Severity of perinatal illness and cerebral cortical growth in preterm infants.

AIM: We have shown previously that the degree of prematurity affects cortical surface area growth. We now addressed the question whether cortical surface area growth after preterm birth is predicted by the severity of peri- and postnatal illness. METHODS: Cortical surface area was measured in 269 images from 111 infants born between 23 and 29 weeks and imaged at 23 to 48 weeks gestational age (GA). The severity of perinatal illness was assessed using the clinical risk index for babies score (CRIB I) and the severity of ongoing illness by the presence of chronic lung disease (CLD). The effects on cortical growth were modelled using generalized least-square regression for random effects with Bonferroni correction. To explore the results further we examined CRIB II, C-reactive protein (CRP) on the second day after birth, and time taken to achieve full enteral feeding. RESULTS: Cortical surface area grew by 12.4% per week. Reduced cortical growth was predicted by adverse CRIB I (-0.15% per week per unit) and development of CLD (-1.18% per week). Secondary analysis showed that growth was related to adverse CRIB II (-0.36% per week per unit) and increasing CRP (-0.03% per week per mMol), but not by the time taken to achieve full enteral feeding. CONCLUSION: After very premature birth illness severity predicts reduced cortical growth.

Specific relations between neurodevelopmental abilities and white matter microstructure in children born preterm.

Survivors of preterm birth have a high incidence of neurodevelopmental impairment which is not explained by currently understood brain abnormalities. The aim of this study was to test the hypothesis that the neurodevelopmental abilities of 2-year-old children who were born preterm and who had no evidence of focal abnormality on conventional MR imaging were consistently linearly related to specific local changes in white matter microstructure. We studied 33 children, born at a median (range) gestational age of 28(+5) (24(+4)-32(+1)) weeks. The children were recruited as infants from the Neonatal Intensive Care Unit at Queen Charlotte's and Hammersmith Hospital in the early neonatal period and imaged at a median corrected age of 25.5 (24-27) months. The children underwent diffusion tensor imaging to measure fractional anisotropy (FA) as a measure of tissue microstructure, and neurodevelopmental assessment using the Griffiths Mental Development Scales [giving an overall developmental quotient (DQ) and sub-quotients scores for motor, personal-social, hearing-language, eye-hand coordination and performance scales] at 2 years corrected age. Tract-based spatial statistics with linear regression analysis of voxel-wise cross-subject statistics were used to assess the relationship between FA and DQ/sub-quotient scores and results confirmed by reduced major axis regression of regions with significant correlations. We found that DQ was linearly related to FA values in parts of the corpus callosum; performance sub-scores to FA values in the corpus callosum and right cingulum; and eye-hand coordination sub-scores to FA values in the cingulum, fornix, anterior commissure, corpus callosum and right uncinate fasciculus. This study shows that specific neurodevelopmental impairments in infants born preterm are precisely related to microstructural abnormalities in particular regions of cerebral white matter which are consistent between individuals. FA may aid prognostication and provide a biomarker for therapeutic or mechanistic studies of preterm brain injury.

Automatic segmentation of brain MRIs of 2-year-olds into 83 regions of interest.

Three-dimensional atlases and databases of the brain at different ages facilitate the description of neuroanatomy and the monitoring of cerebral growth and development. Brain segmentation is challenging in young children due to structural differences compared to adults. We have developed a method, based on established algorithms, for automatic segmentation of young children's brains into 83 regions of interest (ROIs), and applied this to an exemplar group of 33 2-year-old subjects who had been born prematurely. The algorithm uses prior information from 30 normal adult brain magnetic resonance (MR) images, which had been manually segmented to create 30 atlases, each labeling 83 anatomical structures. Each of these adult atlases was registered to each 2-year-old target MR image using non-rigid registration based on free-form deformations. Label propagation from each adult atlas yielded a segmentation of each 2-year-old brain into 83 ROIs. The final segmentation was obtained by combination of the 30 propagated adult atlases using decision fusion, improving accuracy over individual propagations. We validated this algorithm by comparing the automatic approach with three representative manually segmented volumetric regions (the subcortical caudate nucleus, the neocortical pre-central gyrus and the archicortical hippocampus) using similarity indices (SI), a measure of spatial overlap (intersection over average). SI results for automatic versus manual segmentations for these three structures were 0.90+/-0.01, 0.90+/-0.01 and 0.88+/-0.03 respectively. This registration approach allows the rapid construction of automatically labelled age-specific brain atlases for children at the age of 2 years.

Relationship between white matter apparent diffusion coefficients in preterm infants at term-equivalent age and developmental outcome at 2 years.

