Evidence for neurodevelopment disturbances in anterior cingulate cortex of post-mortem schizophrenic brain.
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Brain Damage, Chronic↗
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[Neurodevelopment of children exposed to antiepileptic drugs and psychoactive medication during pregnancy].
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Anticonvulsants↗
Immunological stress at the maternal-foetal interface: a link between neurodevelopment and adult psychopathology.
Maternal infection during pregnancy is associated with a higher incidence of mental disorders, including schizophrenia, in the offspring in later life. Our recent attempt to study this link between prenatal immunological challenge and subsequent psychopathology has led to the establishment of a mouse model demonstrating the emergence of multiple psychotic-like phenotypes following immunological challenge on gestation day (GD) 9. However, little is known about the impact of similar in utero challenge at different times of pregnancy. Here, we compare the efficacy of identical maternal immune stimulation induced by the exposure to polyriboinosinic-polyribocytidilic acid (Poly(I:C)) at a dose of 5mg/kg (i.v.) on distinct days of gestation (GD 6, 9, 13 or 17). The offspring derived were then compared to those collected from vehicle- and non-treated dams in two paradigms of selective associative learning: latent inhibition (LI) and the US-pre-exposure effect (USPEE). LI deficiency was observed in animals born to dams treated with Poly(I:C) on GD 6, 9 or 13, but not in those on GD17. In contrast, a loss of the USPEE was equivalently seen in all Poly(I:C) treatment groups, regardless of treatment times. Evaluation of the acute cytokine response in a separate cohort of pregnant dams receiving Poly(I:C) challenge on either GD9 or GD17 revealed that the ratio of interleukin-10/tumor necrosis factor-alpha was elevated in the GD17 relative to the GD9 group. The present report thus provides evidence that the acute cytokine reaction as well as the long-term pattern of behavioural sequelae of maternal immune challenge can be affected by its precise timing during pregnancy. The present study provides further support to the use of the prenatal Poly(I:C) model in the elucidation of mechanisms involved in the aetiology and disease process of immuno-precipitated neurodevelopmental mental diseases, including but not limited to, schizophrenia.
Analysis of Variance↗
A review of Disrupted-In-Schizophrenia-1 (DISC1): neurodevelopment, cognition, and mental conditions.
Disrupted-In-Schizophrenia-1 (DISC1) is a promising candidate gene for schizophrenia (SZ) and bipolar disorder (BP), but its basic biology remains to be elucidated. Accumulating genetic evidence supports that DISC1 is associated with some aspects of cognitive functions relevant to SZ and BP. Here, we provide a summary of the current updates in biological studies of DISC1. Disrupted-In-Schizophrenia-1, preferentially expressed in the forebrain, has multiple isoforms with potential posttranslational modifications. Disrupted-In-Schizophrenia-1 protein occurs in multiple subcellular compartments, which include the centrosome, microtubule fractions, postsynaptic densities, actin cytoskeletal fractions, the mitochondria, and the nucleus. Recent studies have clarified that DISC1 mediates at least centrosome-dynein cascade and cyclic adenosine monophosphate (cAMP) signaling. Furthermore, both cytogenetic and cell biological studies consistently suggest that an overall loss of DISC1 function (either haploinsufficiency or dominant-negative, or both) may be associated with SZ and BP. On the basis of these findings, production of DISC1 genetically engineered mice is proposed as a promising animal model for SZ and BP. Several groups are currently generating DISC1 mice and starting to characterize them. In this review, the advantages and disadvantages of each animal model are discussed.
Animals↗
Prenatal and postnatal steroid therapy and child neurodevelopment.
In recent years, scientific evidence has accumulated on the potential neuro-toxic effects of perinatal steroid therapy on the incompletely developed brain; therefore, much effort has been directed toward finding the optimal regimen that may reduce lung disease without incurring significant brain injury in fetuses and preterm infants. Current recommendations of the NIH endorse a single course of prenatal steroids in cases of imminent preterm delivery. Postnatal steroid therapy should be limited, according to the American Association of Pediatrics Guide-lines, to selected clinical cases after the first week of life. These cautions aim to decrease possible harmful effects that could affect short- and long-term neuro-developmental outcome in this high-risk population.
Adrenal Cortex Hormones↗
Altering the course of neurodevelopment: a framework for understanding the enduring effects of psychotropic drugs.
