NIHRDataInsights/HRCSData huggingface dataset:
Title: Perception and decision making in schizophrenia
Funder: Medical Research Council

Abstract: I propose to examine the cortical basis of perception and decision making in schizophrenia using the Bayesian formulation of predictive models. The key positive psychotic symptoms of schizophrenia, such as hallucinations and delusions, can be viewed as an abnormality in the normal process of developing beliefs about the state of the world, on the basis of incoming perceptual information. Bayesian statistics enable the modelling of this decision making; combining the weight of experience, or prior knowledge, with new perceptual experiences. I will define an appropriate Bayesian model based on psychophysical data from my experiments and examine the underlying neural infrastructure using functional magnetic resonance imaging. The experiments will examine different aspects of perceptual processing and decision making that underpin this mechanism and the role of both symptomatic status, and relevant pharmacological manipulation, through dopaminergic perturbation, upon the parameters in the model. The working hypothesis is that the usual combination of evidence and prior knowledge (in the Bayesian framework) is altered in schizophrenia, either by a) an incorrect distribution or parameterisation of prior knowledge or b) the mechanism that combines this prior with current sensory input. This hypothesis predicts that new evidence (stimuli) or existing evidence (the prior knowledge) are incorrectly assimilated in schizophrenia, leading to faulty perception and decision making.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: MENTAL HEALTH
Title: A multi-site study of the genetics of child anxiety and predictors of treatment response
Funder: Medical Research Council

Abstract: Background. Anxiety disorders are highly debilitating illnesses. They affect 5-10% of children at any time and show considerable continuity into adulthood. They are influenced by genetic and environmental factors, but the specific genes involved remain largely unknown. The most common treatment is cognitive-behaviour therapy (CBT), which leads to an improvement in around 60% of cases, thus 40% remain anxious. Younger girls tend to do well following CBT, whereas adolescents and males respond less well. Furthermore, those with more severe symptoms and a history of parental anxiety/depression, also respond poorly indicating that treatment response may be partially under genetic influence. Objectives. The two key goals are: first, to identify associations between specific candidate genes and childhood anxiety disorder; second, to consider predictors of treatment response including age, sex, symptom severity, parental psychopathology and specific genetic markers. Design. We will collect DNA from around 2500 children with clinically diagnosed anxiety, the majority of whom are undergoing cognitive-behaviour therapy. Controls consist of 4,000 children from a longitudinal study based at the SGDP Centre. DNA will be extracted from cheek swab samples, and selected markers will be genotyped. Methodology. Anxiety will be assessed before and after treatment and at the 6-month follow-up. Assessment will be made dichotomously (i.e. diagnosis), and by use of questionnaire scales with both the child and parent as reporter. Furthermore, clinicians will complete a standardised improvement scale following treatment. Analyses. Associations between genetic markers and anxiety will be considered first for all anxiety disorders as a single group, and then for each anxiety disorder sub-type individually. Comorbidity with depression and other covariates (e.g. sex) will also be considered. Associations will also be tested with respect to variation in symptom levels (i.e. is there a dose-response for the association such that two copies of a risk allele lead to even higher levels of anxiety). Associations with treatment response will be considered in terms of (a) presence/absence of disorder, (b) change in symptom level and (c) clinical rating of improvement. Again, important covariates such as age, sex, symptoms severity, and parental mental health will also be considered. Scientific and medical opportunities. This programme of research provides the opportunity to collect a unique dataset that will have implications for understanding both the development and treatment of child anxiety. The possibility of predicting treatment outcomes and thus tailoring treatments for children with anxiety disorders is highly valuable in both financial and human cost terms


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: MENTAL HEALTH
Title: Structural brain correlates of an operationally defined high-risk phenotype for schizophrenia: a population based study
Funder: Medical Research Council

