Full Length ArticlesIn vivo observation and biophysical interpretation of time-dependent diffusion in human white matter

•We measure time-dependent DTI (55 ms - 600 ms) in vivo in human white matter.•Pronounced longitudinal and weaker transverse time-dependent diffusion is observed.•Longitudinal time-dependence is attributed to axonal varicosities.•Transverse time-dependence is attributed to the random axon packing geometry.•Varying diffusion time may provide a novel microstructural contrast.

The presence of micrometer-level restrictions leads to a decrease of diffusion coefficient with diffusion time. Here we investigate this effect in human white matter in vivo. We focus on a broad range of diffusion times, up to 600 ms, covering diffusion length scales up to about 30 μm. We perform stimulated echo diffusion tensor imaging on 5 healthy volunteers and observe a relatively weak time-dependence in diffusion transverse to major fiber tracts. Remarkably, we also find notable time-dependence in the longitudinal direction. Comparing models of diffusion in ordered, confined and disordered media, we argue that the time-dependence in both directions can arise due to structural disorder, such as axonal beads in the longitudinal direction, and the random packing geometry of fibers within a bundle in the transverse direction. These time-dependent effects extend beyond a simple picture of Gaussian compartments, and may lead to novel markers that are specific to neuronal fiber geometry at the micrometer scale.