Autism Spectrum Disorder Behaviors Research Articles

Nutritional Supplements in Autism Spectrum Disorder: A Scoping Review

Nutritional Supplements in Autism Spectrum Disorder: A Scoping Review

Effects of Treadmill Exercise on Autistic Behavior and Prefrontal Cortical SHANK Receptors in Autism Spectrum Disorder Model Mice

PURPOSE: The first aim of this study is to change autistic behavior in Shank3B Knock-Out (KO) mice through treadmill exercise (TD), and the second aim is to alter SHANK protein receptors in the prefrontal cortex (PFC) of mice through TD.METHODS: Male mice were divided into Control (11-week-old, n=8), Control+TD (n=8), Shank3B KO (n=8), and Shank3B KO+TD (n=8). Control and Shank3B KO mice were exercised using TD for 2 weeks for 30 minutes each to observe the effects of exercise.RESULTS: Compared to the control group (C57BL/6J), Shank3B KO mice showed excessive self-grooming behavior; however, TD reduced repetitive behavior (<i>p</i><.05). The effect of TD was also seen in the behavior of Shank3B KO mice evaluated by measuring social interaction time using the two-chamber social behavior test and socio-sexual behavior test (<i>p</i><.05 compared to control). Differences were found in C57BL/6J and Shank3B KO mice by assessing proteins such as GluR2, Homer1, phosphorylated GSK-3α/β, and phosphorylated Akt1 in the PFC. The results suggested that TD yielded better outcomes in Shank3B KO+TD mice than in Shank3B KO mice.CONCLUSIONS: TD positively affected behavioral changes in repetitive behavior and social interaction defects in autism spectrum disorder (ASD) model mice. Alterations were also observed in the SHANK glutamate receptor and SHANK sub-signal transporter phosphorylation protein. This suggests that TD is an effective way to improve autistic behavior in ASD. However, further research is necessary to clarify the effects of TD by studying the underlying mechanisms and changes in SHANK proteins and other factors.

Comparative analysis of emotional facial expression recognition and empathy in children with prader-willi syndrome and autism spectrum disorder

BackgroundPrader-Willi Syndrome (PWS) is a rare neurodevelopmental disorder that is often comorbid with Autism Spectrum Disorder (ASD). Due to the close association between these two conditions, and recognizing that Theory of Mind (ToM) is related to social behaviors in ASD, there is a growing interest in studying the reciprocity of social communication between these two groups.MethodThe primary objective of this study was to compare how children (n = 45) with PWS (n = 15), ASD (n = 15), and a control group (n = 15) respond to emotion recognition of facial expressions and empathy, which are both concepts related to ToM. The study utilized two tools named FEEL and Deusto-e-Motion 1.0. We also evaluated the Working Memory index of the WISC-IV scale, the Social Perception domain of the NEPSY-II battery, and the SCQ in both clinical groups.ResultsOur findings suggest that individuals with PWS exhibit lower accuracy in recognizing facial expressions and empathy compared to the control group. Both clinical groups exhibited a delayed reaction time compared to the control group. Children with PWS display difficulties in recognizing emotions of disgust and surprise. In terms of cognitive empathy, children with PWS showed a greater inclination to respond to disgust as compared to children with ASD.ConclusionsThis study represents the initial stage in comprehending the emotional and empathetic abilities of children with PWS and ASD. The findings can provide valuable insights for developing future interventions.

