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Here, we use multisite local field potential recordings and interpretable machine learning to identify large-scale brain networks engaged by repeated opioid exposure and withdrawal. After discovering that repeated fentanyl exposure induces a network of widespread high beta and low gamma oscillations, we then identified a distinct brain network that selectively encodes the emergence and severity of opioid withdrawal. This latter network, termed\n                  <jats:italic>EN-Withdrawal<\/jats:italic>\n                  , is characterized by regional gamma oscillations and widely synchronized delta\/theta oscillations. Its activity patterns predict the emergence of spontaneous and naloxone-precipitated withdrawal across multiple independent cohorts, generalizing across mice, sex, opioids, and dosing regimens, while persisting over multiple days of withdrawal. Using a novel, data-driven severity index, we find that network activity scales with individual behavioral severity without simply reflecting ongoing somatic behaviors or general aversion, suggesting that\n                  <jats:italic>EN-Withdrawal<\/jats:italic>\n                  underlies a withdrawal-induced internal state. Strikingly, network activity predicts the escalation of fentanyl self-administration on a mouse-by-mouse basis in experienced, but not drug-na\u00efve, animals. These findings reveal a neurophysiological substrate of the negative reinforcement cycle of addiction that shapes individual vulnerability.\n                <\/jats:p>","DOI":"10.64898\/2026.05.04.722791","type":"posted-content","created":{"date-parts":[[2026,5,8]],"date-time":"2026-05-08T20:05:18Z","timestamp":1778270718000},"source":"Crossref","is-referenced-by-count":0,"title":["A widespread internal brain state for fentanyl withdrawal"],"prefix":"10.64898","author":[{"given":"Karim","family":"Abdelaal","sequence":"first","affiliation":[{"name":"Dept. of Neurobiology, Duke University Medical Center, Durham, North Carolina 27710, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kathryn K.","family":"Walder-Christensen","sequence":"additional","affiliation":[{"name":"Dept. of Psychiatry and Behavioral Sciences, Duke University Medical Center, Durham, North Carolina 27710, USA"},{"name":"Howard Hughes Medical Institute, Chevy Chase, Maryland 20815, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cameron","family":"Blount","sequence":"additional","affiliation":[{"name":"Dept. of Psychiatry and Behavioral Sciences, Duke University Medical Center, Durham, North Carolina 27710, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kellie M.","family":"Williford","sequence":"additional","affiliation":[{"name":"Dept. of Psychiatry and Behavioral Sciences, Duke University Medical Center, Durham, North Carolina 27710, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marisella","family":"Adams-Grimaldi","sequence":"additional","affiliation":[{"name":"Dept. of Psychology & Neuroscience, Duke University, Durham, North Carolina 27710, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephen D.","family":"Mague","sequence":"additional","affiliation":[{"name":"Dept. of Psychiatry and Behavioral Sciences, Duke University Medical Center, Durham, North Carolina 27710, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1005-6385","authenticated-orcid":false,"given":"David E.","family":"Carlson","sequence":"additional","affiliation":[{"name":"Dept. of Biostatistics and Bioinformatics, Duke University Medical Center, Durham, North Carolina 27710, USA"},{"name":"Dept. of Civil and Environmental Engineering, Duke University, Durham North Carolina 27708, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4280-9994","authenticated-orcid":false,"given":"Kafui","family":"Dzirasa","sequence":"additional","affiliation":[{"name":"Dept. of Neurobiology, Duke University Medical Center, Durham, North Carolina 27710, USA"},{"name":"Dept. of Psychiatry and Behavioral Sciences, Duke University Medical Center, Durham, North Carolina 27710, USA"},{"name":"Howard Hughes Medical Institute, Chevy Chase, Maryland 20815, USA"},{"name":"Dept. of Neurosurgery, Duke University Medical Center, Durham, North Carolina 27710, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2026101207400925000_2026.05.04.722791v2.1","unstructured":"House, T. 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