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


METHODS
Within-subject, randomized, placebo-controlled study.


METHODS
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.


METHODS
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.


METHODS
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.


METHODS
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.
Corlett
Philip R
PR
Brain Mapping Unit, Department of Psychiatry, School of Clinical Medicine, University of Cambridge, Cambridge, England.
Honey
Garry D
GD
Aitken
Michael R F
MR
Dickinson
Anthony
A
Shanks
David R
DR
Absalom
Anthony R
AR
Lee
Michael
M
Pomarol-Clotet
Edith
E
Murray
Graham K
GK
McKenna
Peter J
PJ
Robbins
Trevor W
TW
Bullmore
Edward T
ET
Fletcher
Paul C
PC
D000328:Adult; D001245:Association Learning / Q000187:drug effects*; D010054:Brief Psychiatric Rating Scale / Q000706:statistics & numerical data; D003072:Cognition Disorders / Q000139:chemically induced* / Q000503:physiopathology; D003702:Delusions / Q000139:chemically induced; D004198:Disease Susceptibility / Q000523:psychology; D004305:Dose-Response Relationship, Drug; D005260:Female; D005625:Frontal Lobe / Q000187:drug effects* / Q000503:physiopathology*; D006801:Humans; D007649:Ketamine / Q000494:pharmacology*; D008279:Magnetic Resonance Imaging; D008297:Male; D008962:Models, Theoretical; D010468:Perceptual Disorders / Q000139:chemically induced; D010919:Placebos; D011336:Probability; D011569:Psychiatric Status Rating Scales / Q000706:statistics & numerical data; D011605:Psychoses, Substance-Induced / Q000209:etiology* / Q000503:physiopathology / Q000523:psychology; D011618:Psychotic Disorders / Q000209:etiology* / Q000503:physiopathology
D010919:Placebos; D007649:Ketamine