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Award Year:
2016
Recipients:
University College London

Results

Using visual dysfunction to understand dementia in Parkinson’s disease 06 Dec 2016

Dementia affects half of patients with Parkinson’s disease (PD) but there are no robust measures to predict who is at highest risk. Visual hallucinations are highly distressing to patients and carers but are poorly understood. This Fellowship will use visuo-perceptual dysfunction to predict dementia and understand hallucinations in PD. I have developed a novel test using skewed images to detect visuo-perceptual deficits in Parkinson’s patients. I have also developed a web-based platform to enable this and other visual tests to be accessed by large numbers of patients with PD. In this proposal I will use visual perceptual tests combined with neuroimaging over time to determine the sequence of visuo-perceptual deficits in PD. I will relate these to changes in hallucinations. I will use my web-based platform to identify clinical and genetic associations with visual deficits and determine their role in predicting dementia in PD. Goals 1. Characterise changes in visuo-perception as PD progresses and correlate deficits with brain atrophy. 2. Relate MRI structural connectivity changes with disease progression. 3. Examine clinical and genetic associations of visual dysfunction in PD. 4. Test whether transcranial stimulation can improve visuo-perceptual function in PD. 5. Determine how visual hallucinations become distressing as PD advances.

Amount: £1,223,282
Funder: The Wellcome Trust
Recipient: University College London

Analysis of cytomegalovirus pathogenesis in a human challenge system 30 Nov 2016

Our research has made major contributions to understanding the natural history and pathogenesis of human cytomegalovirus (HCMV) in allograft recipients. Critically, we have demonstrated that biomarkers can be applied to stratify patients most at risk of HCMV disease and thus inform clinical practice to reduce HCMV end-organ disease. This clinical approach of administration of antivirals to individuals with elevated viraemia above designated levels provides a unique opportunity to gain fundamental insight into disease processes in a human challenge model of HCMV infection. A multi-disciplinary consortium has been recruited to apply next generation DNA sequencing, molecular virology and functional immunological assays to identify virus and host cell determinants of disease susceptibility. Whole genome sequencing of virus in organ donors (live and cadaveric) and recipients will be used to track the source, replication kinetics and evolution of HCMV strains in seronegative and seropositive recipients. We will then define in vitro humoral, cell-mediated immunity and natural killer responses against HCMV that correlate with protective immunity against primary infection, reinfection and reactivation in these patient groups. This approach has the potential to provide unique insights into the natural history and pathogenesis of HCMV and identify innovative therapeutic approaches against it.

Amount: £2,669,767
Funder: The Wellcome Trust
Recipient: University College London

Advancing Psychiatric Mapping Translated into Innovations for Care: PsyMaptic-A 05 Dec 2016

My current and previous Wellcome Trust Fellowships (Henry Wellcome, 2009-13; Henry Dale 2014- present) focus on important aetiological questions about psychotic disorders, using epidemiological data. Psychotic disorders are a debilitating set of mental health disorders, characterised by hallucinations, delusions and cognitive deficits. My research demonstrates that these disorders have a robust, replicable social aetiology, with higher incidence rates observed in young people,1–3 men,1–3 ethnic minorities2–7 and people exposed to greater social disadvantage.8–11 In my previous fellowship, I established the largest epidemiological study of first episode psychosis [FEP] in England since 1999, to demonstrate that these substantial mental health inequalities also exist in more rural populations (East Anglia)3,12; rates are over twice as high as expected,3,13 with deprived rural communities experiencing the highest psychosis incidence. This study has generated new Page 5 of 18 aetiological clues, for example by showing that people at "ultra-high risk" of psychosis are exposed to similar social and spatial markers of social disadvantage as FEP patients,14 implicating an aetiological role for social adversities prior to onset. I have also demonstrated that migrants face greatest FEP risk when immigrating in childhood,15 an important period of sociocognitive development. I am attempting to replicate this in my current Fellowship, in a larger longitudinal cohort using Swedish national register data. Using this data, I have already shown that refugees are at elevated psychosis risk compared with other migrants from the same region of origin,7 providing further insights into the possible social determinants of psychosis. Epidemiological data can also inform mental health service planning. In England, Early Intervention in Psychosis [EIP] services assess and treat people with suspected FEP, offering evidence-based multidisciplinary care to improve downstream clinical and social outcomes, shown to be highly costeffective.16 Unfortunately, original policy implementation guidance17 made no provision for the heterogeneity in incidence described above, with services commissioned on a uniform expectation of 15 new cases per 100,000 people-per-year. This was at least half the true incidence,1,3 and over three times lower than the overall referral rate for all suspected FEP, including "false positive" (nonFEP) referrals,3 who still require appropriate psychiatric triage and signposting, and consume additional EIP resources not factored into original guidance. In response, I demonstrated that epidemiological estimates of psychosis risk could be used to better predict the expected FEP incidence in the population at-risk in England,13 nationally and regionally. The tool, known as PsyMaptic, has had substantial impact on policy and commissioning since it was freely-released in 2012 (www.psymaptic.org).16,18–22 Most recently, it has been used to inform national EIP workforce calculations23 following the introduction of Access and Waiting time standards,19 as part of the Department of Health’s commitment to achieving parity of esteem between mental and physical health by 2020.24 Whilst I have demonstrated, via PsyMaptic, that it is possible to translate epidemiological data into effective public mental health,25 some vital methodological limitations require empirical attention. I therefore seek Wellcome Trust enhancement funding to answer four empirical questions to develop and apply novel statistical prediction methodologies to generate sustainable, dynamic populationbased models of future mental health need.

