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.

Author summary

In pathological conditions of epilepsy, the functioning of the neural network crucially depends on the ionic concentrations inside and outside neurons. A number of factors that affect neuronal activity is large. That is why the development of a minimal model that reproduces typical seizures could structure further experimental and analytical studies of the pathological mechanisms. Here, on a base of known biophysical models, we present a simple population-type model that includes only four principal variables, the extracellular potassium concentration, the intracellular sodium concentration, the membrane potential and the synaptic resource diminishing due to short-term synaptic depression. A simple modeled neuron is used as an observer of the population activity. We validate the model assumptions with in vitro experiments. Our model reproduces ictal and interictal events, where the latter result in bursts of spikes in single neurons, and the former represent the cluster of spike bursts. Mathematical analysis reveals that the bursts are spontaneous large-amplitude oscillations, which may cluster after a saddle-node on invariant circle bifurcation in the pro-epileptic conditions. Our consideration has significant bearing in understanding pathological neuronal network dynamics.