Steven P. Miller

Brain injury in premature neonates: A primary cerebral dysmaturation disorder?

With advances in neonatal care, preterm neonates are surviving with an evolving constellation of motor and cognitive disabilities that appear to be related to widespread cellular maturational disturbances that target cerebral gray and white matter. Whereas preterm infants were previously at high risk for destructive brain lesions that resulted in cystic white matter injury and secondary cortical and subcortical gray matter degeneration, contemporary cohorts of preterm survivors commonly display less severe injury that does not appear to involve pronounced glial or neuronal loss. Nevertheless, these milder forms of injury are also associated with reduced cerebral growth. Recent human and experimental studies support that impaired cerebral growth is related to disparate responses in gray and white matter. Myelination disturbances in cerebral white matter are related to aberrant regeneration and repair responses to acute death of premyelinating late oligodendrocyte progenitors (preOLs). In response to preOL death, early oligodendrocyte progenitors rapidly proliferate and differentiate, but the regenerated preOLs fail to normally mature to myelinating cells required for white matter growth. Although immature neurons appear to be more resistant to cell death from hypoxia–ischemia than glia, they display widespread disturbances in maturation of their dendritic arbors, which further contribute to impaired cerebral growth. These complex and disparate responses of neurons and preOLs thus result in large numbers of cells that fail to fully mature during a critical window in development of neural circuitry. These recently recognized forms of cerebral gray and white matter dysmaturation raise new diagnostic challenges and suggest new therapeutic directions centered on reversal of the processes that promote dysmaturation. Ann Neurol 2014;75:469–486

Reduced Fetal Cerebral Oxygen Consumption is Associated With Smaller Brain Size in Fetuses With Congenital Heart Disease

Background— Fetal hypoxia has been implicated in the abnormal brain development seen in newborns with congenital heart disease (CHD). New magnetic resonance imaging technology now offers the potential to investigate the relationship between fetal hemodynamics and brain dysmaturation. Methods and Results— We measured fetal brain size, oxygen saturation, and blood flow in the major vessels of the fetal circulation in 30 late-gestation fetuses with CHD and 30 normal controls using phase-contrast magnetic resonance imaging and T2 mapping. Fetal hemodynamic parameters were calculated from a combination of magnetic resonance imaging flow and oximetry data and fetal hemoglobin concentrations estimated from population averages. In fetuses with CHD, reductions in umbilical vein oxygen content (P<0.001) and failure of the normal streaming of oxygenated blood from the placenta to the ascending aorta were associated with a mean reduction in ascending aortic saturation of 10% (P<0.001), whereas cerebral blood flow and cerebral oxygen extraction were no different from those in controls. This accounted for the mean 15% reduction in cerebral oxygen delivery (P=0.08) and 32% reduction cerebral VO2 in CHD fetuses (P<0.001), which were associated with a 13% reduction in fetal brain volume (P<0.001). Fetal brain size correlated with ascending aortic oxygen saturation and cerebral VO2 (r=0.37, P=0.004). Conclusions— This study supports a direct link between reduced cerebral oxygenation and impaired brain growth in fetuses with CHD and raises the possibility that in utero brain development could be improved with maternal oxygen therapy.

Neonatal pain-related stress, functional cortical activity and visual-perceptual abilities in school-age children born at extremely low gestational age

Summary Neonatal pain‐related stress is associated with altered brain activity and visual‐perceptual abilities in school‐age children born at extremely low gestational age. Abstract Children born very prematurely (≤32 weeks) often exhibit visual‐perceptual difficulties at school‐age, even in the absence of major neurological impairment. The alterations in functional brain activity that give rise to such problems, as well as the relationship between adverse neonatal experience and neurodevelopment, remain poorly understood. Repeated procedural pain‐related stress during neonatal intensive care has been proposed to contribute to altered neurocognitive development in these children. Due to critical periods in the development of thalamocortical systems, the immature brain of infants born at extremely low gestational age (ELGA; ≤28 weeks) may have heightened vulnerability to neonatal pain. In a cohort of school‐age children followed since birth we assessed relations between functional brain activity measured using magnetoencephalogragy (MEG), visual‐perceptual abilities and cumulative neonatal pain. We demonstrated alterations in the spectral structure of spontaneous cortical oscillatory activity in ELGA children at school‐age. Cumulative neonatal pain‐related stress was associated with changes in background cortical rhythmicity in these children, and these alterations in spontaneous brain oscillations were negatively correlated with visual‐perceptual abilities at school‐age, and were not driven by potentially confounding neonatal variables. These findings provide the first evidence linking neonatal pain‐related stress, the development of functional brain activity, and school‐age cognitive outcome in these vulnerable children.

