NIHRDataInsights/HRCSData huggingface dataset:
Title: Cognitive DeveLopment in the Urban Environment (The CLUE study)
Funder: Medical Research Council

Abstract: CLUE investigates if exposure to individual air pollutants, pollutant mixtures, and noise, either separately or in synergy, are associated with cognitive impairments in children. We also examine if cognitive deficits are associated with the induction of systemic oxidative stress and neuroinflammtion, and if these adverse responses are related to the pro-oxidant components of the urban airshed (transition metals, and oxidative gases). The study will make use of data that has been collected as part of the baseline, follow-up and personal monitoring of SCAMP. Personal monitoring involves detailed activity (GPS and activity diaries) and micro-environmental (fixed-site monitoring of noise levels, PM2.5, PM10, NO2, O3, particle number concentrations at home/school, indoors/outdoors) monitoring for 200 children (the investigative cohort) nested within the SCAMP cohort study of 6000 secondary school children in Greater London. These monitoring data will be used to validate, calibrate, and enhance the LHEM air pollution and TRANEX noise models to incorporate indoor environments and address previous exposure misclassification. We will conduct large scale epidemiological analysis on the SCAMP cohort examining cognitive and behavioural development o in relation to estimates of air pollution and noise at birth and through adolescence. We aim to advance mechanistic understanding of the link between traffic-related stressors and neurological impacts by relating biomarkers of exposure (metals) and response (oxidative stress, neuronal injury/inflammation) measured in urine and saliva (in samples already collected at 3 time points in the investigative cohort) to: i) measured/modelled air pollution and noise exposures and ii) cognitive performance and behavioural problems measured at baseline and longitudinally. Plausible mechanistic pathways for cognitive deficits identified through the epidemiological analysis will be supported by linked biomarker evidence.


Research activity codes: 2.4 SURVEILLANCE AND DISTRIBUTION
Health categories: MENTAL HEALTH
Title: The Triple A study (Adolescents with Anorexia and Autism): A search for biomarkers
Funder: Medical Research Council

Abstract: Current research suggests that cognitive and emotion processing difficulties along with autistic symptoms contribute to the maintenance and development of anorexia nervosa (AN). However, these findings are based on work conducted largely in adults with AN and despite the fact that the illness typically develops during adolescence and that illness duration is likely to moderate treatment resistance in AN due to the presence of neuroprogressive changes. Thus, further work is needed to document the neurocognitive profile of AN during the early stage of their illness. The proposed study aims to investigate neurobiological factors that may contribute to the development and maintenance of AN in children and adolescents first presenting for treatment using behavioural assessments and functional magnetic resonance imaging (fMRI). To achieve this aim we will investigate differences in the neural correlates of cognitive and emotional processing between three groups of young people aged 12-18 years, namely 40 patients with AN, 20 young people who have recovered from AN (recAN), and 40 age matched healthy controls (HC). Specifically, we will investigate differences in BOLD signal change during central coherence and emotional processing tasks using a 3T fMRI scanner. We will also explore correlates between resting state BOLD signal and performance on cognitive tasks assessing central coherence and cognitive flexibility conducted outside of the scanner. We will then examine how these differences in BOLD signal change correlate with presence of ASD symptoms as measured during a diagnostic interview in the AN and recAN groups. Finally, we will use supervised machine learning techniques to investigate BOLD signal patterns that predict the state of psychopathology as measured with a battery of self-report questionnaires and interviews at 6-month follow-up in the AN and recAN groups.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;4.2 EVALUATION OF MARKERS AND TECHNOLOGIES
Health categories: MENTAL HEALTH
Title: Early-onset depression: characterising development and identifying risks
Funder: Medical Research Council

