brain injury. Science 244: 798‐800, 1989.
 50.Farook JM, Shields J, Tawfik A, Markand S, Sen T, Smith SB, Brann D, Dhandapani KM, Sen N. GADD34 induces cell death through inactivation of Akt following traumatic brain injury. Cell Death Dis 4: e754, 2013.
 51.Faust K, Horn P, Schneider UC, Vajkoczy P. Blood pressure changes after aneurysmal subarachnoid hemorrhage and their relationship to cerebral vasospasm and clinical outcome. Clin Neurol Neurosurg 125C: 36‐40, 2014.
 52.Foreman BP, Caesar RR, Parks J, Madden C, Gentilello LM, Shafi S, Carlile MC, Harper CR, Diaz‐Arrastia RR. Usefulness of the abbreviated injury score and the injury severity score in comparison to the Glasgow Coma Scale in predicting outcome after traumatic brain injury. J Trauma 62: 946‐950, 2007.
 53.Foster KA, Recker MJ, Lee PS, Bell MJ, Tyler‐Kabara EC. Factors associated with hemispheric hypodensity after subdural hematoma following abusive head trauma in children. J Neurotrauma 31: 1625‐1631, 2014.
 54.Fujita M, Wei EP, Povlishock JT. Effects of hypothermia on cerebral autoregulatory vascular responses in two rodent models of traumatic brain injury. J Neurotrauma 29: 1491‐1498, 2012.
 55.Glushakova OY, Johnson D, Hayes RL. Delayed increases in microvascular pathology after experimental traumatic brain injury are associated with prolonged inflammation, blood‐brain barrier disruption, and progressive white matter damage. J Neurotrauma 31: 1180‐1193, 2014.
 56.Goldstein LE, Fisher AM, Tagge CA, Zhang XL, Velisek L, Sullivan JA, Upreti C, Kracht JM, Ericsson M, Wojnarowicz MW, Goletiani CJ, Maglakelidze GM, Casey N, Moncaster JA, Minaeva O, Moir RD, Nowinski CJ, Stern RA, Cantu RC, Geiling J, Blusztajn JK, Wolozin BL, Ikezu T, Stein TD, Budson AE, Kowall NW, Chargin D, Sharon A, Saman S, Hall GF, Moss WC, Cleveland RO, Tanzi RE, Stanton PK, McKee AC. Chronic traumatic encephalopathy in blast‐exposed military veterans and a blast neurotrauma mouse model. Sci Transl Med 4: 134ra160, 2012.
 57.Greer JE, Hanell A, McGinn MJ, Povlishock JT. Mild traumatic brain injury in the mouse induces axotomy primarily within the axon initial segment. Acta Neuropathol 126: 59‐74, 2013.
 58.Gurkoff G, Shahlaie K, Lyeth B, Berman R. Voltage‐gated calcium channel antagonists and traumatic brain injury. Pharmaceuticals 6: 788‐812, 2013.
 59.Guskiewicz KM, McCrea M, Marshall SW, Cantu RC, Randolph C, Barr W, Onate JA, Kelly JP. Cumulative effects associated with recurrent concussion in collegiate football players: The NCAA Concussion Study. JAMA 290: 2549‐2555, 2003.
 60.Hamm RJ, Dixon CE, Gbadebo DM, Singha AK, Jenkins LW, Lyeth BG, Hayes RL. Cognitive deficits following traumatic brain injury produced by controlled cortical impact. J Neurotrauma 9: 11‐20, 1992.
 61.Harmon KG, Drezner J, Gammons M, Guskiewicz K, Halstead M, Herring S, Kutcher J, Pana A, Putukian M, Roberts W, American Medical Society for Sports M. American Medical Society for Sports Medicine position statement: Concussion in sport. Clin J Sport Med 23: 1‐18, 2013.
 62.Hartmann DA, Underly RG, Watson AN, Shih AY. A murine toolbox for imaging the neurovascular unit. Microcirculation, 2014 [Epub ahead of print].
 63.Helmy A, Carpenter KL, Menon DK, Pickard JD, Hutchinson PJ. The cytokine response to human traumatic brain injury: Temporal profiles and evidence for cerebral parenchymal production. J Cereb Blood Flow Metab 31: 658‐670, 2011.
 64.Helmy A, De Simoni MG, Guilfoyle MR, Carpenter KL, Hutchinson PJ. Cytokines and innate inflammation in the pathogenesis of human traumatic brain injury. Prog Neurobiol 95: 352‐372, 2011.
 65.Hillered L, Vespa PM, Hovda DA. Translational neurochemical research in acute human brain injury: The current status and potential future for cerebral microdialysis. J Neurotrauma 22: 3‐41, 2005.
