Propranolol, a nonselective beta-adrenergic antagonist, has shown potential for improving anxiety in autistic individuals. Heart rate variability (HRV), a noninvasive cardiac marker of autonomic nervous system functioning, may help identify individuals most likely to benefit from propranolol. Objectives: Determine if baseline resting HRV and other cardiac measures predict the response to propranolol for anxiety and core autism symptomology in autistic children and young adults. Methods: Sixty-two autistic individuals (ages 7–24) participated in a two-phase (i.e., a 12-week randomized controlled trial and a 12-week open-label extension) trial of propranolol. Baseline (i.e., resting state, prior to treatment) HRV and other cardiac measures were obtained from an electrocardiogram. Clinical global impression for anxiety symptoms and overall behavioral treatment impact were assessed after the 12-week trial period. Group-level (i.e., all participants) and responder groups (i.e., strong, minimal, and non-responders to propranolol) were analyzed for treatment effects. Results: HRV variables predicted group-level anxiety response to propranolol, particularly for strong responders. Also, lower baseline values of parasympathetic HRV indices were significantly correlated with greater behavioral improvement after treatment with propranolol. Last, several baseline cardiac variables were associated with improvement in multiple behavioral domains after treatment with propranolol. Conclusions: HRV may be a potential biomarker for predicting reduced anxiety and behavioral symptoms in response to propranolol in autistic children and young adults. Identifying autonomic profiles associated with positive treatment outcomes could guide future personalized interventions in autism. The results presented herein should be regarded as preliminary until the findings are replicated in future clinical trials.

BACKGROUND:The Autism Diagnostic Interview, Revised (ADI-R) is a caregiver interview that is widely used as part of the diagnostic assessment for Autism Spectrum Disorder (ASD). Few large-scale studies have reported the sensitivity and specificity of the ADI-R algorithms, which are based on DSM-IV Autistic Disorder criteria. Kim and Lord (Journal of Autism and Developmental Disorders, 2012, 42, 82) developed revised DSM-5-based toddler algorithms, which are only applicable to children under 4 years. The current study developed DSM-5-based algorithms for children ages 4-17 years and examined their performance compared to clinical diagnosis and to the original DSM-IV-based algorithms. METHODS:Participants included 2,905 cases (2,144 ASD, 761 non-ASD) from clinical-research databanks. Children were clinically referred for ASD-related concerns or recruited for ASD-focused research projects, and their caregivers completed the ADI-R as part of a comprehensive diagnostic assessment. Items relevant to DSM-5 ASD criteria were selected for the new algorithms primarily based on their ability to discriminate ASD from non-ASD cases. Algorithms were created for individuals with and without reported use of phrase speech. Confirmatory factor analysis tested the fit of a DSM-5-based two-factor structure. ROC curve analyses examined the diagnostic accuracy of the revised algorithms compared to clinical diagnosis. RESULTS:The two-factor structure of the revised ADI-R algorithms showed adequate fit. Sensitivity of the original ADI-R algorithm ranged from 74% to 96%, and specificity ranged from 38% to 83%. The revised DSM-5-based algorithms performed similarly or better, with sensitivity ranging from 77% to 99% and specificity ranging from 71% to 92%. CONCLUSIONS:In this large sample aggregated from US clinical-research sites, the original ADI-R algorithm showed adequate diagnostic validity, with poorer specificity among individuals without phrase speech. The revised DSM-5-based algorithms introduced here performed comparably to the original algorithms, with improved specificity in individuals without phrase speech. These revised algorithms offer an alternative method for summarizing ASD symptoms in a DSM-5-compatible manner.

