Neural signatures of impaired semantic contextualization in Autism Spectrum Disorder.

BackgroundSensory processing dysfunction (SPD) is a salient feature of autism spectrum disorder (ASD) that has garnered substantial clinical and research attention. Individuals with ASD often exhibit atypical responses to sensory stimuli, including hypersensitivity, hyposensitivity, and seeking behaviors across multiple modalities. These sensory challenges frequently contribute to the disorder’s core symptoms, influencing social interactions, communication abilities, and repetitive behaviors. However, the precise relationship of SPD with ASD characteristics is not well understood. This study aimed to identify the association between SPD behaviors and regression of milestones, severity of ASD, and age of children with ASD. This observational study was conducted on 112 ASD patients (3–16 years, 6.88 SD ± 3.18). The inclusion criteria for ASD patient recruitment required an ASD diagnosis by a healthcare professional, based on the criteria outlined in the Diagnostic and Statistical Manual of Mental Disorders (DSM-5). After signing an informed written consent form, the parents and therapists filled out Winnie Dunn’s Short Sensory Profile (SSP) questionnaire. The data collection included sensitivities on tactile, oral/olfactory, vestibular, proprioception, visual/auditory inputs, and energy profiles of children with ASD, gauged as a typical performance, probable difference, and definite difference using a Likert scale.ResultsThis study highlights the significant association between SPD and ASD factors, such as milestones regression (MR), severity of ASD, and age of patients. Key findings include significant associations between MR and vestibular dysfunction, visual/auditory, and auditory filtering. The study also indicated a significant association between the severity of ASD (CARS scores) and tactile dysregulation (p < 0.001). Furthermore, the age of the patients was significantly correlated with vestibular, visual/auditory processing, auditory filtering, and energy profiles of the ASD patients (p < 0.001).ConclusionsThese findings can be utilized to understand the pattern of sensory challenges associated with ASD factors. They may assist practitioners in developing targeted interventions, potentially reducing costs and intervention time while improving outcomes for individuals with ASD.

This study investigates the relationship between the perceived stress of parents with a child with (characteristics of) an autism spectrum disorder (ASD) and the degree of ASD characteristics within parents. Data from 222 children (mean age 7.8 years) and their primary caregivers, previously collected as part of the Social Spectrum Study, were analyzed. Linear regression analyses were used to investigate the association between experienced parenting stress and the influence of parents’ own ASD characteristics, taking into account relevant covariates. This study shows that the experienced parenting stress does not show a significant relationship with the ASD characteristics of parents when relevant covariates (such as own psychiatric problems, ASD characteristics of the child and the partner relationship) are added. This study finds indications that parenting stress in parents of children with ASD appears to be more strongly related to their general perceived psychopathology than to their specific ASD characteristics. Further replication is warranted, and we advise research into interventions for parents that possibly prevent (further) stress associated with raising a child with ASD (characteristics).

Autism spectrum disorder (ASD) is a set of genetically heterogenous neurodevelopmental disorders characterized by core symptoms including impaired social interaction, communication deficits, and restricted or stereotyped behaviors. While a significant number of cases are not explained by Mendelian inheritance, there is growing evidence for implication of non-coding RNAs (ncRNAs) in the development and inheritance of ASD. Transcriptional studies often face challenges due to patient-specific variations in gene expression and technical differences in preserving RNA integrity. We propose that isolating RNA from DNA/RNA hybrids provides a robust method to reliably capture transcriptional information. We performed a whole transcriptome analysis on blood samples from ASD patients and healthy controls to investigate transcripts associated with DNA/RNA hybrids. We identified 278,300 novel transcripts across 68,487 DNA/RNA hybrid loci, with significant enrichment in exonic and intronic regions. The novel long non-coding RNAs (lncRNAs) we found showed higher expression levels compared to known transcripts. Differential expression analysis revealed 301 significantly upregulated and 401 downregulated known transcripts in ASD samples compared to controls (|log2-fold change| > 1 and adjusted p-value < 0.05). Through qRT-PCR validation, we confirmed the significant upregulation of RN7SK and SMARCC2 associated with DNA/RNA hybrids in ASD patients. Pathway and enrichment analyses highlighted mitochondrial dysfunction and energy metabolism. Our results suggest that ncRNAs can form DNA/RNA hybrids that influence gene expression, providing preliminary insights into the mechanisms of transcriptional dysregulation in ASD.

