Department of Neurology and Stroke, and Hertie Institute for Clinical Brain Research, Eberhard-Karls-University Tübingen, 72076 Tübingen, Germany, International Max Planck Research School, 72076 Tübingen, Germany, Laboratory of Cognitive and Computational Neuroscience, Centre for Biomedical Technology, Universidad Politécnica de Madrid, 28660 Madrid, Spain, School of Psychology, University of East London, E15 4LZ London, United Kingdom, Department of Neurophysiology, Max Planck Institute for Brain Research, 60528 Frankfurt am Main, Germany, Ernst Strüngmann Institute for Neuroscience in Cooperation with Max Planck Society, 60528 Frankfurt am Main, Germany, Functional and Restorative Neurosurgery, University Hospital Tübingen, Eberhard Karls University, 72076 Tübingen, Germany, and Department of Neurology, Goethe-University, 60528 Frankfurt am Main, Germany.
J Neurosci. 2014 Apr 16;34(16):5603-12. doi: 10.1523/JNEUROSCI.5089-13.2014.
Combining transcranial magnetic stimulation (TMS) and electroencephalography (EEG) constitutes a powerful tool to directly assess human cortical excitability and connectivity. TMS of the primary motor cortex elicits a sequence of TMS-evoked EEG potentials (TEPs). It is thought that inhibitory neurotransmission through GABA-A receptors (GABAAR) modulates early TEPs (<50 ms after TMS), whereas GABA-B receptors (GABABR) play a role for later TEPs (at ∼100 ms after TMS). However, the physiological underpinnings of TEPs have not been clearly elucidated yet. Here, we studied the role of GABAA/B-ergic neurotransmission for TEPs in healthy subjects using a pharmaco-TMS-EEG approach. In Experiment 1, we tested the effects of a single oral dose of alprazolam (a classical benzodiazepine acting as allosteric-positive modulator at α1, α2, α3, and α5 subunit-containing GABAARs) and zolpidem (a positive modulator mainly at the α1 GABAAR) in a double-blind, placebo-controlled, crossover study. In Experiment 2, we tested the influence of baclofen (a GABABR agonist) and diazepam (a classical benzodiazepine) versus placebo on TEPs. Alprazolam and diazepam increased the amplitude of the negative potential at 45 ms after stimulation (N45) and decreased the negative component at 100 ms (N100), whereas zolpidem increased the N45 only. In contrast, baclofen specifically increased the N100 amplitude. These results provide strong evidence that the N45 represents activity of α1-subunit-containing GABAARs, whereas the N100 represents activity of GABABRs. Findings open a novel window of opportunity to study alteration of GABAA-/GABAB-related inhibition in disorders, such as epilepsy or schizophrenia.
经颅磁刺激（TMS）与脑电图（EEG）的联合使用构成了一种直接评估人类皮质兴奋性和连通性的强大工具。刺激初级运动皮层会引发一系列 TMS 诱发电场（TEP）。人们认为，通过 GABA-A 受体（GABAAR）的抑制性神经传递会调节早期的 TEP（TMS 后<50ms），而 GABA-B 受体（GABABR）则在晚期 TEP（TMS 后约 100ms）中发挥作用。然而，TEP 的生理基础尚未得到明确阐明。在这里，我们使用药物 TMS-EEG 方法研究了健康受试者中 GABAAR/B 能神经传递对 TEP 的作用。在实验 1 中，我们在一项双盲、安慰剂对照、交叉研究中测试了单剂量阿普唑仑（一种作为全变构正向调节剂作用于包含α1、α2、α3 和α5 亚基的 GABAAR 的经典苯二氮䓬类药物）和唑吡坦（一种主要作用于α1 GABAAR 的正调节剂）的作用。在实验 2 中，我们测试了巴氯芬（GABABR 激动剂）和地西泮（一种经典的苯二氮䓬类药物）与安慰剂对 TEP 的影响。阿普唑仑和地西泮增加了刺激后 45ms 时的负电势（N45）的振幅，并降低了 100ms 时的负成分（N100），而唑吡坦仅增加了 N45。相比之下，巴氯芬特异性地增加了 N100 的振幅。这些结果为 N45 代表含有α1 亚基的 GABAAR 活性，而 N100 代表 GABABR 活性提供了有力证据。这些发现为研究癫痫或精神分裂症等疾病中 GABAAR/B 相关抑制的改变开辟了新的机会。
