Predicting the response to plasticity-inducing protocols of non-invasive brain stimulation (NIBS)

Over the past 30 years a number of methods have been devised that allow us for the first time to stimulate parts of the brain in healthy, conscious individuals without having to remove part of the scalp or undergo neurosurgery. It is a remarkable advance. Even more strikingly, recent developments have made it possible to interact directly with a process known as "synaptic plasticity" which is fundamental to our ability to learn new things. When we learn anything new, a subtle change is made in the way a small number of neurones connect together in the brain and this new circuit is used to store the memory. The new brain stimulation methods can subtly speed up or slow down this process.
The main interest in this method lies in its potential to speed up rehabilitation training after brain injury or disease. For example, after a stroke, the brain has to re-learn how to perform tasks with a damaged set of circuits. Physiotherapy works by giving patients practice in tasks so that their brain can re-learn old skills with a new set of connections. Work has suggested that this process would be speeded up by using the new methods of brain stimulation.
Although very attractive, and overall effective, a problem with the methods is that they vary in effectiveness from one individual to another. The result is that in any clinical trial, some participants perform much better than others. The objective of this proposal is to understand more about why this variation arises, and, more importantly, devise simple predictive measures that can be used to check if an individual is likely to respond to a particular protocol, and if not find an appropriate alternative.
The work will begin by exploring a number of simple measures that have been reported to predict responses to particular brain plasticity protocols and select the most useful of these after a series of studies in 50 healthy volunteers. We will then test in a group of 25 chronic stroke survivors whether these factors will also predict the clinical response of each patient to a single session of therapy. Finally the project will explore the hypothesis that these differences between people depend on subtle differences in the anatomy of the brain. The pattern of folding of the cerebral cortex varies slightly from the "average" pattern in every individual. In addition, the area of cortex where certain functions are represented also varies within a centimetre or so between individuals. We will use sophisticated computer modelling of the way the external brain stimulation is likely to activate regions in individual brains and show that differences in the regions activated can account for differences in a person's response to each protocol. If correct we can use this information in a subsequent study to change stimulator design so that we can target the "correct" locations in an individual brain and maximise chances of responding to any given protocol.

Non-invasive brain stimulation (NIBS), including repetitive transcranial magnetic stimulation (rTMS) and transcranial direct current stimulation (TDCS), is a successful treatment for medically refractory depression and is a potentially useful additional treatment for a wide range of other neurological conditions. However there is considerable inter-individual variation in the response to NIBS in healthy people and this probably explains why many patients respond better/worse to therapeutic applications than others. Recent evidence suggests that a substantial proportion of the inter-individual variance to an rTMS protocol (intermittent theta burst iTBS) can be predicted by much simpler measures of the response to single pulse TMS, which in turn may reflect subtle differences in cortical anatomy/physiology.
The objective of the proposal is to identify predictors of the response to two other commonly used forms of NIBS, TDCS and paired associative stimulation (PAS). Extrapolating from our previous iTBS study this will require testing 50 healthy individuals. We will then test whether these measures predict the response to a single therapeutic intervention (iTBS or cathodal TDCS) for hand function in 25 patients with chronic stroke.
The predictor for PAS will be used in a second experiment. Patients with dystonia have a larger response to PAS than age matched healthy individuals. We will test whether their responses are also predictable from the simple TMS measures that depend on cortical anatomy/physiology. If so then it may be that structural factors rather than intrinsic differences in synaptic plasticity are responsible for the effects.
Finally in collaboration with Dr A Thielscher we will use detailed models of current flow induced in individual brains to test whether individual differences in anatomy can account for much of the variation in TMS/TDCS response.

The main beneficiaries of this research are any patients who are likely to be offered treatment with NIBS protocols, particularly those with disorders of the motor system. If a simple predictor can be found of an individual's potential response to NIBS then it can be used to exclude from trials those participants who have a high probability of receiving no benefit. Conversely the predictors can be used to guide patients to the form of NIBS to which they are most likely to respond. Although the present work will be conducted only on motor areas of cortex, similar rules are likely to hold for other areas, so that even patients without motor symptoms may benefit from future parallel approaches.
If successful, this will improve the response rate in clinical trials such as those presently being undertaken in stroke or chronic pain, and hence improve the quality of life of participants and family, as well as reduce long term treatment costs.
The work is of immediate benefit, at last for patients with disorders of motor control since these predictors can be used even without full understanding of why they are successful. The latter may take longer to develop depending the success of our modelling studies.
A second set of beneficiaries are manufacturers of NIBS machines. If much of the variation in response comes from failure to stimulate selectively the correct population of neurones in the cortex, and if this in turn depends on anatomical factors that determine the distribution of current flow in the brain, then it should be possible to design different configuration of the TMS and TDCS stimulators that will overcome these problems by allowing variable targeting in individual brains.
The appointed therapist who will conduct the research will benefit from the technical training, exposure to clinical trials and will also register for a higher degree (PhD).