Autism Research

BackgroundIndividuals with Autism Spectrum Disorder (ASD) show atypical auditory perception. The N100 event-related potential (ERP) reflects early auditory encoding, predictive coding, and sensory gain. Therefore, this study examined N100 responses to speech stimuli as a neural marker of auditory processing differences in ASD. MethodsEvent-related potentials (ERPs) were recorded using OpenBCI in 12 boys diagnosed with Level 1 ASD (requiring minimal support) and 15 typically developing (TD) peers. Participants passively listened to Romanian sentences systematically varied in pitch (normal, high, low), distance-based intensity (0.5, 1, 2 meters; 65, 59, 53 dB), and spatial presentation (binaural, left, right). N100 amplitudes and latencies were analyzed using Python and SPSS. ResultsASD group indicated significantly reduced N100 amplitudes for normal-pitch stimuli (p = .030, {superscript 2} = .175) and binaural presentation (p = .030, {superscript 2} = .175). Marginal reductions were also observed for low pitch (p = .096, {superscript 2} = .120), speech presented from a 0.5-meter distance (p = .058, {superscript 2} = .147), and unilateral conditions (ps = .066-.077, {superscript 2}s = .130-.142). No group differences emerged for N100 latency. These findings suggest attenuated early auditory responses in ASD to both typical and spatially complex speech cues. ConclusionsResults support predictive coding models proposing reduced sensory precision in ASD. The consistent amplitude attenuation, including near-significant findings, points to subtle but pervasive impairments in early auditory encoding. The use of ecologically valid speech stimuli and portable EEG underscores the translational potential of N100 as a biomarker for early identification and intervention in autism.

Autism Spectrum Disorder (ASD) is a neurodevelopmental disorder characterized by a broad spectrum of behavioral impairments. While multiple genetic and environmental factors are attributed to its cause, biological underpinnings are still poorly understood. We investigated an ASD-associated gene, WAC, for its neurobehavioral aspects using C. elegans and mice. Studies of C. elegans with wac gene deletions (wac-1.1 and wac-1.2) showed enhanced acetylcholine-associated behavior, as indicated by the aldicarb assay. No alteration in acetylcholine levels or acetylcholinesterase activity was observed. Upon further investigation, we found that the elevated cholinergic transmission resulted from increased activity of nicotinic acetylcholine receptors (nAChRs). Additionally, we observed reduced motility and dopamine-associated behaviors, along with a reduced ability to switch from crawling to swimming, a serotonin-dependent behavior. Upregulation in mRNA expression of the lev-1 gene was observed. Conversely, a feedback-counterbalancing response in the form of downregulated genes, acr-2, unc-17, unc-63, and unc-50, was also observed. Surprisingly, lev-1 RNAi did not reverse the enhanced cholinergic transmission in PHX2587 worms, indicating the involvement of other players. To validate our findings, we also assessed CHRNA7 levels in Wac+/- mice. While some genetic compensation was observed in heterozygous mice, we found a direct, inverse correlation between Wac mRNA expression and CHRNA7 levels in the mouse brain cortex, corroborating our findings from C. elegans. Overall, these studies indicate that wac gene deletion in C. elegans exhibits a neurotransmitter alteration that is relatable to ASD. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=61 SRC="FIGDIR/small/709202v1_ufig1.gif" ALT="Figure 1"> View larger version (24K): org.highwire.dtl.DTLVardef@1771dc4org.highwire.dtl.DTLVardef@1434b4eorg.highwire.dtl.DTLVardef@10525ecorg.highwire.dtl.DTLVardef@fcd8a9_HPS_FORMAT_FIGEXP M_FIG C_FIG

