NIHRDataInsights/HRCSData huggingface dataset:
Title: Disorders of attention, awareness and cognitive control
Funder: Medical Research Council

Abstract: Impairments in attention and control are common following acquired brain injury (ABI) and in developmental conditions. They are linked with impoverished outcomes and high costs for health, education and social services. This clinician-led clinical programme addresses fundamental questions of attention and cognitive control, and interactions between control processes and mood. Its aims are to translate from basic cognitive science, via proof-of-concept studies and trials, through to improving clinical practice and well-being. Work in the previous funding period has opened up a new methodological seam for developing our understanding on the hierarchical structure of complex behaviour. By examining processes in the establishment of goal-directed task episodes independently of the particular capacities required during the episode, we can more clearly understand the mechanisms of our rehabilitation interventions and develop new approaches. Discovery work will follow examining the generality of these findings, their neural signatures, their relevance to normal and impaired cognitive control and to mood disorder. It is clear within neuropsychological rehabilitation that simply targeting cognitive performance without considering the highly prevalent mood difficulties is unlikely to produce the hoped-for improvements in outcome. An important step is to develop our basic science examining interactions between cognition and mood following ABI and the effects of potential mood interventions. The longer-term aim will be to develop a brain injury toolkit for clinicians in which particular patterns of cognitive risk for mood disorder can be linked with specific evidence-based intervention recommendations. As with the development of our touchscreen tablet test battery (OCS-BRIDGE), we will approach this in a manner scalable to online provision, anonymous data collection and iterative assessment/intervention optimisation based on large datasets.


Research activity codes: 1.2 PSYCHOLOGICAL AND SOCIOECONOMIC PROCESSES
Health categories: MENTAL HEALTH
Title: A transdiagnostic, translational approach to the understanding, prevention and treatment of mood, anxiety and stress disorders across the lifespan
Funder: Medical Research Council

Abstract: Mood, anxiety and stress-related disorders are highly prevalent mental health difficulties that impact more than half of us during our lifetimes, with first onset typically during childhood or adolescence. They are a leading worldwide cause of disability, service use, economic cost and suffering. Even the best of our current interventions for these disorders leave around half of recipients with clinical levels of distress, with relapse and recurrence common. Improving the treatment and prevention of these conditions is therefore a priority. This translational programme leverages insights from basic discovery science (using a range of methods from neuroimaging, pharmacology, epidemiology and cognitive science), to generate or refine psychological preventions and interventions for these disorders. These interventions are then evaluated within gold-standard randomised controlled trials. The programme therefore spans the entire translational trajectory from theory through data synthesis and discovery cognitive neuroscience to exploratory, definitive and pragmatic trials in the health and education systems The programme is transdiagnostic. Rather than characterising these disorders as distinct diagnostic entities, our thesis is that there are compelling theoretical, empirical and clinical reasons to understand, prevent and treat these conditions collectively. We therefore conceptualise mood, anxiety and stressor disorders as a set of inherently inter-related problems arising from common biological and psychological processes that have become maladaptive, where patterns of dysfunction cut across traditional diagnostic boundaries.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;2.3 PSYCHOLOGICAL, SOCIAL AND ECONOMIC FACTORS;5.6 PSYCHOLOGICAL AND BEHAVIOURAL;6.6 PSYCHOLOGICAL AND BEHAVIOURAL
Health categories: MENTAL HEALTH
Title: A Youth Culturally adapted Manual Assisted Psychological therapy (Y-CMAP) for adolescent Pakistani patients with a recent history of self-harm.
Funder: Medical Research Council

