Terrie E. Inder

Abnormal Cerebral Structure Is Present at Term in Premature Infants

Background. Long-term studies of the outcome of very prematurely born infants have clearly documented that the majority of such infants have significant motor, cognitive, and behavioral deficits. However, there is a limited understanding of the nature of the cerebral abnormality underlying these adverse neurologic outcomes. Aim. The overall aim of this study was to define quantitatively the alterations in cerebral tissue volumes at term equivalent in a large longitudinal cohort study of very low birth weight premature infants in comparison to term-born infants by using advanced volumetric 3-dimensional magnetic resonance imaging (MRI) techniques. We also aimed to define any relationship of such perinatal lesions as white matter (WM) injury or other potentially adverse factors to the quantitative structural alterations. Additionally, we wished to identify the relationship of the structural alterations to short-term neurodevelopmental outcome. Methods. From November 1998 to December 2000, 119 consecutive premature infants admitted to the neonatal intensive care units at Christchurch Women’s Hospital (Christchurch, New Zealand) and the Royal Women’s Hospital (Melbourne, Australia) were recruited (88% of eligible) after informed parental consent to undergo an MRI scan at term equivalent. Twenty-one term-born infants across both sites were recruited also. Postacquisition advanced 3-dimensional tissue segmentation with 3-dimensional reconstruction was undertaken to estimate volumes of cerebral tissues: gray matter (GM; cortical and deep nuclear structures), WM (myelinated and unmyelinated), and cerebrospinal fluid (CSF). Results. In comparison to the term-born infants, the premature infants at term demonstrated prominent reductions in cerebral cortical GM volume (premature infants [mean ± SD]: 178 ± 41 mL; term infants: 227 ± 26 mL) and in deep nuclear GM volume (premature infants: 10.8 ± 4.1 mL; term infants: 13.8 ± 5.2 mL) and an increase in CSF volume (premature infants: 45.6 ± 22.1 mL; term infants: 28.9 ± 16 mL). The major predictors of altered cerebral volumes were gestational age at birth and the presence of cerebral WM injury. Infants with significantly reduced cortical GM and deep nuclear GM volumes and increased CSF volume volumes exhibited moderate to severe neurodevelopmental disability at 1 year of age. Conclusions. This MRI study of prematurely born infants further defines the nature of quantitative cerebral structural abnormalities present as early as term equivalent. The abnormalities particularly involve cerebral neuronal regions including both cortex and deep nuclear structures. The pattern of cerebral alterations is related most significantly to the degree of immaturity at birth and to concomitant WM injury. The alterations are followed by abnormal short-term neurodevelopmental outcome.

Periventricular white matter injury in the premature infant is followed by reduced cerebral cortical gray matter volume at term

Periventricular white matter injury, that is, periventricular leukomalacia (PVL), the dominant form of brain injury in the premature infant, is the major neuropathological substrate associated with the motor and cognitive deficits observed later in such infants. The nature of the relationship of this lesion to the subsequent cognitive deficits is unclear, but such deficits raise the possibility of cerebral cortical neuronal dysfunction. Although cortical neuronal necrosis is not a prominent feature of brain injury in premature infants, the possibility of a deleterious effect of PVL on subsequent cerebral cortical development has not been investigated. An advanced quantitative volumetric three‐dimensional magnetic resonance imaging technique was used to measure brain tissue volumes at term in premature infants with earlier ultrasonographic and magnetic resonance imaging evidence of PVL (mean gestational age at birth, 28.7 ± 2.0 weeks; n = 10), in premature infants with normal imaging studies (mean gestational age at birth, 29.0 ± 2.1 weeks; n = 10), and in control term infants (n = 14). Premature infants with PVL had a marked reduction in cerebral cortical gray matter at term compared with either premature infants without PVL or normal term infants (mean ± SD: PVL, 157.5 ± 41.5 ml; no PVL, 211.7 ± 25.4 ml; normal term, 218.8 ± 21.3 ml). As expected, a reduction in the volume of total brain myelinated white matter was also noted (mean ± SD: PVL, 14.5 ± 4.6 ml; no PVL, 23.1 ± 6.9 ml; normal term, 27.6 ± 10.3 ml). An apparent compensatory increase in total cerebrospinal fluid volume also was found (mean ± SD: PVL, 64.5 ± 15.2 ml; no PVL, 52.0 ± 24.1 ml; normal term, 32.9 ± 13.5 ml). PVL in the premature infant is shown for the first time to be followed by impaired cerebral cortical development. These findings may provide insight into the anatomical correlate for the intellectual deficits associated with PVL in the premature infant.

