1. Anderson C, Wood CI, Franklin L, Iampieri A, Sarsony C. « Getting Autism »: Educators, Parents, and Autistic Adults and Teens Reflect on the Importance of Teachers Who Understand. J Autism Dev Disord;2024 (May 14)

PURPOSE: To explore the perspectives of educators, parents, and individuals on the autism spectrum regarding the qualities of teachers best equipped to support autistic students. METHODS: In qualitative interviews parents of autistic adults (n = 35) discussed experiences they and their child faced during the school years, as did young autistic adults (n = 12) and teens (n = 11). Nineteen educators were also interviewed regarding how autistic students and their teachers were faring in public schools as well as what qualities and skills teachers needed to best support these students. RESULTS: A critical emergent theme was the importance of educators who possess a deep, intuitive understanding of autistic individuals. « Getting autism » involved autism knowledge, obtained through training or experience; an intuitive ability to read, respond to, and appreciate autistic students; and flexibility adapting to these students’ needs. Autistic students, parents, and educators alike experienced a stigmatizing judgement and lack of support from unenlightened individuals in the schools. In contrast, there was great appreciation for those who « got autism » and were able to ease the way of autistic students, or support autism-friendly teachers, in whatever grade or situation. CONCLUSION: Research investigating how to cultivate, support, and reward autism-affirming teachers is needed. This will likely involve both didactic and experiential autism-focused training as well as recognition of the importance of high emotional intelligence and other qualities of teachers who « get autism. » Future research should also explore the effects on these teachers and their students of larger systems, policies, and practices.

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2. Anderson JT, Toolan C, Coker E, Singer H, Pham D, Jackson N, Lord C, Wilson RB. A novel dance intervention program for children and adolescents with developmental disabilities: a pilot randomized control trial. BMC Sports Sci Med Rehabil;2024 (May 14);16(1):109.

BACKGROUND: Organized physical activity programs have been shown to provide wide benefits to participants, though there are relatively few studies examining the impact of these programs for individuals with developmental disabilities. This pilot study was conducted to determine the feasibility and impact of an undergraduate-led dance intervention program for children and adolescents with developmental disabilities. We evaluated the impact of the dance program on motor ability and social skills. METHODS: The study design was a waitlist control clinical trial in which participants were randomized to active and control groups. Eligible participants included male and female children and adolescents between the ages of 4 and 17 years with neurodevelopmental disabilities. The Motor Assessment Battery for Children Checklist and the Social Responsiveness Scale were used to assess change in motor and social skills, respectively. After gathering baseline data, the active group completed 1 h of online dance classes per week for 10 weeks, while the control group entered a 10-week waiting period. All participants then returned for a follow-up visit. Pre- and post-intervention data were analyzed using linear mixed-effects modeling adjusting for age and class attendance with subject random intercept. RESULTS: We recruited and randomized 43 participants with neurodevelopmental disabilities (mean age = 8.63, SD = 2.98), of which 30 participated in dance classes. The attendance rate was 82.6% for the active group and 61.7% for the control group. The active group demonstrated a significant improvement in motor skills in an unpredictable environment, as indicated on the Motor Assessment Battery for Children Checklist (n = 21, p = 0.05). We also observed positive trends in social skills that did not reach significance. CONCLUSIONS: Our results indicate that it is feasible to develop and implement a fully digital dance intervention program for individuals with developmental disabilities. Further, we find that change in motor skills can be detected after just 10 h of low-intensity participation. However, a lack of significant change in social skills coupled with limitations in study implementation suggests further research is needed to determine the full impact of this dance program. TRIAL REGISTRATION: ClinicalTrials.gov Protocol Registration System: Protocol ID 20-001680-AM-00005, registered 17/2/2021 – Retrospectively Registered, https://clinicaltrials.gov/study/NCT04762290 .

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3. Bettoni R, Cantiani C, Riboldi EM, Molteni M, Bulf H, Riva V. Visual statistical learning in preverbal infants at a higher likelihood of autism and its association with later social communication skills. PLoS One;2024;19(5):e0300274.

Visual statistical Learning (SL) allows infants to extract the statistical relationships embedded in a sequence of elements. SL plays a crucial role in language and communication competencies and has been found to be impacted in Autism Spectrum Disorder (ASD). This study aims to investigate visual SL in infants at higher likelihood of developing ASD (HL-ASD) and its predictive value on autistic-related traits at 24-36 months. At 6 months of age, SL was tested using a visual habituation task in HL-ASD and neurotypical (NT) infants. All infants were habituated to a visual sequence of shapes containing statistically predictable patterns. In the test phase, infants viewed the statistically structured, familiar sequence in alternation with a novel sequence that did not contain any statistical information. HL-ASD infants were then evaluated at 24-36 months to investigate the associations between visual SL and ASD-related traits. Our results showed that NT infants were able to learn the statistical structure embedded in the visual sequences, while HL-ASD infants showed different learning patterns. A regression analysis revealed that SL ability in 6-month-old HL-ASD infants was related to social communication and interaction abilities at 24-36 months of age. These findings indicate that early differences in learning visual statistical patterns might contribute to later social communication skills.

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4. Blank E, Gilbert DL, Wu SW, Larsh T, Elmaghraby R, Liu R, Smith E, Westerkamp G, Liu Y, Horn PS, Greenstein E, Sweeney JA, Erickson CA, Pedapati EV. Accelerated Theta Burst Transcranial Magnetic Stimulation for Refractory Depression in Autism Spectrum Disorder. J Autism Dev Disord;2024 (May 15)

PURPOSE: Major depressive disorder (MDD) disproportionately affects those living with autism spectrum disorder (ASD) and is associated with significant impairment and treatment recidivism. METHODS: We studied the use of accelerated theta burst stimulation (ATBS) for the treatment of refractory MDD in ASD (3 treatments daily x 10 days). This prospective open-label 12-week trial included 10 subjects with a mean age of 21.5 years, randomized to receive unilateral or bilateral stimulation of the dorsolateral prefrontal cortex. RESULTS: One participant dropped out of the study due to intolerability. In both treatment arms, depressive symptoms, scored on the Hamilton Depression Rating Scale scores, diminished substantially. At 12 weeks post-treatment, full remission was sustained in 5 subjects and partial remission in 3 subjects. Treatment with ATBS, regardless of the site of stimulation, was associated with a significant, substantial, and sustained improvement in depressive symptomatology via the primary outcome measure, the Hamilton Depression Rating Scale. Additional secondary measures, including self-report depression scales, fluid cognition, and sleep quality, also showed significant improvement. No serious adverse events occurred during the study. Mild transient headaches were infrequently reported, which are expected side effects of ATBS. CONCLUSION: Overall, ATBS treatment was highly effective and well-tolerated in individuals with ASD and co-occurring MDD. The findings support the need for a larger, sham-controlled randomized controlled trial to further evaluate efficacy of ATBS in this population.

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5. Boulton KA, Lee D, Honan I, Phillips NL, Morgan C, Crowle C, Novak I, Badawi N, Guastella AJ. Exploring early life social and executive function development in infants and risk for autism: a prospective cohort study protocol of NICU graduates and infants at risk for cerebral palsy. BMC Psychiatry;2024 (May 14);24(1):359.

