Autism Research

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.

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.

Defective social behavior and cognitive functions are hallmarks of Autism spectrum disorders (ASD). The molecular mechanisms keeping social behavior in a physiological range are largely unknown. We recently found that conditional knockout (cKO) of tmiRNA cluster miR-379-410 in mouse hippocampal neurons leads to hypersocial behavior. Therefore, inhibiting miR-379-410 members might represent a strategy to promote sociability in ASD. As an ASD model, we chose knockdown (KD) of the ASD risk gene Tsc1, a key negative regulator of mTORC1. Acute Tsc1 knockdown (KD) in hippocampal neurons was sufficient to induce hyposociability and memory deficits in adult wild-type mice. In contrast, Tsc1 KD had no effect on sociability in miR-379-410 cKO mice, indicating a requirement of miR-379-410. Furthermore, Tsc1 KD led to upregulation of tmiR-495-3p, and inhibition of this miRNA by antisense oligonucleotides was sufficient to prevent hyposociability and memory impairments. Our findings suggest that miR-495-3p is a key downstream effector of the Tsc1/mTORC1 pathway in sociability, and that targeting miR-495-3p represents a therapeutic avenue for restoring social and cognitive impairments in ASD without affecting mTORC1 homeostasis.

A large subset of ASD associated genes, almost 50% of the highest confidence risk genes listed on the Simons Foundation Autism Research Institute database, are epigenetic modifiers. This suggests that the organization of sensory biology and its coupling to underlying genetic control are an important element underpinning this discord. Furthermore, sensory processing changes in individuals with autism spectrum disorder (ASD) has been a growing area of study in recent years. C. elegans have robust readouts for both developmental and sensory biology allowing these signatures of ASD to be systematically modelled. 52 epigenetic modifiers (65 strains) were selected for study in C. elegans based on gene function, presence of orthologues in C. elegans and the availability of viable putative null strains. This highlighted significant changes to reproduction, gross development and sensory processing across the range of epigenetic modifiers. Each strain was filtered against selective criteria for significant sensory and developmental phenotypes allowing for selective phenotypic profiles to emerge. These were three primary groups, those with sensory perturbations but unaffected gross development (6), developmentally affected genes with intact sensory function (10) and finally genes with impaired gross development and sensory function (11). Thus, this study provides a link between sensory and developmental outcomes in ASD associated mutant strains and suggests that more regular sensory testing should be performed in human cohorts to further refine sub-categorisation of ASD cohorts.

WAC is an autism-associated gene involved in neurodevelopment. However, the effects of reduced WAC function on behavior and synaptic regulation in vivo remain unclear. Taking cues from the previous studies on the wac gene and the C. elegans model of ASD, we elucidated the effects of wac gene deletion on food-leaving behavior, a known parameter linked to ASD associated genes along with the cholinergic pathway. wac-deficient worms exhibited curtailed food-leaving behavior. Notably, observed phenotype was similar to that exhibited by nematodes with mutation in ASD related gene, neuroligin. In addition, wac-deficient worms showed impaired growth, reduced pharyngeal pumping, and lifespan. To examine potential synaptic mechanisms, we analyzed expression of genes related to cholinergic signaling across all developmental stages (L1-L4) through young adult (YA). Stage-specific transcriptional changes were observed, with increased expression of ace-1 and acr-3 at L1, acr-3 at L3, and acr-3, cha-1, lev-1, and lev-10 at L4. The transcriptomic alteration was most prominent at YA stage, exhibiting upregulation of ace-1, cha-1, cho-1, lev-1, lev-10, unc-17, unc-29, unc-38, and unc-50. To identify specific suppressor of upmodulated Ach signaling, RNAi of the upregulated genes was performed. cho-1 was identified as a specific suppressor of elevated Ach signaling. cho-1 encodes a high-affinity choline transporter responsible for choline uptake in the pre-synapse. These studies identify the molecular mechanisms pertaining to up-modulation of cholinergic signaling in wac mutant worms. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=112 SRC="FIGDIR/small/719318v1_ufig1.gif" ALT="Figure 1"> View larger version (24K): org.highwire.dtl.DTLVardef@1bdf8a9org.highwire.dtl.DTLVardef@1104825org.highwire.dtl.DTLVardef@1f09682org.highwire.dtl.DTLVardef@293b08_HPS_FORMAT_FIGEXP M_FIG C_FIG

