NIHRDataInsights/HRCSData huggingface dataset:
Title: Active Assistance for Psychological Therapy (Actissist): Software to improve access and adherence to CBT targeting key relapse indicators in psychosis
Funder: Medical Research Council

Abstract: Schizophrenia is a serious mental illness affecting 2% of the population. The majority of first episode of psychosis (FEP) patients reach remission within 12-months of treatment. However, the early course of psychosis is characterized by repeated relapse; 80% of FEP patients will relapse within 5-years of their initial episode, adversely impacting on their psychosocial development. The early phase following FEP is a critical period. Risk factors for relapse in FEP are non-adherence with medication, substance misuse, carers' critical comments and social isolation. NICE recommends cognitive behavioural therapy (CBT) in the treatment of schizophrenia, and CBT has been successfully applied in the treatment of FEP. However, a shortage of trained clinicians and resource pressures mean that of people with psychosis who could benefit, only 10% have access to CBT. Even those who are offered CBT often experience long delays before receiving treatment, resulting in relapse indicators being missed. Accordingly, there is an urgent need for innovative, cost-effective solutions that improve access to CBT and deliver treatment in a timely manner. Active Assistance for Psychological Therapy (Actissist) will be a smartphone software application that will provide such a solution by delivering an interactive, personalised CBT intervention targeting the key psychosis relapse indicators in FEP. By leveraging the capabilities of smartphones, Actissist will allow patients to create and manage a repository of personally meaningful, multi-media CBT strategies as part of their everyday lives. We envisage Actissist as a reusable platform capable of delivering interventions for many disorders. This research builds on ClinTouch, an MRC funded mobile phone symptom-monitoring system for schizophrenia, by extending the concept to provide psychological intervention. The proposed 26-months project is designed to provide proof of concept, with results informing a future phase III effectiveness trial.


Research activity codes: 6.6 PSYCHOLOGICAL AND BEHAVIOURAL;5.6 PSYCHOLOGICAL AND BEHAVIOURAL
Health categories: MENTAL HEALTH
Title: Increasing understanding of risk factors and outcomes associated with continence problems in children and adolescents
Funder: Medical Research Council

Abstract: We propose a mixed methods approach, including secondary analysis of ALSPAC data and a qualitative study of young people with continence problems to identify risk factors and outcomes associated with incontinence. We will use longitudinal data on wetting and soiling from almost 11,000 children aged 4 - 9 years to identify latent classes (developmental trajectories) of incontinence. The latent classes, identified using Longitudinal Latent Class Analysis (LLCA), will incorporate frequency of wetting/soiling in the models. We will use the latent classes as outcome variables to examine their association with time-invariant covariates using multinomial models incorporating class assignment probabilities to reflect the uncertainty in group membership. We will also explore methods for relating time-varying covariates to the latent classes. We will then use the latent classes of incontinence as exposure variables to examine their association with adolescent outcomes including self-reported wetting/soiling at 14 years and a range of adverse psychosocial outcomes at 14-15 years. We will use weighted logistic regression (Stata) to estimate the odds ratios associated with the adolescent outcomes for each of the atypical latent classes in relation to the normative class. We will conduct semi-structured qualitative interviews to examine the impact of incontinence in young people in relation to their mental health, relationships, social activities, education/school attainment and goals/aspirations for the future. The interview transcripts and free text from the survey will be analysed with NViVO software using iterative thematic analysis to explore salient issues, using constant comparison techniques. We anticipate that the findings of the proposed research will aid identification of children at risk of chronic incontinence and will contribute to patient-centered, age appropriate information resources on issues relating to incontinence in young people.


