Search Results (243)

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: TNRC6B encodes a core effector of the RNA-induced silencing complex and is essential for miRNA-mediated gene silencing. Pathogenic variants in TNRC6B have recently been associated with a neurodevelopmental disorder characterised by developmental delay, intellectual disability, and behavioural difficulties. Methods: We report a three-generation family with a 22q13.1 deletion encompassing only exons 2–23 of TNRC6B. Clinical data were collected from medical records and family interviews, and the findings were compared with those of published cohorts. Results: Affected individuals presented with developmental delay, speech and language impairment, autism spectrum disorder, ADHD, oppositional defiant disorder, craniosynostosis, joint laxity, clinodactyly, and cardiac valve anomalies. The father and paternal grandmother had learning difficulties and neurobehavioral features, while the proband exhibited a more severe phenotype. Conclusions: This report expands the phenotypic spectrum of TNRC6B-related neurodevelopmental disorder, highlighting craniosynostosis, joint and connective tissue features, and cardiac involvement. Our findings also underscore variable expressivity across generations and emphasise the relevance of both copy-number and sequence variants in TNRC6B in patients with neurodevelopmental disorders. Full article

Circadian disruption represents a global health issue associated with cardiometabolic diseases, sleep disturbances, and mood disorders, driven by a pathophysiological network including clock gene dysregulation and impaired melatonin synthesis. Vitamin D exerts pleiotropic effects on metabolic regulation, immune function, neurotransmission, and possibly circadian synchronization. Emerging evidence suggests that vitamin D and its hydroxyderivatives modulate clock gene expression, influence transcriptional regulators such as retinoic acid receptor-related orphan receptors and REV-ERBs, and interact with melatonin synthesis and signaling. Vitamin D deficiency has been associated with metabolic syndrome, impaired sleep quality, and depression. Although interventional studies yield heterogeneous results, higher vitamin D status may confer protective metabolic and neurobehavioral effects. This review summarizes current evidence on the role of vitamin D in circadian disruption and evaluates its potential therapeutic relevance in circadian–metabolic dysregulation. Full article

Background/Objectives: Fibromyalgia is increasingly viewed as a disorder of central sensitization, involving altered nociceptive processing and dysregulated stress and affective neural systems. Evidence supports shared neurobiological mechanisms linking chronic pain, emotional distress, and affect regulation, including corticolimbic and hypothalamic–pituitary–adrenal axis alterations. However, predictive models evaluating psychological distress as markers of these brain-based processes remain scarce. This study aimed to internally validate a preliminary model of fibromyalgia diagnosis using self-reported distress indicators as proxies of central dysregulation. Methods: A case-control design study with 180 participants was performed. Medically diagnosed fibromyalgia cases were recruited via a pain facility or referrals, alongside geographically matched controls from the general population. Psychological variables were conceptualized as neurobehavioral indicators reflecting central sensitization and stress-system dysregulation. Predictors were selected using LASSO penalized regression with 10-fold cross-validation. Retained variables were re-estimated using logistic regression. Model performance was evaluated through Nagelkerke’s pseudo-$R^2$, a likelihood ratio test, and area under the curve (AUC). Internal validation was conducted via 1000-bootstrap resampling with calibration-slope-based shrinkage. Results: The final model included global psychological distress, positive affect, sex, and age ($R^2=0.359$, with good discrimination [AUC = 0.81; optimism-corrected AUC ≈ 0.79]). Higher distress and age were associated with increased odds of fibromyalgia. Conclusions: Self-reported psychological distress, particularly global distress and reduced positive affect, combined with sex and age, showed internal validity in predicting fibromyalgia diagnosis. These findings support the hypothesis that behavioral markers of emotional dysregulation may reflect underlying central sensitization and stress-system alterations implicated in chronic pain. Future research integrating psychological measures with neuroimaging and neuroendocrine markers may further clarify the neural mechanisms linking affective dysregulation and chronic pain vulnerability. Full article

