NIHRDataInsights/HRCSData huggingface dataset:
Title: Neurotransmitters in Opiate and Alcohol Addiction
Funder: Medical Research Council

Abstract: This program of research tackles the brain mechanisms underpinning two of the most prevalent and costly addictions in the UK, those to opioids (heroin) and to alcohol. Using complementary techniques of brain imaging with PET tracers and challenge tests with neurotransmitter-targeted drugs we will build on the findings of our previous work to explore further the role of the dopaminergic system with two of its key modulators, GABA and opioid. PET studies of the dopaminergic system in addiction have had an immense influence on our understanding and we now have the tools to similarly comprehensively investigate GABA and opioid systems To explore if significant findings are of general relevance to addiction rather than being a consequence of prior drug/alcohol use, key experiments will be made in the behavioural addiction of gambling. Specifically we shall explore the following theories: 1. using the first alpha5 subtype-selective GABA-A tracer 11C-Ro154513 (we developed, validated and demonstrated lower levels in alcohol and heroin addicts in key areas involved in addiction eg nucleus accumbens), we shall explore if similar reductions are found in pathological gambling addiction. We shall test the hypothesis that GABA-ergic function is dysregulated in heroin and alcohol addiction by exploiting the fact that 11C-Ro15 4513 is sensitive to changing endogenous GABA levels and by using challenge tests and monitor subjective and objective (EEG, saccadic eye movements) outcomes with the GABA reuptake blocker, tiagabine and GABA-B agonist, baclofen. 2. using the mu selective agonist PET tracer 11C-carfentanil to test the theory that increased endogenous opioids are involved in mediating pleasurable effects of alcohol and are evident in response to salient cues in alcohol, heroin addiction and pathological gambling. We shall test the hypothesis that there is reduced endogenous opioid reserve in alcoholism. We will test the theory that mu opiate receptors are implicated in impulsivity in these addicts. 3. using the DRD2/3 selective dopamine PET tracer 11C-PHNO, with a selective DRD3 antagonist, we will determine whether the dopamine DRD3 receptor levels are increased in heroin addiction as well as in alcohol addiction. Our results will help characterize the brain mechanisms of addiction and so further underpin the evidence base for its being, at least in part, a brain disorder. Our programme will lead to a better understanding of how current treatments work and will assist in the development of new ones.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: MENTAL HEALTH
Title: Neural mechanisms and treatment of compulsive drug seeking habits and relapse in cocaine and alcohol addiction
Funder: Medical Research Council

Abstract: Several inter-related themes in the proposed research programme test hypotheses concerning: (i) Extending our actions-to-habits-to-compulsive drug-seeking hypothesis from stimulant drugs to alcohol. (ii) Investigating the neural mechanisms underlying alcohol seeking habits and the transition to alcohol seeking. This extension is in part motivated by the burgeoning problem of alcohol abuse and will specifically test hypotheses that the acquisition of alcohol seeking habits and compulsion as well as the vulnerability to lose control over alcohol seeking, share common, or depend upon different, neural mechanisms to those engaged during transitions to compulsive cocaine seeking. (iii) Examining serotonergic and limbic-cortical-striatal mechanisms implicated in compulsive cocaine-seeking, including experiments on microPET imaging of a presynaptic 5-HT marker. (iv) Analysing further the limbic cortical control over the functional links between the ventral and dorsal striatum, via serial dopaminergic connectivity with the midbrain, in the establishment of drug seeking habits. (v) Investigating whether individual differences in prefrontal cortical function, as well as impulsivity and anxiety, are vulnerability characteristics (possibly endophenotypes) for loss of control over different addictive drugs. (vi) Investigating potential novel treatments of addiction based on existing drugs used in the treatment of other disorders, but translated to our enhanced understanding of the neural mechanisms of drug seeking, compulsion and relapse. These potential treatments test hypotheses that different treatments may be effective at different stages of the addiction cycle and also whether the same drugs are effective in decreasing drug seeking and relapse across different drug classes. (vii) Continuing our research on drug memory reconsolidation, testing hypotheses concerning fundamental neural mechanisms underlying the destabilisation and restablisation of retrieved memories and the potential for disrupting them. The case has been made for disruption of memory reconsolidation as a treatment for drug addiction and other neuropsychiatric disorders characterised by aberrantly strong and intrusive memories, including post-traumatic stress disorder where there has already been treatment success. (viii) Finally, we propose an experimental medicine study with abstinence-seeking, alcohol-dependent volunteers to test the hypothesis based upon our experimental data that the ?-blocker propranolol, given at the retrieval of alcohol memories elicited by the presence of alcohol-associated stimuli and scripts, will subsequently reduce the impact of those stimuli on subjective craving and its physiological correlates, as well decrease relapse to drinking.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;6.1 PHARMACEUTICALS
Health categories: MENTAL HEALTH
Title: Reward and empathy in autism
Funder: Medical Research Council

