Randomized controlled trial of propranolol on social communication and anxiety in children and young adults with autism spectrum disorder.

RATIONALE: 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. OBJECTIVE: We conducted a double-blinded, placebo-controlled trial of the ß-adrenergic antagonist propranolol in ASD for social interaction, anxiety, and language. METHODS: 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. RESULTS: 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% CI = 1.02-6.52). Expected decreases in heart rate and blood pressure were observed with propranolol, and side effects were uncommon. CONCLUSIONS: Propranolol did not impact social interaction measures or language, but there were indications of a beneficial effect for anxiety. This will need confirmation in a larger multicenter trial, monitoring markers or characteristics to identify those participants most likely to respond to propranolol for anxiety, and determine whether there is a subset of participants that are responsive for other previously reported outcomes.

Remotely supervised at-home delivery of taVNS for autism spectrum disorder: feasibility and initial efficacy.

Background: Transcutaneous 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. Methods: An 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). Results: Across 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. Conclusion: Remotely supervised, proxy-administered, at-home delivery of taVNS is feasible in patients with ASD. Initial efficacy supports pursuing larger scale trials.

Altered Allocation of Vertical Attention in Individuals With Autism Spectrum Disorder.

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.

Corrigendum: Bias in measurement of autism symptoms by spoken language level and non-verbal mental age in minimally verbal children with neurodevelopmental disorders.

[This corrects the article DOI: 10.3389/fpsyg.2022.927847.].

Genome-wide rare variant score associates with morphological subtypes of autism spectrum disorder.

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.

Bias in measurement of autism symptoms by spoken language level and non-verbal mental age in minimally verbal children with neurodevelopmental disorders.

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.

Telehealth cognitive behavioral therapy for insomnia in children with autism spectrum disorder: A pilot examining feasibility, satisfaction, and preliminary findings.

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.

Cognitive behavioral treatment of insomnia in school-aged children with autism spectrum disorder: A pilot feasibility study.

Insomnia is common in autism and associated with challenging behavior and worse parent sleep. Cognitive behavioral treatment for childhood insomnia (CBT-CI) is efficacious in typically developing children, but not yet tested in school-aged children with autism. This single arm pilot tested 8-session CBT-CI in 17 children with autism and insomnia (M age = 8.76 years, SD = 1.99) and their parent(s) (M age = 39.50 years, SD = 4.83). Treatment integrity was assessed for each session [delivery (by therapist), receipt (participant understanding), and enactment (home practice)]. Children and parents wore actigraphs and completed electronic diaries for 2-weeks to obtain objective and subjective sleep onset latency (SOL), total sleep/wake times (TST/TWT), and sleep efficiency (SE) at pre/post/1-month follow-up. Parents also completed the Aberrant Behavior Checklist [irritability, lethargy, stereotypy, hyperactivity, inappropriate speech (e.g., excessive/repetitive, loud self-talk)] at pre/post/1-month. Fifteen children completed all sessions. Average integrity scores were high [90%-delivery/receipt, 87.5%-enactment]. Parents found CBT-CI helpful, age-appropriate, and autism-friendly. Paired samples t-tests (family-wise error controlled) found CBT-CI improved child sleep (objective SOL-18 min, TWT- 34 min, SE-5%; subjective SOL-29 min, TST-63 min, TWT-45 min, SE-8%), and decreased irritability, lethargy, stereotypy, and hyperactivity. At 1-month, objective TST improved, inappropriate speech decreased, but hyperactivity was no longer decreased. Other gains were maintained. Parent sleep (objective SOL-12 min, TST-35 min, TWT-21 min, SE-4%; subjective SOL-11 min, TWT- 31min, SE-11%) and fatigue also improved. At 1-month, gains were maintained. This pilot shows CBT-CI is a feasible treatment that holds promise for improving child and parent sleep and functioning and suggests a randomized controlled trial in school-aged children with autism is worth conducting. Autism Res 2020, 13: 167-176. © 2019 International Society for Autism Research, Wiley Periodicals, Inc. LAY SUMMARY: Insomnia is common in autism and associated with challenging behaviors and poor parent sleep and stress. Cognitive behavioral treatment for childhood insomnia (CBT-CI) has not been tested in school-aged children with autism. This pilot study shows therapists, parents, and children were able to use CBT-CI to improve child and parent sleep, child behavior, and parent fatigue. Parents found CBT-CI helpful, age-appropriate, and autism-friendly. CBT-CI holds promise for treating insomnia in school-aged children with autism and deserves further testing.

