Neural mechanisms and modulations of epilepsy: from experimental and clinical data to computational modelling evidence

The neuronal synchronous discharging may cause an epileptic seizure. Currently, most of the studies conducted to investigate the mechanism of epilepsy are based on EEGs or functional magnetic resonance imaging (fMRI) recorded during the ictal discharging or the resting-state, and few studies have probed into the dynamic patterns during the inter-ictal discharging that are much easier to record in clinical applications. Here, we propose a time-varying network analysis based on adaptive directed transfer function to uncover the dynamic brain network patterns during the inter-ictal discharging. In addition, an algorithm based on the time-varying outflow of information derived from the network analysis is developed to detect the epileptogenic zone. The analysis performed revealed the time-varying network patterns during different stages of inter-ictal discharging; the epileptogenic zone was activated prior to the discharge onset then worked as the source to propagate the activity to other brain regions. Consistence between the epileptogenic zones detected by our proposed approach and the actual epileptogenic zones proved that time-varying network analysis could not only reveal the underlying neural mechanism of epilepsy, but also function as a useful tool in detecting the epileptogenic zone based on the EEGs in the inter-ictal discharging.

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.

The extensive cerebral cortex and subcortical structures are considered as the major regions related to the generalized epileptiform discharges in idiopathic generalized epilepsy. However, various clinical syndromes and electroencephalogram (EEG) signs exist across generalized seizures, such as the loss of consciousness during absence seizures (AS) and the jerk of limbs during myoclonic seizures (MS). It is presumed that various functional systems affected by discharges lead to the difference in syndromes of these seizures. Twenty epileptic patients with MS, 21 patients with AS, and 21 healthy controls were recruited in this study. The functional network connectivity was analyzed based on the resting-state functional magnetic resonance imaging scans. The statistical analysis was performed in three groups to assess the difference in the functional brain networks in two types of generalized seizures. Twelve resting-state networks were identified in three groups. Both patient groups showed common abnormalities, including decreased functional connectivity in salience network (SN), cerebellum network, and primary perceptional networks and decreased connection between SN and visual network, compared with healthy controls. Interestingly, the frontal part of high-level cognitive resting-state networks showed increased functional connectivity (FC) in patients with MS, but decreased FC in patients with AS. Moreover, patients with MS showed decreased negative connections between high-level cognitive networks and primary system. The common alteration in both patient groups, including SN, might reflect a similar mechanism associated with the loss of consciousness during generalized seizures. This study provided the evidence of brain network in generalized epilepsy to understand the difference between MS and AS.