Abstract: Design: A multi-centre single blind RCT with randomisation by individual patients to compare the Y-CMAP in addition to TAU with TAU alone. There is a built in 12-month internal pilot phase with clear stop/go criteria to prove viability to proceed to a full trial across all the study sites. The pilot phase will be judged successful if sufficient GPs, schools and hospitals are recruited to enrol 200 participants in the first 12 months. Assessments will be conducted for both the groups at baseline, 3 (end of intervention),6,9 and 12 months after randomisation Setting: Participants will be recruited from general practices, emergency departments, medical wards of participating hospitals and self-referrals. Intervention: Y-CMAP is based on the principles of Problem Solving and CBT. Sample size: This is based on the primary outcome, repetition of self-harm in 12-month period (yes/no). The TAU arm of the study has an expected self-harm rate of 20% and a clinically important effect would be a reduction to 7.5% in the intervention group. Under these assumptions, and assuming a 5% significance level and 90% power, a study with no clustering would require 158 patients per arm. The study has a partially nested design due to therapist clustering in the Y-CMAP arm. Based on previous analysis of therapist trials we believe that the ICC is likely to have a value between 0.01 and 0.05 for this type of outcome measure. Assuming an ICC of 0.05, and a cluster size of 16 patients per therapist, a Design Effect of 1.75 is calculated This increases the numbers required to 277 per group. Furthermore, there is expected to be a 15% loss to follow-up, and so the final numbers recruited will be 326 per group, 652 in total. Primary outcome measure: Repetition rate of self-harm at 12 months after randomisation as measured by the adapted Suicide Attempt Self-Injury Interview (SASII). Client Service Receipt Inventory (CSRI): We will collect information on the use of health and other services.


Research activity codes: 6.6 PSYCHOLOGICAL AND BEHAVIOURAL
Health categories: MENTAL HEALTH
Title: Mapping Neurodevelopmental Trajectories for Adult Psychiatric Disorder: ALSPAC-MRI-II
Funder: Medical Research Council

Abstract: The Avon Longitudinal Study of Parents and Children (ALSPAC) has shown that 9% of 18 year olds have psychotic experiences (PEs) such as hallucinations and delusions. When persistent, PEs are a strong risk factor for psychotic disorders (eg schizophrenia) and poor psychosocial outcomes. We have recently shown that at age 20, individuals from ALSPAC with PEs have subtle changes in regional brain volumes, and global and local connectivity that cannot be ascribed to the consequences of psychiatric treatment. In a related study, we showed that ALSPAC participants selected on the basis of a high psychosis risk score (PRS) derived from GWAS data also had subtle brain changes. Objectives: To re-scan the same individuals (n=450) at age 26 using multi-modal magnetic resonance imaging (MRI). We will test the hypothesis that persistent PEs are underpinned by anomalous trajectories of brain structural change and abnormalities in function, as compared with those without PEs and against their baseline scans. We will also plot changes in cognition and use the PRS to examine the potential of our brain measures as endophenotypes. Finally we will make use of blood-based inflammatory markers such as IL-6 taken in childhood and age 24, to examine their association with brain changes. Measures: We will use 3-T MRI to obtain detailed structural images of grey/white matter volumes and microstructural MR imaging for white matter tracts. Functional MRI will be carried out during a working memory task and at rest to determine the degree of physiological compromise/compensation in relation to PEs, as well as functional integrity of core cognitive hubs. This project will enable us to map neurodevelopmental changes in a well-studied epidemiological sample with PEs while adjusting for potential confounders. It has the potential to deliver important advances in our understanding of the biological basis of psychotic disorders and to inform primary prevention and early intervention strategies.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: MENTAL HEALTH
Title: THE IMPACT OF EARLY ADVERSITY ON TRAJECTORIES OF BRAIN MATURATION AND MENTAL HEALTH IN YOUNG ADOLESCENTS
Funder: Medical Research Council