 66.Ho KM, Honeybul S, Yip CB, Silbert BI. Prognostic significance of blood‐brain barrier disruption in patients with severe nonpenetrating traumatic brain injury requiring decompressive craniectomy. J Neurosurg 121: 674‐679, 2014.
 67.Hochstadter E, Stewart TC, Alharfi IM, Ranger A, Fraser DD. Subarachnoid hemorrhage prevalence and its association with short‐term outcome in pediatric severe traumatic brain injury. Neurocrit Care 21: 505‐513, 2014.
 68.Hoozemans JJ, van Haastert ES, Eikelenboom P, de Vos RA, Rozemuller JM, Scheper W. Activation of the unfolded protein response in Parkinson's disease. Biochem Biophys Res Commun 354: 707‐711, 2007.
 69.Huh JW, Franklin MA, Widing AG, Raghupathi R. Regionally distinct patterns of calpain activation and traumatic axonal injury following contusive brain injury in immature rats. Dev Neurosci 28: 466‐476, 2006.
 70.Huh JW, Widing AG, Raghupathi R. Midline brain injury in the immature rat induces sustained cognitive deficits, bihemispheric axonal injury and neurodegeneration. Exp Neurol 213: 84‐92, 2008.
 71.Inglese M, Bomsztyk E, Gonen O, Mannon LJ, Grossman RI, Rusinek H. Dilated perivascular spaces: Hallmarks of mild traumatic brain injury. AJNR Am J Neuroradiol 26: 719‐724, 2005.
 72.Izzy S, Muehlschlegel S. Cerebral vasospasm after aneurysmal subarachnoid hemorrhage and traumatic brain injury. Current Treat Options Neurol 16: 278, 2014.
 73.Jalloh I, Carpenter KL, Grice P, Howe DJ, Mason A, Gallagher CN, Helmy A, Murphy MP, Menon DK, Carpenter TA, Pickard JD, Hutchinson PJ. Glycolysis and the pentose phosphate pathway after human traumatic brain injury: Microdialysis studies using 1,2‐C glucose. J Cereb Blood Flow Metab 35: 111‐120, 2015.
 74.Ji X, Tian Y, Xie K, Liu W, Qu Y, Fei Z. Protective effects of hydrogen‐rich saline in a rat model of traumatic brain injury via reducing oxidative stress. J Surg Res 178: e9‐e16, 2012.
 75.Jiang JY, Lyeth BG, Kapasi MZ, Jenkins LW, Povlishock JT. Moderate hypothermia reduces blood‐brain barrier disruption following traumatic brain injury in the rat. Acta Neuropathol 84: 495‐500, 1992.
 76.Jilka SR, Scott G, Ham T, Pickering A, Bonnelle V, Braga RM, Leech R, Sharp DJ. Damage to the salience network and interactions with the default mode network. J Neurosci 34: 10798‐10807, 2014.
 77.Johnson VE, Stewart W, Smith DH. Axonal pathology in traumatic brain injury. Exp Neurol 246: 35‐43, 2013.
 78.Kabadi SV, Faden AI. Neuroprotective strategies for traumatic brain injury: Improving clinical translation. Int J Mol Sci 15: 1216‐1236, 2014.
 79.Katayama Y, Becker DP, Tamura T, Hovda DA. Massive increases in extracellular potassium and the indiscriminate release of glutamate following concussive brain injury. J Neurosurg 73: 889‐900, 1990.
 80.Kay A, Teasdale G. Head injury in the United Kingdom. World J Surg 25: 1210‐1220, 2001.
 81.Kelman C, Reavey‐Cantwell J. Endovascular management of cerebral vasospasm. Neurosurg Focus 37: 1, 2014.
 82.Kim H, Kim GD, Yoon BC, Kim K, Kim BJ, Choi Y, Czosnyka M, Oh BM, Kim DJ. Quantitative analysis of computed tomography images and early detection of cerebral edema for pediatric traumatic brain injury patients: Retrospective study. BMC Med 12: 186, 2014.
 83.Kochanek PM, Bramlett H, Dietrich WD, Dixon CE, Hayes RL, Povlishock J, Tortella FC, Wang KK. A novel multicenter preclinical drug screening and biomarker consortium for experimental traumatic brain injury: Operation brain trauma therapy. J Trauma 71: S15‐S24, 2011.
 84.Koponen S, Taiminen T, Portin R, Himanen L, Isoniemi H, Heinonen H, Hinkka S, Tenovuo O. Axis I and II psychiatric disorders after traumatic brain injury: A 30‐year follow‐up study. Am J Psychiatry 159: 1315‐1321, 2002.
