NIHRDataInsights/HRCSData huggingface dataset:
Title: Disorders of attention and executive function (ACA3)
Funder: Medical Research Council

Abstract: This programme investigates fundamental mechanisms of attention and cognitive control and their clinical assessment/remediation in children and adults. Current understanding of brain mechanisms that produce coherent, goal directed behaviour is limited. Basic science studies within this programme include on the construction of ‘task episodes’ in which control programs for upcoming activity are constructed, enacted and then dismantled. We explore the implications of this hitherto largely unrecognised phenomenon in healthy cognition and its potential relevance to disorganisation of behaviour commonly observed after brain injury including the disruptive influence of co-occurring mood problems. Basic science studies reveal elements of cognitive control that can be enacted based on information that cannot be consciously perceived. Such work is fundamental to any subsequent use of information that does not reach awareness in rehabilitation and mood remediation. Low mood and anxiety are significantly elevated after brain injury. However the mechanisms and interaction with cognitive impairment are poorly understood and little is known about the efficacy of psychological interventions in this group. Basic work examines the role played by cognitive and memory biases in maintaining low mood and the potential efficacy of ‘low impact’ interventions such as Behavioural Activation which make minimal demands on cognitive skills. Spatial biases are another common consequence of brain injury in which patients have reduced awareness for information on one side of space. Clinical results suggest that such biases tend to persist in the context of more general attentional impairments and in states of low arousal. This programme has considered the emergence of similar biases in children and adults as a model for understanding the relationships between spatial awareness, consciousness and alertness. Current studies examine electrophysiological correlates of these changes in attention and spatial awareness as well as the effects of online cognitive training programmes in stroke survivors and children with poor attention. The translation of our science into practical applications is a key theme within the programme, and several projects have gone from basic evaluation of new assessment and rehabilitative instruments through to their clinical release.


Research activity codes: 1.2 PSYCHOLOGICAL AND SOCIOECONOMIC PROCESSES
Health categories: MENTAL HEALTH
Title: E2: Cognitive efficiency and mental control – from basic processes to clinical interventions
Funder: Medical Research Council

Abstract: This programme (see http://www.mrc-cbu.cam.ac.uk/research/emotion/cemhp/) comprises translational research into understanding and treating emotional disorders (in particular, major depressive disorder and post-traumatic stress disorder) across the lifespan. Basic science studies using neuroimaging, experimental psychology, psychophysiology, and behavioural genetics are used to trace the profiles of biased and impaired processing associated with these syndromes, within a transdiagnostic framework. Clinical proof-of-principal research translates these findings into putative therapeutic products, which are then tested in formal clinical trials under the umbrella of the Cambridge Centre for Affective Disorders (http://c2ad.mrc-cbu.cam.ac.uk/). The aim is to understand and refine existing clinical assessments and interventions and to develop novel versions thereof for dissemination within the NHS.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;2.3 PSYCHOLOGICAL, SOCIAL AND ECONOMIC FACTORS;5.6 PSYCHOLOGICAL AND BEHAVIOURAL;6.6 PSYCHOLOGICAL AND BEHAVIOURAL
Health categories: MENTAL HEALTH
Title: Causes, Consequences and Modification of Health Behaviour
Funder: Medical Research Council

Abstract: The overarching aim of this programme is to understand relationships between health behaviours and both physical and mental health outcomes, in order to develop a better understanding of the mechanistic pathways that underline these relationships and identify targets for novel individual and population level interventions. Our specific aims include: - To identify novel genetic instruments relevant to health behaviours for use in Mendelian randomisation (MR) analyses. - To understand the network of causal relationships between health behaviours and a range of physical and mental health outcomes. - To interrogate the mechanistic pathways that underlie causal relationships between behaviour and health and identify targets for intervention. This programme will provide a flow of work that will provide mechanistic insight into causal relationships between health behaviours and both physical and mental health outcomes, and support subsequent intervention development and testing, through existing relationships with other major research groupings and industry partners.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;2.3 PSYCHOLOGICAL, SOCIAL AND ECONOMIC FACTORS
Health categories: MENTAL HEALTH
Title: Dynamics of cell assemblies underlying adaptive and mal-adaptive memories
Funder: Medical Research Council

