NIHRDataInsights/HRCSData huggingface dataset:
Title: Salience network and coordination of brain circuits in schizophrenia.
Funder: Wellcome Trust

Abstract: Schizophrenia is a serious psychiatric disorder that often affects individuals during adolescence resulting in significant academic, occupational, social and relationship disruptions. Various brain abnormalities have been observed in schizophrenia. Brain has a complex, high density wiring pattern (networks). Some networks help us to concentrate on our internal world (self-reflection); others enable interactions with our surroundings. A particular network (Salience Network) acts as a switch b etween internal and external orientations. Abnormalities in this switching process can contribute to disorganisation and distortion of reality (delusions and hallucinations). Currently available antipsychotic drugs influence a chemical transmitter called dopamine, offering partial but not full relief. Targeting other transmitters (e.g. glutamate) could help tackle many disabling symptoms that contribute to poor quality of life in schizophrenia. Glutamate is also crucial for efficient wiring in our brain. We will use brain scans to study whether the switching action of Salience Network is impaired in patients. We will also investigate the link between inefficient wiring and glutamate in this region. This research should increase our understanding of the brain connections in schizophrenia. If successful, these connectivity measures could provide us a tool to assess treatment response and eventually to evaluate new drugs in the future.


Research activity codes: 2.3 PSYCHOLOGICAL, SOCIAL AND ECONOMIC FACTORS
Health categories: MENTAL HEALTH
Title: The transition from unconscious to conscious visual perception in the intact and damaged human brain.
Funder: Wellcome Trust

Abstract: Natural visual scenes present us with a wealth of information, but we only process some of this consciously. This project will investigate why some stimuli are more likely to gain access to consciousness than others, with particular emphasis on the impact that emotionally relevant or familiar information has on access to consciousness. Experiments will rely on healthy human volunteers as well as volunteers with degenerative brain disease or disorders of face recognition. I will use ambiguous v isual displays that cause frequent changes in the observer's conscious experience, together with face images that can carry varying amounts of emotionally relevant or familiar information. How these interactions are processed in the brain will be investigated using functional brain imaging to measure brain activity, as well as during disruption of normal brain function caused by administration of magnetic pulses or medications. This work will shed light on how emotion and familiarity interact wi th consciousness in the normal brain, and how these interactions are disrupted in neurological disease. Understanding these mechanisms will be relevant not just to the specific situations studied, but will also be applicable to a wider range of diseases of visual recognition and emotional function.


Research activity codes: 1.2 PSYCHOLOGICAL AND SOCIOECONOMIC PROCESSES
Health categories: MENTAL HEALTH
Title: Making memories in the mushroom bodies.
Funder: Wellcome Trust

Abstract: Repeating things we wish to memorize often helps us recall them later. Likewise, in our brains, repetitive input to nerve cell contacts leads to the formation of memories. Our memories contribute to, and their use can be controlled by, our motivation. I aim to understand the changes at nerve cell contacts that occur when memories are formed and retrieved. To study memory formation, I will use an organism with complex behaviour and a relatively small brain: the fruit fly. Two distinct sets of neurons involved in memory formation have recently been identified in the fly. I will test the hypothesis that communication between these populations underlies memory formation. I will combine state of the art techniques, which allow me to visualize the structure and function of these neuronal populations independently. First I will study where these neurons form contacts, and how these connections change during memory formation. Next, I will ask how the memory circuitry is modified by an anim al's motivational state, as the neurons responsible for motivational control have also recently been identified in the fly. This will link neuronal transmission directly to an animal's behavior.


