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It has been suggested that individuals with autism are more vulnerable to, and less able to cope with, the effects of stressors than the general population. However, very little work has been done to develop tools such as surveys or questionnaires that assess reactions to stressors in individuals with developmental disabilities. In the present investigation, the Stress Survey Schedule for Persons with Autism and Other Developmental Disabilities (SSS; Groden et al., 2001) was completed for 180 individuals with autism, varying in gender, verbal ability, and age. The results demonstrate that the SSS is a valid tool for identifying which dimensions of stress are perceived to be the most and least stressful for subgroups of persons with autism. [ABSTRACT FROM AUTHOR]

Objective: KeepCalm is a digital mental health application, co-designed with community partners, that incorporates wearable biosensing with support for teams to address challenging behaviors and emotion dysregulation in children on the autism spectrum., Methods: We followed a user-centered design framework. Before app development, we conducted design workshops, needs assessment interviews, a systematic review, and created an Expert Advisory Board. Once we had a working prototype, we recruited 73 participants to test and help improve the app across five testing cycles., Results: Participants rated the app across testing cycles as highly acceptable, appropriate, feasible, and with good usability. Qualitative data indicated that KeepCalm helped teachers (a) be aware of students' previously unrealized triggers, especially for nonspeaking students; (b) prevent behavioral episodes; (c) communicate with parents about behaviors/strategies; and (d) equipped parents with knowledge of strategies to use at home. We learned that in order to make the app acceptable and appropriate we needed to make the app enjoyable/easy to use and to focus development on novel features that augment teachers' skills (e.g., behavioral pattern and stress detection). We also learned about the importance of maximizing feasibility, through in-person app training/support especially regarding the wearable devices, and the importance of having aides involved., Conclusion: Our findings have informed plans for wider-scale feasibility testing so that we may examine the determinants of implementation to inform adaptations and refinement, and gather preliminary efficacy data on KeepCalm's impact on reducing challenging behaviors and supporting emotion regulation in students on the autism spectrum., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Society of Pediatric Psychology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Autistic youth experience several behavioral and emotional characteristics that can predispose them to emotion dysregulation (ED). Current literature examining ED in autism spectrum disorder (ASD) is limited to parent- and self-reported measures, indicating a need for biological or physiological methods to better assess emotion regulation in ASD. Utilizing the autonomic nervous system, specifically heart rate variability (HRV), may be a promising method to objectively measure ED in ASD, given it is one of the body's primary means of regulating physiological arousal. Our pilot study is one of the first to examine the feasibility, utility, and construct validity of HRV along with clinical measures within an intervention targeting ED-specific symptoms in ASD. Participants included 30 autistic youth ages 8-17 years who participated in the pilot study of Regulating Together, a group-based intervention targeting emotion regulation. We demonstrate HRV is feasible, demonstrates adequate test-retest reliability, and is complimentary to clinician- and parent-reported measures. Our preliminary findings also point to certain HRV profiles being indicative of long-term outcomes after receiving treatment. HRV may be a useful, objective tool in determining differential needs of long-term follow-up care for treatment maintenance at screening or baseline stages., (© 2024. The Author(s).)

Challenging behavior, such as aggression, is highly prevalent in children and adolescents on the autism spectrum and can have a devastating impact. Previous reviews of challenging behavior interventions did not include interventions targeting emotion dysregulation, a common cause of challenging behavior. We reviewed emotion dysregulation and challenging behavior interventions for preschoolers to adolescents to determine which evidence-based strategies have the most empirical support for reducing/preventing emotion dysregulation/challenging behavior. We reviewed 95 studies, including 29 group and 66 single case designs. We excluded non-behavioral/psychosocial interventions and those targeting internalizing symptoms only. We applied a coding system to identify discrete strategies based on autism practice guidelines with the addition of strategies common in childhood mental health disorders, and an evidence grading system. Strategies with the highest quality evidence (multiple randomized controlled trials with low bias risk) were Parent-Implemented Intervention, Emotion Regulation Training, Reinforcement, Visual Supports, Cognitive Behavioral/Instructional Strategies and Antecedent-Based Interventions. Regarding outcomes, most studies included challenging behavior measures, while few included emotion dysregulation measures. This review highlights the importance of teaching emotion regulation skills explicitly, positively reinforcing replacement/alternative behaviors, using visuals and metacognition, addressing stressors proactively, and involving parents. It also calls for more rigorously designed studies and for including emotion dysregulation as an outcome/mediator in future trials., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany.)

Psychophysiologists recording electrodermal activity (EDA) often derive measures of slow, tonic activity-skin conductance level (SCL)-and faster, more punctate changes-skin conductance responses (SCRs). A SCR is conventionally considered to have occurred when the local amplitude of the EDA signal exceeds a researcher-determined threshold (e.g., 0.05 μS), typically fixed across study participants and conditions. However, fixed SCR thresholds can preferentially exclude data from individuals with low SCL because their SCRs are smaller on average, thereby reducing statistical power for group-level analyses. Thus, we developed a fixed plus adaptive (FA) thresholding method that adjusts identification of SCRs based on an individual's SC at the onset of the SCR to increase statistical power and include data from more participants. We assess the utility of applying FA thresholding across two independent samples and explore age and race-related associations with EDA outcomes. Study 1 uses wired EDA measurements from 254 healthy adults responding to evocative images and sounds in a laboratory setting. Study 2 uses wireless EDA measurements from 20 children with autism in a clinical environment while they completed behavioral tasks. Compared to a 0.01, 0.03, and 0.05 μS fixed threshold, FA thresholding at 1.9% modestly increases statistical power to detect a difference in SCR rate between tasks with higher vs. lower subjective arousal and reduces exclusion of participants by up to 5% across both samples. This novel method expands the EDA analytical toolbox and may be useful in populations with highly variable basal SCL or when comparing groups with different basal SCL. Future research should test for reproducibility and generalizability in other tasks, samples, and contexts. IMPACT STATEMENTS: This article is important because it introduces a novel method to enhance sensitivity and statistical power in analyses of skin conductance responses from electrodermal data., Competing Interests: Declaration of competing interest Catherine Lord receives royalties for the diagnostic instruments, the ADOS and the ADI-R, all proceeds that were related to this study are donated to charity. The other authors declare no potential conflicts of interest., (Copyright © 2023. Published by Elsevier B.V.)

Background: Irritability, an increased proneness to anger, is a primary reason youth present for psychiatric care. While initial evidence supports the efficacy of exposure-based cognitive behavioral therapy (CBT) for youth with clinically impairing irritability, treatment mechanisms remain unclear. Here, we propose to measure peripheral psychophysiological indicators of arousal-heart rate (HR)/electrodermal activity (EDA)-and regulation-heart rate variability (HRV)-during exposures to anger-inducing stimuli as potential predictors of treatment efficacy. The objective of this study is to evaluate whether in-situ biosensing data provides peripheral physiological indicators of in-session response to exposures., Methods: Blood volume pulse (BVP; from which HR and HRV canl be derived) and EDA will be collected ambulatorily using the Empatica EmbracePlus from 40 youth (all genders; ages 8-17) undergoing six in-person exposure treatment sessions, as part of a multiple-baseline trial of exposure-based CBT for clinically impairing irritability. Clinical ratings of irritability will be conducted at baseline, weekly throughout treatment, and at 3-month and 6-month follow-ups via the Clinical Global Impressions Scale (CGI) and the Affective Reactivity Index (ARI; clinician-, parent-, and child-report). Multilevel modeling will be used to assess within- and between-person changes in physiological arousal and regulation throughout exposure-based CBT and to determine whether individual differences are predictive of treatment response., Discussion: This study protocol leverages a wearable biosensor (Empatica) to continuously record HR/HRV (derived from BVP) and EDA during in-person exposure sessions for youth with clinically impairing irritability. Here, the goal is to identify changes in physiological arousal (EDA, HR) and regulation (HRV) over the course of treatment in tandem with changes in clinical symptoms., Trial Registration: The participants in this study come from an overarching clinical trial (trial registration numbers: NCT02531893 first registered on 8/25/2015; last updated on 8/25/2023). The research project and all related materials were submitted and approved by the appropriate Institutional Review Board of the National Institute of Mental Health (NIMH)., (© 2023. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

