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PubMed2006

Subclinical hypothyroidism and pregnancy.

UNLABELLED: Pregnancy has a considerable impact on thyroid homeostasis that complicates the diagnosis of hypothyroidism. Pregnant women with overt hypothyroidism have appreciable maternal morbidity as well as perinatal morbidity and mortality. Treatment of such women has been shown to improve these outcomes. Controversy regarding the importance of identifying and treating women with subclinical hypothyroidism erupted after several reports have linked variously defined hypothyroidism with impaired neurodevelopment of the fetus. Frequently, these reports are erroneously considered as identifying women with subclinical hypothyroidism, when in fact, none of these studies specifically identified such women. To date, there have been no well-controlled, long-term studies on offspring of pregnant women with subclinical hypothyroidism as contemporaneously defined. Furthermore, these reports have led to conflicting and confusing position statements from several national entities as to whether all pregnant women should be screened for hypothyroidism and treatment prescribed for those found to have subclinical hypothyroidism. Importantly, there are also no published intervention trials specifically assessing the efficacy of such treatment to improve neurodevelopmental outcomes in offspring of women with subclinical hypothyroidism. It is acknowledged that obstetricians are under increasing pressure to screen for and treat pregnant women with subclinical hypothyroidism despite uncertainty that their offspring would benefit from therapy. National endocrine groups recommending such screening and treatment have emphasized that there is a need for large clinical trials to address these issues. Until such studies are completed, routine screening for and treatment of subclinical hypothyroidism during pregnancy is unwarranted and should be considered experimental. TARGET AUDIENCE: Obstetricians and Gynecologists, Family Physicians. LEARNING OBJECTIVES: After completion of this article, the reader should be able to recall the difficulty in identifying and treating women with subclinical hypothyroidism, summarize the current thinking about the laboratory diagnosis of subclinical hypothyroidism, explain that there are no well-controlled studies that indicate that treatment during pregnancy will improve neurodevelopmental outcome, and state that screening during pregnancy at this time is unwarranted.

Female↗

PubMed2006

Schizophrenia and bipolar disorder: differences and overlaps.

PURPOSE OF REVIEW: Following the recent progress mainly in the fields of genetics and neurobiology, the validity of the diagnostic distinction between schizophrenia and bipolar disorder is increasingly challenged. RECENT FINDINGS: Evidence for basic neurobiological processes common for both disorders is expanding with regard to (a) susceptibility genes, (b) neurodevelopment (for example myelination), and (c) brain functions (for example sensory gating, visuospatial achievement). Recent epidemiological studies also stress communalities. SUMMARY: The diagnostic split between schizophrenia and bipolar disorder is unable to define distinct etiological and/or pathophysiological entities.

Bipolar Disorder↗

PubMed2006

Fish oil and mental health: the role of n-3 long-chain polyunsaturated fatty acids in cognitive development and neurological disorders.

Epidemiological and experimental studies have indicated that consumption of more n-3 long-chain polyunsaturated fatty acids may reduce the risk for a variety of diseases, including cardiovascular, neurological and immunological disorders, diabetes and cancer. This article focuses on the role of marine n-3 long-chain polyunsaturated fatty acids in brain functions, including the development of the central nervous system and neurological disorders. An overview of the major animal studies and clinical trials is provided here, focusing on fatty acid supplementation during pregnancy and infancy, and prevention and management of Alzheimer's disease, schizophrenia, depression and attention deficit hyperactive disorder. Although an optimal balance in n-3/n-6 long-chain polyunsaturated fatty acid ratio is important for proper neurodevelopment and cognitive functions, results from randomized controlled trials are controversial and do not confirm any useful effect of supplementation on development of preterm and term infants. The relationship between fatty acid status and mental disorders is confirmed by reduced levels of n-3 long-chain polyunsaturated fatty acids in erythrocyte membranes of patients with central nervous system disorders. Nevertheless, there are very little data supporting the use of fish oil in those patients. The only way to verify whether n-3 long-chain polyunsaturated fatty acids are a potential therapeutic option in the management and prevention of mental disorders is to conduct a large definitive randomized controlled trials similar to those required for the licensing of any new pharmacological treatment.

