Mild head injury increasing the brain's vulnerability to a second concussive impact

Restricted access

Object. Mild, traumatic repetitive head injury (RHI) leads to neurobehavioral impairment and is associated with the early onset of neurodegenerative disease. The authors developed an animal model to investigate the behavioral and pathological changes associated with RHI.

Methods. Adult male C57BL/6 mice were subjected to a single injury (43 mice), repetitive injury (two injuries 24 hours apart; 49 mice), or no impact (36 mice). Cognitive function was assessed using the Morris water maze test, and neurological motor function was evaluated using a battery of neuroscore, rotarod, and rotating pole tests. The animals were also evaluated for cardiovascular changes, blood—brain barrier (BBB) breakdown, traumatic axonal injury, and neurodegenerative and histopathological changes between 1 day and 56 days after brain trauma. No cognitive dysfunction was detected in any group. The single-impact group showed mild impairment according to the neuroscore test at only 3 days postinjury, whereas RHI caused pronounced deficits at 3 days and 7 days following the second injury. Moreover, RHI led to functional impairment during the rotarod and rotating pole tests that was not observed in any animal after a single impact. Small areas of cortical BBB breakdown and axonal injury, observed after a single brain injury, were profoundly exacerbated after RHI. Immunohistochemical staining for microtubule-associated protein—2 revealed marked regional loss of immunoreactivity only in animals subjected to RHI. No deposits of β-amyloid or tau were observed in any brain-injured animal.

Conclusions. On the basis of their results, the authors suggest that the brain has an increased vulnerability to a second traumatic insult for at least 24 hours following an initial episode of mild brain trauma.

Article Information

Address reprint requests to: Tracy K. McIntosh, M.D., Department of Neurosurgery, University of Pennsylvania School of Medicine, 105 Hayden Hall, 3320 Smith Walk, Philadelphia, Pennsylvania 19104–6316. email: mcintosh@seas.upenn.edu.

© AANS, except where prohibited by US copyright law.

Headings

Figures

  • View in gallery

    Graphs demonstrating systemic BP changes measured in mice subjected to a single concussive brain injury (A) and to a second concussion 24 hours later (B). The mice were evaluated at 5-minute intervals over a 1-hour observation period. In both cases, a progressive increase in BP was observed over time during recovery from anesthesia. Neither a single TBI nor RHI was associated with hypotension. Data are presented as means ± SEM.

  • View in gallery

    Bar graphs depicting cognitive function during the MWM tests. Memory scores (A) obtained 7 days after sham injury, single TBI, or RHI are not significantly different among groups. Learning latencies at 56 days and 57 days after injury (five trials averaged, B) show a similar ability among groups of animals to learn the visuospatial task. Scores in the probe trial on Day 58 (C) revealed no significant differences among groups. Data are presented as means ± SEM. The sham-injured group is represented by open bars or circles, single TBI by gray bars or squares, and RHI by black bars or triangles.

  • View in gallery

    Bar graphs depicting neurological motor function determined using a composite neuroscore (A), results of the rotarod test (B), and results of the RP test (C) following sham injury (open bars), single TBI (gray bars), or RHI (black bars). Mice subjected to a single TBI exhibited mild impairment in the neuroscore when compared with sham-injured mice at 3 days postinjury but recovered within 1 week. The RHI caused a more pronounced and prolonged deficit, as detected by significantly lower composite neuroscores (A). The average time remaining on the rotarod over the entire investigation period was significantly lower in animals subjected to RHI (B), whereas no significant deficit could be detected in animals that received a single impact (B). The number of foot-faults made while traversing the RP was not significantly different between control animals and mice subjected to a single TBI (C). Animals subjected to RHI showed an increase in footfaults at 3 days and 56 days after the second impact (C). Data are presented as means + SEM. *p < 0.05 compared with sham-injured animals, **p < 0.001 compared with sham-injured animals, #p < 0.05 compared with a single TBI; ##p < 0.001 compared with animals with a single TBI.

  • View in gallery

    Photomicrographs of histopathological specimens following single TBI or RHI. Nissl staining revealed no overt histological damage or focal lesions in the cortex or hippocampus in animals subjected to either a single TBI (A) or RHI (B) 56 days after injury. Immunostaining for mouse IgG revealed a small area of immunoreactivity restricted to the cortex (arrowhead) in three of five animals subjected to single TBI (C) 48 hours after trauma. Immunoglobulin G immunoreactivity was observed in the cortex, subcortical matter, and hippocampus of four of five animals 1 day after RHI (D, arrowhead). Scale bar = 1 mm.

  • View in gallery

    Bar graphs demonstrating numbers of cells in the CA3 subfield of the hippocampus (A) and the apex of the hilum of the dentate gyrus (B) following sham injury (open bars), single TBI (gray bars), and RHI (black bars). No significant cell loss could be detected in either the left (injured) or right (contralateral) hemisphere in either group or at any time point investigated. Data are presented as means + SEM.

  • View in gallery

    Photomicrographs demonstrating the results of immunohistochemical testing for β-APP following a single TBI or RHI. A–C: Immunoreactivity (arrowheads) was observed in the left (ipsilateral) thalamus 28 days after a single TBI. D–F: Tissue from animals subjected to RHI showed pronounced immunoreactivity in the left thalamus 28 days after RHI. Scale bar = 400 µm for A and D, 100 µm for B, C, E, and F.

