Search Results (717)

Background/Objectives: An important new consideration when studying autism spectrum disorder (ASD) is the bioenergetic mechanisms underlying the relatively recent rapid evolutionary expansion of the human brain, which pose fundamental risks for mitochondrial dysfunction and calcium signaling abnormalities and their potential role in ASD, as recently highlighted by insights from the BTBR mouse model of ASD. The rapid brain expansion taking place as Homo sapiens evolved, particularly in the parietal lobe, led to increased energy demands, making the brain vulnerable to such metabolic disruptions as are seen in ASD. Methods: Mitochondrial dysfunction in ASD is characterized by impaired oxidative phosphorylation, elevated lactate and alanine levels, carnitine deficiency, abnormal reactive oxygen species (ROS), and altered calcium homeostasis. These dysfunctions are primarily functional, rather than being due to mitochondrial DNA mutations. Calcium signaling plays a crucial role in neuronal ATP production, with disruptions in inositol 1,4,5-trisphosphate receptor (ITPR)-mediated endoplasmic reticulum (ER) calcium release being observed in ASD patient-derived cells. Results: This impaired signaling affects the ER–mitochondrial calcium axis, leading to mitochondrial energy deficiency, particularly in high-energy regions of the developing brain. The BTBR mouse model, with its unique Itpr3 gene mutation, exhibits core autism-like behaviors and metabolic syndromes, providing valuable insights into ASD pathophysiology. Conclusions: Various interventions have been tested in BTBR mice, as in ASD, but none have directly targeted the Itpr3 mutation or its calcium signaling pathway. This review presents current genetic, biochemical, and neurological findings in ASD and its model systems, highlighting the need for further research into metabolic resilience and calcium signaling as potential diagnostic and therapeutic targets for ASD. Full article

Background: Understanding the origin and natural organization of early infant vocalizations is important for predicting communication and language abilities in later years. The very frequent production of speech-like vocalizations (hereafter “protophones”), occurring largely independently of interaction, is part of this developmental process. Objectives: This study aims to investigate the gap durations (time intervals) between protophones, comparing typically developing (TD) infants and infants later diagnosed with autism spectrum disorder (ASD) in a naturalistic setting where endogenous protophones occur frequently. Additionally, we explore potential age-related variations and sex differences in gap durations. Methods: We analyzed ~1500 five min recording segments from longitudinal all-day home recordings of 147 infants (103 TD infants and 44 autistic infants) during their first year of life. The data included over 90,000 infant protophones. Human coding was employed to ensure maximally accurate timing data. This method included the human judgment of gap durations specified based on time-domain and spectrographic displays. Results and Conclusions: Short gap durations occurred between protophones produced by infants, with a mode between 301 and 400 ms, roughly the length of an infant syllable, across all diagnoses, sex, and age groups. However, we found significant differences in the gap duration distributions between ASD and TD groups when infant-directed speech (IDS) was relatively frequent, as well as across age groups and sexes. The Generalized Linear Modeling (GLM) results confirmed these findings and revealed longer gap durations associated with higher IDS, female sex, older age, and TD diagnosis. Age-related differences and sex differences were highly significant for both diagnosis groups. Full article

Sensorimotor integration along the gastrointestinal (GI) tract is crucial for normal gut function yet remains poorly understood in the context of neurodevelopmental disorders (NDDs) such as autism spectrum disorder (ASD). The genetic tractability of zebrafish allows investigators to generate molecularly defined models that provide a means of studying the functional circuits of digestion in vivo. Optical transparency during development allows for the use of optogenetics and calcium imaging to elucidate the mechanisms underlying GI-related symptoms associated with ASD. The array of commonly reported symptoms implicates altered sensorimotor integration at various points along the GI tract, from the pharynx to the anus. We will examine the reflex arcs that facilitate swallowing, nutrient-sensing, absorption, peristalsis, and evacuation. The high level of conservation of these processes across vertebrates also enables us to explore potential therapeutic avenues to mitigate GI distress in ASD and other NDDs. Full article

