Association of cumulative prenatal adversity with infant subcortical structure volumes and child problem behavior and its moderation by a coexpression polygenic risk score of the serotonin system.

Prenatal adversity has been linked to later psychopathology. Yet, research on cumulative prenatal adversity, as well as its interaction with offspring genotype, on brain and behavioral development is scarce. With this study, we aimed to address this gap. In Finnish mother-infant dyads, we investigated the association of a cumulative prenatal adversity sum score (PRE-AS) with (a) child emotional and behavioral problems assessed with the Strengths and Difficulties Questionnaire at 4 and 5 years (N = 1568, 45.3% female), (b) infant amygdalar and hippocampal volumes (subsample N = 122), and (c) its moderation by a hippocampal-specific coexpression polygenic risk score based on the serotonin transporter (SLC6A4) gene. We found that higher PRE-AS was linked to greater child emotional and behavioral problems at both time points, with partly stronger associations in boys than in girls. Higher PRE-AS was associated with larger bilateral infant amygdalar volumes in girls compared to boys, while no associations were found for hippocampal volumes. Further, hyperactivity/inattention in 4-year-old girls was related to both genotype and PRE-AS, the latter partially mediated by right amygdalar volumes as preliminary evidence suggests. Our study is the first to demonstrate a dose-dependent sexually dimorphic relationship between cumulative prenatal adversity and infant amygdalar volumes.

Prenatal maternal depressive symptoms are associated with neonatal left amygdala microstructure in a sex-dependent way.

Exposures to prenatal maternal depressive symptoms (PMDS) may lead to neurodevelopmental changes in the offspring in a sex-dependent way. Although a connection between PMDS and infant brain development has been established by earlier studies, the relationship between PMDS exposures measured at various prenatal stages and microstructural alterations in fundamental subcortical structures such as the amygdala remains unknown. In this study, we investigated the associations between PMDS measured during gestational weeks 14, 24 and 34 and infant amygdala microstructural properties using diffusion tensor imaging. We explored amygdala mean diffusivity (MD) alterations in response to PMDS in infants aged 11 to 54 days from birth. PMDS had no significant main effect on the amygdala MD metrics. However, there was a significant interaction effect for PMDS and infant sex in the left amygdala MD. Compared with girls, boys exposed to greater PMDS during gestational week 14 showed significantly higher left amygdala MD. These results indicate that PMDS are linked to infants' amygdala microstructure in boys. These associations may be relevant to later neuropsychiatric outcomes in the offspring. Further research is required to better understand the mechanisms underlying these associations and to develop effective interventions to counteract any potential adverse consequences.

Maternal psychological distress associates with alterations in resting-state low-frequency fluctuations and distal functional connectivity of the neonate medial prefrontal cortex.

Prenatal stress exposure (PSE) has been observed to exert a programming effect on the developing infant brain, possibly with long-lasting consequences on temperament, cognitive functions and the risk for developing psychiatric disorders. Several prior studies have revealed that PSE associates with alterations in neonate functional connectivity in the prefrontal regions and amygdala. In this study, we explored whether maternal psychological symptoms measured during the 24th gestational week had associations with neonate resting-state network metrics. Twenty-one neonates (nine female) underwent resting-state fMRI scanning (mean gestation-corrected age at scan 26.95 days) to assess fractional amplitude of low-frequency fluctuation (fALFF) and regional homogeneity (ReHo). The ReHo/fALFF maps were used in multiple regression analysis to investigate whether maternal self-reported anxiety and/or depressive symptoms associate with neonate functional brain features. Maternal psychological distress (composite score of depressive and anxiety symptoms) was positively associated with fALFF in the neonate medial prefrontal cortex (mPFC). Anxiety and depressive symptoms, assessed separately, exhibited similar but weaker associations. Post hoc seed-based connectivity analyses further showed that distal connectivity of mPFC covaried with PSE. No associations were found between neonate ReHo and PSE. These results offer preliminary evidence that PSE may affect functional features of the developing brain during gestation.

