NIHRDataInsights/HRCSData huggingface dataset:
Title: Neural mechanisms underlying flexible behaviour
Funder: Wellcome Trust

Abstract: I aim to understand how the brain represents the relationships between objects and events in the world, and how these representations can be generalised to allow flexible behaviour in new situations. By combining modelling with experiments in human and macaque, I will investigate these computations at both the cellular and systems level. We have developed models that abstract relational knowledge and predict detailed neuronal representations in rodent hippocampal-frontal circuitry. I will ask whether these building blocks can be extended to explain the sophisticated abstractions and inferences commonplace in primate behaviour. In primates, such abstractions compound hierarchically, and can be combined together, allowing deep inferences. To study these computations, I will develop novel tasks that are high-dimensional, yet amenable to mathematical description. I will use state-of-the-art techniques in humans, validated by high density cellular recordings in macaques, to study representations underlying abstraction, generalisation and inference in medial temporal and frontal cortices. In doing so, I will build new bridges between human and animal neuroscience, between biological and artificial intelligence, and new analytical and experimental tools for integrating across scales of neural activity. Developing such tools is important to bridge the precision of modern neuroscience to humans and thence clinical populations.

Lay abstract: When a waiter asks you for money at the end of a meal, how does your brain understand that it is the food you are paying for? Similar relationships are everywhere in the world and understanding them lets our brains choose good behaviours - our brains contain a model of the relationships between objects and events in the world. My research tries to understand how the electrical firing of brain cells could represent something as complex as this world model. To do this we will create artificial networks of neurons that can learn simple world-models, and compare the activity of these neurons to activity recorded from real brains solving the same problems. These findings will advance fundamental knowledge about the brain, but will also likely lead to new experimental tools that will be translated to psychiatric studies. The research is also of interest to scientists building artificial intelligence.

Research activity codes: 1.2 PSYCHOLOGICAL AND SOCIOECONOMIC PROCESSES
Health categories: MENTAL HEALTH;NEUROLOGICAL
Title: Organization of large neuronal populations during behavior
Funder: Wellcome Trust

Abstract: Behavior arises from the coordinated function of vast numbers of neurons across the brain. However, we lack answers to fundamental questions concerning this coordinated function. How is the activity of multiple brain areas globally structured? How does this global structure relate to the firing of local neuronal populations? And what is the role of this coordination in producing animal behavior? Until recently, these questions were barely answerable: one could only record from tens or hundreds of neurons, and during single behaviors. They are now answerable, thanks to new, powerful techniques available in the brain of the mouse: optical recordings of over 10,000 neurons simultaneously, optical and ultrasound measures of mesoscopic activity in multiple brain regions, next-generation electrode arrays that record thousands of neurons across multiple areas, and temporally targeted optogenetic manipulations. We will combine these techniques to understand how brain-wide neuronal populations operate in the mouse brain during different behavioral conditions: rest, passive sensory stimulation, locomotion, sensory discrimination, and goal-directed navigation. These data will provide an unprecedented view on the neuronal-level organization of populations across the brain during behavior.

Lay abstract: Until recently, our understanding of brain activity has relied on recordings from tens or hundreds of neurons, in a single brain region, in a single behavior. Through such recordings, in our previous joint project we were able to characterize the activity of local populations of about 100 neurons, and to start understanding the circuit mechanisms and behavioral relevance of this activity. The brain, however, operates through the coordinated activity of vast and distributed populations of neurons, which work in flexible teams to achieve diverse behaviors. New techniques are available to capture this coordinated activity. They will now allow us to characterize the basic structure of activity in the whole brain during multiple behaviors, and to understand how every neuron in a local population participates in this activity, how activity in one population influences activity in another, and how these populations underlie performance of different behaviors. Addressing these questions requires a powerful combination of multiple advanced experimental techniques and extensive computational data processing. Our joint laboratory is ideally placed to deliver this combination of approaches, and to offer an unprecedented view on the neuronal-level organization of populations across the brain during behavior.

Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: MENTAL HEALTH;NEUROLOGICAL
Title: Wellcome Centre for Human Neuroimaging
Funder: Wellcome Trust

Abstract: Our overarching vision is to deliver clinically transformative applications of neuroimaging that catalyse the understanding and treatment of patients with neurological and psychiatric disorders. Cornerstone to this is the integration of paradigm-shifting neuroimaging technologies with neuronal and behavioural modelling to establish non-invasive, computationally-derived measures of neuronal function and structure. The resulting methodological innovations will be exploited to provide mechanistic explanations of how the human brain supports sensory, motor and cognitive functions in health, how these mechanisms are affected by disease, how they respond to therapeutic interventions, and how to deliver personalised prognoses. A fundamental tenet of our vision is to conduct our science in a transparent and open manner, and to engage with stakeholders from patient groups and the wider community. Promoting this approach, in conjunction with an inclusive and positive research culture, will remain integral to our vision. Our supportive environment, highly-trained, multidisciplinary staff, innovative technological capacity, and embedded position within the Queen Square Institute of Neurology, creates a dynamic and cooperative critical mass with expertise in the use and development of computational approaches that make our neurobiological questions tractable. These factors provide the capacity to deliver our vision of clinically transformative applications of neuroimaging.


