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

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.

A TMS pulse activates simultaneously many types of excitatory and inhibitory neurones that have different roles in behaviour. Furthermore, the activated proportions of each neural type vary between people probably because of variations in brain anatomy. We have argued that this is a major cause of the high inter-individual variation in after-effects of repetitive TMS (rTMS) protocols. This severely limits the use of rTMS as a therapeutic intervention.
Controllable pulse TMS devices are now available and we have shown that manipulating pulse parameters can increase the selectivity of stimulation. Our pilot data from motor cortex also show that pulse-width controlled and unidirectional rTMS (specifically theta burst protocols; TBS) also has much more reliable effects on cortical excitability. The first part of the project will confirm this by comparing new and standard TBS protocols in a large group of healthy individuals. We will thus have a tool with far more potential for therapeutic application.
However, therapeutic applications require effects on behaviour, and these do not always follow those on excitability. We will therefore test the effectiveness of controllable TBS protocols on motor learning, since this is a vital part of rehabilitation after stroke. Furthermore, our previous work suggested that different forms of motor learning, adaptation learning (to a change in visuomotor gain) and model-free learning (increasing maximal acceleration of a movement) involve different sets of motor cortical neurones. Given the selectivity of controllable pulse TBS we expect these distinct types of learning to be affected by different TBS protocols. The therapeutic implication is that different types of TBS may be required according to individual needs of patients.
Finally it is necessary to show that similar principles apply in the damaged brain of patients after stroke. We will therefore test the most effective TBS protocols on motor learning in chronic stroke.

Public beneficiaries: Enhancing the targeting ability of TMS will have key benefits in the health sector. Repetitive TMS is currently undergoing clinical trials in the UK and other countries as a potential treatment for depression and as an adjunct to rehabilitation after stroke. Indeed, in the USA it is licensed by the FDA for the treatment of medically refractory depression. However, in most conditions the response rate is low (~38%), and this has prevented widespread adoption. The methodologies developed in the proposed research could translate to improved rTMS protocols that more effectively target the involved neural populations in each condition. It will increase efficacy and enhance response and remission rates leading to improved quality of life for patients and carers. If response size and reproducibility can be enhanced rTMS has the potential to become a treatment of choice, particularly for depression and in stroke recovery.
The new methods will also impact on basic research in cognitive neuroscience which uses current methods of brain stimulation to investigate brain function. A more reliable and targeted method will not only give experimental results greater power but they will give researchers new methods to probe the role of specific subpopulations of neurones within a targeted area.


Private Sector beneficiaries: This project will lead to several major methodological developments which can be exploited across a range of research and clinical settings to study and interact with human brain function and behaviour. Manufacturers of devices for non-invasive brain stimulation, both nationally and internationally, will benefit from the methodological developments and from the increased economic value associated with improved brain stimulation methods. In particular we know from informal discussion that the UK companies Rogue Resolutions and Magstim are both awaiting the outcome of our studies before investing in further development of commercial TMS devices.


Staff beneficiaries: The research staff member appointed in this work will develop skills in programming and testing a novel and unique device. He will learn how to disseminate this information to colleagues and inform them of new concepts involved in targeted TMS. Importantly he will be deeply involved in development of the device and crucial for advising on the most appropriate ways to modify software and hardware. Such skills will readily translate into all research and development sectors.
The technical staff involved in the project will also obtain experience in development of a new device that has high potential for being taken up in the commercial sector. Such experience will prove easily transferrable to cutting edge technologies in any field.