Petra Susan Hüppi

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.

Microstructural development of human newborn cerebral white matter assessed in vivo by diffusion tensor magnetic resonance imaging.

Alterations of the architecture of cerebral white matter in the developing human brain can affect cortical development and result in functional disabilities. A line scan diffusion-weighted magnetic resonance imaging (MRI) sequence with diffusion tensor analysis was applied to measure the apparent diffusion coefficient, to calculate relative anisotropy, and to delineate three-dimensional fiber architecture in cerebral white matter in preterm (n = 17) and full-term infants (n = 7). To assess effects of prematurity on cerebral white matter development, early gestation preterm infants (n = 10) were studied a second time at term. In the central white matter the mean apparent diffusion coefficient at 28 wk was high, 1.8 µm2/ms, and decreased toward term to 1.2 µm2/ms. In the posterior limb of the internal capsule, the mean apparent diffusion coefficients at both times were similar (1.2 versus 1.1 µm2/ms). Relative anisotropy was higher the closer birth was to term with greater absolute values in the internal capsule than in the central white matter. Preterm infants at term showed higher mean diffusion coefficients in the central white matter (1.4 ± 0.24 versus 1.15 ± 0.09 µm2/ms, p = 0.016) and lower relative anisotropy in both areas compared with full-term infants (white matter, 10.9 ± 0.6 versus 22.9 ± 3.0%, p = 0.001; internal capsule, 24.0 ± 4.44 versus 33.1 ± 0.6% p = 0.006). Nonmyelinated fibers in the corpus callosum were visible by diffusion tensor MRI as early as 28 wk; full-term and preterm infants at term showed marked differences in white matter fiber organization. The data indicate that quantitative assessment of water diffusion by diffusion tensor MRI provides insight into microstructural development in cerebral white matter in living infants.

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.

Early alteration of structural and functional brain development in premature infants born with intrauterine growth restriction.

Placental insufficiency with fetal intrauterine growth restriction (IUGR) is an important cause of perinatal mortality and morbidity and is subsequently associated with significant neurodevelopmental impairment in cognitive function, attention capacity, and school performance. The underlying biologic cause for this association is unclear. Twenty-eight preterm infants (gestational age 32.5 ± 1.9 wk) were studied by early and term magnetic resonance imaging (MRI). An advanced quantitative volumetric three-dimensional MRI technique was used to measure brain tissue volumes in 14 premature infants with placental insufficiency, defined by abnormal antenatal Doppler measurements and mean birth weights <10th percentile (1246 ± 299 g) (IUGR) and in 14 preterm infants matched for gestational age with normal mean birth weights 1843 ± 246 g (control). Functional outcome was measured at term in all infants by a specialized assessment scale of preterm infant behavior. Premature infants with IUGR had a significant reduction in intracranial volume (mean ± SD: 253.7 ± 29.9 versus 300.5 ± 43.5 mL, p < 0.01) and in cerebral cortical gray matter (mean ± SD: 77.2 ± 16.3 versus 106.8 ± 24.6 mL, p < 0.01) when measured within the first 2 wk of life compared with control premature infants. These findings persisted at term with intracranial volume (mean ± SD: 429.3 ± 47.9 versus 475.9 ± 53.4 mL, p < 0.05) and cerebral cortical gray matter (mean ± SD: 149.3 ± 29.2 versus 189 ± 34.2 mL, p < 0.01). Behavioral assessment at term showed a significantly less mature score in the subsystem of attention-interaction availability in IUGR infants (p ± 0.01). Cerebral cortical gray matter volume at term correlated with attention-interaction capacity measured at term (r = 0.45, p < 0.05). These results suggest that placental insufficiency with IUGR have specific structural and functional consequences on cerebral cortical brain development. These findings may provide insight into the structural-functional correlate for the developmental deficits associated with IUGR.

