Combined Effects of Feedforward Inhibition and Excitation in Thalamocortical Circuit on the Transitions of Epileptic Seizures

Abstract

The mechanisms underlying electrophysiologically observed two-way transitions between absence and tonic-clonic epileptic seizures in cerebral cortex remain unknown. The interplay within thalamocortical network is believed to give rise to these epileptic multiple modes of activity and transitions between them. In particular, it is thought that in some areas of cortex there exists feedforward inhibition from specific relay nucleus of thalamus (TC) to inhibitory neuronal population (IN) which has even more stronger functions on cortical activities than the known feedforward excitation from TC to excitatory neuronal population (EX). Inspired by this, we proposed a modified computational model by introducing feedforward inhibitory connectivity within thalamocortical circuit, to systematically investigate the combined effects of feedforward inhibition and excitation on transitions of epileptic seizures. We first found that the feedforward excitation can induce the transition from tonic oscillation to spike and wave discharges (SWD) in cortex, i.e., the epileptic tonic-absence seizures, with the fixed weak feedforward inhibition. Thereinto, the phase of absence seizures corresponding to strong feedforward excitation can be further transformed into the clonic oscillations with the increasing of feedforward inhibition, representing the epileptic absence-clonic seizures. We also observed the other fascinating dynamical states, such as periodic 2/3/4-spike and wave discharges, reversed SWD and clonic oscillations, as well as saturated firings. More importantly, we can identify the stable parameter regions representing the tonic-clonic oscillations and SWD discharges of epileptic seizures on the 2-D plane composed of feedforward inhibition and excitation, where the physiologically plausible transition pathways between tonic-clonic and absence seizures can be figured out. These results indicate the functional role of feedforward pathways in controlling epileptic seizures and the modified thalamocortical model may provide a guide for future efforts to mechanistically link feedforward pathways in the pathogenesis of epileptic seizures.

Robust closed-loop control of spike-and-wave discharges in a thalamocortical computational model of absence epilepsy

“…(1)) of absence epilepsy by using bifurcation analysis. In order to understand the mechanisms of absence seizures including SWDs, many studies have been conducted on how the model parameters affect the states and their transitions of the system, such as the input constant parameter 61 , direct PY-to-TC excitation c te and feedforward TC-to-PY inhibition c et 62 , and the feedforward inhibition and excitation from TC to cortex 63 . Motivated by the recent experimental results about the bidirectional communications of absence seizures in thalamocortical circuit 32,54,55 , we here focus on the top-down PY-to-TC excitation c te and the feedforward RE-to-TC inhibition c tr .…”

“…It will also be a big challenge to perform integrated qualitative and quantitative analyses of a multi-level computational model of epilepsy that reproduces various brain activities. Second, there are also many paths regulating the genesis and evolution of seizures in the cortico-thalamo-cortical loops 45,46,63,73–75 , and we have only investigated mechanisms of the top-town PY-to-TC excitation and feedforward RE-to-TC inhibition. The next step study would consider more comprehensive dynamical and physiological mechanisms of epileptic seizures with multiple changing parameters, and also other target brain regions for seizure control 45,46 .…”

Dynamic Transitions of Epilepsy Waveforms Induced by Astrocyte Dysfunction and Electrical Stimulation

“…As one of the representatives of the neural field model, Taylor model can perfectly simulate the 2-4 Hz SWD that characterizes absence seizures [37,38]. Recently, scholars have proposed many improved models to study absence epilepsy [39,40]. For examples, Fan et al investigated the combined effects of feedforward inhibition and excitation in thalamocortical circuit on the transition behaviors of epileptic seizures by introducing the feedforward excitation from thalamic relay nucleus to excitatory pyramidal neuronal into the thalamocortical network [39].…”

“…Recently, scholars have proposed many improved models to study absence epilepsy [39,40]. For examples, Fan et al investigated the combined effects of feedforward inhibition and excitation in thalamocortical circuit on the transition behaviors of epileptic seizures by introducing the feedforward excitation from thalamic relay nucleus to excitatory pyramidal neuronal into the thalamocortical network [39]. Liu et al constructed another modified thalamocortical network by considering a disinhibition neural population [40].…”

“…Beverlin et al showed that feedforward inhibition from thalamic relay nucleus (TC) to inhibitory interneuron has even more stronger functions on the cortex than the feedforward excitation from TC to excitatory pyramidal neuronal (PY) [46]. To the best of our knowledge, although Fan et al and Liu et al had considered the above-mentioned physiological phenomena in their computational models separately [39,40], no scholars have considered these two facts at the same time. Motivated by these, we propose a more comprehensive model to systematically investigate the effects of important model parameters on the transition behaviors of epileptic seizures including tonic-clonic and absence seizures.…”