NIHRDataInsights/HRCSData huggingface dataset:
Title: Characterizing the neurobiology of detoxification and early abstinence in opiate addiction: is there a role for NK1 antagonism to improve outcomes?
Funder: Medical Research Council

Abstract: We are one of the few groups in the world to characterize the neurobiology of opiate addiction to improve treatment outcomes. We established the largest multi-centre imaging study of its kind in addiction, the MRC-funded ICCAM platform study which assesses anticipation of monetary reward with the monetary incentive delay task and emotional processing networks with an evocative images task in abstinent substance addiction. We have identified the potential of the following as brain biomarkers for addiction: blunted striatal response during anticipation of reward and amygdalar hyper-reactivity in response to adverse images. We have shown that NK1 antagonism shows therapeutic potential as it normalised the amygdalar hyper-reactivity in polydrug (mostly opiate dependent) addicts. We now need to apply this ICCAM platform to provide evidence whether the NK1 antagonist, aprepitant, is a credible treatment to take forward to a clinical trial in opiate detoxification and early abstinence. We will conduct a double-blind randomised, placebo-controlled crossover study of a single dose of aprepitant in opiate dependent individuals towards the end of their detoxification and again within a few weeks of abstinence. The MR scan protocol will be completed on a 3T Siemens Tim Trio: structural T1 weighted image, diffusion tensor imaging sequence, resting state, ASL, monetary incentive delay task, evocative images task and cue-reactivity task. We will assess neurocognitive correlates to provide behavioural measures of probabilistic reward learning and of emotional processing. A neuropsychological biomarker would be a clinically feasible and cost-effective approach to stratifying patient treatment. Our imaging and neurocognitive datasets provide a uniquely rich dataset to correlate functional brain responses with neuropsychological, clinical and outcome variables.


Research activity codes: 6.1 PHARMACEUTICALS
Health categories: MENTAL HEALTH;NEUROLOGICAL
Title: Setting the 2019 Mental Health Agenda
Funder: Wellcome Trust

Abstract: This proposal is to complement and build on the work United for Global Mental Health (United GMH) is currently undertaking as part of a Wellcome grant. It aims to deliver a plan of action for the first four months of 2019 to shift the scale of ambition and sustain lasting activity on mental health. The proposal plans activities covering four streams: Catalysing commitment at Davos 2019: spurring greater action within the growing global movement and launching WEF"s new programme area Further amplification of the Lancet Report to new audiences Maintaining the Drumbeat using the Friendship Bench Sustaining work of the Blue Print Group through to the end of April 2019 Operational support for United for Global Mental Health The United GMH team will leverage support from Wellcome to mobilise partners, and the wider global mental health community, to maintain the momentum built since July to raise mental health further up the global political agenda in 2019. We are requesting £106,895 from Wellcome to further this work.


Research activity codes: 8.3 POLICY, ETHICS AND RESEARCH GOVERNANCE
Health categories: MENTAL HEALTH;NEUROLOGICAL
Title: Uncovering the neural architecture underlying decisions abstracted from movements
Funder: Medical Research Council

Abstract: Decision making is a core component of normal and abnormal cognitive function. Understanding the neural mechanisms of decision-making will lead to advances in the diagnosis, classification and future treatments of disorders affecting thought and control. Mathematical models of the decision process, based on bounded evidence accumulation, have been developed over decades and are being increasingly leveraged to gain deeper insights into the origins of cognitive deficits arising from a range of brain disorders. However, major gaps remain in our understanding of the neural mechanisms responsible for decision-making, thereby limiting the validity and utility of the models. A successful line of research on perceptual decision-making has established that neurons in the parietal and prefrontal cortex of the rhesus monkey (Macaca mulatta) encode the accumulating evidence bearing on the alternatives. These observations are mainly from neurons in areas of the macaque cortex that are associated with preparation of the actions (e.g. hand or eye movements) for reporting the decision alternatives. However, decisions are often formed without knowledge of what actions they might call for, and under such conditions, effector-selective neural activity does not appear to reflect accumulation dynamics. Recent studies, have identified a novel ‘abstract’ decision signal in non-invasive electrophysiological (EEG) recordings from human decision makers. The signal, termed the central parietal positivity (CPP), represents the accumulation of evidence for decisions irrespective of the sensory or motor requirements of the task, hence the designation, abstract. The neural circuits that give rise to the CPP are likely to explain the capacity to flexibly link decisions to various actions depending on context and goals. However, because the signal has thus far only been observed in EEG recordings from humans, its neural basis is unknown. The proposed aims will (1) establish the neural underpinnings of the CPP by establishing its analogues in single-neuron, multi-neuron, local field potentials and EEG of the macaque and (2) localizing its source in humans through the use of neuroimaging, and electrocorticography (ECoG) from patients undergoing neurosurgery. Both aims draw on an integrated computational effort that combines biophysical modeling, neural networks, and mathematical characterization of the decision process. The knowledge gained through these investigations will increase our understanding of core cognitive capacities whose deficiency contributes to major brain disorders while bridging long-standing methodological gaps in human versus non-human animal investigations.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: MENTAL HEALTH;NEUROLOGICAL
Title: Physiopathology of brain-wide assemblies in adaptive memory
Funder: Medical Research Council

