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

## TL;DR

This study demonstrates that diffusion MRI can detect micrometer-scale axon caliber variations and beading by analyzing a specific power-law time dependence of diffusion, enabling non-invasive microstructural brain imaging.

## Contribution

It introduces a novel diffusion MRI signature sensitive to axon caliber variations and beading, validated through simulations and human brain data, linking microstructure to MRI signals.

## Key findings

- Diffusion time-dependence correlates with axon caliber variation.
- Reduced time-dependence amplitude observed in multiple sclerosis lesions.
- Simulation confirms origin of signature from axon caliber variation.

## Abstract

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 uncover its origins by Monte Carlo simulations in realistic substrates from 3d 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 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.