Leigh Dyet

Moderate Hypothermia to Treat Perinatal Asphyxial Encephalopathy

BACKGROUND Whether hypothermic therapy improves neurodevelopmental outcomes in newborn infants with asphyxial encephalopathy is uncertain. METHODS We performed a randomized trial of infants who were less than 6 hours of age and had a gestational age of at least 36 weeks and perinatal asphyxial encephalopathy. We compared intensive care plus cooling of the body to 33.5 degrees C for 72 hours and intensive care alone. The primary outcome was death or severe disability at 18 months of age. Prespecified secondary outcomes included 12 neurologic outcomes and 14 other adverse outcomes. RESULTS Of 325 infants enrolled, 163 underwent intensive care with cooling, and 162 underwent intensive care alone. In the cooled group, 42 infants died and 32 survived but had severe neurodevelopmental disability, whereas in the noncooled group, 44 infants died and 42 had severe disability (relative risk for either outcome, 0.86; 95% confidence interval [CI], 0.68 to 1.07; P=0.17). Infants in the cooled group had an increased rate of survival without neurologic abnormality (relative risk, 1.57; 95% CI, 1.16 to 2.12; P=0.003). Among survivors, cooling resulted in reduced risks of cerebral palsy (relative risk, 0.67; 95% CI, 0.47 to 0.96; P=0.03) and improved scores on the Mental Developmental Index and Psychomotor Developmental Index of the Bayley Scales of Infant Development II (P=0.03 for each) and the Gross Motor Function Classification System (P=0.01). Improvements in other neurologic outcomes in the cooled group were not significant. Adverse events were mostly minor and not associated with cooling. CONCLUSIONS Induction of moderate hypothermia for 72 hours in infants who had perinatal asphyxia did not significantly reduce the combined rate of death or severe disability but resulted in improved neurologic outcomes in survivors. (Current Controlled Trials number, ISRCTN89547571.)

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.

Abnormal Cortical Development after Premature Birth Shown by Altered Allometric Scaling of Brain Growth

Background We postulated that during ontogenesis cortical surface area and cerebral volume are related by a scaling law whose exponent gives a quantitative measure of cortical development. We used this approach to investigate the hypothesis that premature termination of the intrauterine environment by preterm birth reduces cortical development in a dose-dependent manner, providing a neural substrate for functional impairment. Methods and Findings We analyzed 274 magnetic resonance images that recorded brain growth from 23 to 48 wk of gestation in 113 extremely preterm infants born at 22 to 29 wk of gestation, 63 of whom underwent neurodevelopmental assessment at a median age of 2 y. Cortical surface area was related to cerebral volume by a scaling law with an exponent of 1.29 (95% confidence interval, 1.25–1.33), which was proportional to later neurodevelopmental impairment. Increasing prematurity and male gender were associated with a lower scaling exponent (p < 0.0001) independent of intrauterine or postnatal somatic growth. Conclusions Human brain growth obeys an allometric scaling relation that is disrupted by preterm birth in a dose-dependent, sexually dimorphic fashion that directly parallels the incidence of neurodevelopmental impairments in preterm infants. This result focuses attention on brain growth and cortical development during the weeks following preterm delivery as a neural substrate for neurodevelopmental impairment after premature delivery.

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 Charlottes 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 childrens 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 × 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.

A common neonatal image phenotype predicts adverse neurodevelopmental outcome in children born preterm

Diffuse white matter injury is common in preterm infants and is a candidate substrate for later cognitive impairment. This injury pattern is associated with morphological changes in deep grey nuclei, the localization of which is uncertain. We test the hypotheses that diffuse white matter injury is associated with discrete focal tissue loss, and that this image phenotype is associated with impairment at 2years. We acquired magnetic resonance images from 80 preterm infants at term equivalent (mean gestational age 29(+6)weeks) and 20 control infants (mean GA 39(+2)weeks). Diffuse white matter injury was defined by abnormal apparent diffusion coefficient values in one or more white matter region (frontal, central or posterior white matter at the level of the centrum semiovale), and morphological difference between groups was calculated from 3D images using deformation based morphometry. Neurodevelopmental assessments were obtained from preterm infants at a mean chronological age of 27.5months, and from controls at a mean age of 31.1months. We identified a common image phenotype in 66 of 80 preterm infants at term equivalent comprising: diffuse white matter injury; and tissue volume reduction in the dorsomedial nucleus of the thalamus, the globus pallidus, periventricular white matter, the corona radiata and within the central region of the centrum semiovale (t=4.42 p<0.001 false discovery rate corrected). The abnormal image phenotype is associated with reduced median developmental quotient (DQ) at 2years (DQ=92) compared with control infants (DQ=112), p<0.001. These findings indicate that specific neural systems are susceptible to maldevelopment after preterm birth, and suggest that neonatal image phenotype may serve as a useful biomarker for studying mechanisms of injury and the effect of putative therapeutic interventions.

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.

Early Growth in Brain Volume Is Preserved in the Majority of Preterm Infants

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?

Perinatal cortical growth and childhood neurocognitive abilities

Objective: This observational cohort study addressed the hypothesis that after preterm delivery brain growth between 24 and 44 weeks postmenstrual age (PMA) is related to global neurocognitive ability in later childhood. Methods: Growth rates for cerebral volume and cortical surface area were estimated in 82 infants without focal brain lesions born before 30 weeks PMA by using 217 magnetic resonance images obtained between 24 and 44 weeks PMA. Abilities were assessed at 2 years using the Griffiths Mental Development Scale and at 6 years using the Wechsler Preschool and Primary Scale of Intelligence–Revised (WPPSI-R), the Developmental Neuropsychological Assessment (NEPSY), and the Movement Assessment Battery for Children (MABC). Analysis was by generalized least-squares regression. Results: Mean test scores approximated population averages. Cortical growth was directly related to the Griffiths Developmental Quotient (DQ), the WPPSI-R full-scale IQ, and a NEPSY summary score but not the MABC score and in exploration of subtests to attention, planning, memory, language, and numeric and conceptual abilities but not motor skills. The mean (95% confidence interval) estimated reduction in cortical surface area at term corrected age associated with a 1 SD fall in test score was as follows: DQ 7.0 (5.8–8.5); IQ 6.0 (4.9–7.3); and NEPSY 9.1 (7.5–11.0) % · SD−1. Total brain volume growth was not correlated with any test score. Conclusions: The rate of cerebral cortical growth between 24 and 44 weeks PMA predicts global ability in later childhood, particularly complex cognitive functions but not motor functions.