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。在其引入后的30年中，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）和促进中风后恢复的潜在治疗工具。然而，它仍然是一个相对较钝的工具。它会激活兴奋区域的神经元。其中一些是抑制性的，一些是兴奋性的;一些是中间神经元，一些是投射神经元。因此，我们观察到的生理（EEG或fMRI）和行为（例如反应时间或反应准确性）的影响代表了多个相互作用的电路的净效应。激活的神经类型比例的变化可能因人而异，并导致TMS实验中常见的个体间差异。本项目的目的是通过采用先进的TMS设备来操纵刺激波形的形状和方向性，以增加TMS的选择性。我们将用它来探索运动皮层中选定的神经元群体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向运动皮层定位一群输入，这些输入也受到来自小脑的信息的调制。在从一组已知的备选行动中选择正确的行动时，这些输入将是最重要的。他们还将参与涉及适应新运动参数的任务，例如调节视觉输入增益。这些数据将通过详细的神经生理学研究进行补充，这将有助于我们了解靶向刺激对已识别神经回路（GABA a-，GABAb-和胆碱能连接）的作用。我们将同时收集有关EEG诱发活动的形式以及刺激类型与持续EEG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，并将它们的影响与运动皮层进行比较。最后，我们将研究重复TMS协议的靶向刺激的影响。这些通常被称为“可塑性”协议，因为它们被认为在rTMS后一小时左右改变受刺激区域中突触连接的兴奋性。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。通过靶向特定的神经元群体，我们希望改变rTMS的效果，使其可能更可靠，更好地集中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.