OBJECTIVE: Sibling relationships in early childhood can have a positive impact on children\'s social interaction and communication skills. Similarly, autistic children can benefit from interactions with their siblings, who can serve as readily available partners for social interaction. However, there is a lack of research on the effects of siblings based on specific characteristics of the sibling. Therefore, the aim of this study is to compare social interactions and communication skills of autistic children based on sibling status and characteristics.
METHODS: We conducted a retrospective data review involving 895 autistic children and their siblings at Seoul National University Bundang Hospital. Variety of diagnostic assessments or questionnaires were administered. Based on the characteristics of the data, Quade\'s test for nonparametric analysis of covariance was used to compare autism-related symptoms and levels of functioning of the autistic child according to 1) sibling status, 2) birth order, 3) sex, and 4) diagnosis of the sibling. Pearson correlation was used to explore associations between the sibling age gap and different clinical scores.
RESULTS: Having siblings was associated with fewer difficulties in restricted and repetitive behaviors. Based on the comparison of the Autism Diagnostic Interview-Revised scores, autistic children with multiple siblings demonstrated better nonverbal behaviors. Autistic children with autistic siblings experienced greater difficulties in social interactions and communications, such as peer relationships, sharing enjoyment, and engaging in social imitative play.
CONCLUSIONS: The study revealed differences in social interactions and communication skills of autistic children based on sibling status, birth order, affected sibling, age gap, and sex.

UNASSIGNED: One of the core features of autism spectrum disorder (ASD) is restricted, repetitive patterns of behavior, interests and activities (RRBs). RRBs are known to adversely affect cognition and adaptive functioning. We explored the relationship of RRBs with cognition and adaptive functioning in children with ASD in an Asian setting.
UNASSIGNED: This cross-sectional study was conducted at a tertiary developmental pediatrics center in Singapore from September 2019 to October 2021. Parent-child dyads (parents and their children ≤7 years old diagnosed with ASD) were recruited. Parents completed the Repetitive Behavior Questionnaire-2 (RBQ-2), which reports total score and two subscales - Motor/Sensory Behaviors (RBQ-2 MS) and Rigidity/Routines/Preoccupation with Restricted Interests (RBQ-2 RRPRI). Standardized assessments included Mullen Scales of Early Learning (MSEL) and Vineland Adaptive Behavior Scales (VABS-II). Data analysis utilized descriptive statistics and Pearson\'s correlation.
UNASSIGNED: Parents of 113 children [75.2% male, mean (SD) age 5.0 (1.2) years] participated. Median (IQR) RBQ-2 score was 29.0 (11.0). Significant negative correlations (adjusted for age, gender and family history of ASD) were observed for total RBQ-2 scores with MSEL ELC scores (r = -0.248, n = 101, p = 0.014) and VABS-II ABC scores (r = -0.281, n = 88, p = 0.009). Specifically, these correlations of fair strength were seen only with the RBQ-2 MS subscale for both ELC (r = -0.321, n = 101, p = 0.001) and ABC (r = -0.3478, n = 88, p = 0.001).
UNASSIGNED: In children with ASD, severity of RRBs correlated with adverse cognition and adaptive functioning measures in our study, consistent with Western literature. While our study does not show causality, it adds to literature serving as a foundation for further research for both clinicians and researchers to target RRBs in improving outcomes with children in ASD.

