Cognitive Control Errors in Nonhuman Primates Resembling Those in Schizophrenia Reflect Opposing Effects of NMDA Receptor Blockade on Causal Interactions Between Cells and Circuits in Prefrontal and Parietal Cortices

  • Author Footnotes
    1 EK and SM contributed equally to this work as joint first authors.
    Erich Kummerfeld
    Footnotes
    1 EK and SM contributed equally to this work as joint first authors.
    Affiliations
    Institute for Health Informatics, University of Minnesota, Minneapolis, Minnesota
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  • Author Footnotes
    1 EK and SM contributed equally to this work as joint first authors.
    Sisi Ma
    Footnotes
    1 EK and SM contributed equally to this work as joint first authors.
    Affiliations
    Institute for Health Informatics, University of Minnesota, Minneapolis, Minnesota
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  • Rachael K. Blackman
    Affiliations
    Medical Scientist Training Program, University of Minnesota, Minneapolis, Minnesota

    Department of Neuroscience, University of Minnesota, Minneapolis, Minnesota

    Brain Sciences Center, Veterans Administration Medical Center, Minneapolis, Minnesota
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  • Adele L. DeNicola
    Affiliations
    Department of Neuroscience, University of Minnesota, Minneapolis, Minnesota

    Brain Sciences Center, Veterans Administration Medical Center, Minneapolis, Minnesota
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  • A. David Redish
    Affiliations
    Department of Neuroscience, University of Minnesota, Minneapolis, Minnesota
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  • Sophia Vinogradov
    Affiliations
    Department of Psychiatry, University of Minnesota, Minneapolis, Minnesota
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  • Author Footnotes
    2 DAC and MVC contributed equally to this work as joint senior authors.
    David A. Crowe
    Footnotes
    2 DAC and MVC contributed equally to this work as joint senior authors.
    Affiliations
    Department of Biology, Augsburg University, Minneapolis, Minnesota
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  • Author Footnotes
    2 DAC and MVC contributed equally to this work as joint senior authors.
    Matthew V. Chafee
    Correspondence
    Address correspondence to Matthew Chafee, Ph.D., Department of Neuroscience, University of Minnesota School of Medicine, Brain Sciences Center (11B), Minneapolis VA Medical Center, 1 Veterans Drive, Minneapolis, MN 55417.
    Footnotes
    2 DAC and MVC contributed equally to this work as joint senior authors.
    Affiliations
    Department of Neuroscience, University of Minnesota, Minneapolis, Minnesota

    Brain Sciences Center, Veterans Administration Medical Center, Minneapolis, Minnesota
    Search for articles by this author
  • Author Footnotes
    1 EK and SM contributed equally to this work as joint first authors.
    2 DAC and MVC contributed equally to this work as joint senior authors.
Published:April 08, 2020DOI:https://doi.org/10.1016/j.bpsc.2020.02.013

      Abstract

      Background

      The causal biology underlying schizophrenia is not well understood, but it is likely to involve a malfunction in how neurons adjust synaptic connections in response to patterns of activity in networks. We examined statistical dependencies between neural signals at the cell, local circuit, and distributed network levels in prefrontal and parietal cortices of monkeys performing a variant of the AX continuous performance task paradigm. We then quantified changes in the pattern of neural interactions across levels of scale following NMDA receptor (NMDAR) blockade and related these changes to a pattern of cognitive control errors closely matching the performance of patients with schizophrenia.

      Methods

      We recorded the spiking activity of 1762 neurons along with local field potentials at multiple electrode sites in prefrontal and parietal cortices concurrently, and we generated binary time series indicating the presence or absence of spikes in single neurons or local field potential power above or below a threshold. We then applied causal discovery analysis to the time series to detect statistical dependencies between the signals (causal interactions) and compared the pattern of these interactions before and after NMDAR blockade.

      Results

      Global blockade of NMDAR produced distinctive and frequently opposite changes in neural interactions at the cell, local circuit, and network levels in prefrontal and parietal cortices. Cognitive control errors were associated with decreased interactions at the cell level and with opposite changes at the network level in prefrontal and parietal cortices.

      Conclusions

      NMDAR synaptic deficits change causal interactions between neural signals at different levels of scale that correlate with schizophrenia-like deficits in cognitive control.

      Keywords

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