NIHRDataInsights/HRCSData huggingface dataset:
Title: Beyond dopamine receptors in Schizophrenia - evaluating the role of Phosphodiesterase 10A in disease and treatment using PET imaging.
Funder: Medical Research Council

Abstract: In the 60 years since the first antipsychotic was discovered, the reduction of neurotransmission through the D2 receptor have been the only proven therapeutic mechanism for schizophrenia. However, this mechanism is successful in only 2/3 of all patients, and even in these it is limited by the lack of efficacy against negative and cognitive symptoms. Therefore, there is an urgent need to identify new molecular targets that can address the various symptom dimensions of schizophrenia. Altering neurotransmitter signaling by targeting intracellular mechanisms is a recent approach in the development of novel therapeutic agents. An attractive intracelular target is the phosphodiesterase 10A (PDE10A), a class of enzymes that co-segregates with dopamine D1 and D2 receptors and degrades the intracellular second messengers triggered by dopamine signalling. Interestingly, in preclinical studies PDE10A inhibitors shows a broad-based 'antipsychotic-like' effect, with efficacy against positive as well as cognitive and negative symptoms. These has encouraged several pharmaceutical companies pursuing PDE10A antipsychotic program. However, despite preclinical data and pharmaceutical interest, the status of PDE10A in patients with schizophrenia is unknown as until now there were no reliable methods to assess this in humans. We have recently developed a selective PET radiotracer - [11C]-IMA107 - and used it to image the PDE10A system in healthy controls, showing an effective binding potential and a good signal-to-noise. Our project will use this novel radiotracer to examine if there is an alteration in PDE10A expression in unmedicated schizophrenia patients when compared to healthy volunteers, and if treatment with antipsychotic medication lead to changes in PDE10A expression. This study will provide the first evidence of PDE10 involvement in Schizophrenia and will provide a rational platform and specific guidance for the ongoing pharmaceutical and therapeutic development.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;5.1 PHARMACEUTICALS
Health categories: MENTAL HEALTH
Title: Prenatal and infancy origins of biological and social-cognitive processes in disruptive behaviour problems in children aged 7 - 9 years.
Funder: Medical Research Council

Abstract: The study aims to identify pathways from pregnancy and infancy to mechanisms underpinning aggressive and disruptive behaviours in children. These behaviours commonly start in early childhood, are difficult to treat, and are associated with personality and other psychiatric disorders in adult life. We have hypothesised three pathways characterised by high behavioural and physiological reactivity, low reactivity, and a switch from high to low reactivity, each with distinctive child vulnerabilities and environmental contributions. The aim of the study is to show how biological and social-cognitive and emotional processes in 7 year olds have their origins in these pathways, representing distinct mechanisms in the maintenance of aggressive and disruptive behaviours as evidenced in prediction of those behaviours to age 9 years. We will assess children and parents followed from pregnancy to 4.5 years. Using a two phase design, a general population 'extensive' sample has been followed with brief measures (1286 recruited, 68% retained, 6 assessment points), alongside a stratified 'intensive' subsample (316 recruited, 81% retained, 12 assessment points) studied with a combination of biological, observational and experimental measures rarely found in epidemiological studies. Published findings from this study have provided support for the pathways. At age 7 years we will assess around 300 intensive sample children and their parents with a comprehensive range of measures, many of which we have used before. In addition we will assess children's behavioural and physiological reactions to a social exclusion game, to emotionally arousing pictures, and to scenes depicting children in situations likely to be associated with fear, sadness or anger. We will assess the 'extensive' group of around 840 children with briefer, but related measures. At ages 7 and 9 years we will obtain standardized information about the children's behaviours and emotions from parents, teachers, and children.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;2.3 PSYCHOLOGICAL, SOCIAL AND ECONOMIC FACTORS
Health categories: MENTAL HEALTH
Title: Pathways to psychosis: Investigating environmental, cognitive and genetic mechanisms underlying development of psychotic experiences in young adults
Funder: Medical Research Council