The Gluten-Casein-Free Diet in Children with Autism: A Clinical Results of the Ophthalmic and Behavioral Manifestations

Aim: To evaluate the ophthalmic and behavioral effects of a gluten-free casein-free diet (GCFD) in autism spectrum disorder (ASD). Method: The study was conducted from November 2020 to January 2023. We designed an 8-week clinical trial of GCFD on corneal reflex, pupil size, body mass index (BMI), weight, Autistic Disorder Index, Communication, Social interaction, and Stereotype Behavior. Results: A total of thirty participants completed the trial. GCFD reduced BMI [%95 CI -4.8895 to -2.1305 (P < 0.0001)], weight [%95 CI -8.5153 to -0.0647 (P = 0.0467)], Autistic Disorder Index [%95 CI -28.0359 to -16.2841 (P < 0.0001)], Communication [%95 CI -3.3325 to -1.6675 (P < 0.0001)], Social Interaction [%95 CI -4.3190 to -2.4010 (P < 0.0001)], and Stereotype Behavior [%95 CI -2.3939 to -0.2461 (P =0.01)] significantly. GCFD also reduced left [%95 CI -2.2421 to -1.6779 (P <0.0001)] and right pupil size [%95 CI -2.2999 to -1.7201 (P <0.0001)] significantly. Conversely, corneal reflex was significantly increased [95% CI 0.2159 to 2.1241 (P = 0.01)]. No differences were observed for IPD. Conclusion: This study suggested that the GCFD can effectively control ASD behaviors as well as regulate autonomic functions related to ophthalmic markers such as pupil size and corneal reflex, but more research is needed.

The Mef2c Gene Dose-Dependently Controls Hippocampal Neurogenesis and the Expression of Autism-Like Behaviors.

Mutations in the activity-dependent transcription factor MEF2C have been associated with several neuropsychiatric disorders. Among these, autism spectrum disorder (ASD)-related behavioral deficits are manifested. Multiple animal models that harbor mutations in Mef2c have provided compelling evidence that Mef2c is indeed an ASD gene. However, studies in mice with germline or global brain knock-out of Mef2c are limited in their ability to identify the precise neural substrates and cell types that are required for the expression of Mef2c-mediated ASD behaviors. Given the role of hippocampal neurogenesis in cognitive and social behaviors, in this study we aimed to investigate the role of Mef2c in the structure and function of newly generated dentate granule cells (DGCs) in the postnatal hippocampus and to determine whether disrupted Mef2c function is responsible for manifesting ASD behaviors. Overexpression of Mef2c (Mef2cOE ) arrested the transition of neurogenesis at progenitor stages, as indicated by sustained expression of Sox2+ in Mef2cOE DGCs. Conditional knock-out of Mef2c (Mef2ccko ) allowed neuronal commitment of Mef2ccko cells; however, Mef2ccko impaired not only dendritic arborization and spine formation but also synaptic transmission onto Mef2ccko DGCs. Moreover, the abnormal structure and function of Mef2ccko DGCs led to deficits in social interaction and social novelty recognition, which are key characteristics of ASD behaviors. Thus, our study revealed a dose-dependent requirement of Mef2c in the control of distinct steps of neurogenesis, as well as a critical cell-autonomous function of Mef2c in newborn DGCs in the expression of proper social behavior in both sexes.

Disrupted extracellular matrix and cell cycle genes in autism-associated Shank3 deficiency are targeted by lithium.

The Shank3 gene encodes the major postsynaptic scaffolding protein SHANK3. Its mutation causes a syndromic form of autism spectrum disorder (ASD): Phelan-McDermid Syndrome (PMDS). It is characterized by global developmental delay, intellectual disorders (ID), ASD behavior, affective symptoms, as well as extra-cerebral symptoms. Although Shank3 deficiency causes a variety of molecular alterations, they do not suffice to explain all clinical aspects of this heterogenic syndrome. Since global gene expression alterations in Shank3 deficiency remain inadequately studied, we explored the transcriptome in vitro in primary hippocampal cells from Shank3∆11(-/-) mice, under control and lithium (Li) treatment conditions, and confirmed the findings in vivo. The Shank3∆11(-/-) genotype affected the overall transcriptome. Remarkably, extracellular matrix (ECM) and cell cycle transcriptional programs were disrupted. Accordingly, in the hippocampi of adolescent Shank3∆11(-/-) mice we found proteins of the collagen family and core cell cycle proteins downregulated. In vitro Li treatment of Shank3∆11(-/-) cells had a rescue-like effect on the ECM and cell cycle gene sets. Reversed ECM gene sets were part of a network, regulated by common transcription factors (TF) such as cAMP responsive element binding protein 1 (CREB1) and β-Catenin (CTNNB1), which are known downstream effectors of synaptic activity and targets of Li. These TFs were less abundant and/or hypo-phosphorylated in hippocampi of Shank3∆11(-/-) mice and could be rescued with Li in vitro and in vivo. Our investigations suggest the ECM compartment and cell cycle genes as new players in the pathophysiology of Shank3 deficiency, and imply involvement of transcriptional regulators, which can be modulated by Li. This work supports Li as potential drug in the management of PMDS symptoms, where a Phase III study is ongoing.

