Abnormal deep grey matter development following preterm birth detected using deformation-based morphometry☆
Introduction
Preterm birth is associated with long-term neurodevelopmental impairment including cognitive and behavioral problems (Marlow et al., 1993, McCormick et al., 1996), which are more severe with prolonged exposure to the extra uterine environment (Bhutta et al., 2002, Marlow et al., 2005). The most common known cerebral abnormality in surviving preterm infants at term equivalent age is diffuse white matter injury (Figs. 1a and b), which is seen on conventional imaging in one half to two thirds of survivors and is quantifiable as increased apparent diffusion coefficient (ADC) values on diffusion-weighted imaging (DWI) (Maalouf et al., 1999, Counsell et al., 2003). However, it is not known how diffuse white matter injury affects neural development or function, and this significantly hinders the development of strategies to reduce the problems suffered by preterm infants.
Cystic periventricular leucomalacia (PVL) is associated with loss of thalamic volume in late infancy (Lin et al., 2001), which draws attention to the role of white matter injury in thalamic development. An important role for the deep grey matter in preterm brain injury is suggested by its volume reduction in a dose-dependent manner with degree of prematurity at birth (Inder et al., 2005), which mirrors the prevalence of subsequent neurocognitive impairment among survivors (Bhutta et al., 2002, Marlow et al., 2005).
Cystic PVL is uncommon and cannot account for the high prevalence of neural dysfunction seen in preterm infants. There have been no reports of the effect of the common but poorly understood diffuse white matter lesion on other brain regions, at least in part because of the technological difficulties of making such observations.
To investigate the effect of prematurity and diffuse white matter injury on brain development in the neonatal period, we have combined conventional imaging with DWI and deformation-based morphometry (DBM), which uses image registration and statistical analysis to quantify structural differences between groups. We have applied this quantitative morphometric method to make a non-hypothesis-based survey of the whole brain, to identify structural alterations apparent in preterm infants at term equivalent age, and to examine the effects of diffuse white matter injury on brain structure in early development.
Section snippets
Subjects
Ethical permission for MR studies was granted by the Hammersmith Hospital Research Ethics Committee, and informed parental consent was obtained. Preterm infants were recruited from the Neonatal Intensive Care Unit (NICU) at Queen Charlotte's and Chelsea Hospital (QCCH) between February 2001 and December 2002. Exclusion criteria were infants with congenital central nervous system infection; exposure to postnatal steroids; cystic PVL; hemorrhagic parenchymal infarction, posthemorrhagic
Structural brain changes after preterm birth
The DBM analysis showed an expected volumetric increase in the posterior horns of the lateral ventricles (t = 5.81, P < 0.05), which has been described in previous studies (Peterson et al., 2003). However, the most striking difference between preterm and term infants was an unexpected reduction in the volume within deep grey matter, predominantly the thalami and lentiform nuclei (t = 5.81, P < 0.05) (Fig. 3), which was not apparent on conventional analysis of the T1- and T2-weighted images.
To
Discussion
This is the first use of DBM to perform a non-subjective survey of the whole brain in the neonatal period. We chose a DBM approach rather than the widely used technique of voxel-based morphometry (VBM) for two reasons related to unique physical properties of the brain in the neonatal period. The white matter is predominantly unmyelinated, and tissue classification is problematic, so there are currently no published VBM protocols to classify neonatal cerebral tissue, which is a requisite step in
Acknowledgments
We are grateful to the families who consented to take part in the study and to the nursing and medical staff who participated in scanning the infants. We thank Isha Vaid who assisted in providing the ventricular volume measurements used in the robustness analysis. J. P. Boardman is a Medical Research Council clinical training fellow, K. K. Bhatia and P. Aljabar are recipients of Engineering and Physical Sciences Research Council studentships. We thank the Garfield Weston Foundation, the MRC,
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Structural brain changes following preterm birth.