NIHRDataInsights/HRCSData huggingface dataset:
Title: Over two years for the identification of new genetic causes of hyperekplexia/startle disease
Funder: Action Medical Research

Abstract: Background Startle disease (hyperekplexia) is a brain disorder that affects newborn babies and is characterised by noise or touch induced muscle stiffness and suspension of breathing that can lead to sudden infant death. If diagnosed correctly, children can be treated and the symptoms often improve with age. There are no published estimates of the prevalence of startle disease, but this centre receives between 50 and 100 requests for genetic analysis per year and many more requests from clinicians for advice. Startle disease is an inherited disorder, but mutations in three known genes account for only two fifths of all known cases. This suggests that additional genetic causes of startle disease exist. The research project These researchers will analyse existing patient DNA samples using new technology aimed at identifying hidden causes of disease. Identifying the remaining causes of this under-reported condition should enable the rapid introduction of new genetic tests for affected children in the UK and worldwide. Understanding the genetic causes is vital for the correct treatment of children. For example, one type of mutation associated with startle disease can cause severe breathing problems during early infancy. Doctors are now advised to offer cardiac-respiratory monitoring and resuscitation training for parents in these cases. Children with startle disease may also have epilepsy, learning difficulties or a delay in learning language. Knowing the genetic causes enables a more accurate prediction of the likely educational needs of these children, which will assist parents in gaining access to appropriate support services.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL;REPRODUCTIVE HEALTH AND CHILDBIRTH
Title: The Developing Brain
Funder: Medical Research Council

Abstract: Our research programme uses a multi-disciplinary approach to study the developing brain, the damage it may suffer as a result of prematurity or birth trauma and to develop methods to improve the outcome of vulnerable infants by providing capabilities for more accurate and early diagnosis, and developing and testing novel therapies. Magnetic Resonance Imaging (MRI) is a core technology and we have pioneered its use both for studying the brain in utero and during the neonatal period. This has led to effective biomarkers of brain damage that have been used to test novel cerebral rescue therapies. During the next 4 years we will aim to substantially further develop MR technology including motion tolerant functional imaging methods and patient specific multi-transmit RF techniques that will have wide application in perinatal research and clinical care as well as for use in high field imaging generally. These will be combined with novel analysis techniques to provide a detailed exploration of brain development in utero in both normal and compromised pregnancies and to link in utero findings to post natal studies to further explore effects of prematurity and support development of more effective neural rescue therapies. Key targets will be to characterize developing connectivity and brain function, to link imaging findings to underlying microstructural damage through study of tissue samples and post mortem imaging, and to integrate imaging and genetic methods to explore key childhood syndromes such as autism spectrum disorder and attention deficit hyperactivity disorder (ADHD).


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;4.2 EVALUATION OF MARKERS AND TECHNOLOGIES
Health categories: NEUROLOGICAL;REPRODUCTIVE HEALTH AND CHILDBIRTH
Title: Development of brain activity and motor control in early human life
Funder: Medical Research Council

Abstract: I will use non-invasive neuroimaging techniques to study the maturation of human brain activity related to early spontaneous motor behaviour. This will be accomplished through inter-institutional (King's College London, Imperial College London, University College London, and Columbia University) and multi-disciplinary collaboration (Neonatal medicine, Imaging Sciences, Bioengineering, Neuroscience, Psychology) with colleagues at the forefront of their respective fields. This unique comprehensive approach will ensure that state-of-the-art techniques are used, supported and supervised by the very best team of researchers possible. I will use foetal MRI to visualise in-utero spontaneous movements and then precisely localise the associated brain activity with functional MRI (fMRI). This has never been done before, but will be possible using a recently developed acquisition and image processing pipeline. I will then study spontaneous motor behaviour in preterm and term infants (including a group who have suffered focal brain injury) by precisely measuring movements using accelerometers and will identify associated brain activity using simultaneous EEG-fMRI. This complimentary combination will provide entirely novel detailed information about both the temporal (EEG) and spatial (fMRI) features of the brain activity. I have already performed the first-ever simultaneous EEG-fMRI studies in preterm infants and will build on this further by studying a specific and clinically important question. Finally I will study how motor behaviour and its related brain activity can be altered by multimodal stimulation and associative learning. Precisely controlled stimulation will be achieved using technology which I have pioneered with bioengineering colleagues over the several years, and the related neural activity will be measured with simultaneous EEG-fMRI. To ensure robust methodology, I will collaborate with colleagues who have successfully demonstrated learning in neonates.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: NEUROLOGICAL;REPRODUCTIVE HEALTH AND CHILDBIRTH
Title: Using genome-wide gene expression profiles for early identification of encephalopathic babies at risk of adverse neurological outcomes
Funder: Medical Research Council