Adult↗

PubMed2006

No association between the CNTF null mutation and schizophrenia or personality.

The ciliary neurotrophic factor (CNTF) is a neurotrophic cytokine that plays a critical role in neurodevelopment. On the basis of neurodevelopmental hypothesis, the CNTF gene has been a candidate locus for schizophrenia. Several studies have investigated the association between the null mutation of the gene and schizophrenia, however, with inconsistent results. In the present study, we investigated the association in 222 Japanese patients with schizophrenia and 237 controls. The association between the mutation and personality traits was also studied, to investigate the effect of the mutation in participants from the general population. As a result, no association was observed between the mutation and schizophrenia nor personality traits, evaluated by using the Revised NEO Personality Inventory scores. The present study did not provide evidence for the association between the CNTF gene and schizophrenia or personality traits in the Japanese population.

Alleles↗

PubMed2002

Adverse effects of pain on the nervous systems of newborns and young children: a review of the literature.

There are immediate and long-lasting harmful consequences to the nervous system when infants experience severe or repetitive pain. These effects are especially significant in preterm infants, who are vulnerable to neurological damage during this critical time of neurodevelopment. Painful experiences may cause structural and physiological changes within the nervous system. Repeated painful procedures may result in decreased pain thresholds and hypersensitivity to pain. Immediate harmful effects of pain include physiologic instability and increased incidence of serious complications such as intraventricular hemorrhage. Painful stressors may lead to sleep disturbances, feeding problems, and inability to self-regulate. Long-term effects of pain may include altered pain perception, chronic pain syndromes, and somatic complaints. Repetitive pain in the preterm infant may be associated with attention deficit disorders, learning disorders, and behavioral problems in later childhood. Nursing involvement with pain management is crucial to achieve positive health outcomes for high-risk infants and older children and adults who have experienced repetitive or severe pain as infants.

Humans↗

PubMed2025

Dynamic neuro-immune regulation of psychiatric risk loci in human neurons.

The prenatal environment influences neurodevelopment and subsequent clinical trajectories for psychiatric outcomes in childhood and adolescence. Yet it remains unclear if the impact of maternal and fetal immune activation varies with distinct polygenic risk profiles. Therefore, here we catalogue genotype and environment (GxE) interactions, contrasting allele-specific regulatory activity between inflammatory contexts. We report a cue-specific neuronal massively parallel reporter assay (MPRA) of 220 loci from genome-wide association study (GWAS) linked to ten brain traits/disorders, empirically dissecting the impact of interleukin-6 (IL-6) and interferon-alpha (IFNα) on transcriptional activity. Of 1,469 active candidate regulatory risk elements (MPRA-active CRSs) across three conditions, we identify 316 with dynamic variant-specific effects (MPRA-QTLs) in human induced pluripotent stem cell (hiPSC)-derived glutamatergic neurons. Broadly, across hundreds of variants, neuronal immune-mediated regulatory activity is driven by differences in transcription factor binding and chromatin accessibility, the gene targets of which show pleiotropic enrichments for brain, metabolic, and immune disorders. Dynamic genetic regulation mediates immune effects, informing our understanding of mechanisms governing pleiotropy and variable penetrance. Understanding neurodevelopmental GxE interactions will inform mental health trajectories and resolve mechanisms mediating prenatal risk.

dynamic expression quantitative trait loci↗

PubMed2025

Perinatal Lead (Pb) Exposure Increases Mouse Embryonic Weight and Alters Neuronal Gene Expression.

