The CBIT+TMS Trial: study protocol for a two-phase randomized controlled trial testing neuromodulation to augment behavior therapy for youth with chronic tics.

Background: Comprehensive Behavioral Intervention for Tics (CBIT) is a first-line treatment for tic disorders that aims to improve controllability over tics that an individual finds distressing or impairing. However, it is only effective for approximately half of patients. Supplementary motor area (SMA)-directed neurocircuitry plays a strong role in motor inhibition, and activity in this region is thought to contribute to tic expression. Targeted modulation of SMA using transcranial magnetic stimulation (TMS) may increase CBIT efficacy by improving patient ability to implement tic controllability behaviors. Methods: The CBIT+TMS trial is a two-phase, milestone driven early-stage randomized controlled trial. The trial will test whether augmenting CBIT with inhibitory, noninvasive stimulation of SMA with TMS modifies activity in SMA-mediated circuits and enhances tic controllability in youth ages 12-21 years with chronic tics. Phase 1 will directly compare two rTMS augmentation strategies (1Hz rTMS vs. cTBS) vs. sham in N = 60 participants. Quantifiable, a priori "Go/No Go Criteria" guide the decision to proceed to Phase 2 and selection of the optimal TMS regimen. Phase 2 will compare the optimal regimen vs. sham and test the link between neural target engagement and clinical outcomes in a new sample of N = 60 participants. Discussion: This clinical trial is one of few to date testing TMS augmentation of therapy in a pediatric sample. Results will provide insight into whether TMS is a potentially viable strategy for enhancing CBIT efficacy and reveal potential neural and behavioral mechanisms of change. Trial registration: ClinicalTrials.gov Identifier: NCT04578912.

The CBIT + TMS trial: study protocol for a two-phase randomized controlled trial testing neuromodulation to augment behavior therapy for youth with chronic tics.

BACKGROUND: Comprehensive Behavioral Intervention for Tics (CBIT) is a first-line treatment for tic disorders that aims to improve controllability over tics that an individual finds distressing or impairing. However, it is only effective for approximately half of patients. Supplementary motor area (SMA)-directed neurocircuitry plays a strong role in motor inhibition, and activity in this region is thought to contribute to tic expression. Targeted modulation of SMA using transcranial magnetic stimulation (TMS) may increase CBIT efficacy by improving patients' ability to implement tic controllability behaviors. METHODS: The CBIT + TMS trial is a two-phase, milestone-driven early-stage randomized controlled trial. The trial will test whether augmenting CBIT with inhibitory, non-invasive stimulation of SMA with TMS modifies activity in SMA-mediated circuits and enhances tic controllability in youth ages 12-21 years with chronic tics. Phase 1 will directly compare two rTMS augmentation strategies (1 Hz rTMS vs. cTBS) vs. sham in N = 60 participants. Quantifiable, a priori "Go/No Go Criteria" guide the decision to proceed to phase 2 and the selection of the optimal TMS regimen. Phase 2 will compare the optimal regimen vs. sham and test the link between neural target engagement and clinical outcomes in a new sample of N = 60 participants. DISCUSSION: This clinical trial is one of few to date testing TMS augmentation of therapy in a pediatric sample. The results will provide insight into whether TMS is a potentially viable strategy for enhancing CBIT efficacy and reveal potential neural and behavioral mechanisms of change. TRIAL REGISTRATION: ClinicalTrials.gov NCT04578912 . Registered on October 8, 2020.

Auditory Domain Sensitivity and Neuroplasticity-Based Targeted Cognitive Training in Autism Spectrum Disorder.

Sensory processing, along with the integration of external inputs into stable representations of the environment, is integral to social cognitive functioning; challenges in these processes have been reported in Autism Spectrum Disorder (ASD) since the earliest descriptions of autism. Recently, neuroplasticity-based targeted cognitive training (TCT) has shown promise as an approach to improve functional impairments in clinical patients. However, few computerized and adaptive brain-based programs have been trialed in ASD. For individuals with sensory processing sensitivities (SPS), the inclusion of some auditory components in TCT protocols may be aversive. Thus, with the goal of developing a web-based, remotely accessible intervention that incorporates SPS concerns in the auditory domain, we assessed auditory SPS in autistic adolescents and young adults (N = 25) who started a novel, computerized auditory-based TCT program designed to improve working memory and information processing speed and accuracy. We found within-subject gains across the training program and between pre/post-intervention assessments. We also identified auditory, clinical, and cognitive characteristics that are associated with TCT outcomes and program engagement. These initial findings may be used to inform therapeutic decisions about which individuals would more likely engage in and benefit from an auditory-based, computerized TCT program.

