Supervisors: Prof Molloy and Dr. Turlough Bolger.
Collaborators: Dr. Stan Koe, Dr. Ciara Martin, Dr. David Webb, Dr. John McHugh, Dr. Roisin McNamara, Dr. Ike Ofakor, Mr. John Caird & Mr. Darrach Crimmins, Dr Veronica O'Keane, Dr. Carol Blackburn, Dr. Michael Barrett & Dr. Sean Walsh, Dr. Aisling Snow, Prof. Cathal Moran, Prof. Arun Bodke , Prof. Jim Meaney, Prof Louise Gallagher
PhD student: Dr. Emer Ryan
Institutions: CUH, Tallaght, OLCH, NMH, TCD
Traumatic brain injury (TBI) is more common in childhood and adolescence than at any other time of life and is one of the most common causes of neurological morbidity and includes concussion. Post concussion syndrome (PCS) combines clinical, cognitive and behavioral symptoms and occurs in one in seven school children sustaining an TBI for three months or longer and is associated with persistent inflammation. At present there are no evidence-based clinical guidelines or accurate early tests to predict PCS in children. We aim to prospectively evaluate novel clinical and biochemical markers neurocognitive function at presentation in the Emergency department and at 6 weeks in children presenting with TBI. We will study the evolution of systemic inflammation associated with traumatic brain injury and correlate with neurocognitive and neuroimaging outcomes. In addition a subgroup of children with TBI and age-matched controls will have 3T MRI performed in SJH by a specialized team with expertise in functional MRI. To complement this project we will retrospectively review the records of children with TBI admitted to the Dublin EDs over a 2 year period to quantify the number of cases with moderate, mild and severe symptoms as well as PCS. Children with severe TBI will be recruited from CUH, which will allow validation of biomarkers and neuroimaging using a spectrum of mild to severe TBI. Finally the group will provide an educational module on the management, assessment and followup of children with TBI. This project will commence in 2017 and is funded by NCHF.
Lead PI: Prof Eleanor Molloy TCD.
Project Partners: Dr. Lynne Kelly (TCD) Prof Catherine Greene (RCSI).
Partner Institutions: TCD, RCSI, NMH, CWIUH and Rotunda hospital.
TCD Research Fellow: Dr Lynne Kelly.
Background: GEnder and inflaMmatIoN In neonatal encephalopathy (GEMINI) is a research programme funded through the National Childrens Research Centre in Crumlin (NCRC) and carried out between the three maternity hospital and TCD led by Professor Eleanor Molloy. This project is looking at neonatal brain injury in relation to gender. Neonatal encephalopathy (NE) is one of the commonest causes of neonatal brain injury in full term infants. Research has shown that there is a male disadvantage in the incidence and severity of brain injury in neonatal encephalopathy. Neurodevelopmental differences manifest from an early age in infancy with females having a lower incidence of developmental delay and learning difficulties in comparison with males. This study will examine gender in relation to clinical and immunological outcomes in NE. We will explore three specific areas; 1) Gender specific outcomes for neuroimaging and developmental outcome as well as for inflammatory responses in babies with NE, 2) inflammasome components and TLR signalling and 3) immunometablism in NE and the role of gender. Our aim is to delineate these responses according to gender which may enable cut-off values for clinical outcomes and the possibility of adjunctive therapeutic interventions in the future.
PI: E Molloy, Dr. Dave Coghlan, Dr. Denise McDonald, Dr. John Kelleher, Dr. Suzanne Kelleher, Dr. David Rea, Prof J Meaney, Dr. Arun Bodke, Prof. John O'Leary, Prof. Jan Miletin, Dr. Jana Sembrova
PhD student: Dr. Murwan Omer
Institutions: CWIUH, Tallaght hospital, TCD
Background: Despite rapid progress in neonatal intensive care over the past decades, neonatal mortality from sepsis remains unacceptably high and morbidity includes brain injury and developmental delay. Systemic inflammation related to sepsis has been implicated in many common neonatal complications such as brain, lung, or gastrointestinal injury especially in preterm infants. Modulation of inflammatory signalling during sepsis may improve survival in preterm infants and prevent related neurodevelopmental complications. Activated leucocytes, infection and persistent inflammation have been implicated in the pathogenesis of brain injury and also cerebral palsy. Antenatal inflammation and neonatal outcome: We will evaluate antenatal inflammation using placental pathology results and blood culture results from mother and baby. Detailed clinical multiorgan outcomes including novel renal biomarkers and echocardiography will be quantified using the Modified Neonatal Multi -Organ Dysfunction (NEOMOD) score. Neuroimaging with cranial ultrasound and/or MRI will be performed and developmental followup including 2-year Bayley's developmental scales (BSID III). Inflammatory response to infection and immunomodulation: We will examine pro and anti-inflammatory cytokine responses using whole blood from preterm infants over the first few weeks of life and correlate with antenatal inflammation. We will evaluate neonatal inflammatory cell phenotype and activation of the inflammasome, which is crucial for inflammatory responses and host defense to pathogens as well as being implicated in several inflammatory diseases such as inflammatory bowel disease, rheumatoid arthritis and atherosclerosis. Immunomodulators such as melatonin and specific inflammasome inhibitors will be assessed in vitro as possible methods to ameliorate persistent inflammation.
