Normative high-frequency oscillation phase-amplitude coupling and effective connectivity under sevoflurane

Abstract

Resective surgery for pediatric drug-resistant focal epilepsy often requires extraoperative intracranial electroencephalography recording to accurately localize the epileptogenic zone. This procedure entails multiple neurosurgeries, intracranial electrode implantation and explantation, and days of invasive inpatient evaluation. There is a need for methods to reduce diagnostic burden and introduce objective epilepsy biomarkers. Our preliminary studies aimed to address these issues by using sevoflurane anesthesia to rapidly and reversibly activate intraoperative phase-amplitude coupling between delta and high-frequency activities, as well as high-frequency activity-based effective connectivity. Phase-amplitude coupling can serve as a proxy for spike-and-wave discharges, and effective connectivity describes the spatiotemporal dynamics of neural information flow among regions. Notably, sevoflurane activated these interictal electrocorticography biomarkers most robustly in areas whose resection led to seizure freedom. However, they were also increased in normative brain regions that did not require removal for seizure control. Before using these electrocorticography biomarkers prospectively to guide resection, we should understand their endogenous distribution and propagation pathways, at different anesthetic stages. In the current study, we highlighted the normative distribution of delta and high-frequency activity phase-amplitude coupling and effective connectivity under sevoflurane. Normative data was derived from nineteen patients, whose ages ranged from four to eighteen years and included eleven males. All achieved seizure control following focal resection. Electrocorticography was recorded at an isoflurane baseline, during stepwise increases in sevoflurane concentration, and also during extraoperative slow-wave sleep without anesthesia. Normative electrode sites were then mapped onto a standard cortical surface for anatomical visualization. Dynamic tractography traced white matter pathways that connected sites with significantly augmented biomarkers. Finally, we analyzed all sites --regardless of normal or abnormal status -- to determine whether sevoflurane-enhanced biomarker values could intraoperatively localize the epileptogenic sites. We found that normative electrocorticography biomarkers increased as a function of sevoflurane concentration, especially in bilateral frontal and parietal lobe regions (Bonferroni-corrected p-values <0.05). Callosal fibers directly connected homotopic Rolandic regions exhibiting elevated phase-amplitude coupling. The superior longitudinal fasciculus linked frontal and parietal association cortices showing augmented effective connectivity. Higher biomarker values, particularly at three to four volume percent sevoflurane, characterized epileptogenicity and seizure-onset zone status (Bonferroni-corrected p-values <0.05). Supplementary analysis showed that epileptogenic sites exhibited less augmentation in delta-based effective connectivity. This study helps clarify the normative distribution of, and plausible propagation pathways supporting, sevoflurane enhanced electrocorticographic biomarkers. Future work should confirm that sevoflurane-activated electrocorticography biomarkers can predict postoperative seizure outcomes in larger cohorts, to establish their clinical utility.