The overarching goal of this project is to reveal the microstructural features that underlie the diffusion-time dependent changes in the apparent diffusion coefficient measured diffusion weighted magnetic resonance imaging (DWI) in neural tissue. While time dependent changes in the diffusion coefficient have been measured in numerous previous studies of neural tissue, the exact microstructural characteristics of that underly these changes remain unclear. Uncovering the microstructure that underly these measurements could improve the diagnosis, staging and differentiation of numerous neurological diseases that otherwise show nonspecific changes with DWI. We propose that time dependent changes in diffusion originate primarily from three sources: mean axon diameter, heterogeneity of extra-axonal space, and orientation dispersion. Within this project, we propose to (1) develop and use numerical simulations to test the sensitivity of time dependent diffusion to tissue microstructure, (2) validate time dependent changes in the diffusion coefficient in specific animal models that vary axon diameter, heterogeneity of extra-axonal space, and complexity of white matter, and (3) provide baseline estimates of the time dependent diffusion coefficient and the variability in these measurements in a population of healthy human controls.