Conclusion: This research will improve the understanding of the systemic inflammatory response in preterm infants and the potential for newer adjunctive therapies. In addition these immune markers will assist in prognosis of multi-organ outcomes in preterm infants. This project is funded by NCHF and TCD
Collaborators: Professor William Watson, Dr Amanda O'Neill, Dr. Veronica Donoghue, Drs. Eoghan Mooney, Paul Downey, Prof Geraldine Boylan, Prof Bryan Lynch, Dr. Eva Jiminez, Dr. Denise McDonald, Dr. Suzanne Kelleher and Dr. John Kelleher
PhD student: Dr. Saima Aslam
Institutions: NMH, UCD, TCD, RCSI, UCC
Background: Neonatal brain injury has multifactorial etiology and causes significant neurological morbidity such as cerebral palsy. Therapeutic hypothermia is the only treatment available in term infants with neonatal encephalopathy (altered neurological function). Activated leucocytes, infection and persistent inflammation have been implicated in the pathogenesis of brain injury and cerebral palsy.
Circadian Rhythm and Melatonin: Circadian rhythm plays a key role in innate immune responses and melatonin is an essential regulator. Melatonin has been shown to improve outcomes in combination with hypothermia in animal models of neonatal brain injury. We will explore the mechanism underlying the altered activation of neutrophils and monocytes in neonates with brain injury by examining Circadian rhythm and the use of melatonin for neuroprotection. The key regulators of circadian rhythm BMAL-1 and CRY will be measured in infants with NE and neonatal controls. Persistent Inflammation and Circadian Rhythm: Hypoxia-inducible factor (HIF) 1 alpha is a key transcriptional factor in the hypoxic response and is associated with persistent inflammation. We will examine the role of the hypoxia inducible factor (HIF1 alpha) in persistent or sustained inflammation in NE. We will examine HIF 1 alpha expression in innate immune cells as well as modulation by melatonin.
Conclusion: MRI, clinical and neurodevelopmental outcome will be correlated with circadian rhythm as well as multi-organ dysfunction. This research will improve the understanding of the systemic inflammatory response in infants with brain injury and the potential for therapies such as melatonin in addition to hypothermia.
PI: Eleanor Molloy, Prof Mary King, Dr. Breda Hayes, Dr. Adrienne Foran, Prof John O'Leary, Dr. Claudine Vavasseur, Prof. Afif El-Khuffash, Prof. Martin White, Prof. Rhona Mahony, Dr. Veronica Donoghue, Dr. Eoghan Mooney, Prof. Jan Miletin , Prof. Naomi McCallion, Prof. Jim Meaney, Dr. Deirdre Sweetman, Dr. Paul Downey, Dr. Orla Franklin, Dr. John McHugh, Dr. David Rea, Prof. John Murphy
PhD student: Dr. Mary O'Dea Postdoctoral researcher: Dr. Lynne Kelly
Insitutions: NMH, Rotunda, CWIUH, TCD, UCD, RCSI
Neonatal brain injury (NBI) has a heterogenous aetiology with a high economic and social burden. Neonatal encephalopathy describes the babies who require resuscitation at birth and have an abnormal neurological examination. It remains difficult to predict their developmental outcome. Enhanced inflammatory responses are seen in affected infants and correlate with outcomes. Multiorgan dysfunction is common with renal, hepatic, cardiac and haematological abnormalities.We aim to correlate these inflammatory responses with clinical, neurodevelopmental and MRI outcomes to establish biomarkers of brain injury in neonates. Our translational research group includes laboratory scientists and clinicians to evaluate both inflammatory responses and correlate with multiple organ dysfunction. We have incorporated newer modalities for cardiac function (echo speckle tracking, troponin and BNP), brain imaging (EEG, MRI and fMRI), renal biomarkers (eg.NGAL, cystatin c), placental pathology and haematological indices. This research may allow early recognition of brain injury prior to MRI (Day 5-7) so that new therapies as adjuvants to therapeutic hypothermia can be initiated as soon as possible after birth.Developing clinically useful early biomarkers incorporating clinical outcomes are crucial in this group. Although neurological outcomes are evaluated in the short-term in this patient group there is no assessment of longterm cardiac, renal, immune and haematological status and we aim to coordinate followup of these parameters until at 2 years of age. This project is funded by the HRB
PI: E Molloy
Collaborators: Prof. Adrienne Foran, Dr. Annie Curtis, Dr. Deirdre Sweetman, Dr. Deirdre Murray, Dr. Ellen Crushell, Prof Ger Boylan, Prof Jim Meaney, Ms Mandy Daly, Prof Richard Porter, Prof Terrie Inder, Dr. Veronica Donoghue
