Neonatal Pain-Related Stress Predicts Cortical Thickness at Age 7 Years in Children Born Very Preterm

Background Altered brain development is evident in children born very preterm (24–32 weeks gestational age), including reduction in gray and white matter volumes, and thinner cortex, from infancy to adolescence compared to term-born peers. However, many questions remain regarding the etiology. Infants born very preterm are exposed to repeated procedural pain-related stress during a period of very rapid brain development. In this vulnerable population, we have previously found that neonatal pain-related stress is associated with atypical brain development from birth to term-equivalent age. Our present aim was to evaluate whether neonatal pain-related stress (adjusted for clinical confounders of prematurity) is associated with altered cortical thickness in very preterm children at school age. Methods 42 right-handed children born very preterm (24–32 weeks gestational age) followed longitudinally from birth underwent 3-D T1 MRI neuroimaging at mean age 7.9 yrs. Children with severe brain injury and major motor/sensory/cognitive impairment were excluded. Regional cortical thickness was calculated using custom developed software utilizing FreeSurfer segmentation data. The association between neonatal pain-related stress (defined as the number of skin-breaking procedures) accounting for clinical confounders (gestational age, illness severity, infection, mechanical ventilation, surgeries, and morphine exposure), was examined in relation to cortical thickness using constrained principal component analysis followed by generalized linear modeling. Results After correcting for multiple comparisons and adjusting for neonatal clinical factors, greater neonatal pain-related stress was associated with significantly thinner cortex in 21/66 cerebral regions (p-values ranged from 0.00001 to 0.014), predominately in the frontal and parietal lobes. Conclusions In very preterm children without major sensory, motor or cognitive impairments, neonatal pain-related stress appears to be associated with thinner cortex in multiple regions at school age, independent of other neonatal risk factors.

[1]  Steven P. Miller,et al.  Score for neonatal acute physiology-II and neonatal pain predict corticospinal tract development in premature newborns. , 2013, Pediatric neurology.

[2]  Anders M. Dale,et al.  Cortical Surface-Based Analysis I. Segmentation and Surface Reconstruction , 1999, NeuroImage.

[3]  J. Neil,et al.  Neonatal intensive care unit stress is associated with brain development in preterm infants , 2011, Annals of neurology.

[4]  A. Bhutta,et al.  Ketamine Reduces the Cell Death Following Inflammatory Pain in Newborn Rat Brain , 2007, Pediatric Research.

[5]  I. Aharon,et al.  Three‐dimensional mapping of cortical thickness using Laplace's Equation , 2000, Human brain mapping.

[6]  A. Toga,et al.  Mapping brain asymmetry , 2003, Nature Reviews Neuroscience.

[7]  L. Papile,et al.  Brain injury in premature infants: a complex amalgam of destructive and developmental disturbances , 2010 .

[8]  Merle G Paule,et al.  A pilot study of preemptive morphine analgesia in preterm neonates: effects on head circumference, social behavior, and response latencies in early childhood. , 2012, Neurotoxicology and teratology.

[9]  Chiara Nosarti,et al.  Structural covariance in the cortex of very preterm adolescents: A voxel‐based morphometry study , 2011, Human brain mapping.

[10]  Margot J. Taylor,et al.  Neuroanatomical consequences of very preterm birth in middle childhood , 2012, Brain Structure and Function.

[11]  P. Roland.  Cortical representation of pain , 1992, Trends in Neurosciences.

[12]  M. Kaminski,et al.  Prolonged sedation and/or analgesia and 5-year neurodevelopment outcome in very preterm infants: results from the EPIPAGE cohort. , 2008, Archives of pediatrics & adolescent medicine.

[13]  B. Vohr,et al.  Brain volume reductions within multiple cognitive systems in male preterm children at age twelve. , 2008, The Journal of pediatrics.

[14]  Steven P. Miller,et al.  Neonatal pain-related stress, functional cortical activity and visual-perceptual abilities in school-age children born at extremely low gestational age , 2013, PAIN®.

