NIHRDataInsights/HRCSData huggingface dataset:
Title: The Role of Learning in Chronic Musculoskeletal Pain
Funder: Medical Research Council

Abstract: We address whether maladaptive learning systems contribute to the maintenance of chronic pain. This has been difficult to answer because learning comprises a set of complex, interacting processes, and hence difficult to evaluate and quantify. Based on computational models of learning, we have designed a suite of tasks and analysis tools that probe domain-general value-based and sensorimotor learning. These are implemented online as a set of tablet-based computer games that can be applied easily and widely in observational or longitudinal clinical studies in domestic settings. We will study whether learning metrics can predict clinical outcomes in: i) a longitudinal study of patients with recent onset low back pain, and ii) fibromyalgia patients undergoing an NHS MDT program. We will measure neural changes (using resting-state fMRI) and physical outcomes using a novel video-based tool to quantify movement during physiotherapy exercises. The tools, analysis pipeline and data will all be made free and openly available to the research community. Within the APDP open Datahub, data from our and other partners can be pooled across various conditions, allowing further comprehensive characterisation of how learning is linked to chronic pain. We adopt a systems engineering approach to the development of our tools, in which patients have and will continue to have a fundamental role in the design process itself, necessary to ensure the usability and relevance of the framework to the lived experience of pain. This builds the joint vision of researchers and patients to develop an open platform for integrated multidisciplinary evaluation and treatment. The proposed project will have a lasting impact: building a self-sustaining data generating infrastructure focused on learning mechanisms; providing a technological platform to support innovation in non-pharmacological treatment; and building a UK pain neuroscience and engineering community focused on chronic pain


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: MUSCULOSKELETAL;NEUROLOGICAL
Title: Digital Health: OptiMuscle - Improving health outcomes through the optimization of muscle function
Funder: Medical Research Council

Abstract: Approximately 10% of people in the UK population exhibit some form of dysfunctional breathing. This term describes a range of conditions which are characterised by an impairment in the muscular control of breathing and which can result in breathlessness, hyperventilation and in some cases dizziness. Current clinical assessment techniques and treatments for dysfunctional breathing are low-tech, with clinical management focused around the use of simple breathing exercises. Whilst these exercises do have some effect, we propose that patients would get more benefit from a system which uses biofeedback on muscle patterns to guide breathing re-education. Furthermore, if such a system could be automated, it should be possible to provide breathing re-education to large numbers of people without the need for a clinical specialist to be present. This is important because breathing re-education is often a key part of the clinical management of other health conditions, such as asthma, back pain and anxiety. This project will deliver a completely new digital health system for the clinical management of dysfunctional breathing. The system will use both visual and auditory biofeedback to communicate abnormal muscle function, guiding patients through a process in which they gradually learn the correct muscular control of breathing. To realise this personalised system, we will develop software which can create an individual avatar of the patient and use this to visualise the actions of the breathing muscle in real-time. To avoid the need to directly measure muscles in a clinical setting, we will develop algorithms which can predict muscle activations from an input of simple sensor data which can be collected in a clinical setting, e.g. inexpensive 3D camera. To complement the use of visual biofeedback, we will use auditory biofeedback to convey subtle changes in muscle function and help reinforce the learning of new muscle patterns. Our multimodal (visual and audio) biofeedback system will be integrated into a behaviour change intervention, providing patients with the capability, opportunity and motivation to change their muscle-related breathing behaviours. We will develop our new intervention by working closely with patients to understand their views on how the final system should operate. Once created, we will carry out a small trial on people with dysfunctional breathing to understand the future potential. If this testing provides encouraging results, then we will apply for funding for a larger NHS trial.


Research activity codes: 4.2 EVALUATION OF MARKERS AND TECHNOLOGIES;5.3 MEDICAL DEVICES;7.1 INDIVIDUAL CARE NEEDS
Health categories: MUSCULOSKELETAL;NEUROLOGICAL
Title: Mechanisms of Musculoskeletal Pain
Funder: Versus Arthritis

Abstract: Musculoskeletal (MS) pain is a problem for millions of people in the UK, and attempts to treat it have had mixed success. Neutralising pain-inducing mediators like NGF and TNF may prove useful, but the underlying peripheral pain pathways remain to be defined. Our group have focussed on recent technical advances in mouse genetics to find peripheral neurons that drive pain, silence them with chemo-genetics, and then identify transcripts in these cells. We have experience in screening and testing candidate genes that may prove important in driving pain and have made many transgenic mice with the Cre-loxP system that model human pain conditions. These mice have allowed us to catalyse new drug development programmes in humans with Pharmaceutical companies. With this background we will focus on transgenic mouse models of MS pain focussing on osteoarthritis (OA) , with some work on fibromyalgia, to define the sets of sensory neurons that drive the pain using a new transcriptome classification from the Karolinska Institute. We will silence defined neurons in vivo using DREADDs (see Figure 5) and test whether we can abolish pain associated with particular OA conditions. Having identified key neuronal subsets associated with MS pain, we will pull out mRNA transcripts using TRAP technology (see Figure 6), where epitope- tagged polysomes can be immunoprecipitated before microarray Arthritis Research UK – Invited Research Award Application Form analysis. Strong candidate genes will be identifeid in this way for future studies.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: MUSCULOSKELETAL;NEUROLOGICAL
Title: The role of BMP signalling in diseases of the motor unit
Funder: Wellcome Trust

