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PubMed1995

Marine and freshwater fish oil varying in arachidonic, eicosapentaenoic and docosahexaenoic acids differ in their effects on organ lipids and fatty acids in growing rats.

Arachidonic acid [20:4(n-6)] and docosahexaenoic acid [22:6(n-3)] are important to normal neurodevelopment and visual function. Infants fed formula often have low blood lipid 20:4(n-6) and 22:6(n-3). Consumption of fish oils high in eicosapentaenoic acid [20:5(n-3)] and 22:6(n-3) with no 20:4(n-6) increases tissue 20:5(n-3) and 22:6(n-3) but decreases 20:4(n-6). Some freshwater fish oils contain higher 20:4(n-6) and lower 20:5(n-3) than usual marine fish oils, but their effects on tissue fatty acids are not well known. Therefore, the effects of feeding weaning rats 30 d with 12% (wt/wt) soybean oil [0.0% 20:4(n-6), 20:5(n-3) and 22:6(n-3)], 2% safflower oil with 10% marine fish oil [0.9% 20:4(n-6), 15.1% 20:5(n-3), 7.3% 22:6(n-3)] or 10% freshwater fish oil [3.3% 20:4(n-6), 5.9% 20:5(n-3), 8.0% 22:6(n-3)] on plasma, tissue and brain fatty acids was determined. Levels (g/100 g) of 20:4(n-6) were significantly higher and 20:5(n-3) lower in plasma, liver, kidney and brain of rats fed freshwater fish oil rather than marine fish oil. Marine fish oil, but not freshwater fish oil resulted in a higher brain 20:5(n-3) and 22:6(n-3), and lower 20:4(n-6) than soybean oil. Plasma and liver triglyceride concentrations were significantly lower in rats fed marine fish oil, but not in rats fed soybean oil when compared with those fed freshwater fish oil. The results indicate dietary 20:4(n-6) prevents the decline in plasma and tissue 20:4(n-6) caused by dietary 20:5(n-3) and/or 22:6(n-3). Oils with 20:4(n-6) may affect cholesterol and triglyceride metabolism differently than usual fish oils.

Animals↗

PubMed1998

Programming by early nutrition: an experimental approach.

That events during critical or sensitive periods of development may "program" long-term or life-time structure or function of the organism is well recognized. Evidence for programming by nutrition is established in animals, in whom brief pre- or postnatal nutritional manipulations may program adult size, metabolism, blood lipids, diabetes, blood pressure, obesity, atherosclerosis, learning, behavior and life span. Human epidemiological data link potential markers of early nutrition (size at birth or in infancy) to cardiovascular disease and its risk factors in adulthood. However, these retrospective data cannot prove nutritional cause or underpin health policies. After 16 y, however, of ethical, randomized intervention studies of early nutrition in humans with long-term follow-up to test experimentally the nutritional programming hypothesis, we find that humans, like other species, have sensitive windows for nutrition in terms of later outcomes; for instance, perinatal diet influences neurodevelopment and bone mineralization into mid-childhood. Possible biological mechanisms for storing throughout life the "memory" of early nutritional experience and its expression in adulthood include adaptive changes in gene expression, preferential clonal selection of adapted cells in programmed tissues and programmed differential proliferation of tissue cell types. Animal and human evidence supporting nutritional programming has major potential biological and medical significance.

Animal Nutritional Physiological Phenomena↗

PubMed2003

Micronutrient status during pregnancy and outcomes for newborn infants in developing countries.

More than 9 million neonatal deaths occur each year, 98% of them in developing countries. Neonatal deaths account for two-thirds of deaths in infancy and 40% of deaths before age 5 y. The major direct causes of neonatal death are infections, preterm delivery and asphyxia. Important indirect causes include low birth weight and hypothermia. The present body of work on multiple micronutrient interventions is not sufficient for us to draw conclusions on their effects on neonatal well-being. Because studies have generally concentrated on single micronutrients and a range of outcomes, this paper reviews the findings for individual nutrients and then summarizes the situation. The evidence for the contribution of micronutrient deficiencies to perinatal mortality and duration of gestation is limited, and the evidence base for individual micronutrient effects on neonatal mortality and morbidity is patchy. To translate knowledge into policy, community evaluations of effect and an expanded evidence base that includes affordability, acceptability and scalability are also required. A balance between supply-side and demand-side interventions must be struck, with an emphasis on effect and sustainability. Among the key requirements are randomized, controlled community effectiveness trials of the effect of micronutrient supplementation in pregnancy on perinatal mortality and neurodevelopment, studies on improving adherence and studies on the relation between micronutrient deficiencies and sepsis and neonatal encephalopathy. It would also be helpful to look at mechanisms for bringing the periconceptional period within the ambit of trials.

