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PubMed2001

Antenatal therapies and the developing brain.

This chapter presents a review of basic science and human studies of two commonly used pharmacologic agents (antenatal steroids and magnesium sulfate), in pregnancies at risk of preterm delivery, and examines the effects of these therapies on the developing brain. Very low birthweight (VLBW) infants are known to be at risk of both short-term and long-term neurodevelopmental sequelae; therefore, an understanding of the mechanisms contributing to both neuroprotective and neurotoxic effects of antenatal therapies on the immature brain and potential effects on long-term outcome are critical. Although the short-term beneficial effects of a single course of antenatal steroids are well documented, the experimental animal literature suggests detrimental effects on neurodevelopment of multiple doses. In addition, clinical studies of repeat doses suggest a negative impact on head and brain growth. The animal and human data on the effects of MgSO(4)are also mixed with both beneficial effects or no effects on neurodevelopment. This review will discuss the potential impact of single versus multiple doses and timing of doses on the brain.

Animals↗

PubMed2002

Citalopram in pregnancy and lactation.

BACKGROUND: Although citalopram has gained wide acceptance in the treatment of depression and anxiety disorders, its use during pregnancy and lactation has been poorly characterized. The aim of this study was to examine the efficacy and safety of citalopram in relation to concentrations of citalopram and its metabolites during pregnancy and lactation. METHODS: Eleven mothers taking citalopram and their infants were enrolled in the study, and a control group of 10 women who were not taking medication were prospectively matched for confounding obstetric characteristics at the time of delivery. Plasma and breast milk samples were collected from mother/infant pairs during pregnancy, at delivery, and for up to 2 months after delivery. Trough plasma and breast milk concentrations of citalopram, desmethylcitalopram, and didesmethylcitalopram were measured by HPLC. The pregnancy outcome was recorded, and the neurodevelopment of children was monitored for up to 1 year. RESULTS: Although the citalopram dose of 20 mg to 40 mg once daily resulted in low maternal trough plasma concentrations (range, 46-214 nmol/L) and metabolites during pregnancy, only one subject required an increase of daily dose. The mean didesmethylcitalopram-desmethylcitalopram metabolic ratio was significantly higher during pregnancy (54%, P <.001) than at 2 months after delivery, indicating induction of cytochrome P450 (CYP) 2D6 during pregnancy. At delivery, the trough plasma citalopram, desmethylcitalopram, and didesmethylcitalopram concentrations in the infants were 64%, 66%, and 68% of the maternal concentrations, respectively. The citalopram and metabolite concentrations in the milk were 2- to 3-fold higher compared with maternal plasma concentrations, but the infant citalopram and metabolite plasma concentrations were very low or undetectable. The delivery outcome and the neurodevelopment of all infants up to the age of 1 year were normal. CONCLUSION: Even though the sample size was limited, results from this prospective clinical trial suggest uncomplicated pregnancy outcome in mothers using citalopram during pregnancy and minimal exposure of the infants to citalopram during lactation. However, maternal therapeutic drug monitoring of citalopram should be recommended to minimize fetal exposure.

Adult↗

PubMed2005

Is thyroid inadequacy during gestation a risk factor for adverse pregnancy and developmental outcomes?

