Faculty Bibliography

OBJECTIVE:Prenatal maternal depression (PMD) is a common public health concern, affecting up to 20% of pregnancies worldwide. Children exposed to PMD exhibit early self-regulatory and emotional difficulties, although its impact on the developing fetal brain remains largely unexplored. The amygdala and cerebellum are both implicated in emotion regulation and psychiatric vulnerability, are densely interconnected, and undergo rapid maturation in utero. Characterizing the relationship of PMD symptoms to amygdala-cerebellar connectivity before birth offers a unique opportunity to isolate in utero mechanisms of risk. METHOD/METHODS:In a sample of 123 pregnant participants (61% male fetuses, n = 75), PMD symptoms were assessed between the second to third trimester using the Center for Epidemiologic Studies-Depression Scale. Fetuses underwent functional MRI, and region-to-voxel analyses examined amygdala-cerebellar functional connectivity. Statistical tests focused on an emerging hypothesis regarding fetal amygdala-cerebellar connectivity, while also addressing potential amygdala connectivity effects across the full fetal cerebrum. RESULTS:Higher PMD symptoms were associated with significantly increased functional connectivity between the fetal amygdala and cerebellum. This effect remained significant following small volume correction within the cerebellum and after adjusting for covariates. CONCLUSION/CONCLUSIONS:This is the first study to demonstrate altered amygdala-cerebellum connectivity in the human fetal brain in relation to prenatal maternal depression. These findings extend models of prenatal programming by addressing the earliest stages of human brain development and by highlighting the cerebellum's role in emotional network development. Enhanced amygdala-cerebellar coupling in utero may represent an early neural marker of risk for later emotional dysregulation.

Decades of research on the developmental origins of health and disease highlight how prenatal and perinatal conditions are associated with long-term neurocognitive development. Exposures such as maternal stress, substance use, metabolic disorders, obstetric complications, low birthweight, and preterm birth have been linked to differences in brain, cognition, and mental health. Yet, most prior studies have been limited by small sample sizes, narrow exposure measures, or isolated outcomes. The Adolescent Brain Cognitive Development (ABCD) Study provides an unparalleled opportunity to overcome these limitations with nearly 12,000 children recruited at ages 9-10 across the United States, followed longitudinally with harmonized multimodal MRI, cognitive and behavioral testing, biospecimens, genetic data, and rich environmental measures in a diverse cohort. Retrospective caregiver reports provide key prenatal and perinatal information, which can be prospectively related to neurodevelopmental outcomes across adolescence. This review synthesizes findings from 111 ABCD-based studies published from 2017 to 2026. Results implicate maternal health conditions, substance use, birth outcomes, and cumulative adversity as being associated with variation in brain, cognitive, and behavioral development. Leveraging its size and diversity, ABCD has fostered advanced analytic approaches, such as multimodal integration of imaging and behavioral data, and longitudinal tracking of developmental trajectories, rarely possible elsewhere. While methodological challenges remain, including retrospective reporting and imaging site variability, ABCD offers unique opportunities to clarify pathways of vulnerability and resilience within an observational framework. Insights from this work can inform public health strategies and guide policies to reduce prenatal risks and strengthening early-life environments to optimize developmental outcomes.

OBJECTIVE:To estimate associations of more than minimal prenatal nicotine, alcohol, cannabis, and opioid exposures with gestational age, birth weight, and birth weight for gestational age. METHODS:Data were drawn from the HEALthy Brain and Child Development (HBCD) Study, a multisite, longitudinal study in the United States. Predefined recruitment thresholds for each substance were assessed using maternal self-report, maternal toxicology results, and newborn substance exposure-related diagnoses. Birth outcomes included gestational age at delivery (weeks), birth weight (grams), and birth weight for gestational age (centiles). Mean differences and risk ratios for the associations between substance exposure and birth outcomes were estimated using multilevel mixed-effect linear regression or multilevel mixed-effect Poisson regression. RESULTS:Among 660 mother-infant dyads, 17% (n = 115) of participants met recruitment thresholds for prenatal cannabis, 15% for nicotine (n = 102), 13% for alcohol (n = 86), and 5% for opioids (n = 32). In adjusted models, prenatal cannabis and opioid exposures were each associated with lower birth weight (cannabis: -272.2 [95% CI -444.6 to -99.8] g; opioids: -295.4 [95% CI -574.9 to -15.9] g) and birth weight centiles (cannabis: -8.2 [95% CI -15.3 to -1.1] centiles; opioids: -14.4 [95% CI -25.5, -3.4] centiles), although the results were sensitive to model specifications. Prenatal nicotine and alcohol estimates were in similar directions but not statistically significant. No significant associations between exposures and gestational age at delivery were detected. CONCLUSIONS:In this initial HBCD Study data release, more than minimal exposure to cannabis and opioids was associated with smaller birth size, adding evidence to an inconsistent literature. Future studies from HBCD can more deeply interrogate timing and dose of each substance and expand to childhood outcomes.

