Seminars in Pediatric Neurology
Volume 16, Issue 4 , Pages 167-178 , December 2009

The Encephalopathy of Prematurity—Brain Injury and Impaired Brain Development Inextricably Intertwined

  • Joseph J. Volpe, MD

      Affiliations

    • Corresponding Author InformationAddress reprint requests to Joseph J. Volpe, M.D., Department of Neurology, Children's Hospital, 300 Longwood Ave, CLS 13070, Boston, MA 02115

References 

  1. Volpe JJ. Brain injury in premature infants: A complex amalgam of destructive and developmental disturbances. Lancet Neurol. 2009;8:110–124
  2. Martin JA, Kung HC, Mathews TJ, et al. Annual summary of vital statistics: 2006. Pediatrics. 2008;121:788–801
  3. Woodward LJ, Edgin JO, Thompson D, et al. Object working memory deficits predicted by early brain injury and development in the preterm infant. Brain. 2005;128:2578–2587
  4. Bayless S, Stevenson J. Executive functions in school-age children born very prematurely. Early Hum Dev. 2007;83:247–254
  5. Platt MJ, Cans C, Johnson A, et al. Trends in cerebral palsy among infants of very low birthweight (<1500 g) or born prematurely (<32 weeks) in 16 European centres: A database study. Lancet. 2007;369:43–50
  6. Larroque B, Ancel PY, Marret S, et al. Neurodevelopmental disabilities and special care of 5-year-old children born before 33 weeks of gestation (the EPIPAGE study): A longitudinal cohort study. Lancet. 2008;371:813–820
  7. Kobaly K, Schluchter M, Minich N, et al. Outcomes of extremely low birth weight (<1 kg) and extremely low gestational age (<28 weeks) infants with bronchopulmonary dysplasia: Effects of practice changes in 2000 to 2003. Pediatrics. 2008;121:73–81
  8. Allin M, Walshe M, Fern A, et al. Cognitive maturation in preterm and term born adolescents. J Neurol Neurosurg Psychiatr. 2008;79:381–386
  9. Limperopoulos C, Bassan H, Sullivan NR, et al. Positive screening for autism in ex-preterm infants: Prevalence and risk factors. Pediatrics. 2008;121:758–765
  10. Volpe JJ. Neurology of the Newborn, 5th ed. Philadelphia, PA: Elsevier; 2008;
  11. Lowe J, MacLean PC, Shaffer ML, et al. Early working memory in children born with extremely low birth weight: Assessed by object permanence. J Child Neurol. 2009;24:410–415
  12. Kuban KC, O'Shea TM, Allred EN, et al. Positive screening on the Modified Checklist for Autism in Toddlers (M-CHAT) in extremely low gestational age newborns. J Pediatr. 2009;154:535–540
  13. Johnson S, Marlow N. Positive screening results on the modified checklist for autism in toddlers: Implications for very preterm populations. J Pediatr. 2009;154:478–480
  14. Marlow N, Hennessy EM, Bracewell MA, et al. Motor and executive function at 6 years of age after extremely preterm birth. Pediatrics. 2007;120:793–804
  15. Wood NS, Costeloe K, Gibson AT, et al. The EPICure study: Associations and antecedents of neurological and developmental disability at 30 months of age following extremely preterm birth. Arch Dis Child. 2005;90:F134–FF40
  16. Wolke D, Samara M, Bracewell M, et al. Specific language difficulties and school achievement in children born at 25 weeks of gestation or less. J Pediatr. 2008;152:256–262
  17. Volpe JJ. Encephalopathy of prematurity includes neuronal abnormalities. Pediatrics. 2005;116:221–225
  18. Larroque B, Marret S, Ancel PY, et al. White matter damage and intraventricular hemorrhage in very preterm infants: The EPIPAGE study. J Pediatr. 2003;143:477–483
  19. Miller SP, Cozzio CC, Goldstein RB, et al. Comparing the diagnosis of white matter injury in premature newborns with serial MR imaging and transfontanel ultrasonography findings. AJNR Am J Neuroradiol. 2003;24:1661–1669