Allometry in the corpus callosum in neonates: Sexual dimorphism.

The corpus callosum (CC) is the largest fiber tract in the human brain, allowing interhemispheric communication by connecting homologous areas of the two cerebral hemispheres. In adults, CC size shows a robust allometric relationship with brain size, with larger brains having larger callosa, but smaller brains having larger callosa relative to brain size. Such an allometric relationship has been shown in both males and females, with no significant difference between the sexes. But there is some evidence that there are alterations in these allometric relationships during development. However, it is currently not known whether there is sexual dimorphism in these allometric relationships from birth, or if it only develops later. We study this in neonate data. Our results indicate that there are already sex differences in these allometric relationships in neonates: male neonates show the adult-like allometric relationship between CC size and brain size; however female neonates show a significantly more positive allometry between CC size and brain size than either male neonates or female adults. The underlying cause of this sexual dimorphism is unclear; but the existence of this sexual dimorphism in neonates suggests that sex-differences in lateralization have prenatal origins.

Sex-specific associations between maternal pregnancy-specific anxiety and newborn amygdalar volumes - preliminary findings from the FinnBrain Birth Cohort Study.

Previous literature links maternal pregnancy-specific anxiety (PSA) with later difficulties in child emotional and social cognition as well as memory, functions closely related to the amygdala and the hippocampus. Some evidence also suggests that PSA affects child amygdalar volumes in a sex-dependent way. However, no studies investigating the associations between PSA and newborn amygdalar and hippocampal volumes have been reported. We investigated the associations between PSA and newborn amygdalar and hippocampal volumes and whether associations are sex-specific in 122 healthy newborns (68 males/54 females) scanned at 2-5 weeks postpartum. PSA was measured at gestational week 24 with the Pregnancy-Related Anxiety Questionnaire Revised 2 (PRAQ-R2). The associations were analyzed with linear regression controlling for confounding variables. PSA was associated positively with left amygdalar volume in girls, but no significant main effect was found in the whole group or in boys. No significant main or sex-specific effect was found for hippocampal volumes. Although this was an exploratory study, the findings suggest a sexually dimorphic association of mid-pregnancy PSA with newborn amygdalar volumes.

Maternal pre-pregnancy BMI associates with neonate local and distal functional connectivity of the left superior frontal gyrus.

Maternal obesity/overweight during pregnancy has reached epidemic proportions and has been linked with adverse outcomes for the offspring, including cognitive impairment and increased risk for neuropsychiatric disorders. Prior neuroimaging investigations have reported widespread aberrant functional connectivity and white matter tract abnormalities in neonates born to obese mothers. Here we explored whether maternal pre-pregnancy adiposity is associated with alterations in local neuronal synchrony and distal connectivity in the neonate brain. 21 healthy mother-neonate dyads from uncomplicated pregnancies were included in this study (age at scanning 26.14 ± 6.28 days, 12 male). The neonates were scanned with a 6-min resting-state functional magnetic resonance imaging (rs-fMRI) during natural sleep. Regional homogeneity (ReHo) maps were computed from obtained rs-fMRI data. Multiple regression analysis was performed to assess the association of pre-pregnancy maternal body-mass-index (BMI) and ReHo. Seed-based connectivity analysis with multiple regression was subsequently performed with seed-ROI derived from ReHo analysis. Maternal adiposity measured by pre-pregnancy BMI was positively associated with neonate ReHo values within the left superior frontal gyrus (SFG) (FWE-corrected p < 0.005). Additionally, we found both positive and negative associations (p < 0.05, FWE-corrected) for maternal pre-pregnancy BMI and seed-based connectivity between left SFG and prefrontal, amygdalae, basal ganglia and insular regions. Our results imply that maternal pre-pregnancy BMI associates with local and distal functional connectivity within the neonate left superior frontal gyrus. These findings add to the evidence that increased maternal pre-pregnancy BMI has a programming influence on the developing neonate brain functional networks.

Infant and Child MRI: A Review of Scanning Procedures.

