Abstract
Children surviving premature birth have a high risk of cognitive and learning disabilities and attention deficit. In turn, adverse outcomes are associated with persistent reductions in cerebral growth on magnetic resonance imaging (MRI). It is striking that modern care has been associated with a dramatic reduction in the risk of cystic white matter damage, but modest improvements in terms of neurodevelopmental impairment. This review will explore the hypothesis that the disability is primarily associated with impaired neural connectivity rather than cell death alone. Very preterm infants exhibit reduced thalamocortical connectivity and cortical neuroplasticity compared with term-born controls. In preterm fetal sheep, moderate cerebral ischemia with no neuronal loss, but significant diffuse failure of maturation of cortical pyramidal neurons, was associated with impaired dendritic growth and synapse formation, consistent with altered connectivity. These changes were associated with delayed decline in cortical fractional anisotropy (FA) on MRI. Supporting these preclinical findings, preterm human survivors showed similar enduring impairment of microstructural development of the cerebral cortex defined by FA, consistent with delayed formation of neuronal processes. These findings offer the promise that better understanding of impairment of neural connectivity may allow us to promote normal development and growth of the cortex after preterm birth.
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References
Committee on Understanding Premature Birth and Assuring Healthy Outcomes. Preterm Birth: Causes, Consequences, and Prevention. In: Behrman RE, Butler AS, eds. Washington, DC: Institute of Medicine of the National Academies, 2007. (http://books.nap.edu/openbook.php?record_id=11622&page=1.) Accessed 1 March 2013.
Moore T, Hennessy EM, Myles J, et al. Neurological and developmental outcome in extremely preterm children born in England in 1995 and 2006: the EPICure studies. BMJ (Clinical research ed.) 2012;345:e7961.
Schlapbach LJ, Adams M, Proietti E, et al.; Swiss Neonatal Network & Follow-up Group. Outcome at two years of age in a Swiss national cohort of extremely preterm infants born between 2000 and 2008. BMC Pediatr 2012;12:198.
Baron IS, Erickson K, Ahronovich MD, Baker R, Litman FR . Cognitive deficit in preschoolers born late-preterm. Early Hum Dev 2011;87:115–9.
Hintz SR, Kendrick DE, Wilson-Costello DE, et al.; NICHD Neonatal Research Network. Early-childhood neurodevelopmental outcomes are not improving for infants born at <25 weeks’ gestational age. Pediatrics 2011;127:62–70.
Perlman JM . White matter injury in the preterm infant: an important determination of abnormal neurodevelopment outcome. Early Hum Dev 1998;53:99–120.
Andiman SE, Haynes RL, Trachtenberg FL, et al. The cerebral cortex overlying periventricular leukomalacia: analysis of pyramidal neurons. Brain Pathol 2010;20:803–14.
Rose J, Butler EE, Lamont LE, Barnes PD, Atlas SW, Stevenson DK . Neonatal brain structure on MRI and diffusion tensor imaging, sex, and neurodevelopment in very-low-birthweight preterm children. Dev Med Child Neurol 2009;51:526–35.
Buser JR, Maire J, Riddle A, et al. Arrested preoligodendrocyte maturation contributes to myelination failure in premature infants. Ann Neurol 2012;71:93–109.
Hamrick SE, Miller SP, Leonard C, et al. Trends in severe brain injury and neurodevelopmental outcome in premature newborn infants: the role of cystic periventricular leukomalacia. J Pediatr 2004;145:593–9.
Mullen KM, Vohr BR, Katz KH, et al. Preterm birth results in alterations in neural connectivity at age 16 years. Neuroimage 2011;54:2563–70.
Marlow N, Hennessy EM, Bracewell MA, Wolke D ; EPICure Study Group. Motor and executive function at 6 years of age after extremely preterm birth. Pediatrics 2007;120:793–804.
Rogers CE, Anderson PJ, Thompson DK, et al. Regional cerebral development at term relates to school-age social-emotional development in very preterm children. J Am Acad Child Adolesc Psychiatry 2012;51:181–91.
Kennard MA . Age and other factors in motor recovery from precentral lesions in monkeys. Am J Physiol 1936;115:138–46.
Ment LR, Kesler S, Vohr B, et al. Longitudinal brain volume changes in preterm and term control subjects during late childhood and adolescence. Pediatrics 2009;123:503–11.
