Brain Development Research Articles

Human-specific insights into candidate genes and boosted discoveries of novel loci illuminate roles of neuroglia in reading disorders.

Reading disorders (RD) are human-specific neuropsychological conditions associated with decoding printed words and/or reading comprehension. So far only a handful of candidate genes segregated in families and 42 loci from genome-wide association study (GWAS) have been identified that jointly provided little clues of pathophysiology. Leveraging human-specific genomic information, we critically assessed the RD candidates for the first time and found substantial human-specific features within. The GWAS candidates (i.e., population signals) were distinct from the familial counterparts and were more likely pleiotropic in neuropsychiatric traits and to harbor human-specific regulatory elements (HSREs). Candidate genes associated with human cortical morphology indeed showed human-specific expression in adult brain cortices, particularly in neuroglia likely regulated by HSREs. Expression levels of candidate genes across human brain developmental stages showed a clear pattern of uplifted expression in early brain development crucial to RD development. Following the new insights and loci pleiotropic in cognitive traits, we identified four novel genes from the GWAS sub-significant associations (i.e., FOXO3, MAPT, KMT2E and HTT) and the Semaphorin gene family with functional priors (i.e., SEMA3A, SEMA3E and SEMA5B). These novel genes were related to neuronal plasticity and disorders, mostly conserved the pattern of uplifted expression in early brain development and had evident expression in cortical neuroglial cells. Our findings jointly illuminated the association of RD with neuroglia regulation-an emerging hotspot in studying neurodevelopmental disorders, and highlighted the need of improving RD phenotyping to avoid jeopardizing future genetic studies of RD.

Neural Tracking of Perceived Parent, but Not Peer, Norms Is Associated with Longitudinal Changes in Adolescent Attitudes about Externalizing Behaviors.

Adolescents' perceptions of parent and peer norms about externalizing behaviors influence the extent to which they adopt similar attitudes, yet little is known about how the trajectories of perceived parent and peer norms are related to trajectories of personal attitudes across adolescence. Neural development of midline regions implicated in self-other processing may underlie developmental changes in parent and peer influence. Here, we examined whether neural processing of perceived parent and peer norms in midline regions during self-evaluations would be associated with trajectories of personal attitudes about externalizing behaviors. Trajectories of adolescents' perceived parent and peer norms were examined longitudinally with functional neuroimaging (n = 165; ages 11-16 years across three waves; 86 girls, 79 boys; 29.7% White, 21.8% Black, 35.8% Latinx, 12.7% other/multiracial). Behavioral results showed perceived parent norms were less permissive than adolescents' own attitudes about externalizing behaviors, whereas perceived peer norms were more permissive than adolescents' own attitudes, effects that increased from early to middle adolescence. Although younger adolescents reported less permissive attitudes when they spontaneously tracked perceived parent norms in the ventromedial and medial pFCs during self-evaluations, this effect weakened as they aged. No brain-behavior effects were found when tracking perceived peer norms. These findings elucidate how perceived parent and peer norms change in parallel with personal attitudes about externalizing behaviors from early to middle adolescence and underscore the importance of spontaneous neural tracking of perceived parent norms during self-evaluations for buffering permissive personal attitudes, particularly in early adolescence.

Expression of Dystrophin Dp71 Splice Variants Is Temporally Regulated During Rodent Brain Development.