 85.Korczyn AD. Why have we failed to cure Alzheimer's disease? J Alzheimer Dis 29: 275‐282, 2012.
 86.Kramer AH, Le Roux P. Red blood cell transfusion and transfusion alternatives in traumatic brain injury. Current Treat Options Neurol, 2012 [Epub ahead of print].
 87.Kramer DR, Winer JL, Pease BA, Amar AP, Mack WJ. Cerebral vasospasm in traumatic brain injury. Neurol Res Int 2013: 415813, 2013.
 88.Larner SF, Hayes RL, McKinsey DM, Pike BR, Wang KK. Increased expression and processing of caspase‐12 after traumatic brain injury in rats. J Neurochem 88: 78‐90, 2004.
 89.Larner SF, Hayes RL, Wang KK. Unfolded protein response after neurotrauma. J Neurotrauma 23: 807‐829, 2006.
 90.Lazaridis C, Czosnyka M. Cerebral blood flow, brain tissue oxygen, and metabolic effects of decompressive craniectomy. Neurocrit Care 16: 478‐484, 2012.
 91.Le Heron CJ, Wright SL, Melzer TR, Myall DJ, MacAskill MR, Livingston L, Keenan RJ, Watts R, Dalrymple‐Alford JC, Anderson TJ. Comparing cerebral perfusion in Alzheimer's disease and Parkinson's disease dementia: An ASL‐MRI study. J Cereb Blood Flow Metab 34: 964‐970, 2014.
 92.Lee HC, Chuang HC, Cho DY, Cheng KF, Lin PH, Chen CC. Applying cerebral hypothermia and brain oxygen monitoring in treating severe traumatic brain injury. World Neurosurg 74: 654‐660, 2010.
 93.Levy AS, Orlando A, Salottolo K, Mains CW, Bar‐Or D. Outcomes of a nontransfer protocol for mild traumatic brain injury with abnormal head computed tomography in a rural hospital setting. World Neurosurg 82: e319‐e323, 2014.
 94.Li S, Sun Y, Shan D, Feng B, Xing J, Duan Y, Dai J, Lei H, Zhou Y. Temporal profiles of axonal injury following impact acceleration traumatic brain injury in rats–a comparative study with diffusion tensor imaging and morphological analysis. Int J Legal Med 127: 159‐167, 2013.
 95.Li S, Yang L, Selzer ME, Hu Y. Neuronal endoplasmic reticulum stress in axon injury and neurodegeneration. Ann Neurol 74: 768‐777, 2013.
 96.Liao GP, Olson SD, Kota DJ, Hetz RA, Smith P, Bedi S, Cox CS, Jr. Far‐red tracer analysis of traumatic cerebrovascular permeability. J Surg Res 190: 628‐633, 2014.
 97.Ling G, Bandak F, Armonda R, Grant G, Ecklund J. Explosive blast neurotrauma. J Neurotrauma 26: 815‐825, 2009.
 98.Liu HD, Li W, Chen ZR, Zhou ML, Zhuang Z, Zhang DD, Zhu L, Hang CH. Increased expression of ferritin in cerebral cortex after human traumatic brain injury. Neurol Sci 34: 1173‐1180, 2013.
 99.Liu S, Yin F, Zhang J, Qian Y. The role of calpains in traumatic brain injury. Brain Inj 28: 133‐137, 2014.
 100.Liu Y, Liu Z, Li X, Luo B, Xiong J, Gan W, Jiang M, Zhang Z, Schluesener HJ, Zhang Z. Accumulation of connective tissue growth factor+ cells during the early phase of rat traumatic brain injury. Diagn Pathol 9: 141, 2014.
 101.Long JB, Bentley TL, Wessner KA, Cerone C, Sweeney S, Bauman RA. Blast overpressure in rats: Recreating a battlefield injury in the laboratory. J Neurotrauma 26: 827‐840, 2009.
 102.Maas AI. Neuroprotective agents in traumatic brain injury. Expert Opin Investig Drugs 10: 753‐767, 2001.
 103.Magnuson J, Leonessa F, Ling GS. Neuropathology of explosive blast traumatic brain injury. Curr Neurol Neurosci Rep 12: 570‐579, 2012.
 104.Malhotra JD, Kaufman RJ. Endoplasmic reticulum stress and oxidative stress: A vicious cycle or a double‐edged sword? Antioxid Redox Signal 9: 2277‐2293, 2007.
 105.Mangat HS. Severe traumatic brain injury. Continuum 18: 532‐546, 2012.
