NIHRDataInsights/HRCSData huggingface dataset:
Title: Persistence and emergence of ADHD in young adulthood: Unravelling aetiology using genetics in a population-based longitudinal cohort
Funder: Medical Research Council

Abstract: ADHD is understood as a childhood-onset neurodevelopmental disorder. However, in my recent longitudinal study, less than one-third of individuals with young adult ADHD had ADHD persistent from childhood, while over two-thirds did not have the disorder in childhood. Many questions remain as to the nature of persistent and 'late-onset' ADHD. The aim of my proposed project is to combine data from large-scale genetic studies with a population-based cohort study to investigate the persistence and emergence of ADHD in young adulthood. More specifically, I aim: (1) to assess whether late-onset ADHD is associated with: (a) childhood ADHD polygenic risk score, suggesting childhood and late-onset ADHD share genetic aetiology, or (b) polygenic risk scores for other mental health disorders, such as alcohol dependence and depression, which would suggest late-onset ADHD may be accounted for by other psychopathology that mimics ADHD in young adulthood; (2) to utilize genetic data available in the Psychiatric Genomics Consortium to perform GWAS analyses examining ADHD age of onset as a quantitative trait, as well as to examine whether ADHD polygenic risk score is associated with age of onset among clinical cases of ADHD; (3) to determine whether risk and protective factors in the social environment moderate genetic risk, as assessed by ADHD polygenic risk score, for the emergence and persistence of ADHD in young adulthood; (4) to investigate whether DNA methylomic variation: (a) is associated with polygenic risk score for ADHD in a population-based cohort study, and (b) differs between monozygotic twins discordant for late-onset ADHD (n=49 pairs). This project has important implications and opportunities for researchers and clinicians in understanding young adult ADHD. Investigating the genetic and epigenetic underpinnings of young adult ADHD will provide invaluable insights that will affect the direction of future research and could influence clinical decision-making.


Research activity codes: 2.4 SURVEILLANCE AND DISTRIBUTION
Health categories: MENTAL HEALTH
Title: Public Involvement in Suicide Prevention II: The Stranger on the Bridge
Funder: Medical Research Council

Abstract: BACKGROUND: Suicide is an important public health problem, accounting for over 6,000 UK deaths each year. Approximately one third of these take place in a public place, many involving jumping from bridges and high buildings or use of the railway network. Previous research on preventing suicides in public places has measured the effectiveness of installing physical barriers at particular sites. Little attention has been paid to human behaviour and the potential for a passing stranger to offer emergency life-support to a suicidal person. 'The Stranger on the Bridge' was a 2015 Channel 4 documentary, which told the true story of one such successful intervention. Our aim is to equip more members of the public to recognise and respond to someone who is contemplating suicide in a public place. OBJECTIVES: i) Gain an in-depth understanding of the situation from the point of view of 'rescuers' and 'rescued' ii) Identify tell-tale signs of suicidal intent, public fears about intervening and core components of an effective intervention by a lay person iii) Translate the knowledge into simple, safe and memorable messages, and work with non-academic partners to co-create educational materials. INTERVENTION: Initially, i) a simple leaflet for distribution to members of the public, and an online version of the same, ii) a brief face-to-face training session for staff at locations that are used for suicide, e.g. bridges, cliffs and railways. We will evaluate these in a later study. METHOD: Qualitative interviews with those who have been rescued (n=10) and those who have intervened (n=20) about their experiences. Qualitative interviews using a video vignette with those who have never been involved (n=20) about their attitudes and fears. Thematic analysis of all data. Using the findings, we will provisionally formulate educational messages and draft materials and invite interview participants and non-academic partners to refine and test successive versions.


