Modeling of Traumatic Brain Injury and its Implications in Studying the Pathology of Repeated Mild Impacts to the Head

  • Michael J. Kane
  • Mariana Angoa Pérez
  • Denise I. Briggs
  • David C. Viano
  • Christian W. Kreipke
  • Donald M. Kuhn


Traumatic brain injury (TBI) results from a blow to the head and can range in severity from mild to severe. Mild TBI is the most common form of head injury and constitutes about 80–90 % of all cases. Repetitive mild TBI (rmTBI) has emerged as a significant public health concern as the number of individuals experiencing this type of injury in military combat operations and in athletic endeavors continues to increase at a very high rate. The medical and scientific communities have only just started to grapple with its complexity and are struggling to understanding the underlying pathotrajectory and to develop and implement tests to detect and assess rmTBI. For the most part, routine imaging approaches and standard neuropsychological tests contribute little to the evaluation and management of rmTBI. A better understanding of the pathological consequences of rmTBI, including elucidating the role of hypoperfusion, could be achieved with a validated animal model, but most existing models impart acute injuries that are severe and do not simulate the essential characteristics of head impacts that are known to result in mild concussion in humans. Here we discuss several current models of head trauma in the context of strengths and weaknesses of using these models. We also include a discussion of a new model of rmTBI that involves a blow to the unrestrained head of a mouse. Upon each impact, the subject’s head undergoes rapid acceleration. After as many as five to ten head impacts, mice recover consciousness rapidly and show no signs of skull fracture, edema, intracranial bleeding, or seizure activity. Histological signs of injury include glial activation and a delayed development of tangle-like proteins as seen in human chronic traumatic encephalopathy. This new model closely simulates head impact as seen in humans who experience rmTBI. Initial experimental validation suggests that the pathotrajectory is also very similar to histological signs observed in postmortem human brain from individuals who had sustained rmTBI. Future studies using this new model will hopefully uncover new mechanisms that underlie dysfunctional blood flow and metabolism and, more importantly, the cognitive and behavioral deficits associated with rmTBI.


Traumatic Brain Injury Blast Wave Severe Traumatic Brain Injury Skull Fracture Mild Traumatic Brain Injury 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


  1. Appel SH, Simpson EP (2001) Activated microglia: the silent executioner in neurodegenerative disease? Curr Neurol Neurosci Rep 1:303–305PubMedCrossRefGoogle Scholar
  2. Bales JW, Wagner AK, Kline AE, Dixon CE (2009) Persistent cognitive dysfunction after ­traumatic brain injury: a dopamine hypothesis. Neurosci Biobehav Rev 33:981–1003PubMedCrossRefGoogle Scholar
  3. Benkovic SA, O’Callaghan JP, Miller DB (2004) Sensitive indicators of injury reveal hippocampal damage in C57BL/6 J mice treated with kainic acid in the absence of tonic-clonic seizures. Brain Res 1024:59–76PubMedCrossRefGoogle Scholar
  4. Bessis A, Bechade C, Bernard D, Roumier A (2007) Microglial control of neuronal death and synaptic properties. Glia 55:233–238PubMedCrossRefGoogle Scholar
  5. Block ML, Zecca L, Hong JS (2007) Microglia-mediated neurotoxicity: uncovering the molecular mechanisms. Nat Rev Neurosci 8:57–69PubMedCrossRefGoogle Scholar
  6. Brenner LA, Terrio H, Homaifar BY et al (2010) Neuropsychological test performance in soldiers with blast-related mild TBI. Neuropsychology 24:160–167PubMedCrossRefGoogle Scholar
  7. Buffo A, Rolando C, Ceruti S (2010) Astrocytes in the damaged brain: molecular and cellular insights into their reactive response and healing potential. Biochem Pharmacol 79:77–89PubMedCrossRefGoogle Scholar
