Wellcome Trust Centre for Neuroimaging, University College London, London, United Kingdom; Developmental Neurosciences Programme, UCL Great Ormond Street Institute of Child Health, University College London, London, United Kingdom.
Wellcome Trust Centre for Neuroimaging, University College London, London, United Kingdom; Department of Biomedical Sciences, City University of Hong Long, Hong Kong.
Biol Psychiatry Cogn Neurosci Neuroimaging. 2019 Feb;4(2):140-150. doi: 10.1016/j.bpsc.2018.07.003. Epub 2018 Aug 13.
Disturbances in N-methyl-D-aspartate receptors (NMDARs)-as implicated in patients with schizophrenia-can cause regionally specific electrophysiological effects. Both animal models of NMDAR blockade and clinical studies in patients with schizophrenia have suggested that behavioral phenotypes are associated with reduction in inhibition within the frontal cortex.
Here we investigate event-related potentials to a roving auditory oddball paradigm under ketamine in healthy human volunteers (N= 18; double-blind, placebo-controlled, crossover design). Using recent advances in Bayesian modeling of group effects in dynamic causal modeling, we fit biophysically plausible network models of the auditory processing hierarchy to whole-scalp event-related potential recordings. This allowed us to identify regionally specific effects of ketamine in a distributed network of interacting cortical sources.
We show that the effect of ketamine is best explained as a selective change in intrinsic inhibition, with a pronounced ketamine-induced reduction of inhibitory interneuron connectivity in frontal sources, compared with temporal sources. Simulations of these changes in an integrated microcircuit model shows that they are associated with a reduction in superficial pyramidal cell activity that can explain drug effects observed in the event-related potential.
These results are consistent with findings from invasive recordings in animal models exposed to NMDAR blockers, and provide evidence that inhibitory interneuron-specific NMDAR dysfunction may be sufficient to explain electrophysiological abnormalities induced by NMDAR blockade in human subjects.
N-甲基-D-天冬氨酸受体（NMDAR）的紊乱与精神分裂症患者有关，可导致区域特异性电生理效应。NMDAR 阻断的动物模型和精神分裂症患者的临床研究都表明，行为表型与额叶皮层抑制减少有关。
在这里，我们在健康志愿者（N=18；双盲、安慰剂对照、交叉设计）中使用氯胺酮进行游走听觉Oddball 范式的事件相关电位研究。使用动态因果建模中群体效应贝叶斯建模的最新进展，我们拟合了听觉处理层次结构的生物物理上合理的网络模型到整个头皮事件相关电位记录。这使我们能够在相互作用的皮质源的分布式网络中识别出氯胺酮的区域特异性效应。
我们表明，氯胺酮的作用最好解释为内在抑制的选择性变化，与颞叶来源相比，额叶来源的抑制性中间神经元连接明显减少。在一个集成的微电路模型中对这些变化进行模拟表明，它们与浅层锥体细胞活动的减少有关，这可以解释在事件相关电位中观察到的药物效应。
这些结果与暴露于 NMDAR 阻断剂的动物模型的侵入性记录结果一致，并提供证据表明，抑制性中间神经元特异性 NMDAR 功能障碍可能足以解释 NMDAR 阻断在人类受试者中引起的电生理异常。