Abstract: Autism Spectrum Conditions (ASC) are a set of neurodevelopmental conditions marked by deficits in empathy, i.e. the ability to understand other peoples mental states and emotions and respond appropriately to them. The causes for this deficit in empathy is poorly understood. One model proposes that people with ASC do not empathise with social stimuli because they do not find them rewarding. An alternative model proposes that the lack of reward in response to social stimuli is, in fact, a consequence of the lack of empathy. In order to test these two models, it is imperative to clarify the normative relationship between empathy and reward. The proposed research will examine this relationship in a sample of typical adults, and a sample of adults with ASC, using facial Electromyography (EMG) and functional MRI (fMRI). This will be achieved through the following three experimental aims: 1) To test if varying the reward value associated with specific social stimuli (e.g. faces) leads to increased facial mimicry, a biomarker of empathy. Different neutral faces will be paired with high/low reward values in an implicit conditioned learning paradigm. This will then be followed by passive observation of emotion expressions of the conditioned stimuli identities, while a) facial muscular activity (using EMG) and b) brain activity (using fMRI) will be recorded from participants. This will test whether automatic mimicry, as measured by the activity of a) congruent facial muscles, and b) brain regions involved in empathy (e.g. Inferior Frontal Gyrus), vary as a function of the reward value of social stimuli. 2) To test if mimicking certain faces makes them more rewarding to participants. Participants will be asked to mimic or simply observe a set of faces presented in the first part of the experiment. In the second part they will freely view emotion expressions of these faces, while brain activity will be recorded using fMRI. This will test if neural regions involved in reward processing (e.g. ventral striatum) are more active for mimicked vs nonmimicked faces. 3) Finally, experiments 1) and 2) will be repeated in a set of adults with ASC, to test which of the two models described earlier holds true for this group. These studies will shed new light on the causal pathways and neural mechanisms underlying the abnormal social behaviour in ASC. This knowledge stands to inform and enhance the development of therapies for ASC, that rely on various forms of reward conditioning.


Research activity codes: 2.3 PSYCHOLOGICAL, SOCIAL AND ECONOMIC FACTORS;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: MENTAL HEALTH
Title: The neural basis of gambling cognitions: relevance for vulnerability and treatment of gambling addiction
Funder: Medical Research Council

Abstract: Pathological Gambling is a debilitating and poorly understood condition that is known to have several core similarities with drug addiction. The study team represents a collaboration between cognitive neuroscientists and addiction researchers at the University of Cambridge, Imperial College London and the University of Oxford, and the National Problem Gambling Clinic in the Central and North West London NHS Trust. The clinic is a unique NHS facility for patients with gambling problems, and the proposed work will build upon a current MRC grant to characterise Pathological Gamblers attending the clinic using cognitive and brain pharmacology probes. The proposed work is driven by a cognitive formulation of Pathological Gambling, which proposes that distorted styles of thinking about recent outcomes (e.g. the ?Gambler?s Fallacy?), and inappropriate appraisals of skill (the ?Illusion of Control?), cause gamblers to over-estimate their chances of winning. Two tasks will be used to elicit gambling distortions during functional Magnetic Resonance Imaging (fMRI), in order to visualise and quantify brain responses in reward-related circuitry during the gambling process. One task resembles a slot machine, and detects brain responses to unpredictable wins and ?near-misses?. The second task, to be developed in year 1 of the grant, will elicit biased processing of recent outcomes, in the form of the ?Gambler?s Fallacy? and the ?Hot Hand Belief?. Building on our recent research, we will determine the relevance of these tasks to Pathological Gambling, by comparing brain responses in Pathological Gamblers and healthy controls. By employing a substance misuse control group (individuals with alcohol dependence), we will examine whether these distortions are specific to Pathological Gambling or generalise across the addictions. We will establish the relevance of these distortions to the vulnerability to Pathological Gambling, by studying a fourth group of unaffected biological siblings of Pathological Gamblers. Finally, we will establish the relevance to treatment by assessing the modulation of brain responses in Pathological Gamblers by the opiate antagonist naltrexone, the best-validated pharmacotherapy for Pathological Gambling at the current time.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;6.1 PHARMACEUTICALS
Health categories: MENTAL HEALTH
Title: Genetic and environmental causes of psychotic experiences: A twin cohort study
Funder: Medical Research Council

