Risk Of Neurodevelopmental Disorders Research Articles

Exogenous oxytocin administration during labor and autism spectrum disorder

Oxytocin is a neuropeptide hormone that plays a key role in social behaviour, stress regulation, and mental health. Synthetic oxytocin administration is a common obstetrical practice, and importantly, previous research has suggested that intrapartum exposure may increase the risk of neurodevelopmental disorders, such as autism spectrum disorder (ASD). To examine the association between synthetic oxytocin exposure during labor and ASD diagnosis in the child. This population-based retrospective cohort study compared two cohorts of children: 1) all children born in British Columbia (BC), Canada between April 1, 2000 and December 31, 2014 (n = 414,336 births), and 2) all children delivered at Soroka University Medical Center (SUMC) in Be'er Sheva, Israel between January 1, 2011 and December 31, 2019 (n = 82,892 births). Nine different exposure groups were examined. Cox proportional hazards models were used to estimate crude and adjusted hazard ratios of ASD in both cohorts based on induction and/or augmentation exposures status. To further control for confounding by indication, we conducted sensitivity analyses among a cohort of healthy, uncomplicated deliveries and among a group that was induced only for post-dates. Additionally, we stratified our analyses by infant sex to assess for potential sex differences. In the BC cohort, 170,013 of 414,336 deliveries (41.0%) were not induced or augmented, 107,543 (26.0%) were exposed to oxytocin, and 136,780 (33.0%) were induced or augmented but not exposed to oxytocin. In the Israel cohort, 51,790 of 82,892 deliveries (62.5%) were not induced or augmented, 28,852 (34.8%) were exposed to oxytocin, and 2,250 (2.7%) were induced or augmented but not exposed to oxytocin. Upon adjusting for covariates in the main analysis, significant associations were observed in the Israel cohort, including adjusted hazard ratios (aHRs) of 1.51 (95% CI 1.20, 1.90) for oxytocin augmented births and 2.18 (95% CI 1.32, 3.57) for those induced by means other than oxytocin and not augmented. However, oxytocin induction was not significantly associated with ASD in the Israel cohort. In the Canadian cohort, there were no statistically significant aHRs. Further, no significant sex differences were observed in the fully adjusted models. This study provides support that induction of labor through oxytocin administration does not increase the risk of ASD in the child. Our international comparison of two countries with differences in clinical practice regarding oxytocin administration for induction and/or augmentation suggests that previous studies reporting a significant association were likely confounded by the underlying indication for the induction.

Dynamics of immune cells in the fetal brain upon viral inflammation

Abstract The fetal immune system undergoes many developmental milestones, with several immune cell subsets emerging during pregnancy. Recent evidence has shown that maternal infections during pregnancy can influence offspring immunity in the long term. Moreover, maternal infections are associated with an increased risk for neurodevelopmental disorders in the offspring. Yet, our knowledge of the immune cell dynamics in the fetal brain throughout gestation and their response to inflammation remains limited. We sought to characterize the phenotype of immune cells in murine implantation sites at mid-gestation, a time point equivalent to the beginning of the second trimester in humans. Our preliminary studies revealed specific and robust populations of maternal and fetal immune cells in murine fetal brains. Quite unexpectedly, one of these populations expressed NK1.1, a marker for natural killer cells and innate lymphoid cells. Given that the presence of maternal and fetal NK1.1+ cells in the fetal brains at mid-gestation has not been previously reported, our goal is to determine the phenotype and kinetics of the maternal and fetal NK1.1+ immune cells in the fetal brain during a healthy pregnancy and upon congenital infection.To address this, I will use a high-dimensional sequencing technology, CITE-seq, that allows me to simultaneously study surface markers and gene expression of cells. Maternal immune responses critically impact fetal development during gestation and have long-term health outcomes in offspring. Understanding maternal and fetal immune responses to inflammation will inform the origin of fetal inflammation-driven neurodevelopmental disorders and ultimately improve offspring’s health outcomes. Supported by Packard Foundation Fellowship for Science and Engineering

Maternal immune activation as an epidemiological risk factor for neurodevelopmental disorders: Considerations of timing, severity, individual differences, and sex in human and rodent studies.