Magnetic resonance imaging (MRI) is a safe method to examine human brain. However, a typical MR scan is very sensitive to motion, and it requires the subject to lie still during the acquisition, which is a major challenge for pediatric scans. Consequently, in a clinical setting, sedation or general anesthesia is often used. In the research setting including healthy subjects anesthetics are not recommended for ethical reasons and potential longer-term harm. Here we review the methods used to prepare a child for an MRI scan, but also on the techniques and tools used during the scanning to enable a successful scan. Additionally, we critically evaluate how studies have reported the scanning procedure and success of scanning. We searched articles based on special subject headings from PubMed and identified 86 studies using brain MRI in healthy subjects between 0 and 6 years of age. Scan preparations expectedly depended on subject's age; infants and young children were scanned asleep after feeding and swaddling and older children were scanned awake. Comparing the efficiency of different procedures was difficult because of the heterogeneous reporting of the used methods and the success rates. Based on this review, we recommend more detailed reporting of scanning procedure to help find out which are the factors affecting the success of scanning. In the long term, this could help the research field to get high quality data, but also the clinical field to reduce the use of anesthetics. Finally, we introduce the protocol used in scanning 2 to 5-week-old infants in the FinnBrain Birth Cohort Study, and tips for calming neonates during the scans.

Neonatal amygdala volumes and the development of self-regulation from early infancy to toddlerhood.

Objective: At the broadest level, self-regulation (SR) refers to a range of separate, but interrelated, processes (e.g., working memory, inhibition, and emotion regulation) central for the regulation of cognition, emotion, and behavior that contribute to a plethora of health and mental health outcomes. SR skills develop rapidly in early childhood, but their neurobiological underpinnings are not yet well understood. The amygdala is one key structure in negative emotion generation that may disrupt SR. In the current study, we investigated the associations between neonatal amygdala volumes and mother-reported and observed child SR during the first 3 years of life. We expected that larger neonatal amygdala volumes would be related to poorer SR in children. Method: We measured amygdala volumes from magnetic resonance imaging (MRI) performed at age M = 3.7 ± 1.0. We examined the associations between the amygdala volumes corrected for intracranial volume (ICV) and (a) parent-reported indicators of SR at 6, 12, and 24 months (N = 102) and (b) observed task-based indicators of SR (working memory and inhibitory control) at 30 months of age in a smaller subset of participants (N = 80). Results: Bilateral neonatal amygdala volumes predicted poorer working memory at 30 months in girls, whereas no association was detected between amygdalae and inhibitory control or parent-reported SR. The left amygdala by sex interaction survived correction for multiple comparisons. Conclusions: Neonatal amygdala volume is associated with working memory, particularly among girls, and the association is observed earlier than in prior studies. Moreover, our findings suggest that the neural correlates for parent-reported, compared to observed early life SR, may differ. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

Association of Cumulative Paternal Early Life Stress With White Matter Maturation in Newborns.

Importance: Early life stress (ELS) has been shown to affect brain development and health outcomes. Recent animal studies have linked paternal early stress exposures with next-generation outcomes. Epigenetic inheritance through the male germline has been suggested to be one of the mechanisms. Objectives: To test whether paternal ELS, as measured using the Trauma and Distress Scale, is associated with neonate brain development. Design, Setting, and Participants: This cohort study included data from participants from the prospective 2-generation FinnBrain Birth Cohort, which was collected from 2011 to 2015. Pregnant women and the fathers were consecutively recruited at gestational week 12 from maternity clinics in Finland. Magnetic resonance imaging data were analyzed in 2019. Participants in this study were 72 families (infant, father, mother). Exposure: Paternal exposure to ELS. Main Outcomes and Measures: Fractional anisotropy (FA) values in the major white-matter tracts of the newborn brain. Results: A total of 72 trios (infant, mother, and father) were analyzed. At the time of delivery, the mean (SD) age was 31.0 (4.4) years for fathers and 30.3 (4.5) years for mothers. Forty-one infants (57%) were boys; mean (SD) child age at inclusion was 26.9 (7.2) days from birth and 205 (8) days from estimated conception. Increasing levels of paternal ELS were associated with higher FA values in the newborn brain in the body of the corpus callosum, right superior corona radiata, and retrolenticular parts of the internal capsule. This association persisted after controlling for maternal ELS, maternal socioeconomic status (SES), maternal body mass index, maternal depressive symptoms during pregnancy, child sex, and child age from birth and gestation corrected age when imaged. In additional region-of-interest analyses, the association between FA values and paternal Trauma and Distress Scale sum scores remained statistically significant in the earliest maturing regions of the brain, eg, the genu of the corpus callosum (in the regression models, ß = 0.00096; 95% CI, 0.00034-0.00158; P = .003) and the splenium (ß = 0.00090; 95% CI, 0.00000-0.00180; P = .049). Conclusions and Relevance: This cohort study found a statistically significant association between paternal ELS and offspring brain development. This finding may have far-reaching implications in pediatrics, as it suggests the possibility of a novel route of intergenerational inheritance of ELS on next-generation brain development.

