Abstract
How can one trace the brain’s orderly directed signals amid a tangle of nerve fibers? Because direct access to actual brain signaling is rare in humans, the precise wiring diagrams for cortico-limbic communication during sleep and wake remain essentially unmapped, hampering progress in neuroscience. Now, a unique neurosurgical window on the human brain allows for electrically mapping cortical connections at the hospital, but studies so far have relied on average signals, masking the dynamic nature of signal flow across brain regions and vigilance states. To causally estimate signal flow, we repeatedly probed cortico-limbic networks with short-lived electrical pulses over days and assessed the variable fate of each transmitted signal on a single-trial basis. In the resulting openly available dataset, we characterized signaling probabilities and directionality across thousands of local and long-range cortico-limbic connections over days. Challenging established views, we found that limbic structures send twice as many signals as they receive, in both wakefulness and sleep. Our findings provide a fundamental framework for causally interpreting signal flow in the brain and formulating therapeutic strategies for brain network disorders.
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Data availability
All measurement data can be explored using the accompanying graphical user interface available at https://github.com/neuro-elab/EvM_Connectivity/releases. In addition, the GitHub repository https://github.com/neuro-elab/EvM_Directed-cortico-limbic-dialogue contains the preprocessed data and analysis scripts required to reproduce the main plots presented in the manuscript. Source data are provided with this paper.
Code availability
The code for core calculations made in this study are available in the accompanying graphical user interface (see above). In addition, the GitHub repository https://github.com/neuro-elab/EvM_Directed-cortico-limbic-dialogue contains the preprocessed data and analysis scripts required to reproduce the main plots presented in the manuscript.
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Acknowledgements
The authors thank Karin Somerlik, Thilo Krueger, and Kornelius Lente at Inomed GmBH for the help with developing a programmable interface with the stimulator and switch matrix. The authors also thank the EEG team at Inselspital for their flexibility in accommodating new devices in the recording chain. We thank the patients who agreed to participate in this study. E. van Maren’s salary was supported by the Velux Stiftung (#1232). M.O. Baud’s salary was supported by the Swiss National Science Foundation (Ambizione #179929 and Eccellenza #203339). Some electrophysiology material was financed by the Olga Mayenfisch Stiftung, Zürich.
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E.v.M. programmed the recording-stimulation set-up, collected and analyzed the data, generated the figures, and wrote the first draft of the manuscript. C.G.M. provided the final image analysis and electrode localization pipeline and built the interface for data visualization. R.W. analyzed part of the data and built the interface for data visualization. C.F.M. recruited patients and collected the data. P.N. scored sleep data. M.F. built the recording-stimulation set-up and collected the data. J.A. supervised the setup of the recording-stimulation system. C.P. collected the data. A.T. provided scientific input and edited the manuscript. T.P. provided scientific input on Fig. 1 and edited the manuscript. K.S. provided scientific input and edited the manuscript. M.O.B. obtained authorization for the project, built the recording-stimulation set-up, collected and analyzed the data, wrote the first draft and final version of the manuscript, and provided the scientific oversight of the project. All authors edited the final manuscript.
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Nature Communications thanks Olivier David, who co-reviewed with Cristiana Pinheiro, and the other anonymous reviewer(s) for their contribution to the peer review of this work. A peer review file is available.
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van Maren, E., Mignardot, C.G., Widmer, R. et al. Directed cortico-limbic dialogue in the human brain. Nat Commun (2026). https://doi.org/10.1038/s41467-026-68701-z
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DOI: https://doi.org/10.1038/s41467-026-68701-z