Fatigue is associated with numerous harmful physical and mental health outcomes. Despite the established relationship between sleep and fatigue, research examining sleep variability within a person (i.e. intraindividual variability; IIV) and fatigue is limited. In addition, the associations between child and parent sleep regarding parent fatigue have not been explicitly explored, which could be relevant for parents of autistic children with increased sleep disturbance likelihood. The current study used two weeks of objective sleep (actigraphy) and subjective fatigue data from 81 parents and their children to explore associations among child sleep IIV, parent sleep IIV, and parent average daily fatigue, including evaluating evidence for mediation. Sleep IIV was estimated using a validated Bayesian model. Linear regression analyses indicated that greater parent total sleep time IIV predicted significantly higher fatigue levels. Child sleep IIV was unrelated to parent sleep IIV and fatigue, unsupportive of hypothesized mediation. Similarly, post hoc analyses examining child sleep averages, parent total sleep time IIV, and average parent fatigue were insignificant. Findings cautiously support the uniqueness of total sleep time IIV within parental sleep’s relationship with fatigue, independent of child sleep. Objective sleep IIV should continue to be examined in addition to average levels. Lay abstract Fatigue is associated with numerous harmful physical and mental health outcomes. Despite research indicating a relationship between fatigue and sleep, there has been a limited focus on how the variability of a person’s sleep may be associated with fatigue. In addition, previous studies have not explicitly explored relationships among child sleep, parent sleep, and parent fatigue. Increasing knowledge about this area of research could be particularly relevant for families with autistic children with an increased likelihood of sleep disturbances. The current study used two weeks of objective sleep (actigraphy) data and subjective ratings of parent fatigue from 81 parents and their autistic children to examine associations among child and parent within-person sleep variability regarding average parent fatigue levels. Evidence was assessed for the role of parent sleep variability in hypothesized connections between child sleep variability and parent fatigue. We found that only greater variability in parents’ total sleep time was associated with higher levels of parents’ average daily fatigue rating over the two weeks. Child sleep variability was not significantly associated with parent sleep variability or average daily fatigue. In addition, average levels of child sleep were unrelated to parent total sleep time variability and fatigue. Although cautious interpretation is required, findings support the idea that variability in total sleep time may be a unique aspect of parental sleep’s association with fatigue, independent of child sleep. In addition, sleep variability could be important to consider when examining sleep in addition to average levels of parameters like total sleep time.

BackgroundTranscutaneous auricular vagus nerve stimulation (taVNS) has potential clinical application for autism spectrum disorder (ASD). At-home sessions are necessary to allow delivery of repeated sessions, and remove burden on patients for daily visits, and reduce costs of clinic delivery. Our objective was to validate a protocol for remote supervised administration for home delivery of taVNS using specially designed equipment and platform.MethodsAn open-label design was followed involving administration by caretakers to 12 patients with ASD (ages:7-16). Daily 1-h sessions over 2 weeks were administered under remote supervision. The primary outcome was feasibility, which was assessed by completion rate, stimulation tolerability, and confirmation of programmed stimulation delivery. The secondary measures were initial efficacy assessed by Childhood Anxiety Sensitivity Index-Revised (CASI-R), Parent Rated Anxiety Scale for Youth with ASD (PRAS-ASD), and Clinician Global Impression (CGI) scales. Sleep measures were also tracked using Cleveland Adolescent Sleep Questionnaire (CASQ).ResultsAcross 132 sessions, we obtained an 88.5% completion rate. A total of 22 expected adverse events were reported with headache being the most common followed by transient pain, itchiness, and stinging at the electrode site. One subject dropped out of the study unrelated to the stimulation or the study. Average scores of anxiety (CASI-R, PRAS-ASD, and CGI) and sleepiness (CASQ) were all improved at the 2 week time point. While not powered to determine efficacy, benefits were suggested in this open label pilot.ConclusionRemotely supervised, proxy-administered, at-home delivery of taVNS is feasible in patients with ASD. Initial efficacy supports pursuing larger scale trials.

