1. Correction: Reasonable adjustments for autistic clinicians: A qualitative study. PLoS One. 2025; 20(5): e0325000.

[This corrects the article DOI: 10.1371/journal.pone.0319082.].

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2. An P, Wang C. Preliminary findings on the different gaze patterns on animal-based and human-based picture books in autistic children. Sci Rep. 2025; 15(1): 17491.

Picture books are commonly used as teaching materials for young children. There is a lack of understanding about how autistic children view picture books, raising the question of the type of picture books suitable for children on the autism spectrum. The current study aimed to investigate gaze characteristics of autistic children compared to non-autistic children when viewing animal- and human-based picture books using eye-tracking technology. Twelve pictures were selected from existing picture books (six animal-based, six human-based). Each picture was presented to participants (29 autistic children, M(age) = 52.32 months, male: female = 25:4; 40 non-autistic children, M(age) = 49.56 months, male: female = 24:16; age range = 42-62 months) in a random sequence. Participants’ gaze data were recorded. Autistic children showed longer time to first fixation, shorter total fixation time, and less fixation points to characters in picture books compared to non-autistic children. Animal versus human characters shortened the time to first fixation in autistic but not non-autistic children. Both groups showed greater attention to socially relevant areas, hands and faces, in animal compared to human picture books. Autistic children showed reduced visual attention during picture book viewing compared to non-autistic children. Animal-based picture books were more effective at attracting and maintaining visual attention to socially relevant areas, suggesting their potential as educational tools for autistic children.

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3. Andrade C. Autism Spectrum Disorder, 2: Observations on the Imprecision of the Numerical Value of Risk when Examining Predictors of Risk in Regression. J Clin Psychiatry. 2025; 86(2).

Hundreds of genes and more than a hundred environmental exposures have been identified as potential causes, mediators, or markers of risk for autism spectrum disorder (ASD). The findings for the environmental exposures, almost all occurring during pregnancy, have emerged from regression analyses in observational studies. The risk estimates are most often presented as odds ratios (ORs), sometimes as hazard ratios (HRs), and rarely as relative risks. This article uses gestational exposure to antidepressant drugs and risk of ASD in offspring as a background to explain how estimates of ASD risk in observational studies are commonly interpreted and why and when the usual interpretations are wrong, often very wrong. The article provides discussions on crude and adjusted estimates, ORs and HRs, individual studies and meta-analyses, strategies that help address confounding by unmeasured and unknown variables, and a detailed discussion on the imprecision of the numerical value of the adjusted estimate. The article explains how the value of an OR is not set in stone; different procedures and approaches in analysis of the same data result in different OR values. The article also explains how to evaluate an individual patient’s risk when multiple risk factors are present that may or may not be independent of each other. Finally, the article suggests the presence of an elephant in the room: risk factors that, though independent, may saturate mechanisms that mediate the outcome; so, when simultaneously present, their individual ORs may suggest falsely lower values of risk. This suggestion could explain why ASD is uncommon in the population although the risk factors for ASD are common and many. It is important to be aware of the issues considered in this article when attempting to understand the field, counsel patients, communicate research findings to peers and the public, and frame policy.

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4. Auer GA, Plener PL, Poustka L, Konicar L. Multi-level treatment outcome evaluation in adolescents with autism spectrum disorder. Child Adolesc Psychiatry Ment Health. 2025; 19(1): 58.

