Toward multi-scale computational modeling in developmental disability research.

The field of theoretical neuroscience is gaining increasing recognition. Virtually all areas of neuroscience offer potential linkage points for computational work. In developmental neuroscience, main areas of research are neural development and connectivity, and connectionist modeling of cognitive development. In this paper, we suggest that computational models can be helpful tools for understanding the pathogenesis and consequences of perinatal brain damage and subsequent developmental disability. In particular, designing multi-scale computational models should be considered by developmental neuroscientists interested in helping reduce the risk for developmental disabilities.

Pregnancy disorders that lead to delivery before the 28th week of gestation: an epidemiologic approach to classification.

Epidemiologists have grouped the multiple disorders that lead to preterm delivery before the 28th week of gestation in a variety of ways. The authors sought to identify characteristics that would help guide how to classify disorders that lead to such preterm delivery. They enrolled 1,006 women who delivered a liveborn singleton infant of less than 28 weeks' gestation at 14 centers in the United States between 2002 and 2004. Each delivery was classified by presentation: preterm labor (40%), prelabor premature rupture of membranes (23%), preeclampsia (18%), placental abruption (11%), cervical incompetence (5%), and fetal indication/intrauterine growth restriction (3%). Using factor analysis (eigenvalue = 1.73) to compare characteristics identified by standardized interview, chart review, placental histology, and placental microbiology among the presentation groups, the authors found 2 broad patterns. One pattern, characterized by histologic chorioamnionitis and placental microbe recovery, was associated with preterm labor, prelabor premature rupture of membranes, placental abruption, and cervical insufficiency. The other, characterized by a paucity of organisms and inflammation but the presence of histologic features of dysfunctional placentation, was associated with preeclampsia and fetal indication/intrauterine growth restriction. Disorders leading to preterm delivery may be separated into two groups: those associated with intrauterine inflammation and those associated with aberrations of placentation.

Early postnatal illness severity scores predict neurodevelopmental impairments at 10 years of age in children born extremely preterm.

OBJECTIVE: A neonatal illness severity score, The Score for Neonatal Acute Physiology-II (SNAP-II), predicts neurodevelopmental impairments at two years of age among children born extremely preterm. We sought to evaluate to what extent SNAP-II is predictive of cognitive and other neurodevelopmental impairments at 10 years of age. STUDY DESIGN: In a cohort of 874 children born before 28 weeks of gestation, we prospectively collected clinical, physiologic and laboratory data to calculate SNAP-II for each infant. When the children were 10 years old, examiners who were unaware of the child's medical history assessed neurodevelopmental outcomes, including neurocognitive, gross motor, social and communication functions, diagnosis and treatment of seizures or attention deficit hyperactivity disorder (ADHD), academic achievement, and quality of life. We used logistic regression to adjust for potential confounders. RESULTS: An undesirably high SNAP-II (⩾30), present in 23% of participants, was associated with an increased risk of cognitive impairment (IQ, executive function, language ability), adverse neurological outcomes (epilepsy, impaired gross motor function), behavioral abnormalities (attention deficit disorder and hyperactivity), social dysfunction (autistic spectrum disorder) and education-related adversities (school achievement and need for educational supports. In analyses that adjusted for potential confounders, Z-scores ⩽-1 on 11 of 18 cognitive outcomes were associated with SNAP-II in the highest category, and 6 of 18 were associated with SNAP-II in the intermediate category. Odds ratios and 95% confidence intervals ranged from 1.4 (1.01, 2.1) to 2.1 (1.4, 3.1). Similarly, 2 of the 8 social dysfunctions were associated with SNAP-II in the highest category, and 3 of 8 were associated with SNAP-II in the intermediate category. Odds ratios and 95% confidence intervals were slightly higher for these assessments, ranging from 1.6 (1.1, 2.4) to 2.3 (1.2, 4.6). CONCLUSION: Among very preterm newborns, physiologic derangements present in the first 12 postnatal hours are associated with dysfunctions in several neurodevelopmental domains at 10 years of age. We are unable to make inferences about causality.

