This work investigates the possibilities of applying high-angular-resolution-diffusion-imaging- (HARDI-) based methods in a clinical setting by investigating the performance of non-Gaussian diffusion probability density function (PDF) estimation for a range of b-values and diffusion gradient direction tables. It does so at realistic SNR levels achievable in limited time on a high-performance 3T system for the whole human brain in vivo. We use both computational simulations and in vivo brain scans to quantify the angular resolution of two selected reconstruction methods: Q-ball imaging and the diffusion orientation transform. We propose a new analytical solution to the ODF derived from the DOT. Both techniques are analytical decomposition approaches that require identical acquisition and modest postprocessing times and, given the proposed modifications of the DOT, can be analyzed in a similar fashion. We find that an optimal HARDI protocol given a stringent time constraint (<10？min) combines a moderate b-value (around 2000？s/mm2) with a relatively low number of acquired directions (>48). Our findings generalize to other methods and additional improvements in MR acquisition techniques. 1. Introduction Diffusion-weighted magnetic resonance imaging (DW-MRI) is a clinical medical imaging technique that provides a unique view on the structure of brain white matter in vivo. Right from its early stages, in the early 1990s, DW-MRI was perceived to have immediate value for the evaluation of neuropathologies such as acute ischemic stroke. Since then, numerous advents in diffusion imaging technology have greatly augmented image quality unraveling new clinical applications. Moreover, the debut of diffusion tensor imaging (DTI) and fiber tractography enabled a completely new, noninvasive view on white matter fibre bundles connecting gray matter neural populations, of increasing importance for cognitive neuroimaging applications. With DTI and fiber tractography, the understanding of several neurological and psychiatric disorders, such as schizophrenia, traumas, stroke, and edemas, has been increased, and they have also been applied clinically to aid presurgical planning before intracranial mass resections. In DW-MRI, white matter fiber bundles are probed indirectly by measuring the directional specificity (anisotropy) of local water diffusion. During a small time interval (the “so-called” effective diffusion time ), at each location of the tissue, the diffusion causes a displacement of water molecules. Postprocessing of diffusion-weighted images is fundamentally aimed
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