Frontal alpha asymmetry predicts subsequent social decision-making: A dynamic multilevel, neural, and developmental perspective.

Social motivation, the human desire to engage with others, is likely to underlie higher levels of social cognition and the formation of interpersonal relationships. Yet, this topic has been understudied in adolescents despite the critical developmental and maturational changes that occur during this period and the relevance of social motivation to clinical and neurodevelopmental disorders. Using electroencephalography (EEG) and an implicit-association paradigm (Choose-A-Movie Task; Dubey et al., 2015), we examined how brain responses underlying socially motivated decisions informed future decisions in 54 youth (aged 10-14 years) and 50 young adults (aged 18-33 years). As the first study to use this task during EEG recording, we implemented time-frequency analyses and a trial-by-trial dynamic statistical approach. Results suggested that both age groups preferred low-effort choices and increasingly preferred nonsocial choices over time. P3 amplitude also increased over time and was sensitive to effortful decisions, particularly for adults, but not social content. Both groups showed larger leftward frontal alpha asymmetry (FAA) during nonsocial feedback, and FAA predicted future decisions differently for adults than youth. The current study highlights FAA and trial-by-trial analyses as useful tools in understanding the neural mechanisms underlying socially motivated decisions, which differ across development, time, and individuals.

Visual and auditory attention in individuals with DYRK1A and SCN2A disruptive variants.

This preliminary study sought to assess biomarkers of attention using electroencephalography (EEG) and eye tracking in two ultra-rare monogenic populations associated with autism spectrum disorder (ASD). Relative to idiopathic ASD (n = 12) and neurotypical comparison (n = 49) groups, divergent attention profiles were observed for the monogenic groups, such that individuals with DYRK1A (n = 9) exhibited diminished auditory attention condition differences during an oddball EEG paradigm whereas individuals with SCN2A (n = 5) exhibited diminished visual attention condition differences noted by eye gaze tracking when viewing social interactions. Findings provide initial support for alignment of auditory and visual attention markers in idiopathic ASD and neurotypical development but not monogenic groups. These results support ongoing efforts to develop translational ASD biomarkers within the attention domain.

SETBP1 haploinsufficiency and related disorders clinical and neurobehavioral phenotype study.

To comprehensively investigate the neurodevelopmental profile and clinical characteristics associated with SETBP1 haploinsufficiency disorder (SETBP1-HD) and SETBP1-related disorders (SETBP1-RD). We reported genetic results on 34 individuals, with behavior and clinical data from 22 with SETBP1-HD and 5 with SETBP1-RD, by assessing results from medical history interviews and standardized adaptive, clinical, and social measures provided from Simons Searchlight. All individuals with SETBP1-HD and SETBP1-RD exhibited neurological impairments including intellectual disability/developmental delay (IDD), attention-deficit/hyperactivity disorder, autism spectrum disorder, and/or seizures, as well as speech and language delays. While restricted interests and repetitive behaviors present challenges, a relative strength was observed in social motivation within both cohorts. Individuals with SETBP1-RD reported a risk for heart issues and compared to SETBP1-HD greater risks for orthopedic and somatic issues with greater difficulty in bowel control. Higher rates for neonatal feeding difficulties and febrile seizures were reported for individuals with SETBP1-HD. Additional prominent characteristics included sleep, vision, and gastrointestinal issues, hypotonia, and high pain tolerance. This characterization of phenotypic overlap (IDD, speech challenges, autistic, and attention deficit traits) and differentiation (somatic and heart issue risks for SETBP1-RD) between the distinct neurodevelopmental disorders SETBP1-HD and SETBP1-RD is critical for medical management and diagnosis.

ECHO Autism Washington: Autism Diagnostic Evaluations in Primary Care.

ECHO (Extensions for Community Healthcare Outcomes) Autism is a telementoring learning model to increase community capacity for autism-related health care. Seventy-seven pediatric providers (mostly primary care, seeing exclusively Medicaid patient populations) enrolled in 1 year of ECHO Autism Washington. Analysis of self-report surveys showed a significant increase in autism diagnoses made by ECHO providers after 1 year, F(1, 65) = 7.52, P = .008. Providers who attended more sessions reported making more diagnoses, F(2, 613.26), P = .045. Of note, autism diagnoses were not externally validated. The total number of reported barriers reduced, F(2, 61) = 13.5), P < .001, and confidence ratings increased F(2, 60) = 24.21, P < .001. The average number of diagnostic referrals from ECHO providers to the state's largest autism specialty clinic significantly reduced, t(43) = 4.23, P < .001, with significantly fewer diagnostic referrals made during and after ECHO training compared with a comparison group of 28 non-ECHO providers, t(58.77) = -3.36, P < .001. Overall, 1 year of ECHO Autism Washington participation led to significant changes in autism diagnostic practices.

