Search Results (328)

Background: During the first 2 years of life, human white matter (WM) undergoes rapid development, establishing a structural foundation for later neurodevelopment. Methods: We conducted a mixed-model analysis for repeated measures to investigate the developmental trajectories of functionally distinct 26 WM pathways between preterm and full-term groups during the first 2 years of life using diffusion tensor imaging (total scans = 174; preterm = 58; full-term = 23). Results: We observed significant differences between the preterm and full-term groups in the developmental trajectories associated with motor function (left corticospinal tract and left pre-primary motor cortex connection tracts), visual processing (bilateral pathway between the V1/V2 and V4, PV-MT, pathway connecting the V1/V2 and V5/MT, and optic radiation), and cognition (genu, body, and splenium of the corpus callosum). Furthermore, inter-regional correlation matrix analysis revealed stronger connectivity, specifically within motor- and visual-related pathways, in the preterm group than that for the full-term group, suggesting an adaptive mechanism that supports circuit-level resilience following preterm birth. Moreover, in the model investigating the associations between the WM individual rate of change and long-term neurodevelopmental outcomes, the middle cerebellar peduncle (MCP) tract showed the strongest associations with motor scores, suggesting that faster maturation of the MCP tract may enhance motor functions as a key compensatory mechanism following preterm birth. Conclusions: Delineating the longitudinal change rates of specific WM pathways not only deepens our understanding of the neurodevelopmental sequelae of prematurity but also highlights their potential as early biomarkers to guide timely interventions. Full article

Background: ALG13-CDG is an X-linked N-linked glycosylation disorder caused by pathogenic variants in the glycosyltransferase ALG13, leading to severe neurological manifestations. Despite the clear CNS involvement, the impact of ALG13 dysfunction on human brain glycosylation and neurodevelopment remains unknown. We hypothesize that ALG13-CDG causes brain-specific hypoglycosylation that disrupts neurodevelopmental pathways and contributes directly to cortical network dysfunction. Methods: We generated iPSC-derived human cortical organoids (hCOs) from individuals with ALG13-CDG to define the impact of hypoglycosylation on cortical development and function. Electrophysiological activity was assessed using MEA recordings and integrated with multiomic profiling, including scRNA-seq, proteomics, glycoproteomics, N-glycan imaging, lipidomics, and metabolomics. X-inactivation status was evaluated in both iPSCs and hCOs. Results: ALG13-CDG hCOs showed reduced glycosylation of proteins involved in ECM organization, neuronal migration, lipid metabolism, calcium homeostasis, and neuronal excitability. These pathway disruptions were supported by proteomic and scRNA-seq data and included altered intercellular communication. Trajectory analyses revealed mistimed neuronal maturation with early inhibitory and delayed excitatory development, indicating an E/I imbalance. MEA recordings demonstrated early network hypoactivity with reduced firing rates, immature burst structure, and shortened axonal projections, while transcriptomic and proteomic signatures suggested emerging hyperexcitability. Altered lipid and GlcNAc metabolism, along with skewed X-inactivation, were also observed. Conclusions: Our study reveals that ALG13-CDG is a disorder of brain-specific hypoglycosylation that disrupts key neurodevelopmental pathways and destabilizes cortical network function. Through integrated multiomic and functional analyses, we identify early network hypoactivity, mistimed neuronal maturation, and evolving E/I imbalance that progresses to compensatory hyperexcitability, providing a mechanistic basis for seizure vulnerability. These findings redefine ALG13-CDG as disorders of cortical network instability, offering a new framework for targeted therapeutic intervention. Full article