Catatonia in Down syndrome: systematic approach to diagnosis, treatment and outcome assessment based on a case series of seven patients.

OBJECTIVE: The goal is to expand our knowledge of catatonia occurring in adolescents and young adults with Down syndrome (DS) by describing the first prospective, consecutive, well-characterized cohort of seven young people with DS diagnosed with catatonia and treated between 2013 and 2018, and to assess each patient's treatment responses. Longitudinal assessment of each patient's response to treatment is intended to provide clinicians and psychiatrists a firm foundation from which assess treatment efficacy. STUDY DESIGN: Young adults with Down syndrome were consecutively enrolled in the study as they were diagnosed with catatonia. A comprehensive data set included medical, laboratory, developmental, demographic, family, social and genetic data, including query into disorders for which individuals with DS are at risk. Catatonia was diagnosed based on an unequivocal history of regression, positive Bush-Francis Catatonia Rating Scale and positive response to intravenous lorazepam. Patients' longitudinal progress was monitored using the Catatonia Impact Scale (CIS) developed for this purpose. RESULTS: Seven consecutive DS patients, who presented with unequivocal regression were diagnosed with catatonia and treated for 2.7-6 years using standard-of-care therapies; primarily GABA agonist, lorazepam, electroconvulsive therapy (ECT) and glutamate antagonists (dextromethorphan/quinidine, memantine, minocycline). Responses to each treatment modality were assessed at clinic visits and through weekly electronic CIS reports. CONCLUSION: Seven young adults with DS were diagnosed with catatonia; all responded to Lorazepam and/or ECT therapy with good to very good results. Though ECT most dramatically returned patients to baseline, symptoms often returned requiring additional ECT. Dextromethorphan/quinidine, not used until mid-2017, appeared to reduce the reoccurrence of symptoms following ECT. Though all seven patients improved significantly, each continues to require some form of treatment to maintain a good level of functioning. Findings of a significant number of autoimmune disorders and laboratory markers of immune activation in this population may guide new diagnostic and treatment opportunities.

The Relationship Among Gastrointestinal Symptoms, Problem Behaviors, and Internalizing Symptoms in Children and Adolescents With Autism Spectrum Disorder.

Background: Many individuals with autism spectrum disorder (ASD) have co-occurring gastrointestinal (GI) symptoms, but the etiology is poorly understood. These GI symptoms often coincide with problem behaviors and internalizing symptoms, which reduces the quality of life for these individuals. Methods: This study examined the relationships among GI problems, problem behaviors, and internalizing symptoms in a sample of 340 children and adolescents with ASD who are patients at the University of Missouri Thompson Center for Autism & Neurodevelopmental Disorders. Results: The majority of patients experienced constipation (65%), about half experienced stomachaches or stomach pain (47.9%), and others experienced nausea (23.2%) or diarrhea (29.7%). Young children with aggressive problem behaviors were 11.2% more likely to have co-occurring nausea; whereas, older children showed more complex relationships between internalizing symptoms and GI symptoms. Older children with greater anxiety symptoms were 11% more likely to experience constipation, but 9% less likely to experience stomachaches. Older children with greater withdrawn behavior were 10.9% more likely to experience stomachaches, but 8.7% less likely to experience constipation. Older children with greater somatic complaints were 11.4% more likely to experience nausea and 11.5% more likely to experience stomachaches. Conclusions: Results suggest that the presentation of externalizing problem behavior and internalizing symptoms associated with GI problems differs between young children and older children with ASD. Therefore, behavior may have different relationships with GI symptoms at different ages, which may have implications for the treatment of and clinical approach to GI disturbances in ASD.

Heritable genotype contrast mining reveals novel gene associations specific to autism subgroups.