Pubertal maturation and timing effects on resting state electroencephalography in autistic and comparison youth.

Autistic and comparison individuals differ in resting-state electroencephalography (EEG), such that sex and age explain variability within and between groups. Pubertal maturation and timing may further explain variation, as previous work has suggested alterations in pubertal timing in autistic youth. In a sample from two studies of 181 autistic and 94 comparison youth (8 years to 17 years and 11 months), mixed-effects linear regressions were conducted to assess differences in EEG (midline power for theta, alpha, and beta frequency bands). Alpha power was analyzed as a mediator in the relation between pubertal maturation and timing with autistic traits in the autistic groups to understand the role of puberty in brain-based changes that contribute to functional outcomes. Individuals advanced in puberty exhibited decreased power in all bands. Those who experienced puberty relatively early showed decreased power in theta and beta bands, controlling for age, sex, and diagnosis. Autistic individuals further along in pubertal development exhibited lower social skills. Alpha mediated the relation between puberty and repetitive behaviors. Pubertal maturation and timing appear to play unique roles in the development of cognitive processes for autistic and comparison youth and should be considered in research on developmental variation in resting-state EEG.

Feedback Related Negativity Amplitude is Greatest Following Deceptive Feedback in Autistic Adolescents.

The purpose of this study is to investigate if feedback related negativity (FRN) can capture instantaneous elevated emotional reactivity in autistic adolescents. A measurement of elevated reactivity could allow clinicians to better support autistic individuals without the need for self-reporting or verbal conveyance. The study investigated reactivity in 46 autistic adolescents (ages 12-21 years) completing the Affective Posner Task which utilizes deceptive feedback to elicit distress presented as frustration. The FRN event-related potential (ERP) served as an instantaneous quantitative neural measurement of emotional reactivity. We compared deceptive and distressing feedback to both truthful but distressing feedback and truthful and non-distressing feedback using the FRN, response times in the successive trial, and Emotion Dysregulation Inventory (EDI) reactivity scores. Results revealed that FRN values were most negative to deceptive feedback as compared to truthful non-distressing feedback. Furthermore, distressing feedback led to faster response times in the successive trial on average. Lastly, participants with higher EDI reactivity scores had more negative FRN values for non-distressing truthful feedback compared to participants with lower reactivity scores. The FRN amplitude showed changes based on both frustration and reactivity. The findings of this investigation support using the FRN to better understand emotion regulation processes for autistic adolescents in future work. Furthermore, the change in FRN based on reactivity suggests the possible need to subgroup autistic adolescents based on reactivity and adjust interventions accordingly.

Characterizing the autism spectrum phenotype in DYRK1A-related syndrome.

Likely gene-disrupting (LGD) variants in DYRK1A are causative of DYRK1A syndrome and associated with autism spectrum disorder (ASD) and intellectual disability (ID). While many individuals with DYRK1A syndrome are diagnosed with ASD, they may present with a unique profile of ASD traits. We present a comprehensive characterization of the ASD profile in children and young adults with LGDs in DYRK1A. Individuals with LGD variants in DYRK1A (n = 29) were compared to children who had ASD with no known genetic cause, either with low nonverbal IQ (n = 14) or average or above nonverbal IQ (n = 41). ASD was assessed using the ADOS-2, ADI-R, SRS-2, SCQ, and RBS-R. Quantitative score comparisons were conducted, as were qualitative analyses of clinicians' behavioral observations. Diagnosis of ASD was confirmed in 85% and ID was confirmed in 89% of participants with DYRK1A syndrome. Individuals with DYRK1A syndrome showed broadly similar social communication behaviors to children with idiopathic ASD and below-average nonverbal IQ, with specific challenges noted in social reciprocity and nonverbal communication. Children with DYRK1A syndrome also showed high rates of sensory-seeking behaviors. Phenotypic characterization of individuals with DYRK1A syndrome may provide additional information on mechanisms contributing to co-occurring ASD and ID and contribute to the identification of genetic predictors of specific ASD traits.