  8. Cernak I (2005) Animal models of head trauma. NeuroRx 2:410–422PubMedCrossRefGoogle Scholar
  9. Cernak I (2010) The importance of systemic response in the pathobiology of blast-induced ­neurotrauma. Front Neurol 1:151PubMedGoogle Scholar
  10. Chen AJ, D’Esposito M (2010) Traumatic brain injury: from bench to bedside to society. Neuron 66:11–14PubMedCrossRefGoogle Scholar
  11. Chen Y, Constantini S, Trembovler V, Weinstock M, Shohami E (1996) An experimental model of closed head injury in mice: pathophysiology, histopathology, and cognitive deficits. J Neurotrauma 13:557–568PubMedCrossRefGoogle Scholar
  12. Clemedson CJ (1956) Blast injury. Physiol Rev 36:336–354PubMedGoogle Scholar
  13. Cole JT, Yarnell A, Kean WS et al (2011) Craniotomy: true sham for traumatic brain injury, or a sham of a sham? J Neurotrauma 28:359–369PubMedCrossRefGoogle Scholar
  14. Creeley CE, Wozniak DF, Bayly PV, Olney JW, Lewis LM (2004) Multiple episodes of mild traumatic brain injury result in impaired cognitive performance in mice. Acad Emerg Med 11:809–819PubMedCrossRefGoogle Scholar
  15. DeFord SM, Wilson MS, Rice AC, Clausen T, Rice LK, Barabnova A, Bullock R, Hamm RJ (2002) Repeated mild brain injuries result in cognitive impairment in B6C3F1 mice. J Neurotrauma 19:427–438PubMedCrossRefGoogle Scholar
  16. DeRoss AL, Adams JE, Vane DW, Russell SJ, Terella AM, Wald SL (2002) Multiple head injuries in rats: effects on behavior. J Trauma 52:708–714PubMedCrossRefGoogle Scholar
  17. Dugar A, Patanow C, O’Callaghan JP, Lakoski JM (1998) Immunohistochemical localization and quantification of glial fibrillary acidic protein and synaptosomal-associated protein (mol. wt 25000) in the ageing hippocampus following administration of 5,7- dihydroxytryptamine. Neuroscience 85:123–133PubMedCrossRefGoogle Scholar
  18. Field M, Collins MW, Lovell MR, Maroon J (2003) Does age play a role in recovery from sports-related concussion? a comparison of high school and collegiate athletes. J Pediatr 142:546–553PubMedCrossRefGoogle Scholar
  19. Finnie J (2001) Animal models of traumatic brain injury: a review. Aust Vet J 79:628–633PubMedCrossRefGoogle Scholar
  20. Flierl MA, Stahel PF, Beauchamp KM, Morgan SJ, Smith WR, Shohami E (2009) Mouse closed head injury model induced by a weight-drop device. Nat Protoc 4:1328–1337PubMedCrossRefGoogle Scholar
  21. Foda MA, Marmarou A (1994) A new model of diffuse brain injury in rats. Part II: morphological characterization. J Neurosurg 80:301–313PubMedCrossRefGoogle Scholar
  22. Gavett BE, Stern RA, McKee AC (2011) Chronic traumatic encephalopathy: a potential late effect of sport-related concussive and subconcussive head trauma. Clin Sports Med 30:179–188, xiPubMedCrossRefGoogle Scholar
  23. Goodman MD, Makley AT, Huber NL et al (2011) Hypobaric hypoxia exacerbates the neuroinflammatory response to traumatic brain injury. J Surg Res 165:30–37PubMedCrossRefGoogle Scholar
  24. Guskiewicz KM (2011) Balance assessment in the management of sport-related concussion. Clin Sports Med 30:89–102PubMedCrossRefGoogle Scholar
  25. Guskiewicz KM, Weaver NL, Padua DA, Garrett WE Jr (2000) Epidemiology of concussion in collegiate and high school football players. Am J Sports Med 28:643–650PubMedGoogle Scholar
  26. Guskiewicz KM, Marshall SW, Bailes J, McCrea M, Cantu RC, Randolph C, Jordan BD (2005) Association between recurrent concussion and late-life cognitive impairment in retired professional football players. Neurosurgery 57:719–726PubMedCrossRefGoogle Scholar
  27. Guskiewicz KM, Marshall SW, Bailes J, McCrea M, Harding HP Jr, Matthews A, Mihalik JR, Cantu RC (2007a) Recurrent concussion and risk of depression in retired professional football players. Med Sci Sports Exerc 39:903–909PubMedCrossRefGoogle Scholar
  28. Guskiewicz KM, Mihalik JP, Shankar V, Marshall SW, Crowell DH, Oliaro SM, Ciocca MF, Hooker DN (2007b) Measurement of head impacts in collegiate football players: relationship between head impact biomechanics and acute clinical outcome after concussion. Neurosurgery 61:1244–1252PubMedCrossRefGoogle Scholar
