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Despite known pharmacological properties, little is known regarding the effects of naltrexone on neural circuit function. Thus, a data\u2010driven examination of the neural effects of naltrexone in human subjects may offer novel insight into its treatment mechanisms.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Twenty\u2010one alcohol using males (22 to 39) participated in a double\u2010blind, placebo\u2010controlled crossover study of the effects of naltrexone on brain voxel\u2010wise functional connectivity (<jats:styled-content style=\"fixed-case\">FC<\/jats:styled-content>) using intersubject <jats:styled-content style=\"fixed-case\">FC<\/jats:styled-content> correlation mapping. We first cross\u2010correlated the time series from each gray matter voxel to produce a 6,356\u00a0\u00d7\u00a06,356 <jats:styled-content style=\"fixed-case\">FC<\/jats:styled-content> matrix for each subject and session. We then subtracted the placebo <jats:styled-content style=\"fixed-case\">FC<\/jats:styled-content> matrix from the naltrexone <jats:styled-content style=\"fixed-case\">FC<\/jats:styled-content> matrix. To identify brain regions demonstrating significant reconfiguration of whole\u2010brain <jats:styled-content style=\"fixed-case\">FC<\/jats:styled-content> patterns following naltrexone treatment, we statistically quantified the consistency of patterns of voxel <jats:styled-content style=\"fixed-case\">FC<\/jats:styled-content> changes across subjects. Permutation testing identified significant clusters of voxels undergoing significant reconfiguration. Using the identified clusters in a seed\u2010based FC analysis, we then compared the <jats:styled-content style=\"fixed-case\">FC<\/jats:styled-content> patterns of affected brain areas on placebo versus naltrexone in a paired <jats:italic>t<\/jats:italic>\u2010test. Ridge regression analyses identified self\u2010report measures, including substance use, that significantly predicted individual differences in <jats:styled-content style=\"fixed-case\">FC<\/jats:styled-content> among naltrexone\u2010modulated regions.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Two clusters in the rostral anterior cingulate cortex (<jats:styled-content style=\"fixed-case\">rACC<\/jats:styled-content>)\/ventromedial prefrontal cortex (vm<jats:styled-content style=\"fixed-case\">PFC<\/jats:styled-content>) demonstrated significant modulation of <jats:styled-content style=\"fixed-case\">FC<\/jats:styled-content> by naltrexone. Using these 2 proximal clusters as a single seed, specific <jats:styled-content style=\"fixed-case\">FC<\/jats:styled-content> changes were identified in regions associated with a left frontoparietal network (increasing), as well as visual and motor regions (decreasing). Stronger <jats:styled-content style=\"fixed-case\">FC<\/jats:styled-content> between the <jats:styled-content style=\"fixed-case\">rACC<\/jats:styled-content>\/vm<jats:styled-content style=\"fixed-case\">PFC<\/jats:styled-content> and this set of regions on placebo was associated with more external locus of control, whereas weaker connectivity was associated with greater substance use problems. Naltrexone strengthened these connections most among individuals who reported greater drinking to cope.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>Enhancing connectivity between the <jats:styled-content style=\"fixed-case\">rACC<\/jats:styled-content>\/vm<jats:styled-content style=\"fixed-case\">PFC<\/jats:styled-content>, implicated in alcohol craving, and components of a left frontoparietal network involved in executive control may represent an effective strategy for the treatment of <jats:styled-content style=\"fixed-case\">AUD<\/jats:styled-content>.<\/jats:p><\/jats:sec>","DOI":"10.1111\/acer.13999","type":"journal-article","created":{"date-parts":[[2019,3,8]],"date-time":"2019-03-08T14:09:54Z","timestamp":1552054194000},"page":"965-978","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":22,"title":["Naltrexone Acutely Enhances Connectivity Between the Ventromedial Prefrontal Cortex and a 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