Cortical hyperexcitability is an important pathophysiological mechanism in amyotrophic lateral sclerosis (ALS), reflecting a complex interaction of inhibitory and facilitatory interneuronal processes that evolves in the degenerating brain. The advances in physiological techniques have made it possible to interrogate progressive changes in the motor cortex. Specifically, the direction of transcranial magnetic stimulation (TMS) stimulus within the primary motor cortex can be utilised to influence descending corticospinal volleys and to thereby provide information about distinct interneuronal circuits. Cortical motor function and cognition was assessed in 29 ALS patients with results compared to healthy volunteers. Cortical dysfunction was assessed using threshold-tracking TMS to explore alterations in short interval intracortical inhibition (SICI), short interval intracortical facilitation (SICF), the index of excitation (IE), and stimulus response (SR) curves using a figure-of-eight coil with the coil oriented relative to the primary motor cortex in a posterior-anterior (PA), lateral-medial (LM), and anterior-posterior (AP) direction. Mean SICI, between interstimulus interval (ISI) of 1-to-7 ms, was significantly reduced in ALS patients compared to healthy controls when assessed with the coil oriented in PA (P = 0.044) and LM (P = 0.005) but not the AP (P = 0.08) directions. A significant correlation between mean SICI oriented in a PA direction and the total Edinburgh Cognitive and Behavioural ALS Screen score (Rho = 0.389, P = 0.037) was evident. In addition, the mean SICF, between ISI 1-to-5 ms, was significantly increased in ALS patients when recorded with TMS coil oriented in PA (P = 0.035) and LM (P < 0.001) directions. In contrast, SICF recorded with TMS coil oriented in the AP direction was comparable between ALS and controls (P = 0.482). The IE was significantly increased in ALS patients when recorded with the TMS coil oriented in PA (P = 0.041) and LM (P = 0.003) directions. In ALS patients, a significant increase in the SR curve gradient was evident compared to controls when recorded with TMS coil oriented in PA (P < 0.001), LM (P < 0.001) and AP (P = 0.002) directions. The present study has established that dysfunction of distinct interneuronal circuits mediates the development of cortical hyperexcitability in ALS. Specifically, complex interplay between inhibitory circuits and facilitatory interneuronal populations, that are preferentially activated by stimulation in posterior-to-anterior or lateral-to-medial directions, promotes cortical hyperexcitability in ALS. Mechanisms that underlie dysfunction of these specific cortical neuronal circuits will enhance understanding of the pathophysiological processes in ALS, with the potential to uncover focussed therapeutic targets.

中文翻译：

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不同的神经元回路介导肌萎缩侧索硬化症的皮质过度兴奋

皮质过度兴奋是肌萎缩侧索硬化症 (ALS) 的重要病理生理机制，反映了退化大脑中抑制性和促进性神经元间过程的复杂相互作用。生理技术的进步使得研究运动皮层的渐进变化成为可能。具体来说，初级运动皮层内的经颅磁刺激（TMS）刺激方向可用于影响下降的皮质脊髓齐射，从而提供有关不同神经元间回路的信息。对 29 名 ALS 患者的皮质运动功能和认知进行了评估，并将结果与​​健康志愿者进行了比较。使用阈值跟踪 TMS 评估皮质功能障碍，以探索短间隔皮质内抑制 (SICI)、短间隔皮质内促进 (SICF)、兴奋指数 (IE) 和刺激反应 (SR) 曲线的变化，使用图八个线圈，线圈相对于初级运动皮层沿后前（PA）、外侧-内侧（LM）和前-后（AP）方向定向。当使用 PA (P = 0.044) 和 LM (P = 0.005) 方向的线圈进行评估时，ALS 患者的平均 SICI（刺激间间隔 (ISI) 为 1 至 7 毫秒）显着减少，而健康对照组则不然。 AP (P = 0.08) 方向。PA 方向的平均 SICI 与爱丁堡认知和行为 ALS 筛查总分之间存在显着相关性（Rho = 0.389，P = 0.037）。此外，当使用定向于 PA (P = 0.035) 和 LM (P < 0.001) 方向的 TMS 线圈进行记录时，ALS 患者的 ISI 1 至 5 ms 之间的平均 SICF 显着增加。相比之下，使用沿 AP 方向定向的 TMS 线圈记录的 SICF 在 ALS 和对照之间具有可比性 (P = 0.482)。当 TMS 线圈朝向 PA（P = 0.041）和 LM（P = 0.003）方向记录时，ALS 患者的 IE 显着增加。在 ALS 患者中，当使用定向于 PA（P < 0.001）、LM（P < 0.001）和 AP（P = 0.002）方向的 TMS 线圈进行记录时，与对照相比，SR 曲线梯度显着增加。目前的研究已经证实，不同的中间神经元回路的功能障碍介导了 ALS 中皮质过度兴奋的发展。具体而言，抑制回路和促进性中间神经元群体之间复杂的相互作用（优先通过从后到前或从外侧到内侧方向的刺激激活）促进了 ALS 中的皮质过度兴奋。这些特定皮质神经元回路功能障碍的机制将增强对 ALS 病理生理过程的理解，并有可能发现集中的治疗靶点。