Attention-deficit/hyperactivity disorder (ADHD), brain–derived neurotrophic factor (BDNF), and enuresis are interconnected in several ways, primarily through their potential links to neurodevelopmental factors and brain function. ADHD is considered a neurobehavioral and neuropsychiatric condition characterized by numerous comorbidities, and it represents one of the most frequently encountered neuropsychiatric disorders in clinical practice. Enuresis constitutes a subgroup of intermittent incontinence occurring during sleep that can be further subdivided into monosymptomatic (MNE) and non-monosymptomatic enuresis (NMNE). BDNF plays a crucial role in neurodevelopment, including neuronal growth, proliferation, survival, differentiation, and synaptic plasticity. This narrative review synthesized available literature identified through a systematic search of PubMed/MEDLINE, Science Direct, and Scopus databases (January 2000–December 2025). However, the evidence base is heterogeneous, and findings regarding BDNF in ADHD are inconsistent. Studies examining BDNF in enuresis often involve urinary BDNF, which reflects local bladder production rather than central BDNF activity. Further research is needed to clarify the specific roles of BDNF in the development and manifestation of these conditions and to fully elucidate the complex relationship between BDNF, ADHD, and enuresis. Full article

The ontological categorization of the cellular elements of the brain was proposed over a century ago by Santiago Ramón y Cajal (neurons, astroglia) and Pío del Río-Hortega (oligodendroglia, microglia). It combines histochemical observations of morphology with allied inferences about the specialized functions and origins (ectoderm or mesoderm) of each cellular element. This ontology shapes modern neuroscience, with the main non-neuronal cells—astroglia, oligodendroglia and microglia—viewed as having distinct primary roles relating respectively to the metabolic support, myelination and immunoprotection of neurons, the information signaling cells. Yet contemporary techniques, ranging from electrophysiology to single-cell transcriptomics and ultrahigh resolution spectroscopy, are revealing intersecting molecular profiles and functional capacities of these cell groups, for example metabolic support, neuroimmune and signaling functions in oligodendroglia. Here we identify discrepancies in current glial paradigms, from empirical, evolutionary and pragmatic perspectives. We suggest a subset of small, iron-rich glial cells, usually with few processes, often viewed as oligodendroglia with myelin-related primary functions, instead have iron-related primary functions that are central to all aspects of brain activity. We call these ‘ferriglia’. We discuss implications for pathogenesis across the spectrum of neuropsychiatric and neurological disorders, including neurodegenerative conditions such as Alzheimer’s disease and other less common cognitive, movement and neurobehavioral disorders, stroke and cerebrovascular disease, glioblastoma and other brain cancers and neuroimmune conditions. We also briefly address the question of where ferriglia may reside within existing glial compartments and lineages, implications for the ontological classification of other glial cells, and research challenges that must be overcome going forward. Full article

Background: Celiac disease (CD) is a multisystem immune-mediated disorder increasingly recognized to affect sleep and neurobehavioral functioning. Pediatric data remain limited, and no prior study has examined especially for sleep microstructure in this population. This study evaluates the prevalence and patterns of sleep disturbances in children with CD using the Sleep Disturbance Scale for Children (SDSC) and explores potential electrophysiological correlates through N2 sleep spindle analysis. Methods: Children with biopsy-confirmed CD (n = 31) and age-matched controls (n = 25) completed the SDSC. A subgroup of CD patients with SDSC ≥ 35 and healthy controls underwent quantitative sleep spindle analysis (C3, C4, O1, O2) using automated and visual verification methods combined. Results: Clinically significant sleep disturbances were substantially more prevalent in CD than in controls (77.4% vs. 12%). Excessive somnolence, sleep–wake transition disorders, and sleep hyperhidrosis were the most affected domains. Moreover, among children with CD, those noncompliant with a gluten-free diet exhibited higher rates of excessive somnolence and sleep–wake transition disorders. While spindle parameters did not differ between groups, higher SDSC scores (≥35)—particularly in the somnolence and sleep–wake transition disorder domains—are associated with reduced spindle amplitude and density, suggesting that spindle alterations are linked to sleep disturbance severity rather than disease status per se. Conclusions: Sleep disturbances are common in pediatric CD and worsen with poor dietary adherence. Although sleep microarchitecture is largely preserved, reduced spindle activity is evident in children with higher subjective sleep burden, suggesting that spindle metrics may serve as potential objective markers for sleep disturbance. Longitudinal studies are required for validation. Full article

