Brain injury in premature infants is of enormous public health importance because of the large number of such infants who survive with serious neurodevelopmental disability, including major cognitive deficits and motor disability. This type of brain injury is generally thought to consist primarily of periventricular leukomalacia (PVL), a distinctive form of cerebral white matter injury. Important new work shows that PVL is frequently accompanied by neuronal/axonal disease, affecting the cerebral white matter, thalamus, basal ganglia, cerebral cortex, brain stem, and cerebellum. This constellation of PVL and neuronal/axonal disease is sufficiently distinctive to be termed "encephalopathy of prematurity". The thesis of this Review is that the encephalopathy of prematurity is a complex amalgam of primary destructive disease and secondary maturational and trophic disturbances. This Review integrates the fascinating confluence of new insights into both brain injury and brain development during the human premature period.

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Brain injury in premature infants: a complex amalgam of destructive and developmental disturbances

Application of resting state functional connectivity magnetic resonance imaging (fcMRI) to the study of prematurely born infants enables assessment of the earliest forms of cerebral connectivity and characterization of its early development in the human brain. We obtained 90 longitudinal fcMRI data sets from a cohort of preterm infants aged from 26 weeks postmenstrual age (PMA) through term equivalent age at PMA-specific time points. Utilizing seed-based correlation analysis, we identified resting state networks involving varied cortical regions, the thalamus, and cerebellum. Identified networks demonstrated a regionally variable age-specific pattern of development, with more mature forms consisting of localized interhemispheric connections between homotopic counterparts. Anatomical distance was found to play a critical role in the rate of connection development. Prominent differences were noted between networks identified in term control versus premature infants at term equivalent, including in the thalamocortical connections critical for neurodevelopment. Putative precursors of the default mode network were detected in term control infants but were not identified in preterm infants, including those at term equivalent. Identified patterns of network maturation reflect the intricate relationship of structural and functional processes present throughout this important developmental period and are consistent with prior investigations of neurodevelopment in this population.

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Longitudinal Analysis of Neural Network Development in Preterm Infants

http://pages.stat.wisc.edu/~mchung/teaching/MIA/reading/DTI.alexander.NI.2006.pdf

Diffusion tensor imaging of the corpus callosum in Autism

The adoption into the UK of children who have been reared in severely deprived conditions provides an opportunity to study possible association between very early negative experiences and subsequent brain development. This cross-sectional study was a pilot for a planned larger study quantifying the effects of early deprivation on later brain structure. We used magnetic resonance imaging (MRI) to measure the sizes of three key brain regions hypothesized to be sensitive to early adverse experiences. Our sample was a group of adoptee adolescents (N = 14) who had experienced severe early institutional deprivation in Romania and a group of non-institutionalised controls (N = 11). The total grey and white matter volumes were significantly smaller in the institutionalised group compared with a group of non-deprived, non-adopted UK controls. After correcting for difference in brain volume, the institutionalised group had greater amygdala volumes, especially on the right, but no differences were observed in hippocampal volume or corpus callosum mid-sagittal area. The left amygdala volume was also related to the time spent in institutions, with those experiencing longer periods of deprivation having a smaller left amygdala volume. These pilot findings highlight the need for future studies to confirm the sensitivity of the amygdala to early deprivation.

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Amygdala, Hippocampal and Corpus Callosum Size Following Severe Early Institutional Deprivation: The English and Romanian Adoptees Study Pilot.

Very preterm (VPT) birth is associated with altered cortical development and long-term neurodevelopmental sequelae. We used voxel-based morphometry to investigate white (WM) and grey matter (GM) distribution in VPT adolescents and controls, and the association with gestational age and neonatal ultrasound findings in the VPT individuals. GM and WM volumes were additionally investigated in relation to adolescent neurodevelopmental outcome. Structural MRI data were acquired with a 1.5 Tesla machine in 218 VPT adolescents (<33 weeks, gestation) and 128 controls aged 14-15 years, and analysed using SPM2 software. VPT individuals compared to controls showed reduced GM in temporal, frontal, occipital cortices and cerebellum, including putamen, insula, cuneus, fusiform gyrus, thalamus and caudate nucleus, and increased GM predominantly in temporal and frontal lobes, including cingulate and fusiform gyri and cerebellum. WM loss was concentrated in the brainstem, internal capsule, temporal and frontal regions and the major fasciculi. WM excesses were observed in temporal, parietal and frontal regions. Investigation of the inter-relationships between brain regions and changes revealed that all selected areas where between-group increased and decreased WM and GM volumes differences were observed, were structurally associated, highlighting the influence that abnormalities in one brain area may exert over others. VPT individuals with evidence of periventricular haemorrhage and ventricular dilatation on neonatal ultrasound exhibited the greatest WM and GM alterations. VPT adolescents obtained lower scores than controls on measures of language and executive function and were more likely to show cognitive impairment compared to controls (27% versus 14%, respectively). Several areas where VPT individuals demonstrated decreased GM and WM volume were linearly associated with gestational age and mediated cognitive impairment. To summarize, our data demonstrates that VPT birth is associated with altered brain structure in adolescence. GM and WM alterations are associated with length of gestation and mediate adolescent neurodevelopmental impairment. Thus, anatomical brain changes may contribute to specific cognitive deficits associated with VPT birth and could be used in the identification of those individuals who may be at increased risk for cognitive impairment.

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Grey and white matter distribution in very preterm adolescents mediates neurodevelopmental outcome.

Thinning of the corpus callosum (CC) is often observed in individuals who were born very preterm. Damage to the CC during neurodevelopment may be associated with poor neuropsychological performance. This study aimed to explore any evidence of CC pathology in adolescents aged 14-15 years who were born very preterm, and to investigate the relationship between CC areas and verbal skills. Seventy-two individuals born before 33 weeks of gestation and 51 age- and sex-matched full-term controls received structural MRI and neuropsychological assessment. Total CC area in very preterm adolescents was 7.5% smaller than in controls, after adjusting for total white matter volume (P = 0.015). The absolute size of callosal subregions differed between preterm and full-term adolescents: preterm individuals had a 14.7% decrease in posterior (P < 0.0001) and an 11.6% decrease in mid-posterior CC quarters (P = 0.029). Preterm individuals who had experienced periventricular haemorrhage and ventricular dilatation in the neonatal period showed the greatest decrease in CC area. In very preterm boys only, verbal IQ and verbal fluency scores were positively associated with total mid-sagittal CC size and mid-posterior surface area. These results suggest that very preterm birth adversely affects the development of the CC, particularly its posterior quarter, and this impairs verbal skills in boys.

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Peter W R Woodruff

Papers

Corpus callosum size and very preterm birth: relationship to neuropsychological outcome.