Marielle V. Fortier

Prenatal maternal depression associates with microstructure of right amygdala in neonates at birth.

BACKGROUND Antenatal maternal cortisol levels associate with alterations in the amygdala, a structure associated with emotion regulation, in the offspring. However, because offspring brain and behavior are commonly assessed years after birth, the timing of such maternal influences is unclear. This study aimed to examine the association between antenatal maternal depressive symptomatology and neonatal amygdala volume and microstructure and thus establish evidence for the transgenerational transmission of vulnerability for affective disorders during prenatal development. METHODS Our study recruited Asian mothers at 10 to 13 weeks pregnancy and assessed maternal depression at 26 weeks gestation using the Edinburgh Postnatal Depression Scale. Structural magnetic resonance imaging and diffusion tensor imaging were performed with 157 nonsedated, 6- to 14-day-old newborns and then analyzed to extract the volume, fractional anisotropy, and axial diffusivity values of the amygdala. RESULTS Adjusting for household income, maternal age, and smoking exposure, postconceptual age at magnetic resonance imaging, and birth weight, we found significantly lower fractional anisotropy (p = .009) and axial diffusivity (p = .028), but not volume (p = .993), in the right amygdala in the infants of mothers with high compared with those with low-normal Edinburgh Postnatal Depression Scale scores. CONCLUSIONS The results reveal a significant relation between antenatal maternal depression and the neonatal microstructure of the right amygdala, a brain region closely associated with stress reactivity and vulnerability for mood anxiety disorders. These findings suggest the prenatal transmission of vulnerability for depression from mother to child and that interventions targeting maternal depression should begin early in pregnancy.

Prenatal maternal depression alters amygdala functional connectivity in 6-month-old infants.

Prenatal maternal depression is associated with alterations in the neonatal amygdala microstructure, shedding light on the timing for the influence of prenatal maternal depression on the brain structure of the offspring. This study aimed to examine the association between prenatal maternal depressive symptomatology and infant amygdala functional connectivity and to thus establish the neural functional basis for the transgenerational transmission of vulnerability for affective disorders during prenatal development. Twenty-four infants were included in this study with both structural magnetic resonance imaging (MRI) and resting-state functional MRI (fMRI) at 6 months of age. Maternal depression was assessed at 26 weeks of gestation and 3 months after delivery using the Edinburgh Postnatal Depression Scale. Linear regression was used to identify the amygdala functional networks and to examine the associations between prenatal maternal depressive symptoms and amygdala functional connectivity. Our results showed that at 6 months of age, the amygdala is functionally connected to widespread brain regions, forming the emotional regulation, sensory and perceptual, and emotional memory networks. After controlling for postnatal maternal depressive symptoms, infants born to mothers with higher prenatal maternal depressive symptoms showed greater functional connectivity of the amygdala with the left temporal cortex and insula, as well as the bilateral anterior cingulate, medial orbitofrontal and ventromedial prefrontal cortices, which are largely consistent with patterns of connectivity observed in adolescents and adults with major depressive disorder. Our study provides novel evidence that prenatal maternal depressive symptomatology alters the amygdalas functional connectivity in early postnatal life, which reveals that the neuroimaging correlates of the familial transmission of phenotypes associated with maternal mood are apparent in infants at 6 months of age.

Maternal anxiety and infants' hippocampal development: timing matters.

Exposure to maternal anxiety predicts offspring brain development. However, because children’s brains are commonly assessed years after birth, the timing of such maternal influences in humans is unclear. This study aimed to examine the consequences of antenatal and postnatal exposure to maternal anxiety upon early infant development of the hippocampus, a key structure for stress regulation. A total of 175 neonates underwent magnetic resonance imaging (MRI) at birth and among them 35 had repeated scans at 6 months of age. Maternal anxiety was assessed using the State-Trait Anxiety Inventory (STAI) at week 26 of pregnancy and 3 months after delivery. Regression analyses showed that antenatal maternal anxiety did not influence bilateral hippocampal volume at birth. However, children of mothers reporting increased anxiety during pregnancy showed slower growth of both the left and right hippocampus over the first 6 months of life. This effect of antenatal maternal anxiety upon right hippocampal growth became statistically stronger when controlling for postnatal maternal anxiety. Furthermore, a strong positive association between postnatal maternal anxiety and right hippocampal growth was detected, whereas a strong negative association between postnatal maternal anxiety and the left hippocampal volume at 6 months of life was found. Hence, the postnatal growth of bilateral hippocampi shows distinct responses to postnatal maternal anxiety. The size of the left hippocampus during early development is likely to reflect the influence of the exposure to perinatal maternal anxiety, whereas right hippocampal growth is constrained by antenatal maternal anxiety, but enhanced in response to increased postnatal maternal anxiety.