RationaleNeurodevelopmental disorders (NDDs) are characterised by significant challenges in communication, social interaction, and adaptive function, often impacting quality of life. Previous studies support genetic influences on the communication abilities of individuals with NDD, but were either limited to single genetic conditions or to small cohorts with a limited selection of communication measures. MethodsWe analysed caregiver-reported communication abilities in 79,518 individuals with NDD from the Simons Searchlight and SPARK registries: 4,439 with a CNV-based or monogenic NDD and 75,079 with autism spectrum disorder (ASD) without a known genetic cause (idiopathic ASD) as controls. For analysis, we a priori selected 10 communication-related measures based on their availability in the study cohorts, coverage of distinct communication aspects, and their frequent use in neurodevelopmental phenotyping, yielding 177,328 data points across all study cohorts. The individuals in the Searchlight registry were divided into a Discovery cohort (the 15 most prevalent genetic NDD conditions) and a Confirmation cohort (all other genetic NDD conditions). A second Confirmation cohort was generated using all individuals with genetic ASD forms from the SPARK registry. We then tested each of the three case cohorts and each genetic condition represented in the Discovery cohort against the ASD control cohort. Developmental trajectories were assessed through testing of participants grouped by age at evaluation. ResultsMeasure-level analyses demonstrated significant associations between genetic status and communication abilities, differences in communication abilities between classes of genetic variants (monogenic vs. CNV-based NDDs), and variability between specific genetic NDD conditions. CNV-based NDDs showed milder communication impairment, outperforming idiopathic ASD controls in 9/10 communication measures, whereas monogenic NDD conditions had more pervasive impairments, especially in verbal communication. Although impaired in verbal communication, five monogenic NDD conditions showed at least suggestive strengths in nonverbal and social communication relative to idiopathic ASD controls (CSNK2A1, CTNNB1, SETBP1, MED13L, and PPP2R5D), specifically in using gestures. Developmental trajectory analyses revealed STXBP1 as the gene group at highest risk of developmental stagnation in communication abilities. ConclusionsThese findings underscore the potential of precision speech-language pathology (SLP) approaches tailored to the specific verbal and nonverbal communication strengths and weaknesses of genetic groups. We also provide evidence for measurable improvements and declines in communication abilities with age at the group level, highlighting the need for developmentally informed care. By integrating genetic insights into clinical practice, precision SLP approaches may enhance communication outcomes and developmental progress and improve quality of life for individuals with genetic NDDs.

BackgroundAutism Spectrum Disorder (ASD) is characterized by sensory disruptions, including auditory processing differences, which can significantly impact social, emotional, and cognitive development. This study investigates auditory brainstem development in Autistic children and adults using auditory brainstem responses (ABRs) and acoustic startle responses (ASRs), two key measures of auditory processing. We hypothesize that early hypo-responsivity in children, measured with ABRs, may lead to compensatory neural adaptations, resulting in hyper-reactivity in adulthood, measured by ASRs. MethodsThe study included 40 Autistic children, 57 non-Autistic children, 20 Autistic adults, and 21 non-Autistic adults. Participants underwent peripheral hearing screening, ABR testing at slow and fast click-rates, and ASR measurements. ABR wave and ASR latencies and amplitudes were analyzed. Statistical analyses included mixed-model ANOVAs and Spearmans correlations to examine group differences and associations with age. ResultsAutistic children exhibited increased ABR wave latencies and reduced amplitudes, indicating slower neurotransmission and reduced neural responsivity in the ascending auditory pathway. In contrast, Autistic adults showed normalized ABR latencies but increased ASR magnitude, suggesting hyper-reactivity to auditory stimuli. Age-related correlations revealed that ABR latencies increased with age in non-Autistic participants, while ASR magnitude was negatively correlated with age in non-Autistic participants. The associations were significantly different between groups. ConclusionThe findings support the hypothesis that Autistic children experience auditory brainstem hypo-responsivity, which may normalize in adulthood but lead to maladaptive hyper-reactivity. These results highlight the role of early auditory disruptions in shaping long-term sensory processing and reactivity in Autism, emphasizing the need for further research into the neural mechanisms underlying these differences.

