Bridging Histology and Tractography: First Visualization of the Short-Range Prefrontal Connections in the Human Brain
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Decades of histological research in non-human primates have revealed a dense web of short- range connections underpinning prefrontal cortex (PFC) function. However, translating this anatomical ground-truth to the living human brain has been a major challenge, leaving our understanding of the PFC’s intrinsic wiring incomplete. These short-range fibers are difficult to resolve with non-invasive methods like diffusion tractography, which are often hampered by false positives. Here, we provide the first systematic in-vivo visualization of these pathways in the human brain. By guiding high-resolution probabilistic tractography with established histological findings, we mapped the short-range connections within and between five major PFC subdivisions in 1,003 individuals (547 F, 456 M). Our anatomically-guided approach successfully reconstructed these intricate connections with high precision (>80%) and accuracy (>70%) relative to histological findings. The resulting tracts not only captured broad organizational principles but also replicated fine-grained patterns previously only seen in invasive studies. Furthermore, these connections showed high test-retest reliability within individuals alongside significant variability between them, highlighting a stable yet unique anatomical fingerprint. Ultimately, this study shows how linking histology to tractography provides a powerful framework to advance our understanding of the human connectome and opens avenues to investigate local circuitry that underpins cognition and disease.
Significance statement
Histological studies in non-human primates have shown that the prefrontal cortex is highly interconnected by short-range association fibers. However, these intrinsic connections remain poorly characterized in the human brain, as short-range fibers are particularly difficult to study with tractography due to their small size and vulnerability to false positives. Using high- resolution diffusion MRI data from over 1,000 individuals, we present the first in-vivo visualization of these short-range prefrontal pathways, guided by established histological findings. Our analysis revealed that tractography can capture these fine-scale anatomical patterns with relatively high accuracy and reproducibility. Here, we demonstrate that by guiding tractography by established histological findings, these connections can be visualized in vivo for the first time with high fidelity and reproducibility.
