NIHRDataInsights/HRCSData huggingface dataset:
Title: Improving the effectiveness of therapeutic protocols of repetitive transcranial magnetic stimulation (rTMS)
Funder: Medical Research Council

Abstract: A TMS pulse activates simultaneously many types of excitatory and inhibitory neurones that have different roles in behaviour. Furthermore, the activated proportions of each neural type vary between people probably because of variations in brain anatomy. We have argued that this is a major cause of the high inter-individual variation in after-effects of repetitive TMS (rTMS) protocols. This severely limits the use of rTMS as a therapeutic intervention. Controllable pulse TMS devices are now available and we have shown that manipulating pulse parameters can increase the selectivity of stimulation. Our pilot data from motor cortex also show that pulse-width controlled and unidirectional rTMS (specifically theta burst protocols; TBS) also has much more reliable effects on cortical excitability. The first part of the project will confirm this by comparing new and standard TBS protocols in a large group of healthy individuals. We will thus have a tool with far more potential for therapeutic application. However, therapeutic applications require effects on behaviour, and these do not always follow those on excitability. We will therefore test the effectiveness of controllable TBS protocols on motor learning, since this is a vital part of rehabilitation after stroke. Furthermore, our previous work suggested that different forms of motor learning, adaptation learning (to a change in visuomotor gain) and model-free learning (increasing maximal acceleration of a movement) involve different sets of motor cortical neurones. Given the selectivity of controllable pulse TBS we expect these distinct types of learning to be affected by different TBS protocols. The therapeutic implication is that different types of TBS may be required according to individual needs of patients. Finally it is necessary to show that similar principles apply in the damaged brain of patients after stroke. We will therefore test the most effective TBS protocols on motor learning in chronic stroke.


Research activity codes: 1.2 PSYCHOLOGICAL AND SOCIOECONOMIC PROCESSES;2.4 SURVEILLANCE AND DISTRIBUTION
Health categories: NEUROLOGICAL
Title: Contributions of prefrontal-midbrain-spinal cord network dynamics to the development and maintenance of chronic neuropathic pain.
Funder: Medical Research Council

Abstract: Progressive alterations in the functional connectivity of the medial prefrontal cortex (mPFC) are thought critical to the development of chronic pain in humans but how they relate to sensory and affective disturbances or disease progression is not understood. The mPFC is directly connected with the periaqueductal grey (PAG) and their functional connectivity is altered in chronic pain patients. The PAG is an important component of emotional networks and a key orchestrator of the descending control of spinal nociception; both of which are major determinants of the pain experience. We propose that progressive alterations in mPFC-PAG communication alter the cortical control of the PAG and, in so doing, contribute to sensory and affective aspects of the pain phenotype. Our pilot data show that, in naïve rats, mPFC effects on spinal nociception are dependent, at least in part, on the integrity of direct projections to the PAG. We now wish to use combined anatomical, electrophysiological and behavioural approaches in neuropathic rats to (i) characterise communication between the mPFC and the PAG, and how it engages with nociceptive processing in the spinal dorsal horn, (ii) chart progressive changes to mPFC-PAG network dynamics during neuropathic pain development and (iii) determine functional contributions of PFC-PAG projections to sensory and affective disturbances using chemogenetic approaches. Our overall aim is to interrogate the causal relationships between, and provide mechanistic insights into, progressive alterations in mPFC-PAG-SC networks and the development of the neuropathic pain phenotype. Specifically, to provide novel details on (i) functionally identified mPFC-PAG pathways that will serve as an important reference for other pain researchers and reveal potential therapeutic targets, (ii) the relationship between network alterations and pain symptoms that, together with human imaging data, will help develop biomarkers for components of chronic pain.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL
Title: Decoding Presymptomatic white matter changes in Huntington Disease (WIN-HD)
Funder: Medical Research Council