Brief Report: Above and Beyond Safety: Psychosocial and Biobehavioral Impact of Autism-Assistance Dogs on Autistic Children and their Families.

Autism-Assistance Dogs (AADs) are highly-skilled service animals trained primarily to ensure the safety of an autistic child by preventing elopement and mitigating 'meltdowns'. Although anecdotal accounts and case-studies have indicated that AADs confer benefits above and beyond safety, empirical support anchored in validated clinical, behavioral, and physiological measures is lacking. To address this gap, we studied children and their families before and after receiving a well-trained AAD using a within-subject, repeated-measures design. Notably, this study is the first to assess change in a biomarker for chronic stress in both autistic children and their parents. Final analyses included pre-/post-AAD data from 11 triads (parent/handler-dog-child) demonstrating significantly positive psychosocial and biobehavioral effects of AADs.

Integrating Causal Discovery and Clinically-Relevant Insights to Explore Directional Relationships between Autistic Features, Sex at Birth, and Cognitive Abilities.

Prevalence in autism spectrum disorder (ASD) diagnosis has long been strongly male-biased. Yet, consensus has not been reached on mechanisms and clinical features that underlie sex-based discrepancies. Whereas females may be under-diagnosed because of inconsistencies in diagnostic/ascertainment procedures (sex-biased criteria, social camouflaging), diagnosed males may have exhibited more overt behaviors (e.g., hyperactivity, aggression) that prompted clinical evaluation. Applying a novel network-theory-based approach, we extracted data-driven, clinically-relevant insights from a large, well-characterized sample (Simons Simplex Collection) of 2175 autistic males (Ages = 8.9±3.5 years) and 334 autistic females (Ages = 9.2±3.7 years). Exploratory factor analysis (EFA) and expert clinical review reduced data dimensionality to 15 factors of interest. To offset inherent confounds of an imbalanced sample, we identified a subset of males (N=331) matched to females on key variables (Age, IQ) and applied data-driven CDA using Greedy Fast Causal Inference (GFCI) for three groups (All Females, All Males, and Matched Males). Structural equation modeling (SEM) extracted measures of model fit and effect sizes for causal relationships between sex, age, and, IQ on EFA-selected factors capturing phenotypic representations of autism across sensory, social, and restricted and repetitive behavior domains. Our methodology unveiled sex-specific directional relationships to inform developmental outcomes and targeted interventions.

Utility of Downstream Biomarkers to Assess and Optimize Intranasal Delivery of Oxytocin.

Oxytocin (OT), a mammalian neurohormone associated with social cognition and behavior, can be administered in its synthetic form intranasally (IN) and impact brain chemistry and behavior. IN-OT shows potential as a noninvasive intervention for disorders characterized by social challenges, e.g., autism spectrum disorder (ASD) and anorexia nervosa (AN). To evaluate IN-OT's efficacy, we must quantify OT uptake, availability, and clearance; thus, we assessed OT levels in urine (uOT) before and after participants (26 ASD, 7 AN, and 7 healthy controls) received 40 IU IN-OT or placebo across two sessions using double-blind, placebo-controlled crossover designs. We also measured uOT and plasma (pOT) levels in a subset of participants to compare the two sampling methods. We found significantly higher uOT and pOT following intranasal delivery of active compound versus placebo, but analyses yielded larger effect sizes and more clearly differentiated pre-post-OT levels for uOT than pOT. Further, we applied a two-step cluster (TSC), blinded backward-chaining approach to determine whether active/placebo groups could be identified by uOT and pOT change alone; uOT levels may serve as an accessible and accurate systemic biomarker for OT dose-response. Future studies will explore whether uOT levels correlate directly with behavioral targets to improve dosing for therapeutic goals.

Differential extrinsic brain network connectivity and social cognitive task-specific demands in Autism Spectrum Disorder (ASD).