[15]  R. Beyer,et al.  Effects of Neonatal Stress and Morphine on Murine Hippocampal Gene Expression , 2011, Pediatric Research.

[16]  C. Johnston,et al.  Artificial Rearing of Rat Pups Reveals the Beneficial Effects of Mother Care on Neonatal Inflammation and Adult Sensitivity to Pain , 2009, Pediatric Research.

[17]  Steven P. Miller,et al.  Serial quantitative diffusion tensor MRI of the premature brain: Development in newborns with and without injury , 2002, Journal of magnetic resonance imaging : JMRI.

[18]  Vann Chau,et al.  Procedural pain and brain development in premature newborns , 2012, Annals of neurology.

[19]  M. Braga,et al.  Exploratory Data Analysis , 2018, Encyclopedia of Social Network Analysis and Mining. 2nd Ed..

[20]  N. Bargalló,et al.  Cortical Thickness and Behavior Abnormalities in Children Born Preterm , 2012, PloS one.

[21]  Alan C. Evans,et al.  Neurodevelopmental Trajectories of the Human Cerebral Cortex , 2008, The Journal of Neuroscience.

[22]  J. L. Laprairie,et al.  Preemptive Morphine Analgesia Attenuates the Long-Term Consequences of Neonatal Inflammation in Male and Female Rats , 2008, Pediatric Research.

[23]  K. Anand,et al.  Effects of perinatal pain and stress. , 2000, Progress in brain research.

[24]  Chiara Nosarti,et al.  Adolescents who were born very preterm have decreased brain volumes. , 2002, Brain : a journal of neurology.

[25]  A. Dale,et al.  Cerebral cortex thickness in 15-year-old adolescents with low birth weight measured by an automated MRI-based method. , 2005, Brain : a journal of neurology.

[26]  J. Volpe.  Brain injury in premature infants: a complex amalgam of destructive and developmental disturbances , 2009, The Lancet Neurology.

[27]  B. Barton,et al.  Effects of morphine analgesia in ventilated preterm neonates: primary outcomes from the NEOPAIN randomised trial , 2004, The Lancet.

[28]  J. Feldon,et al.  Comparison of the effects of infant handling, isolation, and nonhandling on acoustic startle, prepulse inhibition, locomotion, and HPA activity in the adult rat. , 2001, Behavioral neuroscience.

[29]  Lorenzo Fabrizi,et al.  Premature infants display increased noxious-evoked neuronal activity in the brain compared to healthy age-matched term-born infants , 2010, NeuroImage.

[30]  A. Basbaum,et al.  The senses : a comprehensive reference , 2008 .

[31]  F. Seguin,et al.  Effects of stress throughout the lifespan on the brain, behaviour and cognition , 2009 .

[32]  B. Vohr,et al.  Volumetric analysis of regional cerebral development in preterm children. , 2004, Pediatric neurology.

[33]  D. Tibboel,et al.  Does neonatal morphine use affect neuropsychological outcomes at 8 to 9years of age? , 2013, PAIN®.

[34]  David W. Haley,et al.  Neonatal procedural pain exposure predicts lower cortisol and behavioral reactivity in preterm infants in the NICU , 2005, Pain.

[35]  A. Dale,et al.  Entorhinal cortical thinning affects perceptual and cognitive functions in adolescents born preterm with very low birth weight (VLBW). , 2012, Early human development.

[36]  Steven P. Miller,et al.  Early brain injury in premature newborns detected with magnetic resonance imaging is associated with adverse early neurodevelopmental outcome. , 2005, The Journal of pediatrics.

[37]  T. Inder.  Early Brain Injury in Premature Newborns Detected With Magnetic Resonance Imaging Is Associated With Adverse Early Neurodevelopmental Outcome , 2007 .

[38]  J. Peters,et al.  Long-term consequences of pain in human neonates. , 2006, Seminars in fetal & neonatal medicine.