Abstract: Our working hypothesis is that oligodendrocyte alterations underlie and exacerbate neurodegeneration in HD. Using new techniques of imaging, neuropathology, cell biology, and genetics, WIN-HD will investigate prodromal white-matter changes in HD patients (22 available human brain tissues and 30 premanifest carriers and 30 gene negative controls for imaging studies) and in mice model. We will use an HD knock-in rodent model and models expressing oligodendrocytes modifiers. We will test the hypothesis that white-matter changes exacerbate the pathogenic cascade in Huntington Disease (HD) characterized by motor and cognitive signs. These changes may include (1) perturbed axon-glia interactions, (2) loss of oligodendroglial functions, and (3) demyelination. The proposal originates from surprising findings: (1) white-matter atrophy occurs far earlier than clinical onset in HD; and (2) extensive white-matter changes are present in mouse models; and (3) expression of the HD-causing protein in oligodendrocytes may contribute to disease progression in mice. For this project, we have assembled experts in the human disorder, in HD rodent models, in human and animal brain imaging and in the molecular and cellular biology of myelination. Together, we will examine white-matter changes well before the onset of disease signs and look for parallel changes in human and rodent models. We will use diffusion-weighted spectroscopy combined with diffusion tensor imaging to distinguish between axonal and glial contribution to white matter changes. Using genetic tools in mice, we will determine the effects of altered oligodendrocyte function on disease progression. Our two-year program will allow us to infer whether neuroprotective therapies should focus on molecular targets that primarily function in oligodendrocytes.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL
Title: Identifying effectors of mutant C9Orf72 ALS/FTD to combat neurodegeneration
Funder: Medical Research Council

Abstract: Hexanucleotide repeat expansions (HRE) in the C9orf72 gene are the most frequent cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Recent studies have identified formation of DNA/RNA quadruplexes, dipeptide repeat proteins (DPR) and altered nucleocytoplasmic transport as potential triggers of GGGGCC (G4C2) related neuronal cell death. The effector pathways leading to neurodegeneration in ALS/FTD remain to be discovered however. The project aims to determine these neurodegenerative effector pathways by combining the power of pure human motor neuron cultures and non-dividing yeast, and in collaboration to validate these in zebrafish models. The specific aims are: 1. To identify potential effectors of G4C2-triggered neurodegeneration by comparative transcriptomic analysis of pure FACS-isolated motor neurons from induced pluripotent stem cells from patients with C9orf72 expansions, gene-corrected lines (using Cas9/CRISPR) and age-matched controls. 2. To classify the intermediates of G4C2-triggered neurodegeneration as aggravating, counteractive or homeostatic, by using gene overexpression/knock down in cultured motor neurons. 3. To establish their genetic hierarchy and molecular interactions in non-dividing S. pombe yeast. 4. To test the effectors as targets for pharmacological therapy in a zebrafish model of G4C2-linked ALS/FTD. In order to achieve these ambitious aims, we have gathered three leading European teams with documented expertise in the field of stem cell biology, ALS pathology and systems biology in this highly innovative and translational project.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL
Title: Towards a unifying theory of Parkinson's disease: Investigation of the biochemical and genetic role of Rab GTPases
Funder: Medical Research Council

Abstract: This proposal builds on our recent exciting discovery that the LRRK2 and PINK1 kinases implicated in Parkinson's, regulate the phosphorylation and activity of Rab GTPases. LRRK2 directly phosphorylates numerous Rab isoforms on a conserved Thr/Ser residue that lies at the centre of its effector binding motif (Thr72-Rab8A), inhibiting association with known effectors GDIs and Rabin-8 that are required for Rab8A activation. Activation of PINK1 induces phosphorylation of a distinct C-terminal residue of Rab isoforms (Ser111-Rab8A) through an as yet unknown intermediate kinase, which inhibits association with Rabin-8. Our findings therefore provide an opportunity to investigate novel biological roles for LRRK2 and PINK1 and the mechanisms implicated in Parkinson's. We will identify the key Rab isoforms that are phosphorylated by LRRK2 and PINK1 in brain and iPSC derived neurons (Alessi/Muqit/Gasser-labs). We will work on delineating how Rab phosphorylation influences downstream signalling pathways (Alessi/Muqit-labs). Finally, we will investigate whether genetic variation in Rab GTPases and their effectors and interactors are linked to Parkinson's susceptibility (Gasser-lab). The results and reagents generated in this study together with the integration of biochemical, clinical and genetic analysis will make a major contribution to the assessment of Rab phosphorylation as central mediators of neurodegeneration.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL
Title: Protection of neurons in vitro and in vivo from Synuclein toxicity by molecular tweezers
Funder: Medical Research Council