Do white cells matter in white matter damage?

Support is provided for the hypothesis that activated leukocytes, especially monocytes/macrophages, contribute to cerebral white matter damage in extremely low gestational age newborns. Much of the evidence is indirect and comes from analogies to brain diseases in adults, and from models of brain damage in adult and newborn animals. If the recruitment of circulating cells to the brain contributes to white matter damage in extremely low gestational age newborns, then minimizing the transendothelial migration of circulating cells by pharmacological manipulation might prevent or reduce the occurrence of neonatal white matter damage and the disabilities that follow.

Brain lesions in newborns exposed to high-dose magnesium sulfate during preterm labor.

High-dosage, tocolytic magnesium sulfate (MgSO4) administered to pregnant women during preterm labor can be toxic, and sometimes lethal, for their newborns (Cochrane Database of Systematic Reviews (relative mortality risk 2.82, 95% confidence interval 1.2-6.6)). Based on the results of the Magnesium and Neurologic Endpoints Trial and the work of many others, a unifying triangular concept is proposed to account for the increased prevalence of brain lesions, with their likely resultant mortality, in neonates and infants exposed to high-dose MgSO4 in the context of preterm labor. We review the evidence that: (1) elevated circulating levels of serum ionized magnesium occurring in mothers, and therefore in their babies, at the time of delivery are associated with subsequent neonatal intraventricular hemorrhage (IVH); (2) neonatal IVH is strongly associated with lenticulostriate vasculopathy (LSV), an unusual mineralizing lesion involving the thalami and basal ganglia of the neonate; and, (3) exposure to 50 g or more of tocolytic MgSO4 during preterm labor is associated with the development of LSV.

Population based study on the outcome of small for gestational age newborns.

OBJECTIVE: To explore whether and how population based data from a regional quality control programme can be used to investigate the hypothesis that small for gestational age (SGA) very low birthweight infants (VLBW, <1500 g) are at increased risk of death, severe intraventricular haemorrhage (IVH), and periventricular leucomalacia (PVL), but at decreased risk of respiratory distress syndrome (RDS). METHODS: Analyses of population based perinatal/neonatal data (1991-96) from a quality control programme in Lower Saxony, Germany. After assessment of data validity and representativeness, exclusion criteria were defined: birth weight >90th centile, severe malformations, siblings of multiple births, and gestational age (GA) <25 or >29 weeks. Outcomes of interest were death, severe IVH, PVL, and RDS. Multivariable analyses were performed by Cox proportional hazard and logistic regression models. RESULTS: Within the data validation procedure, an increase in proportions of both VLBW (from 0.95% in 1991 to 1.11% in 1996; +17%) and SGA (from 22.7% to 27.4%; +21%) infants became apparent (p<0.05). The study population consisted of 1623 infants (173 SGA). Mortality was 12.1% (n = 196), with an adjusted hazard ratio for SGA infants of 2.54, 95% confidence interval (CI) 1.70 to 3.79. Both groups were at similar risk of severe IVH (adjusted odds ratio 0.93, 95% CI 0.5 to 1.65) and PVL (1.54, 95% CI 0.78 to 2.87), but SGA infants had less RDS (0.57, 95% CI 0.35 to 0.93). Male sex, multiple birth, hypothermia (<35.5 degrees C), and sepsis were associated with IVH and RDS. Infants admitted to hospitals with <36 VLBW admissions/year had increased mortality (adjusted hazard ratio 1.56, 95% CI 1.12 to 2.18). CONCLUSIONS: SGA VLBW infants are at increased risk of death, but not of IVH and PVL, and at decreased risk of RDS. That mortality is higher in smaller hospitals needs further investigation.

Association of morphological characteristics with precocious puberty and/or gelastic seizures in hypothalamic hamartoma.