Developing Countries↗

PubMed1993

Prenatal drug exposure: neurodevelopmental outcome and parenting environment.

Examined neurodevelopmental patterns and caregiving environment among 20 infants prenatally exposed to cocaine and 20 drug-free infants. The Brazelton Scale was administered 4 times. Drug-exposed infants had less optimal neurodevelopment than comparison infants at birth, but by 6 weeks only differences in autonomic stability were apparent. Neurodevelopmental performance was related positively to the child-centered quality of the environment. Though support buffered stress in both groups, the effect was more robust among drug-free mothers. Findings support the need to consider neurodevelopmental recovery and the caregiving environment in evaluations of developmental outcome among drug-exposed infants.

Developmental Disabilities↗

PubMed2000

Brief report: effects of pediatric HIV infection on mental and psychomotor development.

OBJECTIVE: To examine the effect of HIV status on infants' mental and psychomotor functioning, controlling for confounding factors such as prenatal drug exposure and birth conditions. METHODS: Twenty HIV-infected and 25 seroreverted infants (ages 3-30 months old) were administered the Bayley Scales of Infant Development (BSID) and a neurological examination at two time points, 4 to 12 months apart. The majority were from ethnic minority, socioeconomically disadvantaged families; 67% of the infants were prenatally drug-exposed. RESULTS: HIV-infected infants had significantly lower scores on the BSID at baseline (mental development) and follow-up (motor development) compared to seroreverters. When HIV and neurological deficits were considered together, HIV+ children with neurological deficits scored significantly lower than HIV+ children without neurological deficits and seroreverters, with and without neurological diagnoses. Prenatal drug exposure was not associated with performance on the BSID. CONCLUSIONS: These data suggest that CNS involvement is a critical pathway by which HIV affects infants' neurodevelopment.

Analysis of Variance↗

PubMed2001

Early brain wiring: activity-dependent processes.

One of the leading theories of the neuropathology of schizophrenia is that it is a developmental disorder of "neural connectivity." To assess this theory, it is first necessary to understand how precise neural connections normally are established. Sensory-driven neural activity has been widely recognized as crucial for this process. Recent studies have revealed a similar requirement for endogenous neural activity generated by the nervous system itself, long before there is any sensory input. These patterns of sensory-driven and endogenously generated neural activity sculpt the precise circuits that are crucial to the many complex functions of the adult brain. This article summarizes the principles of activity-dependent neural development as determined from basic neuroscience experiments, particularly those done using the mammalian visual system, to illustrate the role of patterned activity, neuronal competition, and critical periods in shaping neural circuitry. The potential molecular mechanisms involved in these features of activity-dependent neurodevelopment are discussed and possible links to the etiology of schizophrenia are briefly explored.

Axons↗

PubMed2001

Paternal factors and schizophrenia risk: de novo mutations and imprinting.

There is a strong genetic component for schizophrenia risk, but it is unclear how the illness is maintained in the population given the significantly reduced fertility of those with the disorder. One possibility is that new mutations occur in schizophrenia vulnerability genes. If so, then those with schizophrenia may have older fathers, because advancing paternal age is the major source of new mutations in humans. This review describes several neurodevelopmental disorders that have been associated with de novo mutations in the paternal germ line and reviews data linking increased schizophrenia risk with older fathers. Several genetic mechanisms that could explain this association are proposed, including paternal germ line mutations, trinucleotide repeat expansions, and alterations in genetic imprinting in one or several genes involved in neurodevelopment. Animal models may be useful in exploring these and other explanations for the paternal age effect and they may provide a novel approach for gene identification. Finally, it is proposed that environmental exposures of the father, as well as those of the mother and developing fetus, may be relevant to the etiology of schizophrenia.

