MRI-scale histology validates spatial sensitivity of in-vivo MRI-based axon radius estimation

The axon radius holds promise as a clinical MRI biomarker for neurological disorders. However, in-vivo MRI estimation appears infeasible on clinical scanners and lacks experimental validation. Crucially, existing histology is only sparsely sampled, enabling primarily qualitative assessment. Here, we use large-scale human brain histology, sampling 46 million axons across 35 corpus callosum regions with MRI-like sizes. By demonstrating a significant spatial correlation with histology on an advanced research scanner, we provide quantitative proof that MRI radius estimates reflect underlying microstructure-a critical milestone. The next milestone-translation to clinical scanners-appears feasible with now-available high-gradient systems according to simulations, but would require substantial SNR gains. Yet, we also identify a sensitivity bottleneck in current modeling that may offer a complementary path to improved sensitivity through future modeling advances. Overall, we provide promising evidence for the validity of MRI-based axon radius estimation and identify challenges that must be solved for clinical adoption.