NIHRDataInsights/HRCSData huggingface dataset:
Title: Adaptive processing of spoken language: flexible communication in health, disease and disorder
Funder: Medical Research Council

Abstract: Understanding speech quickly and accurately is a fundamental human ability and the foundation for all our social, educational, and economic achievements. This programme of research explores the computational and neurobiological mechanisms that explain the success of speech perception, comprehension and learning in healthy individuals. By revealing mechanisms that enable listeners to successfully comprehend despite everyday sensory challenges (e.g. noisy or degraded speech) and linguistic challenges (e.g. unfamiliar or ambiguous words) we gain insights into adaptive neural mechanisms that support the acquisition of language skills, their maintenance and retention in adulthood, and the resilience or rehabilitation of language skills after brain injury or disease. This work is important due to the prevalence of language disorders in development and in later life (e.g. following stroke or neurodegeneration), and the severe consequences of language disorders for educational outcomes, economic and social success, and lifelong well-being. Recent research has established two key mechanisms that contribute to successful speech processing in challenging listening situations: (1) predictive computations by which listeners integrate prior knowledge and sensory signals to arrive at optimal interpretations of noisy and ambiguous speech, and (2) neural oscillations that track the rhythm and timing of connected speech. We are exploring these mechanisms as explanations of deficits observed in developmental language disorders, and in neurodegenerative or post-stroke aphasia. Ongoing work seeks to expand our understanding of these predictive and oscillatory computations in other aspects of speech processing including speech production, and higher-level lexical or semantic processing of speech. Our work combines brain imaging (fMRI, MEG) and brain stimulation (TMS, tACS) to determine the causal mechanisms by which neural activity leads to successful spoken language understanding, and to develop new behavioural and neural methods for exploring individual differences in these mechanisms. Findings have application to the development of new diagnostic methods and for language interventions in the classroom, home or clinic.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;1.2 PSYCHOLOGICAL AND SOCIOECONOMIC PROCESSES;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: MENTAL HEALTH;NEUROLOGICAL
Title: Computational prediction of vulnerable points and interventions for dysfunctional synaptic plasticity in neuropsychiatric disorders
Funder: Medical Research Council

Abstract: Neuroscience research groups worldwide are currently studying a new generation of animal models of neuropsychiatric disorders, based on genetic mutations discovered in human patients. The hope is that these animal models will recapitulate the primary biochemical, cellular, and neural circuit changes, and if we discover the key phenotypes in the animal models, we can design better interventions to rescue cognitive symptoms in patients. However, most standard neuroscience techniques are notoriously low-throughput, and it is not obvious where to look in a given animal models for disease phenotypes. These challenges have led to a neuropsychiatric drug development crisis. This project will aim to dramatically speed up this progress by developing a detailed computational model of biochemical signalling during synaptic plasticity induction, that can be used to identify vulnerable points in the cascade. The computational model will be based on abundant data in the literature, and fit to reproduce recent experimental data from rodent in vitro studies from the laboratory of our collaborators at Bristol. The project will deliver three important outputs: first, we will use the computational model to identify a shortlist of synaptic components for which the rules of synaptic plasticity are most sensitive. This list will give predictions to guide experiments on disorder animal models. Second, the computational model itself will be made publicly available for researchers around the world to use and generate predictions for their animal model of interest. Third, based on the simulation results I will develop a new theory for why some synaptic components are more important than others in synaptic plasticity induction, based on the principle of faulty information transmission along biochemical signalling cascades at synapses. This general theory has the potential to guide research on dysfunctional synaptic plasticity in psychiatric disorders for decades to come.


Research activity codes: 2.5 RESEARCH DESIGN AND METHODOLOGIES (AETIOLOGY)
Health categories: MENTAL HEALTH;NEUROLOGICAL
Title: fMRI investigation of the neural mechanisms of Emotional Cognitive Bias Modification as an adjunct therapy to SSRIs in depression.
Funder: Medical Research Council