[39]  L. Galea,et al.  High post-partum levels of corticosterone given to dams influence postnatal hippocampal cell proliferation and behavior of offspring: A model of post-partum stress and possible depression , 2006, Hormones and Behavior.

[40]  David W. Haley,et al.  Altered basal cortisol levels at 3, 6, 8 and 18 months in infants born at extremely low gestational age. , 2007, The Journal of pediatrics.

[41]  Yoshio Takane,et al.  Constrained Principal Component Analysis: A Comprehensive Theory , 2001, Applicable Algebra in Engineering, Communication and Computing.

[42]  M. Kenward,et al.  An Introduction to the Bootstrap , 2007 .

[43]  Altered Long-Range Phase Synchronization and Cortical Activation in Children Born Very Preterm. , 2010, IFMBE proceedings.

[44]  D. Tibboel,et al.  Effects of Repetitive Exposure to Pain and Morphine Treatment on the Neonatal Rat Brain , 2012, Neonatology.

[45]  R. Tibshirani,et al.  An Introduction to the Bootstrap , 1995 .

[46]  C. Johnston,et al.  Naturally occurring variations in maternal care modulate the effects of repeated neonatal pain on behavioral sensitivity to thermal pain in the adult offspring , 2008, PAIN.

[47]  Christopher J. Cannistraci,et al.  Regional brain volume abnormalities and long-term cognitive outcome in preterm infants. , 2000, JAMA.

[48]  K. Anand,et al.  A cross-sectional survey of pain and pharmacological analgesia in Canadian neonatal intensive care units. , 1997, The Clinical journal of pain.

[49]  R. Treede,et al.  Human brain mechanisms of pain perception and regulation in health and disease , 2005, European journal of pain.

[50]  Samantha Arzon,et al.  Running head : WISC-IV ! 1 ! ! ! ! ! ! ! ! ! Wechsler Intelligence Scale for Children ( WISC-IV ) , 2014 .

[51]  Zoltan Nagy,et al.  Effects of Preterm Birth on Cortical Thickness Measured in Adolescence , 2010, Cerebral cortex.

[52]  Justin M Dean,et al.  Prenatal Cerebral Ischemia Disrupts MRI-Defined Cortical Microstructure Through Disturbances in Neuronal Arborization , 2013, Science Translational Medicine.

[53]  Anders M. Dale,et al.  An automated labeling system for subdividing the human cerebral cortex on MRI scans into gyral based regions of interest , 2006, NeuroImage.

[54]  Teresa Cheung,et al.  Magnetoencephalography Reveals Slowing of Resting Peak Oscillatory Frequency in Children Born Very Preterm , 2011, Pediatric Research.

[55]  Arvind Caprihan,et al.  Prematurity affects cortical maturation in early childhood. , 2011, Pediatric neurology.

[56]  G. Escobar,et al.  SNAP-II and SNAPPE-II: Simplified newborn illness severity and mortality risk scores. , 2001, The Journal of pediatrics.

[57]  Y. Takane,et al.  Principal component analysis with external information on both subjects and variables , 1991 .

[58]  Hiroyuki Kidokoro,et al.  Regional cerebral development at term relates to school-age social-emotional development in very preterm children. , 2012, Journal of the American Academy of Child and Adolescent Psychiatry.

[59]  Sébastien Ourselin,et al.  A comparison of voxel and surface based cortical thickness estimation methods , 2011, NeuroImage.

[60]  C. Buss,et al.  Magnetic resonance imaging demonstrates long-term changes in brain structure in children born preterm and exposed to chorioamnionitis. , 2011, American journal of obstetrics and gynecology.

[61]  Ivo D. Dinov,et al.  Sex Matters during Adolescence: Testosterone-Related Cortical Thickness Maturation Differs between Boys and Girls , 2012, PloS one.

[62]  A. Dale,et al.  Cortical Surface-Based Analysis II: Inflation, Flattening, and a Surface-Based Coordinate System , 1999, NeuroImage.