Research activity codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES
Health categories: MENTAL HEALTH;NEUROLOGICAL
Title: Neuronal reward mechanisms
Funder: Wellcome Trust

Abstract: We investigate neuronal reward and economic decision signals in behavioural tasks with designs from learning and economic decision theories, supplemented by selected, closely related neuroimaging experiments. We study the main components of the brain's reward system, including dopamine neurons (reward prediction error), orbitofrontal cortex (economic decision variables), striatum (so far insufficiently characterised reward signals) and amygdala (short- and long-term rewards). We search for reward and decision signals that provide explanations and hardware implementations for the constructs of reward and economic theories. We need to know these fundamental neuronal signals before focussing on cellular and molecular mechanisms, which differs from work on sensory and motor systems whose signals are better characterised. We state three aims: Aim 1: We characterise neuronal processing of skewness-risk, arguably the most frequent risk form. Aim 2: We identify neuronal signals for utility and test formal axioms for utility maximisation, which is supposedly the goal of 'rational' agents. Utility is THE basic economic decision variable that explains most economic choices. Aim 3: We assess neuronal representations of preferences, and bridge the gap between biologically necessary rewards and tradable economic goods, by testing basic assumptions of revealed preference theory.

Lay abstract: No Data Entered

Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: MENTAL HEALTH;NEUROLOGICAL
Title: Sainsbury Wellcome Centre Core Grant Renewal
Funder: Wellcome Trust

Abstract: The Sainsbury Wellcome Centre aims to understand how computation in neural circuits generates flexible behaviour—a complex, scientific challenge that cannot be tackled by any one laboratory. The Centre is in a unique position to reveal general principles that link behaviour to neural processes across scales, by relating algorithms to neural circuits, cells and synapses. We will determine how these neural elements give rise to computations contributing to innate and learned behaviours, and develop a theoretical framework that explains how flexible, adaptive behaviour arises from neural activity. We have assembled outstanding scientific talent in an exceptional environment, with access to shared resources and state-of-the-art facilities that deliver new technologies, empowering bold research. We will exploit new models of scientific collaboration by integrating experiment, theory, data science and engineering, in close partnership with colleagues at the Gatsby Computational Neuroscience Unit. Our multi-disciplinary collaborative approach extends to the training and support of early career researchers, enhancing their success within and beyond our walls. By sharing our resources, knowledge and research culture, and through initiatives with our UCL, UK and international partners, we will collectively advance global efforts to understand the neural underpinnings of behaviour.


Research activity codes: 1.2 PSYCHOLOGICAL AND SOCIOECONOMIC PROCESSES
Health categories: MENTAL HEALTH;NEUROLOGICAL
Title: Maintaining the Extended Mind: Dementia Care and the Relationship Between Justice, Mind and Space
Funder: The British Academy

Abstract: Stories of abuse in care homes have, regrettably, become a staple fixture in public discussion of dementia. While accepting that conditions in present-day institutions are in dire need of improvement, my project will set out and explore the implications of an alternative view. Drawing on medical ethics and the philosophy of mind, I will produce a new philosophical defence of institutional care homes as vital facilitators of agency for people living with advanced dementia, embedded within a broader account of the relationship between justice, mind and space. The aim of this project is to produce a monograph with Oxford University Press. Drawing on theoretical research, while engaging with relevant non-academic stakeholders, this project will speak both to a philosophical audience and in a way that is accessible to policymakers and practitioners, with a view to transforming practices in the sector.


Research activity codes: 8.3 POLICY, ETHICS AND RESEARCH GOVERNANCE
Health categories: MENTAL HEALTH;NEUROLOGICAL
Title: Rehabilitation of Memory following Traumatic Brain Injury - a Phase III Randomised Controlled Trial
Funder: Department of Health (England)

Abstract: Approximately six per cent of patients attending Accident and Emergency departments in the UK every year have a traumatic brain injury (TBI). Many of these patients will have a memory problem as a result of the brain injury. In addition it is a particular problem for military personnel with one study reporting that almost a quarter of all soldiers sustained a TBI after joining the army. Following TBI memory problems are not only persistent but are also debilitating and have a negative effect on quality of life. They affect return to active military services return to civilian work social functioning and interpersonal relationships. Currently TBI patients with memory problems do not always receive follow-up rehabilitation even though their abilities and needs may change once discharged from clinical services.The aim of this study is to compare the clinical effectiveness and cost effectiveness of a group-based memory rehabilitation programme versus current standard care for military personnel and civilians who have sustained a TBI. The trial is a single blind multi-centre Phase III randomised controlled trial.Cognitive rehabilitation is a structured set of therapeutic activities designed to retrain an individual’s memory and other cognitive functions. The intervention is 10 weekly group memory rehabilitation sessions 1.5 hours long.


