Pharmaco-TMS-EEG: Establishing a novel tool for measuring excitability in human cerebral cortex

药物-TMS-EMG，即神经药理学与运动皮层经颅磁刺激（TMS）和手部肌肉肌电图（EMG）记录运动诱发电位的结合，为使用TMS-EMG对运动皮层的兴奋和抑制进行区分无创评估提供了重要的见解[Ziemann et al. 2015，临床神经物理126:1847-68]。在此基础上，颅磁-肌电图在世界范围内被用于检测神经和精神疾病的异常兴奋性。然而，颅磁-肌电图的应用和知识的获取受到了极大的限制，因为记录来自肌肉（而不是大脑），评估仅限于运动皮层（其他地方的刺激没有可量化的反应）。脑电图（EEG）放大器技术的最新进展现在允许直接从大脑记录经颅磁刺激诱发的反应。因此，TMS-EEG有很大的潜力来克服目前实践的TMS-EMG技术的这些局限性。原发性运动皮层局灶性经颅磁刺激可靠地获得具有可重复潜伏期和拓扑的经颅磁刺激诱发脑电图电位（例如，P25、N45、P70、N100和P180）。然而，这些电位的生理机制在很大程度上是未知的。因此，通过实验操作或在疾病条件下观察这些电位的变化，目前仍停留在描述性水平。我们最近开始用中枢神经系统活性药物来表征tms诱发的脑电图电位。我们可以首次证明GABABergic抑制有助于N45和GABABergic抑制N100 [Premoli et al. 2014, J Neurosci 34:5603-12]；Premoli et . 2014, [j].中国生物医学工程学报（英文版）。为了扩展这些数据，并类比于之前大量的药物- tms - emg工作，我们在这里提出了一个系统的tms诱发脑电图电位的药理学表征。我们将重点关注在谷氨酸能和gaba能系统中具有特定作用模式的中枢神经系统活性药物，以及电压门控离子通道的阻滞剂。我们期望从这项研究中获得一种新的、直接的、因此信息量很大的工具来评估人类大脑皮层的兴奋性。该工具一旦具有药物生理特征，在神经和精神疾病的异常脑兴奋性诊断评估中发挥重要作用。

Pharmaco-TMS-EMG, i.e. the combination of neuropharmacology with transcranial magnetic stimulation (TMS) of motor cortex and recording of motor evoked potentials with electromyography (EMG) from a hand muscle has provided important insight to use TMS-EMG for differentiated non-invasive assessment of excitation and inhibition in motor cortex [Ziemann et al. 2015, Clin Neurophysiol 126:1847-68]. On this basis, TMS-EMG is being employed worldwide to detect abnormal excitability in neurological and psychiatric diseases. However, applications and gain of knowledge of TMS-EMG are significantly limited because recordings are made from a muscle (rather than from the brain) and assessment is restricted to motor cortex (no quantifiable responses with stimulation elsewhere). Recent advances in electroencephalography (EEG) amplifier technology allow now recordings of TMS-evoked responses directly from the brain. Therefore, TMS-EEG has a significant potential to overcome these limitations of currently practiced TMS-EMG technology. Focal TMS of primary motor cortex results reliably in TMS-evoked EEG potentials with reproducible latency and topology (e.g., P25, N45, P70, N100, and P180). However, the physiological mechanisms of these potentials are largely unknown. Therefore, observations of alterations of these potentials by experimental manipulation or in disease conditions remain, at present, at the descriptive level. We have started recently, to characterize these TMS-evoked EEG potentials by CNS active drugs. We could show for the first time that GABAAergic inhibition contributes to the N45 and GABABergic inhibition to the N100 [Premoli et al. 2014, J Neurosci 34:5603-12; Premoli et al. 2014, NeuroImage 103C:152-62]. To extend these data, and in analogy to a large body of previous work on pharmaco-TMS-EMG, we propose here a systematic pharmacological characterization of TMS-evoked EEG potentials. We will focus on CNS active drugs with specific modes of action in the glutamatergic and GABAergic system, and on blockers of voltage-gated ion channels. We expect from this research a novel, direct and therefore highly informative tool to assess excitability of the human cerebral cortex. This tool could, as soon as pharmaco-physiologically characterized, play an important role in the diagnostic assessment of abnormal brain excitability in neurological and psychiatric diseases.