OBJECTIVE:Phthalates are recognized endocrine disruptors and emerging neurotoxicants. Prenatal exposure to di-2-ethylhexyl phthalate (DEHP) has been linked to adverse neurodevelopmental and neuropsychiatric outcomes, and maternal oxidative stress may play a mechanistic role in prenatal DEHP's neurotoxicity. MATERIALS AND METHODS/METHODS:Participants were drawn from the New York University Children's Health and Environment Study. Prenatal DEHP exposure and maternal lipid peroxidation were assessed using repeated creatinine-adjusted maternal urinary measurements across pregnancy, collected from January 2016-April 2020. Neonatal brain-derived neurotrophic factor (BDNF) was measured in cord serum (N = 337), and internalizing and externalizing problems were assessed at an average age of 2 years using the Child Behavior Checklist for Ages 1.5-5 (CBCL 1½-5) (N = 824). DEHP metabolites (mEHHP; mEOHP; mECPP) were averaged across pregnancy, and cumulative lipid peroxidation biomarkers (8-iso-PGF2α; 15-PGF2α; 8,15-PGF2α; MDA) were estimated using area-under-the-curve values from linear mixed-effects spline models. Partial least squares path modeling evaluated direct and indirect associations using latent constructs for DEHP exposure, lipid peroxidation, CBCL 1½-5, and socioeconomic status; other covariates were modeled as single variables. Sex differences were assessed using bootstrapping and sex-stratified models, adjusting for maternal and child age, parity, pre-pregnancy body mass index, cotinine exposure, and socioeconomic status. RESULTS:Prenatal DEHP exposure was positively associated with maternal lipid peroxidation in all models (β's = 0.11-0.27). Sex-stratified analyses showed that prenatal DEHP exposure was positively associated with CBCL 1½-5 in male children only (β = 0.11), but not with BDNF in either sex. Maternal lipid peroxidation was not associated with BDNF or CBCL 1½-5 in either sex. CONCLUSION/CONCLUSIONS:Prenatal DEHP exposure is associated with maternal oxidative stress and total behavioral problems in male children only, but maternal oxidative stress does not mediate these relationships. Alternative upstream mechanisms may underlie both maternal oxidative stress and neurobehavioral outcomes. Future studies should investigate endocrine, metabolic, and epigenetic pathways to clarify DEHP neurotoxicity.

Executive function (EF), which includes inhibitory control, working memory, and cognitive flexibility, supports adaptive behavior and predicts long-term academic, social, and mental health outcomes. While EF-related neural networks mature throughout childhood, their earliest developmental origins remain unclear. Large-scale brain systems begin organizing in utero, but whether fetal connectivity prospectively relates to EF has not been tested. We collected resting-state fMRI from 113 fetuses (26-39 weeks gestation). Executive function at age 5 was assessed using the Behavior Rating Inventory of Executive Function-Preschool Version (BRIEF-P), resulting in 52 cases with both usable imaging and outcome data after applying motion and birth-outcome criteria. Whole-brain functional connectivity matrices (197 ROIs) were parcellated into 15 networks, and enrichment analysis identified network pairs with a higher-than-expected density of brain-behavior associations. Six enriched network pairs were associated with global EF, including Frontal, Default Mode Network (DMN), Cerebellar, Salience, and Visual networks. Stronger positive connectivity in Frontal-Salience, DMN-Visual, and Cerebellar-DMN predicted poorer EF, whereas greater negative connectivity in Cerebellar-Visual and Salience-Salience predicted better EF. Subscale analyses revealed both shared and distinct associations across EF domains, with Cerebellar and Salience networks consistently implicated. These findings provide the first evidence linking fetal functional architecture to later EF, highlighting distributed, beyond-frontal systems as early scaffolds of executive control.