Constable RT, Ment LR, Vohr BR, et al. Prematurely born children demonstrate white matter microstructural differences at 12 years of age, relative to term control subjects: an investigation of group and gender effects. Pediatrics 2008;121:306–16.
Bennet L, Davidson JO, Koome M, Gunn AJ . Glucocorticoids and preterm hypoxic-ischemic brain injury: the good and the bad. J Pregnancy 2012;2012:751694.
de Vries LS, Eken P, Groenendaal F, Rademaker KJ, Hoogervorst B, Bruinse HW . Antenatal onset of haemorrhagic and/or ischaemic lesions in preterm infants: prevalence and associated obstetric variables. Arch Dis Child Fetal Neonatal Ed 1998;78:F51–6.
Bell JE, Becher JC, Wyatt B, Keeling JW, McIntosh N . Brain damage and axonal injury in a Scottish cohort of neonatal deaths. Brain 2005;128(Pt 5):1070–81.
Kubota T, Okumura A, Hayakawa F, et al. Combination of neonatal electroencephalography and ultrasonography: sensitive means of early diagnosis of periventricular leukomalacia. Brain Dev 2002;24:698–702.
Low JA, Killen H, Derrick EJ . Antepartum fetal asphyxia in the preterm pregnancy. Am J Obstet Gynecol 2003;188:461–5.
Weinberger B, Anwar M, Hegyi T, Hiatt M, Koons A, Paneth N . Antecedents and neonatal consequences of low Apgar scores in preterm newborns: a population study. Arch Pediatr Adolesc Med 2000;154:294–300.
Helderman JB, O’Shea TM, Kuban KC, et al.; ELGAN study Investigators. Antenatal antecedents of cognitive impairment at 24 months in extremely low gestational age newborns. Pediatrics 2012;129:494–502.
Bennet L, Booth LC, Drury PP, Quaedackers JS, Gunn AJ . Preterm neonatal cardiovascular instability: does understanding the fetus help evaluate the newborn? Clin Exp Pharmacol Physiol 2012;39:965–72.
Logan JW, O’Shea TM, Allred EN, et al.; ELGAN Study Investigators. Early postnatal hypotension is not associated with indicators of white matter damage or cerebral palsy in extremely low gestational age newborns. J Perinatol 2011;31:524–34.
Wu YW, Colford JM Jr . Chorioamnionitis as a risk factor for cerebral palsy: a meta-analysis. JAMA 2000;284:1417–24.
Wikström S, Ley D, Hansen-Pupp I, Rosén I, Hellström-Westas L . Early amplitude-integrated EEG correlates with cord TNF-alpha and brain injury in very preterm infants. Acta Paediatr 2008;97:915–9.
Stoll BJ, Hansen NI, Adams-Chapman I, et al.; National Institute of Child Health and Human Development Neonatal Research Network. Neurodevelopmental and growth impairment among extremely low-birth-weight infants with neonatal infection. JAMA 2004;292:2357–65.
O’Shea TM, Shah B, Allred EN, et al.; ELGAN Study Investigators. Inflammation-initiating illnesses, inflammation-related proteins, and cognitive impairment in extremely preterm infants. Brain Behav Immun 2013;29:104–12.
Leviton A, Fichorova RN, O’Shea TM, et al.; ELGAN Study Investigators. Two-hit model of brain damage in the very preterm newborn: small for gestational age and postnatal systemic inflammation. Pediatr Res 2013;73:362–70.
Rathbone R, Counsell SJ, Kapellou O, et al. Perinatal cortical growth and childhood neurocognitive abilities. Neurology 2011;77:1510–7.
Woodward LJ, Anderson PJ, Austin NC, Howard K, Inder TE . Neonatal MRI to predict neurodevelopmental outcomes in preterm infants. N Engl J Med 2006;355:685–94.
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;55:884–93.
Isaacs EB, Edmonds CJ, Chong WK, Lucas A, Morley R, Gadian DG . Brain morphometry and IQ measurements in preterm children. Brain 2004;127(Pt 12):2595–607.
Giménez M, Junqué C, Narberhaus A, et al. Hippocampal gray matter reduction associates with memory deficits in adolescents with history of prematurity. Neuroimage 2004;23:869–77.
Woodward LJ, Clark CA, Bora S, Inder TE . Neonatal white matter abnormalities an important predictor of neurocognitive outcome for very preterm children. PLoS ONE 2012;7:e51879.
