Mapping mean axon diameter and axonal volume fraction by MRI using temporal diffusion spectroscopy

- Appropriate intra- and extra-axonal diffusion models were proposed and validated.
- Temporal diffusion spectra were acquired to assess rat spinal white matter tracts.
- Mean axon diameter and axonal volume fraction were fit and verified with histology.
- This study establishes a framework using MRI to detect white matter morphology.

Mapping mean axon diameter and intra-axonal volume fraction may have significant clinical potential because nerve conduction velocity is directly dependent on axon diameter, and several neurodegenerative diseases affect axons of specific sizes and alter axon counts. Diffusion-weighted MRI methods based on the pulsed gradient spin echo (PGSE) sequence have been reported to be able to assess axon diameter and volume fraction non-invasively. However, due to the relatively long diffusion times used, e.g. > 20 ms, the sensitivity to small axons (diameter < 2 μm) is low, and the derived mean axon diameter has been reported to be overestimated. In the current study, oscillating gradient spin echo (OGSE) diffusion sequences with variable frequency gradients were used to assess rat spinal white matter tracts with relatively short effective diffusion times (1-5 ms). In contrast to previous PGSE-based methods, the extra-axonal diffusion cannot be modeled as hindered (Gaussian) diffusion when short diffusion times are used. Appropriate frequency-dependent rates are therefore incorporated into our analysis and validated by histology-based computer simulation of water diffusion. OGSE data were analyzed to derive mean axon diameters and intra-axonal volume fractions of rat spinal white matter tracts (mean axon diameter of ~ 1.27-5.54 μm). The estimated values were in good agreement with histology, including the small axon diameters (< 2.5 μm). This study establishes a framework for the quantification of nerve morphology using the OGSE method with high sensitivity to small axons.