MotivationAltered auditory processing likely contributes to core social and attentional impairments in autism spectrum disorder (ASD). The auditory steady-state response (ASSR)-- a neural measure of auditory processing and cortical excitatory-inhibitory balance--has yielded mixed results in ASD. This study uses high density electroencephalography (EEG) to evaluate ASSR in ASD and unaffected siblings to clarify neural mechanisms underlying auditory deficits in autism. MethodsHigh-density 70-channel EEG was recorded in children (8-12 years, IQ >80) with ASD (n=53), typically developing (TD) peers (n=35), and unaffected biological siblings (n=26) during 500-ms binaural click trains (27- and 40-Hz) in an active oddball task. ResultsNo group differences were observed in frequency-following responses (FFR) to 27- or 40-Hz stimuli, although higher 40-Hz power was associated with older age and better behavioral performance in ASD. The broad-band response from 180-250 ms was reduced in ASD for both stimulation frequencies--particularly in the low-frequency (<8 Hz) range--and significantly correlated with IQ and age. Siblings showed intermediate broad-band responses. DiscussionWhile FFRs appeared intact in ASD, we observed reduced broad-band response in the transition period to the steady state FFR, which was specific to low (<8-Hz) frequencies--potentially reflecting reduced synchronization at timescales that correspond with slower, syllabic rhythms ([~]4-8 Hz) occurring in natural speech. Intermediate responses in first-degree relatives suggest that this is related to genetic vulnerability for ASD and highlights its clinical relevance. These findings suggest intact sensory processing in ASD alongside possible top-down auditory feedback deficits, which may serve as heritable neurophysiological markers. Lay AbstractChildren with autism may process sounds differently, which could contribute to challenges with attention and communication. Here, electroencephalography (EEG) measured how the brain responds to rapidly repeating sounds and found that, while basic sound processing was intact, children with autism showed significantly reduced low-frequency responses that may reflect difficulty tracking speech rhythm. Interestingly, unaffected siblings showed an intermediate response, suggesting this may be a heritable marker of neural differences in autism.

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 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.

PurposeMany genes have been identified in autism spectrum disorder (ASD). Yet how many adults with ASD receive recommended genetic testing and their outcomes is unknown. We investigated the percentage of adults with ASD with documented genetic testing in our ASD specialty clinic and the percentage with positive findings. MethodsAdults were identified through search of our data repository and ASD diagnoses confirmed using record review by psychiatrists specializing in ASD. Patients were included (N=630) who had at least one visit with a qualifying clinician between 5/1/2010 and 12/15/2020. Data were collected through manual retrospective record review. ResultsOnly 41% of the adults with ASD (261/630) had a documented history of genetic testing. Genetic testing was declined by patients or families for 11% of records and not recorded in 47%. Mean (SD; range) age for the 261 adults was 28.5 (5.3; 22-58) years; 26% were female and 73% had intellectual disability (ID). The genetic testing method was recorded in 91% (238). Only 54% of these patients had testing using a recommended method (chromosomal array, autism/ID sequencing panel, or exome sequencing). Few adults received testing with sequencing technologies. A genetic cause of ASD was found in 28%. ConclusionASD-related genetic testing is underutilized in adults with ASD. Nearly half of the adults in our sample lacked documentation of genetic testing. Thus, the percentage who received testing may be even lower than reported. Adults with ASD may benefit from having their genetic testing history reviewed in the clinic and the recommended testing performed.

This study comprehensively examines maternal and perinatal conditions associated with autism spectrum disorder (ASD) in a total population sample with individually confirmed diagnoses from South Sweden. Following thorough review of medical records, 996 cases were ascertained and classified based on level of intellectual disability, ASD severity and family-history of ASD. 10 controls per case were randomly selected from the population (N=9,960). Multiple maternal and perinatal conditions were associated with increased risk for ASD, but associations varied by ASD comorbid conditions. Only high maternal BMI was associated with ASD risk across all ASD sub-groups. Results suggest differences in ASD etiology by comorbid subgroups and highlight potential modifiable risk factors.

Social communication difficulties characterize autism spectrum disorders (ASD). Gastrointestinal (GI) symptoms are more common in ASD than in the general population. The identification of GI problems in individuals with ASD is challenging due to their altered pain perception and irregular behaviors. Importantly, GI symptoms and ASD can potentially aggravate each other. However, it is unclear if GI problems cause ASD symptoms or vice versa. A crosstalk between the digestive system, gut microbiota, and the central and enteric nervous systems has been repeatedly reported. The enteric nervous system (ENS) regulates the GI tract with the central nervous system (CNS) and the autonomic nervous system (ANS), as well as independently through specific neural circuits. Several mechanisms contribute to GI problems in ASD, including genetic mutations that affect the enteric nervous system (ENS), dysregulation of the ANS, alterations in gut microbiota, unhealthy dietary preferences, and changes in metabolomic profiles. Furthermore, studies have shown molecular and cellular differences in the GI biopsy of children with and without ASD. These findings highlight the unique nature of GI issues in ASD, underscoring the importance of further investigating the changes that occur in the digestive system and enteric nervous system (ENS) in ASD models.