OBJECTIVE: The aim of this study was to develop a simple reproducible method for the measurement of apparent diffusion coefficient values in the white matter of preterm infants using diffusion-weighted imaging to test the hypothesis that elevated mean apparent diffusion coefficient values are associated with lower developmental quotient scores at 2 years' corrected age. METHODS: We obtained diffusion-weighted imaging in 38 preterm infants at term-equivalent age who had no evidence of overt cerebral pathology on conventional MRI. Mean apparent diffusion coefficient values at the level of the centrum semiovale were determined. The children were assessed using a standardized neurologic examination, and the Griffiths Mental Development Scales were administered to obtain a developmental quotient at 2 years' corrected age. The relationship between mean apparent diffusion coefficient values and developmental quotient was examined. Clinical data relating to postnatal sepsis, antenatal steroid exposure, supplemental oxygen, gender, patent ductus arteriosus, and inotrope requirement were collected, and the mean apparent diffusion coefficient values for each group were compared. RESULTS: The mean (+/-SD) apparent diffusion coefficient value in the white matter was 1.385 +/- 0.07 x 10(-3) mm2/second, and the mean developmental quotient was 108.9 +/- 11.5. None of the children had a significant neurologic problem. There was a significant negative correlation between mean apparent diffusion coefficient and developmental quotient. CONCLUSION: These findings suggest that higher white matter apparent diffusion coefficient values at term-equivalent age in preterm infants without overt lesions are associated with poorer developmental performance in later childhood. Consequently, apparent diffusion coefficient values at term may be of prognostic value for neurodevelopmental outcome in infants who are born preterm and who have no other imaging indicators of abnormality.

Early growth in brain volume is preserved in the majority of preterm infants.

OBJECTIVE: Preterm infants have reduced cerebral tissue volumes in adolescence. This study addresses the question: Is reduced global brain growth in the neonatal period inevitable after premature birth, or is it associated with specific medical risk factors? METHODS: Eighty-nine preterm infants at term equivalent age without focal parenchymal brain lesions were studied with 20 full-term control infants. Using a deformation-based morphometric approach, we transformed images to a reference anatomic space, and we used the transformations to calculate whole-brain volume and ventricular volume for each subject. Patterns of volume difference were correlated with clinical data. RESULTS: Cerebral volume is not reduced compared with term born control infants (p = 0.765). Supplemental oxygen requirement at 28 postnatal days is associated with lower cerebral tissue volume at term (p < 0.001), but there were no significant differences in cerebral volumes attributable to perinatal sepsis (p = 0.515) and quantitatively defined diffuse white matter injury (p = 0.183). As expected, the ventricular system is significantly larger in preterm infants at term equivalent age compared with term control infants (p < 0.001). INTERPRETATION: Cerebral volume is not reduced during intensive care for the majority of preterm infants, but prolonged supplemental oxygen dependence is a risk factor for early attenuation of global brain growth. The reduced cerebral tissue volume seen in adolescents born preterm does not appear to be an inevitable association of prematurity, but rather caused by either specific disease during intensive care or factors operating beyond the neonatal period.

Thalamo-cortical connectivity in children born preterm mapped using probabilistic magnetic resonance tractography.

Our aim was to investigate the feasibility of studying white matter tracts and connections between the thalamus and the cortex in 2-year-old infants who were born preterm by probabilistic magnetic resonance (MR) tractography. Using this approach, we were able to visualize and quantify connectivity distributions in a number of white matter tracts, including the corticospinal tracts, optic radiations, fibers of the genu and splenium of the corpus callosum, superior longitudinal fasciculus and inferior fronto-occipital fasciculus, and to map the distribution within thalamus of fibers connecting to specific cortical regions. In eleven infants with no MR evidence of focal cerebral lesions and appropriate neurodevelopment as shown by general quotient (GQ) scores above 100, we mapped cortical connections to the thalamus that appeared similar to those reported in adults. However, in a proof-of-principle experiment, we examined one further child with marked white matter abnormalities and found that the volume and pattern of thalamo-cortical connections were severely disrupted. This technique promises to be a useful tool for assessing connectivity in the developing brain and in infants with lesions.

Natural history of brain lesions in extremely preterm infants studied with serial magnetic resonance imaging from birth and neurodevelopmental assessment.

OBJECTIVES: The aim was to survey the range of cerebral injury and abnormalities of cerebral development in infants born between 23 and 30 weeks' gestation using serial MRI scans of the brain from birth, and to correlate those findings with neurodevelopmental outcome after 18 months corrected age. METHODS: Between January 1997 and November 2000, consecutive infants born at < 30 weeks' gestational age underwent serial MRI brain scans from birth until term-equivalent age. Infants were monitored after 18 months of age, corrected for prematurity, with the Griffiths Mental Development Scales and neurologic assessment. RESULTS: A total of 327 MRI scans were obtained from 119 surviving infants born at 23 to 30 weeks of gestation. Four infants had major destructive brain lesions, and tissue loss was seen at term for the 2 survivors. Fifty-one infants had early hemorrhage; 50% of infants with term scans after intraventricular hemorrhage had ventricular dilation. Twenty-six infants had punctate white matter lesions on early scans; these persisted for 33% of infants assessed at term. Early scans showed cerebellar hemorrhagic lesions for 8 infants and basal ganglia abnormalities for 17. At term, 53% of infants without previous hemorrhage had ventricular dilation and 80% of infants had diffuse excessive high signal intensity within the white matter on T2-weighted scans. Complete follow-up data were available for 66% of infants. Adverse outcomes were associated with major destructive lesions, diffuse excessive high signal intensity within the white matter, cerebellar hemorrhage, and ventricular dilation after intraventricular hemorrhage but not with punctate white matter lesions, hemorrhage, or ventricular dilation without intraventricular hemorrhage. CONCLUSIONS: Diffuse white matter abnormalities and post-hemorrhagic ventricular dilation are common at term and seem to correlate with reduced developmental quotients. Early lesions, except for cerebellar hemorrhage and major destructive lesions, do not show clear relationships with outcomes.