 106.Marchesi VT. Alzheimer's disease and CADASIL are heritable, adult‐onset dementias that both involve damaged small blood vessels. Cell Mol Life Sci 71: 949‐955, 2014.
 107.Marmarou CR, Liang X, Abidi NH, Parveen S, Taya K, Henderson SC, Young HF, Filippidis AS, Baumgarten CM. Selective vasopressin‐1a receptor antagonist prevents brain edema, reduces astrocytic cell swelling and GFAP, V1aR and AQP4 expression after focal traumatic brain injury. Brain Res 1581: 89‐102, 2014.
 108.Mata‐Mbemba D, Mugikura S, Nakagawa A, Murata T, Ishii K, Li L, Takase K, Kushimoto S, Takahashi S. Early CT findings to predict early death in patients with traumatic brain injury: Marshall and Rotterdam CT scoring systems compared in the major academic tertiary care hospital in northeastern Japan. Acad Radiol 21: 605‐611, 2014.
 109.Mata‐Mbemba D, Mugikura S, Nakagawa A, Murata T, Kato Y, Tatewaki Y, Li L, Takase K, Ishii K, Kushimoto S, Tominaga T, Takahashi S. Intraventricular hemorrhage on initial computed tomography as marker of diffuse axonal injury after traumatic brain injury. J Neurotrauma, 2014 [Epub ahead of print].
 110.McKee AC, Daneshvar DH, Alvarez VE, Stein TD. The neuropathology of sport. Acta Neuropathol 127: 29‐51, 2014.
 111.McKee AC, Stern RA, Nowinski CJ, Stein TD, Alvarez VE, Daneshvar DH, Lee HS, Wojtowicz SM, Hall G, Baugh CM, Riley DO, Kubilus CA, Cormier KA, Jacobs MA, Martin BR, Abraham CR, Ikezu T, Reichard RR, Wolozin BL, Budson AE, Goldstein LE, Kowall NW, Cantu RC. The spectrum of disease in chronic traumatic encephalopathy. Brain 136: 43‐64, 2013.
 112.Milman A, Rosenberg A, Weizman R, Pick CG. Mild traumatic brain injury induces persistent cognitive deficits and behavioral disturbances in mice. J Neurotrauma 22: 1003‐1010, 2005.
 113.Miyauchi T, Wei EP, Povlishock JT. Therapeutic targeting of the axonal and microvascular change associated with repetitive mild traumatic brain injury. J Neurotrauma 30: 1664‐1671, 2013.
 114.Miyauchi T, Wei EP, Povlishock JT. Evidence for the therapeutic efficacy of either mild hypothermia or oxygen radical scavengers after repetitive mild traumatic brain injury. J Neurotrauma 31: 773‐781, 2014.
 115.Molino Y, Jabes F, Lacassagne E, Gaudin N, Khrestchatisky M. Setting‐up an in vitro model of rat blood‐brain barrier (BBB): a focus on BBB impermeability and receptor‐mediated transport. J Vis Exp 88: e51278, 2014.
 116.Moreno JA, Halliday M, Molloy C, Radford H, Verity N, Axten JM, Ortori CA, Willis AE, Fischer PM, Barrett DA, Mallucci GR. Oral treatment targeting the unfolded protein response prevents neurodegeneration and clinical disease in prion‐infected mice. Sci Transl Med 5: 206ra138, 2013.
 117.Moreno JA, Radford H, Peretti D, Steinert JR, Verity N, Martin MG, Halliday M, Morgan J, Dinsdale D, Ortori CA, Barrett DA, Tsaytler P, Bertolotti A, Willis AE, Bushell M, Mallucci GR. Sustained translational repression by eIF2alpha‐P mediates prion neurodegeneration. Nature 485: 507‐511, 2012.
 118.Mori K. Tripartite management of unfolded proteins in the endoplasmic reticulum. Cell 101: 451‐454, 2000.
 119.Munoz P, Humeres A, Elgueta C, Kirkwood A, Hidalgo C, Nunez MT. Iron mediates N‐methyl‐D‐aspartate receptor‐dependent stimulation of calcium‐induced pathways and hippocampal synaptic plasticity. J Biol Chem 286: 13382‐13392, 2011.
 120.Munoz P, Zavala G, Castillo K, Aguirre P, Hidalgo C, Nunez MT. Effect of iron on the activation of the MAPK/ERK pathway in PC12 neuroblastoma cells. Biol Res 39: 189‐190, 2006.
 121.Nakagawa T, Yuan J. Cross‐talk between two cysteine protease families. Activation of caspase‐12 by calpain in apoptosis. J Cell Biol 150: 887‐894, 2000.