Acute and chronic exposure to lead (Pb) during pregnancy is linked to adverse health outcomes, including delayed neurodevelopment in offspring. However, the pathways by which Pb exposure influences long-term health remain poorly understood. To address this, we measured the effects of perinatal Pb exposure on gene expression including imprinted genes, X-linked genes, and sexually dimorphic genes. Female mice were given control or Pb acetate dosed (32 ppm) drinking water two weeks prior to timed mating until embryonic day (E)10-12, upon which whole embryos were collected, weighed, and sexed at E13-15. From a subset of embryo heads (n≥9 per sex per group), we extracted and sequenced RNA. We used linear regression to assess Pb impacts on embryonic weight and gene expression across all mice and stratified by sex. Among the differentially expressed genes, we identified significantly enriched pathways. Pb-exposed embryos weighed more than controls (p=0.007), across both sexes. Collectively, we identified 2,920 differentially expressed genes (FDR<0.05), including 31 imprinted genes and 120 X-linked genes upon Pb exposure. Pb exposure altered expression in gene pathways related to neuronal structure and function as well as sexually dimorphic genes (44 for females; 76 for males). These findings highlight perinatal Pb-linked alterations that may drive later-life health outcomes.

DOHaD↗

PubMed2002

Annotation: attachment disorganisation and psychopathology: new findings in attachment research and their potential implications for developmental psychopathology in childhood.

BACKGROUND: The past 10 years have seen a fruitful line of enquiry building on identification of previously unclassifiable patterns of infant-mother interaction. A critical review of these new findings in attachment theory, highlighting their potential relevance to child psychopathology, is presented. METHOD: Selective literature review relating to disorganised attachment in childhood. RESULTS: Disorganised patterns of attachment have only relatively recently been described. They show characteristic patterns of evolution in development. There is evidence that disorganised attachments are associated with specific forms of distorted parenting, which are distinct from general parental insensitivity and are associated with unresolved loss or trauma in the caregiver. There are also links with aspects of neurodevelopment vulnerability in the child. Attachment disorganisation is a powerful predictor of a range of later social and cognitive difficulties and psychopathology. CONCLUSIONS: The identification of disorganised attachment has greatly increased the potential relevance of attachment theory to general clinical work. However, the concept raises many methodological and theoretical issues. Among issues needing further exploration is the way in which attachment disorganisation relates to children's general mental states and may be affected by cognitive functioning and developmental impairment.

Adolescent↗

PubMed2004

Quantitative risk assessment for developmental neurotoxic effects.

Developmental neurotoxicity concerns the adverse health effects of exogenous agents acting on neurodevelopment. Because human brain development is a delicate process involving many cellular events, the developing fetus is rather susceptible to compounds that can alter the structure and function of the brain. Today, there is clear evidence that early exposure to many neurotoxicants can severely damage the developing nervous system. Although in recent years, there has been much attention given to model development and risk assessment procedures for developmental toxicants, the area of developmental neurotoxicity has been largely ignored. Here, we consider the problem of risk estimation for developmental neurotoxicants from animal bioassay data. Since most responses from developmental neurotoxicity experiments are nonquantal in nature, an adverse health effect will be defined as a response that occurs with very small probability in unexposed animals. Using a two-stage hierarchical normal dose-response model, upper confidence limits on the excess risk due to a given level of added exposure are derived. Equivalently, the model is used to obtain lower confidence limits on dose for a small negligible level of risk. Our method is based on the asymptotic distribution of the likelihood ratio statistic (cf. Crump, 1995). An example is used to provide further illustration.

2,4,5-Trichlorophenoxyacetic Acid↗

PubMed2006

Multidisciplinary assessment at a child development centre: do we conform to recommended standards?