Rett Syndrome (RTT) is a neurodevelopmental disorder characterized by mutations in the MeCP2 gene, predominantly affecting females. Recent work with MeCP2-deficient mouse models showed a significant role in glutamatergic transmission, specifically microglia-produced glutamate and glutaminase upregulation, in RTT pathology. The glutamine antagonist 6-diazo-5-oxo-L-norleucine (DON) is a potent glutaminase inhibitor; however, its use is limited due to systemic toxicities arising from its non-specific inhibition of glutamine-utilizing reactions. In this work, we determined whether dendrimer conjugation of a DON analog, TTM020 (or D-TTM020), results in targeted microglial glutaminase inhibition and behavioral changes in Mecp2 KO and heterozygous mice upon systemic administration. D-TTM020 at 1 mg/kg (drug basis) selectively and significantly inhibits glutaminase enzyme activity in the microglia of Mecp2 KO mice. Biweekly systemic treatment with 1 mg/kg of D-TTM020 improved the neurobehavioral phenotype in symptomatic Mecp2 KO and het mice. D-TTM020 also restored long-term retrieval of conditioned fear memory and improved cue responses during fear extinction after 8 weeks of treatment in symptomatic Mecp2 het mice. Our data indicate that selectively targeting glutamine metabolism in dysregulated glia using dendrimers represents a promising strategy that may offer a therapeutic approach for addressing glutamate dysregulation in RTT. Full article

Background: Iron plays a crucial role in neurotransmitter synthesis, myelination, and neuronal metabolism. Iron deficiency has been associated with a variety of neurodevelopmental disorders, particularly attention-deficit/hyperactivity disorder (ADHD) and autism spectrum disorder (ASD). However, the prevalence, clinical impact, and treatment implications differ between these conditions. Objective: To synthesize current evidence on the prevalence, neurobehavioral consequences, and therapeutic implications of iron deficiency in ADHD and ASD, highlighting convergences and disorder-specific findings. Results: In ADHD, studies using serum ferritin and related peripheral markers show inconsistent associations with core symptom severity, with reported ferritin thresholds for deficiency ranging widely. While some studies suggest links between low ferritin and hyperactivity, inattention, or stimulant response, others report null findings. In contrast, emerging neuroimaging evidence consistently demonstrates reduced brain iron in dopaminergic regions in children. In ASD, the strongest link is between low ferritin and sleep-related motor disturbances, and iron supplementation may improve sleep and motor symptoms. Conclusions: Screening for iron status and targeted supplementation may improve sleep and behavioral outcomes in ADHD and ASD, meriting integration into clinical practice and further randomized controlled trials. Full article

Background/Objectives: Smith–Magenis syndrome (SMS) is a rare neurogenetic disorder caused by a microdeletion in chromosome region 17p11.2 or by pathogenic variants in the RAI1 gene. The syndrome is characterized by a distinctive neurobehavioral profile, including cognitive deficits, sleep disturbances, self-injurious behavior, and typical dysmorphic features. A characteristic diagnostic hallmark is paradoxical melatonin secretion, with increased daytime levels instead of the normal nocturnal peak. This article aims to summarize current knowledge on the etiology, diagnostics, EEG findings, therapy, and prognosis of SMS from a neuropediatric perspective. Methods: A narrative review of the literature on Smith–Magenis syndrome was conducted, focusing on genetic background, clinical features, diagnostic approaches, EEG characteristics, therapeutic strategies, and prognosis. In addition, a detailed clinical case of a 16-year-old female patient with SMS is presented. Results: The reviewed data confirm that SMS is associated with characteristic neurobehavioral abnormalities and sleep–wake rhythm disturbances. EEG findings may include epileptiform activity without overt epilepsy. In the presented case, “Rolandic-type” spike–sharp wave complexes were observed on EEG and are interpreted as an expression of congenital disturbances in brain maturation processes. Therapeutic recommendations addressing behavioral symptoms and sleep regulation are discussed. Conclusions: Smith–Magenis syndrome represents a complex neurodevelopmental disorder with distinctive clinical, neurophysiological, and genetic features. Early recognition of characteristic signs, including sleep disturbances and EEG abnormalities, is essential for appropriate management. A multidisciplinary, individualized therapeutic approach may improve quality of life and long-term outcomes. Full article