Importance: Aggressive behavior is a prevalent and challenging issue in individuals with autism., Objective: To investigate whether changes in peripheral physiology recorded by a wearable biosensor and machine learning can be used to predict imminent aggressive behavior before it occurs in inpatient youths with autism., Design, Setting, and Participants: This noninterventional prognostic study used data collected from March 2019 to March 2020 from 4 primary care psychiatric inpatient hospitals. Enrolled participants were 86 psychiatric inpatients with confirmed diagnoses of autism exhibiting operationally defined self-injurious behavior, emotion dysregulation, or aggression toward others; 16 individuals were not included (18.6%) because they would not wear the biosensor (8 individuals) or were discharged before an observation could be made (8 individuals). Data were analyzed from March 2020 through October 2023., Main Outcomes and Measures: Research staff performed live behavioral coding of aggressive behavior while inpatient study participants wore a commercially available biosensor that recorded peripheral physiological signals (cardiovascular activity, electrodermal activity, and motion). Logistic regression, support vector machines, neural networks, and domain adaptation were used to analyze time-series features extracted from biosensor data. Area under the receiver operating characteristic curve (AUROC) values were used to evaluate the performance of population- and person-dependent models., Results: There were 70 study participants (mean [range; SD] age, 11.9 [5-19; 3.5] years; 62 males [88.6%]; 1 Asian [1.4%], 5 Black [7.1%], 1 Native Hawaiian or Other Pacific Islander [1.4%], and 63 White [90.0%]; 5 Hispanic [7.5%] and 62 non-Hispanic [92.5%] among 67 individuals with ethnicity data). Nearly half of the population (32 individuals [45.7%]) was minimally verbal, and 30 individuals (42.8%) had an intellectual disability. Participant length of inpatient hospital stay ranged from 8 to 201 days, and the mean (SD) length was 37.28 (33.95) days. A total of 429 naturalistic observational coding sessions were recorded, totaling 497 hours, wherein 6665 aggressive behaviors were documented, including self-injury (3983 behaviors [59.8%]), emotion dysregulation (2063 behaviors [31.0%]), and aggression toward others (619 behaviors [9.3%]). Logistic regression was the best-performing overall classifier across all experiments; for example, it predicted aggressive behavior 3 minutes before onset with a mean AUROC of 0.80 (95% CI, 0.79-0.81)., Conclusions and Relevance: This study replicated and extended previous findings suggesting that machine learning analyses of preceding changes in peripheral physiology may be used to predict imminent aggressive behaviors before they occur in inpatient youths with autism. Further research will explore clinical implications and the potential for personalized interventions.

Enhancing production of protein cargoes delivered by gene therapies can improve efficacy by reducing the amount of vector or simply increasing transgene expression levels. We explored the utility of a 126-amino acid collagen domain (CD) derived from the C1qTNF3 protein as a fusion partner to chaperone secreted proteins, extracellular "decoy receptor" domains, and single-chain variable fragments (scFvs). Fusions to the CD domain result in multimerization and enhanced levels of secretion of numerous fusion proteins while maintaining functionality. Efficient creation of bifunctional proteins using the CD domain is also demonstrated. Recombinant adeno-associated viral vector delivery of the CD with a signal peptide resulted in high-level expression with minimal biological impact as assessed by whole-brain transcriptomics. As a proof-of-concept in vivo study, we evaluated three different anti-amyloid Aβ scFvs (anti-Aβ scFvs), alone or expressed as CD fusions, following viral delivery to neonatal CRND8 mice. The CD fusion increased half-life, expression levels, and improved efficacy for amyloid lowering of a weaker binding anti-Aβ scFv. These studies validate the potential utility of this small CD as a fusion partner for secretory cargoes delivered by gene therapy and demonstrate that it is feasible to use this CD fusion to create biotherapeutic molecules with enhanced avidity or bifunctionality., Competing Interests: T.E.G. is a cofounder of Lacerta Therapeutic and Andante Biologics. The other authors declare no competing interests., (© 2023 The Author(s).)

Background: As much as 80% of children on the autism spectrum exhibit challenging behaviors (ie, behaviors dangerous to the self or others, behaviors that interfere with learning and development, and behaviors that interfere with socialization) that can have a devastating impact on personal and family well-being, contribute to teacher burnout, and even require hospitalization. Evidence-based practices to reduce these behaviors emphasize identifying triggers (events or antecedents that lead to challenging behaviors); however, parents and teachers often report that challenging behaviors surface with little warning. Exciting recent advances in biometric sensing and mobile computing technology allow the measurement of momentary emotion dysregulation using physiological indexes., Objective: We present the framework and protocol for a pilot trial that will test a mobile digital mental health app, the KeepCalm app. School-based approaches to managing challenging behaviors in children on the autism spectrum are limited by 3 key factors: children on the autism spectrum often have difficulties in communicating their emotions; it is challenging to implement evidence-based, personalized strategies for individual children in group settings; and it is difficult for teachers to track which strategies are successful for each child. KeepCalm aims to address those barriers by communicating children's stress to their teachers using physiological signaling (emotion dysregulation detection), supporting the implementation of emotion regulation strategies via smartphone pop-up notifications of top strategies for each child according to their behavior (emotion regulation strategy implementation), and easing the task of tracking outcomes by providing the child's educational team with a tool to track the most effective emotion regulation strategies for that child based on physiological stress reduction data (emotion regulation strategy evaluation)., Methods: We will test KeepCalm with 20 educational teams of students on the autism spectrum with challenging behaviors (no exclusion based on IQ or speaking ability) in a pilot randomized waitlist-controlled field trial over a 3-month period. We will examine the usability, acceptability, feasibility, and appropriateness of KeepCalm as primary outcomes. Secondary preliminary efficacy outcomes include clinical decision support success, false positives or false negatives of stress alerts, and the reduction of challenging behaviors and emotion dysregulation. We will also examine technical outcomes, including the number of artifacts and the proportion of time children are engaged in high physical movement based on accelerometry data; test the feasibility of our recruitment strategies; and test the response rate and sensitivity to change of our measures, in preparation for a future fully powered large-scale randomized controlled trial., Results: The pilot trial will begin by September 2023., Conclusions: Results will provide key data about important aspects of implementing KeepCalm in preschools and elementary schools and will provide preliminary data about its efficacy to reduce challenging behaviors and support emotion regulation in children on the autism spectrum., Trial Registration: ClinicalTrials.gov NCT05277194; https://www.clinicaltrials.gov/ct2/show/NCT05277194., International Registered Report Identifier (irrid): PRR1-10.2196/45852., (©Emma H Palermo, Amanda V Young, Sky Deswert, Alyssa Brown, Miranda Goldberg, Evan Sultanik, Jessica Tan, Carla A Mazefsky, Lauren Brookman-Frazee, James C McPartland, Matthew S Goodwin, Jeffrey Pennington, Steven C Marcus, Rinad S Beidas, David S Mandell, Heather J Nuske. Originally published in JMIR Research Protocols (https://www.researchprotocols.org), 26.06.2023.)