Few studies have used task-based functional connectivity (FC) magnetic resonance imaging to examine emotion-processing during the critical neurodevelopmental period of adolescence in Autism Spectrum Disorders (ASDs). Moreover, task designs with pervasive confounds (e.g., lack of appropriate controls) persist because they activate neural circuits of interest reliably. As an alternative approach to "subtracting" activity from putative control conditions, we propose examining FC across an entire task run. By pivoting our analysis and interpretation of existing paradigms, we may better understand neural response to non-focal instances of socially-relevant stimuli that approximate real-world experiences more closely. Hence, using two well-established affective tasks (face-viewing, face-matching) with diverging social-cognitive demands, we investigated extrinsic FC from amygdala (AMG) and fusiform gyrus (FG) seeds in typically-developing (TD; N = 17) and ASD (N = 17) male adolescents (10-18 yo) and clinical correlations (Social Communication Questionnaire; SCQ) of group FC differences. Participant data (4TD, 6ASD) with excessive head-motion were excluded from final analysis. Direct between-group comparisons revealed significant differences between groups for neural response but not task performance (accuracy, reaction time). During face-viewing, we found greater FC from AMG and FG seeds for ASD participants (ASD > TD) in regions involved in the Default Mode and Fronto-Parietal Task Control Networks. During face-matching, we found greater FC from AMG and FG seeds for TD participants (TD > ASD), in regions associated with the Salience, Dorsal Attention, and Somatosensory Networks. SCQ scores correlated positively with regions with group differences on the face-viewing task and negatively with regions identified for the face-matching task. Task-dependent group differences in FC despite comparable behavioral performance suggest that high-functioning ASD may wield compensatory strategies; clinically-correlated FC patterns may associate with differential task-demands, ecological validity, and context-dependent processing. Employing this novel approach may further the development of targeted therapeutic interventions informed by individual differences in the highly heterogeneous ASD population.

Predicting Core Characteristics of ASD Through Facial Emotion Recognition and Eye Tracking in Youth.

Autism Spectrum Disorder (ASD) is a heterogeneous neurodevelopmental disorder (NDD) with a high rate of comorbidity. The implementation of eye-tracking methodologies has informed behavioral and neurophysiological patterns of visual processing across ASD and comorbid NDDs. In this study, we propose a machine learning method to predict measures of two core ASD characteristics: impaired social interactions and communication, and restricted, repetitive, and stereotyped behaviors and interests. Our method extracts behavioral features from task performance and eye-tracking data collected during a facial emotion recognition paradigm. We achieved high regression accuracy using a Random Forest regressor trained to predict scores on the SRS-2 and RBS-R assessments; this approach may serve as a classifier for ASD diagnosis.

Social Cognitive Interventions for Adolescents with Autism Spectrum Disorders: A Systematic Review.

INTRODUCTION: Autism spectrum disorder (ASD), a heterogeneous neurodevelopmental disorder, impacts social experience and functioning throughout the lifespan. Although the postnatal phase of neuroplasticity has been a focus for early interventions in ASD, a second critical period in adolescence has emerged as a promising target for experience-dependent remediation. Interventions addressing the multidimensional construct of social cognition have also shown potential as a therapeutic approach. Yet, to date, evidence-based social cognitive interventions (SCIs) designed for adolescents with ASD are still lacking. In this review, we aim to survey and synthesize the extant literature on SCIs for adolescents with ASD in order to inform next steps for treatment research. METHODS: Using the PRISMA guidelines, we limited our queries to peer-reviewed, English-language journal articles describing SCI trials for adolescents with ASD using a randomized controlled design. RESULTS: Eighteen articles in total met our inclusion/exclusion criteria. We present and discuss these trials using the non-exclusive categories of group-based social skills interventions, experiential-based interventions, and computer-assisted interventions. LIMITATIONS: To ensure a focus on adolescence, we excluded trials with teen-age participants if mean subject age was not between 12-18 years. Also, given the variability across studies in outcome measures, study designs, samples, and effect sizes, findings were incommensurable. CONCLUSIONS: Several reviewed SCIs reported post-treatment improvements in varied domains but findings were inconsistent. Further investigations of existing and novel interventions are warranted; attention to assessing and improving long-term skill transfer is essential. Technology-assisted augmentations may improve treatment efficacy and ecological validity of therapeutic gains.

Hypoconnectivity of insular resting-state networks in adolescents with Autism Spectrum Disorder.

Autism Spectrum Disorder (ASD) is characterized by deficits in social interaction and communication. The anterior insula (AI) participates in emotional salience detection; and the posterior insula (PI) participates in sensorimotor integration and response selection. Meta-analyses have noted insula-based aberrant connectivity within ASD. Given the observed social impairments in ASD and the role of the insula in social information processing (SIP), investigating functional organization of this structure in ASD is important. We investigated differences in resting-state functional connectivity (RSFC) using fMRI in male youths with (N=13; mean=14.6 years; range: 10.2-18.0 years) and without ASD (N=17; mean=14.5 years; range: 10.0-17.5 years). With seed-based FC measures, we compared RSFC in insular networks. Hypoconnectivity was observed in ASD (AI-superior frontal gyrus (SFG); AI-thalamus; PI-inferior parietal lobule (IPL); PI-fusiform gyrus (FG); PI-lentiform nucleus/putamen). Using the Social Communication Questionnaire (SCQ) to assess social functioning, regression analyses yielded negative correlations between SCQ scores and RSFC (AI-SFG; AI-thalamus; PI-FG; PI-IPL). Given the insula's connections to limbic regions, and its role in integrating external sensory stimuli with internal states, atypical activity in this structure may be associated with social deficits characterizing ASD. Our results suggest further investigation of the insula's role in SIP across a continuum of social abilities is needed.