Amount: £204,479
Funder: The Wellcome Trust
Recipient: University College London

Endothelial cell behaviours in vascular health and disease 30 Nov 2016

At the interface between blood and tissues, vascular endothelial cells (ECs) provide signalling hubs for vascular adaptation to physiological needs. Quiescent ECs form a non-thrombotic surface that facilitates the exchange of gases, molecules and cells between blood and tissues, but they respond to hypoxia-induced signals with vascular expansion and regulate leukocyte extravasation in response to injury. Our unpublished observations indicate that the cell surface receptor neuropilin 1 (NRP1) relays signals from the extracellular environment to the endothelial nucleus to enable such context-dependent responses. Thus, we hypothesise that NRP1 integrates growth factor and extracellular matrix signalling with gene transcription programmes to balance EC behaviours that enable vascular growth and to prevent the senescent and proinflammatory endothelial phenotype common to many chronic diseases. To determine how vascular growth and homeostasis depend on NRP1-mediated pathways, we will investigate novel mechanisms by which NRP1 conveys signals for tissue vascularisation, protects ECs from premature senescence and regulates gene transcription for vascular growth and homeostasis. The knowledge gained will significantly advance our understanding of how extracellular signals are integrated with gene regulation to control EC behaviour, and will likely uncover pathways for therapeutic intervention in diseases with vascular dysfunction.

Amount: £1,436,838
Funder: The Wellcome Trust
Recipient: University College London

The mechanisms of photoreceptor cell death 30 Nov 2016

Problems of protein homeostasis (proteostasis) that lead to protein misfolding, improper traffic and aggregation are associated with many forms of neurodegeneration. The neurodegeneration retinitis pigmentosa (RP) offers an excellent paradigm to study why proteostasis is critical for neuronal function and survival. Rhodopsin mutations cause dominant RP and disturb proteostasis, yet the underlying disease mechanisms and effective therapies remain elusive. I will exploit recent advances in gene editing technology and stem cell biology to produce new animal and patient derived models of the most common rhodopsin mutations in the UK. I will use these to address my key goals, i) to define any common disease mechanisms between the different classes of mutation, and ii) identify new therapeutic approaches for rhodopsin RP. I will use a combination of genetic and chemical manipulation of the major cell stress and degradation pathways, and identify the partner proteins of rhodopsin mutants using unbiased proteomic analyses. These complementary studies will be based on a series of interlinked hypotheses to determine how rhodopsin mutations disturb protein homeostasis and if this can be restored. The findings will have broader implications not only for other forms of retinal degeneration, but also neurodegenerative disease where proteostasis is disturbed.

