Bilingualism Predicts Affective Theory of Mind in Autistic Adults.

PURPOSE: This study examined the impact of bilingualism on affective theory of mind (ToM) and social prioritization (SP) among autistic adults compared to neurotypical comparison participants. METHOD: Fifty-two (25 autistic, 27 neurotypical) adult participants (ages 21-35 years) with varying second language (L2) experience, ranging from monolingual to bilingual, completed an affective ToM task. A subset of this sample also completed a dynamic eye-tracking task designed to capture differences in time spent looking at social aspects of a scene (SP). Four language groups were compared on task performance (monolingual autism and neurotypical, bilingual autism and neurotypical), followed by analyses examining the contribution of L2 experience, autism characteristics, and social face prioritization on affective ToM, controlling for verbal IQ. Finally, we conducted an analysis to identify the contribution of SP on affective ToM when moderated by autism status and L2 experience, controlling for verbal IQ. RESULTS: The monolingual autism group performed significantly worse than the other three groups (bilingual autism, monolingual neurotypical, and bilingual neurotypical) on the affective ToM task; however, there were no significant differences between the bilingual autism group compared to the monolingual and bilingual neurotypical groups. For autistic individuals, affective ToM capabilities were positively associated with both verbal IQ and L2 experience but did not relate to autism characteristics or SP during eye tracking. Neurotypical participants showed greater SP during the eye-tracking task, and SP did not relate to L2 or autism characteristics for autistic individuals. SP and verbal IQ predicted affective ToM performance across autism and neurotypical groups, but this relationship was moderated by L2 experience; SP more strongly predicted affective ToM performance among participants with lower L2 experience (e.g., monolingual) and had less of an impact for those with higher L2 experience. CONCLUSION: This study provides support for a bilingual advantage in affective ToM for autistic individuals. SUPPLEMENTAL MATERIAL: https://doi.org/10.23641/asha.25696083.

Striatal dopamine in anhedonia: A simultaneous [11C]raclopride positron emission tomography and functional magnetic resonance imaging investigation.

BACKGROUND: Anhedonia is hypothesized to be associated with blunted mesocorticolimbic dopamine (DA) functioning in samples with major depressive disorder. The purpose of this study was to examine linkages between striatal DA, reward circuitry functioning, anhedonia, and, in an exploratory fashion, self-reported stress, in a transdiagnostic anhedonic sample. METHODS: Participants with (n = 25) and without (n = 12) clinically impairing anhedonia completed a reward-processing task during simultaneous positron emission tomography and magnetic resonance (PET-MR) imaging with [11C]raclopride, a DA D2/D3 receptor antagonist that selectively binds to striatal DA receptors. RESULTS: Relative to controls, the anhedonia group exhibited decreased task-related DA release in the left putamen, caudate, and nucleus accumbens and right putamen and pallidum. There were no group differences in task-related brain activation (fMRI) during reward processing after correcting for multiple comparisons. General functional connectivity (GFC) findings revealed blunted fMRI connectivity between PET-derived striatal seeds and target regions in the anhedonia group. Associations were identified between anhedonia severity and the magnitude of task-related DA release to rewards in the left putamen, but not mesocorticolimbic GFC. CONCLUSIONS: Results provide evidence for reduced striatal DA functioning during reward processing and blunted mesocorticolimbic network functional connectivity in a transdiagnostic sample with clinically significant anhedonia.

Parsing within & between-person dynamics of therapy homework completion and clinical symptoms in two cognitive behavioral treatments for adults with anhedonia.

OBJECTIVE: Homework is a key theoretical component of cognitive-behavioral therapies, however, the effects of homework on clinical outcomes have largely been evaluated between-persons rather than within-persons. METHODS: The effects of homework completion on treatment response were examined in a randomized trial comparing Behavioral Activation Treatment for Anhedonia (BATA, n = 38), a novel psychotherapy, to Mindfulness-Based Cognitive Therapy (MBCT, n=35). The primary endpoint was consummatory reward sensitivity, measured weekly by the Snaith Hamilton Pleasure Scale (SHAPS), up to 15 weeks. Multilevel models evaluated change in SHAPS scores over time and the effects of clinician-reported and participant-reported homework. RESULTS: BATA and MBCT resulted in significant, equivalent reductions in SHAPS scores. Unexpectedly, participants who completed greater mean total amounts of homework did not improve at a faster rate (i.e., no between-person effect). However, sessions with greater than average participant-reported homework completion were associated with greater than average reductions in SHAPS scores (i.e., a within-person effect). For clinician-reported homework, this effect was only evident within the BATA condition. CONCLUSION: This study shows psychotherapy homework completion relates to symptomatic improvement in cognitive-behavioral treatments for anhedonia when session-to-session changes are examined within-person. On the contrary, we found no evidence that total homework completion predicted greater improvements between-person. When possible, psychotherapy researchers should evaluate their constructs of interest across multiple sessions (not just pre/post) to allow more direct tests of hypotheses predicted by theoretical models of individual change processes.

Longitudinal associations between perceived stress and anhedonia during psychotherapy.

