Validation of ketamine as a pharmacological model of thalamic dysconnectivity across the illness course of schizophrenia.
Validation of ketamine as a pharmacological model of thalamic dysconnectivity across the illness course of schizophrenia.
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DOI：
10.1038/s41380-022-01502-0
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发表时间：
2022-05
影响因子：
11
通讯作者：
Mathalon, Daniel H.
中科院分区：
文献类型：
--
作者：
Abram, Samantha V.;Roach, Brian J.;Fryer, Susanna L.;Calhoun, Vince D.;Preda, Adrian;van Erp, Theo G. M.;Bustillo, Juan R.;Lim, Kelvin O.;Loewy, Rachel L.;Stuart, Barbara K.;Krystal, John H.;Ford, Judith M.;Mathalon, Daniel H.
n -甲基- d -天冬氨酸受体（NMDAR）功能障碍是精神分裂症的主要病理生理模型。静息状态功能磁共振成像（rsfMRI）研究表明，精神分裂症的丘脑连接障碍模式涉及与感觉区域的过度连接和与额叶、小脑和丘脑区域的连接不足。当以亚麻醉剂量给健康志愿者服用NMDAR拮抗剂氯胺酮时，会诱发短暂的精神分裂症样症状，并改变rsfMRI丘脑连通性。然而，氯胺酮引起的丘脑连接障碍与精神分裂症丘脑连接障碍的相似程度尚未得到直接测试。目前的双盲、安慰剂对照研究从健康志愿者在rsfMRI期间接受氯胺酮输注获得了丘脑连通性障碍的NMDAR功能减退模型。为了评估氯胺酮诱导的丘脑连接障碍是否由过量谷氨酸释放介导，我们测试了用拉莫三嗪（一种谷氨酸释放抑制剂）预处理是否能减弱氯胺酮的作用。氯胺酮产生强大的丘脑-皮质与感觉和运动区域的超连通性，拉莫三嗪预处理不会降低这种连通性。为了测试氯胺酮丘脑连接障碍模式是否与精神分裂症模式相似，代表氯胺酮丘脑连接障碍效应的全脑模板与个体参与者rsfMRI丘脑连接障碍图相关，生成慢性（SZ）和早期疾病（ESZ）精神分裂症患者、临床精神病高危人群（chrp）和健康对照（HC）的“氯胺酮相似系数”。SZ和ESZ的相似系数高于HC， CHR-P呈中间趋势。氯胺酮相似系数越高，幻觉严重程度越高。因此，用氯胺酮模拟的NMDAR功能减退重现了在精神分裂症病程中观察到的丘脑超连通性，包括精神病发作前的chrp期，并可能导致幻觉的严重程度。
N-methyl-D-aspartate receptor (NMDAR) hypofunction is a leading pathophysiological model of schizophrenia. Resting-state functional magnetic resonance imaging (rsfMRI) studies demonstrate a thalamic dysconnectivity pattern in schizophrenia involving excessive connectivity with sensory regions and deficient connectivity with frontal, cerebellar, and thalamic regions. The NMDAR antagonist ketamine, when administered at sub-anesthetic doses to healthy volunteers, induces transient schizophrenia-like symptoms and alters rsfMRI thalamic connectivity. However, the extent to which ketamine-induced thalamic dysconnectivity resembles schizophrenia thalamic dysconnectivity has not been directly tested. The current double-blind, placebo-controlled study derived an NMDAR hypofunction model of thalamic dysconnectivity from healthy volunteers undergoing ketamine infusions during rsfMRI. To assess whether ketamine-induced thalamic dysconnectivity was mediated by excess glutamate release, we tested whether pre-treatment with lamotrigine, a glutamate release inhibitor, attenuated ketamine’s effects. Ketamine produced robust thalamo-cortical hyper-connectivity with sensory and motor regions that was not reduced by lamotrigine pre-treatment. To test whether the ketamine thalamic dysconnectivity pattern resembled the schizophrenia pattern, a whole-brain template representing ketamine’s thalamic dysconnectivity effect was correlated with individual participant rsfMRI thalamic dysconnectivity maps, generating “ketamine similarity coefficients” for people with chronic (SZ) and early illness (ESZ) schizophrenia, individuals at clinical high-risk for psychosis (CHR-P), and healthy controls (HC). Similarity coefficients were higher in SZ and ESZ than in HC, with CHR-P showing an intermediate trend. Higher ketamine similarity coefficients correlated with greater hallucination severity in SZ. Thus, NMDAR hypofunction, modeled with ketamine, reproduces the thalamic hyper-connectivity observed in schizophrenia across its illness course, including the CHR-P period preceding psychosis onset, and may contribute to hallucination severity.
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影响因子：
19.9
作者：
Cannon TD
通讯作者：
Cannon TD
丘脑皮质功能连接异常与精神分裂症认知缺陷之间的关联
影响因子：
4.6
作者：
Chen, Pinhong;Ye, Enmao;Wang, Lubin
通讯作者：
Wang, Lubin
DOI：
10.1073/pnas.1220826110
发表时间：
2013-07-09
影响因子：
11.1
作者：
Crossley, Nicolas A.;Mechelli, Andrea;Bullmore, Edward T.
通讯作者：
Bullmore, Edward T.
DOI：
10.1111/j.2517-6161.1995.tb02031.x
发表时间：
1995-01-01
影响因子：
5.8
作者：
BENJAMINI, Y;HOCHBERG, Y
通讯作者：
HOCHBERG, Y
DOI：
10.1124/jpet.112.201665
发表时间：
2013-04-01
影响因子：
3.5
作者：
Doyle, O. M.;De Simoni, S.;Mehta, M. A.
通讯作者：
Mehta, M. A.