Dystrophin Dp71 is the major product of the Duchenne muscular dystrophy (DMD) gene in the brain, and its loss in DMD patients and mouse models leads to cognitive impairments. Dp71 is expressed as a range of proteins generated by alternative splicing of exons 71 to 74 and 78, classified in the main Dp71d and Dp71f groups that contain specific C-terminal ends. However, it is unknown whether each isoform has a specific role in distinct cell types, brain regions, and/or stages of brain development. In the present study, we characterized the expression of Dp71 isoforms during fetal (E10.5, E15.5) and postnatal (P1, P7, P14, P21 and P60) mouse and rat brain development. We finely quantified the expression of several Dp71 transcripts by RT-PCR and cloning assays in samples from whole-brain and distinct brain structures. The following Dp71 transcripts were detected: Dp71d, Dp71d∆71, Dp71d∆74, Dp71d∆71,74, Dp71d∆71-74, Dp71f, Dp71f∆71, Dp71f∆74, Dp71f∆71,74, and Dp71fΔ71-74. We found that the Dp71f isoform is the main transcript expressed at E10.5 (> 80%), while its expression is then progressively reduced and replaced by the expression of isoforms of the Dp71d group from E15.5 to postnatal and adult ages. This major finding was confirmed by third-generation nanopore sequencing. In addition, we found that the level of expression of specific Dp71 isoforms varies as a function of postnatal stages and brain structure. Our results suggest that Dp71 isoforms have different and complementary roles during embryonic and postnatal brain development, likely taking part in a variety of maturation processes in distinct cell types.

Intrauterine inflammation and postnatal intravenous dopamine alter the neurovascular unit in preterm newborn lambs

BackgroundIntrauterine inflammation is considered a major cause of brain injury in preterm infants, leading to long-term neurodevelopmental deficits. A potential contributor to this brain injury is dysregulation of neurovascular coupling. We have shown that intrauterine inflammation induced by intra-amniotic lipopolysaccharide (LPS) in preterm lambs, and postnatal dopamine administration, disrupts neurovascular coupling and the functional cerebral haemodynamic responses, potentially leading to impaired brain development. In this study, we aimed to characterise the structural changes of the neurovascular unit following intrauterine LPS exposure and postnatal dopamine administration in the brain of preterm lambs using cellular and molecular analyses.MethodsAt 119–120 days of gestation (term = 147 days), LPS was administered into the amniotic sac in pregnant ewes. At 126-7 days of gestation, the LPS-exposed lambs were delivered, ventilated and given either a continuous intravenous infusion of dopamine at 10 µg/kg/min or isovolumetric vehicle solution for 90 min (LPS, n = 6; LPSDA, n = 6). Control preterm lambs not exposed to LPS were also administered vehicle or dopamine (CTL, n = 9; CTLDA, n = 7). Post-mortem brain tissue was collected 3–4 h after birth for immunohistochemistry and RT-qPCR analysis of components of the neurovascular unit.ResultsLPS exposure increased vascular leakage in the presence of increased vascular density and remodelling with increased astrocyte “end feet” vessel coverage, together with downregulated mRNA levels of the tight junction proteins Claudin-1 and Occludin. Dopamine administration decreased vessel density and size, decreased endothelial glucose transporter, reduced neuronal dendritic coverage, increased cell proliferation within vessel walls, and increased pericyte vascular coverage particularly within the cortical and deep grey matter. Dopamine also downregulated VEGFA and Occludin tight junction mRNA, and upregulated dopamine receptor DRD1 and oxidative protein (NOX1, SOD3) mRNA levels. Dopamine administration following LPS exposure did not exacerbate any effects induced by LPS.ConclusionLPS exposure and dopamine administration independently alters the neurovascular unit in the preterm brain. Alterations to the neurovascular unit may predispose the developing brain to further injury.

Prenatal ultrasound reassessment of the corpus callosum based on cortical connectivity information

IntroductionRoutine prenatal ultrasound assessment of the corpus callosum (CC) does not reflect information on fibrous connections. The primary purpose was to construct detailed reference ranges of quantitative characteristics of the foetal CC based on cortical connectivity information. Secondary goals were to examine for sex differences and assess the validity of the measurement technique for cases with CC dysplasia.Material and methodsPregnant women referred to a tertiary centre for sonographic examination were recruited to undergo a detailed foetal scan from 19 to 40 weeks. The foetal CC was divided into 5 distinct segments using the Hofer & Frahm classification technique. The thickness of each segment and the overall length of the CC were measured. Additionally, a segmental evaluation was conducted on partial agenesis of the CC. The inter- and intraobserver variability were assessed by interclass correlation coefficients. Regression analysis was used to determine the association between the biological measurements and gestational age.ResultsA total of 852 foetuses (403 males and 449 females) were included in the final analysis. Intra- and interobserver reliability coefficients ranged from 0.86 to 0.98 and 0.84 to 0.97, respectively. Reference ranges were established for the thickness and length of its segments. We observed that the biometric measurements of the foetal CC showed a curvilinear increase with gestational age. There was a statistically significant sex effect for the CC. At the average gestation age 29.6 weeks, the genu, anterior midbody, posterior midbody, and isthmus of male foetuses were 0.06280 mm, 0.04435 mm, 0.01731 mm, and 0.01556 mm, respectively, thicker than those of female foetuses, whereas the splenium of the female foetus was 0.06583 mm thicker than the male foetus.ConclusionsThe study uncovers distinct patterns of thickness and length growth in the foetal CC and establishes precise reference ranges. These findings can aid in evaluating normal brain development and conducting comprehensive assessments of CC abnormalities.