  20. Inder TE, Warfield SK, Wang H, et al. Abnormal cerebral structure is present at term in premature infants. Pediatrics. 2005;115:286–294
  21. Miller SP, Ferriero DM, Leonard C, et al. Early brain injury in premature newborns detected with magnetic resonance imaging is associated with adverse early neurodevelopmental outcome. J Pediatr. 2005;147:609–616
  22. Woodward LJ, Anderson PJ, Austin NC, et al. Neonatal MRI to predict neurodevelopmental outcomes in preterm infants. N Engl J Med. 2006;355:685–694
  23. Haynes RL, Folkerth RD, Keefe R, et al. Nitrosative and oxidative injury to premyelinating oligodendrocytes is accompanied by microglial activation in periventricular leukomalacia in the human premature infant. J Neuropathol Exp Neurol. 2003;62:441–450
  24. Back SA, Luo NL, Mallinson RA, et al. Selective vulnerability of preterm white matter to oxidative damage defined by F(2)-isoprostanes. Ann Neurol. 2005;58:108–120
  25. Robinson S, Li Q, Dechant A, et al. Neonatal loss of gamma-aminobutyric acid pathway expression after human perinatal brain injury. J Neurosurg. 2006;104(suppl 6):396–408
  26. Billiards SS, Haynes RL, Folkerth RD, et al. Myelin abnormalities without oligodendrocyte loss in periventricular leukomalacia. Brain Pathol. 2008;18:153–163
  27. Peterson BS, Vohr B, Staib LH, et al. Regional brain volume abnormalities and long-term cognitive outcome in preterm infants. JAMA. 2000;284:1939–1947
  28. Nosarti C, Al-Asady MHS, Frangou S, et al. Adolescents who were born very preterm have decreased brain volumes. Brain. 2002;125:1616–1623
  29. Reiss AL, Kesler SR, Vohr B, et al. Sex differences in cerebral volumes of 8-year-olds born preterm. J Pediatr. 2004;145:242–249
  30. Kesler SR, Ment LR, Vohr B, et al. Volumetric analysis of regional cerebral development in preterm children. Pediatr Neurol. 2004;31:318–325
  31. Allin M, Henderson M, Suckling J, et al. Effects of very low birthweight on brain structure in adulthood. Dev Med Child Neurol. 2004;46:46–53
  32. Fearon P, O'Connell P, Frangou S, et al. Brain volumes in adult survivors of very low birth weight: A sibling-controlled study. Pediatrics. 2004;114:367–371
  33. Lodygensky GA, Rademaker KJ, Zimine S, et al. Structural and functional brain developmental after hydrocortisone treatment for neonatal chronic lung disease. Pediatrics. 2005;116:1–7
  34. Vangberg TR, Skranes J, Dale AM, et al. Changes in white matter diffusion anisotropy in adolescents born prematurely. NeuroImage. 2006;32:1538–1548
  35. Cheong JL, Thompson DK, Wang HX, et al. Abnormal white matter signal on MR imaging is related to abnormal tissue microstructure. AJNR Am J Neuroradiol. 2009;30:623–628
  36. Yang Z, Covey MV, Bitel CL, et al. Sustained neocortical neurogenesis after neonatal hypoxic/ischemic injury. Ann Neurol. 2007;61:199–208
  37. Sizonenko SV, Camm EJ, Dayer A, et al. Glial responses to neonatal hypoxic-ischemic injury in the rat cerebral cortex. Int J Dev Neurosci. 2008;26:37–45
  38. Maalouf EF, Duggan PJ, Rutherford MA, et al. Magnetic resonance imaging of the brain in a cohort of extremely preterm infants. J Pediatr. 1999;135:351–357
  39. Inder TE, Anderson NJ, Spencer C, et al. White matter injury in the premature infant: A comparison between serial cranial ultrasound and MRI at term. AJNR Am J Neuroradiol. 2003;24:805–809
  40. Debillon T, Guyen SN, Muet A, et al. Limitations of ultrasonography for diagnosing white matter damage in preterm infants. Arch Dis Child Fetal Neonatal Ed. 2003;88:F275–FF79
