Biophysical Mechanisms of Microscopic Diffusional Kurtosis in diffusion MRI

The Standard Model of diffusion MRI represents diffusion in tissue using multiple Gaussian components, an approximation that misses key non-Gaussian effects from intra-compartmental structural disorder and/or intercompartmental water exchange. These biophysical mechanisms are conflated in conventional measures such as diffusional kurtosis, and exchange is commonly described using the Kärger model. Here, we develop a Correlation Tensor MRI (CTI) framework that derives the full three-dimensional microscopic-kurtosis tensor and related directional metrics that separate disorder- and Kärger exchange effects. Monte Carlo simulations demonstrate robust disentanglement of these features. In vivo human CTI revealed dominant radial K_μ^⊥ in white matter, consistent with structural disorder. In a rodent ischemic stroke model, elevated axial K_μ^∥ in lesions corresponded to neurite beading, confirmed histologically. In medulloblastoma, reduced directional CTI metrics reflected infiltration by uniformly shaped tumor cells, while in glioma, phenotypes with distinct cellular anisotropy and packing were resolved. These findings show that microscopic kurtosis cannot be neglected under most biological scenarios, and that structural disorder dominates non-Gaussian diffusion, with disease-specific alterations reflecting underlying pathology. Consequently, Kärger exchange alone is unlikely to be an adequate biophysical model in tissues. Our work provides unravels biophysical mechanisms of diffusional kurtosis biology, from humans to animal models.