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When a young child undergoes brain surgery, other invasive brain treatment like radiotherapy; or experiences brain damage for example following a stroke, the brain can adapt. This adaptation (called plasticity) occurs readily in young children's brains, but there is still wide variability in how well a child goes on to develop. As improvements in medicine mean that children's brain diseases are diagnosed earlier, and more survive following invasive treatments, there is an increased need to predict which children will struggle to recover, with the aim of improving their longer-term educational and social outcomes. Our work is focussed on identifying, and helping, the children who are most at risk of failing to fulfil their potential following diagnosis or treatment for brain disease such as epilepsy or brain tumours, damage, or from neurodevelopmental disorders like ADHD. To do this, we need to measure brain activity in young children, at the age when many diagnoses and treatments are taking place: below the age of 7. We use a brain imaging technique called magnetoencephalography (MEG) which allows us to measure changes in neural activity through a cap or helmet lined with sensors. MEG allows us to map healthy brain networks, and identify when brain activity is abnormal. Standard MEG systems are designed for use with adults and don't provide good quality, usable data in children below age 7, because the helmet is too big and the child has to stay very still during the recording. The new generation of MEG systems, called OPM-MEG systems, completely avoid these problems. Our requested OPM-MEG system has an adjustable cap which holds the lightweight sensors directly against the child's head, allowing them to move freely and recording strong signals from the brain. With a cap specially designed for our target age range, this device will be transformational in terms of allowing us to measure changes in brain function over time in our patients. Our 5-year research plan is supported by a trained Clinical Scientist post, jointly paid for by, and appointed to Aston University and Birmingham Children's Hospital. We will use data from our OPM-MEG system alongside information about brain structure (e.g., from MRI scans), clinical information, and measures of the child's social and educational development. One work package is focussed on children who undergo brain surgery or brain radiotherapy, drug treatment for brain disease, or who suffer a stroke and undergo neuro-rehabilitation therapy. We will explore the changes in brain networks that occur from before to after treatment, to identify measures that can help us predict which children are more likely to suffer long term developmental effects, for example in memory or intelligence. The other work package focusses on children who are at risk (e.g., through genetics or environment) of poor intellectual outcomes. We will explore how developmental changes in network connectivity can underpin particular symptoms of developmental disabilities; determine how reliably brain measures can predict symptoms of ADHD; and use our MEG data to help very early detection of early onset dementia in a genetic disorder. Because our planned research is a partnership between scientists, clinicians, and technical staff from both Aston University and Birmingham Children's Hospital, we have the opportunity to feed our findings directly back into clinical care where appropriate, with the overall aim of improving children's lives.

Background: Juvenile idiopathic arthritis is one of the most common autoimmune conditions of childhood, occurring when the immune system mistakenly attacks joints, leading to inflammation and pain. Around 10,000 children in the UK suffer from this debilitating condition. Currently, the majority of patients have ongoing disease even after a decade of treatment. Therefore, more research is needed into how the disease can be cured, rather than just controlled. When the immune system mounts an attack against something, some immune cell types remain behind; keeping a memory of the target it was trying to destroy ('memory cells'). Memory cells ensure the immune system can mount a rapid and effective attack if the target is found again in the body. With arthritis in mice, a specific type of memory cell has been found in the joint, which has the ability to activate inflammation again after the arthritis has resolved. In children with juvenile idiopathic arthritis, cells that resemble this type of memory cell have been found in much higher levels in fluid taken from the joints compared to the blood stream, suggesting they are accumulating where the disease is occurring. In other parts of the body, other cell types anchor memory cells to ensure they remain at sites where they are needed and provide signals to ensure memory cells survive for a long time. It is not clear at present which cells might be doing this in the joint and what role memory cells have in juvenile idiopathic arthritis. Aims and Objectives: I aim to test the question of whether repeat flares of inflammation keep occurring in children with juvenile idiopathic arthritis because these memory cells remain in the joint, resisting treatment. In particular I will investigate whether cells known as fibroblasts, which contribute to the connective tissue of the joint, interact with these memory cells to help them to survive and persist in the joint. The plan is to characterise these cells in the joints of children with arthritis, identifying signalling pathways and processes used by the cells. Advances in technology mean that it is now possible to look at the level of individuals cells to see which proteins these cells are making, providing minute resolution of the cell activities. I will investigate how these cells differ in children who get very severe disease. Finally, in genetically-modified mice with arthritis it is possible to eliminate types of fibroblast cells; I will investigate how this impacts the memory cells in joints. Potential Applications and Benefits: The processes that initiate inflammation may not be the same as those perpetuating it, as the disease process evolves. Understanding the cells and processes causing ongoing inflammation in arthritic joints will likely be key for finally achieving a cure for children and adults with autoimmune arthritis. Currently these memory cells are not directly targeted by any available treatments. If memory cells are contributing to ongoing inflammation, we need to know which signals they are responding to in the joint to target them effectively. Treatments affecting the fibroblasts are under development for adults, but further understanding of fibroblasts in childhood arthritis is needed to determine whether these therapies are also likely to be effective in children. Fluid from the joint is easier to obtain than joint tissue, but the downside is that it captures immune cells much better than connective tissue cells, like fibroblasts. Since we will collect and analyse the tissue and the fluid from the same joints, we will learn how the cells in the fluid reflect the biology in the joint tissue. This understanding provides a starting point for developing new therapies that target fibroblasts and novel tests that improve our selection of treatment.