Felderhoff-Mueser U, Rutherford MA, Squier WV, et al. Relationship between MR imaging and histopathologic findings of the brain in extremely sick preterm infants. AJNR Am J Neuroradiol 1999;20:1349–57.
Takizawa Y, Takashima S, Itoh M . A histopathological study of premature and mature infants with pontosubicular neuron necrosis: neuronal cell death in perinatal brain damage. Brain Res 2006;1095:200–6.
Barkovich AJ, Sargent SK . Profound asphyxia in the premature infant: imaging findings. AJNR Am J Neuroradiol 1995;16:1837–46.
Pierson CR, Folkerth RD, Billiards SS, et al. Gray matter injury associated with periventricular leukomalacia in the premature infant. Acta Neuropathol 2007;114:619–31.
Back SA, Luo NL, Mallinson RA, et al. Selective vulnerability of preterm white matter to oxidative damage defined by F2-isoprostanes. Ann Neurol 2005;58:108–20.
Tymofiyeva O, Hess CP, Ziv E, et al. Towards the “baby connectome”: mapping the structural connectivity of the newborn brain. PLoS ONE 2012;7:e31029.
Ball G, Boardman JP, Rueckert D, et al. The effect of preterm birth on thalamic and cortical development. Cereb Cortex 2012;22:1016–24.
Ball G, Boardman JP, Aljabar P, et al. The influence of preterm birth on the developing thalamocortical connectome. Cortex 2013;49:1711–21.
Limperopoulos C, Chilingaryan G, Guizard N, Robertson RL, Du Plessis AJ . Cerebellar injury in the premature infant is associated with impaired growth of specific cerebral regions. Pediatr Res 2010;68:145–50.
Smyser CD, Inder TE, Shimony JS, et al. Longitudinal analysis of neural network development in preterm infants. Cereb Cortex 2010;20:2852–62.
Pitcher JB, Riley AM, Doeltgen SH, et al. Physiological evidence consistent with reduced neuroplasticity in human adolescents born preterm. J Neurosci 2012;32:16410–6.
Pavlova M, Marconato F, Sokolov A, Braun C, Birbaumer N, Krägeloh-Mann I . Periventricular leukomalacia specifically affects cortical MEG response to biological motion. Ann Neurol 2006;59:415–9.
de Graaf-Peters VB, Hadders-Algra M . Ontogeny of the human central nervous system: what is happening when? Early Hum Dev 2006;82:257–66.
Dean JM, McClendon E, Hansen K, et al. Prenatal cerebral ischemia disrupts MRI-defined cortical microstructure through disturbances in neuronal arborization. Sci Transl Med 2013;5:168ra7.
Sizonenko SV, Camm EJ, Garbow JR, et al. Developmental changes and injury induced disruption of the radial organization of the cortex in the immature rat brain revealed by in vivo diffusion tensor MRI. Cereb Cortex 2007;17:2609–17.
Back SA, Riddle A, Dean J, Hohimer AR . The instrumented fetal sheep as a model of cerebral white matter injury in the premature infant. Neurotherapeutics 2012;9:359–70.
Vinall J, Grunau RE, Brant R, et al. Slower postnatal growth is associated with delayed cerebral cortical maturation in preterm newborns. Sci Transl Med 2013;5:168ra8.
Ball G, Srinivasan L, Aljabar P, et al. Development of cortical microstructure in the preterm human brain. Proc Natl Acad Sci USA 2013;110:9541–6.
Mallard C, Welin AK, Peebles D, Hagberg H, Kjellmer I . White matter injury following systemic endotoxemia or asphyxia in the fetal sheep. Neurochem Res 2003;28:215–23.
Dean JM, van de Looij Y, Sizonenko SV, et al. Delayed cortical impairment following lipopolysaccharide exposure in preterm fetal sheep. Ann Neurol 2011;70:846–56.
Keogh MJ, Bennet L, Drury PP, et al. Subclinical exposure to low-dose endotoxin impairs EEG maturation in preterm fetal sheep. Am J Physiol Regul Integr Comp Physiol 2012;303:R270–8.
Hellstrom IC, Danik M, Luheshi GN, Williams S . Chronic LPS exposure produces changes in intrinsic membrane properties and a sustained IL-beta-dependent increase in GABAergic inhibition in hippocampal CA1 pyramidal neurons. Hippocampus 2005;15:656–64.
