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While its neural substrates have been investigated extensively in TLE, functional imaging studies in FLE are scarce. In this study, we profiled the neural processes underlying cognitive impairment in FLE and directly compared FLE and TLE to establish commonalities and differences. We investigated 172 adult participants (56 with FLE, 64 with TLE and 52 controls) using neuropsychological tests and four functional MRI tasks probing expressive language (verbal fluency, verb generation) and working memory (verbal and visuo-spatial). Patient groups were comparable in disease duration and anti-seizure medication load. We devised a multiscale approach to map brain activation and deactivation during cognition and track reorganization in FLE and TLE. Voxel-based analyses were complemented with profiling of task effects across established motifs of functional brain organization: (i) canonical resting-state functional systems; and (ii) the principal functional connectivity gradient, which encodes a continuous transition of regional connectivity profiles, anchoring lower-level sensory and transmodal brain areas at the opposite ends of a spectrum. We show that cognitive impairment in FLE is associated with reduced activation across attentional and executive systems, as well as reduced deactivation of the default mode system, indicative of a large-scale disorganization of task-related recruitment. The imaging signatures of dysfunction in FLE are broadly similar to those in TLE, but some patterns are syndrome-specific: altered default-mode deactivation is more prominent in FLE, while impaired recruitment of posterior language areas during a task with semantic demands is more marked in TLE. Functional abnormalities in FLE and TLE appear overall modulated by disease load. On balance, our study elucidates neural processes underlying language and working memory impairment in FLE, identifies shared and syndrome-specific alterations in the two most common focal epilepsies and sheds light on system behaviour that may be amenable to future remediation strategies.<\/jats:p>","DOI":"10.1093\/brain\/awac150","type":"journal-article","created":{"date-parts":[[2022,4,30]],"date-time":"2022-04-30T07:11:05Z","timestamp":1651302665000},"page":"935-953","source":"Crossref","is-referenced-by-count":76,"title":["Disorganization of language and working memory systems in frontal versus temporal lobe epilepsy"],"prefix":"10.1093","volume":"146","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7189-9699","authenticated-orcid":false,"given":"Lorenzo","family":"Caciagli","sequence":"first","affiliation":[{"name":"Department of Bioengineering, University of Pennsylvania , Philadelphia, Pennsylvania 19104 , USA"},{"name":"Department of Clinical and Experimental Epilepsy, UCL Queen Square Institute of Neurology , London WC1N 3BG , UK"},{"name":"MRI Unit, Epilepsy Society, Chalfont St Peter, Buckinghamshire SL9 0RJ , UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Casey","family":"Paquola","sequence":"additional","affiliation":[{"name":"Multimodal Imaging and Connectome Analysis Laboratory, McConnell Brain Imaging Centre, Montreal Neurological Institute , Montreal, Quebec H3A 2B4 , Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7941-2918","authenticated-orcid":false,"given":"Xiaosong","family":"He","sequence":"additional","affiliation":[{"name":"Department of Bioengineering, University of Pennsylvania , Philadelphia, Pennsylvania 19104 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christian","family":"Vollmar","sequence":"additional","affiliation":[{"name":"Department of Clinical and Experimental Epilepsy, UCL Queen Square Institute of Neurology , London WC1N 3BG , UK"},{"name":"MRI Unit, Epilepsy Society, Chalfont St Peter, Buckinghamshire SL9 0RJ , UK"},{"name":"Department of Neurology, Ludwig-Maximilians-Universit\u00e4t , 81377 Munich , Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria","family":"Centeno","sequence":"additional","affiliation":[{"name":"Department of Clinical and Experimental Epilepsy, UCL Queen Square Institute of Neurology , London WC1N 3BG , UK"},{"name":"MRI Unit, Epilepsy Society, Chalfont St Peter, Buckinghamshire SL9 0RJ , UK"},{"name":"Epilepsy Unit, Hospital Cl\u00ednic de Barcelona, IDIBAPS , 08036 Barcelona , Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Britta","family":"Wandschneider","sequence":"additional","affiliation":[{"name":"Department of Clinical and Experimental Epilepsy, UCL Queen Square Institute of Neurology , London WC1N 3BG , UK"},{"name":"MRI Unit, Epilepsy Society, Chalfont