NIHRDataInsights/HRCSData huggingface dataset:
Title: Seizures and arousal: Interaction between epileptiform activity and central autonomic control in patients with chronic epilepsy.
Funder: Wellcome Trust

Abstract: Epilepsy is a neurological condition in which patients suffer from recurring seizures (fits). Medications do not work successfully in about one third of patients. My previous research showed that training patients to control the level of arousal can enable them to control their seizures, possibly for years. If we understand more about how this works then we can develop effective treatments and avoid the dangers and costs of uncontrolled seizures. Biofeedback trains people to control their bodi ly arousal: Small electrical changes measured from the surface of the skin reflect how aroused a person is. By displaying these measurements a person can learn over a few lessons to increase or decrease arousal at will. This can be used by patients with epilepsy to stop seizures. I want to understand how this works in the brain. I will use brain scans to look at brain activity when patients are resting, when they are focusing their attention and when they are performing biofeedback. I then want to train patients with biofeedback and rescan the patients to see whether the connections between areas of the brain that are known to work together have reorganized.


Research activity codes: 6.6 PSYCHOLOGICAL AND BEHAVIOURAL;5.6 PSYCHOLOGICAL AND BEHAVIOURAL
Health categories: NEUROLOGICAL
Title: A combinatorial approach for enhancing cell transplantation for neurological diseases via simple and scalable chemistries
Funder: Wellcome Trust

Abstract: Neurological disorders represent a growing healthcare burden, moreover, there are no effective therapies to stop these diseases progressing. Therapies that use cells grown in a lab can aim to either repair damaged brain regions by replacing cells lost to the disease process or to use these cells to deliver agents to protect the brain. The former has reached clinical trials, and whilst in some cases a large benefit can be seen, the process is drastically hindered by poor cell survival following t ransplantation into the brain. This proposed project seeks to overcome this drawback by addressing graft survival through a combination of new biologically functional material constructs. This project aims to produce three of these biomaterials through simple chemistries that can easily be replicated in other research labs and ultimately be scaled up for the clinic. They would deliver oxygen to the transplanted cells improving survival, hold the cells in place increasing safety by stopping mi gration up the needle path, and deliver genes allowing the cells to integrate with the host brain better.


Research activity codes: 5.2 CELLULAR AND GENE THERAPIES
Health categories: NEUROLOGICAL
Title: Pathological mechanisms in human disorders of glycinergic transmission.
Funder: Wellcome Trust

Abstract: Normal behaviours, such as walking and breathing, rely on a balance between excitatory and inhibitory activity in the nervous system. Reduced inhibition results in over-activity causing diseases such as epilepsy and spasticity. In the spinal cord the major inhibitor is glycine, a chemical that decreases the activity of nerve cells by binding to its receptor. Some patients inherit gene mutations in the receptor for glycine causing extreme rigidity and exaggerated startle responses in infancy. Ad ults can develop similar symptoms and some of these patients have antibodies in their blood which bind to their glycine receptors. The project aims to understand how these antibodies interfere with glycine function. By applying antibodies from patients directly to nerve cells in the laboratory, I will determine whether they disrupt glycinergic inhibition, and investigate the detailed mechanisms underlying this disruption. I will also use these methods to improve the detection of antibodies in o ther patients with suspected abnormalities of glycine-mediated inhibition. The second phase of research will investigate which circuits are disrupted in patients by non-invasively stimulating and recording from nerves and muscles. Such studies will be important in understanding the disease process and clinical findings, and provide insights into the regulation of inhibition.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL
Title: A Systematic Programme to Develop and Evaluate the Best Candidate Treatments for Repositioning as Therapies for Alzheimer s Disease (SMART-AD).
Funder: Wellcome Trust

Abstract: We urgently need new treatments for Alzheimers Disease (AD) as the currently available drugs give only limited benefits. Drugs currently used for other conditions could provide exciting opportunities for new and better treatments, but the challenge is to identify the best candidates. Research has identified genetic changes that occur during AD. There has also been a recent explosion in knowledge on how thousands of drugs also affect genes. We will combine this knowledge to identify 100 promising drugs and study their ability to influence genes that we know are involved in AD. The top 20 drugs will be rigorously tested in established assays involving nerve cells in the laboratory to predict their potential as a treatment. The best six will then be tested in the most reliable animal models of AD to provide the robust evidence required to take any drug forward to clinical testing in humans. At each stage an expert panel will oversee the decisions to make sure the drugs to be tested are su itable for people with AD. The overall goal is to find the best drug to take forward to clinical trial with the aim of providing a safe, effective fast-track treatment for this devastating condition.


