Journal Mobile Options
Table of Contents
Vol. 28, No. 4-5, 2006
Issue release date: August 2006
Dev Neurosci 2006;28:380–387

Large Animal Models of Traumatic Injury to the Immature Brain

Duhaime A.-C.
Pediatric Neurosurgery, Children’s Hospital at Dartmouth, Dartmouth Hitchcock Medical Center, Lebanon, N.H., USA

Individual Users: Register with Karger Login Information

Please create your User ID & Password

Contact Information

I have read the Karger Terms and Conditions and agree.

To view the fulltext, please log in

To view the pdf, please log in


Large animal models have been used much less frequently than rodent models to study traumatic brain injury. However, large animal models offer distinct advantages in replicating specific mechanisms, morphology and maturational stages relevant to age-dependent injury responses. This paper reviews how each of these features is relevant in matching a model to a particular scientific question and discusses various scaling strategies, advantages and disadvantages of large animal models for studying traumatic brain injury in infants and children. Progress to date and future directions are outlined.

Copyright / Drug Dosage

Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher or, in the case of photocopying, direct payment of a specified fee to the Copyright Clearance Center.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in goverment regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.


  1. Narayan RK, Michel ME, Ansell B, Baethmann A, Biegon A, Bracken MB, Bullock MR, Choi SC, Clifton GL, Contant CF, Coplin WM, Dietrich WD, Ghajar J, Grady MS, Grossman RG, Hall ED, Heetderks W, Hovda DA, Jallo J, Katz RL, Knoller N, Kochanek PM, Maas AI, Majde J, Marion DW, Marmarou A, Marshall LF, McIntosh TK, Miller E, Mohberg N, Muizelaar JP, Pitts LH, Quinn P, Riesenfeld G, Robertson CS, Strauss KI, Teasdale GM, Temkin N, Tuma R, Wade C, Walker MD, Weinrich M, Whyte J, Wilberger JE Jr, Young AB, Yurkewicz L: Clinical trials in head injury. J Neurotrauma 2002;19:503–557.
  2. Gennarelli TA, Thibault LE: Biomechanics of head injury; in Wilkins RH, Rengachary SS (eds): Neurosurgery. New York, McGraw-Hill, 1985, pp 1531–1536.
  3. Kraus JF, Fife D, Cox P, Ramstein K, Conroy C: Incidence, severity, and external causes of pediatric brain injury. Am J Dis Child 1986;140:687–693.
  4. Kraus JF, Rock A, Hemyari P: Brain injuries among infants, children, adolescents, and young adults. Am J Dis Child 1990;144:684–691.
  5. Centers for Disease Control. Childhood injuries in the United States. Am J Dis Child 1990;144:627–646.

    External Resources

  6. Prange MT, Coats B, Duhaime AC, Margulies SS: Anthropomorphic simulations of falls, shakes, and inflicted impacts in infants. J Neurosurg 2003;99:143–150.
  7. Pellmann EJ, Viano DC, Tucker AM, Casson IR, Waeckerle JF: Concussion in professional football: reconstruction of game impacts and injuries. Neurosurgery 2003;53:799–812.

    External Resources

  8. Pellmann EJ, Viano DC, Tucker AM, Casson IR: Concussion in professional football: location and direction of helmet impacts – part 2. Neurosurgery 2003;53:1328–1340.
  9. Duhaime AC, Alario AJ, Lewander WJ, Schut L, Sutton LN, Seidl T, Nudelman S, Budenz D, Hertle R, Tsiaras W, Loporchio S: Head injury in very young children: mechanism, injury types, and ophthalmologic findings in 100 hospitalized patients younger than 2 years of age. Pediatrics 1992;90:179–185.
  10. Luerssen TG: Head injuries in children. Neurosurg Clin N Am 1991;2:399–410.
  11. Johnson DL, Boal D, Baule R: Role of apnea in nonaccidental head injury. Pediatr Neurosurg 1995;23:305–310.
  12. Duhaime AC, Christian CW, Rorke LB, Zimmerman RA: Nonaccidental head injury in infants – the ‘shaken baby syndrome’. N Engl J Med 1998;338:1822–1829.
  13. Gilles EE, Nelson MD Jr: Cerebral complications of nonaccidental head injury in childhood. Pediatr Neurol 1998;19:119–128.
  14. Gennarelli TA: Animate models of human head injury. J Neurotrauma 1994;11:357–368.
  15. Finnie JW, Blumbergs PC: Animal models – traumatic brain injury. Vet Pathol 2002;39:679–689.
  16. Marmarou A, Montasser A, Foday AE, Van den Brink W, Campell J, Kita H, Demetriadou K: A new model of diffuse brain injury in rats. 1. Pathophysiology and biomechanics. J Neurosurg 1994;80:291–300.
  17. Madsen FF, Reske-Nielsen E: A simple mechanical model using a piston to produce localized cerebral contusion in pigs. Acta Neurochir 1987;88:65–72.
  18. Duhaime AC, Margulies SS, Durham SR, O’Rourke MM, Golden JA, Marwaha S, Raghupathi R: Maturation-dependent response of the piglet brain to scaled cortical impact. J Neurosurg 2000;93:455–462.
  19. Finnie JW, Manavis J, Summersides GE, Blumbergs PC: Brain damage in pigs produced by impact with a non-penetrating captive bolt pistol. Aust Vet J 2003;81:153–155.
  20. Van den Heuvel C, Blumbergs PC, Finnie JW, Manavis J, Jones NR, Reilly PL, Pereira RA: Upregulation of amyloid precursor protein messenger RNA in response to traumatic brain injury: an ovine head impact model. Exp Neurol 1999;159:441–450.
  21. Anderson RW, Brown CJ, Blumbergs PC, McLean AJ, Jones NR: Impact mechanics and axonal injury in a sheep model. J Neurotrauma 2003;20:961–974.
  22. Armstead WM, Kurth CD: Different cerebral hemodynamic responses following fluid percussion brain injury in the newborn and juvenile pig. J Neurotrauma 1994;11:487–497.
  23. Gennarelli TA, Thibault LE: Biomechanics of acute subdural hematoma. J Trauma 1982;22:680–686.
  24. Smith DH, Chen XH, Xu BN, McIntosh TK, Gennarelli TA, Meaney DF: Characterization of diffuse axonal pathology and selective hippocampal damage following inertial brain trauma in the pig. J Neuropathol Exp Neurol 1997;56:822–834.
  25. Hagberg H, Peebles D, Mallard C: Models of white matter injury: comparison of infectious, hypoxic-ischemic, and excitotoxic insults. Ment Retard Dev Disabil Res Rev 2002;8:30–38.
  26. Dobbing J, Sands J: Comparative aspects of the brain growth spurt. Early Hum Dev 1979;311:79–83.