Structural connectivity asymmetry in the neonatal brain

Asymmetry of the neonatal brain is not yet understood at the level of structural connectivity. We utilized DTI deterministic tractography and structural network analysis based on graph theory to determine the pattern of structural connectivity asymmetry in 124 normal neonates. We tracted white matter axonal pathways characterizing interregional connections among brain regions and inferred asymmetry in left and right anatomical network properties. Our findings revealed that in neonates, small-world characteristics were exhibited, but did not differ between the two hemispheres, suggesting that neighboring brain regions connect tightly with each other, and that one region is only a few paths away from any other region within each hemisphere. Moreover, the neonatal brain showed greater structural efficiency in the left hemisphere than that in the right. In neonates, brain regions involved in motor, language, and memory functions play crucial roles in efficient communication in the left hemisphere, while brain regions involved in emotional processes play crucial roles in efficient communication in the right hemisphere. These findings suggest that even at birth, the topology of each cerebral hemisphere is organized in an efficient and compact manner that maps onto asymmetric functional specializations seen in adults, implying lateralized brain functions in infancy.

Brain-derived neurotrophic factor (BDNF) Val66Met polymorphism influences the association of the methylome with maternal anxiety and neonatal brain volumes

Early life environments interact with genotype to determine stable phenotypic outcomes. Here we examined the influence of a variant in the brain-derived neurotropic factor (BDNF) gene (Val66Met), which underlies synaptic plasticity throughout the central nervous system, on the degree to which antenatal maternal anxiety associated with neonatal DNA methylation. We also examined the association between neonatal DNA methylation and brain substructure volume, as a function of BDNF genotype. Infant, but not maternal, BDNF genotype dramatically influences the association of antenatal anxiety on the epigenome at birth as well as that between the epigenome and neonatal brain structure. There was a greater impact of antenatal maternal anxiety on the DNA methylation of infants with the methionine (Met)/Met compared to both Met/valine (Val) and Val/Val genotypes. There were significantly more cytosine-phosphate-guanine sites where methylation levels covaried with right amygdala volume among Met/Met compared with both Met/Val and Val/Val carriers. In contrast, more cytosine-phosphate-guanine sites covaried with left hippocampus volume in Val/Val infants compared with infants of the Met/Val or Met/Met genotype. Thus, antenatal Maternal Anxiety × BDNF Val66Met Polymorphism interactions at the level of the epigenome are reflected differently in the structure of the amygdala and the hippocampus. These findings suggest that BDNF genotype regulates the sensitivity of the methylome to early environment and that differential susceptibility to specific environmental conditions may be both tissue and function specific.

Population differences in brain morphology and microstructure among Chinese, Malay, and Indian neonates.

We studied a sample of 75 Chinese, 73 Malay, and 29 Indian healthy neonates taking part in a cohort study to examine potential differences in neonatal brain morphology and white matter microstructure as a function of ethnicity using both structural T2-weighted magnetic resonance imaging (MRI) and diffusion tensor imaging (DTI). We first examined the differences in global size and morphology of the brain among the three groups. We then constructed the T2-weighted MRI and DTI atlases and employed voxel-based analysis to investigate ethnic differences in morphological shape of the brain from the T2-weighted MRI, and white matter microstructure measured by fractional anisotropy derived from DTI. Compared with Malay neonates, the brains of Indian neonates’ tended to be more elongated in anterior and posterior axis relative to the superior-inferior axis of the brain even though the total brain volume was similar among the three groups. Although most anatomical regions of the brain were similar among Chinese, Malay, and Indian neonates, there were anatomical variations in the spinal-cerebellar and cortical-striatal-thalamic neural circuits among the three populations. The population-related brain regions highlighted in our study are key anatomical substrates associated with sensorimotor functions.

COMT Haplotypes Modulate Associations of Antenatal Maternal Anxiety and Neonatal Cortical Morphology

OBJECTIVE Exposure to antenatal maternal anxiety and complex genetic variations may shape fetal brain development. In particular, the catechol-O-methyltransferase (COMT) gene, located on chromosome 22q11.2, regulates catecholamine signaling in the prefrontal cortex and is implicated in anxiety, pain, and stress responsivity. This study examined whether individual single-nucleotide polymorphisms (SNPs) of the COMT gene and their haplotypes moderate the association between antenatal maternal anxiety and in utero cortical development. METHOD A total of 146 neonates were genotyped and underwent MRI shortly after birth. Neonatal cortical morphology was characterized using cortical thickness. Antenatal maternal anxiety was assessed using the State-Trait Anxiety Inventory at week 26 of pregnancy. RESULTS Individual COMT SNPs (val158met, rs737865, and rs165599) modulated the association between antenatal maternal anxiety and the prefrontal and parietal cortical thickness in neonates. Based on haplotype trend regression analysis, findings also showed that among rs737865-val158met-rs165599 haplotypes, the A-val-G (AGG) haplotype probabilities modulated positive associations of antenatal maternal anxiety with cortical thickness in the right ventrolateral prefrontal cortex and the right superior parietal cortex and precuneus. In contrast, the G-met-A (GAA) haplotype probabilities modulated negative associations of antenatal maternal anxiety with cortical thickness in bilateral precentral gyrus and the dorsolateral prefrontal cortex. CONCLUSIONS These results suggest that the association between maternal anxiety and in utero neurodevelopment is modified through complex genetic variation in COMT. Such genetic moderation may explain, in part, the variation in phenotypic outcomes in offspring associated with maternal emotional well-being.

