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dc.contributor.authorHezemans, Frank H
dc.contributor.authorWolpe, Noham
dc.contributor.authorO'Callaghan, Claire
dc.contributor.authorYe, Rong
dc.contributor.authorRua, Catarina
dc.contributor.authorJones, Simon
dc.contributor.authorMurley, Alexander
dc.contributor.authorHolland, Negin
dc.contributor.authorRegenthal, Ralf
dc.contributor.authorTsvetanov, Kamen A.
dc.contributor.authorBarker, Roger
dc.contributor.authorWilliams-Gray, Caroline H
dc.contributor.authorRobbins, Trevor W
dc.contributor.authorPassamonti, Luca
dc.contributor.authorRowe, James B
dc.date.accessioned2022-05-19T20:00:14Z
dc.date.available2022-05-19T20:00:14Z
dc.date.issued2022-05
dc.date.submitted2021-10-05
dc.identifier.issn1553-734X
dc.identifier.otherpcompbiol-d-21-01786
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/337316
dc.descriptionFunder: Cambridge Trust Vice-Chancellor's Award Award for Medical Sciences
dc.descriptionFunder: Fitzwilliam College scholarship
dc.descriptionFunder: Association of British Neurologists, Patrick Berthoud Charitable Trust
dc.description.abstractApathy is a debilitating feature of many neuropsychiatric diseases, that is typically described as a reduction of goal-directed behaviour. Despite its prevalence and prognostic importance, the mechanisms underlying apathy remain controversial. Degeneration of the locus coeruleus-noradrenaline system is known to contribute to motivational deficits, including apathy. In healthy people, noradrenaline has been implicated in signalling the uncertainty of expectations about the environment. We proposed that noradrenergic deficits contribute to apathy by modulating the relative weighting of prior beliefs about action outcomes. We tested this hypothesis in the clinical context of Parkinson's disease, given its associations with apathy and noradrenergic dysfunction. Participants with mild-to-moderate Parkinson's disease (N = 17) completed a randomised double-blind, placebo-controlled, crossover study with 40 mg of the noradrenaline reuptake inhibitor atomoxetine. Prior weighting was inferred from psychophysical analysis of performance in an effort-based visuomotor task, and was confirmed as negatively correlated with apathy. Locus coeruleus integrity was assessed in vivo using magnetisation transfer imaging at ultra-high field 7T. The effect of atomoxetine depended on locus coeruleus integrity: participants with a more degenerate locus coeruleus showed a greater increase in prior weighting on atomoxetine versus placebo. The results indicate a contribution of the noradrenergic system to apathy and potential benefit from noradrenergic treatment of people with Parkinson's disease, subject to stratification according to locus coeruleus integrity. More broadly, these results reconcile emerging predictive processing accounts of the role of noradrenaline in goal-directed behaviour with the clinical symptom of apathy and its potential pharmacological treatment.
dc.languageen
dc.publisherPublic Library of Science (PLoS)
dc.subjectResearch Article
dc.subjectBiology and life sciences
dc.subjectMedicine and health sciences
dc.subjectSocial sciences
dc.subjectPhysical sciences
dc.subjectResearch and analysis methods
dc.titleNoradrenergic deficits contribute to apathy in Parkinson's disease through the precision of expected outcomes.
dc.typeArticle
dc.date.updated2022-05-19T20:00:13Z
prism.issueIdentifier5
prism.publicationNamePLoS Comput Biol
prism.volume18
dc.identifier.doi10.17863/CAM.84730
dcterms.dateAccepted2022-04-05
rioxxterms.versionofrecord10.1371/journal.pcbi.1010079
rioxxterms.versionVoR
rioxxterms.licenseref.urihttp://creativecommons.org/licenses/by/4.0/
datacite.contributor.supervisoreditor: Ahn, Woo-Young
dc.contributor.orcidHezemans, Frank H [0000-0003-0092-3289]
dc.contributor.orcidWolpe, Noham [0000-0002-4652-7727]
dc.contributor.orcidO'Callaghan, Claire [0000-0001-5698-6364]
dc.contributor.orcidYe, Rong [0000-0003-2529-7755]
dc.contributor.orcidRua, Catarina [0000-0002-0404-4399]
dc.contributor.orcidJones, Simon [0000-0001-9695-0702]
dc.contributor.orcidMurley, Alexander [0000-0003-0813-0670]
dc.contributor.orcidHolland, Negin [0000-0003-3813-0882]
dc.contributor.orcidRegenthal, Ralf [0000-0002-7292-1859]
dc.contributor.orcidTsvetanov, Kamen A. [0000-0002-3178-6363]
dc.contributor.orcidBarker, Roger [0000-0001-8843-7730]
dc.identifier.eissn1553-7358
pubs.funder-project-idBritish Academy (pf160048)
pubs.funder-project-idMedical Research Council (MR/P01271X/1)
pubs.funder-project-idMedical Research Council (MR/R007446/1)
pubs.funder-project-idNational Institute for Health Research (NIHRDH-IS-BRC-1215-20014)
cam.issuedOnline2022-05-09


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