BACKGROUND: Aberrant resting state electroencephalography (rsEEG) is a well-established indicator of psychopathological brain activity in clinical disorders. In Autism Spectrum Disorder (ASD), a substantial body of research reports reduced Alpha activity in the electrocortical resting state of affected individuals. However, effective interventions based on neurophysiological patterns and objective biological markers of treatment outcome remain scarce. METHODS: In this randomized controlled trial, the primary objective was to examine rsEEG changes in adolescents with ASD following 24 sessions of slow cortical potential neurofeedback training (n = 21) compared to a treatment-as-usual control group (n = 20). A repeated-measures analysis of variance was used to assess group differences over time. Additionally, Pearson correlation analyses were conducted to exploratorily investigate associations between rsEEG measures and clinical psychopathology and affective well-being, as assessed via parental and self-report questionnaires at baseline and post-intervention. RESULTS: Analyses revealed significant differences in the development of rsEEG between the intervention groups: while Alpha activity increased in the experimental neurofeedback group, it decreased in the control group, demonstrating an opposite trend. Exploratory analyses showed that Delta activity decreased in both groups, with a more pronounced decrease in the experimental group. Correlational analyses revealed significant associations between subjective-psychological and electrocortical levels: lower alpha power at baseline was related to greater severity of ASD symptoms, while both lower alpha and higher delta power were associated with greater negative affect at baseline. Increases in alpha power after NF-training were linked with enhanced positive affect, whereas reductions in delta power corresponded to decreases in negative affect. CONCLUSIONS: This study provides insights into changes in resting-state neural activity before and after clinical interventions alongside clinical-psychological assessment, overcoming single-level assessments and emphasizing the need for multi-level outcome measures for a more comprehensive treatment evaluation. CLINICAL TRIAL REGISTRATION: DRKS00012339.

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5. Caumes R, Burger P, Mandel JL, Béhal H, Ghoumid J, Smol T. Contribution of families using the GenIDA database to the description of MED13L syndrome and literature review. J Neurodev Disord. 2025; 17(1): 28.

The GenIDA project aims to improve the understanding and management of rare genetic forms of intellectual disability by fostering collaboration among patients, caregivers, healthcare professionals, and research professionals. Clinical data is provided by patients’ families via a structured questionnaire to identify medically relevant insights and better understand the natural history of rare diseases. This study focused on MED13L syndrome, analyzing data from 41 patients in the GenIDA database and comparing it with 102 cases from the scientific literature and 6 new descriptions of patients from our medical center.The GenIDA series confirmed the key features of MED13L syndrome, including global developmental delay, poor speech, intellectual disability, and cardiac defects (OMIM #616789), at frequencies similar to those reported in the literature. The GenIDA series identified a higher prevalence of visual impairment (76%) and highlighted under-recognized musculoskeletal issues, such as foot deformities, which had previously received little attention. This study highlights the value of family-reported data in describing the full phenotype of rare syndromes. A comprehensive review of published cases showed that patients with missense variants have more severe impairments, including increased cardiac defects, global developmental delay, and a higher incidence of epilepsy, than patients with premature truncated variants.These findings highlight the importance of family involvement in rare disease research and the need for further studies to explore genotype-phenotype correlations to improve patient care and outcomes.

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6. Chen SB, Huang CH, Weng SC, Oyang YJ. Detection of pediatric developmental delay with machine learning technologies. PLoS One. 2025; 20(5): e0324204.

OBJECTIVE: Accurate identification of children who will develop delay (DD) is challenging for therapists because recent studies have reported that children who underwent early intervention achieved more favorable outcomes than those who did not. In this study, we have investigated how the frequencies of three types of therapy, namely the physical therapy, the occupational therapy, and the speech therapy, received by a child can be exploited to predict whether the child suffers from DD or not. The effectiveness of the proposed approach is of high interest as these features can be obtained with essentially no cost and therefore a prediction model built accordingly can be employed to screen the subjects who may develop DD before advanced and costly diagnoses are carried out. METHODS: This study has been conducted based on a data set comprising the records of 2,552 outpatients (N = 34,862 visits, mean age = 72.34 months) collected at a hospital in Taiwan from 2012 to 2016. We then built 3 types of machine learning based prediction models, namely the deep neural network models (DNN), the support vector machine (SVM) models, and the decision tree (DT) models, to evaluate the effectiveness of the proposed approach. RESULTS: Experimental results reveal that in terms of the F1 score, which is the harmonic mean of the sensitivity and the positive predictive value, the DT models outperformed the DNN models and the SVM models, if a high level of sensitivity is desired. In particular, the DT model developed in this study delivered the sensitivity at 0.902 and the positive predictive value at 0.723. CONCLUSIONS: What has been learned from this study is that the frequencies of the therapies that a child has received provide valuable information for predicting whether the child suffers from DD. Due to the performance observed in the experiments and the fact that these features can be obtained essentially without any cost, it is conceivable that the prediction models built accordingly can be wide exploited in clinical practices and significantly improve the treatment outcomes of the children who develop DD.

