NIHRDataInsights/HRCSData huggingface dataset:
Title: The role of chromatin remodelling factors in cerebellar development and autism
Funder: Medical Research Council

Abstract: Autism is a complex genetic disorder that affects social development. Recent advances have led to the identification of several autism-associated genes. This proposal will examine the neurodevelopmental role of two of these genes, the chromatin-remodelling factors CHD7 and CHD8. CHD7 is mutated in CHARGE syndrome, which is a syndromic form of autism. We have recently produced new mouse models that reveal key functions of CHD7 in the development of the cerebellum, a part of the brain that is consistently reported to show neuro-anatomical defects in autistic patients. We will use these mouse models to test important questions about the relationship between the genetic control of cerebellar development and autism. First, we will determine the developmental and epigenetic mechanisms that underlie these cerebellar defects. Second, we will use mouse models in which CHD7 is specifically deleted from the developing cerebellum to test to what extent cerebellar defects are responsible for some of the behavioural features characteristic of autism; a critical question remaining in the field. We will build on this model to explore the significant association of CHD8 haploinsufficiency with non-syndromic autism. CHD7 and CHD8 proteins directly interact and our preliminary studies suggest that CHD8 and CHD7 might regulate similar pathways during cerebellar development. To define the mechanisms whereby CHD8 deficiency causes autism, we will identify the functions of CHD8 in brain development and determine the behavioural consequences of CHD8 deletion from the developing cerebellum. Together, these studies will identify new epigenetic mechanisms that can cause cerebellar defects and determine the consequences of cerebellar hypoplasia, in the absence of primary defects in the neocortex, on behaviours characteristic of autism.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: MENTAL HEALTH
Title: LONG TERM NEUROBIOLOGICAL IMPACT OF EARLY DEPRIVATION: IMAGING YOUNG ADULT BRAIN STRUCTURE AND FUNCTION IN THE ENGLISH AND ROMANIAN ADOPTEES STUDY.
Funder: Medical Research Council

Abstract: Our goal is to examine the long term impact of severe early deprivation on adult brain development. Brain imaging experiments will be undertaken with a large cohort of 'orphans' who, following exposure from birth to appalling conditions in Romanian institutions of the 1980s, were adopted to homes in the UK. This sample has already given a rich longitudinal database (follow-ups at 4, 6, 11 and 15 years) and, with ESRC support, we are currently collecting further data from adoptees as they achieve adulthood. The proposed work will build both on this and on a successful imaging pilot study focusing on brain regions thought to be sensitive to early deprivation. Our primary cohort will be compared to: (a) a native UK adopted group; (b) a group of non-adopted non-deprived controls; and-because a subset of the primary cohort have diagnoses of either Autism or ADHD-two groups of non-adopted/non-deprived clinical controls (c) with Autism and (d) with ADHD. By examining the neural impact of the deprivation in relation to its temporal parameters, and by comparing between groups as appropriate, we can address fundamental questions about brain plasticity, sensitive periods, the heterogeneity and specificity of deprivation effects, and the mechanisms of adult psychopathology. We will assess putative adversity-sensitive brain networks using state-of-the-art MRI facilities and imaging techniques. Structural data (volume; cortical thickness and folding; white matter connectivity) will be obtained using T-1 weighted and diffusion tensor imaging. fMRI will record activation generated in networks believed sensitive to early adversity as participants undertake carefully chosen experimental tasks. Biological samples currently being collected will be used to examine whether the effects of deprivation (a) are mediated by alterations in the brain networks controlling stress reactivity; and (b) are moderated by genes controlling brain development.


