Structural Development of Human Fetal Brain

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Abstract Despite its critical significance, little is known about the most dynamic phase of brain development in infancy: 0-2 years. To change the status quo, comprehensive and quantitative infant brain atlases as reference standards for precision health are needed. In addition, diffusion MRI (dMRI) has entered a new era in which dynamic cortical internal microstructural complexity, indexed by e.g. cortical mean kurtosis derived from diffusion kurtosis imaging (DKI), can be studied in the living infant brain noninvasively using more advanced multi-shell dMRI. Furthermore, multi-modality measures offer unparalleled insights into mechanistic structure- function and structure-behavior relationships. Work in the current cycle has focused on structural development of human fetal and preterm brains. Based on high resolution diffusion tensor imaging (DTI) of 150 brains, we have established the atlases and quantified cortical microstructure with cortical fractional anisotropy, validated by histological images and correlated with transcriptomic (RNA) expression. Building upon this work, in the next cycle, we will focus on brain development in infancy, immediately after the fetal period. Specifically, the goal is to establish next-generation dMRI atlases (quantitative UPenn-CHOP infant brain atlases) and to harness a more advanced cortical microstructural mean kurtosis measurement by delineating its 4D spatiotemporal frameworks as well as uncovering its relationship to brain function and behavior during infancy (0-2 years). 160 typically developing infants at 1, 3, 6, 12, 18, 24 months will be recruited. Advanced “connectome-quality” multi-band high-resolution multi-shell dMRI, resting state fMRI (rs-fMRI) and structural MRI will be acquired. High-quality whole-head magnetoencephalography (MEG) will also be acquired. Anatomical labels of all 122 major gray and white matter structures will be built up based on high contrasts from DTI-derived maps. The measurements of DTI-derived metrics will be used for the quantitative components of DTI atlases and age-dependent white matter tract trajectories (Aim 1). Mean kurtosis of the 4th order kurtosis tensor has been shown to be sensitive to cortical internal microstructural changes of infant brains. The spatiotemporal sensitivity of mean kurtosis measures to infant age and cortical region will be investigated (Aim 2). Furthermore, we will establish mechanistic structure-function relationships with multi- modality imaging, including not only multi-shell dMRI, but also rs-fMRI and MEG, all optimized for infant brains (Aim 3). The quantitative infant brain atlases and normal developmental trajectories will provide reference standards for “pre-“diagnostic risk assessment, filling a gap towards precision health for infants (e.g. Z-score maps). Infant cortical microstructure will be delineated noninvasively with 4D spatiotemporal frameworks. With multi-modality strength, the fundamental structure-function and structure-behavior mechanistic relations will set the stage for understanding aberrant brain development in neurodevelopmental disorders such as autistic spectrum disorder and intellectual disabilities in general.