Restricted and repetitive behaviors (RRBs) are one of the characteristics of various neuropsychiatric disorders with complex and diverse molecular mechanisms. Repetitive self-grooming behavior is one of the manifestations of RRBs in humans and rodents. Research on the neural mechanism of repetitive self-grooming behavior is expected to reveal the underlying logic of the occurrence of RRBs. Pax2 is an important member of the paired-box transcription factor family. It is expressed in different regions of the developing central nervous system. Our previous study showed that Pax2 heterozygous gene knockout mice (Pax2+/- KO mice) exhibit significantly increased self-grooming, which suggests that the Pax2 gene is involved in the control of self-grooming behavior, but the molecular mechanism is still unclear. In this study, we further constructed the Pax2 neuron-specific deletion mice (Nestin-Pax2 mice). Targeted metabolomics and transcriptomics techniques was used to analyze. The results showed that there is an excitatory/inhibitory imbalance of the neurotransmitter system and the Arc gene was significantly up-regulated in the prefrontal cortex (PFC) of Nestin-Pax2 mice. This study suggests that the potential regulatory mechanism of the increased repetitive self-grooming behavior in Pax2 gene deletion mice is that the deletion of the Pax2 gene affects the expression of Arc in the PFC, leading to impaired synaptic plasticity and excitatory/inhibitory imbalance, and participating in the occurrence of repetitive self-grooming behavior.

The pupil light reflex (PLR), a marker of neuronal response to light, is a well-studied index of autonomic functioning. Studies have found that autistic children and adults have slower and weaker PLR responses compared to non-autistic peers, suggesting lower autonomic control. Altered autonomic control has also been associated with increased sensory difficulties in autistic children. With autistic traits varying in the general population, recent studies have begun to examine similar questions in non-autistic individuals. The current study looked at the PLR in relation to individual differences in autistic traits in non-autistic children and adults, asking how differences in the PLR could lead to variation in autistic traits, and how this might change across development. Children and adults completed a PLR task as a measure of sensitivity to light and autonomic response. Results showed that, in adults, increased levels of restricted and repetitive behaviors (RRB) were associated with a weaker and slower PLR. However, in children, PLR responses were not associated with autistic traits. Differences in PLR were also found across age groups, with adults showing smaller baseline pupil diameter and stronger PLR constriction as compared with children. The current study expanded on past work to examine the PLR and autistic traits in non-autistic children and adults, and the relevance of these findings to sensory processing difficulties is discussed. Future studies should continue to examine the neural pathways that might underlie the links between sensory processing and challenging behaviors.

Sex differences in the prevalence of neurodevelopmental disorders are particularly evident in autism spectrum disorder (ASD). Heterogeneous symptom presentation and the potential of measurement bias hinder early ASD detection in females and may contribute to discrepant prevalence estimates. We examined trajectories of social communication (SC) and restricted and repetitive behaviors (RRBs) in a sample of infant siblings of children with ASD, adjusting for age- and sex-based measurement bias. We hypothesized that leveraging a prospective elevated familial likelihood sample, deriving data-driven behavioral constructs, and accounting for measurement bias would reveal less discrepant sex ratios than are typically seen in ASD.
We conducted direct assessments of ASD symptoms at 6 to 9, 12 to 15, 24, and 36 to 60 months of age (total nobservations = 1254) with infant siblings of children with ASD (n = 377) and a lower ASD-familial-likelihood comparison group (n = 168; nobservations = 527). We established measurement invariance across age and sex for separate models of SC and RRB. We then conducted latent class growth mixture modeling with the longitudinal data and evaluated for sex differences in trajectory membership.
We identified 2 latent classes in the SC and RRB models with equal sex ratios in the high-concern cluster for both SC and RRB. Sex differences were also observed in the SC high-concern cluster, indicating that girls classified as having elevated social concerns demonstrated milder symptoms than boys in this group.
This novel approach for characterizing ASD symptom progression highlights the utility of assessing and adjusting for sex-related measurement bias and identifying sex-specific patterns of symptom emergence.

Individuals with autism spectrum disorder (ASD) engage in less physical activity than typically-developing peers. This can result in serious negative consequences for individual well-being and may contribute to the physical, behavioral, and emotional challenges associated with ASD. This study explored the potential benefits of trainer-led, individualized, physical fitness sessions specialized for ASD. Eleven individuals (ages 7-24 years) with ASD were assessed at baseline and following 15 fitness sessions. Participants demonstrated improvements in core and lower-body strength and reductions in restricted and repetitive patterns of behavior, along with non-significant but marked reductions in issues with daytime sleepiness. Results suggest the merit of specialized fitness programs and emphasize the need for larger and more rigorous research studies on this topic.

