SEEG Functional Connectivity Measures to Identify Epileptogenic Zones

Abstract

Background and Objective:Functional connectivity (FC) measures can be used to differentiate epileptogenic zones (EZs) from non-EZs in patients with medically refractory epilepsy. However, little work has been done to evaluate stability of stereoelectroencephalography (SEEG) FC measures over time and their relationship with anti-seizure medication (ASM) use – a critical confounder in epilepsy FC studies to date. In this study, we aim to answer the following questions: 1) are SEEG FC measures stable over time, 2) are they influenced by ASMs, and 3) are they impacted by patient data collection state?Methods:In 32 patients with medically-refractory focal epilepsy, we collected a single two-minute prospective SEEG resting-state (awake, eyes closed) data set, and consecutive two-minute retrospective pseudo-rest (awake, eyes open) data sets for days 1-7 post-implantation. ASM dosages were recorded for days 1-7 post-implantation and drug load score (DLS) per day was calculated to standardize and compare across patients. FC was evaluated using directed and nondirected measures. Standard clinical interpretation of ictal SEEG was used to classify brain regions as EZs and non-EZs.Results:Over seven days, presumed EZs consistently had higher FC than non-EZs when using Between Imaginary Coherence (ImCoh) and Partial Directed Coherence (PDC) Inward strength, without accounting for DLS. These measures were demonstrated to be stable over a short-term period of three consecutive days with the same DLS. Between ImCoh FC differences between EZs and non-EZs were reduced with DLS decreases, whereas other measures were not affected by DLS. FC differences between EZs and non-EZs were seen during both resting-state and pseudo-rest conditions; ImCoh values were strongly correlated between the two conditions, whereas PDC values were not.Discussion:Inward and non-directed SEEG FC is higher in presumed EZs versus non-EZs, and measures are stable over time. However, certain measures may be impacted by ASM dose, as Between ImCoh differences between EZs and non-EZs are less pronounced with lower doses, and other measures such as PDC are poorly correlated across recording conditions. These findings allow novel insight into how SEEG FC measures may aid surgical localization, and how they are influenced by ASMs and other factors.

Interictal Functional Connectivity in Focal Refractory Epilepsies Investigated by Intracranial EEG

“…However, Kramer and colleagues demonstrated the emergence of stable network pattern across long-term recordings . Similarly, others studies have reported stability of the functional connectivity results across days of intracranial EEG recordings in patients with epilepsy Jiang et al, 2022;Mormann et al, 2000;Paulo et al, 2022;Schevon et al, 2007). This result strengthens the confidence in the use of connectivity data for EZ delineation purpose in practice.…”

“…Notably, the model performed equally well in the subset of patients who were seizure-free after surgery (higher confidence in the exact definition of the epileptogenic zone). Recently, Paulo and colleagues investigated the impact of time in EMU, changes in antiseizures medications doses, seizure burden, and differences between eyes-closed formal resting-state, and eyes-open pseudoresting states on interictal SEEG FC (imaginary coherence and partial directed coherence computed in the alpha band) (Paulo et al, 2022). They confirmed that non-directed and inward connectivity measures are higher in EZ compared to NIZ, but most importantly demonstrated that: 1) FC measures are stable over time; 2) FC measures are not influenced by the seizure burden; 3) antiseizure medication dose may influenced some FC measures (imaginary coherence with smaller difference between EZ and NIZ in case of smaller dose of antiseizure medication) but not some other (partial directed coherence); 4) the type of resting-state (formal eyes-closed or not) may influence some FC measures (partial directed coherence with higher difference between EZ and NIZ during formal eyes closed resting state) but not some other (imaginary coherence).…”

“…This directionality could be estimated from causality method (Granger causality and its extensions as partial directed coherence (PDC), directed transfer function (DTF)) or using delays and/or asymmetry of non-linear correlation values. The literature in the domain is not unanimous with some studies suggesting a leading role (higher out-connectivity) of the epileptogenic zone (Bettus et al, 2011;Lagarde et al, 2018;Varotto et al, 2012) and some others suggesting a higher inward connectivity toward the epileptogenic zone (Jiang et al, 2022;Paulo et al, 2022;Vlachos et al, 2017). Moreover, using CCEPs, Parker and colleagues highlighted the higher outward connectivity of the epileptogenic zone (Parker et al, 2018) whereas Guo and colleagues did not find significant difference between inward and outward connectivity of the epileptogenic zone (Guo et al, 2020).…”

“…These discrepancies could be due to variable methods used for connectivity estimation. To be noted, some studies using the same method, namely the partial directed coherence (PDC), have opposite results Paulo et al, 2022;Varotto et al, 2012). Another explanation could be the impact of interictal spikes on connectivity directionality, because some authors included spikes in their analyses (Bettus et al, 2011;Lagarde et al, 2018;Varotto et al, 2012) and others did not Paulo et al, 2022).…”

“…To be noted, some studies using the same method, namely the partial directed coherence (PDC), have opposite results Paulo et al, 2022;Varotto et al, 2012). Another explanation could be the impact of interictal spikes on connectivity directionality, because some authors included spikes in their analyses (Bettus et al, 2011;Lagarde et al, 2018;Varotto et al, 2012) and others did not Paulo et al, 2022). Therefore, despite the relatively low effect of epileptic spikes on the overall connectivity value Jiang et al, 2022;Park and Madsen, 2018), it is possible that spikes affect the directionality of connectivity (Karunakaran et al, 2017).…”