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Direct interactions between the human insula and hippocampus during memory encoding

Nature Neuroscience volume 28, pages 1763–1771 (2025)Cite this article

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Abstract

The hippocampus is critical for encoding episodic memories, but how it interacts with cortical regions during this process remains unclear. In this study, 16 participants with implanted electrodes in the insula (217 sites) and hippocampus (131 sites) viewed emotionally valenced words and attempted to recall them. During encoding, one subset of insular neuronal populations showed changes in aperiodic activity that predicted successful recall. These insular changes followed hippocampal theta but preceded hippocampal ripples. Another subset of insular sites responded to word valence, unrelated to memory performance. Direct electrical stimulation of memory-related insular sites evoked early responses in the ipsilateral hippocampus, whereas stimulation of valence-related sites did not. Conversely, stimulating hippocampal sites produced slow, variable signals across all insular sites, suggesting asymmetric communication between the hippocampus and the insula. These findings provide a glimpse of mesoscale hippocampal interactions with functionally selective neuronal populations within a given cortical structure.

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Fig. 1: Structure of the human insula and experimental task design.
Fig. 2: Divergent modes of activity in the insula during encoding of valenced words.
Fig. 3: Hippocampal activity during encoding and its temporal relationship with insular activity.
Fig. 4: Causal and intrinsic interactions between the insular and hippocampal sites.

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Data availability

The raw iEEG data can be obtained from the corresponding author upon request. Supporting data are available at https://osf.io/r2kj8/. The FS_LR space for insula visualization is available at https://osf.io/k89fh/wiki/Surface/. The inflated brain surface with the Julich brain atlas is available at https://julich-brain-atlas.de/

Code availability

Code for ripple detection is available at https://github.com/LBCN-Stanford/ripple_detection. Code specific to other analyses in this study is available at https://github.com/LBCN-Stanford/2025_Insula.

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Acknowledgements

We thank R. Chahal for help in designing the encoding experiment. We thank Z. Lusk for help in experimental data collection and organizing the behavioral results. We thank the EEG tech team for their help in acquiring the data. This work was supported by R21NS113024 from the National Institutes of Health (NINDS) to J.P.

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Author notes

  1. These authors contributed equally: Dian Lyu, James R. Stieger.

Authors and Affiliations

  1. Laboratory of Behavioral and Cognitive Neuroscience, Stanford University School of Medicine, Palo Alto, CA, USA

    Weichen Huang, Dian Lyu, James R. Stieger & Josef Parvizi

  2. Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Palo Alto, CA, USA

    Weichen Huang, Dian Lyu, James R. Stieger & Josef Parvizi

  3. Department of Psychology, Stanford University School of Medicine, Palo Alto, CA, USA

    Ian H. Gotlib & Anthony D. Wagner

  4. Wu Tsai Neurosciences Institute, Stanford University School of Medicine, Stanford, CA, USA

    Ian H. Gotlib, Anthony D. Wagner & Josef Parvizi

  5. Department of Neurosurgery, Stanford University School of Medicine, Palo Alto, CA, USA

    Vivek Buch & Josef Parvizi

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Contributions

Conceptualization: J.P. Data collection: W.H. and D.L. Data analysis: W.H., D.L. and J.R.S. Surgery: V.B. Writing, original draft: W.H. and J.P. Writing, review and editing: W.H., D.L., J.R.S., I.H.G., V.B., A.D.W. and J.P. Supervision and funding: J.P.

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Correspondence to Josef Parvizi.

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Nature Neuroscience thanks Johannes Sarnthein and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Supplementary Methods, Results, Figs. 1–6, Tables 1–3 and References.

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Huang, W., Lyu, D., Stieger, J.R. et al. Direct interactions between the human insula and hippocampus during memory encoding. Nat Neurosci 28, 1763–1771 (2025). https://doi.org/10.1038/s41593-025-02005-1

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