Sex-specific association between infant caudate volumes and a polygenic risk score for major depressive disorder.

Polygenic risk scores for major depressive disorder (PRS-MDD) have been identified in large genome-wide association studies, and recent findings suggest that PRS-MDD might interact with environmental risk factors to shape human limbic brain development as early as in the prenatal period. Striatal structures are crucially involved in depression; however, the association of PRS-MDD with infant striatal volumes is yet unknown. In this study, 105 Finnish mother-infant dyads (44 female, 11-54 days old) were investigated to reveal how infant PRS-MDD is associated with infant dorsal striatal volumes (caudate, putamen) and whether PRS-MDD interacts with prenatal maternal depressive symptoms (Edinburgh Postnatal Depression Scale, gestational weeks 14, 24, 34) on infant striatal volumes. A robust sex-specific main effect of PRS-MDD on bilateral infant caudate volumes was observed. PRS-MDD were more positively associated with caudate volumes in boys compared to girls. No significant interaction effects of genotype PRS-MDD with the environmental risk factor "prenatal maternal depressive symptoms" (genotype-by-environment interaction) nor significant interaction effects of genotype with prenatal maternal depressive symptoms and sex (genotype-by-environment-by-sex interaction) were found for infant dorsal striatal volumes. Our study showed that a higher PRS-MDD irrespective of prenatal exposure to maternal depressive symptoms is associated with smaller bilateral caudate volumes, an indicator of greater susceptibility to major depressive disorder, in female compared to male infants. This sex-specific polygenic effect might lay the ground for the higher prevalence of depression in women compared to men.

Newborn left amygdala volume associates with attention disengagement from fearful faces at eight months.

After 5 months of age, infants begin to prioritize attention to fearful over other facial expressions. One key proposition is that amygdala and related early-maturing subcortical network, is important for emergence of this attentional bias - however, empirical data to support these assertions are lacking. In this prospective longitudinal study, we measured amygdala volumes from MR images in 65 healthy neonates at 2-5 weeks of gestation corrected age and attention disengagement from fearful vs. non-fearful facial expressions at 8 months with eye tracking. Overall, infants were less likely to disengage from fearful than happy/neutral faces, demonstrating an age-typical bias for fear. Left, but not right, amygdala volume (corrected for intracranial volume) was positively associated with the likelihood of disengaging attention from fearful faces to a salient lateral distractor (r = .302, p = .014). No association was observed with the disengagement from neutral or happy faces in equivalent conditions (r = .166 and .125, p = .186 and .320, respectively). These results are the first to link the amygdala volume with the emerging perceptual vigilance for fearful faces during infancy. They suggest a link from the prenatally defined variability in the amygdala size to early postnatal emotional and social traits.

Newborn amygdalar volumes are associated with maternal prenatal psychological distress in a sex-dependent way.

