NIHRDataInsights/HRCSData huggingface dataset:
Title: Scalable TRansdiagnostic Early Assessment of Mental Health (STREAM)
Funder: Medical Research Council

Abstract: Monitoring child neurodevelopment is essential for early identification of children faltering in their developmental trajectory and their eventual referral to effective interventions. Typically, such assessments depend on highly trained professionals administering expensive, proprietary and time consuming tools. This high resource demand poses a challenge in low and middle income countries (LMICs) where skilled personnel are scarce and public awareness of neurodevelopmental symptoms is low. The resulting delay or outright absence of identification of children vulnerable to developmental problems (i.e. 'detection gap') effectively obstructs community-based interventions that have been shown to improve outcomes. Closing this detection gap will depend on task-shifting from scarce experts to more plentiful non-specialist community health workers, via scalable neurodevelopmental assessment tools. The proposed research programme will develop a scalable platform for neurodevelopmental assessment in 0-6 year olds (STREAM) by consolidating work from four current projects by the project team on child mental health in LMIC settings. This open-source platform, running on Android tablet PCs, will be administered on 4000 children in India and Malawi by non-specialist workers. It will comprise a diverse set of assessments of child behaviour, parent-report, and parent-child interaction, and use technological innovations in computer vision and machine learning. Known prenatal and perinatal risk factors will be mapped to the measures generated by STREAM to test the sensitivity of the platform. A random subset of the sample in both countries will be clinically evaluated, to test the utility of the platform in identifying clinical needs and diagnoses. The project objectives will be achieved by an interdisciplinary team of neuroscientists, public health researchers, clinicians, computer scientists, and app developers from UK, India, and Malawi.


Research activity codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES
Health categories: MENTAL HEALTH
Title: Psychological, social & biological predictors of child mental health and development: shared and distinctive risk and protective factors in UK & India
Funder: Medical Research Council

Abstract: We will conduct a longitudinal investigation using two established cohorts to identify shared and distinctive risks and protective factors for child mental health in India and the UK. We have established a cohort infrastructure in the urban slums of Bangalore, successfully following up over 740/909 families (78.5%) through 6 waves of rich data collection from pregnancy to age 2. The Bangalore Child Health and Development Study (BCHADS) was designed with timed assessment, and parallel measurement to our UK Wirral Child Health and Development Study (WCHADS). We propose following up the families of children in the BCHADS study at age 4.5 years and age 7 years with parallel measurement to the WCHADS (already collected). This will make two rich data sets with parallel measures of risk and protective factors for child mental health outcomes from pregnancy onwards, including age 8-10 wks, 6 months, 14 months, 2 years, 4 years and 7 years of age. The two cohorts are unusually well phenotyped with detailed repeated measurement of key likely 'shared risks' and associated 'mechanisms' for conferring risk. We will also assess risk and protective factors that may be 'distinctive' or particularly relevant to the South Asian setting; maternal nutrition in pregnancy, early immune function and associated chronic inflammatory states (given likely increased exposure to infection, poverty and pollution in the slum setting), gender discrimination with cultural favouring of the male child, and the practice of shared-caregiving as opposed to primary maternal rearing in Western societies. We will also advance cross-cultural measurement technologies by developing indices of differential item functioning for common measures, to use in analyses to reduce inferential error when conducting joint analyses of multiple cohort datasets. We will develop new culturally sensitive measures of 'shared' caregiving and gender discrimination in India.


Research activity codes: 2.3 PSYCHOLOGICAL, SOCIAL AND ECONOMIC FACTORS
Health categories: MENTAL HEALTH
Title: Targeting ERK signalling to ameliorate intellectual disability and autism spectrum disorder associated with chromosomal rearrangements at 16p11.2
Funder: Medical Research Council

Abstract: Copy number variants (CNVs - deletions or duplications) in the 16p11.2 chromosomal region are associated with intellectual disability (ID) and autism spectrum disorder (ASD) and other neurodevelopmental disorders (NDD). Recently, converging evidence from human genomic studies as well from mice strongly points to a gene located within 16p11.2, MAPK3 (ERK1), as a key factor for NDD. MAPK3 regulates ERK signalling which is a central player in neurodevelopment, cognition and behaviour, thus representing a potential therapeutic target. We recently found that a short treatment with ERK signalling inhibitors in mice with the 16p11.2 deletion restored key physiological and behavioural deficits, providing a strong rationale for a stratified intervention targeting this pathway. In this multidisciplinary project, firstly patients carrying either deletions or duplications of 16p11.2 will be characterised phenotypically and screened for peripheral alterations in ERK signalling components that can be used as biomarkers to support diagnosis and treatment development for ID/ASD. Secondly, induced pluripotent stem cells (iPSCs) derived from these patients will be used to confirm a role of ERK signalling in the neuronal alterations at the cellular level also using cerebral organoids. Thirdly, functional rescue of the observed cellular phenotypes using appropriate ERK modulators will be investigated and coupled with pharmaco-transcriptomics, with the goal to identify brain-specific downstream ERK targets. Finally, efficacy of a novel ERK activator will be assessed in 16p11.2 duplication model, to validate an experimental therapy for cognitive dysfunction in vivo. At the end of the project, evidence from patients, human cellular models and mouse models will be integrated in a coherent therapeutic approach necessary to proceed to clinical intervention in genetically stratified groups of patients with ID and ASD.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: MENTAL HEALTH
Title: Investigating the Mechanisms of Placebo Anxiolysis
Funder: Medical Research Council