Fathers↗

PubMed2004

Discriminating value of total minor physical anomaly score on the Waldrop physical anomaly scale between schizophrenia patients and normal control subjects.

Minor physical anomalies (MPAs) are slight structural aberrations that are believed to be associated with abnormal neurodevelopment. Studies of schizophrenia patients show that these patients score higher in MPAs than normal controls. The present study attempted to assess the potential value of MPAs as a classifying test in the status schizophrenia patient versus normal control. Seventy-six schizophrenia patients and 82 normal controls were assessed for MPAs using the Waldrop Physical Anomaly Scale, and specificity, sensitivity, and predictive value of the total MPA score were determined. A significantly higher percentage of schizophrenia patients than normal controls had high numbers of MPAs. Total MPA scores higher than 4 showed the most balanced set of sensitivity (76.3%), specificity (72.0%), and positive (71.6%) and negative (76.6%) predictive values for schizophrenia and were the cutoff scores that optimally discriminate schizophrenia patients from normal controls. Schizophrenia patients showed a higher percentage of subjects with prominent MPA scores. The results are consistent with the hypothesis that MPAs might reflect extragenetic stressful events and present total MPA score as a reliable index in distinguishing between schizophrenia patients and normal controls.

Adolescent↗

PubMed1994

Minor physical anomalies in schizophrenia patients, bipolar patients, and their siblings.

Minor physical anomalies (MPAs) are believed to reflect abnormalities in fetal neurodevelopment. Several studies have shown that schizophrenia patients have more MPAs than normal controls, but little is known about the meaning of this increased rate of MPAs. The current study first attempted to determine whether the increased MPAs are associated with schizophrenia in particular or with psychosis in general. Second, the study tested whether the patients' siblings also show an increased rate of MPAs by assessing MPAs in schizophrenia patients, bipolar manic patients, the siblings from each group of patients, and normal controls. The schizophrenia patients had significantly more MPAs than normal controls and bipolar patients. The rate of MPAs in bipolar patients did not differ from normal controls. This pattern suggests that MPAs have some degree of specificity to schizophrenia. Both sibling groups had fewer MPAs than the patients, and this difference was significant for the comparison between schizophrenia patients and their siblings. When viewed within a vulnerability-stress model, the results are consistent with the theory that MPAs may reflect early, largely extra-genetic, stressful events.

Adult↗

PubMed2005

Structural brain imaging evidence for multiple pathological processes at different stages of brain development in schizophrenia.

The underlying neurobiology of emerging psychotic disorders is not well understood. While there is evidence from structural imaging and other studies supporting the popular notion that schizophrenia arises as a consequence of an "early neurodevelopmental" lesion, more recent findings challenge this notion. Evidence, including our own data, suggests that dynamic brain changes occur during the earliest stages of a psychotic illness, including around the time of transition to illness. In this article we review the available longitudinal and relevant cross-sectional structural neuroimaging studies focusing on both the very early neurodevelopmental markers (pre- or perinatal origin) and the later markers (late neurodevelopmental) around the period of transition to illness. Based on our review of recent findings, we suggest that the onset of psychosis is a time of active brain changes, wherein, for a proportion of individuals, (i) an early (pre- and perinatal) neurodevelopmental lesion renders the brain vulnerable to anomalous late (particularly postpubertal) neurodevelopmental processes, as indicated by evidence for accelerated loss of gray matter and aberrant connectivity particularly in prefrontal regions; and (ii) these anomalous neurodevelopmental processes interact with other causative factors associated with the onset of psychosis (e.g., substance use, stress, and dysregulation of the hypothalamic-pituitary-adrenal axis function), which together have neuroprogressive sequelae involving medial temporal and orbital prefrontal regions, as suggested by imaging studies around transition to active illness. However, the pathological processes underlying such progressive changes during "late neurodevelopment" remain unclear but may reflect anomalies of synaptic plasticity, abnormal brain maturation, the adverse effects of stress, or other environmental factors. In this context, the features of schizophrenia, including the neuropsychological deficits and behavioral manifestations, can be understood as direct effects of these multiple pathological processes at various neurodevelopmental stages, including genetic and nongenetic etiological factors.

