Search Results (3,685)

Background: Autism Spectrum Disorder (ASD) is a heterogeneous neurodevelopmental condition for which non-pharmacological interventions remain the primary therapeutic approach. Although research output in this field has increased substantially, a comprehensive synthesis of its developmental trajectory and emerging directions is still lacking. Methods: We conducted a bibliometric analysis of publications on non-pharmacological interventions for ASD indexed in the Web of Science Core Collection between 2001 and 2025. Knowledge structures, research hotspots, and temporal trends were visualized and analyzed using CiteSpace. Results: The field has transitioned from an early focus on behavioral interventions in children to a diversified and interdisciplinary research ecosystem spanning the lifespan. Recent growth has been driven by the integration of neuroscience-based approaches, particularly neuromodulation techniques, alongside continued refinement of behavioral, sensorimotor, and complementary therapies. Increasing attention has been paid to individual heterogeneity, methodological rigor, and mechanism-oriented research. Current frontiers emphasize multimodal intervention strategies, neural plasticity-based mechanisms, and the development of personalized precision intervention frameworks. Conclusions: This bibliometric analysis delineates the intellectual evolution of non-pharmacological intervention research for ASD and identifies key research gaps, particularly the need for longitudinal and pragmatic studies targeting individualized treatment response. The findings provide an evidence-informed overview of current concepts and emerging research directions in non-pharmacological care for ASD, with important implications for future clinical research, intervention design, and strategic research planning. Full article

Proteostasis, defined as the coordinated regulation of protein synthesis, folding, trafficking, and degradation, is essential for maintaining cellular integrity and supporting normal development. During reproduction and early life stages, efficient proteostasis is crucial for gamete quality, successful fertilization, embryonic development, and neurodevelopmental outcomes. Increasing evidence suggests that impaired proteostasis contributes to infertility and may be intertwined with biological vulnerabilities associated with assisted reproductive technologies [ARTs]. This review provides an integrative perspective on the role of disrupted proteostasis in infertility, ART procedures, and neurodevelopmental differences [NDD]. We review epidemiological and molecular findings indicating proteostasis failure in both male and female infertility, with particular emphasis on molecular chaperones. Among these, heat shock protein 60 [Hsp60] is discussed as a central mediator linking mitochondrial function, protein quality control, and reproductive competence. We further highlight that ART procedures coincide with sensitive periods of epigenetic reprogramming and proteostasis regulation during early embryogenesis, indicating that disturbances in proteostasis may affect epigenetic stability and subsequent neurodevelopmental outcomes. In addition, this review emphasizes the importance of proteoforms and proteome complexity as critical determinants of reproductive success and neurodevelopmental robustness in the context of ART. Finally, we discuss the potential of proteomic and chaperone-based biomarkers as emerging tools to optimize ART strategies, improve gamete and embryo selection, and enhance risk assessment and clinical outcomes. The current review underscores proteostasis as a fundamental yet underrecognized mechanism linking reproductive biology, ART outcomes, and long-term neurodevelopment while highlighting future directions for translational investigations. Full article

Background/Objectives: Autism spectrum disorder (ASD) is a neurodevelopmental condition increasingly associated with dysregulated neuroimmune signaling and altered neurotrophic homeostasis. Tumor necrosis factor-alpha (TNF-α) has been implicated in ASD pathophysiology; however, the downstream effects of TNF-α blockade on cytokine–neurotrophin interactions during neurodevelopment remain insufficiently characterized. In this study, we evaluated the effects of infliximab (IFX), a monoclonal anti-TNF-α antibody, on behavioral performance, neuroinflammatory cytokine profiles, glial activation, and brain-derived neurotrophic factor (BDNF) signaling in a propionic acid (PPA)-induced experimental ASD rat model. Methods: Experimental ASD was induced by propionic acid administration in rats. Animals were divided into control and treatment groups. Behavioral performance was assessed using the Morris Water Maze, direct social interaction, and three-chamber sociability tests. Levels of TNF-α, interleukin-1 beta (IL-1β), interleukin-6 (IL-6), and BDNF were measured in serum, hippocampal, and cerebellar tissues. Microglial and astrocytic activation were evaluated using CD11 and GFAP immunohistochemistry. Results: PPA administration resulted in pronounced impairments in learning, memory, and social behaviors, accompanied by elevated proinflammatory cytokine levels, increased BDNF expression, and marked glial activation in the hippocampus and cerebellum. Although IFX treatment significantly reduced TNF-α levels in central tissues, it did not improve behavioral deficits and was associated with persistently elevated IL-1β and IL-6 levels, sustained glial reactivity, and further alterations in BDNF levels. Conclusions: These findings suggest that TNF-α suppression alone does not normalize the disrupted cytokine–neurotrophin axis and may differentially modulate BDNF-related neuroplastic signaling during development. In conclusion, this study indicates that non-selective TNF-α blockade during neurodevelopment fails to confer behavioral benefit in experimental ASD and highlights the importance of considering cytokine–BDNF pathway interactions when designing immunomodulatory strategies for neurodevelopmental disorders. Full article