A workshop entitled, "The Impact of Maternal Thyroid Diseases on the Developing Fetus: Implications for Diagnosis, Treatment, and Screening," was held in Atlanta, Georgia, January 12-13, 2004. This paper reports on the individual session that examined thyroid inadequacy during gestation as a risk factor for adverse pregnancy and developmental outcomes. For this session the following papers were presented: "Adverse Pregnancy Outcomes"; "Thyroid Physiology in the Fetus"; "New England Data: Cretinism Revisited-Preventing Fetal Brain Damage when Mothers Have Subclinical Hypothyroidism"; "Dutch Data: Pregnancy, Maternal Thyroid (Dys)function and Outcome of the Offspring"; and "Report on the Wales Controlled Antenatal Thyroid Screening Study (CATS); A Prospective RCT." These presentations were formally discussed by invited respondents well as others in attendance. Salient points from this session about which there was agreement include the following. Maternal hypothyroidism is associated with complications of pregnancy and adverse effects on the fetus. These risks are greater in women with overt hypothyroidism compared to subclinical hypothyroidism, and also appear to be increased in women with euthyroid autoimmune thyroid disease. If maternal hypothyroidism is treated adequately, this appears to reduce the risk for adverse outcomes. The demonstration of a pattern of ontogeny of fetal cerebral cortex deiodinases and thyroid hormone receptors, beginning by 7-8 weeks' gestation, is circumstantial evidence that thyroid hormone plays an important role in fetal neurodevelopment. Significant fetal thyroid hormone production and secretion does not begin until approximately 20 weeks' gestation. If there is a significant role for thyroid hormone in fetal neurodevelopment before 20 weeks' gestation, it likely is of maternal origin. Studies demonstrate low levels of thyroxine in the fetal coelomic fluid and blood prior to 12-14 weeks' gestation. Published data consistently document a relationship between maternal thyroid deficiency during pregnancy and problems with neuropsychological development of the offspring.

Animals↗

PubMed2006

Effects of n-3 fatty acids during pregnancy and lactation.

n-3 Fatty acids exert important effects on eicosanoid metabolism, membrane properties, and gene expression and therefore are biologically important nutrients. One n-3 fatty acid, docosahexaenoic acid, is an important component of neural and retinal membranes and accumulates rapidly in the brain and retina during the later part of gestation and early postnatal life. It is reasonable to hypothesize that maternal n-3 fatty acid intakes might have significant effects on several pregnancy outcomes as well as on subsequent infant visual function and neurodevelopmental status. Studies, both observational and interventional, assessing the influence of n-3 fatty acids during pregnancy or the early postpartum period on duration of gestation and infant size at birth, preeclampsia, depression, and infant visual function and neurodevelopment have been reported. n-3 Fatty acid intakes (both in terms of absolute amounts of docosahexaenoic acid and eicosapentaenoic acid and the ratio of these 2 fatty acids) varied widely in these studies, however, and no clear consensus exists regarding the effects of n-3 fatty acids on any of these outcomes. The available data suggest a modest effect of these fatty acids on increasing gestational duration and possibly enhancing infant neurodevelopment. Although data from earlier observational studies suggested a potential role of these fatty acids in decreasing the incidence of preeclampsia, this has not been confirmed in randomized, prospective trials. Because of the paucity of data from randomized, prospective, double-blind trials, the effect of n-3 fatty acids on depression during pregnancy or the early postpartum period remains unresolved.

Brain↗

PubMed2003

Prenatal exposure to low-level polychlorinated biphenyls in relation to mental and motor development at 8 months.

The relation between exposure to low levels of polychlorinated biphenyls (PCBs), a class of persistent organic pollutants, and cognitive and motor development in young children has been examined in several studies, and results have varied. The authors evaluated the association between prenatal exposure to PCBs and children's neurodevelopment using data from the Collaborative Perinatal Project. Pregnant women were enrolled from 1959 to 1965 from 12 sites across the United States. PCBs were measured in maternal serum taken during pregnancy. To measure children's mental and psychomotor development at 8 months of age, the authors administered the Bayley Scales of Infant Development (means, 87 (standard deviation, 15) and 88 (standard deviation, 18), respectively). Overall, they did not observe a relation between prenatal PCB exposure and children's mental or psychomotor scores (n = 1,207; multivariate adjusted beta = 0.1 point per micro g/liter increase of PCB, p = 0.71, and beta = 0.5, p = 0.14, respectively). The PCB-psychomotor score relation varied by study center (p < 0.05): The association was direct in some centers, inverse in others. This could not be attributed to variation in the timing or measurement of the child's neurodevelopment or analysis of PCBs because these were standardized across centers. The reasons for variation in results within this study and across other studies remain unclear.

Adult↗

PubMed2004

Single-suture craniosynostosis: a review of neurobehavioral research and theory.

