Wellcome Trust Centre for Neuroimaging, Institute of Neurology, University College London, London WC1N 3BG, UK.
Curr Biol. 2011 Aug 9;21(15):1320-5. doi: 10.1016/j.cub.2011.06.053. Epub 2011 Jul 28.
The contribution of dopamine to working memory has been studied extensively [1-3]. Here, we exploited its well characterized effects [1-3] to validate a novel human in vivo assay of ongoing synaptic [4, 5] processing. We obtained magnetoencephalographic (MEG) measurements from subjects performing a working memory (WM) task during a within-subject, placebo-controlled, pharmacological (dopaminergic) challenge. By applying dynamic causal modeling (DCM), a Bayesian technique for neuronal system identification [6], to MEG signals from prefrontal cortex, we demonstrate that it is possible to infer synaptic signaling by specific ion channels in behaving humans. Dopamine-induced enhancement of WM performance was accompanied by significant changes in MEG signal power, and a DCM assay disclosed related changes in synaptic signaling. By estimating the contribution of ionotropic receptors (AMPA, NMDA, and GABA(A)) to the observed spectral response, we demonstrate changes in their function commensurate with the synaptic effects of dopamine. The validity of our model is reinforced by a striking quantitative effect on NMDA and AMPA receptor signaling that predicted behavioral improvement over subjects. Our results provide a proof-of-principle demonstration of a novel framework for inferring, noninvasively, neuromodulatory influences on ion channel signaling via specific ionotropic receptors, providing a window on the hidden synaptic events mediating discrete psychological processes in humans.
多巴胺对工作记忆的贡献已经得到了广泛的研究[1-3]。在这里，我们利用其特征明确的作用[1-3]，验证了一种新的人类体内突触[4,5]处理的实时测定法。我们在一项基于个体的、安慰剂对照的药理学（多巴胺能）挑战中，让受试者执行工作记忆（WM）任务，同时获取了脑磁图（MEG）测量数据。通过对来自前额叶皮层的 MEG 信号应用动态因果建模（DCM），这是一种用于神经元系统识别的贝叶斯技术[6]，我们证明了在行为人类中，可以通过特定的离子通道推断出突触信号。多巴胺诱导的 WM 表现增强伴随着 MEG 信号功率的显著变化，而 DCM 测定法揭示了相关的突触信号变化。通过估计离子型受体（AMPA、NMDA 和 GABA(A)）对观察到的光谱响应的贡献，我们证明了它们的功能变化与多巴胺的突触效应相符。我们的模型的有效性通过 NMDA 和 AMPA 受体信号的显著定量效应得到了加强，该效应预测了个体的行为改善。我们的结果提供了一个原理证明，证明了一种通过特定离子型受体推断神经调质对离子通道信号影响的新框架，为人类中介离散心理过程的隐藏突触事件提供了一个窗口。
