Amygdala-Prefrontal Structural Connectivity Mediates the Relationship between Prenatal Depression and Behavior in Preschool Boys

Abstract

Prenatal depression is common, underrecognized, and undertreated. It has negative consequences on child behavior and brain development, yet the relationships among prenatal depression, child behavior, and children's brain structure remain unclear. The aim of this study was to determine whether altered brain connectivity mediates relationships between prenatal maternal depressive symptoms and child behavior. This study included 54 human mother-child pairs. Mothers completed the Edinburgh Postnatal Depression Scale during the second and third trimesters of pregnancy and 3 months postpartum. Their children had diffusion MRI at age 4.1 6 0.8 years, and children's behavior was assessed using the Child Behavior Checklist within 6 months of their MRI scan. Structural brain connectivity of the amygdala, fornix, uncinate fasciculus, and cingulum was assessed using fractional anisotropy and mean diffusivity and analyzed with maternal prenatal depressive symptoms as well as child behavior. Third trimester maternal Edinburgh Postnatal Depression Scale scores were positively associated with mean diffusivity in the amygdala-frontal tract and the cingulum, controlling for postpartum depression. Externalizing behavior had a sex interaction in the amygdala-frontal pathway; weaker connectivity (lower fractional anisotropy, higher mean diffusivity) was associated with worse behavior in boys. Amygdala-frontal connectivity mediated the relationship between third trimester depressive symptoms and child externalizing behavior in males. These findings suggest that altered brain structure is a mechanism via which prenatal depressive symptoms can impact child behavior, highlighting the importance of both recognition and intervention in prenatal depression.

Placental DNA methylation marks are associated with maternal depressive symptoms during early pregnancy

“…In addition, a sex-specific gene x environment effect on right hippocampal volumes was found ( Acosta et al, 2020 ). Also several other studies have found association between prenatal exposure to maternal depressive symptoms and brain imaging-derived and behavioral phenotypes ( Hay et al, 2020 ; A. Lee et al, 2019 ; Qiu et al, 2015 ; Rifkin-Graboi et al, 2013 ; Soe et al, 2018 ; van der Knaap et al, 2018 ; Wen et al, 2017 ).…”

“… Lee et al, 2019 ; Qiu et al, 2015 ; Rifkin-Graboi et al, 2013 ; Soe et al, 2018 ; van der Knaap et al, 2018 ; Wen et al, 2017 ). For example, in girls gender specific associations have been found between prenatal exposure to maternal depressive symptoms and larger right amygdala volumes at 4.5 years of age ( Wen et al, 2017 ) and in boys weaker connectivity in the amygdala-frontal pathway and worse externalizing behavior has been detected at the age of 2.9–6.0 years ( Hay et al, 2020 ). Whether these phenotypes are mediated through epigenetic mechanisms remains unclear.…”

Prenatal origins of neuropsychiatric diseases

“…59 Advanced brain imaging studies suggest that neural pathways in newborns exposed to maternal anxiety differ from healthy controls, particularly in regions of the brain controlling sensory and emotional processing, and is predictive of infant childhood behaviour. 60,61 Maternal depression has been linked with adverse offspring health across the lifespan -including preterm birth, low birthweight, and increased stress behaviours in newborns 62 as well as increased affective disorders and developmental problems through childhood. 63 Both maternal anxiety and maternal depression are associated with alterations in glucocorticoid delivery to the foetus and activation of the foetal HPA pathway.…”

“…Elevated prenatal maternal stress levels have been correlated with volumetric changes in the hippocampus and amygdala of the brain and in subsequent behaviour profiles in affected children, suggesting that early foetal exposures to toxic stress influence brain growth and development 59 . Advanced brain imaging studies suggest that neural pathways in newborns exposed to maternal anxiety differ from healthy controls, particularly in regions of the brain controlling sensory and emotional processing, and is predictive of infant childhood behaviour 60,61 . Maternal depression has been linked with adverse offspring health across the lifespan – including preterm birth, low birthweight, and increased stress behaviours in newborns 62 as well as increased affective disorders and developmental problems through childhood 63 .…”

Evolutionary Significance of the Neuroendocrine Stress Axis on Vertebrate Immunity and the Influence of the Microbiome on Early-Life Stress Regulation and Health Outcomes

“…This forms the basis of the stress acceleration hypothesis, which proposes a reprioritization of developmental strategies to more rapidly achieve adult-like functioning in stress and fear-related brain circuitry when under the influence of early-life stress ( Callaghan and Tottenham, 2016 ). This accelerated maturation has been linked to both structural and functional changes in the brain ( Lebel et al, 2016 ), particularly in corticolimbic regions such as the hippocampus and amygdala ( Dannlowski et al, 2012 ; Teicher et al, 2016 ), and connectivity between these regions and the prefrontal cortex ( Hay et al, 2020 ). Given the abundant expression of GRs in the hippocampus and its role in cognition, and the central role of the amygdala in stress responsivity, it is not surprising that stress-related insults associate most strongly with these regions ( Dannlowski et al, 2012 ; Swartz et al, 2015 ).…”