Growing evidence indicates that the defining characteristics of autism spectrum disorder (ASD) are distributed throughout the general population; hence, understanding the correlates of aging in people with high autistic traits could shed light on ASD and aging. 915 members of the Dunedin longitudinal birth cohort completed a measure of autistic traits at age 45. A composite measure of the "pace of aging" was derived by tracking the decline in 19 biomarkers across ages 26, 32, 38, and 45 years. Facial age was also assessed. Reports of perceived health were collected from participants themselves, informants, and interviewers. Higher self-reported autistic traits significantly correlated with a faster pace of aging, older facial age, and poorer self-, informant-, and interviewer-rated health. After control for sex, SES and IQ, autistic traits were significantly associated with each variable: pace of aging (β=0.09), facial age (β=0.08), self- (β=-0.15), informant (β=-0.12), and interviewer-rated (β=-0.17) health. Autistic traits measured at age 45 are associated with faster aging. Participants with high autistic traits appear to be more vulnerable to poor health outcomes, as previously reported for those clinically diagnosed with ASD. Therefore, autistic traits may have important health implications. Replicating these findings in samples of autistic people is needed to identify the mechanism of their effect on aging and physical health to improve outcomes for those with ASD diagnoses or high autistic traits. LAY SUMMARY: The role that autistic traits have in relation to health outcomes has not been investigated. We looked at how physical health and aging (measured with self-reported questions and decline in multiple biological measures) were related to autistic traits (measured with a questionnaire, at age 45). We found that higher autistic traits were associated with poorer reports of physical health, and a faster pace of aging. This suggests that both those with autism and those with higher autistic traits may be more likely to experience poorer health outcomes.

Objectives: Patients with obsessive compulsive disorder (OCD) frequently show traits of autism spectrum disorders (ASD). This is one of the first studies to explore the clinical impact of the overlap between OCD and ASD as a categorical diagnosis.Methods: A cross-sectional survey in 73 adult outpatients with DSM-IV OCD. Autistic traits were measured using the Autism-Spectrum Quotient (AQ). A clinical estimate ASD diagnosis was made by interview using DSM-IV-TR criteria. OCD patients with and without autistic traits or ASD were compared on demographic and clinical parameters and level of OCD treatment-resistance based on treatment history.Results: Thirty-four (47%) patients scored above the clinical threshold on the AQ (≥26) and 21 (27.8%) met diagnostic criteria for ASD. These diagnoses had not been made before. Patients with autistic traits showed a borderline significant increase in OCD symptom-severity (Yale-Brown Obsessive Compulsive Scale (Y-BOCS); p = .054) and significantly increased impairment of insight (Brown Assessment of Beliefs Scale; p = .01). There was a positive correlation between AQ and Y-BOCS scores (p = .04), but not with OCD treatment resistance.Conclusion: There is a high prevalence of previously undiagnosed ASD in patients with OCD. ASD traits are associated with greater OCD symptom-severity and poor insight.