Differences in looking to and processing of audiovisual speech have been theorized to contribute to heterogeneity in language ability in autistic children. Differential audiovisual speech processing has been indexed by event-related potentials (ERPs), specifically via amplitude suppression in response to audiovisual versus auditory-only speech, and linked with vocabulary in school-aged children. This study used an intact-group comparison and concurrent correlational design in infant siblings of autistic children (Sibs-Autism) and non-autistic children (Sibs-NA) to determine whether amplitude suppression is (a) present in infancy, (b) different in Sibs-Autism versus Sibs-NA, and (c) related to looking to audiovisual speech and language abilities. We collected EEG data from 54 infants aged 12-18 months (29 Sibs-Autism; 25 Sibs-NA) while they viewed videos of audiovisual and auditory-only speech, as well as eye tracking and language data. We found significant amplitude differences at the N2 ERP component in response to audiovisual versus auditory-only speech but no significant group differences in ERP amplitudes. Associations between looking to audiovisual speech, amplitude effects, and language were moderated by group, chronological age, and biological sex. Our findings suggest that differential audiovisual speech processing is present in 12-18-month-olds and may explain heterogeneity in looking to audiovisual speech and emerging language ability.

BackgroundPhelan McDermid syndrome (PMS), caused by SHANK3 haploinsufficiency, is a genetic form of autism spectrum disorder (ASD) that provides a genetically defined model for studying ASD-related circuit dysfunction. SHANK3 mutations disrupt synaptic organization and cortical synchrony, leading to attenuated gamma-band auditory steady-state responses (ASSRs). We investigated whether PMS-related electrophysiological signatures could be identified using machine learning and whether similar patterns are present in a subset of individuals with idiopathic ASD (iASD). MethodsEEG recorded during a 40-Hz ASSR paradigm was collected from 123 participants (42 TD aged 2-30, 56 iASD aged 3-31, 25 PMS aged 2-26). We extracted time-series, ERSP, FOOOF-derived spectral, and intertrial phase coherence (ITPC) features. XGBoost models with leave-one-out cross-validation classified PMS versus TD; the best age/sex-adjusted ITPC model was then applied to iASD participants to derive a Synchrony Atypicality Index (SAI). Unsupervised clustering of high-dimensional ITPC features was also performed. ResultsITPC-based models showed the strongest discrimination between TD and PMS participants (AUROC = 0.83). When applied to iASD participants, 35.7% exhibited elevated SAI, indicating a PMS-like gamma-band phase-locking profile. Classification of iASD versus PMS performed poorly in the full sample but improved markedly after excluding high-SAI iASD individuals, consistent with substantial heterogeneity within iASD. Unsupervised clustering of ITPC features identified PMS-enriched clusters that also captured high-SAI iASD participants. Results were consistent after controlling for age in sensitivity analyses. ConclusionsReduced 40-Hz ITPC is a mechanistically interpretable electrophysiological signature of PMS and identifies a biologically meaningful PMS-like subgroup within iASD, supporting biomarker-guided stratification.

Autism spectrum disorder (ASD) is associated with deficits in synaptic plasticity across brain regions. While striatal dysfunction is observed in various mouse models of ASD, the effect of ASD-associated genes on striatal plasticity has not been well characterised. We previously showed that overexpression of the SFARI ASD risk gene eIF4E in transgenic (eIF4E-TG) mice produces ASD-like behaviours and impairs dorsal striatal dopamine release. Here, we examined whether eIF4E overexpression alters striatal synaptic transmission and plasticity. Using microscopy, whole-cell electrophysiology, optogenetics and fast-scan cyclic voltammetry, we assessed dendritic morphology and excitatory synaptic properties of spiny projection neurons (SPNs). The eIF4E-TG mice exhibited higher dendritic spine density, elevated AMPA and NMDA receptor-mediated mEPSC frequency, and reduced AMPA mEPSC amplitude. We also observed an increased induction rate and magnitude of long-term potentiation (LTP) in SPNs, which is NMDA receptor-dependent but is not prevented by pharmacological D1 or D2 receptor antagonism under the conditions tested. Finally, we found that somatic and dendritic Ca2+ signals evoked by brief depolarisation are altered in SPNs from eIF4E-TG mice. Together, these findings are consistent with eIF4E overexpression promoting an NMDA receptor-dependent form of striatal LTP that is not prevented by D1/D2 receptor antagonism.