  41. Inder TE, Wells SJ, Mogridge N, et al. Defining the nature of the cerebral abnormalities in the premature infant—a qualitative magnetic resonance imaging study. J Pediatr. 2003;143:171–179
  42. Counsell SJ, Allsop JM, Harrison MC, et al. Diffusion weighted imaging of the brain in preterm infants with focal and diffuse white matter abnormality. Pediatrics. 2003;112:1–7
  43. Volpe JJ. Cerebral white matter injury of the premature infant—more common than you think. Pediatrics. 2003;112:176–179
  44. Dyet LE, Kennea NL, Counsell SJ, et al. Natural history of brain lesions in extremely preterm infants studied with serial magnetic resonance imaging from birth and neurodevelopmental assessment. Pediatrics. 2006;118:536–548
  45. Krishnan ML, Dyet LE, Boardman JP, et al. Relationship between white matter apparent diffusion coefficients in preterm infants at term-equivalent age and developmental outcome at 2 years. Pediatrics. 2007;120:e604–e609
  46. Counsell SJ, Edwards AD, Chew AT, et al. Specific relations between neurodevelopmental abilities and white matter microstructure in children born preterm. Brain. 2008;131:3201–3208
  47. Volpe JJ. Cerebellum of the premature infant—rapidly developing, vulnerable, clinically important. J Child Neurol. 2009;24:1085–1104
  48. Banker BQ, Larroche JC. Periventricular leukomalacia of infancy (A form of neonatal anoxic encephalopathy). Arch Neurol. 1962;7:386–410
  49. Arai Y, Deguchi K, Mizuguchi M, et al. Expression of b-amyloid precursor protein in axons of periventricular leukomalacia brains. Pediatr Neurol. 1995;13:161–163
  50. Deguchi K, Oguchi K, Takashima S. Characteristic neuropathology of leukomalacia in extremely low birth weight infants. Pediatr Neurol. 1997;16:296–300
  51. Meng SZ, Arai Y, Deguchi K, et al. Early detection of axonal and neuronal lesions in prenatal-onset periventricular leukomalacia. Brain Dev. 1997;19:480–484
  52. Deguchi K, Oguchi K, Matsuura N, et al. Periventricular leukomalacia: relation to gestational age and axonal injury. Pediatr Neurol. 1999;20:370–374
  53. Haynes RL, Billiards SS, Borenstein NS, et al. Diffuse axonal injury in periventricular leukomalacia as determined by apoptotic marker fractin. Pediatr Res. 2008;63:656–661
  54. Huppi PS, Maier SE, Peled S, et al. Microstructural development of human newborn cerebral white matter assessed in vivo by diffusion tensor magnetic resonance imaging. Pediatr Res. 1998;44:584–590
  55. Miller SP, Vigneron DB, Henry RG, et al. Serial quantitative diffusion tensor MRI of the premature brain: Development in newborns with and without injury. J Magn Reson Imaging. 2002;16:621–632
  56. Huppi PS, Murphy B, Maier SE, et al. Microstructural brain development after perinatal cerebral white matter injury assessed by diffusion tensor magnetic resonance imaging. Pediatrics. 2001;107:455–460
  57. Martinussen M, Fischl B, Larsson HB, et al. Cerebral cortex thickness in 15-year-old adolescents with low birth weight measured by an automated MRI-based method. Brain. 2005;128:2588–2596
  58. Anjari M, Srinivasan L, Allsop JM, et al. Diffusion tensor imaging with tract-based spatial statistics reveals local white matter abnormalities in preterm infants. NeuroImage. 2007;35:1021–1027
  59. Counsell S, Shen Y, Boardman JP, et al. Axial and radial diffusivity in preterm infants who have diffuse white matter changes on MRI at term equivalent age. Pediatrics. 2006;117:376–386
  60. Counsell SJ, Dyet LE, Larkman DJ, et al. Thalamo-cortical connectivity in children born preterm mapped using probabilistic magnetic resonance tractography. NeuroImage. 2007;34:896–904
