NIHRDataInsights/HRCSData huggingface dataset:
Title: "I do not see the world as others do." Diminished perceptual adaptation, hypo-priors and autism.
Funder: Medical Research Council

Abstract: Visual perception is a highly dynamic process, continuously recalibrating neural sensitivity to match the characteristics of the current environment. Such adaptation - ubiquitous in sensory systems - represents a rapid form of experience-dependent plasticity in which our current sensory experience is intimately affected by how we viewed the world only moments before. How would the world seem if these processes showed less adaptation? We hypothesize that diminished adaptation shapes the perceptions of people with an autism spectrum condition, and may explain core features of the autism phenotype - especially the restricted and repetitive behaviours and sensory sensitivities. These hypotheses build on our previous work which has shown both that children with autism do not adapt as readily as typical children to changes in facial cues, and that the extent of adaptation is inversely related to degree of autistic symptomatology. We will also use Bayesian methods, a principled framework for deriving inferences in the face of uncertain information, to identify further the mechanisms underpinning diminished adaptation in autism, which we propose is due to fewer prior constraints or "hypo-priors". This proposal uniquely combines human visual psychophysics, computational methods, and developmental psychopathology to probe further the pervasiveness of diminished adaptation in autism (Objective 1) and its computational causes (Objective 2). It is well documented that altered sensations and perceptions in autism can produce adverse effects on these individuals' everyday lives. The outputs of this research will have direct implications for our understanding of these altered perceptions and of the nature of autism itself. Identifying the mechanisms that underlie altered visual perception in autism is critical for the formulation of a new theoretical account of autism and in providing the necessary empirical base from which to develop effective interventions.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: MENTAL HEALTH
Title: How does ethanol alter opioid tolerance?
Funder: Medical Research Council

Abstract: Opioid addicts who die of acute overdose are often found to be taking other non opioid drugs as well, the most common of which is ethanol. Measurement of blood levels indicates that there is an inverse relationship between the amounts of ethanol and opioid present at death. There is to date no good, proven explanation for this relationship. We hypothesize that ethanol alters the level of opioid tolerance thus increasing the dangers for the addict to overdose even when taking their normal or even a lower dose of opioid. To examine this hypothesis we will use a combination of experimental approaches - in vivo respiration monitoring in mice, whole cell brain cell patch clamp recording and in vitro assays of kinase and phosphatase activity- to study the interactions between ethanol and a range of opioid drugs used illicitly or in the therapy of opioid addiction. We will examine whether acute or chronic exposure to ethanol alters the level of opioid tolerance in vivo by altering the responsiveness to opioids of neurones in the brainstem that control respiration. Specifically, we will test whether acute or chronic administration of ethanol alters the levels of tolerance to each opioid drug and then use a combination of pharmacological and transgenic approaches to determine the molecular mechanisms underlying the effects observed. There is considerable evidence that different opioids induce tolerance by different molecular mechanisms and thus potentially ethanol could affect tolerance to some but not all opioid drugs.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: MENTAL HEALTH
Title: Early Prediction of Violence and the Disruptive Behaviour Disorders: Follow-up of the Cardiff Child Development Study
Funder: Medical Research Council

Abstract: The primary aim of the proposed resaerch is to determine if infants' angry aggressiveness is a true precursor to clinically significant symptoms of Disruptive Behaviour Disorders (DBD). We shall complete a prospective longitudinal study of a nationally representative sample of first-born infants, in which families were assessed in pregnancy and at 6, 12, 21 and 33 months post partum, with a final home visit at 6 years of age, when early-onset DBD can be diagnosed reliably. We shall use the wealth of behavioural, cognitive and physiological measures taken in the first 3 years to determine if early aggressiveness does predict DBD; to identify processes that underlie the emerging gender difference in DBD; to test a neurobiological model of the origins of DBD; and to identify social cognitive skills and prosocial tendencies that protect angry, aggressive infants from going on to develop clinically significant DBD, even in the face of other biological and social risk factors. The study will provide a unique base of evidence that will inform future prevention and intervention strategies.