Abstract: Memory is central to behaviour, enabling individuals to infer from past experience how to respond to their ever-changing environment. Nonetheless the recall of certain memory representations, such as those of environments where a drug of abuse was experienced, is undesirable as these can impair the individual’s ability to adapt to its environment and therefore put it at risk. In this programme our goal is to provide a mechanistic understanding of how temporally-structured neuronal activity in the brain underlies memory processes. To this end we seek to determine how pyramidal cell-interneuron dynamics underlie the temporal segregation of cell assemblies in the hippocampus for the coordination of the read-in/encoding of new information with the read-out/retrieval of old stored information. We further investigate how downstream network interactions with the nucleus accumbens mediate the guidance of purposeful behaviour by spatio-contextual memories. In this work, we use a number of complementary techniques to monitor and stimulate neuronal activity in the mouse brain during well-defined behaviour. In so doing, our programme will probe temporally patterned manipulations aimed at rebalancing brain dynamics by the selective enhancing, reprogramming or weakening of the cell assemblies providing brain representations of drug/fear-paired environments. This work is intended to provide principles of intervention of brain areas where network dynamics underlie pathophysiology of memories.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: MENTAL HEALTH
Title: PsySTAR Programme (Psychiatry: Scottish Training in Academic Research Programme)
Funder: Medical Research Council

Abstract: British academic psychiatry needs a new approach. Unparalleled advances in the rest of medicine have supplied research tools that have vast untapped potential to improve the management of psychiatric disorders. The overarching goal of the PsySTAR PhD fellowship programme is to get the next generation of academic psychiatrists to engage with the relevant aspects of basic science and medicine, and thus foster a cadre of psychiatric researchers focused on developing innovative treatments through cutting edge approaches in stem cell biology, epigenetics, developmental programming, animal and computational models, and novel behavioural and psychosocial interventions for treatment and prevention. We propose an innovative mental health clinical research training PhD programme based on the outstanding basic-to-clinical translational research environment and the existing excellence in clinical training in Scotland. PsySTAR brings together leading researchers and centres of excellence in psychiatric genetics, behavioural and clinical neuroscience, brain imaging, epidemiology, biomedicine, the quantitative sciences, social and public health sciences and clinical trial methodology. Trainees will receive concentrated teaching in each of these, with careful mentoring and guidance towards PhD supervisor and project selection, integrated into their first year of specialist training. The PhD will be taken with one or more scientists, often in different locations, with mentoring from an academic psychiatrist, all from units rated world leading/internationally excellent in RAE2008. We will manage the cohort, alongside those in similar clinical PhD schemes, to maximise the added value of critical mass and peer support. We have in Scotland many more trainees applying to psychiatry training schemes than in the rest of the UK, a proven track record of academic training, a well established collaborative research infrastructure and mature NHS and industrypartnerships.


Research activity codes: 1.5 RESOURCES AND INFRASTRUCTURE (UNDERPINNING);2.6 RESOURCES AND INFRASTRUCTURE (AETIOLOGY);3.5 RESOURCES AND INFRASTRUCTURE (PREVENTION);5.9 RESOURCES AND INFRASTRUCTURE (TREATMENT DEVELOPMENT)
Health categories: MENTAL HEALTH
Title: Trajectory of Brain Structure and Function before and after the Onset of Psychosis: a Longitudinal Multicentre Study
Funder: Medical Research Council

Abstract: The aim of this study is to characterise the trajectory of brain structure and function before and after the onset of psychosis. Specifically I will examine changes in the volume of the insula, hippocampus and lateral ventricles and test the hypothesis associated with the theory of Tony Grace that functional connectivity between these regions increases prior to psychosis. A secondary aim is to predict who will develop psychosis by applying machine learning techniques to the longitudinal data. The fellowship is to fund longitudinal MRI scans of subjects with an at risk mental state (ARMS), 25-30% of whom are expected to develop psychosis within 2 years of contacting medical services. The baseline MRI scans are already being collected as part of the EU-GEI project. However there were no plans in the original study to do subsequent scanning. My proposal aims to capitalise on this ARMS sample, which is an order of magnitude larger than any examined in previous studies. Scanning will be completed at 7 centres which each have ARMS clinics and a 3T MRI scanner. ARMS subjects will be scanned at the point of transition and 12 and 24 months after transition; those who do not transition to psychosis and healthy controls will be scanned 3, 12 and 24 months after the baseline scan. Analysis of the structural MRI data will be conducted with FreeSurfer and software developed by my collaborator Paul Thompson and resting state fMRI data will be analysed with FSL MELODIC. I will use support vector machines to predict psychosis transition from the imaging and clinical data which would have immediate translational benefits. Changes in brain structure and function before psychosis raises the intriguing possibility that future therapies may be able to arrest these changes. Charactering the trajectory of these changes would indicate which regions of the brain are first affected, and establish a reference point to compare the effects of preventative treatment strategies.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: MENTAL HEALTH
Title: Amnesia and the medial temporal lobes: an investigation in autoimmune limbic encephalitis
Funder: Medical Research Council