Individuals with autism spectrum disorder (ASD) experience behavioral and emotional symptoms hypothesized to arise from emotion dysregulation (ED), difficulty modulating emotional experience, expression, and intensity in an acceptable and contextually appropriate manner. We developed Regulating Together (RT)-an intensive-outpatient, caregiver-assisted group program to meet the ASD + ED intervention critical need. A within-subjects trial was conducted (5-week-control lead-in period, 5-week-treatment, and 5-and 10-weeks-post-treatment follow-ups). Forty-four youth with ASD + ED (25 8-12, 19 13-18 yr-olds, 88% male, mean FSIQ of 96) participated. Improvements were found in reactivity, emotion regulation knowledge, and flexibility post-treatment and 10-weeks post-treatment. A reduction in inpatient hospitalization rates by 16% from the 12 months pre-RT to 12 months post-RT was observed. RT shows promise to reduce ED in ASD., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

The accumulation of α-synuclein (α-syn) in intracellular formations known as Lewy bodies (LBs) is associated with several neurodegenerative diseases including Parkinson's disease and Lewy Body Dementia. There is still limited understanding of how α-syn and LB formation is associated with cellular dysfunction and degeneration in these diseases. To examine the clearance and production dynamics of α-syn we transduced organotypic murine brain slice cultures (BSCs) with recombinant adeno-associated viruses (rAAVs) to express Dendra2-tagged human wild-type (WT) and mutant A53T α-syn, with and without the addition of exogenous α-syn fibrillar seeds and tracked them over several weeks in culture using optical pulse labeling. We found that neurons expressing WT or mutant A53T human α-syn show similar rates of α-syn turnover even when insoluble, phosphorylated Ser129 α-syn has accumulated. Taken together, this data reveals α-syn aggregation and overexpression, pSer129 α-syn, nor the A53T mutation affect α-syn dynamics in this system. Prion-type seeding with exogenous α-syn fibrils significantly slows α-syn turnover, in the absence of toxicity but is associated with the accumulation of anti-p62 immunoreactivity and Thiazin Red positivity. Prion-type induction of α-syn aggregation points towards a potential protein clearance deficit in the presence of fibrillar seeds and the ease of this system to explore precise mechanisms underlying these processes. This system facilitates the exploration of α-syn protein dynamics over long-term culture periods. This platform can further be exploited to provide mechanistic insight on what drives this slowing of α-syn turnover and how therapeutics, other genes or different α-syn mutations may affect α-syn protein dynamics., (© 2022. The Author(s).)

Challenges with emotion dysregulation, self-injurious behavior (SIB), and aggression are common in autistic individuals. Prior research on the relationships between these behaviors is limited mainly to cross-sectional correlations of parent-report data. Understanding how emotion dysregulation, SIB, and aggression present and relate to one another in real-time could add to our understanding of the context and function of these behaviors. The present study examined the real-time occurrence and temporal relationships between these behaviors in 53 psychiatrically hospitalized autistic youth. Over 500 hours of behavioral observation occurred during everyday activities in the hospital. Start and stop times for instances of overt emotion dysregulation, SIB, and aggression were coded live using a custom mobile phone app. Results indicated large individual variability in the frequency and duration of these behaviors and their co-occurrence. Both SIB and aggression co-occurred with overt emotion dysregulation at above-chance levels, suggesting a role for emotional distress in the occurrence of these behaviors. However, there was substantial variability within and between individuals in co-occurrence, and SIB and aggression often (and for some individuals, almost always) occurred without overt emotion dysregulation. Relatedly, cross-recurrence quantitative analysis revealed that SIB and aggression preceded emotion dysregulation more often than emotion dysregulation preceded SIB and aggression. Future research, perhaps using ambulatory psychophysiological measures, is needed to understand whether emotion dysregulation may sometimes be present but not easily observed during SIB and aggression. LAY SUMMARY: This study provides insight into how overt emotion dysregulation (i.e., visible distress), aggression, and self-injury unfold in real-time for autistic individuals. Participants were 53 autistic youth staying in a psychiatric hospital. Research staff observed participants in everyday activities on the hospital unit and noted instances of aggression, self-injurious behavior, and emotion dysregulation. Results suggest that aggression and self-injury sometimes occur with visible signs of distress but also often occur without visible distress. In addition, observable distress was more common in the moments after these behaviors than in the moments before., (© 2022 International Society for Autism Research and Wiley Periodicals LLC.)

Commercially available wearable biosensors have the potential to enhance psychophysiology research and digital health technologies for autism by enabling stress or arousal monitoring in naturalistic settings. However, such monitors may not be comfortable for children with autism due to sensory sensitivities. To determine the feasibility of wearable technology in children with autism age 8-12 years, we first selected six consumer-grade wireless cardiovascular monitors and tested them during rest and movement conditions in 23 typically developing adults. Subsequently, the best performing monitors (based on data quality robustness statistics), Polar and Mio Fuse, were evaluated in 32 children with autism and 23 typically developing children during a 2-h session, including rest and mild stress-inducing tasks. Cardiovascular data were recorded simultaneously across monitors using custom software. We administered the Comfort Rating Scales to children. Although the Polar monitor was less comfortable for children with autism than typically developing children, absolute scores demonstrated that, on average, all children found each monitor comfortable. For most children, data from the Mio Fuse (96%-100%) and Polar (83%-96%) passed quality thresholds of data robustness. Moreover, in the stress relative to rest condition, heart rate increased for the Polar, F(1,53) = 135.70, p < 0.001, ηp 2  = 0.78, and Mio Fuse, F(1,53) = 71.98, p < 0.001, ηp 2  = 0.61, respectively, and heart rate variability decreased for the Polar, F(1,53) = 13.41, p = 0.001, ηp 2  = 0.26, and Mio Fuse, F(1,53) = 8.89, p = 0.005, ηp 2  = 0.16, respectively. This feasibility study suggests that select consumer-grade wearable cardiovascular monitors can be used with children with autism and may be a promising means for tracking physiological stress or arousal responses in community settings. LAY SUMMARY: Commercially available heart rate trackers have the potential to advance stress research with individuals with autism. Due to sensory sensitivities common in autism, their comfort wearing such trackers is vital to gathering robust and valid data. After assessing six trackers with typically developing adults, we tested the best trackers (based on data quality) in typically developing children and children with autism and found that two of them met criteria for comfort, robustness, and validity., (© 2021 International Society for Autism Research and Wiley Periodicals LLC.)

Objectives: Irritability is a transdiagnostic symptom in developmental psychopathology, conceptualized as a low threshold for frustration and increased proneness to anger. While central to emotion regulation, there is a vital need for empirical studies to explore the relationship between irritability and underlying physiological mechanisms of cardiovascular arousal., Methods: We examined the relationship between irritability and cardiovascular arousal (i.e., heart rate [HR] and heart rate variability [HRV]) in a transdiagnostic sample of 51 youth (M = 12.63 years, SD = 2.25; 62.7% male). Data was collected using the Empatica E4 during a laboratory stop-signal task. In addition, the impact of motion activity, age, medication, and sleep on cardiovascular responses was explored., Results: Main findings showed that irritability was associated with increased HR and decreased HRV during task performance., Conclusions: Findings support the role of peripheral physiological dysregulation in youth with emotion regulation problems and suggest the potential use of available wearable consumer electronics as an objective measure of irritability and physiological arousal in a transdiagnostic sample of youth., (© 2021 The Authors. International Journal of Methods in Psychiatric Research published by John Wiley & Sons Ltd.)

Participants with autism spectrum disorder (ASD) (n = 121, mean [SD] age: 14.6 [8.0] years) and typically developing (TD) controls (n = 40, 16.4 [13.3] years) were presented with a series of videos representing biological motion on one side of a computer monitor screen and non-biological motion on the other, while their eye movements were recorded. As predicted, participants with ASD spent less overall time looking at presented stimuli than TD participants (P < 10 -3 ) and showed less preference for biological motion (P < 10 -5 ). Participants with ASD also had greater average latencies than TD participants of the first fixation on both biological (P < 0.01) and non-biological motion (P < 0.02). Findings suggest that individuals with ASD differ from TD individuals on multiple properties of eye movements and biological motion preference.

