Raymond I. Stark

Cerebral palsy and mental retardation in relation to indicators of perinatal asphyxia. An epidemiologic overview

Although intrapartum asphyxia is established as an important cause of perinatal loss, there is little consensus as to how much of the burden of neurologic handicap in the community is attributable to intrapartum and neonatal asphyxia, as measured clinically. A review of the available epidemiologic information suggests that the role of perinatal events in the genesis of severe mental retardation and cerebral palsy is not as large as popularly thought. Of all neurologic handicaps, cerebral palsy bears the closest relationship to adverse perinatal events, but at least 50% of all cases have no documented depression at the time of birth. No more than 15% of severe mental retardation can be attributed to perinatal events. Severe mental retardation without cerebral palsy does not appear to be attributable to birth asphyxia. The majority of even quite severely asphyxiated babies suffer no detectable neurologic or intellectual sequelae. These epidemiologic observations suggest that resuscitative efforts in mature newborn infants ought not to be too quickly abandoned for fear of late sequelae. At the same time, obstetric intervention based solely on concern for later neurologic development cannot be justified. The most appropriate justification for antenatal and intrapartum monitoring of fetal condition are the established associations of indicators of fetal asphyxia with fetal and neonatal death, and with morbidity in the neonatal period.

Brain injury and neurofunctional deficit in neonatal mice with hypoxic-ischemic encephalopathy

Birth asphyxia accounts for the majority of developmental motor and cognitive deficits. Studies were undertaken to develop a reproducible murine model of perinatal hypoxic-ischemic encephalopathy (HIE) which would permit both anatomic and neurofunctional quantification of injury. Short-term neurofunctional outcomes consisted of three developmental reflexes (righting, cliff aversion and geotaxis) assessed in 7-day-old mouse pups 24 h after unilateral carotid artery ligation followed by inhalation of 8% oxygen. Cerebral infarct volume was dependent on duration of hypoxia, being approximately 2.5-fold greater with longer (60 min) versus shorter (30 min) hypoxia exposure (P=0.001). All three sensorimotor neonatal reflexes assessed at 24 h after HIE injury correlated significantly with long-term neurofunction evaluated using a water-maze test of navigational learning and memory assessed 8 weeks later in the same animals. Cerebral atrophy, a delayed consequence of HIE in this model, also correlated strongly with water-maze performance (r=0.86, P=0.002). These data demonstrate for the first time that murine neonatal sensorimotor reflex performance can be rigorously quantified in the acute phase of perinatal HIE and has strong predictive value not only for anatomic extent of cerebral injury, but also for long-term neurofunctional outcome.

Concentrations of corticotrophin-releasing hormone in the umbilical-cord blood of pregnancies complicated by pre-eclampsia

The effect of pre-eclampsia on concentrations of corticotrophin releasing hormone (CRH) in umbilical-cord blood of fetuses at delivery was studied in order to determine if fetal CRH is elevated in this disorder when compared with uncomplicated pregnancy. Placental CRH may be a regulator of fetal pituitary-adrenal function and we therefore also measured ACTH, cortisol and dehydroepiandrosterone sulfate (DHEAS) in the umbilical-cord blood. The mean umbilical-cord plasma CRH in the fetuses from pregnancies complicated by pre-eclampsia, 667 +/- 153 pg mL-1, was significantly higher than the plasma CRH in the fetuses from normotensive pregnancies, 185 +/- 22 pg mL-1 (P < 0.001). The mean fetal cortisol concentration was significantly higher in pre-eclampsia, than in the normotensive, pregnancies (pre-eclampsia, 13.5 +/- 1.8; normotensive, 7.6 +/- 1.3 micrograms dL-1; P < 0.001). Plasma DHEAS was 217 +/- 23 micrograms dL-1 in the umbilical-cord blood of the fetuses from pregnancies complicated by pre-eclampsia and 281 +/- 35 micrograms dL-1 in the normotensive pregnancies (P < 0.01). Placental CRH synthesis and release, in contrast to hypothalamic CRH, appears to be stimulated by glucocorticoids. In pregnancies complicated by uteroplacental insufficiency, as may occur in pre-eclampsia, placental CRH production may be enhanced by increased fetal glucocorticoids. In turn, placental CRH may modulate fetal pituitary-adrenal steroidogenesis to favour increased cortisol secretion. Thus, placental CRH may play an important role in the fetal response to a compromised intrauterine environment.