Background/Objectives: Autism spectrum disorder (ASD) encompasses several neurodevelopmental disorders, whose onset is correlated to genetic and environmental factors. Although the etiopathogenesis is not entirely clear, the involvement of inflammatory processes, the endocannabinoid system, and alterations in the permeability and composition of the intestinal microbiota are known to occur. Methods: This review systematically explores the literature available to date on the most widely used murine models for the study of ASD, the main biomarkers investigated for the diagnosis of ASD, and the therapeutic potential of probiotics, with a particular focus on the use of strains of Lactiplantibacillus (Lpb.) plantarum in in vivo models and clinical trials for ASD. Results: Several studies have demonstrated that targeting multifactorial biomarkers in animal models and patients contributes to a more comprehensive understanding of the complex mechanisms underlying ASD. Moreover, accumulating evidence supports the beneficial effect of probiotics, including Lpb. plantarum, as a promising alternative therapeutic strategy, capable of modulating gut–brain axis communication. Conclusions: Probiotic supplementation, particularly with selected Lpb. plantarum strains, is emerging as a potential complementary approach for ameliorating ASD-related gastrointestinal and behavioral symptoms. However, further large-scale clinical studies are essential to validate their efficacy and determine optimal treatment protocols and dietary strategies. Full article

Background/Objectives: The hippocampus is an essential part of the central nervous system (CNS); it plays a significant role in social–cognitive memory processing. Prenatal exposure to valproic acid (VPA) can lead to impaired hippocampal functions. In this study, we evaluated the effect of plumbagin (PLB) as a natural product on spatial learning and memory, neuro-morphological changes, and inflammation levels in a VPA-induced autism model during adolescence. Methods: Pregnant Wistar rats received a single intraperitoneal (i.p.) injection of VPA (600 mg/kg) or saline on gestational day 12.5. The male offspring were then categorized and assigned to five groups: Saline+DMSO-, VPA+DMSO-, and VPA+PLB-treated groups at doses of 0.25, 0.5, or 1 mg/kg. Spatial learning and memory were evaluated using the Morris water maze. Histopathological evaluations of the hippocampus were performed using Nissl and hematoxylin–eosin staining, as well as immunofluorescence. The pro-inflammatory cytokine levels were also quantified by quantitative real-time PCR. Results: The findings revealed that a VPA injection on gestational day 12.5 is associated with cognitive impairments in male pups, including a longer escape latency and traveled distance, as well as decreased time spent in the target quadrant. Treatment with PLB significantly enhanced the cognitive function, reduced dark cells, and ameliorated neuronal–morphological alterations in the hippocampus of VPA-exposed rats. Moreover, PLB was found to reduce astrocyte activation and the expression levels of pro-inflammatory cytokines. Conclusions: These findings suggest that PLB partly mitigates VPA-induced cognitive deficits by ameliorating hippocampal inflammation levels. Full article

Background: Neurodevelopmental disorders (NDDs), including autism spectrum disorder (ASD), are genetically complex and often linked to structural genomic variations such as copy number variants (CNVs). Current diagnostic strategies face challenges in interpreting the clinical significance of such variants. Methods: We developed a customized, gene-oriented chromosomal microarray (CMA) targeting 6026 genes relevant to neurodevelopment, aiming to improve diagnostic yield and candidate gene prioritization. A total of 39 patients with unexplained developmental delay, intellectual disability, and/or ASD were analyzed using this custom platform. Systems biology approaches were employed for downstream interpretation, including protein–protein interaction networks, centrality measures, and tissue-specific functional module analysis. Results: Pathogenic or likely pathogenic CNVs were identified in 31% of cases (9/29). Network analyses revealed candidate genes with key topological properties, including central “hubs” (e.g., NPEPPS, PSMG1, DOCK8) and regulatory “bottlenecks” (e.g., SLC15A4, GLT1D1, TMEM132C). Tissue- and cell-type-specific network modeling demonstrated widespread gene involvement in both prenatal and postnatal developmental modules, with glial and astrocytic networks showing notable enrichment. Several novel CNV regions with high pathogenic potential were identified and linked to neurodevelopmental phenotypes in individual patient cases. Conclusions: Customized CMA offers enhanced detection of clinically relevant CNVs and provides a framework for prioritizing novel candidate genes based on biological network integration. This approach improves diagnostic accuracy in NDDs and identifies new targets for future functional and translational studies, highlighting the importance of glial involvement and immune-related pathways in neurodevelopmental pathology. Full article