Background Heterogeneous mental health outcomes during the COVID-19 pandemic are documented in the general population. Such heterogeneity has not been systematically assessed in youth with autism spectrum disorder (ASD) and related neurodevelopmental disorders (NDD). To identify distinct patterns of the pandemic impact and their predictors in ASD/NDD youth, we focused on pandemic-related changes in symptoms and access to services. Methods Using a naturalistic observational design, we assessed parent responses on the Coronavirus Health and Impact Survey Initiative (CRISIS) Adapted For Autism and Related neurodevelopmental conditions (AFAR). Cross-sectional AFAR data were aggregated across 14 European and North American sites yielding a clinically well-characterized sample of N = 1275 individuals with ASD/NDD (age = 11.0 ± 3.6 years; n females = 277). To identify subgroups with differential outcomes, we applied hierarchical clustering across eleven variables measuring changes in symptoms and access to services. Then, random forest classification assessed the importance of socio-demographics, pre-pandemic service rates, clinical severity of ASD-associated symptoms, and COVID-19 pandemic experiences/environments in predicting the outcome subgroups. Results Clustering revealed four subgroups. One subgroup— broad symptom worsening only (20%)—included youth with worsening across a range of symptoms but with service disruptions similar to the average of the aggregate sample. The other three subgroups were, relatively, clinically stable but differed in service access: primarily modified services (23%), primarily lost services (6%), and average services/symptom changes (53%). Distinct combinations of a set of pre-pandemic services, pandemic environment (e.g., COVID-19 new cases, restrictions), experiences (e.g., COVID-19 Worries), and age predicted each outcome subgroup. Limitations Notable limitations of the study are its cross-sectional nature and focus on the first six months of the pandemic. Conclusions Concomitantly assessing variation in changes of symptoms and service access during the first phase of the pandemic revealed differential outcome profiles in ASD/NDD youth. Subgroups were characterized by distinct prediction patterns across a set of pre- and pandemic-related experiences/contexts. Results may inform recovery efforts and preparedness in future crises; they also underscore the critical value of international data-sharing and collaborations to address the needs of those most vulnerable in times of crisis.

Background: Typical adults most frequently orient their attention to other people’s eyes, whereas individuals with autism spectrum disorder (ASD) orient their attention to other people’s mouths. Typical adults also reveal visuospatial biases on tasks such as vertical and horizontal line bisections. Therefore, the difference in face viewing might be related to a more general group difference in the allocation of vertical attention. Objective: To use vertical line bisection and quadrisection tasks to evaluate whether individuals with ASD have a more downward-oriented vertical attentional bias than do typical individuals. Method: We recruited 20 individuals with ASD and 20 control participants matched for age (6–23 years), IQ, and sex. We asked the individuals to bisect and quadrisect lines on the top and bottom when the vertical lines were placed at the intersection of their right, left, and center egocentric sagittal planes and their coronal plane. The distances from the true midpoint and quadripoint were measured, and between-group performances were compared. Results: No significant difference was found between the ASD and control groups for vertical line bisections or lower line quadrisections. However, when the ASD group was compared with the control group for higher line quadrisections, the ASD group exhibited a greater upward deviation. Conclusion: There is no downward vertical attentional spatial bias associated with ASD that could help to explain these individuals’ attentional bias toward the mouth. However, additional studies are required to learn if this atypical upward vertical attentional bias might account for some of the symptoms and signs associated with ASD.

Autism spectrum disorder (ASD) is characterized by impaired social communication and is also frequently characterized by co-occurring anxiety. Propranolol is widely utilized to treat performance and public speaking anxiety. Single-dose psychopharmacological challenge studies suggested benefits using propranolol for verbal tasks and social interaction. We conducted a double-blinded, placebo-controlled trial of the β-adrenergic antagonist propranolol in ASD for social interaction, anxiety, and language. Seventy-four participants with ASD, age 7–24 years, were enrolled and randomized to a 12-week course of propranolol or placebo, with blinded assessments at baseline, 6 weeks, and 12 weeks. The primary outcome was the General Social Outcome Measure-2 (GSOM-2) for social interaction, and secondary outcomes were the Clinician Global Clinical Impression-Improvement (CGI-I) ratings independently conducted for social interaction, anxiety, and language at 6 weeks and 12 weeks. Sixty-nine participants completed the 12-week visit. No significant effect of drug was found for the GSOM-2 or the CGI-I for social interaction or language. CGI-I for anxiety showed greater improvement with propranolol at the 12-week time point (p = 0.045, odds ratio = 2.58 (95

