A putative electrophysiological biomarker of auditory sensory memory encoding is sensitive to pharmacological alterations of excitatory/inhibitory balance in male macaque monkeys

A putative electrophysiological biomarker of auditory sensory memory encoding is sensitive to pharmacological alterations of excitatory/inhibitory balance in male macaque monkeys

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J Psychiatry Neurosci 2018;43(3):182-193

William B. Holliday, BM; Kate Gurnsey, AAS; Robert A. Sweet, MD; Tobias Teichert, PhD

Abstract

Background: The amplitude of the auditory evoked N1 component that can be derived from noninvasive electroencephalographic recordings increases as a function of time between subsequent tones. N1 amplitudes in individuals with schizophrenia saturate at a lower asymptote, thus giving rise to a reduced dynamic range. Reduced N1 dynamic range is a putative electrophysiological biomarker of altered sensory memory function in individuals with the disease. To date, it is not clear what determines N1 dynamic range and what causes reduced N1 dynamic range in individuals with schizophrenia. Here we test the hypothesis that reduced N1 dynamic range results from a shift in excitatory/inhibitory (E/I) balance toward an excitation-deficient or inhibition-dominant state.

Methods: We recorded auditory-evoked potentials (AEPs) while 4 macaque monkeys passively listened to sequences of sounds of random pitch and stimulusonset asynchrony (SOA). Three independent experiments tested the effect of the N-methyl-ᴅ-aspartate receptor channel blockers ketamine and MK-801 as well as the γ-aminobutyric acid (GABA) A receptor–positive allosteric modulator midazolam on the dynamic range of a putative monkey N1 homologue and 4 other AEP components.

Results: Ketamine, MK-801 and midazolam reduced peak N1 amplitudes for the longest SOAs. Other AEP components were also affected, but revealed distinct patterns of susceptibility for the glutamatergic and GABA-ergic drugs. Different patterns of susceptibility point toward differences in the circuitry maintaining E/I balance of individual components.

Limitations: The study used systemic pharmacological interventions that may have acted on targets outside of the auditory cortex.

Conclusion: The N1 dynamic range may be a marker of altered E/I balance. Reduced N1 dynamic range in individuals with schizophrenia may indicate that the auditory cortex is in an excitation-deficient or inhibition-dominant state. This may be the result of an incomplete compensation for a primary deficit in excitatory drive.


Submitted May 8, 2017; Revised Aug. 30, 2017; Revised Oct. 16, 2017; Revised Oct. 27, 2017; Accepted Oct. 27, 2017; Published online first Dec. 13, 2017

Acknowledgements: This work was supported by grants MH113041 to T. Teichert, and MH071533 to R. Sweet. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institute of Mental Health, the National Institutes of Health, the Department of Veterans Affairs, or the United States Government.

Affiliations: From the Department of Psychiatry, University of Pittsburgh, Pittsburgh, PA (Holliday, Gurnsey, Sweet, Teichert); the Department of Neurology, University of Pittsburgh, Pittsburgh, PA (Sweet); the Mental Illness Research, Education, and Clinical Center, VA Pittsburgh Healthcare System, Pittsburgh, PA (Sweet); and the Department of Bioengineering, University of Pittsburgh, Pittsburgh, PA (Teichert).

Competing interests: None declared.

Contributors: W. Holliday, R. Sweet and T. Teichert designed the study. K. Gurnsey and T. Teichert acquired the data, which W. Holliday, R. Sweet and T. Teichert analyzed. W. Holliday and T. Teichert wrote the article, which all authors reviewed. All authors approved the final version to be published and can certify that no other individuals not listed as authors have made substantial contributions to the paper.

DOI: 10.1503/jpn.170093

Correspondence to: T. Teichert, University of Pittsburgh, BST W 1658, 200 Lothrop Street, Pittsburgh, PA 15261; teichert@pitt.edu