Rollins, C. K. | Search bioRxiv

bioRxiv2026

Fetal MRI Reveals Altered Subplate Development in Congenital Heart Disease

Background: The subplate is a transient fetal brain compartment that provides an early foundation for downstream cerebral development. Congenital heart disease (CHD) alters fetal circulation and cerebral substrate delivery, but its impact on subplate development and whether resulting alterations relate to later neurodevelopmental outcomes remain unclear. Methods: In this retrospective observational cohort study, We used fetal MRI to quantify whole-brain, lobar, and regional (17 bilateral cortical regions) subplate volume and thickness to evaluate group differences between 76 fetuses with CHD and 62 typically developing (TD) fetuses scanned between 21-32 weeks of gestation, and estimated individualized deviations from TD developmental trajectories. Associations with fetal hemodynamic indices (substrate delivery score, cerebroplacental ratio [CPR]) and two-year neurodevelopmental outcomes (Bayley Scales of Infant and Toddler Development, N=46 CHD, N=37 TD) were explored. Results: Whole-brain subplate volume was lower in CHD, corresponding to a 5.7% reduction relative to age- and sex-expected values (p=0.003), but this difference was substantially attenuated after accounting for global brain volume (p=0.090). In contrast, regional analyses identified persistent spatially structured deviations beyond global scaling, most consistently involving posterior parietal, occipital and temporal regions, with a left-hemisphere bias in subplate thickness. Normative modelling demonstrated bidirectional regional deviations and increased inter-individual variability in CHD, with extreme subplate volume deviations enriched across 73% of cortical regions (p=0.009). Higher CPR was associated with lower SP thickness deviations, with the association strengthening after accounting for cerebral substrate delivery (p=0.010), although these analyses were exploratory. In CHD fetuses with postnatal follow-up, prenatal subplate deviations showed modest associations with neurodevelopmental outcomes, with right precuneus subplate thickness associated with receptive ({beta}=-11.87, q=0.017) and expressive ({beta}=-14.50, q=0.039) communication on the Bayley, after correction for multiple comparisons. Conclusions: Fetal subplate alterations in CHD are dominated by global reductions in brain growth but also include spatially heterogeneous and individually variable regional deviations beyond global scaling. Exploratory associations with fetal hemodynamics and postnatal neurodevelopment provide hypotheses for future studies investigating the developmental significance of these prenatal alterations.

neuroscience↗

bioRxiv2025

Typical development of the human fetal subplate: regional heterogeneity, growth, and asymmetry assessed by in vivo T2-weighted MRI

The subplate (SP) is a transient fetal brain compartment supporting neuronal migration, axonal ingrowth, and early cortical activity, yet the dynamics of its regional development remain poorly understood in vivo. Using T2-weighted fetal MRI of 68 typically developing fetuses (22-32 weeks gestational age, GA), we developed a semi-automated pipeline to quantify regional SP morphology (thickness, surface area, and volume). SP characteristics scaled strongly with GA and residual brain volume and showed marked regional differences. After correcting for geometric confounds, regional variation of SP thickness persisted, with highest values in parietal and perisylvian regions, suggesting that SP thickness may serve as a sensitive marker of intrinsic developmental differences. Between late 2nd and early 3rd trimester, mean SP thickness increased by 39.2% with large variation across regions ({+/-}11.0 SD), whereas surface area growth was more uniform (64.3% {+/-}0.7 SD). Continuous growth trajectories clustered into distinct spatiotemporal profiles: early-developing regions (e.g., pericentral and medial occipital cortices) contrasted with later-developing regions (prefrontal, temporal, and parietal cortices). These patterns partially recapitulate primary-to-association, medial-to-lateral, and posterior-to-anterior maturational hierarchies, pointing to organized developmental program. SP development also showed region-specific hemispheric asymmetries, including leftward thickness and volume asymmetry in superior temporal and precentral gyri. Some asymmetries amplified, others attenuated or reversed with age, suggesting both transient states and potential precursors of postnatal lateralization. Together, these findings provide a framework for regional SP quantification and position SP morphology, particularly thickness, as a promising early biomarker that might link fetal SP changes to subsequent cortical development and neurodevelopmental outcomes. Significance StatementThe subplate (SP) is a transient fetal brain compartment that provides an early foundation for downstream cerebral development. Using fetal MRI, we show that SP morphology is regionally heterogeneous and that its growth follows distinct regional trajectories. Principal spatiotemporal patterns differentiate early-from later-developing regions and partially recapitulate sensory-to-association hierarchies of cortical maturation. SP also exhibits dynamic hemispheric asymmetries as early as the second trimester, with some amplifying as potential precursors of postnatal lateralization, and others reversing with age, emphasizing the importance of evaluating developmental trajectories rather than single time points. This framework positions SP morphology as an accessible early marker of fetal brain organization with potential relevance for later neurodevelopment.

neuroscience↗