Microplastics (MPs) and antibiotics have emerged as contaminants of global concern, posing potential threats to ecosystem security and organismal health. To investigate the individual and combined toxicity of microplastics (PS-MPs) and sulfamethoxazole (SMX), we conducted a 120 h acute exposure experiment using embryo–larval zebrafish as a toxicological model. Our findings demonstrate that both PS-MPs and SMX can induce neurodevelopmental toxicity in embryo–larval zebrafish during embryonic development. Notably, PS-MPs and SMX exerted a significant synergistic effect. PS-MPs 1 µm in diameter were restricted to the chorion surface of pre-hatching zebrafish, whereas post-hatching, PS-MPs accumulated mainly in the gut and gills, with accumulation levels increasing progressively with exposure duration. Individual exposure to PS-MPs or SMX reduced spontaneous locomotion, decreased heart rate, and shortened body length in embryo–larval zebrafish. In addition to exacerbating these effects, coexposure further increased the incidence of malformations such as pericardial effusion and spinal curvature. PS-MPs and SMX significantly decreased the levels of dopamine (DA), serotonin (5-HT), and γ-aminobutyric acid (GABA) in zebrafish while also suppressing acetylcholinesterase (AChE) activity and increasing acetylcholine (ACh) levels. Moreover, upon coexposure at high concentrations, PS-MPs and SMX acted synergistically to reduce the levels of DA and GABA. The downregulation of key neurodevelopmental genes (elavl3, gap43, and syn2a) and related neurotransmitter pathway genes indicates that PS-MPs and SMX impaired structural development and functional regulation of the nervous system. An integrated biomarker response (IBR) index confirmed that PS-MPs and SMX significantly enhanced developmental neurotoxicity during early neurodevelopment in embryo–larval zebrafish through synergistic effects. Our study provides critical toxicological evidence for the scientific assessment of the ecological risks posed by microplastic–antibiotic cocontamination. Full article

Calcium ions (Ca²⁺) serve as universal second messengers regulating endocrine, neuronal, and metabolic processes. In children and adolescents, tight calcium signaling control is crucial for growth, hormone homeostasis, neuromuscular function, and neurodevelopment. Disruptions in Ca²⁺-dependent pathways—whether genetic, metabolic, or acquired—underlie a spectrum of pediatric endocrine diseases often presenting with neurological manifestations This review summarizes calcium’s roles in hormone secretion, parathyroid and vitamin D metabolism, and neuronal excitability, and discusses monogenic and metabolic disorders affecting calcium sensing and signaling, including CASR, GNA11, AP2S1, STIM1, and ORAI1 mutations. Diagnostic challenges, therapeutic strategies, and future directions for precision medicine in pediatric neuroendocrinology are highlighted, emphasizing early recognition and improved clinical outcomes. Full article

Neonatal neuroinflammation, driven by microglial activation and cytokine signaling, contributes to brain injury and adverse neurodevelopment outcomes. Perinatal inflammatory mediators, including interleukin-6, cyclooxygenase-2, and interleukin-17, prime microglia and influence circuit vulnerability. This study investigated whether oxytocin pretreatment attenuates lipopolysaccharide-induced inflammatory priming in BV-2 microglial cells. BV-2 microglia were preincubated with oxytocin (33 ng/mL) for 2 h, followed by lipopolysaccharide (0.5 µg/mL) for 2 h. Expression of ionized calcium-binding adapter molecule 1, a microglia marker, in BV-2 cells was assessed by immunofluorescence. After lipopolysaccharide treatment, the gene expression of BV-2 cells was assayed at 1, 2, and 6 h post stimulation by RT-qPCR and RNA-seq. Functional characterization of gene expression profile was performed. Analyses of gene expression profile of BV-2 cells by RT-qPCR and RNA-seq revealed that oxytocin pretreatment attenuated lipopolysaccharide-induced transcriptional activation, including interleukin-6 and cyclooxygenase-2 upregulation. Pathway enrichment analyses suggested that oxytocin-responsive genes were linked to the interleukin-17 signaling pathway. Gene Ontology enrichment analysis showed enrichment for genes related to cytokine production, membrane raft, and chemokine activity. Oxytocin pretreatment mitigates lipopolysaccharide-induced microglial activation by modulating the interleukin-17–interleukin-6/cyclooxygenase-2 axis, suggesting its potential role for oxytocin as an endogenous modulator of neuroinflammation during early brain development. Full article