  • View in gallery

    Bar graph showing quantification of β-APP immunoreactivity in the left (ipsilateral) thalamus following sham injury (initial bars [barely visible]), single TBI (gray bars), or RHI (black bars). Immunoreactivity was not significantly different between control animals and mice subjected to a single TBI. Tissue from animals subjected to RHI showed an increase in immunoreactivity 28 days after RHI. Data are presented as means + SEM. *p < 0.005 compared with sham-injured animals, #p < 0.005 compared with animals subjected to a single TBI.

  • View in gallery

    Photomicrographs showing results of immunohistochemical testing for MAP-2 in the left (ipsilateral) cortex. Tissue from sham-injured (control) animals (A) and animals subjected to mild TBI (B) showed long immunoreactive dendrites through the cortex. An RHI resulted in irregular MAP-2 staining in dendritic processes (arrows) 7 days following trauma (C) that developed into an area of MAP-2 loss (arrowheads) by 28 days (D). Scale bar = 100 µm.

References

  • 1.

    Bareyre FMSaatman KEHelfaer MAet al: Alterations in ionized and total blood magnesium after experimental traumatic brain injury: relationship to neurobehavioral outcome and neuroprotective efficacy of magnesium chloride. J Neurochem 73:2712801999Bareyre FM Saatman KE Helfaer MA et al: Alterations in ionized and total blood magnesium after experimental traumatic brain injury: relationship to neurobehavioral outcome and neuroprotective efficacy of magnesium chloride. J Neurochem 73:271–280 1999

  • 2.

    Barone FCWhite RFSpera PAet al: Ischemic preconditioning and brain tolerance: temporal histological and functional outcomes, protein synthesis requirement, and interleukin-1 receptor antagonist and early gene expression. Stroke 29:193719511998Barone FC White RF Spera PA et al: Ischemic preconditioning and brain tolerance: temporal histological and functional outcomes protein synthesis requirement and interleukin-1 receptor antagonist and early gene expression. Stroke 29:1937–1951 1998

  • 3.

    Beck WTMandel HGFabro S: Physiological disposition of pentobarbital in tumor-bearing mice. Cancer Res 35:133313401975Beck WT Mandel HG Fabro S: Physiological disposition of pentobarbital in tumor-bearing mice. Cancer Res 35:1333–1340 1975

  • 4.

    Bijur PEHaslum MGolding J: Cognitive outcomes of multiple mild head injuries in children. J Dev Behav Pediatr 17:1431481996Bijur PE Haslum M Golding J: Cognitive outcomes of multiple mild head injuries in children. J Dev Behav Pediatr 17:143–148 1996

  • 5.

    Blasko IMarx FSteiner Eet al: TNFα plus IFNγ induce the production of Alzheimer β-amyloid peptides and decrease the secretion of APPs. FASEB J 13:63681999Blasko I Marx F Steiner E et al: TNFα plus IFNγ induce the production of Alzheimer β-amyloid peptides and decrease the secretion of APPs. FASEB J 13:63–68 1999

  • 6.

    Blumbergs PCScott GManavis Jet al: Topography of axonal injury as defined by amyloid precursor protein and the sector scoring method in mild and severe closed head injury. J Neurotrauma 12:5655721995Blumbergs PC Scott G Manavis J et al: Topography of axonal injury as defined by amyloid precursor protein and the sector scoring method in mild and severe closed head injury. J Neurotrauma 12:565–572 1995

  • 7.

    Bohnen NJolles J: Neurobehavioral aspects of postconcussive symptoms after mild head injury. J Nerv Ment Dis 180:6836921992Bohnen N Jolles J: Neurobehavioral aspects of postconcussive symptoms after mild head injury. J Nerv Ment Dis 180:683–692 1992

  • 8.

    Cantu RC: Return to play guidelines after a head injury. Clin Sports Med 17:45601998Cantu RC: Return to play guidelines after a head injury. Clin Sports Med 17:45–60 1998

  • 9.

    Cantu RCVoy R: Case report: second impact syndrome: a risk in any contact sport. Physician Sportsmed 23:27341995Cantu RC Voy R: Case report: second impact syndrome: a risk in any contact sport. Physician Sportsmed 23:27–34 1995

  • 10.

    Carbonell WSGrady MS: Regional and temporal characterization of neuronal, glial, and axonal response after traumatic brain injury in the mouse. Acta Neuropathol 98:3964061999Carbonell WS Grady MS: Regional and temporal characterization of neuronal glial and axonal response after traumatic brain injury in the mouse. Acta Neuropathol 98:396–406 1999

  • 11.

    Carbonell WSMaris DOMcCall Tet al: Adaptation of the fluid percussion injury model to the mouse. J Neurotrauma 15:2172291998Carbonell WS Maris DO McCall T et al: Adaptation of the fluid percussion injury model to the mouse. J Neurotrauma 15:217–229 1998

  • 12.

    Chen YConstantini STrembovler Vet al: An experimental model of closed head injury in mice: pathophysiology, histopathology, and cognitive deficits. J Neurotrauma 13:5575681996Chen Y Constantini S Trembovler V et al: An experimental model of closed head injury in mice: pathophysiology histopathology and cognitive deficits. J Neurotrauma 13:557–568 1996

  • 13.

    Chorley JN: Sports-related head injuries. Curr Opin Pediatr 10:3503551998Chorley JN: Sports-related head injuries. Curr Opin Pediatr 10:350–355 1998

  • 14.