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7. Davison KE, Liu T, Belisle RM, Perrachione TK, Qi Z, Gabrieli JDE, Tager-Flusberg H, Zuk J. Right-Hemispheric White Matter Organization Is Associated With Speech Timing in Autistic Children. J Speech Lang Hear Res. 2025: 1-15.

PURPOSE: Converging research suggests that speech timing, including altered rate and pausing when speaking, can distinguish autistic individuals from nonautistic peers. Although speech timing can impact effective social communication, it remains unclear what mechanisms underlie individual differences in speech timing in autism. METHOD: The present study examined the organization of speech- and language-related neural pathways in relation to speech timing in autistic and nonautistic children (24 autistic children, 24 nonautistic children [ages: 5-17 years]). Audio recordings from a naturalistic language sampling task (via narrative generation) were transcribed to extract speech timing features (speech rate, pause duration). White matter organization (as indicated by fractional anisotropy [FA]) was estimated for key tracts bilaterally (arcuate fasciculus, superior longitudinal fasciculus [SLF], inferior longitudinal fasciculus [ILF], frontal aslant tract [FAT]). RESULTS: Results indicate associations between speech timing and right-hemispheric white matter organization (FA in the right ILF and FAT) were specific to autistic children and not observed among nonautistic controls. Among nonautistic children, associations with speech timing were specific to the left hemisphere (FA in the left SLF). CONCLUSION: Overall, these findings enhance understanding of the neural architecture influencing speech timing in autistic children and, thus, carry implications for understanding potential neural mechanisms underlying speech timing differences in autism. SUPPLEMENTAL MATERIAL: https://doi.org/10.23641/asha.28934432.

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8. Guo Q, Kouyama-Suzuki E, Shirai Y, Tabuchi K. Jun N-Terminal Kinase Inhibitor Suppresses CASK Deficiency-Induced Cerebellar Granular Cell Death in MICPCH Syndrome Model Mice. Cells. 2025; 14(10).

Microcephaly with pontine and cerebellar hypoplasia (MICPCH) syndrome is a severe neurodevelopmental disorder caused by a deficiency in the X-linked gene calcium/calmodulin-dependent serine protein kinase (CASK). A better understanding of the role of CASK in the pathophysiology of neurodevelopmental disorders may provide insights into novel therapeutic and diagnostic strategies for MICPCH syndrome and other neurodegenerative diseases. To investigate this, we generated CASK knockout (KO) cerebellar granule (CG) cell culture from CASK floxed (CASK(flox/flox)) mice by infecting lentiviruses expressing codon-improved Cre recombinase (iCre). We performed RNA-sequencing (RNA-seq) on these cells and found that CASK-KO CG cells underwent apoptosis by activating intracellular Jun N-terminal kinase (JNK) signaling and upregulating reactive oxygen species (ROS)-related gene expression. We also performed mouse gait analysis and limb clasping behavior experiments on trans-heterozygous CASK-KO and Hprt-eGFP (CASK(+/-) Hprt(eGFP/+)) mice. The CASK(+/-) Hprt(eGFP/+) mice exhibited cerebellar ataxic phenotypes as judged by the scores of these experiments compared to the CASK wild-type control (CASK(+/+) Hprt(eGFP/+)) mice. Interestingly, the administration of the JNK inhibitor, JNK-IN-8, in CASK-KO CG cell cultures increased CG cell survival by reducing ROS generation. Moreover, injection of JNK-IN-8 into the cerebellum of CASK(+/-) Hprt(eGFP/+) mice suppressed CG cell death and alleviated cerebellar ataxic phenotypes in vivo. In conclusion, JNK-IN-8 suppresses the cell death and activation of the ROS pathway in CASK-KO CG cells in both in vitro and in vivo models, suggesting its potential as a therapeutic strategy for cerebellar neurodegeneration in MICPCH syndrome.

