Abstract
Rationale
Schizophrenia patients consistently show deficits in sensory-evoked broadband gamma oscillations and click-evoked entrainment at 40 Hz, called the 40-Hz auditory steady-state response (ASSR). Since such evoked oscillations depend on cortical N-methyl D-aspartic acid (NMDA)-mediated network activity, they can serve as pharmacodynamic biomarkers in the preclinical and clinical development of drug candidates engaging these circuits. However, there are few test-retest reliability data in preclinical species, a prerequisite for within-subject testing paradigms.
Objective
We investigated the long-term psychometric stability of these measures in a rodent model.
Methods
Female rats with chronic epidural implants were used to record tone- and 40 Hz click-evoked responses at multiple time points and across six sessions, spread over 3 weeks. We assessed reliability using intraclass correlation coefficients (ICC). Separately, we used mixed-effects ANOVA to examine time and session effects. Individual subject variability was determined using the coefficient of variation (CV). Lastly, to illustrate the importance of long-term measure stability for within-subject testing design, we used low to moderate doses of an NMDA antagonist MK801 (0.025–0.15 mg/kg) to disrupt the evoked response.
Results
We found that 40-Hz ASSR showed good reliability (ICC=0.60–0.75), while the reliability of tone-evoked gamma ranged from poor to good (0.33–0.67). We noted time but no session effects. Subjects showed a lower variance for ASSR over tone-evoked gamma. Both measures were dose-dependently attenuated by NMDA antagonism.
Conclusion
Overall, while both evoked gamma measures use NMDA transmission, 40-Hz ASSR showed superior psychometric properties of higher ICC and lower CV, relative to tone-evoked gamma.
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Abbreviations
- ASSR:
-
Auditory steady state response
- CV:
-
Coefficient of variation
- EEG:
-
Electroencephalography
- ICC:
-
Intraclass correlation coefficient
- NMDA:
-
N-methyl D-aspartic acid
- RMS:
-
Root mean square
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Acknowledgement
The authors gratefully acknowledge the help provided in the initial stages of this project by Dr. Ying Liu, Assistant Professor at the Department of Biostatistics and Epidemiology, East Tennessee State University, Johnson City, TN.
Funding
This study was funded by a starter grant from Bill Gatton College of Pharmacy and East Tennessee State University, Johnson City, TN.
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ESM 1
Line plots showing the mean RMS-amplitude value for tone-evoked response (left panel) and 40 Hz ASSR (right panel) for each animal, across six sessions (N=12). (PNG 10289 kb)
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Raza, M.U., Sivarao, D.V. Test-retest reliability of tone- and 40 Hz train-evoked gamma oscillations in female rats and their sensitivity to low-dose NMDA channel blockade. Psychopharmacology 238, 2325–2334 (2021). https://doi.org/10.1007/s00213-021-05856-1
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DOI: https://doi.org/10.1007/s00213-021-05856-1