Epidemiological evidence suggests that one's risk of being diagnosed with a neurodevelopmental disorder (NDD)-such as autism, ADHD, or schizophrenia-increases significantly if their mother had a viral or bacterial infection during the first or second trimester of pregnancy. Despite this well-known data, little is known about how developing neural systems are perturbed by events such as early-life immune activation. One theory is that the maternal immune response disrupts neural processes important for typical fetal and postnatal development, which can subsequently result in specific and overlapping behavioral phenotypes in offspring, characteristic of NDDs. As such, rodent models of maternal immune activation (MIA) have been useful in elucidating neural mechanisms that may become dysregulated by MIA. This review will start with an up-to-date and in-depth, critical summary of epidemiological data in humans, examining the association between different types of MIA and NDD outcomes in offspring. Thereafter, we will summarize common rodent models of MIA and discuss their relevance to the human epidemiological data. Finally, we will highlight other factors that may interact with or impact MIA and its associated risk for NDDs, and emphasize the importance for researchers to consider these when designing future human and rodent studies. These points to consider include: the sex of the offspring, the developmental timing of the immune challenge, and other factors that may contribute to individual variability in neural and behavioral responses to MIA, such as genetics, parental age, the gut microbiome, prenatal stress, and placental buffering.

Effects of maternal vitamin deficiency on the microstructure of the maternal hippocampus and behavior in offspring

ObjectivesNutrition plays a critical role in the brain's function and development. Vitamin B6 in the form of pyridoxal phosphate (PLP) is required for the biosynthesis of several neurotransmitters. As vitamin B6 is not endogenously synthesized, the availability of dietary sources becomes imperative. Due to its contribution to neurological functions, severe vitamin B6 deficiency leads to an increased risk of psychiatric disorders, dementia, and neurodevelopmental disorders. This study aimed to establish a vitamin B6-deficient model in experimental animals and assess the neurodevelopmental effects in their offspring. MethodsTwo- to three-month-old female C57BL/6J mice were used in the study. They were randomly divided into control and vitamin B6-deficient groups. The control group was fed a regular diet containing 6 mg vitamin B6/kg and the vitamin B6-deficient group was fed a customized diet containing 0 mg vitamin B6/kg, for 5 weeks (n = 6). After 5 weeks, plasma PLP was assessed. The animals were bred to generate offspring. The dams were killed following weaning, and the hippocampal neurons were quantified using cresyl violet staining. The offspring were assigned the respective diet post-weaning up to 2 months of age. Learning and memory were assessed using the Morris water maze test. ResultsThe plasma PLP levels confirmed the deficiency in the deficient group compared to the control group. The viable pyramidal neurons in the cornu ammonis 3 (CA3) region of the hippocampus showed a significant difference between the control and deficient groups. Offspring born to deficient dams showed a substantial increase in latency to reach the target quadrant during the probe trial compared to the controls. ConclusionVitamin B6 deficiency reduces memory in dams and their offspring, suggesting the importance of vitamin B6 for both brain function and development.

Developmental pyrethroid exposure causes a neurodevelopmental disorder phenotype in mice.

Neurodevelopmental disorders (NDDs) are a widespread and growing public health challenge, affecting as many as 17% of children in the United States. Recent epidemiological studies have implicated ambient exposure to pyrethroid pesticides during pregnancy in the risk for NDDs in the unborn child. Using a litter-based, independent discovery-replication cohort design, we exposed mouse dams orally during pregnancy and lactation to the Environmental Protection Agency's reference pyrethroid, deltamethrin, at 3 mg/kg, a concentration well below the benchmark dose used for regulatory guidance. The resulting offspring were tested using behavioral and molecular methods targeting behavioral phenotypes relevant to autism and NDD, as well as changes to the striatal dopamine system. Low-dose developmental exposure to the pyrethroid deltamethrin (DPE) decreased pup vocalizations, increased repetitive behaviors, and impaired both fear conditioning and operant conditioning. Compared with control mice, DPE mice had greater total striatal dopamine, dopamine metabolites, and stimulated dopamine release, but no difference in vesicular dopamine capacity or protein markers of dopamine vesicles. Dopamine transporter protein levels were increased in DPE mice, but not temporal dopamine reuptake. Striatal medium spiny neurons showed changes in electrophysiological properties consistent with a compensatory decrease in neuronal excitability. Combined with previous findings, these results implicate DPE as a direct cause of an NDD-relevant behavioral phenotype and striatal dopamine dysfunction in mice and implicate the cytosolic compartment as the location of excess striatal dopamine.

