NIHRDataInsights/HRCSData huggingface dataset:
Title: An integrative approach to unravelling the aetiology of ASD and ADHD in early adulthood: neurophysiology and development in twins
Funder: Medical Research Council

Abstract: Aim: To investigate the aetiology and neurophysiology of ADHD and ASD and associated outcomes in young adulthood. Objectives: (1) To investigate genetic and environmental origins of cognitive-neurophysiological biomarkers of ADHD and ASD in emerging adulthood. (2) Document the aetiological influences and cognitive impairments associated with persistence of ADHD and ASD following high levels of symptoms in middle childhood. (3) To characterize the aetiological relationship between general functioning and mental health and neurophysiological function in young adults with ADHD and/or ASD. Methodology: The research will capitalise on two existing well-characterised sub-cohorts from the MRC-funded Twins Early Development Study (TEDS) that were enriched for ADHD and ASD symptoms in middle childhood (12-15 years). We will assess 300 twin pairs at ages 22-23 on a triad of measurements: (a) cognitive-neurophysiological assessments using EEG during tasks that the applicant and others have previous validated as sensitive to ADHD and ASD in childhood and adulthood; (b) in-person assessment using gold-standard diagnostic tools to obtain rates of ASD, ADHD and co-occurring ASD+ADHD in early adulthood; and (c) in-person interviews focused on mental health problems (anxiety and depression) and adaptive functioning. We will estimate genetic and environmental sources of variance and co-variance between neurophysiological impairment, ADHD and ASD symptoms and mental health/functional outcomes using the quantitative genetic MZ-DZ twin design. Additional longitudinal analyses will investigate influences on stability of ADHD/ASD diagnosis/symptoms and cognitive impairment outcomes. Scientific and clinical opportunities: This project could substantially advance understanding of ADHD and ASD in young adulthood, including risk for poor outcomes, ultimately to provide optimal targets for effective intervention and treatment.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT
Health categories: MENTAL HEALTH
Title: Understanding the neural and cognitive mechanisms of attributional styles and credit assignment in depression
Funder: Medical Research Council

Abstract: Depression is the most common mental illness. In the past, depression has been linked to negative biases in perception, attention or memory. In particular, cognitive theories of depression have suggested negative attributional styles as the root cause of depression. However, the cognitive and neural mechanisms underlying this are not yet known. Recent advances in computational cognitive neuroscience have put forward quantitative descriptions of credit assignment, i.e. learning about the causes of events. I propose to investigate the cognitive and neural mechanisms of different aspects of credit assignment and test whether it can be used to provide an account of neural activity and behaviour associated with attributional styles in depression. I will compare the behaviour of depressed patients with non-depressed participants and measure the neural mechanisms associated with the behaviour. The experiments I propose, focus on 1) how positive or negative events are attributed, to either to the self, environmental features or remain unassigned, 2) how attributions are made to the self or other people and how this information influences social decisions, 3) how emotional responses (as opposed to simpler, more concrete outcomes) are attributed, and how they might, if they unattributed or incorrectly attributed, interfere with other behaviours. To address these questions, I will combine approaches from cognitive neuroscience and psychology. To characterize the behavioural effects, approaches will include computational modelling using approaches from machine learning, Bayesian optimal learning theory and hierarchical modelling. The neural mechanisms and changes in depression will be probed using computational analyses of functional magnetic resonance imaging (fMRI) data involving modelling and pattern classification techniques. The causal involvement of the areas identified using fMRI will be further probed using transcranial direct current stimulation (tDCS).