Visual processing undergoes rapid refinement in the first year of life, supporting the emergence of higher-order cognitive, language, and motor functions. Visual evoked potentials (VEPs) provide a non-invasive measure of visual system maturation that may shed light on heterogeneous developmental trajectories among infants at high familial likelihood for autism. Infants with an older sibling with autism spectrum disorder (N = 177 at 6 months; N = 132 at 12 months) participated in the Infant Brain Imaging Study-Early Prediction (IBIS-EP) study. Pattern-reversal VEPs were recorded at 6 and 12 months, and developmental skills were assessed at 24 months using the Bayley Scales of Infant and Toddler Development (Bayley-III). VEP components were characterized by P1 amplitude, latency, and trial-to-trial variability in latency. Associations with 24-month cognitive, language, and motor scores were examined using general linear models controlling for age, site, sex, and trial count. Robust VEPs were observed at both timepoints, showing age-appropriate morphology and expected developmental changes, including decreases in P1 latency and amplitude from 6 to 12 months. Greater trial-to-trial variability in P1 latency at both timepoints was significantly associated with higher cognitive and language scores at 24 months. Variability in visual cortical response timing was the strongest neural correlate of developmental skills in infancy. These findings suggest that temporal variability in early neural responses may reflect adaptive sensory circuit flexibility rather than inefficiency, potentially facilitating experience-dependent tuning of visual pathways. VEPs offer a mechanistic window into how developing sensory systems scaffold individual differences in early developmental trajectories. Research HighlightsO_LITrial-to-trial variability in visual cortical response timing predicts cognitive and language outcomes at 24 months in infants at familial likelihood for autism. C_LIO_LIMean P1 latency did not predict outcomes, suggesting variability is a more sensitive early neural marker than average response timing. C_LIO_LIGreater neural response variability in infancy may reflect adaptive sensory circuit flexibility rather than noise or inefficient processing. C_LIO_LIVEP-based biomarkers provide a scalable mechanistic window into how early sensory processing scaffolds cognitive and language development. C_LI

The brain generates predictions to prepare for upcoming events. Because the environment is not perfectly predictable, the brain also estimates the certainty of these predictions and adjusts preparatory processes accordingly. Given that autistic individuals often resist even small changes to everyday routines, we hypothesized altered tuning of prediction certainty in autism. To test this, EEG was recorded from adolescents and young autistic adults (n = 20) and from age- and IQ-matched non-autistic adults (n = 19) during a probabilistic cued target identification task during which cue validity was systematically varied across four levels: 100%, 84%, 67%, and 33%. Participants were not informed of the cue-target validity nor when it changed. We focused on two neural signatures of anticipatory readiness, contingent negative variation (CNV) and alpha-band event-related desynchronization (-ERD), and one of cognitive updating: the P3 to targets and to invalid (e.g., a non-target in place of the target) stimuli. Across groups, preparatory activity increased as contextual certainty decreased, with larger CNV amplitudes and stronger -ERD preceding targets in lower-probability contexts, suggesting enhanced preparatory engagement under greater uncertainty. Furthermore, larger CNV amplitudes predicted faster reaction times, indicating functionally significant anticipatory dynamics. However, modulation of both neural preparation and response times as a function of cue-target probability was significantly reduced in the autistic group. In addition, autistic participants showed diminished probability-dependent modulation of the P3b to both targets and invalid stimuli, and coupling between anticipatory activity (CNV) and subsequent updating (P3b) was observed in non-autistic participants whereas it was absent in autism. Together, these findings suggest that while predictive mechanisms are present in autism, anticipatory processes are less flexibly tuned to contextual uncertainty and less effectively linked to subsequent cognitive updating. This reduced adaptability may reflect difficulty adjusting internal predictive models to changing environmental contingencies, potentially contributing to core features of autism such as resistance to change and insistence on sameness. HighlightsO_LIAnticipatory brain mechanisms (CNV and alpha desynchronization) are present in autism and are behaviorally relevant, predicting faster responses. C_LIO_LIAutistic individuals exhibit reduced modulation of anticipatory CNV and alpha activity as a function of cue-target validity. C_LIO_LIP3b responses to both targets and invalid stimuli show diminished sensitivity to contextual probability in autism, consistent with altered prior updating. C_LIO_LIThe link between anticipatory activity and cognitive updating (i.e., CNV to P3b) is disrupted in autism. C_LIO_LIP3a amplitude to invalid stimuli is reduced in autism, suggesting diminished engagement of violation-sensitive processes. C_LIO_LITogether, findings point to less flexible tuning of predictive mechanisms and reduced adaptation to contextual uncertainty in autism. C_LI