Characterizing Sensory Phenotypes of Subgroups with a Known Genetic Etiology Pertaining to Diagnoses of Autism Spectrum Disorder and Intellectual Disability.

We aimed to identify unique constellations of sensory phenotypes for genetic etiologies associated with diagnoses of autism spectrum disorder (ASD) and intellectual disability (ID). Caregivers reported on sensory behaviors via the Sensory Profile for 290 participants (younger than 25 years of age) with ASD and/or ID diagnoses, of which ~ 70% have a known pathogenic genetic etiology. Caregivers endorsed poor registration (i.e., high sensory threshold, passive behaviors) for all genetic subgroups relative to an "idiopathic" comparison group with an ASD diagnosis and without a known genetic etiology. Genetic profiles indicated prominent sensory seeking in ADNP, CHD8, and DYRK1A, prominent sensory sensitivities in SCN2A, and fewer sensation avoidance behaviors in GRIN2B (relative to the idiopathic ASD comparison group).

Serving Individuals With Autism Spectrum Disorder in the Age of COVID-19: Special Considerations for Rural Families.

This position paper explores the needs of rural families of children, adolescents, and adults with autism spectrum disorder (ASD) during the COVID-19 pandemic. Prior to COVID-19, literature portrays elevated stress in families of individuals with ASD and health and socioeconomic disparities for rural and underserved populations. These disparities were exacerbated due to COVID-19 and subsequent lockdowns and economic turmoil. Academic and adaptive skills training were particularly impacted due to school closures, with parents tasked with taking some responsibility for training these skills. Our goals for this article focus on special considerations for rural families regarding (a) neurobiological and developmental impacts of stressful experiences like COVID-19, (b) delineation of the impacts on individuals with ASD and other comorbid and related conditions, and (c) education and intervention needs during these times. Finally, we offer suggestions for future care during pandemic events, including recommendations for improving service delivery under such conditions.

Quantitative EEG Changes in Youth With ASD Following Brief Mindfulness Meditation Exercise.

Mindfulness has growing empirical support for improving emotion regulation in individuals with Autism Spectrum Disorder (ASD). Mindfulness is cultivated through meditation practices. Assessing the role of mindfulness in improving emotion regulation is challenging given the reliance on self-report tools. Electroencephalography (EEG) has successfully quantified neural responses to emotional arousal and meditation in other populations, making it ideal to objectively measure neural responses before and after mindfulness (MF) practice among individuals with ASD. We performed an EEG-based analysis during a resting state paradigm in 35 youth with ASD. Specifically, we developed a machine learning classifier and a feature and channel selection approach that separates resting states preceding (Pre-MF) and following (Post-MF) a mindfulness meditation exercise within participants. Across individuals, frontal and temporal channels were most informative. Total power in the beta band (16-30 Hz), Total power (4-30 Hz), relative power in alpha band (8-12 Hz) were the most informative EEG features. A classifier using a non-linear combination of selected EEG features from selected channel locations separated Pre-MF and Post-MF resting states with an average accuracy, sensitivity, and specificity of 80.76%, 78.24%, and 82.14% respectively. Finally, we validated that separation between Pre-MF and Post-MF is due to the MF prime rather than linear-temporal drift. This work underscores machine learning as a critical tool for separating distinct resting states within youth with ASD and will enable better classification of underlying neural responses following brief MF meditation.

Facial Affect Sensitivity Training for Young Children with Emerging CU Traits: An Experimental Therapeutics Approach.

