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Interictal network dysfunction and cognitive impairment in epilepsy

Nature Reviews Neuroscience volume 26, pages 399–414 (2025)Cite this article

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Abstract

Epilepsy is diagnosed when neural networks become capable of generating excessive or hypersynchronous activity patterns that result in observable seizures. In many cases, epilepsy is associated with cognitive comorbidities that persist between seizures and negatively impact quality of life. Dysregulation of the coordinated physiological network interactions that are required for cognitive function has been implicated in mediating these enduring symptoms, but the causal mechanisms are often elusive. Here, we provide an overview of neural network abnormalities with the potential to contribute to cognitive dysfunction in epilepsy. We examine these pathological interactions across spatial and temporal scales, additionally highlighting the dynamics that arise in response to the brain’s intrinsic capacity for plasticity. Understanding these processes will facilitate development of network-level interventions to address cognitive comorbidities that remain undertreated by currently available epilepsy therapeutics.

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Fig. 1: Network-level dysfunction contributing to cognitive impairment in epilepsy.
Fig. 2: Dysregulation of physiological communication in epileptic networks.
Fig. 3: Potential derangements of plasticity processes in epileptic networks.
Fig. 4: Approaches to network-level interventions aimed at ameliorating cognitive dysfunction in epilepsy.

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Acknowledgements

This work was supported by the National Institutes of Health grant no. R01NS118091 (J.N.G.). The authors thank all Khodagholy and Gelinas laboratory members for their support.

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Authors and Affiliations

  1. Department of Anatomy and Neurobiology, University of California, Irvine, CA, USA

    Jennifer N. Gelinas & Dion Khodagholy

  2. Department of Paediatrics, University of California, Irvine, CA, USA

    Jennifer N. Gelinas

  3. Children’s Hospital of Orange County, Orange, CA, USA

    Jennifer N. Gelinas

  4. Department of Electrical Engineering, University of California, Irvine, CA, USA

    Dion Khodagholy

  5. Department of Biomedical Engineering, University of California, Irvine, CA, USA

    Dion Khodagholy

  6. Department of Materials Science and Engineering, University of California, Irvine, CA, USA

    Dion Khodagholy

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  1. Jennifer N. Gelinas
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J.N.G. and D.K. performed the literature review, discussed article content, and wrote and revised the manuscript.

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Gelinas, J.N., Khodagholy, D. Interictal network dysfunction and cognitive impairment in epilepsy. Nat. Rev. Neurosci. 26, 399–414 (2025). https://doi.org/10.1038/s41583-025-00924-3

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