BACKGROUND: Delays in early social and executive function are predictive of later developmental delays and eventual neurodevelopmental diagnoses. There is limited research examining such markers in the first year of life. High-risk infant groups commonly present with a range of neurodevelopmental challenges, including social and executive function delays, and show higher rates of autism diagnoses later in life. For example, it has been estimated that up to 30% of infants diagnosed with cerebral palsy (CP) will go on to be diagnosed with autism later in life. METHODS: This article presents a protocol of a prospective longitudinal study. The primary aim of this study is to identify early life markers of delay in social and executive function in high-risk infants at the earliest point in time, and to explore how these markers may relate to the increased risk for social and executive delay, and risk of autism, later in life. High-risk infants will include Neonatal Intensive Care Unit (NICU) graduates, who are most commonly admitted for premature birth and/or cardiovascular problems. In addition, we will include infants with, or at risk for, CP. This prospective study will recruit 100 high-risk infants at the age of 3-12 months old and will track social and executive function across the first 2 years of their life, when infants are 3-7, 8-12, 18 and 24 months old. A multi-modal approach will be adopted by tracking the early development of social and executive function using behavioural, neurobiological, and caregiver-reported everyday functioning markers. Data will be analysed to assess the relationship between the early markers, measured from as early as 3-7 months of age, and the social and executive function as well as the autism outcomes measured at 24 months. DISCUSSION: This study has the potential to promote the earliest detection and intervention opportunities for social and executive function difficulties as well as risk for autism in NICU graduates and/or infants with, or at risk for, CP. The findings of this study will also expand our understanding of the early emergence of autism across a wider range of at-risk groups.

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6. Carruthers S, Charman T, Leadbitter K, Ellis C, Taylor L, Moore H, Taylor C, James K, Balabanovska M, Langhorne S, Aldred C, Slonims V, Grahame V, Howlin P, McConachie H, Parr J, Emsley R, Le Couteur A, Green J, Pickles A. Generalisation of Social Communication Skills by Autistic Children During Play-Based Assessments Across Home, School and an Unfamiliar Research Setting. J Autism Dev Disord;2024 (May 14)

We investigated autistic children’s generalisation of social communication over time across three settings during a play-based assessment with different adults and explore the potential moderating effects on generalisation of age, nonverbal IQ and level of restricted and repetitive behaviours. The social communication abilities of 248 autistic children (2-11 years, 21% female, 22% single parent, 60% white) from three UK sites were assessed from 1984 video interactions in three contexts with three different interaction partners (parent/home, teaching assistant/school, researcher/clinic) at baseline, midpoint (+ 7m) and endpoint (+ 12m) within the Paediatric Autism Communication Trial-Generalised (PACT-G), a parent-mediated social communication intervention. Children’s midpoint social communication at home generalised to school at midpoint and to clinic at endpoint. Generalisation was stronger from home to school and clinic than school to home and clinic. Generalisation was not moderated by age, nonverbal IQ or restricted and repetitive behaviour. Broader child development did not explain the pattern of results. The current study is the largest study to date to explore generalisation with autistic children and provides novel insight into their generalisation of social communication skills. Further research is needed to gain a more comprehensive understanding of facilitators of generalisation across settings and interaction partners in order to develop targeted strategies for interventions to enhance outcomes for young autistic children.

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7. Collins KA, Recchia N, Eng GK, Harvey JR, Tobe RH, Stern ER. Sensory over-responsivity and orbitofrontal cortex connectivity in obsessive-compulsive disorder. J Affect Disord;2024 (May 15);353:48-51.

BACKGROUND: Sensory over-responsivity (SOR) in obsessive-compulsive disorder (OCD) is associated with illness severity and functional impairment. However, the neural substrates of SOR in OCD have not yet been directly probed. METHODS: We examined resting-state global functional connectivity markers of SOR in 119 adults with OCD utilizing the CONN-fMRI Functional Connectivity Toolbox for SPM (v21a). We quantified SOR with the sensory sensitivity and sensory avoiding subscales of the Adult and Adolescent Sensory Profile (AASP). We also measured: OCD severity, with the Yale-Brown Obsessive-Compulsive Scale (Y-BOCS) and Obsessive-Compulsive Inventory-Revised (OCI-R); sensory phenomena with the Sensory Phenomena Scale (SPS); general anxiety, with the Beck Anxiety Inventory (BAI); and depressive symptomatology, with Quick Inventory of Depressive Symptoms, Self-Report (QIDS-SR). RESULTS: There was a significant positive relationship of SOR with global connectivity in anterior and medial OFC (Brodmanns area 11, k = 154, x = 14, y = 62, z = -18, whole-brain corrected at FWE p < 0.05). LIMITATIONS: Future investigations should explore neural responses to sensory stimulation tasks in OCD and compare findings with those obtained in other conditions also characterized by high SOR, such as autism spectrum disorder. CONCLUSIONS: This study implicates OFC functional connectivity as a neurobiological mechanism of SOR in OCD and suggests that the substrates of SOR in OCD may be dissociable from both that of other symptoms in OCD, and SOR in other disorders. With replication and extension, the finding may be leveraged to develop and refine treatments for OCD and investigate the pathophysiology of SOR in other conditions.

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8. Dincel M, Karayagmurlu A. An Investigation of Dissociative Symptoms and Related Factors in Autistic Adolescents. J Autism Dev Disord;2024 (May 14)

Despite exposure to trauma and adverse life events being frequently reported in Autism Spectrum Disorder (ASD), few studies have examined the relationship between these factors and dissociative symptoms in the autistic population. The aim of the study is to investigate symptoms of dissociation in autistic adolescents, and to explore factors that could be associated with dissociative symptoms in ASD. This cross-sectional study involved 59 autistic adolescents between 12 and 18 years old, with the mean age of 14.3 ± 1.8. Dissociation, autism characteristics, childhood traumas, peer bullying, and Post-Traumatic Stress Disorder (PTSD) symptoms were assessed using the Adolescent Dissociative Experiences Scale (ADES), the Childhood Autism Rating Scale (CARS), the Childhood Trauma Questionnaire (CTQ), the Nine-Item Child-Adolescent Bullying Screen (CABS-9), and the Child Posttraumatic Stress Reaction Index (CPTS-RI), respectively. Results from the ADES revealed that 12.5% of the participants scored above the threshold for dissociative disorders. In the linear regression model constructed to evaluate factors associated with dissociative symptoms, an increase in dissociative symptoms was statistically significantly associated with an increase in the total CTQ score (p = 0.002) and age (p = 0.006). The findings of the study indicate that dissociative symptoms may occur in autistic adolescents. It is suggested that dissociative symptoms observed in autistic adolescents may particularly be associated with childhood traumas and increasing age. Further research into dissociative symptoms in ASD is warranted, requiring larger sample sizes, specialized measurement scales, and structured interviews.

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9. Gardner L, Campbell JM. Training Law Enforcement Officers About Autism: Evaluation of Adding Virtual Reality or Simulation to a Traditional Training Approach. J Autism Dev Disord;2024 (May 15)

Prevalence rates of autism spectrum disorder (ASD) across the globe and lifespan suggest that law enforcement officers (LEOs) are likely to interact with autistic people in their professional duties. In developed countries, LEOs have professional encounters with autistic individuals, and research strongly supports LEOs need training to increase their knowledge about autism and confidence interacting with autistic people. The purpose of the present study is to compare three training approaches with LEOs: (a) a training presentation alone (P), (b) a training presentation combined with virtual reality simulation (P + VR), and (c) a training presentation combined with in-vivo simulation (P + SIM). The primary outcomes are LEO knowledge of autism and self-reported confidence in responding to autism calls. The present study included 259 LEOS who completed a survey assessing autism knowledge and confidence in level of skill before and after participating in ASD-specific training for LEOs. Findings support that participant knowledge of autism and confidence in responding significantly increased for all LEOs equally across training conditions. Results support that formalized training in ASD significantly impacts LEO’s knowledge of ASD and confidence responding to calls. As such, standardized training for LEOs is needed to assure appropriate knowledge and confidence when responding to calls involving autistic persons.