Abstract: Spinal and bulbar muscular atrophy (SBMA) is an X-linked, adult-onset, neuromuscular disease characterized by lower motor neuron degeneration as result of misfolding and accumulation of mutant Androgen Receptor (AR). In recent years this scenario of selective neuronal vulnerability has been challenged by the discovery that in SBMA, as in other diseases of the motor unit, skeletal muscle, rather than being a mere bystander of motor neuron degeneration, is primarily affected and therapies exclusively targeting muscle ameliorate the pathology in motor neuron while preventing the development of a neuromuscular phenotype in animal models. My goal is to elucidate the molecular mechanisms underlying the intrinsic contribution of skeletal muscle in SBMA pathogenesis. I will investigate the role of the Bone Morphogenetic Protein (BMP) signalling pathway in SBMA pathophysiology, testing the central hypothesis that failure to activate the protective BMP pathway in SBMA muscle in response to denervation causes primary muscle atrophy and affects motor neuron ability to cope with the stress posed by mutant AR. The rationale is to provide a molecular basis for the cell-autonomous and non-cell autonomous roles of muscle in the mechanisms of toxicity in SBMA and other diseases of the motor unit and to identify novel therapeutic targets.

Lay abstract: Spinal and bulbar muscular atrophy (SBMA) is a genetically transmitted neuromuscular disease characterized by muscle weakness and atrophy secondary to dysfunction and death of motor neurons. Recent evidence in SBMA as in other neuromuscular diseases has shown that skeletal muscle also plays a critical role in the disease and strongly influences motor neuron survival. These observations hold great potential for therapeutic impact, particularly because muscle is much more accessible than motor neurons for pharmacological intervention. Focus of my research is to understand the mechanisms causing the muscle atrophy in SBMA and how muscle signals back to motor neurons to affect their function, which are currently elusive. In this study I will investigate the role of the Bone Morphogenic Protein (BMP) pathway in SBMA. The reasons why I chose to study this pathway are twofold: 1) the BMP pathway has been recently found to be the most important regulator of muscle mass and 2) BMPs are known to act as muscle-secreted retrograde signals to motor neurons. Preliminary data have shown that this pathway is severely dysregulated in SBMA. This work has the potential to pave the way for developing a new therapeutic strategy for SBMA and other neuromuscular diseases.

Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: MUSCULOSKELETAL;NEUROLOGICAL
Title: Novel Diagnostic and Therapeutic Insights for Fibromyalgia
Funder: Sir Jules Thorn Charitable Trust

Abstract: Our proposed work will accelerate the development of diagnostic methods and new treatments. We have demonstrated that fibromyalgia is not “all in the head”, and our proposed work will give hope to millions of people living in pain.

Lay abstract: Fibromyalgia syndrome (FMS) is characterised by widespread pain, fatigue, sleep problems, and emotional distress. Despite a prevalence exceeding 2%, FMS has remained medically unexplained, without diagnostic tests or effective treatments. We recently discovered that multiple symptoms of FMS are caused by autoantibodies acting peripherally, outside the central nervous system. This insight will fundamentally change future research and clinical management of FMS. Here we will identify antigens targeted by autoreactive IgG in patients. FMS is associated with small fibre pathology in about half of patients, and we will determine which nerve fibres are affected and explore mechanisms responsible. We have identified a credible ion channel target responsible for nociceptor hyperexcitability and pain, and also identified the first pharmacological tools to evaluate its analgesic potential. FMS is associated with auditory and olfactory abnormalities, and a wealth of literature describes aberrant pain processing in the brain. We will attempt to determine whether autoantibodies are also responsible for these central and cranial nerve manifestations. We transfer symptoms from patients to mice by administration of patient IgG, which ensures that our conclusions have the highest degree of predictive validity. The proposed studies will transform the outlook for fibromyalgia and give hope to millions of people.

Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: MUSCULOSKELETAL;NEUROLOGICAL
Title: A Surgical Retractor That Reduces the Incidence of Complications During Anterior Spinal Surgery
Funder: Innovate UK

Abstract: Axis Spine Technologies Limited (Axis), led by Jonathan Arcos, is a UK medical devices SME working on an innovative retractor system to make anterior spinal surgery easier and safer. Anterior spinal surgery carries a significant risk of serious complications; the retractors used are typically metal, to allow reuse, but this makes them inflexible and opaque on x-rays as well as theoretically able to cause infection. Axis's solution removes the current need for surgeons to work around their retractors' limitations and should reduce surgical injury by 30%.


