Improving the effectiveness of therapeutic protocols of repetitive transcranial magnetic stimulation (rTMS)

经颅磁刺激（TMS）是一种非侵入性和无痛的刺激大脑的方式，在有意识的健康个体，是一种常见的工具，在世界各地的许多实验室。重复性经颅磁刺激（rTMS）在几分钟内施加大量的刺激，对受刺激部位的功能和兴奋性产生持续时间超过刺激时间数分钟或数小时的后效。由于这些方法在健康个体中的成功，人们对将其应用于治疗产生了巨大的兴趣，例如在中风后的康复中。不幸的是，结果好坏参半，成功的证据有限。其中一个原因是，在个体内部和个体之间的后果差异很大。对于运动皮层的rTMS，中风后治疗的常见目标，大多数协议仅在45-60%的参与者中产生“预期”效果。效应的变化发生是因为TMS激活皮层区域内的神经元的混合物，即具有不同功能的兴奋性和抑制性神经元的不同群体。很可能TMS激活不同人的每种类型的不同比例，从而引起个体间的效果差异。我们已经证明，通过使用可控的TMS设备，我们可以修改脉冲的形状和方向，从而增加刺激的选择性。试点数据有力地表明，这会导致更可靠的结果。该项目的第一个目的是通过测量一种流行的rTMS形式（称为theta burst stimulation，TBS）对运动皮层兴奋性的后效，在一大群健康个体中证实这是正确的。尽管运动皮层兴奋性的测量是比较rTMS效果的标准方法，它们在实践中不是最有用的，因为rTMS对皮层兴奋性的影响可能与rTMS对行为的影响不相关。因此，这些实验的第二个目的是表明，更好的控制TBS协议也对运动产生影响。鉴于运动学习在康复中的重要性，我们选择测试TBS对运动学习的影响。此外，由于我们以前的工作表明，不同类型的运动学习涉及运动皮层中不同的神经元，我们将研究两种形式的学习：适应性学习和无模型学习。前者涉及调整已经获得的运动（例如，当移动计算机鼠标时，适应光标的实际位置和视觉感知位置之间的不对准），而后者涉及探索肌肉激活的最佳组合以实现新的目标（例如，学习在新的方向上最大化拇指的加速度）。我们期望不同的TBS协议来改善每种类型的学习。这意味着未来的治疗应用可能需要调整TBS协议，以适应个别患者的缺陷。该项目的第三个目标是确认相同的原则适用于慢性中风幸存者。如果可控TBS是一种有用的治疗方法，那么确认基于健康志愿者的研究结论在中风后受损的大脑中也是正确的是至关重要的。我们将测试TBS的最佳形式对中风中两种类型的运动学习的影响。

Transcranial magnetic stimulation (TMS) is a non-invasive and painless way of stimulating the brain in conscious healthy individuals and is a common tool in many labs worldwide. Repetitive TMS (rTMS) in which a large number of stimuli are applied within a few minutes produces after-effects on the function and excitability of the stimulated site that outlast the period of stimulation for several minutes or hours. Depending on the area stimulated, the after-effects can influence performance of cognitive tasks or learning.Given the success of these methods in healthy individuals, there has been enormous interest in applying them therapeutically, for example in rehabilitation after stroke. Unfortunately the results are mixed and evidence for success limited. One reason for this is that the after-effects vary considerably both within and between individuals. For rTMS of motor cortex, a common target for therapy after stroke, most protocols only produce the "expected" effects in 45-60% participants. The variation in effect occurs because TMS activates a mixture of neurones within a cortical area, i.e. different populations of excitatory and inhibitory neurones with different functions. It is likely that TMS activates a variable proportion of each type in different people, giving rise to the inter-individual differences in effect.We have already shown that it is possible to increase the selectivity of stimulation by using a controllable TMS device in which we can modify the shape and directionality of the pulse. Pilot data strongly suggests that this leads to much more reliable outcomes. The first aim of this project is to confirm this is correct in a large group of healthy individuals by measuring the after-effects on motor cortical excitability of a popular form of rTMS known as theta burst stimulation (TBS).Although measures of motor cortex excitability are the standard way of comparing effects of rTMS, they are not in practice the most useful because rTMS effects on cortical excitability may not correlate with rTMS effects on behaviour. The second aim of these experiments is therefore to show that better controlled TBS protocols also produce effects on movement. Given the importance of motor learning in rehabilitation, we have chosen to test the effects of TBS on motor learning. Furthermore, since our previous work has suggested that different types of motor learning involve different sets of neurones in motor cortex, we will examine two forms of learning: adaptation learning and model-free learning. The former involves adapting a movement that has already been acquired (e.g. adapting to a misalignment between the actual and visually perceived position of a cursor when moving a computer mouse) whereas the latter involves exploring the best combination of muscle activation to achieve a new aim (such as learning to maximise the acceleration of the thumb in a novel direction). We expect different TBS protocols to improve each type of learning. The implication is that future therapeutic applications may need to adapt the TBS protocols to the deficits of individual patients.The third aim of the project is to confirm that the same principles apply in chronic stroke survivors. If controllable TBS is to be a useful therapy, then it is vital to confirm that the conclusions from studies based in healthy volunteers are also true in the damaged brain after stroke. We will test the effects of the optimal forms of TBS on the two types of motor learning in stroke.