Direct interrogation of cortical interneuron circuits in amyotrophic lateral sclerosis.

IF 10.6 1区 医学 Q1 CLINICAL NEUROLOGY
Brain Pub Date : 2024-10-10 DOI:10.1093/brain/awae317
Mehdi A J van den Bos, Parvathi Menon, Nathan Pavey, Mana Higashihara, Matthew C Kiernan, Steve Vucic
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引用次数: 0

Abstract

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 GABA-ergic dysfunction in ALS, through recording focussed cortical output whilst applying TMS over the primary motor cortex contralateral to the site of symptom onset. Using both a single pulse and novel inhibitory paired-pulse paradigms, TMS-EEG studies were undertaken on 21 ALS patients and results compared to 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 30ms (P30), 60 ms (P60) and 190 ms (P190) after TMS stimulus. Negative (N) or downward deflections occur at 44 ms (N44), 100 ms (N100) and 280ms (N280) after T,MS stimulus. The single pulse TEPs recorded in ALS patients demonstrated novel differences suggestive of cortical GABA-ergic dysfunction. When compared to controls, the N100 component was significantly reduced (P<0.05) while the P190 component increased (P<0.05) in ALS patients. Additionally, the N44 component correlated with muscle weakness (r=-0.501, P<0.05). These finding 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. Further, the reduction in SICI, 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 focussed interrogation of the motor cortex utilising novel TMS-EEG combined technologies has established localised dysfunction of GABA-ergic circuits, supporting the notion that cortical hyperexcitability is mediated by cortical disinhibition in ALS. Dysfunction of GABA-ergic circuits correlated with greater clinical disability and disease duration implying pathophysiological significance.

直接检测肌萎缩性脊髓侧索硬化症的皮层中间神经元回路。
皮层过度兴奋是肌萎缩性脊髓侧索硬化症(ALS)的主要致病特征,据信是通过皮层中间神经元复杂的相互作用介导的。迄今为止,还没有一种技术方法可以直接捕捉大脑皮层中间神经元的功能。本研究将经颅磁刺激(TMS)与先进的脑电图相结合,在症状发作部位对侧的初级运动皮层施加 TMS 的同时,通过记录聚焦皮层输出,检查 ALS 中的 GABA 能功能障碍。利用单脉冲和新型抑制性成对脉冲范式,对 21 名 ALS 患者进行了 TMS-EEG 研究,并将结果与健康对照组进行了比较。由 EEG 捕捉到的 TMS 反应会形成一个离散的波形,称为经颅诱发电位(TEP),在 TMS 刺激后的 30 毫秒(P30)、60 毫秒(P60)和 190 毫秒(P190)出现正(P)或向上偏转。负(N)或向下偏转出现在 TMS 刺激后 44 毫秒(N44)、100 毫秒(N100)和 280 毫秒(N280)处。ALS 患者记录的单脉冲 TEPs 显示了新的差异,提示皮质 GABA 能功能障碍。与对照组相比,N100 分量明显减少(P
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来源期刊
Brain
Brain 医学-临床神经学
CiteScore
20.30
自引率
4.10%
发文量
458
审稿时长
3-6 weeks
期刊介绍: Brain, a journal focused on clinical neurology and translational neuroscience, has been publishing landmark papers since 1878. The journal aims to expand its scope by including studies that shed light on disease mechanisms and conducting innovative clinical trials for brain disorders. With a wide range of topics covered, the Editorial Board represents the international readership and diverse coverage of the journal. Accepted articles are promptly posted online, typically within a few weeks of acceptance. As of 2022, Brain holds an impressive impact factor of 14.5, according to the Journal Citation Reports.
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