NIHRDataInsights/HRCSData huggingface dataset:
Title: Improving mental health outcomes in children born with an orofacial cleft: Identifying children at most risk to target clinical provision
Funder: Medical Research Council

Abstract: Children born with a cleft of the lip and/or palate are vulnerable to mental health issues. Through this project, we aim to better understand which children need additional psychological support. We will use a unique large longitudinal cohort, the Cleft Collective. We will supplement this dataset by: 1) collecting additional questionnaire data to study mental health outcomes from childhood to adolescence; 2) linking to National Pupil Database data on educational factors likely to influence or be influenced by mental health. Using these data, we will quantify rates of mental health and neurodevelopmental problems in children born with a cleft by calculating and comparing trajectories of relevant traits between children in the Cleft Collective, children without a cleft but at a high genetic risk of poor mental health (from the ECHO study), and typically developing children from two general population cohorts. To explore genetic risks for mental health issues in individuals born with a cleft, we will use LD-score regression to estimate the genetic correlation and Mendelian randomization to explore causal effects between genetic liability to cleft and psychiatric disorders. We will use multivariable regression to test associations between multiple pre- and post-natal environmental risk factors and mental health outcomes in children in the Cleft Collective. We will also study the effect of timing of surgery and schooling on mental health, by using COVID-19 related disruptions to these factors as a natural experiment. Our epidemiological investigations will provide unique insights into which children born with a cleft are most at risk of mental health issues. Finally, we will hold workshops and focus groups with our existing networks of clinical and patient community collaborators to co-produce a set of guidelines for the NHS cleft teams and teachers to enable them to act on our findings and help improve mental health outcomes for this group of vulnerable children.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: MENTAL HEALTH;NEUROLOGICAL
Title: Cognition and Behaviour
Funder: Medical Research Council

Abstract: The UK Dementia Research Institute (UK DRI) is an initiative funded by the Medical Research Council, Alzheimer's Society and Alzheimer's Research UK. Funding details for UK DRI programmes will be added from 2020. The programme will develop ways to describe behavioural patterns in the home, providing a radical new approach to the assessment of the effects of dementia. A rich 3D description of real-world tasks can be produced using wearable sensors that can measure movement and quantify how behaviour changes during disease. The team will use these to describe how activities of daily living (ADLs) change in dementia at different stages, initially using whole-body sensor suits. These data will enable the identification of the smallest subset of wearable sensors that can derive accurate behavioural descriptions. Ultimately, this will enable artificial intelligence (AI) to be trained to produce similar descriptions from passively acquired data. Mobile EEG will provide opportunities to improve cognitive function. The research will explore whether closed-loop neuromodulation, either using environmental cueing or brain stimulation can improve cognitive function. Using this home EEG system and machine learning approaches to personalised analysis, they will investigate whether perceptual alerts targeted to EEG fluctuations can improve memory function by increasing attentional engagement. Main objectives and research goals: 1. To develop direct measures of real-world behavioural impairment. 2. To develop artificial intelligence that learns patterns of behaviour and provides support through intelligent cueing. 3. To validate CogniTrack as a platform for the longitudinal tracking of cognitive function in dementia. To enhance cognitive function through real-time monitoring of brain activity (EEG) linked to neuromodulation produced by perceptual cueing and non-invasive brain stimulation.


Research activity codes: 5.5 RADIOTHERAPY AND OTHER NON-INVASIVE THERAPIES;2.3 PSYCHOLOGICAL, SOCIAL AND ECONOMIC FACTORS;4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES
Health categories: MENTAL HEALTH;NEUROLOGICAL
Title: Computation and regulation of pain dynamics in the human central nervous system
Funder: Medical Research Council

Abstract: Persistent pain is a major clinical problem, but our understanding of the neural mechanisms underpinning pain is insufficient to treat persistent pain effectively. I focus on the human brain mechanisms that mediate pain perception and behaviour. My approach to the problem draws from recent evidence that the brain interprets (i.e. actively infers) incoming sensory signals based on internal representations (i.e. models) learned from past experience. These neural inferences shape perception and behaviour. It is not known how the brain learns to infer how pain fluctuates in intensity over time, but this question is central to understanding the brain's response to pain. Taking this perspective, I hypothesise that, when receiving persistent nociceptive inputs, the brain computes an internal model of how pain changes over time by learning the temporal statistics of these signals. When new input is detected, this model is used to infer whether pain is likely to increase or decrease in the future. These neural inferences could regulate the transmission of nociceptive inputs from the spinal cord to the brain (as conscious expectations do), thereby controlling pain perception. I will test this new hypothesis using computational modelling, behavioural and neuroimaging experiments in humans. If the brain cannot learn to accurately predict nociceptive inputs, it follows that it would fail to regulate its responses effectively, amplifying pain and pain-related anxiety. I will test this clinical prediction in anxious individuals with a tendency to catastrophize pain, a risk factor for developing chronic pain. Finally, I will develop and test a cognitive intervention to help people more accurately make inferences about pain states; this intervention might be used for the secondary/tertiary prevention and management of chronic pain in vulnerable individuals.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;1.2 PSYCHOLOGICAL AND SOCIOECONOMIC PROCESSES;2.3 PSYCHOLOGICAL, SOCIAL AND ECONOMIC FACTORS
Health categories: MENTAL HEALTH;NEUROLOGICAL
Title: In vivo human addiction biomarkers: towards closed loop deep brain stimulation
Funder: Medical Research Council