Research activity codes: 6.6 PSYCHOLOGICAL AND BEHAVIOURAL
Health categories: MENTAL HEALTH;NEUROLOGICAL
Title: Spike timing in identified neuronal circuits of the medial prefrontal cortex
Funder: Medical Research Council

Abstract: This programme will define neuronal operations in prefrontal circuits supporting memory and decision making. The temporal activity in neuronal circuits of the prefrontal cortex reflects emotional information combined with episodic and spatial memory to guide decisions on behavioural action. In this research program three levels of cortical complexity (co-operation between different cortical areas, diversity of neuronal populations, temporal organisation of cortical networks) will be addressed in the medial prefrontal cortex of the rat, which is homologous to the dorsolateral prefrontal cortex of primates. Previously, it has been described in rats that the firing of prefrontal neurons is correlated to the execution of behaviours and/or decision-making. However, the identity of the recorded neurons and their causal contribution to behaviour could not be established in these studies, which is critical for defining the neuronal circuits underlying executive control. In the medial prefrontal cortex of rodents, single neurons with unknown identity exhibit specific firing patterns during spatial decision-making tasks. However, in the cerebral cortex, highly diverse subsets of neurons with distinct synaptic connectivity, molecular expression profile and contribution to network activity exist. In order to discover how neuronal circuits support higher cognitive functions, thus, it is critical to determine the identity and temporal activity of neurons. In the present programme we will record identified neurons in the medial prefrontal cortex of rats during network oscillations and executive control. We will determine the contribution of identified neurons to prefrontal gamma, spindle and 1 Hz oscillations and we will determine ensemble activity of prefrontal neurons during working memory and decision making tasks. In addition, we will develop a novel juxtacellular recording and labelling technique in freely-moving rats. We will use this new technique to discover the synaptic connectivity, molecular machinery, contributions to synchronised network activity and spike timing of identified neurons during decision making. Furthermore, we will use optogenetic techniques, which allow the reversible manipulation of subsets of neurons. The results of these experiments will determine temporal codes of neuronal circuits underlying the selection of behavioural responses and decision-making.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: MENTAL HEALTH;NEUROLOGICAL
Title: Mechanisms of inhibitory GABA-A and glycine receptor clustering in health and disease
Funder: Medical Research Council

Abstract: Selected inhibitory GABA-A receptor and glycine receptor subtypes are clustered at inhibitory synapses via interactions with the scaffolding protein gephyrin, which in turn is targeted to inhibitory synapses by collybistin, a GDP-GTP exchange factor with neuroligin-dependent activity. We have shown that genetic defects in the human collybistin gene (ARHGEF9) give rise to a range of symptoms consistent with loss of several GABA-AR subtypes, including anxiety, seizures and intellectual disability. Consistent with this hypothesis, studies in knockout mice suggest that collybistin is dispensable for glycine receptor clustering but is required for clustering GABA-ARs containing the alpha1 and alpha2 subunits in the hippocampus and the basolateral amygdala. Loss of these GABA-AR subtypes is accompanied by increased anxiety and reduced spatial learning. Taken together, these findings strongly suggest that additional clustering factors are required for the synaptic localisation of other GABA-AR and GlyR subtypes. This project aims to examine the role of GEFs and gephyrin in inhibitory receptor clustering in health and disease. Our main objectives are to: i) Define the molecular nature of GABA-AR alpha1, alpha2 and alpha3 subunit interactions with gephyrin and collybistin; ii) Establish the role of collybistin-kinesin interactions in synaptic gephyrin clustering; iii) Characterise two novel GEFs (IQSEC2 and IQSEC3) that may be responsible for clustering GlyRs and other GABA-AR subtypes. This will be accomplished using a range of biochemical, molecular biology and confocal imaging techniques to provide key functional insights into the mechanisms underlying inhibitory GABA-AR and GlyR clustering in health and disease.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: MENTAL HEALTH;NEUROLOGICAL
Title: Human neurophysiological and neurochemical correlates of tinnitus: The GABA-gamma hypothesis
Funder: Medical Research Council