Research activity codes: 1.2 PSYCHOLOGICAL AND SOCIOECONOMIC PROCESSES
Health categories: MENTAL HEALTH
Title: Gene regulatory variation in the developing human brain and its role in neuropsychiatric disorders
Funder: Medical Research Council

Abstract: Large-scale genetic studies have successfully identified genetic loci conferring susceptibility to major neuropsychiatric disorders such as schizophrenia. As the most strongly associated variants are typically in non-coding regions of the genome, it is likely that risk is commonly mediated through effects on gene expression. However, the genes that are affected, the way in which they are functionally altered (e.g. up- or down- regulation) and where and when the effects are exerted are currently unclear. Given that several neuropsychiatric disorders are thought to have a neurodevelopmental component, we will explore effects of identified risk variants for these disorders on the expression of proximally located genes in the developing human brain. One hundred foetal brain samples will be genome-wide genotyped for >1 million single nucleotide polymorphisms and the corresponding RNA deep sequenced to provide whole transcriptome measures of gene expression. We will use these data to identify those genes that are differentially expressed in the developing brain in association with neuropsychiatric risk variants and to determine the way in which they are functionally altered. We will also perform a genome-wide assessment of genes that are differentially regulated in the developing human brain as a result of common genetic variation and seek to identify downstream changes in gene expression associated with altered regulation of neuropsychiatric susceptibility genes. These studies will greatly improve our understanding of the aetiology and underlying biology of neuropsychiatric conditions as well as of gene regulation in the developing human brain.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: MENTAL HEALTH
Title: The neurobiology of cognitive affective biases in depression and their role in antidepressant therapy
Funder: Medical Research Council

Abstract: Providing new improved treatments for depression is a priority health care issue. Current understanding of the cause of depression and the mechanisms of action of licensed antidepressant drugs is limited and a major hurdle to providing improved therapeutic interventions. A cognitive theory of depression was first set out in the 1960s by Aaron Beck however methods to test this hypothesis have been limited particularly in the case of non-clinical studies using animals. Data obtained from neuropsychological studies in human participants suggest that negative cognitive processing is a core feature of depressive illness and these deficits can be reversed by antidepressant-induced modification of emotional processing and its impact on new learning and subsequently behaviour. This work suggests that a cognitive neuropsychological theory may best explain the development of depressed mood and the delayed onset of antidepressant efficacy. In order to translate this hypothesis into improved treatments, greater understanding of the relationship between cognitive affective biases and behaviour is essential. In the last decade, major advances have been made in terms of methods to quantify cognitive affective behaviours in animals. Building on these advances, this project will use our affective bias test and novel behavioural tracking approach to investigate the neuropsychological hypothesis of antidepressant drug efficacy. We will also focus a series of neural studies on the infralimbic cortex and amygdala as homologous regions in man have been implicated in depressive illness and negative cognitive affective bias. These studies bring together ideas from human neuropsychological and brain imaging data and aim to generate evidence to support a neuropsychological explanation for the development of depressed mood and how antidepressant treatments interact with emotional processes to modify behaviour.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: MENTAL HEALTH
Title: Immuno-psychiatry: a consortium to test the opportunity for immunotherapeutics in psychiatry
Funder: Medical Research Council

Abstract: The project will build on recent evidence that activation of the innate immune system is often associated with depressive states, and that some anti-inflammatory drugs may have anti-depressant effects, at least in some patients. It is also known that inflammatory states can modify peripheral and central monoamine signalling, and this might explain preliminary clinical data indicating that peripheral inflammation predicts resistance to monoaminergic anti-depressants. To explore and test the therapeutic implications of these observations, we will analyse or re-analyse large prior clinical, epidemiological or experimental datatsets. NHS data will be accessed by an ethically approved system for anonymizing electronic health records in two NHS mental health trusts linked to academic partners (KCL and Cambridge). Longitudinal datasets on general population samples, including biomarker measurements, will be available through partnership with the Whitehall II and ELSA epidemiological studies (UCL). Data on randomized placebo-controlled clinical trials of anti-inflammatory drugs for medical disorders will be re-analysed with a focus on mental health questionnaire scores completed as safety endpoints (GSK and J&J). Genetic and biomarker (PBMC microarray, proteomic) case-control collections on patients with depression and other psychiatric and medical disorders will also be released by GSK. Pharmacogenetic effects will be tested by analysis of genetic and microarray data in partnership with the GENDEP study (KCL). We will also conduct a small number of new lab experiments to measure gene expression changes in human macrophages and other PBMCs in response to pro-inflammatory and pharmacological challenges ex vivo (Edinburgh, GSK). There will be a strong underpinning technical focus on bioinformatics and advanced statistical methods for systems or network-level analysis and visualization of complex immunophenotypes and their relationships to genetic variation (BSU).


