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dc.contributor.authorHerz, Damian Men
dc.contributor.authorHaagensen, Brian Nen
dc.contributor.authorChristensen, Mark Sen
dc.contributor.authorMadsen, Kristoffer Hen
dc.contributor.authorRowe, Jamesen
dc.contributor.authorLøkkegaard, Annemetteen
dc.contributor.authorSiebner, Hartwig Ren
dc.date.accessioned2016-02-02T15:11:30Z
dc.date.available2016-02-02T15:11:30Z
dc.date.issued2015-04-15en
dc.identifier.citationHerz et al. Brain (2015). Volume 138, issue 6: pp. 1658-1666. DOI: 10.1093/brain/awv096en
dc.identifier.issn0006-8950
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/253600
dc.description.abstractDopaminergic signalling in the striatum contributes to reinforcement of actions and motivational enhancement of motor vigour. Parkinson's disease leads to progressive dopaminergic denervation of the striatum, impairing the function of cortico-basal ganglia networks. While levodopa therapy alleviates basal ganglia dysfunction in Parkinson's disease, it often elicits involuntary movements, referred to as levodopa-induced peak-of-dose dyskinesias. Here, we used a novel pharmacodynamic neuroimaging approach to identify the changes in cortico-basal ganglia connectivity that herald the emergence of levodopa-induced dyskinesias. Twenty-six patients with Parkinson's disease (age range: 51–84 years; 11 females) received a single dose of levodopa and then performed a task in which they had to produce or suppress a movement in response to visual cues. Task-related activity was continuously mapped with functional magnetic resonance imaging. Dynamic causal modelling was applied to assess levodopa-induced modulation of effective connectivity between the pre-supplementary motor area, primary motor cortex and putamen when patients suppressed a motor response. Bayesian model selection revealed that patients who later developed levodopa-induced dyskinesias, but not patients without dyskinesias, showed a linear increase in connectivity between the putamen and primary motor cortex after levodopa intake during movement suppression. Individual dyskinesia severity was predicted by levodopa-induced modulation of striato-cortical feedback connections from putamen to the pre-supplementary motor area (P_corrected = 0.020) and primary motor cortex (P_corrected = 0.044), but not feed-forward connections from the cortex to the putamen. Our results identify for the first time, aberrant dopaminergic modulation of striatal-cortical connectivity as a neural signature of levodopa-induced dyskinesias in humans. We argue that excessive striato-cortical connectivity in response to levodopa produces an aberrant reinforcement signal producing an abnormal motor drive that ultimately triggers involuntary movements.
dc.description.sponsorshipThis work was supported by the Danish Medical Research Council (FSS 09-072163), a Grant of Excellence sponsored by The Lundbeck Foundation Mapping, Modulation & Modeling the Control of Actions (ContAct) (R59-A5399 to H.R.S.), the Wellcome Trust (088324 to J.B.R.) and the Medical Research Council (MC-A060-5PQ30 to J.B.R.). The funding sources had no involvement in the undertaking of the study.
dc.languageEnglishen
dc.language.isoenen
dc.publisherOxford University Press
dc.rightsAttribution 2.0 UK: England & Wales*
dc.rights.urihttp://creativecommons.org/licenses/by/2.0/uk/*
dc.subjectParkinson's diseaseen
dc.subjectlevodopa-induced dyskinesiaen
dc.subjectconnectivityen
dc.subjectfunctional MRIen
dc.subjectdynamic causal modellingen
dc.titleAbnormal dopaminergic modulation of striato-cortical networks underlies levodopa-induced dyskinesias in humansen
dc.typeArticle
dc.provenanceZD-13790
dc.description.versionThis is the final version of the article. It first appeared from Oxford University Press via http://dx.doi.org/10.1093/brain/awv096en
prism.endingPage1666
prism.publicationDate2015en
prism.publicationNameBrainen
prism.startingPage1658
prism.volume138en
dc.rioxxterms.funderWellcome Trust
dc.rioxxterms.funderMRC
dc.rioxxterms.projectid088324
dc.rioxxterms.projectidMC-A060-5PQ30
dcterms.dateAccepted2015-02-11en
rioxxterms.versionofrecord10.1093/brain/awv096en
rioxxterms.licenseref.urihttp://www.rioxx.net/licenses/all-rights-reserveden
rioxxterms.licenseref.startdate2015-04-15en
dc.contributor.orcidRowe, James [0000-0001-7216-8679]
dc.identifier.eissn1460-2156
rioxxterms.typeJournal Article/Reviewen
pubs.funder-project-idMEDICAL RESEARCH COUNCIL (G0001354)
pubs.funder-project-idWellcome Trust (088324/Z/09/Z)
pubs.funder-project-idMedical Research Council (MC_U105597119)


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Attribution 2.0 UK: England & Wales
Except where otherwise noted, this item's licence is described as Attribution 2.0 UK: England & Wales