Skip to main content
SpringerLink
Log in

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

  • Chapter
  • First Online:
Cerebral Blood Flow, Metabolism, and Head Trauma

  • 1606 Accesses

Abstract

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.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 129.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 169.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 169.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  • Appel SH, Simpson EP (2001) Activated microglia: the silent executioner in neurodegenerative disease? Curr Neurol Neurosci Rep 1:303–305

    Article  PubMed  CAS  Google Scholar 

  • Bales JW, Wagner AK, Kline AE, Dixon CE (2009) Persistent cognitive dysfunction after ­traumatic brain injury: a dopamine hypothesis. Neurosci Biobehav Rev 33:981–1003

    Article  PubMed  CAS  Google Scholar 

  • 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 1024:59–76

    Article  PubMed  CAS  Google Scholar 

  • Bessis A, Bechade C, Bernard D, Roumier A (2007) Microglial control of neuronal death and synaptic properties. Glia 55:233–238

    Article  PubMed  Google Scholar 

  • Block ML, Zecca L, Hong JS (2007) Microglia-mediated neurotoxicity: uncovering the molecular mechanisms. Nat Rev Neurosci 8:57–69

    Article  PubMed  CAS  Google Scholar 

  • Brenner LA, Terrio H, Homaifar BY et al (2010) Neuropsychological test performance in soldiers with blast-related mild TBI. Neuropsychology 24:160–167

    Article  PubMed  Google Scholar 

  • 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 79:77–89

    Article  PubMed  CAS  Google Scholar 

  • Cernak I (2005) Animal models of head trauma. NeuroRx 2:410–422

    Article  PubMed  Google Scholar 

  • Cernak I (2010) The importance of systemic response in the pathobiology of blast-induced ­neurotrauma. Front Neurol 1:151

    PubMed  Google Scholar 

  • Chen AJ, D’Esposito M (2010) Traumatic brain injury: from bench to bedside to society. Neuron 66:11–14

    Article  PubMed  CAS  Google Scholar 

  • 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 13:557–568

    Article  PubMed  CAS  Google Scholar 

  • Clemedson CJ (1956) Blast injury. Physiol Rev 36:336–354

    PubMed  CAS  Google Scholar 

  • Cole JT, Yarnell A, Kean WS et al (2011) Craniotomy: true sham for traumatic brain injury, or a sham of a sham? J Neurotrauma 28:359–369

    Article  PubMed  Google Scholar 

  • 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 11:809–819

    Article  PubMed  Google Scholar 

  • 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 19:427–438

    Article  PubMed  Google Scholar 

  • DeRoss AL, Adams JE, Vane DW, Russell SJ, Terella AM, Wald SL (2002) Multiple head injuries in rats: effects on behavior. J Trauma 52:708–714

    Article  PubMed  Google Scholar 

  • 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 85:123–133

    Article  PubMed  CAS  Google Scholar 

  • 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 142:546–553

    Article  PubMed  Google Scholar 

  • Finnie J (2001) Animal models of traumatic brain injury: a review. Aust Vet J 79:628–633

    Article  PubMed  CAS  Google Scholar 

  • 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 4:1328–1337

    Article  PubMed  CAS  Google Scholar 

  • Foda MA, Marmarou A (1994) A new model of diffuse brain injury in rats. Part II: morphological characterization. J Neurosurg 80:301–313

    Article  PubMed  CAS  Google Scholar 

  • 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, xi

    Article  PubMed  Google Scholar 

  • Goodman MD, Makley AT, Huber NL et al (2011) Hypobaric hypoxia exacerbates the neuroinflammatory response to traumatic brain injury. J Surg Res 165:30–37

    Article  PubMed  CAS  Google Scholar 

  • Guskiewicz KM (2011) Balance assessment in the management of sport-related concussion. Clin Sports Med 30:89–102

    Article  PubMed  Google Scholar 

  • Guskiewicz KM, Weaver NL, Padua DA, Garrett WE Jr (2000) Epidemiology of concussion in collegiate and high school football players. Am J Sports Med 28:643–650

    PubMed  CAS  Google Scholar 

  • 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 57:719–726

    Article  PubMed  Google Scholar 

  • 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 39:903–909

    Article  PubMed  Google Scholar 

  • 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 61:1244–1252

    Article  PubMed  Google Scholar 

  • Halstead ME, Walter KD (2010) Sport-related concussion in children and adolescents. Pediatrics 126:597–615

    Article  PubMed  Google Scholar 

  • 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 64:1174–1182

    Article  PubMed  Google Scholar 

  • Hanisch UK, Kettenmann H (2007) Microglia: active sensor and versatile effector cells in the normal and pathologic brain. Nat Neurosci 10:1387–1394