Differences in neural activity when processing emotional arousal and valence in autism spectrum disorders.

Individuals with autism spectrum disorders (ASD) often have difficulty recognizing and interpreting facial expressions of emotion, which may impair their ability to navigate and communicate successfully in their social, interpersonal environments. Characterizing specific differences between individuals with ASD and their typically developing (TD) counterparts in the neural activity subserving their experience of emotional faces may provide distinct targets for ASD interventions. Thus we used functional magnetic resonance imaging (fMRI) and a parametric experimental design to identify brain regions in which neural activity correlated with ratings of arousal and valence for a broad range of emotional faces. Participants (51 ASD, 84 TD) were group-matched by age, sex, IQ, race, and socioeconomic status. Using task-related change in blood-oxygen-level-dependent (BOLD) fMRI signal as a measure, and covarying for age, sex, FSIQ, and ADOS scores, we detected significant differences across diagnostic groups in the neural activity subserving the dimension of arousal but not valence. BOLD-signal in TD participants correlated inversely with ratings of arousal in regions associated primarily with attentional functions, whereas BOLD-signal in ASD participants correlated positively with arousal ratings in regions commonly associated with impulse control and default-mode activity. Only minor differences were detected between groups in the BOLD signal correlates of valence ratings. Our findings provide unique insight into the emotional experiences of individuals with ASD. Although behavioral responses to face-stimuli were comparable across diagnostic groups, the corresponding neural activity for our ASD and TD groups differed dramatically. The near absence of group differences for valence correlates and the presence of strong group differences for arousal correlates suggest that individuals with ASD are not atypical in all aspects of emotion-processing. Studying these similarities and differences may help us to understand the origins of divergent interpersonal emotional experience in persons with ASD. Hum Brain Mapp 37:443-461, 2016. © 2015 Wiley Periodicals, Inc.

Physicochemical, nutritional, and sensory qualities of wine grape pomace fortified baked goods.

Wine grape pomace (WGP) as a source of antioxidant dietary fiber (DF) was used to fortify baked goods, including breads, muffins, and brownies. Pinot Noir WGP (RWGP) and Pinot Grigio WGP (WWGP) substituted wheat flour at concentration of 5%, 10%, and 15% for bread, 10%, 15%, 20%, and 25% RWGP for brownies, and 5%, 10%, and 15% RWGP or 10%, 15%, and 20% WWGP for muffins. The finished products were evaluated for total phenolic content (TPC), radical scavenging activity (RSA), and total DF, as well as physicochemical and sensory properties. WGP flour blends were also tested for solvent retention capacity (SRC). The highest TPC and RSA values for bread and muffins were achieved in 15% RWGP fortified samples with TPC and RSA values of 68.32 mg gallic acid equivalent (GAE)/serving and 80.70 AAE mg/serving, respectively for bread, and 2164 mg GAE/serving and 1526 mg AAE/serving, respectively for muffins. Brownies fortified with 10% RWGP had the highest RSA value (115.52 mg AAE/serving) while the control had the highest TPC value (1152 mg GAE/serving). Breads and muffins with 15% RWGP and brownies with 25% RWGP had the highest amount of DF (6.33, 12.32, and 7.73 g/serving, respectively). Sensory evaluation concluded that there is no difference in overall liking of 5% and 10% RWGP breads and muffins or 15% and 20% WGP brownies compared to the controls. This study demonstrated that WGP is a viable functional ingredient in bakery goods to increase TPC, RSA, and DF in consumer's diets.

Using the circumplex model of affect to study valence and arousal ratings of emotional faces by children and adults with autism spectrum disorders.

The affective circumplex model holds that emotions can be described as linear combinations of two underlying, independent neurophysiological systems (arousal, valence). Given research suggesting individuals with autism spectrum disorders (ASD) have difficulty processing emotions, we used the circumplex model to compare how individuals with ASD and typically-developing (TD) individuals respond to facial emotions. Participants (51 ASD, 80 TD) rated facial expressions along arousal and valence dimensions; we fitted closed, smooth, 2-dimensional curves to their ratings to examine overall circumplex contours. We modeled individual and group influences on parameters describing curve contours to identify differences in dimensional effects across groups. Significant main effects of diagnosis indicated the ASD-group's ratings were constricted for the entire circumplex, suggesting range constriction across all emotions. Findings did not change when covarying for overall intelligence.