The pathogenesis of central precocious puberty (PP) and/or gelastic seizures due to a hypothalamic hamartoma (HH) is still under debate. We evaluated the association of clinical symptoms with morphology and localization of the HH in 34 patients. The majority (86.4%) of HHs in patients with isolated PP (n = 22; 68.2% females) revealed a parahypothalamic position without affecting the third ventricle (91%). Half of them were pedunculated, and 40.9% showed a diameter less than 10 mm. In contrast, 11 of 12 patients with seizures, eight of whom were male, presented with a sessile intrahypothalamic hamartoma, 10 of which distorted the third ventricle. Logistic regression analysis revealed an increased relative risk (RR) for epilepsy in males (RR, 4.3; 95% confidence interval, 0.96-19). However, combination of the risk factor gender with intrahypothalamic position (RR, 19; 1.3-285) and distortion of the third ventricle (RR, 10; 0.6-164) reduced the risk associated with male gender to 1.1. The position of a HH and involvement of the third ventricle are likely to be more predictive for clinical characteristics than size and shape. Male gender was associated with an intrahypothalamic HH and epilepsy, suggesting a sexually dimorphic developmental pattern of this heterotopic mass.

Brain damage in preterm newborns: might enhancement of developmentally regulated endogenous protection open a door for prevention?

We present a two-component model of brain white matter damage in preterm neonates. The insult component comprises infection and hypoxia-ischemia, which are both associated with inflammation-related abnormalities in the white matter. The developmental component comprises at least three factors, ie, immaturity of the ependymal/endothelial, oligodendroglial, and endogenous protection systems. All three factors are likely contributors to an increased vulnerability of the preterm newborn's white matter. In this article, we focus on recent developments in oligodendrocyte biology that support the view of certain cytokines and growth factors as oligotrophins based on their capability to enhance oligodendrocyte development or survival. We suggest that research into networks of developmentally regulated endogenous protectors (such as oligotrophins) is necessary to broaden our perspectives in brain injury prevention in preterm newborns.

Fetal vasculitis in preterm newborns: interrelationships, modifiers, and antecedents.

Histologic expressions of the fetal inflammatory response predict preterm delivery and neonatal disorders. We examined 1146 placentas in the Developmental Epidemiology Network data set for histologic evidence of membrane inflammation (subchorionitis, chorionitis, and chorioamnionitis) and fetal vasculitis (acute umbilical vasculitis or chorionic vasculitis). Our main findings are that (1) in the presence of membrane inflammation, fetal vasculitis is common, (2) duration of membrane rupture and gestational age appear to modify the risk of fetal vasculitis, (3) this risk modification differs for the different components of fetal vasculitis, i.e. umbilical and chorionic vasculitis, and (4) antecedents can be identified that appear to increase or decrease the risk of fetal vasculitis among births with membrane inflammation. We conclude that fetal vasculitis, the morphologic component of the fetal inflammatory response, might not be a homogeneous entity and deserves further study.

Decreasing melatonin and 6-hydroxymelatonin sulfate excretion with advancing gestational age in preterm and term newborn male infants.

We investigated the ontogeny of melatonin synthesis during fetal maturation by measuring the melatonin (MLT) and 6-hydroxymelatonin sulfate (MLTS) excretion in the urine of male infants aged 2-7 days and gestational age 26-42 weeks. We found a negative correlation between advancing gestational age and the MLT and MLTS excretion expressed as total 24-h amount, ratio of 24-h amount to creatinine and ratio of 24-h amount to body surface area. The ratio of MLT to MLTS was found to be about ten times higher in the study group than in prepubertal children, which might reflect the immaturity of hepatic sulfation capacities. The total amount of excreted MLT and MLTS was only one-tenth the prepubertal values. No day/night differences in MLT and MLTS excretion could be detected. We conclude that the fetal pineal gland is capable of a limited melatonin synthesis from the 26th week of gestation onwards, with decreasing values reaching its nadir around term. This indicates that the amount of fetal MLT excretion is not determined by synthesizing capacities of the pineal gland but by the development of neural connections to the pineal gland.

Symptom-limited stair climbing as a predictor of postoperative cardiopulmonary complications after high-risk surgery.