    Article  PubMed  CAS  Google Scholar 

  • 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 27:911–921

    Article  PubMed  Google Scholar 

  • Jain KK (2008) Neuroprotection in traumatic brain injury. Drug Discov Today 13:1082–1089

    Article  PubMed  CAS  Google Scholar 

  • 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 18:105–115

    PubMed  CAS  Google Scholar 

  • 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 203:41–49

    Article  PubMed  Google Scholar 

  • 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 26:2233–2243

    Article  PubMed  Google Scholar 

  • 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 14:859–875

    Article  PubMed  CAS  Google Scholar 

  • Kuehn R, Simard PF, Driscoll I et al (2011) Rodent model of direct cranial blast injury. J Neurotrauma 28:2155–2169

    Article  PubMed  Google Scholar 

  • LaPlaca MC, Simon CM, Prado GR, Cullen DK (2007) CNS injury biomechanics and experimental models. Prog Brain Res 161:13–26

    Article  PubMed  CAS  Google Scholar 

  • Laurer HL, Bareyre FM, Lee VM et al (2001) Mild head injury increasing the brain’s vulnerability to a second concussive impact. J Neurosurg 95:859–870

    Article  PubMed  CAS  Google Scholar 

  • 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 27:683–694

    Article  PubMed  Google Scholar 

  • Lighthall JW, Dixon CE, Anderson TE (1989) Experimental models of brain injury. J Neurotrauma 6:83–97

    Article  PubMed  CAS  Google Scholar 

  • 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 26:827–840

    Article  PubMed  Google Scholar 

  • Longhi L, Saatman KE, Fujimoto S et al (2005) Temporal window of vulnerability to repetitive experimental concussive brain injury. Neurosurgery 56:364–374

    Article  PubMed  Google Scholar 

  • 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 24:232–238

    Article  PubMed  Google Scholar 

  • 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 364:2091–2100

    Article  PubMed  CAS  Google Scholar 

  • 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 80:291–300

    Article  PubMed  CAS  Google Scholar 

  • Masel BE, DeWitt DS (2010) Traumatic brain injury: a disease process, not an event. J Neurotrauma 27:1529–1540

    Article  PubMed  Google Scholar 

  • McGeer EG, McGeer PL (1997) The role of the immune system in neurodegenerative disorders. Mov Disord 12:855–858

    Article  PubMed  CAS  Google Scholar 

  • McKee AC, Cantu RC, Nowinski CJ et al (2009) Chronic traumatic encephalopathy in athletes: progressive tauopathy after repetitive head injury. J Neuropathol Exp Neurol 68:709–735

    Article  PubMed  Google Scholar 

  • McKee AC, Gavett BE, Stern RA et al (2010) TDP-43 proteinopathy and motor neuron disease in chronic traumatic encephalopathy. J Neuropathol Exp Neurol 69:918–929

    Article  PubMed  CAS  Google Scholar 

  • Meaney DF, Smith DH (2011) Biomechanics of concussion. Clin Sports Med 30:19–31

    Article  PubMed  Google Scholar 

  • Menon DK (2009) Unique challenges in clinical trials in traumatic brain injury. Crit Care Med 37:S129–S135

    Article  PubMed  Google Scholar 

  • 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 136:971–989

    Article  PubMed  CAS  Google Scholar 

  • 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 29:662–677

    Google Scholar 

  • 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 37–38

    PubMed  Google Scholar 

  • O’Callaghan JP, Miller DB (1993) Quantification of reactive gliosis as an approach to neurotoxicity assessment. NIDA Res Monogr 136:188–212

    PubMed  Google Scholar 

  • Okie S (2005) Traumatic brain injury in the war zone. N Engl J Med 352:2043–2047

    Article  PubMed  CAS  Google Scholar 

  • 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 6:40–46

    Article  PubMed  Google Scholar 

  • Park HK, Fernandez II, Dujovny M, Diaz FG (1999) Experimental animal models of traumatic brain injury: medical and biomechanical mechanism. Crit Rev Neurosurg 9:44–52

    Article  PubMed  Google Scholar 

  • Pellman EJ, Viano DC, Tucker AM, Casson IR (2003a) Concussion in professional football: location and direction of helmet impacts-part 2. Neurosurgery 53:1328–1340

    Article  PubMed  Google Scholar 

  • Pellman EJ, Viano DC, Tucker AM, Casson IR, Waeckerle JF (2003b) Concussion in professional football: reconstruction of game impacts and injuries. Neurosurgery 53:799–812

    PubMed  Google Scholar 

  • Pellman EJ, Viano DC, Casson IR, Tucker AM, Waeckerle JF, Powell JW, Feuer H (2004) Concussion in professional football: repeat injuries–part 4. Neurosurgery 55:860–873