Autism spectrum disorder (ASD) is a neurodevelopmental disease with unknown etiology but high incidence. The objective biomarkers of ASD are urgently awaited to be developed using neuroimaging method including resting-state fMRI (R-fMRI). However, the majority of current R-fMRI studies only examined the static features of brain activity in ASD patients, but neglected the dynamic aspects especially for regional metrics. Furthermore, the concordance of the dynamic regional indices was reported imbedded in human intrinsic brain activity, while its abnormality in ASD is largely unknown. In order to shed light on the abnormity of ASD from dynamic perspective, we analyzed R-fMRI data of 480 ASD male patients and 539 healthy male controls (HC) gathered from ASD public database (ABIDE I/ABIDE II). We used sliding window method to calculate the dynamics of mainstream regional indices of R-fMRI (amplitude of low frequency fluctuations (ALFF), fractional ALFF (fALFF), regional homogeneity (ReHo), voxel-mirrored homotopic connectivity (VMHC), degree centrality (DC) and the correlation with global signal (GSCorr)) and generated the SD statistic maps of these six dynamic regional indices. We performed z-standardization and smoothing on the SD statistic maps. After that, two-sample t -test between the SD statistic maps of ASD group and HC group was performed. We also calculated the concordance of dynamic regional indices for each time point, which is the Kendall’s coefficient of the ALFF, ReHo, DC, GSCorr and VMHC maps across voxels. Two-sample t -test between the SD and mean of concordance time series of ASD group and HC group was performed. We found a significant increase in the dynamics of ALFF and DC in the lateral frontal cortices in ASD patients as compared to HCs. Dorsal lateral frontal cortex (dlPFC) is a critical brain area for cognitive control and execution network. The abnormal activities in dlPFC indicate the disruption of control execution system and the impairment of relevant cognitive function. In the visual related brain areas, the dynamics of ALFF, DC and ReHo showed a decrease in fusiform gyrus, calcarine and lingual gyrus in ASD patients. Recent studies have indicated that the abnormal face processing in children with autism may be related with the impairment in social cognition of them. The deficits in face information processing of ASD patients may stem from the inflexible intrinsic brain activity in visual processing brain area (especially in fusiform gyrus). After further examining the concordance among these dynamic indices, the mean and SD of concordance of patients with ASD was found to be significantly lower than that of the HCs, demonstrating that the ASD patients’ inferior integration ability for different aspects of brain functions. These findings suggest that there exists abnormality in dynamics of spontaneous brain activity and its integration in ASD patients. Dynamic R-fMRI regional indices and the concordance of them could be efficient neuroimaging biomarkers for ASD.

Motor impairments in autism spectrum disorders (ASD) have received far less research attention than core social-communication and cognitive features. Yet, behavioral, neurophysiological, neuroimaging and histopathological studies have documented abnormal motor system development in the majority of individuals with ASD suggesting that these deficits may be primary to the disorder. There are several unique advantages to studying motor development in ASD. First, the neurophysiological substrates of motor skills have been well-characterized via animal and human lesion studies. Second, many of the single-gene disorders associated with ASD also are characterized by motor dysfunctions. Third, recent evidence suggests that the onset of motor dysfunctions may precede the emergence of social and communication deficits during the first year of life in ASD. Motor deficits documented in ASD indicate disruptions throughout the neuroaxis affecting cortex, striatum, the cerebellum and brainstem. Questions remain regarding the timing and development of motor system alterations in ASD, their association with defining clinical features, and their potential for parsing heterogeneity in ASD. Pursuing these questions through neurobiologically informed translational research holds great promise for identifying gene-brain pathways associated with ASD.

BackgroundResearch evidence accumulated in the past years in both rodent and human models for autism spectrum disorders (ASD) have established insulin-like growth factor 1 (IGF-1) as one of the most promising ASD therapeutic interventions to date. ASD is phenotypically and etiologically heterogeneous, making it challenging to uncover the underlying genetic and cellular pathophysiology of the condition; and to efficiently design drugs with widespread clinical benefits. While IGF-1 effects have been comprehensively studied in the literature, how IGF-1 activity may lead to therapeutic recovery in the ASD context is still largely unknown.MethodsIn this study, we used a previously characterized neuronal population derived from induced pluripotent stem cells (iPSC) from neurotypical controls and idiopathic ASD individuals to study the transcriptional signature of acutely and chronically IGF-1-treated cells.ResultsWe present a comprehensive list of differentially regulated genes and molecular interactions resulting from IGF-1 exposure in developing neurons from controls and ASD individuals. Our results indicate that IGF-1 treatment has a different impact on neurons from ASD patients compared to controls. Response to IGF-1 treatment in neurons derived from ASD patients was heterogeneous and correlated with IGF-1 receptor expression, indicating that IGF-1 response may have responder and non-responder distinctions across cohorts of ASD patients. Our results suggest that caution should be used when predicting the effect of IGF-1 treatment on ASD patients using neurotypical controls. Instead, IGF-1 response should be studied in the context of ASD patients’ neural cells.LimitationsThe limitation of our study is that our cohort of eight sporadic ASD individuals is comorbid with macrocephaly in childhood. Future studies will address weather downstream transcriptional response of IGF-1 is comparable in non-macrocephalic ASD cohorts.ConclusionsThe results presented in this study provide an important resource for researchers in the ASD field and underscore the necessity of using ASD patient lines to explore ASD neuronal-specific responses to drugs such as IGF-1. This study further helps to identify candidate pathways and targets for effective clinical intervention and may help to inform clinical trials in the future.