Research activity codes: 1.2 PSYCHOLOGICAL AND SOCIOECONOMIC PROCESSES
Health categories: MENTAL HEALTH
Title: Computational and biological foundations of metacognition.
Funder: Wellcome Trust

Abstract: Awareness of our own thoughts, feelings and decisions is fundamental to the sense of self, and is an important component of consciousness. This type of reflective thought is known as metacognition, or thinking about thinking. Metacognitive deficits have been implicated in a range of dysfunctional behaviours, from failure to comply with medication in schizophrenia to lack of insight awareness of one's condition in neurological conditions. Little is known about the biological mechanisms underpin ning metacognition. Recent work has successfully characterised how particular regions of the brain control decision-making. Using a combination of mathematical models and brain imaging, I will build on this research to characterise how the human brain encodes information about its own decision process. To test whether this activity is necessary for metacognition, I will then disrupt particular areas of the prefrontal cortex through a combination of safe non-invasive techniques in humans and a li mited number of animal lesion studies. Together these data will illuminate how the brain carries out metacognition, and why metacognitive function may be affected following brain damage or disorder.


Research activity codes: 1.2 PSYCHOLOGICAL AND SOCIOECONOMIC PROCESSES
Health categories: MENTAL HEALTH
Title: The Neural Basis of Goal Directed Behaviour.
Funder: Wellcome Trust

Abstract: One way we choose between possible actions is to work out their likely consequences and evaluate how good these outcomes are. This project aims to help understand how the likely outcomes of potential actions are represented in the brain and contribute to decision making. Habitual mechanisms also contribute to decision making; On the way to work I do not think at each junction where the roads lead but instead act on habit. Separating the contribution of habitual and prediction based mecha nisms to value signals in the brain is difficult as both mechanisms often give the same answer; I would go the same way to work if I thought at each junction where the roads led. However, these mechanisms give different evaluations when the value of an outcome changes; For example, on Saturday morning I may find myself halfway to work before I realize I intended to go somewhere else entirely. We will measure how neural activity during decisions changes when outcomes are revalued, in region s of the brains of rodents that are critical for goal directed behaviour. This and other conceptually similar experiments will let us identify computations in the brain which enable outcome predictions to contribute to decision making.


Research activity codes: 1.2 PSYCHOLOGICAL AND SOCIOECONOMIC PROCESSES
Health categories: MENTAL HEALTH
Title: The developmental basis of resting state functional networks, their anatomical and neuropsychological correlates in infants and toddlers, and their involvement in learning disorders.
Funder: Wellcome Trust

Abstract: The way in which different parts of the brain interact contribute to human abilities like language and memory. As we develop and learn different parts of the brain begin to interact preferentially with each other. How this happens and how it relates to brain growth and development is unknown, so in this fellowship I will investigate these networks in healthy children, trying to assess important milestones of network development. To explore how these networks are changed in learning disorders, I will investigate whether they are changed in two common childhood developmental learning disabilities: dyslexia and dyscalculia. These disorders cause the sufferer to have problems with reading and mathematics (respectively) and may be related to changes in how these networks develop.


Research activity codes: 2.3 PSYCHOLOGICAL, SOCIAL AND ECONOMIC FACTORS
Health categories: MENTAL HEALTH
Title: Using Mendelian Randomisation to clarify the causal relationship between tobacco use and other substance use.
Funder: Wellcome Trust

Abstract: Conduct research into the relationship between tobacco and alcohol in both adolescents and adults using standard epidemiological methods along with Mendelian Randomisation. Also, to conduct research into the relationship between cannabis use and other substance use in adolescents using ALSPAC hair sample data.


Research activity codes: 2.3 PSYCHOLOGICAL, SOCIAL AND ECONOMIC FACTORS;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: MENTAL HEALTH
Title: Statistical methods for analysis of low coverage sequences from highly phenotyped individuals with major depression
Funder: Wellcome Trust

Abstract: This project will focus on analysing data from the CONVERGE consortium. Particular challenges that will require some thought are the low coverage of the data (~1x average coverage), the size of the data set (12000 samples) and the large number of phenotypes collected for each sample. It is expected that in the course of the analysis new methods for haplotype imputation of 1x coverage data and rare variant testing with multiple phenotypes will be developed. Specifically, a pipeline to impute genotypes using beagle will be completed, SHAPEIT will be rewritten to deal efficiently with 1x coverage data and an alternate statistical analysis of the CONVERGE genotype and phenotype data using Bayesian methods accounting for multiple phenotypes will be performed


