Prenatal environmental adversity and early white-matter development in the HBCD cohort

The perinatal period represents one of the most dynamic and sensitive windows of neurodevelopment (Dubois et al., 2014; Ouyang et al., 2018), shaped by a complex combination of prenatal and postnatal experiences. Yet, little is known about how cumulative environmental adversity during gestation becomes embedded in white-matter pathways that support emerging learning, memory, and regulation. Structural neuroimaging provides a non-invasive window into these early developmental processes, enabling quantification of white-matter integrity during the earliest months of life. Preclinical work demonstrates that resource deprivation, stress, inflammation, and pollutant exposure disrupt oligodendrocyte differentiation via pro-inflammatory cytokines, oxidative stress, and impaired expression of myelin-related proteins, reducing the number of myelin-producing cells (Fancy et al., 2011; French et al., 2009). Human research supports the view that prenatal environmental conditions, including psychosocial stress, environmental toxins, and socioeconomic disadvantage during pregnancy, can alter fetal neurodevelopment through inflammatory, endocrine, and epigenetic pathways (Monk et al., 2019). These exposures disproportionately affect fronto-limbic pathways supporting early learning and regulation, as shown by altered neonatal microstructure in the cingulum bundle, uncinate fasciculus, and related tracts (Rifkin-Graboi et al., 2013; Dean et al., 2018). Despite these advances, substantial gaps remain. Most studies examine single exposures (e.g., maternal anxiety alone) and few link early microstructural alterations to emerging cognitive and regulatory outcomes. The Healthy Brain and Child Development (HBCD) Study provides an opportunity to examine prenatal environmental burden in relation to early white-matter development using multisite neuroimaging metrics and richly characterized prenatal environmental data. The present study will evaluate whether cumulative prenatal adversity, from geocoded environmental exposures (PM2.5, NO₂, traffic density, green-space), neighborhood socioeconomic indicators, maternal psychosocial stress, and inflammatory biomarkers (CRP, IL-6), predicts infant white-matter microstructure at neonatal (0-1mo) and infant (3-9mo) visits. Environmental indicators and maternal biomarkers will be integrated into a latent “prenatal adversity” factor, enabling a continuous index of cumulative exposure. Diffusion MRI data (N=1462) will be processed using the HBCD pipeline, including neonatal template alignment, and corrections: slice-to-volume motion, susceptibility/eddy-current, bias-field. Approaches such as ComBat, TractSeg tractometry, and fixel-based analysis will yield fractional anisotropy (FA), mean diffusivity (MD), and neurite density (NODDI-ICVF) estimates across major white-matter tracts. We hypothesize that higher prenatal adversity will be associated with alterations in microstructural maturation, particularly within fronto-striatal, uncinate, and cingulum pathways across the first months of life. Further, we will test whether white-matter characteristics indirectly predict early cognitive outcomes assessed at 3-9 months, including Deferred Imitation memory, NBT executive function subtests, Bayley-III composites, and sensory-processing measures. Analyses will use multilevel models and latent-growth structural equation models to examine developmental trajectories and indirect pathways. Infant age, sex, and study site will be included as covariates. Results will clarify how cumulative prenatal adversity shapes early white-matter development and the degree to which these neural pathways support foundational cognitive and regulatory abilities during infancy.