Abstract Introduction Fatigue is related to various adverse health outcomes. Mean levels of some common sleep variables, such as total sleep time (TST), sleep onset latency (SOL), and wake after sleep onset (WASO), have been associated with fatigue. However, intraindividual variability (IIV) of sleep parameters might play an independent role in sleep’s relationship with fatigue. Understanding fatigue is particularly important for parents of children with autism spectrum disorder (ASD) given fatigue's negative associations with positive parenting and implementation of child interventions. This preliminary study examined linear associations between subjective sleep IIV and mean fatigue levels in parents of children on the autism spectrum. Methods The sample included 66 parents who expressed interest in a behavioral treatment sleep study for their school-aged children diagnosed with ASD (6-12 years old; NCT04545606). All parents (Mage=37.03, SD=6.53; 91% female) completed daily electronic diaries over a two-week baseline period. Daily fatigue rating was collected using a visual analog scale (0-100) and averaged within individuals. Within-individual standard deviations of subjective TST, SOL, and WASO were calculated to estimate IIV. Data were analyzed in R (v4.1.2) using multiple linear regression models controlling for participant age, gender, and individual sleep parameter means. Results Bivariate correlations between sleep variable IIV and average fatigue indicated a positive association between TST variability and average fatigue, r(64)=0.33, p<0.01. Multiple regression analyses showed that greater IIV of TST was associated with higher average fatigue (β=0.14, 95%CI [0.01, 0.27], sr2=0.06, p=0.041). No significant associations were found between average fatigue level and IIV of WASO or SOL. Conclusion Results suggest that greater TST variability may be one factor independently contributing to higher fatigue levels in parents of children on the autism spectrum, which warrants further examination of sleep variability in this population. Future research could explore IIV of additional sleep parameters, fatigue IIV as an outcome, alternative methods of sleep measurement, and study designs that address causation. Increased insight into these connections might inform the importance of considering sleep interventions for both children and parents, and potential subsequent treatment benefits. Support (If Any) MU Research Board Grant (McCrae, PI); Department of Defense Autism Research Program (McCrae, PI; W81XWH2010399).

Increasing numbers of children with known genetic conditions and/or intellectual disability are referred for evaluation of autism spectrum disorder (ASD), highlighting the need to refine autism symptom measures to facilitate differential diagnoses in children with cognitive and language impairments. Previous studies have reported decreased specificity of ASD screening and diagnostic measures in children with intellectual disability. However, little is known about how cognitive and language abilities impact the measurement of specific ASD symptoms in this group. We aggregated a large sample of young children (N = 1196; aged 31–119 months) to examine measurement invariance of ASD symptoms among minimally verbal children within the context of the Autism Diagnostic Observation Schedule (ADOS) Module 1. Using confirmatory factor analysis (CFA) and moderated non-linear factor analysis (MNLFA), we examined how discrete behaviors were differentially associated with the latent symptom domains of social communication impairments (SCI) and restricted and repetitive behaviors (RRB) across spoken language levels and non-verbal mental age groupings. While the two-factor structure of SCI and RRB held consistently across language and cognitive levels, only partial invariance was observed for both ASD symptom domains of SCI and RRB. Specifically, four out of the 15 SCI items and one out of the three RRB items examined showed differential item functioning between children with “Few to No Words” and those with “Some Words”; and one SCI item and one RRB item showed differential item functioning across non-verbal mental age groups. Moreover, even after adjusting for the differential item functioning to reduce measurement bias across groups, there were still differences in ASD symptom domain scores across spoken language levels. These findings further underscore the influence of spoken language level on measurement of ASD symptoms and the importance of measuring ASD symptoms within refined spoken language levels, even among those with minimal verbal abilities.

