The focus of the neonatal neurology research group is to better understand brain development and injury in the newborn.  Using advanced magnetic resonance (MR) techniques and bedside brain monitoring we study how white matter injury and systemic illness affects brain development in critically ill newborns.  A better understanding of the factors that impact brain development and injury will allow us to directly improve the neurodevelopmental outcome of high-risk newborns.

Neurodevelopmental impairments are common in newborns delivered prior to term age and in newborns with heart birth defects, and result in a large burden of long-term disability. White matter injury, abnormal brain development and systemic illness are interrelated abnormalities that commonly follow preterm birth or heart birth defects, with focal non-cystic white matter injury being the characteristic pattern of brain injury. Though focal non-cystic white matter injury is associated with diffuse abnormalities of motor and cognitive function, how this happens is unknown. Systemic illness (e.g. infection) and therapy (e.g. steroids) may also be associated with diffuse abnormalities of motor and cognitive function.

Advances in magnetic resonance (MR) technology allow for brain development and injury to be studied safely in critically ill newborns.  MR imaging (MRI) is a sensitive tool to measure brain structure and injury. In particular, deformation morphometry, diffusion tensor imaging, and MR spectroscopic imaging, can be used to quantify brain structure, microstructure and metabolism.  Using advanced magnetic resonance (MR) techniques, as well as bedside brain monitoring, such as amplitude integrated EEG and near infra-red spectroscopy, we study brain development and injury in vulnerable populations of newborns.

Abnormal brain development and injury in premature newborns
In 2003 in British Columbia, more than 5% of all newborns were born prematurely and/or at low birth weight. These children are at very high risk for developmental delays: 5-10% of low birth-weight children exhibit major motor deficits and 25-50% exhibit significant developmental and visual deficits. The most important brain pathology associated with these deficits is injury to the white matter. Our study is characterizing the consequences of abnormal brain development and white matter injury in the premature newborn, including how delayed brain development results in impaired motor and cognitive function. This study builds on our earlier observations that: 1) brain injury in premature newborns is safely detected with MRI before term-equivalent age; 2) focal non-cystic white matter injury is the characteristic pattern of injury in the premature newborn; 3) early brain injury is associated with adverse early neurodevelopmental outcome; and 4) brain injury in the immature brain impairs subsequent brain development.

Brain Injury in Newborns with Congenital Heart Disease
Developmental deficits in children with congenital heart disease are a serious problem and may be seen in more than one third of affected newborns. However, the reasons for these developmental deficits remain unknown and may occur prior to, during or following their cardiac surgery. In this study we are investigating the timing and severity of brain injury in newborns with congenital heart disease using advanced MR imaging techniques in utero, shortly before open-heart surgery and again soon after surgery. As newborns with congenital heart disease, like premature newborns, are also specifically vulnerable to white matter injury, studying these two populations allows us to explore shared mechanisms of white matter injury. Knowing the mechanisms and timing of brain injury in newborns with heart disease will be important for the rational design of studies to evaluate emerging strategies to protect the developing brain from injury.

Many physicians consider brain injury to be the major remaining challenge in caring for critically ill newborns. The ability of advanced MR brain imaging techniques to detect which newborns have abnormalities of the brain will help parents and physicians better care for these critically ill infants. The longer-term goal of my research program will be to test new strategies to prevent brain injury in the human newborn. The advanced MR techniques I am applying in this research program provide us with powerful surrogate markers of brain injury that will allow us to monitor the effect of novel strategies to protect the brain from injury.

Li AM, Chau V, Poskitt KJ, Sargent MA, Lupton BA, Hill A, Roland E, Miller SP.: White matter injury in term newborns with neonatal encephalopathy. Pediatr Res. 2009 Jan;65(1):85-9.

Berman JI, Glass HC, Miller SP, Mukherjee P, Ferriero DM, Barkovich AJ, Vigneron DB, Henry RG.: Quantitative Fiber Tracking Analysis of the Optic Radiation Correlated with Visual Performance in Premature Newborns. AJNR Am J Neuroradiol. 2009 Jan;30(1):120-4.

