{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,17]],"date-time":"2026-07-17T04:36:16Z","timestamp":1784262976492,"version":"3.55.0"},"reference-count":53,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2024,11,28]],"date-time":"2024-11-28T00:00:00Z","timestamp":1732752000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Physiol."],"abstract":"<jats:sec><jats:title>Objective<\/jats:title><jats:p>Although seizures are the cardinal feature, epilepsy is associated with other forms of brain dysfunction including impaired cognition, abnormal sleep, and increased risk of developing dementia. We hypothesized that, given the widespread neurologic dysfunction caused by epilepsy, accelerated brain aging would be seen. We measured the sleep-based brain age index (BAI) in a diverse group of patients with epilepsy. The BAI is a machine learning-based biomarker that measures how much the brain activity of a person during overnight sleep deviates from chronological age-based norms.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>This case\u2013control study drew information of age-matched controls without epilepsy from home sleep monitoring volunteers and from non-epilepsy patients with Sleep Lab testing. Patients with epilepsy underwent in-patient monitoring and were classified by epilepsy type and seizure burden. The primary outcomes measured were BAI, processed from electroencephalograms, and epilepsy severity metrics (years with epilepsy, seizure frequency standardized by year, and seizure burden [number of seizures in life]). Subanalyses were conducted on a subset with NIH Toolbox cognitive testing for total, fluid, and crystallized composite cognition.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>138 patients with epilepsy (32 exclusively focal and 106 generalizable [focal seizures with secondary generalization]) underwent in-patient monitoring, and age-matched, non-epilepsy controls were analyzed. The mean BAI was higher in epilepsy patients vs controls and differed by epilepsy type: \u22120.05 years (controls) versus 5.02 years (all epilepsy, <jats:italic>p<\/jats:italic> &amp;lt; 0.001), 5.53 years (generalizable, <jats:italic>p<\/jats:italic> &amp;lt; 0.001), and 3.34 years (focal, <jats:italic>p<\/jats:italic> = 0.03). Sleep architecture was disrupted in epilepsy, especially in generalizable epilepsy. A higher BAI was positively associated with increased lifetime seizure burden in focal and generalizable epilepsies and associated with lower crystallized cognition. Lifetime seizure burden was inversely correlated with fluid, crystallized, and composite cognition.<\/jats:p><\/jats:sec><jats:sec><jats:title>Significance<\/jats:title><jats:p>Epilepsy is associated with accelerated brain aging. Higher brain age indices are associated with poorer cognition and more severe epilepsy, specifically generalizability and higher seizure burden. These findings strengthen the use of the sleep-derived, electroencephalography-based BAI as a biomarker for cognitive dysfunction in epilepsy.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fphys.2024.1458592","type":"journal-article","created":{"date-parts":[[2024,11,28]],"date-time":"2024-11-28T04:19:57Z","timestamp":1732767597000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":8,"title":["Epilepsy is associated with the accelerated aging of brain activity in sleep"],"prefix":"10.3389","volume":"15","author":[{"given":"Peter N.","family":"Hadar","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mike","family":"Westmeijer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haoqi","family":"Sun","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Erik-Jan","family":"Meulenbrugge","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jin","family":"Jing","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luis","family":"Paixao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ryan