Behavioral symptoms of Alzheimer’s disease and autism spectrum disorder: Insights to guide future non‐pharmacological interventions

AbstractBackgroundMany behavioral and psychiatric symptoms of dementia (BPSD) share similarities with those described in pediatric autism spectrum disorder (ASD), including anxiety, depression, and communication deficits. However, the possibility of late‐life onset of behaviors stereotypic of ASD in Alzheimer’s disease (AD) has been poorly explored. Findings of three studies are presented here to illustrate associations in behaviors between ASD and AD.MethodsCare partners of persons with cognitive impairment (MCI or dementia) from the University of Kentucky Alzheimer’s Disease Research Center community‐based longitudinal cohort were surveyed using the Gilliam Autism Rating Scale‐2 (GARS‐2). Analyses included t‐tests, chi‐square, analysis of variance, and linear regression models to explore frequency of ASD behaviors in this cohort, and the relationship of behaviors represented in the GARS‐2 compared to behavioral categories used in AD assessment (Neuropsychiatric Inventory‐Questionnaire; NPI‐Q). Lastly, cross‐sectional postmortem neuropathological analyses compared “Autism Possible” to “Autism Unlikely” in available cases.ResultsAnalyses included 142 GARS‐2 respondents. A substantial number of participants presented with ASD‐like behaviors, and those with high Autism Index scores had significantly younger age at onset (71.1±11.0 vs. 76.7±8.3; p = 0.034) and more severe cognitive impairment than those who scored in the “Autism Unlikely” range. ASD‐like behaviors were also significantly correlated with BPSD severity ratings (r = 0.47; p < 0.001). In neuropathological analyses, the two groups differed in the frontal and temporal regions, specific to tau pathology.ConclusionThese findings suggest that ASD‐like behaviors may emerge in AD as a result of shared neurological substrates, given that such behaviors are associated with an earlier age of onset and more severe cognitive impairment. With emerging evidence linking BPSD and ASD, additional research is needed to understand shared mechanisms, as well as development of novel treatment approaches to address behavioral symptoms of AD.

Eating and Sensory Features of Children With Autism Spectrum Disorder and Their Typically Developing Peers.

Impaired sensory processing is associated with eating problems. There seem to be no previous studies that compare those who have autism spectrum disorder (ASD) with eating problems (ASD-W) and those with ASD without eating problems (ASD-WO) with typically developing (TD) groups. Comparisons are expected to provide further knowledge to guide the intervention programs. To investigate differences among ASD-W, ASD-WO, and TD groups in eating and sensory features; to detect associations between sensory and eating behaviors and any most involved sensory dimensions; and to search for age-related differences in sensory and eating features in ASD. Nonrandomized comparison study. Questionnaires administered as parent interviews. A total of 165 children were recruited: 117 with ASD and 48 TD children. Standardized questionnaires: the Brief Autism Mealtime Behaviors Inventory for eating problems; the Short Sensory Profile and the Sensory Experience Questionnaire for sensory problems. The ASD-W group showed generalized, impaired eating behaviors and turned out to be the most impaired with regard to sensory responsiveness. No differences in feeding behaviors were found between the ASD-WO and TD groups. All children with ASD showed sensory hyper- or hyporesponsiveness. Four main sensory dimensions were found to be associated with eating behaviors in ASD. No age differences were found in the eating and sensory behaviors of children with ASD. Differing eating and sensory profiles were found between the ASD and TD groups, especially in children with ASD-W. Early eating interventions using sensory stimulations are strongly recommended. What This Article Adds: This study reports novel information derived from the comparisons of children with ASD with eating problems and those with ASD without eating problems with typically developing groups of children.

