Short-range human cortico-cortical white matter fibers have thinner axons and are less myelinated compared to long-range fibers despite a similar g-ratio.

The size and complexity of the human brain require optimally sized and myelinated fibers. White matter fibers facilitate fast communication between distant areas, but also connect adjacent cortical regions via short association fibers. The difference in length and packing density of long and short association fibers pose different requirements on their optimal size and degree of myelination. The fundamental questions of (i) how thick the short association fibers are and (ii) how strongly they are myelinated as compared to long fibers, however, remain unanswered. We present a comprehensive two-dimensional transmission electron microscopic analysis of ~400,000 fibers of human white matter regions with long (corpus callosum) and short fibers (superficial white matter). Using a deep learning approach, we demonstrate a substantially higher fiber diameter and higher myelination thickness (both approximately 25% higher) in corpus callosum than in superficial white matter. Surprisingly, we do not find a difference in the ratio between axon diameter and myelin thickness (g-ratio), which is close to the theoretically optimal value of ~0.6 in both areas (0.54). This work reveals a fundamental principle of brain organization that provides a key foundation for understanding the human brain.