Decoding the microstructural correlate of diffusion MRI

Diffusion imaging has evolved considerably over the past decade. While it provides valuable information about the structural connectivity at the macro- and mesoscopic scale, bridging the gap to the microstructure at the level of single nerve fibers poses an enormous challenge. This is particularly true for the human brain with its large size, its large white-matter volume and availability of histological techniques for studying human whole-brain sections and subsequent 3D reconstruction. Classic post-mortem techniques for studying the fiber architecture of the brain, such as myeloarchitectonic staining or dye tracing, are complemented by novel histological approaches, such as 3D polarized light imaging or optical coherence tomography, enabling unique insight into the fiber architecture from large fiber bundles within deep white matter to single nerve fibers in the cortex. The present review discusses the benefits and challenges of these latest developments in comparison with the classic techniques, with particular focus on the mutual exchange between in vivo and post-mortem diffusion imaging and post-mortem microstructural approaches for understanding the wiring of the brain across different scales.