Abstract: This proposal aims to examine the development of psychotic experiences, at-risk mental states and psychotic disorder from childhood through to early adulthood in the general population, and to investigate social-environmental, cognitive and genetic mechanisms underlying this. We will measure psychotic outcomes in participants of the population-based ALSPAC birth cohort when they are age 24-25, a critical period as this is the peak age of incidence for schizophrenia. ALSPAC has a wealth of detailed information already available on the cohort participants including data from semi-structured interviews of psychotic experiences during childhood and adolescence that will allow us to track these experiences during development and study their impact on functioning and transition into psychotic disorder during early adulthood. We will also examine the effects of social adversity and cannabis use on trajectories of psychotic experiences, and study how deficits in cognitive processes relating to perception and inference relate both to psychotic experiences in early adulthood, and to earlier experiences of social adversity and cannabis use. This work can inform us as to how these environmental exposures lead to development of psychotic phenomena, and help identify targets for interventions. We will also examine how genetic risk for schizophrenia, indexed by a composite measure of common alleles conferring increased risk of this disorder, is manifest phenotypically during development from childhood through early adulthood in a population-based sample, including expression of risk through cognitive processes relating to perception and inference. To address these questions we will use appropriate statistical techniques including structural equation models and mixture modeling techniques to examine changes in repeated measures over time, marginal structural models to deal with time-varying confounding, and multiple imputation to address issues relating to attrition.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;2.3 PSYCHOLOGICAL, SOCIAL AND ECONOMIC FACTORS;2.4 SURVEILLANCE AND DISTRIBUTION
Health categories: MENTAL HEALTH
Title: Reconsolidation and Memory Interference Toolkit (REMIT): Identifying how to destabilise and overwrite maladaptive alcohol memories.
Funder: Medical Research Council

Abstract: The brief period of memory instability during memory reconsolidation represents the first viable approach for directly weakening or overwriting the enduring Maladaptive Motivational Memories (MMMs) that underlie addiction in humans. Pharmacological approaches (e.g. NMDAR blockade) while memories are unstable may prevent restabilisation, thus weakening or erasing MMMs. Behavioural approaches (e.g. presenting new associations) while memories are unstable may update MMMs with adaptive information. These approaches may overcome the major limitations of current addiction treatments, namely the lack of long-term efficacy. However, memory destabilisation does not occur upon every retrieval, leading to the identification of boundary conditions that determine the fate of retrieved memories. The presence of a prediction error at retrieval and the structure of the reminder are critical in destabilising memories, but are currently hard to measure naturalistically. Therefore, despite clinical potential of modifying MMMs via reconsolidation, it is essential to begin with proof-of-principle investigations in humans and identify robust procedures for causing and measuring memory destabilisation in alcohol or drug-using populations. Here, we will examine procedures for destabilising maladaptive alcohol memories in harmful drinkers by manipulating prediction errors during retrieval. We will probe destabilisation with the NMDAR antagonist ketamine, and behaviourally using disgust counter-conditioning during the putative 'reconsolidation window'. Effects of these interventions on harmful drinking will be assessed. Psychophysiological, behavioural and subjective measures during retrieval will be used to derive an independent 'neurobehavioural signature' of destabilisation that can be used in future studies for intervention development.


Research activity codes: 5.1 PHARMACEUTICALS;5.6 PSYCHOLOGICAL AND BEHAVIOURAL
Health categories: MENTAL HEALTH
Title: Do appetitive gut hormones attenuate core behavioural components of addiction to prevent relapse in nicotine and alcohol addiction?
Funder: Medical Research Council

Abstract: Smoking and alcohol abuse and dependence are major health burdens, with significant economic, social and societal impacts. Relapse after abstinence in substance and drug dependence is common and current treatments are limited. Novel therapeutic targets are needed to aid abstinence and prevent relapse through actions on the interacting core behavioural components in addiction. Recent pre-clinical studies in rodents have demonstrated that circulating appetitive gut hormones, such as acyl ghrelin and glucagon-like peptide-1 (GLP-1), which vary with nutritional state, can influence not only appetite and food reward but also consumption of alcohol, nicotine and other drugs of abuse, through brain mesocorticolimbic dopaminergic and opioid systems. It is currently unknown whether these gut hormones can influence such behaviours in human addiction. Furthermore weight gain after smoking cessation, through increases in appetite and food reward, may attenuate health benefits, hinder attempts at abstinence and promote relapse. Building on an established platform of functional MRI and behavioural tasks, the objectives of this Gut Hormones in ADDiction (GHADD) proof-of-concept experimental medicine study are to investigate, in abstaining adults with nicotine and alcohol dependence and healthy controls, whether: (i) suppressing/antagonising the appetitive gut hormone acyl ghrelin attenuates core behavioural components of addiction, including reward sensitivity to cigarettes, alcohol and money, impulsivity/compulsivity including delay discounting and inhibitory motor responses, negative emotional salience; (ii) administration of the anorexigenic gut hormone GLP-1 attenuates core behavioural components of addiction; (iii) suppressing/antagonising acyl ghrelin or administering GLP-1 attenuates reward-hedonic responses to high-calorie foods and appetite. This will provide evidence of the utility of and mechanisms behind these novel therapeutic targets for addiction.


