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Role of N-Methyl-D-Aspartate Receptors in Action-Based Predictive Coding Deficits in Schizophrenia

  • Naomi S. Kort
    Affiliations
    University of California, San Francisco
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  • Judith M. Ford
    Affiliations
    University of California, San Francisco

    San Francisco Veterans Affairs Medical Center
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  • Brian J. Roach
    Affiliations
    Northern California Institute for Research and Education, San Francisco, California
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  • Handan Gunduz-Bruce
    Affiliations
    Yale University School of Medicine, New Haven

    Veterans Affairs Connecticut Healthcare System, West Haven, Connecticut
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  • John H. Krystal
    Affiliations
    Yale University School of Medicine, New Haven

    Veterans Affairs Connecticut Healthcare System, West Haven, Connecticut
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  • Author Footnotes
    1 JJ is currently affiliated with Albert Einstein College of Medicine, Bronx, New York, and CognitionMetrics, LLC, Wilmington, Delaware. RMGR is currently affiliated with Vanderbilt University, Nashville, Tennessee.
    Judith Jaeger
    Footnotes
    1 JJ is currently affiliated with Albert Einstein College of Medicine, Bronx, New York, and CognitionMetrics, LLC, Wilmington, Delaware. RMGR is currently affiliated with Vanderbilt University, Nashville, Tennessee.
    Affiliations
    Clinical Development AstraZeneca Pharmaceuticals, Wilmington, Delaware
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  • Author Footnotes
    1 JJ is currently affiliated with Albert Einstein College of Medicine, Bronx, New York, and CognitionMetrics, LLC, Wilmington, Delaware. RMGR is currently affiliated with Vanderbilt University, Nashville, Tennessee.
    Robert M.G. Reinhart
    Footnotes
    1 JJ is currently affiliated with Albert Einstein College of Medicine, Bronx, New York, and CognitionMetrics, LLC, Wilmington, Delaware. RMGR is currently affiliated with Vanderbilt University, Nashville, Tennessee.
    Affiliations
    Yale University School of Medicine, New Haven
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  • Daniel H. Mathalon
    Correspondence
    Address correspondence to Daniel H. Mathalon, Ph.D., M.D., University of California, Psychiatry Mental Health Service 116-D, SFVAMC 4150 Clement St., San Francisco, CA 94121.
    Affiliations
    University of California, San Francisco

    San Francisco Veterans Affairs Medical Center
    Search for articles by this author
  • Author Footnotes
    1 JJ is currently affiliated with Albert Einstein College of Medicine, Bronx, New York, and CognitionMetrics, LLC, Wilmington, Delaware. RMGR is currently affiliated with Vanderbilt University, Nashville, Tennessee.

      Abstract

      Background

      Recent theoretical models of schizophrenia posit that dysfunction of the neural mechanisms subserving predictive coding contributes to symptoms and cognitive deficits, and this dysfunction is further posited to result from N-methyl-D-aspartate glutamate receptor (NMDAR) hypofunction. Previously, by examining auditory cortical responses to self-generated speech sounds, we demonstrated that predictive coding during vocalization is disrupted in schizophrenia. To test the hypothesized contribution of NMDAR hypofunction to this disruption, we examined the effects of the NMDAR antagonist, ketamine, on predictive coding during vocalization in healthy volunteers and compared them with the effects of schizophrenia.

      Methods

      In two separate studies, the N1 component of the event-related potential elicited by speech sounds during vocalization (talk) and passive playback (listen) were compared to assess the degree of N1 suppression during vocalization, a putative measure of auditory predictive coding. In the crossover study, 31 healthy volunteers completed two randomly ordered test days, a saline day and a ketamine day. Event-related potentials during the talk/listen task were obtained before infusion and during infusion on both days, and N1 amplitudes were compared across days. In the case-control study, N1 amplitudes from 34 schizophrenia patients and 33 healthy control volunteers were compared.

      Results

      N1 suppression to self-produced vocalizations was significantly and similarly diminished by ketamine (Cohen’s d = 1.14) and schizophrenia (Cohen’s d = .85).

      Conclusions

      Disruption of NMDARs causes dysfunction in predictive coding during vocalization in a manner similar to the dysfunction observed in schizophrenia patients, consistent with the theorized contribution of NMDAR hypofunction to predictive coding deficits in schizophrenia.

      Keywords

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      Linked Article

      • I Predict, Therefore I Am: Perturbed Predictive Coding Under Ketamine and in Schizophrenia
        Biological PsychiatryVol. 81Issue 6
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          Predictive coding involves inferences about current sensations based on past experience. We infer what would need to be present (externally and internally) to cause the sensory information we detect (1). The stimuli whose causes are being inferred have transducers (e.g., photoreceptors in the eye, hair cells in the ear) that convert sensory energy into neural activity, which is processed hierarchically within streams that may be relatively encapsulated. However, ultimately these hierarchies converge on a coherent integrated percept (1).
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