Autism spectrum disorder (ASD) is characterised by social communication impairments and repetitive behaviours. Language deficits, including echolalia and restricted vocabulary, heighten caregiver stress and negatively affect the familys quality of life. Although animal models have advanced the understanding of individual ASD traits, their influence on kinship dynamics remains underexplored. To address this issue, we developed a clinically relevant ASD model in common marmosets by prenatal exposure to valproic acid (VPA) to produce ASD-like pups alongside their typically developing parents. We analysed 28,418 kinship calls from nine VPA-exposed and seven unexposed (UE) pups, along with their parents. Kinship vocalisations in VPA families exhibited significant alterations, including increased isolation calls, decreased affiliative calls, disruption of structured repetition patterns, and reduced developmental maturations. These deviations intensified after weaning, suggesting a link between social communicative stressors and altered family dynamics. Parental weight loss was correlated with kinship vocal deviations, potentially reflecting increased caregiver stress. This observation aligns with clinical reports of heightened stress in families raising children with ASD. VPA pups also displayed premature locomotion independence, indicating broader social and communication disruptions. These findings suggest that VPA marmosets are valuable models for investigating ASD-like traits in individuals and kinship-level dynamics. Kinship vocalisations provide critical insights into the interplay between communication impairments and caregiver stress, offering a promising avenue for developing non-invasive biomarkers for ASD-related challenges.

Social and language abilities are closely intertwined during early development. Yet, it is still unknown how neural features underlying early social and language deficits are linked in toddlers with autism spectrum disorders (ASD). We examined functional connectivity of left and right temporal language regions and its correlations with language and social abilities in a cohort of 1- 4 years old toddlers (52 ASD/34 non-ASD). Further, ASD toddlers were stratified into those who strongly prefer social visual stimuli (ASDSoc) vs. those who do not (ASDnonSoc) based on performance on an eye-tracking paradigm. In non-ASD toddlers, connectivity between temporal regions and other language- and social-related cortical regions was significantly correlated with language, communication, and social scores. Conversely, ASD toddlers showed atypical correlations between temporal-visual cortex (cuneus) connectivity and communication ability. This temporal-visual connectivity was also correlated with social visual attention in ASDnonSoc but not in ASDSoc toddlers. These findings suggest language- and social-related functional connectivity was not correlated with language and social functions in ASD toddlers. Abnormal engagement of temporal-visual cortex connectivity may be an early-age signature of ASD and may help explain why interventions targeting social skills and language are so challenging, particularly in those with poor social engagement.

Impaired behavioral flexibility might underlie some of the symptoms associated with autism spectrum disorder (ASD). We investigated whether and how behavioral flexibility is impaired in a mouse model of ASD by testing Shank2-knockout (Shank2-KO) mice in reversal learning. Shank2-KO mice were trained in probabilistic classical conditioning with two odor cues paired with water and air puff. Upon the reversal of cue-outcome contingency, Shank2-KO mice were significantly slower than wild-type mice in reversing their anticipatory licking responses. Shank2-KO mice also showed stronger anticipatory eye closure responses than wild-type mice to the air puff, raising a possibility that the impairment might be because of enhanced negative emotional processing. Indeed, Shank2-KO mice showed intact reversal learning when the strong air puff was replaced with a mild air puff. Shank2-KO mice also showed intact reversal learning between two odor cues predicting rewards with different probabilities. These results indicate that enhanced negative emotional processing suppresses reversal learning despite of intact capability to learn cue-outcome contingency changes in Shank2-KO mice in our behavioral settings. Our findings suggest that behavioral flexibility may be seriously limited by abnormal emotional processing in ASD.