    Clark RSKochanek PMDixon CEet al: Early neuropathologic effects of mild or moderate hypoxemia after controlled cortical impact injury in rats. J Neurotrauma 14:1791891997Clark RS Kochanek PM Dixon CE et al: Early neuropathologic effects of mild or moderate hypoxemia after controlled cortical impact injury in rats. J Neurotrauma 14:179–189 1997

  • 15.

    Collins MWGrindel SHLovell MRet al: Relationship between concussion and neuropsychological performance in college football players. JAMA 282:9649701999Collins MW Grindel SH Lovell MR et al: Relationship between concussion and neuropsychological performance in college football players. JAMA 282:964–970 1999

  • 16.

    Dixon CEClifton GLLighthall JWet al: A controlled cortical impact model of traumatic brain injury in the rat. J Neurosci Methods 39:2532621991Dixon CE Clifton GL Lighthall JW et al: A controlled cortical impact model of traumatic brain injury in the rat. J Neurosci Methods 39:253–262 1991

  • 17.

    Dixon CEHamm RJTaft WCet al: Increased anticholinergic sensitivity following closed skull impact and controlled cortical impact traumatic brain injury in the rat. J Neurotrauma 11:2752871994Dixon CE Hamm RJ Taft WC et al: Increased anticholinergic sensitivity following closed skull impact and controlled cortical impact traumatic brain injury in the rat. J Neurotrauma 11:275–287 1994

  • 18.

    Duhaime ACChristian CWRorke LBet al: Nonaccidental head injury in infants—the “shaken-baby syndrome.” N Engl J Med 338:182218291998Duhaime AC Christian CW Rorke LB et al: Nonaccidental head injury in infants—the “shaken-baby syndrome.” N Engl J Med 338:1822–1829 1998

  • 19.

    Fineman IHovda DASmith Met al: Concussive brain injury is associated with a prolonged accumulation of calcium: a 45Ca autoradiographic study. Brain Res 624:941021993Fineman I Hovda DA Smith M et al: Concussive brain injury is associated with a prolonged accumulation of calcium: a 45Ca autoradiographic study. Brain Res 624:94–102 1993

  • 20.

    Folkerts MMBerman RFMuizelaar JPet al: Disruption of MAP-2 immunostaining in rat hippocampus after traumatic brain injury. J Neurotrauma 15:3493631998Folkerts MM Berman RF Muizelaar JP et al: Disruption of MAP-2 immunostaining in rat hippocampus after traumatic brain injury. J Neurotrauma 15:349–363 1998

  • 21.

    Fox GBFan LLevasseur RAet al: Sustained sensory/motor and cognitive deficits with neuronal apoptosis following controlled cortical impact brain injury in the mouse. J Neurotrauma 15:5996141998Fox GB Fan L Levasseur RA et al: Sustained sensory/motor and cognitive deficits with neuronal apoptosis following controlled cortical impact brain injury in the mouse. J Neurotrauma 15:599–614 1998

  • 22.

    Fox GBLevasseur RAFaden AI: Behavioral responses of C57BL/6, FVB/N, and 129/SvEMS mouse strains to traumatic brain injury: implications for gene targeting approaches to neurotrauma. J Neurotrauma 16:3773891999Fox GB Levasseur RA Faden AI: Behavioral responses of C57BL/6 FVB/N and 129/SvEMS mouse strains to traumatic brain injury: implications for gene targeting approaches to neurotrauma. J Neurotrauma 16:377–389 1999

  • 23.

    Franklin KBJPaxinos G: The Mouse Brain in Stereotaxic Coordinates. San Diego, CA: Academic Press1997Franklin KBJ Paxinos G: The Mouse Brain in Stereotaxic Coordinates. San Diego CA: Academic Press 1997

  • 24.

    Geddes JFVowles GHNicoll JAet al: Neuronal cytoskeletal changes are an early consequence of repetitive head injury. Acta Neuropathol 98:1711781999Geddes JF Vowles GH Nicoll JA et al: Neuronal cytoskeletal changes are an early consequence of repetitive head injury. Acta Neuropathol 98:171–178 1999

  • 25.

    Geddes JFVowles GHRobinson SFet al: Neurofibrillary tangles, but not Alzheimer-type pathology, in a young boxer. Neuropathol Appl Neurobiol 22:12161996Geddes JF Vowles GH Robinson SF et al: Neurofibrillary tangles but not Alzheimer-type pathology in a young boxer. Neuropathol Appl Neurobiol 22:12–16 1996

  • 26.

    Gentleman SMGraham DIRoberts GW: Molecular pathology of head trauma: altered βAPP metabolism and the aetiology of Alzheimer's disease. Prog Brain Res 96:2372461993Gentleman SM Graham DI Roberts GW: Molecular pathology of head trauma: altered βAPP metabolism and the aetiology of Alzheimer's disease. Prog Brain Res 96:237–246 1993

  • 27.

    Gervais FGXu DRobertson GSet al: Involvement of caspases in proteolytic cleavage of Alzheimer's amyloid-beta precursor protein and amyloidogenic A beta peptide formation. Cell 97:3954061999Gervais FG Xu D Robertson GS et al: Involvement of caspases in proteolytic cleavage of Alzheimer's amyloid-beta precursor protein and amyloidogenic A beta peptide formation. Cell 97:395–406 1999

  • 28.

