Elucidation of the Relationship of Cerebral White Matter Injury to Cerebral Cortical Disturbance and Their Developmental Consequences in the Premature Newborn

Lay Summary

Do Cognitive Impairments in Children Born Prematurely Arise from Damage to Brain Axons?

Researchers will use imaging to test the hypothesis that injury to brain cell axons (communication cables) in premature infants alters the brain cells, resulting in cognitive impairment.

Research has found that 70 percent of premature infants weighing less than three pounds at birth do not function cognitively at grade level by age eight.  Studies have indicated that the brain’s white matter, (consisting of axons, the brain cells’ communication cables) is associated with developmental delays in premature infants.  Since the brain’s gray matter (the brain cell bodies) is involved with cognition, however, do gray matter injuries occur separately from white matter injuries, or do injuries to brain axons alter brain cells, producing cognitive deficits?  The researchers suspect that injured axons alter the brain cells, causing cognitive deficits.

Funding will be provided to enable the investigators to develop software for a form of MRI called Diffusion Tensor Imaging (DTI).  The software is necessary to for DTI to produce quantitative 3-D images of the brain’s gray matter.  These images will measure the volume, shape, thickness, and folding patterns of the brain’s gray matter structures.  After imaging the white matter structures of healthy newborns, the findings will be compared to data already obtained from 86 critically ill premature newborns enrolled in a previous study of white matter injuries.

Researchers will identify critical white matter differences between the healthy and injured infants, and then use the specialized DTI software to study gray matter structures in three groups of newborns: healthy premature infants, injured premature infants, and healthy full-term newborns.  The investigators will determine the relationship between white and gray matter alterations in injured premature newborns and compare these to DTI images of the brains of children with cognitive impairments who were born prematurely.  Through this process, the investigators will determine the relationship between white matter injury, gray matter alterations, and long-term developmental disabilities

Significance: The findings should help clarify which injured or altered brain structures in brain-injured premature infants are involved in developmental delays.  This information, in turn, should lead to improved efforts to target early interventions and therapies to prevent cognitive problems in these infants.

Abstract

Elucidation of the Relationship of Cerebral White Matter Injury to Cerebral Cortical Disturbance and Their Developmental Consequences in the Premature Newborn

Cerebral white matter (WM) injury has long been considered the principal form of brain injury in premature infants <32 weeks gestational age or <1500 grams at birth, and thus is hypothesized to be the cause of long-term motor, cognitive, and behavioral disabilities in these children. However, in other neurological disorders of infancy and childhood, cognitive and behavioral deficits relate principally to gray matter (GM) disease, while motor deficits, such as cerebral palsy, relate primarily to WM injury. The central goal of this research is to utilize advanced MRI techniques to explore the hypothesis that WM injury causes GM involvement, leading to cognitive and behavioral deficits in premature infants.

Although this notion is novel, it is supported by initial quantitative MRI studies of premature infants that have, in fact, shown reduced total cortical and subcortical GM but not WM volume in those who have sustained neonatal WM injury. Moreover, it appears that these GM structural abnormalities are indeed strongly correlated with cognitive disturbances measured in older children born prematurely. Hence, the overall aim of this research is to determine the nature of the relationship between neonatal WM injury, GM disturbances, and later cognitive and behavioral disabilities.

To address this goal, we will use advanced MRI techniques to quantitate the regional and temporal characteristics of these disturbances during the neonatal period of infants born prematurely, then will correlate these MRI findings with long-term neurodevelopmental outcome. We will achieve this through three aims. We will first determine the severity and distribution of WM injury using quantitative MRI measures of WM microstructure. Next, we will determine the relationship between WM injury and quantitative measures of cortical/subcortical GM disturbances. Finally, we will determine the relationship between WM and GM disturbances measured in the newborn period and long-term neurodevelopmental impairments.

To conduct this research, we will enroll healthy premature and term-born newborn infants and acquire specialized three-dimensional (3D) volumetric and diffusion tensor MRI sequences at preterm and term age. We will process these data using a series of software algorithms already developed to make measures of WM injury using the diffusion tensor imaging data in combination with measures of regional volumes of areas affected by WM injury. These data will be compared to data already obtained in 86 critically ill premature newborns enrolled in a previous prospective study of WM injury. We will then develop further software algorithms designed particularly for the measurement of 3D aspects of critically important GM structures in newborn brain MRI data. Specifically, these tools will enable us to make quantitative 3D measurements of regional cortical thickness, folding of the cerebral cortex (gyrification), and the shape of the caudate and thalamus, two subcortical GM structures crucial to cognitive function. We will apply these new measures to the entire data set, comparing the results between three groups: preterm infants with or without WM injury and term-born controls. Finally, these neonatal MRI measures will be compared with long-term neurodevelopmental outcome.

Elucidation of the relationship between WM injury, GM disturbances, and long-term neurodevelopmental disabilities will greatly enhance our understanding of the impact of early acquired brain injury on the developing brain. The proposed research will also help to clarify which injured or altered brain structures are critical to later cognitive and behavioral disabilities. Early detection of the gray matter disturbances that best predict cognitive deficits will improve application of appropriate early interventions and therapies designed to optimize the developmental trajectory of these children, long before their cognitive deficits are diagnosed at school age. Moreover, if a separate neuronal (i.e., gray matter) injury is discovered to underlie the long-term cognitive and behavioral impairments, research efforts could then be directed towards the pathogenesis of this distinct injury and its ultimate prevention. Given that approximately 57,000 premature infants are born each year in the U.S., ~50% of whom will develop cognitive impairments, the results of this study have the potential to make a significant impact on an enormous problem.