Motor learning induces myelin-related white matter changes revealed by MRI-based in vivo histology

Motor learning induces widespread brain changes, yet the microstructural mechanisms underlying human white matter (WM) plasticity remain poorly understood. Animal studies have identified roles for neurites, glia, and myelin, but in vivo human evidence has been limited by measurement specificity. Here, we combine multi-contrast quantitative MRI (qMRI), tractometry, and a novel multivariate analysis framework to investigate the microstructural basis of WM plasticity during motor skill learning. In a longitudinal within-subject study, 24 healthy adults completed 4 weeks of balance training following a baseline control period without training. We mapped changes across tractography-defined WM pathways using complementary qMRI markers related to tissue density, myelin, neurite architecture, and iron. Multivariate analysis revealed biologically plausible, behaviorally relevant plasticity in distributed pathways-including the cortico-ponto-cerebello-thalamo-cortical loop, anterior thalamic radiation, and corticospinal tracts-with important contributions from myelin-related metrics. Notably, we observed changes consistent with training-related modulation of the aggregate g-ratio in humans. These spatially distributed effects converged into a single latent dimension predicting neocortical plasticity, suggesting a coordinated, cross-tissue mechanism of brain adaptation. This biologically interpretable framework offers a powerful new approach for investigating WM microstructure in the contexts of plasticity, development, aging, disease, and rehabilitation.