NIHRDataInsights/HRCSData huggingface dataset:
Title: The potential for transcranial direct current stimulation to restore motor function in the vegetative state
Funder: Medical Research Council

Abstract: It is now well accepted that some patients with a prolonged disorder of consciousness (PDOC) retain a much greater deal of cognitive function that initially thought, and are simply unable to produce external purposeful responses. I have recently demonstrated that the lack of voluntary control these patients exhibit can be explained by specific impairments in structural connectivity within the motor system that result in reduced excitatory coupling between thalamus and the primary motor cortex (M1). My proposed project explores the effects of transcranial direct current stimulation (tDCS) on the dynamics of the motor system (with specific focus on M1 and thalamus). While there is vast evidence suggesting tDCS can affect cortical excitability and enhance performance in motor tasks, the mechanisms underlying these effects are very poorly understood. This project aims to characterise such mechanisms in the healthy brain, as a first step in a longer-term research programme that will include future validation of protocols in PDOC patients. I will test a cohort of healthy participants with concurrent tDCS-functional magnetic resonance imaging (fMRI) to measure the online and offline neural effects of different stimulation protocols (which will be designed to be feasible in PDOC patients) both under the stimulating electrodes as well as in remote brain regions. I will use dynamic causal modelling to test specific hypotheses about the effects of tDCS on the coupling of the motor system at rest and during a simple motor task. I will test different theoretically motivated target regions, dosage levels (i.e., number of sessions required to induce changes), and the potential benefits of pairing tDCS with passive motor practice. Finally, I will use state-of-the-art structural MRI analyses (i.e., diffusion tensor tractography, and cortical thickness) to identify markers that predict individual differences in responsiveness to the stimulation.


Research activity codes: 5.6 PSYCHOLOGICAL AND BEHAVIOURAL
Health categories: NEUROLOGICAL
Title: MICA: Optimising brain protection and reducing birth asphyxia disability: safety and efficacy of early high dose MELATONIN and COOLING with late EPO
Funder: Medical Research Council

Abstract: Intrapartum-related events are the 4th leading cause of childhood mortality worldwide and lead to almost 1 million neurodisabled survivors. Infants exposed to a perinatal insult typically present with neonatal encephalopathy (NE). In high income countries, therapeutic hypothermia is a safe and effective therapy reducing adverse outcome by 15%. However, 44-53% of babies still have adverse outcomes; adjunct therapies are needed. Pre-clinical studies have shown that early high dose melatonin can augment hypothermic brain protection; melatonin is likely to be most effective early on after hypoxia by its diverse anti-oxidative mechanisms preventing free radical induced damage. In collaboration with our project partner Chiesi, a novel melatonin formulation has been developed and optimised pharmacokinetics modelled. Both pre-clinical and clinical studies show Epo augments hypothermic brain protection; Epo has beneficial effects in the subacute phase, promoting brain repair and neurogenesis. This is a randomised, placebo controlled pre-clinical safety and efficacy trial (group I pilot PK, 4 randomised groups II-V). We will use the Large White newborn piglet model (age <24h) to assess effects of early melatonin with cooling and late Epo after rewarming on brain protection. Using a clinically relevant primary outcome measure - MRS Lac/NAA in white and grey matter AND immunohistochemistry (TUNEL) we hypothesise: 1. Triple therapy with early MELATONIN (18mg/kg over 2h administered at 1, 24, 48h with Cmax at 3h) with cooling 33.5oC (1-13h) and subacute Epo after rewarming (1000U/kg at 36,48,60,72h) will improve primary outcome measures compared to single therapy (cooling alone) and double therapy (cooling and melatonin or cooling and Epo) 2. Optimising the melatonin dose, timing and infusion rate to obtain Cmax at 3h (instead of 8h in a previous study) improves brain protection Positive results from this study will guide the rapid translation to clinical trials


Research activity codes: 5.1 PHARMACEUTICALS
Health categories: NEUROLOGICAL
Title: Production of a device to obtain continuous ambulatory vestibular assessment (CAVA)
Funder: Medical Research Council

Abstract: Dizziness is a common condition that is responsible for a significant degree of material morbidity and burden on our health service. There are multiple causes of dizziness, and these originate from pathologies affecting a large variety of different organ systems. Dizziness is usually episodic and short-lived, so when a patient presents to their health care provider, examination is often normal. As such, diagnosis is challenging and patients often experience significant delay in receiving a diagnosis. We have developed a prototype device for monitoring dizziness and have tested it in a small group of volunteers. The results showed that our device is capable of accurately, precisely and reliably identifying periods of dizziness over a short period of time. Independent market research has confirmed that our device could meet the required clinical need, would be desired by clinicians, and that there is no equivalent solution currently available. We seek funds to trial our device in a large cohort of healthy volunteers and a large cohort of patients with a defined dizziness syndrome. We will then be positioned well to test our device in a more diverse patient population. Once validated, developed and brought to market, the device would provide early diagnosis and accurate treatment for a significant proportion of the patient population. This would save the NHS money by reducing multiple visits to GP clinics, reducing referrals to multiple specialist clinics, and reducing treatment required from falls and other conditions associated with dizziness.