Blood exosome sensing via neuronal insulin-like growth factor-1 regulates autism-related phenotypes

The development and progression of autism spectrum disorder (ASD) is characterized by multiple complex molecular events, highlighting the importance of the prefrontal brain regions in this process. Exosomes are nanovesicles that play a critical role in intercellular communication. Peripheral systems influence brain function under both physiological and pathological conditions. We investigated whether this influence was mediated by the direct sensing of peripheral blood exosomes by brain cells. Administration of serum exosomes from rats with valproic acid-induced ASD resulted in ASD-related phenotypes in mice, whereas exosomes from normal rats did not exhibit such effects. RNA sequencing and bioinformatics analysis suggested that negative regulation of medial prefrontal cortex (mPFC) insulin-like growth factor 1 (IGF-1) by exosome-derived miR-29b-3p may contribute to these ASD-associated effects. Further evidence showed that miR-29b-3p-enriched exosomes crossed the blood–brain barrier to reach the mPFC, subsequently inducing the suppression of IGF-1 expression in neurons. Optogenetic activation of excitatory neurons in the mPFC improved behavioral abnormalities in exosome-treated mice. The addition of exogenous IGF-1 or inhibition of miR-29b-3p expression in the mPFC also rescued the ASD-related phenotypes in mice. Importantly, administration of miR-29b-3p-enriched serum exosomes from human donors with ASD into the mouse medial prefrontal cortex was sufficient to induce hallmark ASD behaviors. Together, our findings indicate that blood–brain cross-talk is crucial for ASD pathophysiology and that the brain may sense peripheral system changes through exosomes, which could serve as the basis for future neurological therapies.

Heterogeneity of dynamic synergetic configurations of salience network in children with autism spectrum disorder.

Atypical functional connectivity (FC) patterns have been identified in autism spectrum disorders (ASD), especially within salience network (SN) and between SN and default mode network (DMN) and central executive network (CEN). But whether the dynamic configuration of intra-SN and inter-SN (SN with DMN and CEN) FC in ASD is also heterogeneous remains unknown. Based on the resting-state functional magnetic resonance imaging data from 105 ASD and 102 typically-developing controls (TC), we calculated the time-varying FC of intra-SN and inter-SN (SN with DMN and CEN). Then, the joint recurrence features for the time-varying FC were calculated to assess how the SN dynamically recruits different configurations of network segregation and integration in ASD, that is, synergies, from the dynamical systems perspective. We analyzed the differences in synergetic patterns between ASD subtypes obtained by k-means clustering algorithm based on the synergy of SN and TC, and investigated the relationships between synergy of SN and severity of clinical symptoms of ASD for ASD subtypes. Two ASD subtypes were revealed, where the synergy of SN in ASD subtype 1 has lower stability and periodicity compared to the TC, and ASD subtype 2 exhibits the opposite alteration. Synergy of SN for ASD subtype 1 and 2 was found to predict the severity of communication impairments and restricted and repetitive behaviors in ASD, respectively. These results suggest the existence of subtypes with distinct patterns of the synergy of SN in ASD, and provide insight into the complex pathophysiological mechanism of clinical manifestations of ASD.

Decreased functional concordance in male children with autism spectrum disorder.