Brain↗

PubMed2005

Association between the neuregulin 1 gene and schizophrenia: a systematic review.

Chromosome 8p22-p11 has been identified as a locus for schizophrenia in several genome-wide scans, which has been confirmed by meta-analysis of published linkage data. It appears to be 1 of the most robust linkage findings in psychosis. Several attempts have been made to identify the underlying genetic variation that gives rise to this linkage peak, including systematic fine mapping using extended Icelandic pedigrees that have identified an associated haplotype (HAP(ICE)) in the gene neuregulin 1, also known as heuregulin, glial growth factor, NDF43, and ARIA. Neuregulin 1 (NRG1) is a plausible susceptibility gene because of its involvement in neurodevelopment, regulation of glutamate and other neurotransmitter receptor expression, and synaptic plasticity. Encouragingly, this finding was quickly and directly replicated in a Scottish case-control sample by the same investigators with the same approximately 300 kb associated haplotype. Although in Caucasian populations subsequent attempts at replication of this finding have been difficult to interpret, and no individual functional or causative genetic variants have yet been identified, a summary of HAP(ICE) association results in about 4,500 subjects is consistent with a small (odds ratio approximately 1.5) but significant effect of this haplotype on schizophrenia risk. In Chinese Han populations, where HAP(ICE) is not found, there is good evidence from several studies of association with other markers in the same region. Overall, there is convincing but not yet compelling evidence for a role for NRG1 in susceptibility to schizophrenia. Other genes from this region have also been implicated in schizophrenia, not by systematic mapping but by positional candidate gene analysis; these include MSTP131, frizzled-3, and the calcineurin A gamma subunit gene. Not only are these alternative explanations for the linkage seen between chromosome 8p and schizophrenia, but it is equally possible that there is more than 1 susceptibility gene at this locus.

Case-Control Studies↗

PubMed2006

Deconstructing schizophrenia: an overview of the use of endophenotypes in order to understand a complex disorder.

The genetics of schizophrenia has been approached utilizing a variety of methods. One emerging strategy is the use of endophenotypes in order to understand and identify the functional importance of genetically transmitted, brain-based deficits across schizophrenia kindreds. The endophenotype strategy is a topic of this issue of Schizophrenia Bulletin. Endophenotypes are quantitative, heritable, trait-related deficits typically assessed by laboratory-based methods rather than clinical observation. Endophenotypes are seen as closer to genetic variation than are clinical symptoms of schizophrenia, and are therefore closely linked to heritable risk factors. There has been a broad expansion of opportunities available to psychiatric neuroscientists who use the endophenotype strategy to understand the genetic basis of schizophrenia. In this context, genetic variation such as single nucleotide polymorphisms (SNPs) induces abnormalities in endophenotypic domains such as neurocognition, neurodevelopment, metabolism, and neurophysiology. This article discusses the challenges that abound in genetic research of schizophrenia, including issues in ascertainment, epistasis, ethnic diversity, and the potentially normalizing effects of second-generation antipsychotic medications on neurocognitive and neurophysiological measures. Robust strategies for meeting these challenges are discussed in this review and the subsequent articles in this issue. This article summarizes conceptual advances and progress in the measurement and use of endophenotypes in schizophrenia that form the basis of the multisite National Institute of Mental Health Consortium on the Genetics of Schizophrenia. The endophenotype strategy offers powerful and exciting opportunities to understand the genetically conferred neurobiological vulnerabilities and possible new strong inference and molecularly based treatments for schizophrenia.

Antipsychotic Agents↗

PubMed2003

PBPK predictions of perchlorate distribution and its effect on thyroid uptake of radioiodide in the male rat.