Luk WP, Zhang Y, White TD, et al. Adenosine: a mediator of interleukin-1beta-induced hippocampal synaptic inhibition. J Neurosci 1999;19:4238–44.
Summers deLuca L, Gommerman JL . Fine-tuning of dendritic cell biology by the TNF superfamily. Nat Rev Immunol 2012;12:339–51.
Kim IJ, Beck HN, Lein PJ, Higgins D . Interferon gamma induces retrograde dendritic retraction and inhibits synapse formation. J Neurosci 2002;22:4530–9.
Eklind S, Mallard C, Arvidsson P, Hagberg H . Lipopolysaccharide induces both a primary and a secondary phase of sensitization in the developing rat brain. Pediatr Res 2005;58:112–6.
Polglase GR, Miller SL, Barton SK, et al. Initiation of resuscitation with high tidal volumes causes cerebral hemodynamic disturbance, brain inflammation and injury in preterm lambs. PLoS ONE 2012;7:e39535.
Gibson A, Carney S, Wales JK . Growth and the premature baby. Horm Res 2006;65 Suppl 3:75–81.
Ng E, Taddio A, Ohlsson A . Intravenous midazolam infusion for sedation of infants in the neonatal intensive care unit. Cochrane Database Syst Rev 2012;6:CD002052.
Brummelte S, Grunau RE, Chau V, et al. Procedural pain and brain development in premature newborns. Ann Neurol 2012;71:385–96.
Anand KJ, Hall RW, Desai N, et al.; NEOPAIN Trial Investigators Group. Effects of morphine analgesia in ventilated preterm neonates: primary outcomes from the NEOPAIN randomised trial. Lancet 2004;363:1673–82.
Tanokashira D, Morita T, Hayashi K, et al. Glucocorticoid suppresses dendritic spine development mediated by down-regulation of caldesmon expression. J Neurosci 2012;32:14583–91.
Halliday HL, Ehrenkranz RA, Doyle LW . Early (< 8 days) postnatal corticosteroids for preventing chronic lung disease in preterm infants. Cochrane Database Syst Rev 2010:CD001146.
Tam EW, Chau V, Ferriero DM, et al. Preterm cerebellar growth impairment after postnatal exposure to glucocorticoids. Sci Transl Med 2011;3:105ra105.
Goldberg JL, Barres BA . The relationship between neuronal survival and regeneration. Annu Rev Neurosci 2000;23:579–612.
Molnár Z, Kurotani T, Higashi S, Yamamoto N, Toyama K . Development of functional thalamocortical synapses studied with current source-density analysis in whole forebrain slices in the rat. Brain Res Bull 2003;60:355–71.
Riddle A, Maire J, Gong X, et al. Differential susceptibility to axonopathy in necrotic and non-necrotic perinatal white matter injury. Stroke 2012;43:178–84.
Back SA, Tuohy TM, Chen H, et al. Hyaluronan accumulates in demyelinated lesions and inhibits oligodendrocyte progenitor maturation. Nat Med 2005;11:966–72.
Preston M, Gong X, Su W, et al. Digestion products of the PH20 hyaluronidase inhibit remyelination. Ann Neurol 2013;73:266–80.
Wang Y, Cheng X, He Q, et al. Astrocytes from the contused spinal cord inhibit oligodendrocyte differentiation of adult oligodendrocyte precursor cells by increasing the expression of bone morphogenetic proteins. J Neurosci 2011;31:6053–8.
John GR, Shankar SL, Shafit-Zagardo B, et al. Multiple sclerosis: re-expression of a developmental pathway that restricts oligodendrocyte maturation. Nat Med 2002;8:1115–21.
Chung WS, Barres BA . The role of glial cells in synapse elimination. Curr Opin Neurobiol 2012;22:438–45.
Dai X, Lercher LD, Clinton PM, et al. The trophic role of oligodendrocytes in the basal forebrain. J Neurosci 2003;23:5846–53.
Alvarez-Maubecin V, Garcia-Hernandez F, Williams JT, Van Bockstaele EJ . Functional coupling between neurons and glia. J Neurosci 2000;20:4091–8.
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Dean, J., Bennet, L., Back, S. et al. What brakes the preterm brain? An arresting story. Pediatr Res 75, 227–233 (2014). https://doi.org/10.1038/pr.2013.189
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DOI: https://doi.org/10.1038/pr.2013.189
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