Research activity codes: 2.3 PSYCHOLOGICAL, SOCIAL AND ECONOMIC FACTORS;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: MENTAL HEALTH
Title: Time trends in childhood mental health problems: a 40-year cross-cohort comparison
Funder: Medical Research Council

Abstract: Accurate understanding of mental health trends requires the comparison of representative unselected population samples assessed in the same way at different points in time. Cross-cohort comparisons have shown that rates of adolescent emotional and behavioural problems have increased in recent decades and identified some possible contributory factors. Evidence on mental health trends in pre-adolescent children is lacking. The study objectives are i) to test trends in child emotional, conduct and ADHD problems over a forty year period (1965-2008), ii) to test trends in known risk factors (pre- and peri-natal, neurodevelopmental, and early family adversity) and their contribution to trends in child mental health, iii) to assess the impact of child mental health problems on later psychosocial functioning for earlier and later cohorts. The study combines data across five UK population cohorts of seven-year-olds - the National Child Development Study (NCDS, assessed in 1965, N = 13500), the Avon Longitudinal Study of Parents and Children (ALSPAC, assessed in 1998/9, N = 8500), the ONS British Child and Adolescent Mental Health Surveys (assessed in 1999, N = 1000 and in 2004, N = 650), and the Millenium Cohort Study (MCS, assessed in 2008, N = 13500). Comparable parent-rated symptom screens were used in all five studies - the Rutter A scale in 1965 and the Strength and Difficulties Questionnaire (SDQ) in the latter four cohorts. This study draws on a core set of comparable items across the two scales. Minor differences in response format and wording will be addressed using calibration data. The cohorts include comparable assessments of proposed risk factors. Impact of child mental health problems on functioning will be assessed using parent and teacher symptom scores at age 11 (NCDS, ALSPAC, MCS) and age 16 (NCDS, ALSPAC), and exam attainment at age 16 (NCDS, ALSPAC).


Research activity codes: 2.4 SURVEILLANCE AND DISTRIBUTION
Health categories: MENTAL HEALTH
Title: State disinhibition and heavy drinking
Funder: Medical Research Council

Abstract: Individual differences in disinhibition are associated with addiction (including alcohol abuse and dependence). Recent work suggests that disinhibition can fluctuate within individuals, and that heavy drinking occurs when individuals are in a disinhibited state. We will characterise the influence of state fluctuations in disinhibition on heavy drinking in non-dependent heavy drinkers. We will achieve this through a combination of laboratory-based experimental studies, and assessments and interventions conducted using ecological momentary assessment (EMA) and internet-based inhibition training. Study 1 will use EMA techniques to investigate the relationship between naturally-occurring fluctuations in disinhibition and daily drinking in non-dependent heavy drinkers. In studies 2 and 3 we will experimentally manipulate acute stress (study 2) or alcohol cue exposure (study 3) before measuring disinhibition and alcohol-seeking behaviour. We hypothesise that acute stress and alcohol cue exposure will increase both disinhibition and alcohol-seeking behaviour, and that the effects on alcohol-seeking behaviour will be partially mediated by the effects on disinhibition. In study 4 we will examine the efficacy of inhibition training as an intervention to reduce drinking among non-dependent heavy drinkers who are motivated to quit. Participants will complete multiple sessions of inhibition training on the internet over a three week period. Participants will be randomly allocated to receive general inhibition training, inhibition training that is specific to alcohol cues, or a control manipulation. We predict that inhibition training will lead to robust reductions in the frequency and quantity of alcohol consumption, and that these effects will be larger with alcohol-specific inhibition training compared to general inhibition training. This training technique has the potential to be adapted as an adjunct behavioural treatment for problem drinking.


Research activity codes: 2.3 PSYCHOLOGICAL, SOCIAL AND ECONOMIC FACTORS;5.6 PSYCHOLOGICAL AND BEHAVIOURAL
Health categories: MENTAL HEALTH
Title: Hypermobility and autonomic hyperactivity: Relevance for the expression of psychiatric symptoms
Funder: Medical Research Council

Abstract: This proposal aims to test how common constitutional differences in bodily physiology (namely joint hypermobility, postural tachycardia syndrome (PoTs) and vasovagal syncope (VVS) are linked to the clinical expression of psychiatric symptoms, notably anxiety. Key aims: 1. To determine the representation of joint hypermobility and autonomic symptoms (PoTs, VVS) amongst psychiatric clinical groups by survey. 2. To further characterize subjects in terms of autonomic function, symptom expression and responses to medication and thus determine if the profile of psychiatric symptoms differ by autonomic profile - e.g. cardiovascular reactivity (heart rate variability, response to orthostatic challenge) and interoceptive sensitivity. 3. To determine if such constitutional/autonomic differences are related to concepts of self representation e.g. differential susceptibility to rubber hand illusion (Tsakiris et al, 2011), response to false bio-feedback (Gray et al, 2009) and performance in anxiety induction experiments (Kalisch et al, 2005) 4. Use findings of above to characterize patterns of vulnerability and resilience to psychiatric symptoms and differential responses to medication to inform better treatments and selection of medication. In order to acheive these objectives three linked studies will be undertaken: A) Study 1 (Year 1): survey of 400 psychiatric patients to establish relevance of joint hypermobility and autonomic symptoms (PoTs, VVS) to clinical psychopathology and identify / recruit participants for the mechanistic psychophysiology and imaging studies. B) Study 2 (Years 1-2): A psychophysiological and behavioural charecterization of hypermobility, PoTs and VVS. Autonomic study of individuals identified above (estimated to be approx 100). C) Study 3 (Years 2-3): A neuroimaging study of the relationship between hypermobility and clinical anxiety with specific focus on amygdala, autonomic reactivity and interoceptive awareness in 80 individuals.