Defining the nature of the cerebral abnormalities in the premature infant: a qualitative magnetic resonance imaging study.

Abstract Objectives The aim of this study was to define qualitatively the nature and extent of white and gray matter abnormalities in a longitudinal population-based study of infants with very low birth weight. Perinatal factors were then related to the presence and severity of magnetic resonance imaging (MRI) abnormalities. Methods From November 1998 to December 2000, 100 consecutive premature infants admitted to the neonatal intensive care unit at Christchurch Womens Hospital were recruited (98% eligible) after informed parental consent to undergo an MRI scan at term equivalent. The scans were analyzed by a single neuroradiologist experienced in pediatric MRI, with a second independent scoring of the MRI using a combination of criteria for white matter (cysts, signal abnormality, loss of volume, ventriculomegaly, corpus callosal thinning, myelination) and gray matter (gray matter signal abnormality, gyration, subarachnoid space). Results were analyzed against individual item scores as well as the presence of moderate-severe white matter score, total gray matter score, and total brain score. Results The mean gestational age was 27.9±2.4 weeks (range, 23-32 weeks), and mean birth weight was 1063±292 g. The greatest univariate predictors for moderate-severe white matter abnormality were lower gestational age (odds ratio [OR], 1.3; 95% confidence interval [CI], 1.1-1.7; P P P =0.03), inotropic support (OR, 2.7; 95% CI, 1.5-4.5; P P =.01), grade III/IV intraventricular hemorrhage ( P =.015), and the occurrence of a pneumothorax ( P =.05). There was a significant protective effect of intrauterine growth restriction (OR, 0.51; 95% CI, 0.23-0.99; P =.04). Gray matter abnormality was highly related to the presence and severity of white matter abnormality. A unique pattern of cerebral abnormality consisting of significant diffuse white matter atrophy, ventriculomegaly, immature gyral development, and enlarged subarachnoid space was found in 10 of 11 infants with birth gestation Conclusions This MRI study confirms a high incidence of cerebral white matter abnormality at term in an unselected population of premature infants, which is predominantly a result of noncystic injury in the extremely immature infant. We confirm that the major perinatal risk factors for white matter abnormality are related to perinatal infection, particularly maternal fever and infant sepsis, and hypotension with inotrope use. We have defined a distinct pattern of diffuse white and gray matter abnormality in the extremely immature infant.

Longitudinal Analysis of Neural Network Development in Preterm Infants

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.

Adverse neurodevelopment in preterm infants with postnatal sepsis or necrotizing enterocolitis is mediated by white matter abnormalities on magnetic resonance imaging at term.

OBJECTIVES To test the hypothesis that the impact of postnatal sepsis/necrotizing enterocolitis (NEC) on neurodevelopment may be mediated by white matter abnormality (WMA), which can be demonstrated with magnetic resonance imaging (MRI). STUDY DESIGN A prospective cohort of 192 unselected preterm infants (gestational age <30 weeks), who were evaluated for sepsis and NEC, underwent imaging at term-equivalent age and neurodevelopmental outcome at 2 years corrected age with the Bayley Scales of Infant Development. RESULTS Sixty-eight preterm (35%) infants had 100 episodes of confirmed sepsis, and 9 (5%) infants had confirmed NEC. Coagulase-negative staphylococci accounted for 73% (73/100) of the episodes of confirmed sepsis. Infants with sepsis/NEC had significantly more WMA on MRI at term compared with infants in the no-sepsis/NEC group. They also had poorer psychomotor development that persisted after adjusting for potential confounders but which became nonsignificant after adjusting for WMA. CONCLUSIONS Preterm infants with sepsis/NEC are at greater risk of motor impairment at 2 years, which appears to be mediated by WMA. These findings may assist in defining a neuroprotective target in preterm infants with sepsis/NEC.

Neonatal intensive care unit stress is associated with brain development in preterm infants

Although many perinatal factors have been linked to adverse neurodevelopmental outcomes in very premature infants, much of the variation in outcome remains unexplained. The impact on brain development of 1 potential factor, exposure to stressors in the neonatal intensive care unit, has not yet been studied in a systematic, prospective manner.