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;2.5 RESEARCH DESIGN AND METHODOLOGIES (AETIOLOGY)
Health categories: MENTAL HEALTH
Title: Time and decision-making: a study of fluctuating mental capacity and anticipatory decision-making.
Funder: Wellcome Trust

Abstract: The law governing decision-making for people with mental illness has undergone significant changes recently and the implications are still being worked through. A parallel change is increasing philosophical interest in the area. I am proposing a clinically-based study that investigates contemporary problems for the law and psychiatry and associated philosophical problems of personal identity. The investigation will centre on cases of bipolar affective disorder (also known as manic depression ), cases of people who are in delirium in a general hospital and cases of people attending A&E departments in emotional crisis who have self-harmed. My goals are to advance understanding of problems related to fluctuating capacity (mental states which profoundly change) and anticipatory decision-making (also known as advanced directives ) in healthcare. This project is part of a interdisciplinary research strategy in psychiatry/law/philosophy that I seek to develop which will interface with polic y.


Research activity codes: 7.3 MANAGEMENT AND DECISION MAKING
Health categories: MENTAL HEALTH
Title: Refining the computer based system for Avatar Therapy and evaluating its effectiveness in a randomised controlled trial conducted by an independent research team in london
Funder: Wellcome Trust

Abstract: Schizophrenia is a world-wide illness. The introduction of antipsychotic drugs in the 1950s improved the course of the illness for many patients and increased the rate of discharge from psychiatric hospitals. However one in three patients fail to respond to the medication. Many of these are tormented by voices' abusing them and/or commanding them to harm themselves and others. A novel computer-based therapy has been developed, enabling the patient to create a Science 9 talking image of the person they believe is persecuting them (an avatar). A therapist encourages the patient to enter into a dialogue with the avatar and to stand up to it and order it to go away and leave them alone. The therapist modifies the avatar's responses so that it stops abusing the patient and agrees to the patient's demands. A course of up to 7 sessions of 30 minutes each resulted in a considerable reduction in the frequency of the voices' and the degree of distress caused, and a consequent improvement in the quality of life. This striking result needs to be replicated by an independent team of researchers, involving a larger sample of patients, before making this therapy available to all who might need it.


Research activity codes: 6.6 PSYCHOLOGICAL AND BEHAVIOURAL;5.6 PSYCHOLOGICAL AND BEHAVIOURAL
Health categories: MENTAL HEALTH
Title: Learning and sleep: A network dynamic approach.
Funder: Wellcome Trust

Abstract: Learning disability affects 2-3% of the UK population. People with learning disability (PWLD) cope with many educational and lifestyle problems and improving quality of life for PWLD is a national aim. However, efforts to improve cognitive performance have largely been unsuccessful. This may be due to the broad range of primary pathologies, diverse patterns of comorbidity and the large number of PWLD where primary cause is unknown. It is unlikely, from the above clinical picture, that a sing le primary cause of learning disability exists. However, many causes may well converge on a single core cortical process vital to learning and memory at a higher level - the organisation of the activity of nerve cells in the brain during sleep. Sleep is vital for memory consolidation and many disorders associated with PWLD also associate with disrupted electrical brain activity during sleep. Using an array of computational and experimental models, coupled with direct, detailed observations of br ain electrical activity in PWLD the proposed work aims to uncover the mechanisms underlying consolidation of neuronal substrates of memory. Furthermore we aim to test predictions from this mechanistic work in a clinical setting in an attempt to generate new, evidence-based approaches to minimising cognitive deficit.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: MENTAL HEALTH
Title: Sleep and Circadian Neuroscience Institute (SCNi)
Funder: Wellcome Trust