Abstract: Depression constitutes a substantial burden of disease on society, with the DoH estimating economic costs £7.5 billion annually in the UK. Antidepressant drugs are effective, but up to 50% fail to respond to treatment and relapse rates are high. We have developed a Cognitive Bias Modification (CBM) therapy that modifies emotion perception, and targets similar neural processes to SSRIs. We will investigate whether paired psychological and antidepressant treatment have combinatory effects on neural mechanisms that are associated with, and predicted recovery from, low mood. Depression is associated with increased amygdala responses to negative emotional stimuli, and decreased responses to positive emotion. SSRIs rapidly reduce responses to negative emotional stimuli in depressed patients, and these changes predict treatment outcomes. Furthermore, fMRI neurofeedback studies indicate that increasing amygdala activity to positive stimuli leads to mood improvements. Our Cognitive Bias Modification (CBM) intervention induces positive biases when viewing emotional expressions. Earlier fMRI results from adults with low mood demonstrate that our CBM technique increases amygdala activity in response to expressions of happiness but has little effect on responses to negative emotions. Pharmacological antidepressant treatment is most effective when combined with other therapies, but there are few mechanistic studies of adjunctive treatments. Our rationale is that by combining a CBM technique with SSRI in patients, we may harness synergistic effects of both when SSRI induced neurogenesis is high, allowing relearning of responses to emotional stimuli. By modifying emotion perception directly through training and simultaneously through pharmacotherapy, our approach allows us to elucidate the mechanisms that are predictive of treatment success. We will investigate whether our emotional learning task may provide a context to increase the therapeutic effects of SSRI.


Research activity codes: 6.6 PSYCHOLOGICAL AND BEHAVIOURAL
Health categories: MENTAL HEALTH;NEUROLOGICAL
Title: NuBrain: UK Consortium for Optimal Nutrition for Healthy Brain Ageing
Funder: Medical Research Council

Abstract: Whilst some cognitive functions remain stable with age, most people experience age-related decline in cognition which can progress to differing degrees of cognitive impairment or to dementia. Dementia currently affects 47 million people worldwide, and is projected to increase to over 131 million people by 2050, with increased prevalence mainly attributed to ageing population demographics. With the lack of effective curative or preventative pharmacological interventions, there is an urgent need to identify i) at risk individuals and ii) modifiable factors for targeted interventions to support better brain health in our ageing population. Nutrition is emerging as a tractable lifestyle factor to promote healthy brain ageing and reduce dementia risk. Research (mainly observational and often cross-sectional in approach) has identified numerous dietary factors (e.g. DHA, B-vitamins, Vitamin D) that can promote cognitive performance with cell and rodent models providing insights into underlying physiological and molecular mechanisms. However, comprehensive longitudinal or RCT data, using sensitive measures of cognitive function and brain structure, and state-of-the-art detailed nutrition profiling is lacking. Such information is needed in order to gain insight and granularity into which diet derived components are likely to be most effective at a population and population subgroup level. Our vision is to provide a step change in research in the area by developing novel approaches and techniques to further understand the complex interactions between diet and brain health and how we can support appropriate behaviour change in the population. This will be achieved by bringing together a consortium with multi-disciplinary but complimentary areas of expertise to address this specific challenge. The aim is to build a sustainable internationally field-leading consortium in nutrition and brain ageing who can collectively address the fundamental research challenges in this area.


Research activity codes: 2.6 RESOURCES AND INFRASTRUCTURE (AETIOLOGY);3.3 NUTRITION AND CHEMOPREVENTION;3.5 RESOURCES AND INFRASTRUCTURE (PREVENTION)
Health categories: MENTAL HEALTH;NEUROLOGICAL
Title: Resilience against food cravings via environmental enrichment (EE): neuronal ensemble mechanisms
Funder: Medical Research Council

Abstract: Environmental enrichment (EE) in animal housing provides cognitive and physical stimulation. In hungry mice, brief EE exposure powerfully attenuates food seeking triggered by food-associated cues. Also, EE reduces medial prefrontal cortex (mPFC) activity, indicated by decreases in 'Fos', an activity marker that labels behaviourally-relevant neuronal ensembles. This neurobehavioural attenuation is thought to be mediated by reductions in the motivational impact of food cues. Shifts in recruitment, excitability, and encoding (real-time activity) properties of ensembles play a critical role in interpreting such changes. In this project, we will elucidate how EE suppresses cue-reactive food seeking via the mPFC by: i) modulating the recruitment, excitability or encoding properties of an 'existing' food cue reactive ensemble; and/or ii) actively recruiting a 'new' ensemble during cue exposure with unique excitability or encoding properties. We will reveal these novel mechanisms using advanced tools that enable us to examine precise changes in neuronal recruitment, excitability, and cue-encoding. These include: in vivo 2-photon imaging in awake and behaving mice that express calcium indicators of neural activity and fluorescent reporters of Fos-promoter activation; and whole-cell electrophysiology of cue-activated, Fos-expressing neurons. Notably, the imaging method uses a specialised 'microprism' to image the medial PFC that was previously difficult to access due to its location within a brain fissure. These studies will enhance our understanding of how neuronal ensembles can interpret changes in the motivational attributes of food cues by using existing and/or new ensemble representations.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;1.2 PSYCHOLOGICAL AND SOCIOECONOMIC PROCESSES
Health categories: MENTAL HEALTH;NEUROLOGICAL
Title: IMAGINE-2: Stratifying Genomic Causes of Intellectual Disability by Mental Health Outcomes in Childhood and Adolescence
Funder: Medical Research Council