Abstract: Memory is central to adaptation, enabling individuals to infer from past experience how to respond to ever-changing situations. The idea that groups of neurons transiently synchronize their spiking activity to organize information-representing cell assemblies has laid the foundation of scientific investigations carried at the nexus between brain, memory and behaviour. Notably, past work has established how neural dynamics of assemblies in the hippocampus circuit serve memory-guided behaviour. However, memories of important, salient events are expected to span multiple brain circuits, with each circuit processing a particular dimension of mnemonic information. This organisational principle of neurally-distributed memory items could be at the heart of the complexity of the cognitive disabilities associated with natural ageing and certain neurological/psychiatric diseases. Here, we seek to obtain a comprehensive mechanistic explanation of how neuronal activities distributed across brain regions allow the division of representational labour involved in complex, detail-rich memories. We will perform this work while keeping in mind that not all memories serve adaptive behaviour. This is notably the case of strong memories related to drugs of abuse that underpin the expression of maladaptive responses. Throughout this programme, we will deploy a number of cutting-edge strategies, including cell-type-selective and input-defined optogenetic interventions as well as real-time manipulation of brain circuit dynamics, to establish causal links with behavioural phenotypes. We will first determine how temporally-patterned cooperation of neuronal spiking distributed across memory circuits allows brain-wide operations to serve optimal behaviour in situations of uncertainty caused by multiple information streams. We will then investigate how cross-brain-region communication relates to the renewal of behaviourally-extinguished drug-paired memory and associated re-occurrence of drug seeking. We will finally provide a comprehensive description of the macrocircuit and microcircuit mechanisms of inferential reasoning, a higher-order operation that allows combining discrete memory items to infer logical associations between sets of information that have not been directly experienced together. In doing so, our research programme will identify neuronal motifs and pathways supporting memory-guided behaviour. This work is intended to provide principles of interventions to harness network physiopathology of maladaptive memory.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;1.2 PSYCHOLOGICAL AND SOCIOECONOMIC PROCESSES
Health categories: MENTAL HEALTH;NEUROLOGICAL
Title: Circuit-driven neuromodulation in the cognitive domain
Funder: Medical Research Council

Abstract: Neuromodulation using deep brain stimulation (DBS) is a highly successful treatment for the motor symptoms of movement disorders. In comparison, DBS treatment for the cognitive symptoms of brain disorders is in its infancy and has been only partially successful. This suggests the current targets for treating cognitive symptoms are viable, but that current stimulation paradigms are suboptimal. Our goal is to establish novel approaches to neuromodulation of current DBS targets that will improve cognitive symptoms in neurological and psychiatric disorders. These approaches will be designed to modulate specific processes in cortico-basal ganglia-thalamocortical circuits that mediate behaviours relevant to several brain disorders. Specifically, we propose that utilising the temporal dynamics of these neural circuits has the potential to have more direct and powerful effects on cognitive symptoms than current methods. Using experiments in rodents, we will use optogenetic and electrical stimulation to manipulate the timing of activity in connected cortical and subcortical areas, utilising their underlying temporal dynamics to strengthen or weaken their connectivity. This “closed-loop” approach will utilise recordings of neuronal signals, including the phase of ongoing local field potential oscillations and spiking activity, in one area of cortico-basal ganglia-thalamic circuits to control the timing of stimulation delivered to one of its target areas. Our approaches will combine expertise in the cell-type specific composition of cortico-basal ganglia microcircuits and the development of novel methods of brain stimulation. We will target behaviours relevant to several neurological and psychiatric diseases, with the rationale that the crucial first step for novel neuromodulation is to uncover approaches that modulate disease-relevant circuits in a way that leads to reproducible behavioural change. To this end, we will quantify the neurophysiological changes elicited by closed-loop stimulation that occur concurrently with alterations in cognitive task performance. Importantly, we will perform closed-loop manipulations using algorithms that run on self-contained programmable chips. This approach will facilitate the translation of closed-loop algorithms to equivalent platforms in the next generation of human stimulation devices and we will explore collaborations with the medical devices industry to facilitate this. In addition to our translational goals, these studies will provide fundamental insights into how the strength of connectivity between different nodes of cortico-basal ganglia-thalamic loops contribute to the performance of specific behaviours.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;1.2 PSYCHOLOGICAL AND SOCIOECONOMIC PROCESSES
Health categories: MENTAL HEALTH;NEUROLOGICAL
Title: Exploration of memory and language and disorders in these domains
Funder: Medical Research Council

