Induction of Synaptic Plasticity in the Human Brain by individualized biphasic repetitive I-wave Transcranial Magnetic Stimulation

长期增强（LTP）和长期抑制（LTD）形式的突触可塑性被认为是学习和记忆的神经生理关联。这些基础神经生理机制（即LTP和LTD）的损伤被认为在各种医疗条件（如发育障碍）的发展和表型中起关键作用。重复经颅磁刺激(rTMS) -如脉冲刺激（TBS）或四脉冲刺激-是最流行的非侵入性脑刺激方法之一，可用于诱导和研究人类突触可塑性。在基础神经科学以及各种神经系统疾病的治疗中，如耐药抑郁症和中风后康复，它逐渐受到越来越多的关注。在这种情况下，为了减少后效的可变性，个体化的刺激可能很重要。这种可变性可能由称为i波的个别振荡触发。根据它们各自的延迟，主要发现了三个峰值，称为I1-3波，延迟为1.5 ms。它们似乎有助于并调节人类初级运动皮层（M1）的突触可塑性。i波不仅是刚性振荡，与TMS脉冲有及时的关系，而且这些下降波的招募模式和潜伏期是个体间延迟变化的基础，其延迟约为1.5 ms。在这里，具有个体可调TMS参数的新技术，如刺激频率，优化电流和脉冲配置，有可能更好地控制这些影响，并进一步个性化rTMS在人类中的应用。在一项初步工作中，我们发现了一种新的、有效的超快速经颅磁刺激方案，即所谓的四次脉冲θ波爆发刺激（qTBS），它使研究者能够针对所有三个i波，并证明在i波周期内以1.5 ms的刚性刺激间隔诱导突触可塑性。本研究的目的是：(1)利用新建立的四脉冲刺激范式（qTBS）研究i波依赖的超可塑性，了解i波早期和晚期激活对人类M1突触可塑性的作用和相互作用；(2)拓展个体化i波特异性经颅磁刺激的研究成果，通过开发一种新的刺激技术和新的设备，首次覆盖所有三个脉冲可调节的i波；(3)研究个体化经颅磁刺激对运动学习的影响，最终目的是通过使刺激模式适应个体神经生理状况，提高经颅磁刺激在研究和临床实践中的治疗效果。这将通过开发一种新的、可单独调节的磁刺激装置来实现，该装置可以针对所有三个i波的单独潜伏期。

Synaptic plasticity in forms of long-term potentiation (LTP) and long term depression (LTD) is considered to be the neurophysiological correlate of learning and memory. Impairments of these basal neurophysiological mechanisms (i.e. LTP and LTD) are thought to play a pivotal role in the development and phenotype of various medical conditions (e.g. developmental disorder). Repetitive transcranial magnetic stimulation (rTMS) – e.g. theta-burst stimulation (TBS) or quadri-pulse stimulation – is one of the most popular methods for non-invasive brain stimulation that can be used to induce and to investigate synaptic plasticity in humans. It becomes gradually more noticed in basic neuroscience as well as in the treatment of various neurological diseases such as drug resistant depression and rehabilitation after stroke. To reduce variability of after effects in this context, an individualized stimulation may be important. This variability may be triggered by individual oscillations so called I-waves. According to their individual latency, mainly three peaks have been discovered, termed I1-3 waves with a latency of app. 1.5 ms. They seem to contribute to and to modulate synaptic plasticity in human primary motor cortex (M1). I-waves are not only rigid oscillations with timely relation to TMS pulses but the recruitment pattern and latency of these descending volleys underlies inter-individual variability in latencies of around 1.5 ms. Here, new techniques with individual adjustable TMS parameters such as stimulation frequency, optimized current flow and pulse configuration have the potential to better control these effects and to further individualize rTMS application in humans. In a preliminary work, we discovered a new and effective ultra-fast transcranial magnetic stimulation protocol, so called quadri pulse theta burst stimulation (qTBS) that enables the investigator to target all three I-waves and that demonstrated to induce synaptic plasticity at I-wave periodicity with rigid interstimulus intervals of 1.5 ms. The aim of the proposal is to (1) Understand the role and interaction of early and late I-wave activation on synaptic plasticity in human M1 by means of investigation on I-wave dependent metaplasticity using a newly established quadri-pulse stimulation paradigm (qTBS), (2) To extend findings on individualized I-wave specific transcranial magnetic stimulation covering – for the first time – all three I-waves with individual adjustable pulses by developing a new stimulation technique with a new device and to (3) Investigate the influence of individualized TMS on motor learning with the ultimate aim of enhancing therapeutical effects of TMS in research and clinical practice by adapting the stimulation pattern to individual neurophysiological conditions. This is intended to be realized by the development of a new, and individual adjustable magnetic stimulation device that target all three I-waves at their individual latencies.