Abstract: Background: Rapid identification and risk stratification of babies with perinatal asphyxia is required for targeted neuroprotective therapies. Minimal host transcript signature from genome wide expression is currently being developed as a point of care test in several diseases, including bacterial infections. I have recently identified a host transcript signature of perinatal hypoxic-ischemic insult that correlates with brain injury on magnetic resonance imaging. Aims: To examine if a host transcript signature at birth can accurately predict adverse neurological outcomes at 18 months, after neonatal encephalopathy. Methods: I will collect 0.5 ml blood for gene expression (Next Generation Sequencing) within six hours of birth, from a prospective multi-centric cohort of 130 encephalopathic babies. In the discovery part of my project, I will identify a minimal host transcript that is associated with adverse neurological outcomes at 18 months (training set [n= 88]) and examine the prognostic accuracy of this transcript (test set [n= 22]). In the validation part of my project, the most significant differentially expressed genes will be further validated in a different platform (real-time reverse transcription polymerase chain reaction) (n= 20 babies). Finally, I will examine the gene expression pathways associated with long-term neurodisability. Outcome variables and potential benefits: Sensitivity and specificity (with confidence intervals) of the minimal host response transcript will be reported, in addition to specific up and down regulated pathways. This work will underpin the development of a rapid diagnostic test for early detection and risk stratification in neonatal encephalopathy, thus enabling individualised neuroprotective therapies. Pathway analysis may identify specific therapeutic targets.


Research activity codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES
Health categories: NEUROLOGICAL;REPRODUCTIVE HEALTH AND CHILDBIRTH
Title: Assessment of neurodevelopmental teratological risk in large cohorts: feasibility and reliability of parental reporting methods
Funder: Department of Health and Social Care

Abstract: This research will investigate the feasibility and reliability of parent completed ratings of infant development following prenatal exposure to medications. Women with epilepsy who are pregnant will be recruited from the North West and North East of England. Parents will complete measurements of development at 12 and 24 months of age. A formal assessment of development be administered at 24 months of age. If this research finds parent completed reports to be feasible and reliable, such methods could be implemented in the routine screening of medications used in pregnancy to reduce the time it takes to generate and safety/risk information.

Lay abstract: This research will investigate the feasibility and reliability of parent completed ratings of infant development following prenatal exposure to medications. Women with epilepsy who are pregnant will be recruited from the North West and North East of England. Parents will complete measurements of development at 12 and 24 months of age. A formal assessment of development be administered at 24 months of age. If this research finds parent completed reports to be feasible and reliable, such methods could be implemented in the routine screening of medications used in pregnancy to reduce the time it takes to generate and safety/risk information.