Research activity codes: 5.3 MEDICAL DEVICES;6.3 MEDICAL DEVICES
Health categories: NEUROLOGICAL
Title: MICA: Development of gene therapy for the incurable inherited childhood epilepsy, Dravet Syndrome
Funder: Medical Research Council

Abstract: Needs: Infant-onset epilepsy is debilitating and, when caused by mutations in the voltage- gated sodium channel NaV1.1 (Dravet syndrome), incurable and sometimes fatal. It is associated with widespread brain disease manifesting as cognitive and motor disorders which may be seizure-independent. Patients rarely live independently. Anti-epileptic drugs are ineffective. NaV1.1 is notoriously difficult to work with on a molecular basis; its incompatibility with bacterial amplification has stifled attempts at gene therapy, which requires large amount of DNA for vector synthesis Rationale: Over the last 15 years, several gene therapy clinical trials have yielded remarkable results, including trials at UCL for inherited immunological and eye diseases and Haemophilia B. Dr Waddington performed preclinical studies in haemophiliac mice for the latter trial. Recently his team have cured several mouse models of devastating brain diseases including neuronopathic Gaucher Disease (Rahim et al. Hum Gene Ther 25(A14) 2014). The biotech company Touchlight Genetics has developed a process for enzymatic (non-bacterial) amplification of DNA. With Drs Waddington and Karda, they have used this DNA to produce high-titre lentivirus vectors. We aim to restore Nav1.1 expression in the nervous system of the Dravet mouse model by injecting a novel lentiviral vector. This aims to normalise electrophysiological properties, prevent seizures and brain damage Development plan: We propose to establish the first nervous-system-directed study for gene therapy of inherited epilepsy. Crucially, this will exploit enzymatic DNA amplification for high-purity vector production. Here, we request funding for preclinical studies to test vector synthesis feasibility, in vitro efficacy, in vivo potency and biodistribution. Gathered data will, in future, feed into the Investigational Medicinal Product Dossier to obtain Clinical Trial Authorisation from the Medicines and Healthcare Products Regulatory Agency


Research activity codes: 5.2 CELLULAR AND GENE THERAPIES
Health categories: NEUROLOGICAL
Title: Portable sedation device
Funder: Medical Research Council

Abstract: Patients often require sedation in challenging situations, and it is then that they most require drugs to be delivered simply and reliably with minimal compromise to their respiratory and cardiovascular function. This is difficult to achieve with intravenous agents which are hard to adjust to response and can easily accumulate. The use of breathable (volatile) sedation agents which are rapidly breathed out by patients would be an excellent and responsive way of delivering sedation in challenging circumstances. Currently, due to the lack of portable equipment or a shortage of highly trained staff to operate volatile sedation devices currently available, this can be hard to achieve, particularly in pre-hospital medicine, with critically-ill patients, and in the rapidly expanding field of sedation for painful procedures (eg gynaecological treatments, endoscopy, dentistry). Current devices are mostly modifications of the earliest types of anaesthetic devices, and therefore crude, inaccurate and difficult to use. The ability to offer sedation adjusted accurately to response would offer more rapid recovery from sedation and higher patient throughput. We have developed a novel device to deliver established breathable sedation agents using a patented formulation approach, offering considerable benefits in control and stability of sedation drug release. Incorporation of additional control and safety measures will generate a small, lightweight, purpose designed portable sedation device, suitable for use by a wide range of healthcare practitioners, in a wide range of clinical and non-clinical settings. Commercial availability of such technology which is simple and efficient in its use, and would allow patients to receive volatile sedation/anaesthesia in a much wider variety of places would represent a significant step forward in patient care, especially in pre-hospital medicine, community-based treatment, field, military and rural healthcare, including the developing world.