Wayne Velicer is remembered for a mind where mathematical concepts and calculations intrigued him, behavioral science beckoned him, and people fascinated him. Born in Green Bay, Wisconsin on March 4, 1944, he was raised on a farm, although early influences extended far beyond that beginning. His Mathematics BS and Psychology minor at Wisconsin State University in Oshkosh, and his PhD in Quantitative Psychology from Purdue led him to a fruitful and far-reaching career. He was honored several times as a high-impact author, was a renowned scholar in quantitative and health psychology, and had more than 300 scholarly publications and 54,000+ citations of his work, advancing the arenas of quantitative methodology and behavioral health. In his methodological work, Velicer sought out ways to measure, synthesize, categorize, and assess people and constructs across behaviors and time, largely through principal components analysis, time series, and cluster analysis. Further, he and several colleagues developed a method called Testing Theory-based Quantitative Predictions, successfully applied to predicting outcomes and effect sizes in smoking cessation, diet behavior, and sun protection, with the potential for wider applications. With $60,000,000 in external funding, Velicer also helped engage a large cadre of students and other colleagues to study methodological models for a myriad of health behaviors in a widely applied Transtheoretical Model of Change. Unwittingly, he has engendered indelible memories and gratitude to all who crossed his path. Although Wayne Velicer left this world on October 15, 2017 after battling an aggressive cancer, he is still very present among us.

Parkinson's disease is characterized by accumulation of α-synuclein (αSyn). Release of oligomeric/fibrillar αSyn from damaged neurons may potentiate neuronal death in part via microglial activation. Heretofore, it remained unknown if oligomeric/fibrillar αSyn could activate the nucleotide-binding oligomerization domain (NOD)-like receptor (NLR) family pyrin domain-containing 3 (NLRP3) inflammasome in human microglia and whether anti-αSyn antibodies could prevent this effect. Here, we show that αSyn activates the NLRP3 inflammasome in human induced pluripotent stem cell (hiPSC)-derived microglia (hiMG) via dual stimulation involving Toll-like receptor 2 (TLR2) engagement and mitochondrial damage. In vitro, hiMG can be activated by mutant (A53T) αSyn secreted from hiPSC-derived A9-dopaminergic neurons. Surprisingly, αSyn-antibody complexes enhanced rather than suppressed inflammasome-mediated interleukin-1β (IL-1β) secretion, indicating these complexes are neuroinflammatory in a human context. A further increase in inflammation was observed with addition of oligomerized amyloid-β peptide (Aβ) and its cognate antibody. In vivo, engraftment of hiMG with αSyn in humanized mouse brain resulted in caspase-1 activation and neurotoxicity, which was exacerbated by αSyn antibody. These findings may have important implications for antibody therapies aimed at depleting misfolded/aggregated proteins from the human brain, as they may paradoxically trigger inflammation in human microglia., Competing Interests: Competing interest statement: S.A.L. and G.H. are coauthors on a published consensus statement review of cell-death criteria along with several dozen other authors who are authorities in this field [N. M. C. Connolly et al., Cell Death Differ. 25, 542–572 (2018)]. That manuscript was published in order to help nonexperts in the field understand and use criteria for various types of cell death. They also published a similar type of review paper together 10 y ago [G. E. Hardingham, S. A. Lipton, Antioxid. Redox Signal. 14, 1421–1424 (2011)]. However, S.A.L. and G.H. have never formally collaborated or worked together on any laboratory-based scientific project, including the current work.

Commercially available consumer electronics in (smartwatches and wearable biosensors) are increasingly enabling acquisition of peripheral physiological and physical activity data inside and outside of laboratory settings. However, there is scant literature available for selecting and assessing the suitability of these novel devices for scientific use. To overcome this limitation, the current paper offers a framework to aid researchers in choosing and evaluating wearable technologies for use in empirical research. Our seven-step framework includes: (1) identifying signals of interest; (2) characterizing intended use cases; (3) identifying study-specific pragmatic needs; (4) selecting devices for evaluation; (5) establishing an assessment procedure; (6) performing qualitative and quantitative analyses on resulting data; and, if desired, (7) conducting power analyses to determine sample size needed to more rigorously compare performance across devices. We illustrate the application of the framework by comparing electrodermal, cardiovascular, and accelerometry data from a variety of commercial wireless sensors (Affectiva Q, Empatica E3, Empatica E4, Actiwave Cardio, Shimmer) relative to a well-validated, wired MindWare laboratory system. Our evaluations are performed in two studies (N = 10, N = 11) involving psychometrically sound, standardized tasks that include physical activity and affect induction. After applying our framework to this data, we conclude that only some commercially available consumer devices for physiological measurement are capable of wirelessly measuring peripheral physiological and physical activity data of sufficient quality for scientific use cases. Thus, the framework appears to be beneficial at suggesting steps for conducting more systematic, transparent, and rigorous evaluations of mobile physiological devices prior to deployment in studies.

Accumulation of the tau protein in fibrillar intracellular aggregates is a defining feature of multiple neurodegenerative diseases collectively referred to as tauopathies. Despite intensive study of tau, there is limited information on the formation and clearance dynamics of tau inclusions. Using rAAV vectors to mediate expression of Dendra2-tagged human wild-type, P301L and pro-aggregant P301L/S320F tau proteins, with and without the addition of exogenous tau fibrillar seeds, we evaluated tau inclusion dynamics in organotypic brain slice culture (BSC) models using long-term optical pulse labeling methodology. Our studies reveal that tau inclusions typically form in 12-96 h in tauopathy BSC models. Unexpectedly, we demonstrate appreciable turnover of tau within inclusions with an average half-life of ~ 1 week when inclusions are newly formed. When BSCs with inclusions are aged in culture for extended periods, tau inclusions continue to turnover, but their half-lives increase to ~ 2 weeks and ~ 3 weeks after 1 and 2 months in culture, respectively. Individual tau inclusions can be long-lived structures that can persist for months in these BSC models and for even longer in the human brain. However, our data indicate that tau inclusions, are not 'tombstones', but dynamic structures with appreciable turnover. Understanding the cellular processes mediating this inclusion turnover may lead to new therapeutic strategies that could reverse pathological tau inclusion formation.

Immunotherapies designed to treat neurodegenerative tauopathies that primarily engage extracellular tau may have limited efficacy as tau is primarily intracellular. We generated tau-targeting single-chain variable fragments (scFvs) and intrabodies (iBs) from the phosphorylated tau-specific antibodies CP13 and PHF1 and the pan-tau antibody Tau5. Recombinant adeno-associated virus (rAAV) was utilized to express these antibody fragments in homozygous JNPL3 P301L tau mice. Two iBs (CP13i, PHF1i) and one scFv (PHF1s) abrogated tau pathology and delayed time to severe hindlimb paralysis. In a second tauopathy model (rTg4510), CP13i and PHF1i reduced tau pathology, but cognate scFvs did not. These data demonstrate that (1) disease-modifying efficacy does not require antibody effector functions, (2) the intracellular targeting of tau with phosphorylated tau-specific iBs is more effective than extracellular targeting with the scFvs, and (3) robust effects on tau pathology before neurodegeneration only resulted in modest disease modification as assessed by delay of severe motor phenotype., (Copyright © 2020 The Author(s). Published by Elsevier Inc. All rights reserved.)

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.

Importance: Constraint-induced movement therapy (CIMT) is a common treatment for children with unilateral cerebral palsy (CP). Although clinic-based assessments have demonstrated improvements in arm function after CIMT, whether these changes are translated and sustained outside of a clinic setting remains unclear., Objective: Accelerometers were used to quantify arm movement for children with CP 1 wk before, during, and 4 wk or more after CIMT; measurements were compared with those from typically developing (TD) peers., Design: Observational., Setting: Tertiary hospital and community., Participants: Seven children with CP (5 boys, 2 girls; average [AVE] age ± standard deviation [SD] = 7.4 ± 1.2 yr) and 7 TD peers (2 boys, 5 girls; AVE age ± SD = 7.0 ± 2.3 yr)., Intervention: 30-hr CIMT protocol., Outcomes and Measures: Use ratio, magnitude ratio, and bilateral magnitude were calculated from the accelerometer data. Clinical measures were administered before and after CIMT, and parent surveys assessed parent and child perceptions of wearing accelerometers., Results: During CIMT, the frequency and magnitude of paretic arm use among children with CP increased in the clinic and in daily life. After CIMT, although clinical scores showed sustained improvement, the children's accelerometry data reverted to baseline values. Children and parents in both cohorts had positive perceptions of accelerometer use., Conclusions and Relevance: The lack of sustained improvement in accelerometry metrics after CIMT suggests that therapy gains did not translate to increased movement outside the clinic. Additional therapy may be needed to help transfer gains outside the clinic., What This Article Adds: Accelerometer measurements were effective at monitoring arm movement outside of the clinic during CIMT and suggested that additional interventions may be needed after CIMT to sustain benefits., (Copyright © 2020 by the American Occupational Therapy Association, Inc.)