  61. Bassi L, Ricci D, Volzone A, et al. Probabilistic diffusion tractography of the optic radiations and visual function in preterm infants at term equivalent age. Brain. 2008;131:573–582
  62. Drobyshevsky A, Bregman J, Storey P, et al. Serial diffusion tensor imaging detects white matter changes that correlate with motor outcome in premature infants. Dev Neurosci. 2007;29:289–301
  63. McQuillen PS, Sheldon RA, Shatz CJ, et al. Selective vulnerability of subplate neurons after early neonatal hypoxia-ischemia. J Neurosci. 2003;23:3308–3315
  64. Andiman SE, Haynes RL, Folkerth RD, et al. Loss of white matter neurons in periventricular leukomalacia: Implications for cognitive deficits in survivors of prematurity. Soc Neurosci. 2009;(Abstract)
  65. Lin Y, Okumura A, Hayakawa F, et al. Quantitative evaluation of thalami and basal ganglia in infants with periventricular leukomalacia. Dev Med Child Neurol. 2001;43:481–485
  66. Boardman JP, Counsell SJ, Rueckert D, et al. Abnormal deep grey matter development following preterm birth detected using deformation based morphometry. NeuroImage. 2006;32:70–78
  67. Nosarti C, Giouroukou E, Healy E, et al. Grey and white matter distribution in very preterm adolescents mediates neurodevelopmental outcome. Brain. 2007;131:205–217
  68. Kesler SR, Reiss AL, Vohr B, et al. Brain volume reductions within multiple cognitive systems in male preterm children at age twelve. J Pediatr. 2008;152:513–520
  69. Pierson CR, Folkerth RD, Billards SS, et al. Gray matter injury associated with periventricular leukomalacia in the premature infant. Acta Neuropathol. 2007;114:619–631
  70. Ligam P, Haynes RL, Folkerth RD, et al. Thalamic damage in periventricular leukomalacia: Novel pathologic observations relevant to cognitive deficits in survivors of prematurity. Pediatr Res. 2009;65:524–529
  71. Abernethy LJ, Cooke RW, Foulder-Hughes L. Caudate and hippocampal volumes, intelligence, and motor impairment in 7-year-old children who were born preterm. Pediatr Res. 2004;55:884–893
  72. Inder TE, Huppi PS, Warfield S, et al. Periventricular white matter injury in the premature infant is associated with a reduction in cerebral cortical gray matter volume at term. Ann Neurol. 1999;46:755–760
  73. Peterson BS, Anderson AW, Ehrenkranz RA, et al. Regional brain volumes and their later neurodevelopmental correlates in term and preterm infants. Pediatrics. 2003;111:939–948
  74. Isaacs E, Lucas A, Chong WK, et al. Hippocampal volume and everyday memory in children of very low birth weight. Pediatr Res. 2000;47:713–720
  75. Thompson DK, Wood SJ, Doyle LW, et al. Neonate hippocampal volumes: prematurity, perinatal predictors, and 2-year outcome. Ann Neurol. 2008;63:642–651
  76. Armstrong DL, Sauls CD, Goddard-Finegold J. Neuropathologic findings in short-term survivors of intraventricular hemorrhage. Am J Dis Child. 1987;141:617–621
  77. Marin-Padilla M. Developmental neuropathology and impact of perinatal brain damage (II. White matter lesions of the neocortex). J Neuropathol Exp Neurol. 1997;56:219–235
  78. Kinney HC, Armstrong DL. Perinatal neuropathology. In:  Graham DI,  Lantos PE editor. Greenfield's Neuropathology, 7th ed. London, UK: Arnold Publishers; 2002;p. 519–606
  79. Andiman SE, Haynes RL, Trachtenberg FL, et al. The cerebral cortex overlying periventricular leukomalacia: Analysis of pyramidal neurons. Soc Neurosci. 2009;(Abstract)
  80. Dobbing J, Hopewell JW, Lynch A, et al. Vulnerability of developing brain (I. Some lasting effects of x-irradiation). Exp Neurol. 1970;28:442–449
  81. Dobbing J. The later growth of the brain and its vulnerability. Pediatrics. 1974;53:2–6