Research activity codes: 2.3 PSYCHOLOGICAL, SOCIAL AND ECONOMIC FACTORS;2.4 SURVEILLANCE AND DISTRIBUTION
Health categories: MENTAL HEALTH
Title: Molecular mechanisms of long-term Depression in the hippocampus
Funder: Medical Research Council

Abstract: Synaptic plasticity is the process by which synapses can alter their efficiency of transmission; the two main forms are long-term potentiation (LTP) and long-term depression (LTD). The principal excitatory neurotransmitter in the brain, L-glutamate, has its physiological actions via three types of ionotropic receptors, named after the agonists N-methyl-D-aspartate (NMDA), alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) and kainate, as well as a family of G-protein coupled, metabotropic glutamate receptors (mGluRs). Since the discovery that NMDA receptors (NMDARs) are the trigger for LTP at CA1 synapses in the hippocampus and that they are involved in hippocampal-dependent learning and memory it has become very evident that NMDAR-dependent LTP (NMDAR-LTP) is critical for a variety of cognitive processes. More recently, evidence has been accumulating for the importance of LTD, triggered by the activation of NMDARs or mGluRs, in various forms of learning and memory. These plastic processes are critical throughout life, from the connections made during development through to explicit forms of learning and memory into adulthood. Increasingly it is being realised that alterations in LTP and LTD contribute in various ways to a variety of neurological and psychiatric disorders, such as dementia, epilepsy, depression and schizophrenia. For example, we have recently made molecular links between plasticity and disease, which suggests to us that dysregulation in synaptic plasticity may directly contribute to the aetiology of a condition. The purpose of this proposal is to understand how signalling pathways regulate synaptic plasticity in the hippocampus. We will investigate the roles of protein tyrosine kinases/phosphatases in the signalling mechanisms, Ca2+ signalling and how it relates to receptor trafficking . We shall also investigate how these signalling mechanisms relate to plasticity in vivo.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: MENTAL HEALTH
Title: TUNING THE NEURAL CIRCUITRY OF AFFECTIVE BIASES IN DEPRESSION
Funder: Medical Research Council

Abstract: The key methodologies recruited to clarify the reward and punishment circuitry in depression, in order of application throughout the proposed project, are as follows: 1) Computerised tasks will be designed to assess reward and punishment processing circuits. These tasks will use stress of unpredictable electrical shock as novel way to provoke these circuits. One task will assess perception of rewarding and punishing stimuli, whereas the other will assess learning about rewards and punishments under stress and stress no conditions. The speed and accuracy of responding during these tasks will be compared across healthy and depressed individuals. 2) These tasks will then be completed by healthy and depressed individuals in a brain (Magnetic resonance imaging; MRI) scanner so as to examine the neural circuitry involved in reward and punishment processing. 3) Complex statistical analyses (Dynamic causal modelling; DCM) will be completed on the brain imaging data to examine the interactions between brain regions during these tasks. 4) Computational models of reinforcement-learning - which help describe the way that reward and punishment information is processed in the brain -will be used in combination with the brain imaging data to compare the way that healthy and depressed individuals process information. 5) A novel computerised treatment for depression (a 'cognitive vaccine') will be designed for both the healthy and patient populations in an effort to promote the processing of rewards relative to punishments. The effects of this on circuitry will be examined by MRI scanning. 6) Healthy individuals will complete a 3 week selective serotonin reuptake inhibitor (SSRI) antidepressant course (or matched placebo) and the impact of serotonin increases upon these circuits will be examined. 7) New high resolution imaging techniques will be used to examine the impact of SSRIs on processing in small brain regions (e.g. the habenula)


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;6.1 PHARMACEUTICALS
Health categories: MENTAL HEALTH
Title: Neurobiology of response to clozapine in treatment resistant schizophrenia
Funder: Medical Research Council