Research activity codes: 5.1 PHARMACEUTICALS
Health categories: NEUROLOGICAL
Title: Experimental and modelling investigation of a multimodal network controlling rhythmic movements.
Funder: Wellcome Trust

Abstract: Animals can produce multiple but distinct forms of behaviour, for example in: respiration (panting, sighing), feeding (biting, swallowing), or locomotion (walking, trotting). These related forms of activity are generated by multimodal networks. Fundamental to understanding of any neural circuit is knowledge of its anatomy and morphology, its elements, its connectivity and dynamic activity. However, in the complex vertebrate nervous system, these aredifficult to study. We have extensive experimental and theoretical understanding of rhythmic motor pattern generation in young frog tadpoles. They can generate two simple forms of rhythmic movement: swimming and struggling. My aim is to understand how tadpoles can produce both types of rhythmic activity. To do that, I will extend existing knowledge on the anatomical and morphological features of the tadpole locomotor network. I willuse abstract and detailed modelling approaches to investigate generic principles of swimming and struggling. This knowledge will be then incorporated in a biologically-realistic model of the full tadpole locomotor connectome to test predictions on motor behaviour. I expect that my studies will increase our understanding of rhythmic activity production by mutlimodal neuronal networks and advance the analysis of more complex mechanisms controlling human cognitive and motor functions.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: NEUROLOGICAL
Title: Using Caenorhabditis elegans neurodegeneration models to discover neuroprotective compounds
Funder: Wellcome Trust

Abstract: The dramatic increase in lifespan seen over the last century has been accompanied by an equally striking increase in age-related neurodegenerative disorders such as Alzheimers disease. There are few treatments and no cures for these conditions, so there is an urgent need for model systems that can identify new therapeutic compounds and reveal the cellular neuroprotective mechanisms by which these drugs act. We aim to address these issues by using recently developed genome editing techniques to create novel animal and cell culture models of neurodegenerativetauopathies. Disease-causing mutations in the human MAPT gene that encodes tauwill be introduced into C. elegans worms and human neuronal cell cultures via the CRISPR-Cas9 system. These will be used to test the potential of FDA approved drugs for repurposing as therapies for neurodegenerative diseases. Working with expert collaborators in Chemistry, hit compounds will be used as a starting template to derive more potent neuroprotective lead compounds via chemoinformatic and iterative refinement approaches. RNA interference will be carried out in the C. elegans models to identify the potential molecular pathways by which the drugs mediate neuroprotection. Finally, human neuronal cell culture models will be developed to validate the translational potential of the identified compounds.


Research activity codes: 5.1 PHARMACEUTICALS
Health categories: NEUROLOGICAL
Title: Studying ER to synapse trafficking of neuronal receptors to attempt to understand both the spatial segregation and the effect of synaptic activity on trafficking through the secretory pathway
Funder: Wellcome Trust

Abstract: The overall theme of this project is to visualize the synchronous trafficking of multiple di fferent Neuronal receptors through the Secretory Pathway of primary Neurons. Neuronal receptors carry out their function at the Synapse but begin their journey whenthey are threaded into the lumen of the Endoplasmic Reticulum (ER). From the ER receptors journey to the Golgi to be post-translationally modified before trafficking to the synapse to fulfil their role in Synaptic transmission. The unique properties of Neurons and the still outstanding fundamental gaps in knowledge of Neuronal receptor trafficking through the Secretory Pathway are to be investigated. 1.Investigate the route that Golgi resident enzymes take to traffic to Golgi outposts from the ER. 2.Visualize multiple receptors (Heteromers or different classes of receptor) trafficking through the cell. 3.What effect does synaptic activity or lack of have upon Neuronal receptors at different points of receptor trafficking from the ER to the cell surface. 4.Combining RUSH with photoswitchable fluorescent proteins to understand the spatial restriction of the Secretory Pathway at Synaptic sites 5. Investigate disease causing mutations that effect domains of Neuronal receptors involved in trafficking.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: NEUROLOGICAL
Title: Cell toxicity and protein aggregation in Huntington's and related diseases.
Funder: Wellcome Trust

Abstract: Using a yeast cell model of Huntington's disease, we will combine super-resolution fluorescence microscopy and live-cell imaging, to track the development, localisation and final structures of aggregate species in vivo, with electron tomography to determine the 3D structures of the aggregates and their interactions with cellular components. Additionally, we will investigatethe effects of polyglutamine length, Huntingtin sequence and molecular chaperones on the phenotype and fate of individual cells, thereby furthering an understanding of factors affecting toxicity. Such an approach would be transferrable to similar models of neurodegenerative diseases such as Parkinson's disease.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL
Title: Neuroimaging of functional plasticity in multiple sclerosis.
Funder: Wellcome Trust