  82. Back SA, Volpe JJ. Cellular and molecular pathogenesis of periventricular white matter injury. Ment Retard Dev Disabil Res Rev. 1997;3:96–107
  83. Back SA, Khan R, Gan X, et al. A new alamar blue viability assay to rapidly quantify oligodendrocyte death. J Neurosci Methods. 1999;91:47–54
  84. Back SA, Luo NL, Borenstein NS, et al. Late oligodendrocyte progenitors coincide with the developmental window of vulnerability for human perinatal white matter injury. J Neurosci. 2001;21:1302–1312
  85. Kinney HC, Back SA. Human oligodendroglial development: Relationship to periventricular leukomalacia. Semin Pediatr Neurol. 1998;5:180–189
  86. Khwaja O, Volpe JJ. Pathogenesis of cerebral white matter injury of prematurity. Arch Dis Child Fetal Neonatal Ed. 2008;93:F153–FF61
  87. Back SA, Gan X, Li Y, et al. Maturation-dependent vulnerability of oligodendrocytes to oxidative stress-induced death caused by glutathione depletion. J Neurosci. 1998;18:6241–6253
  88. Folkerth RD, Keefe RJ, Haynes RL, et al. Interferon-gamma expression in periventricular leukomalacia in the human brain. Brain Pathol. 2004;14:265–274
  89. Folkerth RD, Haynes RL, Borenstein NS, et al. Developmental lag in superoxide dismutases relative to other antioxidant enzymes in premyelinated human telencephalic white matter. J Neuropathol Exp Neurol. 2004;63:990–999
  90. Li J, Baud O, Vartanian T, et al. Peroxynitrite generated by inducible nitric oxide synthase and NADPH oxidase mediates microglial toxicity to oligodendrocytes. Proc Natl Acad Sci USA. 2005;102:9936–9941
  91. Buntinx M, Moreels M, Vandenabeele F, et al. Cytokine-induced cell death in human oligodendroglial cell lines (I. Synergistic effects of IFN-gamma and TNF-alpha on apoptosis). J Neurosci Res. 2004;76:834–845
  92. Pang Y, Cai ZW, Rhodes PG. Effect of tumor necrosis factor-alpha on developing optic nerve oligodendrocytes in culture. J Neurosci Res. 2005;80:226–234
  93. Talos DM, Follett PL, Folkerth RD, et al. Developmental regulation of alpha-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid receptor subunit expression in forebrain and relationship to regional susceptibility to hypoxic/ischemic injury (II. Human cerebral white matter and cortex). J Comp Neurol. 2006;497:61–77
  94. DeSilva TM, Kinney HC, Borenstein NS, et al. The glutamate transporter is transiently expressed in developing human cerebral white matter. J Comp Neurol. 2007;501:879–890
  95. Karadottir R, Attwell D. Neurotransmitter receptors in the life and death of oligodendrocytes. Neuroscience. 2007;145:1426–1438
  96. Manning SM, Talos DM, Zhou C, et al. NMDA receptor blockade with memantine attenuates white matter deficits in a rat model of periventricular leukomalacia. J Neurosci. 2008;28:6670–6678
  97. Rivest S. Molecular insights on the cerebral innate immune system. Brain Behav Immun. 2003;17:13–19
  98. Rezaie P, Dean A, Male D, et al. Microglia in the cerebral wall of the human telencephalon at second trimester. Cereb Cortex. 2005;15:938–949
  99. Monier A, Evrard P, Gressens P, et al. Distribution and differentiation of microglia in the human encephalon during the first two trimesters of gestation. J Comp Neurol. 2006;499:565–582
  100. Billiards SS, Haynes RL, Folkerth RD, et al. Development of microglia in the cerebral white matter of the human fetus and infant. J Comp Neurol. 2006;497:199–208
  101. Agresti C, D'Urso D, Levi G. Reversible inhibitory effects of interferon-g and tumour necrosis factor-a on oligodendroglial lineage cell proliferation and differentiation in vitro. Eur J Neurosci. 1996;8:1106–1116