UNASSIGNED: Restricted and repetitive behaviors (RRBs) are a core symptom in the diagnosis of autism spectrum disorder (ASD). The complexity of behavioral patterns has called for the creation of phenotypically homogeneous subgroups among individuals with ASD. The purpose of this study was 1) to investigate the different types of RRBs and 2) to explore whether subgroups created by RRBs would show unique levels of functioning in toddlers and young children with ASD.
UNASSIGNED: A total of 313 children with ASD, aged 12-42 months were included in the analysis. The Autism Diagnostic Interview-Revised was used to obtain information on the different types of RRBs by grouping 15 items into six categories. The Vineland Adaptive Behaviors Scale, a parent-reported questionnaire, was used to measure adaptive functioning. A portion of the children were analyzed separately for verbal-related RRBs based on their expressive language level. Two-step cluster analysis using RRB groups as features was used to create subgroups. Analysis of covariance while covarying for age and language was performed to explore the clinical characteristics of each cluster group.
UNASSIGNED: Sensory-related RRBs were the most prevalent, followed by circumscribed interests, interest in objects, resistance to change, and repetitive body movements. A subset of the children was analyzed separately to explore verbal-related RRBs. Four cluster groups were created based on reported RRBs, with multiple RRBs demonstrating significant delays in adaptive functioning.
UNASSIGNED: Heterogeneity of RRBs emerges at a young age. The different patterns of RRBs can be used as valuable information to determine developmental trajectories with better implications for treatment approaches.

UNASSIGNED: Autism spectrum disorder (ASD) is a lifelong condition. Autistic symptoms can persist into adulthood. Studies have reported that autistic symptoms generally improved in adulthood, especially restricted and repetitive behaviors and interests (RRBIs). We explored brain networks that are related to differences in RRBIs in individuals with ASDs among different ages.
UNASSIGNED: We enrolled 147 ASD patients from the Autism Brain Imaging Data Exchange II (ABIDEII) database. The participants were divided into four age groups: children (6-9 years old), younger adolescents (10-14 years old), older adolescents (15-19 years old), and adults (≥20 years old). RRBIs were evaluated using the Repetitive Behaviors Scale-Revised 6. We first explored differences in RRBIs between age groups using the Kruskal-Wallis test. Associations between improvements in RRBIs and age were analyzed using a general linear model. We then analyzed RRBIs associated functional connectivity (FC) links using the network-based statistic method by adjusting covariates. The association of the identified FC with age group, and mediation function of the FC on the association of age-group and RRBI were further analyzed.
UNASSIGNED: Most subtypes of RRBIs improved with age, especially stereotyped behaviors, ritualistic behaviors, and restricted behaviors (p = 0.012, 0.014, and 0.012, respectively). Results showed that 12 FC links were closely related to overall RRBIs, 17 FC links were related to stereotyped behaviors. Among the identified 29 FC links, 15 were negatively related to age-groups. The mostly reported core brain regions included superior occipital gyrus, insula, rolandic operculum, angular, caudate, and cingulum. The decrease in FC between the left superior occipital lobe and right angular (effect = -0.125 and -0.693, respectively) and between the left insula and left caudate (effect = -0.116 and -0.664, respectively) might contribute to improvements in multiple RRBIs with age.
UNASSIGNED: We identified improvements in RRBIs with age in ASD patients, especially stereotyped behaviors, ritualistic behaviors, and restricted behaviors. The decrease in FC between left superior occipital lobe and right angular and between left insula and left caudate might contribute to these improvements. Our findings improve our understanding of the pathogenesis of RRBIs and suggest potential intervention targets to improve prognosis in adulthood.