Slower Postnatal Growth Is Associated with Delayed Cerebral Cortical Maturation in Preterm Newborns

Impaired growth during neonatal intensive care is associated with delayed microstructural development of the cortical gray matter after accounting for prenatal growth, neonatal illness, and brain injury in infants born very preterm. Early Start for Better Brains Despite all of the recent advances in medical care for premature newborns, these infants still often experience complications. In particular, cognitive problems and developmental delays are common in this patient population and can be difficult to predict. Now, two sets of authors have obtained new data that approach this problem from different angles using diffusion tensor magnetic resonance imaging (MRI) in human infants and newborn lambs. Vinall and coauthors examined 95 premature newborn babies who were born at 24 to 32 weeks of gestation. The authors performed two sets of MRI scans on these infants: one scan was done about 2 months before their due dates and the other scan when they reached full term. The authors also tracked the infants’ growth parameters—weight, length, and head size—as well as data on other factors that could affect brain growth, including the presence of infections or other serious illnesses. A detailed analysis of the MRI scans showed that the development of normal brain structure correlated with postnatal growth (and presumably nutrition) even after accounting for any other illnesses the infants may have experienced early in life. Dean et al. took a different approach to studying premature brain development: they analyzed the brain structures of fetal lambs that had experienced ischemia in utero at a time that corresponded to about two-thirds of full gestation time. The lambs were analyzed both by MRI and by histological analysis of the brain at 1, 2, or 4 weeks after an in utero ischemic event, and these data were compared to those of age-matched animals that did not undergo ischemic episodes. Here, the authors also saw abnormalities in brain development by MRI and correlated them with histological and structural aberrations. The growth impairment seen in the animals’ brains by MRI corresponded to disturbances in the branching of neuronal dendrites and abnormal formation of synapse connections with other neurons. More studies are needed to understand how postnatal growth, nutrition, illness, and prenatal ischemia affect the developing brain to develop methods for preventing any resulting injury. In addition, long-term studies should help to determine how differences in brain anatomy and MRI data translate into developmental and cognitive outcomes. Slower postnatal growth is an important predictor of adverse neurodevelopmental outcomes in infants born preterm. However, the relationship between postnatal growth and cortical development remains largely unknown. Therefore, we examined the association between neonatal growth and diffusion tensor imaging measures of microstructural cortical development in infants born very preterm. Participants were 95 neonates born between 24 and 32 weeks gestational age studied twice with diffusion tensor imaging: scan 1 at a median of 32.1 weeks (interquartile range, 30.4 to 33.6) and scan 2 at a median of 40.3 weeks (interquartile range, 38.7 to 42.7). Fractional anisotropy and eigenvalues were recorded from 15 anatomically defined cortical regions. Weight, head circumference, and length were recorded at birth and at the time of each scan. Growth between scans was examined in relation to diffusion tensor imaging measures at scans 1 and 2, accounting for gestational age, birth weight, sex, postmenstrual age, known brain injury (white matter injury, intraventricular hemorrhage, and cerebellar hemorrhage), and neonatal illness (patent ductus arteriosus, days intubated, infection, and necrotizing enterocolitis). Impaired weight, length, and head growth were associated with delayed microstructural development of the cortical gray matter (fractional anisotropy: P < 0.001), but not white matter (fractional anisotropy: P = 0.529), after accounting for prenatal growth, neonatal illness, and brain injury. Avoiding growth impairment during neonatal care may allow cortical development to proceed optimally and, ultimately, may provide an opportunity to reduce neurological disabilities related to preterm birth.