Autism spectrum disorder (ASD) is an early-onset neurodevelopmental condition with altered function of the brain. At present, a variety of functional metrics from neuroimaging techniques have been used to explore ASD neurological mechanisms. However, the concordance of these functional metrics in ASD is still unclear. This study used resting-state functional magnetic resonance imaging data, which were obtained from the open-access Autism Brain Imaging Data Exchange database, including 105 children with ASD and 102 demographically matched typically developing (TD) children. Both voxel-wise and volume-wise functional concordance were calculated by combining the dynamic amplitude of low-frequency fluctuations, dynamic regional homogeneity, and dynamic global signal correlation. Furthermore, a two-sample t-test was performed to compare the functional concordance between ASD and TD groups. Finally, the relationship between voxel-wise functional concordance and Autism Diagnostic Observation Schedule subscores was analyzed using the multivariate support vector regression in the ASD group. Compared with the TD group, we found that ASD showed decreased voxel-wise functional concordance in the left superior temporal pole (STGp), right amygdala, and left opercular part of the inferior frontal gyrus (IFGoper). Moreover, decreased functional concordance was associated with restricted and repetitive behaviors in ASD. Our results found altered brain function in the left STGp, right amygdala, and left IFGoper in ASD by functional concordance, indicating that functional concordance may provide new insights into the neurological mechanisms of ASD.

A Comparison of Family Management Between Families of Children With Autism Spectrum Disorder and Families of Children With Down Syndrome

This cross-sectional study aimed to (1) compare family management between families of children with autism spectrum disorder (ASD) or Down syndrome and (2) evaluate the contribution of the child (ASD behaviors, feeding difficulties, sleep disturbances), caregiver (mental health) and family (social support) factors to the caregiver's perceived condition management ability and effort. Eighty-five caregivers (56 ASD, 29 Down syndrome) completed quantitative instruments online. Data analysis included independent samples t-tests and multiple linear regression. There were no significant differences in the dimensions of family management between groups. More ASD behaviors were associated with lower condition management ability and higher condition management effort. Lower perceived social support and higher caregiver age were associated with lower condition management ability. Integrating care into family life may be more challenging when the child has more social differences and behavioral rigidity. Nursing care should include an assessment of family social support.

Disentangling the Individual-Shared and Individual-Specific Subspace of Altered Brain Functional Connectivity in Autism Spectrum Disorder

BackgroundDespite considerable effort toward understanding the neural basis of autism spectrum disorder (ASD) using case-control analyses of resting-state functional magnetic resonance imaging data, findings are often not reproducible, largely due to biological and clinical heterogeneity among individuals with ASD. Thus, exploring the individual-shared and individual-specific altered functional connectivity (AFC) in ASD is important to understand this complex, heterogeneous disorder. MethodsWe considered 254 individuals with ASD and 295 typically developing individuals from the Autism Brain Imaging Data Exchange to explore the individual-shared and individual-specific subspaces of AFC. First, we computed AFC matrices of individuals with ASD compared with typically developing individuals. Then, common orthogonal basis extraction was used to project AFC of ASD onto 2 subspaces: an individual-shared subspace, which represents altered connectivity patterns shared across ASD, and an individual-specific subspace, which represents the remaining individual characteristics after eliminating the individual-shared altered connectivity patterns. ResultsAnalysis yielded 3 common components spanning the individual-shared subspace. Common components were associated with differences of functional connectivity at the group level. AFC in the individual-specific subspace improved the prediction of clinical symptoms. The default mode network–related and cingulo-opercular network–related magnitudes of AFC in the individual-specific subspace were significantly correlated with symptom severity in social communication deficits and restricted, repetitive behaviors in ASD. ConclusionsOur study decomposed AFC of ASD into individual-shared and individual-specific subspaces, highlighting the importance of capturing and capitalizing on individual-specific brain connectivity features for dissecting heterogeneity. Our analysis framework provides a blueprint for parsing heterogeneity in other prevalent neurodevelopmental conditions.