Abstract: Sleep is a highly complex state arising from an interaction between multiple brain regions, neurotransmitter pathways and hormones, none of which are exclusive to the generation of sleep. This complexity makes sleep very vulnerable to disruption. Small changes in brain function can have a big impact on sleep, and disrupted sleep leads to health problems ranging across increased stress hormones, heart disease, weight abnormalities, reduced immunity, increased risk of cancer, and emotional and cog nitive problems Many mental illnesses are commonly associated with highly disturbed sleep, but the importance of this disruption is frequently overlooked. Significantly, many of the health problems that arise from disturbed sleep are also found in mental illness, but these problems are rarely linked back to sleep abnormalities. Our new data suggests that parallel brain pathways might be affected in mental illness and sleep disturbance. This application aims to bring together neuroscient ists and psychiatrists to understand these common connections. Our aim is to use this understanding to develop new approaches to correct abnormal sleep and so improve the broader health problems and quality of life for patients with mental illness.


Research activity codes: 2.6 RESOURCES AND INFRASTRUCTURE (AETIOLOGY);6.9 RESOURCES AND INFRASTRUCTURE (TREATMENT EVALUATION);5.9 RESOURCES AND INFRASTRUCTURE (TREATMENT DEVELOPMENT);7.4 RESOURCES AND INFRASTRUCTURE (DISEASE MANAGEMENT)
Health categories: MENTAL HEALTH
Title: Optogenetic dissection and treatment of diseased neural circuitry in schizophrenia.
Funder: Wellcome Trust

Abstract: Schizophrenia is a complex brain disease, which, starting from an early age, affects approximately 1% of the population, with enormous social and economic consequences. While positive symptoms, such as hallucinations and delusions, often respond to drugs, the negative and cognitive symptoms, such as apathy and poverty of thought, mostly do not. One likely reason for such a lack of treatment options is that alterations in the brain circuits underlying the symptoms experienced by patients, are poo rly understood, not least because of a shortage of suitable research methods. Here, I propose to use a novel strategy (optogenetics), that allows to express light-responsive ion channels in genetically specified types of nerve cells, which render these and only these cells subject to optical remote control. When the expressing cells are optically activated or inhibited in a behaving transgenic mouse, the improvement of schizophrenia-related symptoms, which these partly mice reproduce, can the n be quantified in behavioural tests. Screening a wide range of cells in that manner causal links between certain cells or neural circuits and schizophrenia-related behaviour are directly revealed, yielding cellular targets for the treatment of schizophrenia, either pharmacologically, by cell- or gene-therapy or by a similar optogenetic intervention.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;5.2 CELLULAR AND GENE THERAPIES
Health categories: MENTAL HEALTH
Title: Fitness to Plead: A Conceptual and Empirical Study.
Funder: Wellcome Trust

Abstract: The right to a fair trial is a fundamental human right. For a trial to be fairthe defendant must be fit to plead . This is currently defined by the Pritchard Test which considers whether the defendant can understand the charges, enter a plea, instruct a lawyer and follow proceedings. When someone is unfit to plead, often due to mental disorder, they are not tried but diverted from the BME CLIN FORM 01/11 Research project criminal justice system e.g. sent to hospital for treatment. The Prichard test dates back to 1836 and is badly in need of reform. It is notup-to-date with modern legal or psychiatric thinking and there are concerns that many vulnerable people are tried unfairly. In 2010, the Law Commission criticised the test and outlined a new approach. They argued that the test should focus on the defendant's decision-making capacity,and called for a standardised psychiatric instrument to support legal professionals in determining unfitness to plead. The aim of this project is to answer that call. It undertakes a three-stage study of fitness to plead in the Criminal Justice System, with the aim of validating and refining an existing video-based assessment instrument, and providing guidance for professionals in determiningfitness to plead.


