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Vol. 32, No. 5-6, 2010
Issue release date: February 2011
Dev Neurosci 2010;32:442–453

Pathophysiological Response to Experimental Diffuse Brain Trauma Differs as a Function of Developmental Age

Cernak I. · Chang T. · Ahmed F.A. · Cruz M.I. · Vink R. · Stoica B. · Faden A.I.
aDepartment of Neuroscience, Georgetown University Medical Center, and bPediatrics and Neurology, Children’s National Medical Center, Washington, D.C., cJohns Hopkins University Applied Physics Laboratory Biomedicine Business Area, National Security Technology Department, Laurel, Md., and dShock Trauma and Anesthesiology Research (STAR) Center, University of Maryland School of Medicine, Baltimore, Md., USA; eDepartment of Pathology, University of Adelaide, Adelaide, S.A., Australia

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The purpose of experimental models of traumatic brain injury (TBI) is to reproduce selected aspects of human head injury such as brain edema, contusion or concussion, and functional deficits, among others. As the immature brain may be particularly vulnerable to injury during critical periods of development, and pediatric TBI may cause neurobehavioral deficits, our aim was to develop and characterize as a function of developmental age a model of diffuse TBI (DTBI) with quantifiable functional deficits. We modified a DTBI rat model initially developed by us in adult animals to study the graded response to injury as a function of developmental age – 7-, 14- and 21-day-old rats compared to young adult (3-month-old) animals. Our model caused motor deficits that persisted even after the pups reached adulthood, as well as reduced cognitive performance 2 weeks after injury. Moreover, our model induced prominent edema often seen in pediatric TBI, particularly evident in 7- and 14-day-old animals, as measured by both the wet weight/dry weight method and diffusion-weighted MRI. Blood-brain barrier permeability, as measured by the Evans blue dye technique, peaked at 20 min after trauma in all age groups, with a second peak found only in adult animals at 24 h after injury. Phosphorus MR spectroscopy showed no significant changes in the brain energy metabolism of immature rats with moderate DTBI, in contrast to significant decreases previously identified in adult animals.

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  1. Schneier AJ, Shields BJ, Hostetler SG, Xiang H, Smith GA: Incidence of pediatric traumatic brain injury and associated hospital resource utilization in the United States. Pediatrics 2006;118:483–492.
  2. Potts MB, Koh SE, Whetstone WD, Walker BA, Yoneyama T, Claus CP, Manvelyan HM, Noble-Haeusslein LJ: Traumatic injury to the immature brain: inflammation, oxidative injury, and iron-mediated damage as potential therapeutic targets. NeuroRx 2006;3:143–153.
  3. Adams JH, Doyle D, Ford I, Gennarelli TA, Graham DI, McLellan DR: Diffuse axonal injury in head injury: definition, diagnosis and grading. Histopathology 1989;15:49–59.
  4. DeKosky ST, Kochanek PM, Clark RS, Ciallella JR, Dixon CE: Secondary injury after head trauma: subacute and long-term mechanisms. Semin Clin Neuropsychiatry 1998;3:176–185.

