Multiple Oscillatory Push–Pull Antagonisms Constrain Seizure Propagation

Objective: Drug-resistant focal epilepsy is widely recognized as a network disease in which epileptic seizure propagation is likely coordinated by different neuronal oscillations such as low-frequency activity (LFA), high-frequency activity (HFA), or low-to-high cross-frequency coupling. However, the mechanism by which different oscillatory networks constrain the propagation of focal seizures remains unclear. Methods: We studied focal epilepsy patients with invasive electrocorticography (ECoG) recordings and compared multilayer directional network interactions between focal seizures either with or without secondary generalization. Within-frequency and cross-frequency directional connectivity were estimated by an adaptive directed transfer function and cross-frequency directionality, respectively. Results: In the within-frequency epileptic network, we found that the seizure onset zone (SOZ) always sent stronger information flow to the surrounding regions, and secondary generalization was accompanied by weaker information flow in the LFA from the surrounding regions to SOZ. In the cross-frequency epileptic network, secondary generalization was associated with either decreased information flow from surrounding regions’ HFA to SOZ's LFA or increased information flow from SOZ's LFA to surrounding regions’ HFA. Interpretation: Our results suggest that the secondary generalization of focal seizures is regulated by numerous within- and cross-frequency push–pull dynamics, potentially reflecting impaired excitation–inhibition interactions of the epileptic network. ANN NEUROL 2019;86:683–694.