Neuroscience and Psychiatry Unit, University of Manchester, Manchester, United Kingdom; Department of Psychiatry, University of Oxford, Warneford Hospital, Oxford, United Kingdom.
Neuroscience and Psychiatry Unit, University of Manchester, Manchester, United Kingdom; Manchester Mental Health and Social Care Trust, Manchester, United Kingdom.
Biol Psychiatry Cogn Neurosci Neuroimaging. 2017 Apr;2(3):253-262. doi: 10.1016/j.bpsc.2016.09.008. Epub 2016 Oct 7.
Working memory (WM) deficits are a core feature of schizophrenia. Electrophysiological studies suggest that impaired early visual processing may contribute to impaired WM in the visual domain. Abnormal N-methyl-D-aspartate (NMDA) receptor function has been implicated both in WM and in early visual processing deficits in schizophrenia. We investigated whether ketamine, a noncompetitive NMDA antagonist, would replicate in healthy volunteers the WM performance and early visual processing abnormalities we and others have reported in patients with schizophrenia.
Forty-four healthy volunteers were randomly assigned to receive intravenous ketamine or placebo. During infusion, the effects of ketamine were recorded using standardized psychiatric scales. Visual evoked potentials (P100 and P300 components) were recorded during performance of a delayed matching to sample task.
Ketamine induced mild psychosis-like symptoms and impaired WM performance. It also significantly increased the P100 amplitude, while P300 amplitude decreased in a load-dependent manner. Amplitudes of P100 during retrieval correlated with cognitive performance only in the placebo group.
We confirmed previous studies showing that ketamine reproduces the impairment of WM performance and smaller P300 amplitudes observed in schizophrenia. However, ketamine increased visual P100 amplitude in contrast to our observation of reduced P100 amplitudes in established schizophrenia. The effects of ketamine on WM and P300 are likely to involve impaired NMDA function, as these receptors are implicated in changes of synaptic strength underlying associative learning and memory. Increased P100 amplitude may reflect the secondary disinhibition of cortical glutamate release that occurs after NMDA blockade.
工作记忆（WM）缺陷是精神分裂症的核心特征。电生理研究表明，早期视觉处理受损可能导致视觉领域 WM 受损。NMDA 受体功能异常与 WM 和精神分裂症患者的早期视觉处理缺陷都有关。我们研究了氯胺酮（一种非竞争性 NMDA 拮抗剂）是否会在健康志愿者中复制我们和其他人在精神分裂症患者中报告的 WM 表现和早期视觉处理异常。
44 名健康志愿者被随机分配接受静脉注射氯胺酮或安慰剂。在输注过程中，使用标准化的精神病学量表记录氯胺酮的影响。在执行延迟匹配样本任务期间记录视觉诱发电位（P100 和 P300 成分）。
氯胺酮引起轻度类精神病症状和 WM 表现受损。它还显著增加了 P100 幅度，而 P300 幅度则以负载依赖的方式降低。仅在安慰剂组中，检索过程中的 P100 幅度与认知表现相关。
我们证实了先前的研究，表明氯胺酮再现了 WM 表现受损和精神分裂症中观察到的较小 P300 幅度。然而，与我们在已建立的精神分裂症中观察到的降低 P100 幅度相反，氯胺酮增加了视觉 P100 幅度。氯胺酮对 WM 和 P300 的影响可能涉及 NMDA 功能受损，因为这些受体涉及与联想学习和记忆相关的突触强度变化。P100 幅度的增加可能反映了 NMDA 阻断后皮质谷氨酸释放的继发性去抑制。
