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Effects of ketamine and midazolam on resting state connectivity and comparison with ENIGMA connectivity deficit patterns in schizophrenia.

Abstract

Subanesthetic administration of ketamine is a pharmacological model to elicit positive and negative symptoms of psychosis in healthy volunteers. We used resting-state pharmacological functional MRI (rsPhfMRI) to identify cerebral networks affected by ketamine and compared them to the functional connectivity (FC) in schizophrenia. Ketamine can produce sedation and we contrasted its effects with the effects of the anxiolytic drug midazolam. Thirty healthy male volunteers (age = 19-37 years) underwent a randomized, three-way, cross-over study consisting of three imaging sessions, with 48 hr between sessions. A session consisted of a control period followed by infusion of placebo or ketamine or midazolam. The ENIGMA rsfMRI pipeline was used to derive two long-distance (seed-based and dual-regression) and one local (regional homogeneity, ReHo) FC measures. Ketamine induced significant reductions in the connectivity of the salience network (Cohen's d: 1.13 ± 0.28, p = 4.0 × 10-3), auditory network (d: 0.67 ± 0.26, p = .04) and default mode network (DMN, d: 0.63 ± 0.26, p = .05). Midazolam significantly reduced connectivity in the DMN (d: 0.77 ± 0.27, p = .03). The effect sizes for ketamine for resting networks showed a positive correlation (r = .59, p = .07) with the effect sizes for schizophrenia-related deficits derived from ENIGMA's study of 261 patients and 327 controls. Effect sizes for midazolam were not correlated with the schizophrenia pattern (r = -.17, p = .65). The subtraction of ketamine and midazolam patterns showed a significant positive correlation with the pattern of schizophrenia deficits (r = .68, p = .03). RsPhfMRI reliably detected the shared and divergent pharmacological actions of ketamine and midazolam on cerebral networks. The pattern of disconnectivity produced by ketamine was positively correlated with the pattern of connectivity deficits observed in schizophrenia, suggesting a brain functional basis for previously poorly understood effects of the drug.

Authors+Show Affiliations

Maryland Psychiatric Research Center, Department of Psychiatry, University of Maryland School of Medicine, Baltimore, Maryland.F. Hoffmann-La Roche, Pharma Research Early Development, Roche Innovation Centre Basel, Basel, Switzerland. Institute of Neuroscience and Medicine, Brain & Behaviour (INM-7), Research Centre Jülich, Jülich, Germany. Institute of Systems Neuroscience, Medical Faculty, Heinrich Heine University Düsseldorf, Düsseldorf, Germany.F. Hoffmann-La Roche, Pharma Research Early Development, Roche Innovation Centre Basel, Basel, Switzerland.School of Pharmacy, Faculty of Medical and Health Sciences, The University of Auckland, Auckland, New Zealand.School of Pharmacy, Faculty of Medical and Health Sciences, The University of Auckland, Auckland, New Zealand.School of Pharmacy, Faculty of Medical and Health Sciences, The University of Auckland, Auckland, New Zealand.Maryland Psychiatric Research Center, Department of Psychiatry, University of Maryland School of Medicine, Baltimore, Maryland.Maryland Psychiatric Research Center, Department of Psychiatry, University of Maryland School of Medicine, Baltimore, Maryland.Institute of Neuroscience and Medicine, Brain & Behaviour (INM-7), Research Centre Jülich, Jülich, Germany. Institute of Systems Neuroscience, Medical Faculty, Heinrich Heine University Düsseldorf, Düsseldorf, Germany.Imaging Genetics Center, Mark & Mary Stevens Neuroimaging & Informatics Institute, Keck School of Medicine, University of Southern California, Marina del Rey, California.Imaging Genetics Center, Mark & Mary Stevens Neuroimaging & Informatics Institute, Keck School of Medicine, University of Southern California, Marina del Rey, California.Maryland Psychiatric Research Center, Department of Psychiatry, University of Maryland School of Medicine, Baltimore, Maryland.Maryland Psychiatric Research Center, Department of Psychiatry, University of Maryland School of Medicine, Baltimore, Maryland.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