Background/Objectives: The first 1000 days of life represent a critical window for growth and neurodevelopment, during which nutrition strongly influences brain development and metabolic programming. In phenylketonuria (PKU), dietary management is essential to prevent neurological impairment and later-life risk of non-communicable diseases (NCDs). This review examines current evidence on PKU from pregnancy through complementary feeding, highlighting the impact of nutritional strategies on neurodevelopmental and metabolic outcomes. Methods: This narrative review, following PRISMA guidelines, used a systematic search of PubMed and Scopus with defined PICO questions. Original research, reviews, and guidelines on PKU nutrition during the first 1000 days were included, emphasizing neurological and metabolic outcomes. Results: Articles addressed prenatal and postnatal factors in PKU. Optimised metabolic control in women with PKU is critical to prevent maternal PKU syndrome, reducing risks of miscarriage, congenital heart defects, microcephaly, and neurocognitive impairment. Pre-conception dietary management, frequent blood Phe monitoring, supplementation with Phe-free protein substitutes (PSs), micronutrients, and emerging pharmacological therapies support maternal and foetal health. Following newborn screening, early dietary treatment in infants with PKU maintains plasma Phe within safe ranges, promoting growth and neurodevelopment. Breastfeeding, combined with Phe-free infant PSs, is feasible, and complementary feeding should be introduced carefully. Frequent monitoring and tailored dietary adjustments, including second-stage PSs, support metabolic control, while data on gut microbiota remain limited. Conclusions: Early multidisciplinary interventions are crucial to optimise metabolic and neurodevelopmental outcomes during this window of opportunity. Further research is needed to address remaining gaps and optimise PKU management across the first 1000 days. Full article

Background: Probiotic supplementation for very preterm infants is a common practice in many neonatal units. Assessing the effects of early postnatal exposure to probiotics on long-term neurodevelopment, growth, and atopy-related outcomes is important. Extremely preterm (EP: <28 weeks) infants enrolled in our previously reported randomized trial (SiMPro) comparing short-term effects of single (SS: B. breve M-16V) versus triple-strain (TS: B. breve M-16V, B. longum subsp. infantis-M63, B. longum subsp. longum-BB536) probiotic provided a unique opportunity to study this issue. Methods: This follow-up study assessed the five-year outcomes of SiMPro trial infants, including neurodevelopment (cognition (Full Scale Intelligence Quotient/ FSIQ using WPPSI-IV), behavior (Strengths and Difficulties Questionnaire), executive function (BRIEF–P)), growth (anthropometry) and blood pressure (BP). Atopy-related outcomes were evaluated at six to seven years using the ISAAC questionnaire. A linear mixed model was used for longitudinal outcomes. Impairment indicators were modeled using logistic regression and adjusted for Socio-Economic Indexes for Areas (SEIFA) centiles. Results: Follow-up rates (SS: 89.2% versus TS: 95%), neurodevelopmental outcomes [severe impairment (FSIQ < 70): SS: 7.4% versus TS: 4.3%; p = 0.68], growth, BMI, and BP were comparable between the SS and TS groups. The total difficulty score or BRIEF–P executive indices, disability rates (none: 66.7% versus 55.4%), and atopy-related outcomes were comparable between groups. Conclusions: Both TS and SS Bifidobacterium probiotic formulations were safe, with comparable neurodevelopmental, growth, and atopy-related outcomes at school age. Full article