Mutations in the synaptic scaffold protein SHANK3 represent one of the most frequent genetic causes of autism spectrum disorder (ASD), yet the circuit mechanisms through which SHANK3 dysfunction leads to behavioral alterations remain incompletely understood. The anterior insular cortex (aINS) is a key integrative hub involved in socio-emotional processing, anxiety regulation, and social cognition, a group of behaviors frequently disrupted in ASD. Here, we investigated whether selective deletion of SHANK3 signaling in glutamatergic neurons of the aINS is sufficient to produce ASD-relevant behavioral and circuit phenotypes. Using conditional Shank3flox4-22 mice combined with stereotaxic viral delivery of Cre recombinase under the CaMKII promoter, we selectively deleted Shank3 in glutamatergic neurons of the aINS. Behavioral phenotyping revealed increased anxiety-like behavior, enhanced repetitive behavior, and impaired social memory, while sociability and locomotor activity were largely preserved. These behavioral alterations were accompanied by genotype-dependent differences in neuronal activity revealed by calcium imaging, indicating disrupted activity dynamics in insular glutamatergic neurons following Shank3 deletion. To assess the broader relevance of these findings, we evaluated the behavioral profile of BTBR T+ Itpr3tf/J mice, a model of idiopathic ASD, in the same battery of behavioral tests. Several behavioral alterations observed following insular Shank3 deletion partially overlapped with those present in BTBR mice, supporting the relevance of aINS Shank3 in ASD-related phenotypes. Together, these findings identify glutamatergic neurons of the aINS as a critical locus through which Shank3 dysfunction can disrupt socio-emotional, cognitive, and repetitive behaviors. Our results highlight the aINS as a key circuit node contributing to ASD-related behavioral alterations and provide mechanistic insight into how synaptic scaffold disruption leads to circuit dysfunction and produces behavioral alterations.

Atypical sensory experiences are highly prevalent in autistic children and include both hyper- and hypo-responsivity, often accompanied by sensory overload. Alpha oscillations (7-13 Hz), which dynamically regulate cortical excitability, represent a plausible neural mechanism underlying these phenomena: reduced alpha activity is associated with enhanced sensory responsiveness, whereas increased alpha supports suppression of external input. Although decreased alpha power has been repeatedly reported in autism, it remains unclear whether this reduction reflects lower oscillatory amplitude or reduced temporal stability of alpha rhythms, two mechanisms with distinct neurophysiological implications. To better characterize alpha activity in autism, we examined resting-state alpha dynamics in non-autistic children (NA; n = 39), autistic children (AU; n = 52), and siblings of autistic children (SIB; n = 26), aged 8-14 years. We combined traditional broadband measures of relative alpha power, parametric separation of periodic and aperiodic activity, and single-event analyses that quantify the temporal structure of alpha oscillations. Both broadband relative alpha power and periodic alpha power were reduced in autism over parietal regions, replicating prior findings. Importantly, ordinal analyses revealed an intermediate profile in siblings, supporting a liability-related gradient of alpha alterations. However, single-event analyses demonstrated that the average amplitude of individual alpha bursts did not differ between groups. Instead, autistic children showed significantly shorter alpha burst duration and reduced alpha abundance (i.e., proportion of time occupied by rhythmic alpha episodes), with siblings again exhibiting intermediate values. Linear regression analyses confirmed that reductions in relative and periodic alpha power were primarily driven by decreased alpha abundance rather than diminished burst amplitude. These findings indicate that altered alpha activity in autism reflects reduced temporal stability and density of alpha events rather than weaker oscillatory amplitude per se. Reduced persistence of alpha rhythms may therefore represent a neural marker of altered cortical excitability and sensory regulation in autism. Lay summaryAutistic children often experience the world differently at the sensory level, including being more easily overwhelmed by sounds, lights, or other stimuli. In this study, we looked at a type of brain activity called alpha rhythms, which help regulate how strongly the brain responds to incoming information. We found that, in autistic children, these alpha rhythms were not weaker when they occurred, but they lasted for a shorter time and happened less often. Siblings of autistic children showed an intermediate pattern. These results suggest that sensory differences in autism may be linked to less stable brain rhythms that normally help control sensory input. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=158 SRC="FIGDIR/small/716324v1_ufig1.gif" ALT="Figure 1"> View larger version (32K): org.highwire.dtl.DTLVardef@1be733dorg.highwire.dtl.DTLVardef@7fea49org.highwire.dtl.DTLVardef@1ee9124org.highwire.dtl.DTLVardef@17af139_HPS_FORMAT_FIGEXP M_FIG C_FIG

