Microstructural correlates of white and gray matter in the healthy human brain: comparative analysis of diffusion biophysical models, inhomogeneous magnetization transfer, and macromolecular proton fraction

Abstract summary Diffusion MRI (dMRI) and magnetization transfer (MT) rely on distinct biophysical principles and provide complementary insights into tissue microstructure. In this study, we investigated associations between microstructural metrics derived from the Standard Model (SMI) in white matter (WM) and the Standard Model with EXchange (SMEX/NEXI) in gray matter (GM) with two MT measures differing in specificity and sensitivity to myelination: the macromolecular proton fraction (MPF) and the inhomogeneous magnetization transfer ratio (ihMTR). Measurements were performed in WM and GM in ten healthy subjects scanned at 3T. In WM, the strongest significant association was observed between ihMTR and the axonal water fraction, consistent with higher myelination in regions of elevated axonal density and limited extra-axonal space. This correlation exceeded that of MPF, supporting the greater specificity of ihMTR to myelin. Interestingly, ihMTR displayed a gradient along the longitudinal axis of the corpus callosum, in agreement with previous histology measurements. Correlation between ihMTR and the extra-axonal perpendicular diffusivity (De⊥), a putative myelination biomarker, was not significant, whereas MPF and De⊥ exhibited a moderate significant positive correlation. Since a negative correlation is expected if reflecting myelination, these results suggest that in healthy tissue De⊥ is mainly influenced by microstructural factors like fiber coherence and packing, the latter most likely affecting MPF but not ihMTR. In GM, ihMTR correlated significantly only with the exchange time (tₑₓ), confirming tex as a proxy for cell membrane permeability modulated by myelin. MPF correlated exclusively with the cell-process fraction (f), suggesting the latter is modulated by total (neuronal and glial) cell membrane density. Overall, findings underscore the complementary and concurring microstructural information captured by these metrics, highlighting their potential to disentangle distinct tissue mechanisms in both healthy and pathological conditions. Future studies incorporating ground-truth histology should validate the precise sensitivity of each metric to various microstructural tissue features. Competing Interest Statement The authors have declared no competing interest.