Computational Modeling of Seizure Dynamics Using Coupled Neuronal Networks: Factors Shaping Epileptiform Activity

Abstract

Epileptic seizure dynamics span multiple scales in space and time. Understanding seizure mechanisms requires identifying the relations between seizure components within and across these scales, together with the analysis of their dynamical repertoire. Mathematical models have been developed to reproduce seizure dynamics across scales ranging from the single neuron to the neural population. In this study, we develop a network model of spiking neurons and systematically investigate the conditions, under which the network displays the emergent dynamic behaviors known from the Epileptor, which is a well-investigated abstract model of epileptic neural activity. This approach allows us to study the biophysical parameters and variables leading to epileptiform discharges at cellular and network levels. Our network model is composed of two neuronal populations, characterized by fast excitatory bursting neurons and regular spiking inhibitory neurons, embedded in a common extracellular environment represented by a slow variable. By systematically analyzing the parameter landscape offered by the simulation framework, we reproduce typical sequences of neural activity observed during status epilepticus. We find that exogenous fluctuations from extracellular environment and electro-tonic couplings play a major role in the progression of the seizure, which supports previous studies and further validates our model. We also investigate the influence of chemical synaptic coupling in the generation of spontaneous seizure-like events. Our results argue towards a temporal shift of typical spike waves with fast discharges as synaptic strengths are varied. We demonstrate that spike waves, including interictal spikes, are generated primarily by inhibitory neurons, whereas fast discharges during the wave part are due to excitatory neurons. Simulated traces are compared with in vivo experimental data from rodents at different stages of the disorder. We draw the conclusion that slow variations of global excitability, due to exogenous fluctuations from extracellular environment, and gap junction communication push the system into paroxysmal regimes. We discuss potential mechanisms underlying such machinery and the relevance of our approach, supporting previous detailed modeling studies and reflecting on the limitations of our methodology.

Author Summary

Neurons communicate via different types of synapses on very fast time scales. The combination of hundred thousand of such interconnected cells within a fluctuating extracellular environment forms a complex network that gives rise to function and behavior via the formation of dynamical patterns of activity. In the context of epilepsy, the functional properties of the network at the source of a seizure are disrupted by a possibly large set of factors at the cellular and molecular levels. It is therefore needed to sacrifice some biological accuracy to model seizure dynamics in favor of macroscopic realizations. Here, we present a neuronal network model that convenes both neuronal and network representations with the goal to describe brain dynamics involved in the development of epilepsy. We compare our modeling results with animal in vivo recordings to validate our approach in the context of seizures. Such system-level methodology has significant bearing in understanding neuronal network dynamics that entangle multiple synaptic and extracellular modalities.