Neonatal Neuroscience

Pre-clinical model of perinatal asphyxia (PI: N Robertson)

Personnel

UCL Institute for Women’s Health:
Dr Nicola Robertson (PI) Reader in Translational neonatal Medicine and Honorary Consultant Neonatologist, UCL Institute for Women’s Health (UCL IfWH)
Prof Gena Raivich, Professor in Perinatal Neuroscience, Institute for Women’s health, UCL
Dr Stuart Faulkner (post doc and lab manager) (UCL IfWH)
Dr Elizabeth Powell (Academic Clinical Fellow, PhD student) (UCL IfWH)
Dr Manigandan Chandrasekaran (neonatal research fellow, MD student) (UCL IfWH)
Dr Csilla Andorka (Research assistant) (UCL IfWH)

ION Physics HEAD OF LAB
Prof Xavier Golay

ION Physicists
Dr David Thomas

UCH Physisicts
Mr Ernest Cady
Dr Alan Bainbridge
Mr David Price

NIRS team

Project Students
Lucy Lecky-Thompson - MSc Neuroscience (ION)

Research objectives

To determine which adjunct therapies are safe and most effective when combined with therapeutic hypothermia.
To determine the optimal temperature for therapeutic hypothermia

Background:

Brain injury around the time of birth continues to be a great tragedy for parents and affected children. Although only 2-3 per 1000 term live-born infants develop acute moderate to severe encephalopathy in developing countries, rates are 10 fold in less developed nations and nearly all cases were normal before birth. The majority of such infants either die, mainly from neural injury or develop neurodevelopmental disabilities. Even among survivors who are not disabled, at least half will show learning difficulties at school.

In an exciting example of successful clinical translation, a series of large randomized clinical trials have now shown that therapeutic hypothermia for infants with neonatal encephalopathy reduces death and disability, including cerebral palsy. Meta-analyses suggest a number needed to treat of 9 (with a relative risk reduction for death and severe disability of 0.81 (95% CI 0.71-0.93, p< 0.002). Therapeutic hypothermia is now widely adopted in clinical practice in the UK. This dramatic advance is the culmination of >40 years of basic and clinical research.

Further advances are urgently needed as, despite this safe and effective therapy, 50% of treated infants still have an adverse outcome. There is increasing evidence that treatment with a variety of agents during the critical period recovery period in the 8-12 hours after birth can augment hypothermic neuroprotection. Robust cerebral magnetic resonance biomarkers are needed to speed up evaluation of co-treatment studies that must detect incremental improvements beyond therapeutic hypothermia.

Our pre-clinical model uses the robust validated outcome biomarker, cerebral lactate/N acetyl aspartate - the same biomarker is used in infants in current neuroprotection trials. Proton MRS lactate metabolite ratios thus translate between our pre-clinical and clinical studies making our model unique and a powerful resource for informing future neuroprotection studies. We also use quantitative immunohistochemical markers: Caspase 3 immunoreactive cellls, TUNEL positive cells and stains for activated microglia (IBA-1)

Our pre-clinical model is currently being used to assess the following adjunct therapies for therapeutic hypothermia:

melatonin
dexmedetomidine (a sedative drug)
prophylactic phenobarbitone & bumetanide

Current funding