Abstract: Our genotype-first study IMAGINE-ID recruited 3402 children from UK NHS Regional Genetics Clinics, whose intellectual disability (ID) is associated with either a pathogenic Copy Number Variant (CNV-75.9%) or Single Nucleotide Variant (SNV-23.6%) or both (0.5%). 84% of consented families provided standardized assessments of their child's mental health, functional adaptation, medical and educational history, and family/social environment. We have data on 4,054 genetic variants, logged for 3,398 individuals, representing 3,117 CNVs (1,534 in recognised syndromes, 1,583 unique) and 944 SNVs in 278 different genes. 57% of IMAGINE-ID participants had one or more psychiatric diagnoses: Autism Spectrum Disorders (38%); ADHD (24%); anxiety disorders (12%); challenging behaviour (13%). 31% had a history of seizures, 57% take anticonvulsant medication. Little specificity was found between genotype and diagnostic phenotype, implying multiple developmental processes lead to broadly similar outcomes. Defining potential subtypes of complex neurodevelopmental disease, based on genetic risk, will be facilitated by the observation of longitudinal trajectories of neurodevelopment into adolescence and early adulthood. We aim to conduct a 5-year longitudinal study of the cohort with annual on-line phenotyping of all participants, supplemented by intensive face-to-face assessments of over 500 young people with highly pathogenic CNV that were intensively studied in our first phase. We have already found that environmental risk factors are key to child adjustment, potentially accounting for the majority of variance in outcomes. In our intensive family study, we will test hypotheses about potential mediating variables: for instance, we know children with an inherited CNV are at greater risk, indicating the importance of family environment. We will measure the role of educational and medical support by linkage to the National Pupil Database and NHS Digital's Hospital Episode Statistics.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;2.3 PSYCHOLOGICAL, SOCIAL AND ECONOMIC FACTORS
Health categories: MENTAL HEALTH;NEUROLOGICAL
Title: Music Interventions for Dementia and Depression in ELderly care: International cluster-randomised trial (MIDDEL)
Funder: Medical Research Council

Abstract: MIDDEL is a multinational pragmatic cluster-randomised trial to determine the effects of two complex music interventions on older adults living in residential care with dementia and depression. As highly prevalent and comorbid conditions in older adults, dementia and depression are associated with individual distress and high and rising societal costs. This trial will provide generalisable results concerning the comparative effects of group music therapy (GMT), recreational choir singing (RCS), their combination, or standard care, in older adults with dementia and depression, including long-term effects on key outcomes (depression, behavioural problems, quality of life, costs). The trial will also enable modelling of trajectories of change and will thereby contribute to an improved understanding of the mechanisms of music interventions. Building on promising results from previous small-scale randomised controlled trials and pilot investigations, this trial will have adequate power to determine clinical effects as well as to explain variation in treatment effects in relation to patient characteristics, thereby contributing to the development of precision medicine in line with the JPND call. Music-based interventions are relevant for both genders and can be tailored to people with different cultural backgrounds. By improving existing interventions and providing evidence-based guidance on their application or discontinuation, this trial is anticipated to benefit the rapidly rising number of people living with dementia, their caregivers, and health systems across countries. A comprehensive set of patient- and service-relevant core outcomes, as well as biomarkers, will be measured. The large sample will ensure sufficient power for stratification of subgroups and to establish the influence of biomarkers on the overall effect of the interventions.


Research activity codes: 6.6 PSYCHOLOGICAL AND BEHAVIOURAL
Health categories: MENTAL HEALTH;NEUROLOGICAL
Title: TEDS 26: A longitudinal genetic approach to understanding the development and intergenerational transmission of common mental health conditions
Funder: Medical Research Council

Abstract: The Twins Early Development Study (TEDS) is the largest longitudinal twin birth cohort in the UK, with 25 years of MRC-funded prospectively assessed data. The focus thus far has been on developmental psychopathology, cognitive development and educational achievement, with physical health and the environment also regularly assessed. We now shift our attention to understanding the development and intergenerational transmission of common mental health conditions. Young adults suffer from debilitating anxiety and depression at increasing and alarming rates. These conditions affect one third of individuals during their lives, disrupting education and employment, and increasing risk of suicide. Despite their high burden, we know relatively little about how to identify those most at risk to enable early intervention. Our objective is to use genetic, environmental and longitudinal data to transform our ability to predict those at heightened risk of anxiety and depression in their twenties, and to understand the intergenerational transmission of related traits. To address this objective, we propose three workstreams. First, we will assess mental health outcomes (N~10,000 twins), to undertake longitudinal and multivariate twin and genomic analyses, and to build risk prediction models. Second, we will link medical records to our pre-existing dataset (N~14,400 primary;~24,000 secondary care) to validate self-reported mental health data, explore links with an array of physical health conditions, and undertake genetic analyses of service use. Third, we will recruit ~4,000 children of the TEDS twins, collecting data annually at ages 1-3 in order to undertake intergenerational transmission analyses. The resulting dataset will offer unrivalled opportunities to explore risk factors for mental health not only by our team but the whole academic community.