Abstract: Drug and alcohol addictions are major public health issues; yet, existing therapeutic approaches show high treatment refractoriness. Addictions are disorders of brain networks. Deep brain stimulation (DBS) is a relatively safe potentially reversible neurosurgical procedure that modifies brain networks and is effective for movement disorders and obsessive-compulsive disorder. Case series show potential DBS efficacy for drug addictions. Critically, the DBS procedure also allows capture of in vivo neurophysiological measures, allowing for anatomically precise direct studies of disease processes in a human model. We propose a theory-driven multidisciplinary study using DBS in treatment refractory alcohol and opioid use disorder targeting the nucleus accumbens and ventral internal capsule. We address core theoretical mechanisms underlying disorders of addiction using direct in vivo recordings of the nucleus accumbens and prefrontal network connectivity. We examine the role of incentive cues and negative emotion, their longitudinal role during abstinence and relationship with addiction-related cognitive processes and underlying neurochemistry. We then address the causal role of time-locked and chronic stimulation on neurophysiology and behaviour to identify stimulation-responsive specific biomarkers. We will begin to develop closed loop feedback stimulation and behavioural regulation targeting these biomarkers. Finally, we assess the potential therapeutic efficacy of DBS for addiction in a pilot randomized controlled trial. Together these studies provide novel direct in vivo mechanistic insights of core theoretical mechanisms of addictions in the living human brain with immediate translational therapeutic impact leading to the emerging potential for precise efficient responsive neuromodulation.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;5.3 MEDICAL DEVICES
Health categories: MENTAL HEALTH;NEUROLOGICAL
Title: The impact of schizophrenia-associated copy number variants on cortical network dynamics
Funder: Medical Research Council

Abstract: The past decade has seen exceptional progress in the identification of genetic risk factors for schizophrenia (SZ), enabling a 'genomics first' approach to psychiatry. One of the most robust genetic findings is that copy number variants (CNVs), involving the deletion or duplication of large (>1 kilobase) sections of DNA, are strongly associated with risk for SZ. These schizophrenia-associated CNVs (SZ-CNVs) offer a powerful route to understanding the neurobiological mechanisms connecting genetics to psychiatric risk. We have shown that SZ-CNVs are enriched for genes involved in synapses, especially the NMDA receptor complex, post-synaptic density and ARC complex. Furthermore, we have shown that diverse SZ-CNVs produce convergent impacts on a range of neurocognitive and psychiatric symptoms. In this proposal we will examine the neural basis of this convergence across SZ-CNVs. We will use magnetoencephalography (MEG) to investigate the impacts of CNVs on cortical activity and functional connectivity in human SZ-CNV carriers, building on our pilot data. We will in parallel study mice bearing syntenic CNVs enabling us to investigate the cellular and circuit-level causes of these MEG connectivity changes using EEG, local field potential recordings and linear electrode arrays. Finally, we will study the functional connectivity of human neurons derived from carriers of SZ-CNVs using induced pluripotent stem cell technology. To integrate data across these different methods we will apply computational modelling to develop a model of the impact of SZ-CNVs on cortical circuits. These models will be evaluated pharmacologically and by investigating their ability to predict psychiatric symptoms and neurocognitive impairments in SZ-CNV carriers. The insights we will gain will provide a better understanding of the pathological effects of CNVs and support genomically-informed approaches to the diagnosis and treatment of psychiatric disorders.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;5.2 CELLULAR AND GENE THERAPIES
Health categories: MENTAL HEALTH;NEUROLOGICAL
Title: Reinforcer-specific value-based decision-making in persistence of and recovery from alcohol use disorder
Funder: Medical Research Council

