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

@article{citeulike:3042620, abstract = {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.}, address = {Brain Mapping Unit, Department of Psychiatry, School of Clinical Medicine, University of Cambridge, Cambridge, England.}, author = {Corlett, P. R. and Honey, G. D. and Aitken, M. R. and Dickinson, A. and Shanks, D. R. and Absalom, A. R. and Lee, M. and Pomarol-Clotet, E. and Murray, G. K. and McKenna, P. J. and Robbins, T. W. and Bullmore, E. T. and Fletcher, P. C. }, citeulike-article-id = {3042620}, doi = {http://dx.doi.org/10.1001/archpsyc.63.6.611}, issn = {0003-990X}, journal = {Archives of general psychiatry}, keywords = {associative\_learning, fmri, human, ketamine, pharmacological, psychosis}, month = {June}, number = {6}, pages = {611--621}, posted-at = {2008-07-25 14:21:35}, priority = {2}, title = {Frontal responses during learning predict vulnerability to the psychotogenic effects of ketamine: linking cognition, brain activity, and psychosis.}, url = {http://dx.doi.org/10.1001/archpsyc.63.6.611}, volume = {63}, year = {2006} }

TY - JOUR ID - citeulike:3042620 L3 - citeulike-article-id:3042620 TI - Frontal responses during learning predict vulnerability to the psychotogenic effects of ketamine: linking cognition, brain activity, and psychosis. JF - Archives of general psychiatry VL - 63 IS - 6 SP - 611 EP - 621 AD - Brain Mapping Unit, Department of Psychiatry, School of Clinical Medicine, University of Cambridge, Cambridge, England. SN - 0003-990X N2 - 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. KW - associative_learning KW - fmri KW - human KW - ketamine KW - pharmacological KW - psychosis AU - Corlett, PR AU - Honey, GD AU - Aitken, MR AU - Dickinson, A AU - Shanks, DR AU - Absalom, AR AU - Lee, M AU - Pomarol-Clotet, E AU - Murray, GK AU - McKenna, PJ AU - Robbins, TW AU - Bullmore, ET AU - Fletcher, PC PY - 2006/06// UR - http://dx.doi.org/10.1001/archpsyc.63.6.611 ER -