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Dopaminergic drug treatment remediates exaggerated cingulate prediction error responses in obsessive-compulsive disorder

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cam.issuedOnline2019-06-14
datacite.isderivedfrom.doi10.1101/225938
dc.contributor.authorMurray, Graham
dc.contributor.authorKnolle, Franziska
dc.contributor.authorErsche, Karen
dc.contributor.authorCraig, Kevin
dc.contributor.authorAbbot, Sanja
dc.contributor.authorShabbir, Shalia
dc.contributor.authorFineberg, Naomi
dc.contributor.authorSuckling, John
dc.contributor.authorSahakian, Barbara
dc.contributor.authorBullmore, Edward
dc.contributor.authorRobbins, Trevor
dc.contributor.orcidMurray, Graham [0000-0001-8296-1742]
dc.contributor.orcidKnolle, Franziska [0000-0002-9542-613X]
dc.contributor.orcidErsche, Karen [0000-0002-3203-1878]
dc.contributor.orcidRobbins, Trevor [0000-0003-0642-5977]
dc.date.accessioned2019-06-21T13:34:32Z
dc.date.available2019-06-21T13:34:32Z
dc.date.issued2019-08
dc.description.abstractRationale: Patients with obsessive-compulsive disorder (OCD) have been found to show exaggerated error responses and prediction error learning signals in a variety of EEG and fMRI tasks, with data converging on the anterior cingulate cortex as a key locus of dysfunction. Considerable evidence has linked prediction error processing to dopaminergic function. Objective: In this study we investigate potential dopaminergic dysfunction during reward processing in the context of OCD. Methods: We studied OCD patients (n=18) and controls (n=18) whilst they learned probabilistic associations between abstract stimuli and monetary rewards in the fMRI scanner involving administration (on separate visits) of: a dopamine receptor agonist, pramipexole 0.5mg; a dopamine receptor antagonist, amisulpride 400mg, and placebo. We fitted a Q-learning computational model to fMRI prediction error responses; group differences were examined in anterior cingulate and nucleus accumbens regions of interest. Results: There were no significant group, drug or interaction effects in number of correct choices; computational modeling suggested a marginally significant difference in learning rates between groups (p=0.089, partial ƞ2=0.1). In the imaging results, there was a significant interaction of group by drug (p=0.013, partial ƞ2=0.13). OCD patients showed abnormally strong cingulate signaling of prediction errors during omission of an expected reward, with unexpected reduction by both pramipexole and amisulpride (p=0.014, partial ƞ2=0.26, 1-β error probability=0.94). Exaggerated cingulate prediction error signaling to omitted reward in placebo was related to trait subjective difficulty in self-regulating behavior in OCD. Conclusions Our data support cingulate dysfunction during reward processing in OCD, and bidirectional remediation by dopaminergic modulation, suggesting that exaggerated cingulate error signals in OCD may be of dopaminergic origin. The results help to illuminate the mechanisms through which dopamine receptor antagonists achieve therapeutic benefit in OCD. Further research is needed to disentangle the different functions of dopamine receptor agonists and antagonists during bidirectional modulation of cingulate activation.
dc.description.sponsorshipSupported by an award from GSK to University of Cambridge (RG45422, Principal Investigator TWR), a Wellcome Trust Senior Investigator Award (104631/Z/14/Z) to TWR, by a MRC Clinician Scientist award (G0701911) to GKM, and by a Betty Behrens Research Fellowship of Clare Hall to KDE. The research was conducted in the University of Cambridge Behavioural and Clinical Neuroscience Institute which was supported by a joint award from the Medical Research Council (G1000183) and Wellcome Trust (093875/Z/10Z)
dc.identifier.doi10.17863/CAM.40967
dc.identifier.eissn1432-2072
dc.identifier.issn0033-3158
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/293857
dc.language.isoeng
dc.publisherSpringer Verlag
dc.publisher.urlhttps://link.springer.com/article/10.1007/s00213-019-05292-2
dc.rightsAttribution 4.0 International
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/
dc.subjectAmisulpride
dc.subjectAnterior cingulate
dc.subjectComputational model
dc.subjectNucleus accumbens
dc.subjectObsessive-compulsive disorder
dc.subjectPramipexole
dc.subjectPrediction error
dc.subjectReward learning
dc.subjectAdult
dc.subjectDopamine
dc.subjectDopamine Agonists
dc.subjectDopamine Antagonists
dc.subjectDouble-Blind Method
dc.subjectFemale
dc.subjectForecasting
dc.subjectGyrus Cinguli
dc.subjectHumans
dc.subjectMagnetic Resonance Imaging
dc.subjectMale
dc.subjectMiddle Aged
dc.subjectNucleus Accumbens
dc.subjectObsessive-Compulsive Disorder
dc.subjectPhotic Stimulation
dc.subjectReward
dc.titleDopaminergic drug treatment remediates exaggerated cingulate prediction error responses in obsessive-compulsive disorder
dc.typeArticle
dcterms.dateAccepted2019-05-29
prism.endingPage12
prism.publicationNamePsychopharmacology
prism.startingPage1
pubs.funder-project-idMedical Research Council (G1000183)
pubs.funder-project-idMedical Research Council (G0001354)
pubs.funder-project-idMedical Research Council (G0701911)
pubs.funder-project-idWellcome Trust (093875/Z/10/Z)
pubs.funder-project-idWellcome Trust (104631/Z/14/Z)
pubs.funder-project-idMedical Research Council (G0701911/1)
rioxxterms.licenseref.startdate2019-05-29
rioxxterms.licenseref.urihttp://creativecommons.org/licenses/by/4.0/
rioxxterms.typeJournal Article/Review
rioxxterms.versionVoR
rioxxterms.versionofrecord10.1007/s00213-019-05292-2

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