Abstract: Major depressive disorder (MDD) is the most common mental illness and is the single leading cause of years lived with disability. Depression that begins early (by the early 20s) predicts particularly poor mental health and social outcomes and a chronic and relapsing course of symptoms over time. The strongest and most common risk factor for early-onset MDD is depression in a parent which increases the risk of depression in offspring by 3 to 4 fold. When depression arises in the offspring of depressed parents, it is likely to begin early and herald a malignant course of symptoms and impairment. Nevertheless, high-risk individuals vary considerably in their absolute level of risk. For preventive and early-identification strategies to be effective in reducing the burden of depression, it is important to understand how depression first develops, to characterise the antecedents of depression and to use this information to develop methods to rapidly and reliably predict who is at highest risk. That is what we aim to do in this proposal. Longitudinal data with repeated assessments of depressive symptomatology, hypothesised antecedents and risks enables us to characterise the early developmental trajectories of depression and its predictors. This proposal takes advantage of the largest existing prospective high-risk sample of the offspring of recurrently depressed parents. We will reassess individuals (4th assessment) in early adult life which is when the incidence of depression peaks. We will characterise the early trajectory of depressive symptoms between adolescence and early adult life in this group. We will identify the factors that predict a chronic long term trajectory of symptoms and early-onset major depressive disorder. We will develop and validate (in an independent sample) a risk prediction algorithm that can be used to quantify individual risk for early-onset depression.


Research activity codes: 2.3 PSYCHOLOGICAL, SOCIAL AND ECONOMIC FACTORS;7.3 MANAGEMENT AND DECISION MAKING
Health categories: MENTAL HEALTH
Title: Neurobiological underpinning of eating disorders: integrative biopsychosocial longitudinal analyses in adolescents
Funder: Medical Research Council

Abstract: This project aims to identify early biomarkers of eating disorders (EDs) by applying Big Data methods to the rich database derived from a representative population of adolescents and a clinical sample of emerging adults with an ED diagnosis. First, we will characterise trajectories of ED symptoms in IMAGEN, the largest and most comprehensively characterised longitudinal gene x neuroimaging cohort n=2000 male and female adolescents followed-up at ages 14, 16, 19 and 23 years. We will classify individuals based on their ED symptoms trajectories, using growth mixture models or generalised estimating equations to model the longitudinal course of disordered eating behaviours, including core ED symptoms, a continuous global index of eating pathology and BMI changes. Next, we will use machine learning procedures based on cross-validated regularised logistic regression combining neuroimaging, genomic and psychometric data modalities to identify correlates of EDs and select the features that best classify individuals who endorse ED symptoms along with those who endorse no ED symptoms at any time point. To identify predictors of ED symptoms, we will use age 14 data to compare individuals who developed ED symptoms over time (symptoms absent at age 14 but present at later ages), or those who recovered (symptoms present at age 14, not at later ages) to those who never developed symptoms. Finally, we will select the most predictive and easily applicable components of our comprehensive profile for validation in a clinical sample. This will be patients, aged 18-25 with a 1st episode of DSM-5 AN or BN (n = 50 /diagnosis), assessed through standardised protocols in a way identical to IMAGEN. This paradigmatic multimodal approach, in which neuroimaging may provide added value compared with the existing standard assessments, may yield potential application for early and differential ED diagnoses.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: MENTAL HEALTH
Title: The developmental role of metabolism, appetite and growth in eating disorders: exploring novel longitudinal risk pathways
Funder: Medical Research Council