OBJECTIVE: To review research and theory regarding the neurobehavioral correlates and outcomes of single-suture, or isolated, craniosynostosis in children. METHODS: A critical review of 17 studies of the hypothesized association between isolated craniosynostosis and neurodevelopment. RESULTS: Isolated craniosynostosis is associated with a three- to fivefold increase in risk for cognitive deficits or learning/language disabilities. The causal basis for this association is unclear. No particular calvarial suture (sagittal, metopic, left or right unilateral coronal) has been associated with higher risk of problems. There is little evidence from quasi-experimental studies that cranioplastic surgery prevents or reduces risk of neurobehavioral impairment. CONCLUSIONS: Future studies would benefit from larger samples and larger control groups; measures of specific neuropsychological functions (in addition to global cognition); analyses of neuropsychological status in relation to the severity and cortical impact of synostosis; and an examination of interactions between synostosis and social/family risk factors on neurodevelopment. Routine neurodevelopmental screening of young children with isolated craniosynostosis is recommended.

Brain↗

PubMed2001

Challenges, status, and opportunities for studying developmental neuropathology in adult schizophrenia.

Neurodevelopmental theories of the pathoetiology of schizophrenia have been at the forefront of schizophrenia research in recent years. Support for these theories is substantial and growing. Epidemiological, phenomenological, and clinical neurobiological research have provided compelling though still circumstantial evidence. Neuropathological investigations also have provided some evidence; however, these have yet to actualize their potential for revealing the cellular and molecular nature of developmental aberrancies in this disease. This article summarizes the clinical evidence suggesting abnormal neurodevelopment in schizophrenia, outlines some of the important anatomic, cellular, and molecular mechanisms of normal central nervous system development, reviews current neuropathological findings relevant to neurodevelopment in schizophrenia, and suggests some new directions and opportunities for discovering the molecular neurodevelopmental basis of the disorder.

Atrophy↗

PubMed1990

Small cerebral hemispheres in adults with Down's syndrome: contributions of developmental arrest and lesions of Alzheimer's disease.

Morphometric analysis was used to measure cross-sectional areas of cerebral structures in middle-aged patients with Down's syndrome (N = 5) for comparison with data obtained from individuals with senile dementia of the Alzheimer type (N = 16) and neuropathologically normal controls (N = 14). Down's syndrome was distinguished from Alzheimer's disease by the 19% lower mean brain weight which was associated with more pronounced reductions in the areas of both cortex and white matter. However, the differences were most striking in the anterior frontal and anterior temporal regions where the effects of arrested neurodevelopment are grossly evident. In addition, in Down's syndrome the amygdala was significantly smaller than in Alzheimer's disease. In both Down's syndrome and Alzheimer's disease, shrinkage of the cortical ribbon was associated with abundant neuritic plaques and neurofibrillary tangles, while white matter atrophy was associated with histopathological evidence of axonal degeneration. These findings suggest that in Down's syndrome the reduction in volume in the posterior portion of the cerebrum relative to controls is largely due to acquired lesions of Alzheimer's disease, whereas anteriorly and within certain subcortical nuclei, the effects of both Alzheimer's disease and arrested neurodevelopment are manifested. Moreover, the finding of white matter lesions in Down's syndrome corroborates the notion that white matter degeneration is a fundamental component of the Alzheimer's disease process.

Alzheimer Disease↗

PubMed2004

Fish intake during pregnancy and early cognitive development of offspring.

BACKGROUND: Fish is a source of many nutrients that can be beneficial during pregnancy, as well as a source of neurotoxicant contaminants such as methylmercury. Previous investigations of fish intake in relation to neurodevelopment have focused on possible damage from contaminants, whereas potential benefits of fish consumption have been relatively unexplored METHODS: We evaluated the association between maternal fish intake during pregnancy and offspring's early development of language and communication skills in a cohort of 7421 British children born in 1991-1992. Fish intake by the mother and child was measured by questionnaire. The child's cognitive development was assessed using adaptations of the MacArthur Communicative Development Inventory at 15 months of age and the Denver Developmental Screening Test at 18 months of age. Mercury was measured in umbilical cord tissue for a subset of 1054 children RESULTS: Total mercury concentrations were low and were not associated with neurodevelopment. Fish intake by the mother during pregnancy, and by the infant postnatally, was associated with higher mean developmental scores. For example, the adjusted mean MacArthur comprehension score for children whose mothers consumed fish 4 or more times per week was 72 (95% confidence interval = 71-74), compared with 68 (66-71) among those whose mothers did not consume fish. CONCLUSIONS: When fish is not contaminated, moderate fish intake during pregnancy and infancy may benefit development.

