Search Results (61)

Autism spectrum disorder (ASD) deals with several symptoms, including language and speech impairment and developmental delays. The main brain regions affected could be the prefrontal cortex (PFC) or the temporal lobe. The detrimental features could include oxidative stress, mitochondrial dysfunction, and neuroinflammation. Most often, these phenomena are interrelated and can lead to one another, creating a vicious cycle. They also influence the regulation of certain genes involved in the pathogenesis of ASD or related behavior. In the brain regions prone to these detrimental features, a cascade of free radicals, inflammatory cytokines, and mitochondrial energy disruptions is initiated. These actions during the prenatal or developmental stage of the child potentially lead to ASD symptomatic features, such as social isolation, communication difficulty, speech and language impairment, cognitive dysfunction, and intellectual disability. The more recent theories, including genetics, epigenetics, and the gut–brain axis, have been demonstrated to play a greater role in ASD pathology, often being associated with the more common ones as mentioned above. We also introduced some of the neurological disorders possessing shared genetic and behavioral traits with ASD. Many genes playing a role in ASD-like features and their potential targeted drugs were explained briefly. However, there are limited therapeutic options, and molecular pathways related to this disorder are less explored. Currently, researchers and therapists are racing to uncover a concrete remedy. This review also provides a brief outline of potential antioxidant, mitochondrial, and anti-inflammatory therapies. We finally included some novel strategies to diagnose and manage autistic pathology and symptoms. 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

Cyclin-dependent kinase-like 5 (CDKL5) deficiency disorder (CDD) is a severe X-linked neurodevelopmental condition characterized by early-onset, intractable epilepsy, motor and cognitive impairment, and autistic-like features. Although constitutive Cdkl5 knockout (KO) models have established the importance of CDKL5 during early brain development, CDKL5’s role in the mature brain remains poorly defined. Here, we employed an inducible, conditional KO model in which Cdkl5 is selectively deleted from forebrain glutamatergic neurons in adult mice to investigate the postdevelopmental functions of CDKL5. Using a total of 48 adult male mice, including Cdkl5^flox/Y(Cre⁺) (n = 30) and Cdkl5^flox/Y(Cre⁻) littermate controls (n = 18), we found that tamoxifen-induced Cdkl5 deletion led to prominent behavioral impairments, including deficits in motor coordination, reduced sociability, and impaired hippocampus-dependent spatial memory, while behavioral features such as hyperactivity and stereotypic jumping, typically present in germline KOs, were absent. Sensory functions, including olfaction and pain perception, were also preserved. At the cellular level, the loss of Cdkl5 resulted in a marked reduction in excitatory synapse density in the cortex and hippocampus, accompanied by increased numbers of immature dendritic spines and decreased mature spines. Neuronal loss in the hippocampal CA1 region and selective microglial activation in the cortex were also observed. These alterations closely resemble those seen in constitutive KO models, underscoring the ongoing requirement for CDKL5 expression in excitatory neurons for maintaining synaptic integrity and neuronal homeostasis in the adult brain. This study underscores the importance of temporally controlled models for investigating the mechanisms underlying CDD pathophysiology in the adult brain. Full article

Propranolol, a nonselective beta-adrenergic antagonist, has shown potential for improving anxiety in autistic individuals. Heart rate variability (HRV), a noninvasive cardiac marker of autonomic nervous system functioning, may help identify individuals most likely to benefit from propranolol. Objectives: Determine if baseline resting HRV and other cardiac measures predict the response to propranolol for anxiety and core autism symptomology in autistic children and young adults. Methods: Sixty-two autistic individuals (ages 7–24) participated in a two-phase (i.e., a 12-week randomized controlled trial and a 12-week open-label extension) trial of propranolol. Baseline (i.e., resting state, prior to treatment) HRV and other cardiac measures were obtained from an electrocardiogram. Clinical global impression for anxiety symptoms and overall behavioral treatment impact were assessed after the 12-week trial period. Group-level (i.e., all participants) and responder groups (i.e., strong, minimal, and non-responders to propranolol) were analyzed for treatment effects. Results: HRV variables predicted group-level anxiety response to propranolol, particularly for strong responders. Also, lower baseline values of parasympathetic HRV indices were significantly correlated with greater behavioral improvement after treatment with propranolol. Last, several baseline cardiac variables were associated with improvement in multiple behavioral domains after treatment with propranolol. Conclusions: HRV may be a potential biomarker for predicting reduced anxiety and behavioral symptoms in response to propranolol in autistic children and young adults. Identifying autonomic profiles associated with positive treatment outcomes could guide future personalized interventions in autism. The results presented herein should be regarded as preliminary until the findings are replicated in future clinical trials. Full article

