Deciphering the developmental order and microstructural patterns of early white matter pathways in a diffusion MRI based fetal brain atlas.

White matter (WM) of the fetal brain undergoes rapid development to form early structural connections. Diffusion magnetic resonance imaging (dMRI) has shown to be a useful tool to depict fetal brain WM in utero, and many studies have observed increasing fractional anisotropy and decreasing diffusivity in the fetal brain during the second-to-third trimester, whereas others reported non-monotonic changes. Unbiased dMRI atlases of the fetal brain are important for characterizing the developmental trajectories of WM and providing normative references for in utero diagnosis of prenatal abnormalities. To date, the sole fetal brain dMRI atlas was collected from a Caucasian/mixed population and was constructed based on the diffusion tensor model with limited spatial resolution. In this work, we proposed a fiber orientation distribution (FOD) based pipeline for generating fetal brain dMRI atlases, which showed better registration accuracy than a diffusion tensor based pipeline. Based on the FOD-based pipeline, we constructed the first Chinese fetal brain dMRI atlas using 89 dMRI scans of normal fetuses at gestational age between 24 and 38 weeks. Complex non-monotonic trends of tensor- and FOD-derived microstructural parameters in eight WM tracts were observed, which jointly pointed to different phases of microstructural development. Specifically, we speculated that the turning point of the diffusivity trajectory may correspond to the starting point of pre-myelination, based on which, the developmental order of WM tracts can be mapped and the order was in agreement with the order of myelination from histological studies. The normative atlas also provided a reference for the detection of abnormal WM development, such as that in congenital heart disease. Therefore, the established high-order fetal brain dMRI atlas depicted the spatiotemporal pattern of early WM development, and findings may help decipher the distinct microstructural events in utero.