Abstract: Schizophrenia affects around 1% of the population in their lifetime but its neurobiological basis is poorly understood. One potential risk factor is psychosis-like symptoms occurring in adolescence. These symptoms are much more common in the population than clinically identified psychosis. We propose to characterise the neural substrate of an operationally defined high risk (HR) phenotype for the later development of schizophrenia based on such symptoms using structural magnetic resonance imaging (MRI) and diffusion tensor imaging (DTI). Previous work using MRI in prodromal patients and those at high genetic risk for schizophrenia has shown subtle abnormalities in grey and white matter. However, such studies are subject to several confounding factors, such as treatment effects, selection bias and limits to generalizability, and the results lack consistency. We plan to build on ongoing work identifying high-risk mental states in late adolescence (17? years) in the Avon Longitudinal Study of Parents and Children (ALSPAC). ALSPAC is a population based cohort and has a wealth of relevant data critically relevant to this proposal including cognitive testing during childhood and stored DNA and the cohort members will be at a crucial stage of adolescent development just prior to the sharp in incidence of schizophrenia in early adulthood. We propose to select at random 125 young people with and 125 without psychosis-like symptoms from the ALSPAC cohort and invite them to undergo MRI. We will carry out voxel-based morphometry and DTI to examine differences between the groups in terms of regional grey matter density/volume and the integrity of white matter. We will also map myelin water fraction from analysis of quantitative relaxometry data which will provide deeper insights into the nature of the white matter changes. We predict that significant changes will be detected in the HR group with symptoms, which will reflect abnormal neurodevelopment (synaptic pruning) - particularly in frontal and medial temporal lobe grey matter and white matter tracts connecting them - and hence a vulnerability to develop a clinical psychotic illness. We will also test the hypothesis and changes in hippocampus do not occur in HR subjects but only in patients with established schizophrenia. In addition, we will be in a position to explore the association between these findings and genetic variation. This project has the potential to deliver important advances in our understanding of the biological basis of schizophrenia and related psychotic disorders, and perhaps to inform the development of therapeutic interventions.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: MENTAL HEALTH
Title: Obtaining valid and reliable estimates of treatment effectiveness from evidence synthesis of psychiatric trials.
Funder: Medical Research Council

Abstract: Background: Establishing the most effective treatment(s) for depression is a population health priority. By 2020 depression will be the second highest cause of disease worldwide, with the cost to the NHS around #9 billion. Evidence synthesis using randomised controlled trials (RCTs) underpins Health Technology Assessment (HTA) and clinical guidelines. However, empirical evidence suggests psychiatric RCTs are susceptible to bias, raising questions about reliability and validity of effect estimates from psychiatric HTA. Two recent methodological developments make it possible to control for bias in psychiatric HTA; Bias-adjusted meta-analysis and Mixed Treatment Comparisons. Aims & Objectives: to examine the suitability of MTC for psychiatric RCTs and assess how biases in evidence synthesis of psychiatric RCTs can be controlled and mitigated to generate more precise, valid estimates of treatment effect. I will; 1. explore the benefits of bias-adjusted MTC compared to standard meta-analysis in the presence of quality-related biases and effect modifiers, 2. assess the effect of extending an MTC network of evidence for depression to include all relevant treatments and assess the ‘risk of bias‘ for each included RCT; 3. explore and compare the effects of bias adjustment on treatment effects estimates in the extended depression network of evidence, using approaches proposed by Turner, Welton and Dias. Design & Methodology: A review of NICE guidelines and Cochrane reviews will be conducted to identify and assemble psychiatric MTC networks of evidence. The networks inform a simulation study to examine the reliability of bias-adjustment, comparing effect estimates from meta-analysis, unadjusted MTC and bias-adjusted MTC in the presence of bias. The substantive part of the project extends an existing network of new-generation antidepressants for depression, including additional treatments and assessing each RCT for bias using the Cochrane risk of bias tool. The extended network forms the basis for an empirical study to explore and compare the effects of bias-adjusted MTC on depression effect estimates, using three recently proposed bias-adjustment methods. Analyses use a Bayesian approach implemented in WinBUGS. Scientific Opportunities: Project outputs will generate validated, reliable treatment effect estimates and rankings for depression; inform a future grant proposal of bias-adjusted MTC for all depression treatments to identify the most effective treatment overall; evaluate the benefits of bias-adjusted MTC compared to meta-analysis in psychiatric HTA inform NICE‘s research agenda regarding the validity and reliability of MTC; identify whether the three MTC bias-adjustment methods can be combined into a single approach.


Research activity codes: 8.4 RESEARCH DESIGN AND METHODOLOGIES (HEALTH SERVICES)
Health categories: MENTAL HEALTH
Title: Development of Cognitive and Imaging Biomarkers Predicting Risk of Self-Blaming Bias and Recurrence in Major Depressio
Funder: Medical Research Council

