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The serotonin hypothesis for <jats:styled-content style=\"fixed-case\">SUDEP<\/jats:styled-content> proposes that modifying serotonergic function significantly alters susceptibility to seizure\u2010induced respiratory arrest (S\u2010<jats:styled-content style=\"fixed-case\">IRA<\/jats:styled-content>). Agents that enhance serotonergic function, including a selective serotonin reuptake inhibitor, fluoxetine, selectively prevent S\u2010<jats:styled-content style=\"fixed-case\">IRA<\/jats:styled-content> in <jats:styled-content style=\"fixed-case\">DBA<\/jats:styled-content>\/1 mice. This study examined fluoxetine\u2010induced changes in brain activity using manganese\u2010enhanced magnetic resonance imaging (<jats:styled-content style=\"fixed-case\">MEMRI<\/jats:styled-content>) to reveal sites in the <jats:styled-content style=\"fixed-case\">DBA<\/jats:styled-content>\/1 mouse brain where fluoxetine acts to prevent S\u2010<jats:styled-content style=\"fixed-case\">IRA<\/jats:styled-content>.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p><jats:styled-content style=\"fixed-case\">DBA<\/jats:styled-content>\/1 mice were subjected to audiogenic seizures (Sz) after saline or fluoxetine (45\u00a0mg\/kg, intraperitoneal) administration. Control <jats:styled-content style=\"fixed-case\">DBA<\/jats:styled-content>\/1 mice received fluoxetine or saline, but Sz were not evoked. A previous <jats:styled-content style=\"fixed-case\">MEMRI<\/jats:styled-content> study established the regions of interest (<jats:styled-content style=\"fixed-case\">ROI<\/jats:styled-content>s) for Sz in the <jats:styled-content style=\"fixed-case\">DBA<\/jats:styled-content>\/1 mouse brain, and the present study examined <jats:styled-content style=\"fixed-case\">MEMRI<\/jats:styled-content> differences in the <jats:styled-content style=\"fixed-case\">ROI<\/jats:styled-content>s of these mouse groups.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>The neural activity in several <jats:styled-content style=\"fixed-case\">ROI<\/jats:styled-content>s was significantly increased in fluoxetine\u2010treated <jats:styled-content style=\"fixed-case\">DBA<\/jats:styled-content>\/1 mice that exhibited Sz but not S\u2010<jats:styled-content style=\"fixed-case\">IRA<\/jats:styled-content> when compared to the saline\u2010treated mice that exhibited both Sz and respiratory arrest. These structures included the periaqueductal gray (<jats:styled-content style=\"fixed-case\">PAG<\/jats:styled-content>), amygdala, reticular formation (sensorimotor\u2010limbic network), K\u00f6lliker\u2010Fuse nucleus, facial\u2010parafacial group (respiratory network), and pontine raphe. Of these <jats:styled-content style=\"fixed-case\">ROI<\/jats:styled-content>s, only the <jats:styled-content style=\"fixed-case\">PAG<\/jats:styled-content> showed significantly decreased neural activity with saline pretreatment when seizure\u2010induced respiratory arrest occurred as compared to saline treatment without seizure.<\/jats:p><\/jats:sec><jats:sec><jats:title>Significance<\/jats:title><jats:p>The <jats:styled-content style=\"fixed-case\">PAG<\/jats:styled-content> is known to play an important compensatory role for respiratory distress caused by numerous exigent situations in normal animals. The pattern of fluoxetine\u2010induced activity changes in the present study suggests that <jats:styled-content style=\"fixed-case\">PAG<\/jats:styled-content> may be the most critical target for fluoxetine's action to prevent seizure\u2010induced sudden death. These findings have potential clinical importance, because there is evidence of anomalous serotonergic function and <jats:styled-content style=\"fixed-case\">PAG<\/jats:styled-content> imaging abnormalities in human <jats:styled-content style=\"fixed-case\">SUDEP<\/jats:styled-content>.<\/jats:p><\/jats:sec>","DOI":"10.1111\/epi.14759","type":"journal-article","created":{"date-parts":[[2019,5,6]],"date-time":"2019-05-06T20:11:57Z","timestamp":1557173517000},"page":"1221-1233","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":13,"title":["Neural activity in the periaqueductal gray and other specific subcortical structures is enhanced when a <scp>selective serotonin reuptake inhibitor<\/scp> selectively prevents seizure\u2010induced sudden death in the <scp>DBA<\/scp>\/1 mouse model of <scp>sudden unexpected death in epilepsy<\/scp>"],"prefix":"10.1111","volume":"60","author":[{"given":"Srinivasa 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