Research activity codes: 5.1 PHARMACEUTICALS
Health categories: MENTAL HEALTH
Title: Biological mechanisms underlying the onset and outcome of cannabis-associated psychosis.
Funder: Medical Research Council

Abstract: The aetiology of schizophrenia involves both genetic vulnerability and several environmental risk factors, of which the most preventable is cannabis use. It is therefore important to establish a) the patterns of exposure to cannabis that are especially likely to provoke psychosis, and b) who is especially vulnerable. My study will build on a large epidemiological EU-FP7 study of first onset psychosis for which I designed the interview regarding drug use. I will examine: a) GWAS and cannabis use data from 2,000 cases and 2,000 controls; b) baseline peripheral blood EWAS data from a subset of cases and controls (N=800) with additional genome-wide RNA data (N=600). The London participants will be followed up at a mean of 5 years and re-sampled for longitudinal EWAS (N=600) and RNA(N=400)profiling analyses. My aims are to: 1. Develop a simple method of assessing patterns of cannabis use which best predict the development of a cannabis-associated psychosis, and so enable identification of those individuals most at risk of a) psychosis onset and b) poor outcome. 2. Establish the proportion of psychosis cases attributable to cannabis use in 5 European countries. 3. Using the GWAs data, to determine the effectiveness of combining Schizophrenia Polygenic Risk scores, including Pathway-informed ones, with information on cannabis use in order to predict a)risk of developing a psychotic disorder; b)clinical and functional outcome 5 years following onset of psychosis. 4. Carry out longitudinal-multidimensional GWAS-guided analyses of a)EWAS and b)genome-wide RNA expression data to identify pathways involved in cannabis-associated psychosis. My work will establish a)those patterns of cannabis use which best predict psychosis, b)easily accessible biological markers of susceptibility to the effect of cannabis in provoking the onset and persistence of psychosis. It will be useful in developing better tailored preventative strategies and may indicate new drug targets.


Research activity codes: 4.2 EVALUATION OF MARKERS AND TECHNOLOGIES
Health categories: MENTAL HEALTH
Title: Brain Associates of Parent Training on Antisocial Behaviour in Children
Funder: Medical Research Council

Abstract: Studies have robustly reported that children with CP have anatomical and functional differences in a well-defined network of regions. These include the 1) amygdala (AMG), 2) anterior cingulate (ACC), ventromedial prefrontal (vmPFC) and temporal cortices, and 3) caudate nucleus and 4) their structural and functional connections. However, no-one has determined whether these differences predict 'risk' and 'resilience' to the persistence of antisocial behaviour, or if they are 'fixed' or 'reversible'. The proposed study will address these key questions by using 'state of the art' imaging techniques to compare brain anatomy, function and 'connectivity' in young CP boys with non-CP controls. We wish to determine if differences in the anatomy and function of AMG, ACC, vmPFC, temporal cortex, caudate, and associated structures in CP boys: a) predict behavioural alteration; and/or b) alter in parallel with reduced antisocial behaviour. To achieve this we will analyse the brain in CP children before and after a well-validated parent training intervention, which has been demonstrated to effectively reduce antisocial behaviour. We will complete a longitudinal follow-up study of 90 boys (aged 5-7 years old) with CP with data gathered at two time points: before (T1), and on completion (T2) of a standard 14-week IY group-parenting programme. Imaging and behavioural measures will take place at T1 and T2. A group of 90 non-CD control boys (aged 5-7 years old) will also undergo imaging, and behavioural measurements, at T1 and T2 to allow quantification of change in patients as a function of intervention while controlling for test-retest effects. If successful, our work will increase our current understanding into the association between macroscopic brain differences in children with CP and antisocial behaviour. This will assist in directing future research into the molecular mechanisms that modulate this relationship.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: MENTAL HEALTH
Title: The reconsolidation of instrumental cocaine-seeking memories
Funder: Medical Research Council

