Joules R, Doyle O M, Schwarz A J, O'Daly O G, Brammer M, Williams S C, Mehta M A
Department of Neuroimaging, Institute of Psychiatry, Psychology & Neuroscience, Kings College London, De Crespigny Park, London, SE5 8AF, UK.
Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN, 46285, USA.
Psychopharmacology (Berl). 2015 Nov;232(21-22):4205-18. doi: 10.1007/s00213-015-3951-9. Epub 2015 May 19.
Ketamine, an N-methyl-D-aspartate receptor (NMDAR) antagonist, has been studied in relation to the glutamate hypothesis of schizophrenia and increases dissociation, positive and negative symptom ratings. Ketamine effects brain function through changes in brain activity; these activity patterns can be modulated by pre-treatment of compounds known to attenuate the effects of ketamine on glutamate release. Ketamine also has marked effects on brain connectivity; we predicted that these changes would also be modulated by compounds known to attenuate glutamate release. Here, we perform task-free pharmacological magnetic resonance imaging (phMRI) to investigate the functional connectivity effects of ketamine in the brain and the potential modulation of these effects by pre-treatment of the compounds lamotrigine and risperidone, compounds hypothesised to differentially modulate glutamate release. Connectivity patterns were assessed by combining windowing, graph theory and multivariate Gaussian process classification. We demonstrate that ketamine has a robust effect on the functional connectivity of the human brain compared to saline (87.5 % accuracy). Ketamine produced a shift from a cortically centred, to a subcortically centred pattern of connections. This effect is strongly modulated by pre-treatment with risperidone (81.25 %) but not lamotrigine (43.75 %). Based on the differential effect of these compounds on ketamine response, we suggest the observed connectivity effects are primarily due to NMDAR blockade rather than downstream glutamatergic effects. The connectivity changes contrast with amplitude of response for which no differential effect between pre-treatments was detected, highlighting the necessity of these techniques in forming an informed view of the mechanistic effects of pharmacological compounds in the human brain.
氯胺酮是一种N-甲基-D-天冬氨酸受体（NMDAR）拮抗剂，已针对精神分裂症的谷氨酸假说进行了研究，它会增加解离感、阳性和阴性症状评分。氯胺酮通过改变大脑活动来影响脑功能；这些活动模式可通过预处理已知能减弱氯胺酮对谷氨酸释放影响的化合物来调节。氯胺酮对脑连接性也有显著影响；我们预测这些变化也会受到已知能减弱谷氨酸释放的化合物的调节。在此，我们进行无任务药理磁共振成像（phMRI），以研究氯胺酮在大脑中的功能连接效应，以及通过预处理拉莫三嗪和利培酮这两种化合物对这些效应的潜在调节作用，这两种化合物被认为可不同程度地调节谷氨酸释放。通过结合加窗、图论和多元高斯过程分类来评估连接模式。我们证明，与生理盐水相比，氯胺酮对人脑的功能连接有显著影响（准确率87.5%）。氯胺酮使连接模式从以皮质为中心转变为以皮质下为中心。这种效应受到利培酮预处理的强烈调节（81.25%），但不受拉莫三嗪预处理的调节（43.75%）。基于这些化合物对氯胺酮反应的不同影响，我们认为观察到的连接效应主要是由于NMDAR阻断，而非下游谷氨酸能效应。连接性变化与反应幅度形成对比，预处理之间未检测到反应幅度的差异，这突出了这些技术对于全面了解药理化合物在人脑中的机制效应的必要性。