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;2.3 PSYCHOLOGICAL, SOCIAL AND ECONOMIC FACTORS
Health categories: MENTAL HEALTH
Title: A multi-omic approach to investigating biological mechanisms related to the aetiology and treatment of major depressive disorder.
Funder: Medical Research Council

Abstract: We will investigate three biological processes associated with major depression disorder (MDD), to discern whether they are causally related, these include: (i) shorter leukocyte telomere lengths; (ii) increased circulating interleukin-6 (IL-6) levels; and (iii) reduced hippocampal neurogenesis (HN). Furthermore, we plan to investigate biological mechanisms mediating antidepressant response. We will achieve this by considering the following aims: (A) The heritability of (i) telomere length and (ii) interleukin-6 levels, and its genetic correlation with MDD. By performing a GWAS and applying genomic-relatedness-matrix restricted maximum likelihood analysis, we will determine: (a) heritability estimates for each biomarker; (b) whether genes responsible for moderating (i) telomere length, or (ii) IL-6 levels, correlate with genes predicting MDD case/control status. (B) Generation of robust polygenic risk scores for (i) leukocyte telomere length and (ii) IL-6 levels. This will involve generation of polygenic risk scores in large GWAS data 'training cohorts' and validating them in other independent 'test cohorts'. (C) To test whether genes predictive of (i) leukocyte telomere length and (ii) IL-6 levels are causally related to MDD. We will apply polygenic risk scores generated in (B), and use Mendelian randomization methods to test if these mechanisms are causally related to MDD. (D) To determine if hippocampal neurogenesis is involved in the pathophysiology of MDD. Through the application of WGCNA to expression data we will determine gene sets driving hippocampal neurogenesis. We will then use genetic pathway analysis to test if genetic differences within this gene set are enriched for associative signal within MDD GWAS data. (E) To determine mechanisms underlying antidepressant response. We will apply genetic pathway analysis to antidepressant pharmacogenetic GWAS data, and test for enriched GO terms, and gene sets relating to antidepressant-induced HN.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: MENTAL HEALTH
Title: A randomised placebo-controlled trial of immunotherapy in patients with psychosis associated with anti-neuronal membrane antibodies (SINAPPS 2)
Funder: Medical Research Council

Abstract: In three separate studies, we found 6-7% of patients with first-episode psychosis had autoantibodies to the N-methyl D-aspartate receptor or the voltage gated potassium channel complex, at high concentration: 3/46 patients in our initial study (Zandi et al., 2011), 14/230 in the MRC-funded PPiP1 study and 3/59 in PPiP2. We have also shown that 2/3 with high antibody levels are resistant to antipsychotics but respond well to immunotherapy (Zandi et al., 2014). We propose a randomised double-blind placebo-controlled trial of immunotherapy as add-on to standard anti-psychotic treatment of antibody-associated psychosis, widening the inclusion criteria to improve recruitment to either first episode psychosis or in relapse. Screening c. 2460 patients with psychosis to identify 160 suitable patients with associated autoantibodies, we shall recruit 80 patients into the trial, following each for 12 months. The primary outcome is time to remission of psychosis, sustained over 6 months (Andreasen et al., 2005). We estimate 20% of placebo-treated participants will achieve this endpoint at one year and that, having discussed with our patient partners, a meaningful treatment effect would be sustained remission in 50%. This can be detected at 80% power with a one-sided p=0.05 with n= 80, allowing for 24 drop outs. A network of neurologists and psychiatrists at 6 sites (Oxford, Cambridge, Birmingham, Nottingham, Southampton and Manchester) are already testing the feasibility of recruitment and immunotherapy of this challenging patient group in the SINAPPS1 study funded by the Stanley Medical Research Institute (Sec 6.8). Now, SINAPPS2 will randomise patients to receive IVIG (2g/kg over 4 days) followed by two rituximab infusions over the next six weeks. Samples collected in this study from people with acute psychosis will be a substantial resource for later discovery science. This study has profound implications for the understanding and management of psychosis.