Advanced Glycation End Products (AGEs) are reactive compounds formed through the non-enzymatic glycation of proteins, lipids, or nucleic acids due to exposure to reducing sugars. They accumulate through endogenous metabolic dysregulation and exogenous dietary intake, particularly high-fat and high-sugar foods prepared at high temperatures. The interaction between AGEs and their receptor, RAGE (receptor for Advanced Glycation End Products), has been implicated in a range of pathological conditions, including diabetes and metabolic syndrome. However, the impact of AGEs accumulation on neurodevelopment remains poorly understood. In this study, we investigated the effects of AGEs on human-induced pluripotent stem cell (iPSC)-derived cerebral organoids comprising neurons, astrocytes, and microglia. Our findings reveal that AGEs induce RAGE expression, leading to microglial activation, increased deposition of amyloid-beta (Aβ) aggregates, and impaired neurodevelopment. Additionally, elevated levels of AGE-modified proteins, along with altered microglial polarization, were observed in cerebral organoids modeling Western Pacific Amyotrophic Lateral Sclerosis and Parkinsonism–Dementia Complex (ALS-PDC). These findings demonstrate AGEs as active drivers of neurodevelopmental disruption and establish a mechanistic link between metabolic stress and increased susceptibility to neurodegenerative disease. Full article

Brain organoids represent three-dimensional structures that allow for human-specific studies in brain development, pathology and therapeutics. These self-organizing systems, formed through the differentiation of human pluripotent stem cells, can mimic important cellular and molecular events of brain development and therefore serve as a platform for the investigation of neurodevelopmental and neurodegenerative diseases, brain injuries, and tumorigenesis. Although brain organoids show promising perspectives in the study of human physiology, existing brain organoid platforms are hindered by issues of under vascularization, immaturity and protocol variability. Nevertheless, the rapid development of new bioengineering, microfluidic and multi-omics tools and approaches allows us to overcome existing problems and increase the physiological significance of these organoids. Brain organoid transplantation and functional studies further enhance the applications of brain organoids in drug screening, disease modeling and personalized medicine. Here, we provide an overview of recent developments in the field of brain organoid cultures, functional characteristics and translational applications. Full article

Background: Autism Spectrum Disorder (ASD) is a complex neurodevelopmental condition marked by heterogeneous behavioral symptoms and systemic comorbidities, including immune and gastrointestinal dysfunctions. Emerging studies suggest that glycosylation—a fundamental post-translational modification regulating cellular communication and immune responses—may play a role in ASD pathophysiology, yet its contribution remains underexplored. Methods: In this study, we developed an integrative transcriptomic and network analysis framework to investigate glycosylation-related gene expression changes and their functional associations in ASD. Using publicly available datasets from bulk and single-cell RNA sequencing of brain and blood tissues, we focused on four prior-knowledge gene subsets: glycogenes, extracellular matrix glycoproteins, immune response genes, and autism risk genes. Results: Differential expression and pathway enrichment analyses revealed consistent dysregulation of glycosylation pathways, including mucin-type O-glycan biosynthesis, glycosaminoglycan metabolism, GPI-anchor formation, and sialylation, across ASD tissues. These transcriptional changes were functionally linked to altered immune signaling (e.g., IL-17, Toll-like receptor, and complement pathways) and synaptic development pathways, forming a distinct glyco-immune axis. Network analysis identified key glycogenes such as GALNT10, NEU1, LMAN2L, and CHST1 as central molecular nodes, interacting with immune and neuronal regulators. Linkage disequilibrium analysis further revealed ASD-associated SNPs influencing the expression of these glycogenes in both blood and brain tissues. Conclusions: Together, these findings support a model in which disrupted glycosylation contributes to ASD pathophysiology by mediating immune dysregulation and altered neuronal connectivity. This study offers a systems-level framework to understand the molecular complexity of ASD and highlights glycogenes as potential biomarkers and targets for future therapeutic exploration. Full article