Background/Objectives: Coupled with the already-problematic background rates of traditional cigarette consumption during pregnancy, the surging epidemic of electronic cigarette usage among pregnant women redoubles the importance of understanding the impacts of nicotine exposure during critical periods of development. To date, a burgeoning body of human epidemiological and animal model research indicates that not only the children but also the grandchildren of maternal smokers are at higher risk for neurodevelopmental disorders such as ADHD, autism, and schizophrenia and are predisposed to neurodevelopmental abnormalities which transcend these diagnoses. However, the roles of discrete cellular sub-populations in these and other intergenerational consequences of smoking during pregnancy remain indeterminate. Methods: Toward the resolution of this void in the literature, the present study characterized alterations in the gene expression profiles of dopamine receptor D1-expressing striatal cells from the first- and second-generation male progeny of female mice that were continuously exposed to nicotine beginning prior to conception, continuing throughout pregnancy, and concluding upon weaning of offspring. Results: Dopamine receptor D1-expressing striatal cells from our mouse models of the children and grandchildren of maternal smokers exhibit differential expression patterns for a multitude of genes that are (1) individually associated with neurodevelopmental disorders, (2) collectively overrepresented in gene set annotations related to brain, behavioral, neurobiological, and epigenomic phenotypes shared among neurodevelopmental disorders, and (3) orthologous to human genes that exhibit differential DNA methylation signatures in the newborns of maternal smokers. Conclusions: Together with our and others’ previous findings, the results of this study support the emerging theory that, by inducing extensive alterations in gene expression that in turn elicit cascading neurobiological changes which ultimately confer widespread neurobehavioral abnormalities, nicotine-induced epigenomic dysregulation may be a primary driver of neurodevelopmental deficits and disorders in the children and grandchildren of maternal smokers. Full article

Background: Gilles de la Tourette syndrome is a neurobehavioral disorder that typically begins in childhood, subsides during puberty, and may reappear in adolescence. Treatment is primarily conservative, involving psychological and pharmacological therapy. Patients who do not respond to conservative therapy may be treated with deep brain stimulation, although this remains an experimental treatment. Methods: In this two-case report we present the first two cases of patients with Gilles de la Tourette syndrome in Slovenia treated with deep brain stimulation of the anteromedial globus pallidus internus. Results: Over an 18-month follow-up period, we observed an improvement in both cases. In the first case, the Yale Global Tic Severity Scale score decreased from 71 (17 for motor tics, 14 for phonic tics, and 40 on the impairment scale) to 44 points (12 motor, 12 phonic, and 20 impairment). In the second case, the score decreased from 72 (16 motor, 16 phonic, and 40 impairment) to 38 points (8 motor, 10 phonic, and 20 impairment). Conclusions: Deep brain stimulation could be a promising treatment for this disorder. However, further research is needed to determine the most suitable patients and targets. Full article

Down Syndrome Regression Disorder (DSRD) is a rare but severe neuropsychiatric condition characterized by abrupt loss of speech, autonomy, and cognitive abilities in individuals with Down syndrome, often associated with immune dysregulation and gut–brain axis dysfunction. We report the case of an 11-year-old girl with Down syndrome who developed developmental regression at age five, in temporal proximity to a family transition (the birth of a younger sibling), with loss of continence, language, and comprehension, alongside persistent behavioral agitation and gastrointestinal symptoms. Laboratory assessment revealed Giardia duodenalis infection, elevated fecal calprotectin and secretory IgA, and microbial imbalance with overgrowth of Streptococcus anginosus and S. sobrinus. The patient received a single oral dose of tinidazole (2 g), daily folinic acid (1 mg/kg), and a 90-day course of transcranial and abdominal photobiomodulation (PBM) (1064 nm, 10 min per site). Post-treatment, stool analysis showed normalized inflammation markers and restoration of beneficial bacterial genera (Bacteroides, Bifidobacterium, Lactobacillus) with absence of Enterococcus growth. Behaviorally, she exhibited marked recovery: CARS-2-QPC decreased from 106 to 91, ABC from 63 to 31, and ATEC from 62 to 57, alongside regained continence, speech, and fine-motor coordination. These outcomes suggest that abdominal and transcranial PBM, by modulating mitochondrial metabolism, mucosal immunity, and microbiota composition, may facilitate systemic and neurobehavioral recovery in DSRD. This translational case supports further investigation of PBM as a non-invasive, multimodal therapy for neuroimmune regression in genetic and developmental disorders including validation through future randomized controlled clinical trials. Full article

