Functional connectivity applications in drug-resistant epilepsy: extending to higher frequencies

For patients with drug-resistant epilepsy (DRE), resective surgery is the most effective
treatment to achieve seizure relief. Since no single diagnostic test can delineate the
epileptogenic zone (EZ), most clinical teams rely on the seizure onset zone (SOZ)
identified with intracranial electroencephalography (iEEG). However, SOZ localisation
requires prolonged recordings, carries risks, and does not always predict surgical
success. This underscores the need for reliable interictal biomarkers to improve
presurgical evaluation. Epilepsy is progressively acknowledged as a network disease, and functional connectivity (FC) studies have highlighted the role of network hubs as potential surgical targets. Yet most studies have focused on conventional frequency bands, leaving higher frequencies (>80 Hz) underexplored, even though high-frequency oscillations (HFOs) are promising epileptogenicity markers. In this thesis, I extend interictal FC investigations at higher frequencies and assess their value in quantifying the epileptogenicity of different brain regions, identifying the EZ, and predicting surgical outcome in patients with DRE. I analyzed iEEG from 18 patients, computing FC in data segments with and without HFOs, using both directed and undirected techniques. Graph-theoretical metrics were compared inside and outside the surgical resection across patients, revealing reduced outward strength and clustering within epileptogenic areas, in all frequencies above beta. Moreover, machine learning models trained on local network properties localised epileptogenic tissue with up to 80% accuracy, while resection of “sink” nodes (outward strength < threshold) predicted outcome with up to 83% accuracy. In addition, I evaluated the temporal variability of FC in patients with multiple-night recordings, and showed that network measures remained stable across four different nights, at multiple levels of analysis. Collectively, these findings suggest that high-frequency interictal FC could be a robust and clinically valuable means of tracing epileptogenicity, and together with existing literature can lay the groundwork for the transition of FC-based biomarkers from research items to presurgical evaluation tools.