Barriers to exclusive breastfeeding practice among HIV-positive mothers in Tanzania. An exploratory qualitative study.

Ensuring optimal nutrition through early breastfeeding is vital for infant mental development and overall health. HIV infections complicate decisions regarding exclusive breastfeeding, jeopardizing effective infant and young child feeding, which affects nutrition and health outcomes. Recognizing the lack of evidence on barriers to infant feeding in the context of HIV in Tanzania, this study was conducted to explore individual, household, and community obstacles in the Ilala district, Dar es Salaam. A case study design employing a qualitative approach was used. The study was executed at the Reproductive and Child Health (RCH) Clinic within Amana Regional Referral Hospital, Mnazi Mmoja Health Centre, and Buguruni Health Centre. Data collection ensued through the purposive sampling of healthcare providers and HIV-positive mothers, utilizing in-depth interview techniques. The textual data accrued were analyzed using inductive and deductive content analysis strategies, thereby enabling the delineation and formulation of principal thematic constructs. The study involved interviews with twenty-seven key informants, encompassing HIV-positive mothers, nurses, clinicians, and community-based healthcare workers. The analysis of these interviews resulted in the identification of three major themes. Firstly, individual barriers to exclusive breastfeeding were delineated, encompassing sub-themes such as occupation-related hectic schedules, early motherhood-related non-compliance to safe infant feeding directives, postpartum depression, and issues related to breast sores and abscesses. Secondly, household-level barriers were identified, highlighting challenges like food insecurity and inaccessibility to key resources, the influence of male partners and family members on decision-making, and barriers arising from non-disclosure of HIV status affecting Exclusive Breastfeeding (EBF) support. Lastly, community-level barriers were explored, revealing a sub-theme related to the low retentivity of HIV-positive women in the Prevention of Mother-to-Child Transmission (PMTCT) programs. Individual barriers encompass practical, psychological, and physical challenges, while household-level obstacles include food insecurity, limited resources, and family dynamics influencing decisions. At the community level, there's a concern about the low retentivity of HIV-positive women in PMTCT programs, indicating broader societal challenges in supporting exclusive breastfeeding. There is a need for tailored interventions at individual, household, and community levels to promote and support optimal infant feeding practices among HIV-positive women.

Identification of human TRIAC transmembrane transporters.