Childhood is a time filled with wondrous changes, as brain plasticity permits experiences to shape the immature brain to meet the demands of the environment. Change occurs at various levels--from neuroanatomy, including within a given region and its connectivity to other regions, to the function of neurotransmitter systems and their reactivity to pharmacological agents in the short- and long-term. The nature and degree to which drug exposure influences the final adult topography is influenced greatly by the maturational phase of these critical factors. Moreover, evidence is slowly emerging that suggests that the long-term effects of drug exposure are delayed and expressed once the vulnerable system reaches maturation (i.e., typically during adulthood). This phenomenon is known as neuronal imprinting and occurs when the effects of drug exposure outlast the drug itself. Thus, understanding the persistent effects critically depends on the window of observation. Embracing this concept should influence how we conduct preclinical assessments of developmental drug exposure, and ultimately how we conduct clinical assessments of drug efficacy, effectiveness, and safety for the treatment of childhood psychiatric disorders. In this article, we present a model to provide a heuristic framework for making predictions about imprinted effects of childhood drug exposure. We then review epidemiological data on attention deficit hyperactivity disorder (ADHD) and childhood depression, prescription practices, and what is known regarding the long-term consequences of drug exposure in these populations. We conclude with a discussion of the current status of preclinical studies on juvenile stimulant exposure.
Adaptation, Physiological↗
Low superior vena cava flow and neurodevelopment at 3 years in very preterm infants.
OBJECTIVES: Low superior vena cava (SVC) flow is common in the first hours after very preterm birth and has a strong association with subsequent periventricular/intraventricular hemorrhage. We report the neurodevelopmental outcome at 3 years of age of very preterm babies who had serial echocardiographic studies, including measures of SVC flow, during the first 48 hours after birth. STUDY DESIGN: A prospective observational study was performed on a cohort of 126 babies (<30 weeks), 103 of whom survived to discharge. Neurodevelopmental follow-up data, which included abnormal developmental quotient, abnormal motor score, and cerebral palsy, were available for 93% of this cohort at 3 years of age. Relations between 3-year outcome and early hemodynamic measures and clinical parameters were explored. RESULTS: After controlling for confounding variables, average SVC flow over the first 24 hours of life was significantly associated with the primary outcome of death or survival with any disability (P=.004) and with the secondary outcome of abnormal developmental quotient (P = .006). A greater number of low SVC flow readings during the first 24 hours was significantly related to death and adverse developmental outcome, but the individual lowest SVC flow was not, suggesting the importance of duration of low SVC flow. After adjustment, there was no significant association between average mean blood pressure over the first 24 hours and abnormal developmental outcome, whereas the proportion of mean blood pressure readings less than the gestational age showed a trend toward an association with death and any disability. CONCLUSIONS: Low early postnatal blood flow to the upper body and brain may be one factor in the causal pathway of impaired preterm neurodevelopmental outcome.
Blood Pressure↗
Low superior vena cava flow during the first postnatal day and neurodevelopment in preterm neonates.
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Blood Pressure↗
Understanding neurodevelopment in premature infants: applied chaos theory.
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Brain↗
Grades I-II intraventricular hemorrhage in extremely low birth weight infants: effects on neurodevelopment.
OBJECTIVE: To quantify the effect of grades I-II intraventricular hemorrhage (IVH) on the neurosensory and cognitive outcomes of extremely low birth weight infants. STUDY DESIGN: Of 706 extremely low birth weight infants without major malformations admitted to our center from 1992 to 2000, 537 survived to 20 months' corrected age (CA) and had cranial ultrasound studies performed, of whom 490 (91%) had complete neurodevelopmental assessments. Infants with severe cranial ultrasound abnormalities or meningitis were excluded, leaving a population of 362 infants, 258 of whom had a normal cranial ultrasound and 104 had an isolated grade I-II IVH. The groups had similar birth weight (808 vs 801 grams) and gestational age (26.5 vs 26.3 weeks). Outcomes of infants with normal cranial ultrasound were compared with those with grades I-II IVH at 20 months' CA. Outcomes included the Bayley Scales of Infant Development Mental Developmental Index (MDI) and major neurosensory abnormality. Logistic regression was used to assess the effect of grades I-II IVH on outcomes while adjusting for other risk factors. RESULTS: Extremely low birth weight infants with grades I-II IVH had a significantly lower mean MDI score than infants with normal cranial ultrasound (74 +/- 16 vs 79 +/- 14, P = .006). They had higher rates of MDI <<70 (45% vs 25%; OR, 2.00; 95% CI, 1.20 to 3.30; P = .008), major neurologic abnormality (13% vs 5%; OR, 2.60; 95% CI, 1.06 to 6.36; P = .036), and neurodevelopmental impairment (47% vs 28%; OR, 1.83; 95% CI, 1.11 to 3.03; P = .018) at 20 months' CA, even when adjusting for confounding factors. CONCLUSIONS: Extremely low birth weight infants with grades I-II IVH have poorer neurodevelopmental outcomes at 20 months' CA than infants with normal cranial ultrasound. Advanced radiologic imaging may indicate additional brain injury associated with grade I-II IVH, which could explain these outcomes.
Brain↗
The neurodevelopment of human sexual orientation.