Fragile X Syndrome (FXS) is a leading genetic cause of autism spectrum disorder (ASD) and results from a genetic mutation which silences the expression of Fragile X Messenger Ribonucleoprotein (FMRP). FMRP serves various roles regulating cellular protein synthesis and ion flux. However, a comprehensive comparison of multidimensional elemental balance (i.e., ionome) between FXS genotypes and tissues remains absent from the literature. Here, we measured the multivariate balance of 10 elements (i.e., ionome) in tissues of wild-type and Fmr1-knockout mice to compare ionomic composition of brain and somatic tissues within and across genotypes. We found that homogenized brain tissue including several regions (brain PMHTH; define at first use) differed in elemental balance between genotypes, according to MANOVA. We failed to observe differences between genotypes in the mean ratio of any individual element in PMHTH, but sodium displayed lower variance in knockout than wild-type PMHTH. Knockout striatum displayed lower variance in potassium than wild-type. Knockout olfactory bulbs contained higher mean iron and displayed higher variance in sodium and copper than wild-type. Wild-type feces contained higher mean magnesium and zinc than knockout. These results align with previous work showing FXS pathologies alter electrolytic and metal ion regulation, neuronal excitability, and gastrointestinal function. Further work is needed to identify the source of overall ionomic differences in heterogeneous brain tissue (PMHTH), which could be due to differences among regions. Future work should additionally test how elemental differences relate to function at the cellular level, as well as patterns of individual intake, digestion, assimilation, and/or excretion.

BackgroundAutism spectrum disorder (ASD) is frequently associated with speech and language difficulties, yet empirical data from Central Asian countries remain scarce. This study examined the association between a diagnosis of childhood autism (ICD-10: F84.0) and the presence of speech development difficulties in a clinical sample from Tajikistan MethodA retrospective cross-sectional study was conducted using clinical records of 85 patients (36 with F84.0; 49 with other psychiatric diagnoses) at the Insight Mental Health Center in Dushanbe, Tajikistan (December 2025-January 2026). Speech difficulties were identified through systematic review of clinical notes. Between-group comparisons were performed using Pearsons {chi}2 test, odds ratios (OR), relative risk (RR), and effect size measures ({varphi} coefficient, Cohens h). ResultsSpeech difficulties were present in 72.2% of the autism group versus 36.7% of the comparison group. The association was statistically significant ({chi}2 = 10.47, p <.01). Children with autism had substantially higher odds of speech difficulties (OR = 4.48, 95% CI [1.76, 11.38]), with a large effect size (Cohens h = 0.73). ConclusionsAutism diagnosis was significantly associated with elevated rates of speech difficulties in this Tajik clinical sample. Practical implicationsThese findings support the systematic inclusion of speech-language assessment and intervention within autism care protocols, particularly in Central Asian healthcare settings where such integration remains limited. HighlightsO_LISpeech difficulties were identified in 72.2% of children with autism (F84.0) in a Tajik clinical sample. C_LIO_LIChildren with autism were 4.5 times more likely to present with speech difficulties than those with other diagnoses (OR = 4.48, 95% CI [1.76, 11.38]). C_LIO_LIThe most prevalent speech pattern was complete absence of expressive speech (nonverbal presentation). C_LIO_LIFindings support the integration of speech-language assessment into standard autism care protocols in Central Asia. C_LIO_LIThis is one of the first empirical reports on autism and speech profiles from Tajikistan. C_LI