Early exposure to toxic metals is a growing concern due to its potential neurodevelopmental effects in children. This study investigates whether exposure to multiple metals during pregnancy influences early developmental outcomes in children aged 12–18 months living in a metropolitan setting. We conducted a prospective cohort study in Rio de Janeiro that included 393 children from PIPA project. Umbilical cord blood samples obtained at birth were processed using ICP-MS (Inductively Coupled Plasma Mass Spectrometry) to quantify metals (arsenic, lead and mercury). The children’s neurodevelopment was assessed with the Denver-II tool. We applied logistic regression analyses to explore the relationship between metal concentrations and developmental outcomes, controlling for possible confounding variables. Higher prenatal arsenic levels were linked to poorer gross motor performance, both in continuous models (OR = 1.65; 95% CI: 1.09–2.51) and in subjects with concentrations above the 95th percentile (OR = 8.84; 95% CI: 2.40–32.61), this was consistent across multi-metal models. A negative relationship between Pb concentrations and gross motor delays was observed, with an estimated Odds Ratio of 0.49 (95% CI: 0.24–0.98). Hg exposure demonstrated no association with neurodevelopment in any model. However, the lack of postnatal arsenic exposure data limits the distinction between prenatal and early childhood effects. These findings underscore the need for the continued monitoring and investigation of combined metal exposures during pregnancy. Future studies integrating prenatal and postnatal exposure assessments are warranted. Full article

Background/Objectives: Children born small-for-gestational-age (SGA) have varying growth patterns and developmental risks. In this study, we aimed to examine the relationship between weight-for-age z-scores (WAZ) at 2 years and neurodevelopmental and obesity outcomes at 6 years in children with SGA. Methods: We conducted a population-based cohort study using the National Health Insurance Service database of South Korea (N = 39,809). WAZ at 2 years was used to categorize children into four groups: G1 (WAZ < −1.28 [10th percentile], n = 9416), G2 (−1.28 ≤ WAZ < 0 [50th percentile], n = 20,322), G3 (0 ≤ WAZ < 1.04 [85th percentile], n = 8280), and G4 (1.04 ≤ WAZ, n = 1791). Neurodevelopment was assessed using the Korean Developmental Screening Test (K-DST). Overweight and obesity were defined using a body mass index-for-age z-score greater than the 85th and 95th percentiles, respectively, at 6 years of age. Adjusted odds ratios (aORs) and prevalence rates were estimated using Poisson and logistic regression models. Group-based comparisons were interpreted as exploratory analyses. Results: The prevalence of suboptimal neurodevelopment was highest in G1 (5.03%), followed by G4 (3.75%) at 6 years. A significantly increased risk of suboptimal K-DST scores was observed in G1 (aOR: 1.544; 95% confidence interval [CI]: 1.253–1.902), whereas a nonsignificant increase was found in G4 (aOR: 1.447; 95% CI: 0.938–2.234). At age 6, the prevalence of obesity was highest in G4 (19.60%), followed by G3 (7.11%), G2 (1.81%), and G1 (0.64%). The G4 group had the highest risk of overweight (aOR: 9.94) and obesity (aOR: 14.29) at 6 years. Conclusions: Weight status at age 2 in children with SGA was significantly associated with neurodevelopmental and obesity risks at age 6. These findings highlight the need for early weight monitoring and interventions to optimize long-term health in children with SGA. Full article

Docosahexaenoic acid (DHA) is a long-chain omega-3 fatty acid essential for neurodevelopment, immune regulation, and key physiological functions during early life. In low- and middle-income countries (LMICs), limited access to DHA-rich foods contributes to disparities in intake and health outcomes. This narrative review describes the current evidence on dietary patterns of DHA intake and supplementation from pregnancy through childhood in LMICs and highlights the implications of these patterns for child health. The review is based on a systematic search conducted in PubMed using Medical Subject Heading (MeSH) terms related to DHA, dietary patterns, health outcomes, and LMICs. Studies published between 2014 and 2025 were screened using Covidence software. Eligible studies included observational, interventional, and review designs that reported DHA through dietary intake, supplementation, or measurement in biological samples during pregnancy, lactation, infancy, or childhood. Data extraction followed the PICOS (Population, Intervention, Comparison, Outcome, Study Design) framework. A total of 76 studies were included. Across LMICs, DHA intake was consistently insufficient among pregnant and lactating women, infants, and children. Reported dietary sources were generally low in DHA content. Intake or supplementation was associated with neurodevelopment, immune response, pregnancy outcomes, and cardiometabolic health, although findings were sometimes mixed or modified by gene–environment interactions. Results varied by study design, contextual factors, income level, and geographic access. Large gaps remain in nationally representative intake data. Despite its physiological relevance, DHA intake remains inadequate in LMICs during early life. This review underscores the importance of improving DHA intake in vulnerable populations and identifies evidence gaps to guide future research and inform context-specific nutrition strategies. Full article