TRIAC (3,5,3'-triiodothyroacetic acid) is a T3-receptor agonist pharmacologically used in patients to mitigate T3 resistance. It is additionally explored to treat some symptoms of patients with inactivating mutations in the thyroid hormone (TH) transporter MCT8 (SLC16A2). MCT8 is expressed along the blood-brain-barrier, on neurons, astrocytes, and oligodendrocytes. Hence, pathogenic variants in MCT8 limit the access of TH into and their functions within the brain. TRIAC was shown to enter the brain independently of MCT8 and to modulate expression of TH-dependent genes. The aim of the study was to identify transporters that facilitate TRIAC uptake into cells. We performed a whole-genome RNAi screen in HepG2 cells stably expressing a T3-receptor-dependent luciferase reporter gene. Validation of hits from the primary and confirmatory secondary screen involved a counter screen with siRNAs and compared the cellular response to TRIAC to the effect of T3, in order to exclude siRNAs targeting the gene expression machinery. MDCK1 cells were stably transfected with cDNA encoding C-terminally myc-tagged versions of the identified TRIAC-preferring transporters. Several individual clones were selected after immunocytochemical characterization for biochemical characterization of their 125I-TRIAC transport activities. We identified SLC22A9 and SLC29A2 as transporters mediating cellular uptake of TRIAC. SLC22A9 encodes the organic anion transporting polypeptide 7 (OAT7), a sodium-independent organic anion transporter expressed in the plasma membrane in brain, pituitary, liver and other organs. Competition with the SLC22A9/OAT7 substrate estrone-3-sulfate reduced 125I-TRIAC uptake. SLC29A2 encodes the equilibrative nucleoside transporter 2 (ENT2), which is ubiquitously expressed including pituitary and brain. Co-incubation with the SLC29A2/ENT2 inhibitor nitrobenzyl-6-thioinosine reduced 125I-TRIAC uptake. Moreover, ABCD1, an ATP-dependent peroxisomal pump, was identified as a 125I-TRIAC exporter in transfected MDCK1 cells. Knowledge of TRIAC transporter expression patterns, also during brain development, may thus in the future help to interpret observations on TRIAC effects as well as understand why TRIAC may not show a desirable effect on cells or organs not expressing appropriate transporters. The identification of ABCD1 highlights the sensitivity of our established screening assay, but it may not hold significant relevance for patients undergoing TRIAC treatment.

Intrapartum exposure to synthetic oxytocin, maternal BMI, and neurodevelopmental outcomes in children within the ECHO consortium

BackgroundSynthetic oxytocin (sOT) is frequently administered during parturition. Studies have raised concerns that fetal exposure to sOT may be associated with altered brain development and risk of neurodevelopmental disorders. In a large and diverse sample of children with data about intrapartum sOT exposure and subsequent diagnoses of two prevalent neurodevelopmental disorders, i.e., attention deficit hyperactivity disorder (ADHD) and autism spectrum disorder (ASD), we tested the following hypotheses: (1) Intrapartum sOT exposure is associated with increased odds of child ADHD or ASD; (2) associations differ across sex; (3) associations between intrapartum sOT exposure and ADHD or ASD are accentuated in offspring of mothers with pre-pregnancy obesity.MethodsThe study sample comprised 12,503 participants from 44 cohort sites included in the Environmental Influences on Child Health Outcomes (ECHO) consortium. Mixed-effects logistic regression analyses were used to estimate the association between intrapartum sOT exposure and offspring ADHD or ASD (in separate models). Maternal obesity (pre-pregnancy BMI ≥ 30 kg/m2) and child sex were evaluated for effect modification.ResultsIntrapartum sOT exposure was present in 48% of participants. sOT exposure was not associated with increased odds of ASD (adjusted odds ratio [aOR] 0.86; 95% confidence interval [CI], 0.71–1.03) or ADHD (aOR 0.89; 95% CI, 0.76–1.04). Associations did not differ by child sex. Among mothers with pre-pregnancy obesity, sOT exposure was associated with lower odds of offspring ADHD (aOR 0.72; 95% CI, 0.55–0.96). No association was found among mothers without obesity (aOR 0.97; 95% CI, 0.80–1.18).ConclusionsIn a large, diverse sample, we found no evidence of an association between intrapartum exposure to sOT and odds of ADHD or ASD in either male or female offspring. Contrary to our hypothesis, among mothers with pre-pregnancy obesity, sOT exposure was associated with lower odds of child ADHD diagnosis.

Embryonic origin of two ASD subtypes of social symptom severity: the larger the brain cortical organoid size, the more severe the social symptoms