Research activity codes: 5.4 SURGERY
Health categories: MUSCULOSKELETAL;NEUROLOGICAL
Title: SqueezAble: Combining novel soft-sensing technology and interactive gamification to revolutionise upper-limb therapy for paediatric cerebral palsy patients
Funder: Innovate UK

Abstract: In the UK there are an estimated 187,000 children living with an arm disability, and 85m worldwide. Without regular occupational therapy for upper limb and hand strength, dexterity and movement range, a child's condition is likely to deteriorate and impact their ability to live in functional independence in adulthood. A child must learn to independently complete unimanual and bimanual activities of daily living (ADLs), requiring them to use their hands individually or both hands simultaneously, to be able to complete everyday tasks like eating, writing and washing. Many arm disabilities are linked to neurological disorders, such as Cerebral Palsy (CP), which affects coordination, precision and timing of movements. In this project, we will work with a group of children with Paediatric CP to test, develop and measure the impact of a new therapeutic device for children's health, SqueezAble. SqueezAble will use a patent-pending soft-sensor technology to create a new paradigm in rehabilitation technology by providing digital analogs of common soft therapy objects like Thera-putty to drive occupational therapy exercises through serious gaming and data capture. Our aim is to demonstrate that SqueezAble is effective when used for upper limb and hand training, specifically to complete unimanual and bimanual activities. The project will include ongoing usability studies to provide insight on design, motivation to play and ability to support functionally-relevant exercises for paediatric OT. Post-project we intend to validate efficacy via a clinical feasibility study. SqueezAble builds on GripAble's work to date, which includes developing novel hardware to train, monitor and measure hand-grip (GripAble Flex). We will also develop new bimanual interactive activities for gaming, which to date have been unimanual. GripAble Flex has shown to enhance therapy and has been validated in Clinical Studies and published in six peer-reviewed journals. The project draws on the expertise of Imperial College London, world-leading specialists in soft-sensor technology and innovation in electroconductive material, within the Department of Bioengineering. While the project has a focus on applications for Paediatric CP, there is significant potential for secondary markets. SqueezAble will have general application in upper limb and hand occupational and physiotherapy, agnostic of disability, disorder or age group e.g flexor tendon rehabilitation for thumb injuries.


Research activity codes: 5.3 MEDICAL DEVICES
Health categories: MUSCULOSKELETAL;NEUROLOGICAL
Title: Feasibility study investigating the effect of a novel splint device on gait characteristics of a paediatric population with footdrop
Funder: Innovate UK

Abstract: An innovative splint is being developed to assist children with footdrop to walk safely and with more energy efficiency. Footdrop is muscle weakness/paralysis resulting in difficulty lifting the front part of the foot, which causes frequent falls. The benefit of using the OrthoPed splint is that ankle muscles will be used to lift the foot when walking, with the OrthoPed splint providing the extra support that the child is lacking. Currently there isn't an active-assisted splint to support small children with moderate footdrop, the OrthoPed splint fills this need. The OrthoPed splint has been tested in a laboratory and is now ready for a feasibility study focussing on recruitment of children with footdrop, useability and compliance with study procedures (walking patterns and gait analysis). This project is in collaboration with the University of Portsmouth and Portsmouth Hospitals University NHS Trust. We will be able to use the data collected to demonstrate that the OrthoPed splint improves the walking pattern of children with footdrop. This should help us to gain further funding in the future for the clinical trials needed before the OrthoPed splint can be sold.


Research activity codes: 5.3 MEDICAL DEVICES
Health categories: MUSCULOSKELETAL;NEUROLOGICAL
Title: Structural studies of proteins involved in neurodegenerative and muscular diseases 2
Funder: Medical Research Council

Abstract: We focus on neurodegeneration and muscular pathologies.||A molecular approach to human genetic diseases More than 12 human genetic diseases have been associated with expansions of nucleotide repeats in their corresponding genes, all identified in the last 10 years. These diseases, currently incurable, are interesting both for their impact in the human population and for the unusual pattern of genetic behaviour. They are grouped into two sub-families according to whether the expansion occurs in coding or non-coding regions. In our group we have started an integrated approach which makes use of different biochemical and biophysical techniques to study the structure and function of the proteins encoded by several genes of the trinucleotide expansion family. Amongst them are FMRP, the protein responsible for fragile x and frataxin, the protein involved for Friedreichs ataxia. We want to understand the cellular role of these proteins and describe the mechanism of molecular recognition with their binding partners. We have also recently setup a systems biology project which aims at understanding the process of iron-sulfur cluster formation, in which frataxin is involved.||How muscles are assembled and regulated Understanding the molecular bases of muscle contraction has been one of the main research topics in biology for the last decades. Besides actin and myosin, which are the main players in muscle contraction, many other proteins have an essential role in determining muscle assembly and regulation. Several interactions have been described recently which are essential to anchor the muscle filaments to the modular proteins, such as titin, nebulin, and alpha-actinin. Dysfunctions in the interactions cause different types of cardio-myopathies and other muscle diseases. We are currently working to determine the structure of a number of protein complexes. This information will eventually allow us to reconstruct the muscle ultrastructure.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: MUSCULOSKELETAL;NEUROLOGICAL
Title: Molecular analysis of neuromuscular and neurological disease
Funder: Medical Research Council