Wine grape pomace as antioxidant dietary fibre for enhancing nutritional value and improving storability of yogurt and salad dressing.

Wine grape pomace (WGP) as a source of antioxidant dietary fibre (ADF) was fortified in yogurt (Y), Italian (I) and Thousand Island (T) salad dressings. During the 3 weeks of storage at 4 °C, viscosity and pH of WGP-Y increased and decreased, respectively, but syneresis and lactic acid percentage of WGP-Y and pH of WGP-I and WGP-T were stable. Adding WGP resulted in 35-65% reduction of peroxide values in all samples. Dried whole pomace powder (WP) fortified products had dietary fibre content of 0.94-3.6% (w/w product), mainly insoluble fractions. Total phenolic content and DPPH radical scavenging activity were 958-1340 mg GAE/kg product and 710-936 mg AAE/kg product, respectively. The highest ADF was obtained in 3% WP-Y, 1% WP-I and 2% WP-T, while 1% WP-Y, 0.5% WP-I and 1% WP-T were mostly liked by consumers based on the sensory study. Study demonstrated that WGP may be used as a functional food ingredient for promoting human health and extending shelf-life of food products.

Effect of different drying methods and storage time on the retention of bioactive compounds and antibacterial activity of wine grape pomace (Pinot Noir and Merlot).

The effects of different drying methods (40 °C conventional and vacuum oven, 25 °C ambient air and freeze dry) on the stability of two red wine grape (Pinot Noir, PN and Merlot, M) byproducts, pomace containing skins and seeds (P) and pomace containing skins only (S) were investigated. Freeze dried samples retained the highest bioactive compounds with total phenolic content (TPC) of 21.19-67.74 mg GAE/g d.m., anthocyanin content (ACY) of 0.35-0.76 mg Mal-3-glu/g d.m., DPPH antiradical scavenge activity (ARS) of 22.01-37.46 mg AAE/g d.m., and total flavanol content (TFC) of 30.16-106.61 mg CE/g d.m., followed with ambient air dried samples. All samples lost significant amount of bioactive compounds during 16 wk of storage at 15 ± 2 °C, in which ambient air and freeze dried samples had TPC reduction of 32-56% and 35-58%, respectively, but ARS in PN-P and M-P still remained more than 50 mg TE/g d.m. Overall, TPC, ARS, and TFC were higher in PN than in M, and higher in pomace than in skins, while reverse results were observed in ACY. Pomace extracts showed higher antibacterial efficiency against Listeria innocua ATCC 51142 than Escherichia coli ATCC 25922 with minimal inhibition concentration (MIC) of 3%, 6%, 4%, and 9% against E. coli, and 2%, 7%, 3%, and 8% against L. innocua for PN-P, PN-S, M-P, and M-S samples, respectively. Dietary fiber content of samples was 57-63% of total dry matter. This study demonstrated that Pinot Noir and Merlot pomace are good sources of antioxidant dietary fibers and may be incorporated into various food products as a functional ingredient. Practical Application: Wine grape pomace (WGP), the byproduct of wine making, is a good source of polyphenols and dietary fibers and may be incorporated into various food products as a functional ingredient. This study reported the effect of four drying methods and storage at 15 ± 2 °C up to 4 months on the retention of polyphenols and antioxidant activity in two types of red WGP (with and without seeds). Antibacterial activity, dietary fiber content and the basic physicochemical properties of dried pomace powder were also reported. The information is essential for developing specific applications of the pomace.

Developmental changes in infant heart rate responses to head-up tilting.

AIM: Newborn infants produce significant heart rate responses to both head-up and head-down tilting: heart rate increases with head-up tilting and decreases with head-down tilting. However, previously we found that, at 2-4 mo of age, heart rate increases were no longer significant following slow head-up tilting. This study was designed to determine if 2-4-mo-old infants have significant increases in heart rate when tilted rapidly. METHODS: Fifty-four infants were tested as newborns or at 2-4 mo of age. Heart rate was measured while infants were tilted to a 30 degrees head-up angle either slowly over a period of 30 s or rapidly in 5 s. RESULTS: Newborns exhibited increases in heart rate using both tilt speeds; however, at 2-4 mo of age, heart rate did not change significantly using either speed of tilting. CONCLUSION: There are significant early developmental changes in cardiac responses to hypotensive challenge. Newborns react like adults, mounting sustained increases in heart rate in response to head-up tilting, but at 2-4 mo of age sustained heart rate responses are no longer significant. Tilt tests may provide a standardized method for assessing autonomic competence during the period of maximum vulnerability to sudden infant death syndrome.