 122.Neuhof C, Neuhof H. Calpain system and its involvement in myocardial ischemia and reperfusion injury. World J Cardiol 6: 638‐652, 2014.
 123.Newcomb JK, Pike BR, Zhao X, Banik NL, Hayes RL. Altered calpastatin protein levels following traumatic brain injury in rat. J Neurotrauma 16: 1‐11, 1999.
 124.Nirula R, Millar D, Greene T, McFadden M, Shah L, Scalea TM, Stein DM, Magnotti LJ, Jurkovich GJ, Vercruysse G, Demetriades D, Scherer LA, Peitzman A, Sperry J, Beauchamp K, Bell S, Feiz‐Erfan I, O'Neill P, Coimbra R. Decompressive craniectomy or medical management for refractory intracranial hypertension: An AAST‐MIT propensity score analysis. J Trauma Acute Care Surg 76: 944‐952; discussion 952‐945, 2014.
 125.Nisenbaum EJ, Novikov DS, Lui YW. The presence and role of iron in mild traumatic brain injury: An imaging perspective. J Neurotrauma 31: 301‐307, 2014.
 126. O'Connor T, Sadleir KR, Maus E, Velliquette RA, Zhao J, Cole SL, Eimer WA, Hitt B, Bembinster LA, Lammich S, Lichtenthaler SF, Hebert SS, DeStrooper B, Haass C, Bennett DA, Vassar R. Phosphorylation of the translation initiation factor eIF2alpha increases BACE1 levels and promotes amyloidogenesis. Neuron 60: 988‐1009, 2008.
 127.Omalu B, Bailes J, Hamilton RL, Kamboh MI, Hammers J, Case M, Fitzsimmons R. Emerging histomorphologic phenotypes of chronic traumatic encephalopathy in American athletes. Neurosurgery 69: 173‐183; discussion 183, 2011.
 128.Omalu B, Hammers JL, Bailes J, Hamilton RL, Kamboh MI, Webster G, Fitzsimmons RP. Chronic traumatic encephalopathy in an Iraqi war veteran with posttraumatic stress disorder who committed suicide. Neurosurg Focus 31: E3, 2011.
 129.Padayachy LC, Rohlwink U, Zwane E, Fieggen G, Peter JC, Figaji AA. The frequency of cerebral ischemia/hypoxia in pediatric severe traumatic brain injury. Child Nerv Syst 28: 1911‐1918, 2012.
 130.Pandya JD, Pauly JR, Nukala VN, Sebastian AH, Day KM, Korde AS, Maragos WF, Hall ED, Sullivan PG. Post‐injury administration of mitochondrial uncouplers increases tissue sparing and improves behavioral outcome following traumatic brain injury in rodents. J Neurotrauma 24: 798‐811, 2007.
 131.Pandya JD, Pauly JR, Sullivan PG. The optimal dosage and window of opportunity to maintain mitochondrial homeostasis following traumatic brain injury using the uncoupler FCCP. Exp Neurol 218: 381‐389, 2009.
 132.Paradis A, Zhang L. Role of endothelin in uteroplacental circulation and fetal vascular function. Curr Vasc Pharmacol 11: 594‐605, 2013.
 133.Park E, Eisen R, Kinio A, Baker AJ. Electrophysiological white matter dysfunction and association with neurobehavioral deficits following low‐level primary blast trauma. Neurobiol Dis 52: 150‐159, 2013.
 134.Pechmann A, Anastasopoulos C, Korinthenberg R, van Velthoven‐Wurster V, Kirschner J. Decompressive craniectomy after severe traumatic brain injury in children: complications and outcome. Neuropediatrics 46: 5‐12, 2015 [Epub ahead of print].
 135.Peek‐Asa C, McArthur D, Hovda D, Kraus J. Early predictors of mortality in penetrating compared with closed brain injury. Brain Inj 15: 801‐810, 2001.
 136.Peskind ER, Brody D, Cernak I, McKee A, Ruff RL. Military‐ and sports‐related mild traumatic brain injury: Clinical presentation, management, and long‐term consequences. J Clin Psychiatry 74: 180‐188; quiz 188, 2013.
 137.Petraglia AL, Plog BA, Dayawansa S, Chen M, Dashnaw ML, Czerniecka K, Walker CT, Viterise T, Hyrien O, Iliff JJ, Deane R, Nedergaard M, Huang JH. The spectrum of neuro‐behavioral sequelae following repetitive mild traumatic brain injury: A novel mouse model of Chronic Traumatic Encephalopathy (CTE). J Neurotrauma 31: 1211‐1224, 2014.