Background/Objectives: Severe neurodevelopmental disorders caused by homozygous ASTN1 variants have recently been reported. The aim of this study is to present the expanded phenotype and prognostic findings through a longitudinal follow-up of a patient with a homozygous ASTN1 variant. Methods: We conducted a 15-year clinical evaluation of a girl who initially presented at 10 years of age. The genetic etiology was investigated using exome sequencing. Results: The patient had a profound intellectual disability, severe expressive language delay, and infantile-onset epilepsy. She also had microcephaly, achieved independent walking at age 7 and had speech limited to only two words at admission. A novel homozygous frameshift variant, c.2096del (p.Cys699Serfs*22), in ASTN1 was identified. Over the follow-up period, her postnatal microcephaly became more pronounced, and she experienced a late relapse into generalized tonic–clonic seizures after a decade-long remission. She remains entirely dependent on caregivers for basic self-care at age 25. Conclusions: ASTN1-related phenotype is associated with a severe neurodevelopmental disease, and the late relapse of seizures after prolonged remission highlights the need for lifelong neurological monitoring and multidisciplinary care. Full article

Background/Objectives: Maternal valaciclovir therapy is increasingly used to reduce fetal viral replication in cases of primary cytomegalovirus (CMV) infection during pregnancy. However, data on its impact on early neurodevelopmental outcomes remain limited. This study aimed to evaluate the association between prenatal valaciclovir exposure and early neurodevelopment in infants with confirmed congenital CMV infection (cCMV). Methods: In this retrospective monocentric cohort study, 30 infants with PCR-confirmed cCMV infection were assessed at 4–8 months of age using the Bayley Scales of Infant and Toddler Development, Third Edition (Bayley-III). Infants were stratified according to prenatal exposure to maternal valaciclovir. Univariate analyses and multivariable linear regression models were performed to evaluate the association between prenatal antiviral exposure and cognitive outcome, adjusting for brain MRI findings and selected clinical variables. Results: Fifteen infants (50%) were exposed to prenatal valaciclovir. Exposed infants demonstrated higher cognitive composite scores compared with unexposed infants (median 105 [IQR 100–110] vs. 90 [85–110]; p = 0.030). In multivariable analysis, prenatal valaciclovir exposure remained significantly associated with higher cognitive scores (β = 11.89, 95% CI 2.86–20.92; p = 0.012), while neonatal MRI abnormalities were not independently associated with outcome. No significant differences were observed in language or motor domains. The final model explained 30% of the variance in cognitive scores (R² = 0.30). Conclusions: Prenatal valaciclovir exposure was associated with higher cognitive composite scores after adjustment for selected covariates. Although causality cannot be inferred, these findings suggest a potential association with early neurodevelopmental outcomes and support the inclusion of functional neurodevelopmental endpoints in future prospective studies. These results should be considered exploratory and hypothesis-generating Full article

Background: The association between emotional dysregulation (ED) and attention-deficit/hyperactivity disorder (ADHD) has been widely documented. However, a consensus has yet to be reached on how to conceptualize this domain within ADHD. Particularly, ADHD + ED may represent a distinct condition, a more severe ADHD, or a comorbidity. We explored these three main hypotheses, investigating clinical differences between patients with ADHD, ADHD + ED, and ED. Methods: In total, 101 participants (ages 18–50) were recruited and divided into four groups: ADHD (N = 23), ED (N = 28), ADHD + ED (N = 27), and HC (N = 23). ADHD and ED were assessed using the Diagnostic Interview for ADHD in adults (DIVA-5) and the Wender–Reimherr Adult Attention Deficit Disorder Scale (WRAADDS). Sociodemographic and clinical variables were compared among the groups. Results: Participants with ADHD and ADHD + ED exhibited comparably high ADHD severity and executive dysfunction ratings. While participants with ADHD + ED shared elevated negative emotionality and higher rates of mood disorders and anxiety disorders with participants with ED compared with those with ADHD, they showed specifically increased developmental and disruptive comorbidities, as well as earlier onset and greater cyclicity of comorbid mood disorders. Psychosocial functional impairments were similarly elevated on average in ADHD + ED and ADHD, but ADHD + ED showed more pronounced and widespread deficits across multiple domains. Conclusions: ADHD + ED is unlikely to represent a more severe form of ADHD but may be more appropriately conceptualized as either a distinct entity or a “comorbid” phenotype. Comparisons with ED without ADHD highlighted clinical features specific to ADHD + ED, including a higher neurodevelopmental load, impulse-control disorders, and a poorer course of mood disorders. Full article