Abstract: There is a need to develop improved treatments for anxiety disorders. Placebo-controlled trials are presently the gold-standard test of a novel anxiolytic. However, placebo treatment can also cause clinical improvement, which has implications for the design and evaluation of clinical trials. Although the placebo response has been much explored in pain, we know little about placebo anxiolysis. Placebo analgesia involves the endogenous opioid system, and converging evidence suggests this system might also be important in the pathophysiology of psychiatric illness (Bandelow et al., 2010) and anxiety regulation (Colasanti et al., 2011). Previous research funded by the MRC has allowed us to extend and validate an experimental 7.5% carbon dioxide (CO2) inhalational human model of anxiety for treatment development. We will use this model to develop an experimental placebo procedure. Using this placebo procedure, we will carry out a randomised triple-blind study of the opioid antagonist naltrexone to test our hypothesis that endogenous opioids mediate placebo anxiolysis. We will seek further evidence for the role of endogenous opioids in anxiety regulation through functional neuroimaging. We will ask healthy participants to undergo functional magnetic resonance imaging (fMRI) while they complete an emotional cognitive reappraisal task under two conditions: naltrexone and placebo. This task is known to activate emotional regulatory circuits in the brain. We will correlate the functional connectivity between opioidergic centres (shown by the contrast placebo>naltrexone) with subsequent response to CO2 challenge. This proposal provides a timely and cost-effective test of the hypothesis that endogenous opioids are important in anxiety regulation. If so, this will provide a step-change in our understanding of placebo anxiolysis. This understanding will inform the design of future clinical trials and allow us to explore novel therapeutic targets for anxiety disorders.


Research activity codes: 5.1 PHARMACEUTICALS
Health categories: MENTAL HEALTH
Title: Examining school attendance as a predictor of self-harm in adolescents: A series of longitudinal studies using linked mental health and education data
Funder: Medical Research Council

Abstract: Background: Self-harm occurs in more than 10% of UK adolescents and is the strongest risk factor for completed suicide. Despite poor school attendance being a visible marker with the potential to aid early identification of difficulties, its role as a predictor of self-harm is not well understood. Aim: To investigate the longitudinal association between school attendance and self-harm in different groups of adolescents and identify clinical, educational and socio-demographic factors which may explain or affect the magnitude of this relationship. Methods: Study 1: I will use routinely-collected, linked mental health and education data from South London and Maudsley NHS Foundation Trust and the National Pupil Database. I will explore the association between school attendance and subsequent presentations to A&E with self-harm in 3 groups of 11-17 year-olds: a) Adolescents resident in 4 South London boroughs (n=113,286), b) Adolescents attending child and adolescent mental health services (CAMHS) at SLaM (n=15,352) and c) Adolescents who have reported suicidal thoughts to CAMHS (n=5400). I will use structured data as well as Natural Language Processing to extract data from free-text. Study 2: Data will be derived from the Resilience, Ethnicity and Adolescent Mental Health study, a school-based prospective cohort study of 4,500 11-14 year olds in South London. Here, I will explore the association between school attendance and subsequent self-reported self-harm. For Study 1, I will conduct time to event analysis using cox regression. For Study 2, I will use multilevel models to take into account clustering within schools. Impact: The methods used will provide a model for using routinely collected data to understand risks and prevent adverse outcomes in young people. Study findings will inform early identification of young people at risk of self-harm and contribute to targeted prevention.