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9. Hammond AW, Morris JR, Gabrielsen T, Smith TB, Medsker N. A systematic review of digital activity schedule use in individuals with autism spectrum disorder and intellectual disability. J Intellect Dev Disabil. 2025: 1-15.

BACKGROUND: This systematic review examined the effectiveness of digital activity schedules as an intervention for individuals with autism spectrum disorder (ASD) or intellectual disability. METHOD: To be included, studies had to use a digitally presented activity schedule, excluding task analyses of single activities or group visual schedules, and the intervention must involve individuals with ASD or intellectual disability as the participants. RESULTS: Seventeen studies met the criteria, involving 58 participants, and focused on leisure, independent living, and academic skills across different age groups, with 82% reporting fidelity of implementation. CONCLUSION: The review found that most interventions were concentrated in early childhood, primarily aimed at teaching leisure activities, and often combined with other concurrent interventions. The settings, participant ages, and interventions varied, with 41% meeting What Works Clearinghouse quality indicators. Future research should focus on interventions implemented in secondary education and independent living skills, with more rigorous methodological standards.

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10. Huang Z, Li Y, Bucci V, Haran JP. Decoding cancer prognosis with deep learning: the ASD-cancer framework for tumor microenvironment analysis. mSystems. 2025; 10(5): e0145524.

Deep learning is revolutionizing biomedical research by facilitating the integration of multi-omics data sets while bridging classical bioinformatics with existing knowledge. Building on this powerful potential, Zhang et al. proposed a semi-supervised learning framework called Autoencoder-Based Subtypes Detector for Cancer (ASD-cancer) to improve the multi-omics data analysis (H. Zhang, X. Xiong, M. Cheng, et al., 2024, mSystems 9:e01395-24, https://doi.org/10.1128/msystems.01395-24). By utilizing autoencoders pre-trained on The Cancer Genome Atlas data, the ASD-cancer framework outperforms the baseline model. This approach also makes the framework scalable, enabling it to process new data sets through transfer learning without retraining. This commentary explores the methodological innovations and scalability of ASD-cancer while suggesting future directions, such as the incorporation of additional data layers and the development of adaptive AI models through continuous learning. Notably, integrating large language models into ASD-cancer could enhance its interpretability, providing more profound insights into oncological research and increasing its influence in cancer subtyping and further analysis.

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11. Kang J, Haslam N, Conway M. Converging Representations of Attention-Deficit/Hyperactivity Disorder and Autism on Social Media: Linguistic and Topic Analysis of Trends in Reddit Data. J Med Internet Res. 2025; 27: e70914.

BACKGROUND: Social media platforms have witnessed a substantial increase in mental health-related discussions, with particular attention focused on attention-deficit/hyperactivity disorder (ADHD) and autism. This heightened interest coincides with growing neurodiversity advocacy. The impact of these changes in the conceptualization of ADHD and autism, and the relationship between the 2 conditions, remains underexplored. OBJECTIVE: We aim to characterize and understand how the relationship between ADHD and autism has evolved in public discourse over the past decade and explore reasons for their growing alignment. METHODS: Using Reddit data from 2012 to 2022, we investigated the frequency of ADHD mentions in r/autism and autism mentions in r/ADHD, compared to commonly mentioned conditions. We analyzed user overlap between the 2 subreddits to track cross-subreddit discussions. Following this, we assessed changes in semantic similarity between ADHD and autism using Word2Vec embedding models, alongside commonly mentioned conditions. Finally, thematic changes in subreddit discussions were explored using BERT-based topic modeling across 2 time periods. RESULTS: Our analysis revealed that ADHD and autism have become progressively more associated across these multiple dimensions. In r/ADHD, there was a steep rise in the proportion of posts mentioning « autism » in 2021, overtaking « bipolar » and « OCD » (obsessive-compulsive disorder) to become the most frequently mentioned condition. Similarly, ADHD mentions increased steadily in r/autism, while the frequency of posts mentioning « OCD, » « PTSD » (posttraumatic stress disorder), and « bipolar » remained stable and low. User overlap between these subreddits grew substantially beginning in 2020. Semantic analysis showed ADHD and autism becoming more closely related from 2019 onward, compared to other conditions. Last, topic modeling indicated growing thematic convergence in ADHD- and autism-related discussions, which reflected an increasing shared emphasis on the experiences of adults with ADHD and autism, challenges in accessing diagnostic assessments, and interpersonal difficulties. CONCLUSIONS: Our study clarifies how discourse around these 2 conditions has converged during a period when they have both attracted rising public attention. These findings contribute to wider discussions about the impacts of rising public interest in mental health concepts. They illustrate that public understandings of relationships between conditions are dynamic and changing in ways that diverge from diagnostic frameworks. Future research should continue investigating changing mental health conceptualizations on social media, as these dynamics are becoming increasingly important for the future of psychiatric practice.