 138.Pop V, Badaut J. A neurovascular perspective for long‐term changes after brain trauma. Transl Stroke Res 2: 533‐545, 2011.
 139.Pun PB, Lu J, Moochhala S. Involvement of ROS in BBB dysfunction. Free Radic Res 43: 348‐364, 2009.
 140.Qutub AA, Popel AS. Reactive oxygen species regulate hypoxia‐inducible factor 1alpha differentially in cancer and ischemia. Mol Cell Biol 28: 5106‐5119, 2008.
 141.Raghupathi R, Margulies SS. Traumatic axonal injury after closed head injury in the neonatal pig. J Neurotrauma 19: 843‐853, 2002.
 142.Ramlackhansingh AF, Brooks DJ, Greenwood RJ, Bose SK, Turkheimer FE, Kinnunen KM, Gentleman S, Heckemann RA, Gunanayagam K, Gelosa G, Sharp DJ. Inflammation after trauma: Microglial activation and traumatic brain injury. Ann Neurol 70: 374‐383, 2011.
 143.Razumovsky A, Tigno T, Hochheimer SM, Stephens FL, Bell R, Vo AH, Severson MA, Marshall SA, Oppenheimer SM, Ecker R, Armonda RA. Cerebral hemodynamic changes after wartime traumatic brain injury. Acta Neurochir Suppl 115: 87‐90, 2013.
 144.Rigg JL, Mooney SR. Concussions and the military: Issues specific to service members. PM R 3: S380‐S386, 2011.
 145.Ringger NC, Tolentino PJ, McKinsey DM, Pike BR, Wang KK, Hayes RL. Effects of injury severity on regional and temporal mRNA expression levels of calpains and caspases after traumatic brain injury in rats. J Neurotrauma 21: 829‐841, 2004.
 146.Rink A, Fung KM, Trojanowski JQ, Lee VM, Neugebauer E, McIntosh TK. Evidence of apoptotic cell death after experimental traumatic brain injury in the rat. Am J Pathol 147: 1575‐1583, 1995.
 147.Ron D, Walter P. Signal integration in the endoplasmic reticulum unfolded protein response. Nat Rev Mol Cell Biol 8: 519‐529, 2007.
 148.Rosenbaum BP, Kelly ML, Kshettry VR, Weil RJ. Neurologic disorders, in‐hospital deaths, and years of potential life lost in the USA, 1988‐2011. J Clin Neurosci 21: 1874‐1880, 2014.
 149.Rostami E, Engquist H, Enblad P. Imaging of cerebral blood flow in patients with severe traumatic brain injury in the neurointensive care. Front Neurol 5: 114, 2014.
 150.Roth TL, Nayak D, Atanasijevic T, Koretsky AP, Latour LL, McGavern DB. Transcranial amelioration of inflammation and cell death after brain injury. Nature 505: 223‐228, 2014.
 151.Rubino S, Zaman RA, Sturge CR, Fried JG, Desai A, Simmons NE, Lollis SS. Outpatient follow‐up of nonoperative cerebral contusion and traumatic subarachnoid hemorrhage: Does repeat head CT alter clinical decision‐making? J Neurosurg 121: 944‐949, 2014.
 152.Rubovitch V, Shachar A, Werner H, Pick CG. Does IGF‐1 administration after a mild traumatic brain injury in mice activate the adaptive arm of ER stress? Neurochem Int 58: 443‐446, 2011.
 153.Ruhe A, Fejer R, Gansslen A, Klein W. Assessing postural stability in the concussed athlete: What to do, what to expect, and when. Sports Health 6: 427‐433, 2014.
 154.Russell KL, Berman NE, Gregg PR, Levant B. Fish oil improves motor function, limits blood‐brain barrier disruption, and reduces Mmp9 gene expression in a rat model of juvenile traumatic brain injury. Prostaglandins Leukot Essent Fatty Acids 90: 5‐11, 2014.
 155.Saito T, Shibasaki K, Kurachi M, Puentes S, Mikuni M, Ishizaki Y. Cerebral capillary endothelial cells are covered by the VEGF‐expressing foot processes of astrocytes. Neurosci Lett 497: 116‐121, 2011.
 156.Salminen A, Kauppinen A, Suuronen T, Kaarniranta K, Ojala J. ER stress in Alzheimer's disease: A novel neuronal trigger for inflammation and Alzheimer's pathology. J Neuroinflammation 6: 41, 2009.