This study explored the effectiveness of VR-based social skills training for students with autism and typically developing students with social difficulties. Six autistic students and five typically developing students from upper elementary grades participated in the study. Participants were recruited based on their willingness to participate, ability to follow instructions, and absence of other significant learning or behavioral disorders. Five VR modules were developed, covering scenarios like classrooms, ticket booths, exhibitions, restaurants, and parks. These modules incorporated foundational social settings and more complex scenarios to enhance emotional regulation and adaptive responses, aligned with the 12-year Basic Education Curriculum Guidelines. The intervention took place from May to July 2023, with participants attending six 30–40 min VR sessions once or twice a week. Various assessment tools measured the impact, focusing on social responses, emotion recognition, and reactions to unexpected situations. Results indicated consistent improvements in conversation speed, expression effectiveness, and environmental adaptation. Social Skills Behavior Checklist scores showed significant differences between pre- and post-tests, while EEG data revealed enhanced empathetic responses among autistic students. Typically, developing students shifted from independent problem-solving to seeking social support. This study highlights the potential of VR as an effective tool for social skills development in both groups. Full article

Background/Objectives: Autism is a complex neurodevelopmental disorder characterized by restricted behaviors and impaired social and communication skills. The exact cause of autism remains unknown. One promising animal model for studying autism is the valproic acid rat model. Due to a 1 to 4 bias for males in autism occurrence, most animal model studies investigate only males and neglect females. However, female autism often appears different from that observed in males. Females are said to be less regularly diagnosed because they can “mask” their symptoms. Female autism is as necessary to investigate as male autism. Methods: Fertile adult female Sprague-Dawley rats were impregnated and injected with valproic acid on gestational day 13. Male and female offspring were subjected to behavioral tests to investigate autistic symptoms. Tests included novel object recognition, balance-beam, Y-maze, hole-board, three-chamber, marble burying, olfactory, light/dark and hot plate tests. Results: The tests revealed that VPA-exposed rats had increased anxiety-like behaviors, hyperactivity, and impaired non-verbal communication. However, they did not display repetitive behaviors or cognitive impairments. Notably, male and female rats showed different autism-like traits, with both showing hyperactivity, and males (but not females) additionally showing impaired sociability and increased anxiety. Conclusions: The findings suggest that prenatal exposure to VPA induces autism-like behaviors in both male and female Sprague-Dawley rat offspring. However, males appear more impacted by VPA exposure as evinced by their display of more autism-like symptoms relative to females. This study provides support for including both sexes in all studies modelling autism, as outcomes are seemingly impacted by the sex being observed. Full article

Many neurobehavioral tests are used for the assessment of human-like behaviors in animals. Most of them were developed in rodents and are used for the assessment of animal models that mimic human neurodevelopmental and neuropsychiatric disorders (NDDs). We have described tests for assessing social behavior, social interaction, and social communication; tests for restricted and repetitive behaviors; tests for cognitive impairment, for sensory stimuli, for anxiety like behavior, and for motor coordination deviations. These tests are used to demonstrate autistic-like behavior as well as other NDDs. We described possible general pitfalls in the performance of such studies, as well as probable individual errors for each group of tests assessing specific behavior. The mentioned pitfalls may induce crucial errors in the interpretation of the results, minimizing the reliability of specific models of defined human NDD. It is imperative to minimize these pitfalls and use sufficient and reliable tests that can demonstrate as many of the traits of the human disorder, grade the severity of the specific deviations and the severity of the tested NDD by using a scoring system. Due to possible gender differences in the clinical presentations of NDD, it is important to carry out studies on males and females. Full article

(1) Background: Autism, as an important global problem that affects many phenotypically different individuals, is associated with electroencephalographic (EEG) abnormalities and adaptability impairment. (2) Materials and Methods: In this retrospective study of a group of 101 autistic children, we aimed to evaluate the presence of EEG abnormalities, adaptive features, and clinical phenotypes via EEG, the Adaptive Behavior Assessment System II (ABAS II) scale, and neurological examination. (3) Results: Our results showed statistically significant associations between the level of adaptability obtained through the ABAS II scale and neurological deficit, specifically in terms of coordination impairment. There were also statistically significant differences between the level of adaptability and clinical phenotypes between autism type groups. (4) Conclusions: This study shows that children with autism are likely to exhibit neurological and adaptive abnormalities. Non-invasive assessment tools, such as EEG recordings, the ABAS II scale, and neurological examination offer valuable support for improved diagnosis and management. Full article