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10. Girolamo T, Birmingham M, Patel K, Ghali S, Campos I, Greene-Pendelton K, Canale R, Larson C, Sterling A, Shogren KA. Self-determination in minoritized autistic adolescents and adults. medRxiv;2024 (May 3)

Self-determination plays an important role in outcomes in autism and shows intersectional disparities. Yet, little is known about the role of individual differences or social drivers of health in the development of self-determination. Understanding these factors is key for developing effective supports. This mixed-methods convergent study examined self-determination in racially and ethnically minoritized autistic individuals and caregivers. Participants ages 13 to 30 ( N = 73) varying widely in language and cognitive ability and caregivers ( n =52) completed the Self-Determination Inventory. Autism traits and sense of community predicted caregiver report of self-determination, and autism traits and language predicted self-report of self-determination, consistent with DisCrit and Diversity Science. Self-Determination Inventory interviews of a subset of participants ( n = 13) and caregivers ( n = 9) were analyzed using inductive thematic analysis. Themes pointed to the role of the intersection of race and disability in shaping self-determination. Altogether, findings point to the importance of these frameworks, environmental influences, and multi-informant perspectives in characterizing self-determination. Future work should focus on the impact of environmental factors in self-determination in minoritized autistic individuals during the transition to adulthood.

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11. Greenberg YDM, Holt R, Allison C, Smith P, Newman R, Boardman-Pretty T, Haidt J, Baron-Cohen S. Moral foundations in autistic people and people with systemizing minds. Mol Autism;2024 (May 14);15(1):20.

BACKGROUND: Do autistic people share the same moral foundations as typical people? Here we built on two prominent theories in psychology, moral foundations theory and the empathizing-systemizing (E-S) theory, to observe the nature of morality in autistic people and systemizers. METHODS: In dataset 1, we measured five foundations of moral judgements (Care, Fairness, Loyalty, Authority, and Sanctity) measured by the Moral Foundations Questionnaire (MFQ) in autistic (n = 307) and typical people (n = 415) along with their scores on the Empathy Quotient (EQ) and Systemizing Quotient (SQ). In dataset 2, we measured these same five foundations along with E-S cognitive types (previously referred to as « brain types ») in a large sample of typical people (N = 7595). RESULTS: Autistic people scored the same on Care (i.e., concern for others) as typical people (h1). Their affective empathy (but not their cognitive empathy) scores were positively correlated with Care. Autistic people were more likely to endorse Fairness (i.e., giving people what they are owed, and treating them with justice) over Care (h2). Their systemizing scores were positively correlated with Fairness. Autistic people or those with a systemizing cognitive profile had lower scores on binding foundations: Loyalty, Authority, and Sanctity (h3). Systemizing in typical people was positively correlated with Liberty (i.e., hypervigilance against oppression), which is a sixth moral foundation (h4). Although the majority of people in all five E-S cognitive types self-identified as liberal, with a skew towards empathizing (h5), the percentage of libertarians was highest in systemizing cognitive types (h6). E-S cognitive types accounted for 2 to 3 times more variance for Care than did sex. LIMITATIONS: Our study is limited by its reliance on self-report measures and a focus on moral judgements rather than behavior or decision-making. Further, only dataset 2 measured political identification, therefore we were unable to assess politics in autistic people. CONCLUSIONS: We conclude that some moral foundations in autistic people are similar to those in typical people (despite the difficulties in social interaction that are part of autism), and some are subtly different. These subtle differences vary depending on empathizing and systemizing cognitive types.

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12. Grönniger B, Fritschka E, Kimpe K, Singh A, Sadowski G. Simultaneous Water Sorption and Crystallization in ASDs 2: Modeling Long-Term Stabilities. Mol Pharm;2024 (May 14)

The physical stability of amorphous solid dispersions (ASDs) is a major topic in the formulation research of oral dosage forms. To minimize the effort of investigating the long-term stability using cost- and time-consuming experiments, we developed a thermodynamic and kinetic modeling framework to predict and understand the crystallization kinetics of ASDs during long-term storage below the glass transition. Since crystallization of the active phrarmaceutical ingredients (APIs) in ASDs largely depends on the amount of water absorbed by the ASDs, water-sorption kinetics and API-crystallization kinetics were considered simultaneously. The developed modeling approach allows prediction of the time evolution of viscosity, supersaturation, and crystallinity as a function of drug load, relative humidity, and temperature. It was applied and evaluated against two-year-lasting crystallization experiments of ASDs containing nifedipine and copovidone or HPMCAS measured in part I of this work. We could show that the proposed modeling approach is able to describe the interplay between water sorption and API crystallization and to predict long-term stabilities of ASDs just based on short-term measurements. Most importantly, it enables explaining and understanding the reasons for different and sometimes even unexpected crystallization behaviors of ASDs.

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13. Jana A, Nath A, Sen P, Kundu S, Alghamdi BS, Abujamel TS, Saboor M, Woon-Khiong C, Alexiou A, Papadakis M, Alam MZ, Ashraf GM. Unraveling the Endocannabinoid System: Exploring Its Therapeutic Potential in Autism Spectrum Disorder. Neuromolecular Med;2024 (May 14);26(1):20.

The salient features of autism spectrum disorder (ASD) encompass persistent difficulties in social communication, as well as the presence of restricted and repetitive facets of behavior, hobbies, or pursuits, which are often accompanied with cognitive limitations. Over the past few decades, a sizable number of studies have been conducted to enhance our understanding of the pathophysiology of ASD. Preclinical rat models have proven to be extremely valuable in simulating and analyzing the roles of a wide range of established environmental and genetic factors. Recent research has also demonstrated the significant involvement of the endocannabinoid system (ECS) in the pathogenesis of several neuropsychiatric diseases, including ASD. In fact, the ECS has the potential to regulate a multitude of metabolic and cellular pathways associated with autism, including the immune system. Moreover, the ECS has emerged as a promising target for intervention with high predictive validity. Particularly noteworthy are resent preclinical studies in rodents, which describe the onset of ASD-like symptoms after various genetic or pharmacological interventions targeting the ECS, providing encouraging evidence for further exploration in this area.

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14. Kanlayaprasit S, Saeliw T, Thongkorn S, Panjabud P, Kasitipradit K, Lertpeerapan P, Songsritaya K, Yuwattana W, Jantheang T, Jindatip D, Hu VW, Kikkawa T, Osumi N, Sarachana T. Sex-specific impacts of prenatal bisphenol A exposure on genes associated with cortical development, social behaviors, and autism in the offspring’s prefrontal cortex. Biol Sex Differ;2024 (May 15);15(1):40.

BACKGROUND: Recent studies have shown that prenatal BPA exposure altered the transcriptome profiles of autism-related genes in the offspring’s hippocampus, disrupting hippocampal neuritogenesis and causing male-specific deficits in learning. However, the sex differences in the effects of prenatal BPA exposure on the developing prefrontal cortex, which is another brain region highly implicated in autism spectrum disorder (ASD), have not been investigated. METHODS: We obtained transcriptome data from RNA sequencing analysis of the prefrontal cortex of male and female rat pups prenatally exposed to BPA or control and reanalyzed. BPA-responsive genes associated with cortical development and social behaviors were selected for confirmation by qRT-PCR analysis. Neuritogenesis of primary cells from the prefrontal cortex of pups prenatally exposed to BPA or control was examined. The social behaviors of the pups were assessed using the two-trial and three-chamber tests. The male-specific impact of the downregulation of a selected BPA-responsive gene (i.e., Sema5a) on cortical development in vivo was interrogated using siRNA-mediated knockdown by an in utero electroporation technique. RESULTS: Genes disrupted by prenatal BPA exposure were associated with ASD and showed sex-specific dysregulation. Sema5a and Slc9a9, which were involved in neuritogenesis and social behaviors, were downregulated only in males, while Anxa2 and Junb, which were also linked to neuritogenesis and social behaviors, were suppressed only in females. Neuritogenesis was increased in males and showed a strong inverse correlation with Sema5a and Slc9a9 expression levels, whereas, in the females, neuritogenesis was decreased and correlated with Anxa2 and Junb levels. The siRNA-mediated knockdown of Sema5a in males also impaired cortical development in utero. Consistent with Anxa2 and Junb downregulations, deficits in social novelty were observed only in female offspring but not in males. CONCLUSION: This is the first study to show that prenatal BPA exposure dysregulated the expression of ASD-related genes and functions, including cortical neuritogenesis and development and social behaviors, in a sex-dependent manner. Our findings suggest that, besides the hippocampus, BPA could also exert its adverse effects through sex-specific molecular mechanisms in the offspring’s prefrontal cortex, which in turn would lead to sex differences in ASD-related neuropathology and clinical manifestations, which deserves further investigation.