PhD Student: Dr. Mary O'Dea
Institutions: CWIUH, NMh, Rotunda, TCD, RCSI
Background: Neonatal brain injury has a multifactorial aetiology and causes significant neurological morbidity such as cerebral palsy. Therapeutic hypothermia (TH) is the only treatment available for neonatal encephalopathy (NE) but morbidity and mortality rates remain high. There is an urgent need for adjunctive therapies to improve neurodevelopmental outcomes. Persistent inflammation: Persistent systemic inflammation has been implicated in neonatal brain injury and identifying new inflammatory biomarkers will help to determine the aetiology of NE and new adjunctive therapies. There is a narrow therapeutic window to activate neuroprotective therapies during ischaemic reperfusion in NE. Ischaemia reperfusion injury occurs when a hypoxic tissue is reperfused rapidly in NE resulting in oxidative damage, cellular apoptosis and atypical immune responses generated through the production of mitochondrial oxygen species (ROS). We demonstrated that immune cell ROS are produced at abnormally high levels in infants with severe NE and increase over the first week of life despite hypothermia therapy. Babies with NE, children aged 4-6years who had NE and age-matched controls will have inflammatory phenotyping to assess persistent immune dysregulation. Detailed 1.5T MRI, MRS and 3.0T MRI and neurological outcome will be correlated with these results. Mechanisms of persistent inflammation & immunomodulation: Exploring immune activation and persistent dysfunction is crucial in the development of new treatments for NE and brain injury and there are several potential targets including: Hypoxia-inducible factor(HIF-1)-alpha and succinate metabolism. HIF1a is a key transcription factor in the hypoxia response and as well as mitochondrial dysfunction and succinate accumulation is associated with persistent inflammation and may be a potential therapeutic target.
Conclusions: Understanding the function and metabolism of systemic inflammatory cells is important in the pathogenesis of neonatal brain injury to find relevant biomarkers of severity.
PI: E Molloy and D McDonald
Collaborators: D Sweetman, B.ElNazir, D.Coughlan, S.Quinn, C.Mc Donnell, D.Webb, J.Murphy, C.McMahon, O.Franklin,O.Smith,B.Nolan,E.Crushell,V.Donoghue, M.Riordran
Funding: NCH foundation
PhD student: Z.ZareenPostdoc: V McEneaney
Perinatal global hypoxia ischaemia is associated with neonatal encephalopathy and results in multi-organ dysfunction. Early multi organ dysfunction in neonates with encephalopathy may persist in later childhood, therefore multi-organ and neurodevelopmental follow up studies are required to ensure complete resolution and avoid complications in later childhood. Predictions about long term outcomes following NE are improving both qualitatively and quantitatively. Better insight into multi organ dysfunction post NE can be gained by using novel biomarkers and new diagnostic tools. Further research with multidisciplinary involvement can provide better predictive data and contribute to improved prognosis. In addition, to gain insight into the long-term effects neurodevelopmental effects of NE, follow-up is required throughout the school age as specific cognitive functions continue to develop throughout childhood
Lead PI: Professor Eleanor Molloy (TCD)
Programme Partners: Professor Geraldine Boylan (UCC), Professor Declan Devane (NUIG), Professor Arun Bokde (TCD), Dr Elizabeth Nixon (TCD), Dr Mark Watson (CRDI)
Partner Institutions: : TCD, UCC, NUIG, CRDI
TCD PhD Scholars: Tim Hurley, Megan Dibble, School of Medicine, Chelo del Rosario, School of Psychology.
Other PhD Scholars: Andreea Pavel (UCC), Fiona Quirke (NUIG)
Background: The HRB Neonatal Encephalopathy PhD Training Network (NEPTuNE) is a major collaborative structured PhD research programme led by Professor Eleanor Molloy (Consultant Neonatologist, Chair and Professor of Paediatrics, TCD and Tallaght Hospital) and co-lead Professor Geraldine Boylan (Professor of Neonatal Physiology and Director of the INFANT Research Centre, UCC). Ireland is at the forefront of research in neonatal brain injury and has collaborative potential to be an international leader in this area. Researchers in this consortium have internationally recognised multidisciplinary expertise in neonatology, paediatrics, neurodevelopment, family-centred care, clinical trials and methodology, pharmacology, epidemiology, biostatistics, translational research and neuroimaging in neonatal brain injury.