Research activity codes: 7.3 MANAGEMENT AND DECISION MAKING
Health categories: MENTAL HEALTH
Title: The impact of emotion on decision making
Funder: Wellcome Trust

Abstract: An animal model will be used to study how cognitive affective bias alters judgement of ambiguous information in order to investigate the neural mechanisms that underlie cognitive changes that occur in mood disorders. A rodent operant affective tone discrimination task (ATDT} will be combined with lesion studies, affective state manipulations, pharmacological challenges, and optogenetic manipulation of specific neural pathways to identify brain regions and neurotransmitters that underpin cognitive affective bias. A cognitive modelling approach will be used to detect more subtle changes in cognitive decision making processes by applying the Ratcliff diffusion model to behavioural data, and using component analysis to extract salient information from model parameters. The key goals of this research are to: investigate the relative contributions of reward and aversion processing in the manifestation of cognitive affective bias using differently valanced versions of the ATDT identify brain areas and neurochemical systems that are important in modifying cognitive judgement bias in response to altering affective state, and examine the effect of antidepressant drugs on this process extract more specific information about aspects of cognitive bias processing that are altered by affective state through mathematical modelling of the decision making process.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: MENTAL HEALTH
Title: The functions of postsynaptic density implicated in psychiatric disorders in associative memory formation.
Funder: Wellcome Trust

Abstract: Variants in the genes coding for postsynaptic density (PSD) proteins Homer1, DLG1 and DLG2 have been linked to psychopathology and schizophrenia. These proteins are functionally linked to postsynaptic glutamate receptors such asAMPA, NMDA and metabotropic glutamate receptors, and are thought to be key mediators of synaptic plasticity. Since associative learning is dependent on NMDA receptor-mediated synaptic plasticity and is impaired in several psychiatric disorders, we aim to determine the roles that PSD proteins including Homer1, DLG1 and DLG2 have in associative learning, with a view to shedding light on their part in psychiatric pathology To do this, we will a) use in situ hybridization to measure the expression of Homer1 transcription variants, Homer1a and Ania-3, DLG1 and DLG2 during key components of associative learning, including memory consolidation, recall andinhibitory learning, through the fear conditioning of adult rats. b) Use antisense­mediated knockdown of these PSD proteins before consolidation, recall and inhibitory learning, as well as knockout rodent models, to evaluate their function in processes required for associative learning. c) Administer mGiu and AMPA receptor-acting drugs to transgenic animals to investigate gene dependence in associative learning processes.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: MENTAL HEALTH
Title: The role of MlR137 and its targets in associative learning.
Funder: Wellcome Trust

Abstract: We aim to determine the role of miR-137 and its targets in associative learning by investigating gene expression during contextual fear conditioning, a rodent model of hippocampal associative plasticity. Allelic variation in MIR137 and a sub-set of its confirmed targets has been associatedwith increased risk of schizophrenia in the latest GWAS. The aim is to focus on the regulation of calcium channel genes by miR-137, including the confirmedtarget CACNA1C, as well as other putative targets found to be associated withschizophrenia. Research would progress to explore the effects of local inhibition of calcium channels in the hippocampus as well as characterisation of a transgenic CACNA1C knock-out model. We further aim to confirm or refute predicted targets of miR-137 that may advance our understanding of this potential pathological pathway contributing to the etiology of schizophrenia.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: MENTAL HEALTH
Title: Using machine learning algorithms to analyse complex genetic data in sub-phenotypes of psychiatric disorders.
Funder: Wellcome Trust

Abstract: The main objective for my PhD will be to apply machine learning methods and algorithms to complex genetic data in an attempt to identify features that characterise different sub­ phenotypes in psychiatric disorders. This will not only look for the contribution of individual genes, but also at possible biological gene-gene interactions and functional pathways. The use of non-parametric machine learning techniques will allow us to go beyond classical statistical (parametric) methods and search for more complex underlying patterns in the data.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: MENTAL HEALTH