Research activity codes: 2.3 PSYCHOLOGICAL, SOCIAL AND ECONOMIC FACTORS
Health categories: MENTAL HEALTH
Title: Cell-specific gene regulation in the developing human brain and genetic risk for neuropsychiatric disorders
Funder: Medical Research Council

Abstract: Large-scale genome-wide association studies (GWAS) have identified hundreds of risk loci that are commonly involved in neuropsychiatric disorders such as schizophrenia. Nearly all of these associations implicate non-coding regions of the genome and are therefore thought to reflect variants affecting gene regulation. Recent data indicate that an appreciable number of risk loci for neuropsychiatric disorders are active in the human prenatal brain, but the cells mediating these effects are unknown. We will perform single cell RNA sequencing and open chromatin profiling (ATAC-Seq) in order to define the constituent cell types of 5 regions of the human 2nd trimester foetal brain and the genomic sites controlling gene expression within them. We will integrate these data with results from large genomic studies of neuropsychiatric disorders in order to delineate cell types of the prenatal brain that mediate genetic risk for these conditions both at the polygenic level (through analyses of partitioned heritability) and at individual high-confidence risk loci. These studies will greatly improve our understanding of the aetiology and cellular basis of neuropsychiatric disorders 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: Neurobiological pathways from trauma exposure to child mental health outcomes in a high adversity South African Birth Cohort
Funder: Medical Research Council

Abstract: Children growing up in many low and middle income country (LMIC) contexts are at high risk of exposure to trauma, which has been identified as a major determinant of poor mental health, accounting for as much as 47% of the overall risk for psychological disorders in children, and has been linked to adverse physical health outcomes. Despite such evidence, there are key limitations to our knowledge in this area. The majority of relevant data derives from high income countries, rather than from LMICs, where exposure to childhood trauma is substantially more common and many children experience multiple adversities. Consequently, we have limited knowledge of trauma as experienced in the types of contexts in which the majority of the world's children live. Moreover, there is extremely limited understanding of the underlying etiological mechanisms, particularly considering neurobiological factors. The mechanisms via which childhood trauma leads to a range of different psychological disorders are particularly poorly studied. We propose to address limitations in our understanding of the consequences of trauma exposure in children through capitalizing on and the Drakenstein Child Health Study (DCHS), a longitudinal South African birth cohort that includes measurement of child trauma from age 2-6 years, with mental health and psychobiological processes being simultaneously assessed. We will complete comprehensive assessments of trauma exposure mental health at 8-9 years in the DCHS, and conduct in-depth analyses of neurobiological pathways from trauma exposure to disorder, studying markers related to stress responding, inflammation, and brain structure. The high prevalence of trauma in the cohort, and the availability of repeated measures of exposure, mental health, and neurobiological mediators will allow us to probe causal effects in a way that has not previously been possible.


Research activity codes: 2.3 PSYCHOLOGICAL, SOCIAL AND ECONOMIC FACTORS
Health categories: MENTAL HEALTH
Title: Human neurocognitive development: Early-stage processing, modifiers, and outcomes
Funder: Medical Research Council

Abstract: Little is currently known about the emergence of ASD and ADHD during infancy, and the modifying factors that may compound or alleviate initial risk. In Part A we will advance our current studies of infants at-risk for a later diagnosis of autism or ADHD by virtue of being young siblings of a diagnosed child, to also include infants diagnosed with Neurofibromatosis 1, a genetic condition that frequently leads to a later ASD or ADHD diagnosis. We will compare the development of brain and cognitive functions in these groups alongside typical (low-risk) infants using a variety of methods such as Near InfraRed Spectroscopy, EEG, eye-tracking, standardised assessments, and parent-infant interaction. This work will allow us to dissociate early stage markers associated with poor synaptic efficiency in posterior sensory and motor cortices, from later developing neurocognitive factors associated with anterior (frontal) systems that can compound or alleviate symptoms in the course of subsequent development. Part A is embedded within national and international collaborative networks in order to increase the number of babies studied on some key measures, and correspondingly increase our ability to detect effects. Birth is the single most dramatic change in environment that a brain experiences in its lifetime, yet its consequences for emerging brain functions remain surprisingly unknown. In Part B we will conduct a basic science study of typical development over this period to ask fundamental questions such as whether individual differences in foetal behaviour are maintained after birth, whether or not there are dramatic changes in brain function triggered by birth, and what is the role of social interaction with other humans during the first weeks of life on infant brain development.


Research activity codes: 1.2 PSYCHOLOGICAL AND SOCIOECONOMIC PROCESSES;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: MENTAL HEALTH
Title: Identifying Neural Signatures of Auditory-Predictive Processing in Schizophrenia: A Multi-Modal Imaging Approach
Funder: Medical Research Council

