Leveraging the Interictal Suppression Hypothesis to Define Epileptic Networks

Vanderbilt University, Nashville TN

Investigators

Abstract

PROJECT SUMMARY/ABSTRACT Epilepsy is a debilitating neurological disorder that affects 50 million people worldwide. Focal epilepsy is the most common form. For one third of patients, medications are insufficient to manage their seizures. Surgery can be curative, but highly depends on the clinical team’s ability to localize seizure origin to a specific volume of tissue deemed the seizure onset zone (SOZ). Even after receiving an invasive workup, where stereotactic electroencephalography (SEEG) leads are implanted intracranially to record seizure activity, 50% of patients continue to have seizures after surgery. This low rate of seizure freedom suggests that we may not be localizing the SOZ entirely and a need to examine the SOZ in relation to broader brain activity. Epilepsy has increasingly been studied as a network disease, which entails examining the physical and dynamic interactions between regions and how these relationships may be abnormal. Through studying the period between seizures (interictal period), our group as well as others observed directed inward connections from areas surrounding the SOZ that appear to decrease the SOZ’s activity. This led to the Interictal Suppression Hypothesis (ISH) which proposes that regions surrounding the SOZ are inhibiting seizure generation. However, it is unclear if seizure generation is related to a change in this inward connectivity. This proposal attempts to address this knowledge gap by examining networks as they evolve from the period between seizures to seizure generation. I specifically hypothesize that seizure generation coincides with a failure of interictal suppression, and that seizure severity is correlated with the degree suppression fails (Aim 1). I will use SEEG recordings from patients in Vanderbilt’s epilepsy monitoring unit to construct networks across four periods: interictal, pre-ictal (before seizure), ictal (seizure onset), and post-ictal (after seizure termination). Then, I will relate changes in SOZ connectivity to seizure spread, duration and clinical severity. In addition to studying network dynamics, I will examine whether a specific region in the brain is directing this activity into the SOZ or if this is a diffuse phenomenon. Given its relevance in seizure propagation, one such region may be the thalamus. I propose to use single pulse stimulation to relate thalamic activity to inward connectivity of the SOZ. I specifically hypothesize that the thalamus will be the largest source of inward connectivity to the SOZ, and that when stimulating the thalamus, SOZ activity will decrease (Aim 2). This proposed fellowship will provide training in a collaborative research atmosphere with expert mentors. Research training will be conducted in an environment that combines an academic medical center with a level 4 epilepsy center, world class research institute, and engineering all on one campus. Studying how epilepsy networks evolve near seizure generation may improve surgical resection by including areas that drive network changes or may improve neuromodulation by targeting areas for stimulation that can maintain the seizure free period.