Abstract: This study builds on novel preliminary data [from prospective data and genetic studies], suggesting that metabolism and growth might have a yet unexplored role in the development of eating disorders. We will use data prospectively collected from the Avon longitudinal Study of Parents and Children (ALSPAC); a longitudinal birth cohort of ~13,000 children enrolled before birth and followed up to age 25. We will use data collected on metabolism, anthropometry and eating throughout childhood, and data on eating disorders we collected [at 3 timepoints in adolescence] and we are currently collecting at age 24. We will test our hypotheses that metabolic profiles, and eating patterns in childhood differentially predict full and sub-threshold eating disorders in adolescence and young adulthood using longitudinal regression models. We will then explore: 1. whether genetic risk scores for Anorexia Nervosa and high BMI are associated with distinct metabolic profiles in mid childhood, growth throughout childhood and childhood under-eating, AN and AN behaviours in adolescence and young adulthood; 2. whether a genetic risk score for high BMI is associated with distinct metabolic profiles in mid childhood, growth throughout childhood, childhood over-eating and loss of control eating, and binge eating and/or purging behaviours and disorders. This project will be foundational in: 1. being the first to study metabolic and appetitive risk factors for eating disorders prospectively, whilst also exploring their underlying genetic structure; 2. leading to new insights into the pathophysiology of eating disorders; 3. helping clarify risk pathways that can then be integrated into a risk model to be tested in larger and more detailed clinical, register-based and population-based studies.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;2.4 SURVEILLANCE AND DISTRIBUTION
Health categories: MENTAL HEALTH
Title: Pathways to self-harm: Biological mechanisms and genetic contribution
Funder: Medical Research Council

Abstract: Self-harm is common in adolescence with community studies indicating a prevalence of between 13% and 18%. Self-harm is associated with a range of adverse outcomes, including an increased risk of suicide. Yet we know little about the aetiology of this behaviour. A history of early life adversity (ELA) is one of the strongest risk factors for self-harm. Long-term health conditions typically result from a complex interplay between social environment and biology. Our research will examine the role of three key biological mechanisms (inflammation, DNA methylation, and puberty (status and timing)) in the pathway between ELA and later self-harm. This work will advance knowledge of the aetiology of self-harm, and could lead to novel approaches for risk detection, treatment and prevention. Most existing studies have focused on suicide attempts yet only a third of adolescents have harmed themselves with suicidal intent. There is increasing interest in non-suicidal self-harm, however it is uncertain whether self-harm with and without suicidal intent are different clinical entities, or part of a continuum of risk. Research has begun to explore differences in psychosocial risk factors for these behaviours, but our understanding of potential differences in their genetic architecture is limited. This work will inform future research studies of self-harm. We propose investigating these key issues for the self-harm field in the ALSPAC cohort; an on-going study of over 13,000 children followed prospectively from birth into adulthood. Participants completed a detailed self-harm questionnaire at age 16 years (N= ~5,000, self-harm prevalence 18.8%). No other cohort has such detailed life-course phenotypic information, along with genetic, epigenetic, biological, and environmental data. To address our research questions we will use appropriate statistical techniques including structural equation models, Mendelian randomisation, polygenic score analysis, and genomic-REML analysis.


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: Understanding maladaptive reward memory in young people who binge eat: Application of novel insights from addiction
Funder: Medical Research Council

Abstract: Recent research has demonstrated technically and clinically tractable methods for behaviourally rewriting maladaptive memories in drug users via reconsolidation. However, no human studies on food memory reconsolidation in binge-eating exist. This is a significant oversight, as the striking theoretical, neurobiological and epidemiological overlap between binge eating disorder (BED) and substance use disorders (SUDs) suggests food-related maladaptive reward memories (MRMs) likely play a central role in aetiology and maintenance of BED. In two studies we will fill this gap in research and explore the role of food-related MRMs by interfering with their reconsolidation in young people who binge eat. Specifically, following a robust, prediction-error driven MRM retrieval (destabilisation) procedure, we will test two forms of adaptive learning (disgust-counterconditioning; CC and cognitive bias modification; CBM) associated with stopping bingeing in response to food cues. In two randomised controlled experiments we will determine whether food-related MRMs are overwritten after memory reactivation using a canonical 3-group design in each study - Grp 1) retrieval + CC or CBM, Grp 2) no retrieval + CC or CBM, Grp 3) retrieval + sham CC or CBM. This will allow us to assess the efficacy-enhancement of CC and CBM training when conducted during food-related MRM reconsolidation, controlling for the effects of simple memory reactivation. We predict larger and enduring reductions in cue-elicited food craving, approach, liking and attentional bias, with associated reductions in bingeing episodes and calorie-intake in Grp 1 of both studies. We will statistically compare the nature and magnitude of these changes following CC vs CBM. Confirmation of these predictions - which are based on solid theoretical and empirical foundations - will suggest a uniquely direct method for interfering with putatively causal MRMs in binge eating, with important implications for treating BED.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: MENTAL HEALTH
Title: Pain perception in looked after young people with self-harm
Funder: Medical Research Council