Research activity codes: 3.1 PRIMARY PREVENTION INTERVENTIONS TO MODIFY BEHAVIOURS OR PROMOTE WELL-BEING
Health categories: MENTAL HEALTH
Title: WHO's Parent Skills Training for developmental disorders: Piloting task-shifting to non-specialists in Ethiopia
Funder: Medical Research Council

Abstract: Background and objectives: The World Health Organization has developed a Parent Skills Training (PST) for caregivers of children with developmental disorders (DD). The PST, consisting of 9 group sessions and 3 home visits, teaches strategies to promote communication and learning and address challenging behaviours. Our team received funding for a feasibility and acceptability pre-pilot of the PST in Ethiopia, facilitated by specialists in the clinic. The PST is ultimately designed to be delivered by non-specialists to allow for scale-up. Before a randomised controlled trial (RCT) evaluation of the fully task-shared PST can be conducted, funding is requested to: 1) Assess the validity and reliability of the PST's proposed outcome measures; 2) Examine the feasibility, acceptability and potential efficacy of delivering the PST programme by non-specialists. Methods: Part 1 (validity and reliability study): Of the PST's proposed outcome measures, 3 questionnaires and 1 video-based measure have not previously been used in Ethiopia. Assessors will be trained to rate video-taped caregiver-child interactions using data from our clinical pre-pilot. To examine the validity and reliability of the 3 questionnaires, data will be collected in 300 help-seeking children presenting with DD (N=150) or other problems (N=150). Part 2 (mixed methods, controlled before-after study): Four groups of 10 caregivers (N=40) will be enrolled in the PST (intervention arm); and contrasted with caregivers (N=40) in the control arm. Feasibility and acceptability will be monitored through participation, attendance, and questionnaire completion records, programme implementation fidelity, and a nested qualitative study. Outcome measures will be collected pre-, midway and post PST, and at 2 month follow-up. Expected outcomes: This study will provide essential input to inform the design of a future RCT. The study findings can also inform implementation of the PST in other low-income countries.


Research activity codes: 6.6 PSYCHOLOGICAL AND BEHAVIOURAL
Health categories: MENTAL HEALTH
Title: Identifying the neural network abnormalities underlying developmental language disorder
Funder: Medical Research Council

Abstract: Approximately 7% of children experience unexplained difficulties in learning their first language, despite relatively typical development in other domains. Surprisingly little is known about the neural correlates of developmental language disorder. We will use state-of-the-art methods for acquisition and analysis of brain imaging data and detailed behavioural testing to study a large population of children with a range of language learning abilities. We will recruit eighty children with impairments previously identified in a large study screening school-aged children in Surrey (SCALES study run by project partner Prof. Norbury) and 80 children experiencing typical language development. We aim to provide a detailed characterisation of the structure and function of the brain networks underlying developmental language disorder in these children. We will specifically test two hypotheses, namely that children with developmental language disorders show: (i) structural and functional alterations in corticostriatal circuits; (ii) atypical structural and functional lateralisation. We will relate different measures of the structure and function of neural networks to the various patterns of performance on verbal and nonverbal behavioural measures. These exploratory analyses will inform and extend our existing theoretical frameworks concerning the neural underpinnings of DLD. Finally, we aim to share our data to allow comparison with other neurodevelopmental disorders, such as autism. The proposed work is important for two reasons: (i) it will enhance our understanding of the specific neural circuits associated with language-learning impairment, and (ii) we will test specific hypotheses about the underlying causal deficit. The findings may also help identify possible routes to intervention and novel therapeutic approaches.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;2.3 PSYCHOLOGICAL, SOCIAL AND ECONOMIC FACTORS
Health categories: MENTAL HEALTH
Title: International Research Programme on Psychoses In Diverse Settings (INTREPID II)
Funder: Medical Research Council

