Department of Clinical and Experimental Epilepsy, UCL Queen Square Institute of Neurology, London, UK.
Chalfont Centre for Epilepsy, Chalfont St. Peter, UK.
Epilepsia. 2020 Sep;61(9):1818-1839. doi: 10.1111/epi.16634. Epub 2020 Aug 12.
Advances in genetics may enable a deeper understanding of disease mechanisms and promote a shift to more personalised medicine in the epilepsies. At present, understanding of consequences of genetic variants mainly relies on preclinical functional work; tools for acquiring similar data from the living human brain are needed. Transcranial magnetic stimulation (TMS), in particular paired-pulse TMS protocols which depend on the function of cortical GABAergic interneuron networks, has the potential to become such a tool. For this report, we identified and reviewed 23 publications on TMS studies of cortical excitability and inhibition in 15 different genes or conditions relevant to epilepsy. Reduced short-interval intracortical inhibition (SICI) and reduced cortical silent period (CSP) duration were the most commonly reported findings, suggesting abnormal GABA - (SICI) or GABA ergic (CSP) signalling. For several conditions, these findings are plausible based on established evidence of involvement of the GABAergic system; for some others, they may inform future research around such mechanisms. Challenges of TMS include lack of complete understanding of the neural underpinnings of the measures used: hypotheses and analyses should be based on existing clinical and preclinical data. Further pitfalls include gathering sufficient numbers of participants, and the effect of confounding factors, especially medications. TMS-EEG is a unique perturbational technique to study the intrinsic properties of the cortex with excellent temporal resolution; while it has the potential to provide further information of use in interpreting effects of genetic variants, currently the links between measures and neurophysiology are less established. Despite these challenges, TMS is a tool with potential for elucidating the system-level in vivo functional consequences of genetic variants in people carrying genetic changes of interest, providing unique insights.
遗传学的进展可能使我们更深入地了解疾病机制，并促进癫痫治疗向更个体化的医学模式转变。目前，对遗传变异后果的理解主要依赖于临床前的功能研究；需要开发工具来从人类活体大脑中获取类似的数据。经颅磁刺激（TMS），特别是依赖于皮质 GABA 能中间神经元网络功能的双脉冲 TMS 方案，有可能成为这样的工具。在本报告中，我们确定并回顾了 23 篇关于 TMS 研究的出版物，这些研究涉及 15 种不同的与癫痫相关的基因或疾病。最常报道的发现是短程抑制（SICI）和皮质静息期（CSP）持续时间减少，这表明 GABA 能（SICI）或 GABA 能（CSP）信号异常。对于几种情况，这些发现是合理的，因为已经有证据表明 GABA 能系统参与其中；对于其他一些情况，它们可能为围绕这些机制的未来研究提供信息。TMS 面临的挑战包括对所使用措施的神经基础缺乏全面了解：假设和分析应基于现有的临床和临床前数据。进一步的陷阱包括收集足够数量的参与者，以及混杂因素的影响，尤其是药物的影响。TMS-EEG 是一种独特的扰动技术，可用于研究皮质的内在特性，具有出色的时间分辨率；虽然它有可能提供更多关于解释遗传变异影响的信息，但目前测量值与神经生理学之间的联系还不太确定。尽管存在这些挑战，但 TMS 是一种具有潜力的工具，可以阐明携带感兴趣的遗传变化的个体中遗传变异的系统水平的体内功能后果，提供独特的见解。