One of the most enduring and controversial questions in the neuroscience of sexual behaviour surrounds the mechanisms which produce sexual attraction to either males or females. Here, evidence is reviewed which supports the proposal that sexual orientation in humans may be laid down in neural circuitry during early foetal development. Behaviour genetic investigations provide strong evidence for a heritable component to male and female sexual orientation. Linkage studies are partly suggestive of X-linked loci although candidate gene studies have produced null findings. Further evidence demonstrates a role for prenatal sex hormones which may influence the development of a putative network of sexual-orientation-related neural substrates. However, hormonal effects are often inconsistent and investigations rely heavily on 'proxy markers'. A consistent fraternal birth order effect in male sexual orientation also provides support for a model of maternal immunization processes affecting prenatal sexual differentiation. The notion that non-heterosexual preferences may reflect generalized neurodevelopmental perturbations is not supported by available data. These current theories have left little room for learning models of sexual orientation. Future investigations, across the neurosciences, should focus to elucidate the fundamental neural architecture underlying the target-specific direction of human sexual orientation, and their antecedents in developmental neurobiology.
Androgens↗
Diffusion tensor imaging of neurodevelopment in children and young adults.
Diffusion tensor magnetic resonance imaging (DTI) was used to study regional changes in the brain's development from childhood (8-12 years, mean 11.1 +/- 1.3, N = 32) to young adulthood (21-27 years, mean 24.4 +/- 1.8, N = 28). Mean diffusivity (Trace/3 apparent diffusion coefficient, ADC) and fractional anisotropy (FA) were measured in 30 regions of interest (ROIs) in 13 distinct brain structures. Correlational analysis was performed to detect changes within 8-12 years and within 21-27 years, and group analysis to compare childhood diffusion properties with young adult values. Increases of fractional anisotropy were seen in the genu of the corpus callosum, splenium of the corpus callosum, corona radiata, putamen, and head of the caudate nucleus within 8-12 years, and also between childhood and young adulthood. Reductions in Trace/3 ADC were observed in 9 of 13 structures within 8-12 years and into young adulthood as well. DTI demonstrates more widespread changes in the brain's microstructure with maturation than previous reports using conventional T1-weighted MRI scans. These findings suggest a continuation of the brain's microstructural development through adolescence.
Adult↗
Neurodevelopment on route p63.
All known members of the p53 gene family, including the two homologs p73 and p63, have multiple biological functions. In neurons, p53 and p73 are known to regulate cell death in the developing and adult nervous system. A report by Jacobs et al. in this issue of Neuron shows that the more ancestral member of this gene family, p63, is an essential proapoptotic protein during neuronal development.
Animals↗
Developmental changes in the expression of ATP7A during a critical period in postnatal neurodevelopment.
ATP7A is a P-type ATPase that transports copper from cytosol into the secretory pathway for loading onto cuproproteins or efflux. Mutations in Atp7a cause Menkes disease, a copper-deficiency disorder fatal in the postnatal period due to severe neurodegeneration. Early postnatal copper injections are known to diminish degenerative changes in some human patients and mice bearing mutations in Atp7a. In situ hybridization studies previously demonstrated that ATP7A transcripts are expressed widely in the brain. ATP7A-specific antibody was used to study the neurodevelopmental expression and localization of ATP7A protein in the mouse brain. Based on immunoblot analyses, ATP7A expression is most abundant in the early postnatal period, reaching peak levels at P4 in neocortex and cerebellum. In the developing and adult brain, ATP7A levels are greatest in the choroid plexus/ependymal cells of the lateral and third ventricles. ATP7A expression decreases in most neuronal subpopulations from birth to adulthood. In contrast, ATP7A expression increases in CA2 hippocampal pyramidal and cerebellar Purkinje neurons. ATP7A is expressed in a subset of astrocytes, microglia, oligodendrocytes, tanycytes and endothelial cells. ATP7A is largely localized to the trans-Golgi network, adopting the cell-specific and developmentally-regulated morphology of this organelle. The presence of ATP7A in the axons of postnatal, but not adult, optic nerve suggests stage-specific roles for this enzyme. In sum, the precisely-regulated neurodevelopmental expression of ATP7A correlates well with the limited therapeutic window for effective treatment of Menkes disease.
Adenosine Triphosphatases↗
Methylmercury and neurodevelopment: longitudinal analysis of the Seychelles child development cohort.