Abstract: Over 80% of the world's population live in developing countries, but less than 10% of research on psychotic disorders is done in these settings. One important implication of this is that we do not have the knowledge to inform the development of accessible, humane, and effective services in more diverse, often low resource settings. Our overall aim in this programme is to address the research question: what is the variability - in incidence, presentation, outcome, and impact - of psychotic disorders in diverse developing countries? We will address this through a five year programme of research in sites in three diverse developing countries: India, Nigeria, and Trinidad, selected to maximise potential comparisons between and within sites. Building on previous pilot work, we will identify, assess in detail, and follow at 2 years, cohorts of 240 cases (with an untreated psychotic disorder) and 240 controls (with no disorder). This will form the basis of four interconnected studies, the primary objectives of which are to describe and compare between and within sites the following aspects of psychotic disorders: (1) incidence and initial presentation, (2) course and outcome, (3) help-seeking by, and impacts on, individuals and families, and (4) the cooccurrence of physical health problems. This will be the most comprehensive characterisation of psychotic disorders in developing countries ever conducted. Our findings will shed light on the nature and origins of heterogeneity in psychotic disorders and inform the development of accessible, humane, and effective services in diverse, low resource settings. As such, our programme will have a substantial impact, both on the field and on provision of care.


Research activity codes: 2.3 PSYCHOLOGICAL, SOCIAL AND ECONOMIC FACTORS
Health categories: MENTAL HEALTH
Title: Brain-enriched voltage-gated calcium channel isoforms: novel, genetically informed, therapeutic targets for psychiatric disorders
Funder: Medical Research Council

Abstract: Robust genetic risk factors have been identified for psychiatric disorders. However, the pathway from gene to pathophysiological insight to novel treatment is yet to be elucidated. The research described here provides the critical first steps in this essential pipeline for arguably the most promising protein family: the voltage-gated calcium channels (VGCCs). Calcium dysfunction has long been implicated in psychiatric illness. Genetic findings suggest a causal role for the VGCCs. Given their disease associations, clear neurobiological function and established 'druggability', they are attractive psychiatric therapeutic targets. However, progress is hampered by a lack of information about the specific VGCC isoforms present in human brain and which of these mediate disease risk. As well as being important to understand links between VGCCs and disease, this information is essential for drug development, since VGCCs also play key roles in the cardiovascular system. This research combines computational and experimental studies to address these unknowns focussing, crucially, on human brain tissue. We will use our unique access to RNASeq data from the largest and highest-quality brain series available from healthy controls and psychiatric patients, to determine the brain transcript profile of VGCCs, and will contrast this with that of peripheral tissues, using publicly available multi-tissue RNASeq data. We will use cutting-edge methods - combining CaptureSeq and long-range PCR with long-read sequencing - to identify all VGCC isoforms, and to disambiguate the full-length transcripts (essential given their large size). We will then test for associations between VGCC isoforms and genetic risk loci, as well as disease status.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: MENTAL HEALTH
Title: Immersive Virtual Reality Cognitive Treatment (VRCT) for persecutory delusions.
Funder: Medical Research Council

Abstract: Problem: Persecutory delusions are a major psychiatric problem, associated with a wide range of adverse outcomes, for which current treatments do not work at all for over 50% of patients. Solution: Our theoretical model views these delusions as unfounded threat beliefs, which persist due to defence behaviours (e.g. avoidance, enhanced vigilance) that prevent disconfirmatory evidence being processed. The treatment implications are that patients: 1. need to go into feared situations and 2. not use defence behaviours. This enables relearning of safety and hence paranoia diminution. However this is very difficult for patients due to severe anxiety. A solution is to use virtual reality (VR) social situations, which are engaging, graded in difficulty, and that patients find much easier to enter. Pilot work: In a randomised controlled study with 30 patients with persecutory delusions, we showed that a single session of our VR cognitive treatment (going into VR feared situations with dropping of defence behaviours) led to a large reduction in the delusions (d=1.3) directly compared to an alternative active treatment (VR exposure treatment). Benefits transferred to the real world. Objective: To produce an affordable, portable, efficacious 'plug and play' VR treatment for delusions. Design: We will develop additional VR situations, obtain patient feedback, and finalise the treatment manual. Treatment effect sizes will be re-established in an internal pilot with 30 patients with delusions randomised to four sessions of VRCT or VR mental relaxation treatment (rated as equally credible). If effect sizes are as expected, then we will continue the trial, testing 90 patients in total in a Phase IIa trial, assessed at 0, 2, 4 (post treatment), 8, 16, and 24 weeks. The primary outcome is level of delusional conviction. Secondary outcomes are real world distress, activity levels, suicidal ideation, and quality of life. Mediation will also be tested.


