School of Psychology, University of Newcastle, Callaghan, NSW, Australia; Priority Centre for Brain and Mental Health Research, Callaghan, NSW, Australia; Hunter Medical Research Institute, Newcastle, NSW, Australia; Schizophrenia Research Institute, Randwick, NSW, Australia.
School of Psychology, University of Newcastle, Callaghan, NSW, Australia; Priority Centre for Brain and Mental Health Research, Callaghan, NSW, Australia; Hunter Medical Research Institute, Newcastle, NSW, Australia.
Schizophr Res. 2018 Jan;191:43-50. doi: 10.1016/j.schres.2017.03.042. Epub 2017 Apr 3.
One of the most robust electrophysiological features of schizophrenia is reduced mismatch negativity, a component of the event related potential (ERP) induced by rare and unexpected stimuli in an otherwise regular pattern. Emerging evidence suggests that mismatch negativity (MMN) is not the only ERP index of deviance detection in the mammalian brain and that sensitivity to deviant sounds in a regular background can be observed at earlier latencies in both the human and rodent brain. Pharmacological studies in humans and rodents have previously found that MMN reductions similar to those seen in schizophrenia can be elicited by N-methyl-d-aspartate (NMDA) receptor antagonism, an observation in agreement with the hypothesised role of NMDA receptor hypofunction in schizophrenia pathogenesis. However, it is not known how NMDA receptor antagonism affects early deviance detection responses. Here, we show that NMDA antagonism impacts both early and late deviance detection responses. By recording EEG in awake, freely-moving rats in a drug-free condition and after varying doses of NMDA receptor antagonist MK-801, we found the hypothesised reduction of deviance detection for a late, negative potential (N55). However, the amplitude of an early component, P13, as well as deviance detection evident in the same component, were increased by NMDA receptor antagonism. These findings indicate that late deviance detection in rats is similar to human MMN, but the surprising effect of MK-801 in increasing ERP amplitudes as well as deviance detection at earlier latencies suggests that future studies in humans should examine ERPs over early latencies in schizophrenia and after NMDA antagonism.
精神分裂症最显著的电生理特征之一是失匹配负波（mismatch negativity，MMN）减少，这是一种由罕见且意外的刺激在规则模式下引发的事件相关电位（event-related potential，ERP）的成分。新出现的证据表明，失匹配负波（MMN）并非哺乳动物大脑中唯一的偏差检测 ERP 指标，并且在人类和啮齿动物的大脑中，在更早的潜伏期内，可以观察到对规则背景中偏差声音的敏感性。人类和啮齿动物的药理学研究之前发现，通过 N-甲基-D-天冬氨酸（N-methyl-D-aspartate，NMDA）受体拮抗作用，可以诱发类似于精神分裂症中所见的 MMN 减少，这一观察结果与 NMDA 受体功能低下在精神分裂症发病机制中的假设作用一致。然而，NMDA 受体拮抗作用如何影响早期偏差检测反应尚不清楚。在这里，我们表明 NMDA 拮抗作用会影响早期和晚期偏差检测反应。通过在无药物条件下，在清醒、自由移动的大鼠中记录脑电图，并在不同剂量的 NMDA 受体拮抗剂 MK-801 后进行记录，我们发现了假设的晚期负电位（N55）的偏差检测减少。然而，早期成分 P13 的振幅以及同一成分中明显的偏差检测，都被 NMDA 受体拮抗作用所增强。这些发现表明，大鼠的晚期偏差检测与人类的 MMN 相似，但 NMDA 受体拮抗剂 MK-801 增加 ERP 振幅以及更早潜伏期偏差检测的惊人效果表明，未来的人类研究应该在精神分裂症和 NMDA 拮抗作用后，检查早期潜伏期的 ERP。