BACKGROUND: A proposed standard for the multidisciplinary assessment (MDA) of children with autism has been recently published by the National Autistic Society. This prompted a review of current practice at the child development centre in our local centre, to judge whether we were able to conform to the proposed national standard. The recommendation is that a child should complete a three-stage assessment process from referral to completion of assessment within 30 weeks, with set times for completion of each stage (6, 7 and 17 weeks respectively). We applied this assessment model to children with a range of neurodevelopment problems, as the process of MDA is the same, irrespective of diagnosis. METHODS: A retrospective analysis of medical and therapy records of all MDAs was carried out between April 2001 and March 2002. RESULTS: In the 12-month period studied, 52 MDAs were performed. Delays occurred, as judged by the standard, at all three stages of the assessment process. A total of 42% of children were seen within 6 weeks of initial referral, 37% within a further 7 weeks for specialist assessment, and 37% within a further 17 weeks for completion of MDA. As delays occurred at all stages, the cumulative total showed that only 19% of children completed all three stages within the recommended 30-week standard. Barriers encountered included waiting times to see professionals, parental non-attendance and prolonged assessment of complex problems. Some of these factors are outside our control, and on removing these factors the data were re-analysed. This resulted in a slight improvement to 45%, 48% and 49% for completion of stages 1, 2 and 3 respectively. The major reason for delay remained the service capacity. CONCLUSION: In our experience the standards proposed by the National Autistic Society are not practical within present resources. We suggest that a reasonable expectation is to complete all assessments, from first concern to completed MDA, should be carried out within 52 weeks with present levels of resources. Any further improvement will require additional resources to reduce waiting times and increase the capacity.

Autistic Disorder↗

PubMed1989

Neuro-developmental study of profoundly mentally handicapped children in hospital care.

Swedish estimates of the need for long-term intensive health care provision for profoundly mentally handicapped children were compared with an Edinburgh survey, and the neurodevelopment and health characteristics of Edinburgh children with profound mental handicap who required prolonged admission are described. The extent of their disabilities indicates the complexity of the task of designing alternatives to their present hospital provision which will adequately meet their health needs.

Abnormalities, Multiple↗

PubMed2006

Different effects of chronic phencyclidine on brain-derived neurotrophic factor in neonatal and adult rat brains.

The N-methyl-D-aspartate (NMDA) receptor and brain-derived neurotrophic factor (BDNF) are both known to play major roles in the normal development of the brain. We have hypothesized that the chronic blockade of NMDA with phencyclidine (PCP) may have a different effect on BDNF synthesis at different stages of development. In an acute experiment, rat pups and adult rats were injected with PCP (2.5, 5 or 10 mg/kg) at postnatal day (PD) 15 or 49, respectively. In a chronic experiment, rat pups were injected daily from PD 5 to PD 14 with PCP (2.5, 5 or 10 mg/kg), while adult rats were injected daily with the same dose from PD 39 to PD 48. BDNF levels in the hippocampus, striatum and frontal cortex were determined by ELISA assay 24 hours after the last injection. Chronic PCP treatment of neonatal rats induced a dose-dependent decrease in BDNF in the hippocampus but not in the frontal cortex and striatum. Single injection of PCP to rat pups showed a slight reduction of BDNF in the hippocampus but only at higher doses. In contrast to neonatal brain, neither acute nor chronic injection of PCP influenced BDNF in adult brain. These findings suggest that chronic blockade of NMDA receptor in the early neonatal period has an inhibitory effect on BDNF synthesis in the hippocampus and may impair normal neurodevelopment in rat pups.

Age Factors↗

PubMed2004

Incidental neurodevelopmental episodes in the etiology of schizophrenia: an expanded model involving epigenetics and development.

