A time-dependent diffusion MRI signature of axon caliber variations and beading

MRI provides a unique non-invasive window into the brain, yet is limited to millimeter resolution, orders of magnitude coarser than cell dimensions. Here, we show that diffusion MRI is sensitive to the micrometer-scale variations in axon caliber or pathological beading, by identifying a signature power-law diffusion time-dependence of the along-fiber diffusion coefficient. We observe this signature in human brain white matter and identify its origins by Monte Carlo simulations in realistic substrates from 3-dimensional electron microscopy of mouse corpus callosum. Simulations reveal that the time-dependence originates from axon caliber variation, rather than from mitochondria or axonal undulations. We report a decreased amplitude of time-dependence in multiple sclerosis lesions, illustrating the potential sensitivity of our method to axonal beading in a plethora of neurodegenerative disorders. This specificity to microstructure offers an exciting possibility of bridging across scales to image cellular-level pathology with a clinically feasible MRI technique. Hong-Hsi Lee et al. identify a characteristic power-law scaling in the time-dependent diffusion MRI signal that can detect micrometer-scale variations in axon caliber or pathological beading. They validate this signature trait using Monte Carlo simulations in axonal microstructure based on electron microscopy of mouse corpus callosum and illustrate the sensitivity of this method by detecting axon beading in a neurodegenerative disorder.