Past studies in autism spectrum disorder (ASD) indicate atypical peripheral physiological arousal. However, the conditions under which these atypicalities arise and their link with behavioral emotional expressions and core ASD symptoms remain uncertain. Given the importance of physiological arousal in affective, learning, and cognitive processes, the current study examined changes in skin conductance level (ΔSCL) in 41 toddlers with ASD (mean age: 22.7 months, SD: 2.9) and 32 age-matched toddlers with typical development (TD) (mean age: 21.6 months, SD: 3.6) in response to probes designed to induce anger, joy, and fear emotions. The magnitude of ΔSCL was comparable during anger (P = 0.206, d = 0.30) and joy (P = 0.996, d = 0.01) conditions, but significantly lower during the fear condition (P = 0.001, d = 0.83) in toddlers with ASD compared to TD peers. In the combined samples, ΔSCL positively correlated with intensity of behavioral emotional expressivity during the anger (r[71] = 0.36, P = 0.002) and fear (r[68] = 0.32, P = 0.007) conditions, but not in the joy (r[69] = -0.15, P = 0.226) condition. Finally, ΔSCL did not associate with autism symptom severity in any emotion-eliciting condition in the ASD group. Toddlers with ASD displayed attenuated ΔSCL to situations aimed at eliciting fear, which may forecast the emergence of highly prevalent internalizing and externalizing problems in this population. The study putatively identifies ΔSCL as a dimension not associated with severity of autism but with behavioral responses in negatively emotionally challenging events and provides support for the feasibility, validity, and incipient utility of examining ΔSCL in response to emotional challenges in very young children. LAY SUMMARY: Physiological arousal was measured in toddlers with autism exposed to frustrating, pleasant, and threatening tasks. Compared to typically developing peers, toddlers with autism showed comparable arousal responses to frustrating and pleasant events, but lower responses to threatening events. Importantly, physiological arousal and behavioral expressions were aligned during frustrating and threatening events, inviting exploration of physiological arousal to measure responses to emotional challenges. Furthermore, this study advances the understanding of precursors to emotional and behavioral problems common in older children with autism. Autism Res 2020, 13: 1476-1488. © 2020 International Society for Autism Research, Wiley Periodicals, Inc., (© 2020 International Society for Autism Research and Wiley Periodicals LLC.)

In preparation for a larger case-control study of children with autism spectrum disorder (ASD) and anxiety, we conducted a pilot study using a noninvasive electrocardiographic device to measure cardiovascular reactivity in 10 children (age range 9-14) with ASD. The 45-minute procedure included 6 conditions: baseline rest, an interview about school, interim rest, an unfair computerized ball-toss game followed by a fair version of the game, and a final rest. Data were successfully collected for 95% of all conditions. Omnibus Skillings-Mack tests suggested that heart rate variability variables including mean heart rate, mean RR interval, and root mean square of successive differences showed statistically significant variation across conditions. The procedure appears feasible and may be an informative biomarker of anxiety in ASD., (Copyright © 2020. Published by Elsevier Inc.)

There is a need for measures to track symptom change in autism spectrum disorder (ASD). We conducted a validation study on a revised version of the Autism Behavior Inventory (ABI), and a short form (ABI-S). Caregivers of individuals (6-54 years) with confirmed diagnoses of ASD (N = 144) completed the ABI and other rating scales at 4 time points. Scale consistency for each domain, 3-5 day test-retest reliability, and construct validity, determined by comparison to pre-specified scales, were all good. Change in the ABI was congruent with changes in other instruments. Collectively, results suggest incipient suitability of the ABI as a measure of changes in core and associated symptoms of ASD.Trial Registration NCT02299700.

Background: Reduction or differences in facial expression are a core diagnostic feature of autism spectrum disorder (ASD), yet evidence regarding the extent of this discrepancy is limited and inconsistent. Use of automated facial expression detection technology enables accurate and efficient tracking of facial expressions that has potential to identify individual response differences., Methods: Children and adults with ASD (N = 124) and typically developing (TD, N = 41) were shown short clips of "funny videos." Using automated facial analysis software, we investigated differences between ASD and TD groups and within the ASD group in evidence of facial action unit (AU) activation related to the expression of positive facial expression, in particular, a smile., Results: Individuals with ASD on average showed less evidence of facial AUs (AU12, AU6) relating to positive facial expression, compared to the TD group (p < .05, r = - 0.17). Using Gaussian mixture model for clustering, we identified two distinct distributions within the ASD group, which were then compared to the TD group. One subgroup (n = 35), termed "over-responsive," expressed more intense positive facial expressions in response to the videos than the TD group (p < .001, r = 0.31). The second subgroup (n = 89), ("under-responsive"), displayed fewer, less intense positive facial expressions in response to videos than the TD group (p < .001; r = - 0.36). The over-responsive subgroup differed from the under-responsive subgroup in age and caregiver-reported impulsivity (p < .05, r = 0.21). Reduced expression in the under-responsive, but not the over-responsive group, was related to caregiver-reported social withdrawal (p < .01, r = - 0.3)., Limitations: This exploratory study does not account for multiple comparisons, and future work will have to ascertain the strength and reproducibility of all results. Reduced displays of positive facial expressions do not mean individuals with ASD do not experience positive emotions., Conclusions: Individuals with ASD differed from the TD group in their facial expressions of positive emotion in response to "funny videos." Identification of subgroups based on response may help in parsing heterogeneity in ASD and enable targeting of treatment based on subtypes., Trial Registration: ClinicalTrials.gov, NCT02299700. Registration date: November 24, 2014.

Objective: The relationship between sleep (caregiver-reported and actigraphy-measured) and other caregiver-reported behaviors in children and adults with autism spectrum disorder (ASD) was examined, including the use of machine learning to identify sleep variables important in predicting anxiety in ASD., Methods: Caregivers of ASD ( n = 144) and typically developing (TD) ( n = 41) participants reported on sleep and other behaviors. ASD participants wore an actigraphy device at nighttime during an 8 or 10-week non-interventional study. Mean and variability of actigraphy measures for ASD participants in the week preceding midpoint and endpoint were calculated and compared with caregiver-reported and clinician-reported symptoms using a mixed effects model. An elastic-net model was developed to examine which sleep measures may drive prediction of anxiety., Results: Prevalence of caregiver-reported sleep difficulties in ASD was approximately 70% and correlated significantly ( p < 0.05) with sleep efficiency measured by actigraphy. Mean and variability of actigraphy measures like sleep efficiency and number of awakenings were related significantly ( p < 0.05) to ASD symptom severity, hyperactivity and anxiety. In the elastic net model, caregiver-reported sleep, and variability of sleep efficiency and awakenings were amongst the important predictors of anxiety., Conclusion: Caregivers report problems with sleep in the majority of children and adults with ASD. Reported problems and actigraphy measures of sleep, particularly variability, are related to parent reported behaviors. Measuring variability in sleep may prove useful in understanding the relationship between sleep problems and behavior in individuals with ASD. These findings may have implications for both intervention and monitoring outcomes in ASD., (Copyright © 2020 Bangerter, Chatterjee, Manyakov, Ness, Lewin, Skalkin, Boice, Goodwin, Dawson, Hendren, Leventhal, Shic, Esbensen and Pandina.)