    Gordon WABrown MSliwinski Met al: The enigma of “hidden” traumatic brain injury. J Head Trauma Rehabil 13:39561998Gordon WA Brown M Sliwinski M et al: The enigma of “hidden” traumatic brain injury. J Head Trauma Rehabil 13:39–56 1998

  • 29.

    Graves ABWhite EKoepsell TDet al: The association between head trauma and Alzheimer's disease. Am J Epidemiol 131:4915011990Graves AB White E Koepsell TD et al: The association between head trauma and Alzheimer's disease. Am J Epidemiol 131:491–501 1990

  • 30.

    Green GAJordan SE: Are brain injuries a significant problem in soccer? Clin Sports Med 17:7958091998Green GA Jordan SE: Are brain injuries a significant problem in soccer? Clin Sports Med 17:795–809 1998

  • 31.

    Guskiewicz KMRiemann BLPerrin DHet al: Alternative approaches to the assessment of mild head injury in athletes. Med Sci Sports Exerc 29 (Suppl 7):S213S2211997Guskiewicz KM Riemann BL Perrin DH et al: Alternative approaches to the assessment of mild head injury in athletes. Med Sci Sports Exerc 29 (Suppl 7):S213–S221 1997

  • 32.

    Hamm RJDixon CEGbadebo DMet al: Cognitive deficits following traumatic brain injury produced by controlled cortical impact. J Neurotrauma 9:11201992Hamm RJ Dixon CE Gbadebo DM et al: Cognitive deficits following traumatic brain injury produced by controlled cortical impact. J Neurotrauma 9:11–20 1992

  • 33.

    Hamm RJPike BRO'Dell DMet al: The rotarod test: an evaluation of its effectiveness in assessing motor deficits following traumatic brain injury. J Neurotrauma 11:1871961994Hamm RJ Pike BR O'Dell DM et al: The rotarod test: an evaluation of its effectiveness in assessing motor deficits following traumatic brain injury. J Neurotrauma 11:187–196 1994

  • 34.

    Hicks RRSmith DHLowenstein DHet al: Mild experimental brain injury in the rat induces cognitive deficits associated with regional neuronal loss in the hippocampus. J Neurotrauma 10:4054141993Hicks RR Smith DH Lowenstein DH et al: Mild experimental brain injury in the rat induces cognitive deficits associated with regional neuronal loss in the hippocampus. J Neurotrauma 10:405–414 1993

  • 35.

    Hogg SMoser PCSanger DJ: Mild traumatic lesion of the right parietal cortex of the rat: selective behavioral deficits in the absence of neurological impairment. Behav Brain Res 93:1431551998Hogg S Moser PC Sanger DJ: Mild traumatic lesion of the right parietal cortex of the rat: selective behavioral deficits in the absence of neurological impairment. Behav Brain Res 93:143–155 1998

  • 36.

    Hovda DABecker DPKatayama Y: Secondary injury and acidosis. J Neurotrauma 9 (Suppl 1):S47S601992Hovda DA Becker DP Katayama Y: Secondary injury and acidosis. J Neurotrauma 9 (Suppl 1):S47–S60 1992

  • 37.

    Hovda DAYoshino AKawamata Tet al: Diffuse prolonged depression of cerebral oxidative metabolism following concussive brain injury in the rat: a cytochrome oxidase histochemistry study. Brain Res 567:1101991Hovda DA Yoshino A Kawamata T et al: Diffuse prolonged depression of cerebral oxidative metabolism following concussive brain injury in the rat: a cytochrome oxidase histochemistry study. Brain Res 567:1–10 1991

  • 38.

    Hsiang JNYeung TYu ALet al: High-risk mild head injury. J Neurosurg 87:2342381997Hsiang JN Yeung T Yu AL et al: High-risk mild head injury. J Neurosurg 87:234–238 1997

  • 39.

    Ishihara THong MZhang Bet al: Age-dependent emergence and progression of a tauopathy in transgenic mice overexpressing the shortest human tau isoform. Neuron 24:7517621999Ishihara T Hong M Zhang B et al: Age-dependent emergence and progression of a tauopathy in transgenic mice overexpressing the shortest human tau isoform. Neuron 24:751–762 1999

  • 40.

    Jenkins LWLu YJohnston WEet al: Combined therapy affects outcomes differentially after mild traumatic brain injury and secondary forebrain ischemia in rats. Brain Res 817:1321441999Jenkins LW Lu Y Johnston WE et al: Combined therapy affects outcomes differentially after mild traumatic brain injury and secondary forebrain ischemia in rats. Brain Res 817:132–144 1999

  • 41.

    Jenkins LWMoszynski KLyeth BGet al: Increased vulnerability of the mildly traumatized rat brain to cerebral ischemia: the use of controlled secondary ischemia as a research tool to identify common or different mechanisms contributing to mechanical and ischemic brain injury. Brain Res 477:2112241989Jenkins LW Moszynski K Lyeth BG et al: Increased vulnerability of the mildly traumatized rat brain to cerebral ischemia: the use of controlled secondary ischemia as a research tool to identify common or different mechanisms contributing to mechanical and ischemic brain injury. Brain Res 477:211–224 1989

  • 42.

    Johansson BBOhlsson AL: Environment, social interaction, and physical activity as determinants of functional outcome after cerebral infarction in the rat. Exp Neurol 139:3223271996Johansson BB Ohlsson AL: Environment social interaction and physical activity as determinants of functional outcome after cerebral infarction in the rat. Exp Neurol 139:322–327 1996

  • 43.