Adult↗

PubMed1997

Chronic lung disease in very low birthweight infants: a 5-year review.

OBJECTIVES: To determine the incidence, clinical spectrum and outcome of very low birthweight (VLBW) infants with chronic lung disease (CLD), and evaluate associated factors. METHODOLOGY: Retrospective review of 265 VLBW infants managed in the NICU from January 1988 to December 1992. RESULTS: The overall neonatal survival rate for VLBW infants was 83%. Sixty-five (25%) infants had CLD, of whom 42% had severe CLD. Mortality in infants with CLD was 11%. In contrast with infants without CLD, CLD infants had significantly higher risk of adverse neurodevelopment with cerebral palsy documented in 13.5% and functional disability recorded in 34.6% at 2 years corrected age. Factors associated with the development of CLD included; decreasing birthweight (OR 0.98, CI 0.97-0.99), septicaemia (OR 4.96, CI 1.57-15.65), necrotizing enterocolitis (OR 119.07, CI 4.98-2845.04), hyaline membrane disease (OR 5.34, CI 1.83-15.55), patent ductus arteriosus (OR 4.46, CI 1.75-11.36) and increasing fraction of inspired oxygen concentration in the first week of life (OR 1.09, CI 1.04-1.14). CONCLUSIONS: Chronic lung disease occurs frequently in VLBW infants and is associated with a high incidence of adverse neurodevelopment. Further studies to clarify the role of non-respiratory factors such as patent ductus arteriosus (PDA) and sepsis in the pathogenesis of CLD may reduce the incidence or prevent the development of CLD in these preterm infants.

Cerebral Palsy↗

PubMedDate not supplied

Clinical significance of isolated paraventricular cysts on cranial ultrasonography.

OBJECTIVES: Isolated paraventricular cysts detected on routine cranial ultrasonography in premature and full term neonates are often incidental findings. The aetiology and clinical significance of these lesions is uncertain. A case control study was designed to attempt to clarify the clinical significance of isolated paraventricular cysts in terms of growth and neurodevelopment. METHODS: Ten infants with isolated paraventricular cysts on neonatal cranial ultrasonography were identified. These were matched with 10 control infants for sex, gestational age and birthweight. All infants were assessed at a corrected age of 18-31 months for growth and neurodevelopment. Two index infants and their controls were excluded from analysis of psychometric data as the neurodevelopmental assessment tools used were different. RESULTS: There was no statistically significant difference between the index and control groups in terms of growth, motor and psychometric assessment at follow up. CONCLUSIONS: The study suggests that isolated paraventricular cysts detected on routine cranial ultrasonography have no prognostic significance. However the study involved a small sample size with limited power of study (power = 0.3). A larger prospective cohort study would help to clarify the clinical significance of this condition.

Case-Control Studies↗

PubMed2006

TAp73 isoforms antagonize Notch signalling in SH-SY5Y neuroblastomas and in primary neurones.

p73, like Notch, has been implicated in neurodevelopment and in the maintenance of the mature central nervous system. In this study, by the use of reporter-gene assays, we demonstrate that C-promoter binding factor-1 (CBF-1)-dependent gene transcription driven by the Notch-1 intracellular domain (N1(ICD)) is potently antagonized by exogenously expressed transactivating (TA) p73 splice variants in SH-SY5Y neuroblastomas and in primary neurones. Time course analysis indicated that the inhibitory effects of TAp73 are direct and are not mediated via the product of a downstream target gene. We found that endogenous TAp73 stabilized by either c-Abl or cisplatin treatment also potently antagonized N1(ICD)/CBF-1-dependent gene transcription. Furthermore, western blotting revealed that exogenous TAp73 suppressed endogenous hairy and enhancer of split-1 (HES-1) protein levels and antagonized the increase in HES-1 protein induced by exogenous N1(ICD) expression. Evidence of a direct physical interaction between N1(ICD) and TAp73alpha was demonstrated by co-immunoprecipitation. Using Notch deletion constructs, we demonstrate that TAp73alpha binds the N1(ICD) in a region C-terminal of aa 2094. Interestingly, DeltaNp73alpha and TAp73alpha(R292H) also co-purified with N1(ICD), but neither inhibited N1(ICD)/CBF-1-dependent transcription. This suggests that an intact transactivation (TA) domain and the ability to bind DNA are necessary for TAp73 to antagonize Notch signalling. Finally we found that TAp73alpha reversed the N1(ICD)-mediated repression of retinoic acid-induced differentiation of SH-SY5Y neuroblastomas, providing functional evidence for an inhibitory effect of TAp73alpha on notch signalling. Collectively, these findings may have ramifications for neurodevelopment, neurodegeneration and oncogenesis.