Sherlock RL, McQuillen PS, Miller SP, Synnes, A on behalf of aCCENT (a Congenital Heart Disease Center of Excellence for Neuroprotective Trials).: Preventing brain injury in newborns with Congenital Heart Disease: Brain imaging and innovative trial designs. Stroke. 2009 Jan:40(1):327-32.

Chau V, Poskitt KJ, Sargent MA, Lupton BA, Hill A, Roland E, Miller SP.: Comparison of computer tomography and magnetic resonance imaging scans on the third day of life in term newborns with neonatal encephalopathy. Pediatrics. 2009 Jan;123(1):319-26.

Glass H, Bonifacio S, Chau V, Glidden D, Poskitt K, Ferriero D, Barkovich A, Miller S.: Recurrent Postnatal Infection Is Associated With Progressive White Matter Injury In Premature Infants. Pediatrics. 2008;122(2):299-305.

Miller SP, McQuillen PS, Hamrick S, Xu D, Glidden DV, Charlton N, Karl T, Azakie A, Ferriero DM, Barkovich AJ, Vigneron DB.  Abnormal brain development in newborns with Congenital Heart Disease.  New England Journal of Medicine. 2007; 357(19):1928-38.

McQuillen PS, Barkovich AJ, Hamrick SEG, Perez M, Ward P, Glidden DV, Azakie A, Karl T, Miller SP. Temporal and Anatomic Risk Profile of Brain Injury with Neonatal Repair of Congenital Heart Defects. Stroke. 2007;38(2):736-741.

Miller SP, Wu YW, Lee J, Lammer EJ, Iovannisci DM, Glidden DV, Bonifacio SL, Collins A, Shaw GM, Barkovich AJ, Ferriero DM. Candidate Gene Polymorphisms Do Not Differ Between Newborns with Stroke and Normal Controls.  Stroke. 2006; 37(11): 2678-83

Barkovich AJ, Miller SP, Bartha A, Newton N, Hamrick SEG, Mukherjee P, Xu D, Partridge JC, Ferriero DM, Vigneron DB.  MRI, MRS, and DTI of sequential studies in neonates with encephalopathy.  Am J Neuroradiol 2006 March; 27(3): 533-47.

Partridge SC, Vigneron DB, Charleton NN, Berman JI, Henry RG, Mukherjee P, McQuillen P, Karl T, Barkovich AJ, Miller SP. Pyramidal tract maturation following brain injury in newborns with heart disease. Annals of Neurology 2006 April; 59(4): 640-51.
 
McQuillen PS, Hamrick SEG, Perez M, Barkovich AJ, Glidden DV, Karl T, Teitel D, Miller SP. Balloon Atrial Septostomy is Associated with Preoperative Stroke in Neonates with Transposition of the Great Arteries. Circulation 2006; 113(2):280-5. 

Miller SP, Ferriero DM, Leonard C, Piecuch R, Glidden DV, Partridge JC, Perez M, Mukherjee P, Vigneron DB, Barkovich AJ. Early Brain Injury in Premature Newborns Detected with MRI is Associated with Adverse Early Neurodevelopmental Outcome. Journal of Pediatrics. 2005; 147(5):609-616. 

Miller SP, Ramaswamy V, Michelson D, Barkovich AJ, Holshouser B, Wycliffe N, Glidden DV, Deming D, Partridge JC, Wu YW, Ashwal S, Ferriero DM. Patterns of Brain Injury in Term Neonatal Encephalopathy. Journal of Pediatrics, 2005; 146(4): 453-60.

Canadian Institutes of Health Research (CIHR), Clinician Scientist (Phase 2)
Michael Smith Foundation for Health Research, Scholar.
Member, Society for Pediatric Research
Member, American Neurological Association
Melvin Grumbach Award for Excellence in Pediatric Research, University of California San Francisco – 2002

Wendy Soulikias RN- Research Nurse
Mark Chalmers – Respiratory Therapist
Janet Rigney  – Study Coordinator
Vann Chau MD FRCPC – Postdoctoral Fellow
Elysia Adams – Master’s Student (UBC Neuroscience)