Fingerprinting Spatiotemporal Patterns of Brain Maturation with Combined Diffusion-Relaxometry Microstructure Imaging

PROJECT SUMMARY AND ABSTRACT Brain maturation involves intricate and concurrent cellular changes throughout childhood and adolescence. With the capability to noninvasively track whole brain development, MRI holds the promise to enhance our understanding of normative brain maturation and facilitate the identification of neurodevelopmental disorders. However, the commonly used measures from structural and diffusion MRI, such as cortical thickness or fractional anisotropy, lack the sensitivity and specificity required to differentiate between biological processes such as synaptic pruning and myelination. These processes influence the diffusion MRI signal, not just through morphological changes in cellular organization but also via physical properties like T2/T2*, affected by alterations in chemical composition such as iron concentration. Current neuroimaging measures are confounded by these multifaceted influences, at the expense of validity and interpretability in brain maturation studies. A central hypothesis of this proposal is that these confounding influences can be disentangled through the next generation combined diffusion-relaxometry microstructure imaging and myelin specific imaging, providing increased statistical power in detecting developmental changes spatiotemporally. To test the hypothesis, we will develop acquisition and analysis methods for combined diffusion-relaxometry microstructure imaging and myelin water imaging that can be applied to neurodevelopmental populations. The goal is to collectively provide a unique fingerprint of neurodevelopment by disentangling the developmental changes in cell body density, neurite density, cell size, subcellular T2/T2*, and myelination. The K99 phase will supplement the applicant’s expertise in microstructural imaging methods, by providing training in developmental neuroscience, with a focus on understanding biological factors relevant to microstructural development; statistical approaches to analyzing age effects on brain-area dependent microstructure; and study design and administration for adolescent neuroimaging studies. This training will position the applicant well for collecting pilot datasets and validating the proposed methods during the R00 phase. Leveraging the latest advances in human MRI scanners, this project will undertake significant innovations in imaging acquisition, microstructural modeling, and quantitative analysis. The objectives include: i) Develop practical, highly accelerated acquisition protocols for detailed microstructure mapping with cutting-edge MRI sequences and commercially available ultra-strong diffusion gradients; ii) Develop machine learning tools for unbiased and efficient estimation of microstructural parameters at the individual level; iii) Develop a cross-subject, registration-free microstructural analysis pipeline that is robust to morphological differences across age groups; iv) Collect pilot datasets from a developmental cohort and assess the power of the developed microstructural fingerprint to detect cellular changes. We will share the rich datasets and novel insights of brain maturation through this project. We will disseminate the optimized imaging protocols and computational tools to the scientific community, with the aim of benefitting a wider range of applications.