Background/Objectives: Autism spectrum disorder (ASD) is characterized by impaired social interaction and repetitive stereotyped behavior. Effective interventions for the core autistic symptoms are currently limited. Methods: This study employed a valproic acid (VPA)-induced mouse model of ASD to assess the preventative effects of L-proline supplementation on ASD-like behaviors. The method of 16S rRNA sequencing and untargeted metabolomics analyses were conducted to investigate the modulation of gut microbiota and gut metabolites by L-proline. Results: The results indicated that L-proline supplementation significantly prevented ASD-like behavioral disorders, including alleviating social communication deficits and reducing repetitive behavior in the ASD mice. The 16S rRNA sequencing analysis revealed that L-proline regulated the composition and structure of gut microbiota. L-Proline supplementation enhances the abundance of the Verrucomicrobia at the phylum level and the Akkermansia at the genus level, while concurrently reducing the abundance of the Patescibacteria at the phylum level, as well as the Ileibacterium, Candidatus_Saccharimonas, and Lachnospiraceae_UCG-006 at the genus level in the VPA-induced mouse model for ASD. Additionally, the untargeted metabolomics results indicated that L-proline also modified the gut metabolite profiles. Functional analysis of the gut microbiota and KEGG pathway enrichment analysis of differential metabolites between the L-proline-supplemented and VPA groups corroborated that L-proline decreased pathways related to nucleotide metabolism, taurine and hypotaurine metabolism, and pyruvate metabolism, while increasing pathways involved in alpha-linolenic acid metabolism and phenylalanine, tyrosine, and tryptophan biosynthesis. The integrative metabolomic and microbiome analyses showed strong connections between the gut metabolites and gut microbiota affected by L-proline. These findings suggest that the modulatory effects of L-proline on gut microbiota and its metabolites may play a crucial role in preventing autism in mice. Conclusions: These findings suggest that dietary L-proline may represent a viable, effective option for preventing the physiological and behavioral deficits associated with ASD in mice. Full article

Background/Objectives: Tic disorders are neurodevelopmental conditions often associated with comorbidities like attention deficit hyperactivity disorder (ADHD) and autism spectrum disorder (ASD). Our aims were: (a) in a sample of youth with tic disorders to explore the clinical and psychopathological characteristics of different phenotypes based on the presence of comorbid ADHD and/or ASD and gender; (b) in a subgroup of patients treated with Aripiprazole, to evaluate symptoms variation over time and to identify potential predictors of response. Methods: A total of 95 subjects with tic disorders (age range 6 to 17.9 years, mean 11.1 ± 2.11 years, 80 males) were naturalistically recruited. Questionnaires and semi-structured interviews were administered to assess the symptomatology and investigate the presence of psychiatric comorbidities (Clinic Global Impression-Severity (CGI-S), Children’s Global Assessment Scale (C-GAS), Yale Global Tic Severity Scale (YGTSS), Premonitory Urge for Tics Scale (PUTS), Child Yale–Brown Obsessive Compulsive Scale for Children (CYBOCS), Child Behavior Checklist 6–18 (CBCL 6–18), Conners’ Parent Rating Scale-Revised—short form (CRSR-S), Reactivity Intensity Polarity Stability Questionnaire—youth version (RIPoSt-Y), and Social Communication Questionnaire—lifetime version (SCQ); Autism Diagnostic Observation Scale—second version (ADOS-2) and Autism Diagnostic Interview—revised version (ADI-R) were administered where ASD was suspected). A total of 22 subjects treated with Aripiprazole were reassessed through the use of some of the clinical measures used at baseline. Results: The presence of ADHD was associated with higher externalizing problem scores on the CBCL 6–18, while ASD was linked to higher internalizing problem scores. A positive correlation was found between the ADHD–ASD interaction and increased internalizing symptoms on CBCL 6–18 and higher ADOS-2 scores. Patients treated with Aripiprazole showed significant improvement across all scales during follow-up. ADHD was identified as a negative predictor of reduced tic severity on the YGTSS. Conclusions: Comorbid neurodevelopmental disorders, such as ADHD or ASD, result in worse emotional and behavioral functioning in patients with tic disorders. ADHD–ASD interaction may be linked to more internalizing symptoms and autistic behaviors. Aripiprazole improves overall clinical outcomes, although comorbid ADHD may hinder the reduction of tic symptoms. Full article

