Monosynaptic connections link functionally similar regions in human cortex

Xu, R.; Bush, A.; Takahashi, A.; Sisterson, N.; Walton, A.; Hutchinson, S.; Kammen, A.; Neudorfer, C.; Kokkinos, V.; Nanda, P.; Jhingan, N.; Marvi, A.; Fung, A.; Duraivel, S.; Hosseini, E.; Casto, C.; Valenzuela, C.; Yee, S.; Kirsch, J.; Fedorenko, E.; Kanwisher, N. G.; Desimone, R.; Richardson, R. M.

doi:10.64898/2026.05.19.726279

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bioRxiv · 10.64898/2026.05.19.726279

Monosynaptic connections link functionally similar regions in human cortex

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Abstract

The functional organization of human cortex has been mapped in considerable detail1-5, yet the axonal connections linking these areas remain largely unknown. This gap precludes inferring either the computational pathways through cortical networks or the principles governing why each area connects to its particular target regions. Here, in patients undergoing intracranial monitoring for epilepsy, we used concurrent electrical stimulation and functional magnetic resonance imaging (es-fMRI), validated previously against tracer studies in nonhuman primates6, to map anatomical connectivity of cortical sites across the whole brain, and combined these maps with task and resting-state fMRI in the same individuals. Es-fMRI revealed four main findings. First, connectivity followed an asymmetric functional-similarity principle: connected sites tended to share similar functional profiles, but, because connectivity is sparse, most pairs of functionally similar sites were not connected. Second, although connectivity also declines with distance7, the functional profile explained three times as much variance in connectivity as distance did, and long-range connections were the most functionally specific. Third, es-fMRI revealed direct monosynaptic links between established functional regions, including between the fusiform face area (FFA)2 and the temporoparietal junction (TPJ)3 for social cognition. Fourth, resting-state functional connectivity (rsFC) of a stimulation site was only weakly correlated with that sites es-fMRI connectivity. Together, these results provide a first principled link between anatomical connectivity and functional organization in the human cortex, and establish es-fMRI as a scalable approach to building a tracer-grade connectome of the human brain.

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Xu, R., Bush, A., Takahashi, A., Sisterson, N., Walton, A., Hutchinson, S., Kammen, A., Neudorfer, C., Kokkinos, V., Nanda, P., Jhingan, N., Marvi, A., Fung, A., Duraivel, S., Hosseini, E., Casto, C., Valenzuela, C., Yee, S., Kirsch, J., Fedorenko, E., Kanwisher, N. G., Desimone, R., Richardson, R. M.. 2026-05-20. Monosynaptic connections link functionally similar regions in human cortex. https://doi.org/10.64898/2026.05.19.726279

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