Association between maternal influenza vaccination and neurodevelopmental disorders in childhood: a longitudinal, population-based linked cohort study

ObjectiveTo assess the association between in utero exposure to seasonal inactivated influenza vaccine (IIV) and the risk of a diagnosis of a neurodevelopmental disorder in early childhood.DesignRetrospective cohort study.SettingPopulation-based birth...

The correlation between prenatal maternal active smoking and neurodevelopmental disorders in children: a systematic review and meta-analysis

ObjectiveTo systematically evaluate the association between maternal active smoking during pregnancy and Tourette syndrome (TS), chronic tic disorder (CTD), and developmental coordination disorder (DCD) in children, and to provide evidence-based medical references to reduce the incidence of neurodevelopmental disorders in children.MethodWe searched PubMed, Web of Science, Embase, and Cochrane Library to obtain relevant articles published before 4 August 2021. Two reviewers independently assessed the articles for eligibility and extracted data.ResultsWe included eight studies involving a total of 50,317 participants (3 cohort, 3 case–control, and 2 cross-sectional studies). The pooled effect estimates suggested that prenatal maternal active smoking is related to an increased risk of neurodevelopmental disorders (OR = 1.91, 95% CI: 1.30–2.80), especially DCD (OR = 2.25, 95% CI: 1.35–3.75). Maternal active smoking during pregnancy is not associated with TS (OR = 1.07, 95% CI: 0.66–1.73) in children.ConclusionIn this meta-analysis, we found evidence for a correlation between active smoking exposure in pregnant women and neurodevelopmental disorders in children. Owing to the differences in sample size, smoking categories and diagnostic methods, further research is needed to validate our results.

Executive Function, Attention and Autism Symptomatology in School-Aged Children with Cerebral Palsy

Objective: Children diagnosed with cerebral palsy have been reported to be at increased risk of executive function deficits and neurodevelopmental disorders. This population-based cohort study aimed to assess executive function, attention, behaviour, and autism symptomatology in school-aged children with CP, using parent-report measures that can provide insight into everyday functioning in these neurodevelopmental domains. Methods: 74 participants (male n = 51) mean age 9 years 9 months, SD 1 year 1.2 months (range 8 years 0 months to 12 years 11 months), GMFCS I = 45 (60.8%), II = 17 (23%), III = 8 (10.8%), and IV = 4 (5.4%), were assessed on measures of attention and behaviour (Conners-3), executive function (BRIEF), and autism symptomatology (AQ10-Child). Analysis was via one-sample t-tests and MANCOVAs. Results: Participants’ scores were elevated in comparison to the general population in all domains, while 29.1% of participants scored above the cut-off level on an autism symptomatology screener. Greatest impairment was reported for working memory (M = 60.7, SD = 10.0, t(72) = 9.2, p < .001), peer relations (M = 72.7, SD = 16.2, t(73) = 12.0, p < .001), and inattention subscales (M = 66.3, SD = 12.5, t(73) = 11.2, p < .001). No statistically significant differences were found for different GMFCS levels on domains of executive functioning. A statistically significant difference was found between GMFCS levels for inattention F(3, 71) = 3.83, p = .013, partial η2 = 0.162, with most elevated scores associated with GMFCS level II (M = 74.1, SD = 14.2). Conclusion: EF, attention and behavioural difficulties, and autism symptomatology are commonly reported in school-aged children with CP. Screening for these comorbidities using ratings scales will assist with early diagnosis and targeted intervention.