Abstract: Aim: To determine how different regions within the medial temporal lobe (MTL) contribute to human memory and its impairment in neurological disease Objectives: 1. Characterise the cognitive and neuroanatomical profile of autoimmune limbic encephalitis 2. Test competing theoretical models of MTL function in a large cohort of amnesic patients 3. Develop a neurobiologically-motivated test of MTL function for clinical use in memory disorders Methodology: I will investigate the effects of MTL damage in a unique, Oxford-based cohort of patients with limbic encephalitis associated with antibodies to the voltage-gated potassium channel complex (VGKC-LE). Patients and matched controls will undergo detailed neuropsychological testing and MR imaging (at 3T and 7T). I will determine how clinical variables, e.g. antibody type/titre and treatment type/duration, affect lesion extent and cognitive outcome. I will test an influential new account of MTL function (the 'Binding of Items and Contexts' model) against more established, 'unitary' accounts in a subset of VGKC-LE patients with focal, bilateral MTL damage. Six experiments will explore whether regions of the MTL contribute differentially to both short- and long-term memory for items, contexts and their binding. I will apply this work to develop a neurobiologically motivated, clinical test of MTL function that will be validated in a longitudinal study of patients with mild cognitive impairment. Scientific and medical opportunities: The results of this study are likely to lead to improvements in the treatment and monitoring of VGKC-LE. The characterised cohort will be an invaluable resource for addressing many other questions about MTL function. A better understanding of the neural basis of memory will facilitate early diagnosis of patients with disorders such as Alzheimer's disease, appropriate patient inclusion into clinical trials and thus more efficient development of targeted therapeutic interventions.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES
Health categories: MENTAL HEALTH
Title: Adult Determinants of Late Life Depression, Cognitive Decline and Physical Functioning - The Whitehall II Ageing Study
Funder: Medical Research Council

Abstract: We propose to examine mid-life factors as determinants of key age-related conditions: late-life depression, cognitive decline and physical functioning in the Whitehall II prospective cohort study (WII) of 10,308 London-based civil servants, established in 1985. Using new data collected at a 7th clinical screening to define endpoints and 30 years of prospective follow-up, we hypothesise that mid-life trajectories of inflammatory, vascular, and metabolic factors will make major contributions to later life depression, cognitive impairment, and functional health. We will examine the role of socioeconomic status, social engagement and cognitive reserve as contextual influences ('the causes of the causes'), and quantify the importance of lifestyle factors through adulthood. Confirming generalisability in other studies, we will translate observed effects into impact on the prevalence of functional limitations and disability-free life expectancy using projected risk factor distributions in the general population. Where appropriate, we will develop multi-factorial predictive algorithms, like those previously developed for cardiovascular diseases, to facilitate early identification of adverse ageing outcomes. The proposed clinic will include the following measures: psychiatric disorders via computerised interview (CIS-R) and symptoms scales; cognitive function via 6 tests (MMSE, memory, reasoning, fluency, vocabulary, trail making test); physical function via 5 tests (walking speed, chair rises, grip strength, finger tapping, lung function); anthropometry; blood-based measures; hair cortisol; and socioeconomic, social, psychological and behavioural factors, including 9-day accelerometer data and the facial expression recognition. To provide complementary data, participants are linked to national health registers for surveillance of cause-specific morbidity and mortality. Findings of the programme will inform health policies at national and international levels.


Research activity codes: 2.4 SURVEILLANCE AND DISTRIBUTION
Health categories: MENTAL HEALTH
Title: Linear and non-linear brain changes over the transition to psychosis
Funder: Medical Research Council

Abstract: The course of schizophrenia is associated with significant brain changes. Exactly when these changes occur is a matter of debate, with significant evidence now available for progressive volumetric declines early in the illness (the first 12 to 24 months post-onset). However, there is additional evidence for the decline beginning before that, during the prodromal period. In this study we seek to replicate findings of progressive structural brain changes across the transition to psychosis in a group identified as at ultra high risk for psychosis. Furthermore we will extend these findings to establish the precise trajectory of these changes, whether measures of functional connectivity also show such change, and to what extent they can be used in pattern classification algorithms to improve predictions of who will or will not develop a psychotic illness. We propose to recruit 120 young people meeting criteria for the at-risk mental state, based on the presence of attenuated psychotic symptoms and/or a family history of schizophrenia or personal history of schizotypal personality disorder. Those with the greatest risk of transition to psychosis, along with 24 healthy controls, will be scanned repeatedly over the subsequent year to establish the longitudinal trajectories of brain structural and functional changes over the onset of psychosis. Specifically, we will use a linear mixed model regression approach to capture the dynamics of the pathological processes before and just after transition in both cortical thickness and measures of global network topology. We will use a machine learning approach to analyse longitudinal brain changes associated with different clinical courses. This will allow us to model transition probabilities and improve prediction of outcome. We hypothesise that the most rapid brain changes will be seen either side of transition, and that longitudinal brain changes will provide better prediction of later transition than baseline images.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: MENTAL HEALTH
Title: Defining the disturbance in cortical glutamate and GABA function in psychosis, its origins and consequences
Funder: Medical Research Council