Research activity codes: 6.6 PSYCHOLOGICAL AND BEHAVIOURAL
Health categories: MENTAL HEALTH
Title: Active Assistance for Psychological Therapy 2.0 (Actissist 2.0): Digital Intervention for Co-producing care in psychosis.
Funder: Medical Research Council

Abstract: Severe mental illness (SMI) such as schizophrenia affects 24 million people worldwide, with societal costs estimated at nearly £12bn in England. Onset typically occurs in early adulthood and up to 80% relapse within 5-years, resulting in unscheduled acute care and adverse effects on psychosocial development. The main treatment for psychosis is medication and psychosocial interventions. Currently, the delivery of psychosocial interventions for psychosis by scheduled appointment can result in psychosis relapse indicators either being missed or treated too late. There is a need for innovative, timely, efficient and cost-effective solutions to improve the speed and quality of recovery in psychosis, over and above conventional drug and psychosocial treatments. The NHS has a clear digital agenda for addressing mental health challenges, aiming to fully harness the information technology revolution, and self-management in long-term conditions is a cornerstone of NHS policy. Smartphones offer an unprecedented opportunity to drive improvements in treatment quality, efficiency, cost, access and facilitate self-management. Supported by MRC DPFS funding (MR/L005301/1), we have developed a user-informed, personalised, smartphone app, Actissist, that delivers a theory-driven psychological intervention that is unconstrained by traditional service settings. We have shown that patients complete the intervention swiftly in the course of daily life over 12-weeks and that this technology is feasible, safe and acceptable. The primary aim of the current proposal, Actissist 2.0, is to refine the software and conduct an efficacy study in psychosis. Actissist 2.0 supports active shared decision-making about treatment. Results will inform a future Phase III effectiveness trial and shape where digital interventions fit on the healthcare pathway, including opportunities for commercial partnerships.


Research activity codes: 6.6 PSYCHOLOGICAL AND BEHAVIOURAL
Health categories: MENTAL HEALTH
Title: Development of cellular models of hypothalamic disorders
Funder: Medical Research Council

Abstract: Obesity affects over 10 million adults in the UK and is arguably the greatest challenge facing our health care system. Efforts to treat obesity are hampered by the fact that the mechanisms causing obesity are still poorly understood. A large body of evidence ranging from animal lesion and genetic studies to monogenic and GWAS studies have identified as obesity as largely a disease of the brain. In particular, neurones in the hypothalamus are central regulators of feeding behaviour whose loss or dysfunction is sufficient to cause severe obesity. I have developed a method to generate human hypothalamic neurones from pluripotent stem cells. Human stem cell-derived hypothalamic neurones share cardinal features of their counterparts in the brain. Furthermore, I used the CRISPR/Cas9 system to modify the genomes of human stem cells to generate knock-in reporters for cell types of interest. One cell type of particular interest is the hypothalamic neurone that produces neuropeptide Y (NPY) and agouti-related peptide (AgRP). These NPY/AgRP neurones so potently stimulate feeding that their ablation in the adult brain leads to a cessation of feeding to the point of starvation, and their specific activation via pharmacogenetic or optogenetic methods stimulates immediate and voracious feeding. As a New Blood MRC fellow, I will develop human stem cell-derived NPY/AgRP neurones into a tractable system for studying obesity. In particular, the secretion of NPY and AgRP peptides from these cells is detectable by ELISA. I will test the hypothesis that candidate obesity-associated mutations in genes that are highly enriched in NPY/AgRP neurones alter neuropeptide release. Since AgRP is a melanocortin peptide that directly inhibits the MC4R receptor found on feeding-inhibitory second order neurones, this phenotype would have a clear mechanistic link to obesity.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: MENTAL HEALTH
Title: Flexible scheduling to prevent the development of disabling resistance to change
Funder: Medical Research Council