Research activity codes: 2.3 PSYCHOLOGICAL, SOCIAL AND ECONOMIC FACTORS;4.2 EVALUATION OF MARKERS AND TECHNOLOGIES
Health categories: MENTAL HEALTH
Title: Predicting clinical and functional outcomes in psychosis using machine learning
Funder: Medical Research Council

Abstract: Background Psychotic disorders are responsible for an enormous burden of illness upon individuals and society as a whole (Perala 2007). Structural, functional and DTI MRI studies have shown that the onset of psychosis is associated with changes in brain structure and function (Smieskova 2010 and Pettersson-Yeo 2011). However, it has been difficult to apply such group level findings to a clinical population at the level of the affected individual. This may reflect the overlapping genetic, neurobiological and clinical features of current diagnostic classification systems, which cannot reliably predict the course and outcome of psychotic disorders (Van Os 1997). Aims My project aims to analyse clinical and neuroimaging data of patients with psychotic disorders using Support Vector Machine learning (SVM) and Machine Kernel Learning (MKL) in order to generate more robust systems for classifying illness and predicting outcomes at the level of the affected individual. Methods (i) SVM analysis of data of patients with psychosis from a large, prospective case register (CRIS) to characterise clinical and functional outcomes and predict these with baseline clinical data at first episode. (ii) Individual SVM analysis of clinical data, structural MRI, DTI and fMRI of patients with first episode psychosis to predict the same outcomes. (iii) Analysis of clinical and neuroimaging data using MKL to investigate if combining modalities increases predictive power. Implications Prediction algorithms generated from this project will be further validated using a prospective dataset with the aim of subsequently evaluating successful algorithms in clinical studies. Generating reliable algorithms for predicting outcomes in psychosis may help to develop more effective and personalised treatments.


Research activity codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES
Health categories: MENTAL HEALTH
Title: Behavioural and neurophysiological effects of schizophrenia risk genes: a multi-locus, pathway based approach
Funder: Medical Research Council

Abstract: Our research is based on the recent discovery of several genetic risk variants for schizophrenia and the observation that most cases of schizophrenia carry several (and only partly overlapping) common variants that each only contribute a small amount to disease risk. Because little is know about the downstream effects of these variants, we combine neuroimaging, neuropsychology and molecular genetics to elucidate their effects on brain and behaviour. Because power has been an issue in previous studies in this area, we have developed a new approach using healthy participant groups pre-selected for their polygenic risk scores from an existing genotyped cohort (ALSPAC). We will compare high and low genetic risk individuals on imaging and behavioural measures that have been proposed as candidate markers for schizophrenia. Examples include measures of reward sensitivity, associative learning, oscillatory brain activity, cognitive inhibition and maturation of white matter. We hypothesise that high risk individuals will show changes similar to those observed in schizophrenia patients on these measures. More specifically, though, we expect risk variants that cluster along specific biological pathways, for example those of synaptic plasticity or myelination, to be associated with some of these intermediate phenotypes but not with others. Our study is powered to detect these associations. We will also probe, in an exploratory fashion, the effects of single risk variants on the full range of neural and behavioural phenotypes acquired. Our research will provide an answer to the question whether intermediate phenotypes proposed by the current biological models can index genetic risk of schizophrenia, and whether they provide evidence for different neural effects of genes on different pathways. If the expected results are obtained, this could pave the way for a future biological stratification of schizophrenia, and for the identification of new pathways for drug development.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: MENTAL HEALTH
Title: Pre-school autism intervention and autism development: a longitudinal follow up of the Preschool Autism Communication Trial (PACT)
Funder: Medical Research Council