Abstract: Memories can be destabilised by their retrieval. This allows those memories to be diminished by disrupting the reconsolidation process that restabilises the memory. We have previously demonstrated that the reconsolidation of pavlovian cue-reward memories can be disrupted by systemic NMDA receptor antagonism in both sucrose- and cocaine-seeking settings. More recently, we have shown that instrumental lever press-food memories can be diminished by disrupting memory reconsolidation, similarly by systemic NMDA receptor antagonism. In this project, we will test the hypothesis that disruption of instrumental memory reconsolidation (through both NMDA receptor antagonism) is an effective method of reducing relapse to cocaine-seeking behaviour. In rats self-administering cocaine intravenously, we will destabilise the instrumental cocaine memory in conjunction with either systemic injections of MK-801 or local intracerebral infusions of protein synthesis inhibitors, and test the impact of these treatments upon subsequent cue-induced, stress-induced and cocaine-induced cocaine seeking. We will test the hypothesis that disrupting instrumental memory reconsolidation is more effective than impairing pavlovian memory reconsolidation for reducing stress-induced and cocaine-induced relapse. Moreover, combined targeting of both instrumental and pavlovian memories is hypothesised to be most effective at reducing cue-induced cocaine seeking. The expected results will greatly inform our understanding of the basic mechanisms of instrumental memory reconsolidation. As experimental impairment of appetitive memory reconsolidation is suggested to be a potential therapeutic strategy for maladaptive cue-induced reward seeking in drug addiction and some forms of obesity, such basic scientific understanding is an essential prerequisite for any future translational application.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;5.1 PHARMACEUTICALS
Health categories: MENTAL HEALTH
Title: Identification of the higher-order cognitive mechanisms by which prefrontal and anterior cingulate circuits regulate negative emotion
Funder: Medical Research Council

Abstract: The dysregulation of negative emotions, in particular fear and anxiety, is a prominent symptom of a variety of neuropsychiatric disorders including Anxiety, Depression, Obsessive-Compulsive disorder and Schizophrenia. Unfortunately, the range of potential treatments is relatively restricted and the level of treatment success, highly variable. This is due in part to the diverse set of cognitive control processes including predictability, controllability, contextual control and selective attention that regulate our emotions. Fundamental understanding of the neural mechanisms that underlie these cognitive control processes and their interaction in regulating our emotions, is however, lacking. Clinical studies reveal altered activity within prefrontal and cingulate regions associated with emotion dysregulation. Thus, by fractionating and mapping the component control processes that constitute the top-down regulatory mechanisms of prefrontal and anterior cingulate cortices we will provide the necessary new insights into the varied causes of anxiety. This will allow for more precise diagnostics and hence therapeutic approaches. Thus this proposal will determine the specific involvement of primate subgenual and dorsal anterior cingulate cortex, anterior orbitofrontal cortex and ventrolateral prefrontal cortex in these control processes that regulate negative emotion. Specifically, we will investigate the effects of temporary inactivations of these regions on expression and extinction of conditioned fear, sustained anxiety and cost-benefit analysis of reward and punishment in decision-making. Interactions within the PFC and with downstream structures e.g. amygdala, BNST will be studied using crossed disconnections and viral vectors incorporating Designer Receptors Exclusively Activated by Designer Drugs into target brain pathways. Changes in activity of functional circuits following targeted prefrontal lesions will be investigated using 18F-Fluorodeoxyglucose microPET.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: MENTAL HEALTH
Title: Abubakar;Pwani;Adolescent Executive Functioning Association with Scholastic Outcomes, Risk Taking Behavior and Medical Adherence in the Context of HIV
Funder: Medical Research Council

Abstract: At least 2.3 million children in Africa are infected by HIV most of whom were vertically infected. A further 60 million are exposed to HIV, mainly by exposure to HIV in utero. With the increased availability of anti-retrovirals in Africa, a significant number of children vertically infected with HIV are surviving to adolescence and may increase their exposure through risky behaviour. There is a growing concern about the outcomes of HIV positive adolescents, particularly in the following key areas: poor educational outcomes, lack adherence to prescribed medication and involvement in risky sexual and drug-related behavior. Little is known of the impact of HIV on neuropsychological function of infected and exposed but uninfected adolescents in Africa. I am specifically interested in executive functioning (EF) since this function influences social, emotional and behavioral outcomes. The objective of this study is to investigate the impact of HIV exposure (both infection and exposed uninfected) in children who have survived to early adolescence on their EF and its association to scholastic outcomes, medical adherence and risk taking behaviour. A total of 552 (184 HIV infected, 184 HIV exposed uninfected and 184 unexposed randomly selected from an established database) adolescents aged 10-14 years shall be recruited. A longitudinal study design will be used. Each adolescent will be assessed thrice, within a 24 months period with 12 months between each assessment. Measures of EF (working memory, cognitive flexibility and inhibitory control) and functional abilities will be administered. Additionally scholastic abilities, adaptive behavior, risk taking behavior and adherence to medication will be assessed. Biomedical and psychosocial data (home environment, parent-adolescent relationship and socio-economic status) will be collected. Data will be analysed with multivariate analysis of covariance and other advanced statistical approaches using structural equation modelling.


Research activity codes: 5.6 PSYCHOLOGICAL AND BEHAVIOURAL
Health categories: MENTAL HEALTH