OBJECTIVE: This article delineates best practices in the application of the experimental therapeutics framework for evaluating interventions within the context of randomized controlled trials (RCTs), offering a methodological primer and guiding framework for this approach. We illustrate these practices using an ongoing clinical trial conducted within the framework of a National Institute of Mental Health exploratory phased-innovation award for the development of psychosocial therapeutic interventions for mental disorders (R61/R33), describing the implementation of a novel "Facial Affect Sensitivity Training" (FAST) intervention for children with callous-unemotional (CU) traits. CU traits (e.g., lack of guilt or remorse, low empathy, shallow affect) are an established risk factor for persistent and severe youth misconduct, which reflect impairment in identified neurocognitive mechanisms that interfere with child socialization, and predict poor treatment outcomes, even with well-established treatments for disruptive behavior. METHOD: We outline the stages, goals, and best practices for an experimental therapeutics framework. In the FAST trial, we assert that impaired sensitivity for emotional distress cues (fear and/or sadness) is mechanistically linked to CU traits in children, and that by targeting sensitivity to facial affect directly via a computerized automated feedback and incentive system, we can exert downstream effects on CU traits. RESULTS: In the context of an open pilot trial, we found preliminary support for feasibility and mechanism engagement using FAST. CONCLUSIONS: We summarize pilot study limitations and how they are being addressed in the R61/R33 RCTs, as well as challenges and future directions for psychosocial experimental therapeutics.

Dynamic cognitive inhibition in the context of frustration: Increasing racial representation of adolescent athletes using mobile community-engaged EEG methods.

Introduction: Concussive events and other brain injuries are known to reduce cognitive inhibition, a key aspect of cognition that supports ones' behaviors and impacts regulation of mood or affect. Our primary objective is to investigate how induction of negative affect (such as frustration) impacts cognitive inhibition and the dynamic process by which youth athletes modulate responses. Secondary objective is to address the lack of Black representation in the scientific literature that promotes brain health and investigates pediatric sports-related brain injury. In particular, neuroscience studies predominantly include White participants despite broad racial representation in sport, in part due to technological hurdles and other obstacles that challenge research access for Black participants. Methods: Using electroencephalography (EEG), we evaluate the dynamic brain processes associated with cognitive inhibition in the context of frustration induction in adolescent athletes during pre-season conditioning (i.e., prior to contact; N = 23) and a subset during post-season (n = 17). Results: The N2 component was sensitive to frustration induction (decreased N2 amplitude, slower N2 latency), although effects were less robust at postseason. Trial-by-trial changes indicated a steady decrease of the N2 amplitude during the frustration block during the preseason visit, suggesting that affective interference had a dynamic effect on cognitive inhibition. Lastly, exploratory analyses provide preliminary evidence that frustration induction was less effective for athletes with a previous history of concussion or migraines (trending result) yet more effective for athletes endorsing a history with mental health disorders. Discussion: We emphasize the urgent need to improve representation in cognitive neuroscience, particularly as it pertains to brain health. Importantly, we provide detailed guides to our methodological framework and practical suggestions to improve representative participation in studies utilizing high-density mobile EEG.

The CHD8/CHD7/Kismet family links blood-brain barrier glia and serotonin to ASD-associated sleep defects.

Sleep disturbances in autism and neurodevelopmental disorders are common and adversely affect patient's quality of life, yet the underlying mechanisms are understudied. We found that individuals with mutations in CHD8, among the highest-confidence autism risk genes, or CHD7 suffer from disturbed sleep maintenance. These defects are recapitulated in Drosophila mutants affecting kismet, the sole CHD8/CHD7 ortholog. We show that Kismet is required in glia for early developmental and adult sleep architecture. This role localizes to subperineurial glia constituting the blood-brain barrier. We demonstrate that Kismet-related sleep disturbances are caused by high serotonin during development, paralleling a well-established but genetically unsolved autism endophenotype. Despite their developmental origin, Kismet's sleep architecture defects can be reversed in adulthood by a behavioral regime resembling human sleep restriction therapy. Our findings provide fundamental insights into glial regulation of sleep and propose a causal mechanistic link between the CHD8/CHD7/Kismet family, developmental hyperserotonemia, and autism-associated sleep disturbances.

Sleep Problems in Children with ASD and Gene Disrupting Mutations.