Amount: £1,529,466
Funder: The Wellcome Trust
Recipient: University College London

Psychophysics of predictive motor control: a novel model of post-stroke fatigue 01 Jun 2016

Fatigue in neurological conditions, unlike exercise induced fatigue, is chronic, irreversible and does not arise from altered sensory afferent input from peripheral musculature. A distinctive feature of such fatigue is requirement of high effort for everyday activity. Normally, everyday activity feels relatively effortless. This is due to re-afferent sensory feedback from voluntary movement being attenuated under normal circumstances (sensory attenuation). I propose that neurological perceptual fatigue is a result of poor attenuation of re-afferent sensory feedback making even the simplest of movements feel effortful. Using a combination of behavioural and electroencephalography techniques, in a series of systematic experiments, I will study the interaction between self-reported fatigue, effort, behavioural and neural correlates of sensory attenuation. Furthermore, using brain stimulation techniques I will modulate sensory attenuation to determine the direction of causality between fatigue and neural processing. I will study chronic stroke survivors where post-stroke fatigue is a major problem. Fatigue is commonly seen as a neuropsychiatric symptom in neurological conditions and what I propose is a significant shift away from fatigue as a psychiatric problem and towards neurological fatigue being a sensorimotor disorder. The proposed project is also likely to identify a potential therapeutic target to develop interventions for neurological fatigue.

Amount: £905,754
Funder: The Wellcome Trust
Recipient: University College London

A Symposium on Enhancing Engagement, Co-production, and Collaborative Meaning-Making in Qualitative Health Research 30 Jun 2016

Traditional "lone researcher" models of qualitative research have shifted to include more collaborative ways of researching, with research participants and other stakeholders viewed as partners in the co-production of knowledge. As well as working alongside "lay researchers", qualitative researchers increasingly work in teams with colleagues unfamiliar with qualitative methods. This is largely driven by calls to engage the public in the production of knowledge and penetrate borders between disciplines. As a result, research is assumed to become more relevant to users’ needs, ethical, and broadly applicable, and is key to requirements of funding bodies and the Research Excellence Framework. However, such collaboration is complex and creates challenges for qualitative researchers. We will explore these issues in a one-day symposium hosted by University College London (UCL), and attended by 150 UK and international delegates. The symposium will provide a platform to develop critical perspectives on: How collaborative relationships are established and embedded, and particularly how qualitative researchers are positioned in multidisciplinary teams; How research designs, data interpretation and reporting are negotiated and enacted; The extent to which "lay researchers" offer the views and experiences of groups they represent and how marginalised groups are accommodated. Keywords: qualitative research, health, collaboration, engagement, symposium

Amount: £5,000
Funder: The Wellcome Trust
Recipient: University College London

A cross-cohort comparison of unhealthily low BMI in early adolescence – a feasibility study and development of research protocol 31 Jan 2016

Childhood thinness (unhealthily low body mass index) has been linked to poorer health and development but has received relatively little research attention in high income countries. Contemporary routine data reported by the National Child Measurement Programme (NCMP) point towards a possible U-shaped socio-economic gradient in thinness in 10-11 year olds (whereby those living in the most and least deprived areas have elevated rates of thinness). However, since the main focus of the NCMP is overweight and obesity, this social patterning in thinness has not been emphasised or further investigated. The U-shaped socio-economic distribution in thinness may be explained by food poverty in more disadvantaged areas, and issues of body image and eating disorders in more advantaged groups. UK cohort studies provide an untapped resource for examining this issue, because they contain rich, individual-level data, spanning different time periods (exposed to different social and economic contexts). However cross-cohort comparisons can be challenging and require a lot of input at the planning stage. This proposal therefore comprises of a feasibility study for a cross-cohort investigation of individual-level socio-economic inequalities in thinness in young people (and possible reasons behind them).

Amount: £2,100
Funder: The Wellcome Trust
Recipient: University College London

A phase I clinical trial of DARC 30 Sep 2016

Preclinical development of a novel diagnostic for glaucoma. Glaucoma is the major cause (15 per cent) of irreversible blindness worldwide. A recent UK report suggested 10 per cent earlier detection of glaucoma would save £1billion/year in treatment costs alone.Professor Francesca Cordeiro and colleagues from the Institute of Ophthalmology at University College London, have been given Translation Award support to fund the preclinical development of their Detection of Apoptosing Retinal Cells (DARC) Technology. DARC is a novel technique that utilises the unique optical properties of the eye to allow direct visualisation of dying nerve cells. If successful, early diagnosis and treatment would mean that DARC will increase patient benefit and decrease burden of care costs.