Abstract: Neurodevelopmental disorders including autism spectrum disorder (ASD), fragile X (FXS) and Prader-Willi syndromes (PWS), are characterised by highly disabling resistance to change. This resistance to change appears to be associated with specific deficits in cognitive flexibility (task switching). The development of children's cognitive flexibility is sensitive to environmental experience; and our work with individuals with PWS indeed suggests that limited flexibility in routines, perhaps particularly in early school years, may hinder subsequent ability to deal with change appropriately. We hypothesise that increasing flexibility in children's routines in early childhood will decrease the subsequent development of disability linked to resistance to change; and that this effect will be mediated by gains in cognitive flexibility. We plan to test this hypothesis in a future pilot randomised controlled study (the main study). In the present work we propose to develop a caregiver led flexible visual scheduling intervention, capable of increasing the flexibility in children's routines. The intervention will capitalise on current best practise, which includes use of visual schedules. A collaborative design process will be conducted with the parents of children with ASD, FXS or PWS; and with relevant teachers and intervention practitioners. The design will include multiple stages of flexible scheduling prototype development and refinement to maximise acceptability, followed by beta-testing to identify and address primary potential limits to feasibility. A tool for monitoring intervention implementation will be developed in a parallel process. The feasibility of flexible scheduling implementation; and its capacity to increase flexibility in children's routines; will be evaluated over one month. Planned outcome measures for the future pilot study will be administered and assessed for feasibility.


Research activity codes: 5.6 PSYCHOLOGICAL AND BEHAVIOURAL
Health categories: MENTAL HEALTH
Title: School based mental health intervention for young people: development and feasibility study of a digital information prescription intervention.
Funder: Medical Research Council

Abstract: YP aged 12-18y have the highest incidence and prevalence of mental illness across the lifespan [3,4]. Public health approaches to mental ill health are strongly advocated nationally and internationally [16, 17]. Indicated prevention interventions can reduce the incidence of new cases of mental disorder; these target individuals showing early signs of poor mental health and they aim to avoid progression to a fully-fledged disorder [15]. Although UK schools have responsibility for supporting YPs mental health, they are without a well-evidenced, sustainable early intervention programme. We will develop and feasibility test a digital information prescription intervention for delivery in secondary schools to indicated YP aged 14-18y, along with a sister intervention for parents. Information prescription encourages people to act on accurate, personalised information and guidance about their difficulties, and covers the affective, cognitive and behavioural determinants of good mental health [18,19]. An early phase study is required as existing information prescription interventions for adult mental health [e.g.11,12] are unsuitable and unworkable for delivery in schools to YP. Adopting a comprehensively co-design process with YP, parents, schools and other stakeholders, we will generate intervention content and the technical and software delivery platform, along with training materials and key design features including theoretical frameworks, implementation model, recruitment criteria, user defined outcomes, prototype journey, risk management protocol, referral pathways, change measurement and feasibility and acceptability benchmarks. We will assess information standards and communication power of intervention content before a feasibility and acceptability study in four pilot sites, where we will also test candidate outcome measures for the main study, alongside an exploratory health economics assessment. Outcomes will inform the design of an RCT.


Research activity codes: 3.1 PRIMARY PREVENTION INTERVENTIONS TO MODIFY BEHAVIOURS OR PROMOTE WELL-BEING;5.6 PSYCHOLOGICAL AND BEHAVIOURAL
Health categories: MENTAL HEALTH