Basic Helix-Loop-Helix Proteins↗

PubMed1998

Cellular and molecular neuropathology of the olfactory epithelium and central olfactory pathways in Alzheimer's disease and schizophrenia.

Specific deficits in odor detection threshold, identification, and memory have been recognized in a variety of disorders including the neurodegenerative disorder, Alzheimer's disease (AD), and the psychiatric illness, schizophrenia, which is likely due to abnormalities in neurodevelopment. Neuropathological abnormalities in peripheral and central olfactory systems have been described in both disorder. In the olfactory, epithelium, dystrophic neurites that are immunoreactive for tau, neurofilaments and other polypeptides, as well as deposits of beta-amyloid have been observed, and these findings have been thought to contribute to the olfactory dysfunction of these disorders. However, similar findings also occur in the olfactory epithelium of many normal individuals and those with various other neurodegenerative diseases. In contrast, neuropathological studies have reported selective vulnerability of central olfactory pathways for the accumulation of neurofibrillary pathology in AD, and for cytoarchitectural, neuronal morphometric, and cytoskeletal protein abnormalities suggestive of abnormal neurodevelopment in schizophrenia. Thus, it is likely that the olfactory impairments associated with these diseases are due to damage within central olfactory pathways, and that they are further amplified by the less specific impairments associated with age-related sensory neuroepithelial abnormalities. Finally, both the olfactory epithelium and central olfactory pathways represent model systems in which to study the neurobiology of these disorders, which ultimately may yield clues with diagnostic and therapeutic utility.

Alzheimer Disease↗

PubMed2025

Lipidomic profiling of mouse brain and human neuron cultures reveals a role for Mboat7 in mTOR-dependent neuronal migration.

Mutations in lipid regulator genes are a frequent cause of autism spectrum disorder, including those regulating phosphatidylinositol (PI) and phosphoinositide 3-kinase signaling. MBOAT7 encodes a key acyltransferase in PI synthesis and is mutated in an autism-related condition with neurodevelopmental delay and epilepsy. Using liquid chromatography-tandem mass spectrometry, we analyzed the PI-associated glycerolipidome in mice and humans during neurodevelopment and found dynamic regulation at times corresponding to neural apoptosis in the brains of Mboat7 knockout mice. Mboat7 function was necessary for polyunsaturated lipid synthesis and cortical neural migration, and loss resulted in massive accumulation of the precursor lysophosphatidylinositol and hyperactive mTOR signaling. Inhibiting mTOR signaling rescued migration defects. Our findings demonstrate roles for lipid remodeling during neurodevelopment and implicate lipid regulation in neuronal migration, revealing potential paths to treatment for MBOAT7 deficiency.

Animals↗

PubMed2005

Developmental outcome in newborn infants treated for acute respiratory failure with extracorporeal membrane oxygenation: present experience.