Abstract: This project applies computational methods to characterise the internal mechanics of value-based decision-making (VBDM) in alcohol use disorder (AUD). We developed a decision-making task in which participants choose between alcoholic drinks (in one block) and alcohol-free reinforcement (in a different block). A drift diffusion model is fitted to choice and response time data, to yield VBDM parameters (evidence accumulation rate and response threshold) for each reinforcer. Specific objectives are as follows: 1. We will identify the VBDM profiles that characterise AUD and recovery. Using a case-control design, the following groups will complete the VBDM task: (1) people with AUD, (2) people who have recovered from AUD, and (3) a control group of light drinkers. 2. We will identify how VBDM changes during craving episodes, and which VBDM parameters are predictive of drinking behaviour. Using a between-subjects design, participants with AUD will be randomized to complete either an alcohol craving induction procedure or a control procedure, before completing the VBDM task and offered alcohol to drink in the laboratory. Dependent measures are VBDM parameters and the volume of alcohol consumed. 3. We will track changes in VBDM following a contingency management intervention, and identify which VBDM parameters are predictive of reductions in drinking at follow-up. Using a between-subjects design, participants with AUD will be randomized to either a contingency management intervention in which they receive financial incentives for abstaining from alcohol over three-weeks, or a yoked control intervention. Dependent measures are VBDM parameters at the end of the intervention period and drinking behaviour at one-month follow-up. Outcomes from the project include validation of a conceptual framework and measurement tool of the cognitive-motivational constructs that impede recovery. In future work, those constructs could be targeted by personalized interventions


Research activity codes: 1.4 METHODOLOGIES AND MEASUREMENTS;5.6 PSYCHOLOGICAL AND BEHAVIOURAL
Health categories: MENTAL HEALTH;NEUROLOGICAL
Title: Molecular mechanisms regulating early life stress induced alteration of Oxytocin
Funder: Medical Research Council

Abstract: This project will identify molecular mechanisms by which early life stress (ELS) exposure alters brain Oxytocin (Oxt) level. ELS profoundly changes adult behaviour and is a primary risk factor for developing psychiatric diseases. Oxt, a key regulator of social behaviour, has been implicated in social dysfunction after ELS as studies have shown alteration of Oxt or Oxt receptor levels following experimental ELS manipulation. Despite this association, currently the underlying molecular mechanism by which ELS regulates Oxt level is poorly understood. Animal studies of ELS using rodents highlight the importance of controlling stressor type, exposure and duration in order to achieve robust results. Recently, we developed a novel ELS model using optogenetics in zebrafish. In this model, using light, we could control precisely the level of cortisol, main stress hormone in zebrafish, during development allowing an unprecedented control of ELS exposure. We have obtained a pilot data demonstrating that ELS alters Oxt level in a subset of Oxt-positive cells. Building upon our pilot data, the goals of this project are to 1) identify exact subset of ELS-sensitve Oxt cells using single-cell RNA sequencing and single-cell projection analyses, 2) identify and validate molecules that regulate Oxt expression following ELS by combining cell-type-specific expression profiling, open chromatin analysis, and candidate molecule testing in zebrafish and 3) manipulate identified Oxt regulators in a cell-type specific manner and assess the effects of the manipulation in restoring normal Oxt level in ELS-exposed animals. Upon successful completion, this project will have identified molecular mechanisms by which ELS regulates Oxt level and developed a method to restore proper Oxt level in ELS-exposed animals. These studies will establish a platform for future approaches to restore normal social behavior in ELS fish and in other vertebrate models of ELS.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;6.6 PSYCHOLOGICAL AND BEHAVIOURAL
Health categories: MENTAL HEALTH;NEUROLOGICAL
Title: 'Opioid overdose deaths: Understanding the lethal interactions between benzodiazepines and opioids to develop new harm reduction strategies
Funder: Medical Research Council

Abstract: Poly-drug use of benzodiazepines (BZs) and opioids are an increasingly fatal combination but why BZs increase the risk of opioid overdose is not known. We will take an integrated qualitative and experimental approach to determine - How and why opioid users also use BZs - How BZs and opioids interact to cause fatal respiratory depression 1. We will interview drug-users using a standardised topic guide exploring socio-demographic characteristics, health conditions, initiation and motivation of using BZs with opioids, how BZs are used alongside opioids and the role of different types of BZs and opioids in non-fatal overdose experiences. Interview participants will be sampled purposefully in three sites (Glasgow, Teesside, Bristol) reflecting varying opioid death rates and poly drug use, supported by our collaborators. Patient and public involvement will inform the study design and interviews will be conducted in collaboration with trained peer researchers. Data from each site will be triangulated and analysed using the framework method. 2. Using laboratory studies in mice to determine the mechanism(s) underlying BZ/opioid interactions we will: - record from respiratory control centre neurons to investigate whether BZs and opioids interact at the mu-opioid receptor or single neuron level - investigate whether the interaction occurs at the network level by interfering with the neuronal control of respiration - study how the combined effects of the drugs alter different respiratory parameters in the whole animal. We will investigate additive/synergistic effects of BZs and opioids, whether BZs affect the ability of naloxone to reverse the opioids, and whether BZs reverse tolerance to the effects of opioids. To determine if the interactions depend on specific drugs we will use three opioids (morphine (active metabolite of heroin), methadone, and buprenorphine) and the BZs (diazepam, etizolam and alprazolam) that are most associated with opioid overdose.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: MENTAL HEALTH;NEUROLOGICAL
Title: Investigating Glutamate and Opioid Mechanisms of Antidepressant Response to Ketamine (GO-MARK)
Funder: Medical Research Council