Rates of maternal weight gain over the course of pregnancy and offspring risk of neurodevelopmental disorders

BackgroundPrevious studies have suggested that gestational weight gain (GWG) outside an optimal range increases the risks of neurodevelopmental disorders (NDDs) in offspring including autism spectrum disorder (ASD), intellectual disability (ID), and attention deficit/hyperactivity disorder (ADHD). The sequential development of the fetal brain suggests that its vulnerability may vary depending on the timing of exposure. Therefore, we aimed to investigate the associations of not only gestational age-standardized total GWG (GWG z-scores) but also the rate of GWG (RGWG) in the second and third trimesters with risks of NDDs in offspring.MethodsIn this population-based cohort study, we used maternal weight data from antenatal care records collected for 57,822 children born to 53,516 mothers between 2007 and 2010 in the Stockholm Youth Cohort. Children were followed from 2 years of age to December 31, 2016. GWG z-scores and RGWG (kg/week) in the second and third trimesters were considered as continuous variables in cox regression models, clustered on maternal identification numbers. Nonlinear relationships were accommodated using restricted cubic splines with 3 knots. RGWG were also categorized according to the 2009 US Institute of Medicine (IOM) guidelines for optimal GWG. According to the IOM guidelines, the optimal rate of GWG for the second and third trimesters for underweight, normal weight, overweight, and obese categories were 0.44–0.58, 0.35–0.50, 0.23–0.33, and 0.17–0.27 kg/week, respectively.ResultsDuring a mean follow-up of 5.4 years (until children were on average 7.4 years old), 2205 (3.8%) children were diagnosed with NDDs, of which 1119 (1.9%) received a diagnosis of ASD, 1353 (2.3%) ADHD, and 270 (0.5%) ID. We observed a J-shaped association between total GWG z-score and offspring risk of NDDs, with higher total GWG (GWG z-score = 2) associated with 19% increased risk of any NDD (95% CI = 3–37%) and lower total GWG (GWG z-score = − 2) associated with 12% increased risk of any NDDs (95% CI = 2–23%), compared to the reference (GWG z-score = 0). In the second trimester, lower RGWG (0.25 kg/week) was associated with a 9% increased risk of any NDD diagnosis (95% CI = 4–15%) compared to the median of 0.57 kg/week, with no apparent relationship between higher RGWG and risk of NDDs. In the third trimester, there was no apparent association between lower RGWG and risk of NDDs, though higher RGWG (1 kg/week) was associated with a 28% increased risk of NDD diagnosis (95% CI = 16–40%), compared to the median (0.51 kg/week). When considering categorized RGWG, we found that slow weight gain in the second trimester followed by rapid weight gain in the third trimester most significantly increased the risk of ADHD (HRadjusted = 1.55, 1.13–2.13) and ID (HRadjusted = 2.53, 1.15–5.55) in offspring. The main limitations of our study are the relatively few years for which detailed GWG data were available and the relatively short follow-up for the outcomes, limiting power to detect associations and misclassifying children who receive an NDD diagnosis later in childhood.ConclusionsThe relationship between maternal weight gain and children’s risk of NDDs varied according to timing in pregnancy, with the greatest risks associated with slow weight gain in the second trimester and rapid weight gain in the third trimester.

Sex-Specific Neurodevelopmental Outcomes Among Offspring of Mothers With SARS-CoV-2 Infection During Pregnancy

Prior studies using large registries have suggested a modest increase in risk for neurodevelopmental diagnoses among children of mothers with immune activation during pregnancy, and such risk may be sex-specific. To determine whether in utero exposure to SARS-CoV-2 is associated with sex-specific risk for neurodevelopmental disorders up to 18 months after birth, compared with unexposed offspring born during or prior to the COVID-19 pandemic period. This retrospective cohort study included the live offspring of all mothers who delivered between January 1 and December 31, 2018 (born and followed up before the COVID-19 pandemic), between March 1 and December 31, 2019 (born before and followed up during the COVID-19 pandemic), and between March 1, 2020, and May 31, 2021 (born and followed up during the COVID-19 pandemic). Offspring were born at any of 8 hospitals across 2 health systems in Massachusetts. Polymerase chain reaction evidence of maternal SARS-CoV-2 infection during pregnancy. Electronic health record documentation of International Statistical Classification of Diseases and Related Health Problems, Tenth Revision diagnostic codes corresponding to neurodevelopmental disorders. The COVID-19 pandemic cohort included 18 355 live births (9399 boys [51.2%]), including 883 (4.8%) with maternal SARS-CoV-2 positivity during pregnancy. The cohort included 1809 Asian individuals (9.9%), 1635 Black individuals (8.9%), 12 718 White individuals (69.3%), and 1714 individuals (9.3%) who were of other race (American Indian or Alaska Native, Native Hawaiian or other Pacific Islander, more than 1 race); 2617 individuals (14.3%) were of Hispanic ethnicity. Mean maternal age was 33.0 (IQR, 30.0-36.0) years. In adjusted regression models accounting for race, ethnicity, insurance status, hospital type (academic center vs community), maternal age, and preterm status, maternal SARS-CoV-2 positivity was associated with a statistically significant elevation in risk for neurodevelopmental diagnoses at 12 months among male offspring (adjusted OR, 1.94 [95% CI 1.12-3.17]; P = .01) but not female offspring (adjusted OR, 0.89 [95% CI, 0.39-1.76]; P = .77). Similar effects were identified using matched analyses in lieu of regression. At 18 months, more modest effects were observed in male offspring (adjusted OR, 1.42 [95% CI, 0.92-2.11]; P = .10). In this cohort study of offspring with SARS-CoV-2 exposure in utero, such exposure was associated with greater magnitude of risk for neurodevelopmental diagnoses among male offspring at 12 months following birth. As with prior studies of maternal infection, substantially larger cohorts and longer follow-up will be required to reliably estimate or refute risk.