Research activity codes: 4.2 EVALUATION OF MARKERS AND TECHNOLOGIES
Health categories: NEUROLOGICAL;REPRODUCTIVE HEALTH AND CHILDBIRTH
Title: Extracellular vesicles produced by hiPSC-derived mesenchymal stem cells (iEV) for the neuroprotection of the brain following neonatal encephalopathy.
Funder: Medical Research Council

Abstract: Neonatal encephalopathy (NE) is a devastating cause of infant mortality and neuro-developmental disability. There is robust clinical and preclinical evidence for the brain repair potential of primary mesenchymal stem cells (MSC). However, primary MSC undergo replicative senescence during in vitro expansion. This represents an issue of standardisation, as new donors need to be identified repeatedly to isolate new MSC batches, which constitutes a barrier to clinical implementation. Luckily, MSC can be derived from pluripotent progenitors (iMSCs) and replace the use of primary MSCs. We recently evidenced the neuroprotective effects of iMSC in a preclinical mouse model of NE and showed in a pilot study that intracerebral injection of the extracellular vesicles produced by iMSCs (iEVs) decreased brain lesion size and improved behavioural outcome through vesicular MFGE8. Using a preclinical model of NE and human cerebral organoids, we aim to validate iEVs as a treatment for NE and determine whether engineering iEVs to contain higher amounts of MFGE8 confers superior neuroprotective efficacy to iEVs. We will first engineer iEVs to enrich or deplete their vesicular MFGE8 content (iEV-MFGE8-enriched and iEV-MFGE8-depleted) in order to study the molecular function of MFGE8. We will then use the Rice-Vannucci mouse model of NE to determine the short-term and long-term (longitudinal analysis) cellular and molecular mechanisms of action of iEVs, iEV-MFGE8-enriched and iEV-MFGE8-depleted, PBS alone and human recombinant MFGE8 (hrMFGE8) following a single ipsilateral intracerebro-ventricular injection in post-natal day 10 mice (males and females). In complement, to increase the physiological relevance of our data, we will use oxygen-glucose deprived (OGD) human cerebral organoids cultivated in millifluidic conditions to determine the neuroprotective effects of these treatments on recipient human brain cell phenotype and the molecular mechanisms involved.


Research activity codes: 6.2 CELLULAR AND GENE THERAPIES
Health categories: NEUROLOGICAL;REPRODUCTIVE HEALTH AND CHILDBIRTH
Title: MRC Transition Support Award CSF Tomoki Arichi
Funder: Medical Research Council

Abstract: The research of the fellowship and transition award uses non-invasive neuroimaging techniques to study the maturation of human brain activity related to early spontaneous motor behaviour. This is being carried out through inter-institutional (KCL, Imperial College London, UCL, INSERM, Oxford University) and multi-disciplinary collaboration (Neonatal medicine, Imaging Sciences, Bioengineering, Neuroscience). This unique comprehensive approach ensures that state-of-the-art techniques are used to answer important questions grounded in fundamental neuroscience, all being carried out within a research environment with colleagues at the forefront of their respective fields. This will include using foetal fMRI to study the brain activity associated with emerging patterns of motor behaviour. Although challenging, across the 4 years of the fellowship, we have built a comprehensive pipeline of acquisition and processing methods (multi-slice and multi-shot acquisition sequence, dynamic B0 field correction, motion-tolerant reconstruction) and an analysis pipeline (denoising of physiological noise and motion correction). The TSA will provide entirely novel world-first insights into the earliest stages of in-utero human brain activity by systematically apply this methodology. I am also studying the neural correlates of emerging motor behaviour in early human infancy using novel sensor technology and fMRI compatible robotics. The associated brain activity is characterised with simultaneous EEG-fMRI, which provides complimentary information about both temporal (EEG) and spatial (fMRI) features. I have already performed the first-ever infant studies using this method (Arichi et al. eLife 2017) and have optimised the methods further over the fellowship. In the TSA, I will build on this with multi-contrast tissue information and normative growth curves (developed using Gaussian Process Regression) and make the data open for dissemination to academic and clinical colleagues.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: NEUROLOGICAL;REPRODUCTIVE HEALTH AND CHILDBIRTH
Title: Monotherapy treatment of epilepsy in pregnancy: congenital malformation outcomes in the child
Funder: Department of Health and Social Care