[63]  Dick Tibboel,et al.  Routine morphine infusion in preterm newborns who received ventilatory support: a randomized controlled trial. , 2003, JAMA.

[64]  Vann Chau,et al.  Slower Postnatal Growth Is Associated with Delayed Cerebral Cortical Maturation in Preterm Newborns , 2013, Science Translational Medicine.

[65]  Chiara Nosarti,et al.  Grey and white matter distribution in very preterm adolescents mediates neurodevelopmental outcome. , 2008, Brain : a journal of neurology.

[66]  Alan C. Evans,et al.  Cortical thickness analysis examined through power analysis and a population simulation , 2005, NeuroImage.

[67]  Cortical thickness measurement using Eulerian PDEs and surface-based global topological information , 2009, NeuroImage.

[68]  A. Mirsky,et al.  Physiology and Neurobiology of Stress and Adaptation : Central Role of the Brain , 2007 .

[69]  S Minoshima,et al.  Selective opiate modulation of nociceptive processing in the human brain. , 2000, Journal of neurophysiology.

[70]  Jerry L. Prince,et al.  An Eulerian PDE approach for computing tissue thickness , 2003, IEEE Transactions on Medical Imaging.

[71]  R. Bellù,et al.  Opioids for neonates receiving mechanical ventilation. , 2008, The Cochrane database of systematic reviews.

[72]  L. Low,et al.  Acute Pain and a Motivational Pathway in Adult Rats: Influence of Early Life Pain Experience , 2012, PloS one.

[73]  S. Maccari,et al.  Effects of prenatal restraint stress on the hypothalamus–pituitary–adrenal axis and related behavioural and neurobiological alterations , 2007, Psychoneuroendocrinology.

[74]  E. Cadenas,et al.  Physiology and Neurobiology of Stress and Adaptation: Central Role of the Brain , 2007 .

[75]  G D Pearlson,et al.  Site of opioid action in the human brain: mu and kappa agonists' subjective and cerebral blood flow effects. , 1998, The American journal of psychiatry.

[76]  A. Bhutta,et al.  Interactions of inflammatory pain and morphine in infant rats: long-term behavioral effects , 2001, Physiology & Behavior.

[77]  F. Champagne,et al.  Stress During Gestation Alters Postpartum Maternal Care and the Development of the Offspring in a Rodent Model , 2006, Biological Psychiatry.

[78]  R. Grunau,et al.  Neonatal pain, parenting stress and interaction, in relation to cognitive and motor development at 8 and 18months in preterm infants , 2009, Pain.

[79]  Eileen Luders,et al.  Asymmetries of cortical thickness: effects of handedness, sex, and schizophrenia , 2007, Neuroreport.

[80]  C J Hodge,et al.  The spinothalamic tract. , 1990, Critical reviews in neurobiology.

[81]  H. Flor,et al.  Cerebral processing of pain in school-aged children with neonatal nociceptive input: An exploratory fMRI study , 2010, PAIN.

[82]  D. Tibboel,et al.  Long-term effects of routine morphine infusion in mechanically ventilated neonates on children’s functioning: Five-year follow-up of a randomized controlled trial , 2011, PAIN.

[83]  Suzanne E. Welcome,et al.  Longitudinal Mapping of Cortical Thickness and Brain Growth in Normal Children , 2022 .

[84]  Y. Takane,et al.  Constrained Principal Component Analysis: Various Applications , 2002 .

[85]  C. Nemeroff,et al.  Long-Term Behavioral Effects of Repetitive Pain in Neonatal Rat Pups , 1999, Physiology & Behavior.

[86]  Y. Benjamini,et al.  Controlling the false discovery rate: a practical and powerful approach to multiple testing , 1995 .

[87]  S. Derbyshire,et al.  Modeling pain circuits: how imaging may modify perception. , 2007, Neuroimaging clinics of North America.