NIHRDataInsights/HRCSData huggingface dataset:
Title: Machine learning to understand brain development
Funder: Medical Research Council

Abstract: We will analyse images acquired from 820 preterm infants (as part of ePrime) and an existing dataset of 50 control infants. Network characterisation will be performed using graph theoretical approaches and combined with measures of shape and appearance (Bullmore and Sporns 2009, Aljabar et al. 2011). Techniques for mapping low-dimensional manifold representations of high-dimensional datasets will be optimised and applied to provide a more complete characterisation of the developing brain-comprising anatomy on a macro- and micro-scale and functional development of neural networks. Using these techniques, features will be extracted that describe the influences of prematurity at birth, and a number of potentially modifiable perinatal risk factors, including postnatal sepsis (Adams-Chapman and Stoll 2006) and neonatal respiratory morbidity (Doyle and Anderson 2010), on the developing brain. This will be performed with post hoc comparisons of image-derived data with clinical metadata collected as part of the ongoing image acquisition project and by incorporating the metadata into the models provided by manifold learning (Wolz et al. 2011). In addition, we aim to identify early markers of poor neurodevelopment outcome. Outcome data will be available for the full cohort after two years and will be used to assess the predictive power of the machine learning techniques described above. By combining a unique dataset, advanced imaging and high-level, exploratory statistical analysis this project will identify potential biomarkers for future developmental performance and provide tools for assessing efficacy of therapeutic intervention in this at-risk population. Adams-Chapman I, Stoll BJ. 2006. Curr Opin Infect Dis 19:290-297 Aljabar P et al. 2011. IEEE Trans Med Imaging: doi:10.1109/TMI.2011.2162529 Bullmore E, Sporns O. 2009. Nat Rev Neurosci 10:186-198 Doyle LW, Anderson PJ. 2010. Neonatology 97:388-394 Wolz R et al. 2011. ISBI: From Nano to Macro 1:1637-1640


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL;REPRODUCTIVE HEALTH AND CHILDBIRTH
Title: The role of DISC1 in synaptic function and circuit formation during critical periods of cortical development
Funder: Medical Research Council

Abstract: We will conduct four main experiments on DISC1-cc mutants, where the trangene product (amino acids 671-852 of DISC1) is made available within the cell by administration of tamoxifen. The transgene is constitutively expressed in excitatory forebrain neurones under the control of the CaMKII promoter. Tamoxifen binds to the ligand binding domain (LBD) of the oestrogen receptor (which is made as a fusion protein with DISC1-cc). The LBD does not bind natural oestrogen. Binding tamoxifen causes LBD-DISC1-cc to dissociate from heat shock proteins and the proteasome degradation pathway and is therefore free to interact with DISC1's natural binding partners such as Lis and Nudel. The gene is active for a period of between 6 and 24 hours following a single tamoxifen injection. In these studies we activate DISC1-cc at various time points from the second postnatal week to one month of age and study the effect on 1. experience-dependent plasticity in the barrel cortex 2. dendritic development in layer III, IV and layer V neurones of barrel cortex and prefrontal cortex 3. input circuits to layer III and V neurones and 4. the synaptic plasticity properties of the layer IV to III pathway, including spike timing LTP, experience-dependent GluR1 insertion and the natural development of synaptic transmission (NMDA/AMPA ratios, conversion of silent to active synapses) during the second postnatal week. In each case DISC1-cc will only affect circuit development from a point in development beyond the end of neocortical neuronal migration.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: NEUROLOGICAL;REPRODUCTIVE HEALTH AND CHILDBIRTH
Title: Iodine status in pregnancy and child neurodevelopment: the influence of genetic variation, selenium status and thyroid function on the relationship
Funder: Medical Research Council