Amount: £271,521
Funder: The Wellcome Trust
Recipient: University College London

A computer assisted system to reduce auditory hallucinations unresponsive to antipsychotic medication 30 Sep 2016

About 25% of people with schizophrenia continue to suffer with persecutory auditory hallucinations despite drug treatment. Their capacity to work and make relationships is grossly impaired, often for the rest of their life. Professor Julian Leff from University College London and colleagues at Speech, Hearing and Phonetics, UCL have developed and evaluated a novel therapy based on computer technology which enables each patient to create an avatar of the entity (human or non-human) that they believe is talking to them. The therapist promotes a dialogue between the patient and the avatar in which the avatar progressively comes under the patient's control. This translation award aims to refine the system, streamline the technology to make it more user-friendly and evaluate the system by a randomised controlled trial conducted by an independent team of researchers at the Institute of Psychiatry, King's College London.

Amount: £34,060
Funder: The Wellcome Trust
Recipient: University College London

Investigating the development of visual object perception from noisy images 01 Apr 2016

As we perceive the world, our brain continuously makes educated guesses about what we will see next. These inferences allow us to distinguish objects in our field of vision without having to examine every detail. This is known as the Bayesian model of visual perception. Recent evidence suggests that object recognition tasks for which such inferences are likely to be crucial may develop well into adolescence. There is anecdotal evidence that children find tasks such as identifying objects in poor lighting conditions or when borders are unclear (Bova, 2007) very difficult, even when they know exactly what the object they are looking for looks like (Yoon, 2007). This suggests that the robust object perception described in Bayesian models of the adult system takes surprisingly long to develop. This piece of research will test this hypothesis by (a) measuring children’s ability to recognize objects in a distorted ("noisy") image, and (b) testing how expectations about the objects (e.g. what it will look like) can improve perception. This aims to further our understanding of how the brain learns to use existing knowledge to interpret new sensory information, and make better inferences about the world.

Amount: £2,000
Funder: The Wellcome Trust
Recipient: University College London

Use of Electrical Impedance Tomography in Detection of Acute Stroke 01 Apr 2016

The key goal of my research is to determine whether a new Electrical Impedance Tomography system which has been developed at UCL, is suitable for use in imaging stroke patients. This system would provide a fast, safe, and inexpensive method of distinguishing between strokes resulting from cerebral ischaemia and haemorrhage. If the different types of stroke could be distinguished on site by paramedics it would enable treatment and 'clot busting' drugs to be administered immediately, increasing patient survival significantly. I will be conducting the final clinical studies of this system, on patients who are admitted to the Acute Admissions Unit at UCH. I will identify suitable patients who have suffered a stroke and, with consent, take readings using the new EIT system. The images produced will be optimised using newly developed techniques, and compared to MRI and CT images. After the main bulk of data collection, the rest of my project will involve refining the accuracy of the instrumentation, including calibration, assessment, and reduction of electrode noise. I will then analyse the data produced, using Matlab, and evaluate whether the new EIT system is suitable for use in clinical applications.

Amount: £2,000
Funder: The Wellcome Trust
Recipient: University College London

Improved High Frequency Calibration for Dosimetry in Focussed Ultrasound Surgery 01 Apr 2016

Ultrasound at high intensities can cause tissue damage, therefore knowing the intensities used in clinical application is paramount. Ultrasound source outputs are calibrated using hydrophones, following a primary standard calibration at the National Physical Laboratory (NPL) in the UK. Yet uncertainty in the primary calibrations is surprisingly high: around 10% and growing with frequency (NPL 2014). The primary calibration uses optical interferometry for the measurements. This project will investigate one source of uncertainty in this procedure: the effect of the tension in the optically-reflecting membrane. The rig for these experiments will be designed and built following the design shown in Figure (1). There are three key goals: a) Create a measurement rig that can measure the normal incidence acoustic pressure transmission coefficient of a stretched mylar membrane as a function of frequency, membrane tension, and membrane thickness. b) Based on previous work in the literature (Thomas 1976; Romilly 1969; Lamb 1957; Ingard 1954; Chen et al. 2014), construct a mathematical and/or numerical model of the motion of a membrane under tension when a sound wave is incident, and make for comparison with the measurements. c) Formulate advice to the National Physical Laboratory on how to minimize this uncertainty.