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12. Li JL, Washington-Nortey M, Kifle TH, Cotier F, Hoekstra RA. The Role of Extended Family Members in the Lives of Autistic Individuals and Their Parents: A Systematic Review and Meta-Synthesis. Clin Child Fam Psychol Rev. 2025.

Extended family members play an important role in meeting the care needs of autistic individuals, yet family support policies and practices often overlook this role. We aimed to synthesise qualitative research on the role played by extended family members in the lives of autistic individuals and their parents and identify cultural patterns. We searched eight databases and selected relevant studies through a two-stage screening process. We synthesised the results and discussions described in the selected studies using template analysis. The review included 42 studies (40 qualitative; 2 mixed methods), reporting on 1048 parents and 2140 grandparents. While aunts, uncles, and cousins were not direct participants, their roles were described in participants’ narratives. Three main themes were developed: (1) types of support from extended family members, including emotional, financial, instrumental, and informational support; (2) unhelpful or lack of support from extended family members, including misunderstanding about autism, absence of support with caregiving, and negative attitudes and discriminatory behaviours against autistic individuals as well as their parents; (3) factors influencing the role of extended family members, including individuals, family unit, family interaction characteristics, and a journey towards acceptance and cultural influences. Novel findings on the influence of culture suggested in cultures highly valuing family interdependence, extended relatives play a more prominent support role, yet the emphasis on family reputation might hinder the acceptance of autism by extended relatives. Based on a family systems approach, we recommend priorities for intervention development and clinical practice to support the effective involvement of extended family members.

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13. Nagajothi N, Jauregui R, Grossman SN. Multiple Hypovitaminoses Presenting as Optic Disc Swelling in a Child with Autism Spectrum Disorder and Restrictive Eating. J Child Neurol. 2025: 8830738251339570.

Optic disc swelling, frequently associated with vitamin A toxicity, is infrequently linked to vitamin A deficiency. This report describes a 6-year-old male with autism spectrum disorder (ASD) and avoidant restrictive food intake disorder who presented with xerophthalmia, optic disc swelling, vision changes, and deficiencies in vitamins A, B(1), and iron. The patient’s behavioral dysregulation posed important challenges for the evaluation, diagnosis, and treatment of his hypovitaminoses. This case underscores the importance of considering multiple nutritional deficiencies as the etiology of optic disc swelling in pediatric populations with autism spectrum disorder and avoidant restrictive food intake disorder, diagnoses that have increased in frequency. Early recognition and intervention can prevent further complications such as visual loss and improve outcomes.

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14. Nosratiyan N, Hamzeh O, Ghasemi-Kasman M. Plumbagin Alleviates Social Behavior Deficits in a Valproic Acid Model of Autism by Reducing Glial Activation and Oxidative Stress in the Cerebellum. Neurochem Res. 2025; 50(3): 168.