Appropriate animal models of human diseases are a cornerstone in the advancement of science and medicine. To create animal models of neuropsychiatric and neurobehavioral diseases such as autism spectrum disorder (ASD) necessitates the development of sufficient neurobehavioral measuring tools to translate human behavior to expected measurable behavioral features in animals. If possible, the severity of the symptoms should also be assessed. Indeed, at least in rodents, adequate neurobehavioral and neurological tests have been developed. Since ASD is characterized by a number of specific behavioral trends with significant severity, animal models of autistic-like behavior have to demonstrate the specific characteristic features, namely impaired social interactions, communication deficits, and restricted, repetitive behavioral patterns, with association to several additional impairments such as somatosensory, motor, and memory impairments. Thus, an appropriate model must show behavioral impairment of a minimal number of neurobehavioral characteristics using an adequate number of behavioral tests. The proper animal models enable the study of ASD-like-behavior from the etiologic, pathogenetic, and therapeutic aspects. From the etiologic aspects, models have been developed by the use of immunogenic substances like polyinosinic-polycytidylic acid (PolyIC), lipopolysaccharide (LPS), and propionic acid, or other well-documented immunogens or pathogens, like Mycobacterium tuberculosis. Another approach is the use of chemicals like valproic acid, polychlorinated biphenyls (PCBs), organophosphate pesticides like chlorpyrifos (CPF), and others. These substances were administered either prenatally, generally after the period of major organogenesis, or, especially in rodents, during early postnatal life. In addition, using modern genetic manipulation methods, genetic models have been created of almost all human genetic diseases that are manifested by autistic-like behavior (i.e., fragile X, Rett syndrome, SHANK gene mutation, neuroligin genes, and others). Ideally, we should not only evaluate the different behavioral modes affected by the ASD-like behavior, but also assess the severity of the behavioral deviations by an appropriate scoring system, as applied to humans. We therefore propose a scoring system for improved assessment of ASD-like behavior in animal models. Full article

Bi-allelic disruptive variants (nonsense, frameshift, and splicing variants) in KDM5B have been identified as causative for autosomal recessive intellectual developmental disorder type 65. In contrast, dominant variants, usually disruptive as well, have been more difficult to implicate in a specific phenotype, since some of them have been found in unaffected controls or relatives. Here, we describe individuals with likely pathogenic variants in KDM5B, including eight individuals with dominant missense variants. This study is a retrospective case series of 21 individuals with variants in KDM5B. We performed deep phenotyping and collected the clinical information and molecular data of these individuals’ family members. We compared the phenotypes according to variant type and to those previously described in the literature. The most common features were developmental delay, impaired intellectual development, behavioral problems, autistic behaviors, sleep disorders, facial dysmorphism, and overgrowth. DD, ASD behaviors, and sleep disorders were more common in individuals with dominant disruptive KDM5B variants, while individuals with dominant missense variants presented more frequently with renal and skin anomalies. This study extends our understanding of the KDM5B-related neurodevelopmental disorder and suggests the pathogenicity of certain dominant KDM5B missense variants. Full article

The Fawn-hooded rat has long been used as a model for various peripheral and central disorders and the data available indicate that the social behavior of this strain may be compromised. However, a thorough description of the Fawn-hooded rat is unavailable in this regard. The objective of the present study was to investigate various aspects of the Fawn-hooded rat’s social behavior in depth. Our results show that several facets of socio-communicational behavior are impaired in the RjIbm(m):FH strain, including defective ultrasonic vocalizations in pups upon maternal deprivation, reduced social play in adolescence and impaired social novelty discrimination in adulthood. In addition, Fawn-hooded rats exhibited heightened tactile sensitivity and hyperactivity. The defects observed were comparable to those induced by prenatal valproate exposure, a widely utilized model of autism spectrum disorder. Further on, the pro-social drug R-baclofen (0.25–1 mg/kg) reversed the autistic-like defects observed in Fawn-hooded rats, specifically the deficiency in ultrasonic vocalization, tactile sensitivity and social novelty discrimination endpoints. In conclusion, the asocial, hypersensitive and hyperactive phenotype as well as the responsivity to R-baclofen indicate this variant of the Fawn-hooded rat strain may serve as a model of autism spectrum disorder and could be useful in the identification of novel drug candidates. Full article

Severe gastrointestinal symptoms (GIS) and food hypersensitivity are tightly associated in young individuals with autism spectrum disorders (ASD). Here, we explored the relationship of GIS (gastrointestinal severity index, ROMA IV criteria, Bristol scale), ASD-like behaviors (Childhood Autism Rating Scale), and certain sociodemographic/clinical traits (epidemiological survey) with serum immunoreactivity (IgG, IgA, IgE titers) towards bovine milk caseins (BMC; by ELISA) and subfractions (by immunoblotting) in thirty-one pediatric patients (~3–15 y, 77% male) with mild-to-severe GIS and ASD-like behaviors. In total, 42%, 25%, and 23% of all participants exhibited no (IgG−/IgA−), mono (IgG+/IgA−), or dual (IgG+/IgA+) immunoreactivity to BMC, respectively; the trend was significantly associated with the severity of the GIS and ASD-like behaviors, regurgitations, and self-reported allergies (OR: 1 → (1.9–3.1) → 13.5–16.0)]. No IgE+ response to BMC was found. Dual responders were α > κ > β-casein, though nonspecific reactivity to other protein fractions was also observed. The IgA+ > IgG+ but not IgE+ response to BMC (mainly α-casein) seems to be related to the severity of GIS and ASD-like behaviors, although a larger number of ASD patients are needed to draw a causal association. Full article