31633254

Citation

Adhikari, Bhim M., et al. "Effects of Ketamine and Midazolam On Resting State Connectivity and Comparison With ENIGMA Connectivity Deficit Patterns in Schizophrenia." Human Brain Mapping, 2019.
Adhikari BM, Dukart J, Hipp JF, et al. Effects of ketamine and midazolam on resting state connectivity and comparison with ENIGMA connectivity deficit patterns in schizophrenia. Hum Brain Mapp. 2019.
Adhikari, B. M., Dukart, J., Hipp, J. F., Forsyth, A., McMillan, R., Muthukumaraswamy, S. D., ... Kochunov, P. (2019). Effects of ketamine and midazolam on resting state connectivity and comparison with ENIGMA connectivity deficit patterns in schizophrenia. Human Brain Mapping, doi:10.1002/hbm.24838.
Adhikari BM, et al. Effects of Ketamine and Midazolam On Resting State Connectivity and Comparison With ENIGMA Connectivity Deficit Patterns in Schizophrenia. Hum Brain Mapp. 2019 Oct 21; PubMed PMID: 31633254.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Effects of ketamine and midazolam on resting state connectivity and comparison with ENIGMA connectivity deficit patterns in schizophrenia. AU - Adhikari,Bhim M, AU - Dukart,Juergen, AU - Hipp,Joerg F, AU - Forsyth,Anna, AU - McMillan,Rebecca, AU - Muthukumaraswamy,Suresh D, AU - Ryan,Meghann C, AU - Hong,L Elliot, AU - Eickhoff,Simon B, AU - Jahandshad,Neda, AU - Thompson,Paul M, AU - Rowland,Laura M, AU - Kochunov,Peter, Y1 - 2019/10/21/ PY - 2019/04/25/received PY - 2019/09/27/revised PY - 2019/10/09/accepted PY - 2019/10/22/entrez KW - effect size KW - regional homogeneity KW - resting-state functional connectivity JF - Human brain mapping JO - Hum Brain Mapp N2 - Subanesthetic administration of ketamine is a pharmacological model to elicit positive and negative symptoms of psychosis in healthy volunteers. We used resting-state pharmacological functional MRI (rsPhfMRI) to identify cerebral networks affected by ketamine and compared them to the functional connectivity (FC) in schizophrenia. Ketamine can produce sedation and we contrasted its effects with the effects of the anxiolytic drug midazolam. Thirty healthy male volunteers (age = 19-37 years) underwent a randomized, three-way, cross-over study consisting of three imaging sessions, with 48 hr between sessions. A session consisted of a control period followed by infusion of placebo or ketamine or midazolam. The ENIGMA rsfMRI pipeline was used to derive two long-distance (seed-based and dual-regression) and one local (regional homogeneity, ReHo) FC measures. Ketamine induced significant reductions in the connectivity of the salience network (Cohen's d: 1.13 ± 0.28, p = 4.0 × 10-3), auditory network (d: 0.67 ± 0.26, p = .04) and default mode network (DMN, d: 0.63 ± 0.26, p = .05). Midazolam significantly reduced connectivity in the DMN (d: 0.77 ± 0.27, p = .03). The effect sizes for ketamine for resting networks showed a positive correlation (r = .59, p = .07) with the effect sizes for schizophrenia-related deficits derived from ENIGMA's study of 261 patients and 327 controls. Effect sizes for midazolam were not correlated with the schizophrenia pattern (r = -.17, p = .65). The subtraction of ketamine and midazolam patterns showed a significant positive correlation with the pattern of schizophrenia deficits (r = .68, p = .03). RsPhfMRI reliably detected the shared and divergent pharmacological actions of ketamine and midazolam on cerebral networks. The pattern of disconnectivity produced by ketamine was positively correlated with the pattern of connectivity deficits observed in schizophrenia, suggesting a brain functional basis for previously poorly understood effects of the drug. SN - 1097-0193 UR - https://www.unboundmedicine.com/medline/citation/31633254/Effects_of_ketamine_and_midazolam_on_resting_state_connectivity_and_comparison_with_ENIGMA_connectivity_deficit_patterns_in_schizophrenia L2 - https://doi.org/10.1002/hbm.24838 DB - PRIME DP - Unbound Medicine ER -