Optimizing the utility of diffusion imaging for discovering genetic and environmental influences on neural development, degeneration, and disease

The complex interplay of nature and nurture make each individual unique in several ways; however, certain combinations of genetic and environmental factors lend themselves to devastating neurological diseases, whose mechanistic pathways are not fully understood. Many of these disorders damage and deteriorate the white matter neural connections within the brain. Non-invasive imaging techniques have recently been used to map structural variation in the living human brain; yet now, with the growing advances in diffusion-based magnetic resonance imaging (dMRI) techniques and its wide scale availability, we are able to uncover more about the interworking connections of the brain than ever before. In the work presented in this thesis, the utility of dMRI is explored. First, we examine the stability and reliability of diffusion imaging protocols --- these acquisition protocols are often limited by a clinical time constraint and therefore trade-offs are made, which may compromise directional or spatial resolution and can affect signal-to-noise or reproducibility in brain maps. Next, we explore the degree to which genetic interpretations from the same individuals can be affected by the choice of imaging protocol. A preliminary investigation into different methods of population-based analyses lends itself to a large heritability study of brain fiber asymmetry. Knowledge of the genetic influence on brain fiber integrity motivates a study of the most pressing global nutritional deficiency, iron, and its genetic correlates, on the healthy human brain structure. Methods presented are then carried forward on genetic and environmental fiber mapping experiments independently, studying the microstructural effect of a single Alzheimer's disease risk gene on healthy young adults and also cerebrovascular confounds in HIV patients. Finally, the brain's network and organization is visualized as a matrix describing the degree of physical connections between functional cortical regions through tractography and cortical parcellation. The degree of genetic and environmental influence on the ``human connectome is then estimated. These works mark only the beginning of this line of research, which will be further expanded with studies of connectivity biomarkers, viral and gene interactions, and global efforts in combining data to expand the search for genes influencing brain microstructure.