NIHRDataInsights/HRCSData huggingface dataset:
Title: Attention, neglect, and related modulations of sensory processing: an integrated approach to causal interplay between remote but interconnected regions of the normal and damaged human brain.
Funder: Wellcome Trust

Abstract: Our perception of the visual world, and our sense of touch, is not determined solely by the stimulation entering our eyes or contacting our skin. Instead, our visual and tactile perceptions can depend strongly on what we choose to attend to or remember. Scientists have known for many years that specific parts of the brain are devoted to processing either visual or tactile input, but more recently it has been shown that these sensory-specific brain areas are modulated by 'higher level' brain area s involved in directing attention or maintaining goals. Moreover, it has also been discovered that patients with damage to these higher-level brain areas (for instance, after a stroke) can show visual and/or tactile deficits, even though their basic visual and tactile systems remain demonstrably intact. We will use new causal approaches, combining brain stimulation with brain imaging plus perceptual measures, to discover how higher-level brain areas (specifically, regions in parietal and frontal cortex) modulate our senses of vision and touch; how this can go wrong after brain injury; and how the resulting deficits might in future be rehabilitated.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;1.2 PSYCHOLOGICAL AND SOCIOECONOMIC PROCESSES
Health categories: NEUROLOGICAL
Title: Activity codes for neuronal maturation in the olfactory bulb: development and adult neurogenesis.
Funder: Wellcome Trust

Abstract: As the brain develops, electrical events occur in its cells. Abolishing these events can have dramatic effects on a brain cell's identity, its position, its shape, and its connections with other cells. Electrical activity is therefore crucial for brain development, but we know very little about the exact patterns of activity required. The proposed project aims to uncover these patterns, using tools that give us precise control over the electrical activity occurring in particular brain cells at particular points in time. Specifically, we aim to uncover the activity patterns that are 'best' for forming synapses the connections between brain cells and dendrites brain cells' information-receiving structures. An especially interesting part of the brain in which to explore these questions is the olfactory bulb (OB), which processes information about smells. Unlike most other areas of the brain, the OB continually changes its cells throughout life. This means we can not only de scribe the activity patterns required for developing the OB in early life, but also compare them with patterns needed for re-modelling the OB in adulthood. This information is important for treatments trying to replace human brain cells lost through injury or disease.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: NEUROLOGICAL
Title: Optimisation of cognitive and behavioural control in Parkinson's disease and Frontotemporal degeneration.
Funder: Wellcome Trust

Abstract: As the population gets older, diseases caused by degeneration of the brain will be more common. Despite progress in understanding the biology of these illnesses, there is a big gap between our knowledge of what is happening in brain cells and how to improve patient treatments. I will study two diseases, Parkinson s disease and Frontotemporal Dementia, because of some similarities in the parts of the brain affected and because they both need better treatments. Frontotemporal dementia has very fe w treatment options, and there are drawbacks to the availble treatments for Parkinson s disease. We must therefore build better bridges between test tube research and the patients everyday problems with thinking and action. To do this, I will lead a team at the Cambridge University Department of Clinical Neurosciences to test three drugs. I will measure the effects of treatment by brain scanning while patients do different psychology tests e.g. choosing and controlling actions. We chose the three drugs because of their potential in previous animal and human research, and safety when used to treat other problems We hope the results will lead on to clinical trials in the near future.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;6.1 PHARMACEUTICALS
Health categories: NEUROLOGICAL
Title: Harnessing noradrenergic endogenous analgesia.
Funder: Wellcome Trust

Abstract: The perception of pain is regulated by an in-built system of neurones that can control the processing of pain signals, termed the endogenous analgesic system. A group of neurones that synthesise and release noradrenaline play a pivotal role in this pain control system. We have designed novel viral vectors to selectively change the genetic expression of proteins in these cells which allows us to experimentally alter their activity. We propose that increasing the excitability of the noradrenerg ic neurones will provide a pain killing effect. We will use two main approaches to excite just the noradrenergic neurones either by expressing a light sensitive protein (channelrhodopsin) that enables pulses of blue light to rapidly excite the cells or by introducing an enzyme (pertussis) that removes an inhibitory influence on the neurones to increase their excitability over the long-term. We will test these approaches in rat models of acute and chronic pain to see whether activation of the n oradrenergic neurones reduces pain. We will also undertake studies to help understand how these pain-killing effects are achieved in the spinal cord and to identify new targets for the viral vectors. We hope that these investigations will identify new ways to produce analgesia.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: NEUROLOGICAL
Title: Building and shaping the central nervous system in higher vertebrates: an integrative approach.
Funder: Wellcome Trust

