NIHRDataInsights/HRCSData huggingface dataset:
Title: The Typical and Atypical Development of the Social Brain During Infancy
Funder: Medical Research Council

Abstract: This proposal addresses the developmental origins of the human ?social brain? network. We will study brain functions and behaviour in typically developing human infants and toddlers, and those at elevated risk for a later diagnosis of autism (infants with an older sibling already diagnosed: ASD-sibs), to investigate three hypotheses: (1) infants are biased to attend to social stimuli, and these biases contribute to the postnatal emergence of the cortical social brain network; (2) the specificity and localisation of this network emerges postnatally through an interactive specialisation process; and (3) in autism there is a failure of one or more of these biases, or attention mechanisms, which subsequently disrupts the typical emergence of social cognitive functions. In section A, we will conduct a multi-method longitudinal study testing infants and ASD-sibs at 6 and 12 months. Assessment of ASD symptoms in the at-risk group will be conducted at 2 and 3 years old. The low-risk controls will be assessed in other measures of attention and social cognition at these ages. The results of this study will (a) test the above hypotheses, (b) assess whether the ?broader autism phenotype? exists in infancy, and (c) reveal the brain function and behavioural measures in infancy that best predict a later diagnosis of autism. In section B we will further test hypotheses (1) and (2) in a series of studies with typical low-risk infants. Specifically, we will trace the neurodevelopment of (a) orienting to faces, (b) the importance of direct (mutual) gaze, (c) the functions of the superior temporal sulcus in relation to dynamic social stimuli, (d) the interaction between different streams of face processing, and (e) the temporal dynamics of live social interaction. The results of the basic research in section B will underpin future studies of infants at-risk for ASD and related disorders.


Research activity codes: 2.3 PSYCHOLOGICAL, SOCIAL AND ECONOMIC FACTORS;1.2 PSYCHOLOGICAL AND SOCIOECONOMIC PROCESSES
Health categories: MENTAL HEALTH
Title: Molecular Genetics of Schizophrenia
Funder: Medical Research Council

Abstract: Schizophrenia (SZ) is a severe psychiatric disorder with a lifetime risk of approximately 1% and around 80% heritability. Recent genomic studies support expectations from population genetics that susceptibility is likely to reflect a large number of risk alleles occupying a spectrum of frequencies and effect sizes. Thus, genome-wide association studies (GWAS) support the existence of many common risk alleles, and although each individual allele confers small effects (odds ratios 1.2), en masse these contribute a significant role to population risk. At the other end of the spectrum, an important role for rare alleles is supported by the demonstration that rare genomic copy number variants (CNVs) contribute to disease risk, and that at least some of these rare alleles confer relatively large effects on risk (OR~10). Given the marked reduction in fecundity associated with schizophrenia, rare alleles of large effect must be maintained in the population by de novo mutation. Our recent work on CNVs in SZ, as well as work on point mutations in SZ and intellectual disability, highlights the value of seeking these de novo events as a highly efficient means of identifying pathogenic mutations. Our recent CNV work also shows that identification of specific disrupted genes (eg NRXN1) and of enrichment of mutations in genes coding for functionally related proteins can provide important pointers to disease pathways. Initially we will use whole-exome sequencing to detect de novo mutations in SZ in 700 well-characterised parent-proband trios. This will build on current pilot work with the Wellcome Trust Sanger Institute (WTSI) and involve collaboration with, and substantial leveraged funding from, the Broad Institute and Mount Sinai School of Medicine. After a synthesis of those data with those from emerging sequencing programmes and GWAS, we will use targeted sequencing in exceptionally large case-control samples to confirm the pathogenic status of individual mutations and genes, and to explore pleiotropic effects in phenotypes for which the genetic risk overlaps with schizophrenia. As in our CNV work, we will combine computational biology with increasingly refined and experimentally derived systems annotations to identify biological systems of pathogenic relevance. Following our work on CNVs, an initial major focus will be to explore systematically components of the synaptic machinery in collaboration with the G2C group at WTSI, but the whole-exome scale of our study will allow us to extend systems-wide analyses into the remaining exome to identify further novel loci and pathogenic systems


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: MENTAL HEALTH
Title: Bipolar -II Disorder
Funder: Medical Research Council

Abstract: Bipolar II disorder is characterized by episodes of hypomania, but more frequent episodes of depression superimposed on persistent subsyndromal symptoms The morbidity of this disorder is high and it is known that such patients have significant functional impairments and poor quality of life. There have been very few studies targeted specifically at examining treatment options for this patient group. The paucity of the evidence and the need for research to prioritize work on this sub-type of Bipolar Disorder was recently highlighted by the NICE Guidelines in Bipolar Disorders. We propose to recruit a cohort of 180 Bipolar II patients from the primary and secondary care services in one geographical area. The phenotype will be established using the well-validated and reliable SCID instrument and patients recruited will be screened to ensure they meet the recognized inclusion criteria for treatment trials and observational studies.