Background: Alcohol use disorder (AUD) is associated with chronic heavy or repeated binge alcohol abuse, which can cause alcohol-related brain damage (ARBD) marked by neurobehavioral, cognitive, and motor deficits. The anterior frontal lobe and cerebellar vermis are two of the major targets of ARBD in humans with AUD and in experimental alcohol exposed models. Alcohol’s neurotoxic and neurodegenerative effects include impairments in signaling through insulin and insulin-like growth factor (IGF) pathways that regulate energy metabolism. This human AUD study was inspired by a recent report suggesting that dysfunction of the frontal lobe incretin network in experimental ARBD is linked to known impairments in brain insulin/IGF signaling. Objective: The overarching goal was to investigate whether AUD is associated with dysfunction of the brain’s incretin network, focusing on the cerebellum and frontal lobe. Methods: Fresh frozen postmortem cerebellar vermis and anterior frontal lobe tissues from adult male AUD (n = 6) and control (n = 6) donors were processed for protein extraction. Duplex enzyme-linked immunosorbent assays (ELISAs) were used to assess immunoreactivity to neurofilament light chain (NfL) as a marker of neurodegeneration. A multiplex ELISA was used to measure immunoreactivity to a panel of gut hormones, including incretin polypeptides. Results: AUD was associated with significantly increased NfL immunoreactivity in both the cerebellar vermis and anterior frontal lobe. However, the patterns of AUD-related alterations in gut hormone immunoreactivity differed regionally. AUD reduced pancreatic polypeptide immunoreactivity in the cerebellar vermis, and GIP, GLP-1, leptin, and ghrelin in the frontal lobe. Conclusions: (1) Increased NfL may serve as a useful biomarker of neurodegeneration in AUD. (2) AUD’s adverse effects on neuroendocrine signaling networks differ in the cerebellar vermis and anterior frontal region, although both are significant targets of ARBD. (3) The finding of AUD-associated reductions in frontal lobe GIP and GLP-1 suggests that therapeutic targeting with incretin receptor agonists may help restore energy metabolism and neurobehavioral and cognitive functions linked to their networks. Full article

Background: Bullying in university settings is a significant yet understudied contributor to psychological distress. Differentiating the sources of victimization, may reveal distinct risk profiles associated with mental health and substance use outcomes. Objective: To evaluate the frequency and risk factors associated with bullying victimization among medical students, and to identify associations with mental disorders and substance use. Methods: A nested case–control cohort study was conducted with 124 medical students. Participants completed nine validated psychometric instruments evaluating neurobehavioral traits, emotional distress, substance use, and scholar bullying. Bivariate and multivariate regression models were used to estimate coefficients and odds ratios for key outcomes. Results: 42.7% of the students reported victimization, with teacher harassment (37.1%) more frequent than peer harassment (27.4%); 22.6% experienced both. Teacher harassment was primarily characterized by intentional harm (78%); peer harassment involved abuse of authority (63%). ADHD, severe stress, and substance use were associated with teacher-related victimization, while peer victimization was linked to ADHD, stress, impulsivity, and suicide risk. Childhood abuse, high stress levels, and non-heterosexual orientation as predictors of teacher harassment (p < 0.05). Notably, students with a non-heterosexual orientation were over six times more likely to report teacher harassment, highlighting the disproportionate vulnerability of sexual minorities within academic power dynamics. Conclusions: Teacher- and peer-related harassment are prevalent and often co-occur, with teacher-perpetrated bullying emerging as both more frequent and more strongly associated with mental health and identity-based vulnerabilities. Students with ADHD, high stress levels, and non-heterosexual orientation are at significantly greater risk. These findings emphasize the need for institutional accountability, inclusive academic policies, and targeted mental health support to protect vulnerable students and prevent harm within educational environments. Full article