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、无痛的刺激有意识健康个体大脑的方法，是世界上许多实验室的常用工具。重复性经颅磁刺激（rTMS）是指在几分钟内施加大量刺激，对受刺激部位的功能和兴奋性产生后效，这种后效持续数分钟或数小时。根据受刺激区域的不同，其后遗症会影响认知任务或学习的表现。鉴于这些方法在健康人身上的成功，人们对将它们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，结果喜忧参半，成功的证据有限。其中一个原因是，个人内部和个人之间的后遗症差异很大。对于运动皮层的rTMS（中风后治疗的常见目标），大多数方案仅在45-60%的参与者中产生“预期”效果。效果的变化是因为经颅磁刺激激活了皮质区域内的混合神经元，即具有不同功能的不同群体的兴奋性和抑制性神经元。很可能经颅磁刺激在不同的人身上激活了不同比例的每种类型，从而产生了个体间的效果差异。我们已经证明，通过使用可控的经颅磁刺激装置，我们可以修改脉冲的形状和方向，从而增加刺激的选择性是可能的。试点数据有力地表明，这将导致更加可靠的结果。该项目的第一个目标是通过测量一种流行的rTMS形式，即θ波爆发刺激（TBS）对运动皮层兴奋性的影响，在一大群健康个体中证实这一点是正确的。虽然运动皮层兴奋性的测量是比较rTMS效果的标准方法，但在实践中它们并不是最有用的，因为rTMS对皮层兴奋性的影响可能与rTMS对行为的影响并不相关。因此，这些实验的第二个目的是表明更好地控制TBS协议也会对运动产生影响。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，由于我们之前的工作表明，不同类型的运动学习涉及运动皮层中不同的神经元集，我们将研究两种形式的学习：适应性学习和无模型学习。前者涉及适应已经获得的运动（例如，在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一致），而后者涉及探索肌肉激活的最佳组合以实现新目标（例如学习在新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方案以适应个体患者的缺陷。该项目的第三个目的是确认同样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，那么至关重要的是要确认基于健康志愿者的研究结论也适用于中风后受损的大脑。我们将测试最佳形式的TBS对中风患者两种类型运动学习的影响。

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.