Abstract: Suicide is the second leading cause of death in adolescents and self-harm is the best predictor of death by suicide. Looked after young people (LAYP) have a lifetime prevalence of self-harm of 30-40%, 3-4 times greater than that in the general population. The aim of this proposal is to investigate the aetiology and mechanisms of self-harm. Objectives are to investigate pain sensitivity in youths with (1) a very high risk of self-harm; (2) the first episode of self-harm; (3) multiple episodes of self-harm. Previous studies indicate that people with self-harm have a higher pain threshold. What is not knows is: (1) how specific is the relationship between clinical variables and pain sensitivity? (2) Are pain sensitivity differences present before self-harm starts? (3) Is pain sensitivity associated with frequency of self-harm? To investigate these questions, 104 LAYP aged 12-17 will be recruited via Glasgow register of LAYP (n=900). 26 LAYP with no self-harm, 26 with a single episode of self-harm, 26 with multiple episodes (5 or more) and age and sex-matched 26 healthy controls (HC) will be included. The primary outcome measure will be cold pain threshold. Ramped thermal stimuli will be applied using a Peltier-based contact thermode followed by standardised sensory tests. Social exclusion will be simulated using Cyberball. Pain thresholds will be measured at rest and post-stress. Between-group comparisons will be done using two-sample t-tests and 2 way mixed ANOVA including one within-subject factor (baseline versus stress induction) and one between-subject factor (frequency of self-harm). We anticipate cold pain threshold differences of ~6.5C (SD 8.1, d=0.86) between HC and LAYP with multiple self-harm, with two other groups demonstrating intermediate values. With the alpha set at 0.05 (two-tailed) and power at 80%, 26 patients in each treatment group will be required. Understanding pain sensitivity may provide a key insight into the nature of self-harm.


Research activity codes: 4.2 EVALUATION OF MARKERS AND TECHNOLOGIES
Health categories: MENTAL HEALTH
Title: Regulatory genomic profiling in schizophrenia
Funder: Medical Research Council

Abstract: We propose the first comprehensive analysis of regulatory genomic variation associated with schizophrenia. Given evidence for a neurodevelopmental component to the aetiology of schizophrenia, we will also annotate patterns of gene regulation across development of the human cortex, enabling us to explore the hypothesis that disease-associated loci are dynamically regulated during this critical period. We will first profile key markers of genomic regulation (DNA methylation (5mC), DNA hydroxymethylation (5hmC), and lysine H3K27 acetylation (H3K27ac)) in purified neuronal nuclei isolated from post-mortem prefrontal cortex tissue from >400 schizophrenia cases and matched controls. We will next extend these analyses to human fetal cortex samples spanning ~7 to 20 weeks post-conception, enabling us to annotate functional genomic domains in the developing cortex and test the hypothesis that there is an enrichment of neurodevelopmentally-dynamic loci in regions of schizophrenia-associated regulatory genomic variation. Alternative splicing and RNA isoforms dramatically increase the protein-coding potential of the human genome during development. Our third aim is to employ novel long-read sequencing approaches to undertake the first comprehensive analysis of RNA splicing and isoform diversity in both the developing and adult human cortex, exploring the role of alternative splicing in schizophrenia. Finally, we will examine how schizophrenia-associated genetic variation influences regulatory genomic processes in the developing and adult cortex, building on our recent work showing that schizophrenia GWAS loci are enriched for 5mC quantitative trait loci in the developing brain. Building on findings from our previous MRC-funded research, our integrated-genomics approach will enable us to explore the dynamic regulation of gene function during human brain development and its relevance to the aetiology of schizophrenia.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: MENTAL HEALTH
Title: MICA:Translational validation of 5HT7 antagonists for the treatment of cognitive impairment in bipolar disorder: a proof of concept neuroimaging study
Funder: Medical Research Council