Due to perchlorate's (ClO4-) ability to competitively inhibit thyroid iodide (I-) uptake through the sodium-iodide symporter (NIS), potential human health risks exist from chronic exposure via drinking water. Such risks may include hypothyroidism, goiter, and mental retardation (if exposure occurs during critical periods in neurodevelopment). To aid in predicting perchlorate's effect on normal I- kinetics, we developed a physiologically-based pharmacokinetic (PBPK) model for the adult male rat. The model structure describes simultaneous kinetics for both anions together with their interaction at the NIS, in particular, the inhibition of I- uptake by ClO4-. Subcompartments and Michaelis-Menten (M-M) kinetics were used to describe active uptake of both anions in the thyroid, stomach, and skin. Separate compartments for kidney, liver, plasma, and fat were described by passive diffusion. The model successfully predicts both 36ClO4- and 125I- kinetics after iv doses of 3.3 mg/kg and 33 mg/kg, respectively, as well as inhibition of thyroid 125I- uptake by ClO4- after iv doses of ClO4- (0.01 to 3.0 mg/kg). The model also predicts serum and thyroid ClO4- concentrations from 14-day drinking water exposures (0.01 to 30.0 mg ClO4-/kg/day) and compensation of perchlorate-induced inhibition of radioiodide uptake due to upregulation of the thyroid. The model can be used to extrapolate dose metrics and correlate observed effects in perchlorate toxicity studies to other species and life stages, such as rat gestation (Clewell et al., 2003). Because the model successfully predicts perchlorate's interaction with iodide, it provides a sound basis for future incorporation of the complex hypothalamic-pituitary-thyroid feedback system.

Animals↗

PubMed2003

Early developmental neurotoxicity of a PCB/organochlorine mixture in rodents after gestational and lactational exposure.

The developmental and neurobehavioral effects of gestational and lactational exposure to a mixture of 14 polychlorinated biphenyls (PCBs) and 11 organochlorine pesticides was examined and compared against the commercial PCB mixture Aroclor 1254. The mixture was based on blood levels reported in Canadian populations living in the Great Lakes/St. Lawrence basin. Pregnant Sprague-Dawley rats were dosed orally with 0.013, 0.13, 1.3, or 13 mg/kg of the chemical mixture or 15 mg/kg of Aroclor 1254 from gestation day (GD) 1 to postnatal day (PND) 23. The highest mixture dose decreased maternal gestation and lactation body weight, and produced high mortality rates (80% overall) and reductions in offspring weight that persisted to adulthood. Aroclor 1254 produced smaller but persistent decreases in offspring weight without affecting maternal weight or offspring mortality. Aroclor 1254 and 13 mg/kg of the mixture produced comparable decreases in maternal and offspring serum T4 levels and comparable alterations to maternal thyroid morphology. Aroclor 1254 delayed the righting reflex and ear opening, accelerated eye opening, and reduced grip strength at PNDs 10-14. The mixture at 13 mg/kg delayed negative geotaxis in addition to delaying righting reflex and ear opening and reducing grip strength but had no effect on eye opening. Lower mixture doses (0.13 and 1.3 mg/kg) also delayed ear opening but affected no other parameters. Developmental exposure to the chemical mixture was found to be more toxic than exposure to Aroclor 1254 and produced a different profile of effects on early neurodevelopment. This PCB/organochlorine pesticide mixture affects mortality, growth, thyroid function, and neurobehavioral development in rodents.

Administration, Oral↗

PubMed2004

Developmental exposure to 4-hydroxy-2,3,3',4',5-pentachlorobiphenyl (4-OH-CB107): long-term effects on brain development, behavior, and brain stem auditory evoked potentials in rats.

