Frontal responses during learning predict vulnerability to the psychotogenic effects of ketamine: linking cognition, brain activity, and psychosis

Arch Gen Psychiatry. 2006 Jun;63(6):611-21. doi: 10.1001/archpsyc.63.6.611.


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.

Publication types

  • Comparative Study
  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Association Learning / drug effects*
  • Brief Psychiatric Rating Scale / statistics & numerical data
  • Cognition Disorders / chemically induced*
  • Cognition Disorders / physiopathology
  • Delusions / chemically induced
  • Disease Susceptibility / psychology
  • Dose-Response Relationship, Drug
  • Female
  • Frontal Lobe / drug effects*
  • Frontal Lobe / physiopathology*
  • Humans
  • Ketamine / pharmacology*
  • Magnetic Resonance Imaging*
  • Male
  • Models, Theoretical
  • Perceptual Disorders / chemically induced
  • Placebos
  • Probability
  • Psychiatric Status Rating Scales / statistics & numerical data
  • Psychoses, Substance-Induced / etiology*
  • Psychoses, Substance-Induced / physiopathology
  • Psychoses, Substance-Induced / psychology
  • Psychotic Disorders / etiology*
  • Psychotic Disorders / physiopathology


  • Placebos
  • Ketamine