Epilepsy treatment remains a major challenge, with nearly 30% of people continuing to experience seizures despite the availability of over 20 antiepileptic drugs. One of the major challenges to improving epilepsy treatment is the heterogeneity of epilepsy pathophysiology. Antiepileptogenic (i.e. drugs used to prevent the development of epilepsy) and antiseizure (i.e. drugs used to stop epileptic seizures) treatments need to be developed and chosen on an individualized basis, according to a precision medicine paradigm. Therefore, it is vital to identify biomarkers that can help to guide epilepsy treatments. Epilepsy pathophysiology reflects altered cortical network excitability. Transcranial magnetic stimulation (TMS) is a non-invasive tool which is applied extracranially with time-varying magnetic fields to measure cortical physiology. TMS has high temporal resolution and can expose causal relations after stimulation due to the temporal sequence of evoked activity. TMS has been used to probe cortical excitability in genetic epileptic encephalopathies. For example, in Dravet Syndrome, a distinct neurophysiological phenotype has been identified, suggesting the role of TMS as a putative biomarker of mutation-driven cortical pathophysiology and a rapid readout predictor of drug effect. TMS has also shown how cortical excitability correlates with seizure control and epilepsy duration in chronic epilepsy. TMS is a great tool to understand disease biology in vivo, and subsequently guide and monitor individualized treatments. The study by Andreasson et al. is a great example of such applications of TMS in children with epilepsy. Their findings further support the potential role of TMS as a biomarker of drug response. There are, however, some controversial issues which need to be addressed for future applications. TMS combined with electromyography only measures excitability from the motor cortex, and its responses are also affected by the excitability of corticospinal and spinal neurons. Currently, the correlation of resting motor threshold (RMT) with epilepsy type remains uncertain, with some evidence of lower RMT values in generalized epilepsies, and no significant evidence in focal epilepsies. Methods for RMT determination vary across previous studies, with subsequent issues in the reproducibility of outcome. Similarly, methodological differences and reproducibility issues have emerged in studies using long-interval intracortical inhibition measures as a biomarker in epilepsy, emphasizing the need for prospective multicentre studies to test and validate the reproducibility of TMS protocols and measures. Furthermore, to interpret variation in RMT and other singleand paired-pulse TMS measures, there are a number of potential confounding factors that should be taken into account. These include age, hemispheric dominance, presence of brain lesions, circadian differences, cognitive function, hormonal fluctuations, and possibly others. The role of these factors should be clearly established to minimize interindividual variability and enhance the use of TMS as a biomarker for epilepsy management. Once the reliability and reproducibility of TMS protocols are consolidated, the potential of this technique to investigate epilepsy pathophysiology and treatment is high. Combining TMS with electroencephalography is likely to increase its spatial resolution, by allowing direct probing of cortical excitability even in non-motor areas, bypassing sensorimotor pathways and subcortical structures. Furthermore, the direct measurement of cortical potentials in response to stimulation may allow the investigation of small populations of neurons. When compared to other neuroimaging methodologies like magnetic resonance imaging, this could show subtle functional disturbances in very focal brain regions, which is beneficial given the interindividual phenotypic variability in epilepsy. Further studies are warranted, but pharmaco-TMS may soon become a reliable tool to monitor and predict clinical treatment outcome and to develop new antiepileptogenic therapies on an individualized basis.

中文翻译：

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经颅磁刺激作为儿童癫痫治疗反应的生物标志物

癫痫治疗仍然是一项重大挑战，尽管有 20 多种抗癫痫药物可供使用，但仍有近 30% 的人继续癫痫发作。改善癫痫治疗的主要挑战之一是癫痫病理生理学的异质性。抗癫痫药（即用于预防癫痫发展的药物）和抗癫痫药（即用于阻止癫痫发作的药物）需要根据精准医学范式在个体化的基础上开发和选择。因此，确定有助于指导癫痫治疗的生物标志物至关重要。癫痫病理生理学反映了皮质网络兴奋性的改变。经颅磁刺激 (TMS) 是一种非侵入性工具，它在颅外应用时变磁场来测量皮质生理。TMS 具有较高的时间分辨率，并且由于诱发活动的时间序列，可以在刺激后暴露因果关系。TMS 已被用于探测遗传性癫痫性脑病的皮质兴奋性。例如，在 Dravet 综合征中，已经确定了一种独特的神经生理学表型，这表明 TMS 作为突变驱动的皮层病理生理学的假定生物标志物和药物作用的快速读出预测因子的作用。TMS 还显示皮质兴奋性如何与慢性癫痫的癫痫发作控制和癫痫持续时间相关。TMS 是了解体内疾病生物学并随后指导和监测个性化治疗的绝佳工具。Andreasson 等人的研究。是 TMS 在癫痫儿童中的此类应用的一个很好的例子。他们的发现进一步支持了 TMS 作为药物反应生物标志物的潜在作用。然而，有一些有争议的问题需要在未来的应用中解决。TMS 结合肌电图仅测量运动皮层的兴奋性，其反应也受皮质脊髓和脊髓神经元兴奋性的影响。目前，静息运动阈值 (RMT) 与癫痫类型的相关性仍不确定，有证据表明全身性癫痫的 RMT 值较低，而局灶性癫痫没有显着证据。RMT 测定方法因先前的研究而异，随后的结果可重复性问题。相似地，在使用长间隔皮质内抑制措施作为癫痫生物标志物的研究中出现了方法学差异和可重复性问题，强调需要前瞻性多中心研究来测试和验证 TMS 协议和措施的可重复性。此外，要解释 RMT 和其他单脉冲和成对脉冲 TMS 测量的变化，应考虑许多潜在的混杂因素。这些包括年龄、半球优势、大脑病变的存在、昼夜节律差异、认知功能、荷尔蒙波动，以及其他可能的因素。应明确确定这些因素的作用，以最大限度地减少个体差异并加强 TMS 作为癫痫治疗生物标志物的使用。一旦 TMS 协议的可靠性和可重复性得到巩固，该技术在研究癫痫病理生理学和治疗方面的潜力就很高。将 TMS 与脑电图相结合可能会提高其空间分辨率，即使在非运动区域也可以直接探测皮层兴奋性，绕过感觉运动通路和皮层下结构。此外，响应刺激的皮层电位的直接测量可能允许对小群神经元进行调查。与磁共振成像等其他神经影像学方法相比，这可能会显示非常局灶性大脑区域的细微功能障碍，鉴于癫痫的个体间表型变异性，这是有益的。有必要进一步研究，