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

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.

Is High‐Frequency Activity at Seizure Onset Inhibitory? A Stereoelectroencephalographic Study of Motor Cortex Seizures

“…This opens new insights into the relationship between epileptogenic (electrical) and symptomatogenic (clinical) phenomena. Furthermore, activity-dependent elevated extracellular potassium and chloride concentration could represent an intermediate mechanism for the transition between increased FSII firing and excitatory bursting activity following the HFA (Gentiletti et al 28 ). Depolarization block of these interneurons has been shown to initiate the rebound of pyramidal cell discharge (C alin et al 29 ).…”

An exploratory computational analysis in mice brain networks of widespread epileptic seizure onset locations along with potential strategies for effective intervention and propagation control

“…The design of patient-specific neurostimulation patterns for seizure suppression has also been a subject of study, as evidenced by Sandler et al ( 2018 ), offering tailored solutions to individual patients. Additionally, the interplay between neural activity and ion concentration changes in localized seizures has been elucidated by Gentiletti et al ( 2022 ), stressing the critical role of computational methods in deciphering complex neurophysiological processes. Nowadays there are already several devices (approved by the U.S. Food and Drug Administration) aiming to reduce the frequency of seizures, namely Vagus Nerve Stimulation (VNS), Responsive Neurostimulation (RNS), and Deep Brain Stimulation (DBS) (see Skrehot et al, 2023 and references therein for a recent review).…”

An exploratory computational analysis in mice brain networks of widespread epileptic seizure onset locations along with potential strategies for effective intervention and propagation control

“…The design of patient-specific neurostimulation patterns for seizure suppression has also been a subject of study, as evidenced by (Sandler et al, 2018), offering tailored solutions to individual patients. Additionally, the interplay between neural activity and ion concentration changes in localized seizures has been elucidated by (Gentiletti et al, 2022), stressing the critical role of computational methods in deciphering complex neurophysiological processes. Nowadays there are already several devices (approved by the U.S. Food and Drug Administration) aiming to reduce the frequency of seizures, namely Vagus Nerve Stimulation (VNS), Responsive Neurostimulation (RNS), and Deep Brain Stimulation (DBS) (see (Skrehot et al, 2023) and references therein for a recent review).…”