Prenatal Maternal Cortisol Has Sex‐Specific Associations with Child Brain Network Properties

Abstract Elevated maternal cortisol concentrations have the potential to alter fetal development in a sex‐specific manner. Female brains are known to show adaptive behavioral and anatomical flexibility in response to early‐life exposure to cortisol, but it is not known how these sex‐specific effects manifest at the whole‐brain structural networks. A prospective longitudinal study of 49 mother child dyads was conducted with serial assessments of maternal cortisol levels from 15 to 37 gestational weeks. We modeled the structural network of typically developing children (aged 6‐9 years) and examined its global connectome properties, rich‐club organization, and modular architecture. Network segregation was susceptible only for girls to variations in exposure to maternal cortisol during pregnancy. Girls generated more connections than boys to maintain topologically capable and efficient neural circuits, and this increase in neural cost was associated with higher levels of internalizing problems. Maternal cortisol concentrations at 31 gestational weeks gestation were most strongly associated with altered neural connectivity in girls, suggesting a sensitive period for the maternal cortisol‐offspring brain associations. Our data suggest that girls exhibit an adaptive response by increasing the neural network connectivity necessary for maintaining homeostasis and efficient brain function across the lifespan.

[1]  Danielle S Bassett,et al.  Cognitive fitness of cost-efficient brain functional networks , 2009, Proceedings of the National Academy of Sciences.

[2]  H. Mcardle,et al.  A common cause for a common phenotype: The gatekeeper hypothesis in fetal programming , 2012, Medical hypotheses.

[3]  H E Stanley,et al.  Classes of small-world networks. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[4]  E. Davis,et al.  Prenatal treatment with glucocorticoids sensitizes the hpa axis response to stress among full-term infants. , 2011, Developmental psychobiology.

[5]  A. Kavelaars,et al.  Neonatal glucocorticoid treatment: Long-term effects on the hypothalamus–pituitary–adrenal axis, immune system, and problem behavior in 14–17 year old adolescents , 2015, Brain, Behavior, and Immunity.

[6]  K. Sneppen,et al.  Specificity and Stability in Topology of Protein Networks , 2002, Science.

[7]  Mason A. Porter,et al.  Robust Detection of Dynamic Community Structure in Networks , 2012, Chaos.

[8]  J. Bremner,et al.  MR-based in vivo hippocampal volumetrics: 2. Findings in neuropsychiatric disorders , 2005, Molecular Psychiatry.

[9]  Paul A Taylor,et al.  Geometric analysis of the b-dependent effects of Rician signal noise on diffusion tensor imaging estimates and determining an optimal b value. , 2011, Magnetic resonance imaging.

[10]  Terrence J Sejnowski,et al.  Communication in Neuronal Networks , 2003, Science.

[11]  Jean-Loup Guillaume,et al.  Fast unfolding of communities in large networks , 2008, 0803.0476.

[12]  T. Bale,et al.  Sex-Specific Programming of Offspring Emotionality after Stress Early in Pregnancy , 2008, The Journal of Neuroscience.

[13]  R. Gitau,et al.  Fetal exposure to maternal cortisol , 1998, The Lancet.

[14]  Tore Opsahl,et al.  Prominence and control: the weighted rich-club effect. , 2008, Physical review letters.

[15]  Charles D. Spielberger,et al.  State-Trait Anxiety Inventory for Adults , 2012 .

[16]  G. Chrousos,et al.  Glucocorticoid action networks and complex psychiatric and/or somatic disorders , 2007, Stress.

[17]  E. Davis,et al.  Neurobehavioral risk is associated with gestational exposure to stress hormones , 2012, Expert review of endocrinology & metabolism.

[18]  V. Clifton,et al.  Identification of Eight Different Isoforms of the Glucocorticoid Receptor in Guinea Pig Placenta: Relationship to Preterm Delivery, Sex and Betamethasone Exposure , 2016, PloS one.

[19]  S. Collishaw,et al.  Investigating Environmental Links Between Parent Depression and Child Depressive/Anxiety Symptoms Using an Assisted Conception Design , 2011, Journal of the American Academy of Child and Adolescent Psychiatry.

[20]  Massimo Marchiori,et al.  Economic small-world behavior in weighted networks , 2003 .

[21]  Rex E. Jung,et al.  Sex differences in the relationship between white matter connectivity and creativity , 2016 .

