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      The Epileptor Model: A Systematic Mathematical Analysis Linked to the Dynamics of Seizures, Refractory Status Epilepticus, and Depolarization Block

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          Abstract

          One characteristic of epilepsy is the variety of mechanisms leading to the epileptic state, which are still largely unknown. Refractory status epilepticus (RSE) and depolarization block (DB) are other pathological brain activities linked to epilepsy, whose patterns are different and whose mechanisms remain poorly understood. In epileptogenic network modeling, the Epileptor is a generic phenomenological model that has been recently developed to describe the dynamics of seizures. Here, we performed a detailed qualitative analysis of the Epileptor model based on dynamical systems theory and bifurcation analysis, and investigate the dynamic evolution of “normal” activity toward seizures and to the pathological RSE and DB states. The mechanisms of the transition between states are called bifurcations. Our detailed analysis demonstrates that the generic model undergoes different bifurcation types at seizure offset, when varying some selected parameters. We show that the pathological and normal activities can coexist within the same model under some conditions, and demonstrate that there are many pathways leading to and away from these activities. We here archive systematically all behaviors and dynamic regimes of the Epileptor model to serve as a resource in the development of patient-specific brain network models, and more generally in epilepsy research.

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          Most cited references11

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          NEURAL EXCITABILITY, SPIKING AND BURSTING

          Bifurcation mechanisms involved in the generation of action potentials (spikes) by neurons are reviewed here. We show how the type of bifurcation determines the neuro-computational properties of the cells. For example, when the rest state is near a saddle-node bifurcation, the cell can fire all-or-none spikes with an arbitrary low frequency, it has a well-defined threshold manifold, and it acts as an integrator; i.e. the higher the frequency of incoming pulses, the sooner it fires. In contrast, when the rest state is near an Andronov–Hopf bifurcation, the cell fires in a certain frequency range, its spikes are not all-or-none, it does not have a well-defined threshold manifold, it can fire in response to an inhibitory pulse, and it acts as a resonator; i.e. it responds preferentially to a certain (resonant) frequency of the input. Increasing the input frequency may actually delay or terminate its firing. We also describe the phenomenon of neural bursting, and we use geometric bifurcation theory to extend the existing classification of bursters, including many new types. We discuss how the type of burster defines its neuro-computational properties, and we show that different bursters can interact, synchronize and process information differently.
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            Chaos and commotion in the wake of cortical spreading depression and spreading depolarizations.

            Punctuated episodes of spreading depolarizations erupt in the brain, encumbering tissue structure and function, and raising fascinating unanswered questions concerning their initiation and propagation. Linked to migraine aura and headache, cortical spreading depression contributes to the morbidity in the world's migraine with aura population. Even more ominously, erupting spreading depolarizations accelerate tissue damage during brain injury. The once-held view that spreading depolarizations may not exist in the human brain has changed, largely because of the discovery of migraine genes that confer cortical spreading depression susceptibility, the application of sophisticated imaging tools and efforts to interrogate their impact in the acutely injured human brain.
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              Refractory status epilepticus: a prospective observational study.

              Status epilepticus (SE) that is resistant to two antiepileptic compounds is defined as refractory status epilepticus (RSE). In the few available retrospective studies, estimated RSE frequency is between 31% and 43% of patients presenting an SE episode; almost all seem to require a coma induction for treatment. We prospectively assessed RSE frequency, clinical predictors, and outcome in a tertiary clinical setting. Over 2 years we collected 128 consecutive SE episodes (118 patients) in adults. Clinical data and their relationship to outcome (mortality and return to baseline clinical conditions) were analyzed. Twenty-nine of 128 SE episodes (22.6%) were refractory to first- and second-line antiepileptic treatments. Severity of consciousness impairment and de novo episodes were independent predictors of RSE. RSE showed a worse outcome than non-RSE (39% vs. 11% for mortality; 21% vs. 63% for return to baseline clinical conditions). Only 12 patients with RSE (41%) required coma induction for treatment. This prospective study identifies clinical factors predicting the onset of SE refractoriness. RSE appears to be less frequent than previously reported in retrospective studies; furthermore, most RSE episodes were treated outside the intensive care unit (ICU). Nonetheless, we confirm that RSE is characterized by high mortality and morbidity.
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                Author and article information

                Journal
                eNeuro
                eNeuro
                eneuro
                eneuro
                eNeuro
                eNeuro
                Society for Neuroscience
                2373-2822
                31 January 2020
                16 March 2020
                Mar-Apr 2020
                : 7
                : 2
                : ENEURO.0485-18.2019
                Affiliations
                [1]Aix Marseille University, INSERM, INS, Institut de Neurosciences des Systèmes, 13005 Marseille, France
                Author notes

                The authors declare no competing financial interests.

                Author contributions: K.E.H. and V.K.J. designed research; K.E.H. performed research; K.E.H. analyzed data; K.E.H., C.B., and V.K.J. wrote the paper.

                This research received financial support from the following agencies: Fondation pour la Recherche Médicale (Grant DIC20161236442 to Viktor K. Jirsa), European Commission’s Human Brain Project (Grant H2020-720270), and the SATT Sud-Est (TVB-Epilepsy). The work has been carried out within the FHU (Fédération Hospitalo-Universitaire) EPINEXT (Epilepsy and Disorders of Neuronal Excitability) with the support of the A*MIDEX project (ANR-11-IDEX-0001-02) funded by the “Investissements d'Avenir” French Governement program managed by the French National Research Agency (ANR).

                Correspondence should be addressed to Viktor K. Jirsa at viktor.jirsa@ 123456univ-amu.fr .
                Author information
                https://orcid.org/0000-0003-3014-1966
                Article
                eN-NWR-0485-18
                10.1523/ENEURO.0485-18.2019
                7096539
                32066612
                07ecf076-28ed-4ecb-bbdc-74081e8e8d37
                Copyright © 2020 El Houssaini et al.

                This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International license, which permits unrestricted use, distribution and reproduction in any medium provided that the original work is properly attributed.

                History
                : 10 December 2018
                : 10 October 2019
                : 28 October 2019
                Page count
                Figures: 53, Tables: 6, Equations: 464, References: 17, Pages: 54, Words: 00
                Funding
                Funded by: http://doi.org/10.13039/501100002915Fondation pour la Recherche Médicale (FRM)
                Award ID: DIC20161236442
                Funded by: European Commission's Brain Project
                Award ID: H2020-720270
                Funded by: Federation Hospitalo-Universitaire (FHU)
                Award ID: ANR-11-IDEX-0001-02
                Categories
                3
                Research Article: New Research
                Disorders of the Nervous System
                Custom metadata
                March/April 2020

                bifurcation analysis,depolarization block,dynamical systems theory,epilepsy,neural mass model,refractory status epilepticus

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