Abstract: The proposed study aims to uncover the genetic and environmental aetiology of psychotic experiences in late adolescence. The project will employ the classic twin design, as well as genetic association analyses. During the proposed project, called the Longitudinal Experiences And Perceptions study (LEAP), 4000 monozygotic and dizygotic twin pairs from the MRC-funded Twins Early Development Study (TEDS) will be studied. TEDS is a large UK-based cohort of twins that is representative of the general population and that has been assessed longitudinally since childhood. The twins, who will be 15-18-years-old at the start of the project, will be assessed on psychotic experiences over three years. In the first two years, self- and parent-report assessments of paranoia, hallucinations, grandiosity, cognitive disorganization, anhedonia and negative symptoms will be conducted using a detailed battery of dimensional measures. Twin model-fitting will be conducted to estimate the degree of genetic and environmental influences on psychotic experiences in the general population (Aim 1), and to address to what degree different types of psychotic experiences, such as paranoia and hallucinations, share overlapping genetic and environmental causes (Aim 2). The study will also test the degree to which psychotic experiences share overlapping genetic and environmental causes with other types of psychopathology, such as depression and anxiety (Aim 3). Repeated assessments will be used to reveal to what extent causal influences on psychotic experiences are stable across adolescence (Aim 4). A gene-environment correlation approach will determine whether ?environments?, such as life events, drug use, and harsh parental discipline, share genetic influences with psychotic experiences (Aim 5). In the final year of the project, we will conduct clinical interviews on twins who show persistent high levels of psychotic experiences. We will test whether psychotic symptoms characteristic of individuals at ultra high risk for psychosis share the same causes as milder psychotic experiences in adolescents. In the only non-twin design analysis, genome-wide significant genes previously associated with psychosis will be tested for their association with dimensional psychotic experiences (Aim 6). The proposed project aims to characterise for the first time the aetiology of psychotic experiences in adolescence. It is hoped that by understanding the causes of psychotic experiences in 15- to 18-year-olds this knowledge can inform the development of early interventions. The long-term goal is to alter the paths of vulnerable individuals for the better by reducing their risk of having psychotic experiences.


Research activity codes: 2.3 PSYCHOLOGICAL, SOCIAL AND ECONOMIC FACTORS;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: MENTAL HEALTH
Title: Cognitive and social processes in the pathway to psychosis
Funder: Medical Research Council

Abstract: There is a high incidence of seemingly benign psychotic symptoms, such as hearing voices, in the general population, in accordance with the continuum view of psychosis. Cognitive models of psychosis propose that interpretations (?appraisals?) of these experiences are key to determining the transition from anomalous experience to psychotic symptom. Our pilot data show that psychotic patients are more likely to think their experiences are caused by someone else (?personalising? appraisals), and less likely to have ?normalising? or ?psychological? appraisals (eg that they are part of the normal range of human experience), than individuals displaying psychotic-like experiences with a diagnosed mental illness. However, few studies have investigated appraisals in controlled experimental studies, or the psychosocial factors associated with maladaptive appraisals: rather, they are based on interviews asking individuals to reflect on their own, intermingled experiences and appraisals, or on factors related to the presence of psychotic experiences, but not their appraisals. Two studies are proposed to bridge this gap. The first will compare appraisals in healthy individuals with those experiencing psychotic-like anomalies with and without ?need for care? on experimental tasks inducing anomalous experiences. The second will investigate which psychosocial vulnerabilities proposed by cognitive models are related to pathological appraisals. Our central research question is this: do specific interpretations (i.e., ?appraisals?) of psychotic-like experiences differentiate individuals with clinical psychosis from those with benign anomalous experiences, as postulated by recent cognitive models of psychosis? Secondly, which psychosocial and cognitive risk factors identified by cognitive models are related to maladaptive appraisals of anomalous experiences?


Research activity codes: 2.3 PSYCHOLOGICAL, SOCIAL AND ECONOMIC FACTORS
Health categories: MENTAL HEALTH
Title: Predicting drug response in schizophrenia: are clinical & cognitive tests a cost-effective alternative to neuroimaging?
Funder: Medical Research Council

Abstract: Although antipsychotic drugs are effective in the treatment of schizophrenia, the response to medication varies considerably from one patient to another, both in terms of therapeutic and adverse effects, and is unpredictable. As a result, finding the most suitable antipsychotic for a given patient often involves a trial-and-error approach which prolongs patient suffering and increases health care costs. There is therefore an urgent need for a better understanding of how we can best predict response to treatment in a given patient. Neuroimaging measures may be useful in predicting antipsychotic response, but scanning is a relatively expensive investigation that is not routinely used in clinical practice. Demographic, clinical and cognitive measures may provide a more practical, cost-effective alternative, but their predictive value at an individual level has yet to be tested. The aim of the present project is to examine how to best predict the response to antipsychotic medication in a given patient with first episode schizophrenia. We will compare three classes of predictors: (i) structural MRI scans; (ii) demographic and psychopathological measures which are routinely acquired in a clinical setting; (iii) cognitive measures which are not part of a routine clinical assessment, but could be acquired at relatively little extra cost. Two hundred patients with first episode schizophrenia will undergo a structural Magnetic Resonance Imaging (MRI) scan and receive a comprehensive demographic, clinical and cognitive assessment. All of them will be given the same antipsychotic (amisulpride) and will be clinically assessed over a period of 4 weeks; this will allow us to examine treatment response, both in terms of symptom remission and side-effects. We will then use Support Vector Machine to investigate the value of pre-treatment neuroanatomical, demographic, clinical and cognitive information for predicting treatment response. Our main hypothesis is that the combination of demographic, psychopathological and cognitive data will provide comparable predictive power to neuroimaging data. If so, the former would represent a practical, cost-effective alternative to brain scans. The results will have direct implications for clinical practice and their translational implementation will be greatly facilitated by King s Health Partners, a recently formed Academic Health Science Centre. The project will provide excellent value for money to the MRC as the costs of subject recruitment and data acquisition are already covered by an ongoing project.