Background: Recombinant adeno-associated virus (rAAV) is widely used in the neuroscience field to manipulate gene expression in the nervous system. However, a limitation to the use of rAAV vectors is the time and expense needed to produce them. To overcome this limitation, we evaluated whether unpurified rAAV vectors secreted into the media following scalable PEI transfection of HEK293T cells can be used in lieu of purified rAAV., Methods: We packaged rAAV2-EGFP vectors in 30 different wild-type and mutant capsids and subsequently collected the media containing secreted rAAV. Genomic titers of each rAAV vector were assessed and the ability of each unpurified virus to transduce primary mixed neuroglial cultures (PNGCs), organotypic brain slice cultures (BSCs) and the mouse brain was evaluated., Results: There was ~ 40-fold wide variance in the average genomic titers of the rAAV2-EGFP vector packaged in the 30 different capsids, ranging from a low ~ 4.7 × 10 10 vector genomes (vg)/mL for rAAV2/5-EGFP to a high of ~ 2.0 × 10 12 vg/mL for a capsid mutant of rAAV2/8-EGFP. In PNGC studies, we observed a wide range of transduction efficiency among the 30 capsids evaluated, with the rAAV2/6-EGFP vector demonstrating the highest overall transduction efficiency. In BSC studies, we observed robust transduction by wild-type capsid vectors rAAV2/6, 2/8 and 2/9, and by capsid mutants of rAAV2/1, 2/6, and 2/8. In the in vivo somatic brain transgenesis (SBT) studies, we found that intra-cerebroventricular injection of media containing unpurified rAAV2-EGFP vectors packaged with select mutant capsids resulted in abundant EGFP positive neurons and astrocytes in the hippocampus and forebrain of non-transgenic mice. We demonstrate that unpurified rAAV can express transgenes at equivalent levels to lysate-purified rAAV both in vitro and in vivo. We also show that unpurified rAAV is sufficient to drive tau pathology in BSC and neuroinflammation in vivo, recapitulating previous studies using purified rAAV., Conclusions: Unpurified rAAV vectors secreted into the media can efficiently transduce brain cells in vitro and in vivo, providing a cost-effective way to manipulate gene expression. The use of unpurified virus will greatly reduce costs of exploratory studies and further increase the utility of rAAV vectors for standard laboratory use.

Hypothalamic-pituitary-adrenal (HPA) axis dysfunction contributes to numerous human diseases and disorders. We developed a high-affinity monoclonal antibody, CTRND05, targeting corticotropin-releasing factor (CRF). In mice, CTRND05 blocks stress-induced corticosterone increases, counteracts effects of chronic variable stress, and induces other phenotypes consistent with suppression of the HPA axis. CTRND05 induces skeletal muscle hypertrophy and increases lean body mass, effects not previously reported with small-molecule HPA-targeting pharmacologic agents. Multiorgan transcriptomics demonstrates broad HPA axis target engagement through altering levels of known HPA-responsive transcripts such as Fkbp5 and Myostatin and reveals novel HPA-responsive pathways such as the Apelin-Apelin receptor system. These studies demonstrate the therapeutic potential of CTRND05 as a suppressor of the HPA axis and serve as an exemplar of a potentially broader approach to target neuropeptides with immunotherapies, as both pharmacologic tools and novel therapeutics., (© 2019 Futch et al.)

The protein α-synuclein (αsyn) forms pathologic aggregates in a number of neurodegenerative diseases including Lewy body dementia (LBD) and Parkinson's disease (PD). It is unclear why diseases such as LBD may develop widespread αsyn pathology, while in Alzheimer's disease with amygdala restricted Lewy bodies (AD/ALB) the αsyn aggregates remain localized. The amygdala contains αsyn aggregates in both LBD and in AD/ALB; to understand why αsyn pathology continues to progress in LBD but not in AD/ALB, tissue from the amygdala and other regions were obtained from 14 cases of LBD, 9 cases of AD/ALB, and 4 controls for immunohistochemical and biochemical characterization. Utilizing a panel of previously characterized αsyn antibodies, numerous unique pathologies differentiating LBD and AD/ALB were revealed; particularly the presence of dense neuropil αsyn aggregates, astrocytic αsyn, and αsyn-containing dystrophic neurites within senile plaques. Within LBD, these unique pathologies were predominantly present within the amygdala. Biochemically, the amygdala in LBD prominently contained specific carboxy-truncated forms of αsyn which are highly prone to aggregate, suggesting that the amygdala may be prone to initiate development of αsyn pathology. Similar to carboxy-truncated αsyn, it was demonstrated herein that the presence of aggregation prone A53T αsyn is sufficient to drive misfolding of wild-type αsyn in human disease. Overall, this study identifies within the amygdala in LBD the presence of unique strain-like variation in αsyn pathology that may be a determinant of disease progression.

Unpredictable and potentially dangerous aggressive behavior by youth with Autism Spectrum Disorder (ASD) can isolate them from foundational educational, social, and familial activities, thereby markedly exacerbating morbidity and costs associated with ASD. This study investigates whether preceding physiological and motion data measured by a wrist-worn biosensor can predict aggression to others by youth with ASD. We recorded peripheral physiological (cardiovascular and electrodermal activity) and motion (accelerometry) signals from a biosensor worn by 20 youth with ASD (ages 6-17 years, 75% male, 85% minimally verbal) during 69 independent naturalistic observation sessions with concurrent behavioral coding in a specialized inpatient psychiatry unit. We developed prediction models based on ridge-regularized logistic regression. Our results suggest that aggression to others can be predicted 1 min before it occurs using 3 min of prior biosensor data with an average area under the curve of 0.71 for a global model and 0.84 for person-dependent models. The biosensor was well tolerated, we obtained useable data in all cases, and no users withdrew from the study. Relatively high predictive accuracy was achieved using antecedent physiological and motion data. Larger trials are needed to further establish an ideal ratio of measurement density to predictive accuracy and reliability. These findings lay the groundwork for the future development of precursor behavior analysis and just-in-time adaptive intervention systems to prevent or mitigate the emergence, occurrence, and impact of aggression in ASD. Autism Res 2019, 12: 1286-1296. © 2019 International Society for Autism Research, Wiley Periodicals, Inc. LAY SUMMARY: Unpredictable aggression can create a barrier to accessing community, therapeutic, medical, and educational services. The present study evaluated whether data from a wearable biosensor can be used to predict aggression to others by youth with autism spectrum disorder (ASD). Results demonstrate that aggression to others can be predicted 1 min before it occurs with high accuracy, laying the groundwork for the future development of preemptive behavioral interventions and just-in-time adaptive intervention systems to prevent or mitigate the emergence, occurrence, and impact of aggression to others in ASD., (© 2019 International Society for Autism Research, Wiley Periodicals, Inc.)

Background and Objectives: Social robots (SRs) are increasingly present in medical and educational contexts, but their use in inpatient pediatric settings has not been demonstrated in studies. In this study, we aimed to (1) describe the introduction of SR technology into the pediatric inpatient setting through an innovative partnership among a pediatric teaching hospital, robotics development, and computational behavioral science laboratories and (2) present feasibility and acceptability data., Methods: Fifty-four children ages 3 to 10 years were randomly exposed to 1 of 3 interventions: (1) interactive SR teddy bear; (2) tablet-based avatar version of the bear; or (3) plush teddy bear with human presence. We monitored intervention enrollment and completion patterns, obtained qualitative feedback on acceptability of SR use from child life-specialist stakeholders, and assessed children's positive and negative affect, anxiety, and pain intensity pre- and postintervention., Results: The intervention was well received and appeared feasible, with 93% of those enrolled completing the study (with 80% complete parent data). Children exposed to the SR reported more positive affect relative to those who received a plush animal. SR interactions were characterized by greater levels of joyfulness and agreeableness than comparison interventions. Child life specialist stakeholders reported numerous potential benefits of SR technology in the pediatric setting., Conclusions: The SR appears to be an engaging tool that may provide new ways to address the emotional needs of hospitalized children, potentially increasing access to emotionally targeted interventions. Rigorous development and validation of SR technology in pediatrics could ultimately lead to scalable and cost-effective tools to improve the patient care experience., Competing Interests: POTENTIAL CONFLICT OF INTEREST: The authors have indicated they have no potential conflicts of interest to disclose., (Copyright © 2019 by the American Academy of Pediatrics.)