Amount: £2,000
Funder: The Wellcome Trust
Recipient: University College London

Intracellular sodium and its effect on neuronal Gene Expression 01 Apr 2016

This project will involve investigating the effects of intracellular sodium on the gene expression in Dorsal root ganglion neurons. The key aims of the project will be to determine the role of sodium mediated signalling in neuronal gene expression. To determine this, high affinity sodium binding protein will be investigated; a cloned DNA construct of the protein will be transfected in to HEK (Human Embryonic Kidney) cells and then DRG neurons with a Nav1.7 knock out. The effect of low intracellular sodium concentration on expression of Penk will be assesed by analysis of the DRG neurons.

Amount: £1,750
Funder: The Wellcome Trust
Recipient: University College London

The Neuroscience of Nudge 01 Apr 2016

Nudges are simple behavioural methods designed to influence decision making by taking advantage of people’s implicit biases. One important type of nudge is known as "anchoring." The simple presentation of an irrelevant number affects people’s decisions by shifting estimations towards that number. This behavioural effect is well understood although the mechanism behind the unconscious bias remains unclear. The brain bases of this effect has received surprisingly little attention in the literature. One study found that the medial prefrontal cortex played a crucial role in anchoring theory-of-mind decisions in a social context, suggesting that activity within cortical networks intrinsic to the task is shaped by this extrinsic information. I propose to initiate this investigation by piloting an fMRI experiment to investigate the neural correlates of anchoring in reasoning about uncertainty. The aim is to collect a preliminary data set from a small sample of healthy adults (n=12) to explore whether the experimental paradigm: yields robust behavioural anchoring effects, identifies brain regions whose activity is affected by these anchoring effects, and tests whether these effects are parametric modulated. I predict that within prefrontal regions engaged by the task, I will observe parametric modulation based on the amplitude of the behavioural anchoring effect.

Amount: £2,000
Funder: The Wellcome Trust
Recipient: University College London

BRAINEACv2: a resource for the interpretation of genetic variation in multiple regions of the adult human brain 16 Jun 2016

We aim to create BRAINEACv2, a resource for the investigation of the impact of genetic variation on gene expression in adult human brain. This resource will include three types of data: expression quantitative trait loci (eQTL), allele-specific expression and gene co-expression networks. Given the regional, cellular and molecular complexity of human brain, we believe there is a strong case for the creation of a tissue-specific resource. At present no comprehensive resource of this kind exists. However, our own public resource, BRAINEACv1, provides strong evidence for the popularity of such a resource with ~900 users from >80 countries accessing the website monthly. If funded BRAINEACv2 will represent a step-change improvement. It will include all 3 types of data described above (eQTL, ASE and co-expression networks), incorporate RNA-seq based gene expression quantification results and will include data from other major consortia (e.g. the North American Brain Expression Consortium). Given the success we have already demonstrated in creating a brain-specific resource for variant interpretation in human brain, we are well placed to deliver a new, comprehensive resource capable of meeting the growing interest in the understanding of the genetic regulation of gene expression in adult human brain.

Amount: £205,514
Funder: The Wellcome Trust
Recipient: University College London

Understanding cellular organisation: from archaea to eukaryotes 05 Jul 2016

We know surprisingly little about the basic logic, topology or origins of eukaryotic cell architecture even though such an understanding is fundamental to most biomedical research. Until recently, the proteins responsible for shaping eukaryotic cells (including Actin/Tubulin/coatamers/ESCRTIII) were thought to be unique to eukaryotes. This changed with the discovery of close homologues in TACK/Loki-family archaea. Despite the important part played by these proteins during eukaryogenesis, we know little about their functions in the context of archaea. To determine how these cytoskeletal systems with origins in archaea contributed to the emergence of internal compartments that define eukaryotes, our team will use metagenomic sampling and phylogenomics to trace their evolutionary history, and a combination of approaches, including live super-resolution microscopy and electron tomography to carry out a comparative analysis of their ultrastructure, dynamics and function in both archaea and eukaryotes. Ultimately, we expect this evolutionary cell biological analysis to make a start towards an understanding of archaeal cell biology, to reveal the likely path of eukaryogenesis, and to reveal underlying principles of eukaryotic cell biology that so far have eluded us. In doing so, we expect this fundamental research to have a signficant impact in the future on human health and disease.