Review of neurodevelopmental disorders in patients with HNF1B gene variations.

This review investigates the association between neurodevelopmental disorders (NDD) and variations of the gene HNF1B. Heterozygous intragenetic mutations or heterozygous gene deletions (17q12 microdeletion syndrome) of HNF1B are the cause of a multi-system developmental disorder, termed renal cysts and diabetes syndrome (RCAD). Several studies suggest that in general, patients with genetic variation of HNF1B have an elevated risk for additional neurodevelopmental disorders, especially autism spectrum disorder (ASD) but a comprehensive assessment is yet missing. This review provides an overview including all available studies of patients with HNF1B mutation or deletion with comorbid NDD with respect to the prevalence of NDDs and in how they differ between patients with an intragenic mutation or 17q12 microdeletion. A total of 31 studies was identified, comprising 695 patients with variations in HNF1B, (17q12 microdeletion N = 416, mutation N = 279). Main results include that NDDs are present in both groups (17q12 microdeletion 25.2% vs. mutation 6.8%, respectively) but that patients with 17q12 microdeletions presented more frequently with any NDDs and especially with learning difficulties compared to patients with a mutation of HNF1B. The observed prevalence of NDDs in patients with HNF1B variations seems to be higher than in the general population, but the validity of the estimated prevalence must be deemed insufficient. This review shows that systematical research of NDDs in patients with HNF1B mutations or deletions is lacking. Further studies regarding neuropsychological characteristics of both groups are needed. NDDs might be a concomitant of HFN1B-related disease and should be considered in clinical routine and scientific reports.

Umbilical cord-derived mesenchymal stromal cell therapy to prevent the development of neurodevelopmental disorders related to low birth weight

Low birth weight (LBW) increases the risk of neurodevelopmental disorders (NDDs) such as attention-deficit/hyperactive disorder and autism spectrum disorder, as well as cerebral palsy, for which no prophylactic measure exists. Neuroinflammation in fetuses and neonates plays a major pathogenic role in NDDs. Meanwhile, umbilical cord-derived mesenchymal stromal cells (UC-MSCs) exhibit immunomodulatory properties. Therefore, we hypothesized that systemic administration of UC-MSCs in the early postnatal period may attenuate neuroinflammation and thereby prevent the emergence of NDDs. The LBW pups born to dams subjected to mild intrauterine hypoperfusion exhibited a significantly lesser decrease in the monosynaptic response with increased frequency of stimulation to the spinal cord preparation from postnatal day 4 (P4) to P6, suggesting hyperexcitability, which was improved by intravenous administration of human UC-MSCs (1 × 105 cells) on P1. Three-chamber sociability tests at adolescence revealed that only LBW males exhibited disturbed sociability, which tended to be ameliorated by UC-MSC treatment. Other parameters, including those determined via open-field tests, were not significantly improved by UC-MSC treatment. Serum or cerebrospinal fluid levels of pro-inflammatory cytokines were not elevated in the LBW pups, and UC-MSC treatment did not decrease these levels. In conclusion, although UC-MSC treatment prevents hyperexcitability in LBW pups, beneficial effects for NDDs are marginal.

