White matter microstructure and cognitive abilities in 28-year-old offspring prenatally exposed to maternal anxiety: A prospective exploratory multimodal brain imaging study

Prenatal exposure to maternal psychological distress (PEMPD) can affect brain development and cognition, but its long-term impact on adult white matter (WM) microstructure and cognition remains unclear. In an exploratory study, we examined 28-year-old offspring (n = 52) exposed to high maternal anxiety (HA group; State Anxiety > 43) or low-to-medium maternal anxiety (LMA group; State Anxiety ≤ 43) at 12-22 weeks of gestation, a critical period for WM development. Whole WM voxel-based analysis assessed microstructural differences using diffusion magnetic resonance imaging (dMRI), including standard diffusion tensor imaging (DTI), advanced methods such as diffusion kurtosis imaging, neurite orientation dispersion and density imaging, and myelin water imaging. Group differences in WM and cognition (Vocabulary, Perceptual Organization, Processing Speed) were tested using ANCOVAs respectively MANOVA (Holm-Bonferroni-corrected) adjusting for birth weight and postnatal maternal anxiety. The HA group showed lower radial and mean diffusivity and a trend for lower isotropic volume fraction) in the left superior corona radiata. Vocabulary scores were consistently lower in the HA group across ages 14-15 and 28 (moderate effect). The left-lateralized WM differences may reflect altered axonal architecture or cellular composition, possibly originating in utero. The use of advanced and complementary microstructural metrics highlights subtle WM alterations that mayshape neurodevelopmental trajectories and underlie later cognitive outcomes.