BACKGROUND: The Seychelles Child Development Study (SCDS) has been longitudinally following a cohort of over 700 children enrolled in 1989. Their mothers consumed a diet high in fish during pregnancy. Repeated examination of the SCDS cohort at six different ages through age 11 years has shown no pattern of adverse effects. Some early appearing beneficial associations between both prenatal and postnatal hair MeHg and several child development endpoints were noted. We hypothesized these might be related to micronutrients in the fish, but they were not found when the children reached middle school age. These findings suggest that the associations observed between MeHg and developmental outcomes may vary with developmental stage. METHOD: We examined the main cohort of the SCDS to determine if this might be true using a longitudinal multiple regression analysis design that focused on those endpoints that were repeatedly measured at different ages. The primary endpoint analyzed was global cognition, involving a measure of developmental quotient or IQ. Secondary analyses included other domains such as Reading and Mathematics scholastic achievement, social behavior, and memory. Analyses involved two different approaches, one including incorporation of a passage of time variable, the other including a difference of scores across time points. RESULTS: No significant associations were found between prenatal MeHg exposure and any of the repeatedly measured endpoints. CONCLUSIONS: These results suggest that even when individual subject variance is controlled there was no consistent pattern of associations between child development outcomes and prenatal exposures to MeHg from maternal consumption of a diet high in fish. The Seychellois diet contains about 10 times more ocean fish than is typically consumed by US citizens. Our primary focus on IQ should further inform growing scientific interest in the analysis of the risks and benefits of fish consumption on overall cognitive ability.
Child↗
Expanding roles of programmed cell death in mammalian neurodevelopment.
Programmed cell death is an orchestrated form of cell death in which cells are actively involved in their own demise. During neural development in mammals, many progenitor cells, immature cells or differentiated cells undergo the most clearly characterized type of cell death, apoptosis. Several pathways of apoptosis have been linked to neural development, but according to the numerous and striking phenotypes observed when apoptotic genes are inactivated, the mitochondrial death-route is the most important pathway in this context. Here, we discuss the relative importance of pro-growth/pro-death factors in the control of neural tissue development. We also discuss the impact of studying programmed cell death in development in order to better understand the basis of several human diseases and embryonic defects of the nervous system.
Animals↗
Disturbances of brain maturation and neurodevelopment during chronic renal failure in infancy.
Fifteen infants with moderate to severe congenital renal disease were prospectively studied by serial renal, neurodevelopmental, neurophysiologic, and anthropometric assessments. The observation period ranged from 3 to 25 months (mean = 10.9). Eight patients maintained a Mental Development Index (MDI) above the 16th percentile (greater than -1 SD) and comprised group 1. Of the remaining seven patients (group 2), three had an MDI less than 16th percentile when first studied and four had serial decreases of the MDI to less than 16th percentile. Although motor development was more delayed in group 2 at study entry, there were no significant changes of motor performance levels for either group during the study period. Group 2 patients had smaller length (p less than 0.05) and head circumference (p less than 0.05) standard deviation scores in comparison with group 1, and they had higher serum creatinine values (mean = 3.8 vs 1.3 mg/dl, respectively; p less than 0.01). By spectral electroencephalography, the expected progressive increase of the frequency of cerebral cortical background activity with age was demonstrated in group 1 but was not seen in group 2 (multivariate analysis of variance p less than 0.03). This increase of faster-frequency activity was primarily manifested in the left cerebral hemisphere of group 1 patients (p less than 0.01), a finding that was also absent in group 2. The frequent occurrence of neurodevelopmental abnormalities in infants with renal failure is possibly a consequence of impaired dominant hemispheric maturation in the first several years of life, which is clinically manifested as deterioration of cognitive function.
Cephalometry↗
The outcome of very low birth weight neonates (</=1500 g) rescued by inhaled nitric oxide: neurodevelopment in early childhood.
Although inhaled nitric oxide (INO) improves oxygenation in critically ill neonates, the neurodevelopmental outcome of premature neonates with severe hypoxemic respiratory failure treated with INO has not been reported. Mortality and prospective neurodevelopmental assessment in early childhood were studied in a cohort of 24 very low birth weight neonates (</=1500 g) consecutively admitted from 1993 to 1997 and rescued with INO because of severe hypoxemic respiratory failure (oxygenation index 28 to 52) unresponsive to aggressive conventional treatment. Significant improvements in arterial oxygen tension and oxygenation index with lower inspired oxygen concentration and less ventilator support after initiating INO were observed (P <.05, analysis of variance). Despite the dramatic improvement in systemic oxygenation, the mortality rate was high (14 of 24, 58%). Only 6 of 23 had normal cranial ultrasonographies. At 13 to 40 (22 +/- 10) months of adjusted age, 10 survivors had Bayley Scales mental and psychomotor developmental indexes of 81 +/- 21 and 64 +/- 22, respectively. Of the 10 children, 5 (50%) were disabled, 2 (20%) were developmentally delayed, and 3 (30%) had normal development. In view of the poor outcome in very low-birth-weight neonates rescued by INO, randomized controlled trials are required to examine the role of INO in premature neonates. Before, during, and after INO therapy, cranial ultrasonography is recommended.
Administration, Inhalation↗