  29. Halstead ME, Walter KD (2010) Sport-related concussion in children and adolescents. Pediatrics 126:597–615PubMedCrossRefGoogle Scholar
  30. Hamberger A, Viano DC, Saljo A, Bolouri H (2009) Concussion in professional football: morphology of brain injuries in the NFL concussion model–part 16. Neurosurgery 64:1174–1182PubMedCrossRefGoogle Scholar
  31. Hanisch UK, Kettenmann H (2007) Microglia: active sensor and versatile effector cells in the normal and pathologic brain. Nat Neurosci 10:1387–1394PubMedCrossRefGoogle Scholar
  32. Homsi S, Piaggio T, Croci N, Noble F, Plotkine M, Marchand-Leroux C, Jafarian-Tehrani M (2010) Blockade of acute microglial activation by minocycline promotes neuroprotection and reduces locomotor hyperactivity after closed head injury in mice: a twelve-week follow-up study. J Neurotrauma 27:911–921PubMedCrossRefGoogle Scholar
  33. Jain KK (2008) Neuroprotection in traumatic brain injury. Drug Discov Today 13:1082–1089PubMedCrossRefGoogle Scholar
  34. Kanayama G, Takeda M, Niigawa H et al (1996) The effects of repetitive mild brain injury on cytoskeletal protein and behavior. Methods Find Exp Clin Pharmacol 18:105–115PubMedGoogle Scholar
  35. Kane MJ, Angoa-Perez M, Briggs DI, Viano DC, Kreipke CW, Kuhn DM (2012) A mouse model of human repetitive mild traumatic brain injury. J Neurosci Methods 203:41–49PubMedCrossRefGoogle Scholar
  36. Kilbourne M, Kuehn R, Tosun C, Caridi J, Keledjian K, Bochicchio G, Scalea T, Gerzanich V, Simard JM (2009) Novel model of frontal impact closed head injury in the rat. J Neurotrauma 26:2233–2243PubMedCrossRefGoogle Scholar
  37. Konrad K, Gauggel S, Manz A, Scholl M (2000) Inhibitory control in children with traumatic brain injury (TBI) and children with attention deficit/hyperactivity disorder (ADHD). Brain Inj 14:859–875PubMedCrossRefGoogle Scholar
  38. Kuehn R, Simard PF, Driscoll I et al (2011) Rodent model of direct cranial blast injury. J Neurotrauma 28:2155–2169PubMedCrossRefGoogle Scholar
  39. LaPlaca MC, Simon CM, Prado GR, Cullen DK (2007) CNS injury biomechanics and experimental models. Prog Brain Res 161:13–26PubMedCrossRefGoogle Scholar
  40. Laurer HL, Bareyre FM, Lee VM et al (2001) Mild head injury increasing the brain’s vulnerability to a second concussive impact. J Neurosurg 95:859–870PubMedCrossRefGoogle Scholar
  41. Levin HS, Wilde E, Troyanskaya M et al (2010) Diffusion tensor imaging of mild to moderate blast-related traumatic brain injury and its sequelae. J Neurotrauma 27:683–694PubMedCrossRefGoogle Scholar
  42. Lighthall JW, Dixon CE, Anderson TE (1989) Experimental models of brain injury. J Neurotrauma 6:83–97PubMedCrossRefGoogle Scholar
  43. Long JB, Bentley TL, Wessner KA, Cerone C, Sweeney S, Bauman RA (2009) Blast overpressure in rats: recreating a battlefield injury in the laboratory. J Neurotrauma 26:827–840PubMedCrossRefGoogle Scholar
  44. Longhi L, Saatman KE, Fujimoto S et al (2005) Temporal window of vulnerability to repetitive experimental concussive brain injury. Neurosurgery 56:364–374PubMedCrossRefGoogle Scholar
  45. Maas AI, Marmarou A, Murray GD, Teasdale SG, Steyerberg EW (2007) Prognosis and clinical trial design in traumatic brain injury: the IMPACT study. J Neurotrauma 24:232–238PubMedCrossRefGoogle Scholar
  46. Mac Donald CL, Johnson AM, Cooper D et al (2011) Detection of blast-related traumatic brain injury in U.S. military personnel. N Engl J Med 364:2091–2100PubMedCrossRefGoogle Scholar
  47. Marmarou A, Foda MA, van den Brink W, Campbell J, Kita H, Demetriadou K (1994) A new model of diffuse brain injury in rats. Part I: pathophysiology and biomechanics. J Neurosurg 80:291–300PubMedCrossRefGoogle Scholar
  48. Masel BE, DeWitt DS (2010) Traumatic brain injury: a disease process, not an event. J Neurotrauma 27:1529–1540PubMedCrossRefGoogle Scholar