Autism spectrum disorder (ASD) is a neurodevelopmental disorder that affects multiple brain regions, including the cerebellum. It is characterized by behavioral alterations that significantly impact various aspects of patients’ lives. The present study was conducted to examine the anti-inflammatory, antioxidant, and neuromodulatory activities of plumbagin (PLB) in a valproic acid (VPA)-induced autism model. Pregnant rats received an intraperitoneal (i.p.) injection of VPA (600 mg/kg) on day 12.5 of pregnancy. After birth, offspring were orally administered different doses of PLB (0.25, 0.5, and 1 mg/kg) from days 7 to 35. Social interaction and preference were assessed via a three-chamber social assay. Hematoxylin‒eosin (H&E) staining was performed to observe histopathological changes in the cerebellum. Moreover, astrocyte and microglial activation were evaluated by immunostaining. The gene expression levels of Nrf2, HO-1, BDNF, SIRT1, IL-6, IL-1β, TNF-α, and TGF-β1 were evaluated via quantitative real-time PCR (qRT‒PCR). These findings revealed that PLB treatment significantly alleviates social impairments. PLB ameliorated the loss of Purkinje cells and the number of activated astrocytes and microglia in the cerebellum. PLB administration also upregulated the gene expression of Nrf2, HO-1, BDNF, SIRT1, and TGF-β1 and downregulated the IL-6 expression level. Overall, it seems that PLB diminishes autism-related damage in the cerebellum through neuromodulatory activities and attenuation of oxidative stress and inflammation.

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15. Onat M, Mert Kılıç DES, Nas Ünver AB, Özyurt G, Şenses Dinç G, Çöp E. The relationship between autistic traits, social media addiction, and loneliness in adolescents with ADHD. Pediatr Int. 2025; 67(1): e70064.

BACKGROUND: Our study aims to investigate the relationship between autistic traits, social media addiction, and loneliness among adolescents diagnosed with attention-deficit/hyperactivity disorder (ADHD) and to compare our findings with healthy controls. METHODS: A total of 90 adolescents aged 14-18 years, 50 of them diagnosed with ADHD and 40 healthy controls, were included in our study. Adolescents participating in our study were evaluated with the Conners’ Parent Rating Scale-Revised: Short Form (CPRS-R:S), the Autism Spectrum Quotient-Adolescent Version (AQ-Adolescent), the 9-item Social Media Disorder Scale (SMD) and the UCLA Loneliness Scale Short Form (ULS-8). The SPSS 25.0 program was used in the analysis. p < 0.05 was accepted as the significance level. RESULTS: It is found that adolescents diagnosed with ADHD had statistically significantly higher scores on the communication, social skill, imagination, attention switching subscales, and total score of the AQ-Adolescent compared to healthy controls. Moreover, adolescents diagnosed with ADHD obtained statistically significantly higher scores from the SMD and the ULS-8 compared to healthy controls. The ULS-8 showed a significant positive correlation with the AQ-Adolescent and the SMD in the ADHD group. It was also found that only loneliness may be associated with the risk of developing social media addiction in adolescents with ADHD. CONCLUSIONS: The results of our study indicate that adolescents diagnosed with ADHD are susceptible to encountering challenges regarding social difficulties, feelings of loneliness, and social media addiction. It is believed that it may be essential to address these factors when dealing with social media addiction, which is prevalent among adolescents diagnosed with ADHD.

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16. Oxtoby K. The consultant anaesthetist who established a support group for autistic doctors. Bmj. 2025; 389: r784.

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17. Pedapati EV, Ethridge LE, Liu Y, Liu R, Sweeney JA, DeStefano LA, Miyakoshi M, Razak K, Schmitt LM, Moore DR, Gilbert DL, Wu SW, Smith E, Shaffer RC, Dominick KC, Horn PS, Binder D, Erickson CA. Frontal cortex hyperactivation and gamma desynchrony in Fragile X syndrome: Correlates of auditory hypersensitivity. PLoS One. 2025; 20(5): e0306157.