Background: Currently, no medications are approved to treat core symptoms of autism spectrum disorder (ASD). One barrier to ASD medication development is the lack of validated outcome measures able to detect symptom change. Current ASD interventions are often evaluated using retrospective caregiver reports that describe general clinical presentation but often require recall of specific behaviors weeks after they occur, potentially reducing accuracy of the ratings. My JAKE, a mobile and Web-based mobile health (mHealth) app that is part of the Janssen Autism Knowledge Engine-a dynamically updated clinical research system-was designed to help caregivers of individuals with ASD to continuously log symptoms, record treatments, and track progress, to mitigate difficulties associated with retrospective reporting., Objective: My JAKE was deployed in an exploratory, noninterventional clinical trial to evaluate its utility and acceptability to monitor clinical outcomes in ASD. Hypotheses regarding relationships among daily tracking of symptoms, behavior, and retrospective caregiver reports were tested., Methods: Caregivers of individuals with ASD aged 6 years to adults (N=144) used the My JAKE app to make daily reports on their child's sleep quality, affect, and other self-selected specific behaviors across the 8- to 10-week observational study. The results were compared with commonly used paper-and-pencil scales acquired over a concurrent period at regular 4-week intervals., Results: Caregiver reporting of behaviors in real time was successfully captured by My JAKE. On average, caregivers made reports 2-3 days per week across the study period. Caregivers were positive about their use of the system, with over 50% indicating that they would like to use My JAKE to track behavior outside of a clinical trial. More positive average daily reporting of overall type of day was correlated with 4 weekly reports of lower caregiver burden made at 4-week intervals (r=-0.27, P=.006, n=88) and with ASD symptoms (r=-0.42, P<.001, n=112)., Conclusions: My JAKE reporting aligned with retrospective Web-based or paper-and-pencil scales. Use of mHealth apps, such as My JAKE, has the potential to increase the validity and accuracy of caregiver-reported outcomes and could be a useful way of identifying early changes in response to intervention. Such systems may also assist caregivers in tracking symptoms and behavior outside of a clinical trial, help with personalized goal setting, and monitoring of progress, which could collectively improve understanding of and quality of life for individuals with ASD and their families., Trial Registration: ClinicalTrials.gov NCT02668991; https://clinicaltrials.gov/ct2/show/NCT02668991., (©Abigail Bangerter, Nikolay V. Manyakov, David Lewin, Matthew Boice, Andrew Skalkin, Shyla Jagannatha, Meenakshi Chatterjee, Geraldine Dawson, Matthew S Goodwin, Robert Hendren, Bennett Leventhal, Frederick Shic, Seth Ness, Gahan Pandina. Originally published in JMIR Mental Health (http://mental.jmir.org), 26.03.2019.)

One of the core diagnostic features of autism spectrum disorder (ASD) is engagement in stereotypical motor movements, although the etiology of this repetitive behavior is unknown. Since the 1960s, it has been hypothesized that stereotypical motor movements serve a homeostatic regulation function, and thereby a putative coupling mechanism to cardiovascular arousal. However, to date, surprisingly few reports explicitly assess cardio-somatic coupling and stereotypical motor movements. The present exploratory study investigates coupling of stereotypical body rocking and hand flapping to heart rate and heart rate variability (HRV) in a convenience sample (n = 10) of children and young adults with moderate to profound ASD. Motor movements were recorded via video and three-axis accelerometry, and simultaneous electrocardiographic signals were obtained to determine cardiovascular indices at or around the onset of naturalistically occurring stereotypy. Analysis of the heart rate revealed both repetitive body rocking and hand flapping in particular were found to associate with a strikingly similar cardiovascular pattern of acceleration and deceleration unrelated to physical demands associated with the movements themselves. Furthermore, neither type of stereotypical movement provoked directional change in heart rate variability. The implications of these results and opportunities for future research are discussed., (Copyright © 2019. Published by Elsevier B.V.)

Objective: The Janssen Autism Knowledge Engine (JAKE®) is a clinical research outcomes assessment system developed to more sensitively measure treatment outcomes and identify subpopulations in autism spectrum disorder (ASD). Here we describe JAKE and present results from its digital phenotyping (My JAKE) and biosensor (JAKE Sense) components. Methods: An observational, non-interventional, prospective study of JAKE in children and adults with ASD was conducted at nine sites in the United States. Feedback on JAKE usability was obtained from caregivers. JAKE Sense included electroencephalography, eye tracking, electrocardiography, electrodermal activity, facial affect analysis, and actigraphy. Caregivers of individuals with ASD reported behaviors using My JAKE. Results from My JAKE and JAKE Sense were compared to traditional ASD symptom measures. Results: Individuals with ASD ( N = 144) and a cohort of typically developing (TD) individuals ( N = 41) participated in JAKE Sense. Most caregivers reported that overall use and utility of My JAKE was "easy" (69%, 74/108) or "very easy" (74%, 80/108). My JAKE could detect differences in ASD symptoms as measured by traditional methods. The majority of biosensors included in JAKE Sense captured sizable amounts of quality data (i.e., 93-100% of eye tracker, facial affect analysis, and electrocardiogram data was of good quality), demonstrated differences between TD and ASD individuals, and correlated with ASD symptom scales. No significant safety events were reported. Conclusions: My JAKE was viewed as easy or very easy to use by caregivers participating in research outside of a clinical study. My JAKE sensitively measured a broad range of ASD symptoms. JAKE Sense biosensors were well-tolerated. JAKE functioned well when used at clinical sites previously inexperienced with some of the technologies. Lessons from the study will optimize JAKE for use in clinical trials to assess ASD interventions. Additionally, because biosensors were able to detect features differentiating TD and ASD individuals, and also were correlated with standardized symptom scales, these measures could be explored as potential biomarkers for ASD and as endpoints in future clinical studies. Clinical Trial Registration: https://clinicaltrials.gov/ct2/show/NCT02668991 identifier: NCT02668991.

Facial expression is impaired in autism spectrum disorder (ASD), but rarely systematically studied. We focus on the ability of individuals with ASD to produce facial expressions of emotions in response to a verbal prompt. We used the Janssen Autism Knowledge Engine (JAKE ® ), including automated facial expression analysis software (FACET) to measure facial expressions in individuals with ASD (n = 144) and a typically developing (TD) comparison group (n = 41). Differences in ability to produce facial expressions were observed between ASD and TD groups, demonstrated by activation of facial action units (happy, scared, surprised, disgusted, but not angry or sad). Activation of facial action units correlated with parent-reported social communication skills. This approach has potential for diagnostic and response to intervention measures.Trial Registration NCT02299700.

Eye-tracking studies have demonstrated that individuals with autism spectrum disorder sometimes show differences in attention and gaze patterns. This includes preference for certain nonsocial objects, heightened attention to detail, and more difficulty with attention shifting and disengagement, which may be associated with restricted and repetitive behaviors. This study utilized a visual exploration task and replicates findings of reduced number of objects explored and increased fixation duration on high autism interest objects in a large sample of individuals with autism spectrum disorder (n = 129, age 6-54 years) in comparison with a typically developing group. These findings correlated with parent-reported repetitive behaviors. Additionally, we applied recurrent quantification analysis to enable identification of new eye-tracking features, which accounted for temporal and spatial differences in viewing patterns. These new features were found to discriminate between autism spectrum disorder and typically developing groups and were correlated with parent-reported repetitive behaviors. Original and novel eye-tracking features identified by recurrent quantification analysis differed in their relationships to reported behaviors and were dependent on age. Trial Registration: NCT02299700. Autism Research 2018, 11: 1554-1566. © 2018 International Society for Autism Research, Wiley Periodicals, Inc. LAY SUMMARY: Using eye-tracking technology and a visual exploration task, we showed that people with autism spectrum disorder (ASD) spend more time looking at particular kinds of objects, like trains and clocks, and look at fewer objects overall than people without ASD. Where people look and the order in which they look at objects were related to the restricted and repetitive behaviors reported by parents. Eye-tracking may be a useful addition to parent reports for measuring changes in behavior in individuals with ASD., (© 2018 International Society for Autism Research, Wiley Periodicals, Inc.)