Research activity codes: 4.2 EVALUATION OF MARKERS AND TECHNOLOGIES;6.1 PHARMACEUTICALS
Health categories: MENTAL HEALTH
Title: Low coverage sequencing for the detection and analysis of genomic structural variants in schizophrenia
Funder: Medical Research Council

Abstract: Schizophrenia is a devastating disorder characterised by paranoid delusions and auditory hallucinations. The outcome is generally poor with profound social and economic consequences. Current medication is limited,has distressing side effects and generally fails to ameliorate negative symptoms such as lack of emotion, poverty of speech and motivation. There is clear evidence for a role for genetics in the aetiology of schizophrenia and meta-analyses of large genome wide association studies have begun to identify genes and pathways potentially important for schizophrenia. The same studies have provided evidence for the role of rare variation in the form of large chromosomal deletions and duplications as risk factors for schizophrenia. We propose to employ low coverage whole genome sequencing to detect structural variants in a large cohort of schizophrenic patients with extensive genetic, clinical and endophenotypic information drawn from the Wellcome Trust Case Control Consortium 2 study of Endophenotypes in Psychosis. We will correlate high confidence and verified rare structural variants with liability to schizophrenia using comparable control data from the UK10K project and we plan to correlate structural variant burden with selected quantitative brain structural, neurophysiological and cognitive data in these patients and their relatives. For rare structural variants showing nominal association with schizophrenia supported by segregation patterns within families and/or additional evidence, we will seek to replicate our findings in large independent disease cohorts. Whole genome sequencing is able to detect structural variants (such as inversions) missed by array based approaches and has the potential to localise breakpoints at the nucleotide level. New approaches using similar low coverage whole genome sequencing data have begun to target the ?non-accessible genome?, that portion of the genome characterised by low copy repetitive sequences but which contains highly duplicated gene families of potential neurobiological importance. In addition the family based nature of our sample and the rich endophenotype information available is unique. Our approach is also distinct from and complementary to exome sequencing projects such as the UK10K project managed by our collaborators at the Sanger centre (http://www.uk10k.org/).


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: MENTAL HEALTH
Title: Development Clinical Studies - fMRI-based neurofeedback as a treatment tool for depression
Funder: Medical Research Council

Abstract: Depression is the second most common illness in primary health care and disrupts the everyday functioning of over 100 million people worldwide. Depression is a severe mood disorder that is characterised by clinical features such as loss of interest and pleasure in previously enjoyable activities, cognitive and emotional impairment, psychomotor retardation, and disturbances in sleep and appetite. 20-40% of all patients do not benefit from traditional treatment methods such as psychotherapy or anti-depressant medication. This project will investigate a potential new treatment method: functional magnetic resonance imaging (fMRI)-based neurofeedback. In this method people undergo fMRI-scanning and receive continuously updated feedback about the activity level in a certain brain area, which they use to learn to control their own brain activity. It has previously been shown that chronic pain patients experienced considerably less pain after exercising control over a brain area involved in pain processing. In our project feedback from a region involved in positive emotion processing will be provided so that depressed patients can learn to regulate their emotional state. A pilot study of this method from our group has shown that depressed patients are both able to regulate their emotion network and experience significant improvements in mood. The present project will investigate this new method of neurofeedback of emotion regions (NFE) in a larger group of patients and compare its effects with those of a control intervention with ?sham? feedback [neurofeedback control: NFC]). We expect that the active neurofeedback procedure will produce clinical benefits, as measured with clinical scales, self-rating questionnaires and quality of life scales, which are superior to those produced by the sham intervention. The whole-brain neuroimaging data that will be acquired as part of the project will elucidate the brain mechanisms through which this intervention operates. The project will also include the development of a framework for a future trial to assess the cost effectiveness of the intervention and strategies for its implementation in clinical practice.


Research activity codes: 6.6 PSYCHOLOGICAL AND BEHAVIOURAL
Health categories: MENTAL HEALTH