    External Resources

  5. Yakovlev AG, Faden AI: Mechanisms of neural cell death: implications for development of neuroprotective treatment strategies. NeuroRx 2004;1:5–16.
  6. Bittigau P, Sifringer M, Pohl D, Stadthaus D, Ishimaru M, Shimizu H, Ikeda M, Lang D, Speer A, Olney J, Ikonomidou C: Apoptotic neurodegeneration following trauma is markedly enhanced in the immature brain. Ann Neurol 1999;45:724–735.
  7. Pullela R, Raber J, Pfankuch T, Ferriero DM, Claus CP, Koh SE, Yamauchi T, Rola R, Fike JR, Noble-Haeusslein LJ: Traumatic injury to the immature brain results in progressive neuronal loss, hyperactivity and delayed cognitive impairments. Dev Neurosci 2006;28:396–409.
  8. Towfighi J, Mauger D: Temporal evolution of neuronal changes in cerebral hypoxia-ischemia in developing rats: a quantitative light microscopic study. Brain Res Dev Brain Res 1998;109:169–177.
  9. Tsuru-Aoyagi K, Potts MB, Trivedi A, Pfankuch T, Raber J, Wendland M, Claus CP, Koh SE, Ferriero D, Noble-Haeusslein LJ: Glutathione peroxidase activity modulates recovery in the injured immature brain. Ann Neurol 2009;65:540–549.
  10. Liu CL, Siesjo BK, Hu BR: Pathogenesis of hippocampal neuronal death after hypoxia-ischemia changes during brain development. Neuroscience 2004;127:113–123.
  11. McIntosh TK, Faden AI, Bendall MR, Vink R: Traumatic brain injury in the rat: alterations in brain lactate and pH as characterized by 1H and 31P nuclear magnetic resonance. J Neurochem 1987;49:1530–1540.
  12. 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.
  13. Tong W, Igarashi T, Ferriero DM, Noble LJ: Traumatic brain injury in the immature mouse brain: characterization of regional vulnerability. Exp Neurol 2002;176:105–116.
  14. Marmarou A, Foda MA, van den Brink W, Campbell J, Kita H, Demetriadou K: A new model of diffuse brain injury in rats. Part 1. Pathophysiology and biomechanics. J Neurosurg 1994;80:291–300.
  15. Adelson PD, Dixon CE, Robichaud P, Kochanek PM: Motor and cognitive functional deficits following diffuse traumatic brain injury in the immature rat. J Neurotrauma 1997;14:99–108.
  16. Cernak I, Vink R, Zapple DN, Cruz MI, Ahmed F, Chang T, Fricke ST, Faden AI: The pathobiology of moderate diffuse traumatic brain injury as identified using a new experimental model of injury in rats. Neurobiol Dis 2004;17:29–43.
  17. Elliott KA, Jasper H: Measurement of experimentally induced brain swelling and shrinkage. Am J Physiol 1949;157:122–129.
  18. Uyama O, Okamura N, Yanase M, Narita M, Kawabata K, Sugita M: Quantitative evaluation of vascular permeability in the gerbil brain after transient ischemia using Evans blue fluorescence. J Cereb Blood Flow Metab 1988;8:282–284.
  19. Faden AI, Knoblach SM, Cernak I, Fan L, Vink R, Araldi GL, Fricke ST, Roth BL, Kozikowski AP: Novel diketopiperazine enhances motor and cognitive recovery after traumatic brain injury in rats and shows neuroprotection in vitro and in vivo. J Cereb Blood Flow Metab 2003;23:342–354.
  20. Heath DL, Vink R: Traumatic brain axonal injury produces sustained decline in intracellular free magnesium concentration. Brain Res 1996;738:150–153.
  21. Vink R, Heath DL, McIntosh TK: Acute and prolonged alterations in brain free magnesium following fluid percussion-induced brain trauma in rats. J Neurochem 1996;66:2477–2483.
  22. Heath DL, Vink R: Brain free magnesium concentration is predictive of motor outcome following traumatic axonal brain injury in rats. Magnes Res 1999;12:269–277.
  23. Gupta RK, Benovic JL, Rose ZB: The determination of the free magnesium level in the human red blood cell by 31P NMR. J Biol Chem 1978;253:6172–6176.
  24. Vink R, Faden AI, McIntosh TK: Changes in cellular bioenergetic state following graded traumatic brain injury in rats: determination by phosphorus 31 magnetic resonance spectroscopy. J Neurotrauma 1988;5:315–330.
  25. Schmued L, Kyriakidis K, Heimer L: In vivo anterograde and retrograde axonal transport of the fluorescent rhodamine-dextran-amine, Fluoro-Ruby, within the CNS. Brain Res 1990;526:127–134.
  26. Ahmed F, MacArthur L, de Bernardi MA, Mocchetti I: Retrograde and anterograde transport of HIV protein gp120 in the nervous system. Brain Behav Immun 2009;23:355–364.
  27. Li FH, Fisher M: Diffusion-weighted and perfusion magnetic resonance imaging and ischemic stroke. Drugs Today (Barc) 1996;32:615–627.