Abstract: The aim of this PhD is to determine the disease modifying effect of exercise interventions for Multiple Sclerosis (MS) patients. Aerobic exercise has been shown to slow neurological disease progression and symptom severity in animal models and cross-sectionally in human. Limited intervention data exists and understanding of the relationship between aerobic fitness, MS symptoms and brain structural and functional characteristics is limited. For the main experiment, 30 patients will undergo structural and functional magnetic resonance imaging (MRI) during rest, a CO2 challenge and cognitive tests to assess memory and reaction time. Using MRI techniques we will measure the brain changes following a structured exercise intervention. The key outcome measures will be changes in fitness (VO2 peak), balance, cerebral blood flow (CBF), cerebral blood volume (CBV), grey matter volume (GMV) and white matter microstructural changes assessed using diffusion weighted imaging (DWI). This research add to knowledge of the mechanisms of exercise-related neuroprotection by combining CBF and structuralmeasures before and after an exercise intervention.


Research activity codes: 5.7 PHYSICAL
Health categories: NEUROLOGICAL
Title: Biomarkers discovery in the progressive bulbar palsy/amyotrophic lateral sclerosis clinical spectrum: combined tissue and fluid-phase proteomics
Funder: Wellcome Trust

Abstract: The main obstacle in the development of effective treatments for neurodegenerative disorders is the lack of tests that allow an early recognition of the disease, the prediction of its natural progression and to measure the true effectiveness of a therapy. As a consequence, clinical trials have failed to deliver consistent results in Progressive Bulbar Palsy (PBP), a rare and fatal neuromuscular disorders with a rapid progression to impairment of speech, swallowing and to respiratory failure. Here we propose to study molecular factors including those participating in the immune response to motor cell degeneration as a mean of obtaining signals that are informative of the stage and progression in PBP. The proposed "proteomic" approach will allow the isolation of differentially-regulated proteins from blood cells and from affected brain tissue and of the same markers in matched plasma samples. A large resource of biological specimens taken from PBP patients will be tested to confirm whether any of the initially selected targets can be used to monitor the disease. This study wants to establish an effective strategy for an early diagnosis and for the prediction of the severity of the disease in a rare but disabling and fatal neurological disorder.


Research activity codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES
Health categories: NEUROLOGICAL
Title: Reanimating faces: Creating an iPad/mobile device application to facilitate rehabilitation following Bell's Palsy
Funder: Wellcome Trust

Abstract: We take our facial expressions for granted, but damage to the nerves that move our facial muscles causes many problems Difficulties eating, drinking, speaking, or smiling due to facial paralysis can cause social isolation and psychological problems The condition affects about 15,000 people every year. Facial paralysis is difficult to treat. Physiotherapy targeted exercises of the facial muscles can improve patients' facial function and lead to improved quality of life. Unfortunately, the NHS cannot always offer physiotherapy, yet special exercises are known to speed recovery, reduce the chance of spasms and improve function. In theory patients could help themselves by doing their own daily physiotherapy but we find that they struggle to do the exercises properly because of a lack of feedback. Having treated hundreds of facial palsy patients, we believe we have a way to help patients recover. We have devised a system using commonplace computers such as iPads to track facial movements and measure recovery. Using this system we can accurately measure the extent of the asymmetry by sending the images and data from the patient's home to the physiotherapists office. We can then guide recovery and provide motivation, especially for children.


Research activity codes: 7.1 INDIVIDUAL CARE NEEDS;5.7 PHYSICAL
Health categories: NEUROLOGICAL
Title: The role of inherited and acquired mitochondrial DNA mutations in Dementia with Lewy Bodies.
Funder: Wellcome Trust

Abstract: Dementia with Lewy Bodies (DLB) is the second most common form of dementia. Examination of brains from deceased patients show tangles of proteins called Lewy bodies and low activity of a molecule called complex I. High levels of mutations in mitochondrial DNA (a type of DNA inherited only from your mother) have been found within the brain of patients, though whether they contribute to causing Lewy bodies or low complex I activity is unknown. Using state-of-the-art DNA sequencing technology I aim to map-out the location of mitochondrial DNA mutations within the brain of patients. This will help determine whether they cause Lewy bodies or complex I impairment. In addition, I aim to establish whether the mutations start during a patient's lifetime, or whether some have been inherited from their mother. At the same time, I will let mice with mitochondrial DNA mutations breed with other mice which carry a gene which causes Lewy bodies to form. This will help determine whether mitochondr ial DNA mutations contribute to the disease and make it worse. Understanding the type of mutations, whether they are inherited, and whether they make the disease worse could transform the way we understand, test for, and treat the disease.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL
Title: Effect of beta2-adrenergic receptor agonists on the acetylcholine receptor clustering pathway in congenital myasthenic syndromes.
Funder: Wellcome Trust