[22]  E. Bullmore,et al.  A Resilient, Low-Frequency, Small-World Human Brain Functional Network with Highly Connected Association Cortical Hubs , 2006, The Journal of Neuroscience.

[23]  D. Halpern Sex Differences in Cognitive Abilities , 1986 .

[24]  N. Jovanov-Milošević,et al.  The development of cerebral connections during the first 20-45 weeks' gestation. , 2006, Seminars in fetal & neonatal medicine.

[25]  O. Sporns,et al.  The economy of brain network organization , 2012, Nature Reviews Neuroscience.

[26]  B. Shahbaba,et al.  Maternal cortisol over the course of pregnancy and subsequent child amygdala and hippocampus volumes and affective problems , 2012, Proceedings of the National Academy of Sciences.

[27]  K. Braun,et al.  Changes of spine density and dendritic complexity in the prefrontal cortex in offspring of mothers exposed to stress during pregnancy , 2006, The European journal of neuroscience.

[28]  Santo Fortunato,et al.  Consensus clustering in complex networks , 2012, Scientific Reports.

[29]  C. Buss,et al.  Fetal Exposure to Maternal Depressive Symptoms Is Associated With Cortical Thickness in Late Childhood , 2015, Biological Psychiatry.

[30]  Elysia Poggi Davis,et al.  Maturation of the human fetal startle response: evidence for sex-specific maturation of the human fetus. , 2009, Early human development.

[31]  S. Maier,et al.  Medial prefrontal cortex determines how stressor controllability affects behavior and dorsal raphe nucleus , 2005, Nature Neuroscience.

[32]  E. Davis,et al.  Is there a viability-vulnerability tradeoff? Sex differences in fetal programming. , 2013, Journal of psychosomatic research.

[33]  Dmitri B. Chklovskii,et al.  Wiring Optimization in Cortical Circuits , 2002, Neuron.

[34]  O. Sporns Networks of the Brain , 2010 .

[35]  D. Pfaff,et al.  Sexually dimorphic responses to early adversity: Implications for affective problems and autism spectrum disorder , 2014, Psychoneuroendocrinology.

[36]  D. Rueckert,et al.  Rich-club organization of the newborn human brain , 2014, Proceedings of the National Academy of Sciences.

[37]  O. Sporns,et al.  High-cost, high-capacity backbone for global brain communication , 2012, Proceedings of the National Academy of Sciences.

[38]  J. Torday,et al.  Sex Differences in Fetal Lung Maturation1,2 , 2015 .

[39]  A. Gabory,et al.  Placental contribution to the origins of sexual dimorphism in health and diseases: sex chromosomes and epigenetics , 2013, Biology of Sex Differences.

[40]  Richard F. Betzel,et al.  Modular Brain Networks. , 2016, Annual review of psychology.

[41]  C. Spielberger State‐Trait Anxiety Inventory , 2010 .

[42]  G. Chrousos,et al.  The human glucocorticoid receptor: Molecular basis of biologic function , 2010, Steroids.

[43]  J. Buitelaar,et al.  Prenatal maternal cortisol levels and infant behavior during the first 5 months. , 2003, Early human development.

[44]  M. Bellani,et al.  Brain anatomy of major depression II. Focus on amygdala , 2011, Epidemiology and Psychiatric Sciences.

[45]  O. Sporns,et al.  Rich-Club Organization of the Human Connectome , 2011, The Journal of Neuroscience.

[46]  J. Kingdom,et al.  Sex-specific basis of severe placental dysfunction leading to extreme preterm delivery. , 2012, Placenta.

[47]  Alessandro Vespignani,et al.  Detecting rich-club ordering in complex networks , 2006, physics/0602134.

[48]  Olaf Sporns,et al.  Complex network measures of brain connectivity: Uses and interpretations , 2010, NeuroImage.

[49]  Roger Smith,et al.  Endocrine regulation of human fetal growth: the role of the mother, placenta, and fetus. , 2006, Endocrine reviews.

[50]  J. Lawn,et al.  Long-term neurodevelopmental outcomes after intrauterine and neonatal insults: a systematic review , 2012, The Lancet.

[51]  J. Giedd,et al.  Review: magnetic resonance imaging of male/female differences in human adolescent brain anatomy , 2012, Biology of Sex Differences.