Neonatal Pain-Related Stress Predicts Cortical Thickness at Age 7 Years in Children Born Very Preterm

Background Altered brain development is evident in children born very preterm (24–32 weeks gestational age), including reduction in gray and white matter volumes, and thinner cortex, from infancy to adolescence compared to term-born peers. However, many questions remain regarding the etiology. Infants born very preterm are exposed to repeated procedural pain-related stress during a period of very rapid brain development. In this vulnerable population, we have previously found that neonatal pain-related stress is associated with atypical brain development from birth to term-equivalent age. Our present aim was to evaluate whether neonatal pain-related stress (adjusted for clinical confounders of prematurity) is associated with altered cortical thickness in very preterm children at school age. Methods 42 right-handed children born very preterm (24–32 weeks gestational age) followed longitudinally from birth underwent 3-D T1 MRI neuroimaging at mean age 7.9 yrs. Children with severe brain injury and major motor/sensory/cognitive impairment were excluded. Regional cortical thickness was calculated using custom developed software utilizing FreeSurfer segmentation data. The association between neonatal pain-related stress (defined as the number of skin-breaking procedures) accounting for clinical confounders (gestational age, illness severity, infection, mechanical ventilation, surgeries, and morphine exposure), was examined in relation to cortical thickness using constrained principal component analysis followed by generalized linear modeling. Results After correcting for multiple comparisons and adjusting for neonatal clinical factors, greater neonatal pain-related stress was associated with significantly thinner cortex in 21/66 cerebral regions (p-values ranged from 0.00001 to 0.014), predominately in the frontal and parietal lobes. Conclusions In very preterm children without major sensory, motor or cognitive impairments, neonatal pain-related stress appears to be associated with thinner cortex in multiple regions at school age, independent of other neonatal risk factors.

Brain injury and development in newborns with critical congenital heart disease.

Objective: To determine the relationship between radiologically identifiable brain injuries and delayed brain development as reflected by brain metabolic and microstructural integrity. Methods: Term newborns with congenital heart disease (CHD) (120 preoperatively and 104 postoperatively) were studied with MRI to determine brain injury severity (BIS), microstructure reflected by fractional anisotropy (FA) and average diffusivity (Dav), and metabolism reflected by N-acetylaspartate (NAA)/choline (Cho) and lactate/Cho. Brain development is characterized by increasing NAA/Cho and white matter FA, and by decreasing Dav and lactate/Cho. Results: Newly acquired brain injury was common (41% preoperative, 30% postoperative). Lower white matter FA (p = 0.005) and lower NAA/Cho (p = 0.01) were associated with increasing preoperative BIS. Higher neonatal illness severity scores (p = 0.03), lower preoperative oxygen saturation (p = 0.002), hypotension (p < 0.001), and septostomy (p = 0.002) were also predictive of higher preoperative BIS. Preoperative FA, Dav, and NAA/Cho did not predict new postoperative BIS. Increasing preoperative BIS predicted higher postoperative Dav (p = 0.002) and lactate/Cho (p = 0.008). Within the postoperative scan, new brain injuries were associated with lower white matter FA (p = 0.04). Postoperative BIS (new lesions) was associated with lower postoperative systolic (p = 0.03) and mean (p = 0.05) blood pressures. Conclusions: Brain injuries in newborns with CHD are strongly related to abnormalities of brain microstructural and metabolic brain development, especially preoperatively. Both newly acquired preoperative and postoperative brain injuries are related to potentially modifiable clinical risk factors.

Invasive Procedures in Preterm Children: Brain and Cognitive Development at School Age

BACKGROUND: Very preterm infants (born 24–32 weeks’ gestation) undergo numerous invasive procedures during neonatal care. Repeated skin-breaking procedures in rodents cause neuronal cell death, and in human preterm neonates higher numbers of invasive procedures from birth to term-equivalent age are associated with abnormal brain development, even after controlling for other clinical risk factors. It is unknown whether higher numbers of invasive procedures are associated with long-term alterations in brain microstructure and cognitive outcome at school age in children born very preterm. METHODS: Fifty children born very preterm underwent MRI and cognitive testing at median age 7.6 years (interquartile range, 7.5–7.7). T1- and T2-weighted images were assessed for the severity of brain injury. Magnetic resonance diffusion tensor sequences were used to measure fractional anisotropy (FA), an index of white matter (WM) maturation, from 7 anatomically defined WM regions. Child cognition was assessed using the Wechsler Intelligence Scale for Children–IV. Multivariate modeling was used to examine relationships between invasive procedures, brain microstructure, and cognition, adjusting for clinical confounders (eg, infection, ventilation, brain injury). RESULTS: Greater numbers of invasive procedures were associated with lower FA values of the WM at age 7 years (P = .01). The interaction between the number of procedures and FA was associated with IQ (P = .02), such that greater numbers of invasive procedures and lower FA of the superior WM were related to lower IQ. CONCLUSIONS: Invasive procedures during neonatal care contribute to long-term abnormalities in WM microstructure and lower IQ.