    External Resources

  27. Dickerson JWT, Dobbing J: Prenatal and postnatal growth and development of the central nervous system of the pig. Proc R Soc London 1967;166:384–395.

    External Resources

  28. Flynn TJ: Developmental changes of myelin-related lipids in brain of miniature swine. Neurochem Res 1984;9:935–945.
  29. Buckley NM: Maturation of circulatory system in three mammalian models of human development. Comp Biochem Physiol 1986;83A:1–7.

    External Resources

  30. Wootton R, Flecknell PA, John M: Accurate measurement of cerebral metabolism in the conscious, unrestrained neonatal piglet. 1. Blood flow. Biol Neonate 1982;41:209–220.
  31. Durham SR, Raghupathi R, Helfaer MA, Marwaha S, Duhaime AC: Age-related differences in acute physiologic response to focal traumatic brain injury in piglets. Pediatr Neurosurg 2000;33:76–82.
  32. Takahashi T, Shirane R, Sato S, Yoshimoto T: Developmental changes of cerebral blood flow and oxygen metabolism in children. Am J Neuroradiol 1999;20:917–922.
  33. Zwienenberg M, Muizelaar JP: Severe pediatric head injury: the role of hyperemia revisited. J Neurotrauma 1999;16:937–943.
  34. Harada J, Takaku A, Endo S, Kuwayama N, Fukuda O: Differences in critical cerebral blood flow with age in swine. J Neurosurg 1991;75:103–107.
  35. Bauer R, Walter B, Vollandt R, Zwiener U: Intrauterine growth restriction ameliorates the effects of gradual hemorrhagic hypotension on regional cerebral blood flow and brain oxygen uptake in newborn piglets. Pediatr Res 2004;56:639–646.
  36. Pampiglione G: Some aspects of development of cerebral function in mammals. Proc R Soc Med 1971;64:429–435.
  37. Saito T, Watanabe Y, Nemoto T, Kasuya E, Sakumoto R: Radiotelemetry recording of electroencephalogram in piglets during rest. Physiol Behav 2005;84:725–731.
  38. Gavilanes AWD, Vles JSH, von Siebenthal K, Reulen JP, Neiman FH, van Sprundel R, Blanco CE: Electrocortical brain activity, cerebral haemodynamics and oxygenation during progressive hypotension in newborn piglets. Clin Neurophysiol 2000;112:52–59.