    Article  PubMed  Google Scholar 

  • Pellman EJ, Viano DC, Casson IR, Arfken C, Feuer H (2005) Concussion in professional football: players returning to the same game–part 7. Neurosurgery 56:79–90

    PubMed  Google Scholar 

  • 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 58:263–274

    Article  PubMed  Google Scholar 

  • Planel E, Richter KE, Nolan CE et al (2007) Anesthesia leads to tau hyperphosphorylation through inhibition of phosphatase activity by hypothermia. J Neurosci 27:3090–3097

    Article  PubMed  CAS  Google Scholar 

  • 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 55:1158–1166

    Article  PubMed  CAS  Google Scholar 

  • 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 28:396–409

    Article  PubMed  CAS  Google Scholar 

  • 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 20:369–380

    Article  PubMed  CAS  Google Scholar 

  • 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 1076:216–224

    Article  PubMed  CAS  Google Scholar 

  • 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 69:795–804

    Article  PubMed  CAS  Google Scholar 

  • Tanielian T, Jaycox LH (2008) Invisible wounds of War: psychological and cognitive injuries, their consequences, and services to assist recover. RAND Corporation, Santa Monica, CA

    Google Scholar 

  • 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 24:14–23

    Article  PubMed  Google Scholar 

  • 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 22:42–75

    Article  PubMed  Google Scholar 

  • 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 22:446–454

    PubMed  CAS  Google Scholar 

  • 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 46:717–757

    Article  PubMed  Google Scholar 

  • Viano DC, Pellman EJ (2005) Concussion in professional football: biomechanics of the striking player–part 8. Neurosurgery 56:266–280

    Article  PubMed  Google Scholar 

  • 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 57:1154–1172

    Article  PubMed  Google Scholar 

  • Viano DC, Casson IR, Pellman EJ (2007) Concussion in professional football: biomechanics of the struck player–part 14. Neurosurgery 61:313–327

    Article  PubMed  Google Scholar 

  • Viano DC, Hamberger A, Bolouri H, Saljo A (2009) Concussion in professional football: animal model of brain injury–part 15. Neurosurgery 64:1162–1173

    Article  PubMed  Google Scholar 

  • 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):213–226

    Article  PubMed  Google Scholar 

  • 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 28:2171–2183

    Article  PubMed  Google Scholar 

  • Weber JT (2007) Experimental models of repetitive brain injuries. Prog Brain Res 161:253–261

    Article  PubMed  Google Scholar 

  • 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 28:1–11

    Article  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Psychiatry and Behavioral Neurosciences, Wayne State University School of Medicine, Detroit, MI, USA

    Michael J. Kane PhD, Mariana Angoa Pérez PhD, Denise I. Briggs BS & Donald M. Kuhn PhD

  2. John D. Dingell VA Medical Center, Research and Development Service, Detroit, MI, USA

    Michael J. Kane PhD, Mariana Angoa Pérez PhD, Denise I. Briggs BS, Christian W. Kreipke PhD & Donald M. Kuhn PhD

  3. ProBiomechanics LLC, Bloomfield Hills, MI, 48304-2952, USA

    David C. Viano PhD

  4. Department of Biomedical Engineering, School of Engineering, Wayne State University, Detroit, MI, 48201-1916, USA

    David C. Viano PhD

Authors
  1. Michael J. Kane PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Mariana Angoa Pérez PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Denise I. Briggs BS
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. David C. Viano PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Christian W. Kreipke PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Donald M. Kuhn PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Donald M. Kuhn PhD .

Editor information

Editors and Affiliations

  1. , Health Science Specialist, John D. Dingell VA Medical Center, 4646 John R Street, Detroit, 48201, Michigan, USA

    Christian W. Kreipke

  2. School of Medicine, Anatomy and Cell Biology, Wayne State University, 540 East Canfield, Detroit, 48201, Michigan, USA

    Jose A. Rafols

Rights and permissions

Reprints and permissions

Copyright information

© 2013 Springer Science+Business Media New York

About this chapter

Cite this chapter

Kane, M.J., Pérez, M.A., Briggs, D.I., Viano, D.C., Kreipke, C.W., Kuhn, D.M. (2013). Modeling of Traumatic Brain Injury and its Implications in Studying the Pathology of Repeated Mild Impacts to the Head. In: Kreipke, C., Rafols, J. (eds) Cerebral Blood Flow, Metabolism, and Head Trauma. Springer, New York, NY. https://doi.org/10.1007/978-1-4614-4148-9_3

Download citation

Publish with us

Policies and ethics

Search

Navigation