  102. Andrews T, Zhang P, Bhat NR. TNF-a potentiates IFNg-induced cell death in oligodendrocyte progenitors. J Neurosci Res. 1998;54:574–583
  103. Xie Z, Wei M, Morgan TE, et al. Peroxynitrite mediates neurotoxicity of amyloid b-peptide 1-42- and lipopolysaccharide-activated microglia. J Neurosci. 2002;22:3484–3492
  104. Lehnardt S, Massillon L, Follet P, et al. Activation of innate immunity in the CNS triggers neurodegeneration through a Toll-like receptor 4-dependent pathway. Proc Natl Acad Sci USA. 2003;100:8514–8519
  105. Lechpammer M, Manning SM, Samonte F, et al. Minocycline treatment following hypoxic-ischemic injury attenuates white matter injury in a rodent model of periventricular leukomalacia. Neuropathol Appl Neurobiol. 2008;34:379–393
  106. Kostovic I, Judas M. Correlation between the sequential ingrowth of afferents and transient patterns of cortical lamination in preterm infants. Anat Rec. 2002;267:1–6
  107. Kostovic I, Judas M, Rados M, et al. Laminar organization of the human fetal cerebrum revealed by histochemical markers and magnetic resonance imaging. Cereb Cortex. 2002;12:536–544
  108. Haynes RL, Borenstein NS, DeSilva TM, et al. Axonal development in the cerebral white matter of the human fetus and infant. J Comp Neurol. 2005;484:156–167
  109. Kostovic I, Jovanov-Milosevic N. The development of cerebral connections during the first 20-45 weeks' gestation. Semin Fetal Neonatal Med. 2006;11:415–422
  110. Kostovic I, Judas M. Transient patterns of cortical lamination during prenatal life: do they have implications for treatment?. Neurosci Biobehav Rev. 2007;31:1157–1168
  111. Bystron I, Blakemore C, Rakic P. Development of the human cerebral cortex: Boulder Committee revisited. Nat Rev Neurosci. 2008;9:110–122
  112. Volpe JJ. Subplate neurons—missing link in brain injury of the premature infant?. Pediatrics. 1996;97:112–113
  113. McConnell SK, Ghosh A, Shatz CJ. Subplate neurons pioneer the first axon pathway from the cerebral cortex. Science. 1989;245:978–982
  114. Ghosh A, Antonini A, McConnell SK, et al. Requirement for subplate neurons in the formation of thalamocortical connections. Nature. 1990;347:179–181
  115. Ghosh A, Shatz CJ. Involvement of subplate neurons in the formation of ocular dominance columns. Science. 1992;255:1441–1443
  116. Kanold PO, Kara P, Reid RC, et al. Role of subplate neurons in functional maturation of visual cortical columns. Science. 2003;301:521–525
  117. Kanold PO. Transient microcircuits formed by subplate neurons and their role in functional development of thalamocortical connections. NeuroReport. 2004;15:2149–2153
  118. Bystron I, Molnar Z, Otellin V, et al. Tangential networks of precocious neurons and early axonal outgrowth in the embryonic human forebrain. J Neurosci. 2005;25:2781–2792
  119. Letinic K, Zoncu R, Rakic P. Origin of GABAergic neurons in the human neocortex. Nature. 2002;417:645–649
  120. Tan SS. Developmental neurobiology: cortical liars. Nature. 2002;417:605–606
  121. Inta D, Alfonso J, von Engelhardt J, et al. Neurogenesis and widespread forebrain migration of distinct GABAergic neurons from the postnatal subventricular zone. Proc Natl Acad Sci USA. 2008;105:20994–20999
  122. Petanjek Z, Berger B, Esclapez M. Origins of cortical GABAergic neurons in the cynomolgus monkey. Cereb Cortex. 2009;19:249–262
  123. Bayer SA, Altman J. The Human Brain During the Third Trimester: Atlas of Human Central Nervous System Development. London, UK: CRC Press; 2004;
  124. Letinic K, Rakic P. Telencephalic origin of human thalamic GABAergic neurons. Nat Neurosci. 2001;4:931–936