Analysis of specific risk factors of neurodevelopmental disorder in hearing-impaired infants under ten months of age: "EnTNDre" an opening research stemming from a transdisciplinary partnership.

Approximately 20% of children born with severe to profound hearing loss (HL) have an associated disorder that poses a neurodevelopmental risk [1]. The objective of this study is to identify the criteria and profiles of deaf infants at risk of neurodevelopmental disorders (NDD) to provide early intervention. Twenty-two infants aged three to ten months with bilateral congenital deafness were included. Each child attended a consultation with a psychiatrist specializing in the development of hearing-impaired infants as part of their ENT follow-up. The quality of their early development was analyzed using the Olliac grid and well-known postural and sensorimotor criteria. The children were then classified into three groups: normal examination (Group 1), evident NDD (Group 2), and intermediate examination (Group 3). Early medical history, the etiology of deafness, cerebral imaging, and vestibular test results were collected and compared in the different groups. The average age of the children at the time of observation was seven months (3-10 months). All had sensorineural HL, with identified causes in 13 out of 22 cases: five cases of connexin 26 gene mutation, three cases of CHARGE syndrome, two CMV infections, one Usher syndrome, one GATA3 mutation, and one LHPL5 mutation. The average score on the Olliac grid was nine (0-15), and abnormal postural and sensorimotor behaviors were found in 15 cases out of 22 (68%). 27% of the children were classified in Group 1, 45% in Group 2, and 27% in Group 3. Children with non-isolated HL, abnormal brain MRI (8/22), malformations outside the auditory system (10/22), vestibular impairments (9/22), and/or CMV infections (2/22) were distributed as follows: 2/6 in Group 1, 9/10 in Group 2, and 3/6 in Group 3. 8/22 children had suffered perinatal complications (0/6 in Group 1, 6/10 in Group 2, and 2/5 in Group 3). Only one child had a first-degree relative with NDD. He belonged to Group 2. To our knowledge, this paper is the first to describe the development of infants with congenital deafness. It is based on an observation time that had been included in the procedure of multidisciplinary evaluations prior to cochlear implantation (CI), thanks to the partnership between a psychiatric center for deaf children and an ENT-pediatric implantology service. This consultation was aimed at assessing the quality of neurodevelopment and identifying NDD without a specific referral, with good acceptability for families. Using the Olliac grid and postural and sensorimotor criteria developed to be assessed in the routine care consultation, we identified evident early signs of NDD in 45% of infants. This group (Group 2) requires early, targeted, developmental support. Some children in an intermediate zone (Group 3) require further observation and support. The very early identification of NDD seems to be relevant in the care of hearing-impaired infants. The use of the Olliac grid and developmental scales seems relevant to identifying infants at risk for NDD.

Correlation between BDNF levels and folic acid levels at baseline in drug-naïve First Episode Psychosis

IntroductionSchizophrenia is a severe and common psychiatric disorder characterized by disturbed brain development. Brain-derived neurotrophic factor (BDNF) mediates differentiation and survival of neurons as well as synaptic plasticity during the brain development. Several studies have shown decreased serum levels of BDNF in chronic, first episode, and drug naïve schizophrenia patients. Folate provides the substrate for intracellular methylation reactions that are essential to normal brain development and function. Abnormal folate metabolism has been implicated in schizophrenia. For example, reduced maternal folate intake associated with an increased risk for schizophrenia. Also, low blood levels of folate have been reported in patients with schizophrenia, and are associated with clinical manifestation especially in the negative symptom domain.ObjectivesWith this study, we want to know how BDNF levels at baseline in drug-naïve FEP are associated with folic acid.MethodsFifty drug-naïve FEP treated between April 2013 and July 2017 at the ETEP Program at Hospital del Mar were included. Inclusion criteria were: 1) age 18-35 years; 2) DSM-IV-TR criteria for brief psychotic disorder, schizophreniform disorder, schizophrenia or unspecified psychosis; 3) no previous history of severe neurological medical conditions or severe traumatic brain injury; 4) presumed IQ level &gt; 80, and 5) no substance abuse or dependence disorders except for cannabis and/or nicotine use. All patients underwent an assessment at baseline including sociodemographic and clinical variables. Fasting blood samples were obtained before administering any medication at baseline and used to determine folic acid and BDNF levels.ResultsIn our drug-naïve FEP sample, folic acid levels showed a significative positive correlation with BDNF levels at baseline (r = 0.584; p = 0.003). Moreover, we did a lineal regression model that showed that the baseline variables that better predict BDNF levels were folic acid levels, and cannabis use.ConclusionsOur results are consistent with the findings from some of previous studies that also shows that lower folic acid levels are associated with lower BNDF levels at baseline in drug-naïve FEP. Folate deficiency is associated with cerebrovascular and neurological diseases, and mood disorders. The importance of folate in the nervous system was initially demonstrated in studies that established a greatly increased risk of neurodevelopmental disorders in the offspring of folate-deficient pregnant women. In the adult, epidemiological studies have linked lack of folate to neurodegenerative and neuropsychiatric diseases. However, the mechanisms by which chronic folate deficiency adversely affects CNS function are incompletely understood. Some studies in animals models have hypothesized that folate deficiency in animals could be associated with pyramidal cell loss and reduced hippocampal BDNF.Disclosure of InterestNone Declared

