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Frontal Responses During Learning Predict Vulnerability to the Psychotogenic Effects of Ketamine
Linking Cognition, Brain Activity, and Psychosis
Philip R. Corlett, BA;
Garry D. Honey, PhD;
Michael R. F. Aitken, PhD;
Anthony Dickinson, PhD, FRS;
David R. Shanks, PhD;
Anthony R. Absalom, MB, ChB, MD, FRCA;
Michael Lee, MB, BS, FRCA;
Edith Pomarol-Clotet, PhD, MRCPsych;
Graham K. Murray, MRCPsych;
Peter J. McKenna, PhD, MRCPsych;
Trevor W. Robbins, PhD, FRS;
Edward T. Bullmore, PhD, MRCPsych;
Paul C. Fletcher, PhD, MRCPsych
Arch Gen Psychiatry. 2006;63:611-621.
Context Establishing a neurobiological account of delusion formation that links cognitive processes, brain activity, and symptoms is important to furthering our understanding of psychosis.
Objective To explore a theoretical model of delusion formation that implicates prediction error–dependent associative learning processes in a pharmacological functional magnetic resonance imaging study using the psychotomimetic drug ketamine.
Design Within-subject, randomized, placebo-controlled study.
Setting Hospital-based clinical research facility, Addenbrooke's Hospital, Cambridge, England. The work was completed within the Wellcome Trust and Medical Research Council Behavioral and Clinical Neuroscience Institute, Cambridge.
Participants Fifteen healthy, right-handed volunteers (8 of whom were male) with a mean ± SD age of 29 ± 7 years and a mean ± SD predicted full-scale IQ of 113 ± 4 were recruited from within the local community by advertisement.
Interventions Subjects were given low-dose ketamine (100 ng/mL of plasma) or placebo while performing a causal associative learning task during functional magnetic resonance imaging. In a separate session outside the scanner, the dose was increased (to 200 ng/mL of plasma) and subjects underwent a structured clinical interview.
Main Outcome Measures Brain activation, blood plasma levels of ketamine, and scores from psychiatric ratings scales (Brief Psychiatric Ratings Scale, Present State Examination, and Clinician-Administered Dissociative States Scale).
Results Low-dose ketamine perturbs error-dependent learning activity in the right frontal cortex (P = .03). High-dose ketamine produces perceptual aberrations (P = .01) and delusion-like beliefs (P = .007). Critically, subjects showing the highest degree of frontal activation with placebo show the greatest occurrence of drug-induced perceptual aberrations (P = .03) and ideas or delusions of reference (P = .04).
Conclusions These findings relate aberrant prediction error–dependent associative learning to referential ideas and delusions via a perturbation of frontal cortical function. They are consistent with a model of delusion formation positing disruptions in error-dependent learning.
Author Affiliations: Brain Mapping Unit, Department of Psychiatry, School of Clinical Medicine (Mr Corlett and Drs Honey, Pomarol-Clotet, Murray, McKenna, Bullmore, and Fletcher) and Department of Anaesthesiology (Drs Absalom and Lee), Addenbrooke's Hospital, and Department of Experimental Psychology (Drs Aitken, Dickinson, and Robbins), University of Cambridge, Cambridge, England; and Department of Psychology, University College London, London, England (Dr Shanks).
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