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.

Passive non-neuronal brain cells called astrocytes have emerged as a critical yet grossly understudied part of brain machinery. Atrocytes take up released neurotransmitters, maintain ionic homeostasis of the extracellular space, and generate a variety of molecular signlas that regulate neural circuit activity. However, the emerging difference between animal and human astroglia in their morphology and physiology threatens the harm-benefit ratio of animal preparations in this important field of neuroscience and neurology. In this respect, realistic computational models of astroglia and astroglia-neuronal networks could provide hypothesis testing, mechanistic physiological insights, and an inter-species knowledge transfer that are unattainable in animal experiments. Exploring such models ought to minimise animal experimentation with no loss of knowledge, yet the methodology to create the corresponding modelling environment is only beginning to emerge. Thus, the present project aims to combine an experimental methodological approach, on the one hand, and open-access computer-simulation platforms, on the other, that would shift the weight of knowledge-based glial research from animals to human tissue preparations and realistic computational models. This will be achieved through the three objectives: (i) to establish working experimental protocols for up-to-date studies of human astroglia in organised brain tissue, making them a commonly accessible, viable alternative to animal brain tissue research strategies, (ii) to create an open-access computational platform that enables exploratory investigation of realistic biophysical models of astroglia, thus reducing similarly aimed experimental trials in animals, and (iii) to generate an experimental data library adaptable for the functional comparison of animal and human astroglia, thus providing a guidance on potentially implausible extrapolation of animal data to human brain astroglia.

Neuromuscular diseases (NMD) are an important group of disabling conditions affecting about 150,000 children and adults in the UK. They are caused by impairment of peripheral nerve and/or skeletal muscle function. Patients with these diseases develop muscle weakness and the severity can range from death in childhood or early adult life through to life long disability & dependence. Many patients also have heart and breathing muscle weakness which can add to disability and sometimes be fatal. These NMD conditions are commonly genetic and may run in families. They can also be acquired-for example through antibody attack as in "autoimmune" NMD or due to premature degeneration of muscle. Genetic examples include muscular dystrophy (~1 in 3500), Charcot Marie Tooth (CMT) neuropathy (~1 in 2500) and mitochondrial diseases (~1 in 5000). Acquired examples include chronic nerve inflammation (~1 in 1500) and a muscle degeneration/inflammation condition called inclusion body myositis (~1 in 10,000). It is clear that NMD represent an important unmet health burden for the nation. However, relative to other neurological diseases such as epilepsy and multiple sclerosis, NMD have received less attention by government and other UK funding bodies. This is despite the excellent clinical infrastructure provided by several large clinical neuromuscular centres and the nationally commissioned NHS funding for care and diagnosis of some NMD lead by MRC Centre PI's (eg congenital muscular dystrophy, channelopathies and mitochondrial diseases). Furthermore, there has been significant progress in NMD discovery science, frequently lead by internationally high profile UK clinicians and scientists, but translation of this scientific discovery into clear benefit for UK patients has been disappointing so far. We set up this MRC Centre to develop ways to bridge this "translational gap" between scientific discovery and patient benefit. We identified six main reasons (obstacles) why scientific discoveries were not clearly benefiting patients. We developed specific core activities to overcome each obstacle. Most notably we found there was a lack of UK trials culture for these conditions. That means that there were not many trials happening, doctors treating patients did not think there was much that could be done, and patients were not being given the opportunity to get involved in the research & trials that were happening. By setting up key core activites, in just four years, we have shifted the situation towards a trial and experimental medicine culture in the UK. Key activities we developed & which are now valuable UK available resources: 1. Stratified cohorts: collections of patients eligible for entry into trials and research 2. Experimental trials support: a system of coordination and support to enable testing of new therapies in patients 3. Neuromuscular human cell biobank: collecting muscle cells from patients to test new therapies 4. MRI biomarker studies: using MRI scans to accurately measure muscles and assess if experimental treatments are working 5. Training programmes to train more young scientists to undertake trials and develop new therapies 6. Getting clinicians & animal scientists working closely together to work out which are the best cell & animal models on which to test new therapies These core activities & our clinician scientist networks have resulted in a ten-fold increase in clinical trials & an even larger increase in patients entered into research cohorts. We now want to build on this success to embed a trials culture in UK practice. In the UK there is no other centre that focuses on systematically linking discovery research to experimental medicine for NMD. This MRC Centre has lead the UK efforts in the last four years. The mission of a renewed MRC Centre is to achieve impact by translating science into experimental medicine & find treatments for adults & children with disabling/fatal neuromuscular diseases.

Hospital neurology and neurophysiology services are increasingly overwhelmed. With a growing and ageing population, the incidence of many brain conditions (such as dementia and epilepsy) are rapidly increasing. Compounded by the COVID-19 pandemic, there are now over 10,000 people in the UK waiting more than a year for an appointment with a neurologist. Things must change! The purpose of our Network is to address these challenges through the development of new technologies that enable diagnosis and management in the community. These services could be provided in a community diagnostic hub, by high-street healthcare professionals, in a GP surgery, in a mobile unit or even in the home environment. Our focus will be on new digital solutions built around neural interfacing, signal processing, machine learning and mathematical modelling. We will work closely with partners developing technologies for measuring brain, eye, spinal, and peripheral nerve activity using wearable technology and minimally invasive devices. Collectively, this will contribute to a significant increase in capacity that will augment the expertise provided in neurology services. To achieve this, we will build a network of partners with backgrounds spanning academia, industry, hospitals and GP surgeries, charities and policy makers. Crucially we will ensure that people with lived experience of neurological conditions are at the heart of our network. Their experience will inform debate and shape our research priorities, ensuring feasibility and acceptability of emerging technologies. We will empower people from different backgrounds and career stages to work together on challenging problems whose solutions will lead to societal benefit. To enable this we plan a suite of activities built around the principles of connect, communicate and collaborate. To connect people we will build a website and social media presence, create a public representation group and build new parnterships. We will establish a mentorship scheme and post opportunities for people at different career stages to undertake secondments with partner organisations. To facilitate communication, we will engage with stakeholders including the public, people with neurological conditions, healthcare providers and policy makers. We will host workshops on emerging areas of interest, as well as an annual conference to celebrate findings from across the network. To enable collaboration we will host events including stake-holder led study groups, sandpits and research incubators: where teams of partners will work collaboratively in a facilitated environment, conducting feasibility studies over 6-9 months.