Intra- and extra-axonal axial diffusivities in the white matter: which one is faster?

TL;DR

This study used gadolinium contrast in rats to validate whether intra-axonal or extra-axonal axial diffusivity is faster in white matter, supporting the intra-axonal diffusivity being higher.

Contribution

It provides experimental evidence favoring the intra-axonal axial diffusivity as higher, using contrast-enhanced diffusion MRI and modeling in rat brain white matter.

Findings

Gadolinium reduced extracellular water signal and increased intra-axonal water fraction.

Post-Gd data supported intra-axonal diffusivity being higher than extra-axonal.

Results aligned with recent diffusion tensor studies.

Abstract

A two-compartment model of diffusion in white matter, which accounts for intra- and extra-axonal spaces, is associated with two plausible mathematical scenarios: either the intra-axonal axial diffusivity is higher than the extra-axonal (Branch 1), or the opposite (Branch 2). This duality calls for an independent validation of compartment axial diffusivities, to determine which of the two cases holds. The aim of the present study was to use an intracerebroventricular injection of a gadolinium-based contrast agent to selectively reduce the extracellular water signal in the rat brain, and compare diffusion metrics in the genu of the corpus callosum before and after gadolinium infusion. The diffusion metrics considered were diffusion and kurtosis tensor metrics, as well as compartment-specific estimates of the WMTI-Watson two-compartment model. A strong decrease in genu T1 and T2 relaxation times post-Gd was observed (p < 0.001), as well as an increase of 48% in radial kurtosis (p < 0.05), which implies that the relative fraction of extracellular water signal was selectively decreased. This was further supported by a significant increase in intra-axonal water fraction as estimated from the two-compartment model, for both branches (p < 0.01 for Branch 1, p < 0.05 for Branch 2). However, pre-Gd estimates of axon dispersion in Branch 1 agreed better with literature than those of Branch 2. Furthermore, comparison of post-Gd changes in diffusivity and dispersion between data and simulations further supported Branch 1 as the biologically plausible solution, i.e. the intra-axonal axial diffusivity is higher than the extra-axonal one. This result is fully consistent with other recent measurements of compartment axial diffusivities that used entirely different approaches, such as diffusion tensor encoding.