Pandemic city: Village-in-a-dish unlocks dynamic genetic effects in the brain.

In this issue, Wells etal. combine genetic multiplexing ("village-in-a-dish") and Stem-cell-derived NGN2-accelerated Progenitors (SNaPs) to evaluate genotype-phenotype relationships across 100 donors in the context of Zika virus infection in the developing brain. This resource will be broadly applicable in uncovering how genetic variation underlies risk for neurodevelopmental disorders.

Exploring the impact of COVID-19 on newborn neurodevelopment: a pilot study

The COVID-19 pandemic can seize the opportunity to explore the hypothesis of prenatal exposure to viral infections increases the risk for neurodevelopmental disorders. Advancing our knowledge in this regard would improve primary prevention of mental disorders in children. For this pilot study, six-week-old infants born to mothers exposed (n = 21) or unexposed (n = 21) to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) were assessed in Santander-Cantabria (Spain) using the Neonatal Behavioral Assessment Scale (NBAS). Groups comparisons were performed to explore the effects that infection and timing of exposure (in terms of the three trimesters of pregnancy). The infants’ competencies and performances on the NBAS were generally similar in the exposed and unexposed to SARS-CoV-2 groups. The most significant difference found was a less optimally response to cuddliness (item on the state regulation domain) particularly in infants born to mothers exposed in the third trimester of pregnancy, and in pull-to-sit (item on the motor system domain). Although our interpretations must be careful, these preliminary results highlight the possible association between prenatal SARS-CoV-2 exposure and poorer development in motor skills and infant interactive behavior. Further longitudinal studies are needed to explore these relationships and disentangle the biological mechanisms implicated.

Vasopressin, and not oxytocin, receptor gene methylation is associated with individual differences in receptive joint attention in chimpanzees (Pan troglodytes).

Joint attention (JA) is an important milestone in human infant development and is predictive of the onset of language later in life. Clinically, it has been reported that children at risk for or with a diagnosis of autism spectrum disorder (ASD) perform more poorly on measures of JA compared to neurotypical controls. JA is not unique to humans but has also been reported in great apes and to a lesser extent in more distantly related monkeys. Further, individual differences in JA among chimpanzees are associated with polymorphisms in the vasopressin and oxytocin genes, AVPR1A and OXTR. Here, we tested whether individual variation in DNA methylation of OXTR and AVPR1A were associated with performance on JA tasks in chimpanzees. We found that individual differences in JA performance was associated with AVPR1A methylation, but not OXTR methylation in the chimpanzees. The collective results provide further evidence of the role of AVPR1A in JA abilities in chimpanzees. The results further suggest that methylation values for AVPR1A may be useful biomarkers for identifying individuals at risk for ASD or related neurodevelopmental disorders associated with impairments in JA abilities.