Research activity codes: 6.1 PHARMACEUTICALS
Health categories: MENTAL HEALTH
Title: Intellectual Disability and Mental Health: Assessing Genomic Impact on Neurodevelopment (IMAGINE)
Funder: Medical Research Council

Abstract: Our study aims to evaluate the impact of rare CNV on risk of mental health disorder in childhood and adulthood by utilizing data on individuals with ID tested by array CGH within NHS UK genetics services. From data mining and prospective recruitment, we will focus on clinically significant CNV (and - potentially - on SNV too). We will be conducting internet-based population phenotyping on up to 5000 children by June 2019. We take advantage of existing NHS resources and validated, inexpensive and appropriate methodologies for on-line phenotyping [84% of UK families have internet access at home]. The study offers remarkable value for money. It comprises two primary workstreams (WS1 & WS2), which are closely interconnected and complementary. First, a national 'extensive' survey of children with ID who possess CNV abnormalities reported as clinically significant from aCGH, based on data mining and prospective recruitment from UK Regional Genetics Centres (RGC). WS1 focuses on behavioural adjustment in children of school age. Nearly all assessments are on-line, or by telephone, using standardized measures of behavioural adjustment, social circumstances and medical history. Recruitment commenced in 2015. WS2 is conducting an 'intensive' phenotyping of individuals with CNV-associated ID, focusing on a small number of genetic anomalies previously reported to be associated with high risk of adverse mental health outcome and poor adaptive functioning [especially deletions at 1q21.1, 15q11.2, 15q13.3, 16p11.2]. Children with the selected CNVs are sourced from the national phenotypic study. Adults with ID carrying the same CNVs, also sourced from UK NHS RGC, will be recruited to study long-term outcomes. Dedicated research teams test participants in their homes. Over the past year, we have completed a feasibility study that has achieved all our objectives. We have shown that online testing yields valid data on adjustment and that it is acceptable to families.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: MENTAL HEALTH
Title: The Computational Psychiatry of Major Depressive Disorder
Funder: Medical Research Council

Abstract: Aims. I will develop tasks to quantify (using computational models) behaviour and mood in multiple decision domains affected by depression. These tasks will allow identification of candidate behavioural biomarkers for patient stratification for use in rapid assessment and treatment assignment. Methodology. I will use computational modelling to quantify decision making and mood in three behavioural tasks, providing a wide range of measures that might be affected by antidepressant medication and by depression. Functional MRI scanning of depressed patients will allow examination of the neural circuits that determine mood and behaviour in health and in depression. I will use pharmacological studies in healthy and depressed subjects to examine effects of two different types of antidepressants (a serotonergic drug and a glutamatergic drug) on behaviour and mood. I will combine lab testing with smartphone-based data collection to longitudinally track remitted medication-free patients over 14 months, to look for predictors of relapse based on behaviour/mood model parameters. Scientific and Medical Opportunities. This project will provide important insights into the computational and neurobiological mechanisms that determine mood in healthy and depressed subjects. It will test a novel lab-smartphone approach that aims to provide longitudinal data in depressed subjects that may predict relapse probability. Behaviour/mood parameter measurements before ketamine treatment may be useful for predicting which patients are mostly likely to respond to that treatment. Pharmacological results will increase knowledge of the roles of serotonin and glutamate in decision making and mood. Clearer understanding of the neural mechanisms that underlie decision making and mood that are affected by depression and antidepressant treatment could have significant medical benefit for improving the assessment and treatment of depression.


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: Preterm birth and neuropsychiatric genetic risks: a pilot investigation
Funder: Medical Research Council