Background: The STAG1 gene has been related to a poorly known form of intellectual disability, known as Intellectual Developmental Disorder, Autosomal Dominant 47 (MRD47). Functionally, MRD47 is part of the Cohesinopathies, a small family of rare genetic disorders caused by defective cohesin complex, whose activity is essential for sister chromatid cohesion and therefore for chromatin organization. Chromatin state modulation is an entangled process finely modulated by a large number of actors that, if altered, give rise to the so-called Chromatinopathies. The clinical and biological overlap among these families of conditions on one hand poses significant challenges during diagnostic definition, and, on the other, may help delineate more accurate management guidelines. Methods: Starting from the report of a novel pathogenic variant in the STAG1 gene, we performed a retrospective clinical and molecular review of all previously reported patients affected by this rare disorder. Once clinical and photographic data of all published patients were collected, we used Face2Gene deep learning technology to analyze STAG1 facial phenotype, comparing it to both Chromatinopathy and Cohesinopathy profiles. Results: Our clinical and molecular re-evaluation of reported cases confirms MRD47 as a mainly neurodevelopmental disorder. Through artificial intelligence technology, we were able to first create the gestaltic profile of MRD47. Face2Gene analyses of this composite phenotype, although limited by the tool’s analysis modalities, demonstrates the strong overlap of STAG1 disorder with Chromatinopathies. Conclusions: The present literature review, together with gestaltic analyses of the STAG1-related phenotype, underscores the strong resemblance of MRD47 to epigenetic machinery disorders. The present case brings to light once more the biological and phenotypical entanglement of Cohesinopathies and Chromatinopathies, hinting at STAG1 as the joining chain. Full article

Neonatal hypoxic ischemic encephalopathy (HIE) is a common birth complication that can cause death or lifelong disabling conditions like cerebral palsy, epilepsy, and autism. It is well established that maternal infection and inflammation are significant risk factors for HIE but reasons for this increase in neurological risk to the offspring remain unknown. Inflammation or infection are associated with epigenetic changes and may contribute to the increased risk of neurodevelopmental disability in exposed offspring. Here, we analyzed and compared DNA methylation patterns in brain monocytes isolated from control, maternal immune activation (MIA), and an inflammation sensitized HIE (IS-HIE) CF-1 mouse model at postnatal day 7. We found that maternal inflammation induced significant methylation differences in neonates relative to control samples in both MIA and IS-HIE samples with no significant differences identified between the MIA and IS-HIE groups. MIA samples showed hypermethylation at loci involving craniofacial development and transcription factors important for regulating neurodevelopment and immune function. MIA samples also demonstrated significant hypermethylation at multiple mitochondrial genome CpGs. These findings suggest that maternal inflammation induces epigenetic alterations in fetal brain immune cells that are detectable in neonates. These changes may contribute to heightened neurodevelopmental risk in offspring following hypoxic injury, highlighting potential molecular pathways for future therapeutic targeting. Full article

Postsecondary institutions are seeing an increased prevalence of student mental health concerns and disabilities, highlighting the need for campus-based approaches that support student well-being. While college campuses provide many services to support students, occupational therapists are largely absent from these support systems, despite growing interest in this emerging field of practice. This program description and implementation case study examines preliminary indicators of feasibility for the WILL Thrive program, which delivered occupational therapy (OT) services on a college campus through a Level II fieldwork placement. Feasibility was examined across domains of acceptability, demand and implementation using an integrated approach combining a needs assessment, service development and process evaluation. Data sources included environmental observations, surveys, stakeholder interviews and process evaluation measures, including service delivery tracking, referral patterns, and resource utilization. Referrals and service utilization in this case were most frequently observed among students reporting neurodevelopmental and mental health-related functional challenges, providing preliminary indicators of potential service users, though a small, heterogeneous sample size limits generalizability. Referral patterns and engagement from the wellness center and accessibility staff highlight preliminary strengths of the program, including early indicators of acceptability and demand. In contrast, implementation barriers were also identified, including limited campus-wide understanding of the OT scope and role and constraints in on-campus OT supervision. Findings offer early, exploratory signals of feasibility for integrating OT services through an OT fieldwork II model and suggest that OT may complement existing campus supports by addressing participation-focused, functionally orientated needs. Results should be viewed as preliminary and inform future implementation studies that include systematic outcome measures, comparative analysis with existing services, and broader assessment across diverse higher education contexts. Full article