Abstract: RESEARCH OBJECTIVES: Mental disorders usually develop in young individuals, and the risk is increased by exposure to early adversity, such as childhood maltreatment, adverse life events, and area-level disadvantage. We will establish: 1) How and when individual and area-level early adversity affects brain development (i.e., longitudinal growth trajectory of brain areas involved in psychiatric disorders, built on three longitudinal brain MRI scans); 2) Whether these alterations in growth trajectory are associated with the onset of specific psychopathology domains; and 3) If these alterations in growth trajectory are explained by persistent alterations in the levels of inflammatory markers. EXPERIMENTAL DESIGN: We will study n=440 children and young adolescents (age 11-14) from two funded school-based longitudinal cohorts. We will enrich the existing data by collecting additional neuroimaging and immune markers measures in n=220 subjects from each cohort, selected for presence (n=110) or absence (n=110) of early adversity: - In REACH (UK; original sample n=4010), with three MRI assessments over three years, and serum samples for immune biomarkers; - In IMAGEN (Six EU countries; original sample n=2000) (three MRI assessments already available), with measures of immune markers in already collected serum samples; We will model the relationship between early adversity, brain growth, psychopathology domains, and immune markers, using multivariable statistical models. APPLICATION OF RESULTS: Characterising the biological changes associated with risk of mental health problems can ultimately provide evidence for targeting interventions to the most vulnerable individuals.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: MENTAL HEALTH
Title: Recognition of non-emotional bodily states in the self and others: A novel investigation in autism and eating disorders
Funder: Medical Research Council

Abstract: The project will investigate the ability to recognise one's own and others' non-emotional (as opposed to emotional) internal bodily states. Many individuals with psychological disorders, including Autism Spectrum Disorder (ASD) and Feeding and Eating Disorders (EDs), have impaired interoception - the process of perceiving signals from inside one's body (such as cardiac and respiratory signals, temperature, pain, nausea, hunger, and satiety). Difficulties recognising one's own emotions is associated with difficulties recognising others' emotions (e.g. from facial expressions). It is therefore likely that difficulties recognising one's own non-emotional bodily states are associated with difficulties recognising others' non-emotional bodily states, due to poor understanding of these states. Failing to recognise that another is experiencing nausea, pain, hunger, etc. will impair social interactions, as the observer would fail to respond to the individual appropriately. Further, one's ability to recognise these states in others is likely to affect one's ability to care for them, for example if one has a role caring (e.g. as a parent or in a medical setting). The project will investigate recognition of one's own and others' non-emotional bodily states in three groups of people: those with ASD, those with EDs, and control participants with no past or present mental illness. Three tasks will be used to assess recognition of others' bodily states in different modalities (static images of body postures, dynamic point light displays and auditory vocalisations). A training study will determine whether improvement of one's own interoceptive abilities leads to better recognition of others' bodily states. A final study will determine whether individuals can recognise genuine, naturally evoked bodily states, rather than bodily states that are posed by actors. Findings are expected to inform clinical interventions to improve recognition of one's own and others' bodily states.


Research activity codes: 2.3 PSYCHOLOGICAL, SOCIAL AND ECONOMIC FACTORS
Health categories: MENTAL HEALTH
Title: Identifying and characterising a cellular blood biomarker in treatment-resistant depression
Funder: Medical Research Council

Abstract: Background: There is an increasing appreciation that interactions between the immune system and the brain are clinically important. Animals and humans exposed to inflammatory insults demonstrate sickness behaviours that are similar to clinical features of major depressive disorder (MDD). Some patients with MDD have increased circulating levels of pro-inflammatory markers. Treatment resistant depression (TRD) is particularly associated with immune abnormalities including increased circulating CRP and IL6, and increased whole-blood IL1B and TNF gene expression. However, effect sizes from current whole-blood assays are too small for their use as clinical biomarkers in depression, possibly because the disease-related signals are diluted or obscured by the heterogeneous mixture of cells in peripheral blood. Objectives: We aim to develop a cell-subset specific biomarker of inflammation in TRD, with a larger effect-size than current whole-blood markers. On the basis of animal models and preliminary human data, we hypothesise that patients with TRD have increased numbers of inflammatory, glucocorticoid-resistant monocytes in peripheral blood. We thus expect to find this biomarker within a monocyte subset. Methods: To develop this biomarker, I will conduct a series of experiments. Initially, I will use cytometry and RNA sequencing data to investigate the peripheral immune profile of TRD at progressively finer scales of cellular resolution, from PBMCs to sorted cell subsets to single cells. Subsequently I will optimise a more pragmatic qPCR or cytometry biomarker of TRD, and test whether this new biomarker can predict treatment response in an upcoming trial of a novel anti-inflammatory drug for TRD. Opportunities: This proposal leverages newly available datasets and the latest cellular processing technologies to advance the development of biomarkers, and to provide mechanistic insight into the cellular changes underlying the inflammation associated with TRD.