    Jordan BDRelkin NRRavdin LDet al: Apolipoprotein E ϵ4 associated with chronic traumatic brain injury in boxing. JAMA 278:1361401997Jordan BD Relkin NR Ravdin LD et al: Apolipoprotein E ϵ4 associated with chronic traumatic brain injury in boxing. JAMA 278:136–140 1997

  • 44.

    Jordan SEGreen GAGalanty HLet al: Acute and chronic brain injury in United States National Team soccer players. Am J Sports Med 24:2052101996Jordan SE Green GA Galanty HL et al: Acute and chronic brain injury in United States National Team soccer players. Am J Sports Med 24:205–210 1996

  • 45.

    Kanayama GTakeda MNiigawa Het al: The effects of repetitive mild brain injury on cytoskeletal protein and behavior. Methods Find Exp Clin Pharmacol 18:1051151996Kanayama G Takeda M Niigawa H et al: The effects of repetitive mild brain injury on cytoskeletal protein and behavior. Methods Find Exp Clin Pharmacol 18:105–115 1996

  • 46.

    Kelly JPNichols JSFilley CMet al: Concussion in sports. Guidelines for the prevention of catastrophic outcome. JAMA 266:286728691991Kelly JP Nichols JS Filley CM et al: Concussion in sports. Guidelines for the prevention of catastrophic outcome. JAMA 266:2867–2869 1991

  • 47.

    Koelfen WFreund MDinter Det al: Long-term follow up of children with head injuries-classified as “good recovery” using the Glasgow Outcome Scale: neurological, neuropsychological and magnetic resonance imaging results. Eur J Pediatr 156:2302351997Koelfen W Freund M Dinter D et al: Long-term follow up of children with head injuries-classified as “good recovery” using the Glasgow Outcome Scale: neurological neuropsychological and magnetic resonance imaging results. Eur J Pediatr 156:230–235 1997

  • 48.

    Krege JHHodgin JBHagaman JRet al: A noninvasive computerized tail-cuff system for measuring blood pressure in mice. Hypertension 25:111111151995Krege JH Hodgin JB Hagaman JR et al: A noninvasive computerized tail-cuff system for measuring blood pressure in mice. Hypertension 25:1111–1115 1995

  • 49.

    Lancon JAHaines DEParent AD: Anatomy of the shaken baby syndrome. Anat Rec 253:13181998Lancon JA Haines DE Parent AD: Anatomy of the shaken baby syndrome. Anat Rec 253:13–18 1998

  • 50.

    Levin HSMattis SRuff RMet al: Neurobehavioral outcome following minor head injury: a three-center study. J Neurosurg 66:2342431987Levin HS Mattis S Ruff RM et al: Neurobehavioral outcome following minor head injury: a three-center study. J Neurosurg 66:234–243 1987

  • 51.

    Lewen ALi GLOlsson Yet al: Changes in microtubule-associated protein 2 and amyloid precursor protein immunoreactivity following traumatic brain injury in rat: influence of MK-801 treatment. Brain Res 719:1611711996Lewen A Li GL Olsson Y et al: Changes in microtubule-associated protein 2 and amyloid precursor protein immunoreactivity following traumatic brain injury in rat: influence of MK-801 treatment. Brain Res 719:161–171 1996

  • 52.

    Lowenstein DHThomas MJSmith DHet al: Selective vulnerability of dentate hilar neurons following traumatic brain injury: a potential mechanistic link between head trauma and disorders of the hippocampus. J Neurosci 12:484648531992Lowenstein DH Thomas MJ Smith DH et al: Selective vulnerability of dentate hilar neurons following traumatic brain injury: a potential mechanistic link between head trauma and disorders of the hippocampus. J Neurosci 12:4846–4853 1992

  • 53.

    Lyeth BGJenkins LWHamm RJet al: Prolonged memory impairment in the absence of hippocampal cell death following traumatic brain injury in the rat. Brain Res 526:2492581990Lyeth BG Jenkins LW Hamm RJ et al: Prolonged memory impairment in the absence of hippocampal cell death following traumatic brain injury in the rat. Brain Res 526:249–258 1990

  • 54.

    Marmarou AFoda MAvan den Brink Wet al: A new model of diffuse brain injury in rats. Part I: Pathophysiology and biomechanics. J Neurosurg 80:2913001994Marmarou A Foda MA van den Brink W et al: A new model of diffuse brain injury in rats. Part I: Pathophysiology and biomechanics. J Neurosurg 80:291–300 1994

  • 55.

    Masdeu JCVan Heertum RLKleiman Aet al: Early single-photon emission computed tomography in mild head trauma. A controlled study. J Neuroimaging 4:1771811994Masdeu JC Van Heertum RL Kleiman A et al: Early single-photon emission computed tomography in mild head trauma. A controlled study. J Neuroimaging 4:177–181 1994

  • 56.

    Matser EJKessels AGLezak MDet al: Neuropsychological impairment in amateur soccer players. JAMA 282:9719731999Matser EJ Kessels AG Lezak MD et al: Neuropsychological impairment in amateur soccer players. JAMA 282:971–973 1999

  • 57.

    Matser JTKessels AGJordan BDet al: Chronic traumatic brain injury in professional soccer players. Neurology 51:7917961998Matser JT Kessels AG Jordan BD et al: Chronic traumatic brain injury in professional soccer players. Neurology 51:791–796 1998

  • 58.

