title: Dopamine, Salience, and Response Set Shifting in Prefrontal Cortex.
abstract: Dopamine is implicated in multiple functions, including motor execution, action learning for hedonically salient outcomes, maintenance, and switching of behavioral response set. Here, we used a novel within-subject psychopharmacological and combined functional neuroimaging paradigm, investigating the interaction between hedonic salience, dopamine, and response set shifting, distinct from effects on action learning or motor execution. We asked whether behavioral performance in response set shifting depends on the hedonic salience of reversal cues, by presenting these as null (neutral) or salient (monetary loss) outcomes. We observed marked effects of reversal cue salience on set-switching, with more efficient reversals following salient loss outcomes. L-Dopa degraded this discrimination, leading to inappropriate perseveration. Generic activation in thalamus, insula, and striatum preceded response set switches, with an opposite pattern in ventromedial prefrontal cortex (vmPFC). However, the behavioral effect of hedonic salience was reflected in differential vmPFC deactivation following salient relative to null reversal cues. l-Dopa reversed this pattern in vmPFC, suggesting that its behavioral effects are due to disruption of the stability and switching of firing patterns in prefrontal cortex. Our findings provide a potential neurobiological explanation for paradoxical phenomena, including maintenance of behavioral set despite negative outcomes, seen in impulse control disorders in Parkinson's disease.
authors.affiliation: Wellcome Trust Centre for Neuroimaging, Institute of Neurology, University College London, London WC1N 3BG, UK.
authors.forename: T
authors.initials: T
authors.lastname: Shiner
authors.affiliation: Wellcome Trust Centre for Neuroimaging, Institute of Neurology, University College London, London WC1N 3BG, UK Nuffield Department of Clinical Neurosciences, University of Oxford, John Radcliffe Hospital, Oxford OX3 9DU, UK.
authors.forename: M
authors.initials: M
authors.lastname: Symmonds
authors.affiliation: Wellcome Trust Centre for Neuroimaging, Institute of Neurology, University College London, London WC1N 3BG, UK Ageing Research Center, Karolinska Institute, SE-113 30 Stockholm, Sweden.
authors.forename: M
authors.initials: M
authors.lastname: Guitart-Masip
authors.affiliation: Wellcome Trust Centre for Neuroimaging, Institute of Neurology, University College London, London WC1N 3BG, UK Center for Neural Science, New York University, New York, NY 10003, USA Department of Experimental Psychology, University of Oxford, Oxford OX1 3UD, UK.
authors.forename: S M
authors.initials: SM
authors.lastname: Fleming
authors.affiliation: Wellcome Trust Centre for Neuroimaging, Institute of Neurology, University College London, London WC1N 3BG, UK.
authors.forename: K J
authors.initials: KJ
authors.lastname: Friston
authors.affiliation: Wellcome Trust Centre for Neuroimaging, Institute of Neurology, University College London, London WC1N 3BG, UK.
authors.forename: R J
authors.initials: RJ
authors.lastname: Dolan
mesh_terms: D000328:Adult; D001288:Attention / Q000187:drug effects / Q000502:physiology*; D001931:Brain Mapping; D003342:Corpus Striatum / Q000187:drug effects / Q000502:physiology; D003463:Cues; D004298:Dopamine / Q000502:physiology*; D015259:Dopamine Agents / Q000494:pharmacology; D006801:Humans; D007980:Levodopa / Q000494:pharmacology; D008279:Magnetic Resonance Imaging; D008297:Male; D017397:Prefrontal Cortex / Q000187:drug effects / Q000502:physiology*; D012193:Reversal Learning / Q000502:physiology*; D013788:Thalamus / Q000187:drug effects / Q000502:physiology; D055815:Young Adult
chemical_list: D015259:Dopamine Agents; D007980:Levodopa; D004298:Dopamine
keywords: dopamine; fMRI; prefrontal cortex; reversal learning; set shifting