Current Conceptual Understanding of the Epileptogenic Network From Stereoelectroencephalography-Based Connectivity Inferences

Abstract

Localization of the epileptogenic zone (EZ) is crucial in the surgical treatment of focal epilepsy. Recently, EEG studies have revealed that the EZ exhibits abnormal connectivity, which has led investigators to now consider connectivity as a biomarker to localize the EZ. Further, abnormal connectivity of the EZ may provide an explanation for the impact of focal epilepsy on more widespread brain networks involved in typical cognition and development. Stereo-electroencephalography (sEEG) is a well-established method for localizing the EZ that has recently been applied to examine altered brain connectivity in epilepsy. In this manuscript, we review recent computational methods for identifying the EZ using sEEG connectivity. Findings from previous sEEG studies indicate that during interictal periods, the EZ is prone to seizure generation but concurrently receives inward connectivity preventing seizures. At seizure onset, this control is lost, allowing seizure activity to spread from the EZ. Regulatory areas within the EZ may be important for subsequently ending the seizure. After the seizure, the EZ appears to regain its influence on the network, which may be how it is able to regenerate epileptiform activity. However, more research is needed on the dynamic connectivity of the EZ in order to build a biomarker for EZ localization. Such a biomarker would allow for patients undergoing sEEG to have electrode implantation, localization of the EZ, and resection in a fraction of the time currently needed, preventing patients from having to endure long hospital stays and induced seizures.

MEG abnormalities and mechanisms of surgical failure in neocortical epilepsy

“…Our third mechanism hypothesized that if strong cortical abnormalities existed beyond the proposed resection site, a localized resection may not fully suppress seizures postsurgically. Widespread abnormalities have been reported previously using diffusion MRI data in epilepsy, 36,37 with some studies attributing widespread abnormalities to an underlying epileptogenic network facilitating the spread of seizures to distant regions 7,38 . Our marker of surgical failure may reflect this epileptogenic network.…”

Source-sink connectivity: A novel interictal EEG marker for seizure localization

“…The source-sink hypothesis is supported by clinical evidence based on the levels of glutamate and glutamate receptors in the brain [55][56][57][58] and iEEG studies that have demonstrated strong inward (inhibitory) connectivity to the EZ regions during rest. 59,60,63,64 We evaluated the predictive value of the SSI by a) rating the correspondence between the hypothesized CA-EZ and regions with high SSIs and b) building a random forest to model the probability of a successful surgery as a function of the source-sink metrics, and compared the performance to that of HFOs, a commonly used interictal iEEG feature. The analysis was performed on data from 65 patients treated across 6 clinical centers.…”

“…Several studies have demonstrated a high inward directed influence to the EZ at rest. 55,[67][68][69] In a recent study Narasimhan et al 67 stated that high inward connectivity may reflect inhibitory input from other regions to prevent the onset and spread of seizure activity, but the direction of these signals may flip when seizure activity begins. This is supported by iEEG studies in neocortical epilepsy demonstrating functional isolation of epileptogenic areas at rest 70,71 and that increased synchronization in seizure-onset regions may be suggestive of an inhibitory surround.…”

A game theory based analysis of network connectivity reveals that state transition is crucial for epilepsy surgery outcome prediction

“…We used a game rule 11 (maximin) to calculate gains across scenarios (random epochs) that represent possible game states, assuming that EN nodes would score better than NN nodes. We expected that far from seizures, EN nodes, which lack part of the regulatory feedback from NN 12 , would be more active but unable to turn the game balance (Figure 1), due to their limited number -the EN is smaller and surrounded by NN. During seizure time, conversely, both EN and NN should display significant connectivity change, the NN counteracting or falling under the influence of the EN (seizure propagation).…”