title: Ketamine interactions with biomarkers of stress: a randomized placebo-controlled repeated measures resting-state fMRI and PCASL pilot study in healthy men.
abstract: Ketamine, an NMDA receptor antagonist, is increasingly used to study the link between glutamatergic signaling dysregulation and mood and chronic pain disorders. Glutamatergic neurotransmission and stress corticosteroids (cortisol in human) are critical for Ca(2+) mediated neuroplasticity and behavioral adaptation. The mechanisms of action of glutamatergic neurotransmission and stress corticosteroids on the NMDA-receptors of the hippocampus have been long investigated in animals, but given little attention in human studies. In this randomized single-blinded placebo-controlled crossover study (12 healthy young men), five sets of resting-state fMRI (RSFMRI), pseudocontinuous arterial spin labeling (PCASL), and corresponding salivary cortisol samples were acquired over 4h, at given intervals under pharmacokinetically-controlled infusion of subanesthetic ketamine (20 & 40mg/70kg/h). An identical procedure was repeated under a sham placebo condition. Differences in the profile of ketamine versus placebo effect over time were examined. Compared to placebo, ketamine mimicked a stress-like response (increased cortisol, reduced calmness and alertness, and impaired working memory). Ketamine effects on the brain included a transient prefrontal hyperperfusion and a dose-related reduction of relative hippocampal perfusion, plus emerging hyperconnectivity between the hippocampus and the occipital, cingulate, precuneal, cerebellar and basal ganglia regions. The spatiotemporal profiles of ketamine effects on different hippocampal subnetworks suggest a topographically dissociable change in corticohippocampal functional connectivity. We discuss our findings in the context of the negative feedback inhibition theory of the hippocampal stress-control. This pilot study provides a methodological framework for multimodal functional neuroimaging under resting-state conditions, which may be generalized for translational studies of glutamatergic- or stress-related etiology of neuropsychiatric disorders.
authors.affiliation: Department of Anesthesiology, Leiden University Medical Center, Leiden, The Netherlands; Leiden Institute for Brain and Cognition (LIBC), Leiden University, Leiden, The Netherlands; Department of Radiology, Leiden University Medical Center, 2300 RC Leiden, The Netherlands; Montreal Neurological Institute, McGill University, Montreal, Canada. Electronic address: n.mahani@lumc.nl.
authors.forename: Najmeh
authors.initials: N
authors.lastname: Khalili-Mahani
authors.affiliation: Department of Anesthesiology, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Marieke
authors.initials: M
authors.lastname: Niesters
authors.affiliation: Department of Radiology, Leiden University Medical Center, 2300 RC Leiden, The Netherlands; Institute of Psychology, Leiden University, Leiden, The Netherlands.
authors.forename: Matthias J
authors.initials: MJ
authors.lastname: van Osch
authors.affiliation: SILS-CNS, University of Amsterdam, Amsterdam, The Netherlands.
authors.forename: Melly
authors.initials: M
authors.lastname: Oitzl
authors.affiliation: Leiden Institute for Brain and Cognition (LIBC), Leiden University, Leiden, The Netherlands; Department of Radiology, Leiden University Medical Center, 2300 RC Leiden, The Netherlands; Charité Universitätsmedizin Berlin, Division of Mind and Brain Research, Department of Psychiatry and Psychotherapy, Berlin, Germany.
authors.forename: Ilya
authors.initials: I
authors.lastname: Veer
authors.affiliation: Leiden Institute for Brain and Cognition (LIBC), Leiden University, Leiden, The Netherlands.
authors.forename: Mark
authors.initials: M
authors.lastname: de Rooij
authors.affiliation: Department of Neurology, Leiden University Medical Center, 2300 RC Leiden, The Netherlands.
authors.forename: Joop
authors.initials: J
authors.lastname: van Gerven
authors.affiliation: Department of Radiology, Leiden University Medical Center, 2300 RC Leiden, The Netherlands.
authors.forename: Mark A
authors.initials: MA
authors.lastname: van Buchem
authors.affiliation: Donders Institute for Brain, Cognition and Behaviour; Centre for Cognitive Neuroimaging, Radboud University, Nijmegen, The Netherlands.
authors.forename: Christian F
authors.initials: CF
authors.lastname: Beckmann
authors.affiliation: Leiden Institute for Brain and Cognition (LIBC), Leiden University, Leiden, The Netherlands; Department of Radiology, Leiden University Medical Center, 2300 RC Leiden, The Netherlands; Institute of Psychology, Leiden University, Leiden, The Netherlands.
authors.forename: Serge A R B
authors.initials: SA
authors.lastname: Rombouts
authors.affiliation: Department of Anesthesiology, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Albert
authors.initials: A
authors.lastname: Dahan
mesh_terms: D000328:Adult; D015415:Biomarkers / Q000032:analysis; D001921:Brain / Q000187:drug effects / Q000502:physiology*; D018592:Cross-Over Studies; D006624:Hippocampus / Q000187:drug effects / Q000502:physiology; D006801:Humans; D006854:Hydrocortisone / Q000032:analysis; D007649:Ketamine / Q000494:pharmacology*; D008279:Magnetic Resonance Imaging; D008297:Male; D010865:Pilot Projects; D012146:Rest; D012463:Saliva / Q000737:chemistry; D016037:Single-Blind Method; D013113:Spin Labels; D013315:Stress, Psychological / Q000503:physiopathology*; D055815:Young Adult
chemical_list: D015415:Biomarkers; D013113:Spin Labels; D007649:Ketamine; D006854:Hydrocortisone