Fragile X syndrome (FXS) is an X-linked disorder that often leads to intellectual disability, anxiety, and sensory hypersensitivity. While sound sensitivity (hyperacusis) is a distressing symptom in FXS, its neural basis is not well understood. It is postulated that hyperacusis may stem from temporal lobe hyperexcitability or dysregulation in top-down modulation. Studying the neural mechanisms underlying sound sensitivity in FXS using scalp electroencephalography (EEG) is challenging because the temporal and frontal regions have overlapping neural projections that are difficult to differentiate. To overcome this challenge, we conducted EEG source analysis on a group of 36 individuals with FXS and 39 matched healthy controls. Our goal was to characterize the spatial and temporal properties of the response to an auditory chirp stimulus. Our results showed that males with FXS exhibit excessive activation in the frontal cortex in response to the stimulus onset, which may reflect changes in top-down modulation of auditory processing. Additionally, during the chirp stimulus, individuals with FXS demonstrated a reduction in typical gamma phase synchrony, along with an increase in asynchronous gamma power, across multiple regions, most strongly in the temporal cortex. Consistent with these findings, we observed a decrease in the signal-to-noise ratio, estimated by the ratio of synchronous to asynchronous gamma activity, in individuals with FXS. Furthermore, this ratio was highly correlated with performance in an auditory attention task. Compared to controls, males with FXS demonstrated elevated bidirectional frontotemporal information flow at chirp onset. The evidence indicates that both temporal lobe hyperexcitability and disruptions in top-down regulation play a role in auditory sensitivity disturbances in FXS. These findings have the potential to guide the development of therapeutic targets and back-translation strategies.

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18. Pretorius L, Coetzee JA, Santos APD, Smith C. Modulating autism spectrum disorder pathophysiology using a trace amine-focused approach: targeting the gut. Mol Med. 2025; 31(1): 198.

Autism spectrum disorder (ASD) affects approximately 1% of the population directly, but also a much higher proportion (family and caregivers) indirectly. Although ASD is characterized by high prevalence of anxiety and poor gastrointestinal health, current treatment strategies are mainly focused on neurological symptomatic treatment, with little to no attention to gut health. Furthermore, many psychiatric drugs used for management of secondary neurological symptoms, are known to exacerbate gut health issues and neurological dysregulation across the gut-brain axis.Trace amines are neurotransmitter-like substances synthesized endogenously in the human brain – in trace amounts – but also in high abundance by the microbiome. Emerging evidence suggests dysregulation of the trace amine system in ASD. Since trace aminergic signalling is central to regulatory system homeostasis, we hypothesize targeting this system in the ASD context. Given the various sources of trace amines, we suggest that normalization of functional dysbiosis in terms of trace aminergic signalling – rather than microbial compositional dysbiosis – should be a focus in medicines development. In addition, a holistic consideration including also other factors at play in determining trace aminergic signalling outcome – such as receptor binding, enzymatic role players, etc. – is required to fully elucidate and therapeutically modify the pathophysiology of regulatory systems implicated in ASD.This review firstly provides a brief overview of trace amine dysregulation in ASD for context. Secondly, we formulate our hypothesis on how this may therapeutically address symptomology, with consideration of cellular and molecular mechanism interplay across the gut-brain axis. Finally, we provide a critical assessment of advances in therapeutics development and drug re-purposing, gaps in knowledge and priorities for medicines development going forward.

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19. Si Y, Zhang H, Du L, Deng Z. Abnormalities of brain dynamics based on large-scale cortical network modeling in autism spectrum disorder. Neural Netw. 2025; 189: 107561.

Synaptic increase is a common phenomenon in the brain of autism spectrum disorder (ASD). However, the impact of increased synapses on the neurophysiological activity of ASD remains unclear. To address this, we propose a large-scale cortical network model based on empirical structural connectivity data using the Wendling model, which successfully simulates both pathological and physiological electroencephalography (EEG) signals. Building on this, the EEG functional network is constructed using the phase lag index, effectively characterizing the functional connectivity. Our modeling results indicate that EEG activity and functional network properties undergo significant changes by globally increasing synaptic coupling strength. Specifically, it leads to abnormal neural oscillations clinically reported in ASD, including the decreased dominant frequency, the decreased relative power in the α band and the increased relative power in the δ+θ band, particularly in the frontal lobe. At the same time, the clustering coefficient and global efficiency of the functional network decrease, while the characteristic path length increases, suggesting that the functional network of ASD is inefficient and poorly integrated. Additionally, we find insufficient functional connectivity across multiple brain regions in ASD, along with decreased wavelet coherence in the α band within the frontal lobe and between the frontal and temporal lobes. Considering that most of the synaptic increases in ASD are limited, brain regions are further randomly selected to increase the local synaptic coupling strength. The results show that disturbances in local brain regions can also facilitate the development of ASD. This study reveals the intrinsic link between synapse increase and abnormal brain activity in ASD, and inspires treatments related to synapse pruning.