 157.Sanelli PC, Pandya A, Segal AZ, Gupta A, Hurtado‐Rua S, Ivanidze J, Kesavabhotla K, Mir D, Mushlin AI, Hunink MG. Cost‐effectiveness of CT angiography and perfusion imaging for delayed cerebral ischemia and vasospasm in aneurysmal subarachnoid hemorrhage. AJNR Am J Neuroradiol 35: 1714‐1720, 2014.
 158.Sano R, Reed JC. ER stress‐induced cell death mechanisms. Biochim Biophys Acta 1833: 3460‐3470, 2013.
 159.Schafer DP, Jha S, Liu F, Akella T, McCullough LD, Rasband MN. Disruption of the axon initial segment cytoskeleton is a new mechanism for neuronal injury. J Neurosci 29: 13242‐13254, 2009.
 160.Schaible EV, Windschugl J, Bobkiewicz W, Kaburov Y, Dangel L, Kramer T, Huang C, Sebastiani A, Luh C, Werner C, Engelhard K, Thal SC, Schafer MK. 2‐Methoxyestradiol confers neuroprotection and inhibits a maladaptive HIF‐1alpha response after traumatic brain injury in mice. J Neurochem 129: 940‐954, 2014.
 161.Scheper W, Nijholt DA, Hoozemans JJ. The unfolded protein response and proteostasis in Alzheimer disease: Preferential activation of autophagy by endoplasmic reticulum stress. Autophagy 7: 910‐911, 2011.
 162.Schiera G, Bono E, Raffa MP, Gallo A, Pitarresi GL, Di Liegro I, Savettieri G. Synergistic effects of neurons and astrocytes on the differentiation of brain capillary endothelial cells in culture. J Cell Mol Med 7: 165‐170, 2003.
 163.Shahlaie K, Keachie K, Hutchins IM, Rudisill N, Madden LK, Smith KA, Ko KA, Latchaw RE, Muizelaar JP. Risk factors for posttraumatic vasospasm. J Neurosurg 115: 602‐611, 2011.
 164.Shin SS, Pathak S, Presson N, Bird W, Wagener L, Schneider W, Okonkwo DO, Fernandez‐Miranda JC. Detection of white matter injury in concussion using high‐definition fiber tractography. Prog Neurol Surg 28: 86‐93, 2014.
 165.Shohami E, Biegon A. Novel approach to the role of NMDA receptors in traumatic brain injury. CNS Neurol Disord Drug Targets 13: 567‐573, 2014.
 166.Small GW, Kepe V, Siddarth P, Ercoli LM, Merrill DA, Donoghue N, Bookheimer SY, Martinez J, Omalu B, Bailes J, Barrio JR. PET scanning of brain tau in retired national football league players: Preliminary findings. Am J Geriatr Psychiatry 21: 138‐144, 2013.
 167.Smith DH, Chen XH, Iwata A, Graham DI. Amyloid beta accumulation in axons after traumatic brain injury in humans. J Neurosurg 98: 1072‐1077, 2003.
 168.Smith DW, Bailes JE, Fisher JA, Robles J, Turner RC, Mills JD. Internal jugular vein compression mitigates traumatic axonal injury in a rat model by reducing the intracranial slosh effect. Neurosurgery 70: 740‐746, 2012.
 169.Streit WJ, Mrak RE, Griffin WS. Microglia and neuroinflammation: A pathological perspective. J Neuroinflammation 1: 14, 2004.
 170.Susman M, DiRusso SM, Sullivan T, Risucci D, Nealon P, Cuff S, Haider A, Benzil D. Traumatic brain injury in the elderly: Increased mortality and worse functional outcome at discharge despite lower injury severity. J Trauma 53: 219‐223; discussion 223‐214, 2002.
 171.Sutton RL, Lescaudron L, Stein DG. Unilateral cortical contusion injury in the rat: Vascular disruption and temporal development of cortical necrosis. J Neurotrauma 10: 135‐149, 1993.
 172.Szmydynger‐Chodobska J, Chung I, Kozniewska E, Tran B, Harrington FJ, Duncan JA, Chodobski A. Increased expression of vasopressin v1a receptors after traumatic brain injury. J Neurotrauma 21: 1090‐1102, 2004.
 173.Szmydynger‐Chodobska J, Fox LM, Lynch KM, Zink BJ, Chodobski A. Vasopressin amplifies the production of proinflammatory mediators in traumatic brain injury. J Neurotrauma 27: 1449‐1461, 2010.
 174.Tavazzi B, Signoretti S, Lazzarino G, Amorini AM, Delfini R, Cimatti M, Marmarou A, Vagnozzi R. Cerebral oxidative stress and depression of energy metabolism correlate with severity of diffuse brain injury in rats. Neurosurgery 56: 582‐589; discussion 582‐589, 2005.