St Peter, Buckinghamshire SL9 0RJ , UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Urs","family":"Braun","sequence":"additional","affiliation":[{"name":"Department of Bioengineering, University of Pennsylvania , Philadelphia, Pennsylvania 19104 , USA"},{"name":"Department of Psychiatry and Psychotherapy, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg , Mannheim , Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9203-5344","authenticated-orcid":false,"given":"Karin","family":"Trimmel","sequence":"additional","affiliation":[{"name":"Department of Clinical and Experimental Epilepsy, UCL Queen Square Institute of Neurology , London WC1N 3BG , UK"},{"name":"MRI Unit, Epilepsy Society, Chalfont St Peter, Buckinghamshire SL9 0RJ , UK"},{"name":"Department of Neurology, Medical University of Vienna , Vienna , Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sjoerd B","family":"Vos","sequence":"additional","affiliation":[{"name":"Department of Clinical and Experimental Epilepsy, UCL Queen Square Institute of Neurology , London WC1N 3BG , UK"},{"name":"MRI Unit, Epilepsy Society, Chalfont St Peter, Buckinghamshire SL9 0RJ , UK"},{"name":"Centre for Medical Image Computing, University College London , London , UK"},{"name":"Neuroradiological Academic Unit, UCL Queen Square Institute of Neurology, University College London , London , UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Meneka K","family":"Sidhu","sequence":"additional","affiliation":[{"name":"Department of Clinical and Experimental Epilepsy, UCL Queen Square Institute of Neurology , London WC1N 3BG , UK"},{"name":"MRI Unit, Epilepsy Society, Chalfont St Peter, Buckinghamshire SL9 0RJ , UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pamela J","family":"Thompson","sequence":"additional","affiliation":[{"name":"Department of Clinical and Experimental Epilepsy, UCL Queen Square Institute of Neurology , London WC1N 3BG , UK"},{"name":"MRI Unit, Epilepsy Society, Chalfont St Peter, Buckinghamshire SL9 0RJ , UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9930-6469","authenticated-orcid":false,"given":"Sallie","family":"Baxendale","sequence":"additional","affiliation":[{"name":"Department of Clinical and Experimental Epilepsy, UCL Queen Square Institute of Neurology , London WC1N 3BG , UK"},{"name":"MRI Unit, Epilepsy Society, Chalfont St Peter, Buckinghamshire SL9 0RJ , UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9395-1478","authenticated-orcid":false,"given":"Gavin P","family":"Winston","sequence":"additional","affiliation":[{"name":"Department of Clinical and Experimental Epilepsy, UCL Queen Square Institute of Neurology , London WC1N 3BG , UK"},{"name":"MRI Unit, Epilepsy Society, Chalfont St Peter, Buckinghamshire SL9 0RJ , UK"},{"name":"Department of Medicine, Division of Neurology, Queen\u2019s University , Kingston, Ontario , Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1373-0681","authenticated-orcid":false,"given":"John S","family":"Duncan","sequence":"additional","affiliation":[{"name":"Department of Clinical and Experimental Epilepsy, UCL Queen Square Institute of Neurology , London WC1N 3BG , UK"},{"name":"MRI Unit, Epilepsy Society, Chalfont St Peter, Buckinghamshire SL9 0RJ , UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6183-4493","authenticated-orcid":false,"given":"Dani S","family":"Bassett","sequence":"additional","affiliation":[{"name":"Department of Bioengineering, University of Pennsylvania , Philadelphia, Pennsylvania 19104 , USA"},{"name":"Department of Physics and Astronomy, University of Pennsylvania , Philadelphia, PA 19104 , USA"},{"name":"Department of Electrical and 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Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2022,5,2]]},"reference":[{"key":"2023030117485642800_","doi-asserted-by":"crossref","first-page":"1139","DOI":"10.1111\/j.1528-1157.2000.tb00319.x","article-title":"Intractable seizures of frontal lobe origin: clinical characteristics, localizing signs, and results of surgery","volume":"41","author":"Jobst","year":"2000","journal-title":"Epilepsia"},{"key":"2023030117485642800_","doi-asserted-by":"crossref","first-page":"144","DOI":"10.1016\/j.cortex.2011.11.012","article-title":"Epilepsy and the frontal lobes","volume":"48","author":"O\u2019Muircheartaigh","year":"2012","journal-title":"Cortex"},{"key":"2023030117485642800_","doi-asserted-by":"crossref","first-page":"514","DOI":"10.1016\/j.seizure.2008.01.007","article-title":"Frontal lobe epilepsy: clinical characteristics, surgical outcomes and diagnostic 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