title: Ketamine effects on memory reconsolidation favor a learning model of delusions.
abstract: Delusions are the persistent and often bizarre beliefs that characterise psychosis. Previous studies have suggested that their emergence may be explained by disturbances in prediction error-dependent learning. Here we set up complementary studies in order to examine whether such a disturbance also modulates memory reconsolidation and hence explains their remarkable persistence. First, we quantified individual brain responses to prediction error in a causal learning task in 18 human subjects (8 female). Next, a placebo-controlled within-subjects study of the impact of ketamine was set up on the same individuals. We determined the influence of this NMDA receptor antagonist (previously shown to induce aberrant prediction error signal and lead to transient alterations in perception and belief) on the evolution of a fear memory over a 72 hour period: they initially underwent Pavlovian fear conditioning; 24 hours later, during ketamine or placebo administration, the conditioned stimulus (CS) was presented once, without reinforcement; memory strength was then tested again 24 hours later. Re-presentation of the CS under ketamine led to a stronger subsequent memory than under placebo. Moreover, the degree of strengthening correlated with individual vulnerability to ketamine's psychotogenic effects and with prediction error brain signal. This finding was partially replicated in an independent sample with an appetitive learning procedure (in 8 human subjects, 4 female). These results suggest a link between altered prediction error, memory strength and psychosis. They point to a core disruption that may explain not only the emergence of delusional beliefs but also their persistence.
authors.affiliation: Department of Psychiatry, Ribicoff Research Facility, Yale University, New Haven, Connecticut, United States of America. philip.corlett@yale.edu
authors.forename: Philip R
authors.initials: PR
authors.lastname: Corlett
authors.forename: Victoria
authors.initials: V
authors.lastname: Cambridge
authors.forename: Jennifer M
authors.initials: JM
authors.lastname: Gardner
authors.forename: Jennifer S
authors.initials: JS
authors.lastname: Piggot
authors.forename: Danielle C
authors.initials: DC
authors.lastname: Turner
authors.forename: Jessica C
authors.initials: JC
authors.lastname: Everitt
authors.forename: Fernando Sergio
authors.initials: FS
authors.lastname: Arana
authors.forename: Hannah L
authors.initials: HL
authors.lastname: Morgan
authors.forename: Amy L
authors.initials: AL
authors.lastname: Milton
authors.forename: Jonathan L
authors.initials: JL
authors.lastname: Lee
authors.forename: Michael R F
authors.initials: MR
authors.lastname: Aitken
authors.forename: Anthony
authors.initials: A
authors.lastname: Dickinson
authors.forename: Barry J
authors.initials: BJ
authors.lastname: Everitt
authors.forename: Anthony R
authors.initials: AR
authors.lastname: Absalom
authors.forename: Ram
authors.initials: R
authors.lastname: Adapa
authors.forename: Naresh
authors.initials: N
authors.lastname: Subramanian
authors.forename: Jane R
authors.initials: JR
authors.lastname: Taylor
authors.forename: John H
authors.initials: JH
authors.lastname: Krystal
authors.forename: Paul C
authors.initials: PC
authors.lastname: Fletcher
mesh_terms: D000328:Adult; D001245:Association Learning / Q000502:physiology*; D016022:Case-Control Studies; D003214:Conditioning, Classical; D003702:Delusions / Q000503:physiopathology*; D005239:Fear / Q000523:psychology*; D005260:Female; D006801:Humans; D007649:Ketamine / Q000494:pharmacology*; D008279:Magnetic Resonance Imaging; D008297:Male; D008568:Memory / Q000187:drug effects* / Q000502:physiology; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors*
chemical_list: D016194:Receptors, N-Methyl-D-Aspartate; D007649:Ketamine