Epidemiological data favors genetic predisposition for schizophrenia, a common and complex mental disorder in most populations. Search for the genes involved using candidate genes, positional cloning, and chromosomal aberrations including triplet repeat expansions have established a number of susceptibility loci and genomic sites but no causal gene(s) with a proven mechanism of action. Recent genome-wide gene expression studies on brains from schizophrenia patients and their matched controls have identified a number of genes that show an alteration in expression in the diseased brains. Although it is not possible to offer a cause and effect association between altered gene expression and disease, such observations support a neurodevelopmental model in schizophrenia. Here, we offer a mechanism of this disease, which takes into account the role of developmental noise and diversions of the neural system. It suggests that the final outcome of a neural developmental process is not fixed and exact. Rather it develops with a variation around the mean. More important, the phenotypic consequence may cross the norm as a result of fortuitous and/or epigenetic events. As a result, a normal genotype may develop as abnormal with a disease phenotype. More important, susceptible genotypes may have reduced penetrance and develop as a normal phenocopy. The incidental episodes in neurodevelopment will explain the frequency of schizophrenia in most populations and high discordance of monozygotic twins.

Brain↗

PubMed1994

Outcome of resuscitated apparently stillborn infants: a ten year review.

This study addresses the dilemma of whether to attempt resuscitation of the previously undiagnosed fresh stillborn infant and evaluates factors predictive of survival and long-term outcome. We reviewed the clinical spectrum, immediate complications and long-term outcome of 45 successfully resuscitated apparently stillborn infants (34 term, 11 preterm) who were admitted to the Intensive Care Nursery. Significant obstetric and intrapartum events were identified in 34 (75%) infants while 11 (25%) had no apparent risk factors. Of the 39 infants with neonatal complications, 37 had hypoxic-ischaemic encephalopathy (HIE: Sarnat stage 1 in 5, stage 2 in 15, stage 3 in 17); 12 (27%) had oliguria, 10 (22%) had hypotension, 7 (16%) experienced hypoglycaemia, 4 (9%) had disseminated intravascular coagulopathy (DIC) and 1 (2%) had persistent pulmonary hypertension of the newborn (PPHN). Fourteen infants (31%) died in the neonatal period and four (9%) died during infancy. Risks of death and adverse neurodevelopment were significantly increased in infants with stage 2 or 3 HIE (P < 0.005). Follow-up assessment of 24 of the 27 surviving infants revealed a normal outcome in 15 (63%), severe disability in six (25%), moderate disability in two (8%) and mild disability in one (4%) infant. The positive predictive value of stage 2 or 3 HIE was 70% for mortality and 80% for morbidity. One-third (15/45) of successfully resuscitated apparently stillborn infants were normal at follow-up assessment and the outcome for these infants was predicted with complete accuracy by the stage of HIE present during the neonatal period.

Apgar Score↗

PubMed2006

Health service utilisation of a regional cohort of very preterm infants over the first 2 years of life.

AIM: Very preterm infants represent major consumers of health services following neonatal discharge. We examined the health service utilisation of a regional cohort of very preterm infants over the first 2 years of life, including the association with neurodevelopmental outcome. METHODS: A regionally based 2-year cohort of 100 very preterm infants along with a comparison sample of 104 full term control infants matched for sex, time and place of birth were recruited. Perinatal and social background factors that predispose very preterm infants to increased risk of subsequent general practitioner (GP) and hospital service use were identified. At 2 years, all children underwent a neurodevelopmental assessment, Bayley Scales of Infant Development (BSID-II). Details of children's medical contacts obtained by parent interview were cross-checked against GP and hospital records/databases. RESULTS: Very preterm infants had a similar number of GP visits to term infants but more outpatient hospital visits. Fifty-three (55%) very preterm infants were admitted to hospital on 131 occasions compared with 26 (26%) term infants on 37 occasions (p<0.001). The main reason for hospitalisation in the preterm cohort was respiratory disorder. The frequency of hospital admissions was significantly related to birthweight (P=0.01), gestational age (P<0.001) and the number of people living in the family household (P=0.02). No associations were found between hospital admission and neurodevelopment at 2 years. CONCLUSION: Very preterm infants had higher rates of hospital admissions and visits than term infants unrelated to neurodevelopmental outcome at 2 years of age. These findings highlight that very preterm birth is associated with ongoing health morbidity.

Age Distribution↗

PubMed2006

Neurodevelopmental outcomes and surgery in neonates.