Background: Early-life gut microbiota colonization plays a significant role in the neurodevelopment of infants and young children. However, the causal relationship between early-life gut microbiota colonization and neurodevelopment in preterm infants has not yet been conclusively established. Our research will initiate the PIGMAN (Premature Infants Gut Microbiota Assembly and Neurodevelopment) cohort study to systematically examine the dynamic interplay between gut microbiota developmental trajectories and neurodevelopmental processes in preterm infants. Methods: This study will employ a longitudinal cohort design and utilize data from the PIGMAN cohort, examining the interplay between gut microbiota metabolism and neurodevelopmental outcomes. The study design incorporates longitudinal stool sample collection, which will be analyzed through 16S rRNA gene sequencing and metagenomic shotgun sequencing, enabling comprehensive characterization of microbial community dynamics and functional metabolic pathways. Anticipated Results: Advanced analytical approaches incorporating causal inference methodologies will be implemented to identify significant microbial and metabolic biomarkers associated with neurodevelopmental outcomes in preterm neonates, and to establish causal pathways between these biomarkers and neurodevelopment. These analytical advancements will facilitate the construction of predictive models that utilize temporal microbial signatures and metabolite trajectories as prognostic indicators for neurodevelopmental outcomes. Causal inference method evaluations will further reveal that specific gut-derived metabolites, particularly those involved in cholesterol metabolism and neural signaling pathways—such as bile acids and GABA (gamma-aminobutyric acid)—exhibit superior predictive capacity for cognitive development trajectories. Anticipated Conclusions: The findings will collectively suggest that longitudinal metabolic profiling of the gut ecosystem, when combined with causal network analysis, provides a novel paradigm for developing clinically actionable predictive models of neurodevelopment in vulnerable preterm populations. Full article

Despite valuable insights into the individual roles of genetic factors and personality traits, their combined contribution to addiction susceptibility remains insufficiently characterized. Within this framework, the potential influence of epigenetic mechanisms, particularly those mediated by the gut microbiome, also remains underexplored. This comprehensive review aims to address these gaps in an integrative manner by examining: (i) the association of gene regulation with personality traits; (ii) the genetics of substance use disorders; (iii) the roles of genes and personality in addiction; and (iv) epigenetic influences on addiction, with a particular focus on the role of the gut microbiome. Genetic influences on personality act primarily via regulatory variants that modulate gene expression during neurodevelopment, shaping cognitive, emotional, and behavioral traits that contribute to individual differences. Substance use disorders share partially overlapping genetic foundations, with specific loci, heritability estimates, and causal pathways differing across substances, reflecting both shared vulnerability and substance-specific genetic influences on addiction susceptibility. Impulsivity, novelty-seeking, and stress responsiveness are heritable personality traits that interact to shape susceptibility to substance use disorders, with genetic factors modulating risk across different forms of addiction. Environmental factors, early-life stress, and social influences interact with the gut microbiome to shape neurobiological and behavioral pathways that modulate addiction risk. These interactions highlight the multifactorial nature of substance use disorders, in which epigenetic, microbial, and psychosocial mechanisms converge to influence susceptibility, progression, and maintenance of addictive behaviors. Full article

