{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,22]],"date-time":"2026-03-22T09:49:04Z","timestamp":1774172944747,"version":"3.50.1"},"reference-count":37,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2022,2,24]],"date-time":"2022-02-24T00:00:00Z","timestamp":1645660800000},"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. Neurosci."],"abstract":"<jats:sec><jats:title>Background<\/jats:title><jats:p>In epilepsy, cognitive difficulties are common, partly a consequence of anti-seizure medications (ASM), and cognitive side-effects are often considered to be more disabling than seizures and significantly affect quality of life. Functional MRI during verbal fluency tasks demonstrated impaired frontal activation patterns and failed default mode network deactivation in people taking ASM with unfavourable cognitive profiles. The cognitive effect of ASMs given at different dosages in monotherapy, or in different combinations, remains to be determined.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Here, we compared the effects of different drug loads on verbal fluency functional MRI (fMRI) in people (i) taking dual therapy of ASMs either considered to be associated with moderate (levetiracetam, lamotrigine, lacosamide, carbamazepine\/oxcarbazepine, eslicarbazepine, valproic acid; <jats:italic>n<\/jats:italic> = 119, 56 females) or severe (topiramate, zonisamide) side-effects; <jats:italic>n<\/jats:italic> = 119, 56 females), (ii) taking moderate ASMs in either mono-, dual- or triple-therapy (60 subjects in each group), or (iii) taking different dosages of ASMs with moderate side-effect profiles (<jats:italic>n<\/jats:italic> = 180). \u201cDrug load\u201d was defined as a composite value of numbers and dosages of medications, normalised to account for the highest and lowest dose of each specific prescribed medication.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>In people taking \u201cmoderate\u201d ASMs (<jats:italic>n<\/jats:italic> = 119), we observed higher verbal-fluency related to left inferior frontal gyrus and right inferior parietal fMRI activations than in people taking \u201csevere\u201d ASMs (<jats:italic>n<\/jats:italic> = 119). Irrespective of the specific ASM, people on monotherapy (<jats:italic>n<\/jats:italic> = 60), showed greater frontal activations than people taking two (<jats:italic>n<\/jats:italic> = 60), or three ASMs (<jats:italic>n<\/jats:italic> = 60). People on two ASMs showed less default mode (precuneus) deactivation than those on monotherapy. In people treated with \u201cmoderate\u201d ASMs (<jats:italic>n<\/jats:italic> = 180), increased drug load correlated with reduced activation of language-related regions and the right piriform cortex.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>Our study delineates the effects of polytherapy and high doses of ASMs when given in monotherapy on the functional anatomy of language. Irrespective of the cognitive profile of individual ASMs, each additional ASM results in additional alterations of cognitive activation patterns. Selection of ASMs with moderate cognitive side effects, and low doses of ASMs when given in polytherapy, could reduce the cognitive effect.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fnins.2021.787272","type":"journal-article","created":{"date-parts":[[2022,2,24]],"date-time":"2022-02-24T09:46:28Z","timestamp":1645695988000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":12,"title":["Effect of Anti-seizure Medications on Functional Anatomy of Language: A Perspective From Language Functional Magnetic Resonance Imaging"],"prefix":"10.3389","volume":"15","author":[{"given":"Fenglai","family":"Xiao","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lorenzo","family":"Caciagli","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Britta","family":"Wandschneider","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Bhavini","family":"Joshi","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sjoerd