Acute ketamine dysregulates task-related gamma-band oscillations in thalamo-cortical circuits in schizophrenia

Grent-'t-Jong, T. et al. (2018) Acute ketamine dysregulates task-related gamma-band oscillations in thalamo-cortical circuits in schizophrenia. Brain, 141(8), pp. 2511-2526. (doi: 10.1093/brain/awy175) (PMID:30020423) (PMCID:PMC6061682)

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Abstract

Hypofunction of the N-methyl-d-aspartate receptor (NMDAR) has been implicated as a possible mechanism underlying cognitive deficits and aberrant neuronal dynamics in schizophrenia. To test this hypothesis, we first administered a sub-anaesthetic dose of S-ketamine (0.006 mg/kg/min) or saline in a single-blind crossover design in 14 participants while magnetoencephalographic data were recorded during a visual task. In addition, magnetoencephalographic data were obtained in a sample of unmedicated first-episode psychosis patients (n = 10) and in patients with chronic schizophrenia (n = 16) to allow for comparisons of neuronal dynamics in clinical populations versus NMDAR hypofunctioning. Magnetoencephalographic data were analysed at source-level in the 1–90 Hz frequency range in occipital and thalamic regions of interest. In addition, directed functional connectivity analysis was performed using Granger causality and feedback and feedforward activity was investigated using a directed asymmetry index. Psychopathology was assessed with the Positive and Negative Syndrome Scale. Acute ketamine administration in healthy volunteers led to similar effects on cognition and psychopathology as observed in first-episode and chronic schizophrenia patients. However, the effects of ketamine on high-frequency oscillations and their connectivity profile were not consistent with these observations. Ketamine increased amplitude and frequency of gamma-power (63–80 Hz) in occipital regions and upregulated low frequency (5–28 Hz) activity. Moreover, ketamine disrupted feedforward and feedback signalling at high and low frequencies leading to hypo- and hyper-connectivity in thalamo-cortical networks. In contrast, first-episode and chronic schizophrenia patients showed a different pattern of magnetoencephalographic activity, characterized by decreased task-induced high-gamma band oscillations and predominantly increased feedforward/feedback-mediated Granger causality connectivity. Accordingly, the current data have implications for theories of cognitive dysfunctions and circuit impairments in the disorder, suggesting that acute NMDAR hypofunction does not recreate alterations in neural oscillations during visual processing observed in schizophrenia.

Item Type:Articles
Additional Information:The project was supported by the LOEWE grant Neuronale Koordination Forschungsschwerpunkt Frankfurt (NeFF).
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Uhlhaas, Professor Peter and Grent-'T-Jong, Dr Tineke and Gajwani, Dr Ruchika and Gross, Professor Joachim
Authors: Grent-'t-Jong, T., Rivolta, D., Gross, J., Gajwani, R., Lawrie, S. M., Schwannauer, M., Heidegger, T., Wibral, M., Singer, W., Sauer, A., Scheller, B., and Uhlhaas, P. J.
College/School:College of Medical Veterinary and Life Sciences > Institute of Health and Wellbeing > Mental Health and Wellbeing
College of Medical Veterinary and Life Sciences > Institute of Neuroscience and Psychology
Journal Name:Brain
Publisher:Oxford University Press
ISSN:0006-8950
ISSN (Online):1460-2156
Published Online:17 July 2018
Copyright Holders:Copyright © 2018 The Authors
First Published:First published in Brain 141(8):2511-2526
Publisher Policy:Reproduced under a Creative Commons License

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
640693Using Magnetoencephalography to Investigate Aberrant Neural Synchrony in Prodromal Schizophrenia: A Translational Biomarker ApproachPeter UhlhaasMedical Research Council (MRC)MR/L011689/1RI NEUROSCIENCE & PSYCHOLOGY