Focal seizures are organized by feedback between neural activity and ion concentration changes

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Abstract

Human and animal EEG data demonstrate that focal seizures start with low-voltage fast activity, evolve into rhythmic burst discharges and are followed by a period of suppressed background activity. This suggests that processes with dynamics in the range of tens of seconds govern focal seizure evolution. We investigate the processes associated with seizure dynamics by complementing the Hodgkin-Huxley mathematical model with the physical laws that dictate ion movement and maintain ionic gradients. Our biophysically realistic computational model closely replicates the electrographic pattern of a typical human focal seizure characterized by low voltage fast activity onset, tonic phase, clonic phase and postictal suppression. Our study demonstrates, for the first time in silico, the potential mechanism of seizure initiation by inhibitory interneurons via the initial build-up of extracellular K⁺ due to intense interneuronal spiking. The model also identifies ionic mechanisms that may underlie a key feature in seizure dynamics, i.e., progressive slowing down of ictal discharges towards the end of seizure. Our model prediction of specific scaling of inter-burst intervals is confirmed by seizure data recorded in the whole guinea pig brain in vitro and in humans, suggesting that the observed termination pattern may hold across different species. Our results emphasize ionic dynamics as elementary processes behind seizure generation and indicate targets for new therapeutic strategies.

Data availability

All experimental data and analysis code is provided.Source data and analysis code (Matlab) is provided for Figure 2.Source data is provided for Figure 3ASource data and analysis code (Matlab) is provided separately for Figure 6A, 6B, 6C.Source data and analysis code (Matlab) is provided for Figure 6 - figure supplement 1.The model NEURON files with a code reproducing Figure 2 (main simulation results) ispublicly available at Model DB database (http://modeldb.yale.edu/267499).

The following data sets were generated

1. Suffczynski P
2. Gentiletti D
(2022) A focal seizure model with ion concentration changes
ModelDB, http://modeldb.yale.edu/267499.

http://modeldb.yale.edu/267499

Article and author information

Author details

Damiano Gentiletti

Department of Biomedical Physics, University of Warsaw, Warsaw, Poland

Competing interests
The authors declare that no competing interests exist.
Marco de Curtis

Epilepsy Unit, Istituto Neurologico Carlo Besta, Milan, Italy

Competing interests
The authors declare that no competing interests exist.
Vadym Gnatkovsky

Epilepsy Unit, Istituto Neurologico Carlo Besta, Milan, Italy

Competing interests
The authors declare that no competing interests exist.
Piotr Suffczynski

Department of Biomedical Physics, University of Warsaw, Warsaw, Poland

For correspondence
suffa@fuw.edu.pl

Competing interests
The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0000-0002-2300-1415

Funding

Associazione Paolo Zorzi for the Neuroscience (EPICARE)

Marco de Curtis
Vadym Gnatkovsky

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Copyright

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.