Abstract: The aim of this research is to understand the neurobiology of response to clozapine in treatment resistant schizophrenia (TRS), as this will aid future drug development and support earlier clozapine initiation in patients most likely to benefit. Our recent research suggests that TRS may be associated with increased glutamate levels in the anterior cingulate cortex, which may explain why dopaminergic antipsychotics fail in these patients. There is some evidence that clozapine may alter brain glutamatergic and GABAergic neurotransmission, but this has never been tested directly. We hypothesise that response to clozapine in TRS will be associated with increases in GABA, decreases in brain glutamate levels and decreases in regional brain perfusion. Our secondary hypothesis is that patients with the lowest GABA and perfusion and highest glutamate levels before starting clozapine will show the greatest response to treatment. The sample will include 60 patients with TRS. All data will be acquired before and after 12 weeks of clozapine treatment. Regional brain glutamate and GABA levels will be estimated using proton magnetic resonance spectroscopy (1H-MRS), and perfusion using pulsed continuous arterial spin labelling (pCASL) in a single MRI scanning session. Severity of schizophrenia symptoms will be assessed, primarily using the positive and negative syndrome scale. Analysis will determine the associations between changes in brain glutamate, GABA and perfusion levels and symptomatic response to clozapine. In a second analysis we will determine these neuroimaging variables at baseline are predictive of subsequent response, using multivariate pattern recognition analysis will be used to classify the cases according to clinical outcome (response versus non-response). This research will aid the development of new (non-dopamiergic) antipsychotics, and biomarkers to predict response to clozapine or stratify patients in clinical trials of new drugs.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES
Health categories: MENTAL HEALTH
Title: Bipolar Lithium Imaging Structure and Spectroscopy
Funder: Medical Research Council

Abstract: AIM: To better understand lithium response in bipolar disorder (BD). OBJECTIVES: 1. Comprehensively evaluate the effects of lithium on the brain in BD. 2. Optimise and advance lithium multinuclear magnetic resonance (MR) techniques. 3. Characterise lithium response using clinical and biological data. METHODS: Euthymic adults with BD (type I or II) recruited from NE of England healthcare services, excluding patients with contraindications to MR scanning, current/recent harmful drug or alcohol use, comorbid diagnosis, impairment of capacity or current detention. Cross-sectional study of two groups: i) BD patients taking lithium for up to 5 years (n=80); ii) matched BD patients taking other mood stabilisers but naive to lithium (n=40). In a structured interview, diagnosis will be confirmed and a thorough clinical and archival assessment of each patient's BD undertaken. Blood samples will be taken for medication levels. Patients will complete tests of psychomotor processing speed and attention. MR sequences will include anatomical, quantitative relaxometry, diffusion tensor imaging, proton and phosphorous spectroscopy plus quantitative lithium spectroscopy and novel whole brain lithium imaging. ANALYSIS Complementary MR analyses to explore the influence of lithium within the frameworks of its actions on neuroprotection, cellular hydration and biophysical changes to the MR signal. With respect to lithium response, a new rating system will be developed; comparative and correlative analysis of MR, cognitive and clinical data will be performed; patients will also be clustered purely on the basis of their MR data before back-referencing to clinical characteristics. NOVEL OUTPUT 1. A new clinical tool for rating lithium response, suitable for future prospective investigation of predictive factors. 2. High resolution 3D Li7 imaging. 3. Robust MR measures of lithium's effects (accounting for its actions on hydration and signal generation)


Research activity codes: 4.2 EVALUATION OF MARKERS AND TECHNOLOGIES;6.1 PHARMACEUTICALS
Health categories: MENTAL HEALTH
Title: In vivo microstructural neuroimaging in infants at risk of developing neurocognitive delay or neurobehavioural disorders
Funder: Medical Research Council