Research activity codes: 7.1 INDIVIDUAL CARE NEEDS;2.3 PSYCHOLOGICAL, SOCIAL AND ECONOMIC FACTORS
Health categories: MENTAL HEALTH
Title: Preventing substance misuse: Randomised Controlled Trial of the Strengthening Families 10-14 Programme
Funder: Medical Research Council

Abstract: Adolescent risk behaviour, including substance misuse (alcohol, tobacco and illegal drugs), anti-social behaviour and crime has a substantial impact on the UK economy and the health of its population. These behaviours are associated with morbidity and mortality among adolescents, poor education, social exclusion and health damaging behaviours, and poor health over the life course. They contribute substantially to social inequalities in health in adolescence and adulthood. This research application is for a randomised controlled trial of a substance misuse prevention intervention ? the Strengthening Families Programme (SFP) 10-14 UK. The SFP10-14 for young people aged 10-14 years and their parents is a population-based universal prevention programme for alcohol, tobacco and drug misuse in young people. Research in the United States has found the SFP10-14 to be effective in delaying the onset of alcohol use, and reducing levels of smoking. In other studies, later onset of alcohol and drug use has been shown to be associated with reduced lifetime prevalence of alcohol and drug problems US-based cost-benefit assessments have indicated that the SFP10-14 can be cost-effective at the population level for preventing alcohol misuse, other alcohol problems and also for tobacco use prevention. The SFP10-14 is thus a promising intervention and has recently been culturally adapted for use in the UK where it is gaining popularity. However, the current evidence base for the programme is derived exclusively from the US from just two trials conducted by the same research team, and there is a need to evaluate the SFP10-14?s effectiveness in a UK context, particularly in relation to the contrasting legislative frameworks and cultures surrounding alcohol in this country. The proposed trial will take place in six local authority areas in Wales. Families who are referred to the programme will be screened for eligibility before being allocated to intervention/control groups. Key outcome measures (measured at 2 years) will include: number of occasions young people report ever having been really drunk; reported use of cannabis; weekly smoking; unauthorised absence from school; GCSE performance; and age of initiation of alcohol and tobacco consumption. A process evaluation of programme delivery will be undertaken to examine fidelity and acceptability of the intervention to participating families, and key changes in family functioning. Economic analysis will also be conducted to examine the cost effectiveness of the SFP10-14. Findings from the research will be used to directly inform policy and practice in the field of substance misuse prevention.


Research activity codes: 3.1 PRIMARY PREVENTION INTERVENTIONS TO MODIFY BEHAVIOURS OR PROMOTE WELL-BEING
Health categories: MENTAL HEALTH
Title: Importance of 11-beta-hydroxysteroid dehydrogenase (HSD-1) in the consequences of chronic alcohol consumption
Funder: Medical Research Council

Abstract: Alcoholism is a chronic disorder with high personal and NHS costs. There is little effective treatment, and 80 - 90% of abstinent alcoholics relapse within 12 months. A large proportion of alcoholics have cognitive deficits. The mechanisms of the memory problems are not understood, but clinical and preclinical studies suggest the hypothalamo-pituitary-adrenal axis is important and this system is also implicated in the development of alcohol dependence. There is considerable clinical and experimental evidence that alcohol withdrawal plays a major role in causing the memory deficits and this offers a window of opportunity for intervention. Until recently, adrenal release into plasma was thought to be the only source of glucocorticoid in the brain, but local synthesis of glucocorticoids by 11-beta-hydroxysteroid dehydrogenase (HSD-1) is now known to occur in several tissue, including brain. Our recent laboratory investigations have shown that chronic alcohol treatment and withdrawal increases the concentrations of glucocorticoid in specific areas of the brain, particularly in the prefrontal cortex and hippocampus that are key areas in memory function. High glucocorticoid levels are known to be neurotoxic and to cause cognitive deficits. Experimental evidence suggests that the raised concentrations of glucocorticoids in the CNS are involved in the cognitive deficits caused by withdrawal from chronic alcohol treatment; in previous work we found two types of drug treatment which prevented the memory loss also reduced or prevented the rises in glucocorticoid. This proposal investigates the mechanism of the increases in brain glucocorticoid after chronic alcohol treatment, in particular the role of the HSD-1 enzyme, and the effects of selective HSD-1 inhibitors on the memory loss. Activity and expression of hexose-6-phosphate dehydrogenase (H6PDH) that controls affects HSD-1 activity via NADPH levels will also be studied. Higher NADPH levels increase the reductase activity of HSD-1, which is the direction of glucocorticoid synthesis. The effects of two new, very selective HSD-1 inhibitors will be examined on memory loss after withdrawal from chronic alcohol treatment and on regional brain corticosterone levels. One of these compounds is effective against brain HSD-1 while the other is not, although both are known to enter the brain. Measurements also will be made of HSD-1 and H6PDH activity and expression during and after chronic alcohol treatment. The studies will show the extent to which HSD-1 contributes to the memory loss caused by long term alcohol consumption and whether or not HSD-1 inhibition might provide a useful therapeutic approach.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: MENTAL HEALTH
Title: MRI measures of brain structure and function as predictors of medium-term response to psychotherapy in adolescent MDD
Funder: Medical Research Council

