White Matter Pathways and Cognition: Insights from Large-Scale Diffusion MRI Analyses

Abstract

Cognition enables us to understand and safely interact with each other and our surrounding environment, making it a critical component of human health. The white matter pathways form the brain’s neural connections, providing a structural foundation for cognition. However, how the connectivity and microstructural properties of the white matter pathways relate to human cognitive abilities remains unclear. Diffusion MRI (dMRI) enables non-invasive, in vivo mapping of these pathways and quantification of their tissue microstructure and connectivity. This dissertation investigates how white matter pathways, measured with dMRI, relate to cognitive performance by leveraging two large neuroimaging datasets: the Adolescent Brain Cognitive Development (ABCD) study and the Human Connectome Project-Young Adult (HCP-YA). This dissertation leverages an atlas-based machine learning approach to consistently parcellate the white matter pathways across thousands of participants. In Chapter 1, we examine the relationship between long-range association tracts and cognitive performance in over 800 young adults. We find lateralized associations: left-hemisphere tracts relate more strongly to semantic memory, while right-hemisphere tracts relate to emotion perception, underscoring distinct contributions of association pathways to language and social cognition. Chapter 2 evaluates cerebellar white matter pathways in over 9,000 participants across childhood and young adulthood. We identify consistent associations between cerebellar microstructure and cognition across datasets, with key differences suggestive of maturational change from childhood to adulthood. Chapter 3 investigates the role of sex hormones in shaping cognition through white matter microstructure at puberty. Using salivary hormone levels and dMRI data from over 8,000 pre-adolescent children, we find that testosterone is associated with white matter microstructure and mediates cognitive performance in males, but not females at the onset of puberty. Together, these studies provide new insight into how white matter microstructure supports cognition across developmental stages, cognitive domains, brain regions, and individual differences. This work advances our understanding of the neurobiological architecture of human cognition using large-scale diffusion MRI and cognitive datasets.