Abstract: Background: The underlying neural substrates for childhood neurocognitive and neourbehavioural disorders are not well defined. We will assess neurite morphology in 3 groups of at risk infants to increase our understanding of the microstructural neuropathology associated with these conditions and establish new imaging biomarkers to identify infants who will benefit from treatment and assess efficacy of potential treatments. Aims: i. Assess neurite morphology (neurite density, Vic and orientation dispersion index, ODI) in 3 groups; preterm infants, infants with CHD and those at high risk of developing ASD, and compare these measures to those obtained in healthy controls. ii. Test the hypothesis that neurocognitive and neurobehavioural performance in these subjects at 2 years is associated with Vic and ODI measures in the early neonatal period. Methods: We will study 100 infants born at <32 weeks GA within 2 weeks of birth and at term, 100 term born infants at risk of ASD, 35 infants with CHD and 35 term controls. Perinatal clinical data will be collected. MRI will be performed on a 3T system sited on the Neonatal Intensive Care Unit. The precise parameters for d-MRI will be optimised, but we will acquire a low b value and a high b value shell. Measures of Vic and ODI will be obtained using neurite orientation dispersion and density imaging (NODDI) analysis. Group-wise voxel based and machine learning based analyses of standard diffusion (fractional anisotropy, FA, mean diffusivity, MD, axial and radial diffusivity, AD and RD) and NODDI measures will be performed to i. compare subject groups to term controls ii. Correlate Vic, ODI, FA, MD, AD and RD with neurodevelopmental performance at 2. Projected outputs: This work will provide improved imaging and analysis tools for the neonatal population, enhanced characterisation of brain development and injury and will facilitate the prediction of neurodevelopmental outcome and the testing of therapeutic interventions.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: MENTAL HEALTH
Title: Using Magnetoencephalography to Investigate Aberrant Neural Synchrony in Prodromal Schizophrenia: A Translational Biomarker Approach
Funder: Medical Research Council

Abstract: In this project, we will apply state-of-the-art magnetoencephalography (MEG) towards examining neural synchrony in participants at ultra-high-risk (UHR) for the development of schizophrenia (ScZ) with the aim of establishing a diagnostic index. Specifically, we will recruit 100 participants meeting UHR-criteria over a two year period from psychiatric services in Glasgow and Edinburgh as well as from the data base of the Edinburgh High Risk study. Following the initial assessment of UHR-status, monthly mental-state monitoring for the first six-months will be implemented to detect transition to psychosis. After this period, UHR-subjects will receive monitoring assessments every 3 months up to a total of 2 years. MEG-activity will be obtained during a visuo-spatial WM-paradigm as well as during a perceptual task which requires participants to detect a sine-wave grating. In addition, resting-state activity will be measured. Time-frequency representations will be estimated at the sensor and source-level. Moreover, time course of oscillatory activity within a specified frequency band will be investigated for source-connectivity based on a Partial Directed Coherence (PDC) approach and cross-frequency coupling. In addition to MEG-data, we will obtain estimates of GABA and Glutamate levels through proton magnetic resonance spectroscopy (MRS) to examine relationship between neural synchrony and excitatory-inhibition (E/I) balance parameters. MEG, MRS and MRI-measurements will be complimented by detailed psychopathological (CAARMS, SPI-A) and neuropsychological testing. To develop a diagnostic index, we will employ a multivariate machine learning technique towards the development of a biomarker which compares controls, converted and non-converted UHR-participants. This will be informed by our Information theoretic analysis of the different MEG-parameters as well as the complimentary information from neuropsychology, psychopathology and MRS-data.


Research activity codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES
Health categories: MENTAL HEALTH
Title: MICA: STRATA - Schizophrenia: Treatment Resistance And Therapeutic Advances
Funder: Medical Research Council

Abstract: A third of patients with schizophrenia fail to respond to standard dopamine-blocking antipsychotic drugs. This is a major clinical problem, causing immense personal and family suffiering and costing billions in health, social care and lost productivity. Two converging streams of findings from our consortium suggest that abnormalities of the glutamate system may identify patients who are non-responsive to dopamine blockers (T-Non-Resp). Imaging studies have shown that T-Non-Resp patients have abnormal glutamate systems, but seemingly normal dopamine systems. Meanwhile, genetic research has demonstrated that T-Non-Resp patients have an excess of genetic abnormalities in glutamate system pathways, but fewer abnormalities in dopamine pathways, than typical patients with schizophrenia. Fortunately, several pharmaceutical companies in our consortium are already developing drugs acting on the glutamate system which are currently in phase II/III. OBJECTIVES: (1) To develop an imaging and/or genetic based stratification strategy that will help identify patients who do not respond well to current dopamine-blocking treatments; (2) To develop a multi-centre clinical trials network to deliver standardised stratified clinical trials; (3) To develop a quantitative understanding of the health economic implications, patient and clinician acceptability of such an approach; (4) Using this network, to conduct a proof-of-concept stratified medicine trial, to test the ability of the stratifier to predict response to an add-on glutamatergic drug and improvements that a stratified approach would make to both clinical and pharmacoeconomic outcomes.