The relationship between screen time before bedtime and behaviors of preschoolers with autism spectrum disorder and the mediating effects of sleep

BackgroundThere are overlapping effects of screen time and sleep on children’s behavior. The purpose of this study was to explore the relationship of screen time with behavior problems in children with autism spectrum disorder (ASD) and the probable mediating effects of sleep, in order to provide evidence for the need for clinical identification and intervention.MethodsA sample of 358 preschoolers with ASD were included. We investigated the children’s basic characteristics of sex and age, ASD symptoms (ABC, CARS, and ADOS-2), neurodevelopment (GDS-C), sleep habits (CSHQ), and behavior (CBCL). Pearson correlation tests were used to determine the direct correlations among children’s screen time, CBCL, and CSHQ. Linear regression analysis was used to explore whether screen time predicted total score of CBCL. Multi-step linear regression analysis was used to investigate the mediating effect of sleep on the relationship between screen time and total score of CBCL.ResultsScreen time before bedtime was correlated with CBCL and CSHQ, which indicated that screen time before bedtime was correlated with sleep and behavior in children with ASD. Screen time before bedtime was a predictor of CBCL total score (indicating children’s behavior), and CSHQ total score (indicating children’s sleep habits) played a partial mediating role between screen time before bedtime and children’s behavior.ConclusionClinicians should support and educate parents of children with ASD, which should focus on managing screen time, especially screen time before bedtime.

Association between Neuroligin-1 polymorphism and plasma glutamine levels in individuals with autism spectrum disorder

Unravelling the relationships between candidate genes and autism spectrum disorder (ASD) phenotypes remains an outstanding challenge. Endophenotypes, defined as inheritable, measurable quantitative traits, might provide intermediary links between genetic risk factors and multifaceted ASD phenotypes. In this study, we sought to determine whether plasma metabolite levels could serve as endophenotypes in individuals with ASD and their family members. We employed an untargeted, high-resolution metabolomics platform to analyse 14,342 features across 1099 plasma samples. These samples were collected from probands and their family members participating in the Autism Genetic Resource Exchange (AGRE) (N=658), compared with neurotypical individuals enrolled in the PrecisionLink Health Discovery (PLHD) program at Boston Children's Hospital (N=441). We conducted a metabolite quantitative trait loci (mQTL) analysis using whole-genome genotyping data from each cohort in AGRE and PLHD, aiming to prioritize significant mQTL and metabolite pairs that were exclusively observed in AGRE. Within the AGRE group, we identified 54 significant associations between genotypes and metabolite levels (P<5.27×10-11), 44 of which were not observed in the PLHD group. Plasma glutamine levels were found to be associated with variants in the NLGN1 gene, a gene that encodes post-synaptic cell-adhesion molecules in excitatory neurons. This association was not detected in the PLHD group. Notably, a significant negative correlation between plasma glutamine and glutamate levels was observed in the AGRE group, but not in the PLHD group. Furthermore, plasma glutamine levels showed a negative correlation with the severity of restrictive and repetitive behaviours (RRB) in ASD, although no direct association was observed between RRB severity and the NLGN1 genotype. Our findings suggest that plasma glutamine levels could potentially serve as an endophenotype, thus establishing a link between the genetic risk associated with NLGN1 and the severity of RRB in ASD. This identified association could facilitate the development of novel therapeutic targets, assist in selecting specific cohorts for clinical trials, and provide insights into target symptoms for future ASD treatment strategies. This work was supported by the National Institute of Health (grant numbers: R01MH107205, U01TR002623, R24OD024622, OT2OD032720, and R01NS129188) and the PrecisionLink Biobank for Health Discovery at Boston Children's Hospital.