    External Resources

  28. Donkin JJ, Nimmo AJ, Cernak I, Blumbergs PC, Vink R: Substance P is associated with the development of brain edema and functional deficits after traumatic brain injury. J Cereb Blood Flow Metab 2009;29:1388–1398.
  29. Adelson PD, Robichaud P, Hamilton RL, Kochanek PM: A model of diffuse traumatic brain injury in the immature rat. J Neurosurg 1996;85:877–884.
  30. Ommaya AK, Goldsmith W, Thibault L: Biomechanics and neuropathology of adult and paediatric head injury. Br J Neurosurg 2002;16:220–242.
  31. Ommaya AK, Grubb RL Jr, Naumann RA: Coup and contre-coup injury: observations on the mechanics of visible brain injuries in the rhesus monkey. J Neurosurg 1971;35:503–516.
  32. McPherson GK, Kriewall TJ: The elastic modulus of fetal cranial bone: a first step towards an understanding of the biomechanics of fetal head molding. J Biomech 1980;13:9–16.
  33. Dennis M: Developmental plasticity in children: the role of biological risk, development, time, and reserve. J Commun Disord 2000;33:321–331, quiz 332.
  34. Graham DI, Ford I, Adams JH, Doyle D, Lawrence AE, McLellan DR, Ng HK: Fatal head injury in children. J Clin Pathol 1989;42:18–22.
  35. Armstead WM: Age and cerebral circulation. Pathophysiology 2005;12:5–15.
  36. Blomgren K, Zhu C, Hallin U, Hagberg H: Mitochondria and ischemic reperfusion damage in the adult and in the developing brain. Biochem Biophys Res Commun 2003;304:551–559.
  37. Fan P, Yamauchi T, Noble LJ, Ferriero DM: Age-dependent differences in glutathione peroxidase activity after traumatic brain injury. J Neurotrauma 2003;20:437–445.
  38. Waters KA, Machaalani R: NMDA receptors in the developing brain and effects of noxious insults. Neurosignals 2004;13:162–174.
  39. Duhaime AC: Large animal models of traumatic injury to the immature brain. Dev Neurosci 2006;28:380–387.
  40. Derugin N, Ferriero DM, Vexler ZS: Neonatal reversible focal cerebral ischemia: a new model. Neurosci Res 1998;32:349–353.
  41. Lustyik G, Nagy I: Alterations of the intracellular water and ion concentrations in brain and liver cells during aging as revealed by energy-dispersive X-ray microanalysis of bulk specimens. Scan Electron Microsc 1985:323–337.

    External Resources

  42. Bullock R, Maxwell WL, Graham DI, Teasdale GM, Adams JH: Glial swelling following human cerebral contusion: an ultrastructural study. J Neurol Neurosurg Psychiatry 1991;54:427–434.
  43. Marmarou A, Fatouros PP, Barzo P, Portella G, Yoshihara M, Tsuji O, Yamamoto T, Laine F, Signoretti S, Ward JD, Bullock MR, Young HF: Contribution of edema and cerebral blood volume to traumatic brain swelling in head-injured patients. J Neurosurg 2000;93:183–193.
  44. Adelson P, Dixon C, Kochanek P: Long-term dysfunction following diffuse traumatic brain injury in the immature rat. J Neurotrauma 2000;17:273–282.
  45. Duffy TE, Kohle SJ, Vannucci RC: Carbohydrate and energy metabolism in perinatal rat brain: relation to survival in anoxia. J Neurochem 1975;24:271–276.
  46. Schuchmann S, Buchheim K, Heinemann U, Hosten N, Buttgereit F: Oxygen consumption and mitochondrial membrane potential indicate developmental adaptation in energy metabolism of rat cortical neurons. Eur J Neurosci 2005;21:2721–2732.
  47. Hida K, Suzuki N, Kwee IL, Nakada T: pH-lactate dissociation in neonatal anoxia: Proton and 31P NMR spectroscopic studies in rat pups. Magn Reson Med 1991;22:128–132.
  48. Suzuki N, Kwee IL, Nakada T: Brain maturation and response to anoxia: 31P NMR spectroscopic studies in rat pups. Magn Reson Med 1992;24:205–212.
  49. Robertson CL, Bucci CJ, Fiskum G: Mitochondrial response to calcium in the developing brain. Brain Res Dev Brain Res 2004;151:141–148.

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