Background: Neurodevelopmental disorders, including autism spectrum disorder (ASD) and attention-deficit/hyperactivity disorder (ADHD), are increasingly recognized as conditions arising from multifaceted interactions among genetic predisposition, environmental exposures, and epigenetic modifications. Among epigenetic mechanisms, non-coding RNAs (ncRNAs), including microRNAs (miRNAs), long non-coding RNAs (lncRNAs), and PIWI-interacting RNAs (piRNAs), have gained attention as pivotal regulators of gene expression during neurodevelopment. These RNA species do not encode proteins but modulate gene expression at transcriptional and post-transcriptional levels, thereby influencing neuronal differentiation, synaptogenesis, and plasticity. Objectives: This systematic review critically examines and synthesizes the most recent findings, particularly in the post-COVID transcriptomic research era, regarding the role of ncRNAs in the pathogenesis, diagnosis, and potential treatment of neurodevelopmental disorders. Methods: A comprehensive literature search was conducted to identify studies reporting on the expression profiles, functional implications, and clinical relevance of ncRNAs in neurodevelopmental disorders, across both human and animal models. Results: Here, we highlight that multiple classes of ncRNAs are differentially expressed in individuals with ASD and ADHD. Notably, specific miRNAs and lncRNAs demonstrate potential as diagnostic biomarkers with high sensitivity and specificity. Functional studies further reveal that ncRNAs actively contribute to pathogenic mechanisms by modulating neuronal gene networks. Conclusions: Emerging experimental data indicate that the exogenous administration of certain ncRNAs may reverse molecular and behavioral phenotypes, supporting their therapeutic promise. These findings broaden our understanding of neurodevelopmental regulation and open new avenues for personalized diagnostics and targeted interventions in clinical neuropsychiatry. Full article

Background/Objectives: Atypical sensory processing is increasingly recognized as a transdiagnostic dimension of neurodevelopmental disorders (NDDs), with critical implications for emotional and behavioral regulation. This study aimed to identify distinct sensory profiles in preschool children with NDDs and to examine their associations with emotional–behavioral and cognitive/developmental functioning. Methods: A total of 263 children (aged 21–71 months) diagnosed with autism spectrum disorder (ASD), language disorder (LD), or other NDDs (ONDD) were recruited. Sensory processing was assessed using the SPM-P, emotional–behavioral functioning was assessed via the CBCL 1½–5, and cognitive/developmental levels were assessed through standardized instruments. Latent profile analysis (LPA) was conducted to identify sensory subtypes. Group comparisons and multinomial logistic regression were used to examine profile characteristics and predictors of profile membership. Results: Three sensory profiles emerged: (1) Multisystemic Sensory Dysfunction (20.1%), characterized by pervasive sensory and emotional difficulties, primarily observed in ASD; (2) Typical Sensory Processing (44.9%), showing normative sensory and emotional functioning, predominantly LD; and (3) Mixed Subclinical Sensory Processing (35%), with subclinical-range scores across multiple sensory and emotional domains, spanning all diagnoses. Higher cognitive functioning and fewer internalizing symptoms significantly predicted membership in the typical profile. A gradient of symptom severity was observed across profiles, with the Multisystemic group showing the most pronounced emotional–behavioral impairments. Conclusions: Distinct sensory–emotional phenotypes were identified across diagnostic categories, supporting a dimensional model of neurodevelopment. Sensory profiles were strongly associated with emotional functioning, independently of diagnostic status. Early sensory assessment may therefore offer clinically meaningful insights into emotional vulnerability and inform targeted interventions in preschool populations with NDDs. Full article

This research highlights the importance of Emotion Aware Technologies (EAT) and their implementation in serious games to assist children with Autism Spectrum Disorder (ASD) in developing social-emotional skills. As AI is gaining popularity, such tools can be used in mobile applications as invaluable teaching tools. In this paper, a new AI framework application is discussed that will help children with ASD develop efficient social-emotional skills. It uses the Jetpack Compose framework and Google Cloud Vision API as emotion-aware technology. The framework is developed with two main features designed to help children reflect on their emotions, internalise them, and train them how to express these emotions. Each activity is based on similar features from literature with enhanced functionalities. A diary feature allows children to take pictures of themselves, and the application categorises their facial expressions, saving the picture in the appropriate space. The three-level minigame consists of a series of prompts depicting a specific emotion that children have to match. The results of the framework offer a good starting point for similar applications to be developed further, especially by training custom models to be used with ML Kit. Full article

