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.
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).
A focal seizure model with ion concentration changesModelDB, http://modeldb.yale.edu/267499.
- 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.
- Joseph V Raimondo, University of Cape Town, South Africa
- Received: March 18, 2021
- Accepted: July 12, 2022
- Accepted Manuscript published: August 2, 2022 (version 1)
© 2022, Gentiletti et al.
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.
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