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

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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.

Original languageEnglish (US)
Pages (from-to)705-714
Number of pages10
JournalBiological Psychiatry: Cognitive Neuroscience and Neuroimaging
Volume5
Issue number7
DOIs
StatePublished - Jul 2020

Bibliographical note

Funding Information:
Support for this work was provided by the National Institutes of Health (Grant No. R01MH107491 [to MVC], Grant Nos. R01MH080318 and R01MH112688 [to ADR], Grant No. NCRR 1UL1TR002494-01 [to EK and SM], Grant Nos. T32 GM008244 and T32 HD007151 [to RKB], Grant No. F31MH109238 [to ALD], and Grant Nos. R01MH081051 , R21MH110208-01A1 , and R21MH110208-01A1 [to SV]); and by the University of Minnesota Wilfred Wetzel Graduate Fellowship (to RKB). This material is the result of work supported with resources and the use of facilities at the Minneapolis Veterans Administration Health Care System.

Funding Information:
Support for this work was provided by the National Institutes of Health (Grant No. R01MH107491 [to MVC], Grant Nos. R01MH080318 and R01MH112688 [to ADR], Grant No. NCRR 1UL1TR002494-01 [to EK and SM], Grant Nos. T32 GM008244 and T32 HD007151 [to RKB], Grant No. F31MH109238 [to ALD], and Grant Nos. R01MH081051, R21MH110208-01A1, and R21MH110208-01A1 [to SV]); and by the University of Minnesota Wilfred Wetzel Graduate Fellowship (to RKB). This material is the result of work supported with resources and the use of facilities at the Minneapolis Veterans Administration Health Care System. The contents do not represent the views of the U.S. Department of Veterans Affairs or the U.S. government. RKB's contribution to this article was from work she conducted as an M.D./Ph.D. student at the University of Minnesota and in her private capacity. The opinions expressed in this article are the author's own and do not reflect the views of the National Institutes of Health, the Department of Health and Human Services, or the U.S. government. We thank Dean Evans for his lab and project management as well as for assistance with surgeries, animal care, and neural recordings; Dale Boeff for his assistance with neurophysiological recording system design and construction as well as for computer programming for signal processing and data analysis; and Sofia Sakellaridi for her assistance with neural recordings. We also thank the Center for Causal Discovery for developing and supporting the open source Tetrad software package. SV is on the scientific advisory boards of Mindstrong, Verily, and Alkermes. She has served as a site principal investigator on a National Institute of Mental Health Small Business Innovation Research grant to Posit Science. All other authors report no biomedical financial interests or potential conflicts of interest.

Publisher Copyright:
© 2020 Society of Biological Psychiatry

Keywords

  • AX-CPT
  • Causal modeling
  • Cognitive control
  • NMDA
  • Neural dynamics
  • Primate
  • Schizophrenia

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