A neonate requiring major surgery in 2006 has a greater prospect of survival than ever before. Increasingly, however, there is awareness that critical illness may affect later neurodevelopment. Pre-existing conditions in addition to the physiologic stresses associated with cardiac and general surgery are implicated but remain unavoidable in the case of significant structural abnormalities such as transposition of the great arteries or congenital diaphragmatic hernia. For those affected by neurodevelopmental impairment, there is a significant cost to the child, family and society. Current research focuses on the preventable causes of brain injury, before, during and after the intervention, and the rate of impairment in apparently uncomplicated procedures. In contrast to the quantity of neurodevelopmental outcome data following cardiac surgery, there remain few outcome studies dealing with non-cardiac surgery despite such intervention being two to three times more common. There appear to be compelling clinical and economic arguments for the instigation of formalised population-based developmental assessments for all infants undergoing major surgery.

Australia↗

PubMed2004

Effects of ventral hippocampal lesion on thermal and mechanical nociception in neonates and adult rats.

The proper maturation of the hippocampus is essential for the development of different behaviours, including memory, pain responses and avoidance. The mechanisms involved in the neurodevelopment of nociception have also been implicated in several neuropsychiatric disorders. The neonatal lesion of the ventral hippocampus (VH) in rats, an animal model of schizophrenia, can be utilized to study the developmental neurobiology of animal behaviour. We examined the nociceptive responses in this animal model at different stages of development. Rat pups were lesioned at postnatal day 7 by injecting ibotenic acid into the VH bilaterally, and then tested for thermal and mechanical nociception at the age of 35, 65 and 180 days. The nociceptive tests used were the hot plate (HP), paw pressure (PP) and tail flick (TF) tests. Another group of adult rats had the same lesion in the VH and then underwent the same tests at 28, 56 and 168 days post-lesions. When compared with sham controls, the rats with neonatal VH lesion showed decreased latency for the HP and PP tests only after puberty. The TF test showed significant increase in latency for both groups at age 65 and 180 days. The adult rats with VH lesion showed no major changes over all periods of testing. These results suggest that early lesion of VH can alter the development of the neural mechanisms involved in the processing of thermal and mechanical nociception.

Age Factors↗

PubMed2005

Differential expression of calcineurin A subunit mRNA isoforms during rat hippocampal and cerebellar development.

Calcineurin (protein phosphatase 2B) is a calcium-dependent serine-threonine phosphatase. It has diverse roles and is centrally involved in synaptic plasticity. The catalytic A subunit of calcineurin has three isoforms, alpha, beta and gamma. Their expression and ontogeny in the brain has not been systematically investigated; such data become important with a report that PPP3CC, the gene encoding calcineurin Agamma, is a susceptibility gene for schizophrenia, and the finding that its expression is decreased in the disorder. We used in situ hybridization histochemistry to measure the relative transcript abundance of calcineurin Agamma and the other catalytic isoforms, Aalpha and Abeta, during development of the Sprague-Dawley rat hippocampus and cerebellum. All three isoforms are present in both regions at all time points [embryonic day 19 (E19) to postnatal day 42 (P42)] and undergo developmental regulation, but differ in their ontogenic profile. Calcineurin Aalpha and Abeta mRNAs increased from E19 through to adulthood, whereas Agamma mRNA was most highly expressed during early developmental stages. Calcineurin Aalpha and Abeta mRNAs positively correlated with synaptophysin mRNA (a synaptic marker), whilst Agamma mRNA was either unrelated to, or negatively correlated, with this transcript. These data confirm that all three calcineurin A subunits are expressed in the rodent brain, and indicate that calcineurin Agamma may have different roles than Aalpha and Abeta. The data also suggest a potential importance of calcineurin Agamma in neurodevelopment, and in the genetically influenced neurodevelopmental disturbance that is thought to underlie schizophrenia.

Age Factors↗