title: Acute ketamine administration alters the brain responses to executive demands in a verbal working memory task: an FMRI study.
abstract: We have used functional MRI to determine the effects of ketamine on brain systems activated in association with a working memory task. Healthy volunteers received intravenous infusions of placebo, ketamine at 50 ng/ml plasma concentration, and ketamine at 100 ng/ml. They were scanned while carrying out a verbal working memory task in which we varied the executive requirements (manipulation vs maintenance processes) and the mnemonic load (three vs five presented letters). We previously showed that ketamine produces a specific behavioral impairment in the manipulation task. In the current study, we modified tasks in order to match performance across drug and placebo conditions, and used an event-related fMRI design, allowing us to remove unsuccessful trials from the analysis. Our results suggest a task-specific effect of ketamine on working memory in a brain system comprising frontal cortex, parietal cortex, and putamen. When subjects are required to manipulate presented letters into alphabetical order, as opposed to maintaining them in the order in which they were presented, ketamine is associated with significantly greater activity in this system, even under these performance-matched conditions. No significant effect of ketamine was seen in association with increasing load. This suggests that our findings are not explicable in terms of a nonspecific effect of ketamine when task difficulty is increased. Rather, our findings provide evidence that the predominant effects of low, subdissociative doses of ketamine are upon the control processes engaged by the manipulation task. Furthermore, we have shown that ketamine's effects may be elucidated by fMRI even when overt behavioral measures show no evidence of impairment.
authors.affiliation: Department of Psychiatry, University of Cambridge, Cambridge, UK.
authors.forename: R A E
authors.initials: RA
authors.lastname: Honey
authors.forename: G D
authors.initials: GD
authors.lastname: Honey
authors.forename: C
authors.initials: C
authors.lastname: O'Loughlin
authors.forename: S R
authors.initials: SR
authors.lastname: Sharar
authors.forename: D
authors.initials: D
authors.lastname: Kumaran
authors.forename: E T
authors.initials: ET
authors.lastname: Bullmore
authors.forename: D K
authors.initials: DK
authors.lastname: Menon
authors.forename: T
authors.initials: T
authors.lastname: Donovan
authors.forename: V C
authors.initials: VC
authors.lastname: Lupson
authors.forename: R
authors.initials: R
authors.lastname: Bisbrown-Chippendale
authors.forename: P C
authors.initials: PC
authors.lastname: Fletcher
mesh_terms: D000328:Adult; D000704:Analysis of Variance; D001921:Brain / Q000098:blood supply / Q000187:drug effects*; D001931:Brain Mapping; D003657:Decision Making / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D018691:Excitatory Amino Acid Antagonists / Q000008:administration & dosage* / Q000097:blood; D005260:Female; D006801:Humans; D007649:Ketamine / Q000008:administration & dosage* / Q000097:blood; D008279:Magnetic Resonance Imaging / Q000379:methods; D008297:Male; D008570:Memory, Short-Term / Q000187:drug effects*; D008875:Middle Aged; D011930:Reaction Time / Q000187:drug effects; D013997:Time Factors; D014706:Verbal Learning / Q000187:drug effects*
chemical_list: D018691:Excitatory Amino Acid Antagonists; D007649:Ketamine