Abstract: The work aims to test the novel GABA-gamma hypothesis of tinnitus generation, which I have proposed. This postulates that gamma-band oscillations in tinnitus are driven by GABA-ergic neurons and do not give rise to the perception of tinnitus (as is currently believed), but actually constitute an inhibitory process which treatments should aim to enhance rather than suppress. Regardless of the hypothesis' correctness, this study aims to characterise cortical mechanisms underlying tinnitus in neurophysiological, focusing on gamma oscillations, and neurochemical, focusing on GABA, terms that have not yet been addressed. Cortical GABA, especially, has never been measured in the context of tinnitus. The techniques used are magnetoencephalography (MEG), from which source reconstructions in auditory cortex and other brain regions are made, and magnetic resonance spectroscopy (MRS) to measure auditory cortex GABA concentration. 12 patients and 12 controls are required for each modality. Group comparisons are made between tinnitus and control groups, and also a correlational analysis within the tinnitus groups between each measure and current tinnitus intensity. MEG is performed on two occasions per patient to provide within-subject measures of changes in tinnitus intensity, and patients' responses to sounds of varying unpleasantness are measured to probe mechanisms behind hyperacusis and the affective components of tinnitus. The results will have implications for multiple fields of tinnitus research, and for the wider study of perception and gamma oscillations. We particularly aim to produce a model that will translate into the in-vitro study of tinnitus-related oscillations and its use to test pharmacological therapies. Early and direct collaboration is planned to this end with a local research group in Newcastle.


Research activity codes: 2.3 PSYCHOLOGICAL, SOCIAL AND ECONOMIC FACTORS;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: MENTAL HEALTH;NEUROLOGICAL
Title: The neuropathophysiology associated with Syngap mutations: further evidence for an mGluR5 signaling axis in ID/ASD
Funder: Medical Research Council

Abstract: SYNGAP is a key signalling enzyme that is highly abundant in the postsynaptic density where it regulates glutamate receptor signalling. De novo truncation mutations of a single copy of SYNGAP lead to autosomal dominant non-syndromic intellectual disability (NSID). A recent study of 155 cases of NSID showed that 6 (4%) had mutations in SYNGAP. If this prevalence is extrapolated to the entire population, mutations in SYNGAP may be amongst the most common causes of ID (for comparison fragile X syndrome (FXS) accounts for <1% of ID). Our proposal stems from the fact that there is a significant convergence in the pathophysiological consequences of genetic deletion of Fmr1 and a single copy of Syngap in mice - both show exaggerated and protein synthesis-independent mGluR5-induced LTD, both transgenic lines have increased locomotor activity and show impaired spatial and associative learning. Developmentally, SynGAP and FMRP show a similar time-course of expression and both mutants show reduced cellular segregation without altering the whisker pattern of thalamocortical axons in somatosensory cortex. Furthermore, both show alterations in dendritic spines. Taken together, these findings have led us to hypothesize that SynGAP, like fragile X mental retardation protein (FMRP), is part of the mGluR5 axis of ID and phenotypes associated with the loss of SynGAP will be rescued by reducing mGluR5 signalling - as they are in mouse models of FXS. To address this hypothesis we will utilise the experimental strength of two brain regions, the hippocampus and the primary somatosensory cortex. Both brain regions have been extensively studied in Fmr1-/y mice. The former has provided the prototypical phenotypes associated with the loss of FMRP. The latter has provided essential insight into the developmental role of FMRP and provides an excellent system to elucidate the pathophysiology of genetic mutations form synapse to circuit.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: MENTAL HEALTH;NEUROLOGICAL
Title: Inequalities in access to good quality care in dementia in the UK
Funder: The Dunhill Medical Trust

Abstract: People with dementia have high rates of mental and physical ill-health. In a small study, we found people with dementia from more deprived backgrounds were less likely to receive drugs to help with symptoms We aim to carry out the first large, comprehensive study to investigate whether there are inequalities in the mental and physical healthcare people with dementia receive in the UK. We will use the THIN database of 11 million people (>20,000 with a dementia diagnosis), the largest epidemiological dataset for dementia. This is nationally representative, including 562 General practices. We will investigate socioeconomic, regional, rural-urban, age and gender variation in use of anti-dementia drugs, psychoactive drugs, primary care consultations (surgery and home visits) and preventative care including blood pressure, weight/body mass index monitoring and influenza vaccination in people with dementia. We will investigate how relationships between socio-demographic factors and dementia care received may have changed over time


Research activity codes: 8.1 ORGANISATION AND DELIVERY OF SERVICES
Health categories: MENTAL HEALTH;NEUROLOGICAL
Title: Genetic, neurological and cognitive determinants of success and failure in learning a first language.
Funder: Wellcome Trust

Abstract: Overarching question: What are the origins and functional significance of cerebral lateralization for language? Subsidiary questions: Can lateralization for different aspects of language be dissociated? How does atypical cerebral lateralization relate to language impairment? Is cerebral lateralization significantly heritable?


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;1.2 PSYCHOLOGICAL AND SOCIOECONOMIC PROCESSES
Health categories: MENTAL HEALTH;NEUROLOGICAL