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This single-arm mechanistic trial (ClinicalTrials.gov, NCT04424407) examined fronto-limbic and sleep mechanisms of CBT-I\u2019s antidepressant response in 48 participants (64% female; age 25\u201360) with insomnia and depression symptoms. Participants completed functional magnetic resonance imaging (fMRI), polysomnography (PSG), and symptom assessments before and after 6 CBT-I sessions. CBT-I resulted in reduced amygdala reactivity to fearful faces (\n                    <jats:italic>d<\/jats:italic>\n                    \u2009=\u20090.55,\n                    <jats:italic>p<\/jats:italic>\n                    \u2009=\u20090.008). Depression and sleep (objective and self-reported insomnia symptoms also improved. However, fMRI-assessed fronto-limbic changes were not associated with a reduction of depressive symptom severity. Instead, reduced depressive symptoms correlated with reduced self-reported insomnia symptoms (\n                    <jats:italic>p<\/jats:italic>\n                    \u2009=\u20090.001,\n                    <jats:italic>\u03b7<\/jats:italic>\n                    <jats:sup>2<\/jats:sup>\n                    <jats:italic>p<\/jats:italic>\n                    \u2009=\u20090.19) and increased objective sleep efficiency (\n                    <jats:italic>p<\/jats:italic>\n                    \u2009=\u20090.04,\n                    <jats:italic>\u03b7<\/jats:italic>\n                    <jats:sup>2<\/jats:sup>\n                    <jats:italic>p<\/jats:italic>\n                    \u2009=\u20090.10). Notably, pre-treatment PSG-assessed sleep efficiency, but not fronto-limbic function nor insomnia symptoms, predicted reduced depressive symptoms (\n                    <jats:italic>p<\/jats:italic>\n                    \u2009=\u20090.007,\n                    <jats:italic>\u03b7<\/jats:italic>\n                    <jats:sup>2<\/jats:sup>\n                    <jats:italic>p<\/jats:italic>\n                    \u2009=\u20090.16), suggesting that lower objective sleep efficiency prior to treatment may be associated with greater antidepressant benefit from CBT-I.\n                  <\/jats:p>","DOI":"10.1038\/s41386-026-02431-0","type":"journal-article","created":{"date-parts":[[2026,5,7]],"date-time":"2026-05-07T14:21:11Z","timestamp":1778163671000},"page":"1657-1668","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Examining fronto-limbic brain and sleep mechanisms of antidepressant effects in cognitive-behavioral therapy for insomnia"],"prefix":"10.1038","volume":"51","author":[{"given":"Adam J.","family":"Krause","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Raquel","family":"Osorno","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Natalie L.","family":"Solomon","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maryam","family":"Ahmadi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pandora","family":"Lam","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Olivia","family":"Magana","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emilija","family":"Blozyte-Sakenis","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Leah N.","family":"Harris","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Madeline C.","family":"Babros","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sarah S.","family":"Izabel","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rebecca A.","family":"Bernert","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9987-7360","authenticated-orcid":false,"given":"Leanne M.","family":"Williams","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3624-3090","authenticated-orcid":false,"given":"James J.","family":"Gross","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7996-6454","authenticated-orcid":false,"given":"Jun","family":"Ma","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1846-6920","authenticated-orcid":false,"given":"Laura C.","family":"Lazzeroni","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jerome A.","family":"Yesavage","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rachel","family":"Manber","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8547-0161","authenticated-orcid":false,"given":"Jared M.","family":"Saletin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6382-4312","authenticated-orcid":false,"given":"Andrea N.","family":"Goldstein-Piekarski","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,5,7]]},"reference":[{"key":"2431_CR1","doi-asserted-by":"publisher","first-page":"873","DOI":"10.1093\/sleep\/30.7.873","volume":"30","author":"D Neckelmann","year":"2007","unstructured":"Neckelmann D, Mykletun A, Dahl AA. 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