Research activity codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES;4.2 EVALUATION OF MARKERS AND TECHNOLOGIES
Health categories: MENTAL HEALTH
Title: What are the clinical and educational risk factors for poor academic outcomes in children with Autistic Spectrum Disorder?
Funder: Medical Research Council

Abstract: I will establish cross-sectional and longitudinal individual clinical profiles (e.g. socio-demographic, co-occurring disorders, initial symptom severity, impairment, home, neighbourhood and service use factors) for a large ASD child cohort and model clinical predictors of pharmacotherapy use (drug type, class switches, polypharmacy). Text mining algorithms and structured fields in CRIS will provide data on a range of baseline clinical factors and pharmacological treatment. I will then explore associations between clinical profiles and academic outcomes in children with ASD, which will include academic attainment, school drop-out, attendance and exclusion rates. I will estimate the risk of these outcomes according to clinical profiles, including co-occurring disorder. CRIS will be linked with the National Pupil Database, a longitudinal dataset containing educational and census information since 2002, for all children who have been enrolled in state education. This will provide individual level longitudinal education performance data. I will then model the clinical predictors, treatment exposures (drug type, duration of treatment), treatment response exposures ( effect sizes derived from validated psychometric scales and normalised against outcome data provided by CAMHS Outcome Research Consortium) against multiple education outcomes. I will estimate the risk of specific education outcomes according to ASD clinical profiles and co-occurring disorders and whether these risks are modified by medication use and treatment response.


Research activity codes: 2.3 PSYCHOLOGICAL, SOCIAL AND ECONOMIC FACTORS;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: MENTAL HEALTH
Title: Identifying and measuring key cognitions in suicidal and non-suicidal self-harm
Funder: Medical Research Council

Abstract: Aims Self-harm (SH) is 'self-poisoning or self-injury, irrespective of the apparent purpose of the act'. Despite the dangerousness, prevalence and financial cost, SH has received relatively sparse research attention and remains poorly understood. There is very little longitudinal research and the predominance of behavioural theories means that existing measures either assess SH behaviour (e.g., SH methods), or SH functions (antecedents and consequences). The Fellowship aims to examine additional aspects of the phenomenology of SH by developing a questionnaire which examines the key cognitions which drive SH behaviour and then examining the longitudinal influence of those cognitions on SH behaviour. Objectives 1) Develop and validate a psychometrically-robust, theory-driven, self-report measure of key SH cognitions in adults; 2) Use that measure to compare a cognitive explanation of SH against existing behavioural and functional theories of SH and known SH risk factors; 3) Explore differences between suicidal and non-suicidal SH over time; 4) Examine the extent to which SH cognitions are a cause and/or a consequence of psychological problems over time. Methodology Individuals aged 18+ who SH, recruited via SH support websites, advertisements and local mental health services (depending on ethical and practical issues). A Delphi methodology will be used to develop the questionnaire: items will be generated and revised by SH experts, clinicians and individuals who SH. A battery of questionnaires pertaining to mental health problems, SH behaviour, current SH theories, suicidality, and known SH risk factors will be administered 6-9 months apart. Scientific and medical opportunities The proposed Fellowship would lay the foundation for subsequent research examining cognitive factors in SH, the development and evaluation of a cognitive-behavioural theory and treatment for SH, and could influence the development of future policy (e.g. NICE guidelines).


