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We investigated the potential neurophysiologic mechanism of action (MOA) of neurobehavioral therapy (NBT) using resting\u2010state functional MRI seed\u2010based whole\u2010brain functional connectivity within these regions in adults with FS. We hypothesized that NBT would induce changes in functional connectivity in parallel with improving seizure frequency and behavioral outcomes.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Forty patients with traumatic brain injury and FS (TBI+FS) underwent 12 weekly sessions of NBT and provided pre\u2010\/post\u2010intervention resting\u2010state functional magnetic resonance imaging (MRI), seizure logs, and behavioral assessments. Fifty\u2010five individuals with TBI without FS (TBI\u2010only) completed the same measures, received standard medical care but not NBT, and functional MRI ~12\u2009weeks apart. For each key region, two\u2010sample <jats:italic>t<\/jats:italic>\u2010tests assessed direct group comparison. Repeated measures analysis of covariance assessed how group differences evolved over time and how these changes were modulated by the changes in seizure frequency, diagnosis duration, or behavioral scores (false discovery rate corrected at <jats:italic>p<\/jats:italic>\u2009&lt;\u2009.05).<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>With NBT, seed\u2010based whole\u2010brain functional connectivity was significantly higher between right anterior insula and left supplementary motor area in TBI+FS compared to TBI\u2010only, and between left anterior insula and left postcentral gyrus in seizure\u2010free TBI+FS compared to those who were not seizure\u2010free. Percentage decrease in seizure frequency with NBT was associated with lower functional connectivity between bilateral insula and left superior medial frontal gyrus in patients with FS. Improvements in behavioral measures did not correspond to changes in functional connectivity.<\/jats:p><\/jats:sec><jats:sec><jats:title>Significance<\/jats:title><jats:p>The study underscores the relationship between the changes in resting\u2010state functional connectivity of the anterior insula in FS and treatment response to NBT and illustrates the potential neurophysiologic MOA of NBT for the treatment of FS; it suggests an independence of this MOA from the potential effects of NBT on behavioral measures.<\/jats:p><\/jats:sec>","DOI":"10.1111\/epi.18401","type":"journal-article","created":{"date-parts":[[2025,4,5]],"date-time":"2025-04-05T11:36:33Z","timestamp":1743852993000},"page":"2881-2893","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["Neurobehavioral therapy in functional seizures: Investigation of mechanism of action with resting\u2010state functional <scp>magnetic resonance imaging<\/scp>"],"prefix":"10.1111","volume":"66","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5936-6627","authenticated-orcid":false,"given":"Jerzy P.","family":"Szaflarski","sequence":"first","affiliation":[{"name":"Department of Neurology, Heersink School of Medicine University of Alabama at Birmingham  Birmingham Alabama USA"},{"name":"University of Alabama at Birmingham Epilepsy Center (UABMC), Heersink School of Medicine University of Alabama at Birmingham  Birmingham Alabama USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4901-3852","authenticated-orcid":false,"suffix":"Jr.","given":"W. Curt","family":"LaFrance","sequence":"additional","affiliation":[{"name":"Department of Psychiatry Rhode Island Hospital, Brown University  Birmingham Alabama USA"},{"name":"Department of Neurology Rhode Island Hospital, Brown University  Providence Rhode Island USA"},{"name":"Center for Neurorestoration and Neurotechnology VA Providence Healthcare System  Providence Rhode Island USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rodolphe","family":"Nenert","sequence":"additional","affiliation":[{"name":"Department of Neurology, Heersink School of Medicine University of Alabama at Birmingham  Birmingham Alabama USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6888-9000","authenticated-orcid":false,"given":"Jane B.","family":"Allendorfer","sequence":"additional","affiliation":[{"name":"Department of Neurology, Heersink School of Medicine University of Alabama at Birmingham  Birmingham Alabama USA"},{"name":"Department 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