Research activity codes: 5.3 MEDICAL DEVICES
Health categories: NEUROLOGICAL
Title: Understanding the mechanisms of atrophy associated with spinal cord injury: the application of MRI-based in vivo histology and ex vivo histology
Funder: Medical Research Council

Abstract: During the first year after spinal cord injury (SCI), extensive morphometric changes within the central nervous system occur above the level of lesion, with the magnitude of atrophy relating to the degree of clinical impairment. The range of microstructural processes that underlie these observed morphometric changes cannot be disentangled because of the complex dependence of morphometric measures on multiple physical magnetic resonance imaging (MRI) micro-scale properties (e.g. T1, T2* and proton density). This in turn makes it difficult to draw specific conclusions about the underlying cause of the observed volumetric changes. We aim to use in vivo histology based on MRI (hMRI) to establish the missing link between measured MRI signals and the underlying tissue microstructure across the neuroaxis by developing advanced biophysical models to describe this relationship and map tissue properties, e.g. fibre and myelin densities. Methodological developments in the realm of hMRI will provide specific metrics for histological cross-validation and shed light on the mechanisms underpinning morphometric changes in SCI. This will enable us to directly visualize the anatomical evidence for anterograde and retrograde degeneration, repair, and plasticity as well as providing crucial insights over and above the existing clinical descriptors, which are insensitive to subtle treatments effects. These insights will help to improve diagnosis, personalized medicine, stratification and therapy monitoring in neurodegeneration (e.g. by simultaneously measuring myelin and axonal density, we will be able to distinguish between reversible demyelination and irreversible axonal degeneration - key processes of SCI. This potential improvement in diagnosis, stratification and therapy could also help in designing more targeted clinical trials by stratifying patient cohorts making such trials more efficient and less expensive.


Research activity codes: 2.5 RESEARCH DESIGN AND METHODOLOGIES (AETIOLOGY)
Health categories: NEUROLOGICAL
Title: Building blocks of molecular complexity: the neuronal cytoskeleton in health and disease
Funder: Medical Research Council

Abstract: The billions of neurons in the human brain require the microtubule (MT) cytoskeleton machinery to set up and maintain their diverse organisation and function. The importance of MTs for human health is reinforced because malfunction leads to diverse diseases of the nervous system. MTs are also critical in the context of brain repair therapies for treatment of physical injury or stroke. Investigation of the molecular operation and regulation of the MT cytoskeleton is thus essential to understand healthy neuronal diversity and function, and to characterise its disruption in disease. The aims of this research are to investigate the molecular building blocks of complexity in the neuronal MT machinery. We will dissect how heterogeneity in the MT subunits affects activities of MT-associated proteins and neuronal transport motors. We will investigate three families of important neuronal MT regulators - doublecortins, CAMSAPs, ensconsins - to elucidate the molecular mechanisms by which they regulate MTs and control cargo trafficking through interactions with motors. These components of the MT machinery will be reconstituted with increasing complexity to illuminate how their distinct molecular properties contribute to neuronal diversification and tuning. Cryo-electron microscopy enables unprecedented insight into cellular machinery and will be the major method used in the proposed research. Biochemical and biophysical assays will provide a functional context for our structural discoveries and allow us to test our hypotheses using protein engineering. To place our molecular discoveries in a cellular context, we will study the operation of the MT machinery in neurons using cryo-electron tomography. We will visualise the organisation of MTs in neurons and elucidate the impact of disruption of specific machinery components on them. Through this integrated programme of research, we will uncover regulatory mechanisms of the MT machinery with important implications for human health.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: NEUROLOGICAL
Title: Investigating how the novel hormone kisspeptin modulates sexual and emotional brain processing in response to odour cues.
Funder: Medical Research Council

Abstract: Psychosexual dysfunction affects 1 in 3 individuals and costs the NHS over £32 million/year. The novel hormone kisspeptin is a crucial activator of the reproductive axis and is also expressed in the limbic system where its role is largely unknown. Recent work shows kisspeptin signalling in the amygdala modulates reproductive hormones in rodents and visual-evoked sexual brain processing in healthy men. This suggests the presence of a kisspeptin-mediated psycho-neuroendocrine framework uniting sexual and emotional brain processing with reproduction. In this way, kisspeptin may modulate psychosexual function. Olfaction underpins many mating behaviours through the actions of odours that elicit specific behaviours in animals and humans. Recent data in rodents show kisspeptin neurons interconnect the olfactory bulb, amygdala and hypothalamus. The functional relevance of these connections is demonstrated by loss of olfactory-mediated partner preference in kisspeptin receptor knock-out male mice. However kisspeptin's role as a hormonal regulator between olfactory-limbic-reproductive (OLR) brain structures has not been examined in humans. My pilot fMRI data shows limbic brain areas activated in men by female fragrance odour correspond to areas enhanced by kisspeptin. This suggests kisspeptin and olfaction modulate similar limbic pathways in humans. I propose to use advanced fMRI techniques coupled with olfactory, facial perception and psychometric tasks to determine how kisspeptin mediates OLR brain activity and associated behaviours in humans. Additionally, I will perform in vivo animal experiments to identify how kisspeptin crosses the blood-brain barrier to mediate these effects. Collectively, this project will determine how kisspeptin accesses the brain to modulate sexual and emotional brain processing in response to olfactory cues and answer key questions regarding kisspeptin BBB transport for the development of kisspeptin as a treatment for psychosexual disorders.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: NEUROLOGICAL
Title: TDP-43 biomarker development in amyotrophic lateral sclerosis
Funder: Medical Research Council