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15. Keehn B, Monahan P, Enneking B, Ryan T, Swigonski N, McNally Keehn R. Eye-Tracking Biomarkers and Autism Diagnosis in Primary Care. JAMA Netw Open;2024 (May 1);7(5):e2411190.

IMPORTANCE: Finding effective and scalable solutions to address diagnostic delays and disparities in autism is a public health imperative. Approaches that integrate eye-tracking biomarkers into tiered community-based models of autism evaluation hold promise for addressing this problem. OBJECTIVE: To determine whether a battery of eye-tracking biomarkers can reliably differentiate young children with and without autism in a community-referred sample collected during clinical evaluation in the primary care setting and to evaluate whether combining eye-tracking biomarkers with primary care practitioner (PCP) diagnosis and diagnostic certainty is associated with diagnostic outcome. DESIGN, SETTING, AND PARTICIPANTS: Early Autism Evaluation (EAE) Hub system PCPs referred a consecutive sample of children to this prospective diagnostic study for blinded eye-tracking index test and follow-up expert evaluation from June 7, 2019, to September 23, 2022. Participants included 146 children (aged 14-48 months) consecutively referred by 7 EAE Hubs. Of 154 children enrolled, 146 provided usable data for at least 1 eye-tracking measure. MAIN OUTCOMES AND MEASURES: The primary outcomes were sensitivity and specificity of a composite eye-tracking (ie, index) test, which was a consolidated measure based on significant eye-tracking indices, compared with reference standard expert clinical autism diagnosis. Secondary outcome measures were sensitivity and specificity of an integrated approach using an index test and PCP diagnosis and certainty. RESULTS: Among 146 children (mean [SD] age, 2.6 [0.6] years; 104 [71%] male; 21 [14%] Hispanic or Latine and 96 [66%] non-Latine White; 102 [70%] with a reference standard autism diagnosis), 113 (77%) had concordant autism outcomes between the index (composite biomarker) and reference outcomes, with 77.5% sensitivity (95% CI, 68.4%-84.5%) and 77.3% specificity (95% CI, 63.0%-87.2%). When index diagnosis was based on the combination of a composite biomarker, PCP diagnosis, and diagnostic certainty, outcomes were concordant with reference standard for 114 of 127 cases (90%) with a sensitivity of 90.7% (95% CI, 83.3%-95.0%) and a specificity of 86.7% (95% CI, 70.3%-94.7%). CONCLUSIONS AND RELEVANCE: In this prospective diagnostic study, a composite eye-tracking biomarker was associated with a best-estimate clinical diagnosis of autism, and an integrated diagnostic model including PCP diagnosis and diagnostic certainty demonstrated improved sensitivity and specificity. These findings suggest that equipping PCPs with a multimethod diagnostic approach has the potential to substantially improve access to timely, accurate diagnosis in local communities.

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16. Kim JH, Koh IG, Lee H, Lee GH, Song DY, Kim SW, Kim Y, Han JH, Bong G, Lee J, Byun H, Son JH, Kim YR, Lee Y, Kim JJ, Park JW, Kim IB, Choi JK, Jang JH, Trost B, Lee J, Kim E, Yoo HJ, An JY. Short tandem repeat expansions in cortical layer-specific genes implicate in phenotypic severity and adaptability of autism spectrum disorder. Psychiatry Clin Neurosci;2024 (May 15)

AIM: Short tandem repeats (STRs) are repetitive DNA sequences and highly mutable in various human disorders. While the involvement of STRs in various genetic disorders has been extensively studied, their role in autism spectrum disorder (ASD) remains largely unexplored. In this study, we aimed to investigate genetic association of STR expansions with ASD using whole genome sequencing (WGS) and identify risk loci associated with ASD phenotypes. METHODS: We analyzed WGS data of 634 ASD families and performed genome-wide evaluation for 12,929 STR loci. We found rare STR expansions that exceeded normal repeat lengths in autism cases compared to unaffected controls. By integrating single cell RNA and ATAC sequencing datasets of human postmortem brains, we prioritized STR loci in genes specifically expressed in cortical development stages. A deep learning method was used to predict functionality of ASD-associated STR loci. RESULTS: In ASD cases, rare STR expansions predominantly occurred in early cortical layer-specific genes involved in neurodevelopment, highlighting the cellular specificity of STR-associated genes in ASD risk. Leveraging deep learning prediction models, we demonstrated that these STR expansions disrupted the regulatory activity of enhancers and promoters, suggesting a potential mechanism through which they contribute to ASD pathogenesis. We found that individuals with ASD-associated STR expansions exhibited more severe ASD phenotypes and diminished adaptability compared to non-carriers. CONCLUSION: Short tandem repeat expansions in cortical layer-specific genes are associated with ASD and could potentially be a risk genetic factor for ASD. Our study is the first to show evidence of STR expansion associated with ASD in an under-investigated population.

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17. Kim YJ, Kim K, Lee Y, Min HW, Ko YH, Lee BR, Hur KH, Kim SK, Lee SY, Jang CG. The mutated cytoplasmic fragile X mental retardation 1 (FMR1)-interacting protein 2 (CYFIP2 S968F) regulates cocaine-induced reward behaviour and plasticity in the nucleus accumbens. Br J Pharmacol;2024 (May 15)

BACKGROUND AND PURPOSE: Cytoplasmic fragile X mental retardation 1 (FMR1)-interacting protein 2 (CYFIP2), as a component of the Wiskott-Aldrich syndrome protein family verprolin-homologous protein (WAVE) regulatory complex, is involved in actin polymerization, contributing to neuronal development and structural plasticity. Mutating serine-968 to phenylalanine (S968F) in CYFIP2 causes an altered cocaine response in mice. The neuronal mechanisms underlying this response remain unknown. EXPERIMENTAL APPROACH: We performed cocaine reward-related behavioural tests and examined changes in synaptic protein phenotypes and neuronal morphology in the nucleus accumbens (NAc), using CYFIP2 S968F knock-in mice to investigate the role of CYFIP2 in regulating cocaine reward. KEY RESULTS: CYFIP2 S968F mutation attenuated cocaine-induced behavioural sensitization and conditioned place preference. Cocaine-induced c-Fos was not observed in the NAc of CYFIP2 S968F knock-in mice. However, c-Fos induction was still evident in the medial prefrontal cortex (mPFC). CYFIP2 S968F mutation altered cocaine-associated CYFIP2 signalling, glutamatergic protein expression and synaptic density in the NAc following cocaine exposure. To further determine the role of CYFIP2 in NAc neuronal activity and the mPFC projecting to the NAc activity-mediating reward response, we used optogenetic tools to stimulate the NAc or mPFC-NAc pathway and observed that optogenetic activation of the NAc or mPFC-NAc pathway induced reward-related behaviours. This effect was not observed in the S968F mutation in CYFIP2. CONCLUSION AND IMPLICATIONS: These results suggest that CYFIP2 plays a role in controlling cocaine-mediated neuronal function and structural plasticity in the NAc, and that CYFIP2 could serve as a target for regulating cocaine reward.

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18. Kovacheva E, Gevezova M, Maes M, Sarafian V. The mast cells – Cytokines axis in Autism Spectrum Disorder. Neuropharmacology;2024 (May 15);249:109890.

