Structural network-specific effect of extreme capsule stimulation for drug-resistant focal epilepsy

Treatment for drug-resistant epilepsy in poor candidates for resection surgeries remains challenging. The prevailing deep brain stimulation of subcortical nuclei is effective but exhibits heterogeneous efficacy and unpredictable side effects. Therefore, the investigation of novel deep brain stimulation targets is of paramount importance. Here, we focused on the unique structure known as the extreme capsule (EC), which is a 'butterfly'-like structure passing through the uncinate fasciculus, the inferior fronto-occipital fasciculus and the convergence of the short association fibres connecting to the insula. We investigated the modulatory effect of EC stimulation in 11 drug-resistant epilepsy patients (mean age, 28 years; eight males and three females) who underwent stereo-electroencephalography as part of presurgical evaluation. One electrode was extended to the EC ipsilateral to the presumed seizure onset zone. Structural connectivity to the EC derived from structural human connectome data (n = 1065) was estimated to compare with the effective connectivity to the EC using single-pulse stimulation at 1 Hz during the resting state. To assess the modulatory effect of EC stimulation, we used stepwise incremental stimulation ranging from 5 to 145 Hz in a cyclical pattern. We evaluated how neural activity across distributed cortical areas synchronized with EC stimulation frequencies, in addition to the changes in interictal epileptiform discharges and ripples during the stimulation period compared with the baseline. Moreover, 1 Hz burst stimulation mode was applied to refine the stimulation protocol further. We showed that the EC effective connectivity aligned well with the EC structural network. We also observed that the synchronized and desynchronized modulatory effect of EC stimulation was frequency specific across all the patients. Most importantly, we found that the modulatory effect of EC stimulation was constrained by its structural connectivity. Specifically, high-frequency stimulation of the EC significantly suppressed the epileptic discharges in the ipsilateral orbitofrontal lobe, occipital gyrus, inferior frontal gyrus, insula and temporal pole, which were inside the EC structural network rather than outside it (P < 0.001). Of note, EC 1 Hz burst stimulation demonstrated a comparable inhibitory efficacy to conventional high-frequency stimulation (ANOVA, F = 5.331, P < 0.001). This proof-of-concept study demonstrates that the EC is a promising deep brain stimulation target for treating substantial focal epilepsy with seizure originating from EC structurally connected cortex. It also demonstrates the feasibility of transforming knowledge of white matter node stimulation for seizures originating from its physically connected cortex and offers a promising therapeutic approach using alternative stimulation methods.