Northoff Georg, Richter Andre, Bermpohl Felix, Grimm Simone, Martin Ernst, Marcar Valentine Leslie, Wahl Constance, Hell Daniel, Boeker Heinz
Department of Neurology, Division of Behavioral Neurology, Beth Israel Deaconess Medical Center, Harvard Medical School, 330 Brookline Avenue, Boston, MA 02215, USA.
Schizophr Res. 2005 Jan 1;72(2-3):235-48. doi: 10.1016/j.schres.2004.04.009.
Based on animal data, NMDA receptor hypofunction has been suggested as a model for positive symptoms in schizophrenia. NMDA receptor hypofunction affects several corticolimbic brain regions, of which the posterior cingulate seems to be the most sensitive. However, empirical support for a crucial role of posterior cingulate NMDA hypofunction in the pathophysiology of positive symptoms is still missing in humans. We therefore conducted an fMRI study using the NMDA antagonist ketamine in healthy human subjects during episodic memory retrieval, which is supposed to activate the posterior cingulate.
We investigated 16 healthy subjects which were assigned to either placebo (n = 7; saline) or ketamine (n = 9; 0.6 mg/kg/h) group in a double-blind study design. All subjects received their infusion while performing an episodic memory retrieval task in the scanner. Immediately after the fMRI session, psychopathological effects of ketamine were measured using the Altered States of Consciousness Questionnaire.
The placebo group showed BOLD signal increases in the posterior and anterior cingulate during retrieval. Signal increases were significantly lower in the ketamine group. Lower signal increases in the posterior cingulate correlated significantly with positive (i.e. psychosis-like) symptoms induced by ketamine.
The present study for the first time demonstrates a relationship between NMDA receptors, posterior cingulate and positive (i.e. psychosis-like) symptoms in humans. Confirming findings from animal studies, it supports the hypothesis of a pathophysiological role of NMDA receptor hypofunction in the posterior cingulate in schizophrenia.
基于动物数据，N-甲基-D-天冬氨酸（NMDA）受体功能减退被认为是精神分裂症阳性症状的一种模型。NMDA受体功能减退会影响多个皮质边缘脑区，其中后扣带回似乎最为敏感。然而，在人类中，后扣带回NMDA功能减退在阳性症状病理生理学中起关键作用的实证支持仍然缺失。因此，我们在健康人类受试者进行情景记忆检索期间，使用NMDA拮抗剂氯胺酮开展了一项功能磁共振成像（fMRI）研究，情景记忆检索理应会激活后扣带回。
我们在一项双盲研究设计中调查了16名健康受试者，他们被分配到安慰剂组（n = 7；生理盐水）或氯胺酮组（n = 9；0.6毫克/千克/小时）。所有受试者在扫描仪中执行情景记忆检索任务时接受输液。fMRI扫描结束后，立即使用意识状态改变问卷测量氯胺酮的精神病理学效应。
安慰剂组在检索期间后扣带回和前扣带回的血氧水平依赖（BOLD）信号增强。氯胺酮组的信号增强明显更低。后扣带回较低的信号增强与氯胺酮诱发的阳性（即类精神病性）症状显著相关。
本研究首次证明了人类中NMDA受体、后扣带回与阳性（即类精神病性）症状之间的关系。该研究证实了动物研究的结果，支持了NMDA受体功能减退在精神分裂症后扣带回病理生理学中起作用的假说。