Abstract: BACKGROUND/AIM The neural mechanisms underlying the antidepressant effects of ketamine are yet to be fully determined. In addition to NMDA receptor antagonism, glutamatergic activation and changes in functional connectivity, ketamine also produces mu-opioid system activation. This study aims to determine the acute effects of ketamine on brain glutamate dynamics and functional connectivity in major depressive disorder (MDD), relating these findings to antidepressant response and establish if pre-treatment with a mu-opioid receptor antagonist, naltrexone, attenuates any of these effects. OBJECTIVES 1. To characterise brain glutamate level dynamics in the anterior cingulate cortex (ACC) during ketamine infusion and whether pre-treatment with naltrexone modulates any changes. 2. To investigate the effect of ketamine on functional connectivity and whether naltrexone modulates changes. 3. To examine if there is a relationship between changes in depressive symptoms, glutamate levels and/or specific alterations in functional connectivity following ketamine administration, and whether naltrexone attenuates any of these effects. METHODS The study is a randomised, double-blind, crossover design with two treatment conditions: oral placebo or oral naltrexone 50mg, preceding ketamine infusion (0.5mg/kg) during neuroimaging in 24 subjects with MDD. Neuroimaging consists of functional proton magnetic resonance spectroscopy, to examine brain glutamate dynamics in the ACC and resting-state functional magnetic resonance imaging, to examine changes in functional connectivity pre and post ketamine. SCIENTIFIC AND MEDICAL OPPORTUNITIES This research will provide invaluable information, not only on the mechanism of action of ketamine, but also on aspects of depression itself. Results may help identify predictive biomarkers of response and treatment targets that can be tested in future studies to develop more personalised and effective treatment strategies for depression.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;6.1 PHARMACEUTICALS
Health categories: MENTAL HEALTH;NEUROLOGICAL
Title: Complement C3aR in adolescent synaptic pruning and risk for anxiety
Funder: Medical Research Council

Abstract: Anxiety disorders present a significant socioeconomic burden across age-groups, but particularly in adolescence where their occurrence predicts greater subsequent risk for a range of psychiatric disorders. Adolescence is associated with substantial changes in brain structure and function, with key alterations in synapse organisation orchestrated via synaptic pruning. Evidence shows a major role for microglia and the complement C3b/CR3 axis in synaptic pruning in areas such as the visual system during early postnatal development, but a key question to be addressed here is the extent to which complement drives adolescent synaptic pruning in brain areas mediating anxiety. We will explore a new role for a different part of the complement system, the complement C3a receptor (C3aR), in sculpting the adolescent brain via microglia-mediated synaptic pruning. We have found that homozygous knockout of C3aR leads to widespread reductions in synapse density in vivo and heightened microglial phagocytosis in vitro. In addition, C3aR-/- mice show profound adult anxiety phenotypes (https://doi.org/10.1101/685537). We therefore hypothesise that C3aR exerts inhibitory effects on microglia-mediated synaptic pruning, and that reduced C3aR signalling leads to excessive synaptic elimination during adolescence, consequently disrupting anxiety-related brain circuitries and leading to anxiety-phenotypes. We will conduct a comprehensive survey of adolescent synaptic pruning in brain regions relevant to anxiety and assess the role of C3aR. These data will directly inform future work in which we would aim to investigate causal links between C3aR-mediated aberrant pruning and anxiety by pharmacologically modulating microglial activity. In parallel, we will probe the structural and functional brain changes arising from C3aR-mediated faulty synaptic pruning via clinically translational, longitudinal non-invasive imaging, that will be correlated with behavioural anxiety phenotypes.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;2.3 PSYCHOLOGICAL, SOCIAL AND ECONOMIC FACTORS
Health categories: MENTAL HEALTH;NEUROLOGICAL