Autism spectrum disorder (ASD) is a severe, complex neurodevelopmental disorder, characterized by impairments in social interaction and communication with restricted and stereotyped behavior patterns. ASD symptoms result from a complex interaction between genetic and environment factors. Food intolerances, allergies, altered intestinal permeability (leaky gut), immune dysregulation, neuroinflammation and oxidative stress may trigger ASD symptoms. ASD patients have shown increased urinary levels of β-casomorphin and gliadorphin peptides produced by incomplete digestion of gluten proteins and milk casein. “Leaky gut” may facilitate the transport of these peptides into the central nervous system (CNS) inducing direct “opioid activity” and thus affecting neurotransmission. ASD patients on gluten and/or casein-free diet have shown improvement in most behavior and cognitive scores. Immune dysregulation leads to a neuroinflammatory response that correlates between immune dysfunction with behavioral and cognitive impairments in ASD patients. Genetic variants of the MET gene (7q31.2) are risk factors for ASD. The MET receptor participates in brain cortex and cerebellum development and in gastrointestinal and immunological functions. A high percentage of ASD children have shown non-celiac gluten sensitivity, an immune reaction against gluten in subjects not affected with celiac disease with prominent mucosal eosinophil infiltration and increased blood eosinophilia. ASD patients have shown alterations in brain anatomy involved in language and social interaction skills, correlating with specific aspects of ASD symptoms. ASD behavior results from abnormal interactions between the opioid system and various pathways together with anatomical alterations in the CNS. Individualized diagnosis and prognostic predictions should provide effective personalized therapies in ASD patients.

Systemic heterogeneity in autism spectrum disorder revealed by individualized structural covariance network analysis.

The brain represents the state of the world around us based upon a stream of ambiguous sensory data. This requires the integration of different sources of information, including information received from different sense modalities, and information drawn from past experience. Bayesian theories of perception provide an approach to characterising how systematic differences in the probabilistic integration of information in the brain may underlie the differences that occur between individuals in their perceptual experience. The present thesis explores how perceptual, motor and social aspects of autism spectrum disorder (ASD) may emerge from variation in the neurocognitive processes described by Bayesian theories. A focus is on the predictive processing model of brain function, which links Bayesian theories of perception to neural mechanisms. The thesis includes empirical studies that examine perceptual, sensorimotor and cognitive aspects of ASD. ASD and nonclinical autistic traits are first examined in the context of body perception; concerning, specifically, how the brain represents the state of the limbs based on visual, tactile and proprioceptive information, and how this sensory information is integrated with prior expectations regarding the body. These processes are investigated using a multisensory perceptual illusion: the rubber hand illusion. ASD is associated with a largely typical perceptual experience of this illusion, indicating intact multisensory integration in the context of body representation. A reduced influence of the illusion on motor function, however, supports a difference in ASD in the integration of expectations for limb position (influenced by the illusion) with conflicting sensory (proprioceptive) signals. The integration of incoming information with existing expectations about the environment is also examined in the context of statistical learning. A computerised task is developed to assess the integration of iterative feedback with prior information as participants predict the location of a noisy set of visual markers. The hypothesis tested is that features of ASD are associated with a persistently higher weighting of incoming information in driving inference, at the expense of expectations developed from recent experience; in this more cognitive context, these data provide evidence against this hypothesis, suggesting that a more context-dependent atypicality in information processing in ASD is more likely than that initially hypothesised. The thesis also develops theoretical and philosophically-relevant treatments of how the symptoms of ASD may emerge from differences in brain function characterised within a Bayesian framework. This includes drawing on recent theoretical developments regarding the role of volatility processing and action in maintaining optimal inference on the environment. In addition, models of Bayesian inference in the brain can be extended to the social domain. For instance, the process of representing the mental states of other people (i.e., theory of mind) can be cast in terms of implicit inference on the external causes of sensory signals. In light of these expanded models of predictive processing, the differences in information processing hypothesised to occur in ASD have implications not just for perception, but also for motor behaviours, social cognition and social interaction. The overall view that emerges is that diverse aspects of ASD may be captured in terms of how incoming sensory signals are integrated, in a probabilistic manner, with the brain’s hierarchical and multimodal model of its environment. A promising direction for this field is in developing this idea in the context of action (i.e., active inference) and more recent models of how the brain estimates the optimal weighting of sensory information. This area of research has the potential to provide a nuanced perspective on the neurocognitive basis of ASD and the relationship between sensory mechanisms and autistic behaviours.