Research activity codes: 4.2 EVALUATION OF MARKERS AND TECHNOLOGIES
Health categories: MENTAL HEALTH
Title: Fentanyl Overdose Deaths: Underlying Mechanisms
Funder: Medical Research Council

Abstract: Fentanyls have become deadly drugs of abuse in the USA. Fentanyl interacts primarily with mu opioid receptors (MOPr) and is 50 - 100 times more potent than morphine in depressing respiration. In vitro studies on recombinant MOPrs do not predict that fentanyl would be more potent in vivo than other opioids such as morphine. We hypothesise that fentanyls interact with MOPr in novel ways that do not conform to classical theories of ligand-receptor binding. To facilitate the development of effective interventions to combat overdose we need a full understanding of why fentanyls are so potent, why they are more resistant to naloxone reversal and whether they are still effective in individuals tolerant to other opioid drugs. We propose - to utilise time-resolved Forster Resonance Energy Transfer to study whether fentanyls exhibit rapid drug-receptor association kinetics allowing them to rebind and reactivate MOPrs rather than diffuse away from the vicinity of the receptors. - to assess the degree to which increased lipophilicity promotes plasma membrane interactions, increasing the local concentrations of fentanyls in the vicinity of the MOPr. - to perform Molecular Dynamics simulations of ligand-MOPr interactions to determine whether fentanyls can access the binding pocket of the receptor directly from the membrane lipid through a hydrophobic pathway. - to use the data gathered above to develop a mathematical model of agonist rebinding in situations of limited diffusion (e.g. interstitial spaces). - to monitor respiration and respiratory muscle rigidity in mice to examine how fentanyls depress respiration and to determine the contribution of chest wall rigidity. - to examine whether highly lipophilic MOPr antagonists more readily reverse respiratory depression by fentanyls. - to determine whether 'on top' use of fentanyls can break through tolerance to respiratory depression that has been induced by prolonged exposure to heroin, methadone or buprenorphin


Research activity codes: 2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT
Health categories: MENTAL HEALTH
Title: Analysis of the substrate network and neurodevelopmental functions of the intellectual disability enzyme, zDHHC9
Funder: Medical Research Council

Abstract: Mutations in the ZDHHC9 gene cause intellectual disability, epilepsy, hypotonia, and speech and attention deficits. These physiological changes are accompanied by hypoplasia of the corpus callosum, a brain region that connects the cerebral hemispheres. ZDHHC9 encodes an enzyme that mediates S-acylation, an important post-translational modification of intracellular proteins. We have investigated the effects of knocking out (KO) Zdhhc9 in mice. Analyses of these mice uncovered learning and memory deficits and hypotonia, consistent with the phenotype of humans with ZDHHC9 mutations. In addition, the mice exhibit anxiety changes that are common in other mouse models of intellectual disability. Furthermore, MRI-based volumetric analysis showed that the corpus callosum is reduced by 36% in Zdhhc9 KO mice compared to their wild-type littermates. Overall, these findings provide compelling evidence supporting the utility of the Zdhhc9 KO mice to investigate molecular and cellular changes that lead to neurological impairments in humans. With this in mind, the aims of this project are to: (i) identify cellular and molecular changes underlying corpus callosum hypoplasia in KO mice; (ii) identify the brain substrate network of zDHHC9, and pinpoint substrates linked to corpus callosum hypoplasia; and (iii) determine if the KO mice exhibit the full spectrum of deficits seen in humans with ZDHHC9 mutations by analysing oromotor and attention behaviour. Addressing these aims will provide new insight into the molecular and cellular pathways linked to intellectual disability and other neurodevelopmental deficits in humans with ZDHHC9 mutations, and may also unveil novel pathways that are disrupted in similar but more common neurological disorders.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: MENTAL HEALTH
Title: Emotional dysregulation, self-harm and eating disorders: a mechanistic investigation
Funder: Medical Research Council