Abstract: Shaping and generating the early central nervous system of the amniote embryo are key events in embryonic development. At present, they are still poorly understood, in spite of their fundamental and medical significance. An integrated study of amniote neurulation as a dynamic process is now possible in the chick embryo an excellent representative of amniotes (reptiles, birds and mammals, including humans). We will characterise individual cell behaviours underlying morphogenesis of the early neural tissue and their molecular control. The data from these reductionist approaches will be incorporated into a computer model of the neurula to understand the shaping of the whole tissue and embryo. We will also study the naturally occurring stem cells that build the main embryonic axis. These stem cell-like populations are of tremendous importance, as they generate the entire axial tissues and most of the future central nervous system. How are these cells renewed? When do these stem cell niches arise, and what signals are responsible for their maintenance? These questions will be addressed by combining direct observations, molecular characterisation and genetic manipulations. Ultimately, we aim at providing an integrated view of early morphogenesis in higher vertebrates, filling a significant gap in our understanding of amniotes.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: NEUROLOGICAL
Title: The fusion of optical and magnetic resonance spectroscopy technologies to deliver novel multimodal methods to investigate brain injury in adults and neonates.
Funder: Wellcome Trust

Abstract: My aim is to combine two techniques currently being used to monitor brain injury in adults and premature babies; near-infrared spectroscopy (NIRS) and magnetic resonance spectroscopy (MRS). The fusion of these two techniques will provide greater understanding of the mechanisms underlying brain injury and hence inform the development and application of treatment and neuro-protection strategies such as brain cooling. NIRS is an optical technique that uses low light levels to measure the distribut ion of oxygen and blood in the brain, how oxygen is being utilised and tissue temperature. Magnetic resonance techniques rely upon the use of strong magnetic fields, which are harmless to biological tissue, to obtain anatomical images and measurements of known metabolites (e.g. molecules that generate energy or are bioproducts of energy production). I will start by developing a novel magnet compatible multichannel NIRS system capable of measuring regional brain tissue oxygenation, oxygen utili sation and temperature; I will then develop methodologies and software that will allow the synchronous data acquisition from NIRS and MRS. I will test the systems integration and then carry out studies in adult, neonatal humans and neonatal animal model. I will finally use a mathematical model to translate the measured signals into clinical information.


Research activity codes: 1.4 METHODOLOGIES AND MEASUREMENTS;2.5 RESEARCH DESIGN AND METHODOLOGIES (AETIOLOGY)
Health categories: NEUROLOGICAL
Title: Investigating attentional function and cognitive fluctuations in Lewy body disease: a functional magnetic imaging and electrophysiological study.
Funder: Wellcome Trust

Abstract: Lewy body dementia (LBD) is the second most common cause of degenerative dementia after Alzheimer s disease in older people and includes dementia with Lewy bodies (DLB) and Parkinson s disease with dementia (PDD). LBD is a progressive condition that ultimately leads to death. People with LBD suffer considerable disability and distress and can experience problems with movement control, visual hallucinations and fluctuations in their ability to think clearly. In particular, the fluctuations seem t o be particularly common in LBD but we do not understand yet what causes them. The proposed study seeks to understand more about the causes of the fluctuations in thinking ability that occur in LBD. We will look at how activity patterns change in the brains of people with LBD using magnetic resonance imaging and electrical scalp recordings when they are doing a simple picture task on a computer. These tests will tell us more about the cause of the fluctuations and how the brain activity goes wr ong in LBD. Knowing more will help us diagnose the condition better and earlier. It will also help us in developing effective treatments to improve the quality of life for people with LBD.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL
Title: Axoglial interactions during myelination in the CNS.
Funder: Wellcome Trust

Abstract: Myelin, the insulation around nerve fibres in our brain, allows fast nerve impulses to move along the fibre and also keeps it healthy. Myelin is destroyed in Multiple Sclerosis (MS). Early on in the disease, we know that the myelin is repaired. As time goes by, however, this repair fails and many patients will become disabled as a result of the nerve fibre degeneration that follows. To discover why this repair fails, scientists have looked at the brains of patients who have died with MS and m ade a remarkable discovery in many cases there are plenty of the cells that form myelin (called oligodendrocytes) but these cells cannot repair. Rather they seem to be stuck at the stage where they have made contact with the nerve fibres that need new myelin but then cannot start or initiate the steps that lead to making the myelin itself. It is this process of initiation that we have therefore set out to study. Once we have identified these molecules, then we could find out if they do work normally in MS and if not develop drugs that promote their activity and so repair the brains of these patients.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: NEUROLOGICAL
Title: Stochastic resonance in olfactory sensory perception.
Funder: Wellcome Trust

