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Relationship of resting brain hyperconnectivity and schizophrenia-like symptoms produced by the NMDA receptor antagonist ketamine in humans

Abstract

N-methyl-D-aspartate glutamate receptor (NMDA-R) antagonists produce schizophrenia-like positive and negative symptoms in healthy human subjects. Preclinical research suggests that NMDA-R antagonists interfere with the function of gamma-aminobutyric acid (GABA) neurons and alter the brain oscillations. These changes have been hypothesized to contribute to psychosis. In this investigation, we evaluated the hypothesis that the NMDA-R antagonist ketamine produces alterations in cortical functional connectivity during rest that are related to symptoms. We administered ketamine to a primary sample of 22 subjects and to an additional, partially overlapping, sample of 12 subjects. Symptoms before and after the experimental session were rated with the Positive and Negative Syndrome Scale (PANSS). In the primary sample, functional connectivity was measured via functional magnetic resonance imaging almost immediately after infusion began. In the additional sample, this assessment was repeated after 45 min of continuous ketamine infusion. Global, enhanced functional connectivity was observed at both timepoints, and this hyperconnectivity was related to symptoms in a region-specific manner. This study supports the hypothesis that pathological increases in resting brain functional connectivity contribute to the emergence of positive and negative symptoms associated with schizophrenia.

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Acknowledgements

We wish to thank the following individuals: Drs Michelle Hampson and Pawel Skudlarski provided many interesting discussions of connectivity, in general, and of this project, specifically. Cheryl Lacadie helped informally with a number of image processing and software issues. Kathleen Maloney, Julie Holub, Cara Cordeaux and Nikia McFadden served as research assistants. Nursing care was provided by the Yale Center for Clinical Investigation and the Biostudies Unit, Neurobiological Diagnostic Studies Unit of the VA CT Healthcare System, West Haven, CT. MRI technologists Hedy Sarofin and Karen A Martin supplied expert assistance for this complex MRI protocol.

Sources of financial support include: Yale-Pfizer Alliance (NRD); National Alliance for Research on Schizophrenia and Depression-Distinguished Investigator Award (JHK) and Young Investigator Award (ZB); Conte Center Calcium Signaling and Prefrontal Deficits in Schizophrenia, NIMH; National Center Post Traumatic Stress Disorder, Clinical Neurosciences Division, West Haven, CT, National Institute on Alcohol Abuse and Alcoholism, 2P50 AA 012870; U.S. Department of Veterans Affairs Alcohol Research Center; NIH National Center for Research Resources CTSA Grant Number UL1 RR024139; NIH Grant Number K23-MH077914, and the State of CT Department of Mental Health and Addiction Services.

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Correspondence to N R Driesen.

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JHK consults for several pharmaceutical and biotechnology companies with compensation less than $10 000 per year. All other authors declare that they have no conflict of interest.

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Driesen, N., McCarthy, G., Bhagwagar, Z. et al. Relationship of resting brain hyperconnectivity and schizophrenia-like symptoms produced by the NMDA receptor antagonist ketamine in humans. Mol Psychiatry 18, 1199–1204 (2013). https://doi.org/10.1038/mp.2012.194

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  • DOI: https://doi.org/10.1038/mp.2012.194

Keywords

  • gamma-aminobutyric acid
  • functional connectivity
  • ketamine
  • N-methyl-D-aspartate
  • psychosis
  • schizophrenia

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