Abstract: Self-harm has a prevalence of 13 - 18% in adolescence. It is associated with a range of adverse outcomes, including increased risk of suicide. Eating disorders have a prevalence of 6% in adolescent girls and a standardised mortality ratio of 2 - 6. There is significant comorbidity: up to 50% of those with an eating disorder self-harm, and 25% of the excess mortality in anorexia nervosa is due to suicide. Yet, we know little about why these mental health conditions co-occur. One possible common precursor is emotional dysregulation, the inability to be aware of, accept, regulate, and modify emotional reactions. To enhance knowledge about possible aetiological links between emotional dysregulation, eating disorders and self-harm, we propose a mixed-methods investigation with three studies. Study 1: Using existing data from a large population-based cohort study (ALSPAC), we will investigate associations between childhood emotional dysregulation and later self-harm and eating disorders. We will also investigate three plausible mediators in the pathway between emotional dysregulation and later self-harm and eating disorders: facial emotion recognition, social cognition and bullying. Study 2: A longitudinal Ecological Momentary Assessment study, in 12-25 year olds with self-harm and/or an eating disorder. Participants will be asked to rate their emotions, thoughts and behaviours on a smart phone, at 4 times each day for a fortnight. They will be followed-up 3 months later. Study 3: A longitudinal qualitative study, nested within Study 2. We will explore young peoples' experiences of managing difficult emotions, and how these relate to their self-harm and eating disorder behaviour. This work will advance knowledge of the aetiology of self-harm and eating disorders, and could lead to novel approaches for prevention and treatment.


Research activity codes: 2.3 PSYCHOLOGICAL, SOCIAL AND ECONOMIC FACTORS
Health categories: MENTAL HEALTH
Title: Establishing causal relationships between biopsychosocial predictors and correlates of eating disorders and their mediation by neural pathways
Funder: Medical Research Council

Abstract: This project aims to identify early biomarkers of eating disorders (EDs) by applying Big Data methods to the rich database derived from a representative population of adolescents and a clinical sample of emerging adults with a current or previous ED diagnosis. First, we investigate causality of ED risk factors in the IMAGEN population cohort of n=2000 male and female adolescents followed-up at ages 14, 16, 19 and 23 years. We will investigate how biopsychosocial correlates and environmental risk factors such as adverse life events will influence these relationships and how their effects may be mediated by alterations in neural networks. Next, we will use machine learning procedures based on cross-validated regularised logistic regression combining neuroimaging, genomic and psychometric data modalities to identify correlates of EDs and select the features that best classify individuals who endorse ED symptoms along with those who endorse no ED symptoms at any time point. To identify predictors of ED symptoms, we will use age 14 IMAGEN data to compare individuals who developed ED symptoms over time (symptoms absent at age 14 but present at later ages), or those who recovered (symptoms present at age 14, not at later ages) to those who never developed symptoms. Finally, we will select the most predictive and easily applicable components of our comprehensive profile for validation in a clinical sample. These will be patients aged 18-25, with a 1st episode of DSM-5 AN or BN at first assessment (baseline) and followed-up with a second (after 2-years) assessment as well as patients fully recovered from a AN or BN diagnosis (n = 50 /diagnosis). All groups will be assessed through standardised protocols in a way identical to IMAGEN. This paradigmatic multimodal approach, in which neuroimaging may provide added value compared with the existing standard assessments, may yield potential application for early and differential ED diagnoses.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;2.3 PSYCHOLOGICAL, SOCIAL AND ECONOMIC FACTORS
Health categories: MENTAL HEALTH