Immp2l knockdown in male mice increases stimulus-driven instrumental behaviour but does not alter goal-directed learning or neuron density in cortico-striatal circuits in a model of Tourette syndrome and autism spectrum disorder

Cortico-striatal neurocircuits mediate goal-directed and habitual actions which are necessary for adaptive behaviour. It has recently been proposed that some of the core symptoms of autism spectrum disorder (ASD) and Gilles de la Tourette syndrome (GTS), such as tics and other repetitive behaviours, may emerge because of imbalances in these neurocircuits. We have recently developed a model of ASD and GTS by knocking down Immp2l, a mitochondrial gene frequently associated with these disorders. The current study sought to determine whether Immp2l knockdown (KD) in male mice alters flexible, goal- or cue- driven behaviour using procedures specifically designed to examine response-outcome and stimulus-response associations, which underlie goal-directed and habitual behaviour, respectively. Whether Immp2l KD alters neuron density in cortico-striatal neurocircuits known to regulate these behaviours was also examined. Immp2l KD mice and wild type-like mice (WT) were trained on Pavlovian and instrumental learning procedures where auditory cues predicted food delivery and lever-press responses earned a food outcome. It was demonstrated that goal-directed learning was not changed for Immp2l KD mice compared to WT mice, as lever-press responses were sensitive to changes in the value of the food outcome, and to contingency reversal and degradation. There was also no difference in the capacity of KD mice to form habitual behaviours compared to WT mice following extending training of the instrumental action. However, Immp2l KD mice were more responsive to auditory stimuli paired with food as indicated by a non-specific increase in lever response rates during Pavlovian-to-instrumental transfer. Finally, there were no alterations to neuron density in striatum or any prefrontal cortex or limbic brain structures examined. Thus, the current study suggests that Immp2l is not necessary for learned maladaptive goal or stimulus driven behaviours in ASD or GTS, but that it may contribute to increased capacity for external stimuli to drive behaviour. Alterations to stimulus-driven behaviour could potentially influence the expression of tics and repetitive behaviours, suggesting that genetic alterations to Immp2l may contribute to these core symptoms in ASD and GTS. Given that this is the first application of this battery of instrumental learning procedures to a mouse model of ASD or GTS, it is an important initial step in determining the contribution of known risk-genes to goal-directed versus habitual behaviours, which should be more broadly applied to other rodent models of ASD and GTS in the future.

The brain serotonin system in autism.

Autism spectrum disorders (ASDs) are among themost common neurodevelopmental diseases. These disorders are characterized by lack of social interaction, byrepetitive behavior, and often anxiety and learning disabilities. The brain serotonin (5-HT) system is known to becrucially implicated in a wide range of physiological functions and in the control of different kinds of normal and pathological behavior. A growing number of studies indicate the involvement of the brain 5-HT system in the mechanisms underlying both ASD development and ASD-related behavioral disorders. There are some review papers describing the role of separate key players of the 5-HT system in an ASD and/or autistic-like behavior. In this review, we summarize existing data on the participation of all members of the brain 5-HT system, namely, 5-HT transporter, tryptophan hydroxylase 2, MAOA, and 5-HT receptors, in autism in human and various animal models. Additionally, we describe the most recent studies involving modern techniques for invivo regulation of gene expression that are aimed at identifying exact roles of 5-HT receptors, MAOA, and 5-HT transporter inthe mechanisms underlying autistic-like behavior. Altogether, results of multiple research articles show that the brain 5-HT system intimately partakes in the control of some types of ASD-related behavior, and that specific changes in a function of a certain 5-HT receptor, transporter, and/or enzyme may normalize this aberrant behavior. These data give hope that some of clinically used 5-HT-related drugs have potential for ASD treatment.