When a young child undergoes brain surgery, other invasive brain treatment like radiotherapy; or experiences brain damage for example following a stroke, the brain can adapt. This adaptation (called plasticity) occurs readily in young children's brains, but there is still wide variability in how well a child goes on to develop. As improvements in medicine mean that children's brain diseases are diagnosed earlier, and more survive following invasive treatments, there is an increased need to predict which children will struggle to recover, with the aim of improving their longer-term educational and social outcomes. Our work is focussed on identifying, and helping, the children who are most at risk of failing to fulfil their potential following diagnosis or treatment for brain disease such as epilepsy or brain tumours, damage, or from neurodevelopmental disorders like ADHD. To do this, we need to measure brain activity in young children, at the age when many diagnoses and treatments are taking place: below the age of 7. We use a brain imaging technique called magnetoencephalography (MEG) which allows us to measure changes in neural activity through a cap or helmet lined with sensors. MEG allows us to map healthy brain networks, and identify when brain activity is abnormal. Standard MEG systems are designed for use with adults and don't provide good quality, usable data in children below age 7, because the helmet is too big and the child has to stay very still during the recording. The new generation of MEG systems, called OPM-MEG systems, completely avoid these problems. Our requested OPM-MEG system has an adjustable cap which holds the lightweight sensors directly against the child's head, allowing them to move freely and recording strong signals from the brain. With a cap specially designed for our target age range, this device will be transformational in terms of allowing us to measure changes in brain function over time in our patients. Our 5-year research plan is supported by a trained Clinical Scientist post, jointly paid for by, and appointed to Aston University and Birmingham Children's Hospital. We will use data from our OPM-MEG system alongside information about brain structure (e.g., from MRI scans), clinical information, and measures of the child's social and educational development. One work package is focussed on children who undergo brain surgery or brain radiotherapy, drug treatment for brain disease, or who suffer a stroke and undergo neuro-rehabilitation therapy. We will explore the changes in brain networks that occur from before to after treatment, to identify measures that can help us predict which children are more likely to suffer long term developmental effects, for example in memory or intelligence. The other work package focusses on children who are at risk (e.g., through genetics or environment) of poor intellectual outcomes. We will explore how developmental changes in network connectivity can underpin particular symptoms of developmental disabilities; determine how reliably brain measures can predict symptoms of ADHD; and use our MEG data to help very early detection of early onset dementia in a genetic disorder. Because our planned research is a partnership between scientists, clinicians, and technical staff from both Aston University and Birmingham Children's Hospital, we have the opportunity to feed our findings directly back into clinical care where appropriate, with the overall aim of improving children's lives.

Brain cells are electrically excitable, meaning that they communicate with each other through tiny voltage 'spikes'. How likely a brain cell is to spike is related to how easily excitable it is. However, excitability of brain cells is not a static thing, it changes in response to recent activity, and we call this homeostatic scaling (HS). HS keeps brain cell spiking activity in a kind of special zone where the amount of excitation in brain cells is kept at just the right rate for them to 'talk' to each other without everyone talking at once. Epilepsy is a neurological (brain) disease which is characterised by seizures. Seizures are periods of time when networks of brain cells are too active and are uncontrollably excited and spiking. If uncontrolled excitation spreads to brain regions that control movement, then too many brain cells are 'talking at the same time' and we can see seizures as changes in movement such as jerks and twitches. The problem with our current treatment of epilepsy is that we can't stop seizures in as many as a third of people, and of the ones that we do treat successfully, about a third will stop responding to the drugs. If you add these two groups together, then about half of people with epilepsy are not being helped enough by their medication. Most of the drugs that are used in epilepsy aim to stop seizures from happening, and for this reason, they often work in similar ways and aim at the same targets in the brain. What is needed is a new approach, looking at how epilepsy establishes itself in vulnerable brain areas, and how we might be abel to stop this process from happening. Like brain excitability, epilepsy itself is not static, rather, it is an ever-changing process, where the excitability of brain cells and networks is altered by the epileptic seizures themselves. This means that the high activity of a seizure might drive down the excitability of the brain cells, as a kind of compensation that helps to prevent seizures in the short term. This kind of compensatory change happens through HS, just like in non-epileptic brains. We think this HS process goes wrong in epilepsy, overcompensating for seizure activity and making networks so 'quiet' that a process of re-compensation happens which makes individual brain cells start to become super-excitable. This project aims to test this idea by looking at how different amounts of epileptic activity in the brain can alter its excitability. In rats with implanted brain electrodes that broadcast brain activity using a Wi-Fi system, we will map how brain cells alter their excitability in response to seizures and how this change in spiking is related to how cells communicate via their thousands of synapses. We predict that if there are a lot of seizures, synapses will decrease their activity and brain cells will become more likely to spike. We will test antiepileptic drugs, and new drugs designed to interfere with HS to see if they can prevent seizures from developing or reduce their intensity. Finally, we will test this all in human brain, using samples of living tissue taken from children with difficult to treat epilepsies who have had to have some brain tissue removed to stop the seizures. The people in our project team are epilepsy specialists, epilepsy surgeons, molecular biologists and scientists from GW Pharma, the company responsible for the newest successful antoepilepsy drug, Epidiolex (CBD). Together, we are going to be able to make animal models of epilepsy processes, test that they happen in human brain and explore how new antiepileptic drugs can interfere in how epilepsy is established in the brain. Answers to these questions will mean that we can focus on making drugs that target the processes undelying epilepsy, modifying the disease itself instead of just stopping the symptoms. Our project will help future patients, clinicians treating epilepsy and providing scientists with new knowledge from which to further other projects.