    Mattiasson GJPhilips MFTomasevic Get al: The rotating pole test: evaluation of its effectiveness in assessing functional motor deficits following experimental head injury in the rat. J Neurosci Methods 95:75822000Mattiasson GJ Philips MF Tomasevic G et al: The rotating pole test: evaluation of its effectiveness in assessing functional motor deficits following experimental head injury in the rat. J Neurosci Methods 95:75–82 2000

  • 59.

    Maxwell WLPovlishock JTGraham DL: A mechanistic analysis of nondisruptive axonal injury: a review. J Neurotrauma 14:4194401997Maxwell WL Povlishock JT Graham DL: A mechanistic analysis of nondisruptive axonal injury: a review. J Neurotrauma 14:419–440 1997

  • 60.

    McIntosh TKNoble LAndrews Bet al: Traumatic brain injury in the rat: characterization of a midline fluid-percussion model. Cent Nerv Syst Trauma 4:1191341987McIntosh TK Noble L Andrews B et al: Traumatic brain injury in the rat: characterization of a midline fluid-percussion model. Cent Nerv Syst Trauma 4:119–134 1987

  • 61.

    McIntosh TKVink RNoble Let al: Traumatic brain injury in the rat: characterization of a lateral fluid-percussion model. Neuroscience 28:2332441989McIntosh TK Vink R Noble L et al: Traumatic brain injury in the rat: characterization of a lateral fluid-percussion model. Neuroscience 28:233–244 1989

  • 62.

    Melvin JWEvans FG: A strain energy approach to the mechanics of skull fracture: 710871 in Backaitis SH (ed): Biomechanics of Impact Injury and Injury Tolerances of the Head-Neck Complex: PT-43. Warrendale, PA: SAE1993 pp 661680Melvin JW Evans FG: A strain energy approach to the mechanics of skull fracture: 710871 in Backaitis SH (ed): Biomechanics of Impact Injury and Injury Tolerances of the Head-Neck Complex: PT-43. Warrendale PA: SAE 1993 pp 661–680

  • 63.

    Mills JReiner PB: Regulation of amyloid precursor protein cleavage. J Neurochem 72:4434601999Mills J Reiner PB: Regulation of amyloid precursor protein cleavage. J Neurochem 72:443–460 1999

  • 64.

    Mittl RLGrossman RIHiehle JFet al: Prevalence of MR evidence of diffuse axonal injury in patients with mild head injury and normal head CT findings. AJNR 15:158315891994Mittl RL Grossman RI Hiehle JF et al: Prevalence of MR evidence of diffuse axonal injury in patients with mild head injury and normal head CT findings. AJNR 15:1583–1589 1994

  • 65.

    Morris RGGarrud PRawlins JNet al: Place navigation impaired in rats with hippocampal lesions. Nature 297:6816831982Morris RG Garrud P Rawlins JN et al: Place navigation impaired in rats with hippocampal lesions. Nature 297:681–683 1982

  • 66.

    Murai HPierce JERaghupathi Ret al: Twofold overexpression of human β-amyloid precursor proteins in transgenic mice does not affect the neuromotor, cognitive, or neurodegenerative sequelae following experimental brain injury. J Comp Neurol 392:4284381998Murai H Pierce JE Raghupathi R et al: Twofold overexpression of human β-amyloid precursor proteins in transgenic mice does not affect the neuromotor cognitive or neurodegenerative sequelae following experimental brain injury. J Comp Neurol 392:428–438 1998

  • 67.

    Nakamura MRaghupathi RMerry DEet al: Overexpression of Bcl-2 is neuroprotective after experimental brain injury in transgenic mice. J Comp Neurol 412:6816921999Nakamura M Raghupathi R Merry DE et al: Overexpression of Bcl-2 is neuroprotective after experimental brain injury in transgenic mice. J Comp Neurol 412:681–692 1999

  • 68.

    Nakamura MSaatman KEGalvin JEet al: Increased vulnerability of NFH-LacZ transgenic mouse to traumatic brain injury-induced behavioral deficits and cortical damage. J Cereb Blood Flow Metab 19:7627701999Nakamura M Saatman KE Galvin JE et al: Increased vulnerability of NFH-LacZ transgenic mouse to traumatic brain injury-induced behavioral deficits and cortical damage. J Cereb Blood Flow Metab 19:762–770 1999

  • 69.

    National Research Council: Guide for the Care and Use of Laboratory Animals. Washington, DC: National Academy Press1996National Research Council: Guide for the Care and Use of Laboratory Animals. Washington DC: National Academy Press 1996

  • 70.

    Nedd KSfakianakis GGanz Wet al: 99mTc-HMPAO SPECT of the brain in mild to moderate traumatic brain injury patients: compared with CT—a prospective study. Brain Inj 7:4694791993Nedd K Sfakianakis G Ganz W et al: 99mTc-HMPAO SPECT of the brain in mild to moderate traumatic brain injury patients: compared with CT—a prospective study. Brain Inj 7:469–479 1993

  • 71.

    Newcombe FRabbitt PBriggs M: Minor head injury: pathophysiological or iatrogenic sequelae? J Neurol Neurosurg Psychiatry 57:7097161994Newcombe F Rabbitt P Briggs M: Minor head injury: pathophysiological or iatrogenic sequelae? J Neurol Neurosurg Psychiatry 57:709–716 1994

  • 72.