[52]  Olaf Sporns,et al.  Longer gestation is associated with more efficient brain networks in preadolescent children , 2014, NeuroImage.

[53]  Claudia Buss,et al.  Maternal Care Modulates the Relationship between Prenatal Risk and Hippocampal Volume in Women But Not in Men , 2007, The Journal of Neuroscience.

[54]  E. Davis,et al.  Antenatal glucocorticoid treatment is associated with diurnal cortisol regulation in term-born children , 2016, Psychoneuroendocrinology.

[55]  L. Radloff The CES-D Scale , 1977 .

[56]  Olaf Sporns,et al.  Children's intellectual ability is associated with structural network integrity , 2016, NeuroImage.

[57]  T. Achenbach Manual for the ASEBA preschool forms & profiles : an integrated system of multi-informant assessment , 2000 .

[58]  Edward T. Bullmore,et al.  Efficiency and Cost of Economical Brain Functional Networks , 2007, PLoS Comput. Biol..

[59]  D. Hedges,et al.  Hippocampal and amygdala volumes in children and adults with childhood maltreatment‐related posttraumatic stress disorder: A meta‐analysis , 2008, Hippocampus.

[60]  P. Vernon,et al.  Heritability Estimates of Intelligence in Twins: Effect of Chorion Type , 2001, Behavior genetics.

[61]  V. Glover,et al.  In utero cortisol and testosterone exposure and fear reactivity in infancy , 2010, Hormones and Behavior.

[62]  Alan C. Evans,et al.  Age- and Gender-Related Differences in the Cortical Anatomical Network , 2009, The Journal of Neuroscience.

[63]  N. Myrianthopoulos,et al.  The effects of chorion type on variation in IQ in the NCPP twin population. , 1978, American journal of human genetics.

[64]  A. Chicz–DeMet,et al.  Prenatal exposure to maternal depression and cortisol influences infant temperament. , 2007, Journal of the American Academy of Child and Adolescent Psychiatry.

[65]  V. Clifton Review: Sex and the human placenta: mediating differential strategies of fetal growth and survival. , 2010, Placenta.

[66]  C. Epperson,et al.  Sex differences and stress across the lifespan , 2015, Nature Neuroscience.

[67]  Marlon J. A. Jetten,et al.  Evidence of female-specific glial deficits in the hippocampus in a mouse model of prenatal stress , 2011, European Neuropsychopharmacology.

[68]  J. Torday,et al.  Sex differences in fetal lung maturation. , 1981, The American review of respiratory disease.

[69]  E. Davis,et al.  Prenatal psychobiological predictors of anxiety risk in preadolescent children , 2012, Psychoneuroendocrinology.

[70]  Alex R. Smith,et al.  Sex differences in the structural connectome of the human brain , 2013, Proceedings of the National Academy of Sciences.

[71]  C. Aiken,et al.  Sex differences in developmental programming models. , 2013, Reproduction.

[72]  M. Gunnar,et al.  Antenatal betamethasone treatment has a persisting influence on infant HPA axis regulation , 2006, Journal of Perinatology.

[73]  O. Sporns,et al.  Mapping the Structural Core of Human Cerebral Cortex , 2008, PLoS biology.

[74]  Paul A. Taylor,et al.  FATCAT: (An Efficient) Functional And Tractographic Connectivity Analysis Toolbox , 2013, Brain Connect..

[75]  P. Uhlhaas,et al.  Preferential Detachment During Human Brain Development: Age- and Sex-Specific Structural Connectivity in Diffusion Tensor Imaging (DTI) Data , 2013, Cerebral cortex.

[76]  V. Latora,et al.  Efficient behavior of small-world networks. , 2001, Physical review letters.

[77]  Nitish Thakor,et al.  Progressive Gender Differences of Structural Brain Networks in Healthy Adults: A Longitudinal, Diffusion Tensor Imaging Study , 2015, PloS one.

[78]  Elysia Poggi Davis,et al.  Fetal Glucocorticoid Exposure Is Associated with Preadolescent Brain Development , 2013, Biological Psychiatry.

[79]  Neil Marlow,et al.  Neonatal and infant outcome in boys and girls born very prematurely , 2012, Pediatric Research.

[80]  D. Tulchinsky,et al.  Glucocorticoid metabolism in human placenta, decidua, myometrium and fetal membranes. , 1982, Journal of steroid biochemistry.