Abstract: Everybody hates noise - static obscures your television signal and street noise disturbs your sleep. But what if noise was actually useful? Theorists modeling the nervous system have long suggested just that: a small amount of noise could, in fact, enhance the detection of weak signals. Despite these models, no one has found a mechanism inside the brain for producing this useful noise. I hypothesize that a recently discovered class of neurons in the olfactory system of the fruit fly Drosophila m ay provide just such an internal source of noise, and that this noise serves to boost otherwise undetectable olfactory signals, as if static helped you hear your stereo better. Using specific gene targeting techniques, I will first characterize the activity of these apparently noise-producing neurons, and then remove them from the olfactory circuit to observe what happens to olfaction in these flies. Are they less able to detect faint odours, as manifested by reduced behavioural preferences t oward and against certain odours? Are neurons in their brain less likely to fire in response to faint odours? I will address these questions by looking into their brains, recording responses from their neurons, and observing their behaviour in response to odour stimulation.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: NEUROLOGICAL
Title: The asymmetric brain: from genes to circuits and behaviour.
Funder: Wellcome Trust

Abstract: Although humans are largely left-right symmetric, there are lots of asymmetries both within our bodies and brains. Brain asymmetry is most obvious in terms of handedness but there are many other hidden asymmetries. For instance, left hemisphere strokes have much more severe consequences upon speech production than equivalent strokes on the right. Brain asymmetry is very important for efficient brain function and defects in brain asymmetry are linked to conditions such as schizophrenia and dy slexia. Despite their importance, we have little idea how brain asymmetries develop nor do we know the nature of the brain connections that underlie functional asymmetries. Brain asymmetries are not unique to humans and indeed are found in all animals. Our previous work has helped to establish the zebrafish embryo as the best vertebrate model system in which to study the genetic basis of brain asymmetry and identify the differences in connections between left and right sides of the brain. In this project, we will determine the mechanisms by which certain genes break symmetry in the brain and initiate a chain of events that leads to asymmetric connectivity. We will also use imaging techniques to link activity in the asymmetric brain circuits to behaviour.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: NEUROLOGICAL
Title: A new systems approach to therapeutic target selection in degenerative neurological disease
Funder: Wellcome Trust

Abstract: We will develop a new approach to selecting and verifying novel therapeutic targets in degenerative neurological diseases, piloting this innovation in Parkinson s disease (PD). To this end, we will use dynamic causal models (DCMs) that allow electrophysiological data to be fitted by biologically plausible (conductance-based), neural-mass models of coupled sources. Data will be derived from simultaneous electrophysiological recordings of neuronal network activity at multiple sites in the basal ga nglia and cortex in dopamine-intact (control) rats and 6-hydroxydopamine-lesioned (Parkinsonian) rats, as well as from simultaneous recordings from more restricted sites in patients undergoing functional neurosurgery. Bayesian inversion will then be used to derive estimates of extrinsic parameters (internuclear connectivities) and intrinsic parameters (intranuclear connectivities and conductances) in the DCMs. We will focus on those parameters that are similar in Parkinsonian rodents and PD pati ents, but differ in control rodents and in patients without PD. The importance of candidate differences will then be confirmed using techniques drawn from neuroeconomics and finally targeted in the Parkonsonian rodents to confirm their utility as candidate therapeutic approaches. Importantly, we will not restrict ourselves to the modeling and testing of pharmacological interventions, but also exploit the potential for surgical intervention through lesioning and deep brain stimulation.