STUDY OBJECTIVE: Thoracotomy, sternotomy, and upper abdominal laparotomy are associated with high rate of postoperative cardiopulmonary complications (POCs). We hypothesized that symptom-limited stair climbing predicts POCs after high-risk surgery. DESIGN: A prospective evaluation of 83 patients undergoing thoracotomy, sternotomy, and upper abdominal laparotomy surgery. METHODS: The 52 men and 31 women completed symptom-limited stair climbing. A separate investigator, blinded to the number of flights of stairs climbed, assessed 30-day actual outcomes for POCs, including pneumonia, atelectasis, mechanical ventilation for > 48 h, reintubation, myocardial infarction, congestive heart failure, arrhythmia, pulmonary embolus, and death within 30 days of surgery. The operations performed included 31 lobectomies, 6 wedge resections, 3 pneumonectomies, 3 substernal thymectomies, 1 substernal thyroidectomy, 23 colectomies, 3 laparotomies, 7 abdominal aortic aneurysm repairs, 5 esophagogastrectomies, and 1 nephrectomy. RESULTS: POCs occurred in 21 of 83 patients (25%) overall, in 9 of 44 patients undergoing thoracotomy/sternotomy (20%), and in 12 of 39 patients undergoing upper abdominal laparotomy (31%). Of those unable to climb one flight of stairs, 89% developed a POC. No patient able to climb the maximum of seven flights of stairs had a POC. The inability to climb two flights of stairs was associated with a positive predictive value of 82% for the development of a POC. The number of days in the hospital postoperatively decreased with a patient's increased ability to climb stairs. CONCLUSIONS: Symptom-limited stair climbing offers a simple, inexpensive means to predict POCs after high-risk surgery.

Hypothalamic hamartomas: with special reference to gelastic epilepsy and surgery.

This study presents six patients with hypothalamic hamartomas diagnosed on the basis of magnetic resonance imaging. Histological confirmation was performed in three patients who underwent surgery. Immunohistological assays were used to determine the neurosecretory pattern. Four patients presented with epilepsy, including gelastic seizures. Other symptoms included behavioral abnormalities in four patients and precocious puberty and visual impairment in two patients. One patient presented associated developmental defects. Good results without morbidity were achieved with surgical resectioning in two patients with large hamartomas associated with behavioral abnormalities and gelastic epilepsy that was unresponsive to conventional medical treatment and in one patient with visual impairment. We propose a classification of the hypothalamic hamartomas based on topographical and clinical data obtained from 36 selected cases in the literature and six of our own cases. This classification should help to classify the various treatment methods and the surgical risks into four subgroups (Types la, lb, lla, and llb). We conclude that the surgical approach is a realistic alternative in certain cases, including large and broad-based Type llb hamartomas associated with gelastic epilepsy and behavioral disorders.

Topography of cerebral white-matter disease of prematurity studied prospectively in 1607 very-low-birthweight infants.

