title: Noradrenaline transporter blockade increases fronto-parietal functional connectivity relevant for working memory.
abstract: Experimental animal work has demonstrated that dopamine and noradrenaline play an essential role in modulating prefrontal cortex-mediated networks underlying working memory performance. Studies of functional connectivity have been instrumental in extending such notions to humans but, so far, have almost exclusively focussed on pharmacological agents with a predominant dopaminergic mechanism of action. Here, we investigate the effect of a single dose of atomoxetine 60mg, a noradrenaline transporter inhibitor, on working memory performance and associated functional connectivity during an n-back task in 19 healthy male volunteers. Atomoxetine increased functional connectivity between right anterior insula and dorsolateral prefrontal cortex, precentral gyrus, posterior parietal cortex and precuneus during the high-working memory load condition of the n-back task. Increased atomoxetine-induced insula-dorsolateral prefrontal cortex functional connectivity during this condition correlated with decreased reaction time variability and was furthermore predicted by working memory capacity. These results show for the first time that noradrenaline transporter blockade-induced increases in cortical catecholamines accentuate fronto-parietal working memory-related network integrity. The observation of significant inter-subject variability in response to atomoxetine has implications for inverted-U frameworks of dopamine and noradrenaline function, which could be useful to predict drug effects in clinical disorders with variable treatment response.
authors.affiliation: University of Maryland School of Medicine, Department of Psychiatry; Maryland Psychiatric Research Center, MD, USA. Electronic address: dhernaus@mprc.umaryland.edu.
authors.forename: Dennis
authors.initials: D
authors.lastname: Hernaus
authors.affiliation: Department of Psychiatry and Neuropsychology, South Limburg Mental Health Research and Teaching Network, EURON, School for Mental Health and NeuroScience MHeNS Maastricht University, Maastricht, The Netherlands.
authors.forename: Marta Ma
authors.initials: MM
authors.lastname: Casales Santa
authors.affiliation: Department of Psychiatry and Neuropsychology, South Limburg Mental Health Research and Teaching Network, EURON, School for Mental Health and NeuroScience MHeNS Maastricht University, Maastricht, The Netherlands.
authors.forename: Jan Stefan
authors.initials: JS
authors.lastname: Offermann
authors.affiliation: Department of Psychiatry and Neuropsychology, South Limburg Mental Health Research and Teaching Network, EURON, School for Mental Health and NeuroScience MHeNS Maastricht University, Maastricht, The Netherlands.
authors.forename: Thérèse
authors.initials: T
authors.lastname: Van Amelsvoort
mesh_terms: D000293:Adolescent; D018759:Adrenergic Uptake Inhibitors / Q000494:pharmacology*; D000328:Adult; D000069445:Atomoxetine Hydrochloride / Q000494:pharmacology*; D001931:Brain Mapping; D002540:Cerebral Cortex / Q000000981:diagnostic imaging / Q000187:drug effects* / Q000378:metabolism; D018592:Cross-Over Studies; D004311:Double-Blind Method; D007839:Functional Laterality / Q000187:drug effects; D064368:Healthy Volunteers; D006801:Humans; D007091:Image Processing, Computer-Assisted; D008279:Magnetic Resonance Imaging; D008297:Male; D008570:Memory, Short-Term / Q000187:drug effects* / Q000502:physiology; D009415:Nerve Net / Q000000981:diagnostic imaging / Q000187:drug effects*; D010100:Oxygen / Q000097:blood; D011930:Reaction Time / Q000187:drug effects; D055815:Young Adult
chemical_list: D018759:Adrenergic Uptake Inhibitors; D000069445:Atomoxetine Hydrochloride; D010100:Oxygen
keywords: Cognition; Dopamine; FMRI; Noradrenaline; Prefrontal cortex; Working memory