Abstract Introduction Research indicates parent and child sleep onset latency (SOL) are positively correlated. In addition, parents who have difficulty sleeping may be more tired and report using negative parenting behaviors, such as verbal hostility. Experiencing verbal hostility may increase child anxiety and make it harder for them to fall asleep. Given that up to 80% of children with ASD experience sleep problems, it is important to understand potential relations among sleep and parenting behavior in this population. The current study examined whether verbal hostility moderated the relationship between parent and child SOL. Methods The sample (N=56) consisted of parents (90% female) reporting on their children aged 6-12 (M=8.63, SD = 2.00; 77% male) who expressed interest in a study exploring behavioral treatments for sleep. All children were diagnosed with ASD and had parent reported sleep complaints (e.g., difficulty falling asleep, waking up in the night). Baseline data were examined in the current analyses. Measures included an average of parent and child SOL on daily sleep diaries over 14 days of baseline. Verbal hostility was measured using the verbal hostility subscale on the Parenting Styles and Dimensions Questionnaire – Short Version. Covariates included child and parent age. Results Moderation analyses were conducted using SPSS PROCESS. Parent and child SOL were significantly correlated (r(55)=.28, p=.04). Parent nor child SOL were correlated with verbal hostility. The interaction between parent SOL and verbal hostility t (1, 55) = 5.34, p = .02 was significantly associated with child SOL, such that higher levels of verbal hostility exacerbated the association between greater parent and child SOL. Conclusion These results suggest that the association between parent and child SOL depends in part on the level of verbal hostility a parent uses to discipline their child with ASD. Future research should utilize longitudinal and experimental methodology to determine the causality of these relationships. In addition, teaching positive parenting techniques to parents of children with ASD may be an important component to behavioral sleep treatment so that both child sleep and disciplinary strategies are targeted. Support (If Any) United States Department of Defense USAMRAA Autism Research Program (McCrae, PI; CTA W81XWH2010399).

Defining different genetic subtypes of autism spectrum disorder (ASD) can enable the prediction of developmental outcomes. Based on minor physical and major congenital anomalies, we categorize 325 Canadian children with ASD into dysmorphic and nondysmorphic subgroups. We develop a method for calculating a patient-level, genome-wide rare variant score (GRVS) from whole-genome sequencing (WGS) data. GRVS is a sum of the number of variants in morphology-associated coding and non-coding regions, weighted by their effect sizes. Probands with dysmorphic ASD have a significantly higher GRVS compared to those with nondysmorphic ASD ( P = 0.03). Using the polygenic transmission disequilibrium test, we observe an over-transmission of ASD-associated common variants in nondysmorphic ASD probands ( P = 2.9 × 10 −3 ). These findings replicate using WGS data from 442 ASD probands with accompanying morphology data from the Simons Simplex Collection. Our results provide support for an alternative genomic classification of ASD subgroups using morphology data, which may inform intervention protocols.

A full list of the SPARK Consortium members appears at the end of this paper. Abstract Despite the known heritable nature

Insomnia is common in children with autism. Cognitive behavioral treatment for childhood insomnia may improve sleep and functioning in children with autism and their parents, but delivery involving multiple office visits limits accessibility. This single-arm pilot study tested telehealth delivery of eight-session cognitive behavioral treatment for childhood insomnia in 17 children (6–12 years) with autism spectrum disorder and insomnia and their parent(s). Treatment integrity was assessed each session ( delivery, by therapist; receipt, participant understanding; and enactment, home practice). Treatment satisfaction was assessed after treatment. Children and parents wore actigraphs and completed electronic diaries for 2 weeks, children completed 5-min Holter Monitoring (assessed heart rate variability, physiological arousal indicator), and parents completed Aberrant Behavior Checklist before and after 1 month. Average integrity scores were high (98%, delivery; 93%, receipt; and 82%, enactment). Parents found cognitive behavioral treatment for childhood insomnia helpful, age-appropriate, and autism-friendly. Paired-samples t-tests (family-wise error controlled) indicated telehealth cognitive behavioral treatment for childhood insomnia improved child and parent sleep ( objective and subjective) and functioning (child—decreased irritability, lethargy, stereotypy, hyperactivity; parent—decreased fatigue). At 1 month, inappropriate speech also decreased, but hyperactivity was no longer decreased. Other gains were maintained. Most children demonstrated reduced arousal following treatment. This pilot shows telehealth cognitive behavioral treatment for childhood insomnia is feasible and may improve child and parent sleep, child behavior and arousal, and parent fatigue. A randomized controlled trial of telehealth cognitive behavioral treatment for childhood insomnia for children with autism is needed. Lay abstract Insomnia is common in children with autism. Cognitive behavioral treatment for childhood insomnia (CBT-CI) may improve sleep and functioning in children with autism and their parents, but typical delivery involving multiple office visits can make it difficult for some children to get this treatment. This pilot study tested telehealth delivery of CBT-CI using computers, which allowed children and their parents to get the treatment at home. This pilot shows therapists that parents and children were able to use telehealth CBT-CI to improve child and parent sleep, child behavior and arousal, and parent fatigue. Parents found telehealth CBT-CI helpful, age-appropriate, and autism-friendly. Telehealth CBT-CI holds promise for treating insomnia in school-aged children with autism and deserves further testing.