B.","family":"Vos","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Andrea","family":"Hill","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Marian","family":"Galovic","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lili","family":"Long","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Daichi","family":"Sone","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Karin","family":"Trimmel","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Josemir W.","family":"Sander","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Dong","family":"Zhou","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Pamela J.","family":"Thompson","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sallie","family":"Baxendale","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"John S.","family":"Duncan","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Matthias J.","family":"Koepp","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2022,2,24]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"2037","DOI":"10.1002\/sim.3150","article-title":"A critical appraisal of propensity-score matching in the medical literature between 1996 and 2003.","volume":"27","author":"Austin","year":"2008","journal-title":"Stat. Med."},{"key":"B2","doi-asserted-by":"publisher","first-page":"318","DOI":"10.1016\/j.yebeh.2016.11.025","article-title":"Reprint of: the new approach to epilepsy classification: cognition and behavior in adult epilepsy syndromes.","volume":"64","author":"Baxendale","year":"2016","journal-title":"Epilepsy Behav."},{"key":"B3","doi-asserted-by":"publisher","first-page":"197","DOI":"10.1348\/014466504323088051","article-title":"Monitoring cognitive changes: psychometric properties of six cognitive tests.","volume":"43","author":"Bird","year":"2004","journal-title":"Br. J. Clin. Psycho."},{"key":"B4","doi-asserted-by":"publisher","first-page":"E65","DOI":"10.3174\/ajnr.A5345","article-title":"American society of functional neuroradiology\u2013recommended fMRI paradigm algorithms for presurgical language assessment.","volume":"38","author":"Black","year":"2017","journal-title":"Am. J. Neuroradio."},{"key":"B5","doi-asserted-by":"publisher","first-page":"e2427","DOI":"10.1212\/WNL.0000000000010645","article-title":"Thalamus and focal to bilateral seizures: a multiscale cognitive imaging study.","volume":"95","author":"Caciagli","year":"2020","journal-title":"Neurology."},{"key":"B6","doi-asserted-by":"publisher","first-page":"2670","DOI":"10.1093\/brain\/awz215","article-title":"Abnormal hippocampal structure and function in juvenile myoclonic epilepsy and unaffected siblings.","volume":"142","author":"Caciagli","year":"2019","journal-title":"Brain"},{"key":"B7","doi-asserted-by":"publisher","first-page":"570","DOI":"10.1111\/j.1528-1157.1997.tb01142.x","article-title":"Reappraisal of polytherapy in epilepsy: a critical review of drug load and adverse effects.","volume":"38","author":"Deckers","year":"1997","journal-title":"Epilepsia"},{"key":"B8","doi-asserted-by":"publisher","first-page":"420","DOI":"10.1016\/S1474-4422(15)00383-X","article-title":"Brain imaging in the assessment for epilepsy surgery.","volume":"15","author":"Duncan","year":"2016","journal-title":"Lancet Neurol."},{"key":"B9","doi-asserted-by":"publisher","first-page":"1618","DOI":"10.1111\/j.1528-1167.2012.03533.x","article-title":"Widespread epileptic networks in focal epilepsies: EEG-fMRI study.","volume":"53","author":"Fahoum","year":"2012","journal-title":"Epilepsia"},{"key":"B10","doi-asserted-by":"publisher","first-page":"21","DOI":"10.1016\/j.clinph.2013.06.182","article-title":"EEG\u00e2\u20ac\u201cfMRI in focal epilepsy: local activation and regional networks.","volume":"125","author":"Flanagan","year":"2013","journal-title":"Clin. Neurophysiol."