BackgroundSocial affective and communication symptoms are central to autism spectrum disorder (ASD), yet their severity differs across toddlers: Some toddlers with ASD display improving abilities across early ages and develop good social and language skills, while others with “profound” autism have persistently low social, language and cognitive skills and require lifelong care. The biological origins of these opposite ASD social severity subtypes and developmental trajectories are not known.MethodsBecause ASD involves early brain overgrowth and excess neurons, we measured size and growth in 4910 embryonic-stage brain cortical organoids (BCOs) from a total of 10 toddlers with ASD and 6 controls (averaging 196 individual BCOs measured/subject). In a 2021 batch, we measured BCOs from 10 ASD and 5 controls. In a 2022 batch, we tested replicability of BCO size and growth effects by generating and measuring an independent batch of BCOs from 6 ASD and 4 control subjects. BCO size was analyzed within the context of our large, one-of-a-kind social symptom, social attention, social brain and social and language psychometric normative datasets ranging from N = 266 to N = 1902 toddlers. BCO growth rates were examined by measuring size changes between 1- and 2-months of organoid development. Neurogenesis markers at 2-months were examined at the cellular level. At the molecular level, we measured activity and expression of Ndel1; Ndel1 is a prime target for cell cycle-activated kinases; known to regulate cell cycle, proliferation, neurogenesis, and growth; and known to be involved in neuropsychiatric conditions.ResultsAt the BCO level, analyses showed BCO size was significantly enlarged by 39% and 41% in ASD in the 2021 and 2022 batches. The larger the embryonic BCO size, the more severe the ASD social symptoms. Correlations between BCO size and social symptoms were r = 0.719 in the 2021 batch and r = 0. 873 in the replication 2022 batch. ASD BCOs grew at an accelerated rate nearly 3 times faster than controls. At the cell level, the two largest ASD BCOs had accelerated neurogenesis. At the molecular level, Ndel1 activity was highly correlated with the growth rate and size of BCOs. Two BCO subtypes were found in ASD toddlers: Those in one subtype had very enlarged BCO size with accelerated rate of growth and neurogenesis; a profound autism clinical phenotype displaying severe social symptoms, reduced social attention, reduced cognitive, very low language and social IQ; and substantially altered growth in specific cortical social, language and sensory regions. Those in a second subtype had milder BCO enlargement and milder social, attention, cognitive, language and cortical differences.LimitationsLarger samples of ASD toddler-derived BCO and clinical phenotypes may reveal additional ASD embryonic subtypes.ConclusionsBy embryogenesis, the biological bases of two subtypes of ASD social and brain development—profound autism and mild autism—are already present and measurable and involve dysregulated cell proliferation and accelerated neurogenesis and growth. The larger the embryonic BCO size in ASD, the more severe the toddler’s social symptoms and the more reduced the social attention, language ability, and IQ, and the more atypical the growth of social and language brain regions.

C.6 Sex differences in neurodevelopmental outcomes and brain development from early-life to 8-years in preterm males and females

Background: Sex is associated with differences in early outcomes with preterm males at greater risk for mortality and morbidity. The objective of this study was to examine preterm sex differences in neurodevelopmental outcomes and brain development from early-life to 8-years. Methods: A prospective cohort of preterm infants born 24-32 weeks gestation were followed to 8-years with standardized measures. MRI scans were performed after birth, term-equivalent age and 8-years. Associations between sex, risk factors, brain volumes, white matter fractional anisotropy (FA) and outcomes were assessed using generalized estimating equations. Results: Preterm males (N=83) and females (N=72) had similar risk factors, brain injury and pain exposure. Sex was a predictor of cognitive scores (P=0.02) and motor impairment (P=0.03), with males having lower cognitive scores and higher motor impairment over time. There was a sex effect for FA (P=0.04), with males having lower FA over time. There were significant sex-brain injury and sex-pain interactions for cognitive and motor outcomes. Conclusions: In this longitudinal study, preterm males had lower cognitive scores and greater motor impairment, which may relate to differences in white matter maturation. Effects of brain injury and pain on outcomes is moderated by sex, indicating a differential response to early-life adversity in preterm males and females.

Evaluating performance and applications of sample-wise cell deconvolution methods on human brain transcriptomic data.