Research activity codes: 2.3 PSYCHOLOGICAL, SOCIAL AND ECONOMIC FACTORS
Health categories: MENTAL HEALTH
Title: dr Deepak Srivastava
Funder: Medical Research Council

Abstract: Oestrogen is a powerful regulator of cognition and neural circuitry. Recent data indicate that oestrogens are an effective adjunct treatment for schizophrenia. Oestrogens can influence the development of cortical neurons and I have shown that oestrogens increase dendritic spine number and regulate synaptic expression of AMPA and NMDA glutamate receptors. However, the role of brain-synthesised oestrogens in the development of cortical neurons is not known. Furthermore, we do not have a detailed understanding of the molecular mechanisms underlying oestrogenic modulation of dendritic spines and glutamate receptors are not known. Using a multidisciplinary approach integrating molecular and cellular studies with advanced imaging techniques, I will pursue these Specific Aims: 1) I will use in utero electroporation to express shRNA against aromatase, the key enzyme needed for the production of oestrogens in the brain. I will then use 2-photon laser scanning microscopy to image brain sections to determine the role of brain-synthesised oestrogens on cortical neuron migration, dendrite formation and synaptogenesis. 2) I will use a combination of pharmacological agents, shRNA, FRET-biosensors and mutant constructs with confocal imaging of fixed or live cultured cortical neurons to dissect the molecular pathways required for oestrogen-modulation of neuronal signalling and dendritic spines. 3) To assess the ability of oestrogens to modulate glutamate receptors synaptic expression, I will use combination of pharmacological agents, shRNA, mutant constructs, labelling of surface receptors and ph-sensitive GFP-tagged constructs with confocal imaging of fixed or live cultured cortical neurons dissect the molecular pathways required for oestrogen-regulation of glutamate receptor trafficking.


Research activity codes: 5.2 CELLULAR AND GENE THERAPIES
Health categories: MENTAL HEALTH
Title: MICA: Improving self-regulation skill in children: a feasibility study
Funder: Medical Research Council

Abstract: Self-regulation' is the ability to regulate thoughts, feelings, impulses and behaviour. Our ability to self regulate determines how well we are able to manage the stresses of everyday life, including adverse events. It is an important influence on our physical and mental health and wellbeing, throughout the life course. TakeTen is designed to improve self-regulation skills in children and adolescents. A computer game provides an innovative, visual form of heart rate variability biofeedback that sensitises children to their physiological responses to stimuli. Interaction with the software teaches them how best to manage their responses in ways that reduce stress and maximise problem-solving and learning. Having used the biofeedback software to develop Respiratory Sinus Arrhythmia (to regulate their emotional and physiological responses 'in real time'), children next learn how to generalise and maintain these skills in the absence of computer feedback, using a guided meditation (Journey to my safe place). This enables children to incorporate the strategies learned into their daily lives. TakeTen is in the early stages of development, but has attracted considerable interest from the Public Health Agency (NI), the Education Department, and the Education and Training Inspectorate. The proposed feasibility study is designed to: (i) develop a sound logic model; (ii) develop a programme manual, (iii) ascertain the feasibility of trialling TakeTen in primary schools, where it has the potential to maximise public health benefits, namely reduced incidence of behaviour problems and bullying, improved executive function, reduced stress and anxiety, and associated improvements in educational attainment and health outcomes. The study will assess acceptability, demand, implementation, practicality and integration and address issues pertinent to an impact evaluation. The project will be steered by an advisory group including representatives of the target population.