Autism Spectrum Disorder (ASD) is a neurodevelopmental disturbance, diagnosed in early childhood. It is associated with varying degrees of dysfunctional communication and social skills, repetitive and stereotypic behaviors. Regardless of the constant increase in the number of diagnosed patients, there are still no established treatment schemes in global practice. Many children with ASD have allergic symptoms, often in the absence of mast cell (MC) positive tests. Activation of MCs may release molecules related to inflammation and neurotoxicity, which contribute to the pathogenesis of ASD. The aim of the present paper is to enrich the current knowledge regarding the relationship between MCs and ASD by providing PPI network analysis-based data that reveal key molecules and immune pathways associated with MCs in the pathogenesis of autism. Network and enrichment analyzes were performed using receptor information and secreted molecules from activated MCs identified in ASD patients. Our analyses revealed cytokines and key marker molecules for MCs degranulation, molecular pathways of key mediators released during cell degranulation, as well as various receptors. Understanding the relationship between ASD and the activation of MCs, as well as the involved molecules and interactions, is important for elucidating the pathogenesis of ASD and developing effective future treatments for autistic patients by discovering new therapeutic target molecules.

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19. Kunze M, Wei Q, Bacon-Yates A, Pompan E, Lockwood H, Witthuhn N. Promoting Reciprocal Relationships with Flexibility, Coaching, and Teaching (PRRFCT Match): A Virtual Parent-Mediated Intervention Package for Young Children with Developmental Disabilities. J Autism Dev Disord;2024 (May 15)

This study aimed to evaluate Promoting Reciprocal Relationships with Flexibility, Coaching, and Teaching (PRRFCT Match), a parent-mediated naturalistic developmental behavioral intervention package. An expansion from an earlier pilot study (see Kunze et al., 2021), PRRFCT Match incorporates virtual coaching between a novice coach and parent to implement evidence-based, applied behavior analytic (ABA) techniques during play to increase engagement and decrease unengaged behavior exhibited by their young child with developmental delays (26-50 months old). Ten parent-child dyads were matched with a coach in this concurrent multiple baseline design across participants. Simulating the clinical training level of a novice early interventionist, nine graduate student clinicians received training as coaches on PRRFCT Match implementation and weekly supervision by a research team member. All aspects of training and intervention were delivered virtually. A visual analysis of the data combined with Tau-U revealed a strong basic effect between clinician coaching and parent strategy use. For child participants, a visual analysis and Tau-U results suggest that most increased engagement and decreased their unengaged behavior during the intervention. High variability, overlap, and high engagement at baseline are discussed. This study shows promise for the PRRFCT Match intervention package. The ABA technologies mediated by parents during play increased child engagement and decreased unengagement for most participants.

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20. Lei X, Xie XN, Yang JX, Li YM. The emerging role of extracellular vesicles in the diagnosis and treatment of autism spectrum disorders. Psychiatry Res;2024 (May 8);337:115954.

Autism spectrum disorders (ASD) are neurodevelopmental conditions characterized by restricted, repetitive behavioral patterns and deficits in social interactions. The prevalence of ASD has continued to rise in recent years. However, the etiology and pathophysiology of ASD remain largely unknown. Currently, the diagnosis of ASD relies on behavior measures, and there is a lack of reliable and objective biomarkers. In addition, there are still no effective pharmacologic therapies for the core symptoms of ASD. Extracellular vesicles (EVs) are lipid bilayer nanovesicles secreted by almost all types of cells. EVs play a vital role in cell-cell communications and are known to bear various biological functions. Emerging evidence demonstrated that EVs are involved in many physiological and pathological processes throughout the body and the content in EVs can reflect the status of the originating cells. EVs have demonstrated the potential of broad applications for the diagnosis and treatment of various brain diseases, suggesting that EVs may have also played a role in the pathological process of ASD. Besides, EVs can be utilized as therapeutic agents for their endogenous substances and biological functions. Additionally, EVs can serve as drug delivery tools as nano-sized vesicles with inherent targeting ability. Here, we discuss the potential of EVs to be considered as promising diagnostic biomarkers and their potential therapeutic applications for ASD.

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21. Lopez-Espejo MA, Nuñez AC, Saez V, Ruz M, Moscoso OC, Vives A. The Influence of Social and Developmental Factors on the Timing of Autism Spectrum Disorder Diagnosis of Preschool-Aged Children: Evidence from a Specialized Chilean Center. J Autism Dev Disord;2024 (May 14)

We investigated the influence of developmental and social factors on the age of autism diagnosis (AoD) in a cohort of toddlers living in Chile. A cross-sectional study was conducted among 509 preschool children diagnosed with autism spectrum disorder [M = 40.2 months (SD = 8.6), girls: 32%] in the neurodevelopmental unit of a university clinic in Santiago, Chile (2015-2023). Structural changes in the annual trend of AoD were tested. Generalized linear models (gamma distribution) with and without interaction terms were used for the multivariate analysis, adjusting for gender, residential area, year of diagnosis, developmental variables (language regression, delayed walking, and use of expressive verbal language), and primary caregiver age and education level (CEL). 95% confidence intervals of the unstandardized regression coefficients (B) were calculated using 1000 bootstrap resampling to estimate associations. AoD increased between 2021-2022 and decreased in 2023. Female gender (B = 2.72 [1.21-4.23]), no history of language regression (B = 3.97 [1.66-6.28]), and the presence of expressive verbal language at diagnosis (B = 1.57 [0.05-3.08]) were associated with higher AoD. Children whose caregivers had tertiary education were diagnosed earlier than those with ≤ 12 years of formal education. Although the influence of CEL increased with caregiver age, differences between CEL groups were significant only for caregivers aged ≥ 30 years. Improved education and early screening for clinical features of autism among healthcare professionals and the community, with a focus on young children without highly apparent developmental concerns and those from vulnerable social groups, are warranted.

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22. Maroon M, Haddad F, Doornaert E, Allman B, Schmid S. Investigating gene-environment interaction on attention in a double-hit model for Autism Spectrum Disorder. PLoS One;2024;19(5):e0299380.

Autism Spectrum Disorder (ASD) is a neurodevelopmental behavioral disorder characterized by social, communicative, and motor deficits. There is no single etiological cause for ASD, rather, there are various genetic and environmental factors that increase the risk for ASD. It is thought that some of these factors influence the same underlying neural mechanisms, and that an interplay of both genetic and environmental factors would better explain the pathogenesis of ASD. To better appreciate the influence of genetic-environment interaction on ASD-related behaviours, rats lacking a functional copy of the ASD-linked gene Cntnap2 were exposed to maternal immune activation (MIA) during pregnancy and assessed in adolescence and adulthood. We hypothesized that Cntnap2 deficiency interacts with poly I:C MIA to aggravate ASD-like symptoms in the offspring. In this double-hit model, we assessed attention, a core deficit in ASD due to prefrontal cortical dysfunction. We employed a well-established attentional paradigm known as the 5-choice serial reaction time task (5CSRTT). Cntnap2-/- rats exhibited greater perseverative responses which is indicative of repetitive behaviors. Additionally, rats exposed to poly I:C MIA exhibited premature responses, a marker of impulsivity. The rats exposed to both the genetic and environmental challenge displayed an increase in impulsive activity; however, this response was only elicited in the presence of an auditory distractor. This implies that exacerbated symptomatology in the double-hit model may situation-dependent and not generally expressed.

