Department of Pharmaceutical Sciences, Bill Gatton College of Pharmacy, East Tennessee State University, VA Building 7, Room 324, Maple Ave, Johnson City, TN, 37604, USA.
Psychopharmacology (Berl). 2021 Aug;238(8):2325-2334. doi: 10.1007/s00213-021-05856-1. Epub 2021 May 4.
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.
We investigated the long-term psychometric stability of these measures in a rodent model.
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.
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.
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.
精神分裂症患者在感官诱发的宽带伽马振荡和 40Hz 的点击诱发的同步（称为 40Hz 听觉稳态反应（ASSR））方面始终表现出缺陷。由于这种诱发的振荡依赖于皮质 N-甲基-D-天冬氨酸（NMDA）介导的网络活动，因此它们可以作为候选药物在临床前和临床开发中作用于这些回路的药效动力学生物标志物。然而，在临床前物种中，这些措施的测试-再测试可靠性数据很少，这是进行个体内测试范式的前提。
我们在啮齿动物模型中研究了这些措施的长期心理测量稳定性。
使用具有慢性硬膜外植入物的雌性大鼠，在 3 周内的 6 个疗程中，在多个时间点记录音调和 40Hz 点击诱发的反应。我们使用组内相关系数（ICC）评估可靠性。另外，我们使用混合效应方差分析检查时间和疗程的影响。使用变异系数（CV）确定个体的变异性。最后，为了说明长期测量稳定性对个体内测试设计的重要性，我们使用低至中等剂量的 NMDA 拮抗剂 MK801（0.025-0.15mg/kg）破坏诱发反应。
我们发现 40Hz ASSR 具有良好的可靠性（ICC=0.60-0.75），而音调诱发的伽马范围从较差到良好（0.33-0.67）。我们注意到时间但没有疗程的影响。与音调诱发的伽马相比，ASSR 显示出更低的变异性。两种措施均被 NMDA 拮抗作用剂量依赖性地减弱。
总体而言，虽然两种诱发的伽马措施都使用 NMDA 传递，但与音调诱发的伽马相比，40Hz ASSR 具有更高 ICC 和更低 CV 的优越心理计量特性。
