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

手的自主运动与分布式大规模皮质运动网络中的协调神经元活动相关。有效连接的任务依赖性增加，特别是辅助运动区（SMA）和初级运动皮层（M1）之间的连接，将驾驶活动汇集到主动活动的M1中。手麻痹的中风患者通常表现出SMA-M1连接的任务依赖性增加和同病灶M1激活的障碍。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MR导航配对关联经颅磁刺激（PAS）技术结合经颅直流电刺激（tDCS），以诱导合作尖峰时间依赖可塑性（STDP）样。我们将专门针对SMA-M1连接，以加强该途径有效连接的任务依赖性增加。我们期望SMA-M1通路的加强将增强运动表现和运动学习过程。在第一步中，将在具有高可塑性变化潜力的年轻健康受试者中进行实验，以探索SMA-M1 PAS和M1-tDCS组合对运动性能和学习的影响。在第二步中，成功的方案将应用于老年健康受试者，预期可塑性变化的可能性降低，最终的转化目标是将这些方案（作为本项目的扩展）应用于中风患者，旨在改善其麻痹手的功能。通过双线圈经颅磁刺激和MEG/EEG获得刺激诱导的静息状态和任务依赖性有效SMA-M1连接变化的读数。此外，将通过标准化运动测试评估运动表现和运动学习的变化。该项目的目的是，第一次，在调制生理动态连接状态的特定皮质-皮质投影（SMA-M1）的人脑通过定时和特定部位的非侵入性局灶性脑刺激，凭借PAS和tDCS的一种新的组合。计划的实验依赖于广泛的前期工作，并基于超极化的轴突终端的SMA-M1的投影由阳极M1-tDCS，和协同性的STDP，这在细胞生理学是一个完善的原则，以提高诱导突触可塑性。我们预计，最终，这种创新的定时和特定部位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.