The objective of this study was to evaluate to what extent (1) the characteristics of localization, distribution, and size of echodense and echolucent abnormalities enable individuals to be designated as having either periventricular hemorrhagic infarction or periventricular leukomalacia and (2) the characteristics of periventricular hemorrhagic infarction and periventricular leukomalacia are independent occurrences. The population for this study consisted of 1607 infants with birthweights of 500 to 1500 g, born between January 1991 and December 1993, who had at least one cranial ultrasound scan read independently by at least two ultrasonographers. The ultrasound data collection form diagrammed six standard coronal views. The cerebrum was divided into 17 zones in each hemisphere. All abnormalities were described as being echodense or echolucent and were classified on the basis of their size, laterality, location, and evolution. Eight percent (134/1607) of infants had at least one white-matter abnormality. The prevalence of white-matter disease decreased with increasing gestational age. Most abnormalities were small or medium sized and unilateral; only large echodensities tended to be bilateral and asymmetric. Large abnormalities, whether echodense or echolucent, were more likely than smaller abnormalities to be widespread, and the extent of cerebral involvement was independent of whether abnormalities were unilateral or bilateral. Large abnormalities were relatively more likely than small abnormalities to involve anterior planes. Small abnormalities, whether echodense or echolucent, or whether unilateral or bilateral, preferentially occurred near the trigone. Using the characteristics of location, size, and laterality/symmetry, we were able to allocate only 53% of infants with white-matter abnormalities to periventricular hemorrhagic infarction or periventricular leukomalacia. Assuming that periventricular leukomalacia and periventricular hemorrhagic infarction are independent and do not share risk factors, and that each occurs in approximately 5% of infants, we would have expected 0.25%, or about 4 individuals, to have abnormalities with characteristics of both periventricular leukomalacia and periventricular hemorrhagic infarction, whereas we found 63 such infants. Most infants with white-matter disease could not be clearly designated as having periventricular hemorrhagic infarction or periventricular leukomalacia only. Periventricular hemorrhagic infarction contributes to the risk of periventricular leukomalacia occurrence, or the two sorts of abnormalities share common risk antecedent factors. The descriptive term echodense or echolucent and the generic term white-matter disease of prematurity should be used instead of periventricular leukomalacia or periventricular hemorrhagic infarction when referring to sonographically defined white-matter abnormalities.

Infection remote from the brain, neonatal white matter damage, and cerebral palsy in the preterm infant.

This review synthesizes the literature supporting the hypothesis that infection during or even before pregnancy remote from the fetal brain leads to neonatal white matter damage (NWMD) and its long-term sequelae, including cerebral palsy. First, a framework of five dimensions is presented, including the spectrum of NWMD, its relationship with gestational age, its clinical spectrum, the expressions and correlates of infection, and the mother/child dyad. Second, a summary of the plethora of support for the remote infection/NWMD-hypothesis is presented by drawing on studies published over the past three decades. Although an epidemiological perspective is prominent, we invoke molecular explanations (especially the cytokine hypothesis) for observed associations. Third, the article concludes with a section on future studies needed to characterize and eliminate (pre-) pregnancy infections in the mother and to identify and evaluate potentially neuroprotective strategies in the fetus.

Fetal growth restriction is not associated with a reduced risk for bilateral spastic cerebral palsy in very-low-birthweight infants.

OBJECTIVE: To evaluate the influence of confounding and sampling bias on the relationship between fetal growth restriction in a very-low-birthweight-defined cohort (VLBW, < or =1500 g) and bilateral spastic cerebral palsy (BSCP) at early school-age. METHODS: Three hundred twenty-four of 407 long-term survivors of a regional cohort of VLBW newborns were followed until age 6 years. We categorized as small for gestational age (SGA) all infants whose birthweight Z-score was below -2 relative to published reference values. Uni- and multivariable logistic regression models were fit to estimate the risk of BSCP associated with SGA in the total sample, in subsamples defined by gestational age, and in a gestational age-matched case-control sample. RESULTS: In the total sample, no child below 28 weeks was SGA, and no child above 32 weeks had an appropriate birthweight for gestational age (AGA). The prevalence of BSCP was 14% in AGA and 2% in SGA infants. In both uni- and multivariable logistic regression analyses of the total sample, SGA was associated with a prominently reduced risk of BSCP (odds ratios range from 0.1 to 0.2, all 95% confidence limits exclude 1.0). However, analyses performed in samples defined by different gestational age cutoffs (24--31 weeks, 28--31 weeks) and in a sample using three gestational age-matched controls per BSCP-case did not show a protection by growth restriction (odds ratios range from 0.8 to 2.2, all 95% confidence limits include 1.0). CONCLUSIONS: In VLBW-defined samples, the apparent protective effect of SGA for BSCP can be explained, at least in part, by the highly skewed distribution of SGA over the available gestational age range. From this follows that study cohorts should be defined by gestational age and not by birthweight. In distorted samples like this one, even controlling for gestational age does not reduce the illusion of a reduced cerebral palsy risk for growth restricted infants. Only restriction of the sample by gestational age and/or matching for gestational age reveals the absence of this apparent protective effect.