Perinatal exposure to bisphenol a alters early adipogenesis in the rat

Background The causes of the current obesity pandemic have not been fully elucidated. Implication of environmental endocrine disruptors such as bisphenol A (BPA) on adipose tissue development has been poorly investigated. Objectives The aim of the present study was to evaluate the effects of perinatal exposure to BPA on early adipose storage at weaning. Methods Pregnant Sprague-Dawley rats had access to drinking water containing 1 mg/L BPA from day 6 of gestation through the end of lactation. Pups were weaned on postnatal day (PND) 21. At that time, we investigated perigonadal adipose tissue of pups (weight, histology, gene expression). For the remaining animals, we recorded body weight and food intake for animals on either standard chow or a high-fat diet. Results Gestational exposure to BPA did not alter the sex ratio or litter size at birth. On PND1, the weight of male and female BPA-exposed pups was increased. On PND21, body weight was increased only in females, in which parametrial white adipose tissue (pWAT) weight was increased about 3-fold. This excess of pWAT was associated with adipocyte hypertrophy and overexpression of lipogenic genes such as C/EBP-α (CAAT enhancer binding protein alpha), PPAR-γ (peroxisome proliferator-activated receptor gamma), SREBP-1C (sterol regulatory element binding protein-1C), LPL (lipoprotein lipase), FAS (fatty acid synthase), and SCD-1 (stearoyl-CoA desaturase 1). In addition, gene expression of SREBP-1C, FAS, and ACC (acetyl-CoA carboxylase) was also increased in liver from BPA-exposed females at PND21, without a change in circulating lipids and glucose. After weaning, perinatal BPA exposure predisposed to overweight in a sex- and diet-dependent manner. We observed no change in food intake due to perinatal BPA exposure in rats on either standard chow or a high-fat diet. Conclusions Perinatal exposure to a low dose of BPA increased adipogenesis in females at weaning. Adult body weight may be programmed during early life, leading to changes dependent on the sex and the nutritional status. Although further studies are required to understand the mechanisms of BPA action in early life, these results are particularly important with regard to the increasing prevalence of childhood obesity and the context-dependent action of endocrine disruptors.

Late Gestation Cerebellar Growth Is Rapid and Impeded by Premature Birth

Objective. Cognitive impairments and academic failure are commonly reported in survivors of preterm birth. Recent studies suggest an important role for the cerebellum in the development of cognitive and social functions. The objective of this study was to examine the impact of prematurity itself, as well as prematurity-related brain injuries, on early postnatal cerebellar growth with quantitative MRI. Methods. Advanced 3-dimensional volumetric MRI was performed and cerebellar volumes were obtained by manual outlining in preterm (<37 weeks) and healthy term-born infants. Intracranial and total brain volumes were also calculated. Results. A total of 169 preterm and 20 healthy full-term infants were studied; 145 had preterm MRI (pMRI), 75 had term MRI (tMRI), and 51 underwent both pMRI and tMRI. From 28 weeks’ postconceptional age to term, mean cerebellar volume (177%) in preterm infants increased at a much faster rate than did mean intracranial (110%) or mean brain (107%) volumes. Smaller cerebellar volume was significantly related to lower gestational age at birth and to intracranial and total brain volumes. Mean cerebellar volume of preterm infants at tMRI was significantly smaller than the volumes of term-born infants. Cerebellar growth impairment was correlated strongly with associated brain injuries, even in the absence of direct cerebellar injury. Conclusions. Our data suggest that the growth of the immature cerebellum is particularly rapid during late gestation. However, this accelerated growth seems to be impeded by premature birth and associated brain injury. The long-term neurodevelopmental disabilities seen in survivors of premature birth may be attributable in part to impaired cerebellar development.

Imaging biomarkers of outcome in the developing preterm brain

The neurodevelopmental disabilities of those who were born prematurely have been well described, yet the underlying alterations in brain development that lead to these changes remain poorly understood. Processes that are vulnerable to injury in the developing brain include maturation of oligodendrocyte precursors and genetically programmed changes in cortical connectivity; recent data have indicated that diffuse injury of the white matter accompanied by neuronal and axonal disruption is common in prematurely born infants. Recent advances in MRI include diffusion tensor imaging and sophisticated image analysis tools, such as functional connectivity, voxel-based morphometry, and mathematical morphology-based cortical folding strategies. These advanced techniques have shown that white matter structure is dependent on gestational age and have started to provide important information about the dynamic interactions between development, injury, and functional recovery in the preterm brain. Identification of early biomarkers for outcome could enable physicians and scientists to develop targeted pharmacological and behavioural therapies to restore functional connectivity.