Similar patterns of cortical expansion during human development and evolution

The cerebral cortex of the human infant at term is complexly folded in a similar fashion to adult cortex but has only one third the total surface area. By comparing 12 healthy infants born at term with 12 healthy young adults, we demonstrate that postnatal cortical expansion is strikingly nonuniform: regions of lateral temporal, parietal, and frontal cortex expand nearly twice as much as other regions in the insular and medial occipital cortex. This differential postnatal expansion may reflect regional differences in the maturity of dendritic and synaptic architecture at birth and/or in the complexity of dendritic and synaptic architecture in adults. This expression may also be associated with differential sensitivity of cortical circuits to childhood experience and insults. By comparing human and macaque monkey cerebral cortex, we infer that the pattern of human evolutionary expansion is remarkably similar to the pattern of human postnatal expansion. To account for this correspondence, we hypothesize that it is beneficial for regions of recent evolutionary expansion to remain less mature at birth, perhaps to increase the influence of postnatal experience on the development of these regions or to focus prenatal resources on regions most important for early survival.

A Surface-Based Analysis of Hemispheric Asymmetries and Folding of Cerebral Cortex in Term-Born Human Infants

We have established a population average surface-based atlas of human cerebral cortex at term gestation and used it to compare infant and adult cortical shape characteristics. Accurate cortical surface reconstructions for each hemisphere of 12 healthy term gestation infants were generated from structural magnetic resonance imaging data using a novel segmentation algorithm. Each surface was inflated, flattened, mapped to a standard spherical configuration, and registered to a target atlas sphere that reflected shape characteristics of all 24 contributing hemispheres using landmark constrained surface registration. Population average maps of sulcal depth, depth variability, three-dimensional positional variability, and hemispheric depth asymmetry were generated and compared with previously established maps of adult cortex. We found that cortical structure in term infants is similar to the adult in many respects, including the pattern of individual variability and the presence of statistically significant structural asymmetries in lateral temporal cortex, including the planum temporale and superior temporal sulcus. These results indicate that several features of cortical shape are minimally influenced by the postnatal environment.

Early detection of periventricular leukomalacia by diffusion-weighted magnetic resonance imaging techniques.

Periventricular leukomalacia (PVL), the principal form of brain injury in the premature infant, is characterized by overt focal necrotic lesions in periventricular white matter and less prominent, more diffuse cerebral white matter injury. The early detection of the latter, diffuse component of PVL is not consistently possible with conventional brain imaging techniques. We demonstrate the early detection of the diffuse component of PVL by diffusion-weighted magnetic resonance imaging (DWI). In a premature infant with no definite cerebral abnormality detectable by cranial ultrasonography or conventional magnetic resonance imaging, DWI showed a striking bilateral decrease in water diffusion in cerebral white matter. The DWI abnormality (ie, decreased apparent diffusion coefficient) was similar to that observed with acute cerebral ischemic lesions in adults. At 10 weeks of age, conventional magnetic resonance imaging and ultrasonography showed striking changes consistent with PVL, including the presence of small cysts. The observations indicate the importance of DWI in the early identification of the diffuse component of PVL and also perhaps the role of ischemia in the pathogenesis of the lesion.

Posthaemorrhagic ventricular dilatation in the premature infant: natural history and predictors of outcome

Objective: To investigate the natural history and predictors of outcome of posthaemorrhagic ventriculomegaly in the very low birthweight (VLBW) infant. Methods: All VLBW infants admitted between September 1994 and September 1997 to the neonatal intensive care units of Brigham and Womens Hospital (Boston), Childrens Hospital (Boston), and Christchurch Womens Hospital (New Zealand) with germinal matrix intraventricular haemorrhage (IVH) were identified. All charts and ultrasound scans were reviewed to define the natural history and perinatal and/or postnatal factors of value in prediction of the course of posthaemorrhagic ventriculomegaly. Progressive ventricular dilatation (PVD) was defined from the results of serial cranial ultrasound scans. Results: A total of 248 VLBW infants had evidence of IVH (22% of all VLBW infants, mean (SD) gestational age 26.8 (2.6) weeks). A quarter of the infants exhibited PVD. Spontaneous arrest of PVD occurred without treatment in 38% of infants with PVD. Of the remaining 62% with persistent PVD, 48% received non-surgical treatment only (pharmacological and/or drainage of cerebrospinal fluid by serial lumbar punctures), 34% received surgical treatment with insertion of a ventriculoperitoneal reservoir and/or shunt, and 18% died. The development of PVD after IVH and adverse short term outcome, such as the requirement for surgery, were predicted most strongly by the severity of IVH. Conclusions: These data reflect the natural history of PVD in the 1990s and show that, despite a slight reduction in its overall incidence, there appears to be a more aggressive course, with appreciable mortality and morbidity in the extremely premature infant. The major predictor of adverse short term outcome, defined as death or need for surgical intervention, was the severity of IVH. These findings may be valuable for the management of very small premature infants.