Abstract: Iodine, through thyroid hormones, is crucial for brain development, particularly during pregnancy. Though the UK is considered iodine-sufficient, my work and that of others has shown mild-to-moderate iodine deficiency in UK pregnant women. We have shown that the level of iodine deficiency in the UK is affecting child cognition. Urinary iodine was measured in 951 women of the Avon Longitudinal Study of Parents and Children (ALSPAC) and the group was mildly-to-moderately iodine deficient. Children of the 61% of women deficient in iodine had a higher risk of being in the bottom quartile of IQ scores at age 8, reading accuracy at age 9, and key stage 2 maths scores than children whose mothers were not deficient in iodine. The overarching aim of this project is to investigate factors that influence maternal iodine status and the consequent effect on child neurodevelopmental outcomes. The project will also develop methods of identifying iodine deficiency in individuals in the clinical setting. The project will investigate genetic variation in pathways of iodine and thyroid metabolism on measured iodine status in pregnancy and the consequent effect on child outcomes in ALSPAC. Associations between maternal selenium, iodine status and thyroid function will be studied in ALSPAC. The effect of selenium supplementation on maternal thyroid function and iodine status will be evaluated using data from a low-dose (60mcg/day) selenium supplementation trial in UK pregnant women (SPRINT). The fellowship will provide research time required to be involved in two randomised controlled trials - in pregnant women and schoolchildren - to assess the effect of iodine supplementation on child cognition. Finally, as there is currently no method for diagnosing iodine deficiency in individuals, the project will explore alternative biomarkers of individual iodine status assessment in pregnancy and methods to identify those at risk of deficiency in the clinical setting.


Research activity codes: 2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT;3.3 NUTRITION AND CHEMOPREVENTION
Health categories: NEUROLOGICAL;REPRODUCTIVE HEALTH AND CHILDBIRTH
Title: Investigating newborn brain function and behaviour associated with prematurity and brain injury
Funder: Medical Research Council

Abstract: Conventional brain-imaging techniques detect structural pathological lesions, however subtle injury can occur undetected leading to lifelong neurodisability. Improving our understanding of infant brain function (resting-state functional connectivity) and behaviour will provide a more comprehensive picture of infant neurodevelopmental potential. The project aims to investigate early development of brain function and behavior in infants to develop a clinical biomarker for brain injury. A novel cap with optical and electrical sensors will be placed on the infant's head while remaining in their cot. This cap uses the combined techniques of diffuse optical imaging (DOI) with electroencephalography (EEG) to non-invasively monitor RSFC within the haemodynamic and electrical brain signals. This technology is safe and has been used by the research group previously to study seizure activity in the newborn and more recently to investigate RSFC. The Neonatal Behavioral Assessment Scale (NBAS) is a standardised, clinical examination of infant neurology and behaviour. Poor performance is associated with increased risk of adverse cognitive and behavioural outcome in early childhood and will be used to evaluate behaviour in this study. Infants will be enrolled into a follow-up programme to compare early functional and behavioural measures with longer term neurodevelopment. Three distinct studies will be carried out on different cohorts of infants for the following objectives 1. To establish a normal reference of RSFC: healthy term and near-term infants 2. To investigate the impact of extreme prematurity on behaviour and formation of RSFC: infants <32 weeks gestation 3. To investigate the impact of brain injury on behaviour and formation of RSFC: preterm and term infants with evidence of acquired brain injury By demonstrating the effects of prematurity and brain injury on RSFC and behaviour, it will be possible to produce biomarkers for clinical application.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL;REPRODUCTIVE HEALTH AND CHILDBIRTH
Title: Cerebral Magnetic Resonance Biomarkers for Prediction of Adverse Neurodevelopmental Outcome in Neonatal Encephalopathy
Funder: Department of Health (England)

Abstract: Permanent brain damage can occur in babies due to a lack of oxygen just before birth; often these occur following a completely normal pregnancy and are not preventable. Brain cooling reduces this injury to an extent; however we need better treatments that can reduce the brain damage further. Whilst there are several such promising treatments, to know if these really work, we need to study thousands of babies with this condition over several years, which is extremely challenging. However by using a magnetic resonance (MR) technique doctors would be able to predict the long term outcome of the affected infant soon after birth; thus (1) doctors can do above mentioned studies very quickly with a small number of babies and therefore will be able to offer more effective treatments to reduce brain injury (2) parents can know the long term outcome of their baby soon after birth rather than waiting anxiously for years (3) in severely affected infants who are likely to develop major disabilities like cerebral palsy doctors often recommend withdrawal of life support, considering the poor quality of life the infant may have, if he or she survives. This new technique will help doctors to make such decisions more accurately


Research activity codes: 4.2 EVALUATION OF MARKERS AND TECHNOLOGIES
Health categories: NEUROLOGICAL;REPRODUCTIVE HEALTH AND CHILDBIRTH
Title: Wellcome Trust Clinical PhD Programme in International Health at the LSHTM: 'Perinatal infection as a risk factor for neonatal encephalopathy amongst term infants in Uganda: an unmatched case control study'.
Funder: Wellcome Trust