Abstract: Preterm birth and genetic inheritance are two potent, very early risk factors for neuropsychiatric disorders. Our aim is to utilise a large, on-going UK database that includes very preterm births (<32 weeks gestation) to resolve important questions about the relationships between these risk factors and later neuropsychiatric disorder. Why do we need to address these questions now? It is because preterm birth rates have risen sharply in the last few decades to around 10-15%, survival has improved to over 90% and at least 1 in 4 of those born preterm develop an impairing psychiatric disorder by childhood. However, not all do and the reasons for variation in mental health outcomes are uncertain. Some preterm birth studies suggest a family history of psychiatric disorder further contributes to risk, others suggest it might not. Alternative investigations indicate preterm birth is a marker of pre-existing fetal genetic or developmental anomaly which could overlap with neuropsychiatric genetic risks. For this proposal, we will capitalise on the existence of the UK Neonatal Collaborative which involves all neonatal units in England, Scotland and Wales (n=200) and the National Neonatal Research Database (NNRD) that holds rich clinical and demographic data on all babies admitted to these NHS neonatal units (~6,000 very preterm births per year). The first aim involves testing one genetic hypothesis, that one class of neuropsychiatric genetic risk, namely rare (<1%) CNVs, is enriched in a very preterm birth sample of n=500. The second aim is to examine, in partnership with families, clinicians, researchers and the national newborn charity and parent advocacy organisation, Bliss, the processes that will enable us to conduct a future, prospectively phenotyped, whole-population genetic study. This would include electronically-linking anonymised genetic data to UK health outcome information and creating a "consent-to-contact" sample to permit future direct phenotyping.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: MENTAL HEALTH
Title: Neurobehavioural mechanisms of addiction: vulnerability, circuits and drug memories
Funder: Medical Research Council

Abstract: This programme has three overarching aims: (i) to test the hypothesis that loss-of-control over drug seeking habits is the basis of compulsive drug use; (ii) to specify the underlying circuitry and mechanisms; (iii) to define vulnerability traits that predict the propensity compulsively to seek drugs, and identify their neural correlates; (iv) further investigate the mechanisms of drug memory plasticity, especially reconsolidation, extinction and interactions between them, at molecular and systems levels. In (i), we propose to use our refined models of compulsive cocaine, heroin and alcohol seeking and in (ii) investigate causal mechanisms in underlying circuitry using chemogenetic (DREADDs) and optogenetic techniques, as well as in vivo electrophysiology. By comparing three addictive drug classes, we seek to define commonalities and differences in the underlying psychological mechanisms and neural circuitry, involving the amygdala, ventral and dorsal striatum, prefrontal and insula cortex. In (iii) we will use longitudinal MRI, combined with in vivo electrophysiology and 'hotspot' molecular imaging to identify the neural correlates of behavioural traits associated with addiction (e.g. impulsivity, locomotor reactivity to novelty, anxiety, novelty preference, sign/goal tracking, decision-making, response learning) and then investigate the degree to which they predict the development of compulsive drug seeking. Thus, we seek to define 'addiction neurobehavioural endophenotypes' across three major addictive drug classes. In (iv) we will use our established behavioural approaches to define the molecular and neural systems basis of drug memory destabilisation, restabilisation (reconsolidation), extinction and 'super-extinction' and the degree to which the impact of drug-cue elicited memories can be diminished to reduce the propensity to relapse, including in animals that compulsively seek drugs. This approach has significant potential for translation to the clinic.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: MENTAL HEALTH
Title: MICA: Targeting neuro-inflammation in Schizophrenia
Funder: Medical Research Council

Abstract: Schizophrenia affects about 1 in 100 people and is a leading cause of disability in adults. Current drug treatments, antipsychotics, are not effective or poorly tolerated in ~three-quarters of patients. Moreover, they essentially use the same dopamine receptor blocking mechanism. Therefore, there is an urgent need to identify alternative molecular targets to develop new treatment for this disorder. Recent studies have shown that microglia activation plays a role in schizophrenia. Activated microglia express high levels of TSPO. Studies using TSPO PET tracers, such as [11C]-PK11195, have shown increased binding in patients with schizophrenia with large effect sizes (from 0.9 to 1.8), and increases are also seen in the prodromal phase of schizophrenia. Greater TSPO binding was positively correlated with greater symptom severity. However, it is still unknown if activated microglia play a primary role in the symptoms and brain changes seen in schizophrenia or whether changes are of secondary relevance. The key test is to reverse microglial activation and determine the effect on symptoms. To achieve this purpose we will use natalizumab, a monoclonal antibody that specifically targets microglia. We have shown that this antibody reduces microglia activity in multiple sclerosis patients. In our study we will use [11C]-PK11195 PET imaging in conjunction with brain imaging, peripheral and central inflammatory markers and clinical assessment, in order to achieve the following objectives: 1) to assess if treatment with natalizumab will lead to a reduction in microglia activity when compared to placebo; 2) to determine if a reduction in microglial activity is associated with a reduction in schizophrenic symptom severity; 3) to determine if changes in microglial activity are directly associated with changes in pro-inflammatory cytokines; 4) to determine if changes in microglial activity are directly associated with structural brain changes.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: MENTAL HEALTH
Title: Selenium in early life to enhance neurodevelopment in unfavourable settings (SELENIUS)
Funder: Medical Research Council