Sample-wise deconvolution methods estimate cell-type proportions and gene expressions in bulk tissue samples, yet their performance and biological applications remain unexplored, particularly in human brain transcriptomic data. Here, nine deconvolution methods were evaluated with sample-matched data from bulk tissue RNA sequencing (RNA-seq), single-cell/nuclei (sc/sn) RNA-seq, and immunohistochemistry. A total of 1,130,767 nuclei per cells from 149 adult postmortem brains and 72 organoid samples were used. The results showed the best performance of dtangle for estimating cell proportions and bMIND for estimating sample-wise cell-type gene expressions. For eight brain cell types, 25,273 cell-type eQTLs were identified with deconvoluted expressions (decon-eQTLs). The results showed that decon-eQTLs explained more schizophrenia GWAS heritability than bulk tissue or single-cell eQTLs did alone. Differential gene expressions associated with Alzheimer's disease, schizophrenia, and brain development were also examined using the deconvoluted data. Our findings, which were replicated in bulk tissue and single-cell data, provided insights into the biological applications of deconvoluted data in multiple brain disorders.

An Advance Learning Platform for Slow Learners

LearnIt is an innovative educational system crafted to identify and support slow learners through advanced technological solutions. It employs the MERN stack (MongoDB, Express.js, React.js, Node.js) to offer a personalized learning environment tailored to meet individual student needs. This system not only enhances the educational experience for students but also provides tools to facilitate effective communication between teachers and parents, ensuring a cohesive support network for the learner. Additionally, LearnIt empowers educators with data-driven insights, allowing for informed decision-making and targeted interventions. The traditional educational model often overlooks the unique needs of slow learners, resulting in disengagement and poor academic performance. LearnIt addresses this challenge by integrating comprehensive assessment tools and personalized learning strategies within its platform. By identifying slow learners early, the system provides timely interventions that can significantly improve their learning trajectory. The use of the MERN stack ensures that LearnIt is both scalable and responsive. The assessment and monitoring module is at the core of LearnIt’s functionality. The development of LearnIt involved a detailed analysis of the educational needs of slow learners, incorporating feedback from educators, parents, and the students themselves. This user-centered approach ensured that the system's design and functionality were closely aligned with real-world requirements. Key modules of LearnIt include user management, assessment and monitoring, and communication tool. The user management module handles registration, authentication, and role-based access control, ensuring secure and personalized experiences for all users. The assessment and monitoring module is at the core of LearnIt’s functionality. It includes tools for creating and administering assessments, tracking student performance, and generating detailed reports. This module helps in identifying slow learners by analyzing their performance data and providing actionable insights to educators. With these insights, teachers can develop customized learning plans that address the specific needs of each student, fostering an inclusive and effective educational environment. Communication is another critical component of LearnIt. The platform includes features that facilitate seamless communication between teachers, parents, and students. This ensures that parents are kept informed about their child's progress and can collaborate with teachers to provide consistent support. Effective communication helps in building a supportive learning ecosystem, which is essential for the success of slow learners. The implementation of LearnIt has shown promising results. Preliminary studies indicate that the system significantly improves the identification and support of slow learners. LearnIt represents a significant advancement in the field of educational technology. By focusing on the needs of slow learners and leveraging the capabilities of the MERN stack, it offers a comprehensive solution that enhances learning outcomes. The system's personalized approach, combined with robust data analytics and effective communication tools, ensures that every student receives the support they need to thrive. As we continue to refine and expand LearnIt, its impact on educational equity and student success will undoubtedly grow, offering new opportunities for learners who have been historically underserved by traditional educational models. Keywords: Slow learners, education, literacy, mental development, intelligence.

Delayed motor, mental and speech development and congenital brain malformations: the first description of Zhu–Tokita–Takenouchi–Kim syndrome in Russia

Delayed motor, mental and speech development and congenital brain malformations: the first description of Zhu–Tokita–Takenouchi–Kim syndrome in Russia

Developmental isoform diversity in the human neocortex informs neuropsychiatric risk mechanisms.

RNA splicing is highly prevalent in the brain and has strong links to neuropsychiatric disorders; yet, the role of cell type-specific splicing and transcript-isoform diversity during human brain development has not been systematically investigated. In this work, we leveraged single-molecule long-read sequencing to deeply profile the full-length transcriptome of the germinal zone and cortical plate regions of the developing human neocortex at tissue and single-cell resolution. We identified 214,516 distinct isoforms, of which 72.6% were novel (not previously annotated in Gencode version 33), and uncovered a substantial contribution of transcript-isoform diversity-regulated by RNA binding proteins-in defining cellular identity in the developing neocortex. We leveraged this comprehensive isoform-centric gene annotation to reprioritize thousands of rare de novo risk variants and elucidate genetic risk mechanisms for neuropsychiatric disorders.

