Cardiff University Brain Research Imaging Centre, School of Psychology, Cardiff University, UK.
Department of Engineering Mathematics, Merchant Venturers School of Engineering, University of Bristol, UK.
Neuroimage. 2017 Nov 1;161:19-31. doi: 10.1016/j.neuroimage.2017.08.034. Epub 2017 Aug 12.
The ability to quantify synaptic function at the level of cortical microcircuits from non-invasive data would be enormously useful in the study of neuronal processing in humans and the pathophysiology that attends many neuropsychiatric disorders. Here, we provide proof of principle that one can estimate inter-and intra-laminar interactions among specific neuronal populations using induced gamma responses in the visual cortex of human subjects - using dynamic causal modelling based upon the canonical microcircuit (CMC; a simplistic model of a cortical column). Using variability in induced (spectral) responses over a large cohort of normal subjects, we find that the predominant determinants of gamma responses rest on recurrent and intrinsic connections between superficial pyramidal cells and inhibitory interneurons. Furthermore, variations in beta responses were mediated by inter-subject differences in the intrinsic connections between deep pyramidal cells and inhibitory interneurons. Interestingly, we also show that increasing the self-inhibition of superficial pyramidal cells suppresses the amplitude of gamma activity, while increasing its peak frequency. This systematic and nonlinear relationship was only disclosed by modelling the causes of induced responses. Crucially, we were able to validate this form of neurophysiological phenotyping by showing a selective effect of the GABA re-uptake inhibitor tiagabine on the rate constants of inhibitory interneurons. Remarkably, we were able to recover the pharmacodynamics of this effect over the course of several hours on a per subject basis. These findings speak to the possibility of measuring population specific synaptic function - and its response to pharmacological intervention - to provide subject-specific biomarkers of mesoscopic neuronal processes using non-invasive data. Finally, our results demonstrate that, using the CMC as a proxy, the synaptic mechanisms that underlie the gain control of neuronal message passing within and between different levels of cortical hierarchies may now be amenable to quantitative study using non-invasive (MEG) procedures.
从非侵入性数据中定量研究皮质微电路水平上的突触功能，如果能应用于人类神经元处理和许多神经精神疾病的病理生理学研究，将具有巨大的价值。在这里，我们提供了一个原理性的证明，即可以使用人类受试者视觉皮层中的诱导伽马响应，通过基于经典微电路（CMC；皮质柱的简化模型）的因果模型来估计特定神经元群体之间的层间和层内相互作用。使用大样本正常受试者中诱导（光谱）响应的可变性，我们发现伽马响应的主要决定因素取决于浅层锥体神经元和抑制性中间神经元之间的递归和内在连接。此外，β响应的变化是由深锥体神经元和抑制性中间神经元之间的内在连接的个体差异介导的。有趣的是，我们还表明，增加浅层锥体神经元的自我抑制会抑制伽马活动的幅度，同时增加其峰值频率。这种系统的和非线性的关系只有通过建模诱导反应的原因才能揭示出来。至关重要的是，我们通过显示 GABA 再摄取抑制剂噻加宾对抑制性中间神经元的速率常数的选择性影响，验证了这种神经生理表型的方法。值得注意的是，我们能够在几个小时的时间内，根据每个受试者的情况，恢复这种效果的药效动力学。这些发现表明有可能测量特定于群体的突触功能 - 及其对药物干预的反应 - 使用非侵入性数据提供微观神经元过程的个体特异性生物标志物。最后，我们的结果表明，使用 CMC 作为代理，现在可以使用非侵入性（MEG）程序对皮层层次结构内和之间不同水平的神经元信息传递的增益控制的突触机制进行定量研究。
