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.

中文翻译：

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雌性大鼠中音调和 40 Hz 列车诱发的伽马振荡的重测可靠性及其对低剂量 NMDA 通道阻断的敏感性

 基本原理

精神分裂症患者始终表现出感觉诱发的宽带伽玛振荡和 40 Hz 喀哒声诱发的夹带缺陷，称为 40 Hz 听觉稳态反应 (ASSR)。由于这种诱发振荡取决于皮质 N-甲基 D-天冬氨酸 (NMDA) 介导的网络活动，因此它们可以作为参与这些回路的候选药物的临床前和临床开发中的药效生物标志物。然而，临床前物种的重测可靠性数据很少，而这是受试者内测试范式的先决条件。

 客观的

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。

 方法

使用慢性硬膜外植入物的雌性大鼠在多个时间点和 6 个疗程（持续 3 周）记录音调和 40 Hz 咔哒声诱发的反应。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来检查时间和会话效应。使用变异系数（CV）确定个体受试者变异性。最后，为了说明长期测量稳定性对于受试者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 (0.025–0.15 mg/kg) 来破坏诱发反应。

 结果

我们发现 40 Hz ASSR 显示出良好的可靠性（ICC=0.60–0.75），而音调诱发伽玛的可靠性从差到好（0.33–0.67）。我们记录了时间，但没有记录会话效果。受试者的 ASSR 表现出比音调诱发伽马值更低的方差。这两种措施均因 NMDA 拮抗作用而呈剂量依赖性减弱。

 结论

总体而言，虽然两种诱发伽马测量均使用 NMDA 传输，但相对于音调诱发伽马，40 Hz ASSR 显示出更高的 ICC 和更低的 CV 的优越心理测量特性。