1. Brain injury and its consequences in extremely premature babies John Wyatt Perinatal Brain Protection and Repair Group University College London

4. Survival of babies 23-25 weeks gestation UCLH 1981-2000 (as percentage of admissions to NICU) Riley et al. Acta Paediatrica 2008; 97:159-65

5. Percentage of surviving extremely preterm infants with neurodevelopmental impairment at 1 year of age, UCLH 1981-2000 Riley et al. Acta Paediatrica 2008; 97:159-65

6. Neurodevelopmental outcome at 8 years of age < 28 weeks 28 – 32 weeks (n = 137) (n = 445) Disability 23% 12% Brain lesion detected 48% 22% by ultrasound Vollmer et al, Pediatrics 2003, 112, 1108-1114

7. EPICURE nationwide study of all babies in UK and Ireland, born 22-25 weeks gestation in 1995. Assessment at 6 years of age Out of 241 survivors: • 15 were unable to walk due to cerebral palsy • 27 had severe learning difficulties • 4 blind and 7 severe hearing loss • Total of 32 had any severe disability Marlow et al. NEJM 2005; 325: 9-19

8. Cognitive (IQ) scores for ex-premature infants at 6 years of age compared with class mates

9. White matter loss in the ex-preterm brain

10. Thinning of corpus callosum

11. Rate of cortical development is maximal between 22 weeks and term

13. 25 wks GA 27 wks GA 32 wks GA

14. Rate of synaptic development • ~ 1011 neurons in CNS • Each neuron develops ~ 103 synapses • Therefore total of ~ 1014 synapses created – majority are formed between 22 and 40 weeks of gestation = ~ 5 x 1011 synapses per day =~ 3 x 108 synapses per minute!

15. Cranial MRI scans at 14 years in a cohort of ex-preterm infants MRIEx-preterm Term controls Normal 23% 71% Equivocal 21% 24% Abnormal 56% 5% Stewart et al, Lancet 1999, 353: 1653-1657

16. MRI abnormalities in ex-preterm adolescents at 14 years • MRI abnormalities correlated with abnormal behaviour scores. • MRI abnormalities did not correlate with IQ, with neurological signs or with need for extra educational help.

17. Grey matter changes in ex-preterm adolescents Nosarti et al, Brain 2002, 125, 1616-1623

18. White matter changes in ex-preterm adolescents Nosarti et al, Brain 2002, 125, 1616-1623

19. Changed brain microstructure following developmental care programme Als et al. Pediatrics 2004, 113, 846-857

20. Possible mechanisms of improved outcome following perinatal brain injury • Cell differentiation and replacement from neuronal and glial precursor stem cells • Refinement and selection of dendritic synaptic connections • Rerouting of white matter connections • Development of alternative cortical processing strategies

21. Conclusions • White matter injury in extremely premature infants is the most important cause of long term neurodevelopmental disability. • The developing central nervous system has remarkable potential for repair and compensation following perinatal injury • New therapeutic approaches are required to translate experimental findings into practical therapies whilst babies are undergoing intensive care and following discharge from hospital

22. Centre for Perinatal Brain Protection & Repair Obstetrics & Gynaecology, Paediatrics & Child HealthMedical Physics & Bioengineering UCL NHS Trust Chiara Nosarti Fran O'Brien Claire Price Larry Rifkin Kate Riley Nikki Robertson Maeve Rooney Simon Roth Teresa Rushe Al Santhouse Alison Skinner Faraneh Vargha-Khadem Brigitte Vollmer Acknowledgements Ann Stewart Osmund Reynolds Matt Allin Topun Austin Jenny Baudin Alan Connolly David Edwards Michelle de Haan Angela Huertas-Ceballos David Gadian Robin Murray Brian Neville