Charting the Normal Development of Structural Brain Connectivity in Utero using Diffusion MRI

Understanding the structural connectivity of the human brain during fetal life is essential for uncovering the early foundations of neural function and vulnerability to developmental disorders. Diffusion-weighted MRI (dMRI) enables noninvasive mapping of white-matter pathways and construction of the brain's structural connectome, but its application to the fetal brain has been constrained by limited data and the technical challenges of fetal dMRI analysis. Here, we present the largest study to date of in utero brain connectivity, analyzing high-quality dMRI data from 198 fetuses between 22 and 37 gestational weeks from the Developing Human Connectome Project. We applied advanced fetal-specific tools for brain segmentation, parcellation, and tractography, and used fiber bundle capacity to weight connections. We reconstructed individual structural connectomes and characterized their developmental trajectories. Graph-theoretical analysis revealed consistent increases in both integration and segregation metrics across gestation, alongside stable small-world properties. Bootstrapping confirmed the robustness of nodal and edge-wise developmental patterns, and a sigmoid growth model identified a narrow time window (approximately 27.5-30.5 weeks) of rapid connectivity strengthening. In addition, we introduced a new method for constructing age-specific connectome templates by aggregating individual subject connectomes. Our analysis shows that this approach outperforms spatial alignment and image-space averaging, yielding templates that preserve individual topology and support accurate age prediction. Together, these findings provide a reasonable normative map of fetal brain structural connectivity and establish a foundation for future studies of atypical development and early indicators of neurological risk.