Sleep difficulties are pervasive in autism spectrum disorder (ASD), yet how sleep problems relate to underlying biological mechanisms such as genetic etiology is unclear, despite recent reports of profound sleep problems in children with ASD-associated de novo likely gene disrupting (dnLGD) mutations, CHD8, DYRK1A, and ADNP. We aimed to inform etiological contributions to ASD and sleep by characterizing sleep problems in individuals with dnLGD mutations. Participants (N = 2886) were families who completed dichotomous questions about sleep problems within a medical history interview for their child with ASD (age 3-28 years). Confirmatory factor analyses compared between those with ASD and a dnLGD mutation and those with idiopathic ASD (i.e., no known genetic event, NON) highlighted four domains (sleep onset, breathing issues, nighttime awakenings, and daytime tiredness) with sleep onset as a strong factor for both groups. Overall, participant predictors indicated that internalizing behavioral problems and lower cognitive scores were related to increased sleep problems. Internalizing problems were also related to increase nighttime awakenings in the dnLGD group. As an exploratory aim, patterns of sleep issues are described for genetic subgroups with unique patterns including more overall sleep issues in ADNP (n = 19), problems falling asleep in CHD8 (n = 22), and increased daytime naps in DYRK1A (n = 23). Implications for considering genetically defined subgroups when approaching sleep problems in children with ASD are discussed.

Modeling temporal dynamics of face processing in youth and adults.

A hierarchical model of temporal dynamics was examined in adults (n = 34) and youth (n = 46) across the stages of face processing during the perception of static and dynamic faces. Three ERP components (P100, N170, N250) and spectral power in the mu range were extracted, corresponding to cognitive stages of face processing: low-level vision processing, structural encoding, higher-order processing, and action understanding. Youth and adults exhibited similar yet distinct patterns of hierarchical temporal dynamics such that earlier cognitive stages predicted later stages, directly and indirectly. However, latent factors indicated unique profiles related to behavioral performance for adults and youth and age as a continuous factor. The application of path analysis to electrophysiological data can yield novel insights into the cortical dynamics of social information processing.

The Role of Racial and Developmental Experience on Emotional Adaptive Coding in Autism Spectrum Disorder.

Sensitivity to emotional face aids in rapid detection and evaluation of others, such that by school-age, children and youth exhibit adult-like patterns when the prolonged viewing of an emotional face distorts the perception of a subsequent face. However, the developmental considerations of this phenomenon (known as emotional adaptive coding) are unclear given ongoing maturational and experiential changes, including the influence of own-race experiences or the lack of face expertise, as is evident in autism spectrum disorder (ASD). This study addressed whether emotional adaptive coding is sensitive to factors of face perception expertise, specifically self-race and developmental experience, in adults (age 19-28 years) and youth (age 10-16 years). Emotional adaptive coding was not influenced by race expertise (i.e., other versus same race identity) in White and Asian adults. Emotional adaptation coding during childhood and adolescence is consistent with adults, though youth with ASD exhibited stronger adaptor after-effects in response to other-race faces, relative to TD youth and adults. By extending prior work to examine the integration of race and emotional adaptive coding in ASD, we discovered that the strength of response in ASD is atypical when viewing other-race faces, which clarifies the role of racial and facial experience on emotional face adaption.

Social attention to activities in children and adults with autism spectrum disorder: effects of context and age.

BACKGROUND: Diminished visual monitoring of faces and activities of others is an early feature of autism spectrum disorder (ASD). It is uncertain whether deficits in activity monitoring, identified using a homogeneous set of stimuli, persist throughout the lifespan in ASD, and thus, whether they could serve as a biological indicator ("biomarker") of ASD. We investigated differences in visual attention during activity monitoring in children and adult participants with autism compared to a control group of participants without autism. METHODS: Eye movements of participants with autism (n = 122; mean age [SD] = 14.5 [8.0] years) and typically developing (TD) controls (n = 40, age = 16.4 [13.3] years) were recorded while they viewed a series of videos depicting two female actors conversing while interacting with their hands over a shared task. Actors either continuously focused their gaze on each other's face (mutual gaze) or on the shared activity area (shared focus). Mean percentage looking time was computed for the activity area, actors' heads, and their bodies. RESULTS: Compared to TD participants, participants with ASD looked longer at the activity area (mean % looking time: 58.5% vs. 53.8%, p < 0.005) but less at the heads (15.2% vs. 23.7%, p < 0.0001). Additionally, within-group differences in looking time were observed between the mutual gaze and shared focus conditions in both participants without ASD (activity: Δ = - 6.4%, p < 0.004; heads: Δ = + 3.5%, p < 0.02) and participants with ASD (bodies: Δ = + 1.6%, p < 0.002). LIMITATIONS: The TD participants were not as well characterized as the participants with ASD. Inclusion criteria regarding the cognitive ability [intelligence quotient (IQ) > 60] limited the ability to include individuals with substantial intellectual disability. CONCLUSIONS: Differences in attention to faces could constitute a feature discriminative between individuals with and without ASD across the lifespan, whereas between-group differences in looking at activities may shift with development. These findings may have applications in the search for underlying biological indicators specific to ASD. Trial registration ClinicalTrials.gov identifier NCT02668991.