Maternal psychological distress during pregnancy (PPD)1 has been associated with changes in offspring amygdalar and hippocampal volumes. Studies on child amygdalae suggest that sex moderates the vulnerability of fetal brains to prenatal stress. However, this has not yet been observed in these structures in newborns. Newborn studies are crucial, as they minimize the confounding influence of postnatal life. We investigated the effects of maternal prenatal psychological symptoms on newborn amygdalar and hippocampal volumes and their interactions with newborn sex in 123 newborns aged 2-5 weeks (69 males, 54 females). Based on earlier studies, we anticipated small, but statistically significant effects of PPD on the volumes of these structures. Maternal psychological distress was measured at gestational weeks (GW)2 14, 24 and 34 using Symptom Checklist-90 (SCL-90, anxiety scale)3 and Edinburgh Postnatal Depression Scale (EPDS)4 questionnaires. Newborn sex was found to moderate the relationship between maternal distress symptoms at GW 24 and the volumes of left and right amygdala. This relationship was negative and significant only in males. No significant main effect or sex-based moderation was found for hippocampal volumes. This newborn study provides evidence for a sex-dependent influence of maternal psychiatric symptoms on amygdalar structural development. This association may be relevant to later psychopathology.

Newborn white matter microstructure moderates the association between maternal postpartum depressive symptoms and infant negative reactivity.

Maternal postpartum depression is a prominent risk factor for aberrant child socioemotional development, but there is little understanding about the neural phenotypes that underlie infant sensitivity to maternal depression. We examined whether newborn white matter fractional anisotropy (FA), a measure of white matter maturity, moderates the association between maternal postpartum depressive symptoms and infant negative reactivity at 6 months. Participants were 80 mother-infant dyads participating in a prospective population-based cohort, and included families whose newborns underwent a magnetic resonance/diffusion tensor imaging scan at 2-5 weeks of age and whose mothers reported their own depressive symptoms at 3 and 6 months postpartum and infant negative emotional reactivity at 6 months. The whole-brain FA moderated the association between maternal depressive symptoms and mother-reported infant negative reactivity at 6 months after adjusting for the covariates. Maternal depressive symptoms were positively related to infant negative reactivity among infants with high or average FA in the whole brain and in corpus callosum and cingulum, but not among those with low FA. The link between maternal depressive symptoms and infant negative reactivity was moderated by newborn FA. The variation in white matter microstructure might play a role in child susceptibility to parental distress.

Resting-state networks of the neonate brain identified using independent component analysis.

Resting-state functional magnetic resonance imaging (rs-fMRI) has been successfully used to probe the intrinsic functional organization of the brain and to study brain development. Here, we implemented a combination of individual and group independent component analysis (ICA) of FSL on a 6-min resting-state data set acquired from 21 naturally sleeping term-born (age 26 ± 6.7 d), healthy neonates to investigate the emerging functional resting-state networks (RSNs). In line with the previous literature, we found evidence of sensorimotor, auditory/language, visual, cerebellar, thalmic, parietal, prefrontal, anterior cingulate as well as dorsal and ventral aspects of the default-mode-network. Additionally, we identified RSNs in frontal, parietal, and temporal regions that have not been previously described in this age group and correspond to the canonical RSNs established in adults. Importantly, we found that careful ICA-based denoising of fMRI data increased the number of networks identified with group-ICA, whereas the degree of spatial smoothing did not change the number of identified networks. Our results show that the infant brain has an established set of RSNs soon after birth.

A Novel Approach for Manual Segmentation of the Amygdala and Hippocampus in Neonate MRI.