Amount: £1,122,019
Funder: The Wellcome Trust
Recipient: University College London

Why do Norovirus pandemics occur and how can we control them? 05 Jul 2016

Noroviruses cause annual epidemics of gastrointestinal infection resulting in significant ill-health and disruption to health services. Frequent genetic mutation causing drift of epidemic strains and recombination leads to worldwide spread of pandemic strains. Approximately 3 million cases/annum occur in the UK with health-care costs exceeding £100M1. The advent of new vaccines against two genotypes is encouraging. However, ignorance about the drivers of norovirus strain evolution and spread is a barrier to effective vaccine design and deployment. This multidisciplinary consortium will investigate, through integrated studies, host and pathogen factors that lead to epidemic and pandemic norovirus spread and affect disease severity. Our international team has expertise in norovirus genome sequencing, phylogenetic analysis, norovirus antigen mapping, public health epidemiology and mathematical modelling. We will make use of existing clinical and public health datasets and samples, and an ongoing community study of norovirus burden to answer questions about transmission and carriage. Norovirus genome sequencing and phylogeography, in the context of international sequence-databases and antigenic mapping of sera will elucidate the origins and evolution of pandemic strains and outbreaks. Mathematical models, developed and fitted to the available data will provide novel insights into norovirus pathogenesis and transmission, informing vaccine design and immunisation strategies.

Amount: £2,825,452
Funder: The Wellcome Trust
Recipient: University College London

The Countdown to 2030: Global Health and Climate Action 30 Sep 2016

Climate change threatens to undermine the foundations of human wellbeing, and to reverse the last five decades of gains in global health. The 2015 Lancet Commission on Health and Climate Change concludes that the barriers to tackling climate change and improving public health are no longer economic or technological, but largely political. The report also concludes that "tackling climate change could be the greatest global health opportunity of the 21st century", with reduced greenhouse gas emissions yielding substantial health (and economic) gains. The Commission is an institutional collaboration between European and Chinese academic centres, led by University College London, Tsinghua University (Beijing), the University of Exeter, and Sweden’s Stockholm Resilience Centre and Umea University. It published its work on the 23rd of June, 2015 in The Lancet, with 11 launch events around the world. The authors of the Commission report recognise the need to carry their work forward- and to help deliver the required change. They propose a "Countdown to 2030: Global Health and Climate Action" as a mechanism for tracking progress on the implementation of policies designed to respond to climate change and protect public health. This idea draws upon the success of the Countdown to Child Survival, which galvanised evidence, interest and action to improve progress on child mortality over the past decade. The Countdown will exist as an independent, international, and multi-disciplinary coalition of organizations. The combined networks of The Lancet and the partner institutions will be utilized to ensure global reach to academics, policymakers, and the health community. It will produce an annual synthesis report on (i) the health impacts of climate change; (ii) progress in mitigation policies and the extent to which they protect and promote public health; (iii) progress with broader adaptation action to reduce population vulnerability, to build climate resilience, and to implement low carbon, sustainable health systems. The Countdown will continue its collaboration with The Lancet, who commit to publishing these Countdown Reports, as well as a number of related country- or issue-specific articles throughout each year.

Amount: £499,186
Funder: The Wellcome Trust
Recipient: University College London

Role of grid cell replay in consolidation and navigation 11 Feb 2016

I aim to build a neural level understanding of how information about the environment is stored, updated, and retrieved from memory. To this end I will study spatial memory and its representation in the rodent hippocampal formation. The results from experimental work including multi-site single unit recordings, pharmacological and optogenetic interventions, along with behavioural manipulations, will be combined with state of the art computational modelling. In turn computational work will suggest and refine further experimental manipulations. This joined-up approach is necessary to close the existing gap between our current neural-level understanding of the brain and cognitive functions. My key goals are to understand: 1) How entorhinal and hippocampal spatial representations are modulated by the level of certainty an animal has about the spatial configuration of its environment. 2) The role of cholinergic modulation in signalling environmental novelty, and more generally spatial u ncertainty. In particular, the effect of cholinergic modulation on theta-frequency rhythmicity and the scale of spatial representations. 3) How changes in the scale of the entorhinal spatial representation may contribute to, and even trigger, memory formation.

Amount: £143,293
Funder: The Wellcome Trust
Recipient: University College London