van den Bos Mehdi A J, Menon Parvathi, Pavey Nathan, Higashihara Mana, Kiernan Matthew C, Vucic Steve
Brain and Nerve Research Centre, Concord Clinical School, The University of Sydney, Sydney, NSW 2139, Australia.
Concord Repatriation General Hospital, Sydney, NSW 2139, Australia.
Brain. 2025 Apr 3;148(4):1169-1179. doi: 10.1093/brain/awae317.
Cortical hyperexcitability is a key pathogenic feature of amyotrophic lateral sclerosis (ALS), believed to be mediated through complex interplay of cortical interneurons. To date, there has been no technological approach to facilitate the direct capture of cortical interneuron function. Through combination of transcranial magnetic stimulation (TMS) with advanced EEG, the present study examined GABAergic dysfunction in ALS by recording focused cortical output whilst applying TMS over the primary motor cortex contralateral to the site of symptom onset. Using both a single-pulse and a novel inhibitory paired-pulse paradigm, TMS-EEG studies were undertaken on 21 ALS patients and results compared with healthy controls. TMS responses captured by EEG form a discrete waveform known as the transcranial evoked potential (TEP), with positive (P) or upward deflections occurring at 30 (P30), 60 (P60) and 190 ms (P190) after TMS stimulus. Negative (N) or downward deflections occur at 44 (N44), 100 (N100) and 280 ms (N280) after TMS stimulus. The single-pulse TEPs recorded in ALS patients demonstrated novel differences suggestive of cortical GABAergic dysfunction. When compared with controls, the N100 component was significantly reduced (P < 0.05), whereas the P190 component increased (P < 0.05) in ALS patients. Additionally, the N44 component was correlated with muscle weakness (r = -0.501, P < 0.05). These findings were supported by reduced paired-pulse inhibition of TEP components in ALS patients (P60, P < 0.01; N100, P < 0.005), consistent with dysfunction of cortical interneuronal GABAA-ergic circuits. Furthermore, the reduction in short-interval intracortical inhibition, as reflected by changes in paired-pulse inhibition of the N100 component, was associated with longer disease duration in ALS patients (r = -0.698, P < 0.001). In conclusion, intensive and focused interrogation of the motor cortex using novel TMS-EEG combined technologies has established localized dysfunction of GABAergic circuits, supporting the notion that cortical hyperexcitability is mediated by cortical disinhibition in ALS. Dysfunction of GABAergic circuits was correlated with greater clinical disability and disease duration, implying pathophysiological significance.
皮质兴奋性过高是肌萎缩侧索硬化症（ALS）的一个关键致病特征，据信是由皮质中间神经元的复杂相互作用介导的。迄今为止，尚无技术手段能够直接捕捉皮质中间神经元的功能。通过将经颅磁刺激（TMS）与先进的脑电图（EEG）相结合，本研究通过记录聚焦的皮质输出，同时在症状发作部位对侧的初级运动皮质上施加TMS，来研究ALS中的GABA能功能障碍。使用单脉冲和一种新型抑制性配对脉冲范式，对21例ALS患者进行了TMS-EEG研究，并将结果与健康对照进行比较。由EEG捕获的TMS反应形成一种离散波形，称为经颅诱发电位（TEP），在TMS刺激后30（P30）、60（P60）和190毫秒（P190）出现正向（P）或向上偏转。负向（N）或向下偏转在TMS刺激后44（N44）、100（N100）和280毫秒（N280）出现。在ALS患者中记录的单脉冲TEP显示出提示皮质GABA能功能障碍的新差异。与对照组相比，ALS患者的N100成分显著降低（P<0.05），而P190成分增加（P<0.05）。此外，N44成分与肌肉无力相关（r=-0.501，P<0.05）。这些发现得到了ALS患者TEP成分配对脉冲抑制降低的支持（P60，P<0.01；N100，P<0.005），这与皮质中间神经元GABAA能回路功能障碍一致。此外，N100成分配对脉冲抑制变化所反映的短间隔皮质内抑制降低与ALS患者的病程延长相关（r=-0.698，P<0.001）。总之，使用新型TMS-EEG联合技术对运动皮质进行密集和聚焦的研究已经证实了GABA能回路的局部功能障碍，支持了皮质兴奋性过高是由ALS中的皮质去抑制介导的这一观点。GABA能回路功能障碍与更大程度的临床残疾和病程相关，这意味着其具有病理生理学意义。