},{"key":"B11","doi-asserted-by":"crossref","first-page":"63","DOI":"10.1111\/j.1528-1167.2009.02238.x","article-title":"Rational polytherapy.","volume":"50","author":"French","year":"2009","journal-title":"Epilepsia"},{"key":"B12","doi-asserted-by":"publisher","first-page":"690","DOI":"10.1001\/jamaneurol.2019.0204","article-title":"Association of piriform cortex resection with surgical outcomes in patients with temporal lobe epilepsy.","volume":"76","author":"Galovic","year":"2019","journal-title":"JAMA Neurol."},{"key":"B13","doi-asserted-by":"publisher","first-page":"39","DOI":"10.1016\/j.neuropsychologia.2015.01.031","article-title":"Distinct functional connectivity of the hippocampus during semantic and phonemic fluency.","volume":"69","author":"Glikmann-Johnston","year":"2015","journal-title":"Neuropsychologia"},{"key":"B14","doi-asserted-by":"crossref","first-page":"791","DOI":"10.1016\/j.neuron.2017.07.011","article-title":"Precision functional mapping of individual human brains.","volume":"95","author":"Gordon","year":"2017","journal-title":"Neuron"},{"key":"B15","doi-asserted-by":"publisher","first-page":"6","DOI":"10.1186\/1471-2377-1-6","article-title":"Carbamazepine reduces memory induced activation of mesial temporal lobe structures: a pharmacological fMRI-study.","volume":"1","author":"Jokeit","year":"2001","journal-title":"BMC Neurol."},{"key":"B16","doi-asserted-by":"crossref","first-page":"314","DOI":"10.1056\/NEJM200002033420503","article-title":"Early identification of refractory epilepsy.","volume":"342","author":"Kwan","year":"2000","journal-title":"N. Engl. J. Med."},{"key":"B17","doi-asserted-by":"publisher","first-page":"904","DOI":"10.1212\/WNL.0b013e31822c90f2","article-title":"Converging PET and fMRI evidence for a common area involved in human focal epilepsies.","volume":"77","author":"Laufs","year":"2011","journal-title":"Neurology"},{"key":"B18","doi-asserted-by":"publisher","first-page":"423","DOI":"10.1093\/scan\/nsp052","article-title":"Type I and type II error concerns in fMRI research: re-balancing the scale.","volume":"4","author":"Lieberman","year":"2009","journal-title":"Soc. Cogn. Affect. Neurosci."},{"key":"B19","doi-asserted-by":"publisher","first-page":"121","DOI":"10.2165\/00023210-200923020-00003","article-title":"Antiepileptic drug-induced cognitive adverse effects: potential mechanisms and contributing factors.","volume":"23","author":"Mula","year":"2009","journal-title":"CNS Drugs."},{"key":"B20","doi-asserted-by":"publisher","first-page":"579","DOI":"10.1006\/ebeh.2001.0285","article-title":"Language disturbances as side effects of topiramate and zonisamide therapy.","volume":"2","author":"Ojemann","year":"2001","journal-title":"Epilepsy Behav."},{"key":"B21","doi-asserted-by":"publisher","first-page":"897","DOI":"10.2165\/00023210-200519110-00001","article-title":"Overtreatment in epilepsy.","volume":"19","author":"Perucca","year":"2005","journal-title":"CNS Drugs."},{"key":"B22","doi-asserted-by":"publisher","first-page":"375","DOI":"10.1684\/epd.2011.0469","article-title":"Montreal cognitive assessment in cryptogenic epilepsy patients with normal mini-mental state examination scores.","volume":"13","author":"Phabphal","year":"2011","journal-title":"Epileptic Dis."},{"key":"B23","doi-asserted-by":"publisher","first-page":"623","DOI":"10.1038\/317623a0","article-title":"A crucial epileptogenic site in the deep prepiriform cortex.","volume":"317","author":"Piredda","year":"1985","journal-title":"Nature"},{"key":"B24","first-page":"29","article-title":"The impact of antiepileptic polytherapy on mood and cognitive function.","volume":"111","author":"R\u00f6sche","year":"2011","journal-title":"Acta Neurol. Belgica"},{"key":"B25","doi-asserted-by":"publisher","first-page":"404","DOI":"10.1016\/j.yebeh.2010.05.009","article-title":"Cortical and subcortical contributions to absence seizure onset examined with EEG\/fMRI.","volume":"18","author":"Szaflarski","year":"2010","journal-title":"Epilepsy Behav."