  49. McGeer EG, McGeer PL (1997) The role of the immune system in neurodegenerative disorders. Mov Disord 12:855–858PubMedCrossRefGoogle Scholar
  50. McKee AC, Cantu RC, Nowinski CJ et al (2009) Chronic traumatic encephalopathy in athletes: progressive tauopathy after repetitive head injury. J Neuropathol Exp Neurol 68:709–735PubMedCrossRefGoogle Scholar
  51. McKee AC, Gavett BE, Stern RA et al (2010) TDP-43 proteinopathy and motor neuron disease in chronic traumatic encephalopathy. J Neuropathol Exp Neurol 69:918–929PubMedCrossRefGoogle Scholar
  52. Meaney DF, Smith DH (2011) Biomechanics of concussion. Clin Sports Med 30:19–31PubMedCrossRefGoogle Scholar
  53. Menon DK (2009) Unique challenges in clinical trials in traumatic brain injury. Crit Care Med 37:S129–S135PubMedCrossRefGoogle Scholar
  54. Morales DM, Marklund N, Lebold D et al (2005) Experimental models of traumatic brain injury: do we really need to build a better mousetrap? Neuroscience 136:971–989PubMedCrossRefGoogle Scholar
  55. Mott JW (1917) The microscopic examination of the brains of two med dead of commotio cerebri (shell shock) without visible external injury. Br Med J 29:662–677Google Scholar
  56. O’Callaghan JP (1998) Astrocytes: key players in mediation or modulation of neurotoxic responses? commentary on forum position paper [comment]. Neurotoxicology 19:35–36, discussion 37–38PubMedGoogle Scholar
  57. O’Callaghan JP, Miller DB (1993) Quantification of reactive gliosis as an approach to neurotoxicity assessment. NIDA Res Monogr 136:188–212PubMedGoogle Scholar
  58. Okie S (2005) Traumatic brain injury in the war zone. N Engl J Med 352:2043–2047PubMedCrossRefGoogle Scholar
  59. Omalu BI, Hamilton RL, Kamboh MI, DeKosky ST, Bailes J (2010) Chronic traumatic encephalopathy (CTE) in a national football league player: case report and emerging medicolegal practice questions. J Forensic Nurs 6:40–46PubMedCrossRefGoogle Scholar
  60. Park HK, Fernandez II, Dujovny M, Diaz FG (1999) Experimental animal models of traumatic brain injury: medical and biomechanical mechanism. Crit Rev Neurosurg 9:44–52PubMedCrossRefGoogle Scholar
  61. Pellman EJ, Viano DC, Tucker AM, Casson IR (2003a) Concussion in professional football: location and direction of helmet impacts-part 2. Neurosurgery 53:1328–1340PubMedCrossRefGoogle Scholar
  62. Pellman EJ, Viano DC, Tucker AM, Casson IR, Waeckerle JF (2003b) Concussion in professional football: reconstruction of game impacts and injuries. Neurosurgery 53:799–812PubMedGoogle Scholar
  63. Pellman EJ, Viano DC, Casson IR, Tucker AM, Waeckerle JF, Powell JW, Feuer H (2004) Concussion in professional football: repeat injuries–part 4. Neurosurgery 55:860–873PubMedCrossRefGoogle Scholar
  64. Pellman EJ, Viano DC, Casson IR, Arfken C, Feuer H (2005) Concussion in professional football: players returning to the same game–part 7. Neurosurgery 56:79–90PubMedGoogle Scholar
  65. Pellman EJ, Lovell MR, Viano DC, Casson IR (2006) Concussion in professional football: recovery of NFL and high school athletes assessed by computerized neuropsychological testing–part 12. Neurosurgery 58:263–274PubMedCrossRefGoogle Scholar
  66. Planel E, Richter KE, Nolan CE et al (2007) Anesthesia leads to tau hyperphosphorylation through inhibition of phosphatase activity by hypothermia. J Neurosci 27:3090–3097PubMedCrossRefGoogle Scholar
  67. Plassman BL, Havlik RJ, Steffens DC et al (2000) Documented head injury in early adulthood and risk of Alzheimer’s disease and other dementias. Neurology 55:1158–1166PubMedCrossRefGoogle Scholar
  68. Pullela R, Raber J, Pfankuch T et al (2006) Traumatic injury to the immature brain results in progressive neuronal loss, hyperactivity and delayed cognitive impairments. Dev Neurosci 28:396–409PubMedCrossRefGoogle Scholar
  69. Stahel PF, Shohami E, Younis FM et al (2000) Experimental closed head injury: analysis of neurological outcome, blood–brain barrier dysfunction, intracranial neutrophil infiltration, and neuronal cell death in mice deficient in genes for pro-inflammatory cytokines. J Cereb Blood Flow Metab 20:369–380PubMedCrossRefGoogle Scholar