Parents who have been diagnosed with depression often report that their children have poor sleep behaviors. This relationship may occur because the children of parents with depression are more likely experience poor psychosocial functioning, which can negatively impact their sleep. Children with Autism Spectrum Disorder (ASD) are particularly at risk for sleep difficulties, and it is important to better understand these relationships as scant to no research has been done which investigates parental depression, child psychosocial functioning, and child sleep among children with ASD. The current study examined whether parental perception of their child’s psychosocial functioning mediated the relationship between parental depression and their child’s sleep behaviors. The sample (N=36) consisted of parents (81% female) reporting on their children aged 6–12 (M=8.56, SD = 1.86; 75% male). All children were diagnosed with ASD and had sleep complaints as reported by their parents. Children and their parents were recruited because they expressed interest in a behavioral treatment sleep study and these data come from the baseline data collection associated with that study. Measures included Sleep Behaviors factor from the Child Sleep Health Questionnaire (CSHQ), the Pediatric Symptom Checklist (PSC), and a question asking if the parent had been diagnosed with depression. Analyses were conducting using AMOS 27.0. Child psychosocial functioning significantly mediated (β = .12) the relation between parental depression and child sleep behavior. Parents who had been diagnosed with depression were more likely to report greater child psychosocial difficulties (β =.39, p = .01) and child psychosocial difficulties were associated with a greater likelihood of the child having worse sleep behavior (β =.32, p = .04). The direct effect between parental depression and child sleep behavior was not significant. These results indicate that child psychosocial functioning may help to explain the connection between diagnosed parental depression and poor child sleep behavior among children with ASD. This suggests that psychosocial functioning may be an important aspect to target in sleep interventions, particularly for children with ASD. University of Missouri Research Board Grant (McCrae, PI); United States Department of Defense USAMRAA Autism Research Program (McCrae, PI; CTA AR190047).

Abstract Introduction Parents who have been diagnosed with depression often report that their children are not compliant and have difficulty falling asleep. Parents with depression are less likely to be consistent or enforce bedtimes resulting in the child having less bedtime rules and getting less sleep. Overtime this may mean the child develops poor sleep habits and difficulty falling asleep. Although these relationships have yet to be studied in children with Autism Spectrum Disorder (ASD), it is an important area given the high prevalence of children with ASD who have sleep difficulties. The current study examined whether parent-reported child sleep onset latency mediated the relationship between parental depression and child non-compliance. Methods The sample (N=50) consisted of parents (81% female) reporting on their children aged 6–12 (M=8.63, SD = 2.00; 76% male). All children were diagnosed with ASD and had parent reported sleep complaints. Children and their parents were recruited because they expressed interest in a behavioral treatment sleep study and these data come from the baseline data collection associated with that study. Measures included sleep onset latency on the Child Sleep Health Questionnaire (CSHQ), an item on the Pediatric Symptom Checklist (PSC) which asked if a child follows rules, and a question asking if the parent had been diagnosed with depression. Results Analyses were conducting using AMOS 27.0. Slightly less than half (45%) of parents reported having been diagnosed with depression. Parent-reported child sleep onset latency significantly mediated (β =.13) the relation between parental depression and non-compliance. Parents who had been diagnosed with depression were associated with greater child sleep onset latency (β =.32, p = .04) and greater child sleep onset latency was associated with greater non-compliance (β =.40, p = .01). The direct effect between parental depression and non-compliance was not significant. Conclusion These results suggest that difficulty falling asleep may help to explain why children of parents who have depression are not compliant. Future research should utilize longitudinal and experimental methodology to determine the causality of these relationships. Support (if any) University of Missouri Research Board Grant (McCrae, PI); United States Department of Defense USAMRAA Autism Research Program (McCrae, PI; CTA AR190047).