Cardiovascular reactivity during spousal conflict is considered to be one of the main pathways for relationship distress to impact physical, mental, and relationship health. However, the magnitude of association between cardiovascular reactivity during laboratory marital conflict and relationship functioning is small and inconsistent given the scope of its importance in theoretical models of intimate relationships. This study tests the possibility that cardiovascular data collected in laboratory settings downwardly bias the magnitude of these associations when compared to measures obtained in naturalistic settings. Ambulatory cardiovascular reactivity data were collected from 20 couples during two relationship conflicts in a research laboratory, two planned relationship conflicts at couples' homes, and two spontaneous relationship conflicts during couples' daily lives. Associations between self-report measures of relationship functioning, individual functioning, and cardiovascular reactivity across settings are tested using multilevel models. Cardiovascular reactivity was significantly larger during planned and spontaneous relationship conflicts in naturalistic settings than during planned relationship conflicts in the laboratory. Similarly, associations with relationship and individual functioning variables were statistically significantly larger for cardiovascular data collected in naturalistic settings than the same data collected in the laboratory. Our findings suggest that cardiovascular reactivity during spousal conflict in naturalistic settings is statistically significantly different from that elicited in laboratory settings both in magnitude and in the pattern of associations with a wide range of inter- and intrapersonal variables. These differences in findings across laboratory and naturalistic physiological responses highlight the value of testing physiological phenomena across interaction contexts in romantic relationships., (© 2018 Family Process Institute.)

Autonomic nervous systems in the human body are named for their operation outside of conscious control. One rare exception is voluntarily generated piloerection (VGP)-the conscious ability to induce goosebumps-whose physiological study, to our knowledge, is confined to three single-individual case studies. Very little is known about the physiological nature and emotional correlates of this ability. The current manuscript assesses physiological, emotional, and personality phenomena associated with VGP in a sample of thirty-two individuals. Physiological descriptions obtained from the sample are consistent with previous reports, including stereotypical patterns of sensation and action. Most participants also reported that their VGP accompanies psychological states associated with affective states (e.g., awe) and experience (e.g., listening to music), and higher than typical openness to new experiences. These preliminary findings suggest that this rare and unusual physiological ability interacts with emotional and personality factors, and thus merits further study., Competing Interests: The authors declare there are no competing interests.

Accurately determining pain levels in children is difficult, even for trained professionals and parents. Facial activity and electro- dermal activity (EDA) provide rich information about pain, and both have been used in automated pain detection. In this paper, we discuss preliminary steps towards fusing models trained on video and EDA features respectively. We compare fusion models using original video features and those using transferred video features which are less sensitive to environmental changes. We demonstrate the benefit of the fusion and the transferred video features with a special test case involving domain adaptation and improved performance relative to using EDA and video features alone.

Accurately determining pain levels in children is difficult, even for trained professionals and parents. Facial activity provides sensitive and specific information about pain, and computer vision algorithms have been developed to automatically detect Facial Action Units (AUs) defined by the Facial Action Coding System (FACS). Our prior work utilized information from computer vision, i.e., automatically detected facial AUs, to develop classifiers to distinguish between pain and no-pain conditions. However, application of pain/no-pain classifiers based on automated AU codings across different environmental domains results in diminished performance. In contrast, classifiers based on manually coded AUs demonstrate reduced environmentally-based variability in performance. In this paper, we train a machine learning model to recognize pain using AUs coded by a computer vision system embedded in a software package called iMotions. We also study the relationship between iMotions (automatically) and human (manually) coded AUs. We find that AUs coded automatically are different from those coded by a human trained in the FACS system, and that the human coder is less sensitive to environmental changes. To improve classification performance in the current work, we applied transfer learning by training another machine learning model to map automated AU codings to a subspace of manual AU codings to enable more robust pain recognition performance when only automatically coded AUs are available for the test data. With this transfer learning method, we improved the Area Under the ROC Curve (AUC) on independent data from new participants in our target domain from 0.67 to 0.72.

Objective pain assessment is required for appropriate pain management in the clinical setting. However, clinical gold standard pain assessment is based on subjective methods. Automated pain detection from physiological data may provide important objective information to better standardize pain assessment. Specifically, electrodermal activity (EDA) can identify features of stress and anxiety induced by varying pain levels. However, notable variability in EDA measurement exists and research to date has demonstrated sensitivity but lack of specificity in pain assessment. In this paper, we use timescale decomposition (TSD) to extract salient features from EDA signals to identify an accurate and automated EDA pain detection algorithm to sensitively and specifically distinguish pain from no-pain conditions.

It has been suggested that changes in physiological arousal precede potentially dangerous aggressive behavior in youth with autism spectrum disorder (ASD) who are minimally verbal (MV-ASD). The current work tests this hypothesis through time-series analyses on biosignals acquired prior to proximal aggression onset. We implement ridge-regularized logistic regression models on physiological biosensor data wirelessly recorded from 15 MV-ASD youth over 64 independent naturalistic observations in a hospital inpatient unit. Our results demonstrate proof-of-concept, feasibility, and incipient validity predicting aggression onset 1 minute before it occurs using global, person-dependent, and hybrid classifier models.

Objective: Electrodermal activity (EDA) is a noninvasive measure of sympathetic activation often used to study emotions, decision making, and health. The use of "ambulatory" EDA in everyday life presents novel challenges-frequent artifacts and long recordings-with inconsistent methods available for efficiently and accurately assessing data quality. We developed and validated a simple, transparent, flexible, and automated quality assessment procedure for ambulatory EDA data., Methods: A total of 20 individuals with autism (5 females, 5-13 years) provided a combined 181 h of EDA data in their home using the Affectiva Q Sensor across 8 weeks. Our procedure identified invalid data using four rules: First, EDA out of range; second, EDA changes too quickly; third, temperature suggests the sensor is not being worn; and fourth, transitional data surrounding segments identified as invalid via the preceding rules. We identified invalid portions of a pseudorandom subset of our data (32.8 h, 18%) using our automated procedure and independent visual inspection by five EDA experts., Results: Our automated procedure identified 420 min (21%) of invalid data. The five experts agreed strongly with each other (agreement: 98%, Cohen's κ: 0.87) and, thus, were averaged into a "consensus" rating. Our procedure exhibited excellent agreement with the consensus rating (sensitivity: 91%, specificity: 99%, accuracy: 92%, κ: 0.739 [95% CI = 0.738, 0.740])., Conclusion: We developed a simple, transparent, flexible, and automated quality assessment procedure for ambulatory EDA data., Significance: Our procedure can be used beyond this study to enhance efficiency, transparency, and reproducibility of EDA analyses, with free software available at http://www.cbslab.org/EDAQA.

We test the hypothesis that changes in preceding physiological arousal can be used to predict imminent aggression proximally before it occurs in youth with autism spectrum disorder (ASD) who are minimally verbal (MV-ASD). We evaluate this hypothesis through statistical analyses performed on physiological biosensor data wirelessly recorded from 20 MV-ASD youth over 69 independent naturalistic observations in a hospital inpatient unit. Using ridge-regularized logistic regression, results demonstrate that, on average, our models are able to predict the onset of aggression 1 minute before it occurs using 3 minutes of prior data with a 0.71 AUC for global, and a 0.84 AUC for person-dependent models.