We report the dynamic anatomical sequence of human cortical gray matter development between the age of 4 -21 years using quantitative four-dimensional maps and time-lapse sequences. Thirteen healthy children for whom anatomic brain MRI scans were obtained every 2 years, for 8 -10 years, were studied. By using models of the cortical surface and sulcal landmarks and a statistical model for gray matter density, human cortical development could be visualized across the age range in a spatiotemporally detailed time-lapse sequence. The resulting time-lapse ''movies'' reveal that (i) higher-order association cortices mature only after lower-order somatosensory and visual cortices, the functions of which they integrate, are developed, and (ii) phylogenetically older brain areas mature earlier than newer ones. Direct comparison with normal cortical development may help understanding of some neurodevelopmental disorders such as childhood-onset schizophrenia or autism.H uman brain development is structurally and functionally a nonlinear process (1-3), and understanding normal brain maturation is essential for understanding neurodevelopmental disorders (4, 5). The heteromodal nature of cognitive brain development is evident from studies of neurocognitive performance (6, 7), functional imaging (functional MRI or positronemission tomography) (8-10), and electroencephalogram coherence studies (1, 2, 10). Prior imaging studies show regional nonlinear changes in gray matter (GM) density during childhood and adolescence with prepubertal increase followed by postpubertal loss (11)(12)(13)(14). The GM density on MRI is an indirect measure of a complex architecture of glia, vasculature, and neurons with dendritic and synaptic processes. Studies of GM maturation show a loss in cortical GM density over time (15,16), which temporally correlates with postmortem findings of increased synaptic pruning during adolescence and early adulthood (17-19). Here we present a study of cortical GM development in children and adolescents by using a brain-mapping technique and a prospectively studied sample of 13 healthy children (4-21 years old), who were scanned with MRI every 2 years for 8-10 years. Because the scans were obtained repeatedly on the same subjects over time, statistical extrapolation of points in between scans enabled construction of an animated time-lapse sequence (''movie'') of pediatric brain development. We hypothesized that GM development in childhood through early adulthood would be nonlinear as described before and would progress in a localized, region-specific manner coinciding with the functional maturation. We also predicted that the regions associated with more primary functions (e.g., primary motor cortex) would develop earlier compared with the regions that are involved with more complex and integrative tasks (e.g., temporal lobe).The result is a dynamic map of GM maturation in the pre-and postpubertal period. Our results, while highlighting the remarkable heterogeneity, show that the cortical GM development appears to f...

Objective To assess the utility of clinical predictors of persistent respiratory morbidity in extremely low gestational age newborns (ELGAN). Study Design We enrolled ELGAN (<29 weeks’ gestation) at ≤7 postnatal days and collected antenatal and neonatal clinical data through 36 weeks’ post-menstrual age. We surveyed caregivers at 3, 6, 9 and 12 months corrected age to identify post-discharge respiratory morbidity, defined as hospitalization, home support (oxygen, tracheotomy, ventilation), medications, or symptoms (cough/wheeze). Infants were classified as post-prematurity respiratory disease (PRD, the primary study outcome), if respiratory morbidity persisted over ≥2 questionnaires. Infants were classified with severe respiratory morbidity if there were multiple hospitalizations, exposure to systemic steroids or pulmonary vasodilators, home oxygen after 3 months or mechanical ventilation, or symptoms despite inhaled corticosteroids. Mixed effects models generated with data available at one day (perinatal) and 36 weeks’ postmenstrual age were assessed for predictive accuracy. Results Of 724 infants (918±234g, 26.7±1.4 weeks’ gestational age) classified for the primary outcome, 68.6% had PRD; 245/704 (34.8%) were classified as severe. Male sex, intrauterine growth restriction, maternal smoking, race/ethnicity, intubation at birth, and public insurance were retained in perinatal and 36-week models for both PRD and respiratory morbidity severity. The perinatal model accurately predicted PRD (c-statistic 0.858). Neither the 36-week model nor the addition of bronchopulmonary dysplasia (BPD) to the perinatal model improved accuracy (0.856, 0.860); c-statistic for BPD-alone was 0.907. Conclusion Both BPD and perinatal clinical data accurately identify ELGAN at risk for persistent and severe respiratory morbidity at one year. Trial registration ClinicalTrials.gov: NCT01435187

Introduction: We sought to determine the relationship between the degree of stomach herniation by antenatal sonography and neonatal outcomes in fetuses with isolated left-sided congenital diaphragmatic hernia (CDH). Materials and Methods: We retrospectively reviewed neonatal medical records and antenatal sonography of fetuses with isolated left CDH cared for at a single institution (2000-2012). Fetal stomach position was classified on sonography as follows: intra-abdominal, anterior left chest, mid-to-posterior left chest, or retrocardiac (right chest). Results: Ninety fetuses were included with 70% surviving to neonatal discharge. Stomach position was intra-abdominal in 14% (n = 13), anterior left chest in 19% (n = 17), mid-to-posterior left chest in 41% (n = 37), and retrocardiac in 26% (n = 23). Increasingly abnormal stomach position was linearly associated with an increased odds of death (OR 4.8, 95% CI 2.1-10.9), extracorporeal membrane oxygenation (ECMO; OR 5.6, 95% CI 1.9-16.7), nonprimary diaphragmatic repair (OR 2.7, 95% CI 1.4-5.5), prolonged mechanical ventilation (OR 5.9, 95% CI 2.3-15.6), and prolonged respiratory support (OR 4.0, 95% CI 1.6-9.9).All fetuses with intra-abdominal stomach position survived without substantial respiratory morbidity or need for ECMO. Discussion: Fetal stomach position is strongly associated with neonatal outcomes in isolated left CDH. This objective tool may allow for accurate prognostication in a variety of clinical settings.

Objectives To describe the natural history of pulmonary hypertension (PH) and the risk of death and pulmonary morbidity associated with the persistence of PH through the neonatal hospitalization for these infants. Study design We performed a retrospective cohort study of infants with CDH cared for at UCSF (2002-12). Infants with other major anomalies or syndromes were excluded (n=43). Clinical echocardiograms were performed weekly for up to 6 weeks or until PH resolved off respiratory support or until hospital discharge. Echocardiograms were re-read by a blinded reviewer and categorized by severity of elevation in estimated pulmonary arterial pressure. PH was defined as ≥2/3 systemic blood pressure. Severity was determined by a hierarchy of ductus arteriosus level shunt, interventricular septal position, and tricuspid regurgitant jet velocity. Results Of 140 infants with ≥1 echo, 98 resolved their PH prior to death/discharge. Mean time to resolution was 18d (median 14d, IQR 8, 21d). Those with persistence of PH had a higher rate of ECMO (p<0.001) and death (p<0.001), and fewer ventilator-free days (p<0.001). Persistence of PH at 14d predicted mortality (AUC 0.87) and adverse respiratory outcomes (AUC 0.80-0.83). Conclusions The majority of infants with congenital diaphragmatic hernia (CDH) resolve PH between 1 and 3 weeks of life. At 2 weeks of age, severity of PH by echocardiogram strongly predicts short-term pulmonary morbidity and death. Further evaluation of physiological alterations during that time may lead to novel therapies for severe CDH.