Strengthening the SMA-M1 connection of human motor cortex by a novel non-invasive brain stimu-lation protocol to enhance motor performance and learning

手部的随意运动与分布的大规模皮质运动网络中的协调神经元活动有关。任务依赖性的有效连通性增加，特别是辅助运动区（SMA）和初级运动皮层（M1）之间的连接，将驱动活动引入主动活跃的M1。伴有手部轻瘫的中风患者通常表现出这种任务依赖性SMA-M1连接增加和同侧M1激活的损伤。这些异常的程度与麻痹手的运动临床缺陷相关。在这里，我们提出了一种新的磁共振导航配对联想经颅磁刺激（PAS）技术结合经颅直流电刺激（tDCS）来诱导合作尖峰时间依赖的可塑性（STDP）样。我们将专门针对SMA-M1连接，以加强该途径有效连通性的任务依赖性增加。我们预计，SMA-M1通路的加强将增强运动表现和运动学习过程。首先，我们将在具有可塑性变化高潜力的年轻健康受试者中进行实验，以探索SMA-M1 PAS和M1-tDCS联合使用对运动表现和学习的影响。在第二步中，成功的方案将应用于预期可塑性变化可能性降低的老年健康受试者，最终的转化目标是将这些方案应用于中风患者（作为本项目的延伸），以改善其麻痹手的功能。通过配对线圈经颅磁刺激和MEG/EEG获得刺激引起的静息状态和任务依赖的有效SMA-M1连通性变化的读数。此外，运动表现和运动学习的变化将通过标准化运动测试进行评估。该项目旨在首次通过PAS和tDCS的新组合，通过时间和部位特异性的非侵入性局灶性脑刺激，调节人类大脑特定皮质-皮质投射（SMA-M1）的生理动态连接状态。计划中的实验依赖于广泛的前期工作，并基于SMA-M1投射轴突末端通过阳极M1-tDCS的超极化，以及STDP的协同性，这在细胞生理学中是增强突触可塑性诱导的既定原理。我们期望，最终，这种创新的时间和部位特异性非侵入性脑刺激技术将对提高中风患者的神经康复成功率产生重大影响。

Voluntary movements of the hand are associated with coordinated neuronal activity in a distributed large-scale cortical motor network. Task-dependent increases in effective connectivity, in particular of the connection between supplementary motor area (SMA) and primary motor cortex (M1), funnel driving activity into the voluntarily active M1. Stroke patients with hand paresis typically show im-pairments of this task-dependent increase of SMA-M1 connectivity and activation of the ipsilesional M1. The degree of these abnormalities correlates with motor clinical deficits of the paretic hand. Here we propose a novel MR-navigated paired associative transcranial magnetic stimulation (PAS) technique in combination with transcranial direct current stimulation (tDCS) to induce cooperative spike-timing dependent plasticity (STDP)-like. We will specifically target the SMA-M1 connection to strengthen task-dependent increases in effective connectivity of this pathway. We expect that strengthening of the SMA-M1 pathway will enhance motor performances and motor learning pro-cesses. In a first step, the experiments will be performed in young healthy subjects with a high po-tential for plastic change to explore the effects of combined SMA-M1 PAS and M1-tDCS on motor performance and learning. In a second step, successful protocols will be applied to elderly healthy subjects with an expected reduced potential for plastic change, with the ultimate translational aim to apply these protocols (in an extension of this project) to stroke patients with the intention to im-prove function of their paretic hand. Readouts of stimulation-induced changes in resting-state and task-dependent effective SMA-M1 connectivity will be obtained by paired-coil transcranial magnetic stimulation and MEG/EEG. In addition, changes in motor performance and motor learning will be assessed by standardized motor tests. The proposed project aims, for the first time, at modulating physiological dynamic connectivity states of a specific cortico-cortical projection (SMA-M1) of the human brain by timing- and site-specific non-invasive focal brain stimulation, by virtue of a novel combination of PAS and tDCS. The planned experiments rely on extensive preliminary work, and are based on hyperpolarization of axon terminals of the SMA-M1 projection by anodal M1-tDCS, and cooperativity of STDP, which in cellular physiology is a well-established principle to enhance induction of synaptic plasticity. We expect that, ultimately, this innovative timing- and site-specific non-invasive brain stimulation tech-nique will have significant impact in enhancing neurorehabilitation success of stroke patients.