 175.Truettner JS, Hu B, Alonso OF, Bramlett HM, Kokame K, Dietrich WD. Subcellular stress response after traumatic brain injury. J Neurotrauma 24: 599‐612, 2007.
 176.Turner RC, Dodson SC, Rosen CL, Huber JD. The science of cerebral ischemia and the quest for neuroprotection: Navigating past failure to future success. J Neurosurg 118: 1072‐1085, 2013.
 177.Turner RC, Naser ZJ, Bailes JE, Smith DW, Fisher JA, Rosen CL. Effect of slosh mitigation on histologic markers of traumatic brain injury: Laboratory investigation. J Neurosurg 117: 1110‐1118, 2012.
 178.Ueda Y, Walker SA, Povlishock JT. Perivascular nerve damage in the cerebral circulation following traumatic brain injury. Acta Neuropathol 112: 85‐94, 2006.
 179.van der Eerden AW, Khalilzadeh O, Perlbarg V, Dinkel J, Sanchez P, Vos PE, Luyt CE, Stevens RD, Menjot de Champfleur N, Delmaire C, Tollard E, Gupta R, Dormont D, Laureys S, Benali H, Vanhaudenhuyse A, Galanaud D, Puybasset L, Consortium N. White matter changes in comatose survivors of anoxic ischemic encephalopathy and traumatic brain injury: Comparative diffusion‐tensor imaging study. Radiology 270: 506‐516, 2014.
 180.Wang Y, Arun P, Wei Y, Oguntayo S, Gharavi R, Valiyaveettil M, Nambiar MP, Long JB. Repeated blast exposures cause brain DNA fragmentation in mice. J Neurotrauma 31: 498‐504, 2014.
 181.Wilberger JE, Jr., Harris M, Diamond DL. Acute subdural hematoma: Morbidity, mortality, and operative timing. J Neurosurg 74: 212‐218, 1991.
 182.Wilson CD, Shankar JJ. Diagnosing vasospasm after subarachnoid hemorrhage: CTA and CTP. Can J Neurol Sci 41: 314‐319, 2014.
 183.Xiong Y, Mahmood A, Chopp M. Animal models of traumatic brain injury. Nat Rev Neurosci 14: 128‐142, 2013.
 184.Xu FF, Sun S, Ho AS, Lee D, Kiang KM, Zhang XQ, Wang AM, Wu EX, Lui WM, Liu BY, Leung GK. Effects of progesterone vs. dexamethasone on brain oedema and inflammatory responses following experimental brain resection. Brain Inj 28: 1594‐1601, 2014.
 185.Xu ZS, Yao A, Chu SS, Paun MK, McClintic AM, Murphy SP, Mourad PD. Detection of mild traumatic brain injury in rodent models using shear wave elastography: Preliminary studies. J Ultrasound Med 33: 1763‐1771, 2014.
 186.Yeh DD, Schecter WP. Primary blast injuries–an updated concise review. World J Surg 36: 966‐972, 2012.
 187.Yeoh S, Bell ED, Monson KL. Distribution of blood‐brain barrier disruption in primary blast injury. Ann Biomed Eng 41: 2206‐2214, 2013.
 188.Yi JH, Hazell AS. Excitotoxic mechanisms and the role of astrocytic glutamate transporters in traumatic brain injury. Neurochem Int 48: 394‐403, 2006.
 189.Zhang QG, Laird MD, Han D, Nguyen K, Scott E, Dong Y, Dhandapani KM, Brann DW. Critical role of NADPH oxidase in neuronal oxidative damage and microglia activation following traumatic brain injury. PloS One 7: e34504, 2012.
 190.Zhang YP, Cai J, Shields LB, Liu N, Xu XM, Shields CB. Traumatic brain injury using mouse models. Transl Stroke Res 5: 454‐471, 2014.
 191.Zhong N, Ramaswamy G, Weisgraber KH. Apolipoprotein E4 domain interaction induces endoplasmic reticulum stress and impairs astrocyte function. J Biol Chem 284: 27273‐27280, 2009.

Contact Editor

Submit a note to the editor about this article by filling in the form below.

* Required Field

How to Cite

Aric F. Logsdon, Brandon P. Lucke‐Wold, Ryan C. Turner, Jason D. Huber, Charles L. Rosen, James W. Simpkins. Role of Microvascular Disruption in Brain Damage from Traumatic Brain Injury. Compr Physiol 2015, 5: 1147-1160. doi: 10.1002/cphy.c140057