A.","family":"Tesh","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Madalena","family":"Da Silva Cardoso","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pierrick","family":"Arnal","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rhoda","family":"Au","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chol","family":"Shin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Soriul","family":"Kim","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert J.","family":"Thomas","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sydney S.","family":"Cash","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"M. Brandon","family":"Westover","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2024,11,28]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"19","DOI":"10.1111\/J.1600-0404.2005.00523.X","article-title":"Behaviour, cognition and epilepsy","volume":"182","author":"Aldenkamp","year":"2005","journal-title":"Acta Neurol. Scand. Suppl."},{"key":"B2","doi-asserted-by":"publisher","first-page":"107027","DOI":"10.1016\/J.YEBEH.2020.107027","article-title":"Cognitive rehabilitation and prehabilitation in people with epilepsy","volume":"106","author":"Baxendale","year":"2020","journal-title":"Epilepsy and Behav."},{"key":"B3","doi-asserted-by":"publisher","first-page":"S39","DOI":"10.1016\/J.YEBEH.2003.07.005","article-title":"Epilepsy and sleep disturbance","volume":"4","author":"Bazil","year":"2003","journal-title":"Epilepsy Behav."},{"key":"B4","doi-asserted-by":"publisher","first-page":"79","DOI":"10.1016\/J.PHRS.2016.03.003","article-title":"Addressing the burden of epilepsy: many unmet needs","volume":"107","author":"Beghi","year":"2016","journal-title":"Pharmacol. Res."},{"key":"B5","doi-asserted-by":"publisher","first-page":"357","DOI":"10.1016\/S1474-4422(18)30454-X","article-title":"Global, regional, and national burden of epilepsy, 1990\u20132016: a systematic analysis for the Global Burden of Disease Study 2016","volume":"18","author":"Beghi","year":"2019","journal-title":"Lancet Neurol."},{"key":"B6","doi-asserted-by":"publisher","first-page":"266","DOI":"10.1038\/S41380-018-0098-1","article-title":"Brain age and other bodily \u2018ages\u2019: implications for neuropsychiatry","volume":"24","author":"Cole","year":"2019","journal-title":"Mol. Psychiatry"},{"key":"B7","doi-asserted-by":"publisher","first-page":"115","DOI":"10.1016\/J.NEUROIMAGE.2017.07.059","article-title":"Predicting brain age with deep learning from raw imaging data results in a reliable and heritable biomarker","volume":"163","author":"Cole","year":"2017","journal-title":"Neuroimage."},{"key":"B8","doi-asserted-by":"publisher","first-page":"362","DOI":"10.14283\/jpad.2023.30","article-title":"Lecanemab: appropriate use recommendations","volume":"10","author":"Cummings","year":"2023","journal-title":"J. Prev. Alzheimer\u2019s Dis."},{"key":"B9","doi-asserted-by":"publisher","first-page":"e035767","DOI":"10.1136\/BMJOPEN-2019-035767","article-title":"Why are epilepsy mortality rates rising in the United States? A population-based multiple cause-of-death study","volume":"10","author":"Degiorgio","year":"2020","journal-title":"BMJ Open"},{"key":"B10","doi-asserted-by":"publisher","first-page":"1611","DOI":"10.2147\/NSS.S327221","article-title":"Nocturnal brain activity differs with age and sex: comparisons of sleep EEG power spectra between young and elderly men, and between 60\u201380-year-old men and women","volume":"13","author":"Eggert","year":"2021","journal-title":"Nat. Sci. Sleep."},{"key":"B11","doi-asserted-by":"publisher","first-page":"210","DOI":"10.1016\/J.EPLEPSYRES.2014.10.017","article-title":"Cognitive rehabilitation in epilepsy: an evidence-based review","volume":"109","author":"Farina","year":"2015","journal-title":"Epilepsy Res."},{"key":"B12","doi-asserted-by":"publisher","first-page":"3332","DOI":"10.1002\/HBM.22405","article-title":"Idiopathic-generalized epilepsy shows profound white matter diffusion\u2014tensor imaging alterations","volume":"35","author":"Focke","year":"2014","journal-title":"Hum. Brain Mapp."},{"key":"B13","doi-asserted-by":"publisher","first-page":"69","DOI":"10.1097\/00004691-199801000-00009","article-title":"Sleep deprivation activates epileptiform discharges independent of the activating effects of sleep","volume":"15","author":"Fountain","year":"1998","journal-title":"J. Clin. Neurophysiol."},{"key":"B14","doi-asserted-by":"publisher","first-page":"55","DOI":"10.1016\/J.CORTEX.2021.03.031","article-title":"Network topology of the cognitive phenotypes of temporal lobe epilepsy","volume":"141","author":"Garcia-Ramos","year":"2021","journal-title":"Cortex"},{"key":"B15","doi-asserted-by":"publisher","first-page":"189","DOI":"10.1136\/ARCHDISCHILD-2017-313421","article-title":"Sleep and epilepsy: unfortunate bedfellows","volume":"104","author":"Gibbon","year":"2019","journal-title":"Arch. Dis. Child."},{"key":"B16","volume-title":"Sleep, epilepsies, and cognitive impairment","author":"Halasz","year":"2017"},{"key":"B17","doi-asserted-by":"publisher","first-page":"731","DOI":"10.1038\/s41582-021-00555-z","article-title":"Neurobehavioural comorbidities of epilepsy: towards a network-based precision taxonomy","volume":"17","author":"Hermann","year":"2021","journal-title":"Nat. Rev. Neurol."},{"key":"B18","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1016\/J.CLINPH.2020.09.029","article-title":"Night-to-night variability of sleep electroencephalography-based brain age measurements","volume":"132","author":"Hogan","year":"2021","journal-title":"Clin. Neurophysiol."},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.3389\/FNEUR.2021.643450","article-title":"Gender and socioeconomic disparities in global burden of epilepsy: an analysis of time trends from 1990 to 2017","volume":"12","author":"Hu","year":"2021","journal-title":"Front. Neurol."},{"key":"B20","doi-asserted-by":"publisher","first-page":"41","DOI":"10.1016\/J.CORTEX.2019.02.022","article-title":"Cognitive slowing and its underlying neurobiology in temporal lobe epilepsy","volume":"117","author":"Hwang","year":"2019","journal-title":"Cortex"},{"key":"B21","doi-asserted-by":"publisher","first-page":"zsaa112","DOI":"10.1093\/SLEEP\/ZSAA112","article-title":"Expert-level automated sleep staging of long-term scalp electroencephalography recordings using deep learning","volume":"43","author":"Jaoude","year":"2020","journal-title":"Sleep"},{"key":"B22","doi-asserted-by":"publisher","first-page":"e1750","DOI":"10.1212\/WNL.0000000000207127","article-title":"Development of expert-level classification of seizures and rhythmic and periodic patterns during EEG interpretation","volume":"100","author":"Jing","year":"2023","journal-title":"Neurology"},{"key":"B23","doi-asserted-by":"publisher","first-page":"103","DOI":"10.1001\/JAMANEUROL.2019.3485","article-title":"Development of expert-level automated detection of epileptiform discharges during electroencephalogram interpretation","volume":"77","author":"Jing","year":"2020","journal-title":"JAMA Neurol."},{"key":"B24","doi-asserted-by":"publisher","first-page":"e3248","DOI":"10.1212\/WNL.0000000000011080","article-title":"Dementia in late-onset epilepsy: the atherosclerosis risk in communities study","volume":"95","author":"Johnson","year":"2020","journal-title":"Neurology"},{"key":"B25","doi-asserted-by":"publisher","first-page":"388","DOI":"10.1016\/S0006-3223(03)00469-4","article-title":"Depression in epilepsy: prevalence, clinical semiology, pathogenic mechanisms, and treatment","volume":"54","author":"Kanner","year":"2003","journal-title":"Biol. Psychiatry"},{"key":"B26","doi-asserted-by":"publisher","first-page":"106","DOI":"10.1038\/NRNEUROL.2015.243","article-title":"Management of psychiatric and neurological comorbidities in epilepsy","volume":"12","author":"Kanner","year":"2016","journal-title":"Nat. Rev. Neurol."},{"key":"B27","doi-asserted-by":"publisher","first-page":"106","DOI":"10.1016\/S1474-4422(15)00225-2","article-title":"Comorbidities of epilepsy: current concepts and future perspectives","volume":"15","author":"Keezer","year":"2016","journal-title":"Lancet Neurol."},{"key":"B28","doi-asserted-by":"publisher","first-page":"1816","DOI":"10.1523\/JNEUROSCI.2009-20.2020","article-title":"Focal sleep spindle deficits reveal focal thalamocortical dysfunction and predict cognitive deficits in sleep activated developmental epilepsy","volume":"41","author":"Kramer","year":"2021","journal-title":"J. Neurosci."},{"key":"B29","doi-asserted-by":"publisher","first-page":"zsab058","DOI":"10.1093\/SLEEP\/ZSAB058","article-title":"HIV increases sleep-based brain age despite antiretroviral therapy","volume":"44","author":"Leone","year":"2021","journal-title":"Sleep"},{"key":"B30","first-page":"159","article-title":"Sleep and epilepsy: strange bedfellows no more","volume":"50","author":"Louis","year":"2011","journal-title":"Minerva Pneumol."},{"key":"B31","doi-asserted-by":"publisher","first-page":"1587","DOI":"10.1111\/J.1528-1157.1999.TB02044.X","article-title":"Lateralizing value of interictal spikes on overnight sleep-EEG studies in temporal lobe epilepsy","volume":"40","author":"Malow","year":"1999","journal-title":"Epilepsia"},{"key":"B32","doi-asserted-by":"publisher","first-page":"2197","DOI":"10.1016\/S0140-6736(12)61689-4","article-title":"Disability-adjusted life years (DALYs) for 291 diseases and injuries in 21 regions, 1990-2010: a systematic analysis for the Global Burden of Disease Study 2010","volume":"380","author":"Murray","year":"2012","journal-title":"Lancet"},{"key":"B33","doi-asserted-by":"publisher","first-page":"106","DOI":"10.1016\/J.PEDIATRNEUROL.2006.09.014","article-title":"Sleep spindle abnormalities in children with generalized spike-wave discharges","volume":"36","author":"Myatchin","year":"2007","journal-title":"Pediatr. Neurol."},{"key":"B34","doi-asserted-by":"publisher","first-page":"E2072","DOI":"10.1212\/WNL.0000000000009414","article-title":"Teaching NeuroImages: epileptiform K-complexes in genetic generalized epilepsy: common but underappreciated","volume":"94","author":"Nascimento","year":"2020","journal-title":"Neurology"},{"key":"B35","unstructured":"NIH toolbox for assessment of neurological and behavioral function | blueprint"},{"key":"B36","doi-asserted-by":"publisher","first-page":"465","DOI":"10.1038\/nrneurol.2016.98","article-title":"Cognitive and neurodevelopmental comorbidities in paediatric epilepsy","volume":"12","author":"Nickels","year":"2016","journal-title":"Nat. Rev. Neurol."},{"key":"B37","doi-asserted-by":"publisher","first-page":"e13622","DOI":"10.1111\/JSR.13622","article-title":"Sleep and epilepsy: a snapshot of knowledge and future research lines","volume":"31","author":"Nobili","year":"2022","journal-title":"J. Sleep. Res."},{"key":"B38","doi-asserted-by":"publisher","first-page":"150","DOI":"10.1016\/J.NEUROBIOLAGING.2019.12.015","article-title":"Excess brain age in the sleep electroencephalogram predicts reduced life expectancy","volume":"88","author":"Paixao","year":"2020","journal-title":"Neurobiol. Aging"},{"key":"B39","doi-asserted-by":"publisher","first-page":"419376","DOI":"10.1155\/2014\/419376","article-title":"Through diffusion tensor magnetic resonance imaging to evaluate the original properties of neural pathways of patients with partial seizures and secondary generalization by individual anatomic reference atlas","volume":"2014","author":"Peng","year":"2014","journal-title":"Biomed. Res. Int."},{"key":"B40","doi-asserted-by":"publisher","first-page":"487","DOI":"10.1016\/j.jpsychores.2004.02.001","article-title":"Sleep and quantitative EEG in neurodegenerative disorders","volume":"56","author":"Petit","year":"2004","journal-title":"J. Psychosom. Res."},{"key":"B41","first-page":"S25","article-title":"Effect of anticonvulsants on nocturnal sleep in epilepsy","volume":"54","author":"Placidi","year":"2000","journal-title":"Neurology"},{"key":"B42","doi-asserted-by":"publisher","first-page":"836321","DOI":"10.3389\/FNEUR.2022.836321","article-title":"Assessment of anxiety in patients with epilepsy: a literature review","volume":"13","author":"Rauh","year":"2022","journal-title":"Front. Neurol."},{"key":"B43","doi-asserted-by":"publisher","first-page":"798","DOI":"10.1002\/ANA.25710","article-title":"Insufficient sleep, electroencephalogram activation, and seizure risk: Re-evaluating the evidence","volume":"87","author":"Rossi","year":"2020","journal-title":"Ann. Neurol."},{"key":"B44","doi-asserted-by":"publisher","first-page":"11137","DOI":"10.1038\/s41598-022-15147-0","article-title":"Focal epilepsy disrupts spindle structure and function","volume":"12","author":"Schiller","year":"2022","journal-title":"Sci. Rep."},{"key":"B45","doi-asserted-by":"publisher","first-page":"735","DOI":"10.1016\/S0140-6736(19)33064-8","article-title":"Epilepsy in older people","volume":"395","author":"Sen","year":"2020","journal-title":"Lancet"},{"key":"B46","doi-asserted-by":"publisher","first-page":"156","DOI":"10.1097\/WNP.0000000000000239","article-title":"Epileptiform K-complexes and sleep spindles: an underreported phenomenon in genetic generalized epilepsy","volume":"33","author":"Seneviratne","year":"2016","journal-title":"J. Clin. Neurophysiol."},{"key":"B47","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1214\/09-STS313","article-title":"Matching methods for causal inference: a review and a look forward","volume":"25","author":"Stuart","year":"2010","journal-title":"Stat. Sci."},{"key":"B48","doi-asserted-by":"publisher","first-page":"112","DOI":"10.1016\/J.NEUROBIOLAGING.2018.10.016","article-title":"Brain age from the electroencephalogram of sleep","volume":"74","author":"Sun","year":"2019","journal-title":"Neurobiol. Aging"},{"key":"B49","doi-asserted-by":"publisher","first-page":"5","DOI":"10.1186\/s41983-019-0141-4","article-title":"Sleep pattern in epilepsy patients: a polysomnographic study","volume":"56","author":"Tork","year":"2020","journal-title":"Egypt. J. Neurology, Psychiatry Neurosurg."},{"key":"B50","doi-asserted-by":"publisher","first-page":"567","DOI":"10.1017\/S1355617714000320","article-title":"The cognition battery of the NIH toolbox for assessment of neurological and behavioral function: validation in an adult sample","volume":"20","author":"Weintraub","year":"2014","journal-title":"J. Int. Neuropsychol. Soc."},{"key":"B51","doi-asserted-by":"publisher","first-page":"e2017357","DOI":"10.1001\/JAMANETWORKOPEN.2020.17357","article-title":"Association of sleep electroencephalography-based brain age index with dementia","volume":"3","author":"Ye","year":"2020","journal-title":"JAMA Netw. Open"},{"key":"B52","doi-asserted-by":"publisher","first-page":"zsac286","DOI":"10.1093\/SLEEP\/ZSAC286","article-title":"Dementia detection from brain activity during sleep","volume":"46","author":"Ye","year":"2023","journal-title":"Sleep"},{"key":"B53","doi-asserted-by":"publisher","first-page":"101","DOI":"10.1016\/J.SLEEP.2021.02.007","article-title":"Rapid eye movement sleep disturbance in patients with refractory epilepsy: a polysomnographic study","volume":"81","author":"Yeh","year":"2021","journal-title":"Sleep. Med."}],"container-title":["Frontiers in Physiology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fphys.2024.1458592\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,11,28]],"date-time":"2024-11-28T04:20:01Z","timestamp":1732767601000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fphys.2024.1458592\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,11,28]]},"references-count":53,"alternative-id":["10.3389\/fphys.2024.1458592"],"URL":"https:\/\/doi.org\/10.3389\/fphys.2024.1458592","relation":{},"ISSN":["1664-042X"],"issn-type":[{"value":"1664-042X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,11,28]]},"article-number":"1458592"}}