Abstract: Parkinson disease (PD) is hallmarked by the deposition of aggregated alpha-synuclein (alpha-syn) species into intra-neuronal Lewy bodies (LB) and Lewy neurites (LN) inclusions while in multiple system atrophy (MSA) alpha-syn aggregates form oligodendroglial inclusions. The development of therapeutic strategies to block cell death in PD and MSA has been limited by a lack of understanding of the mechanisms driving neurodegeneration. However, increasing evidence of multiple pivotal roles of alpha-syn in the pathogenesis of PD and MSA has led to consider the therapeutic potential of several strategies aimed at reducing alpha-synuclein toxicity. Our objective is to build upon the unique experimental cell (Primary rodent neurons and glial cells - Human neurons derived from PD patients) and animal models of PD (SNCAOVX transgenic mouse and human PD-derived alpha-syn seed-injected mouse) and MSA (PLP-SYN transgenic mouse and human MSA-derived alpha-syn seed-injected mouse), developed by this consortium, for testing whether the prototypical molecular tweezer CLR01, shown to inhibit aggregation and toxicity of other amyloidogenic proteins, could protect neurons in vitro and in vivo from PD / MSA-associated synaptotoxicity and reduce PD and MSA's disease-like alpha-syn pathology. The project will thus (in)validate the molecular tweezers CLR01 for PD and/or MSA indications.


Research activity codes: 3.3 NUTRITION AND CHEMOPREVENTION;5.1 PHARMACEUTICALS
Health categories: NEUROLOGICAL
Title: Therapeutic targeting of impaired lysosomal flux in Alzheimer's disease
Funder: Medical Research Council

Abstract: We propose that TRPML1 becomes dysfunctional in the AD brain, and via age-related alterations in AD risk genes, and that modulating TRPML1 function will clear both Abeta and tau pathology. This highly original approach builds on solid foundations from the complementary strengths of all members of the collaborating teams; identifying risk genes for AD and early changes in AD brain systems that directly affect EAL function, as well as specific defects in the TRPML1 and lysosomal system that negatively affect the catabolism of APP in AD models. We hypothesise that PI-mediated control of TRPML1-mediated lysosomal flux, which is critical for functional neuronal longevity, becomes progressively defective in AD brain and causes failure in APP/Abeta and tau clearance. This ties in with our complementary research findings in AD pathology, lysosomal systems and AD genetics. Specifically, re: genetics our realisation that a number of genes (APOE4, PICALM, BIN1 and CD2AP) that confer risk for developing late-onset AD (LOAD), have direct binding sites and regulate PI(4,5)P2 or regulate PI(3,5)P2 /PI(4,5)P2 levels (INPP5D), the major molecular switch that turns TRPML1 on / off respectively. Together, this provides the progressive possibility that these risk genes via their regulation of PI(3,5)P2 /PI(4,5)P2, alter TRPML1 function in AD. This is a totally original and transformative approach linking PI system control to lysosomal defects in AD as a major new approach to understand genetic predisposition, diagnosis and treatment of AD.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL
Title: Determining the mechanisms of nigro-striatal dysfunction in SGCE mutation positive Myoclonus Dystonia using an iPSC-derived neuronal cell model
Funder: Medical Research Council