Late Measures of Brain Injury After Neonatal Hypoxia–Ischemia in Mice

Background and Purpose— This work was undertaken to determine to what degree long-term neurofunctional outcome of neonatal hypoxic–ischemic (HI) brain injury in mice correlates with anatomical extent of cerebral damage assessed by magnetic resonance imaging (MRI) and histopathology. Methods— On postnatal day 7, mice were subjected to HI. At 7 to 9 weeks after HI neurofunctional outcome was assessed by water-maze, rota-rod, and open-field test performance, followed by cerebral MRI and histopathology evaluation. Results— At 10 weeks after HI, MRI revealed ipsilateral brain atrophy alone or with porencephalic cyst formation and contralateral ventriculomegaly. Adult HI-affected mice, especially those that developed a porencephalic cyst, demonstrated significant neurofunctional deficit compared with age-matched naïve mice. HI-affected mice with ipsilateral cerebral atrophy but without porencephaly demonstrated no or an intermediate level of neurofunctional deficit. Neurobehavioral assessment of mice subjected to HI insult revealed a strong correlation between degree of brain injury and functional neurohandicap. Conclusions— This is the first study to demonstrate that long-term neurofunctional outcome in mice after a neonatal HI correlates tightly with anatomical pattern/extent of cerebral damage, defined by MRI and histopathology.

Prenatal nicotine-exposure alters fetal autonomic activity and medullary neurotransmitter receptors: implications for sudden infant death syndrome

During pregnancy, exposure to nicotine and other compounds in cigarette smoke increases the risk of the sudden infant death syndrome (SIDS) two- to fivefold. Serotonergic (5-HT) abnormalities are found, in infants who die of SIDS, in regions of the medulla oblongata known to modulate cardiorespiratory function. Using a baboon model, we tested the hypothesis that prenatal exposure to nicotine alters 5-HT receptor and/or transporter binding in the fetal medullary 5-HT system in association with cardiorespiratory dysfunction. At 87 (mean) days gestation (dg), mothers were continuously infused with saline (n = 5) or nicotine (n = 5) at 0.5 mg/h. Fetuses were surgically instrumented at 129 dg for cardiorespiratory monitoring. Cesarean section delivery and retrieval of fetal medulla were performed at 161 (mean) dg for autoradiographic analyses of nicotinic and 5-HT receptor and transporter binding. In nicotine-exposed fetuses, high-frequency heart rate variability was increased 55%, possibly reflecting increases in the parasympathetic control of heart rate. This effect was more pronounced with greater levels of fetal breathing and age. These changes in heart rate variability were associated with increased 5-HT(1A) receptor binding in the raphé obscurus (P = 0.04) and increased nicotinic receptor binding in the raphé obscurus and vagal complex (P < 0.05) in the nicotine-exposed animals compared with controls (n = 6). The shift in autonomic balance in the fetal primate toward parasympathetic predominance with chronic exposure to nicotine may be related, in part, to abnormal 5-HT-nicotine alterations in the raphé obscurus. Thus increased risk for SIDS due to maternal smoking may be partly related to the effects of nicotine on 5-HT and/or nicotinic receptors.

Reduced functional connectivity in visual evoked potentials in children with autism spectrum disorder

OBJECTIVE An analysis of EEG synchrony between homologous early visual areas tested the hypothesis that interhemispheric functional connectivity during visual stimulation is reduced in children with autism compared to controls. METHODS EEG power and coherence within and between two homologous regions of the occipital cortex were measured during long latency flash visual evoked potentials. Measures were compared between two groups of children (5.5-8.5years), one with autism spectrum disorders and the other with typical development. RESULTS In and below the theta band, interhemispheric synchrony was reduced in autistic subjects compared to typical controls by as much as 50%. Above the theta band interhemispheric synchrony in autistic children became indistinguishable from what would occur for uncorrelated cortical activity. Interhemispheric synchrony in autistic subjects was decreased in spite of bilaterally increased power. Wavelet power showed autistic children had a more rapid initial response to stimulation, a slower recovery, and more modulation at longer latencies. CONCLUSIONS Results suggest that the sensory cortices of autistic children are hypersensitive to stimulation with concurrent diminished functional connectivity between hemispheres. SIGNIFICANCE Simultaneously increased intrahemispheric power and decreased interhemispheric synchronization of elementalvisual information suggests either that power increases cause poor interhemispheric connectivity or that processes, such as thalamocortical regulation, impact power and coherence independently.