Research activity codes: 6.1 PHARMACEUTICALS
Health categories: MENTAL HEALTH
Title: A novel lithium-mimetic drug for the management of impulse control disorder
Funder: Medical Research Council

Abstract: Deficits in impulse control are a prominent feature of diverse psychiatric illnesses including bipolar and related mood disorders, addictions and impulse conduct disorders. Impulsivity is also strongly associated with suicidality and relapse to drug-seeking behaviour, and is a significant predictor of relapse and worse clinical outcomes in alcohol and substance dependence, and pathological gambling. Drug therapies of impulsivity are few, and those available are poorly tolerated as exemplified by lithium. Lithium is the mainstay therapy for bipolar disorder, reduces risk of suicide, and is effective in clinical trials of pathological gambling. Despite its significant benefits lithium is poorly tolerated, and has severe side-effects including renal damage. All this makes a compelling case to develop alternative drugs to control impulsivity. The solution may be a drug that has the unique therapeutic profile of lithium without its adverse effects. Lithium's mechanism is unclear but a leading idea is inhibition of inositol monophosphatase (IMPase), causing reduced transmitter signalling via the phosphoinositide (PI) pathway. Recently, we "reprofiled" a library of drugs found safe but without efficacy in clinical trials for other indications, and identified a potent IMPase inhibitor, ebselen. Ebselen is reported safe in humans, and without signs of lithium's adverse effects. In animals ebselen inhibits IMPase at clinical doses, and has lithium-like effects including reduced 5-HT2 and dopamine receptor function. These effects are important as they can be linked to decreased impulsivity. This proposal will initiate a developmental pathway comprising an animal to human study of ebselen's potential for reducing impulsivity. The pathway will seek critical evidence that ebselen reduces impulsivity, and that this effect is dose-dependent and maintained. Efficacy in our models will fast-track ebselen to clinical trials in patient groups characterised by poor impulse control.


Research activity codes: 5.1 PHARMACEUTICALS
Health categories: MENTAL HEALTH
Title: The role of social factors in dissociation and threat processing in psychosis
Funder: Medical Research Council

Abstract: Aims To investigate the role of social-rank related threats, such as those linked to stigmatisation (external threat) and shame (internal threat), on outcome in psychosis, and to test the feasibility of a psychological intervention for psychosis designed to target the regulation of social threat processing. Objectives To inform bio-psycho-social models of psychosis, and to advance psychological treatments for people with psychosis. Methodologies 1. An online questionnaire study will test the moderating effects of social-rank threat on the relationship between dissociative traits and psychotic states in a healthy population. Online data will be collected from 700 participants, with a 6-month follow-up. 2. An experience-sampling method (ESM) study will test the daily-life causal relationships between social-rank threat and psychotic symptoms in clinical (n=20) and non-clinical (n=20) groups matched for dissociative traits. Data will be collected at 10 points per day for 6 days. 3. A longitudinal study will test the moderating effect of social-rank threat on the longitudinal relationship between dissociative traits and psychotic states in a 'non-clinical in crisis' population with psychotic-like experiences. 29 participants will provide data at T1 (in crisis), T2 (3 months) and T3 (6 months). 4. A case series study (n=18) will test the feasibility of delivering and evaluating Compassion-Focussed-CBT for psychosis which aims to regulate threat processing, with a positive impact on psychotic symptoms. Opportunities This research will aid the integration of cognitive approaches to psychosis with models of trauma processing and compassion-focused approaches, which have firm roots in neuroscience, and will provide opportunities for future psychological and neurological explorations of interpersonal factors and threat processing in psychosis. The treatment study will provide information on parameters for the design of future studies to evaluate efficacy.


Research activity codes: 2.3 PSYCHOLOGICAL, SOCIAL AND ECONOMIC FACTORS
Health categories: MENTAL HEALTH