Abstract: Importance/Opportunities Depressive disorders are the leading cause of disability. One prominent reason for this is the recurrence of major depressive (MD) episodes. The neuroanatomical basis of vulnerability to recurrence is unknown. Using fMRI to identify the neuroanatomical basis of cognitive abnormalities is the most promising approach to bridge the gap between clinical and molecular-genetic manifestations of MD. Such imaging biomarkers enable the development of refined disease models and stratification of diagnostic groups. Background Current neuroanatomical models explain MD by abnormalities in neural circuits underlying negative emotions. The unresolved conundrum, however, is to explain why excessive negative feelings occur when MD patients blame themselves (manifesting as feeling guilt or self-worthlessness), but not when blaming others. This self-blaming bias cannot be accounted for by models of MD that rely solely on overall increases in negative emotions. Preliminary data In an fMRI pilot study in patients with a history of MD (a group with strongly increased vulnerability for MD recurrence), but fully remitted symptoms, we showed that functional decoupling in a specific brain network during self-blaming feelings distinguishes this group from controls. This decoupling was selective for self-blame but did not occur when blaming others and therefore explains vulnerability to self-blaming bias. Aims/Objectives Despite these encouraging results, it is unknown whether these fMRI abnormalities prospectively predict risk for MD recurrence. The principle aim of this project is to test this hypothesis. In addition, I will determine whether structural MRI measures, that have demonstrated potential predictive value in one previous study and a novel cognitive test measure can independently predict recurrence. Methodology Here, I propose two studies: 1) a case-control study to examine whether our pilot data can be reproduced in a larger group (N=57 patients with remitted MD vs. N=57 never-depressed controls); 2) a longitudinal study to investigate prediction of recurrence in unmedicated patients with fully remitted MD (N=120) within 14 months of clinical follow-up (3 visits) to test whether fMRI abnormalities have predictive value, independently of clinical predictors and in comparison with structural MRI and novel cognitive measures. Impact/Novelty Whereas previous research in MD has focused on imaging biomarkers of remission from the depressed state, this project will provide the first fMRI biomarker of recurrence. Without establishing the neuroanatomical traits conferring vulnerability to recurrence, as aimed for here, core pathophysiological aspects of MD will remain unexplained. If successful, this project will lead to improved prevention and development of novel treatments.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: MENTAL HEALTH
Title: Understanding and treating persecutory delusions: an interventionist-causal model approach
Funder: Medical Research Council

Abstract: Persecutory delusions are the most distressing delusion type, the most likely to be acted upon, and are a predictor of admission to psychiatric hospital. Existing treatments, pharmacological and psychological, are only partially effective. It is therefore urgent that we demonstrate the mechanisms underlying this important clinical experience in order to develop better treatments. Statisticians and philosophers of science, and now a number of psychologists and psychiatrists in relation to mental illness, are highlighting the need to adopt an ‘interventionist-causal‘ approach, illuminating causal inference by manipulating key factors. For instance, if paranoia builds upon negative cognitions about the self then altering such negative ideas will change paranoid thinking. The manipulations have the benefit of being readily incorporated into treatments. The objective of the new fellowship programme is to carry out a series of interventionist-causal studies of clinical and non-clinical paranoia, drawing upon the applicant‘s theoretical model, which can then be used to develop a better cognitive treatment. Because paranoid thought typically concerns others‘ behaviour, a key feature of the research will be the use throughout of virtual reality social environments. Four novel randomised controlled studies will be carried out testing causal roles in paranoia for anomalous experiences, cognitive interpretation, and affective processes. The role of the misinterpretation of anomalous experiences will first be tested by intravenous administration of delta-9-tetrahydrocannabinol (the active ingredient of cannabis). Included will be the first examination of the effects of cannabis on paranoia-related cognitive processing. The effect of visual perceptual anomalies will then be examined in a study that will enable virtual environments to be used as a learning tool. The theoretical model hypothesis that persecutory delusions are threat beliefs maintained by safety behaviours will be tested by repeated behavioural experiments in virtual reality, based on methods developed for anxiety disorders. A focused intervention for low self-esteem will be used to examine the effect on paranoia of decreasing negative ideas about the self. The culmination of the research will be a fifth study that provides an initial test of a new targeted modular treatment for persecutory delusions. The programme uniquely applies developments in theory, methodology, technology and treatment. A close interplay is made between theory, experiment, and treatment development. It will lead to: a much stronger theoretical understanding of persecutory delusions; new knowledge about the effects of cannabis; the first use of virtual reality to treat psychosis; and, importantly, a targeted treatment for persistent paranoia.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: MENTAL HEALTH
Title: Developmental Dyslexia: An Educational Neuroscience Approach
Funder: Medical Research Council