    External Resources

  39. Ioroi T, Peeters-Scholte C, Post I, Leusink C, Groenendaal F, van Bel F: Changes in cerebral haemodynamics, regional oxygen saturation and amplitude-integrated continuous EEG during hypoxia-ischaemia and reperfusion in newborn piglets. Exp Brain Res 2002;144:172–177.
  40. Barks JDE, Silverstein FS: Excitatory amino acids contribute to the pathogenesis of perinatal hypoxic-ischemic brain injury. Brain Pathol 1992;2:235–243.
  41. DiGiacomo JE, Pane CR, Gwiazdowski S, Mishra OP, Delivoria-Papadopoulos M: Effect of graded hypoxia on brain cell membrane injury in newborn piglets. Biol Neonate 1992;61:25–32.
  42. Wagerle LC, Kumar SP, Delivoria-Papadopoulos M: Effect of sympathetic nerve stimulation on cerebral blood flow in newborn piglets. Pediatr Res 1986;20:131–135.
  43. Shaver E, Duhaime AC, Curtis M, Gennarelli LM, Barrett R: Experimental acute subdural hematoma in infant piglets. Pediatr Neurosurg 1996;25:123–129.
  44. Bauer R, Walter B, Torossian A, Fritz H, Schlonski O, Jochum T, Hoyer D, Reinhart K, Zwiener U: A piglet model for evaluation of cerebral blood flow and brain oxidative metabolism during gradual cerebral perfusion pressure decrease. Pediatr Neurosurg 1999;30:62–69.
  45. Raghupathi R, Margulies SS: Traumatic axonal injury after closed head injury in the neonatal pig. J Neurotrauma 2002;19:843–853.
  46. Kurth CD, Levy WJ, McCann J: Near-infrared spectroscopy cerebral oxygen saturation thresholds for hypoxia-ischemia in piglets. J Cereb Blood Flow Metab 2002;22:335–341.
  47. Loepke AW, Golden JA, McCann JC, Kurth CD: Injury pattern of the neonatal brain after hypothermic low-flow cardiopulmonary bypass in a piglet model. Anesth Analg 2005;101:340–348.
  48. Roohey T, Raju TNK, Moustogiannis AN: Animal models for the study of perinatal hypoxic-ischemic encephalopathy: a critical review. Early Hum Dev 1997;47:115–146.
  49. Inder T, Neil J, Toder B, Rees S: Non-human primate models of neonatal brain injury. Semin Perinatol 2004;28:396–404.
  50. Prins MI, Hovda DA: Traumatic brain injury in the developing rat: effects of maturation on Morris water maze acquisition. J Neurotrauma 1998;15:799–811.
  51. Grundl PD, Biagas KV, Kochanek PM, Schiding JK, Barmada MA, Nemoto EM: Early cerebrovascular response to head injury in immature and mature rats. J Neurotrauma 1994;11:135–148.
  52. Biagas KV, Grundl PD, Kochanek PM, Schiding JK, Nemoto EN: Posttraumatic hyperemia in immature, mature, and aged rats: autoradiographic determination of cerebral blood flow. J Neurotrauma 1996;13:189–200.
  53. Bittigau P, Pohl D, Sifringer M, Shimizu H, Ikeda M, Ishimaru M, Stadhaus D, Fuhr S, Dikranian K, Olney JW, Ikonomidou C: Modeling pediatric head trauma: mechanisms of degeneration and potential strategies for neuroprotection. Restor Neurol Neurosci 1998;13:11–23.
  54. Duhaime AC, Hunter JV, Grate LL, Kim A, Demidenko E, Golden JA, Harris C: Magnetic resonance imaging studies of age-dependent responses to scaled focal brain injury in the piglet. J Neurosurg 2003;99:542–548.
  55. Duhaime AC, Saykin AJ, McDonald BC, Dodge CP, Eskey CJ, Darcey TM, Grate LL, Tomashosky P: Functional magnetic resonance imaging of the primary somatosensory cortex in piglets. J Neurosurg (Pediatr) 2006;104(suppl 4):259–264.
  56. Armstead WM: Age-dependent cerebral hemodynamic effects of traumatic brain injury in newborn and juvenile pigs. Microcirculation 2000;7:225–235.
  57. Armstead WM: Age dependent NMDA contribution to impaired hypotensive cerebral hemodynamics following brain injury. Brain Res Dev Brain Res 2002;139:19–28.
  58. Armstead WM, Cines DB, Higazi AA: Plasminogen activators contribute to age-dependent impairment of NMDA cerebrovasodilation after brain injury. Brain Res Dev Brain Res 2005;156:139–146.
  59. Finnie JW, Van den Heuvel C, Gebski V, Manavis J, Summersides GE, Blumbergs PC: Effect of impact on different regions of the head of lambs. J Comp Pathol 2001;124:159–164.
  60. Finnie JW, Blumbergs PC, Manavis J: Multifocal cerebellar granular layer necrosis in traumatically head-injured lambs. Vet Pathol 1999;36:256–258.
  61. Durham SR: Maturation-dependent response to traumatic subdural hematoma in the immature porcine brain (abstract). 33rd Annual Meeting of the American Association of Neurological Surgeons/Congress of Neurological Surgeons Section on Pediatric Neurological Surgery, 2004. San Francisco, American Association of Neurological Surgeons, 2004.
  62. Margulies SS, Thibault KL: Infant skull and suture properties: measurements and implications for mechanisms of pediatric brain injury. J Biomech Eng 2000;122:364–371.
  63. Prange MT, Margulies SS: Regional, directional, and age-dependent properties of the brain undergoing large deformation. J Biomech Eng 2002;124:244–252.
  64. Raghupathi R, Mehr MF, Helfaer MA, Margulies SS: Traumatic axonal injury is exacerbated following repetitive closed head injury in the neonatal pig. J Neurotrauma 2004;21:307–316.

Pay-per-View Options
Direct payment This item at the regular price: USD 9.00
Payment from account With a Karger Pay-per-View account (down payment USD 150) you profit from a special rate for this and other single items.
This item at the discounted price: USD 8.00