One size does not fit all: detecting attention in children with autism using machine learning

AbstractDetecting the attention of children with autism spectrum disorder (ASD) is of paramount importance for desired learning outcome. Teachers often use subjective methods to assess the attention of children with ASD, and this approach is tedious and inefficient due to disparate attentional behavior in ASD. This study explores the attentional behavior of children with ASD and the control group: typically developing (TD) children, by leveraging machine learning and unobtrusive technologies such as webcams and eye-tracking devices to detect attention objectively. Person-specific and generalized machine models for face-based, gaze-based, and hybrid-based (face and gaze) are proposed in this paper. The performances of these three models were compared, and the gaze-based model outperformed the others. Also, the person-specific model achieves higher predictive power than the generalized model for the ASD group. These findings stress the direction of model design from traditional one-size-fits-all models to personalized models.

Intraneuronal accumulation of amyloid-β peptides as the pathomechanism linking autism and its co-morbidities: epilepsy and self-injurious behavior - the hypothesis.

Autism spectrum disorder (ASD) is associated with enhanced processing of amyloid-β precursor protein (APP) by secretase-α, higher blood levels of sAPPα and intraneuronal accumulation of N-terminally truncated Aβ peptides in the brain cortex - mainly in the GABAergic neurons expressing parvalbumin - and subcortical structures. Brain Aβ accumulation has been also described in epilepsy-the frequent ASD co-morbidity. Furthermore, Aβ peptides have been shown to induce electroconvulsive episodes. Enhanced production and altered processing of APP, as well as accumulation of Aβ in the brain are also frequent consequences of traumatic brain injuries which result from self-injurious behaviors, another ASD co-morbidity. We discuss distinct consequences of accumulation of Aβ in the neurons and synapses depending on the Aβ species, their posttranslational modifications, concentration, level of aggregation and oligomerization, as well as brain structures, cell types and subcellular structures where it occurs. The biological effects of Aβ species which are discussed in the context of the pathomechanisms of ASD, epilepsy, and self-injurious behavior include modulation of transcription-both activation and repression; induction of oxidative stress; activation and alteration of membrane receptors' signaling; formation of calcium channels causing hyper-activation of neurons; reduction of GABAergic signaling - all of which lead to disruption of functions of synapses and neuronal networks. We conclude that ASD, epilepsy, and self-injurious behaviors all contribute to the enhanced production and accumulation of Aβ peptides which in turn cause and enhance dysfunctions of the neuronal networks that manifest as autism clinical symptoms, epilepsy, and self-injurious behaviors.

Brain-Derived Neurotrophic Factor (BDNF) in Mechanisms of Autistic-like Behavior in BTBR Mice: Crosstalk with the Dopaminergic Brain System.

Disturbances in neuroplasticity undoubtedly play an important role in the development of autism spectrum disorders (ASDs). Brain neurotransmitters and brain-derived neurotrophic factor (BDNF) are known as crucial players in cerebral and behavioral plasticity. Such an important neurotransmitter as dopamine (DA) is involved in the behavioral inflexibility of ASD. Additionally, much evidence from human and animal studies implicates BDNF in ASD pathogenesis. Nonetheless, crosstalk between BDNF and the DA system has not been studied in the context of an autistic-like phenotype. For this reason, the aim of our study was to compare the effects of either the acute intracerebroventricular administration of a recombinant BDNF protein or hippocampal adeno-associated-virus-mediated BDNF overexpression on autistic-like behavior and expression of key DA-related and BDNF-related genes in BTBR mice (a widely recognized model of autism). The BDNF administration failed to affect autistic-like behavior but downregulated Comt mRNA in the frontal cortex and hippocampus; however, COMT protein downregulation in the hippocampus and upregulation in the striatum were insignificant. BDNF administration also reduced the receptor TrkB level in the frontal cortex and midbrain and the BDNF/proBDNF ratio in the striatum. In contrast, hippocampal BDNF overexpression significantly diminished stereotypical behavior and anxiety; these alterations were accompanied only by higher hippocampal DA receptor D1 mRNA levels. The results indicate an important role of BDNF in mechanisms underlying anxiety and repetitive behavior in ASDs and implicates BDNF-DA crosstalk in the autistic-like phenotype of BTBR mice.