    Olsson YRinder LLindgren Set al: Studies on vascular permeability changes in experimental brain concussion. 3. A comparison between the effects of single and repeated sudden mechanical loading of the brain. Acta Neuropathol 19:2252331971Olsson Y Rinder L Lindgren S et al: Studies on vascular permeability changes in experimental brain concussion. 3. A comparison between the effects of single and repeated sudden mechanical loading of the brain. Acta Neuropathol 19:225–233 1971

  • 73.

    O'Meara ESKukull WASheppard Let al: Head injury and risk of Alzheimer's disease by apolipoprotein E genotype. Am J Epidemiol 146:3733841997O'Meara ES Kukull WA Sheppard L et al: Head injury and risk of Alzheimer's disease by apolipoprotein E genotype. Am J Epidemiol 146:373–384 1997

  • 74.

    Perez-Pinzon MAAlonso OKraydieh Set al: Induction of tolerance against traumatic brain injury by ischemic preconditioning. Neuroreport 10:295129541999Perez-Pinzon MA Alonso O Kraydieh S et al: Induction of tolerance against traumatic brain injury by ischemic preconditioning. Neuroreport 10:2951–2954 1999

  • 75.

    Pierce JESmith DHTrojanowski JQet al: Enduring cognitive, neurobehavioral and histopathological changes persist for up to one year following severe experimental brain injury in rats. Neuroscience 87:3593691998Pierce JE Smith DH Trojanowski JQ et al: Enduring cognitive neurobehavioral and histopathological changes persist for up to one year following severe experimental brain injury in rats. Neuroscience 87:359–369 1998

  • 76.

    Pierce JETrojanowski JQGraham DIet al: Immunohistochemical characterization of alterations in the distribution of amyloid precursor proteins and β-amyloid peptide after experimental brain injury in the rat. J Neurosci 16:108310901996Pierce JE Trojanowski JQ Graham DI et al: Immunohistochemical characterization of alterations in the distribution of amyloid precursor proteins and β-amyloid peptide after experimental brain injury in the rat. J Neurosci 16:1083–1090 1996

  • 77.

    Piper IRThomson DMiller JD: Monitoring weight drop velocity and foam stiffness as an aid to quality control of a rodent model of impact acceleration neurotrauma. J Neurosci Methods 69:1711741996Piper IR Thomson D Miller JD: Monitoring weight drop velocity and foam stiffness as an aid to quality control of a rodent model of impact acceleration neurotrauma. J Neurosci Methods 69:171–174 1996

  • 78.

    Raghupathi RFernandez SCMurai Het al: BCL-2 overexpression attenuates cortical cell loss after traumatic brain injury in transgenic mice. J Cereb Blood Flow Metab 18:125912691998Raghupathi R Fernandez SC Murai H et al: BCL-2 overexpression attenuates cortical cell loss after traumatic brain injury in transgenic mice. J Cereb Blood Flow Metab 18:1259–1269 1998

  • 79.

    Rimel RWGiordani BBarth JTet al: Moderate head injury: completing the clinical spectrum of brain trauma. Neurosurgery 11:3443511982Rimel RW Giordani B Barth JT et al: Moderate head injury: completing the clinical spectrum of brain trauma. Neurosurgery 11:344–351 1982

  • 80.

    Roberts GWAllsop DBruton C: The occult aftermath of boxing. J Neurol Neurosurg Psychiatry 53:3733781990Roberts GW Allsop D Bruton C: The occult aftermath of boxing. J Neurol Neurosurg Psychiatry 53:373–378 1990

  • 81.

    Roberts GWWhitwell HLAcland PRet al: Dementia in a punch drunk wife. Lancet 335:9189191990Roberts GW Whitwell HL Acland PR et al: Dementia in a punch drunk wife. Lancet 335:918–919 1990

  • 82.

    Saatman KEGraham DIMcIntosh TK: The neuronal cytoskeleton is at risk after mild and moderate brain injury. J Neurotrauma 15:104710581998Saatman KE Graham DI McIntosh TK: The neuronal cytoskeleton is at risk after mild and moderate brain injury. J Neurotrauma 15:1047–1058 1998

  • 83.

    Samii ABadie HFu Ket al: Effects of an N-type calcium channel antagonist (SNX 111; Ziconotide) on calcium-45 accumulation following fluid-percussion injury. J Neurotrauma 16:8798921999Samii A Badie H Fu K et al: Effects of an N-type calcium channel antagonist (SNX 111; Ziconotide) on calcium-45 accumulation following fluid-percussion injury. J Neurotrauma 16:879–892 1999

  • 84.

    Scheff SWBaldwin SABrown RWet al: Morris water maze deficits in rats following traumatic brain injury: lateral controlled cortical impact. J Neurotrauma 14:6156271997Scheff SW Baldwin SA Brown RW et al: Morris water maze deficits in rats following traumatic brain injury: lateral controlled cortical impact. J Neurotrauma 14:615–627 1997

  • 85.

    Scherbel URaghupathi RNakamura Met al: Differential acute and chronic responses of tumor necrosis factor-deficient mice to experimental brain injury. Proc Natl Acad Sci USA 96:872187261999Scherbel U Raghupathi R Nakamura M et al: Differential acute and chronic responses of tumor necrosis factor-deficient mice to experimental brain injury. Proc Natl Acad Sci USA 96:8721–8726 1999

  • 86.