Abstract: Language is a fundamental ability that is core to almost every aspect of our personal, social and professional lives. Consequently, when this ability is compromised, people can have severe disabilities. Language impairments are common across multiple forms of acute and chronic neurological disease including stroke, multiple types and subtypes of dementia (core to the primary progressive aphasias and prominent secondary symptoms in other dementia sub-/types), acute neurological diseases, etc. The core goals of our long-term cognitive-clinical neuroscience research programme, therefore, are to (i) understand the cognitive, computational and neural bases of healthy language and semantic function; (ii) investigate the nature of language and semantic disorders across multiple aetiologies; and (iii) explore the variable changes in these systems in the context of spontaneous recovery/decline and neurorehabilitation. Our research programme will continue to focus upon semantic cognition, language and their disorders. We will continue to use combinations of different clinical and cognitive neuroscience methods to garner convergent, novel insights into these disorders as well as embracing new emerging methods and data. We will continue to use combinations of different methods to garner convergent, novel evidence as well as embracing new emerging methods and data – afforded by the facilities available at the CBU (e.g., MR-TMS and focussed ultrasound stimulation (FUS)), in Cambridge (7T MRI; patient recruitment through clinical neuroscience and stoke collaborations) and with our national and international collaborating teams (e.g., novel sparse decoding methods (Madison-Wisconsin) of MRI, MEG as well as cortical electrode recordings (Kyoto & Kobe)). Through these specific topics, we will also embrace an emerging potential grand challenge – what makes neurocognitive systems dynamic, plastic and “well-engineered”? Understanding the neurocognitive bases of these design features will be important for establishing how cognitive systems can be flexible and efficient in normal operation, how they respond to damage and, in turn, how to maximise their recovery.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;1.2 PSYCHOLOGICAL AND SOCIOECONOMIC PROCESSES;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;2.3 PSYCHOLOGICAL, SOCIAL AND ECONOMIC FACTORS
Health categories: MENTAL HEALTH;NEUROLOGICAL
Title: Cognitive and neurobiological mechanisms underlying memory control.
Funder: Medical Research Council

Abstract: This programme seeks to identify the mechanisms that enable us to control memory and thought. Specifically, we seek to understand how attentional control interacts with brain structures involved in memory to suppress traces that interfere with our cognitive or emotional goals. We use behavioural, fMRI, ERP, TMS, lesion studies, and animal models to examine inhibitory control over memory at multiple levels of analysis essential to bridging brain and mind. Our work focuses on a fundamental question about memory control: given a potent reminder to an unwanted thought, can people stop retrieval? This question cuts to the heart of significant theoretical and practical issues: How do we control the focus of consciousness? How do resilient people limit unpleasant remindings after a trauma and perseverative thoughts more broadly? Developing a multi-level mechanistic model of memory control will play a critical role in understanding and remediating disordered control over intrusive thoughts, whether in PTSD (flashbacks), depression (ruminations), anxiety (worries), or in OCD (obsessive thoughts). In the next five years, we will study the control of unwanted memories at the level of local circuits and even the cellular and molecular level to identify how stopping retrieval reduces the sway that unwanted thoughts hold on our mental lives. For example, we will test the medial septal pacemaker suppression hypothesis as a circuit mechanism of hippocampal downregulation; and whether suppression regulates emotion via extinction circuitry. Magnifying this work’s impact, we will extend our work to include both 3T and 7T fMRI and build on our rodent model of memory inhibition. Using optogenetics and molecular neuroscience methods in the rodent hippocampus and frontal cortex, we will test circuit and cellular mechanisms of memory inhibition with unprecedented specificity. Complementing these theoretical developments, we will apply our framework to understand disordered memory control in PTSD, and in perseverative thoughts trans-diagnostically. Capitalizing on our recent discoveries, we will test whether control over intrusive thoughts can be improved with GABA agonist drugs and a training intervention, charting a course towards translating our basic science. We will develop an App to broad access to the training intervention we developed and increase the impact of our basic science.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;1.2 PSYCHOLOGICAL AND SOCIOECONOMIC PROCESSES
Health categories: MENTAL HEALTH;NEUROLOGICAL
Title: Adaptive and maladaptive brain plasticity
Funder: Medical Research Council