Abstract: Bipolar disorder is one the most disabling mental health disorders and is associated with widespread cognitive deficits. Cognitive impairment is an important treatment target in bipolar disorder as cognitive deficits are associated with poor functional outcomes. Importantly, there are no effective treatments for cognitive impairment in bipolar disorder. Converging evidence indicates that serotonin 5HT7 receptor antagonists have great potential as new treatments for cognitive impairment in bipolar disorder. However, no human mechanistic, proof of concept, studies are available which validate 5HT7 antagonists for the treatment of cognitive impairment in bipolar disorder. The aim of this study is to examine whether the selective 5HT7 antagonist JNJ-18038683 modulates cognition related brain activity (proof of target) and, in cognitively impaired people with bipolar disorder, impaired brain activity (proof of principle). We will also examine JNJ-18038683 effects on cognitive performance. The study will use a randomized, counterbalanced, double-blind, placebo controlled, cross-over design to examine the effects of one-week administration of JNJ-18038683 and placebo on cognition related brain activity and cognitive performance in 34 cognitively impaired people with bipolar disorder and 34 healthy controls. Participants will complete a baseline clinical and cognitive assessment visit where cognitive performance will be assessed using the ISBD-BANC cognitive battery. Participants will be assessed on day 7 of each treatment using functional MRI to determine effects on cognition and emotional processing brain activations and cerebral blood flow, and using the ISBD-BANC to determine effects on cognitive performance. The proposed research will provide new insights into the effects of 5HT7 receptor antagonism on brain function and cognitive performance which may validate 5HT7 receptor antagonism as a tractable treatment mechanism for cognitive impairment in bipolar disorder.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;4.2 EVALUATION OF MARKERS AND TECHNOLOGIES
Health categories: MENTAL HEALTH
Title: Cluster randomised controlled trial (RCT) for late life depression in socioeconomically deprived areas of São Paulo, Brazil (PROACTIVE)
Funder: Medical Research Council

Abstract: The proportion of elderly people is growing throughout the world. Depression is common and disabling among elderly people and often goes unrecognised and untreated. This will be a two-arm cluster randomised controlled trial to compare the effectiveness and cost-effectiveness of a psychosocial, community-based intervention delivered by Community Health Workers (CHWs) employed within the existing primary care system with an 'enhanced' usual care to treat depressed old adults from low socioeconomic backgrounds in São Paulo, Brazil. Participants will be recruited among those aged 60 or older who are registered with the participating Family Health Units (clusters). These units will be randomised to one of the two treatment groups. The intervention arm, with strong community-based and task-shifted components, consists of 8 to 11 home sessions, depending on severity of depression. CHWs will be supported with tablet computers to deliver the intervention and to receive supervision and support. Those participants who do not improve with the intervention, as shown by clearly specified algorithms, will be discussed in supervision and regular team meetings and further clinical decisions adopted if needed. The control group will receive 'enhanced' usual care in so far as improved identification and periodic assessments of high-risk cases treated as per a 'high-risk' protocol. Recovery rates (PHQ-9 scores <10) will be compared across arms at 8 and 12 months after entering the trial using an intention-to-treat analysis. Direct and indirect costs in both arms will be measured to undertake a cost-effectiveness analysis. We anticipate a total of 1,440 participants, registered in 20 FHUs (clusters) yielding a power of 86.5% for a 15 percentage point difference (25% to 40%) in recovery rates at 8 months. Our research team has developed and successfully tested the feasibility and acceptability of the proposed intervention in primary care in São Paulo (RCUK/FAPESP).


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