Impact of white matter injury on neural network development in premature infants

Christopher Smyser, M.D.

St. Louis Children's Hospital

Department of Neurology, Department of Pediatrics
Funded in October, 2012: $200000 for 3 years


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MRI technique may predict preterm infants’ risk of cerebral palsy, other motor disabilities

Investigators will determine whether a new type of imaging, Functional Connectivity MRI, can effectively identify pre-term infants with injuries to the brain’s white matter (communication cables) that place them at greatest risk of developing cerebral palsy or other motor deficits.
Very pre-term infants (less than 30 weeks gestational age) now survive at high rates following care in Neonatal Intensive Care Units (NICUs), but nearly 50 percent develop mild to severe motor deficits, including up to 15 percent who develop cerebral palsy. Previous MRI studies have shown the prevalence of structural injury to the brain’s white matter, the cables of nerve cell axons that connect brain regions. Damage is particularly significant in “resting state” motor networks, which are functional neural connections that exist even when a person is not undertaking a specific task. But later developmental outcomes for these infants are highly variable. Notably, preterm infants with similar
patterns of white matter injury can have vastly different motor outcomes, while some preterm infants without injury develop abnormal motor function.  The investigators hypothesize that Functional Connectivity MRI (fcMRI) in combination with structural MRI imaging will provide functional and structural correlations that can serve as a biomarker for identifying which premature infants are at risk of developing motor disabilities.
The fcMRI technique detects patterns of blood oxygenation fluctuations that indicate patterns of functional connections—and their abnormalities—in motor and other networks (vision, attention and language). The researchers have studied non-injured preterm infants. Now they will study 40 preterm infants with white matter injury to compare results and see whether fcMRI can predict which preterm infants will develop motor deficits. They will image the infants in the NICU and compare these results to findings from standardized developmental testing performed at 18 months of age. Additionally, investigators will compare scans of infants with similar white matter injury patterns but different motor outcomes. Analyses will enable them to: 1) characterize variations in network development related to extent of injury; 2) delineate the relationship between motor network development and motor performance; and 3) identify potential adaptive processes that preserve normal motor function in the presence of injury.
Significance: If fcMRI imaging is found to be a sensitive and specific biomarker of premature infants at high risk of developing motor disabilities, the findings could be used to implement existing rehabilitation strategies at the earliest stage and to design more targeted new rehabilitation techniques.



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Despite advances in perinatal and neonatal care, premature birth remains a major public health issue because of the continuing high rates of later motor and cognitive disabilities faced by survivors. Brain injury is common in prematurely-born infants, frequently involving the cerebral white matter. Recent studies in prematurely-born infants have applied magnetic resonance imaging (MRI) to investigate the effects of cerebral injury on neurodevelopmental outcome. They demonstrate that white matter injury (WMI), identified on conventional MRI sequences, is the best predictor of later disability. However, there remains a wide variation in outcomes between infants with similar conventional MRI WMI patterns. Improved neuroimaging techniques that reflect functional, in addition to structural, abnormalities may assist in better defining the nature of the deficits in prematurely-born infants. This will allow clinicians to devise improved rehabilitative interventions that may reduce the later severity of impairments.


Functional connectivity MRI (fcMRI) measures spontaneous, temporal correlations in blood oxygen level dependent (BOLD) signal to identify networks of functional cerebral connections, termed resting state networks (RSNs). This methodology is well-suited to the assessment of the newborn brain and has been increasingly applied in neurodevelopmental investigations. Prior study from our laboratory applied fcMRI to characterize the development of early functional cerebral connections in preterm and healthy, term-born infants. Though infants with WMI were excluded from the initial inquiry, recent preliminary investigation demonstrated WMI significantly affects motor RSN development in this population. Expanded application of fcMRI to investigate the relationship between WMI and RSN development may provide structural and functional correlations that improve prediction of later disability in preterm infants.


This study will apply fcMRI to investigate preterm infants with WMI to establish the relationship between motor RSNs, injury, and outcome. To accomplish this, prematurely-born infants with WMI will be prospectively recruited from the St. Louis Children’s Hospital Neonatal Intensive Care Unit (NICU). Infants will undergo term equivalent MRI scans, including acquisition of anatomic and fcMRI sequences. Subjects will also undergo comprehensive neurodevelopmental assessment at 18 months of age. fcMRI measures for neural networks in regions responsible for motor function will be compared for infants with and without cerebral white matter injury. fcMRI results will also be correlated with motor outcome data obtained from neurodevelopmental assessment at 18 months of age. Finally, differences in functional connections within motor networks for infants with differing motor outcomes despite similar patterns of WMI will be investigated.


This study is designed to engender a deeper understanding of the effect of WMI on motor outcome and the pathway to neurodevelopmental disability. Establishment of fcMRI as a sensitive and specific imaging biomarker enabling identification of infants at high risk for poor neurodevelopmental outcome during the newborn period will allow early targeting of therapy services. Ultimately, this study aims to make possible improved outcomes for very preterm infants and provide a foundation for systematic improvement in NICU practices and development of targeted neuroprotective strategies.


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Christopher Smyser, M.D.

Dr. Christopher Smyser is a Pediatric Neurologist at Washington University/St. Louis Children’s Hospital, where he is an Assistant Professor of Neurology and Pediatrics. Dr. Smyser received his B.S.E. in Biomedical Engineering with highest distinction from the University of Iowa. After graduating, he was employed as an engineer in the Departments of Neurology and Radiology at the University of Iowa. He then matriculated in medical school at the University of Iowa College of Medicine, where he received his M.D. and finished his pediatrics residency. He completed his pediatric neurology residency at St. Louis Children's Hospital, serving as chief resident in his final year, after which he became a member of Washington University’s faculty. Dr. Smyser's research is focused upon development and application of advanced neuroimaging techniques, including functional connectivity MRI (fcMRI), to investigate the earliest forms of neural network development in preterm and term infants. He undertakes these efforts as a member of the Washington University Neonatal Developmental Research (WUNDER) Laboratory. His current research centers upon examining cerebral abnormalities associated with neurodevelopmental impairment in prematurely-born infants and children. This work has yielded new insight into early brain development, providing a foundation for future investigation dedicated to identifying infants at risk for adverse neurodevelopmental outcomes and assisting efforts targeting neuroprotection. His clinical efforts focus upon directing and providing service on the multidisciplinary Washington University Neonatal Neurology Clinical Service, designed to provide optimal neurological care for infants at risk for poor neurodevelopmental outcomes beginning during their initial hospitalization and continuing following discharge.


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Smyser CD, Inder TE, Hill JE, Degnan AJ, Snyder AZ, Shimony JS, Neil JJ. "Longitudinal analysis of neural network development in preterm infants." Pediatric Academic Societies, 2009, Baltimore, MD.

Smyser CD, Shimony JS, Hill JE, Degnan AJ, Inder TE, Neil JJ. "Spontaneous BOLD fluctuations for evaluating development in preterm infants." American Society of Neuroradiology, 2009, Vancouver, British Columbia.