Evaluating heterogeneity in ASD symptomatology, cognitive ability, and adaptive functioning among 16p11.2 CNV carriers.

Individuals with 16p11.2 copy number variant (CNV) show considerable phenotypic heterogeneity. Although autism spectrum disorder (ASD) is reported in approximately 20-23% of individuals with 16p11.2 CNVs, ASD-associated symptoms are observed in those without a clinical ASD diagnosis. Previous work has shown that genetic variation and prenatal and perinatal birth complications influence ASD risk and symptom severity. This study examined the impact of genetic and environmental risk factors on phenotypic heterogeneity among 16p11.2 CNV carriers. Participants included individuals with a 16p11.2 deletion (N = 96) or duplication (N = 77) with exome sequencing from the Simons VIP study. The presence of prenatal factors, perinatal events, additional genetic events, and gender was studied. Regression analyses examined the contribution of each risk factor on ASD symptomatology, cognitive functioning, and adaptive abilities. For deletion carriers, perinatal and additional genetic events were associated with increased ASD symptomatology and decrements in cognitive and adaptive functioning. For duplication carriers, secondary genetic events were associated with greater cognitive impairments. Being female sex was a protective factor for both deletion and duplication carriers. Our findings suggest that ASD-associated risk factors contribute to the variability in symptom presentation in individuals with 16p11.2 CNVs. LAY SUMMARY: There are a wide range of autism spectrum disorder (ASD) symptoms and abilities observed for individuals with genetic changes of the 16p11.2 region. Here, we found perinatal complications contributed to more severe ASD symptoms (deletion carriers) and additional genetic mutations contributed to decreased cognitive abilities (deletion and duplication carriers). A potential protective factor was also observed for females with 16p11.2 variations. Autism Res 2020, 13: 1300-1310. © 2020 International Society for Autism Research, Wiley Periodicals, Inc.

Co-occurring medical conditions among individuals with ASD-associated disruptive mutations.

Children with autism spectrum disorder (ASD) are at risk for co-occurring medical conditions, many of which have also been reported among individuals with mutations in ASD-associated genes. This study examined rates of co-occurring medical conditions across 301 individuals with disruptive mutations to 1 of 18 ASD-risk genes in comparison to rates of conditions in an idiopathic ASD sample. Rates of gastrointestinal problems, seizures, physical anomalies, and immune problems were generally elevated, with significant differences in rates observed between groups. Results may inform medical care of individuals with ASD-associated mutations and research into mechanisms of co-occurring medical conditions in ASD.

Clinical Phenotypes of Carriers of Mutations in CHD8 or Its Conserved Target Genes.

BACKGROUND: Variants disruptive to CHD8 (which codes for the protein CHD8 [chromodomain-helicase-DNA-binding protein 8]) are among the most common mutations revealed by exome sequencing in autism spectrum disorder (ASD). Recent work has indicated that CHD8 plays a role in the regulation of other ASD-risk genes. However, it is unclear whether a possible shared genetic ontology extends to the phenotype. METHODS: This study (N = 143; 42.7% female participants) investigated clinical and behavioral features of individuals ascertained for the presence of a known disruptive ASD-risk mutation that is 1) CHD8 (CHD8 group) (n = 15), 2) a gene targeted by CHD8 (target group) (n = 22), or 3) a gene without confirmed evidence of being targeted by CHD8 (other gene group) (n = 106). RESULTS: Results indicated shared features between the CHD8 and target groups that included less severe adaptive deficits in communication skills, similar functional language, more social motivation challenges in those with ASD, larger head circumference, higher weight, and lower seizure prevalence relative to the other gene group. CONCLUSIONS: These similarities suggest broader genetic ontology accounts for aspects of phenotypic heterogeneity. Improved understanding of the relationships between related disruptive gene events may lead us to improved understanding of shared mechanisms and lead to more focused treatments for individuals with known genetic mutations.