The Interictal Suppression Hypothesis in Focal Epilepsy: Electrographic and Structural Evaluation

Abstract

Why are people with focal epilepsy not constantly seizing? Previous molecular work has implicated gamma-aminobutyric acid balance as integral to seizure generation and termination, but is the high-level distributed brain network involved in suppressing seizures? Recent intracranial electrographic evidence has suggested that seizure onset zones have an increased inward connectivity. Accordingly, we hypothesize that seizure onset zones are actively suppressed by the rest of the brain network during interictal states. We tested this hypothesis on 81 subjects with drug resistant focal epilepsy undergoing presurgical evaluation. We utilized intracranial electrographic resting-state and neurostimulation recordings to evaluate the network connectivity of seizure onset, propagative, and non-involved regions. We then utilized diffusion imaging to acquire estimates of white matter connectivity to evaluate structure-function coupling effects on connectivity findings. Finally, using our observations, we generated a resting-state classification model to assist clinicians in detecting seizure onset and propagative zones without the need for multiple ictal recordings. Our findings indicate that seizure onset and propagative zones demonstrate markedly increased inward connectivity and decreased outward connectivity on both resting-state and neurostimulation analyses. When controlling for distance between regions, the difference between inward vs. outward connectivity remained stable up to 80 mm between brain connections. Structure-function coupling analyses revealed that seizure onset zones exhibit abnormally enhanced coupling (hypercoupling) of surrounding regions compared to presumably healthy tissue. Using these observations, our classification models achieved a maximum held-out testing set accuracy of 92.0{+/-}2.2%. These results indicate that seizure onset zones are actively segregated and suppressed by a widespread brain network. Furthermore, this electrographically observed functional suppression is disproportionate to any observed structural connectivity alterations of the seizure onset zones. These findings have implications for the identification of seizure onset zones using only brief resting-sate recordings to reduce patient morbidity and augment the presurgical evaluation of drug resistant epilepsy. Furthermore, testing of the interictal suppression hypothesis can provide insight into potential new resective, ablative, and neuromodulation approaches to improve surgical success rates in those suffering from drug resistant focal epilepsy.