Using a comprehensive atlas and predictive models to reveal the complexity and evolution of brain-active regulatory elements.

Most genetic variants associated with psychiatric disorders are located in noncoding regions of the genome. To investigate their functional implications, we integrate epigenetic data from the PsychENCODE Consortium and other published sources to construct a comprehensive atlas of candidate brain cis-regulatory elements. Using deep learning, we model these elements' sequence syntax and predict how binding sites for lineage-specific transcription factors contribute to cell type-specific gene regulation in various types of glia and neurons. The elements' evolutionary history suggests that new regulatory information in the brain emerges primarily via smaller sequence mutations within conserved mammalian elements rather than entirely new human- or primate-specific sequences. However, primate-specific candidate elements, particularly those active during fetal brain development and in excitatory neurons and astrocytes, are implicated in the heritability of brain-related human traits. Additionally, we introduce PsychSCREEN, a web-based platform offering interactive visualization of PsychENCODE-generated genetic and epigenetic data from diverse brain cell types in individuals with psychiatric disorders and healthy controls.

The Proportions of Term or Late Preterm Births After Exposure to Early Antenatal Corticosteroids, and Outcomes: Systematic Review and Meta-Analysis of 1.6 Million Infants

(BMJ. 2023;382:e076035 | doi: 10.1136/bmj-2023-076035 l. http://dx.doi.org/10.1136/bmj-2023-076035) Preterm birth is a major cause of morbidity and mortality in both newborns and children. Women at risk of preterm delivery often receive antenatal corticosteroids, depending on their gestational age. These steroids enhance fetal lung maturation; however, unnecessary corticosteroid exposure is a concern. Guidelines recommend tracking and minimizing such exposure to discourage overuse. Animal studies indicate potential risks to fetal brain development and long-term health. This systematic review explored the outcomes of infants exposed to early antenatal corticosteroids, emphasizing the importance of their reasonable use in mitigating risks.

Knockdown of NeuroD2 leads to seizure-like behaviour, brain neuronal hyperactivity and a leaky blood-brain barrier in a Xenopus laevis tadpole model of DEE75.

Developmental and Epileptic Encephalopathies (DEE) are a genetically diverse group of severe, early onset seizure disorders. DEE are normally identified clinically in the first six months of life by the presence of frequent, difficult to control seizures and accompanying stalling or regression of development. DEE75 results from de novo mutations of the NEUROD2 gene that result in loss of activity of the encoded transcription factor, and the seizure phenotype was shown to be recapitulated in Xenopus tropicalis tadpoles. We used CRISPR/Cas9 to make a DEE75 model in Xenopus laevis, to further investigate the developmental aetiology. NeuroD2.S CRISPR/Cas9 edited tadpoles were more active, swam faster on average, and had more seizures (C-shaped contractions resembling unprovoked C-start escape responses) than their sibling controls. Live imaging of Ca2+ signalling revealed prolongued, strong signals sweeping through the brain, indicative of neuronal hyperactivity. While the resulting tadpole brain appeared grossly normal, the blood-brain barrier was found to be leakier than that of controls. Additionally, the TGFβ antagonist Losartan was shown to have a short-term protective effect, reducing neuronal hyperactivity and reducing permeability of the blood-brain barrier. Treatment of NeuroD2 CRISPant tadpoles with 5 mM Losartan decreased seizure events by more than fourfold compared to the baseline. Our results support a model of DEE75 resulting from reduced NeuroD2 activity during vertebrate brain development, and indicate that a leaky blood-brain barrier contributes to epileptogenesis.

Isavuconazole Induces Neurodevelopment Defects and Motor Behaviour Impairment in Zebrafish Larvae.

