title: Ketamine Dysregulates the Amplitude and Connectivity of High-Frequency Oscillations in Cortical-Subcortical Networks in Humans: Evidence From Resting-State Magnetoencephalography-Recordings.
abstract: Hypofunctioning of the N-methyl-D-aspartate receptor (NMDA-R) has been prominently implicated in the pathophysiology of schizophrenia (ScZ). The current study tested the effects of ketamine, a dissociative anesthetic and NMDA-R antagonist, on resting-state activity recorded with magnetoencephalography (MEG) in healthy volunteers. In a single-blind cross-over design, each participant (n = 12) received, on 2 different sessions, a subanesthetic dose of S-ketamine (0.006 mg/Kg) and saline injection. MEG-data were analyzed at sensor- and source-level in the beta (13-30 Hz) and gamma (30-90 Hz) frequency ranges. In addition, connectivity analysis at source-level was performed using transfer entropy (TE). Ketamine increased gamma-power while beta-band activity was decreased. Specifically, elevated 30-90 Hz activity was pronounced in subcortical (thalamus and hippocampus) and cortical (frontal and temporal cortex) regions, whilst reductions in beta-band power were localized to the precuneus, cerebellum, anterior cingulate, temporal and visual cortex. TE analysis demonstrated increased information transfer in a thalamo-cortical network after ketamine administration. The findings are consistent with the pronounced dysregulation of high-frequency oscillations following the inhibition of NMDA-R in animal models of ScZ as well as with evidence from electroencephalogram-data in ScZ-patients and increased functional connectivity during early illness stages. Moreover, our data highlight the potential contribution of thalamo-cortical connectivity patterns towards ketamine-induced neuronal dysregulation, which may be relevant for the understanding of ScZ as a disorder of disinhibition of neural circuits.
authors.affiliation: Department of Neurophysiology, Max Planck Institute for Brain Research, Frankfurt am Main, Germany; Ernst Strüngmann Institute for Neuroscience (ESI) in cooperation with Max Planck Society (ESI), Frankfurt am Main, Germany; School of Psychology, University of East London (UEL), London, UK;
authors.forename: Davide
authors.initials: D
authors.lastname: Rivolta
authors.affiliation: Department of Neurology, Goethe University, Frankfurt am Main, Germany;
authors.forename: Tonio
authors.initials: T
authors.lastname: Heidegger
authors.affiliation: Clinic for Anesthesia, Intensive Care Medicine and Pain Therapy, Johann Wolfgang Goethe University Frankfurt am Main, Germany;
authors.forename: Bertram
authors.initials: B
authors.lastname: Scheller
authors.affiliation: Department of Neurophysiology, Max Planck Institute for Brain Research, Frankfurt am Main, Germany; Ernst Strüngmann Institute for Neuroscience (ESI) in cooperation with Max Planck Society (ESI), Frankfurt am Main, Germany;
authors.forename: Andreas
authors.initials: A
authors.lastname: Sauer
authors.affiliation: MEG Unit, Goethe University, Frankfurt am Main, Germany;
authors.forename: Michael
authors.initials: M
authors.lastname: Schaum
authors.affiliation: Department of Neurophysiology, Max Planck Institute for Brain Research, Frankfurt am Main, Germany; Ernst Strüngmann Institute for Neuroscience (ESI) in cooperation with Max Planck Society (ESI), Frankfurt am Main, Germany;
authors.forename: Katharina
authors.initials: K
authors.lastname: Birkner
authors.affiliation: Department of Neurophysiology, Max Planck Institute for Brain Research, Frankfurt am Main, Germany; Ernst Strüngmann Institute for Neuroscience (ESI) in cooperation with Max Planck Society (ESI), Frankfurt am Main, Germany; Frankfurt Institute for Advanced Studies (FIAS), Frankfurt am Main, Germany;
authors.forename: Wolf
authors.initials: W
authors.lastname: Singer
authors.affiliation: MEG Unit, Goethe University, Frankfurt am Main, Germany;
authors.forename: Michael
authors.initials: M
authors.lastname: Wibral
authors.affiliation: Department of Neurophysiology, Max Planck Institute for Brain Research, Frankfurt am Main, Germany; Ernst Strüngmann Institute for Neuroscience (ESI) in cooperation with Max Planck Society (ESI), Frankfurt am Main, Germany; Institute of Neuroscience and Psychology, University of Glasgow, Glasgow, UK peter.uhlhaas@glasgow.ac.uk.
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Uhlhaas
mesh_terms: D000328:Adult; D001611:Beta Rhythm / Q000187:drug effects*; D001921:Brain / Q000187:drug effects*; D018592:Cross-Over Studies; D018691:Excitatory Amino Acid Antagonists / Q000008:administration & dosage / Q000494:pharmacology*; D005260:Female; D065818:Gamma Rhythm / Q000187:drug effects*; D006801:Humans; D007649:Ketamine / Q000008:administration & dosage / Q000494:pharmacology*; D015225:Magnetoencephalography; D008297:Male; D009415:Nerve Net / Q000187:drug effects*; D009434:Neural Pathways / Q000187:drug effects; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors*; D016037:Single-Blind Method
chemical_list: D018691:Excitatory Amino Acid Antagonists; D016194:Receptors, N-Methyl-D-Aspartate; D007649:Ketamine
keywords: GABA; MEG; NMDA-receptor; gamma-band oscillations; ketamine; schizophrenia