There is still no approved medication for the core symptoms of autism spectrum disorder (ASD). This network meta-analysis investigated pharmacological and dietary-supplement treatments for ASD.
We searched for randomized-controlled-trials (RCTs) with a minimum duration of seven days in ClinicalTrials.gov, EMBASE, MEDLINE, PsycINFO, WHO-ICTRP (from inception up to July 8, 2018), CENTRAL and PubMed (up to November 3, 2021). The co-primary outcomes were core symptoms (social-communication difficulties-SCD, repetitive behaviors-RB, overall core symptoms-OCS) measured by validated scales and standardized-mean-differences (SMDs). Associated symptoms, e.g., irritability/aggression and attention-deficit/hyperactivity disorder (ADHD) symptoms, dropouts and important side-effects, were investigated as secondary outcomes. Studies in children/adolescents and adults were analyzed separately in random-effects pairwise and network meta-analyses.
We analyzed data for 41 drugs and 17 dietary-supplements, from 125 RCTs (n = 7450 participants) in children/adolescents and 18 RCTs (n = 1104) in adults. The following medications could improve at least one core symptom domain in comparison with placebo: aripiprazole (k = 6 studies in analysis, SCD: SMD = 0.27 95% CI [0.09, 0.44], RB: 0.48 [0.26, 0.70]), atomoxetine (k = 3, RB:0.49 [0.18, 0.80]), bumetanide (k = 4, RB: 0.35 [0.09, 0.62], OCS: 0.61 [0.31, 0.91]), and risperidone (k = 4, SCM: 0.31 [0.06, 0.55], RB: 0.60 [0.29, 0.90]; k = 3, OCS: 1.18 [0.75, 1.61]) in children/adolescents; fluoxetine (k = 1, RB: 1.20 [0.45, 1.96]), fluvoxamine (k = 1, RB: 1.04 [0.27, 1.81]), oxytocin (k = 6, RB:0.41 [0.16, 0.66]) and risperidone (k = 1, RB: 0.97 [0.21,1.74]) in adults. There were some indications of improvement by carnosine, haloperidol, folinic acid, guanfacine, omega-3-fatty-acids, probiotics, sulforaphane, tideglusib and valproate, yet imprecise and not robust. Confidence in these estimates was very low or low, except moderate for oxytocin. Medications differed substantially in improving associated symptoms, and in their side-effect profiles.
Most of the studies were inadequately powered (sample sizes of 20-80 participants), with short duration (8-13 weeks), and about a third focused on associated symptoms. Networks were mainly star-shaped, and there were indications of reporting bias. There was no optimal rating scale measuring change in core symptoms.
Some medications could improve core symptoms, although this could be likely secondary to the improvement of associated symptoms. Evidence on their efficacy and safety is preliminary; therefore, routine prescription of medications for the core symptoms cannot be recommended. Trial registration PROSPERO-ID CRD42019125317.

The neuroanatomy of autism spectrum disorder (ASD) shows highly heterogeneous developmental trajectories across individuals. Mapping atypical brain development onto clinical phenotypes, and establishing their molecular underpinnings, is therefore crucial for patient stratification and subtyping. In this longitudinal study we examined intra- and inter-individual differences in the developmental trajectory of cortical thickness (CT) in childhood and adolescence, and their genomic underpinnings, in 33 individuals with ASD and 37 typically developing controls (aged 11-18 years). Moreover, we aimed to link regional atypical CT development to intra-individual variations in restricted and repetitive behavior (RRB) over a two-year time period. Individuals with ASD showed significantly reduced cortical thinning in several of the brain regions functionally related to wider autism symptoms and traits (e.g., fronto-temporal and cingulate cortices). The spatial patterns of the neuroanatomical differences in CT were enriched for genes known to be associated with ASD at a genetic and transcriptomic level. Further, intra-individual differences in CT correlated with within-subject variability in the severity of RRBs. Our findings represent an important step towards characterizing the neuroanatomical underpinnings of ASD across development based upon measures of CT. Moreover, our findings provide important novel insights into the link between microscopic and macroscopic pathology in ASD, as well as their relationship with different clinical ASD phenotypes.