Background and Objectives: After undergoing a Fontan operation, children with single-ventricle physiology are at a risk of neurodevelopmental impairment; data from the Korean population are scarce. We characterized the neurocognitive profiles of early school-aged Fontan patients and evaluated the feasibility of a sedation-free ultrafast brain magnetic resonance imaging (MRI) protocol for volumetric analysis. Methods: This prospective study screened 25 children who had undergone Fontan surgery and were in grades 1–3 (8–11 years of age) in 2023. After excluding children with a history of seizure, epilepsy, or brain infarction, 11 participants underwent standardized neurocognitive evaluation. Among them, four with extreme full-scale intelligence quotient (FSIQ) underwent 3T sedation-free ultrafast brain MRI (total scan time, 3 min 22 s), including volumetry-capable three-dimensional T1-weighted imaging. Six age-matched children served as controls. MRI volumetric analysis was exploratory and limited to a small subset of Fontan participants (n = 4), restricting statistical power and generalizability. Between-group comparisons were performed using Welch’s t-test, with Hedges’ g calculated as the effect size. Results: Mean FSIQ was 85.2 ± 24.3, with 36% patients with <85 FSIQ. Working memory (64%) and processing speed (55%) were most frequently impaired. Cerebellar volumes were lower in Fontan patients than in controls, although these differences were not statistically significant (left: 59.74 ± 8.86 vs. 72.26 ± 6.92 mL; right: 60.63 ± 7.70 vs. 71.54 ± 7.01 mL; very large effect sizes). Hippocampal volumes tended to be lower, and cerebellar volume showed a positive but non-significant correlation with processing speed. White matter hyperintensities and microbleeds were observed in two patients, both with impaired processing speed. Conclusions: School-aged Fontan patients exhibited selective deficits in working memory and processing speed, while exploratory MRI analysis suggested lower cerebellar volumes in the Fontan group. The ultrafast sedation-free MRI protocol proved feasible for volumetric assessment and, when combined with neurocognitive assessments, may support future milestone-based surveillance and early intervention for at-risk children. Full article

The microbiota–gut–brain axis (MGBA) is a complex bidirectional communication network integrating neural, endocrine, immune, and metabolic pathways linking intestinal microbiota to central nervous system function. Increasing evidence indicates that microbiota-derived signals are critical regulators of neurodevelopment and may contribute to vulnerability to neurodegenerative disorders across the lifespan. In this narrative review, we synthesize experimental and clinical evidence to define the key biological mechanisms underlying microbiota–brain interactions. Converging data indicate that immune activation, barrier dysfunction, and microbial metabolites, particularly short-chain fatty acids and tryptophan-derived compounds, represent central mediators linking gut dysbiosis to neuroinflammatory and neurodegenerative processes. Early-life microbial perturbations, driven by factors such as antibiotic exposure, diet, and psychosocial stress, appear to induce long-term immunometabolic programming that may increase susceptibility to neurological disorders later in life. Clinical studies consistently associate dysbiosis with neurodevelopmental conditions and major neurodegenerative diseases, including Alzheimer’s disease and Parkinson’s disease; however, causal relationships remain incompletely defined due to heterogeneity and the predominance of observational data. Overall, the available evidence supports a lifespan model in which microbiota-driven immune and metabolic dysregulation contributes to both early neurodevelopmental trajectories and late-life neurodegeneration. While microbiome-based biomarkers and therapeutic strategies show promise, their clinical translation requires validation in longitudinal and interventional studies. Full article

Attention deficit hyperactivity disorder (ADHD) is a neurodevelopmental disorder characterized by inattention, hyperactivity, and impulsivity, compounded by difficulties in emotional regulation, which have sparked growing interest due to their relationship with emotional intelligence (EI). Background/Objectives: The objective of this study was to analyze the effectiveness and characteristics of interventions aimed at developing EI in people diagnosed with ADHD. Methods: A systematic review was conducted following PRISMA 2020 in the Web of Science, Scopus, PubMed, Dialnet, ERIC, and SpringerLink databases. After applying inclusion and exclusion criteria and evaluating methodological quality, 31 studies were selected. Results: The evidence shows that children and adolescents with ADHD have lower levels of EI than the typically developing population, especially in emotional regulation, stress management, adaptability, and interpersonal skills. Interventions focused on emotional training have demonstrated improvements in emotional competencies, self-control, ADHD symptoms, and social functioning. However, variations are observed according to age, clinical subtype, the presence of comorbidities, and the type of informant, as well as heterogeneity in the assessment instruments used. Conclusions: Strengthening EI emerges as a promising complementary strategy for improving the emotional and social adaptation of people with ADHD. It is recommended to move toward longitudinal studies and more personalized interventions tailored to the clinical and developmental characteristics of the disorder. Full article