Hierarchical X-ray microscopy and mesoscopic diffusion MRI in the same brain reveal the human connectome across scales

Chourrout, M.; Gong, T.; Schalek, R.; Keenlyside, A.; Balbastre, Y.; Karlupia, N.; Gonzales, R. A.; Huszar, I. N.; Wanjau, E.; Brunet, J.; Urban, T.; Dejea, H.; Stansby, D.; Gunalan, K.; Glickman, B.; Gaibor, E. J.; Scherick, J. J.; Bintsi, K.-M.; Mauri, C.; Analoro, C.; Ghosh, S. S.; Bellier, A.; Fischl, B. R.; Augustinack, J.; Tafforeau, P.; Maffei, C.; Lee, P. D.; Lichtman, J. W.; Yendiki, A.; Walsh, C. L.

doi:10.64898/2026.04.02.716198

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bioRxiv · 10.64898/2026.04.02.716198

Hierarchical X-ray microscopy and mesoscopic diffusion MRI in the same brain reveal the human connectome across scales

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Abstract

We present a multimodal pipeline for 3D imaging of cerebral white-matter archi-tecture across scales, from whole-brain axonal projections down to individual myelinated axons. After diffusion MRI, an adult ex vivo human hemisphere undergoes label-free imaging with Hierarchical Phase-Contrast Tomography (HiP-CT) from 20 {micro}m/voxel in the whole hemisphere to 2 {micro}m/voxel in areas of interest, with intrinsic cross-scale alignment. A 4 cm tissue block extracted from the hemisphere is reimaged with HiP-CT at 0.857 {micro}m/voxel, enabling direct visualisation of single myelinated axons. After osmium staining, micro-CT at 0.364 {micro}m/voxel and electron microscopy at 4 nm/voxel are acquired in biop-sies from the tissue block to validate the presence of myelinated axons in the label-free HiP-CT contrast. Spanning three orders of magnitude in resolution, these co-registered multimodal datasets bridge microscopic wiring and macro-scopic brain organisation, providing a foundation for anatomically grounded whole-brain connectomics.

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Chourrout, M., Gong, T., Schalek, R., Keenlyside, A., Balbastre, Y., Karlupia, N., Gonzales, R. A., Huszar, I. N., Wanjau, E., Brunet, J., Urban, T., Dejea, H., Stansby, D., Gunalan, K., Glickman, B., Gaibor, E. J., Scherick, J. J., Bintsi, K.-M., Mauri, C., Analoro, C., Ghosh, S. S., Bellier, A., Fischl, B. R., Augustinack, J., Tafforeau, P., Maffei, C., Lee, P. D., Lichtman, J. W., Yendiki, A., Walsh, C. L.. 2026-04-06. Hierarchical X-ray microscopy and mesoscopic diffusion MRI in the same brain reveal the human connectome across scales. https://doi.org/10.64898/2026.04.02.716198

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