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

在分布的大规模皮质运动网络中，手的随意运动与协调的神经元活动有关。任务相关的有效连接增加，特别是辅助运动区(SMA)和初级运动皮质(M1)之间的连接，将驱动活动引导到自愿激活的M1。手性瘫痪的中风患者典型地表现出这种任务依赖性的SMA-M1连接性增加和同侧M1的激活。这些异常的程度与瘫痪手的运动临床缺陷有关。在这里，我们提出了一种新的MR导航的成对联合经颅磁刺激(PAS)技术，并结合经颅直流电刺激(TDC)来诱导协同峰时依赖性可塑性(STDP)样。我们将特别以SMA-M1连接为目标，以加强这一途径的有效连接的任务依赖性增加。我们预计，SMA-M1通路的加强将提高运动能力和运动学习过程。在第一步中，这些实验将在年轻的健康受试者中进行，这些受试者具有高可塑性，以探索联合使用SMA-M1PAS和M1-tDCSs对运动能力和学习能力的影响。在第二步，成功的方案将被应用于预期减少整形可能性的老年健康受试者，最终的翻译目标是将这些方案(在该项目的扩展中)应用于中风患者，意图改善他们瘫痪的手的功能。通过成对线圈经颅磁刺激和脑磁图，将获得刺激引起的静息状态和任务相关的有效SMA-M1连接性的读数。此外，运动能力和运动学习的变化将通过标准化的运动测试进行评估。这项拟议的项目首次旨在通过PAS和tDCs的新组合，通过时间和地点特定的非侵入性局灶性脑刺激来调节人脑特定皮质-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，并基于阳极M1-tDCs对SMA-M1投射的轴突终末的超极化以及STDP的协同性，这在细胞生理学中是增强突触可塑性诱导的公认原则。我们期望，最终，这种创新的、时间和地点特定的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.