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23. Masjedi N, Clarke EB, Lord C. Development of Restricted and Repetitive Behaviors from 2-19: Stability and Change in Repetitive Sensorimotor, Insistence on Sameness, and Verbal Behaviors in a Longitudinal Study of Autism. J Autism Dev Disord;2024 (May 14)

This study examined trajectories of repetitive sensorimotor (RSM), insistence on sameness (IS), and verbal RRBs from ages 2-19 in a well-characterized longitudinal cohort. We also tested the factor structure of the ADI-R restricted and repetitive behavior (RRB) domain at age 19 and the inclusion of a verbal RRBs factor, in addition to previously identified RSM and IS factors, at ages 9 and 19. The ADI-R was administered to 193 participants at five timepoints from 2 to 19. Confirmatory factor analysis (CFA) was used to examine the factor structure of ADI-R RRB data. Change in RRB subtypes was examined using group-based trajectory modeling and multilevel modeling. RSM and IS behaviors generally decreased from 2 to 19, with some participants experiencing increases from ages 2-9. 46.46% of participants experienced increasing verbal RRBs from 2 to 9, followed by a plateau from 9 to 19. The remaining participants had few to no verbal RRBs throughout development. Multilevel modeling indicated ADOS CSS scores were associated with change in RSM trajectories only. Child IQ was not associated with change in any RRB trajectories. CFA indicated previously-derived RSM and IS factors fit age 19 ADI-R data well. The inclusion of a third factor, verbal RRBs, worsened goodness-of-fit statistics and was ultimately omitted. Our findings suggest the RRB factor structure of the ADI remains consistent into early adulthood and illustrate developmental continuity and change in RRBs. For autistic individuals with fluent speech, RRB presentation may be influenced by verbal ability in ways that are highly variable, but clinically meaningful.

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24. Muès M, Schaubroeck S, Demurie E, Roeyers H. Factors associated with receptive and expressive language in autistic children and siblings: A systematic review. Autism Dev Lang Impair;2024 (Jan-Dec);9:23969415241253554.

BACKGROUND & AIMS: Language abilities of autistic children and children at elevated likelihood for autism (EL-siblings) are highly heterogeneous, and many of them develop language deficits. It is as of yet unclear why language abilities of autistic children and EL-siblings vary, although an interaction of multiple influential factors is likely at play. In this review, we describe research articles that identify one or multiple of such factors associated with the receptive or expressive language abilities of autistic children and EL-siblings since the introduction of the DSM-5. Our aim was to identify and summarize factors that are linked to language development in autistic children and siblings in the recent literature to ultimately gain insight into the heterogeneity of language abilities in these children. METHODS: The search strategy of this review followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. The following databases were consulted: Embase, MEDLINE, Web of Science Core Collection, and Scopus. Inclusion criteria for studies were the presence of a sample of autistic children no older than 7 years old who were diagnosed with autism spectrum disorder per the criteria of the DSM-5. Intervention studies and studies without an explicitly reported language measure were excluded. Risk of bias assessment was completed using the Newcastle-Ottawa Scales. Ultimately, 55 articles were included in this review. MAIN CONTRIBUTION: Fifty-six factors were identified to be related to receptive or expressive language abilities of autistic children and EL-siblings. They were grouped into three main categories: biological factors; psychosocial and environmental factors; and age-related and developmental factors, each with different subcategories. Although many of the identified variables were only examined in one article, some well-researched associated factors were reported across multiple studies and were present in both autistic children and EL-siblings, in particular joint attention, nonverbal cognitive abilities and frontal EEG power. Better insight in these factors associated with language abilities in autistic children and siblings at elevated likelihood can inform future intervention strategies to reduce language deficits and its corresponding negative consequences in these children. CONCLUSIONS: Our results confirm that multiple different factors likely underlie language deficits in autism. Important aspects that should be considered are, among others, social factors such as joint attention, child characteristics such as nonverbal cognition, and neurocognitive factors.

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25. Murthy S, Parker Harris S, Hsieh K. Information needs of caregivers of adults with intellectual and/or developmental disabilities in India. J Intellect Disabil;2024 (May 15):17446295241254933.

Many families of adults with intellectual and/or developmental disabilities in India experience difficulty in accessing services/supports, due to lack of awareness/knowledge of disability rights/laws and available services, and in accessing the services. There remains insufficient research on the information needs of these caregivers and on designing interventions that aim to increase their awareness/knowledge about human rights and supports/services. A strengths-based mixed methods needs assessment was conducted to understand the information needs of these family caregivers. Results showed that caregivers ≥50 years had significantly higher information needs than younger caregivers. Specifically, caregivers with no proficiency in English needed more information on the available services for the care recipients (n = 100). Qualitative results showed that very few caregivers had any awareness or access to information on human rights, disability-related laws/policies or available supports/services (n = 15). Study findings underscore the government’s role in improving awareness-raising initiatives and imparting the information in multiple Indian languages.

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26. Naderpour M, Jabbari Moghaddam Y, Abbasi A, Ariafar A, Poorshiri B. Autism’s Impact on Cochlear Implantation Surgery Outcomes in Deaf Children. Iran J Otorhinolaryngol;2024 (May);36(3):451-457.

INTRODUCTION: Cochlear implants (CI) provide a hearing sense for severe to profound hearing-impaired patients, both adults and children, and they are a broadly effective and accepted therapeutic method for those patients. Also, Deaf children with comorbidities, including autism spectrum disorders (ASDs), undergo cochlear implantation. ASDs are a group of developing disorders characterized by abnormalities in social interaction and communication with limited repetitive patterns of behavior. This study aimed to assess the effect of Autism on CI surgery outcomes in Deaf Children. MATERIALS AND METHODS: We followed 12 autistic patients with cochlear implantation and 12 non-autistic cochlear-implanted patients for two years. The Categories of Auditory Performance (CAP) and Speech Intelligibility Rating (SIR) scores were used to assess 6, 12, and 24 months after cochlear implantation surgery. RESULTS: During the 24-month follow-up, the CAP means scores increased in both groups, and SIR and CAP progresses were considerably greater in non-ASD children (P<0.001). However, in ASD children, the progress of CAP and SIR variables were significant, with 99% and 95% confidence, respectively, at 24 months after surgery. CONCLUSION: Although the CIs could improve hearing performance in autistic patients, speech development after CIs in autistic children could affected by several factors, including the severity of autism, and this can be effective in providing pre-implant counseling to parents. The application of the alternative communication methods could be taken into account as a potential rehab technique.

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27. Nix K, Siegel A, Smith JV, Wells EM, Atmore K. Individualized Care Delivery for Children With Autism and Related Disabilities Undergoing Overnight Video Electroencephalography (EEG): One Hospital’s Experience With a Coordinated Team Approach. J Child Neurol;2024 (May 15):8830738241252849.

Background and Purpose: Children with developmental disabilities have increased risk of epilepsy and need for overnight video electroencephalographic (EEG) monitoring. However, video EEGs have historically been considered difficult to complete for this population. An autism support service at a pediatric tertiary care hospital implemented a coordinated team approach to help children with developmental disability tolerate overnight video EEGs. The project included completion of a caregiver-report preprocedure questionnaire that then was shared with the multidisciplinary team and used to create individualized care plans. The current study aims to describe rates of video EEG completion and need for lead placement under general anesthesia among children with autism and related disabilities who received these supports. Methods: Rates of video EEG completion and general anesthesia use were analyzed for children referred to the support service between April 2019 and November 2021. Results: A total of 182 children with developmental disability (mean age ( )= 10.3 years, 54.9% diagnosed with autism) met inclusion criteria. 92.9% (n = 169) of children successfully completed EEG (leads on ≥12 hours). Only 19.2% (n = 35) required general anesthesia for video EEG lead placement. The majority (80.2%) of parents (n = 146) completed the preprocedure questionnaire. Video EEG outcomes did not differ based on completion of the questionnaire. Parent-reported challenges with communication and cooperation were associated with shorter video EEG duration and greater use of general anesthesia. Conclusions: These findings suggest that most children with developmental disability can complete video EEG with sufficient support. Preprocedure planning can identify children who would benefit from additional accommodations. Further research is necessary to clarify which supports are most helpful.

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28. Panda PK, Elwadhi A, Gupta D, Palayullakandi A, Tomar A, Singh M, Vyas A, Kumar D, Sharawat IK. Effectiveness of IMPUTE ADT-1 mobile application in children with autism spectrum disorder: An interim analysis of an ongoing randomized controlled trial. J Neurosci Rural Pract;2024 (Apr-Jun);15(2):262-269.