The gross anatomy of the infant brain at term is fairly similar to that of the adult brain, but structures are immature, and the brain undergoes rapid growth during the first 2 years of life. Neonate magnetic resonance (MR) images have different contrasts compared to adult images, and automated segmentation of brain magnetic resonance imaging (MRI) can thus be considered challenging as less software options are available. Despite this, most anatomical regions are identifiable and thus amenable to manual segmentation. In the current study, we developed a protocol for segmenting the amygdala and hippocampus in T2-weighted neonatal MR images. The participants were 31 healthy infants between 2 and 5 weeks of age. Intra-rater reliability was measured in 12 randomly selected MR images, where 6 MR images were segmented at 1-month intervals between the delineations, and another 6 MR images at 6-month intervals. The protocol was also tested by two independent raters in 20 randomly selected T2-weighted images, and finally with T1 images. Intraclass correlation coefficient (ICC) and Dice similarity coefficient (DSC) for intra-rater, inter-rater, and T1 vs. T2 comparisons were computed. Moreover, manual segmentations were compared to automated segmentations performed by iBEAT toolbox in 10 T2-weighted MR images. The intra-rater reliability was high ICC ≥ 0.91, DSC ≥ 0.89, the inter-rater reliabilities were satisfactory ICC ≥ 0.90, DSC ≥ 0.75 for hippocampus and DSC ≥ 0.52 for amygdalae. Segmentations for T1 vs. T2-weighted images showed high consistency ICC ≥ 0.90, DSC ≥ 0.74. The manual and iBEAT segmentations showed no agreement, DSC ≥ 0.39. In conclusion, there is a clear need to improve and develop the procedures for automated segmentation of infant brain MR images.

Test-retest reliability of Diffusion Tensor Imaging metrics in neonates.

Diffusion tensor imaging (DTI) has been widely used in children and adults to study the microstructural features of the brain. Its use in neonate brains has been limited. Neonate brains are almost completely unmyelinated, and this together with the tendency for babies to move during a scanning session may affect the reliability of the measurements. Here we divided a 96 direction acquisition into three segments, and analysed the intra scan test-retest reliability for pairs of segments. Each segment was subjected to a rigorous quality control, and from the surviving data we chose 25 diffusion encoding directions from each segment, and assessed the pairwise reliability of the most common DTI metrics. This pairwise reliability was assessed for data from 86 infants. We used tract-based spatial statistics (TBSS), voxelwise and ROI analysis schemes, to see potential differential effects of analysis strategy and post processing on the obtained DTI metrics. We found that intra class correlation coefficient (ICC) values were generally high (ICC > 0.80). Residual motion in the data, after quality control, was not found to associate with the diffusion metrics. The results indicate that DTI metrics from neonate data can be reliable, even at relatively low angular resolution that are common for neonate scans. The results lend confidence to the use of neonate DTI data in cross sectional and longitudinal analyses in brain white matter skeleton. Future studies should assess the reliability of fiber tracking techniques in neonate data.

Prevalence and Risk Factors of Incidental Findings in Brain MRIs of Healthy Neonates-The FinnBrain Birth Cohort Study.

Background: Birth is a traumatic event with molding forces directed to the fetal skull, which may result in intracranial hemorrhages. However, the knowledge on prevalence and risk factors of incidental brain magnetic resonance imaging (MRI) findings in infants is still inconclusive. Methods: The prevalence and nature of incidental MRI findings were assessed in a birth cohort of 175 asymptomatic infants. The role of delivery method as well as other potential risk factors for intracranial hemorrhages were evaluated. The infants underwent 3T MRI at the age of 2-5 weeks, and the neurological status of the infants with an incidental finding was evaluated by a pediatric neurologist. Information on the delivery method, duration of delivery, parity, used anesthesia, oxytocin induction, and Apgar score was gathered to evaluate their association with the prevalence of hemorrhages. Results: Incidental intracranial hemorrhages were detected in 12 infants (6.9%), all following spontaneous or assisted vaginal delivery. Vacuum-assistance was found to be a risk factor for subdural hemorrhages with an odds ratio (OR) of 4.7 (95% CI [1.18; 18.9], p = 0.032). All infants were evaluated to develop normally by their clinical status. Conclusions: Incidental intracranial hemorrhages are relatively common among infants born by vaginal delivery. They are often of little clinical significance within the first years of life and have unlikely consequences for later neurodevelopment either. Despite their benign character, investigators should be prepared to share this information with parents competently as the findings can cause parental anxiety, and especially as the popularity of MRI as a research tool is increasing.