Abstract: Aims Generate a neuronal cell model for SGCE mutation-positive Myoclonus Dystonia (MD) using patient derived fibroblasts Characterise this model to determine changes to monoaminergic neurotransmission at the nigro-striatal junction Background Dystonia is a common and disabling movement disorder. Poor understanding of its pathophysiology has led to few effective treatment options. MD is one of few genetically determined dystonias caused by fully penetrant, autosomal dominant mutations (epsilon-sarcoglycan gene, SGCE), providing a unique opportunity for investigation. Previous studies suggest that disruption of the nigro-striatal junction, specifically dopamine-2-receptor (D2R) function, is central to pathogenesis. My previous work involved detailed phenotyping of a large MD cohort (n=30). Two mutation types will be used to develop induced pluripotent stem cell (iPSC) lines: nonsense (c.289C>T,p.Arg97X) and missense (c.622G>A,p.Gly441Asp) mutations. Methodology IPSC lines will be generated using Sendai virus vector techniques and differentiated using dual SMAD inhibition and Activin A into midbrain dopaminergic and striatal medium spiny neurons (MSNs) respectively. Characterisation of the neuronal models will include measurement of dopamine synthetic enzymes, transport proteins and the density and distribution of dopamine receptors. A co-culture platform of the two neuronal cell types will undergo phenotyping using electrophysiological techniques, calcium imaging and detailing of dendritic spine morphology. Control neuronal models will include those from healthy, unrelated individuals and isogenic 'rescue' cell lines of the MD patient samples by use of CRISPR technology. Scientific and Medical opportunities This project provides an excellent model system with which to investigate the cellular mechanisms that underlie dystonia pathogenesis. Findings from this work will inform future studies, particularly the identification of novel therapeutic targets.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL
Title: The role of astrocytes in early pathogenesis of motor neuron disease: a mechanistic study of neuronal degeneration and synaptic alterations
Funder: Medical Research Council

Abstract: The overarching aim of my proposal is to explore emerging AC-mediated pathomechanisms in MND with a view to identify novel and common targets for this incurable disease. This is immensely relevant and timely as alternative therapies require precise understanding of non-neuron dependent processes that may contribute to MN pathology. ACs have a central and shared role in non-cell autonomous MN degeneration. However, the lack of precise understanding of basic adaptive versus pathogenic responses have put AC centred therapeutic discovery on hold, in part, due to inadequate tools. Therefore my objectives are to reveal alterations of AC response to MN damage and its impact on MNs, integrating state-of-art human and mouse models of MND. Specifically, my related goals are to examine whether 1) AC intracellular signalling, in particular STAT3 pathways, relevant for neuroprotection and communication is disturbed; 2) communication specifically via AC processes and exosome mediated communication are perturbed; 3) altered AC interactions worsen intrinsic MN/synapse degeneration. These will be addressed in patient derived hiPSC-AC or AC-MN co-cultures carrying SOD1 or C9ORF72 mutations, covering a major pathological spectrum of MND, in addition to being the two major genetic forms. Using transgenic SOD1/GFAP-Cre mouse slice cultures provide a further advantage of AC-specific genetic manipulations and simultaneous functional assessments on ACs and MNs in an environment simulating in vivo pathology. The two complementary systems provide a powerful platform to discover alterations to recently discovered key regulator pathways in neuromodulation, including Ca2+-oscillation in astrocytic processes. Integrating functional observations with AC and MN specific RNA-sequencing will help mine transcriptome-wide data using a priori hypotheses. I anticipate that this will increase the yield of discovery and facilitate the development of desperately needed novel therapies.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL
Title: Pathological mechanisms underlying Progressive Myoclonus Epilepsy
Funder: Medical Research Council

Abstract: We are investigating how mutations in GOSR2 - a Golgi t-SNARE fundamentally required for ER-Golgi trafficking in the secretory pathway - cause a devastating neurological disorder, Progressive Myoclonus Epilepsy (PME). GOSR2-PME is characterised by myoclonus, ataxia and tonic-clonic seizures. Symptoms begin early in life and increase in severity with time, such that patients often die between the ages of 20-40 years old. The secretory pathway is universally required for transport and secretion of proteins, lipids and complex carbohydrates. Paradoxically, mutations in GOSR2 cause a relatively selective neuronal phenotype, yet the mechanisms by which GOSR2 mutations impact neuronal development and/or circuit function in PME are unclear. To address this, we have developed novel Drosophila models of GOSR2-PME. We have found that PME-linked mutations in the Drosophila orthologue of GOSR2 (membrin) result in profound changes in organismal development and synaptic morphology. PME-mutant Drosophila larvae exhibit reduced locomotion and pharate adults are unable to successfully eclose from the pupal case, likely due to motor defects. At the Drosophila neuromuscular junction, we observe significant synaptic retraction and abnormal morphology of presynaptic boutons, coupled with alterations in the presynaptic cytoskeleton. These neurodevelopmental alterations are intriguing, since GOSR2-PME patients exhibit signs of sensory neuronopathy and motorneuron denervation. Our Drosophila model will now provide a platform to dissect the molecular basis of these alterations in synaptic development, and significantly enhance our understanding of PME pathophysiology.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL
Title: Brain Machine Interfaces based on Subcortical LFP Signals for Neuroprosthetic Control and Neurofeedback Therapy
Funder: Medical Research Council