Abstract: In this project, combined MEG and high-field 7T fMRI are used to identify electrophysiological signatures and layer-specific information flow of feedforward (FF) vs. feedback (FB) mediated information processing during auditory predictive processing in normal and abnormal brain functioning. To this end, 30 healthy controls, 30 ScZ patients and 30 CHR-participants will be recruited. Data will be obtained during a novel auditory oddball paradigm that involves a quantitative manipulation of predictability of sound sequences. Specifically, the contributions of spectral and layer-specific fMRI-signatures of FF- and FB-processing towards auditory-predictive processing during normal brain functioning and in ScZ will be identified. For the MEG and 7T fMRI-data, time-frequency representations will be estimated in three regions of interest (ROIs) (A1, A2, IFG). MEG-data will be analyzed for ERF-signals, time-frequency information and Granger causality. For the 7T fMRI data, we will use a DCM model that reflects the parametric variation of predictability seen in the MMN response in the MEG-data. Moreover, MEG and 7T fMRI-data will be complemented by Magnetic Resonance Spectroscopy (MRS) measurements of GABA and Glutamate/Glutamine (Glx) in A1/2 as well as in IFG as well as computational modeling to relate neuroimaging data to alterations in Excitation/Inhibition balance (E/I-balance), a crucial pathophysiological mechanism in ScZ. The approach is expected to elucidate the role of FF and FB processing during both normal and abnormal brain functioning with high-spatial, spectral and temporal resolution. In addition, fundamental insights into underlying mechanisms of cognitive deficits in ScZ are expected, informed by the relationship and directional influence found between aberrant bottom-up information processing and top-down cognitive impairments.


Research activity codes: 1.2 PSYCHOLOGICAL AND SOCIOECONOMIC PROCESSES
Health categories: MENTAL HEALTH
Title: Reducing Relapse for People with Schizophrenia in Jakarta, Indonesia: Developing a culturally-relevant, evidence-based Family Intervention
Funder: Medical Research Council

Abstract: Schizophrenia is among the most disabling conditions in low resource settings and 90% of those who need treatment do not receive it. Consequently, much of the burden of care is transferred to families who often lack knowledge and expertise, support and experience significant impacts on their quality of life. Family interventions (FIp) are routine psychosocial interventions in high-income settings and have a robust evidence base for their efficacy in reducing relapse, improving functioning and family environment. The aim of this research is to adapt and refine an existing, effective intervention for relatives and carers of people with schizophrenia and test whether it is feasible to conduct a full trial of this intervention and assess acceptability. This study comprises three phases: In Phase 1 we will conduct stakeholder consultation groups to obtain stakeholder preferences and priorities for content, format and delivery of FIp. We will then explore key informants views on wider implementation within primary care settings to ascertain factors that will assist and hinder intervention implementation during feasibility testing. In Phase 2, we will convene stakeholder workshops to gain consensus on the intervention components, delivery format and identify the training needs of healthcare professionals. We will present the expert consensus panel with a synthesis of evidence from existing reviews and phase 1 findings and using modified nominal group techniques, we will gain consensus on intervention content, format and delivery. We will develop a manual to support delivery of the intervention and training resources to support sustainable implementation. In Phase 3, we will evaluate the feasibility and acceptability of delivering culturally-adapted FIp to reduce relapse in people with schizophrenia. Our aim is to provide evidence to support the process of testing a culturally-adapted intervention in a full trial.


Research activity codes: 3.1 PRIMARY PREVENTION INTERVENTIONS TO MODIFY BEHAVIOURS OR PROMOTE WELL-BEING;7.3 MANAGEMENT AND DECISION MAKING
Health categories: MENTAL HEALTH
Title: Neurocognitive signatures predicting risk of recurrent depression
Funder: Medical Research Council

Abstract: IMPORTANCE Depression is a leading cause of disability, mainly because of recurrent major depressive (MDD) episodes. Why some patients experience recurring MDD whilst others remain well is poorly understood. Identifying the neurocognitive mechanisms of how MDD evolves from its asymptomatic precursors will enable the development of better treatments and improve long-term outcomes. BACKGROUND Patients with MDD show biases towards blaming themselves for failure. We have identified the associated neural network including anterior temporal and limbic forebrain regions. Combining a novel cognitive test with self-blame-related hyper-connectivity and standard clinical measures in remitted MDD prospectively predicted who will develop recurrence on an individual basis (83% cross-validated accuracy). GAP-OF-KNOWLEDGE Despite these encouraging results, it is unknown 1) whether the identified neurocognitive risk factors of recurrence can be replicated in a larger independent sample, 2) whether MRI could be replaced by additional psychological/biochemical measures for individual risk prediction 3) whether the neural signature is associated with the only established biochemical correlate of recurrence risk (cortisol response), and 4) how this increases vulnerability to recurrence after stressful life events measured weekly via a mobile app. AIMS/METHODOLOGY To answer these questions, we propose to enrol 150 medication-free patients recovered from MDD as in our previous study. Initial MRI and cortisol measures will be used to predict recurrence after 14 months. IMPACT This project will enhance our understanding of recurrence risk factors, which is necessary to develop better long-term treatments by: 1) informing the design of future psychological and neuromodulation interventions, and 2) contributing to developing a prognostic marker for selection of patients at high recurrence risk in trials, thereby increasing statistical power for developing preventative treatments.


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