Brain in Congenital Heart Disease Across the Lifespan: The Cumulative Burden of Injury

The number of patients surviving with congenital heart disease (CHD) has soared over the last 3 decades. Adults constitute the fastest-growing segment of the CHD population, now outnumbering children. Research to date on the heart-brain intersection in this population has been focused largely on neurodevelopmental outcomes in childhood and adolescence. Mutations in genes that are highly expressed in heart and brain may cause cerebral dysgenesis. Together with altered cerebral perfusion in utero, these factors are associated with abnormalities of brain structure and brain immaturity in a significant portion of neonates with critical CHD even before they undergo cardiac surgery. In infancy and childhood, the brain may be affected by risk factors related to heart disease itself or to its interventional treatments. As children with CHD become adults, they increasingly develop heart failure, atrial fibrillation, hypertension, diabetes mellitus, and coronary disease. These acquired cardiovascular comorbidities can be expected to have effects similar to those in the general population on cerebral blood flow, brain volumes, and dementia. In both children and adults, cardiovascular disease may have adverse effects on achievement, executive function, memory, language, social interactions, and quality of life. Against the backdrop of shifting demographics, risk factors for brain injury in the CHD population are cumulative and synergistic. As neurodevelopmental sequelae in children with CHD evolve to cognitive decline or dementia during adulthood, a growing population of CHD can be expected to require support services. We highlight evidence gaps and future research directions.

Parent behaviors moderate the relationship between neonatal pain and internalizing behaviors at 18 months corrected age in children born very prematurely

Summary Positive parent interaction and lower parenting stress may help to ameliorate the negative long‐term effects of neonatal pain on later stress‐sensitive behaviors in preterm children. ABSTRACT Children born very preterm (≤32 weeks gestation) exhibit greater internalizing (anxious/depressed) behaviors compared to term‐born peers as early as 2 years corrected age (CA); however, the role of early stress in the etiology of internalizing problems in preterm children remains unknown. Therefore, we examined the relationship between neonatal pain and internalizing behavior at 18 months CA in children born very preterm and examined whether parent behavior and stress moderated this relationship. Participants were 145 children (96 very preterm, 49 full term) assessed at 18 months CA. Neonatal data were obtained from medical and nursing chart review. Neonatal pain was defined as the number of skin‐breaking procedures. Cognitive ability was measured with the Bayley Scales of Infant Development II. Parents completed the Parenting Stress Index III, Child Behavior Checklist 1.5–5, and participated in a videotaped play session with their child, which was coded using the Emotional Availability Scale IV. Very preterm children displayed greater Internalizing behaviors compared to full‐term control children (P = .02). Parent Sensitivity and Nonhostility moderated the relationship between neonatal pain and Internalizing behavior (all P < .05); higher parent education (P < .03), lower Parenting Stress (P = .001), and fewer children in the home (P < .01) were associated with lower Internalizing behavior in very preterm children, after adjusting for neonatal medical confounders, gender, and child cognitive ability (all P > .05). Parent Emotional Availability and stress were not associated with Internalizing behaviors in full‐term control children. Positive parent interaction and lower stress appears to ameliorate negative effects of neonatal pain on stress‐sensitive behaviors in this vulnerable population.

Structural Network Analysis of Brain Development in Young Preterm Neonates

Preterm infants develop differently than those born at term and are at higher risk of brain pathology. Thus, an understanding of their development is of particular importance. Diffusion tensor imaging (DTI) of preterm infants offers a window into brain development at a very early age, an age at which that development is not yet fully understood. Recent works have used DTI to analyze structural connectome of the brain scans using network analysis. These studies have shown that, even from infancy, the brain exhibits small-world properties. Here we examine a cohort of 47 normal preterm neonates (i.e., without brain injury and with normal neurodevelopment at 18 months of age) scanned between 27 and 45 weeks post-menstrual age to further the understanding of how the structural connectome develops. We use full-brain tractography to find white matter tracts between the 90 cortical and sub-cortical regions defined in the University of North Carolina Chapel Hill neonatal atlas. We then analyze the resulting connectomes and explore the differences between weighting edges by tract count versus fractional anisotropy. We observe that the brain networks in preterm infants, much like infants born at term, show high efficiency and clustering measures across a range of network scales. Further, the development of many individual region-pair connections, particularly in the frontal and occipital lobes, is significantly correlated with age. Finally, we observe that the preterm infant connectome remains highly efficient yet becomes more clustered across this age range, leading to a significant increase in its small-world structure.