Abstract: Our research focusses on the development of a therapy for the devastating progressive wasting disease, Duchenne muscular dystrophy (DMD) and the use of animal models to study to study movement and behavioural disorders in man. It has been known for more than a decade that DMD is caused by the absence of the large muscle protein dystrophin, which results in a fragile muscle membrane. Patients are usually confined to a wheelchair before the age of twelve and die in their early twenties. There is currently no effective treatment. The development of therapy for DMD is challenging because dystrophin is a large structural protein that needs to be delivered to all muscles. We are focussing on the pharmacological up-regulation of the dystrophin-related protein, utrophin as this could be used for all patients independent of the type of mutation. We have collaborated with Summit plc in the high throughput screening for drugs which might increase levels of utrophin in muscle. One candidate drug, SMTC1100 is currently being taken forward to Phase 2 trials by Summit plc. We have developed an improved screening cell line in order to identify further drugs in the future. The second approach to therapy involves exon skipping using U7snRNA AAV vectors. We are exploring ways of improving the efficiency of exon skipping and are investigating strategies for multiexon skipping so that this approach can be used to treat more patients with different mutations. We are analysing several mouse mutants which show movement and behavioural abnormalities. One mutant, named bella, is a recessive mutant which is deleted for the gene Oxr1. We have shown that Oxr1 is involved in protection of the cell in oxidative stress. Interestingly, Oxr1 levels are increased in the spinal cord of Amyotrophic lateral sclerosis (ALS) patients. In an animal model of the disease, Oxr1 levels are increased before the onset of symptoms We are currently exploring the function of Oxr1 and its role in neurodegenerative diseases. It may be that OXr1 is an early marker of disease which may provide clues to approaches to delaying disease onset. We have also identified a mouse with a mutation in SNAP-25, named blind-drunk, as a potential model for schizophrenia. We have demonstrated that these animals have abnormal circadian rhythms which are very similar to those seen in schizophrenia patients. We are currently investigating the gene expression changes which might underlie these observations. We are also exploring circadian rhythms in other mouse models of neurodegenerative diseases (Alzheimers, Parkinsons) as patients with these disorders also show sleep abnormalities. These studies may identify new pathways which could be targeted for therapies.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;5.2 CELLULAR AND GENE THERAPIES
Health categories: MUSCULOSKELETAL;NEUROLOGICAL
Title: Balancing Nociceptive Activity in the Developing Spinal Cord
Funder: Medical Research Council

Abstract: Plantar hindpaw incision in the first postnatal week, but not at older ages, is associated with an enhanced response to subsequent incision. Factors in the spinal cord that contribute to developmentally-regulated alterations in nociceptive sensitivity include: activity-dependent changes in neuronal circuitry; neuronal apoptosis; and microglial reactivity. To assess the long-term effects of neonatal surgical injury, neuronal and microglial responses to adult incision will be compared in animals with prior injury, and in age and gender-matched controls. Outcomes will include: i) behavioural and electrophysiological measures of spinal reflex sensitivity to allow quantification of the response to both threshold and suprathreshold stimuli; ii) in vivo extracellular recordings in the spinal cord to directly quantify dorsal horn neuronal sensitivity; and iii) complementary tissue analysis and functional measures: tissue analysis and evaluation of the degree and distribution of activation by MAPK phosphorylation (pERK in neurons and p-p38 in microglia); plus dose-dependent effects of inhibitors of phosphorylation on behavioural hyperalgesia. The ability of mechanistically distinct neonatal analgesics (morphine or ketamine vs saline) to balance the effects of neonatal injury will be assessed by effects on: i) acute hyperalgesia, apoptosis, and microglial reactivity; ii) long-term hyperalgesic and microglial response to subsequent adult incision (in rats and mice). Microglial contributions to enhanced sensitivity will be assessed by: i) in vivo imaging for detailed temporal and spatial changes in neonatal and adult mice with microglial-specific fractalkine receptor CX3CR1 locus replaced with the gene encoding green fluorescent protein; ii) effects of neonatal microglial inhibition (minocycline) or ablation (intrathecal Mac1-saporin).


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