},{"key":"B26","doi-asserted-by":"publisher","first-page":"395","DOI":"10.1212\/wnl.0000000000003532","article-title":"Practice guideline summary: Use of fMRI in the presurgical evaluation of patients with epilepsy: report of the guideline development, dissemination, and implementation subcommittee of the american academy of neurology.","volume":"88","author":"Szaflarski","year":"2017","journal-title":"Neurology"},{"key":"B27","doi-asserted-by":"publisher","first-page":"1281","DOI":"10.1093\/brain\/awl047","article-title":"Absence and myoclonic status epilepticus precipitated by antiepileptic drugs in idiopathic generalized epilepsy.","volume":"129","author":"Thomas","year":"2006","journal-title":"Brain"},{"key":"B28","doi-asserted-by":"publisher","first-page":"2406","DOI":"10.1093\/brain\/awy164","article-title":"Left temporal lobe language network connectivity in temporal lobe epilepsy.","volume":"141","author":"Trimmel","year":"2018","journal-title":"Brain"},{"key":"B29","doi-asserted-by":"publisher","first-page":"1710","DOI":"10.1093\/brain\/awr098","article-title":"Motor system hyperconnectivity in juvenile myoclonic epilepsy: a cognitive functional magnetic resonance imaging study.","volume":"134","author":"Vollmar","year":"2011","journal-title":"Brain"},{"key":"B30","doi-asserted-by":"publisher","first-page":"1165","DOI":"10.1212\/WNL.0000000000003736","article-title":"Effect of topiramate and zonisamide on fMRI cognitive networks.","volume":"88","author":"Wandschneider","year":"2017","journal-title":"Neurology"},{"key":"B31","doi-asserted-by":"publisher","first-page":"1508","DOI":"10.1212\/WNL.0000000000000910","article-title":"Levetiracetam reduces abnormal network activations in temporal lobe epilepsy.","volume":"83","author":"Wandschneider","year":"2014","journal-title":"Neurology"},{"key":"B32","doi-asserted-by":"publisher","first-page":"450","DOI":"10.1016\/j.yebeh.2012.09.015","article-title":"Monitoring the cognitive effects of antiepileptic pharmacotherapyapproaching the individual patient.","volume":"26","author":"Witt","year":"2013","journal-title":"Epilepsy Behav."},{"key":"B33","doi-asserted-by":"publisher","first-page":"1954","DOI":"10.1016\/j.euroneuro.2015.07.027","article-title":"Adverse cognitive effects of antiepileptic pharmacotherapy: each additional drug matters.","volume":"25","author":"Witt","year":"2015","journal-title":"Eur. Neuropsychophar."},{"key":"B34","doi-asserted-by":"publisher","first-page":"291","DOI":"10.1111\/epi.16720","article-title":"Does the accumulated antiepileptic drug load in chronic epilepsy reflect disease severity?","volume":"25","author":"Witt","year":"2020","journal-title":"Epilepsia"},{"key":"B35","doi-asserted-by":"publisher","first-page":"699","DOI":"10.1212\/01.wnl.0000078815.03224.57","article-title":"Language lateralization by Wada test and fMRI in 100 patients with epilepsy.","volume":"61","author":"Woermann","year":"2003","journal-title":"Neurology"},{"key":"B36","doi-asserted-by":"crossref","first-page":"1362","DOI":"10.1111\/epi.14448","article-title":"Effects of carbamazepine and lamotrigine on functional magnetic resonance imaging cognitive networks.","volume":"59","author":"Xiao","year":"2018","journal-title":"Epilepsia"},{"key":"B37","doi-asserted-by":"publisher","first-page":"250","DOI":"10.1016\/j.eplepsyres.2012.12.007","article-title":"The effect of topiramate on cognitive fMRI.","volume":"105","author":"Yasuda","year":"2013","journal-title":"Epilepsy Res."}],"container-title":["Frontiers in Neuroscience"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fnins.2021.787272\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,2,24]],"date-time":"2022-02-24T09:46:33Z","timestamp":1645695993000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fnins.2021.787272\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,2,24]]},"references-count":37,"alternative-id":["10.3389\/fnins.2021.787272"],"URL":"https:\/\/doi.org\/10.3389\/fnins.2021.787272","relation":{},"ISSN":["1662-453X"],"issn-type":[{"value":"1662-453X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,2,24]]},"article-number":"787272"}}