Isavuconazole is a broad-spectrum antifungal drug used for the treatment of serious infections caused by invasive aspergillosis and mucormycosis in adults. With the continuous use of this drug, its safety and environmental impact have received increasing attention. However, information on the adverse effects of the drug is very limited. Fish is a particularly important model for assessing environmental risks. In this study, the aquatic vertebrate zebrafish was used as a model to study the toxic effects and mechanisms of isavuconazole. We exposed zebrafish embryos to 0.25, 0.5, and 1mg/L of isavuconazole 6h after fertilization. The results showed that at 72 hpf, isavuconazole exposure reduced heart rate, body length, and survival of zebrafish embryos compared to controls. Secondly, when isavuconazole reached a certain dose level (0.25mg/L), it caused morphological changes in the Tg(elavl3:eGFP) transgenic fish line, with the head shrunk, the body bent, the fluorescence intensity becoming weaker, the abnormal motor behaviour, etc. At the same time, exposure of zebrafish embryos to isavuconazole downregulated acetylcholinesterase (AchE) and adenosine triphosphate (ATPase) activities but upregulated oxidative stress, thereby disrupting neural development and gene expression of neurotransmitter pathways. In addition, astaxanthin partially rescued the neurodevelopmental defects of zebrafish embryos by downregulating oxidative stress. Thus, our study suggests that isavuconazole exposure may induce neurodevelopment defects and behavioural disturbances in larval zebrafish.

Maternal thyroid function in early pregnancy and offspring school performance and neurodevelopmental disorders.

Thyroid hormones are critical for neural development, and during the first trimester of pregnancy the fetus relies fully on maternal thyroid hormone production. To investigate the associations between maternal thyroid hormone levels in the first trimester with the child's school performance, risk of attention deficit hyperactivity disorder (ADHD) and autism spectrum disorder (ASD). From the Copenhagen Primary Care Laboratory Pregnancy Database information on first trimester TSH and fT4 measurements in mothers of children born in 2000-2014 were linked with information on the child's standardized test scores in school, ADHD (patient record diagnoses and medication) and ASD (patient record diagnoses) until end of 2018. Associations of TSH and fT4 with the outcomes were individually assessed by linear mixed models and Cox regression models. The analyses were stratified by preexisting maternal thyroid disorders. TSH measurements were available for 17,909 mother-child dyads. Among those with children born in 2000-2009, 6,126 had a standardized school test score and were analyzed for the association between maternal thyroid hormone levels and child's school performance, and no support for an association was found. The association between thyroid hormone levels and child's risk of ADHD and ASD were analyzed for the 17,909 dyads and with no support for an association between thyroid hormone levels and these neurodevelopmental disorders. Stratification by preexisting maternal thyroid disorders did not affect the results. We found no evidence for associations between first trimester maternal thyroid hormone levels and child's school performance, or risk of ADHD or ASD.

The role of cortical structural variance in deep learning-based prediction of fetal brain age

BackgroundDeep-learning-based brain age estimation using magnetic resonance imaging data has been proposed to identify abnormalities in brain development and the risk of adverse developmental outcomes in the fetal brain. Although saliency and attention activation maps have been used to understand the contribution of different brain regions in determining brain age, there has been no attempt to explain the influence of shape-related cortical structural features on the variance of predicted fetal brain age.MethodsWe examined the association between the predicted brain age difference (PAD: predicted brain age–chronological age) from our convolution neural networks-based model and global and regional cortical structural measures, such as cortical volume, surface area, curvature, gyrification index, and folding depth, using regression analysis.ResultsOur results showed that global brain volume and surface area were positively correlated with PAD. Additionally, higher cortical surface curvature and folding depth led to a significant increase in PAD in specific regions, including the perisylvian areas, where dramatic agerelated changes in folding structures were observed in the late second trimester. Furthermore, PAD decreased with disorganized sulcal area patterns, suggesting that the interrelated arrangement and areal patterning of the sulcal folds also significantly affected the prediction of fetal brain age.ConclusionThese results allow us to better understand the variance in deep learning-based fetal brain age and provide insight into the mechanism of the fetal brain age prediction model.