  125. Montero VM. The interneuronal nature of GABAergic neurons in the lateral geniculate nucleus of the rhesus monkey: A combined HRP and GABA-immunocytochemical study. Exp Brain Res. 1986;64:615–622
  126. Montero VM, Zempel J. The proportion and size of GABA-immunoreactive neurons in the magnocellular and parvocellular layers of the lateral geniculate nucleus of the rhesus monkey. Exp Brain Res. 1986;62:215–223
  127. Abitz M, Nielsen RD, Jones EG, et al. Excess of neurons in the human newborn mediodorsal thalamus compared with that of the adult. Cereb Cortex. 2007;17:2573–2578
  128. Huppi PS, Warfield S, Kikinis R, et al. Quantitative magnetic resonance imaging of brain development in premature and mature newborns. Ann Neurol. 1998;43:224–235
  129. Kapellou O, Counsell SJ, Kennea NL, et al. Abnormal cortical development after premature birth shown by altered allometric scaling of brain growth. PLoS Med. 2006;3:e265
  130. Follett PL, Rosenberg PA, Volpe JJ, et al. NBQX attenuates excitotoxic injury in developing white matter. J Neurosci. 2000;20:9235–9241
  131. Back SA, Han BH, Luo NL, et al. Selective vulnerability of late oligodendrocyte progenitors to hypoxia-ischemia. J Neurosci. 2002;22:455–463
  132. Bell MJ, Hallenbeck JM. Effects of intrauterine inflammation on developing rat brain. J Neurosci Res. 2002;70:570–579
  133. Duncan JR, Cock ML, Scheerlinck J-PY, et al. White matter injury after repeated endotoxin exposure in the preterm ovine fetus. Pediatr Res. 2002;52:941–949
  134. Deng W, Rosenberg PA, Volpe JJ, et al. Calcium-permeable AMPA/kainate receptors mediate toxicity and preconditioning by oxygen-glucose deprivation in oligodendrocyte precursors. Proc Natl Acad Sci USA. 2003;100:6801–6806
  135. Yoshioka A, Bacskai B, Pleasure D. Pathophysiology of oligodendroglial excitotoxicity. J Neurosci Res. 1996;46:427–438
  136. McDonald JW, Althomsons SP, Hyrc KL, et al. Oligodendrocytes from forebrain are highly vulnerable to AMPA/kainate receptor-mediated excitotoxicity. Nat Med. 1998;4:291–297
  137. Matute C, Alberdi E, Domercq M, et al. The link between excitotoxic oligodendroglial death and demyelinating diseases. Trends Neurosci. 2001;24:224–230
  138. Itoh T, Beesley J, Itoh A, et al. AMPA glutamate receptor-mediated calcium signaling is transiently enhanced during development of oligodendrocytes. J Neurochem. 2002;81:390–402
  139. Sanchez-Gomez MV, Alberdi E, Ibarretxe G, et al. Caspase-dependent and caspase-independent oligodendrocyte death mediated by AMPA and kainate receptors. J Neurosci. 2003;23:9519–9528
  140. Rosenberg PA, Dai W, Gan XD, et al. Mature myelin basic protein expressing oligodendrocytes are insensitive to kainate toxicity. J Neurosci Res. 2003;71:237–245
  141. Deng W, Yue Q, Rosenberg PA, et al. Oligodendrocyte excitotoxicity determined by local glutamate accumulation and mitochondrial function. J Neurochem. 2006;96:213–222
  142. Salter MG, Fern R. NMDA receptors are expressed in developing oligodendrocyte processes and mediate injury. Nature. 2005;438:1167–1171
  143. Karadottir R, Cavelier P, Bergersen LH, et al. NMDA receptors are expressed in oligodendrocytes and activated in ischaemia. Nature. 2005;438:1162–1166
  144. Matute C. Oligodendrocyte NMDA receptors: A novel therapeutic target. Trends Mol Med. 2006;12:289–292
  145. Micu I, Jiang Q, Coderre E, et al. NMDA receptors mediate calcium accumulation in myelin during chemical ischaemia. Nature. 2006;439:988–992
  146. Bjartmar C, Yin X, Trapp BD. Axonal pathology in myelin disorders. J Neurocytol. 1999;28:383–395