Abstract: Throughout the fellowship, I will benefit from the supervision of individuals with extensive practical experience and producing outstanding work in this field and I will work in institutions with an international reputation in the field of tropical medical research. During the three-year period I will attend at least one relevant international conference. How the proposed work fits in with current research within the laboratory The proposed study is in line with experience in studies of maternal and child health of Professor Elliott's existing collaboration, and with their interest in the influences of the intrauterine environment on subsequent neonatal and infant outcomes, and the relationship between infections 11nd "non-communicable" diseases outcomes. This study fits in with the broader strategy of the MRC/UVRI Research Unit to currently develop studies in the field of non-communicable diseases in response to a request by the Ugandan Ministry of Health. This study also fits with the Perinatal Brain Research Strategy at the UCL Institute for Women's Health. The research lead for Academic Neonatology is Dr Robertson; her team uses translational experimental models to refine and optimize neonatal neuroprotection in both developed and developing countries. Clinical studies of neonatal neuroprotection are on-going in transitional countries such as the Indian sub-continent. However, in low-resource settings such as Uganda, previous work has shown the importance of first understanding the risk factors associated with neonatal encephalopathy. In 2005, the Uganda Women's Health Initiative was set up in ' conjunction with the UCL Women's Health Institute, Makerere University, Mulago Hospital and Hospice Africa. The aim of this Initiative was to try to make a difference to the health of women and their infants in Uganda; the initiative has already successfully conducted work in cervical screening which has been adopted by the Ministry of Health in Uganda for national roll out and is influencing planning Africa wide.


Research activity codes: 2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT
Health categories: NEUROLOGICAL;REPRODUCTIVE HEALTH AND CHILDBIRTH
Title: How the brain senses CO2
Funder: Medical Research Council

Abstract: We seek to understand the mechanisms by which brain senses the partial pressure of CO2 (PCO2) in arterial blood. Chemosensory reflexes regulate breathing to keep arterial PCO2 (and PO2) within tightly defined limits and thus maintain acid-base balance. Although disorders of chemosensory mechanisms are potentially life threatening, especially in the context of other pathologies such as congestive heart failure, knowledge of their underlying mechanisms remains surprisingly incomplete. We have recently discovered a new molecular transducer for CO2 chemoreception ?the connexin 26 (Cx26) hemichannel. During elevated arterial PCO2 (hypercapnia), increased CO2 binding to Cx26 causes it to open more and hence release more ATP. This ATP excites the respiratory network and causes the adaptive increase in breathing to hypercapnia. Cx26 is also sensitive to decreases in PCO2; closure of the channel, resulting in reduced ATP release, decreases the respiratory drive during hypocapnia and consequently helps to maintain PCO2. Cx26 is widely distributed throughout the brain in the subpial astrocytes and leptomeninges. This raises two important and major questions. Which are the key tissues and cell types for respiratory chemosensing ?the astrocytes or the leptomeninges? How can gating of a gap junction hemichannel be directly altered by CO2? We shall address these two problems in a coordinated fashion. Firstly, we shall develop the transgenic tools to delete Cx26 in selected cell types and regions. We shall then examine the effect on responses to CO2. This will provide definitive causal evidence linking Cx26 to the behavioural adaptive reflexes in responses to changes in PCO2 and will allow us to determine the most critical cellular components and regions for central CO2 chemosensing. Secondly, we shall make chimeric constructs by inserting structural motifs of Cx26 (CO2-sensitive) into a non-CO2-sensitive homologous connexin to identify the critical domains of the molecule. We shall complement the identification of key structural components by loss-of-function mutagenesis. We shall definitively test our favoured hypothesis that CO2 alters Cx26 hemichannel gating via carbamylation of a lysine residue by utilizing 15N-13C NMR spectroscopy to demonstrate directly the existence of the hypothesized carbamate group. The NMR studies will assist the design of the mutagenesis strategy and complement the functional evaluation of the mutant channels: we expect the existence of a carbamate group to be present in those mutant channels that are CO2-sensitive and absent in those that are not.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: NEUROLOGICAL;RESPIRATORY
Title: Recovery of normal breathing after chronic paralysis
Funder: Medical Research Council

