{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,6,24]],"date-time":"2026-06-24T05:50:18Z","timestamp":1782280218340,"version":"3.54.5"},"posted":{"date-parts":[[2025,3,20]]},"group-title":"Neuroscience","reference-count":140,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2025,3,20]],"date-time":"2025-03-20T00:00:00Z","timestamp":1742428800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/www.biorxiv.org\/about\/FAQ#license"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2025,3,19]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>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.<\/jats:p>\n                <jats:p>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 \u2014regardless of normal or abnormal status \u2014 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 &lt;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 &lt;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.<\/jats:p>","DOI":"10.1101\/2025.03.18.644050","type":"posted-content","created":{"date-parts":[[2025,3,23]],"date-time":"2025-03-23T01:33:31Z","timestamp":1742693611000},"source":"Crossref","is-referenced-by-count":0,"title":["Normative high-frequency oscillation phase-amplitude coupling and effective connectivity under sevoflurane"],"prefix":"10.64898","author":[{"given":"Ethan","family":"Firestone","sequence":"first","affiliation":[{"name":"Department of Pediatrics, Children\u2019s Hospital of Michigan, Detroit Medical Center, Wayne State University, Detroit, Michigan, 48201, USA"},{"name":"Department of Physiology, Wayne State University, Detroit, Michigan 48201, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hiroshi","family":"Uda","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Children\u2019s Hospital of Michigan, Detroit Medical Center, Wayne State University, Detroit, Michigan, 48201, USA"},{"name":"Department of Neurosurgery, Osaka Metropolitan University Graduate School of Medicine, Osaka, 5458585, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Naoto","family":"Kuroda","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Children\u2019s Hospital of Michigan, Detroit Medical Center, Wayne State University, Detroit, Michigan, 48201, USA"},{"name":"Department of Epileptology, Tohoku University Graduate School of Medicine, Sendai, 9808575, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kazuki","family":"Sakakura","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Children\u2019s Hospital of Michigan, Detroit Medical Center, Wayne State University, Detroit, Michigan, 48201, USA"},{"name":"Department of Neurosurgery, University of Tsukuba, Tsukuba, Ibaraki, 3058575, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Masaki","family":"Sonoda","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Children\u2019s Hospital of Michigan, Detroit Medical Center, Wayne State University, Detroit, Michigan, 48201, USA"},{"name":"Department of Neurosurgery, Yokohama City University, Yokohama, Kanagawa, 2360004, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Riyo","family":"Ueda","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Children\u2019s Hospital of Michigan, Detroit Medical Center, Wayne State University, Detroit, Michigan, 48201, USA"},{"name":"Department of Epileptology, National Center Hospital, National Center of Neurology and Psychiatry, Tokyo, 1878551, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yu","family":"Kitazawa","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Children\u2019s Hospital of Michigan, Detroit Medical Center, Wayne State University, Detroit, Michigan, 48201, USA"},{"name":"Department of Neurology and Stroke Medicine, Yokohama City University, Yokohama, Kanagawa, 2360004, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Min-Hee","family":"Lee","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Children\u2019s Hospital of Michigan, Detroit Medical Center, Wayne State University, Detroit, Michigan, 48201, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeong-Won","family":"Jeong","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Children\u2019s Hospital of Michigan, Detroit Medical Center, Wayne State University, Detroit, Michigan, 48201, USA"},{"name":"Department of Neurology, Children\u2019s Hospital of Michigan, Detroit Medical Center, Wayne State University, Detroit, Michigan, 48201, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aimee F.","family":"Luat","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Children\u2019s Hospital of Michigan, Detroit Medical Center, Wayne State University, Detroit, Michigan, 48201, USA"},{"name":"Department of Neurology, Children\u2019s Hospital of Michigan, Detroit Medical Center, Wayne State University, Detroit, Michigan, 48201, USA"},{"name":"Department of Pediatrics, Central Michigan University, Mt. Pleasant, Michigan, 48858, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael J.","family":"Cools","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery, Children\u2019s Hospital of Michigan, Detroit Medical Center, Detroit, Michigan, 48201, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sandeep","family":"Sood","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery, Children\u2019s Hospital of Michigan, Detroit Medical Center, Detroit, Michigan, 48201, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8391-4067","authenticated-orcid":false,"given":"Eishi","family":"Asano","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Children\u2019s Hospital of Michigan, Detroit Medical Center, Wayne State University, Detroit, Michigan, 48201, USA"},{"name":"Department of Neurology, Children\u2019s Hospital of Michigan, Detroit Medical Center, Wayne State University, Detroit, Michigan, 48201, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2026041200170094000_2025.03.18.644050v1.1","doi-asserted-by":"crossref","first-page":"384","DOI":"10.1016\/j.seizure.2021.07.010","article-title":"Intellectual outcome from 1 to 5 years after epilepsy surgery in 81 children and adolescents: a longitudinal study","volume":"91","year":"2021","journal-title":"Seizure"},{"key":"2026041200170094000_2025.03.18.644050v1.2","doi-asserted-by":"crossref","first-page":"107882","DOI":"10.1016\/j.neuropsychologia.2021.107882","article-title":"Social brain networks: resting-state and task-based connectivity in youth with and without epilepsy","volume":"157","year":"2021","journal-title":"Neuropsychologia"},{"key":"2026041200170094000_2025.03.18.644050v1.3","doi-asserted-by":"publisher","DOI":"10.1212\/WNL.0000000000011839"},{"key":"2026041200170094000_2025.03.18.644050v1.4","doi-asserted-by":"publisher","DOI":"10.1056\/NEJM200108023450501"},{"key":"2026041200170094000_2025.03.18.644050v1.5","doi-asserted-by":"publisher","DOI":"10.1056\/nejmoa1615335"},{"key":"2026041200170094000_2025.03.18.644050v1.6","doi-asserted-by":"publisher","DOI":"10.1212\/WNL.0000000000008966"},{"key":"2026041200170094000_2025.03.18.644050v1.7","doi-asserted-by":"publisher","DOI":"10.3171\/ped.2004.100.2.0110"},{"key":"2026041200170094000_2025.03.18.644050v1.8","doi-asserted-by":"publisher","DOI":"10.3109\/9780203091708-107"},{"key":"2026041200170094000_2025.03.18.644050v1.9","doi-asserted-by":"publisher","DOI":"10.1093\/brain\/awp025"},{"key":"2026041200170094000_2025.03.18.644050v1.10","doi-asserted-by":"publisher","DOI":"10.1111\/EPI.13515"},{"key":"2026041200170094000_2025.03.18.644050v1.11","doi-asserted-by":"publisher","DOI":"10.1111\/epi.13298"},{"key":"2026041200170094000_2025.03.18.644050v1.12","first-page":"1","article-title":"Utility of invasive electroencephalography in children 3 years old and younger with refractory epilepsy","volume":"26","year":"2020","journal-title":"J Neurosurg Pediatr"},{"key":"2026041200170094000_2025.03.18.644050v1.13","doi-asserted-by":"crossref","first-page":"1897","DOI":"10.1111\/epi.16959","article-title":"Epilepsy surgery in infants up to 3 months of age: safety, feasibility, and outcomes: a multicenter, multinational study","volume":"62","year":"2021","journal-title":"Epilepsia"},{"key":"2026041200170094000_2025.03.18.644050v1.14","doi-asserted-by":"crossref","first-page":"474","DOI":"10.1097\/WNP.0000000000000794","article-title":"American SEEG Consortium, supported by The American Clinical Neurophysiology Society. 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