Abstract: Adolescent major depressive disorder (MDD) is a challenging clinical condition associated with considerable morbidity and mortality as well as poor outcome in adult life, and has been relatively under-investigated by neuroimaging studies to date. Symptomatic response to clinically recommended psychological treatments is variable, but little is known about the neurobiological basis of this variability in adolescent patients and there are few tools available to predict therapeutic response. This proposal will evaluate candidate neuroimaging markers and predictors of response to psychological treatment of adolescents with MDD in the context of a larger-scale, NIHR-funded study of symptomatic and social outcomes measured up to 1.5 years after treatment. Consistent with existing data on adult MDD, we hypothesise i) that depressive disorder in adolescents will be associated with abnormalities of brain function in a fronto-limbic brain system including the amygdala, anterior cingulate cortex and prefrontal cortex; ii) that these abnormalities at baseline assessment will be ?normalized? by cognitive behavioural therapy; and iii) that baseline measures of fronto-limbic brain structure and function will be predictive of medium-term clinical and social response to psychological treatments. These hypotheses will be tested by acquiring baseline structural and functional MRI data, immediately prior to initiation of treatment, from a cohort of 120 adolescent MDD patients randomised to one of three psychological treatments: cognitive behavioural therapy (CBT), brief psychodynamic psychotherapy or active clinical care, as part of the IMPACT clinical trial. The subset of 40 patients randomised to receive CBT will be scanned on a second occasion 20 weeks later, after completion of psychotherapy. Functional MRI data will be acquired during performance of emotion-processing and emotionally valent executive and memory tasks, as well as while subjects are at rest. Brain structure will be measured by conventional MRI and diffusion tensor imaging. Image analysis will involve innovative approaches to assessment of endogenous dynamics and complex brain networks in addition to well-validated methods for non-parametric inference on more conventional activation and morphometric statistics. These imaging markers measured in patients at baseline and follow-up will be compared to the same markers measured in an age-matched group of healthy volunteers (N=40) to test hypotheses (i) and (ii); baseline markers on all patients will be used to test hypothesis (iii) and validate candidate neuroimaging predictors of treatment response.


Research activity codes: 2.3 PSYCHOLOGICAL, SOCIAL AND ECONOMIC FACTORS;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: MENTAL HEALTH
Title: Violence against adults with severe mental illness compared with the UK general population
Funder: Medical Research Council

Abstract: Aims To investigate the extent, correlates and impact of violence against adults with severe mental illness (SMI), and to compare findings with the UK general population Objectives To determine the prevalence of interpersonal violence against adults with SMI To test the hypothesis that victimisation prevalence is higher in SMI patients compared with the general population, after controlling for gender, age and residential area To identify demographic, socio-economic and behavioural factors associated with victimisation, and to test the hypothesis that SMI modifies the effect of significant correlates including substance misuse and social deprivation To test the hypothesis that service contact and associated cost are greater in victimised SMI patients compared with non-victimised SMI patients To qualitatively explore the strategies used by SMI patients to cope with repeated violence Design A cross-sectional survey of violence against SMI patients using the British Crime Survey (BCS) questionnaire (the same instrument used by the Home Office in its annual survey of violence against the general population of England and Wales). A qualitative study of the experiences of SMI patients in coping with repeated victimisation. Methodology Setting and participants The patient study population will be a random sample of adults with schizophrenia or bipolar disorder who are under the care of mental health services in one of five North London boroughs. The general population comparison sample will be drawn from the Home Office BCS database. Measurements The BCS questionnaire will be used to measure the following dimensions of self-reported experiences of victimisation: frequency, nature, correlates, physical and psychological impact, and contacts with health services or police. Additional measures (instrument) used among SMI patients will include diagnosis (OPCRIT), symptoms severity (BPRS), disability (DASII), social support (MOS-SSS), childhood abuse (CTQ) and service contacts (CSRI). Qualitative study I will conduct semi-structured interviews with a purposive sample of patients who experienced repeated violence, and compare the coping strategies of patients where the abuse was on-going with those where the abuse had stopped, using thematic analysis to extract relevant themes. Scientific and medical opportunities A recent government initiative to tackle the impact of violence is currently being piloted in the health sector, but has limitations among people with SMI because the extent, correlates and impact of abuse in this population are not known. The proposed study will directly address these unknowns and provide essential, timely information for prevention policy in this vulnerable group. Word count:399