Research activity codes: 5.1 PHARMACEUTICALS;5.4 SURGERY
Health categories: NEUROLOGICAL
Title: A confocal microscope facility for the Wolfson Centre for Age-Related Diseases at King's College London
Funder: Wellcome Trust

Abstract: The Wolfson Centre for Age-Related Diseases (CARD) is a relatively new centre at King s College London housing 24 research groups focused on understanding the molecular basis of age-related diseases, pain, and regeneration. The CARD currently lacks a confocal microscope facility and this impedes the ability of many of the groups to perform state-of-the art imaging experiments. This application will enable the purchase of a high quality confocal microscope. Examples of the ongoing studies that w ill benefit from this include those aimed at understanding the role of the endocannabinoid system in adult neurogenesis, visualisation of microglia following spinal cord injury, modelling neural cell fate in the Drosophila CNS and studies aimed at harnessing pro-survival pathways in degenerating neurons. These studies are performed using a variety of experimental paradigms including stem cell lines, primary neuronal cultures, in vivo spinal cord injury models, Drosophila and additionally through retrospective studies using patient tissue. To fully exploit these paradigms confocal imaging is essential. The confocal facility will add value to ongoing projects as well as greatly increasing the potential of future studies within the CARD.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL
Title: Defining common mechanisms that guide tangential neuronal migration in the mammalian brain.
Funder: Wellcome Trust

Abstract: During brain development, nerve cells are often generated far away from the sites they will ultimately occupy in the mature brain, and they therefore have to migrate to reach their final position. Interest in neuronal migration has never been greater, because recent investigations have shown that migration abnormalities lead to severe brain defects in humans. Two distinctly different modes of migration have been identified so far: radial and tangential. During radial migration, neurons move perp endicular to the surface of the brain using the support of glial fibres. During tangential migration, neurons move long distances, often coursing parallel to the surface of the brain. Three neuronal systems that utilise tangential migration in the developing mammalian brain have received considerable attention: first, the cortical interneurons; second, gonadotropin-releasing hormone neurons; and third, interneuron progenitors of the olfactory bulb. We propose to elucidate the molecular mechanism s that guide these diverse groups of neurons through all phases of their migratory journeys, focussing on chemoattractant and chemorepellent signals that are likely involved in all three systems Studies of the mechanisms involved in tangential neuronal migration will enhance our understanding of several different types of birth defects that affect the human brain.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: NEUROLOGICAL
Title: Identification of astrocytic factors that regulate myelination.
Funder: Wellcome Trust

Abstract: The aim of this project is to identify key genes involved in functional phenotypes of astrocytes which affect myelination. This will be carried out as follows: i) Assess if cross talk between glial cells and axons promote myelination by generating myelinating cultures on astrocyte monolayers. ii) Validate resulting candidate genes by qRT-PCR iii) Determine if potential candidate genes identified in the microarray can affect myelination using recombinant protein, antibody and in situ RNA hybridization approach.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: NEUROLOGICAL
Title: Optogenetic manipulation of interneuron function.
Funder: Wellcome Trust

Abstract: Inhibitory neurons in the grey matter of the brain (interneurons) play important but poorly understood roles in information processing, in precise timing of neuronal activity, and in regulating the overall excitability of the brain. Progress in understanding these functions has been held back by difficulties in recording from interneurons or manipulating their activity, mainly because they represent a minority of neurons in the cortex and because interneurons themselves are highly diverse. We an d others have recently developed new methods to identify different classes of interneurons by expressing fluorescent markers, and we propose to combine these methods with a radically new approach to impose electrical activity in neurons via light-sensitive proteins. If successful these methods will give us an unprecedented ability to ask how different populations of developing interneurons contribute to signal processing and to population activity. We will also apply the tools developed here to attempt to interrupt experimental seizure activity, by inducing firing of inhibitory interneurons by precisely patterned light flashes.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: NEUROLOGICAL
Title: Investigation of endothelial cell ICAM-1 signalling pathways and their role in controlling lymphocyte migration to the CNS.
Funder: Wellcome Trust

Abstract: The blood vessels of the central nervous system (CNS) form a selective barrier between the blood and the tissues of the brain and retina. In diseases such as multiple sclerosis, however, white blood cells (leukocytes) are able to migrate through this barrier and cause severe damage to the tissue. How leukocytes traffic into the CNS is complex but endothelial cells, which form the cell lining of the blood vessel wall, are known to play a major role in this process. To gain access to the CNS adher ent leukocytes must penetrate the vessel wall by inducing changes in the endothelial cell that cause it to actively facilitate the passage of the leukocyte. In this study we will reveal in greater detail the role of the endothelial cell in performing this critical function of supporting leukocyte migration. By enhancing our understanding of the fundamental mechanisms governing inflammatory diseases of the CNS we will improve our chances of identifying new therapeutic targets which in the future may be used for the treatment of multiple sclerosis and posterior uveitis.


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