Identifying differences in brain activities and an accurate detection of autism spectrum disorder using resting state functional-magnetic resonance imaging : A spatial filtering approach.

Children with autism spectrum disorders (ASD) present deficits in regulation of their emotions which have a great impact on their mental health and well-being. There are several studies showing the connection between executive functions deficits and emotion dysregulation in the context of an ASD diagnosis. Our study aims to investigate which among the executive functions can predict the emotional dysregulation in children with ASD, if there is an association between the ASD specific characteristics and their ability to regulate their emotions and to identify if there are possible mediators of this relationship. To reach our objective, we enrolled 60 children with ASD (mean age 8.5 years) whose parents completed standardised measurements for executive functions, emotional dysregulation, and ASD characteristics. We found a positive association between ASD characteristics’ severity and emotional dysregulation, as well as some significant predictors among specific executive functions and emotional dysregulation. Moreover, executive functioning mediates the relationship between the ASD characteristics and emotion regulation. Our research provides a better understanding of the relationship between ASD characteristics, executive functions, and emotion regulation.

IntroductionA common comorbidity in autism spectrum disorder (ASD) children is gastrointestinal problems, and a possible link between active gastrointestinal inflammation and autism has been suggested. Faecal calprotectin (FC) is a non-invasive marker for of gastrointestinal inflammation.AimTo study the level of FC as a marker of bowel inflammation in children with ASD and its possible relation to gastrointestinal manifestations.Material and methodsCalprotectin levels were assessed in stool samples of 40 ASD children. Autism severity was assessed by the Childhood Autism Rating Scale (CARS). Severity of gastrointestinal symptoms was assessed using a modified version of the 6-Item Gastrointestinal Severity Index (6-GSI) questionnaire. A control group of 40 healthy children matched for age and sex with the cases was also included to compare their levels of FC.ResultsGastrointestinal symptoms were present in 82.5% of children with autism; the most reported offensive stool odour (70%) and the least diarrhoea (17.5%), and a high 6-GSI score was observed in 35% of ASD children. FC levels were elevated in 35% of the cases and in 25% of the control group. The mean levels of FC of cases were significantly elevated compared to levels of controls. FC levels positively correlated with severity of gastrointestinal symptoms (6-GSI) in autistic patients. There was positive correlation between CARS and 6-GSI.ConclusionsGastrointestinal manifestations are a common comorbidity in autistic patients. ASD patients have significantly higher FC levels than healthy controls. FC levels are strongly correlated with the severity of gastrointestinal manifestations in ASD children. So, gastrointestinal manifestations among autistic patients could be caused by gastrointestinal inflammation.

We examined temperament and character profiles of 128 adults with autism spectrum disorder (ASD) or attention deficit and hyperactivity disorder (ADHD). Participants completed the abbreviated Temperament and Character Inventory. The ASD and ADHD groups showed distinct temperament profiles (ADHD: high novelty seeking, ASD: low reward dependence, high harm avoidance) and low character scores in both groups. We then stratified ASD and ADHD into current substance use disorder (SUD+), former (SUD;), or no history of Substance Use Disorder (SUD-). Novelty seeking and reward dependence were only significantly lower for ASD/SUD-, but normal for ASD/SUD; and ASD/SUD+ subgroups. Persistence scores were highest in both SUD; subgroups. We concluded that temperament profiles of ASD and ADHD patients differ significantly, and are similar to profiles reported in earlier studies, but appear to depend on the SUD status. Surprisingly, normal social orientation is found in ASD patients with former or current SUD. High persistence scores characterize patients who overcome SUD.