Antecedents of cerebral palsy in very low-birth weight infants.

Research from the last two decades provides directions for efforts to prevent CP in VLBW infants. The pathogenesis of CP seems to involve factors operating both during pregnancy and in the neonatal period. The most important prenatal factor appears to be intrauterine infection. Perinatal infection and other risk factors, such as the death of a co-twin, placental abruption, and cerebral ischemia, could trigger a cytokine cascade resulting in damage to the developing brain. The low frequency of intrauterine infection in mothers with preeclampsia might explain the apparent protective effect of this disorder. If the brain damage attributed to intrauterine infection and other risk factors involves cytokines as intermediates, then blockade of the proinflammatory cascade or promotion of endogenous inhibitors might prevent CP. Other potentially preventive strategies include corticosteroids given to mothers (but not those given to neonates) and thyroid hormone.

Possible strategies to protect the preterm brain against the fetal inflammatory response.

The accruing evidence that a fetal inflammatory response is the link between antenatal infection and white matter damage in the preterm newborn infant offers room for speculation how this harmful sequence could be interrupted. Enhancement of endogenous protection, response modification, and damage limitation downstream could be helpful strategies for intervention design. Appropriate observational and experimental studies are needed before clinical interventions can be initiated.

Systems Epidemiology: What's in a Name?

Systems biology is an interdisciplinary effort to integrate molecular, cellular, tissue, organ, and organism levels of function into computational models that facilitate the identification of general principles. Systems medicine adds a disease focus. Systems epidemiology adds yet another level consisting of antecedents that might contribute to the disease process in populations. In etiologic and prevention research, systems-type thinking about multiple levels of causation will allow epidemiologists to identify contributors to disease at multiple levels as well as their interactions. In public health, systems epidemiology will contribute to the improvement of syndromic surveillance methods. We encourage the creation of computational simulation models that integrate information about disease etiology, pathogenetic data, and the expertise of investigators from different disciplines.

Early postnatal hypotension is not associated with indicators of white matter damage or cerebral palsy in extremely low gestational age newborns.

OBJECTIVE: To evaluate, in extremely low gestational age newborns (ELGANs), relationships between indicators of early postnatal hypotension and cranial ultrasound indicators of cerebral white matter damage imaged in the nursery and cerebral palsy diagnoses at 24 months follow-up. STUDY DESIGN: The 1041 infants in this prospective study were born at <28 weeks gestation, were assessed for three indicators of hypotension in the first 24 postnatal hours, had at least one set of protocol cranial ultrasound scans and were evaluated with a structured neurological exam at 24 months corrected age. Indicators of hypotension included: (1) lowest mean arterial pressure (MAP) in the lowest quartile for gestational age; (2) treatment with a vasopressor; and (3) blood pressure lability, defined as the upper quartile of the difference between each infant's lowest and highest MAP. Outcomes included indicators of cerebral white matter damage, that is, moderate/severe ventriculomegaly or an echolucent lesion on cranial ultrasound and cerebral palsy diagnoses at 24 months gestation. Logistic regression was used to evaluate relationships among hypotension indicators and outcomes, adjusting for potential confounders. RESULT: Twenty-one percent of surviving infants had a lowest blood pressure in the lowest quartile for gestational age, 24% were treated with vasopressors and 24% had labile blood pressure. Among infants with these hypotension indicators, 10% percent developed ventriculomegaly and 7% developed an echolucent lesion. At 24 months follow-up, 6% had developed quadriparesis, 4% diparesis and 2% hemiparesis. After adjusting for confounders, we found no association between indicators of hypotension, and indicators of cerebral white matter damage or a cerebral palsy diagnosis. CONCLUSION: The absence of an association between indicators of hypotension and cerebral white matter damage and or cerebral palsy suggests that early hypotension may not be important in the pathogenesis of brain injury in ELGANs.