Brain metabolite composition during early human brain development as measured by quantitative in vivo 1H magnetic resonance spectroscopy

Biochemical maturation of the brain can be studied noninvasively by 1H magnetic resonance spectroscopy (MRS) in human infants. Detailed time courses of cerebral tissue contents are known for the most abundant metabolites only, and whether or not premature birth affects biochemical maturation of the brain is disputed. Hence, the last trimester of gestation was observed in infants born prematurely, and their cerebral metabolite contents at birth and at expected term were compared with those of fullterm infants. Successful quantitative short‐TE 1H MRS was performed in three cerebral locations in 21 infants in 28 sessions (gestational age 32–43 weeks). The spectra were analyzed with linear combination model fitting, considerably extending the range of observable metabolites to include acetate, alanine, aspartate, cholines, creatines, γ‐aminobutyrate, glucose, glutamine, glutamate, glutathione, glycine, lactate, myo‐inositol, macromolecular contributions, N‐acetylaspartate, N‐acetylaspartylglutamate, o‐phosphoethanolamine, scyllo‐inositol, taurine, and threonine. Significant effects of age and location were found for many metabolites, including the previously observed neuronal maturation reflected by an increase in N‐acetylaspartate. Absolute brain metabolite content in premature infants at term was not considerably different from that in fullterm infants, indicating that prematurity did not affect biochemical brain maturation substantially in the studied population, which did not include infants of extremely low birthweight. Magn Reson Med 48:949–958, 2002.

The early development of brain white matter: a review of imaging studies in fetuses, newborns and infants

Studying how the healthy human brain develops is important to understand early pathological mechanisms and to assess the influence of fetal or perinatal events on later life. Brain development relies on complex and intermingled mechanisms especially during gestation and first post-natal months, with intense interactions between genetic, epigenetic and environmental factors. Although the babys brain is organized early on, it is not a miniature adult brain: regional brain changes are asynchronous and protracted, i.e. sensory-motor regions develop early and quickly, whereas associative regions develop later and slowly over decades. Concurrently, the infant/child gradually achieves new performances, but how brain maturation relates to changes in behavior is poorly understood, requiring non-invasive in vivo imaging studies such as magnetic resonance imaging (MRI). Two main processes of early white matter development are reviewed: (1) establishment of connections between brain regions within functional networks, leading to adult-like organization during the last trimester of gestation, (2) maturation (myelination) of these connections during infancy to provide efficient transfers of information. Current knowledge from post-mortem descriptions and in vivo MRI studies is summed up, focusing on T1- and T2-weighted imaging, diffusion tensor imaging, and quantitative mapping of T1/T2 relaxation times, myelin water fraction and magnetization transfer ratio.

Clinical Proton MR Spectroscopy in Central Nervous System Disorders

A large body of published work shows that proton (hydrogen 1 [(1)H]) magnetic resonance (MR) spectroscopy has evolved from a research tool into a clinical neuroimaging modality. Herein, the authors present a summary of brain disorders in which MR spectroscopy has an impact on patient management, together with a critical consideration of common data acquisition and processing procedures. The article documents the impact of (1)H MR spectroscopy in the clinical evaluation of disorders of the central nervous system. The clinical usefulness of (1)H MR spectroscopy has been established for brain neoplasms, neonatal and pediatric disorders (hypoxia-ischemia, inherited metabolic diseases, and traumatic brain injury), demyelinating disorders, and infectious brain lesions. The growing list of disorders for which (1)H MR spectroscopy may contribute to patient management extends to neurodegenerative diseases, epilepsy, and stroke. To facilitate expanded clinical acceptance and standardization of MR spectroscopy methodology, guidelines are provided for data acquisition and analysis, quality assessment, and interpretation. Finally, the authors offer recommendations to expedite the use of robust MR spectroscopy methodology in the clinical setting, including incorporation of technical advances on clinical units.