Functional connectivity (FC) analyses of intracranial EEG (iEEG) signals can potentially improve the mapping of epileptic networks in drug-resistant focal epilepsy. However, it remains unclear whether FC-based metrics provide additional value beyond established epilepsy biomarkers such as epileptic spikes and high-frequency oscillations (HFOs). Using interictal iEEG data from 26 patients, we estimated FC across eight frequency bands (4-290 Hz) using amplitude envelope correlation (AEC) and phase locking value (PLV). From the resulting FC-matrices, we estimated two graph metrics each to derive 32 FC-based features. We also extracted features related to spikes, HFOs, and power spectral densities (PSD). A trained support vector machine (SVM) classifier predicted seizure onset zones (SOZs) with an area under the ROC curve (AUC) of 0.91 for node-level 4-fold cross-validation (CV), 0.69 for patient-level 4-fold CV, and 0.73 for patient-level leave-one-out CV. Notably, gamma-band graph features from AECs outperformed spikes and HFOs in SOZ prediction when using an equivalent number of features. Our results strongly suggest that AEC-based features may provide more information about epileptogenicity compared to PLV-based features. Furthermore, machine learning provides a robust approach for identifying useful FC-based features and integrating information from putative biomarkers of epilepsy to better localize epileptogenic networks.

Biomarkers; Epileptogenicity; Functional connectivity; Intracranial EEG; Machine learning; Seizure onset zone.

Declarations. Competing interests: The authors declare no competing interests. Ethics statement: This study was performed in compliance with the guidelines and regulations of a study protocol approved by the Institutional Review Board of the Medical College of Wisconsin (PRO15813). Informed consent was obtained from all patients and/or their legal guardians.