Abstract: Respiratory failure is the leading cause of morbidity and mortality following acute and chronic spinal cord injury (SCI). This is largely due to diaphragm paralysis resulting from damage to descending bulbospinal projections. The human respiratory motor system shows no endogenous recovery from SCI acutely or chronically after injury. Nonetheless, we have shown that total recovery of respiratory motor function is possible 1.5 years following cervical SCI following modification of the extracellular matrix (ECM) at the phrenic motor pool. However, this was achieved using methods that could not be readily applied to human patients. Here, we aim to assess two clinically applicable methods of ECM modification to determine if total and persistent recovery of normal respiratory motor function can be achieved at chronic stages following SCI. Through the use of these drugs, we shall be also able to determine if restoration of respiratory function is reliant on regeneration or plasticity while assessing the anatomical and physiological mechanism for this recovery: the degree to which it relies upon endogenous plasticity, the motor circuity involved, and the function and mechanism of the ECM involvement. Further, we shall assess the degree to which paralysed diaphragm muscle losses, and can regain, mechanical function following SCI and treatment and start development of a tool which will utilise respiratory parameters to assess the severity of SCI and predict treatment outcomes. Finally, we shall explore and identify the endogenous alterations to the respiratory motor system which occur over time following trauma. These data will inform the optimal time for treatment application post SCI. Collectively, this project will demonstrate the mechanism of functional recovery within the respiratory motor system as a whole following chronic and severe cervical trauma while allowing for greater translation of ideas and treatments for chronic SCI into the clinic.


Research activity codes: 5.1 PHARMACEUTICALS
Health categories: NEUROLOGICAL;RESPIRATORY
Title: An integrated epidemiological approach to understanding the relationship between lung health and multi-morbidity
Funder: Medical Research Council

Abstract: The WHO estimates that dementia will affect 80 million people in 20 years, so there is an urgent need to identify modifiable risk factors. Mild cognitive impairment is associated with a 5-10% annual conversion rate to dementia but is considered a potentially reversible state. 3 million people live with COPD in the UK, the majority have two or more long-term health conditions, it is therefore a disease of 'multi-morbidity'. (MRC strategic theme 'living a long and healthy life') The majority of observational studies provide evidence for an independent association between lung function and cognitive impairment. However a number of unmeasured or unaccounted confounders are likely to bias this relationship. Objectives & Methods Part 1: Two-sample Mendelian Randomisation using existing Genome Wide Association Studies to determine the causal association between lung function, cognitive impairment and risk of dementia Mendelian Randomization (MR) is a form of analysis that uses genetic variants as instrumental variables. Using summary data from GWAS consortia in two-sample MR increases statistical power, particularly in relation to testing effects on binary disease outcomes, such as Alzheimer's Disease (AD) or Cognitive Impairment (CI). Part 2: Determine if early life course lung function trajectories are associated with cognitive dysfunction and multi-morbidity using existing longitudinal data from the ALSPAC cohort. Several measures of functional cognition and comorbidity are available from the ALSPAC clinic at 24 years. Four FEV1 trajectories from childhood to early adulthood were identified in using latent profile modelling: persistently high (4%), normal (45%), below average (44%), and persistently low (7%). Setting the normal FEV1 trajectory as the baseline group, we will use multinomial logistic regression model to investigate the risk (betas & 95%CIs) of the membership of other trajectories per unit increase of a continuous measure of functional cognition.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL;RESPIRATORY
Title: Interaction of anaesthetics and their combinations with carotid body glomus cell and background potassium channel response to hypoxia
Funder: Medical Research Council

Abstract: Anaesthetics depress human ventilatory hypoxic responses (VHR) with a specific order of potency (halothane>isoflurane>sevoflurane), diminishing the body's defence against hypoxia-related injury. Although we know how the carotid body may detect hypoxia, little is known about anaesthetic depression. We identified an O2-sensitive (TASK-like two-pore domain) background K+ (KB) channel, also sensitive to halothane, making it a candidate receptor for the anaesthetic effect. We then reported anaesthetics (halothane and isoflurane) depress glomus cell hypoxic response and increase KB channel activity, with the same order of potency as on whole-body VHR. We have recently discovered that while halothane strongly activates KB channels, isoflurane does so only weakly (ie, isoflurane is a partial agonist). Common non-halogenated agents also have effects upon hypoxic responses ranging from inhibitory (eg, propofol) to excitatory (eg, N2O). These agents are reported to inhibit, activate or have no effect on cloned TASK channels but we wish to extend observations to native channels in isolated type-1 cells. Specifically, we wish (a) to ascertain which agents activate KB channels and if so, whether weakly or strongly; (b) to test whether the ability to activate KB channels is associated with an ability to inhibit glomus cell hypoxic response; (c) to test the possibility that agents which weakly activate KB channels can antagonise agents that strongly activate KB channels; (d) to characterise the specific channels using transgenic (knockout) mice. Finally, in a forward- translational approach, we wish (e) to assess if similar interactions between agents can be demonstrated at whole-body level in humans.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: NEUROLOGICAL;RESPIRATORY