Abstract: The project aims to evaluate the specific role of selenium (Se) in relation to other nutrients and trace elements in favouring brain and behavioural plasticity. The central hypothesis that will be tested is the role of oxidative stress and inflammation as key processes connecting diet, peripheral tissues and brain development. Two isocaloric diets differing in Se content will be given to pregnant and lactating female rats and to their offspring till adulthood. The role of Se in supporting brain and behaviour development will be also assessed in presence of lead (Pb) an environmental stressor able to affect cognitive development that is a concern in some European countries. The project has been organized in 5 work packages aimed at dissecting the effects of the different diets on behavioural development, cognitive functions, hippocampal synaptic plasticity and peripheral and central inflammation, using. ex vivo and in vitro approaches and transcriptomic, proteomic, metabolomics/lipidomic, measurement of oxidative stress and inflammatory pathways in different target organs. The offspring of the two sexes at different ages will be separately considered to emphasize sex-differences in neurodevelopment. The experimental studies will be reinforced by the observation obtained from an ongoing EU human birth cohort where exposure to Pb, micronutrients, lifestyle have been measured in children in association with assessment of cognitive, language and motor development.


Research activity codes: 2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT;3.3 NUTRITION AND CHEMOPREVENTION
Health categories: MENTAL HEALTH
Title: Identification of dietary modulators of cognitive aging & brain plasticity and proof of concept of efficacy for preventing/reversing cognitive decline
Funder: Medical Research Council

Abstract: There is a need to uncover the exact dietary bioactives that underlie an individual's risk and resilience to cognitive decline associated with ageing. Furthermore, the roles of dietary modulators must be understood at the neurobiological level to effectively exploit the protective bioactives identified, in order to develop targeted dietary interventions for the prevention and slowing down of cognitive decline. We hypothesize that (i) there exists a combination of dietary bioactives capable of modulating cognition and brain plasticity, (ii) dietary modulation of brain plasticity and cognition starts in early-life and occurs throughout life and (iii) exposure to stress/genetic predisposition are vulnerability factors to consider. We propose a translational project across nutrition, epidemiology, and neurosciences leveraging human data/serum samples and mouse models and using innovative approaches of: (i) dietary exposure assessment (the food metabolome), (ii) human brain plasticity (in vitro parabiosis to assess neurogenesis and microglial function, lipidomics to assess neuronal integrity), and (iii) cognitive ageing modeling (early-life stress mouse model). D-CogPlast will start with a discovery stage in humans, aimed at identifying a set of dietary bioactives from the food metabolome associated with cognitive decline, along with vulnerable populations, in 200 individuals with accelerated cognitive decline over 13+ years against 200 individuals with preserved cognition. This will be further validated in 400 participants from a separate cohort. The second stage will be to investigate the ability of the identified set of bioactives predictive of cognitive decline to modulate brain plasticity and neuronal integrity. The third stage will consist in a proof-of-principle dietary intervention with identified bioactives in a mouse model of cognitive decline.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT;3.3 NUTRITION AND CHEMOPREVENTION
Health categories: MENTAL HEALTH