OBJECTIVE: To describe the later health status of newborn infants who received extracorporeal membrane oxygenation (ECMO) for acute respiratory failure in the era after the UK ECMO trial. DESIGN: Prospective follow up study of newborn infants who received ECMO at a single centre between January 1997 and January 2001. SETTING: Departments of ECMO and Paediatric Intensive Care, University Hospitals of Leicester. PATIENTS: All babies who received ECMO within 14 days of birth. INTERVENTIONS: Neurodevelopment screening using the schedule for growing skills-II (SGS-II) assessment tool. MAIN OUTCOME MEASURES: Survival at 12 months of age by disease and functional development at follow up. RESULTS: A total of 145 neonates received ECMO for treatment of respiratory failure. Of these, 108 (75%) were alive at 1 year of age. There were no deaths in children treated for respiratory failure secondary to meconium aspiration syndrome (73/145). Ninety three (86% of survivors) infants attended a follow up visit at 11-19 months postnatal age. Eighty two were classed as normal, seven as having "impairment", and four as having "severe disability". CONCLUSIONS: Most newborn infants with acute respiratory failure treated with ECMO will have a normal neurodevelopment screening assessment at 11-19 months of postnatal age. There is no evidence to suggest that changes in neonatal practice since the UK ECMO trial have led to changes in outcome of infants undergoing ECMO therapy.

Acute Disease↗

PubMed1994

A randomised multicentre study of human milk versus formula and later development in preterm infants.

Whether breast milk influences later neurodevelopment has been explored in non-randomised studies, potentially confounded by social and demographic differences between feed groups. Here in a strictly randomised prospective multicentre trial, Bayley psychomotor and mental development indices (PDI and MDI) were assessed at 18 months postterm in survivors of 502 preterm infants assigned to receive, during their early weeks, mature donor breast milk or a preterm formula. These diets were compared as sole enteral feeds or as supplements to the mother's expressed breast milk. No differences in outcome at 18 months were seen between the two diet groups despite the low nutrient content of donor milk in relation to the preterm formula and to the estimated needs of preterm infants. These results contrast with those reported from our parallel two centre study that compared infants randomly assigned a standard term formula or the preterm formula during their early weeks; those fed standard formula, now regarded as nutritionally insufficient for preterm infants, were substantially disadvantaged in PDI and MDI at 18 months post-term. It is shown here that infants from that study fed solely on standard formula had significantly lower developmental scores at 18 months than those fed on donor breast milk in the present study; yet the standard formula had a higher nutrient content than the donor milk. Thus, donor milk feeding was associated with advantages for later development that may have offset any potentially deleterious effects of its low nutrient content for preterm infants. As these outcome advantages were not confounded by the social and educational biases usually associated with mothers' choice to breast feed, our data add significant support to the view that breast milk promotes neurodevelopment.

Child Development↗

PubMed2002

Incremental learning in biological and machine learning systems.

Incremental learning concepts are reviewed in machine learning and neurobiology. They are identified in evolution, neurodevelopment and learning. A timeline of qualitative axon, neuron and synapse development summarizes the review on neurodevelopment. A discussion of experimental results on data incremental learning with recurrent artificial neural networks reveals that incremental learning often seems to be more efficient or powerful than standard learning but can produce unexpected side effects. A characterization of incremental learning is proposed which takes the elaborated biological and machine learning concepts into account.

Algorithms↗

PubMedDate not supplied

Effect of docosahexaenoic acid content of maternal diet on auditory brainstem conduction times in rat pups.

Previous studies of dietary docosahexaenoic acid (DHA; 22:6n-3) effects on neurodevelopment have focused mainly on effects on the visual system; these studies may be confounded by effects on the retina rather than on neural pathways. Auditory brainstem conduction times (ABCTs) provide an alternate measure of central neural development. We conducted a dose-response study in which ABCTs were measured in pups whose dams were fed diets containing one of three levels of DHA (2, 4 or 6% of total fatty acids) from a single cell oil. Diets were fed during pregnancy and lactation, and pups were randomly cross-fostered on postnatal day 3 to minimize litter effects. ABCTs showed a dose-response effect, with higher levels of dietary DHA being associated with longer conduction times on postnatal day 31 (p < 0.05). Higher dietary DHA was reflected in pup cerebrums collected on postnatal days 3 and 31, and levels of arachidonic acid (AA, 20:4n-6) were inversely related to levels of DHA. This study demonstrated that the auditory brainstem response is sensitive for identifying effects of diet on neurodevelopment, and that supplementing the maternal diet with high levels of DHA may negatively impact development of the central auditory system of offspring.

Animals↗