Test-retest reliability of tone- and 40 Hz train-evoked gamma oscillations in female rats and their sensitivity to low-dose NMDA channel blockade

• Published in: Psychopharmacology Vol. 238; no. 8; pp. 2325 - 2334
• Main Authors: Raza, Muhammad Ummear, Sivarao, Digavalli V.
• Format: Journal Article
• Language: English
• Published: Berlin/Heidelberg Springer Berlin Heidelberg 01.08.2021; Springer; Springer Nature B.V
• Subjects: Acoustic Stimulation - methods; Acoustic Stimulation - standards; Animals; Antagonism; Aspartic acid; Auditory pathways; Biomedical and Life Sciences; Biomedicine; Dizocilpine Maleate - pharmacology; Dosage; Dosage and administration; Dose-Response Relationship, Drug; Drug development; Entrainment; Evaluation; Evoked Potentials, Auditory - drug effects; Evoked Potentials, Auditory - physiology; Excitatory Amino Acid Agonists - pharmacology; Excitatory Amino Acid Antagonists - pharmacology; Female; Gamma Rhythm - drug effects; Gamma Rhythm - physiology; Glutamic acid receptors (ionotropic); Mental disorders; Methyl aspartate; N-Methyl-D-aspartic acid receptors; Neurosciences; Original Investigation; Oscillation; Oscillations; Pharmacodynamics; Pharmacology/Toxicology; Physiological aspects; Psychiatry; Quantitative psychology; Rats; Rats, Sprague-Dawley; Receptors, N-Methyl-D-Aspartate - agonists; Receptors, N-Methyl-D-Aspartate - antagonists & inhibitors; Receptors, N-Methyl-D-Aspartate - physiology; Reproducibility of Results; Schizophrenia; United States; Pharmacodynamic biomarker; Test-retest reliability; EEG; NMDA; Auditory steady-state response; Gamma oscillations; ASSR
• ISSN: 0033-3158; 1432-2072
• DOI: 10.1007/s00213-021-05856-1

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.