Though the genetic etiology of autism is complex, our understanding can be improved by identifying genes and gene-gene interactions that contribute to the development of specific autism subtypes. Identifying such gene groupings will allow individuals to be diagnosed and treated according to their precise characteristics. To this end, we developed a method to associate gene combinations with groups with shared autism traits, targeting genetic elements that distinguish patient populations with opposing phenotypes. Our computational method prioritizes genetic variants for genome-wide association, then utilizes Frequent Pattern Mining to highlight potential interactions between variants. We introduce a novel genotype assessment metric, the Unique Inherited Combination support, which accounts for inheritance patterns observed in the nuclear family while estimating the impact of genetic variation on phenotype manifestation at the individual level. High-contrast variant combinations are tested for significant subgroup associations. We apply this method by contrasting autism subgroups defined by severe or mild manifestations of a phenotype. Significant associations connected 286 genes to the subgroups, including 193 novel autism candidates. 71 pairs of genes have joint associations with subgroups, presenting opportunities to investigate interacting functions. This study analyzed 12 autism subgroups, but our informatics method can explore other meaningful divisions of autism patients, and can further be applied to reveal precise genetic associations within other phenotypically heterogeneous disorders, such as Alzheimer's disease.

Abnormal transient pupillary light reflex in individuals with autism spectrum disorders.

Computerized binocular infrared pupillography was used to measure the transient pupillary light reflex (PLR) in both children with autism spectrum disorders (ASDs) and children with typical development. We found that participants with ASDs showed significantly longer PLR latency, smaller constriction amplitude and lower constriction velocity than children with typical development. The PLR latency alone can be used to discriminate the ASD group from the control group with a cross-validated success rate of 89.6%. By adding the constriction amplitude, the percentage of correct classification can be further improved to 92.5%. In addition, the right-lateralization of contraction anisocoria that was observed in participants with typical development was not observed in those with ASDs. Further studies are necessary to understand the origin and implications of these observations. It is anticipated that as potential biomarkers, these pupillary light reflex measurements will advance our understanding of neurodevelopmental differences in the autism brain.

Weak gender effects on transient pupillary light reflex.

We investigated the gender effects on transient pupillary light reflex (PLR) in healthy young adults between 18 and 22 years old. Both dark-adapted and light-adapted PLRs were measured using green and red stimuli of different intensities. The results indicate that females had significantly larger relative constriction amplitudes than males in a dark-adapted condition. This gender effect depends on the stimulus intensities. The relative constriction amplitude in female subjects increased faster than it did in the males with the stimulus intensity. We did not observe any significant gender differences in the other PLR parameters, including latency, constriction speed, and recovery speed.

Sex-specific lateralization of contraction anisocoria in transient pupillary light reflex.

PURPOSE: Contraction anisocoria describes a phenomenon in which the pupil of a directly illuminated eye constricts more than the pupil of the consensual (not illuminated) eye. The purpose of this study was to investigate the lateralization of contraction anisocoria in young female and male subjects. METHODS: Infrared binocular pupillography was used to measure pupillary light reflex (PLR) in 44 healthy children (23 girls, 21 boys) from 6 to 16 years of age. Measurements were conducted in both light-adapted and dark-adapted conditions with different stimulus intensities. Relative constriction amplitude was obtained by dividing the maximal pupil area change by the initial static pupil area. Contraction anisocoria was calculated by subtracting relative constriction amplitude in the consensual eye from that of the direct eye. Values of contraction anisocoria obtained by stimulating a subject's right or left eye were compared to determine any potential lateralization. RESULTS: It was found that stimulating the right eye led to larger contraction anisocoria than stimulating the left eye. Such right-side lateralization of contraction anisocoria is much greater in males than in females. In addition, the effects of sex were related to the ambient light level and stimulus intensity. CONCLUSIONS: These results provide evidence that contraction anisocoria is more laterally asymmetric in males than in females.

A context-sensitive active contour for 2D corpus callosum segmentation.

We propose a new context-sensitive active contour for 2D corpus callosum segmentation. After a seed contour consisting of interconnected parts is being initialized by the user, each part will start to deform according to its own motion law derived from high-level prior knowledge, and is constantly aware of its own orientation and destination during the deformation process. Experimental results demonstrate the accuracy and robustness of our algorithm.