{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,16]],"date-time":"2026-10-16T18:45:10Z","timestamp":1792176310854,"version":"4.4.0"},"reference-count":89,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2023,2,23]],"date-time":"2023-02-23T00:00:00Z","timestamp":1677110400000},"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. Pediatr."],"abstract":"<jats:p>The opioid epidemic is an ongoing public health crisis, and children born following prenatal opioid exposure (POE) have increased risk of long-term cognitive and behavioral sequelae. Clinical studies have identified reduced gray matter volume and abnormal white matter microstructure in children with POE but impacts on whole-brain functional brain connectivity (FC) have not been reported. To define effects of POE on whole brain FC and white matter injury in adult animals, we performed quantitative whole-brain structural and functional MRI. We used an established rat model of POE in which we have previously reported impaired executive function in adult rats analogous to persistent neurocognitive symptoms described in humans with POE. Pregnant Sprague-Dawley rat dams received continuous methadone (12\u2005mg\/kg\/day) vs. saline infusion for 28 days via osmotic mini-pumps, exposing rats to pre- and postnatal opioid until weaning. At young adult age (P60), POE and saline exposed offspring underwent <jats:italic>in vivo<\/jats:italic> MRI included diffusion tensor imaging and functional MRI (fMRI). Results indicate that fractional anisotropy (FA) was decreased in adult animals with POE [<jats:italic>n<\/jats:italic>\u2009=\u200911] compared to animals that received saline [<jats:italic>n<\/jats:italic>\u2009=\u20099] in major white matter tracts, including the corpus callosum (<jats:italic>p<\/jats:italic>\u2009&amp;lt;\u20090.001) and external capsule (<jats:italic>p<\/jats:italic>\u2009&amp;lt;\u20090.01). This change in FA was concomitant with reduced axial diffusivity in the external capsule (<jats:italic>p<\/jats:italic>\u2009&amp;lt;\u20090.01) and increased radial diffusivity in the corpus callosum (<jats:italic>p<\/jats:italic>\u2009&amp;lt;\u20090.01). fMRI analyses reveal brainwide FC was diffusely lower in POE (<jats:italic>p<\/jats:italic>\u2009&amp;lt;\u200910<jats:sup>\u22126<\/jats:sup>; 10% of variance explained by group). Decreased connectivity in cortical-cortical and cortico-basal ganglia circuitry was particularly prominent with large effect sizes (Glass's \u0394\u2009&amp;gt;\u20091). Taken together, these data confirm POE reduces brainwide functional connectivity as well as microstructural integrity of major white matter tracts. Altered neural circuitry, dysregulated network refinement, and diffuse network dysfunction have been implicated in executive function deficits that are common in children with POE. FC may serve as a translatable biomarker in children with POE.<\/jats:p>","DOI":"10.3389\/fped.2023.1139378","type":"journal-article","created":{"date-parts":[[2023,2,23]],"date-time":"2023-02-23T09:47:21Z","timestamp":1677145641000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":18,"title":["In utero methadone exposure permanently alters anatomical and functional connectivity: A preclinical evaluation"],"prefix":"10.3389","volume":"11","author":[{"given":"Eric M.","family":"Chin","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuma","family":"Kitase","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nethra K.","family":"Madurai","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shenandoah","family":"Robinson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lauren L.","family":"Jantzie","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2023,2,23]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1542\/peds.2018-3801","article-title":"Public health surveillance of prenatal opioid\u00a0exposure in mothers and infants","volume":"143","author":"Honein","year":"2019","journal-title":"Pediatrics"},{"key":"B2","year":""},{"key":"B3","doi-asserted-by":"publisher","first-page":"e12895","DOI":"10.1111\/adb.12895","article-title":"Enduring consequences of perinatal fentanyl exposure in mice","volume":"26","author":"Alipio","year":"2021","journal-title":"Addict Biol"},{"key":"B4","doi-asserted-by":"publisher","first-page":"279","DOI":"10.15585\/mmwr.mm6709e1","article-title":"Vital signs: trends in emergency department visits for suspected opioid overdoses\u2014united States, July 2016-September 2017","volume":"67","author":"Vivolo-Kantor","year":"2018","journal-title":"MMWR Morb Mortal Wkly Rep"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1542\/peds.2016-2651","article-title":"Neonatal abstinence syndrome and high school performance","volume":"139","author":"Oei","year":"2017","journal-title":"Pediatrics"},{"key":"B6","year":""},{"key":"B7","author":"Howse","year":""},{"key":"B8","year":""},{"key":"B9","doi-asserted-by":"publisher","first-page":"108350","DOI":"10.1016\/j.drugalcdep.2020.108350","article-title":"The economic burden of opioid use disorder and fatal opioid overdose in the United States, 2017","volume":"218","author":"Florence","year":"2021","journal-title":"Drug Alcohol Depend"},{"key":"B10","doi-asserted-by":"publisher","first-page":"901","DOI":"10.1097\/MLR.0000000000000625","article-title":"The economic burden of prescription opioid overdose, abuse, and dependence in the United States, 2013","volume":"54","author":"Florence","year":"2016","journal-title":"Med Care"},{"key":"B11","doi-asserted-by":"publisher","first-page":"529","DOI":"10.1057\/s41271-020-00239-w","article-title":"Opioid exposure in newborns: lessons learned from fetal alcohol spectrum disorder","volume":"41","author":"Ogunyankin","year":"2020","journal-title":"J Public Health Policy"},{"key":"B12","doi-asserted-by":"publisher","first-page":"750","DOI":"10.1111\/dmcn.14117","article-title":"Childhood neurodevelopment after prescription of maintenance methadone for opioid dependency in pregnancy: a systematic review and meta-analysis","volume":"61","author":"Monnelly","year":"2019","journal-title":"Dev Med Child Neurol"},{"key":"B13","doi-asserted-by":"publisher","first-page":"650","DOI":"10.1038\/jp.2015.36","article-title":"Increasing incidence and geographic distribution of neonatal abstinence syndrome: united States 2009 to 2012","volume":"35","author":"Patrick","year":"2015","journal-title":"J Perinatol"},{"key":"B14","doi-asserted-by":"publisher","first-page":"272","DOI":"10.1016\/j.neuroscience.2021.03.014","article-title":"Maternal opioid exposure culminates in perturbed murine neurodevelopment and hyperactive phenotype in adolescence","volume":"463","author":"Schlagal","year":"2021","journal-title":"Neuroscience"},{"key":"B15","doi-asserted-by":"publisher","first-page":"47","DOI":"10.1038\/s41572-018-0045-0","article-title":"Neonatal abstinence syndrome","volume":"4","author":"Coyle","year":"2018","journal-title":"Nat Rev Dis Primers"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.1542\/peds.2016-4070","article-title":"Committee on substance USE, prevention. 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