Abstract: This proposal will identify if dysregulation of glutamate release initiates and sustains the development of schizophrenia in humans. The role of excessive glutamate release and whether it results from oxidative stress or inflammation, or perturbs long and short range cortical networks in patients will be investigated. Regional brain measurements in patients with early onset and established illness and age-matched controls will compare aspects of glutamate function and mechanisms which may lead to disease. 13C and 1H magnetic resonance spectroscopy (MRS) will measure glutamate, glutamine, GABA and glutathione and the conversion rate between glutamate and glutamine. These will indicate: the balance between excitation (glutamate) and inhibition (GABA); the rate of neurotransmitter release (conversion); and the oxidative status of the brain regions (glutathione). Studies of gamma oscillations using magneto-encephalography, already known to be modulated by GABA in normal brain, will establish whether cortical networks are disturbed in schizophrenia and linked to abnormal neurotransmitter function. Positron emission tomography (PET) will be used to assess the burden of inflammation, determining whether a postulated link to schizophrenia exists and whether this too is related to alterations in neurotransmitters and brain oxidative stress. This proposal should confirm or refute a role for glutamate in causing schizophrenia. If refuted, efforts can be concentrated on other targets, but if confirmed, this will open new avenues for the development of targeted psychological and pharmacological therapy and provide biomarkers to evaluate them with.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: MENTAL HEALTH
Title: The Development of Social, Attention, and Perception Abilities in Typical and At-risk Infants
Funder: Medical Research Council

Abstract: Diagnosis of developmental disorders such as ASD and ADHD rarely occurs prior to 3 years, resulting in little being known about the emergence of these disorders during infancy. In Part A of the grant we will expand our existing study of infant siblings at familial risk for ASD to also include infants at familial risk for ADHD/attention difficulties. We will compare the development of social and attention abilities using several baby-friendly neuroimaging methods (sMRI, fMRI, NIRS, EEG, ERP), eye-tracking and touch screen tasks, parent-infant interaction, and questionnaire and clinical assessments. By studying infants at-risk for ASD and ADHD on the same measures at 4, 8-10, 14-16, 24 and 36 months we can determine how specific early markers are for particular later outcomes, and address issues about the early development of co-morbidity. Part A is embedded within collaborative national and international networks that will increase sample size and power for key measures. In Part B we will initiate work on potential early interventions by building on our recent study demonstrating improved attention skills in low-risk infants following training on gaze-contingent attention "games". We will extend this training study in several ways to make it more applicable to groups of infants at-risk, including increasing the training period and following up the effects of training more frequently. While we know much about the early development of vision and auditory processing, comparatively little research has been done on tactile perception. This is important to study, as it is a primary mode of interaction with parents. In Part C we will use several imaging methods to develop new paradigms for tracking the neurodevelopment of basic tactile perception, social touch, and the emerging multi-sensory perception of the infant's own body.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;5.6 PSYCHOLOGICAL AND BEHAVIOURAL
Health categories: MENTAL HEALTH
Title: Clinical Psychopharmacology of Depression
Funder: Medical Research Council

Abstract: The aim of the proposal is to study the role of the neurotransmitters, serotonin (5-HT) and glutamate in the pathophysiology of depression using state-of-the-art imaging in the form of positron emission tomography (PET) and magnetic resonance imaging at 7 Tesla (7T). A key objective is to establish a model of endogenous 5-HT release in healthy volunteers using [11C]CUMI-101 in conjunction with PET. Our MRS investigations will focus on the link between glutamate, inflammation and depression by studying the effect of treatment with the cytokine, interferon-alpha, on MRS glutamate and mood in patients with hepatitis C and comparing these data to MRS glutamate changes seen in a large group of depressed patients stratified according to peripheral inflammatory markers such as C-reactive protein (CRP). Finally we will assess in depressed patients how stratification for inflammatory status affects clinical response to serotonin potentiating treatment with the selective serotonin re-uptake inhibitor (SSRI), escitalopram. The overall objective in these latter studies is to use stratification by inflammatory markers to improve our understanding of the pathophysiology of depression and help predict response to first line SSRI treatment.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES
Health categories: MENTAL HEALTH