Background/Objectives: Preterm infants are at risk for developmental delays due to immature brain development and increased sensitivity to environmental stress. Genetic factors, such as polymorphisms in *OXTR* rs2268490, *COMT* rs4818, and *GRIN2B*, may influence these vulnerabilities and affect neurodevelopment. Methods: We recruited 91 preterm infants (<35 weeks gestation) admitted to the NICU at Hanyang University Seoul Hospital between January 2020 and December 2022. Brain MRIs were conducted at term-equivalent age, and DNA samples were analyzed for SNPs. Neurodevelopmental assessments were performed at 18 months corrected age using the Korean Developmental Screening Test (K-DST) and Bayley Scales of Infant Development, Third Edition (BSID-III). Results: Carriers of the minor alleles in *OXTR* rs2268490 showed significantly lower language and adaptive behavior, and *COMT* rs4818, rs740603 showed significantly lower social–emotional scores on BSID-III. *OXTR* rs2268490 was also associated with altered brain network metrics, including decreased small-worldness (p = 0.012) and increased global (p = 0.038) and local efficiency (p = 0.042). Conclusions: Polymorphisms in the *OXTR* genes are associated with differences in brain network organization and neurodevelopmental outcomes in preterm infants. These variants may influence how environmental factors affect early brain development, highlighting the importance of genetic screening and early intervention. Full article

Background: Nephrocalcinosis, characterized by the deposition of calcium salts within the renal parenchyma, is frequently identified incidentally in pediatric patients and may be associated with underlying genetic disorders. Sotos syndrome, a rare congenital overgrowth condition associated with neurodevelopment delay and congenital defects caused by mutations or deletions in the NSD1 gene, has been sporadically linked to renal abnormalities, including nephrocalcinosis. Clinical presentation: We report a case of a male patient with Sotos syndrome and concurrent nephrocalcinosis, in whom genetic analysis revealed a microdeletion of chromosome 5q35 with a 2.2 Mb deletion encompassing both NSD1 and SLC34A1 genes. The SLC34A1 gene encodes the NaPi-IIa sodium–phosphate cotransporter, essential for phosphate reabsorption in the renal proximal tubule. Haploinsufficiency of SLC34A1 is implicated in dysregulated phosphate and calcium homeostasis, predisposing to hypercalciuria and nephrocalcinosis. Longitudinal follow-up demonstrated biochemical stability, resolution of nephrocalcinosis, and preserved renal function, supporting the hypothesis of an age-dependent attenuation in NaPi-IIa function. Conclusions: This case underscores the relevance of contiguous gene deletions in shaping complex clinical phenotypes and highlights the importance of early wide clinical screening in patients with Sotos syndrome to mitigate long-term renal complications. Full article

Background: The gut microbiota plays a crucial role in brain development and function, especially in early life. Disruptions in the pediatric microbiota–gut–brain axis have been linked to neurodevelopmental and psychiatric disorders. We hypothesize that early-life dysbiosis can perturb neurodevelopment via the pediatric microbiota–gut–brain axis, increasing risk and/or severity of neuropsychiatric outcomes, and that microbiota-targeted strategies may mitigate this risk. Methods: We conducted a narrative review by searching PubMed, Scopus, and Web of Science up to January 2025 for studies addressing pediatric microbiota, neuropsychiatric development, and interventions. Human and animal studies were included if they provided mechanistic or clinical insights. Results: Key determinants of microbiota development in childhood include mode of delivery, feeding practices, antibiotic exposure, diet, and environment. Altered microbial composition has been associated with autism spectrum disorder, attention-deficit/hyperactivity disorder, mood disorders, anxiety, and anorexia nervosa. Mechanistic pathways involve immune modulation, neural signaling (including the vagus nerve and enteric nervous system), and microbial metabolites such as short-chain fatty acids. Interventions targeting the microbiota—ranging from dietary strategies and probiotics to psychobiotics and fecal microbiota transplantation—show promise but require further pediatric-focused trials. Conclusions: The pediatric microbiota–gut–brain axis represents a critical window for neuropsychiatric vulnerability and intervention. Early-life strategies to support a healthy microbiota may help reduce the risk or severity of psychiatric disorders. Future research should prioritize longitudinal pediatric cohorts and clinical trials to translate mechanistic insights into precision interventions. Full article