Abstract: The core aim is to identify the most relevant pathological form of TDP-43 in human biofluids and to establish the key pathological protein pathways involved in TDP-43 pathology for potential therapeutic targeting as well as biomarker development. Objectives: A) enrich pathological forms of TDP-43 and identify candidate TDP-43 peptides to measure in patient samples; B) isolate pathological TDP-43 and its interacting proteins from novel ALS disease cellular models and identify interactors involved in pathogenesis. Methodology: Cerebrospinal fluid, serum and case-matched post mortem tissue from ALS patients studied as part of the BioMOx cohort, and healthy controls, will be enriched for ubiquitinated and phosphorylated proteins and subsequently immunoprecipitated for TDP-43. Using liquid chromatography tandem mass spectrometry (LC-MS/MS) samples will be analysed for disease relevant TDP-43 peptides and validated using multiple reaction monitoring (MRM) in biofluid samples from patients with ALS, mimic disorders (e.g. multifocal motor neuropathy), neurodegenerative disease controls, and healthy controls, followed by subsequent MRM validation in an independent cohort prior to immunoassay development. To study human TDP-43 and detect its interacting proteins, we will use mouse embryonic stem cell derived spinal motor neurons expressing human TDP-43 WT and TDP-43 M337V. TDP-43 will be immunoprecipitated and its interactors analysed using LC-MS/MS and tested for relevance in human disease by using human induced pluripotent stem cell derived motor neurons from an ALS M337V mutation carrier and human post mortem tissue. The discovery of biomarkers reflecting the major pathology in ALS will profoundly influence the clinical and scientific implication for early identification of ALS patients and allow earlier access to therapeutic trials. Such biomarkers will facilitate monitoring of therapeutic response and has potential for the identification of novel drug targets.


Research activity codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES
Health categories: NEUROLOGICAL
Title: Spinal cord repair from endogenous stem cells in the spinal niche
Funder: Medical Research Council

Abstract: We hypothesize that small differences in the environment of zebrafish and mammals spinal stem/progenitor cells determine regenerative success or failure. We need to characterize and compare the cellular diversity and differential properties of adult spinal cord stem cell niches in zebrafish, rodents and human. We will elucidate the molecular mechanisms controlling niche dormancy vs activation and stem cell fate after spinal cord injury, exploring why mammals spinal cord stem cell do not generate neurons after SCI. We will explore the human spinal cord stem cell niche and generate human spinal cord stem cell lines for further investigation of human niche cell properties. We aim to enhance functional repair after mammalian spinal cord injury by defining innovative tools (nanobodies) and identifying molecules to manipulate the activity and fate of spinal cord neural stem and progenitor cells after injury.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: NEUROLOGICAL
Title: Cellular and molecular insights into neurodegeneration mediated by the C9orf72 gene mutation
Funder: Medical Research Council

Abstract: Motor neurone disease or amyotrophic lateral sclerosis (ALS) is a rapidly progressive and incurable neurodegenerative disorder, characterised by paralysis, due to loss of motor neurones (MNs). The underlying mechanism of cell-type specificity and death is unknown. The seminal discovery that a hexanucleotide, repeat expansion in the C9orf72 gene underlies the most common cause of familial ALS (and also another, non-motor, illness, frontotemporal lobar degeneration, FTLD) makes it an attractive model for the study of the cellular and molecular mechanisms of neurodegeneration. Combining genetic discoveries with technological advances in human induced pluripotent stem cells (iPSCs) and genome editing offers unprecedented opportunities to develop new experimental human models of neurological disease. Specifically, a potentially robust approach to interrogate the consequences of mutations in C9orf72 expressed at physiological levels is to study MNs derived from iPSCs obtained from patients with ALS carrying the C9orf72 mutant gene on an isogenic control background, permitting direct causality to be assigned to any phenotype, since the only variable is the mutation of interest. My proposed research aims to use my host group's already validated 3 independent patient-derived mutant C9orf72 iPSC lines, with isogenic pairs, to generate MNs. Based on recent observations from both my host group's laboratory and that of others, I hypothesise that, first, there is a common cellular (morphological) phenotype - that of reduced neurite outgrowth length - and, second, there is a common molecular signature as demonstrated by examining the transcriptome. A series of experiments will inform a final set of experiments, whereby, through overexpression/knockdown of identified candidate genes or targeted pharmacological manipulation(s) of pathways identified from the transcriptomic work, a successful rescue strategy can be demonstrated to reverse the cellular phenotypic deficit.


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