Autism spectrum disorder (ASD) is a neurodevelopmental condition, with ex vivo studies suggesting its neurobiological origin as early as the first and second trimester of pregnancy. Functional MRI studies using graph-theoretical approaches have isolated features in the global connectome architecture that distinguish toddlers with ASD from their typically developing peers. Additionally, functional connectivity patterns in the infant brain have shown to be predictive of later ASD diagnosis. An important yet unexplored question in the literature is whether graph-theoretical differences are evident prior to infancy, in the brain of fetuses who will later exhibit ASD traits in early childhood. In this study, we address this question using a sample of 88 children with both quality-assured fetal brain resting-state functional MRI data and standardized parent assessment of ASD traits including social-emotional and social communication skills and repetitive and restricted behaviors at age 3. Multiple regression analyses revealed no significant associations between fetal global graph features (e.g., network segregation, integration, and small-world architecture) and ASD traits at age 3 (p's > 0.1). Therefore, our findings do not provide support for prenatal emergence of global topographical differences of brain functional organization in fetuses who later develop ASD traits. However, this does not rule out the possibility of other neural signatures in the fetal functional connectome that may predict autistic traits and future ASD diagnosis.

Maternal psychological distress during pregnancy and the early postpartum period is a risk factor for dysregulated affective and regulatory function in young infants. Animal models suggest that perinatal stress may alter offspring development via allopregnanolone (ALLO) exposure. For example, variations in placentally derived ALLO in preterm infants have been linked with altered fetal neurodevelopment. However, no studies have investigated naturalistic variations in ALLO concentrations in maternal milk as a potential moderator of associations between maternal distress and infant temperament during the postnatal period. The current study assesses associations among ALLO concentrations in human milk, maternal psychological distress, and infant temperament in 81 mother-infant dyads (31 females) measured at approximately 6.5 months postpartum (M = 6.55 months, range = 5.5-8 months). Results indicated that human milk ALLO concentration moderated effects of maternal psychological distress on infant regulatory capacity. Specifically, there was a negative association between maternal psychological distress and regulatory capacity in infants of mothers with below-mean ALLO concentrations, but not in infants of mothers with above-mean ALLO concentrations. However, there were no effects of ALLO on infant negative affect or surgency/positive affect. This study provides some of the first preliminary evidence that ALLO concentrations in human milk may moderate associations between maternal psychological distress and infant regulatory capacity.

Accumulating evidence from neuroimaging studies has implicated widespread disruptions in brain connectivity in autism spectrum disorder (ASD), with altered connectivity patterns reported as early as infancy. However, it remains unexplored whether functional connectivity differences are evident prior to birth in the brain of fetuses who will later exhibit autistic traits in early childhood. In this study, we leveraged a longitudinal sample of 62 children with both quality-assured fetal brain resting-state MRI data and a parent-report measure of autistic traits at age 3 years. Enrichment analysis was employed to identify network pairs significantly correlated with autistic traits. Specificity analysis was conducted by additionally controlling for other childhood psychopathology. Our results demonstrated significant correlations between autistic traits and functional connectivity in the cingulate-left temporal and right prefrontal-left operculum network pairs in both the primary and specificity analyses. Visual network connectivity with prefrontal and opercular regions was also implicated. These network pairs demonstrated positive associations with autistic traits, indicating that stronger connectivity between these network pairs was associated with higher autistic traits. In contrast, weaker cerebellum-right operculum connectivity was associated with higher autistic traits, uniquely in the specificity analysis. This study provides the first in vivo evidence prospectively linking variation in functional network connectivity in the fetal brain to autistic traits in toddlerhood. These findings extend the current understanding of the prenatal brain origins of ASD and highlight the potential of fetal rs-fMRI as a tool to identify neural signatures related to social-emotional development and ASD likelihood.

Iron plays a vital role in early brain development, supporting critical processes such as myelination, dendritogenesis, and neurotransmitter synthesis. The perinatal period marks a crucial transition from the intrauterine to the extrauterine environment, requiring significant brain adaptation to new stimuli and metabolic demands. However, tight spatiotemporal resolution capturing the timing and sequence of brain iron changes surrounding this critical transition has yet to be achieved. Leveraging a longitudinal perinatal cohort with 147 multi-echo MRI scans spanning from 25 to 60 post-conceptual gestational weeks, we mapped brain iron growth trajectories with R2* estimation across fetal, newborn and neonatal periods. We also examined whether sex, gestational age at birth, and birth weight influence R2* developmental trajectories. We found that parietal and superior temporal regions predominately show linear growth trajectories throughout the perinatal period across birth, while the occipital cortex, the temporal pole, inferior temporal regions and a subset of frontal regions exhibit non-linear trends. For most of the non-linear trajectories, growth rates peak around 40 weeks, highlighting the critical window of birth transition for brain R2* change. These results provide the first longitudinal insights into R2* development across birth, uncovering distinct regional growth patterns that may align with different phases of neurodevelopment.