title: Confidence and psychosis: a neuro-computational account of contingency learning disruption by NMDA blockade.
abstract: A state of pathological uncertainty about environmental regularities might represent a key step in the pathway to psychotic illness. Early psychosis can be investigated in healthy volunteers under ketamine, an NMDA receptor antagonist. Here, we explored the effects of ketamine on contingency learning using a placebo-controlled, double-blind, crossover design. During functional magnetic resonance imaging, participants performed an instrumental learning task, in which cue-outcome contingencies were probabilistic and reversed between blocks. Bayesian model comparison indicated that in such an unstable environment, reinforcement learning parameters are downregulated depending on confidence level, an adaptive mechanism that was specifically disrupted by ketamine administration. Drug effects were underpinned by altered neural activity in a fronto-parietal network, which reflected the confidence-based shift to exploitation of learned contingencies. Our findings suggest that an early characteristic of psychosis lies in a persistent doubt that undermines the stabilization of behavioral policy resulting in a failure to exploit regularities in the environment.
authors.affiliation: Service de Psychiatrie, Centre Hospitalier Sainte-Anne, Université Paris Descartes, Sorbonne Paris Cité, Faculté de Médecine Paris Descartes, Paris, France.|Motivation, Brain, and Behavior Lab, Centre de Neuro-Imagerie de Recherche, Institut du Cerveau et de la Moelle épinière, Groupe Hospitalier Pitié-Salpêtrière, Paris, France.|INSERM U975, CNRS UMR 7225, UPMC-P6, UMR S 1127, Paris Cedex 13, France.
authors.forename: F
authors.initials: F
authors.lastname: Vinckier
authors.affiliation: Service de Psychiatrie, Centre Hospitalier Sainte-Anne, Université Paris Descartes, Sorbonne Paris Cité, Faculté de Médecine Paris Descartes, Paris, France.|Department of Psychiatry and Behavioural and Clinical Neuroscience Institute, University of Cambridge, Cambridge, UK.|Laboratoire de "Physiopathologie des maladies Psychiatriques", Centre de Psychiatrie et Neurosciences U894, INSERM; Université Paris Descartes, Sorbonne Paris Cité, Paris, France.
authors.forename: R
authors.initials: R
authors.lastname: Gaillard
authors.affiliation: Laboratoire de Neurosciences Cognitives (LNC), INSERM U960, Ecole Normale Supérieure (ENS), Paris, France.|Institute of Cognitive Neurosciences (ICN), University College London (UCL), London, UK.
authors.forename: S
authors.initials: S
authors.lastname: Palminteri
authors.affiliation: Motivation, Brain, and Behavior Lab, Centre de Neuro-Imagerie de Recherche, Institut du Cerveau et de la Moelle épinière, Groupe Hospitalier Pitié-Salpêtrière, Paris, France.|INSERM U975, CNRS UMR 7225, UPMC-P6, UMR S 1127, Paris Cedex 13, France.
authors.forename: L
authors.initials: L
authors.lastname: Rigoux
authors.affiliation: Service de Psychiatrie, Centre Hospitalier Sainte-Anne, Université Paris Descartes, Sorbonne Paris Cité, Faculté de Médecine Paris Descartes, Paris, France.|Laboratoire de "Physiopathologie des maladies Psychiatriques", Centre de Psychiatrie et Neurosciences U894, INSERM; Université Paris Descartes, Sorbonne Paris Cité, Paris, France.
authors.forename: A
authors.initials: A
authors.lastname: Salvador
authors.affiliation: Monash Clinical and Imaging Neuroscience, School of Psychological Sciences and Monash Biomedical Imaging, Monash University, Victoria, Australia.
authors.forename: A
authors.initials: A
authors.lastname: Fornito
authors.affiliation: Division of Anaesthesia, University of Cambridge, Cambridge, UK.|Addenbrooke's Hospital, Cambridge, UK.
authors.forename: R
authors.initials: R
authors.lastname: Adapa
authors.affiliation: Service de Psychiatrie, Centre Hospitalier Sainte-Anne, Université Paris Descartes, Sorbonne Paris Cité, Faculté de Médecine Paris Descartes, Paris, France.|Laboratoire de "Physiopathologie des maladies Psychiatriques", Centre de Psychiatrie et Neurosciences U894, INSERM; Université Paris Descartes, Sorbonne Paris Cité, Paris, France.
authors.forename: M O
authors.initials: MO
authors.lastname: Krebs
authors.affiliation: Motivation, Brain, and Behavior Lab, Centre de Neuro-Imagerie de Recherche, Institut du Cerveau et de la Moelle épinière, Groupe Hospitalier Pitié-Salpêtrière, Paris, France.|INSERM U975, CNRS UMR 7225, UPMC-P6, UMR S 1127, Paris Cedex 13, France.
authors.forename: M
authors.initials: M
authors.lastname: Pessiglione
authors.affiliation: Department of Psychiatry and Behavioural and Clinical Neuroscience Institute, University of Cambridge, Cambridge, UK.|Cambridge and Peterborough Foundation Trust, Cambridge, UK.
authors.forename: P C
authors.initials: PC
authors.lastname: Fletcher
mesh_terms: D000328:Adult; D001499:Bayes Theorem; D003214:Conditioning, Classical / Q000187:drug effects; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D007649:Ketamine / Q000378:metabolism* / Q000494:pharmacology*; D007858:Learning / Q000187:drug effects*; D008279:Magnetic Resonance Imaging; D008297:Male; D011605:Psychoses, Substance-Induced; D011618:Psychotic Disorders / Q000378:metabolism* / Q000503:physiopathology; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors
chemical_list: D016194:Receptors, N-Methyl-D-Aspartate; D007649:Ketamine