Disrupted processing of social cues and altered social behaviors are among the core symptoms of autism spectrum disorders (ASDs), and they emerge as early as the first year of life. These differences in sensory abilities may affect the ability of children with ASDs to securely attach to a caregiver and experience caregiver buffering of stress. Prenatal exposure to valproic acid (VPA) has been used to model some aspects of ASDs in rodents. Here, we asked whether prenatal VPA exposure altered infant rats behavioral responsivity to maternal olfactory cues in an odor preference test and affected maternal buffering of infants stress responsivity to shock. In the odor preference test, one-week old rats treated with VPA during pregnancy appeared to have impaired social recognition and/or may be less motivated to approach social odors in early infancy. These effects were particularly prominent in female pups. In two-week old rats, VPA-exposed pups and saline-exposed pups showed similar preferences for home cage bedding. Although VPA-exposed pups may initially have a deficit in this attachment-related behavior they do recover typical responses to home cage bedding in later infancy. Both control and VPA-exposed pups showed robust stress hormone responses to repeated shocks, an effect which was blocked when a calm mother was present during shock exposure. No sex differences in the effect of maternal presence on the stress response to shock and no interactions between sex and prenatal drug exposure were observed. Although VPA-exposed pups may show impaired responsivity to maternal cues in early infancy, maternal presence is still capable of regulating the stress response in VPA-exposed pups. In this study we demonstrate the importance of utilizing multiple batteries of tests in assessing behavior, dissecting the behavior on one test into different components. Our results inform about the underlying behavioral characteristics of some of the ASD phenotypes, including sex differences reported by clinical studies, and could shed light on potential opportunities for intervention.

Several disciplines have approached the relationship between autism spectrum disorder (ASD) and music, but most of this understanding comes from cognitive sciences. This complex relationship has been studied by exploring how music-based interventions (MI) can benefit individuals with ASD. This systematic review and meta-analysis synthesize a range of evidence regarding the therapeutic effects of music on different aspects, including communication, behavior, social engagement, attention, and quality of life for those with ASD. Additionally, it contextualizes these effects within current research on the musical perception and processing abilities of ASD individuals, emphasizing how they perceive and process music. The studies reviewed employ a variety of methodologies, from randomized controlled trials to qualitative research, showcasing a wide array of interventions such as active music-making, music listening, and improvisational techniques. Despite substantial heterogeneity across studies, the findings point to a moderate overall benefit of MI, particularly in areas such as social interaction, expressive language, and quality of life. Given the evidence supporting the context-sensitive and domain-specific benefits of musical abilities in individuals with ASD, along with the positive outcomes highlighted in various studies, we conclude that music represents a valuable therapeutic tool for ASD. It engages individuals on emotional, cognitive, and social levels, providing a non-invasive and enjoyable way to enhance therapeutic outcomes. Future research should focus on individual differences, harmonization of outcome measures, and long-term effectiveness, paving the way for more personalized and neurodiversity-affirming intervention models.

BackgroundAltered patterns of eye-movements during scene exploration, and atypical gaze preferences in social settings, have long been noted as features of the Autism phenotype. While these are typically attributed to differences in social engagement and interests (e.g., preferences for inanimate objects over face stimuli), there are also reports of differential saccade measures to non-social stimuli, raising the possibility that fundamental differences in visuo-sensorimotor processing may be at play. Here, we tested the plasticity of the eye-movement system using a classic saccade-adaptation paradigm to assess whether individuals with ASD make typical adjustments to their eye-movements in response to experimentally introduced errors. Saccade adaptation can be measured in infants as young as 10 months, raising the possibility that such measures could be useful as early neuromarkers of ASD risk. MethodsSaccade amplitudes were measured while children and adults with ASD (N=41) and age-matched typically developing (TD) individuals (N=68) made rapid eye-movements to peripherally presented targets. During adaptation trials, the target was relocated from 20-degrees to 15-degrees from fixation once a saccade to the original target location was initiated, a manipulation that leads to systematic reduction in saccade amplitudes in typical observers. ResultsNeither children nor adults with ASD showed any differences relative to TD peers in their abilities to appropriately adapt saccades in the face of persistently introduced errors. ConclusionsOf the three studies to date of saccade adaptation in ASD, none have shown frank deficits in saccade adaptation. Unlike prior studies, we found no evidence for a slower adaptation rate during the early adaptation phase, and no of evidence greater variance of saccade amplitudes in ASD. In post-hoc analysis, there was evidence for larger primary saccades to non-adapted targets, a finding requiring replication in future work.

Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by early onset deficits in social behavior and repetitive behavior. Chromodomain helicase DNA binding protein (CHD8) is one of the genes with the strongest association to autism. Alongside with the core symptoms of ASD, individuals with ASD are reported to have gastrointestinal (GI) problems, and a majority of individuals with CHD8 mutations display GI problems. However, the relationship between autism related genes, such as CHD8, gastrointestinal function, and autism related behaviours are yet very unclear. In the current study, we found that mice haploinsufficient for CHD8 have leaky gut, a dysregulated transcriptome in gut epithelial cells, decreased gut tuft cells and goblet cells, and an increase in microbial load. Specific deletion of CHD8 in gut epithelial cells induced an increase in anxiety-related behaviours in, a phenotype that is often observed in autism and full body knockdown of CHD8, in addition to decreased tuft cells. In addition, antibiotic treatment of CHD8 haploinsufficient mice attenuates sociability deficits. Therefore, the current study determines a pathway for autism-related GI deficits, and how these deficits may play a direct role in the development of autism-related behaviours.

BackgroundThere are substantial differences in the characteristics of males and females with an autism spectrum disorder (ASD), yet there is little knowledge surrounding the mechanistic underpinnings of these differences. The valproic acid (VPA) rodent model is the most widely used model for the study of idiopathic ASD, but almost all of the studies have used male rodents. MethodTo fill this knowledge gap, we evaluated sex differences for neuronal activity, morphology, and glycogen synthase kinase-3 (GSK-3) signaling in primary cortical (CTX) and hippocampal (HIP) neurons prepared from rats exposed to VPA in utero. In vivo, sex-specific VPA-induced alterations in the frontal CTX transcriptome at birth were also determined. ResultsOverall, VPA induced more robust changes in neuronal function and structure in the CTX than in the HIP. Male- and female-derived primary CTX neurons from rats exposed to prenatal VPA had elevated activity and showed more disorganized firing. In the HIP, only the female VPA neurons showed elevated firing, while the male VPA neurons exhibited disorganized activity. Dendritic arborization of CTX neurons from VPA rats was less complex in both sexes, though this was more pronounced in the females. Conversely, both female and male HIP neurons from VPA rats showed elevated complexity distal to the soma. Female VPA CTX neurons also had an elevated number of dendritic spines. The relative activity of the and {beta} isoforms of GSK-3 were suppressed in both female and male VPA CTX neurons, with no changes in the HIP neurons. On postnatal day 0, alterations in CTX genes associated with neuropeptides (e.g., penk, pdyn) and receptors (e.g., drd1, adora2a) were seen in both sexes, though they were downregulated in females and upregulated in males. LimitationsPrimary neuron studies may not recapitulate findings performed in vivo or at later stages of development. ConclusionTogether these findings suggest that substantial sex differences in neuronal structure and function in the VPA model may have relevance to the reported sex differences in idiopathic ASD.