OBJECTIVES: IMPUTE Inc., a software firm dedicated to healthcare technology, has developed a mobile medical application known as IMPUTE ADT-1 for children with autism spectrum disorder (ASD) based on the principle of applied behavior analysis. MATERIALS AND METHODS: The primary objective of this trial was to compare the efficacy of add-on treatment with IMPUTE ADT-1 in children with ASD aged two to six years as compared to standard care alone for 12 weeks (in terms of change in Autism Diagnostic Observation Schedule [ADOS-2] scores). The secondary objective of the study was to assess the compliance with IMPUTE ADT-1 among participants and also to evaluate the feedback of parents regarding IMPUTE ADT-1 at the end of 12 weeks. The application provides personalized programs tailored to each user’s needs, and the program evolves based on the user’s progress. It also utilizes face tracking, eye tracking, and body tracking to gather behavior-related information for each child and apply it in reinforcement learning employing artificial intelligence-based algorithms. RESULTS: Till the time of interim analysis, 37 and 33 children had completed 12-week follow-up in IMPUTE ADT-1 and control arm. At 12 weeks, as compared to baseline, change in social affect domain, repetitive ritualistic behavior domain, total ADOS-2 score, and ADOS-2 comparison score was better in the intervention group as compared to the control group (P < 0.001 for all). A total of 30 (81%), 28 (75%), and 29 (78%) caregivers in the IMPUTE ADT-1 group believed that the ADT-1 app improved their child's verbal skills, social skills, and reduced repetitive behavior, respectively. CONCLUSION: IMPUTE ADT-1 mobile application has the efficacy to improve the severity of autism symptoms in children. Parents of these children also feel that the application is beneficial for improving the socialization and verbal communication of their children.

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29. Qiu L, Zhai J. A hybrid CNN-SVM model for enhanced autism diagnosis. PLoS One;2024;19(5):e0302236.

Autism is a representative disorder of pervasive developmental disorder. It exerts influence upon an individual’s behavior and performance, potentially co-occurring with other mental illnesses. Consequently, an effective diagnostic approach proves to be invaluable in both therapeutic interventions and the timely provision of medical support. Currently, most scholars’ research primarily relies on neuroimaging techniques for auxiliary diagnosis and does not take into account the distinctive features of autism’s social impediments. In order to address this deficiency, this paper introduces a novel convolutional neural network-support vector machine model that integrates resting state functional magnetic resonance imaging data with the social responsiveness scale metrics for the diagnostic assessment of autism. We selected 821 subjects containing the social responsiveness scale measure from the publicly available Autism Brain Imaging Data Exchange dataset, including 379 subjects with autism spectrum disorder and 442 typical controls. After preprocessing of fMRI data, we compute the static and dynamic functional connectivity for each subject. Subsequently, convolutional neural networks and attention mechanisms are utilized to extracts their respective features. The extracted features, combined with the social responsiveness scale features, are then employed as novel inputs for the support vector machine to categorize autistic patients and typical controls. The proposed model identifies salient features within the static and dynamic functional connectivity, offering a possible biological foundation for clinical diagnosis. By incorporating the behavioral assessments, the model achieves a remarkable classification accuracy of 94.30%, providing a more reliable support for auxiliary diagnosis.

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30. Ralston M, Osman A, Suryadevara P, Cleland E. Effect of Ketamine Treatment on Social Withdrawal in Autism and Autism-Like Conditions. Clin Neuropharmacol;2024 (May-Jun 01);47(3):97-100.

OBJECTIVE: Ketamine and esketamine have been used in the field of psychiatry to alleviate conditions such as major depressive disorder. Our objective was to evaluate the current literature on the use of ketamine for symptoms of social withdrawal in autism spectrum disorder (ASD) and autism-like conditions. METHODS: A comprehensive search of PubMed and Web of Science was conducted to identify literature involving the use of ketamine to treat symptoms of autism and social withdrawal. Patients with comorbid disorders were also included. RESULTS: Two original studies were found, showing mixed results on the use of ketamine for ASD. The use of esketamine found no statistically significant results, whereas the use of intravenous ketamine was shown to alleviate symptoms of social withdrawal especially in the short term. Neither study reported a significant amount of serious adverse events. Five case reports were also included, showing decreased depressive symptoms and evidence of increased social condition. CONCLUSIONS: Research on the use of ketamine for ASD and ASD-related conditions is limited. Evidence of improved social condition exists, but further studies should be conducted to increase sample power and test various doses and methods of administration.

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31. Santos M, Aprígio LCS, Lima J, Miranda FDF, Araújo CM, Taveira KVM, Salgado-Azoni CA. Impact of reading intervention on the phonological awareness of children with autism spectrum disorder: a systematic review and meta-analysis. Codas;2024;36(3):e20220336.

PURPOSE: To review studies that have intervention in reading with impacts on phonological awareness in children with autism spectrum disorder. RESEARCH STRATEGIES: Searches took place until February 2021 in Cochrane, Embase, ERIC (Education Resources Information Center), LILACS (Latin American and Caribbean Health Sciences Literature), PubMed/Medline, Scopus, Web of Science and gray literature databases. SELECTION CRITERIA: The review included experimental studies with preschoolers and schoolchildren with ASD. Two independent reviewers selected the studies and, in case of disagreement, a third reviewer was consulted. DATA ANALYSIS: Joanna Briggs Institute checklists were used for risk of bias. A random effects meta-analysis was performed and the certainty of the evidence was assessed using the GRADE tool. RESULTS: Eight studies with some impact on phonological awareness were reviewed. The risk of bias was low and moderate. The certainty of the evidence was low for randomized trials and very low for non-randomised trials. Comparison of pre- and post-therapy on the Preschool Literacy Test (TOPEL) showed that children with ASD improved phonological awareness, with a mean difference between baseline and post-therapy of 6.21 (95% CI = 3.75-8.67; I2 = 0%). CONCLUSION: Shared reading and software activities with words and phrases can alter phonological awareness. These results support further research with larger samples and a detailed description of the intervention to observe its effectiveness in phonological awareness.

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32. Srivastava S, Yang F, Prohl AK, Davis PE, Capal JK, Filip-Dhima R, Bebin EM, Krueger DA, Northrup H, Wu JY, Warfield SK, Sahin M, Zhang B. Abnormality of Early White Matter Development in Tuberous Sclerosis Complex and Autism Spectrum Disorder: Longitudinal Analysis of Diffusion Tensor Imaging Measures. J Child Neurol;2024 (May 15):8830738241248685.

Background: Abnormalities in white matter development may influence development of autism spectrum disorder in tuberous sclerosis complex (TSC). Our goals for this study were as follows: (1) use data from a longitudinal neuroimaging study of tuberous sclerosis complex (TACERN) to develop optimized linear mixed effects models for analyzing longitudinal, repeated diffusion tensor imaging metrics (fractional anisotropy, mean diffusivity) pertaining to select white matter tracts, in relation to positive Autism Diagnostic Observation Schedule-Second Edition classification at 36 months, and (2) perform an exploratory analysis using optimized models applied to all white matter tracts from these data. Methods: Eligible participants (3-12 months) underwent brain magnetic resonance imaging (MRI) at repeated time points from ages 3 to 36 months. Positive Autism Diagnostic Observation Schedule-Second Edition classification at 36 months was used. Linear mixed effects models were fine-tuned separately for fractional anisotropy values (using fractional anisotropy corpus callosum as test outcome) and mean diffusivity values (using mean diffusivity right posterior limb internal capsule as test outcome). Fixed effects included participant age, within-participant longitudinal age, and autism spectrum disorder diagnosis. Results: Analysis included data from n = 78. After selecting separate optimal models for fractional anisotropy and mean diffusivity values, we applied these models to fractional anisotropy and mean diffusivity of all 27 white matter tracts. Fractional anisotropy corpus callosum was related to positive Autism Diagnostic Observation Schedule-Second Edition classification (coefficient = 0.0093, P = .0612), and mean diffusivity right inferior cerebellar peduncle was related to positive Autism Diagnostic Observation Schedule-Second Edition classification (coefficient = -0.00002071, P = .0445), though these findings were not statistically significant after multiple comparisons correction. Conclusion: These optimized linear mixed effects models possibly implicate corpus callosum and cerebellar pathology in development of autism spectrum disorder in tuberous sclerosis complex, but future studies are needed to replicate these findings and explore contributors of heterogeneity in these models.