Complement component C1q mediates mitochondria-driven oxidative stress in neonatal hypoxic-ischemic brain injury

Hypoxic–ischemic (HI) brain injury in infants is a leading cause of lifelong disability. We report a novel pathway mediating oxidative brain injury after hypoxia–ischemia in which C1q plays a central role. Neonatal mice incapable of classical or terminal complement activation because of C1q or C6 deficiency or pharmacologically inhibited assembly of membrane attack complex were subjected to hypoxia–ischemia. Only C1q−/− mice exhibited neuroprotection coupled with attenuated oxidative brain injury. This was associated with reduced production of reactive oxygen species (ROS) in C1q−/− brain mitochondria and preserved activity of the respiratory chain. Compared with C1q+/+ neurons, cortical C1q−/− neurons exhibited resistance to oxygen–glucose deprivation. However, postischemic exposure to exogenous C1q increased both mitochondrial ROS production and mortality of C1q−/− neurons. This C1q toxicity was abolished by coexposure to antioxidant Trolox (6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid). Thus, the C1q component of complement, accelerating mitochondrial ROS emission, exacerbates oxidative injury in the developing HI brain. The terminal complement complex is activated in the HI neonatal brain but appeared to be nonpathogenic. These findings have important implications for design of the proper therapeutic interventions against HI neonatal brain injury by highlighting a pathogenic priority of C1q-mediated mitochondrial oxidative stress over the C1q deposition-triggered terminal complement activation.

Spatial correlation of the infant and adult electroencephalogram

OBJECTIVE To examine the effects of volume conduction of current on measurements of spatial correlation in the high-density electroencephalogram (EEG) at extremes of human development: infancy and adulthood. METHODS To calculate theoretical spatial correlation of EEG from volume conduction of uncorrelated cortical sources and compare theory with observations of intra/interhemispheric coherence. RESULTS Result verified prediction of reduced spatial correlation in infants due to volume conduction. Theoretical magnitude of spatial correlation from volume conduction demonstrated as lower bound on observed magnitude of coherence (MC). MC of adults is greater than MC of infants. Adult intrahemispheric MC is greater than interhemispheric MC. Scalp muscle electromyogram (EMG) produces artifactually low values of MC. CONCLUSIONS Volume conduction of current from uncorrelated cortical sources produces an erroneous component of spatial correlation that is smaller in infants than adults. The increased MC in adults is indicative of increased adult neuronal myelination. EMG artifact causes erroneous observations of coherence. SIGNIFICANCE Measured EEG spatial correlation contains contributions from both neural activity and volume conduction of current. This is an important issue when measurements are used to deduce physiological correlates of neuropsychological phenomena. Measurements of the neural component of spatial correlation are more accurate early in life because of reduced volume conduction.

C1q-Deficiency Is Neuroprotective Against Hypoxic-Ischemic Brain Injury in Neonatal Mice

Background and Purpose— This study was undertaken to determine whether the initial component of the classical complement (C) activation pathway contributes to hypoxic-ischemic brain injury in neonatal mice. Methods— Hypoxia-ischemia (HI) was produced in C1q−/− and wild-type (WT) neonatal mice. At 24 hours after HI, neonatal mouse reflex performance and cerebral infarct volume were assessed. Long-term outcomes were measured by water-maze performance and degree of cerebral atrophy at 7 to 8 weeks after HI. Activation of circulating neutrophils, and C1q, C3, and neutrophil deposition in brains were examined. Results— C1q−/− mice were significantly protected against HI (mean±SE infarct volume in C1q−/− mice=17.3±5.5% versus 53.6±6.8% in WT mice; P<0.0001) and exhibited significantly less neurofunctional deficit compared with WT mice. Immunostaining revealed significantly greater deposition of C3 (and C1q) as well as granulocytes in the infarcted brains in WT mice compared with C1q−/− animals. Activation of circulating leukocytes was significantly decreased in C1q−/− mice compared with WT mice, which correlated strongly (r=0.7) with cerebral infarct volumes. Conclusions— Cerebral deposition of C1q and C3 after hypoxic-ischemic insult is associated with significantly greater neurologic damage in WT mice compared with C1q−/− mice, providing strong evidence that the classical C pathway contributes to the hypoxic-ischemic brain injury. Significantly decreased activation of circulating neutrophils associated with diminished local accumulation and attenuation of brain injury in C1q−/− mice suggests a potential cellular mechanism by which C1q mediates neurodegeneration in HI.

Vasopressin secretion induced by hypoxia in sheep: Developmental changes and relationship to β-endorphin release☆☆☆

To investigate the developmental changes in the secretion of vasopressin and the potential role of beta-endorphin as a stimulus to the release of vasopressin, the concentrations of these peptides were measured in fetal, newborn, and adult sheep after episodes of induced hypoxia. The studies confirm that hypoxia is a potent stimulus to the release of both vasopressin and beta-endorphin in the fetal animal. In both the newborn lamb and the ewe, more profound hypoxia is necessary for a similar release. In the fetus, the release of both vasopressin and beta-endorphin after hypoxia increased with gestational maturation. A comparison of control concentrations of both peptides, the discordance of release in the newborn lamb, and the absence of a change in concentrations of vasopressin with infusion of beta-endorphin implies that these hormones are released in parallel but independently during hypoxic stress.