Abstract: We study the extent to which brain areas supporting perception and action are shaped by experience. Our research focuses on hand representation and how it is modulated by hand loss and consequential compensatory behaviour. We aim to develop a mechanistic understanding of the neural basis of hand function and dysfunction, and understand how we could use technology to increase hand functionality in able and disabled individuals at all ages. A primary model for this work is studying differently abled individuals, and arm amputees in particular. We integrate methods from the fields of neuroscience, experimental psychology, engineering and rehabilitation to comprehensively study how habitual behaviour, such as prosthesis usage or motor augmentation, shapes brain plasticity. Key science questions include: (1) Input-loss versus input-driven plasticity? We are interested in understanding the potential link between sensory deprivation (input loss) and adaptive behaviour. (2) Brain plasticity and adaptive behaviour across development. To understand the extent to which behaviour shapes functional brain organisation, we study the brain as new behaviour is being developed, both habitually in children and during skill learning in adults. (3) Neural mechanisms of phantom sensations and pain. We aim to develop new paradigms in order to probe the mechanisms underlying the generation of phantom sensations and PLP both within and beyond the sensorimotor system. (4) Artificial limb representation for motor substitution. Our work explores whether neural resources, uniquely developed for hand representation, become repurposed to support artificial limbs, and whether neural “embodiment” of prosthetic limbs can be improved. (5) Brain plasticity for body augmentation. We wish to understand what resources can the brain employ to control a body part that has never been there before? To facilitate this research, the research programme is augmented by independent funding obtained from the Wellcome Trust (Senior Research Fellowship), European Research Council (Starting Grants), UKRI Frontier Research Guarantee scheme (to underwrite a successful ERC Consolidator Grants) and UK Engineering and Physical Sciences Research Council (Research Grant). We hope that our research will enable clinical populations and those relying on motor augmentation to take advantage of the benefits of brain plasticity, rather than to suffer from their adverse effects.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: MENTAL HEALTH;NEUROLOGICAL
Title: Decision making and dementia: from mechanisms to clinical trials
Funder: Medical Research Council

Abstract: The program aims to improve cognition, survival and quality of life of those affected by neurodegenerative disease. It focuses on neurocognitive systems which are proximate to the clinical phenotypes caused by Alzheimer’s disease and frontotemporal lobar degeneration, in the context of normal ageing. Part 1 seeks to understand and restore behaviours, that are common to many dementias and movement disorders. The term behaviour encompasses the actions one takes and the decisions or goals that lie behind those actions. Apathy and impulsivity are of particular interest, because of their paradoxical positive correlation in disease, their prognostic significance, and their readiness for symptomatic trials. In this program, we formalise behaviour as decisions to act vs to not act (including inhibition) in two complementary types of model: first, the accumulation-to-threshold of the neural basis of evidence; and second, the dynamics of hierarchical networks implementing inferences and predictions of the causes of sensory inputs. The context in which decisions are made is critical, and the program therefore distinguishes transient sensory evidence from enduring contextual beliefs and their predictions. By linking these models to physiological and pharmacological systems, we move towards precision medicine: precision not in terms of gene or molecular aetiology but precision of the chemical, physiological and cognitive processes underlying dementia phenotypes. Part 2 develops the concept of cognitive physiology further, in terms of generative models of brain function. We draw on large scale data from collaborations (eg. MRC Dementias Platform UK synaptic health theme, Deep and Frequent Phenotyping study, BIOFIND consortium), and CBU based programs (eg. Cambridge Centre for Ageing and Neuroscience and clinical series of Alzheimer’s disease, frontotemporal dementia, Progressive Supranuclear Palsy). The framework of dynamic causal modelling is used to integrate modalities (magnetoencephalography, 7T-MR spectroscopy, PET markers of pathology) to explain phenotypic heterogeneity, identify common mechanisms, and predict treatment response.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: MENTAL HEALTH;NEUROLOGICAL