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33. Tian Y, Qiao H, Zhu LQ, Man HY. Sexually dimorphic phenotypes and the role of androgen receptors in UBE3A-dependent autism spectrum disorder. bioRxiv;2024 (May 4)

Autism spectrum disorders (ASDs) are characterized by social, communication, and behavioral challenges. UBE3A is one of the most common ASD genes. ASDs display a remarkable sex difference with a 4:1 male to female prevalence ratio; however, the underlying mechanism remains largely unknown. Using the UBE3A-overexpressing mouse model for ASD, we studied sex differences at behavioral, genetic, and molecular levels. We found that male mice with extra copies of Ube3A exhibited greater impairments in social interaction, repetitive self-grooming behavior, memory, and pain sensitivity, whereas female mice with UBE3A overexpression displayed greater olfactory defects. Social communication was impaired in both sexes, with males making more calls and females preferring complex syllables. At the molecular level, androgen receptor (AR) levels were reduced in both sexes due to enhanced degradation mediated by UBE3A. However, AR reduction significantly dysregulated AR target genes only in male, not female, UBE3A-overexpressing mice. Importantly, restoring AR levels in the brain effectively normalized the expression of AR target genes, and rescued the deficits in social preference, grooming behavior, and memory in male UBE3A-overexpressing mice, without affecting females. These findings suggest that AR and its signaling cascade play an essential role in mediating the sexually dimorphic changes in UBE3A-dependent ASD.

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34. Wadle SL, Ritter TC, Wadle TTX, Hirtz JJ. Topography and Ensemble Activity in the Auditory Cortex of a Mouse Model of Fragile X Syndrome. eNeuro;2024 (May);11(5)

Autism spectrum disorder (ASD) is often associated with social communication impairments and specific sound processing deficits, for example, problems in following speech in noisy environments. To investigate underlying neuronal processing defects located in the auditory cortex (AC), we performed two-photon Ca(2+) imaging in FMR1 (fragile X messenger ribonucleoprotein 1) knock-out (KO) mice, a model for fragile X syndrome (FXS), the most common cause of hereditary ASD in humans. For primary AC (A1) and the anterior auditory field (AAF), topographic frequency representation was less ordered compared with control animals. We additionally analyzed ensemble AC activity in response to various sounds and found subfield-specific differences. In A1, ensemble correlations were lower in general, while in secondary AC (A2), correlations were higher in response to complex sounds, but not to pure tones. Furthermore, sound specificity of ensemble activity was decreased in AAF. Repeating these experiments 1 week later revealed no major differences regarding representational drift. Nevertheless, we found subfield- and genotype-specific changes in ensemble correlation values between the two times points, hinting at alterations in network stability in FMR1 KO mice. These detailed insights into AC network activity and topography in FMR1 KO mice add to the understanding of auditory processing defects in FXS.

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35. Wilson RB, Vangala S, Reetzke R, Pierges A, Ozonoff S, Miller M. Objective measurement of movement variability using wearable sensors predicts ASD outcomes in infants at high likelihood for ASD and ADHD. Autism Res;2024 (May 15)

Early motor delays and differences are common among children with autism spectrum disorder (ASD) and attention-deficit/hyperactivity disorder (ADHD). Yet, little work has shown whether there are early atypical motor signs that differentiate these groups. Quantitative measures of movement variability hold promise for improving the identification of subtle and specific differences in motor function among infants and toddlers at high likelihood for ASD and ADHD. To this end, we created a novel quantitative measure of movement variability (movement curvature) and conducted a preliminary investigation as to whether this measure improves outcome predictions. We used a wearable triaxial accelerometer to evaluate continuous motion-based activity in infants at high and low likelihood for ASD and ADHD at 12, 18, 24, and 36 months of age. At 36 months, participants were categorized into three outcome groups: ASD (n = 19), ADHD concerns (n = 17), and a comparison group (n = 82). We examined group differences in movement curvature and whether movement curvature is predictive of a later ASD or ADHD concerns classification. We found that movement curvature was significantly lower in infants with later ASD diagnosis at 18, 24, and 36 months of age compared to infants with either ADHD concerns or those in the comparison group. Movement curvature was also a significant predictor of ASD at 18, 24, and 36 months (AUC 0.66-0.71; p = 0.005-0.039) and when adjusting for high ASD likelihood at 18 and 24 months (AUC 0.90, p = 0.05-0.019). These results indicate that lower movement curvature may be a feature of early motor differences in infants with later ASD diagnosis as early as 18 months of age.

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36. Xie X, Zhou R, Fang Z, Zhang Y, Wang Q, Liu X. Seeing beyond words: Visualizing autism spectrum disorder biomarker insights. Heliyon;2024 (May 15);10(9):e30420.

OBJECTIVE: This study employs bibliometric and visual analysis to elucidate global research trends in Autism Spectrum Disorder (ASD) biomarkers, identify critical research focal points, and discuss the potential integration of diverse biomarker modalities for precise ASD assessment. METHODS: A comprehensive bibliometric analysis was conducted using data from the Web of Science Core Collection database until December 31, 2022. Visualization tools, including R, VOSviewer, CiteSpace, and gCLUTO, were utilized to examine collaborative networks, co-citation patterns, and keyword associations among countries, institutions, authors, journals, documents, and keywords. RESULTS: ASD biomarker research emerged in 2004, accumulating a corpus of 4348 documents by December 31, 2022. The United States, with 1574 publications and an H-index of 213, emerged as the most prolific and influential country. The University of California, Davis, contributed significantly with 346 publications and an H-index of 69, making it the leading institution. Concerning journals, the Journal of Autism and Developmental Disorders, Autism Research, and PLOS ONE were the top three publishers of ASD biomarker-related articles among a total of 1140 academic journals. Co-citation and keyword analyses revealed research hotspots in genetics, imaging, oxidative stress, neuroinflammation, gut microbiota, and eye tracking. Emerging topics included « DNA methylation, » « eye tracking, » « metabolomics, » and « resting-state fMRI. » CONCLUSION: The field of ASD biomarker research is dynamically evolving. Future endeavors should prioritize individual stratification, methodological standardization, the harmonious integration of biomarker modalities, and longitudinal studies to advance the precision of ASD diagnosis and treatment.

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37. Zhou X, Hong X, Wong PCM. Autistic Traits Modulate Social Synchronizations Between School-Aged Children: Insights From Three fNIRS Hyperscanning Experiments. Psychol Sci;2024 (May 14):9567976241237699.

The current study investigated how autistic traits modulate peer interactions using functional near-infrared spectroscopy (fNIRS) hyperscanning. Across three experiments, we tested the effect of copresence, joint activity, and a tangible goal during cooperative interactions on interbrain coherence (IBC) in school-aged children between 9 and 11 years old. Twenty-three dyads of children watched a video alone or together in Experiment 1, engaged in joint or self-paced book reading in Experiment 2, and pretended to play a Jenga game or played for real in Experiment 3. We found that all three formats of social interactions increased IBC in the frontotemporoparietal networks, which have been reported to support social interaction. Further, our results revealed the shared and unique interbrain connections that were predictive of the lower and higher parent-reported autism-spectrum quotient scores, which indicated child autistic traits. Results from a convergence of three experiments provide the first evidence to date that IBC is modulated by child autistic traits.

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