Maternal cortisol is associated with neonatal amygdala microstructure and connectivity in a sexually dimorphic manner

Abstract

The mechanisms linking maternal stress in pregnancy with infant neurodevelopment in a sexually dimorphic manner are poorly understood. We tested the hypothesis that maternal hypothalamic-pituitary-adrenal axis activity, measured by hair cortisol concentration (HCC), is associated with microstructure, structural connectivity, and volume of the infant amygdala. In 78 mother-infant dyads, maternal hair was sampled postnatally, and infants underwent magnetic resonance imaging at term-equivalent age. We found a relationship between maternal HCC and amygdala development that differed according to infant sex. Higher HCC was associated with higher left amygdala fractional anisotropy (β = 0.677, p=0.010), lower left amygdala orientation dispersion index (β = −0.597, p=0.034), and higher fractional anisotropy in connections between the right amygdala and putamen (β = 0.475, p=0.007) in girls compared to boys. Furthermore, altered amygdala microstructure was only observed in boys, with connectivity changes restricted to girls. Maternal cortisol during pregnancy is related to newborn amygdala architecture and connectivity in a sexually dimorphic manner. Given the fundamental role of the amygdala in the emergence of emotion regulation, these findings offer new insights into mechanisms linking maternal health with neuropsychiatric outcomes of children.

In search of sex-related mediators of affective illness

“…Because mood dysregulation does not reside in a specific brain region nor does it rely solely on changes at any one physiologic level, causeand-effect with regards to these differences cannot be inferred. A change in transcription, for instance, may be [41,268]; locus coeruleus structural dimorphism [54] Regional morphology differences following prenatal stress [55-60] E2 impact on physiologic development [269] E2 neuroprotective in brain injury [270]; neuronal loss in the prefrontal cortex, hippocampus, hypothalamus, and amygdala following OVX [271] Human Women increased gray/white matter ratio [42,43]; gray matter density differences in several brain regions [45]; different developmental rates [46,47]; cortical surface area trajectory [272]; volumetric differences at birth [273] In childhood stress: lower gray matter thickness and caudate volumes in females, decreased thickness of rostral anterior cingulate cortex in males [64]; amygdala differences following prenatal stress [65][66][67][68][69]; differences in cortical gyrification [70] Volumetric changes during different menstrual phases [274,275]; regional differences between OCP users and cycling women [275] Effects of menstrual cycle on hippocampus in PMDD [276] Network connectivity Animal Sex differences in circuits implicated in parenting behavior [277] Differential network activation in response to pain [278][279][280]; differences in network organization following prenatal ethanol exposure [281] Dendritic spine density fluctuation during estrous cycle [166]; E2-dependent reward circuitry [282] Hippocampal/PFC remodeling following stress mediated by E2 [122] Human DMN…”

“…A meta-analysis of data obtained by the Enhancing Neuroimaging Genetics through Meta-Analysis (ENIGMA) consortium demonstrated that, in cases of childhood maltreatment, greater maltreatment severity was associated with lower gray matter thickness and caudate volumes in adolescent and adult females, whereas in males, greater maltreatment severity was associated with decreased thickness of rostral anterior cingulate cortex [64]. Postnatal maternal depression has been associated with greater fractional anisotropy of the amygdala in female children [65], and several studies have demonstrated sex-specific effects of prenatal maternal stress on subsequent amygdala structure in newborns, with differential effects seen on volume [65][66][67][68] and microstructure [69]. One recent study demonstrated sex-specific effects of early perinatal stress on cortical gyrification, with young adult women who were previously exposed to stress either in-utero or during the first 18 months of life showing higher temporal gyrification and greater propensity for mood disturbance [70].…”

Perinatal determinants of neonatal hair glucocorticoid concentrations

“…The Stress Response Systems in Mothers and Preterm Infants study is a longitudinal cohort assessing the role of glucocorticoids in the early life programming of health and disease ( Stoye et al, 2020 ). Participants were mother-term (≥ 37 weeks’ gestational age) and mother-preterm dyads (≤ 32 weeks’) with births at the Royal Infirmary, Edinburgh between March 2018 and August 2019.…”

“…Furthermore, preterm infants are at increased risk of later adverse metabolic ( Parkinson et al, 2013 ) and neurodevelopmental ( Johnson and Marlow, 2017 ) outcomes, phenotypes observed in preclinical models following excess perinatal glucocorticoid exposure ( Moisiadis and Matthews, 2014a ). Whilst there is evidence that noxious environmental stimuli ( Vinall and Grunau, 2014 ) and postnatal high dose dexamethasone adversely affect neurodevelopment ( Baud, 2004 ), little is known about the importance of cortisol exposure for a preterm population ( Stoye et al, 2020 ). Characterisation of cortisol concentrations through traditional methods, including saliva and serum, have proven challenging in this population, as saliva volumes are frequently insufficient for analysis ( Mörelius et al, 2016 ), and infants have an insufficient circulatory reserve to allow for repeated blood sampling.…”

Breast may not always be best: moderation of effects of postnatal depression by breastfeeding and infant sex

“…Such changes to the fetal/infant HPA axis confer susceptibility to later psychopathology [ 8 ], and accumulating evidence suggests that these effects are sex-dependent. For example, exposure to prenatal psychological stress/increased maternal cortisol is associated with reduced birthweight [ 9 ], fearful temperament [ 10 ], increased negative emotionality [ 11 , 12 ], changes in HPA function [ 8 ], adolescent depression [ 8 ], and changes in amygdala size [ 13 ] and connectivity [ 14 , 15 ], all in females only. This suggests that females are specifically susceptible to maternal psychological distress in early development, mediated by glucocorticoid pathways.…”