Quantifying Corticospinal Tract Development and Motor Outcome Following Neonatal Brain Injury

Patrick McQuillen, M.D.

University of California, San Francisco

Funded in December, 2005: $100000 for 3 years
LAY SUMMARY . ABSTRACT . HYPOTHESIS . SELECTED PUBLICATIONS .

LAY SUMMARY

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Exploring the Link Between Congenital Heart Defects and Motor Problems Through Imaging

The investigators will combine two types of imaging to determine how congenital heart defects in newborns contribute to their subsequent development of motor problems, such as in walking.

Two-thirds of children born with congenital heart defects later develop difficulties with motor problems, especially walking.  Initial studies indicate that these infants are prone to small brain injuries resulting from tiny strokes.  The investigators hypothesize that abnormalities in the corticospinal tract, the pathway that relays the brain signals that control voluntary movement, can be identified using a combination of two imaging techniques, and that these abnormalities will be associated with the infants’ later problems in walking.

The two imaging techniques will be used before and after the infants undergo surgery to correct their heart deficit.  One technique is “diffusion tensor tractography,” which measures the microstructure of the corticospinal tract.  The other imaging technique is “magnetic resonance spectroscopic imaging” (MRS), which measures brain metabolism.  The imaging studies will be used to compare three groups of infants: those born with a congenital heart defect that have had tiny brain injuries, those with a congenital heart defect but no brain injuries, and healthy infants. The children will be re-imaged at 30 months to see whether abnormalities in the corticospinal tract in children with the corrected heart deficit who had sustained tiny brain injuries differ from children in the two groups who did not sustain brain injuries.

Significance: Understanding how brain injury in the newborn results in subsequent motor deficits is the first step toward determining how to intervene to prevent the motor problems from developing.  Moreover, if this combined imaging approach is successful, it can be applied to studying other development problems, such as those that often arise in low-birth weight premature infants.

ABSTRACT

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Quantifying Corticospinal Tract Development and Motor Outcome Following Neonatal Brain Injury

Neurodevelopmental impairment is common in term newborns with congenital heart disease, including specific deficits of gross and fine motor function. Data from our cohort and others suggest that newborns with congenital heart disease are prone to focal and multi-focal brain injuries prior to corrective heart surgery as well as in the intra- and post-operative periods. The mechanisms by which these focal and multi-focal brain injuries result in widespread deficits of motor function are largely unknown.

The corticospinal tract is the major pathway for voluntary motor function. In a preliminary investigation using diffusion tensor tractography, a sensitive measure of brain microstructure, to evaluate corticospinal tract development in term newborns with congenital heart disease, we found that newborns with brain injury prior to cardiac surgery had impaired maturation of the corticospinal tracts from the pre- to post-operative periods. The impairments in corticospinal tract development were observed even when abnormalities on conventional MRI did not directly involve this motor pathway.

The overall hypotheses of this prospective cohort study are that (i) diffusion tensor tractography and magnetic resonance (MR) spectroscopic imaging can sensitively measure micro-structural and metabolic development of the corticospinal tracts in the neonatal brain, and (ii) impaired development of the corticospinal tracts, as measured by diffusion tensor tractography and MR spectroscopic imaging in the neonatal period, is strongly associated with abnormalities of motor system function in infancy and childhood.

These hypotheses will be addressed in a prospective cohort of 74 newborns with congenital heart disease studied before and after corrective heart surgery with advanced MR techniques and then followed to 30 months of age to determine their motor function. Given the high incidence of brain injury prior to surgery in these newborns, serially studied term newborns with congenital heart disease provide a unique opportunity to study the effect of early injury on subsequent brain development.

Specific Aim 1: To quantify the development of the corticospinal tracts using diffusion tensor tractography, a measure of tract microstructure, and three-dimensional MR spectroscopic imaging, a measure of tract metabolism.
Hypothesis: The development of corticospinal tract connectivity and metabolism can be quantified using diffusion tensor tractography and MR spectroscopic imaging (MRSI), respectively.
Approach: We will use novel advanced MR techniques to measure corticospinal tract development before heart surgery (pre-operative scan) and again after heart surgery (post-operative scan): diffusion tensor tractography (DTI) for connectivity and MR spectroscopic imaging (MRSI) for metabolism.