In the present study the developmental neurotoxic effects of the PCB metabolite 4-OH-2,3,3',4',5-pentachlorobiphenyl (4-OH-CB107) were compared with effects caused by a mixture of parent polychlorinated biphenyl (PCB) congeners (Aroclor 1254). Pregnant female Wistar rats were exposed to 0.5 or 5 mg 4-OH-CB107, or 25 mg Aroclor 1254 per kg body weight from gestation days 10 to 16. Plasma thyroid hormone levels were significantly decreased in the offspring of all treatment groups at postnatal day 4 (PND 4). Behavioral experiments using an open field paradigm revealed an impaired habituation in male offspring of all treatment groups at PND 130. Passive avoidance experiments indicated significant influences on the time course of step-down latencies across trials in exposed male rats. Catalepsy induced by haloperidol showed increases in latencies to movement onset in female offspring exposed to 0.5 mg 4-OH-CB107 compared to Aroclor 1254 treated offspring at PND 168-175. Male offspring exposed to 4-OH-CB107 or Aroclor 1254 showed decreases in latencies compared to control animals. Brain stem auditory evoked potentials (BAEPs) measured at PND 300-310 showed significant increases in auditory thresholds in the low frequency range between Aroclor 1254 and 4-OH-CB107 (5 mg/kg bw) treated animals. Measurements of neurotransmitter levels revealed effects of Aroclor 154 exposure on both the dopaminergic and the serotonergic systems, whereas 4-OH-CB107 exposure affected dopaminergic and noradrenergic systems, with slight but not significant effects on the serotonergic system. These results indicate that 4-OH-CB107 is able to induce long-term effects on behavior and neurodevelopment. The observed effects for 4-OH-CB107 are similar to, but in some aspects different from, the effects observed after Aroclor 1254 exposure.

Animals↗

PubMed1996

MRI morphometric analysis and neuropsychological function in patients with neurofibromatosis.

Volumes of cerebral gray and white matter were measured in 22 children with neurofibromatosis type 1 (NF1) and in 20 controls. Judgment of Line Orientation (JLO) and the Developmental Test of Visual-Motor Integration (DTVMI) were administered to 16 of the NF1 patients. General linear models analysis of covariance revealed significantly larger brain volumes in NF1 children than in controls, particularly in white matter, and particularly in girls. JLO and DTVMI performance were positively related to right-hemisphere gray-matter volume. The results implicate a failure of growth control in NF1, leading to aberrant neurodevelopment. Our findings also suggest a basis for refined understanding of learning disabilities, which are a prominent feature of NF1.

Adolescent↗

PubMed1998

Abnormalities of Wnt signalling in schizophrenia--evidence for neurodevelopmental abnormality.

The Wnt signalling pathway is central to normal brain development in vertebrates and invertebrates and mediates cell fate determination, cell adhesion and cell proliferation. However, its relevance to disorders of cerebral development in man is untested. We evaluated the potential involvement of the Wnt signalling pathway in schizophrenia, a disorder of neurodevelopment origin in which alterations in neuronal lamination and orientation have been described. Using immunohistochemistry and semi-quantitative rating scales, we examined the distribution of two components of the Wnt signalling pathway, beta-catenin and gamma-catenin in the hippocampus and subiculum of 12 schizophrenic (DSMIIR criteria) and 14 control subjects. Both catenins were distributed as intraneuronal diffuse and/or ring shaped forms. The diffuse staining of both forms catenin were reduced in the CA3 and beta-catenin was also reduced in the CA4 hippocampal subregion among schizophrenic subjects. These alternations may represent the basis of the developmental brain abnormalities found in schizophrenia and would have functionally important consequences in the adult.

Adult↗

PubMed2000

Gender differences in the functional organization of the brain for working memory.

Gender differences in brain activation during working memory tasks were examined with fMRI. Seventeen right-handed subjects (nine males, eight females) were studied with four different verbal working memory tasks of varying difficulty using whole brain echo-planar fMRI. Consistent with prior studies, we observed activation of the lateral prefrontal cortices (LPFC), the parietal cortices (PC), and additionally, caudate activation in both sexes. The volume of activated brain tissue increased with increasing task difficulty. For all four tasks, the male subjects showed bilateral activation or right-sided dominance (LPFC, PC and caudate), whereas females showed activation predominantly in the left hemisphere. The task performance data demonstrated higher accuracy and slightly slower reaction times for the female subjects. Our results show a highly significant (p < 0.001) gender differences in the functional organization of the brain for working memory. These gender-specific differences in functional organization of the brain may be due to gender-differences in problem solving strategies or the neurodevelopment. Therefore, gender matching or stratification is required for studies of brain function using imaging techniques.

Adult↗