Programme Projects:
Changes in circadian rhythm are common in many illnesses including neonatal brain injury and neonatal encephalopathy (NE). NE is associated with persistent abnormal systemic inflammatory responses that may be amenable to immunomodulation as an adjunct to therapeutic hypothermia. Alterations in circadian rhythm affect immune function and are associated with changes in melatonin, which has anti-inflammatory properties. Understanding the role of the circadian rhythm in neonatal brain injury and inflammation may lead to simple therapeutic measures such as decreasing the duration duration of light exposure to increase endogenous melatonin production. Therefore, we wish to investigate whether alteration of the circadian rhythm in babies with NE decrease inflammation and improve outcome.
This project will focus on the neurodevelopmental, cognitive, linguistic and socio-emotional follow-up of NE infants, using standardised developmental assessments. A further focus of the study will be on parent-infant interactions as predictive of a host of developmental outcomes, including self-regulation, linguistic and cognitive competencies and executive functioning. The influence of neurobiological risk, such as that which may arise from NE, may disrupt parent-infant interaction and influence the course of development, as has been shown in the context of prematurity. To date, no research has considered the nature of parent-infant interactions in the context of NE.
NEON: Investigate the functional brain changes in neonatal encephalopathy (NE) infants and the associated behavioral and cognitive consequences – TCD, Professor Arun Bokde, Megan Dibble
The goal of this project is to investigate the functional brain changes in neonatal encephalopathy (NE) infants and the associated behavioral and cognitive consequences. The project will use brain imaging data (structural MRI, functional MRI, diffusion imaging) to quantify the functional integrity of the neural networks and examine potential associations with inflammatory markers and clinical phenotypes. The student will be involved in data acquisition, analysis and writing reports on research results.
SERENdiPITY: Study of ElectRoENcephalogram, heart rate variability and clinical parameters as early biomarkers of hyPoxic-Ischaemic encephalopaThY in newborn infants – UCC, Professor Geraldine Boylan, Andreea Pavel
The aim of this project is to use detailed analysis of electroencephalography (EEG) in newborn infants to identify characteristic features or ‘biomarkers’ of encephalopathy (all causes) and to identify features that are most predictive of poor neurodevelopmental outcome.
COHESION: Develop a Core Outcome Set for use in clinical trials, and other studies, for interventions for the treatment of Neonatal Encephalopathy – NUIG, Professor Declan Devane, Fiona Quirke
The aim of this project is to develop a Core Outcome Set for use in clinical trials, and other studies, for interventions for the treatment of Neonatal Encephalopathy.
Programme Publications to date:
Diffusion Weighted Imaging in Neonatal Encephalopathy: A Systematic Review, Megan Dibble, Mary I. O’Dea, Tim Hurley, Angela T. Byrne , Gabrielle Colleran, Eleanor J. Molloy and Arun L. W. Bokde
PUFFIN Study: POINT OF CARE ULTRASOUND FOR FUNCTIONAL MULTI-ORGAN EVALUATION IN NEONATAL ENCEPHALOPATHY
PI: Prof E MolloyCollaborators: Dr Eoghan Laffan, Prof Jan Miletin, Dr Franscisco Meza, Dr Anne Doolan, Prof Martin White, Dr Pamela O’Connor, Dr. Jana Semberova, Dr John Kelleher, Prof Afif El Khuffash, Prof Naomi McCallion, Dr Anna Curley, Dr Claudine Vavasseur, Prof Nikki Robertson, Prof Derek DohertyFunding: Health Research Board, Ireland and Trinity College DublinPhD student:Dr Aoife BranaganDescription: Neonatal encephalopathy results in signifigant mortality and morbidity in survivors. At present the only therapy available is therapeutic hypothermia. Despite the impact of therapeutic hypothermia on outcomes, 50% of survivors will have a disability.The hypoxic injury in neonatal encephalopathy is not confined to the brain. The multiorgan injury and systemic inflammation which occurs has been shown to correlate with outcomes, while the longer-term impact of is also becoming clearer with ongoing research as these infants get older. The use of neonatologist performed ultrasound is becoming more prevalent in NICU in the diagnosis and management of multiorgan injury.We hope that by examining the utility of ultrasound in the diagnosis and management of multi-organ dysfunction, and by examining both routine and novel biomarkers of organ dysfunction, we will be able to improve the management of multiorgan dysfunction, and therefore overall multiorgan dysfunction outcome. We will also assess potential adjuvant treatment strategies to therapeutic hypothermia with the hope of improving developmental and general health outcomes