Specific Aim 2: To compare the development of the corticospinal tracts from the pre- to post-operative periods (a) in term newborns with heart disease to normal controls, and (b) among newborns with heart disease and in newborns with focal and multi-focal brain injury on MR imaging to those without these brain injuries.
Hypothesis: Corticospinal tract development will be impaired in newborns with focal and multi-focal brain injury, such as stroke, relative to newborns without these injuries.
Approach: We will use pre- and post-operative high-resolution MR imaging and diffusion tensor imaging to determine the presence of structural focal and multi-focal brain injuries.

Specific Aim 3: To determine the association of neonatal corticospinal tract development, as measured by diffusion tensor tractography and MR spectroscopic imaging, with gross and fine motor function at 30 months of age in these term newborns with congenital heart disease.
Hypothesis: Impaired corticospinal tract development will be predictive of abnormal gross and fine motor function at 30 months of age.
Approach: Motor outcome will be determined at 30 months of age using the Peabody Developmental Motor Scales, an age appropriate standardized quantitative measure of gross and fine motor function.

Understanding how brain injury in the newborn results in subsequent motor deficits is of critical importance to being able to intervene appropriately to prevent developmental deficits following neonatal brain injury. Though newborns with congenital heart disease will be specifically studied in this proposal, this understanding is also relevant to brain injury in other populations of newborns at high risk of motor and cognitive impairments, such as those born prematurely or those with neonatal encephalopathy. While this proposal will focus on motor pathways and function, it will also establish the approach to understand deficits of cognitive function resulting from neonatal brain injury. Finally, the development of accurate in vivo measures of brain injury in newborns will also help parents and physicians better care for newborns with heart disease by providing important prognostic information. This early prognostic information will allow newborns at high risk of motor impairments to receive rehabilitative services at the most appropriate time.

HYPOTHESIS

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Hypothesis:
Neurodevelopmental impairment is common in full-term newborns with congenital heart disease, including specific deficits of gross and fine motor function.  Advanced magnetic resonance imaging can sensitively measure micro-structural and metabolic development of the corticospinal tracts and can be used to detect impaired development in newborns with congenital heart disease who are prone to perioperative focal and multifocal brain injuries.

Goals:
1. To quantify the development of the corticospinal tracts using diffusion tensor tractography, a measure of tract microstructure, and three-dimensional MR spectroscopic imaging, a measure of tract metabolism in term newborns.

2. To compare the development of the corticospinal tracts from the pre- to post-operative periods (a) in term newborns with congenital heart disease to normal controls, and (b) among newborns with congenital heart disease, in those with focal and multi-focal brain injury on MR imaging to those without these brain injuries.

3. To determine the association of neonatal corticospinal tract development, as measured by diffusion tensor tractography and MR spectroscopic imaging, with gross and fine motor function at 30 months of age in these term newborns with congenital heart disease.

Methods:
We will use novel advanced MR techniques to measure corticospinal tract development before heart surgery (pre-operative scan) and again after heart surgery (post-operative scan): diffusion tensor tractography (DTI) for connectivity and MR spectroscopic imaging (MRSI) for metabolism. Motor outcome will be determined at 30 months of age using the Peabody Developmental Motor Scales, an age appropriate standardized quantitative measure of gross and fine motor function.

SELECTED PUBLICATIONS

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McQuillen P.S., Hamrick S.E., Perez M.J., Barkovich A.J., Glidden D.V., Karl T.R., Teitel D., and Miller S.P.  Balloon atrial septostomy is associated with preoperative stroke in neonates with transposition of the great arteries.  Circulation. 2006 Jan 17;113(2):280-5.

Miller S.P.*, McQuillen P.S.*, Vigneron D.B., Glidden D.V., Barkovich A.J., Hamrick S.E.G., Azakie A., and Karl T.M.  Preoperative brain injury in newborns with transposition of the great arteries.  Ann Thorac Surg. 2004 May;77(5):1698-706
*indicates these authors contributed equally to this manuscript.