Maternal preconception circulating blood biomarker mixtures, child behavioural symptom scores and the potential mediating role of neonatal brain microstructure: the S-PRESTO cohort

Human brain development starts in the embryonic period. Maternal preconception nutrition and nutrient availability to the embryo may influence brain development at this critical period following conception and early cellular differentiation, thereby affecting offspring neurodevelopmental and behavioural disorder risk. However, studying this is challenging due to difficulties in characterizing preconception nutritional status and few studies have objective neurodevelopmental imaging measures in children. We investigated the associations of maternal preconception circulating blood nutrient-related biomarker mixtures (~15 weeks before conception) with child behavioural symptoms (Child Behaviour Checklist (CBCL), aged 3 years) within the Singapore Preconception Study of Long-Term Maternal and Child Outcomes (S-PRESTO) study. The CBCL preschool form evaluates child behaviours based on syndrome scales and Diagnostic and Statistical Manual of Mental Disorders (DSM) oriented scales. These scales consist of internalizing problems, externalizing problems, anxiety problems, pervasive developmental problems, oppositional defiant, etc. We applied data-driven clustering and a method for modelling mixtures (Bayesian kernel machine regression, BKMR) to account for complex, non-linear dependencies between 67 biomarkers. We used effect decomposition analyses to explore the potential mediating role of neonatal (week 1) brain microstructure, specifically orientation dispersion indices (ODI) of 49 cortical and subcortical grey matter regions. We found that higher levels of a nutrient cluster including thiamine, thiamine monophosphate (TMP), pyridoxal phosphate, pyridoxic acid, and pyridoxal were associated with a higher CBCL score for internalizing problems (posterior inclusion probability (PIP) = 0.768). Specifically, thiamine independently influenced CBCL (Conditional PIP = 0.775). Higher maternal preconception thiamine level was also associated with a lower right subthalamic nucleus ODI (P-value = 0.01) while a lower right subthalamic nucleus ODI was associated with higher CBCL scores for multiple domains (P-value < 0.05). One potential mechanism is the suboptimal metabolism of free thiamine to active vitamin B1, but additional follow-up and replication studies in other cohorts are needed.

Maternal anxiety, exposure to the COVID-19 pandemic and socioemotional development of offspring

The COVID-19 pandemic context may predispose mothers to increased maternal psychopathology, which may be associated with offspring socioemotional development. The aim of this study is to analyze the relationships between prenatal anxiety and depression and exposure to the COVID-19 pandemic with offspring socioemotional development, controlling for postnatal anxiety and depression. A total of 105 mother-child dyads were assessed in pre- and postnatal periods. Questionnaires were used to assess the impact of the pandemic, indicators of psychopathology, and the socioemotional development of the offspring. Results suggest that negative pandemic experiences are indirectly associated with offspring socioemotional development via prenatal maternal anxiety symptomatology and after controlling for postnatal anxiety and depression. These indicators predispose to emotional deficits and increase the risks of psychopathological and neurodevelopmental disorders. It is important to adopt health policies that provide timely assessment of development in early childhood to reduce the risks associated with these deficits.

The impact of intestinal atresia on educational and mental health outcomes in school-aged children: A case–control cohort study

To assess real-world educational outcomes, neurodevelopmental disorders and mental health disorders in patients with intestinal atresia (IA) and compare these to outcomes to age-matched controls. We performed a retrospective case-control study of children with IA born between 1991 and 2017. We evaluated educational outcomes using an Early Developmental Instrument, Grades 3, 7 and 8 assessments, Grade 9 completion and performance, high school graduation, and neurodevelopmental and mental health disorders using International Classification of Diseases codes available from a population-based dataset. We identified a total of 94 IA cases and 940 date-of-birth-matched controls. Cases with chromosomal anomalies were more likely to fail the Early Developmental Instrument (OR = 2.88, p = 0.037), Grade 8 reading (OR = 2.94, p = 0.043) and Grade 12 (OR = 3.25, p = 0.036); cases without chromosomal anomalies were at no greater risk than their peers of failing to meet expectations and did not have an increased risk of anxiety (OR = 0.48, p = 0.12), depression (OR = 0.74, p = 0.6) or hyperactivity disorder (OR = 1.92, p = 0.087). Our study demonstrated that IA patients without chromosomal anomalies are not at higher risk of neurodevelopmental and mental health disorders than controls. These results will offer more accurate outcome predictions for parents of children with IA.