The causes of severe neuropsychiatric deteriorations among patients with previously stable autism spectrum disorder (ASD) are poorly understood and present substantial challenges for care. We aimed to characterize the prevalence of autoimmune and inflammatory conditions and markers, as well as musculoskeletal findings, among youth with ASD experiencing a suspected post-infectious neuropsychiatric deterioration. The Stanford Immune Behavioral Health (IBH) Clinic is a specialty program for youth with neuropsychiatric deteriorations that are suspected to be post-infectious (non-psychosocial). We report findings for 43 consecutive patients with ASD (70% male [30 of 43]) evaluated in the IBH Clinic. The average (SD) age at clinical presentation was 12.0 (4.0) years. Juvenile arthritis was diagnosed in 15 patients (35%), predominantly enthesitis-related arthritis (ERA) and psoriatic arthritis (PsA). Seven patients had ultrasonographic evidence of joint effusions and/or synovitis without meeting juvenile idiopathic arthritis (JIA) criteria. Autoimmune conditions other than arthritis were observed in 9 patients (21%). The mean (SD) age at arthritis and other autoimmune condition diagnoses were 16.2 (5.5) and 12.7 (4.9) years, respectively. We observe markers of immune activation during neuropsychiatric deteriorations in over half of patients (60% [26 of 43]), including markers of autoimmunity (33% [12 of 36]), complement activation (41% [13 of 32]), immune dysregulation/inflammation (11% [4 of 37]), and vasculopathy (30% [13 of 43]). One-third (37% [16 of 43]) demonstrated two or more markers. These data underscore the importance of targeted immune evaluation--including musculoskeletal imaging and inflammatory marker screening--in ASD patients who have had a suspected post-infectious behavioral regression. Lay SummaryIn this cohort study of 43 patients with autism spectrum disorder (ASD) and suspected post-infectious deteriorations, more than half had laboratory markers of immune activation (using a limited panel), one-third had joint inflammation (confirmed by ultrasound), and additional autoimmune conditions were observed in 21%. From this, we conclude that patients with ASD who experience a suspected post-infectious neuropsychiatric deterioration may have underlying inflammation which may contribute to neuropsychiatric and behavioral regressions, highlighting the importance of immunologic and rheumatologic evaluation in clinical assessment.

Previously we found that female autistic youth (Aut-F) showed reduced brain response in dorsal striatum (putamen) when viewing human motion, alongside larger rare copy number variants that included genes expressed in early striatal development. Thus, striatal differences may characterize Aut-F, but broader systems-level and behavioral implications of these differences remain unexplored. We conducted secondary data analysis of the sex-balanced cohort (8-17y) in which we first discovered these patterns, in order to: 1) understand how functional connectivity between putamen and frontal targets might vary from the non-autistic population, and differ by sex; and 2) explore which brain connectivity and phenotypic features best predicted executive function. Using psychophysiological interaction analysis (N=184), we found that Aut-F youth (n=45) showed reduced functional connectivity between left anterior putamen (Pa) and dorsal premotor cortex/pre-supplementary motor area versus matched non-autistic female peers (NAut-F; n=45), suggesting reduced engagement of a typical Pa-frontal pathway for attentional regulation. Best subsets regression (N=200) indicated that left Pa-left dorsolateral prefrontal functional connectivity explained significant variance in executive functioning across all participants, controlling for neurotype. These results suggest that striatal differences in Aut-F may have adaptive consequences in part due to impacts on connectivity between Pa and frontal regions important for attentional control. Lay summaryWe previously found that female autistic people show differences in a part of the brain called the striatum. Some parts of the striatum connect to the frontal lobe of the brain, and may help people control their attention and behavior. We studied how the striatum "talked to" the frontal lobe in autistic girls. We found out that this communication is lower in autistic than non-autistic girls. We also found out that how much striatum "talks to" frontal lobe helps explain differences in how well both autistic and non-autistic youth of both sexes control their attention and behavior.