Abstract: We plan 3 year follow-up of at least 80% of the existing PACT cohort to test mediation/process hypotheses arising from observational studies. The unique strength of this proposal is that the initial randomisation in the PACT trial allows for a causal interpretation of subsequent effects in a way that is not possible in observational studies. We use a "hybrid trial" design(1,2); consisting of 1) initial randomised allocation to two parallel groups, 2) an intervention in one arm targeted at key theory-based variables and including analysis of mediation, and 3) the current follow-on observational study of subsequent development. Our findings on treatment effect and causal mediation in the original PACT trial, together with convergent findings from independent longitudinal observation studies in relevant areas of autism development, generate causal hypotheses on the effect of parent child dyadic communication (altered by the intervention) on downstream child and family outcomes, including language and communication, autism symptoms, and family functioning. Follow-up also includes our own innovative service-user generated family functioning questionnaire and measurement of longer-term intervention effects on parental care burden and service usage. This innovative hybrid trial design has not been undertaken before in autism and will enable the causal analysis of some key developmental hypotheses related to early autism development, as well as measurement of generalized effects of intervention that may have taken time to develop. This approach will be innovative in the autism literature and have significant application in service development and intervention planning. 1) Howe et al. (2002) Dev Psychopath, 14: 673-94; 2) Green et al. (2008) Brit J Psychiat, 192: 323-325


Research activity codes: 6.6 PSYCHOLOGICAL AND BEHAVIOURAL
Health categories: MENTAL HEALTH
Title: Developing methods for understanding mechanism in complex interventions
Funder: Medical Research Council

Abstract: This is a proposal to develop novel methodology to support the evaluation of complex interventions in particular in mental health research. Although the recognition of the potential role of multiple therapeutic components is integral to the development of the complex intervention the mechanism by which improvements in clinical outcomes are brought about typically remains to be evaluated during the trial phase and the evaluation of putative mediators is a key research objective of an explanatory EME trial. This proposal will further develop causal inference methods for explanatory analyses to provide innovative and more powerful methodology that enables researchers to extract the most accurate information from expensive trials conducted using the latest research designs. In particular we propose to extend statistical and econometric methods to trials collecting factor and/or longitudinal data. We will also develop and implement strategies for efficiently exploiting data provided by series of trials and by trials nested within or complemented by observational data. We will address the statistical challenge of data being missing by design in such series of studies by utilising external calibration samples or data collected as part of the nested design to identify parameters describing mediation processes. We further propose to assess model-averaging as a general approach for combining instrumental variables and Baron and Kenny-type estimators to gain power. Finally, in parallel we will develop guidelines for enhanced design and measurement protocols to enable optimally informative explanatory analyses of trials of complex interventions.


Research activity codes: 8.4 RESEARCH DESIGN AND METHODOLOGIES (HEALTH SERVICES)
Health categories: MENTAL HEALTH
Title: Methylomic profiling in schizophrenia: towards an integrated genetic-epigenetic approach
Funder: Medical Research Council

Abstract: We propose a comprehensive genome-wide analysis of epigenetic dysfunction associated with schizophrenia (SZ) using cutting-edge methodologies to identify novel pathways involved in pathogenesis. We will examine genome-wide patterns of DNA methylation in a unique collection of samples. First, via collaboration with research groups involved in the UK10K consortium, we will undertake methylomic analysis using the Illumina Infinium 450K array in SZ samples (n=1700) and matched controls (n=1700) from ongoing genome-wide association study (GWAS) and exome sequencing projects, enabling us to perform an integrated epigenetic-genetic analytical strategy and representing the largest epigenome-wide association study yet undertaken. Specific SZ-associated differentially methylated regions (DMRs) will be verified and subsequently replicated in another set of samples using the Sequenom EpiTYPER platform and bisulfite pyrosequencing. Validated DMRs will also be examined longitudinally in a high-risk prodromal cohort to investigate epigenetic changes associated with the transition into disease. Second, we will examine genome-wide patterns of DNA methylation in MZ twin-pairs discordant for SZ using the largest collection of such samples ever assessed. This will enable us to examine the epigenome independent of any underlying genomic sequence variation and allow us to fully control for factors such as age, sex and the early (pre- and peri-natal) environment while providing further independent validation/replication for SZ-associated regions implicated in Aim 1. Third, we will use post-mortem brain samples obtained from SZ cases and controls to examine the extent to which disease-associated epigenetic marks detected in the periphery reflect changes occurring in functionally-relevant tissues. A key element of data analysis will involve the integration of epigenetic information with GWAS data, exome sequencing and other clinical/demographic data using novel methods developed in our lab.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: MENTAL HEALTH