Individuals diagnosed with Autism Spectrum Disorder (ASD) generally have altered responses to social reward, which the "social motivation" hypothesis posits as the primary contributor to their social deficits. Aberrant perception of rewarding faces is considered to be one of the most significant markers of this hypothesis. The orbitofrontal cortex (OFC) plays an important role in modulating reward and arousal responses to happy faces but few studies have investigated whether young autistic children with limited cognitive or language ability have altered neural and behavioral responses to reward related tasks. We therefore conducted an eye-tracking task where autistic (n = 36) and typically developing (n = 36) young children (aged 2.5-6 years) viewed the faces of happy children or of simplified faces (emoticons), combined with OFC activation measurement using functional near infrared spectroscopy (fNIRS), to compare ASD and typically developing (TD) children. Results revealed no differences between the two groups for time spent viewing happy faces although TD children spent more time looking at the eyes of real faces and at the mouths of emoticons whereas children with ASD did not. Children with ASD showed a greater pupil diameter (PD) and OFC activation compared to TD children during presentation of happy faces. Indeed, greater PD and OFC responses were predictive of greater adaptive behavior difficulties and severity of symptoms. Our results therefore demonstrate different gaze patterns and greater arousal and brain reward system responses to happy faces in young children with ASD which are incongruent with social motivation hypothesis. Availability of dataOur ethics approval does not permit public archiving of individual anonymized raw data. Those who wish to access the raw data should contact the corresponding author. Access will be granted to named individuals who adhere to the ethical procedures governing the reuse of sensitive data. They must complete a formal data sharing agreement to obtain the data. The data that support the main group different finding figures related anonymized data of this study are openly available via the Open Science Framework (OSF) Repository https://osf.io/sxkhc/?view_only=6eb51e64a9b54fce909b5ff6eacdc668 Ethics approval statementThe study was conducted in accordance with the principles of the Declaration of Helsinki. It was approved by the Local Ethics Committee (number 202165). Research Highlights[bullet] The present study examined whether altered social reward processing in ASD is caused by reduced behavioral and neural responses to rewarding stimuli. [bullet]Typically developing children showed a preference for viewing specific informative facial features (such as child eyes or emoticon mouths), children with autism did not. [bullet]Children with autism enhanced arousal (pupil dilation) and brain reward (orbitofrontal cortex) responses to happy child faces. [bullet]Altered, gaze patterns, arousal and brain reward responses were highly predictive of adaptive behavior abilities and autistic symptom severity.

Individuals with autism spectrum disorder (ASD) often exhibit atypical auditory processing, yet it remains unclear whether and how the integration of simple acoustic features and contextual information is impacted in ASD. One real-world example of this integration is the auditory looming bias, the prioritized processing and perception of approaching auditory stimuli. We designed a paradigm that presents intensity-rising (looming) and intensity-falling (receding) auditory stimuli to 3-4-year-old children with ASD (n = 21), children with sensory processing concerns who do not have ASD (SPC; n = 16) and children with typical development (TD; n = 30). We recorded neural responses using electroencephalography (EEG) and found evidence of looming bias in the SPC and TD groups, as indexed by greater P1 peak amplitude during the looming than receding stimuli (TD: t(64) = 6.87, p < .001; SPC: t(64) = 4.07, p < .001). But this finding was not present in the ASD group (p = .194). Additionally, the ASD group showed reduced differentiation between looming and receding stimuli, as indicated by significantly lower Rise-Fall Difference Score (RFDS) in comparison to the TD group (Z = -3.00, padj = .008). These findings suggested altered context-dependent modulation of sensory input in ASD.

BackgroundDifficulties with speech-in-noise perception in autism spectrum disorders (ASD) may be associated with impaired analysis of speech sounds, such as vowels, which represent the fundamental phoneme constituents of human speech. Vowels elicit early (< 100 ms) sustained processing negativity (SPN) in the auditory cortex that reflects the detection of an acoustic pattern based on the presence of formant structure and/or periodic envelope information (f0) and its transformation into an auditory "object". MethodsWe used magnetoencephalography (MEG) and individual brain models to investigate whether SPN is altered in children with ASD and whether this deficit is associated with impairment in their ability to perceive speech in the background of noise. MEG was recorded while boys with ASD and typically developing boys passively listened to sounds that differed in the presence/absence of f0 periodicity and formant structure. Word-in-noise perception was assessed in the separate psychoacoustic experiment using stationary and amplitude modulated noise with varying signal-to-noise ratio. ResultsSPN was present in both groups with similarly early onset. In children with ASD, SPN associated with processing formant structure was reduced predominantly in the cortical areas lateral to and medial to the primary auditory cortex, starting at [~] 150 - 200 ms after the stimulus onset. In the left hemisphere, this deficit correlated with impaired ability of children with ASD to recognize words in amplitude-modulated noise, but not in stationary noise ConclusionsThese results suggest that perceptual grouping of vowel formants into phonemes is impaired in children with ASD and that, in the left hemisphere, this deficit contributes to their difficulties with speech perception in fluctuating background noise.