Abstract: Research into BMI has, to date, almost exclusively focused on signals obtained from the cerebral cortex. The clinical application of BMI faces grand challenges including the lack of longevity in the neural spiking recorded over the cortex for decoding movement related information, and the difficulty in reliable and accurate prediction of gripping force required to develop neuroprosthetics of clinical grade. My previous research has identified the important role of local field potentials (LFP) recorded from the basal ganglia in encoding movement related information such as motor effort and gripping force, suggesting that these signals can be used to deliver graded force generation via a robotic hand. Compared to neural spikes, the long-term stability of LFP signals offers significant advantages for long-term performance and reliability of the BMI over time. In addition, new developments in implantable devices, which offer the capacity for chronic recording, real-time processing and wireless data transmission, afford an unparalleled opportunity to utilize deep brain signals for BMI control. I propose to exploit this research opportunity and our understanding about the role of basal ganglia in motor control, to develop new approaches for BMI based on LFP signals recorded from the basal ganglia. I will build the first robotic mechanism interfacing with subcortical structures - the basal ganglia, and use the new framework to control a prosthetics hand with graded gripping force. This will also allow me to investigate the neural basis of the learning process in the use of a neuroprosthetic hand in human subjects. Secondly, I will use the system to provide neurofeedback training to regulate pathological oscillations in the basal ganglia associated with Parksinson's disease, and to study the functional changes in the cortico-basal ganglia network induced by neurofeedback training.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: NEUROLOGICAL
Title: The role of neuregulin-1 signalling in modulating repair and functional recovery following spinal cord injury
Funder: Medical Research Council

Abstract: Spinal cord injury (SCI) results in profound and often lifelong disability, and there are no regenerative therapies. Despite the severe pathological and neurological deficits associated with SCI, some degree of spontaneous functional recovery is normally observed. Better understanding of underlying endogenous regenerative mechanisms could provide novel treatment avenues. We recently found that Neuregulin-1 (Nrg1), a growth factor which exists in multiple distinct isoforms, contributes to functional recovery following SCI. In this proposal we aim to understand the mechanisms by which Nrg1 signalling mediates spontaneous repair, remyelination and recovery after SCI and investigate whether targeted over expression of specific Nrg1 isoforms can improve functional outcome. Our previous and preliminary data suggest that Nrg1 signalling controls the differentiation of centrally derived glial progenitor cells into functional remyelinating cells after SCI. We will use transgenic technology to ablate Nrg1 receptors specifically in central glial progenitors and will determine the glial cell types (oligodendrocytes vs Schwann cells) regulated by Nrg-1 signalling and their functional importance, in mice with clinically relevant SCI (Aim 1). We also have evidence that specific Nrg1 isoforms mediate different aspects of endogenous repair after SCI. We will use viral vector-mediated axonal expression to determine whether manipulating Nrg1 isoforms can accelerate and enhance remyelination, resolve pathophysiology and improve functional outcome after SCI (Aim 2). Finally, secreted isoforms of Nrg1 are important in muscle spindle function and maintenance, which is important for optimum recovery following SCI. We will use isoform specific ablation to investigate whether muscle spindle-spinal cord communication is Nrg1-dependent (Aim 3). This work may lead to novel target-specific therapies for enhancing repair and improving functional outcome after SCI and other CNS disorders.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: NEUROLOGICAL