Abstract: Developmental dyslexia (DD) affects 7% of schoolchildren and presents a major obstacle to educational success. Children with DD have specific problems with reading and spelling that are not due to low intelligence, poor educational opportunities or overt sensory or neurological damage. Subtle sensory/neural problems are however likely. Here we adopt an educational neuroscience approach better to understand the potential sensory and neural causes of DD with the aim of identifying biomarkers for the early identification of children at risk, which would enable earlier remediation. We focus on understanding the mechanisms of atypical phonological development (the core feature of DD across different languages) at the neural, cognitive and sensory levels. To this end we propose a ?temporal sampling? framework based on prior MRC-funded work, intended to capture both the temporal properties of speech and the temporal properties of the oscillatory neural networks that are thought to sample the auditory input. We test this framework using behavioural, physiological and neuroimaging approaches. This innovative perspective integrates adult neuroimaging and contemporary speech science data with infancy and child phonological data, bringing together literatures that have to date not overlapped. Our proposal is that auditory neural and sensory processes work differently in dyslexic brains, with impaired envelope perception and possibly enhanced perception of temporal fine structure. Behaviourally this may lead to impaired syllable level mechanisms and (possibly) over-specified segment-level mechanisms This results developmentally in speech-based representations that work for language but not for literacy. Complementary studies of cognitive and linguistic features provide information for theory-driven educational interventions, which are also informed by current work with typically-developing 4- and 5-year-olds. This multi-level research strategy should identify a range of neural and cognitive biomarkers of risk for reading/ language disorders, as well as identify factors relevant to designing educational interventions. The proposal tests the temporal sampling framework with 112 children with and without dyslexia who have been followed since age 7. Now aged 13-15 years on average, the participants will be tested with EEG and fNIRS imaging, and MEG once they are aged 16 years. The imaging work examines the integrity of phase locking to lower modulation frequencies, which our psychoacoustic data on amplitude envelope onset (rise time) suggest is impaired across languages. The physiology explores peripheral auditory neural mechanisms The behavioural work tests the predicted associated impairments in syllable stress, prosodic perception and musical rhythm, seeking factors that can form the basis of remediation.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: MENTAL HEALTH
Title: GABA-A receptors in accumbens neural circuits underlying drug abuse: novel targets for treatment?
Funder: Medical Research Council

Abstract: GABAergic neurons are intimately involved in several brain systems that play decisive roles in development of addictions, but their particular importance has not hitherto been a focus of research. We have recently provided evidence of a role for the alpha2-subtype of GABA-A receptor in the function of accumbens motivational systems in mice, and demonstrated a genetic association between haplotypes of the gene encoding this subunit and human cocaine addiction (Dixon et al, PNAS, 2010). We will now study in non-addicted human volunteers whether such haplotypes give rise to biomarkers for addiction, and behavioural endophenotypes that may confer risk for development of addictive behaviours, particularly as a consequence of stressors. In parallel, we will use genetic manipulations of mouse genes encoding the alpha2, and other subtypes (alpha4,alpha5, and delta subtypes) of GABA-A receptor, and drugs specific to such subtypes, to study the consequences of such manipulation on the function of accumbal medium spiny neurons, and for behaviours known to model aspects of addiction-related behaviours in mice. We will thus develop methods for studying therapeutic effects in humans, as well as identify potential pharmacological and behavioural targets for future therapies.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: MENTAL HEALTH
Title: New drugs for addiction: focus on attenuating core behavioural components of heroin, cocaine and alcohol addiction
Funder: Medical Research Council

Abstract: Substance Use Disorders are of large and growing prevalence and carry substantial morbidity, mortality and public costs, yet pharmacotherapy is at an early stage of development. While social context, public health policy and psychological approaches are clearly relevant to development and treatment of addiction they are of both limited efficacy and specificity, underlining the need for pharmacotherapy. Despite the proven utility of some drug interventions for addiction [eg methadone, buprenorphine, naltrexone for heroin dependence and acamprosate and naltrexone for alcohol dependence] many patients do not respond. There are no proven pharmacotherapies for cocaine. There is a pressing need to develop novel pharmacotherapies acting across a broader range of components of addictive processes. To this end, there have been major advances in recent years in the understanding of the neurobiology of addiction which offers a new approach to identifying drug targets based on brain mechanisms Our cluster will use a new experimental medicine research ?platform? and work with new potential drug treatments provided in part by our industrial stakeholder GlaxoSmithKline [GSK]. This initial cluster application develops a platform to assess candidate brain systems underpinning relapse at molecular, network and behavioural levels by assessing three high-likelihood, theoretically critical, target mechanisms comprising: dopamine DRD3 receptors, for relapse prevention primarily by reducing cue-reactivity/craving and impulsivity; ?-opioid receptors, which mediate the reinforcing effects of opioids and are also implicated in impulsivity and hence relapse, especially under conditions of stress; and NK1 receptors, implicated in both stress and reward responses. These drugs will be assessed with novel psychological and fMRI paradigms in human alcohol, heroin and cocaine addicts and in parallel preclinical studies. The platform will then be available for the study of other candidate treatment approaches for addiction that may include for example orexin antagonists and appetite regulating peptides.


Research activity codes: 5.1 PHARMACEUTICALS;6.1 PHARMACEUTICALS
Health categories: MENTAL HEALTH