Background: Valproic acid (VPA) is a medication used to treat epilepsy, bipolar disorder, and migraine. If taken during pregnancy, it can cause neural tube defects (NTDs) and leads to offspring ASD behavioral phenotype. It has recently been found that early postnatal VPA exposure can also induce the ASD phenotype, but the details of model production and intervention still need further investigation. Dimethylmalonic acid (DMM), a competitive inhibitor of succinate dehydrogenase, blocks the key element succinate of OXPHOS, decreasing the secretion of anti-inflammatory cytokines and ROS production. However, it is still unclear whether DMM is involved in the repair of developmental brain injuries. Objectives: The aim of this study was to evaluate the intervention effect and optimal dosage of DMM on behavioral phenotypes using a neonatal mouse VPA autism model. Methods: This experiment consists of two parts. The first part observed the effects of different concentrations of VPA on the development and neurobehavioral phenotype of mice. The second part determined the intervention effect of DMM on a developmental VPA autism model and determined the optimal therapeutic dose. Results: We found that the 40 mg/mL concentration had a greater impact on the neural reflex damage in mice. Moreover, DMM treatment can partially improve the neurobehavioral damage in the VPA model, and 20 mg/kg has the best intervention effect. Conclusions: This study provides valuable model construction data for further exploring the mechanism of DMM treatment for an ASD phenotype induced by VPA exposure in neonates. Full article

Background. Parents of autistic children face challenges that can negatively affect the quality of the parent–child relationship. This study aimed to explore the potential protective role of parental resolution about positive (closeness) and negative (conflict and dependence) aspects of the parent–child relationship, with parenting stress and caregiving burden as mediators. Methods. A cross-sectional study (ethical approval: CE n. 92949) was conducted with 51 Italian parents of autistic children. A multiple mediation model was tested. Results. Parental resolution had a significant total effect (β = 0.012; BootLLCI = 0.002; BootULCI = 0.024) and a significant direct effect on the parent–child relationship (β = 0.223; BootLLCI = 0.058; BootULCI = 0.389), indicating that resolving the child’s diagnosis could potentially influence parents’ perceptions of their relationship with their child, possibly leading to views of it being somewhat closer, experiencing fewer conflicts, and involving a lower degree of dependence. An indirect effect via parenting stress was also significant (β = −0.130; BootLLCI = −0.009; BootULCI = −0.291), while caregiving burden did not show a mediating effect. Conclusion: Despite the exploratory and cross-sectional nature of this study, the findings highlight the importance of promoting family well-being in the context of autism. The findings may inform future research on parental resources and guide clinicians in developing intervention programmes to mitigate the emotional impact of receiving a child’s autism diagnosis. Full article

Background/Objectives: Repetitive behaviors such as hand flapping, body rocking, and head shaking characterize Autism Spectrum Disorder (ASD) while functioning as early signs of neurodevelopmental variations. Traditional diagnostic procedures require extensive manual observation, which takes significant time, produces subjective results, and remains unavailable to many regions. The research introduces a real-time system for the detection of ASD-typical behaviors by analyzing body movements through the You Only Look Once (YOLOv11) deep learning model. Methods: The system’s multi-layered design integrates monitoring, network, cloud, and typical ASD behavior detection layers to facilitate real-time video acquisition, wireless data transfer, and cloud analysis along with ASD-typical behavior classification. We gathered and annotated our own dataset comprising 72 videos, yielding a total of 13,640 images representing four behavior classes that include hand flapping, body rocking, head shaking, and non_autistic. Results: YOLOv11 demonstrates superior performance compared to baseline models like the sub-sampling (CNN) (MobileNet-SSD) and Long Short-Term Memory (LSTM) by achieving 99% accuracy along with 96% precision and 97% in recall and the F1-score. Conclusions: The results indicate that our system provides a scalable solution for real-time ASD screening, which might help clinicians, educators, and caregivers with early intervention, as well as ongoing behavioral monitoring. Full article

Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by restricted social communication and repetitive behaviors. Prenatal stress is critical in neurodevelopment and increases risk for ASD, particularly in those with greater genetic susceptibility to stress. Docosahexaenoic acid (DHA) is one of the most abundant ω-3 fatty acids in the membrane phospholipids of the mammalian brain, and dietary DHA plays an important role in brain development and maintenance of brain structure. In this study, we investigated whether peri-natal supplementation of DHA can alleviate autistic-like behaviors in a genetic risk/stress mouse model and how it alters lipid peroxidation activity and GABAergic system gene expression in the forebrain. Pregnant heterozygous serotonin transporter knockout (SERT-KO) and wild-type (WT) dams were placed in either non-stressed control conditions or chronic variable stress (CVS) conditions and fed either a control diet or a DHA-rich (1% by weight) diet. Offspring of each group were assessed for anxiety and autism-associated behavior at post-natal day 60 using an open field test, elevated plus maze test, repetitive behavior, and the 3-chamber social approach test. A liquid chromatography-mass spectrometry (LC-MS)-based method was used to follow changes in levels of lipid peroxidation products in the cerebral cortex. Male offspring of prenatally stressed SERT-het KO dams exhibited decreased social preference behaviors and increased repetitive grooming behaviors compared to WT control offspring. Moreover, DHA supplementation in male SERT-het mice decreased frequency of grooming behaviors albeit showing no associated effects on social behaviors. Regardless of stress conditions, supplementation of DHA to the WT mice did not result in alterations in grooming nor social interaction in the offspring. Furthermore, no apparent changes were observed in the lipid peroxidation products comparing the stressed and non-stressed brains. Gad2 was downregulated in the cortex of female offspring of prenatally stressed SERT-KO dams, and this change appeared to be rescued by DHA supplementation in offspring. Gad2 was upregulated in the striatum of male offspring of prenatally stressed SERT-KO dams, but DHA did not significantly alter the expression compared to the control diet condition. Full article

Motor deficits, including atypical gait, are common in individuals with autism spectrum disorder (ASD), although the precise nature and cause of this co-occurrence is unclear. Because walking is a natural activity and gait timing is a metric that is relatively accessible to measurement, we explored whether autistic gait could be described solely in terms of the timing of gait parameters. The aim was to establish whether temporal analysis, including machine learning models, could be used as a group classifier between ASD and typically developing (TD) individuals. Thus, we performed a high-resolution temporal analysis of gait on two age-matched groups of male participants: one group with high-functioning ASD and a comparison TD group (each N = 16, age range 7 to 35 years). The primary data were collected using a VICON^® 3D motion analysis system. Significant increased temporal variability of all gait parameters tested was observed for the ASD group compared to the TD group (p < 0.001). Further machine learning analysis showed that the temporal variability of gait could be used as a group classifier for ASD. Of the twelve models tested, the best-fitting model type was random forest. The temporal analysis of gait with machine learning algorithms may be useful as a future ASD diagnostic aid. Full article

Autism spectrum disorder (ASD) encompasses a range of neurodevelopmental conditions characterized by impairments in social abilities and communication. Studying appropriate animal models can enhance our understanding of the neural mechanisms underlying these conditions, potentially leading to improved treatment and intervention strategies. Modeling impairments in linguistic development and vocal communication caused by autism had been a challenging goal for a long time. Prenatal valproic acid (VPA) treatment has been successfully used to induce ASD-like behavioral symptoms in several vertebrate species including birds. Applying VPA-treatment on songbirds, therefore, offers a promising research paradigm to model ASD. In this study, we investigated the effect of embryonic VPA treatment on song learning in the highly social zebra finch (Taeniopygia guttata). Fertilized eggs were injected with either 0.45 µmol VPA or a saline solution on day 9 of incubation, and hatchlings were allowed to stay with their parents until day 35 post-hatching to facilitate song learning from the father. Once male offsprings reached adulthood, their songs were recorded and compared to those of their fathers. VPA-exposed males exhibited significantly greater similarity to their fathers’ songs compared to control males (74% vs. 31%, respectively), suggesting a reduced ability to modify and develop their own vocal patterns as subadults. Additionally, they showed higher entropy in their songs compared to controls (−1.4 vs. −1.7), indicating more disorganized vocalizations. These findings suggest that prenatal VPA exposure disrupts typical song learning and vocal development in zebra finches, likely by affecting neural mechanisms involved in vocal learning and crystallization of the songs. Our study suggests VPA treatment in songbirds provides a useful tool to model and investigate linguistic developmental disorders related to ASD in humans. Full article