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.