Maternal sensitivity, infant limbic structure volume and functional connectivity: a preliminary study.

Mechanisms underlying the profound parental effects on cognitive, emotional and social development in humans remain poorly understood. Studies with nonhuman models suggest variations in parental care affect the limbic system, influential to learning, autobiography and emotional regulation. In some research, nonoptimal care relates to decreases in neurogenesis, although other work suggests early-postnatal social adversity accelerates the maturation of limbic structures associated with emotional learning. We explored whether maternal sensitivity predicts human limbic system development and functional connectivity patterns in a small sample of human infants. When infants were 6 months of age, 20 mother–infant dyads attended a laboratory-based observational session and the infants underwent neuroimaging at the same age. After considering age at imaging, household income and postnatal maternal anxiety, regression analyses demonstrated significant indirect associations between maternal sensitivity and bilateral hippocampal volume at six months, with the majority of associations between sensitivity and the amygdala demonstrating similar indirect, but not significant results. Moreover, functional analyses revealed direct associations between maternal sensitivity and connectivity between the hippocampus and areas important for emotional regulation and socio-emotional functioning. Sensitivity additionally predicted indirect associations between limbic structures and regions related to autobiographical memory. Our volumetric results are consistent with research indicating accelerated limbic development in response to early social adversity, and in combination with our functional results, if replicated in a larger sample, may suggest that subtle, but important, variations in maternal care influence neuroanatomical trajectories important to future cognitive and emotional functioning.

Morphology and microstructure of subcortical structures at birth: A large-scale Asian neonatal neuroimaging study

This paper presents the growth pattern and sexual dimorphism of the thalamus and basal ganglia in a large-scale Asian neonatal cohort using both T2-weighted magnetic resonance imaging (MRI) and diffusion tensor imaging (DTI). Our study observed a robust growth of the thalamus and basal ganglia (caudate, putamen, globus pallidus, and anterior limb of internal capsule) beyond the overall brain growth in the early postnatal period (36-43 weeks of the gestational age). Additionally, the microstructure of the two structures was integrated as reflected by an increase in fractional anisotropy (FA) and a decrease in axial and radial water diffusivities in the first few weeks of life. Sexual dimorphism was only observed in the whole brain growth and the left thalamic volume but not in the other volumes or DTI measures of the basal ganglia and thalamus at birth. Even though the pattern of sexual dimorphism in the total brain volume is present at birth and persists throughout postnatal brain development, sexual dimorphisms of the basal ganglia and thalamus differ from those found in later stages of brain development, indicating that regionally distinct patterns of postnatal brain development between males and females arise after birth.

Faster eating rates are associated with higher energy intakes during an ad libitum meal, higher BMI and greater adiposity among 4-5 year-old children: results from the Growing Up in Singapore Towards Healthy Outcomes (GUSTO) cohort

Faster eating rates are associated with increased energy intake, but little is known about the relationship between childrens eating rate, food intake and adiposity. We examined whether children who eat faster consume more energy and whether this is associated with higher weight status and adiposity. We hypothesised that eating rate mediates the relationship between child weight and ad libitum energy intake. Children (n 386) from the Growing Up in Singapore Towards Healthy Outcomes cohort participated in a video-recorded ad libitum lunch at 4·5 years to measure acute energy intake. Videos were coded for three eating-behaviours (bites, chews and swallows) to derive a measure of eating rate (g/min). BMI and anthropometric indices of adiposity were measured. A subset of children underwent MRI scanning (n 153) to measure abdominal subcutaneous and visceral adiposity. Children above/below the median eating rate were categorised as slower and faster eaters, and compared across body composition measures. There was a strong positive relationship between eating rate and energy intake (r 0·61, P<0·001) and a positive linear relationship between eating rate and childrens BMI status. Faster eaters consumed 75 % more energy content than slower eating children (Δ548 kJ (Δ131 kcal); 95 % CI 107·6, 154·4, P<0·001), and had higher whole-body (P<0·05) and subcutaneous abdominal adiposity (Δ118·3 cc; 95 % CI 24·0, 212·7, P=0·014). Mediation analysis showed that eating rate mediates the link between child weight and energy intake during a meal (b 13·59; 95 % CI 7·48, 21·83). Children who ate faster had higher energy intake, and this was associated with increased BMI z-score and adiposity.