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As the noradrenergic system is likely to support cognitive functions including attention and executive control, other clinical uses of clonidine have recently gained popularity for the treatment of neuropsychiatric disorders like attention\u2010deficit hyperactivity disorder or Tourette syndrome, but the mechanism of action is still unclear. Here, we test the hypothesis that the noradrenergic system regulates the activity of subthalamo\u2010motor cortical loops, and that this influence can be modulated by clonidine. We used pharmacological manipulation of clonidine in a placebo\u2010controlled study in combination with subthalamic nucleus\u2010deep brain stimulation (<jats:styled-content style=\"fixed-case\">STN<\/jats:styled-content>\u2010<jats:styled-content style=\"fixed-case\">DBS<\/jats:styled-content>) in 16 Parkinson's disease patients performing a reaction time task requiring to refrain from reacting (proactive inhibition). We recorded electroencephalographical activity of the whole cortex, and applied spectral analyses directly at the source level after advanced blind source separation. We found only one cortical source localized to the supplementary motor area (<jats:styled-content style=\"fixed-case\">SMA<\/jats:styled-content>) that supported an interaction of pharmacological and subthalamic stimulation. Under placebo, <jats:styled-content style=\"fixed-case\">STN<\/jats:styled-content>\u2010<jats:styled-content style=\"fixed-case\">DBS<\/jats:styled-content> reduced proactive alpha power in the <jats:styled-content style=\"fixed-case\">SMA<\/jats:styled-content>, a marker of local inhibitory activity. This effect was associated with the speeding\u2010up of movement initiation. Clonidine substantially increased proactive alpha power from the <jats:styled-content style=\"fixed-case\">SMA<\/jats:styled-content> source, and canceled out the benefits of <jats:styled-content style=\"fixed-case\">STN<\/jats:styled-content>\u2010<jats:styled-content style=\"fixed-case\">DBS<\/jats:styled-content> on movement initiation. These results provide the first direct neural evidence in humans that the tonic inhibitory activity of the subthalamocortical loops underlying the control of movement initiation is coupled to the noradrenergic system, and that this activity can be targeted by pharmacological agents acting on alpha\u2010adrenergic receptors.<\/jats:p><\/jats:sec><jats:sec><jats:label\/><jats:p>\n<jats:boxed-text content-type=\"graphic\" position=\"anchor\"><jats:graphic xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" mimetype=\"image\/png\" position=\"anchor\" specific-use=\"enlarged-web-image\" xlink:href=\"graphic\/jnc14447-fig-0005-m.png\"><jats:alt-text>image<\/jats:alt-text><\/jats:graphic><\/jats:boxed-text>\n<\/jats:p><\/jats:sec>","DOI":"10.1111\/jnc.14447","type":"journal-article","created":{"date-parts":[[2018,4,20]],"date-time":"2018-04-20T07:17:36Z","timestamp":1524208656000},"page":"333-347","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":22,"title":["Clonidine modulates the activity of the subthalamic\u2010supplementary motor loop: evidence from a pharmacological study combining deep brain stimulation and electroencephalography recordings in Parkinsonian patients"],"prefix":"10.1111","volume":"146","author":[{"given":"Charlotte","family":"Spay","sequence":"first","affiliation":[{"name":"Universit\u00e9 de Lyon  Lyon France"},{"name":"Universit\u00e9 Lyon 1  Villeurbanne France"},{"name":"INSERM, U 1028 Lyon Neuroscience Research Center  Lyon France"},{"name":"CNRS, UMR 5292 Lyon Neuroscience Research 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