Dataset Information

Minimal model of interictal and ictal discharges "Epileptor-2".

ABSTRACT: Seizures occur in a recurrent manner with intermittent states of interictal and ictal discharges (IIDs and IDs). The transitions to and from IDs are determined by a set of processes, including synaptic interaction and ionic dynamics. Although mathematical models of separate types of epileptic discharges have been developed, modeling the transitions between states remains a challenge. A simple generic mathematical model of seizure dynamics (Epileptor) has recently been proposed by Jirsa et al. (2014); however, it is formulated in terms of abstract variables. In this paper, a minimal population-type model of IIDs and IDs is proposed that is as simple to use as the Epileptor, but the suggested model attributes physical meaning to the variables. The model is expressed in ordinary differential equations for extracellular potassium and intracellular sodium concentrations, membrane potential, and short-term synaptic depression variables. A quadratic integrate-and-fire model driven by the population input current is used to reproduce spike trains in a representative neuron. In simulations, potassium accumulation governs the transition from the silent state to the state of an ID. Each ID is composed of clustered IID-like events. The sodium accumulates during discharge and activates the sodium-potassium pump, which terminates the ID by restoring the potassium gradient and thus polarizing the neuronal membranes. The whole-cell and cell-attached recordings of a 4-AP-based in vitro model of epilepsy confirmed the primary model assumptions and predictions. The mathematical analysis revealed that the IID-like events are large-amplitude stochastic oscillations, which in the case of ID generation are controlled by slow oscillations of ionic concentrations. The IDs originate in the conditions of elevated potassium concentrations in a bath solution via a saddle-node-on-invariant-circle-like bifurcation for a non-smooth dynamical system. By providing a minimal biophysical description of ionic dynamics and network interactions, the model may serve as a hierarchical base from a simple to more complex modeling of seizures.

SUBMITTER: Chizhov AV

PROVIDER: S-EPMC6005638 | biostudies-literature | 2018 May

REPOSITORIES: biostudies-literature

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Minimal model of interictal and ictal discharges "Epileptor-2".

Chizhov Anton V AV Zefirov Artyom V AV Amakhin Dmitry V DV Smirnova Elena Yu EY Zaitsev Aleksey V AV

PLoS computational biology 20180531 5

Seizures occur in a recurrent manner with intermittent states of interictal and ictal discharges (IIDs and IDs). The transitions to and from IDs are determined by a set of processes, including synaptic interaction and ionic dynamics. Although mathematical models of separate types of epileptic discharges have been developed, modeling the transitions between states remains a challenge. A simple generic mathematical model of seizure dynamics (Epileptor) has recently been proposed by Jirsa et al. (2 ...[more]

PMID: 29851959

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Project description:In organotypic hippocampal slice cultures, principal neurons form aberrant excitatory connections with other principal cells in response to slicing induced deafferentation, similar to mechanisms underlying epileptogenesis in posttraumatic epilepsy. To investigate the consequences of this synaptogenesis, the authors recorded field-potential activity from area CA3 during perfusion with the complete growth medium used during incubation. At 7 days in vitro, slice cultures only displayed multiunit activity. At 14 days in vitro, the majority displayed population bursts reminiscent of interictal-like spikes, but sustained synchronous activity was rare. Band-pass filtering of interictal discharges revealed fast ripple-like complexes, similar to in vivo recordings. Spontaneous ictal-like activity became progressively more prevalent with age: at 21 days in vitro, 50% of organotypic hippocampal slice cultures displayed long-lasting, ictal-like discharges that could be suppressed by phenytoin, whereas interictal activity was not suppressed. The fraction of cultures displaying ictal events continually increased with incubation time. Quantification of population spike activity throughout epileptogenesis using automatic detection and clustering algorithms confirmed the appearance of interictal-like activity before ictal-like discharges and also revealed high-frequency pathologic multiunit activity in slice cultures at 14 to 17 days in vitro. These experiments indicate that interictal-like spikes precede the appearance of ictal-like activity in a reduced in vitro preparation. Epileptiform activity in cultures resembled in vivo epilepsy, including sensitivity to anticonvulsants and steadily increasing seizure incidence over time, although seizure frequency and rate of epileptogenesis were higher in vitro. Organotypic hippocampal slice cultures comprise a useful model system for investigating mechanisms of epileptogenesis as well as developing antiepileptic and antiepileptogenic drugs.

Project description:ObjectiveThis study was undertaken to evaluate the influence that subject-specific factors have on intracranial interictal epileptiform discharge (IED) rates in persons with refractory epilepsy.MethodsOne hundred fifty subjects with intracranial electrodes performed multiple sessions of a free recall memory task; this standardized task controlled for subject attention levels. We utilized a dominance analysis to rank the importance of subject-specific factors based on their relative influence on IED rates. Linear mixed-effects models were employed to comprehensively examine factors with highly ranked importance.ResultsAntiseizure medication (ASM) status, time of testing, and seizure onset zone (SOZ) location were the highest-ranking factors in terms of their impact on IED rates. The average IED rate of electrodes in SOZs was 34% higher than the average IED rate of electrodes outside of SOZs (non-SOZ; p < .001). However, non-SOZ electrodes had similar IED rates regardless of the subject's SOZ location (p = .99). Subjects on older generation (p < .001) and combined generation (p < .001) ASM regimens had significantly lower IED rates relative to the group taking no ASMs; newer generation ASM regimens demonstrated a nonsignificant association with IED rates (p = .13). Of the ASMs included in this study, the following ASMs were associated with significant reductions in IED rates: levetiracetam (p < .001), carbamazepine (p < .001), lacosamide (p = .03), zonisamide (p = .01), lamotrigine (p = .03), phenytoin (p = .03), and topiramate (p = .01). We observed a nonsignificant association between time of testing and IED rates (morning-afternoon p = .15, morning-evening p = .85, afternoon-evening p = .26).SignificanceThe current study ranks the relative influence that subject-specific factors have on IED rates and highlights the importance of considering certain factors, such as SOZ location and ASM status, when analyzing IEDs for clinical or research purposes.

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Minimal model of interictal and ictal discharges "Epileptor-2".

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Minimal model of interictal and ictal discharges "Epileptor-2".

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