Exploring the physiology and behavioural relevance of circuits in the human motor cortex with a novel transcranial magnetic stimulation device

经颅磁刺激是一种非侵入性和无痛的方式刺激大脑在有意识的健康个体。自其问世以来的30年里，它已成为认知神经科学的主要工具，也是治疗各种神经系统疾病（如抑郁症）和增强中风后康复的潜在治疗工具。然而，它仍然是一个相对生硬的工具。它激活了兴奋区域的混合神经元。有些是抑制性的，有些是兴奋性的；有些是中间神经元，有些是投射神经元。因此，我们在生理上（EEG或fMRI）和行为上（如反应时间或反应准确性）观察到的影响代表了多个相互作用电路的净效应。不同的人被激活的神经类型的比例不同，这导致了在经颅磁刺激实验中常见的巨大的个体间差异。该项目的目的是通过采用先进的经颅磁刺激装置来操纵刺激波形的形状和方向性，从而提高经颅磁刺激的选择性。我们将用它来探索运动皮层中选定的神经元群在运动准备和学习过程中的作用，这在以前是不可能的。我们还将证明，同样的原理也可能适用于大脑皮层的额叶区域。我们有一些试点数据，这些数据已经确定了我们在本提案中重点关注的重要脉冲参数。在运动皮层中，我们期望通过一组参数，我们将能够从运动前区定位到运动皮层的输入，这些输入也被小脑的信息所调节。这些输入对于从一组已知的备选行动中选择正确的行动是最重要的。他们还会参与一些任务，包括适应新的运动参数，比如视觉输入增益的调节。这些数据将通过详细的神经生理学研究加以补充，这将有助于我们了解靶向刺激对已识别的神经回路（GABAa-， GABAb-和胆碱能连接）的作用。我们将同时收集有关脑电图诱发活动的形式以及刺激类型与持续脑电图节律的相互作用的数据。这将使我们能够将我们的工作扩展到其他皮层区域，并将它们与运动皮层的影响进行比较。最后，我们将研究目标刺激对重复TMS协议的影响。这些通常被称为“可塑性”协议，因为它们被认为在rTMS后一个小时左右改变了受刺激区域突触连接的兴奋性。它们很重要，因为它们用于治疗环境，例如治疗抑郁症或中风后的康复。通过针对特定的神经元群，我们希望改变rTMS的效果，使其更可靠，更专注于它可能用于治疗的疾病。

Transcranial magnetic stimulation is a non-invasive and painless way of stimulating the brain in conscious healthy individuals. In the 30 years since its introduction it has become a mainstay tool in cognitive neuroscience as well as a potential therapeutic tool to treat a variety of neurological conditions such as depression and to enhance recovery after stroke. However, it is still a relatively blunt tool. It activates a mixture of neurones in an excited area. Some of these are inhibitory, some excitatory; some are interneurons and some are projection neurones. Thus the effect we observe physiologically (on EEG or fMRI) and behaviourally (e.g. reaction times or response accuracy) represents a net effect of multiple interacting circuits. Variations in the proportions of neural types activated can vary between people and contribute to the large inter-individual differences that are common in TMS experiments. The aim of this project is to increase selectivity of TMS by employing an advanced TMS device to manipulate the shape and directionality of the stimulus waveform. We will use it to explore the role of selected populations of neurones in motor cortex during movement preparation and learning in a way that previously has not been possible. We will also show that the same principles may also apply to frontal areas of the cortex.We have some pilot data which has identified important pulse parameters that we focus on in the present proposal. In the motor cortex we expect that with one set of parameters we will be able to target a population of inputs to motor cortex from premotor areas that are also modulated by information from cerebellum. These inputs will be most important in choosing the right action from a known set of alternative actions. They will also participate in tasks involving adaptation to new movement parameters, such as modulation of visual input gain. This data will be complemented by detailed neurophysiological investigations that will help us to understand the actions of targeted stimulation on identified neural circuits (GABAa-, GABAb- and cholinergic connections). We will in parallel collect data about the form of EEG evoked activity and the interaction of stimulus types with ongoing EEG rhythms. This will allow us to extend our work to other cortical areas and compare their effects with that on motor cortex. Finally we will examine effects of targeted stimulation on repetitive TMS protocols. These are often referred to as "plasticity" protocols since they are thought to change the excitability of synaptic connections in the stimulated area for an hour or so after rTMS. They are important because they are used in therapeutic setting, for example to treat depression or rehabilitation after stroke. By targeting specific populations of neurones we expect to change the effects of rTMS, making it potentially more reliable and better focussed to the disorders it may be used to treat.