PurposeNavigational ability develops throughout childhood alongside the maturation of brain regions supporting egocentric and allocentric processing. In Autism Spectrum Disorder (ASD), atypical hippocampal development may impact flexible spatial memory; however, findings on navigational ability in autistic children remain inconsistent. This study aimed to compare both objective and perceived navigation ability in children with ASD and typically developing (TD) peers. MethodTwenty-six children with high-functioning ASD and twenty-five age- and gender-matched TD children (M_age = 12.04 years, SD = 1.64) completed a battery of navigational tasks from the Spatial Performance Assessment for Cognitive Evaluation (SPACE), including Path Integration, Egocentric Pointing, Mapping, Associative Memory, and Perspective Taking. Perceived navigation ability was assessed using the Santa Barbara Sense of Direction (SBSOD) scale. ResultsNo significant group differences were observed across any objective navigation tasks. However, children with ASD reported significantly lower perceived navigation ability compared to TD peers. ConclusionThese findings suggest a dissociation between perceived and actual navigational ability in ASD. By early adolescence, objective navigation performance appears intact, potentially reflecting sufficient maturation of underlying neural systems or the presence of compensatory mechanisms. The results underscore the importance of incorporating objective, task-based measures when assessing cognitive abilities in autistic populations.

Minimally verbal autistic individuals (mvASD) are often presumed to have severe cognitive and language impairments based on their poor performance on standardized assessments requiring voluntary motor responses, such as pointing. However, emerging evidence suggests that these individuals may possess latent cognitive abilities. Here, we introduce the Cued Looking Paradigm (CLP), a novel eye-tracking method that bypasses motor requirements by capturing automatic gaze responses to language-based stimuli. In our study, 35 minimally verbal autistic adolescents and adults were presented with spoken or written words, followed by a pair of images (target and foil) as their eye movements were recorded. Among mvASD participants with usable eye-tracking data (n = 30), the majority (80%) demonstrated hidden receptive language and reading abilities, as evidenced by eye-gaze measures, including temporal dynamics and spatial displacement, that were comparable to those observed in neurotypical controls. In contrast, the same mvASD individuals averaged only 57% accuracy when asked to read and point to the target picture, revealing a significant gap between reporting via pointing and actual lexical-semantic knowledge. Furthermore, pupil dilation analysis during tasks indicated reduced arousal recruitment in mvASD participants, potentially implicating dysregulation of the locus coeruleus-norepinephrine (LC-NE) system associated with the performance gap between pointing and eye-gaze. These findings challenge assumptions of global intellectual limitation while confirming specific lexical-semantic competence among mvASD individuals. Results highlight the need for, and provide, alternative- assessments that bypass manual motor responses. The CLP shows promise for revealing cognitive and language abilities, with important implications for both research and education. Significance StatementStandard language tests implicitly assume that a person can point or speak. Although minimally verbal individuals can point, this response may not reliably reflect comprehension. Using a simple eye-tracking task that replaces pointing with automatic gaze shifts, we show that most mvASD participants accurately match spoken or written words to pictures--even though they fail the same task when pointing is required. This finding challenges the assumption that absence of speech is typically associated with absence of understanding and reveals bias in common assessments. Tools that bypass manual motor demands by using eye movements, such as the Cued Looking Paradigm, together with changes in assessment and intervention, could transform diagnosis, guide education, and open new research avenues on covert language processing.

The mechanistic role of the third visual pathway in autism spectrum disorder (ASD) remains unknown. We previously developed a neurofeedback therapy for autism targeting the posterior superior temporal sulcus (pSTS), a region in this network that underlies the perception and imagery of emotional facial expressions, resulting in improvements in adaptive behavior and recognition of fear in facial expressions. Here, we investigated the impact of this 5-session therapy on the functional connectivity of that core region of the third visual pathway. We found evidence for a profound reorganization of this network with treatment-induced decreases in connectivity between low-level visual areas, the pSTS, and the posterior occipital face area (OFA), and increased connectivity with higher-level visual regions (fusiform face area - FFA), right middle STS (mSTS), and parietal cortex. These changes, suggesting the restoration of connectivity in regions known to be underconnected in ASD, such as mSTS and pSTS, and in a set of regions belonging to the temporoparietal junction and the ventral attention network, which are known to be involved in broader aspects of social cognition, were positively associated with clinical improvements. The demonstration of treatment response associated with network reconfiguration paves the way for multicentric trials to probe this observed reorganization as a treatment target.