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 development of drug candidates engaging these circuits. However, there is little test-retest reliability data in preclinical species, a prerequisite for within-subject testing paradigms.
Objectives We investigated the long-term 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 responses.
Results We found that 40 Hz ASSR showed good reliability (ICC=0.60-0.75) while the reliability of tone-evoked gamma ranged from fair 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 measures use NMDA transmission, 40 Hz ASSR showed superior psychometric properties of higher ICC and lower CV, relative to tone-evoked gamma.
Competing Interest Statement
The authors have declared no competing interest.
Footnotes
Source of funding. This study was funded by a starter grant from Bill Gatton College of Pharmacy and East Tennessee State University, Johnson City, TN.
Conflict of interest. None.
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