Research activity codes: 5.6 PSYCHOLOGICAL AND BEHAVIOURAL;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;2.3 PSYCHOLOGICAL, SOCIAL AND ECONOMIC FACTORS
Health categories: MENTAL HEALTH;NEUROLOGICAL
Title: The role of glutamatergic function in the pathophysiology of treatment-resistant schizophrenia and the potential of novel treatment targeting it
Funder: Medical Research Council

Abstract: Treatment-resistant schizophrenia (TRS) occurs in approximately 30% of patients with schizophrenia. Clozapine is the only approved medication for TRS but is poorly tolerated, has serious side-effects, and is not effective for many patients, leaving large numbers of patients without an effective treatment. Evidence indicates patients with TRS do not show dopamine dysregulation, in contrast to patients with schizophrenia who respond to first-line antipsychotics. Instead they show glutamatergic dysfunction. Specifically, glutamate and Glx levels have been shown to be elevated in the anterior cingulate cortex (ACC), as assessed by magnetic resonance spectroscopy (MRS), in TRS patients when compared to responders and controls. However, these studies were cross-sectional so they cannot show causality, and therefore it is still unknown if glutamate plays a primary role in the symptoms and brain changes seen in TRS. The key test is to ameliorate glutamate abnormalities and determine if this leads to an improvement in symptoms. To achieve this purpose we will use riluzole, a drug that reduces pre-synaptic glutamate release. Importantly, we showed in a small proof-of-concept study that riluzole reduces glutamate/Glx levels in the ACC in TRS patients. However, this study did not test if reducing glutamate indices led to a reduction in symptoms. We will use a double-blind study design to randomise patients to riluzole or placebo for a period of 56 days. We will measure glutamate/Glx in the ACC of TRS patients at baseline and at the end of the study. Results from this study will be fundamental to: i) determine if riluzole will lead to a reduction in glutamate indices when compared to placebo; ii) if reduction in glutamate indices are associated with a reduction in symptom severity when compared to placebo. The study will provide critical information on the role of glutamate in the neurobiology of TRS and the potential of glutamatergic drugs to treat TRS.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;5.1 PHARMACEUTICALS
Health categories: MENTAL HEALTH;NEUROLOGICAL
Title: Memory-based sequential decision making: neural computations and shaping effects of mood
Funder: Medical Research Council

Abstract: Our prior experience is a powerful guide for the decisions we make about the future. My research aims to provide a more complete understanding of the neurocomputational mechanisms underlying the influence of memory and mood on goal-directed decision-making in humans. Methodology: Experiments will examine how healthy participants learn about and make decisions about pursuing rewarding goals, especially when this involves some risk of failure. After learning, participant's choices will inform a computational model of individual differences in goal valuation and aversion to the risk of failure. By using magnetoencephalography (MEG), I will acquire time-resolved measures of memory reactivation supporting decision-making, including rapid sequential replay of experiences. Replay is known to play a necessary role in memory-based choice in rodents, and I have recently identified and localized episodic replay to the human hippocampus. Here, I will examine how the strength of replay of potential paths relates to planning to either pursue or avoid a risky goal. Experiments will examine the effects of transient as well as experimentally-induced mood on these decision-making processes, allowing me to test whether negative mood decreases subjective estimates of goal success, and whether this is related to greater replay of memories of goal failure. Finally, optically-pumped MEG will be used in focused studies of decision-related representations in the prefrontal cortex, and, via new intra-mouth sensors, the hippocampus. Scientific and Medical Opportunities: By illuminating how memory guides goal-directed behavior, and how our behavior is influenced by mood, this research aims to provide a foundation for future translational work on learning and experience-based risk taking. By determining for the first time how incidental mood affects goal-directed planning, future work can directly translate to studies of mood disorders.


Research activity codes: 6.6 PSYCHOLOGICAL AND BEHAVIOURAL;3.1 PRIMARY PREVENTION INTERVENTIONS TO MODIFY BEHAVIOURS OR PROMOTE WELL-BEING
Health categories: MENTAL HEALTH;NEUROLOGICAL