Abstract: Congenital myasthenia is a disorder that affects signal transmission between muscles and nerves. Signal transmission occurs at specialized transmission sites. Congenital myasthenia can be caused by a variety of gene defects encoding proteins within this transmission site. Recently, my supervisor's group discovered a spectacular improvement with a drug, called salbutamol, in some congenital myasthenic patients. In these patients, the gene code for a protein with a crucial function in stabilizat ion of the transmission site is typically faulted. Why salbutamol leads to improvement, is unknown. Based on some first data from the host laboratory, I hypothesize that salbutamol might play a role in stabilizing the transmission site. I will study this potential effect of salbutamol in different diseases models. My study further aims to identify the point(s) where the salbutamol cascade might interact with the natural pathway that stabilizes the transmission site. The detailed understanding of the working mechanism of salbutamol is clinically important. This could lead to the detection of a specific drug target, resulting in new drug design with fewer side effects and a better drug choice for distinct myasthenic subgroups. Our findings might also benefit patients with brain or spinal cord disorders involving transmission sites between nerves.


Research activity codes: 5.1 PHARMACEUTICALS
Health categories: NEUROLOGICAL
Title: Basal ganglia network degeneration and cortical network compensation in Huntington's disease.
Funder: Wellcome Trust

Abstract: Huntington's disease (HD) is a progressive and fatal hereditary disease, which predominantly affects the brain. HD begins with the loss of brain cells deep inside the brain and then spreads to affect the outer layers of the brain. This results in problems with movement, thinking and behaviour. Different areas of the brain communicate with each other through brain connections. In HD these connections are abnormal. My objective is to characterise these brain connection abnormalities and investi gate how they relate to the subtle symptoms seen in the pre-manifest stage of HD, before the onset of overt movement problems Diffusion magnetic resonance imaging (MRI) can be used to look at structural brain connections, while functional MRI in people at rest can be used to look at functional connections. Graph theory, a mathematical technique, will be applied to these imaging methods. Understanding how HD affects the brain through the loss of connections in some areas and increase in o thers will help us understand the way in which HD causes neurological damage and how the brain attempts to compensate for this. The knowledge gained from this research will also help inform us about other conditions such as Parkinson's disease.


Research activity codes: 2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT
Health categories: NEUROLOGICAL
Title: General principles underlying the assembly of cortical inhibitory circuits
Funder: Wellcome Trust

Abstract: The cerebral cortex is the nerve tissue that covers most of our brain. It consists of several billion neurons, and it is folded into many gyri and sulci to fit inside the skull. The cerebral cortex enables us to perceive the world around us, to think and make decisions, but we still have a very vague idea of how it works. Our laboratory aims to understand the general principles governing the formation of the cerebral cortex, because we think that this will help us to understand its function. In the next few years, we will concentrate our efforts on elucidating the molecular mechanisms controlling the development of inhibitory neurons in the cerebral cortex. In particular, we would like to understand how much of the information needed in this process is genetically encoded, and what is the influence of the environment in the formation of this complex structure. Our work may also help us to get a better understanding of disorders such as autism and schizophrenia.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: NEUROLOGICAL
Title: Reward mechanisms underlying apathy in Parkinson's disease.
Funder: Wellcome Trust

Abstract: Apathy is a disabling condition characterized by severe lack of motivation. It is very common in Parkinson's disease(PD), affecting up to 60%of patients and causing a significant health burden. Problems in brain areas that process how much we value rewards and the effort we would exert to obtain them might contribute to apathy. However, exactly how is poorly understood, limiting treatments. PD patients lack the brain chemical dopamine, which is known to be important in the brain's reward and effort system. Using novel tests of how much we value rewards and the effort we are willing to exert to obtain them, I will test PD patients na ve to dopamine medication and those treated with dopamine. I predict that PD patients with apathy will be less motivated by reward, and that motivation will be reduced further by effort in these individuals. I want to test whether dopamine can reduce the effect effort has on how much patients devalue rewards. In addition, I will use scanning technique s to localize brain areas that are important for reward and effort, and investigate whether activity in these regions relates to apathy. This will further our knowledge of apathy and treatment of the condition.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL