NIHRDataInsights/HRCSData huggingface dataset:
Title: The impact of COMT inhibition on behaviour and neural activity, and its modulation by genotype and acute stress.
Funder: Medical Research Council

Abstract: COMT metabolises catechols, notably dopamine, and is an attractive neuropsychiatric drug target. Variation in COMT activity, as influenced by the Val158Met polymorphism, or by COMT inhibition, impacts on cortical dopamine-modulated behaviours, especially working memory, and their neural correlates. The effects are consistent with an inverted-U, whereby either low or high dopamine signalling impairs performance. Indeed, the inverted-U model predicts that the effects of COMT inhibition will differ according to Val158Met genotype; our recent study using the COMT inhibitor tolcapone showed this convincingly for working memory and, unexpectedly, for risk aversion. The present proposal will extend these findings in two experimental medicine studies of Val158Met homozygote men, given tolcapone or placebo, in a randomised double-blind design. The first study examines tolcapone's impact on validated tests of reward and emotional processing, and investigates whether these effects are genotype-dependent; we predict that tolcapone will have opposing effects in the two homozygote groups. Stress interacts with Val158Met to affect cognition and neural activity, but it is not known if this interaction is affected by COMT inhibition. Thus, in the second study, we will examine how an acute stressor (a traumatic film) affects working memory and emotional processing, and the neural correlates using fMRI. We predict that acute stress will differentially affect responses to tolcapone vs. placebo, dependent on genotype. Tolcapone is used in Parkinson's disease and being trialled for several other disorders. A full understanding of the range of phenotypes impacted by COMT inhibitors is critical to advance their therapeutic candidacy; it is also essential to understand how these effects are altered by stress, given the key role of stress in psychiatric conditions. The work will provide a powerful examination of the potential of pharmacogenetics for stratified treatments in psychiat


Research activity codes: 6.1 PHARMACEUTICALS
Health categories: MENTAL HEALTH;NEUROLOGICAL
Title: MICA: Training and Novel Probes Programme in PET Neurochemistry - PET Call
Funder: Medical Research Council

Abstract: Technical Summary To address one of the major restrictions in the use of the molecular imaging technique of positron emission tomography (PET) for neuroscience research at Cambridge, the lack of trained PET chemist to design and prepare the required brain imaging probes, proposed is an integrated programme of training and research. In partnership with PET centres, academic and industrial, in the UK and US we have constructed a training programme designed to train a post-doctoral scientist with a PhD background in chemistry to "group leader" capability within four years. Integrated with this training, is, i) the implementation a radioligand for mGluR5 receptors which will applied in our preclinical programme to understand the role of these receptors in neuropsychiatric disorders such as depression, obsessive compulsive disorder (OCD), drug addiction and schizophrenia, and ii) in collaboration with GE Healthcare to implement a NMDA radioligand to be applied in clinical studies on traumatic brain injury. In the later stages of the programme the trainee will focus on development of novel imaging probes for imaging the tropomyosin-related kinase receptor B for future application in neuropsychiatric research.


Research activity codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES
Health categories: MENTAL HEALTH;NEUROLOGICAL
Title: Function of the thalamo-cortical pathway in sensory-guided behaviour
Funder: Medical Research Council

Abstract: In order to investigate the role of thalamus in whisker-guided behaviour, it is extremely helpful to be able to measure precisely how the whiskers are moving (whisker kinematics) whilst simultaneously measuring neuronal activity. Technical breakthroughs have now made this possible and the techniques are established in the Petersen lab in Manchester. We will train head-fixed mice to perform a go/no-go object localisation task: the object (a metal pole) is positioned in either a go location or a no-go location. The animal is rewarded for licking on go trials and punished for licking on no-go trials. A high speed camera (1000 frames/s) will be used to measure whisker kinematics and, simultaneously, we will use microelectrode arrays to record activity of thalamic neurons. Neuroinformatics plays a crucial role in this project. Will use algorithms developed by the PI to extract whisker kinematics from the video data and use clustering methods developed the co-PI to analyse the neuronal data. To investigate how thalamus represents the location of an object (Obj 1,3), we will quantify how well alternative neural codes, involving either single neurons and populations of neurons, represent pole location; and we will test our hypothesis that neurons in the higher order POM nucleus correlate more closely with the mouse's decision than neurons in the first order VPM nucleus. To investigate what kinematic features of whisker movement (e.g., angle to the snout, angular velocity) evoke thalamic activity (Obj 2,3), we will extract time series of these kinematic features from the high speed video record and correlate them with the spikes of individual thalamic neurons. We will test a computational model previously developed by the PI using anaesthetised data and, if necessary extend it. To investigate the role of cortical feedback in modulating thalamic responses (Obj 4), we will make simultaneous recordings from barrel cortex and VPM/POM.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: MENTAL HEALTH;NEUROLOGICAL
Title: Executive functions from infancy into early childhood: Measuring robust cognitive and neural markers of development and risk
Funder: Medical Research Council

Abstract: Executive functions (EFs) are a set of cognitive abilities that allow us to guide our behaviour and make adaptive decisions. They provide us with the ability to control our thoughts and actions, solve problems, and multi-task. Without EFs we would be largely controlled by immediate circumstances and habitual responses. EFs are particularly challenged in young children, who struggle to maintain and manipulate information in working memory, inhibit strong response tendencies and shift between different perspectives and actions. They are also compromised in children with developmental disorders and those with academic and social difficulties. Between 3 and 5 years of age EF skills improve rapidly. However, little is known about EFs before this age. This is due to the lack of psychometrically adequate EF tasks for this age group. With this proposal, I aim to push down the boundary for successful EF assessment by designing a new task battery specifically for 9- to 30-month-old children. Tasks will be structurally similar across age, ensuring that they measure the same construct at different time points. Once tasks have been psychometrically validated, I plan to undertake a longitudinal study of 200 children. Children will be assessed on the new battery along with concurrent measures of brain activity. This will provide important knowledge on the very earliest development of EFs, the biological substrate of this development, and individual trajectories. Outcomes in terms of behaviour problems and early signs of attention-deficit/hyperactivity disorder will be assessed so that potentially problematic EF trajectories can be identified earlier than presently possible. This is an important step towards improved diagnosis and intervention for children at risk of poor EFs and associated developmental disorders. The task battery will be made available to other researchers and clinicians, providing a new tool for others to use in an area where none currently exists.


Research activity codes: 1.2 PSYCHOLOGICAL AND SOCIOECONOMIC PROCESSES;2.5 RESEARCH DESIGN AND METHODOLOGIES (AETIOLOGY);4.2 EVALUATION OF MARKERS AND TECHNOLOGIES
Health categories: MENTAL HEALTH;NEUROLOGICAL
Title: MRC Centre for Neurodevelopmental Disorders
Funder: Medical Research Council

Abstract: The MRC Centre for Neurodevelopmental Disorders will bring together world-leading researchers in psychiatry, neonatology, neurology and neuroscience with the goal of identifying the biological mechanisms underlying neurodevelopmental disorders. This synergy will lead to breakthroughs in understanding which would otherwise not be possible. To reach this goal, we will combine mechanistic studies on patients and the genetic discoveries that are becoming available through the work of large sequencing consortia to guide our interrogation of specific brain circuits in both animal models and humans. In addition, we will explore how environmental factors influence the impact of disease susceptibility genes, both in humans and in animal models. Our research will focus on epilepsy, autism spectrum disorder and schizophrenia, three disorders that are largely caused by abnormal brain development. These are high prevalence diseases which cause long-term burden, and are very difficult to treat. In addition, although these conditions represent a spectrum of diseases with broad sets of causes and clinical manifestations, they have overlapping phenotypes and genetics, which are suggestive of common deficits. The research focus of the new Centre is justified by our top clinical expertise in this field, the access to large patient populations, and our existing high-profile research programmes on neurodevelopment. In five years, we will contribute to dissolving the boundaries that exist across clinical disciplines and that prevent an integrated understanding of common versus distinct biological mechanisms in neurodevelopmental disorders. Our unique combination of basic and clinical researchers will train and nurture the next generation of scientific leaders in the field, equipped with a translational agenda and a multidisciplinary set of skills. Finally, we also expect the Centre to develop new collaborations with Industry to identify and test new treatments for these disorders.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: MENTAL HEALTH;NEUROLOGICAL
Title: Neural network alterations in Rett Syndrome
Funder: Medical Research Council

Abstract: Rett syndrome is a devastating neurological disorder affecting females and is caused by mutations in the gene encoding methyl-CpG binding protein 2 (MeCP2). Affected girls develop normally during the first 6 to 18 months of life but quickly regress, losing acquired language, motor and cognitive abilities. Previous work has demonstrated alterations in neuronal connectivity and synaptic communication in mouse models of RTT. However, few studies have focused on the consequences of these alterations at the network or behavioural levels. We have recently made the surprising discovery that loss of MeCP2 function impairs the generation of gamma oscillations and their coherence between regions. How MeCP2 regulates gamma oscillations and coordinates the function of synapses involved in its generation remains unclear. We hypothesise that cognitive deficits in Rett syndrome occur by disrupting inhibition-dependent synchronisation of neuronal activity leading to impairments in neuronal oscillations. In our first aim, we will characterise hippocampal gamma oscillations in mouse models of Rett syndrome in vitro and in vivo. In our second aim, we will define the cellular and synaptic mechanisms by which loss of MeCP2 perturbs gamma oscillations. In the third aim, will identify the causal role for specific interneuron classes in the breakdown of gamma oscillations. In this final aim, we will also examine whether activation of silenced Mecp2 allele in specific interneuron classes can rescue the function of gamma oscillations in mouse models of Rett syndrome. These aims will settle several fundamental questions about MeCP2's roles in regulating synaptic coordination, will yield important insights into the neural network mechanisms that lead to the manifestation of behavioural alterations, and could yield promising candidate therapies.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: MENTAL HEALTH;NEUROLOGICAL
Title: Mechanisms of motivation and their disturbance in neurological disease
Funder: Medical Research Council

Abstract: Rewards drive us to perform well. Recently I have shown how motivation can incentivise us to be both accurate and fast, improving performance beyond its normal limits and breaking long-established concepts of speed-accuracy trade-off. Motivation is frequently disrupted in neurological conditions, ranging from Parkinson's disease (PD) and neurodegenerative disorders, to acquired brain injury. The consequence can be profound clinical apathy, or impulse control disorders, which have enormous individual, social and economic impacts on patients. Given their clinical importance, these syndromes remain under-recognised, poorly characterised, and only coarse nonspecific drug treatments are available. One crucial question arises: If we can sometimes perform well, why not all the time? Building on my recent work, I will apply a unifying framework to quantitatively predict behavioural improvements by reward. These recent theoretical advances will then be translated to the clinical domain, applying them to symptoms of disease and neuromodulatory drugs. This fellowship will allow me to combine my skills in computational methods, behavioural research and clinical practice to develop a unique and independent niche that is widely relevant and applicable. First I will validate and test the generality of my framework in healthy people. Further studies will ask whether dopamine may be a key currency in which the brain "pays" for the cost of control, studying the effects of drugs in health, alterations seen in PD, and after focal isolated damage to the medial prefrontal cortex. Finally, in a highly novel study of cholinesterase inhibitors in PD, a treatment for cognitive dysfunction, I will explore the hypothesis that acetylcholine may also have noise-reduction functions, but in more posterior brain regions. Together these basic science and clinical studies allow us to characterise and modulate motivation and its dysfunction, with broad potential clinical impact.


Research activity codes: 1.2 PSYCHOLOGICAL AND SOCIOECONOMIC PROCESSES;5.1 PHARMACEUTICALS
Health categories: MENTAL HEALTH;NEUROLOGICAL
Title: The diagnostic and prognostic utility of electrophysiological responses to speech in post-traumatic coma and prolonged disorders of consciousness
Funder: Medical Research Council

Abstract: The ability to move in response to verbal commands is a diagnostic milestone in recovery from coma that also provides a target for rehabilitation. The relative preservation in coma of the auditory-motor cortical network that supports this ability may predict the potential for that network to support consciousness subsequently. Hearing speech that describes action ('kick') produces rapid and automatic activation in an auditory-motor network, known as semantic embodiment. Due to the overlap between these functional networks, the relative preservation of the network that supports movement to command may be estimated at the bedside via electroencephalographic (EEG) markers of semantic embodiment. We will test a cohort of post-traumatic coma patients for evidence of semantic embodiment after withdrawal of sedation. We will determine outcome at 1-year through telephone interview (Glasgow Outcome Scale Extended) and multiple assessments with the Coma Recovery Scale-Revised for those progressing to a prolonged disorder of consciousness (PDOC). Multinomial ordinal regression will determine the prognostic value of EEG markers of speech processing, with outcome categorised as good (at least functional communication), command-following (at least MCS plus), or no command-following (at most MCS minus), thus providing greater functional specificity in prognosis that can stratify patients for earlier rehabilitation or inform discussions of best interests and prior wishes. The diagnostic utility of EEG markers of speech processing will also be tested in PDOC patients at follow-up. To aid in interpretation of each patient's specific neurocognitive preservation, dynamic causal modelling of simultaneous EEG-fMRI data will characterise the network interactions that underlie EEG markers of semantic embodiment in healthy individuals, specifically in relation to the network that supports movement to command.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: MENTAL HEALTH;NEUROLOGICAL
Title: IMPC: Cognitive and ethological characterisation of mice lacking melatonin MT2 receptors
Funder: Medical Research Council

Abstract: Melatonin is a hormone made by a small gland at the base of the brain, which regulates sleep/wake patterns and circadian rhythms. Apart from these well-characterised roles, melatonin also acts in poorly-understood ways to affect cognitive processes such as alertness, and to modulate the brain circuitry underlying psychiatric diseases such as depression, schizophrenia and bipolar disorder. This project will perform an initial characterisation of mice lacking one of the proteins through which melatonin exerts its actions on brain cells, known as the melatonin MT2 receptor. Mice lacking the melatonin MT2 receptor appear perfectly normal, although there is some evidence to suggest that their sleeping patterns may be slightly disturbed, and that they may have some memory deficits in simple tests. The study will examine a) whether their daily activity and sleeping patterns differ from normal mice; b) the extent to which their brain chemistry is altered in the circuitry associated with psychiatric diseases such as depression, schizophrenia and bipolar disorder; and c) whether they have impaired performance in a cognitive task closely related to that used in human clinical studies - where the mice can select a series of responses using a touchscreen, and hence demonstrate their ability to sustain attention. The results will reveal the extent to which loss of melatonin's effects on the MT2 receptor may contribute to deficits in wakefulness and alertness, and to susceptibility to psychiatric disease. This will set the stage for future more detailed characterisation of the physiological and pathological function of MT2 receptors, and is likely to illuminate the exploitation of MT2 receptors as a target for current and future psychiatric drug development. In addition, if the specific circuitry associated with affective/psychotic diseases is compromised in these mice, the information will open a new avenue to studying treatment strategies aimed at normalising functional activity in this network.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: MENTAL HEALTH;NEUROLOGICAL
Title: Modulatory Capacity: Biomarkers for pain sensitization and response to psychological treatment for pain
Funder: Medical Research Council

Abstract: Why certain individuals develop chronic pain is an enduring clinical and scientific question. It has been demonstrated that psychophysical measures of central facilitation and inhibition of pain predict the development of chronic pain following surgery. On this basis, it has been proposed that individuals prone to central facilitation of pain represent a "pro-nociceptive phenotype". Other research indicates that high levels of negative affect might also predispose some individuals to persistent pain. Finally, neuroimaging findings demonstrate that functional connectivity of pain, emotion and reward regions can characterise individuals who develop chronic pain. Taken together, these converging lines of data suggest that combining psychophysical, psychological and neuroimaging assessments might allow us to identify individuals at risk of developing persistent pain. This program of research will develop a multi-modal assessment battery for the ability to adaptively employ central pain modulation circuitry. This battery will be used within the context of an experimental model of prolonged pain exposure that we have developed. We will test the hypothesis that individuals with a pro-nociceptive phenotype will experience the greatest increase in pain sensitisation over time. Importantly, it has been shown that individuals with a pro-nociceptive phenotype are most responsive to treatments aimed at mitigating central faciliatory processes, leading to the conclusion that identifying such individual might also help us direct them to appropriate treatment. We have shown that central facilitation of pain can be reversed with cognitive behavioural therapy. We will therefore test whether individuals with a pro-nociceptive phenotype will be most responsive to this intervention. Realisation of these aims would contribute to an earlier and more proactive approach to treating pain before it becomes chronic, potentially streamlining pain management within the NHS and beyond.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;1.2 PSYCHOLOGICAL AND SOCIOECONOMIC PROCESSES
Health categories: MENTAL HEALTH;NEUROLOGICAL
Title: MICA: SRC inhibition as a potential target for Parkinson's disease psychosis
Funder: Medical Research Council

Abstract: Parkinson's disease (PD) psychosis can affect around half of the patient population. The visual hallucinations and other disturbances can be extremely distressing and debilitating resulting in poorer quality of life and increased caregiver burden. While dopaminergic treatments are central to treating psychoses unrelated to PD, the serotonin system is implicated in PD psychosis and pimavanserin, a 5-HT2A inverse agonist, has recently received approval for treatment of PD psychosis in the USA. The serotoninergic dysfunction underpinning PD psychosis is not understood although studies in animals and with psychedelics point to dimerisation of the 5-HT2A and mGlu2 receptors and overrecruitment of specific downstream signalling pathways. Src kinase inhibition is a potential mechanisms for blocking the 'hallucinogenic' effects of the 5-HT2A receptor agonism. We have already demonstrated that the src-kinase inhibitor saracatinib can reduce the intensity of psilocybin-induced psychedelic effect and attenuate social cognition changes and brain responses in healthy volunteers. We propose to test the effects of 10 days of saracatinib or placebo (2-way cross-over design) in 20 patients with PD psychosis as a proof of concept for the specific molecular pathway of this disease symptom cluster. Existing literature suggests PD psychosis can result from aberrent bottom-up and top-down processing so we will use functional imaging and EEG to test the effects of saracatinib on brain networks associated with visual processing and their higher level components of perception. Patients will be tested twice, after 10 days of placebo and after 10 days x 100 mg saracatinib, assessing effects on visual processing networks with fMRI and prediction error markers with mismatch negativity EEG. Subjective ratings will also be recorded.


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