Research activity codes: 3.1 PRIMARY PREVENTION INTERVENTIONS TO MODIFY BEHAVIOURS OR PROMOTE WELL-BEING
Health categories: MENTAL HEALTH
Title: Spontaneous recognition tasks and the 3Rs
Funder: National Centre for the Replacement, Refinement and Reduction of Animals in Research

Abstract: Spontaneous tasks of object exploration are becoming common in testing memory in rodents. However, these tasks require large numbers of animals to provide enough data to interpret the results appropriately. In addition, these tasks are not normally suited to testing complex forms of memory, meaning studies on the neurobiology of these more complex forms of memory (such as episodic memory – the memory of past events in one’s life) continue to be studied in primates. The project aims to develop a task in rodents that both tests forms of complex memory in spontaneous tasks in rodents (replacing the need for primates in these studies) and refines the procedures for these tasks such that fewer animals can be used to provide the same (or greater) interpretive power with less handling, leading to lower levels of stress in the animals. In addition, the development of a precisely controlled task in animals will allow the student to develop non-animal alternatives to understanding the neural basis of episodic memory in humans.


Research activity codes: 1.5 RESOURCES AND INFRASTRUCTURE (UNDERPINNING);1.2 PSYCHOLOGICAL AND SOCIOECONOMIC PROCESSES
Health categories: MENTAL HEALTH
Title: Reducing the number of non-human primates in research by developing a rodent model of selective attention
Funder: National Centre for the Replacement, Refinement and Reduction of Animals in Research

Abstract: This proposal is to develop and validate a rodent model of spatial attention in the visual pathway. Using computer-based image analysis to control head position and thus visual stimulus, we will assess if cueing spatial location improves performance and reaction times in a change detection task. We hypothesise that rodents will be able to use spatial cues to allocate endogenous attention, and that evidence for attention will be provided by a reduction in reaction time, and an improvement in accuracy, for spatial locations that are cued. We will establish whether endogenous attention can be engaged by a prior spatial cue, or by blocking of experimental trials, both of which are effective in humans and non-human primates.


Research activity codes: 1.5 RESOURCES AND INFRASTRUCTURE (UNDERPINNING);1.2 PSYCHOLOGICAL AND SOCIOECONOMIC PROCESSES
Health categories: MENTAL HEALTH
Title: Development of a patient derived cellular model of circadian disruption in bipolar disorder
Funder: National Centre for the Replacement, Refinement and Reduction of Animals in Research

Abstract: Sleep and circadian rhythm disruption (SCRD) are now recognized to be common comorbidities in patients suffering from bipolar disorder. Examples include SCRD in patients with bipolar disorder as well as associated animal models of neuropsychiatric disorders and conversely, psychiatric phenotypes in mouse models with clock mutations. Although SCRD is invariably associated with neuropsychiatric illness, SCRD is rarely treated, as there are very few treatment options. Moreover, there is emerging evidence that addressing SCRD in individuals with psychiatric disorders may also have positive effects on their symptoms In order to address this need,we are interested in the development of drugs that modulate circadian rhythms To then end, we need suitable system to model SCRD at the in vitro level. Here, we propose to develop a cellular model derived from bipolar patient fibroblasts that faithfully represent the endogenous rhythm.This in vitro correlate of SCRD will be highly informative on endogenous clock deficits in bipolar disease. Further, this will provide a robust cell-based model of SCRD that can replace a large number of animal models, that are the only currently available alternative. We will test drugs known to alter circadian rhythms on our patient-derived fibroblast model and have an effect on mood (e.g. lithium)l and test the predictive capacity of our model to find drugs that modulate circadian rhythms and thereby mood. Our work will have the following impacts: 1) Studying the rhythms from patient derived fibroblasts would inform us of the clock deficits and provide us with molecular targets for drug discovery and potentially new drugs from our drug screen 2) Using patient-derived cells would significantly reduce the use of rodents including transgenic mice to model circadian rhythm deficits in mood disorders by replacing it with a relevant human model. 3) This model, if successful, could be extended to awide range of conditions that are comorbid with SCRD.


Research activity codes: 2.6 RESOURCES AND INFRASTRUCTURE (AETIOLOGY);2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: MENTAL HEALTH