Cross-Frequency Coupling in Childhood Absence Epilepsy

Objective: Absence seizures are the prototypic primarily generalized seizures, but there is incomplete understanding regarding their generation and maintenance. A core network for absence seizures has been defined, including focal cortical and thalamic regions that have frequency-dependent interactions. The purpose of this study was to investigate within-frequency coupling and cross-frequency coupling (CFC) during human absence seizures, to identify key regions (hubs) within the absence network that contribute to propagation and maintenance. Methods: Thirteen children with new-onset and untreated childhood absence epilepsy had over 60 typical absence seizures during both electroencephalography-functional magnetic resonance imaging (fMRI) and magnetoencephalography (MEG) recordings. The spatial map of the ictal network was defined using fMRI and used as prior information for MEG connectivity. A multilayer network approach was used to investigate within-frequency coupling and CFC for canonical frequency bands. A rigorous null-modeling approach was used to determine connections outside the noise floor. Results: Strong coupling between beta and gamma frequencies, within the left frontal cortex, and between the left frontal and right parietal regions was observed. There was also strong connectivity between left frontal and right parietal nodes within the gamma band. Multilayer versatility analysis identified a cluster of network hubs in the left frontal region. Interpretation: Cortical regions commonly identified as being critical for absence seizure generation (frontal cortex, precuneus) have strong CFC and within-frequency coupling between beta and gamma bands. As nonpharmacologic treatments, such as neuromodulation, become available for generalized epilepsies, detailed mechanistic understanding of how "diffuse" seizures are generated and maintained will be necessary to provide optimal outcomes.