    Smith DHChen XHNonaka Met al: Accumulation of amyloid β and tau and the formation of neurofilament inclusions following diffuse brain injury in the pig. J Neuropathol Exp Neurol 58:9829921999Smith DH Chen XH Nonaka M et al: Accumulation of amyloid β and tau and the formation of neurofilament inclusions following diffuse brain injury in the pig. J Neuropathol Exp Neurol 58:982–992 1999

  • 87.

    Smith DHNakamura MMcIntosh TKet al: Brain trauma induces massive hippocampal neuron death linked to a surge in β-amyloid levels in mice overexpressing mutant amyloid precursor protein. Am J Pathol 153:100510101998Smith DH Nakamura M McIntosh TK et al: Brain trauma induces massive hippocampal neuron death linked to a surge in β-amyloid levels in mice overexpressing mutant amyloid precursor protein. Am J Pathol 153:1005–1010 1998

  • 88.

    Smith DHSoares HDPierce JSet al: A model of parasagittal controlled cortical impact in the mouse: cognitive and histopathologic effects. J Neurotrauma 12:1691781995Smith DH Soares HD Pierce JS et al: A model of parasagittal controlled cortical impact in the mouse: cognitive and histopathologic effects. J Neurotrauma 12:169–178 1995

  • 89.

    Stagliano NEPerez-Pinzon MAMoskowitz MAet al: Focal ischemic preconditioning induces rapid tolerance to middle cerebral artery occlusion in mice. J Cereb Blood Flow Metab 19:7577611999Stagliano NE Perez-Pinzon MA Moskowitz MA et al: Focal ischemic preconditioning induces rapid tolerance to middle cerebral artery occlusion in mice. J Cereb Blood Flow Metab 19:757–761 1999

  • 90.

    Strugar JSass KJBuchanan CPet al: Long-term consequences of minimal brain injury: loss of consciousness does not predict memory impairment. J Trauma 34:5555591993Strugar J Sass KJ Buchanan CP et al: Long-term consequences of minimal brain injury: loss of consciousness does not predict memory impairment. J Trauma 34:555–559 1993

  • 91.

    Tang YPNoda YHasegawa Tet al: A concussive-like brain injury model in mice (I): impairment in learning and memory. J Neurotrauma 14:8518621997Tang YP Noda Y Hasegawa T et al: A concussive-like brain injury model in mice (I): impairment in learning and memory. J Neurotrauma 14:851–862 1997

  • 92.

    Tang YPNoda YHasegawa Tet al: A concussive-like brain injury model in mice (II): selective neuronal loss in the cortex and hippocampus. J Neurotrauma 14:8638731997Tang YP Noda Y Hasegawa T et al: A concussive-like brain injury model in mice (II): selective neuronal loss in the cortex and hippocampus. J Neurotrauma 14:863–873 1997

  • 93.

    Tanno HNockels RPPitts LHet al: Breakdown of the blood-brain barrier after fluid percussive brain injury in the rat. Part 1: Distribution and time course of protein extravasation. J Neurotrauma 9:21321992Tanno H Nockels RP Pitts LH et al: Breakdown of the blood-brain barrier after fluid percussive brain injury in the rat. Part 1: Distribution and time course of protein extravasation. J Neurotrauma 9:21–32 1992

  • 94.

    Tokutomi THirohata MMiyagi Tet al: Posttraumatic edema in the corpus callosum shown by MRI. Acta Neurochir Suppl 70:80831997Tokutomi T Hirohata M Miyagi T et al: Posttraumatic edema in the corpus callosum shown by MRI. Acta Neurochir Suppl 70:80–83 1997

  • 95.

    Tysvaer ATStorli OVBachen NI: Soccer injuries to the brain. A neurologic and electroencephalographic study of former players. Acta Neurol Scand 80:1511561989Tysvaer AT Storli OV Bachen NI: Soccer injuries to the brain. A neurologic and electroencephalographic study of former players. Acta Neurol Scand 80:151–156 1989

  • 96.

    Waxweiler RJThurman DSniezek Jet al: Monitoring the impact of traumatic brain injury: a review and update. J Neurotrauma 12:5095161995Waxweiler RJ Thurman D Sniezek J et al: Monitoring the impact of traumatic brain injury: a review and update. J Neurotrauma 12:509–516 1995

  • 97.

    Yoshino AHovda DAKawamata Tet al: Dynamic changes in local cerebral glucose utilization following cerebral conclusion in rats: evidence of a hyper- and subsequent hypometabolic state. Brain Res 561:1061191991Yoshino A Hovda DA Kawamata T et al: Dynamic changes in local cerebral glucose utilization following cerebral conclusion in rats: evidence of a hyper- and subsequent hypometabolic state. Brain Res 561:106–119 1991

  • 98.

    Zhang CRaghupathi RSaatman KEet al: Riluzole attenuates cortical lesion size, but not hippocampal neuronal loss, following traumatic brain injury in the rat. J Neurosci Res 52:3423491998Zhang C Raghupathi R Saatman KE et al: Riluzole attenuates cortical lesion size but not hippocampal neuronal loss following traumatic brain injury in the rat. J Neurosci Res 52:342–349 1998

TrendMD

Cited By

Metrics

Metrics

All Time Past Year Past 30 Days
Abstract Views 200 200 40
Full Text Views 223 223 7
PDF Downloads 124 124 5
EPUB Downloads 0 0 0

PubMed

Google Scholar