Research activity codes: 2.3 PSYCHOLOGICAL, SOCIAL AND ECONOMIC FACTORS;2.4 SURVEILLANCE AND DISTRIBUTION;8.5 RESOURCES AND INFRASTRUCTURE (HEALTH SERVICES)
Health categories: MENTAL HEALTH
Title: Origins of learning difficulties and behaviour problems: from behavioural genetics to behavioural genomics
Funder: Medical Research Council

Abstract: Learning difficulties are among the most common problems in childhood and can have a major impact on outcomes later in life. Our programme of research brings together quantitative genetic and molecular genetic strategies to understand the genetic and environmental origins of learning difficulties and associated behaviour problems The research will capitalise on the Twins Early Development Study (TEDS), the premier study of UK twins assessed since infancy as part of our continuous MRC programme grant funding (G500079) since 1995. During 2010-15, we will assess 5000 TEDS twin pairs after age 16, a crucial developmental turning point at the end of school and puberty as children begin to make their own way in their worlds. Testing such a large sample has been made possible by the use of an innovative battery of Web-based tests developed in TEDS. In collaboration with 12 former TEDS students, we will focus on testing genetic hypotheses at age 16 that have emerged from our TEDS research in childhood in reading, language and speech, mathematics, science, general cognitive ability, as well as school performance (GCSE), co-morbid behaviour problems, and home and school environments. We will continue to apply state-of-the-art model-fitting analyses to test hypotheses about development (e.g., genetic change and continuity from age to age), multivariate links between disorders (e.g., genetic co-morbidity and heterogeneity), and genotype-environment (GE) interplay (e.g., GE correlation and GE interaction). These quantitative genetic analyses have charted the course for our molecular genetic research which will benefit from 2 million DNA markers (SNPs and CNVs) that we have recently obtained for each of 4000 TEDS children (Affymetrix 6.0 GeneChip microarrays). These genomic data will greatly increase our ability to conduct genome-wide association (GWA) studies of the major domains of TEDS. The overall hypothesis is that our multiple-stage QTL (quantitative trait locus) GWA design guided by our quantitative genetic analyses will be able to detect and replicate SNP/CNV associations. Although each SNP/CNV association is likely to have only a small effect, multiple SNP/CNV associations can be aggregated for each phenotype in what we call a ?QTL set?. These QTL sets will be uniquely useful as indices of genetic risk in behavioural genomic research on the developmental, multivariate and GE interplay origins of learning difficulties and associated behaviour problems


Research activity codes: 2.3 PSYCHOLOGICAL, SOCIAL AND ECONOMIC FACTORS;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: MENTAL HEALTH
Title: Developmental pathways into adolescent substance abuse: neurophysiologic, genetic and environmental determinants
Funder: Medical Research Council

Abstract: Early onset and progression to adolescent substance abuse is genetically influenced and has been consistently shown to be associated with later risk for substance use disorders. Behavioural constructs, such as impulsivity, sensation seeking and harm avoidance are thought to be involved in mediation of increased genetic risk for substance abuse. However, neurophysiologic processes which mediate genetic risk might not be reflected in behavioural phenotypes due to compensatory factors, but may instead be revealed by functional neuroimaging. Understanding how neurophysiological processes mediate genetic risk but also how moderating environmental factors alter risk or resilience for adolescent substance abuse may identify neurobehavioural determinants which prove crucial for the development of targeted interventions. We propose to identify and to characterize a multidimensional risk profile of determinants for adolescent substance abuse, including abuse of alcohol, nicotine and cannabis based on longitudinal observations of subjects characterized in the IMAGEN study, the first cross sectional, multi-centre functional and structural genetic-neuroimaging study of a cohort of 2000+ 14 year old adolescents which investigates the neurophysiologic and genetic basis of individual differences in behaviours relevant for the development of substance abuse, including reward response, impulsivity and emotional reactivity. To this end we will complement the existing IMAGEN study by adding repeated longitudinal assessments of substance use patterns, behavioural development as well as psychosocial stress and exposure to licit and illicit substances covering adolescence up to the age of 18 years. Longitudinal analysis of the IMAGEN dataset will allow a systematic, genome-wide analysis of gene x environment interactions and their neurobehavioural mediation resulting in adolescent alcohol, nicotine and cannabis abuse. We will replicate our findings in the Avon Longitudinal Study of Parents and Children (ALSPAC), a regional birth cohort of 10.000 individuals. Integrated analysis of the IMAGEN and the ALSPAC study will allow us to better understand the complex interplay of genetic, developmental and environmental factors leading to adolescent substance abuse and relate them to neurobehavioural mechanisms as measured in neuroimaging analyses.


Research activity codes: 2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: MENTAL HEALTH