  70. Statler KD, Alexander H, Vagni V, Holubkov R, Dixon CE, Clark RS, Jenkins L, Kochanek PM (2006) Isoflurane exerts neuroprotective actions at or near the time of severe traumatic brain injury. Brain Res 1076:216–224PubMedCrossRefGoogle Scholar
  71. Svetlov SI, Prima V, Kirk DR, Gutierrez H, Curley KC, Hayes RL, Wang KK (2010) Morphologic and biochemical characterization of brain injury in a model of controlled blast overpressure exposure. J Trauma 69:795–804PubMedCrossRefGoogle Scholar
  72. Tanielian T, Jaycox LH (2008) Invisible wounds of War: psychological and cognitive injuries, their consequences, and services to assist recover. RAND Corporation, Santa Monica, CAGoogle Scholar
  73. Terrio H, Brenner LA, Ivins BJ, Cho JM, Helmick K, Schwab K, Scally K, Bretthauer R, Warden D (2009) Traumatic brain injury screening: preliminary findings in a US army brigade combat team. J Head Trauma Rehabil 24:14–23PubMedCrossRefGoogle Scholar
  74. Thompson HJ, Lifshitz J, Marklund N, Grady MS, Graham DI, Hovda DA, McIntosh TK (2005) Lateral fluid percussion brain injury: a 15-year review and evaluation. J Neurotrauma 22:42–75PubMedCrossRefGoogle Scholar
  75. Uryu K, Laurer H, McIntosh T, Pratico D, Martinez D, Leight S, Lee VM, Trojanowski JQ (2002) Repetitive mild brain trauma accelerates abeta deposition, lipid peroxidation, and cognitive impairment in a transgenic mouse model of Alzheimer amyloidosis. J Neurosci 22:446–454PubMedGoogle Scholar
  76. Van Boven RW, Harrington GS, Hackney DB et al (2009) Advances in neuroimaging of traumatic brain injury and posttraumatic stress disorder. J Rehabil Res Dev 46:717–757PubMedCrossRefGoogle Scholar
  77. Viano DC, Pellman EJ (2005) Concussion in professional football: biomechanics of the striking player–part 8. Neurosurgery 56:266–280PubMedCrossRefGoogle Scholar
  78. Viano DC, Casson IR, Pellman EJ, Bir CA, Zhang L, Sherman DC, Boitano MA (2005) Concussion in professional football: comparison with boxing head impacts–part 10. Neurosurgery 57:1154–1172PubMedCrossRefGoogle Scholar
  79. Viano DC, Casson IR, Pellman EJ (2007) Concussion in professional football: biomechanics of the struck player–part 14. Neurosurgery 61:313–327PubMedCrossRefGoogle Scholar
  80. Viano DC, Hamberger A, Bolouri H, Saljo A (2009) Concussion in professional football: animal model of brain injury–part 15. Neurosurgery 64:1162–1173PubMedCrossRefGoogle Scholar
  81. Viano DC, Hamberger A, Bolouri H, Saljo A (2012) Evaluation of three animal models for concussion and serious brain injury. Ann Biomed Eng 40(1):213–226PubMedCrossRefGoogle Scholar
  82. Wang Y, Wei Y, Oguntayo S, Wilkins W, Arun P, Valiyaveettil M, Song J, Long JB, Nambiar MP (2011) Tightly coupled repetitive blast-induced traumatic brain injury: development and characterization in mice. J Neurotrauma 28:2171–2183PubMedCrossRefGoogle Scholar
  83. Weber JT (2007) Experimental models of repetitive brain injuries. Prog Brain Res 161:253–261PubMedCrossRefGoogle Scholar
  84. Yeo RA, Gasparovic C, Merideth F, Ruhl D, Doezema D, Mayer AR (2011) A longitudinal proton magnetic resonance spectroscopy study of mild traumatic brain injury. J Neurotrauma 28:1–11PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2013

Authors and Affiliations

  • Michael J. Kane
    • 1
    • 2
  • Mariana Angoa Pérez
    • 1
    • 2
  • Denise I. Briggs
    • 1
    • 2
  • David C. Viano
    • 3
    • 4
  • Christian W. Kreipke
    • 2
  • Donald M. Kuhn
    • 1
    • 2
  1. 1.Department of Psychiatry and Behavioral NeurosciencesWayne State University School of MedicineDetroitUSA
  2. 2.John D. Dingell VA Medical Center, Research and Development ServiceDetroitUSA
  3. 3.ProBiomechanics LLCBloomfield HillsUSA
  4. 4.Department of Biomedical Engineering, School of EngineeringWayne State UniversityDetroitUSA

Personalised recommendations