  147. Biffiger K, Bartsch S, Montag D, et al. Severe hypomyelination of the murine CNS in the absence of myelin-associated glycoprotein and fyn tyrosine kinase. J Neurosci. 2000;20:7430–7437
  148. Gotow T, Leterrier JF, Ohsawa Y, et al. Abnormal expression of neurofilament proteins in dysmyelinating axons located in the central nervous system of jimpy mutant mice. Eur J Neurosci. 1999;11:3893–3903
  149. Lappe-Siefke C, Goebbels S, Gravel M, et al. Disruption of Cnp1 uncouples oligodendroglial functions in axonal support and myelination. Nat Genet. 2003;33:366–374
  150. Rasband MN, Tayler R, Kaga Y, et al. CNP is required for maintenance of axon-glia interactions at nodes of Ranvier in the CNS. Glia. 2005;50:86–90
  151. Dutta R, Trapp BD. Pathogenesis of axonal and neuronal damage in multiple sclerosis. Neurology. 2007;68:S22–S31
  152. Roy K, Murtie JC, El-Khodor BF, et al. Loss of erbB signaling in oligodendrocytes alters myelin and dopaminergic function, a potential mechanism for neuropsychiatric disorders. Proc Natl Acad Sci USA. 2007;104:8131–8136
  153. Nakazawa T, Nakazawa C, Matsubara A, et al. Tumor necrosis factor-alpha mediates oligodendrocyte death and delayed retinal ganglion cell loss in a mouse model of glaucoma. J Neurosci. 2006;26:12633–12641
  154. Drobyshevsky A, Song SK, Gamkrelidze G, et al. Developmental changes in diffusion anisotropy coincide with immature oligodendrocyte progression and maturation of compound action potential. J Neurosci. 2005;25:5988–5997
  155. Wilkins A, Majed H, Layfield R, et al. Oligodendrocytes promote neuronal survival and axonal length by distinct intracellular mechanisms: a novel role for oligodendrocyte-derived glial cell line-derived neurotrophic factor. J Neurosci. 2003;23:4967–4974
  156. Dai X, Lercher LD, Clinton PM, et al. The trophic role of oligodendrocytes in the basal forebrain. J Neurosci. 2003;23:5846–5853
  157. Du YZ, Dreyfus CF. Oligodendrocytes as providers of growth factors. J Neurosci. 2002;68:647–654
  158. Skranes J, Vangberg TR, Kulseng S, et al. Clinical findings and white matter abnormalities seen on diffusion tensor imaging in adolescents with very low birth weight. Brain. 2007;130:654–666
  159. Sizonenko SV, Sirimanne E, Mayall Y, et al. Selective cortical alteration after hypoxic-ischemic injury in the very immature rat brain. Pediatr Res. 2003;54:263–269
  160. McCarran WJ, Goldberg MP. White matter axon vulnerability to AMPA/kainate receptor-mediated ischemic injury is developmentally regulated. J Neurosci. 2007;27:4220–4229
  161. Tekkok SB, Goldberg MP. AMPA/kainate receptor activation mediates hypoxic oligodendrocyte death and axonal injury in cerebral white matter. J Neurosci. 2001;21:4237–4248
  162. Wakita H, Tomimoto H, Akiguchi I, et al. Axonal damage and demyelination in the white matter after chronic cerebral hypoperfusion in the rat. Brain Res. 2002;924:63–70
  163. Northington FJ, Ferriero DM, Flock DL, et al. Delayed neurodegeneration in neonatal rat thalamus after hypoxia-ischemia is apoptosis. J Neurosci. 2001;21:1931–1938
  164. Ghosh A, Shatz CJ. A role for subplate neurons in the patterning of connections from thalamus to neocortex. Development. 1993;117:1031–1047
  165. Romanko MJ, Rothstein RP, Levison SW. Neural stem cells in the subventricular zone are resilient to hypoxia/ischemia whereas progenitors are vulnerable. J Cereb Blood Flow Metab. 2004;24:814–825

 This work was supported by the NINDS, Grant Number P01-NS038475.

PII: S1071-9091(09)00063-1

doi: 10.1016/j.spen.2009.09.005

Seminars in Pediatric Neurology
Volume 16, Issue 4 , Pages 167-178 , December 2009