Diffusion-weighted magnetic resonance imaging (MRI) has allowed unprecedented non-invasive mapping of brain neural connectivity in vivo by means of fiber tractography applications. Fiber tractography has emerged as a useful tool for mapping brain white matter connectivity prior to surgery or in an intraoperative setting. The advent of high angular resolution diffusion-weighted imaging (HARDI) techniques in MRI for fiber tractography has allowed mapping of fiber tracts in areas of complex white matter fiber crossings. Raw HARDI images, as a result of elevated diffusion-weighting, suffer from depressed signal-to-noise ratio (SNR) levels. The accuracy of fiber tractography is dependent on the performance of the various methods extracting dominant fiber orientations from the HARDI-measured noisy diffusivity profiles. These methods will be sensitive to and directly affected by the noise. In the first part of the thesis this issue is addressed by applying an objective and adaptive smoothing to the noisy HARDI data via generalized cross-validation (GCV) by means of the smoothing splines on the sphere method for estimating the smooth diffusivity profiles in three dimensional diffusion space. Subsequently, fiber orientation distribution functions (ODFs) that reveal dominant fiber orientations in fiber crossings are then reconstructed from the smoothed diffusivity profiles using the Funk-Radon transform. Previous ODF smoothing techniques have been subjective and non-adaptive to data SNR. The GCV-smoothed ODFs from our method are accurate and are smoothed without external intervention facilitating more precise fiber tractography. Diffusion-weighted MRI studies in amyotrophic lateral sclerosis (ALS) have revealed significant changes in diffusion parameters in ALS patient brains. With the need for early detection of possibly discrete upper motor neuron (UMN) degeneration signs in patients with early ALS, a HARDI study is applied in order to investigate diffusion-sensitive changes reflected in the diffusion tensor imaging (DTI) measures axial and radial diffusivity as well as the more commonly used measures fractional anisotropy (FA) and mean diffusivity (MD). The hypothesis is that there would be added utility in considering axial and radial diffusivities which directly reflect changes in the diffusion tensors in addition to FA and MD to aid in revealing neurodegenerative changes in ALS. In addition, applying adaptive smoothing via GCV to the HARDI data further facilitates the application of fiber tractography by automatically eliminating spurious noisy peaks in reconstructed ODFs that would mislead fiber tracking.