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20. Wang BM, Mills Z, Jones HF, Montgomery JM, Lee KY. Presymptomatic Biological, Structural, and Functional Diagnostic Biomarkers of Autism Spectrum Disorder. J Neurochem. 2025; 169(5): e70088.

Autism spectrum disorder (ASD) is a common neurodevelopmental disorder clinically diagnosed by persistent deficits in three areas of social communication and interaction, plus at least two of four types of restricted repetitive behaviors. ASD has been shown to be caused by genetic predisposition and environmental factors; however, the heterogeneity of ASD complicates its diagnosis and treatment. Early behavioral interventions have shown significant benefits, emphasizing the urgent need for reliable diagnostic biomarkers to enhance long-term outcomes. Here we provide a systematic review that outlines current findings on genetic and neurological biomarkers for presymptomatic ASD diagnoses, assessed prior to the observation of behavioral manifestations. Specifically, we offer insights into the mechanisms of presymptomatic neurological, biological, structural, and functional markers for ASD, compare outcomes across studies, and critically assess their limitations and implications. Recent findings highlight genotype-guided therapeutic strategies in animal models, such as dietary zinc supplementation for reversing ASD-associated behaviors by synaptic deficits. However, the differential efficacy based on underlying genotypes, along with challenges in identifying reliable genomic biomarkers prior to symptom onset, indicates the need for further research. Notably, recent advancements in imaging technologies like magnetic resonance imaging, electroencephalography, and pupillometry have shown promising markers in neonates, and at 3 and 9 months old, respectively. Newer developments in magnetoencephalography hardware can facilitate the much-needed infant ASD studies. It is important to note that many of these biomarker findings are preliminary, and further validation for clinical use is required. Continued research is needed to advance the practicality, reliability, and acceptability of these biomarkers to improve ASD diagnosis and treatment strategies.

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21. Xia J, Bajpai AK, Liu Y, Yu L, Dong Y, Li F, Chen F, Lu L, Feng S. Systems Genetics Reveals the Gene Regulatory Mechanisms of Arrb2 in the Development of Autism Spectrum Disorders. Genes (Basel). 2025; 16(5).

BACKGROUND: Autism spectrum disorder (ASD) involves complex interactions between genetic and environmental factors. Recent studies suggest that dysregulation of β-arrestin2 (Arrb2) in the central nervous system is linked to ASD. However, its specific mechanisms remain unknown. METHODS: This study employs a systems genetics approach to comprehensively investigate Arrb2 in multiple brain tissues, including the amygdala, cerebellum, hippocampus, and prefrontal cortex, using BXD recombinant inbred (RI) strains. In addition, genetic variance analysis, correlation analysis, expression quantitative trait loci (eQTL) mapping, and functional annotation were used to identify the key downstream targets of Arrb2, validated by quantitative reverse transcription polymerase chain reaction (qRT-PCR) and Western blotting (WB). RESULTS: Arrb2 exhibited expression variations across the four brain regions in BXD mice. eQTL mapping revealed that Arrb2 is cis-regulated, and increased Arrb2 expression levels were significantly correlated with ASD-like symptoms, such as impaired social interactions and abnormal learning and memory. Furthermore, protein-protein interaction (PPI) network analysis, tissue correlation, functional relevance to autism, and differential expression identified eight downstream candidate genes regulated by Arrb2. The experimental results demonstrated that deletion of Arrb2 led to the downregulation of Myh9, Dnmt1, and Brd4 expression, along with protein kinase A (PKA)-induced hyperactivation of Synapsin I. These findings suggest that Arrb2 may contribute to the pathogenesis of autism by modulating the expression of these genes. CONCLUSIONS: This study highlights the role of Arrb2 in ASD pathogenesis and identifies Myh9, Dnmt1, and Brd4 as key downstream regulators. These findings provide new insights into the molecular mechanisms of ASD and pave the way for novel therapeutic targets.

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