Abstract: In the UK approximately 2,500 women with epilepsy have a baby each year. Antiseizure medications (ASMs) used to treat the epilepsy can convey an increased risk to the developing fetus. To date four ASMs have been associated with a clear increased risk of congenital anomalies and/or reduced fetal growth. Comprehensive evidence is therefore required to support the careful selection of appropriate ASMs in women of childbearing age. Our review has been central to the UK Medicines and Healthcare Product Regulatory Agency’s 2021 safety review of ASMs and their associated fetal risk and has been cited in both academic publications and clinical guidelines. The 2021 Committee for Human Medicine’s review highlighted that continued collection of evidence for the newer or rarer used ASMs is essential. This review team is multidisciplinary in nature, including both clinical and academic experts. The original review included 50 studies with over 5000 participants. This update will expand its original inclusion criteria to include secondary use database studies. Their inclusion will require updates to the risk of bias parameters and an extension in collaborators but is estimated to add an additional 1000 ASM exposed pregnancy outcomes. Since publication in 2017, the review continues to be amongst The Cochrane Epilepsy Group’s top 10 most accessed and cited reviews.

Lay abstract: See Plain English Summary

Research activity codes: 6.1 PHARMACEUTICALS
Health categories: NEUROLOGICAL;REPRODUCTIVE HEALTH AND CHILDBIRTH
Title: Neural circuits underlying fertility
Funder: Wellcome Trust

Abstract: This programme aims to establish in detail the characteristics and in vivo significance of the arcuate (ARNKISS) and rostral periventricular area of the third ventricle (RP3VKISS) kisspeptin neurons in driving the pulsatile and surge patterns of luteinising hormone (LH), respectively. Genetic cFOS-dependent activation and rabies trans-synaptic strategies will enable permanent GFP/mCherry tagging of RP3VKISS neurons activated at the time of the surge, or projecting directly to GnRH neurons, for subsequent electrophysiological and RNAseq analyses. GCaMP-based fiber photometry and GRIN lens miniscopes will be used to evaluate RP3VKISS neuron and population activity. This will be combined with microfluidics delivering pharmacological agents or adeno-associated viruses bearing CRISPR components to interrogate the key factors regulating the activity of RP3VKISS neurons in vivo. Studies aimed at understanding how the ARNKISS neurons synchronise to generate LH pulses will use the same strategies in addition to expansion microscopy and brain slice dual calcium and electrophysiological recordings. Novel strategies for slowing LH pulses in an animal model of polycystic ovary syndrome will be explored. It is expected that the in-depth understanding of these two kisspeptin populations will provide opportunities for developing new therapeutics aimed at the beneficial regulation of fertility in the clinic.

Lay abstract: The brain plays a key role in regulating the fertility of an individual. A network of cells in the brain use the gonadotropin-releasing hormone (GnRH) neuron to control the pituitary gland that, in turn, regulates the ovary or testis. Recent studies have shown that two different populations of neurons within this network making the same chemical (called kisspeptin) have important roles. One is involved in generating pulses of GnRH secretion in both males and females, while the other is responsible for the huge surge release of hormone that occurs only in females to cause ovulation. This programme will use sophisticated neuroscience approaches in mouse models to investigate in detail the properties of these two populations of kisspeptin neurons and determine how they control the GnRH neuron. Understanding these cells will begin the pathway that allows us to generate new therapies for the treatment of infertility in humans.

Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: NEUROLOGICAL;REPRODUCTIVE HEALTH AND CHILDBIRTH
Title: Antiepileptic drug (AED) management in Pregnancy: An evaluation of effectiveness cost effectiveness and acceptability of dose adjustment strategies
Funder: Department of Health (England)

Abstract: Epilepsy affects 0.5-1% of general population. Approximately one third of people receiving AEDs are of reproductive age. There is a 10-fold increase in mortality among pregnant women with epilepsy which greatly exceeds the two to three-fold mortality rate observed in all people with epilepsy. These were invariably a direct consequence of seizures. There is one in 250 pregnancies exposed to anti-epileptic drugs (AEDs). AED exposure in-utero is associated with congenital malformation. The general consensus is that the risks of uncontrolled convulsive seizures in the mother outweigh the potential teratogenic risk from AEDs and most women with active epilepsy are advised to continue with their medication during pregnancy. The blood levels of various AEDs fall in pregnant women with epilepsy due to physiological changes in pregnancy. Monitoring of serum AED levels in each trimester and after delivery has been recommended by the American Academy of Neurologists. In the UK however the NICE (National Institute for Health and Clinical Excellence) and SIGN (Scottish Intercollegiate Guidelines Network) guidelines do not recommend regular AED monitoring in pregnancy due to paucity of evidence. EMPiRE is a multicentre randomised controlled trial that aims to evaluate whether AED dose adjustment based on serum AED levels reduces the risk of seizure deterioration in pregnancy compared to management based on clinical factors only. All pregnant women with epilepsy on one or more of the following AEDs: lamotrigine carbamazepine phenytoin levetiracetam will be eligible for recruitment. We aim to recruit 1000 participants from 40 centres throughout the UK. We will qualitatively assess the views and experiences of pregnant women with epilepsy. In addition to that cost-effectiveness analysis will be undertaken by comparing different management strategies using a decision-analytic model based health economic evaluation.


Research activity codes: 7.3 MANAGEMENT AND DECISION MAKING
Health categories: NEUROLOGICAL;REPRODUCTIVE HEALTH AND CHILDBIRTH
Title: Is ischaemic post-conditoning neuroprotective following perinatal asphyxia?
Funder: Medical Research Council

Abstract: Perinatal asphyxia occurs in 1-2 per 1000 births in the UK and is associated with death or major neurodevelopmental impairment. The early induction of therapeutic hypothermia after birth is a significant advance, however, it prevents adverse outcome in only ~50% of cooled infants. There is therefore an unmet need to develop novel, non-invasive approaches which can be used alone or in combination with hypothermia to augment neuroprotection. Remote ischemic post-conditioning (IPostC) is a novel therapeutic approach initially described in myocardial ischemia. Remote IPostC involves repeated episodes of inflation and deflation of a cuff around the limbs to induce short-lived episodes of mild ischemia. The neuroprotective efficacy of remote IPostC in cerebral ischemia is evident in rodent models of stroke reducing cerebral infarction up to 50%. We aim to address these research questions in a large validated animal model of perinatal asphyxia with outcome biomarkers : 1. brain 1H MRS lactate/N acetyl aspartate; 2. quantitative Tunel+ cells 8 brain regions: A. Is remote IPostC at resuscitation after transient hypoxia-ischaemia neuroprotective? B. Does the therapeutic window of IPostC last up to 3 h. C. Does remote IPostC (immediate and delayed) augment therapeutic hypothermia? After surgical preparation, randomization will be (n=14 / group): (i) No intervention (ii) Immediate remote IPostC (iii) Delayed remote IPostC at 3h (iv) Therapeutic hypothermia from 4-22h (cooling) (v) Immediate remote IPost C and cooling (vi) Delayed remote IPostC at 3h and cooling Continuous NIRS, physiological monitoring, interleaved MRI and EEG will be recorded for 48h after resuscitation. Because of its simplicity, cost-effectiveness and safety, remote IPostC could be applied in an infant with moderate/severe encephalopathy in most neonatal units. This technology may be complementary to hypothermia and used in settings where hypothermia is not available or safe.


Research activity codes: 5.3 MEDICAL DEVICES
Health categories: NEUROLOGICAL;REPRODUCTIVE HEALTH AND CHILDBIRTH