BACKGROUND: Chronic stress alters reward sensitivity and contributes to the emergence of anhedonia. In clinical samples, the perception of stress is a strong predictor of anhedonia. While there is substantial evidence demonstrating psychotherapy reduces perceived stress, little is known regarding the effects of treatment-related decreases in perceived stress on anhedonia. METHODS: The current study investigated reciprocal relations between perceived stress and anhedonia using a cross-lagged panel model approach in a 15-week clinical trial examining the effects of Behavioral Activation Treatment for Anhedonia (BATA), a novel psychotherapy to treat anhedonia, compared to a Mindfulness-Based Cognitive Therapy (MBCT) comparison intervention (ClinicalTrials.gov Identifiers NCT02874534 and NCT04036136). RESULTS: Treatment completers (n = 72) experienced significant reductions in anhedonia (M = -8.94, SD = 5.66) on the Snaith-Hamilton Pleasure Scale (t(71) = 13.39, p < .0001), and significant reductions in perceived stress (M = -3.71, SD = 3.88) on the Perceived Stress Scale (t(71) = 8.11, p < .0001) following treatment. Across all treatment-seeking participants (n = 87), a longitudinal autoregressive cross-lagged model revealed significant paths showing that higher levels of perceived stress at treatment Week 1 predicted reductions in anhedonia at treatment Week 4; lower levels of perceived stress at Week 8 predicted reductions in anhedonia at Week 12. Anhedonia did not significantly predict perceived stress at any stage of treatment. CONCLUSIONS: This study showed specific timing and directional effects of perceived stress on anhedonia during psychotherapy treatment. Individuals with relatively high perceived stress at the start of treatment were more likely to report relatively lower anhedonia a few weeks into treatment. At mid-treatment, individuals with low perceived stress were more likely to report lower anhedonia towards the end of treatment. These results demonstrate that early treatment components reduce perceived stress, thus allowing for downstream changes in hedonic functioning during mid-late treatment. The findings presented here suggest it will be critically important for future clinical trials evaluating novel interventions for anhedonia to measure stress levels repeatedly, as an important mechanism of change. TRIAL NAME: Development of a Novel Transdiagnostic Intervention for Anhedonia - R61 Phase. TRIAL URL: https://clinicaltrials.gov/ct2/show/NCT02874534. TRIAL REGISTRATION NUMBER: NCT02874534.

Epithelial-intrinsic defects in TGFßR signaling drive local allergic inflammation manifesting as eosinophilic esophagitis.

Allergic diseases are a global health challenge. Individuals harboring loss-of-function variants in transforming growth factor-ß receptor (TGFßR) genes have an increased prevalence of allergic disorders, including eosinophilic esophagitis. Allergic diseases typically localize to mucosal barriers, implicating epithelial dysfunction as a cardinal feature of allergic disease. Here, we describe an essential role for TGFß in the control of tissue-specific immune homeostasis that provides mechanistic insight into these clinical associations. Mice expressing a TGFßR1 loss-of-function variant identified in atopic patients spontaneously develop disease that clinically, immunologically, histologically, and transcriptionally recapitulates eosinophilic esophagitis. In vivo and in vitro, TGFßR1 variant-expressing epithelial cells are hyperproliferative, fail to differentiate properly, and overexpress innate proinflammatory mediators, which persist in the absence of lymphocytes or external allergens. Together, our results support the concept that TGFß plays a fundamental, nonredundant, epithelial cell-intrinsic role in controlling tissue-specific allergic inflammation that is independent of its role in adaptive immunity.

Multilevel growth curve analyses of behavioral activation for anhedonia (BATA) and mindfulness-based cognitive therapy effects on anhedonia and resting-state functional connectivity: Interim results of a randomized trial✰.

BACKGROUND: The neural mechanisms associated with anhedonia treatment response are poorly understood. Additionally, no study has investigated changes in resting-state functional connectivity (rsFC) accompanying psychosocial treatment for anhedonia. METHODS: We evaluated a novel psychotherapy, Behavioral Activation Therapy for Anhedonia (BATA, n = 38) relative to Mindfulness-Based Cognitive Therapy (MBCT, n = 35) in a medication-free, transdiagnostic, anhedonic sample in a parallel randomized controlled trial. Participants completed up to 15 sessions of therapy and up to four 7T MRI scans before, during, and after treatment (n = 185 scans). Growth curve models estimated change over time in anhedonia and in rsFC using average region-of-interest (ROI)-to-ROI connectivity within the default mode network (DMN), frontoparietal network (FPN), salience network, and reward network. Changes in rsFC from pre- to post-treatment were further evaluated using whole-network seed-to-voxel and ROI-to-ROI edgewise analyses. RESULTS: Growth curve models showed significant reductions in anhedonia symptoms and in average rsFC within the DMN and FPN over time, across BATA and MBCT. There were no differences in anhedonia reductions between treatments. Within-person, changes in average rsFC were unrelated to changes in anhedonia. Between-person, higher than average FPN rsFC was related to less anhedonia across timepoints. Seed-to-voxel and edgewise rsFC analyses corroborated reductions within the DMN and between the DMN and FPN over time, across the sample. CONCLUSIONS: Reductions in rsFC within the DMN, FPN, and between these networks co-occurred with anhedonia improvement across two psychosocial treatments for anhedonia. Future anhedonia clinical trials with a waitlist control group should disambiguate treatment versus time-related effects on rsFC.

A simultaneous [11C]raclopride positron emission tomography and functional magnetic resonance imaging investigation of striatal dopamine binding in autism.

The social motivation hypothesis of autism posits that autism spectrum disorder (ASD) is characterized by impaired motivation to seek out social experience early in life that interferes with the development of social functioning. This framework suggests that impaired mesolimbic dopamine function underlies compromised responses to social rewards in ASD. Although this hypothesis is supported by functional magnetic resonance imaging (fMRI) studies, no molecular imaging study has evaluated striatal dopamine functioning in response to rewards in ASD. Here, we examined striatal functioning during monetary incentive processing in ASD and controls using simultaneous positron emission tomography (PET) and fMRI. Using a bolus + infusion protocol with the D2/D3 dopamine receptor antagonist [11C]raclopride, voxel-wise binding potential (BPND) was compared between groups (controls = 12, ASD = 10) in the striatum. Striatal clusters showing significant between-group BPND differences were used as seeds in whole-brain fMRI general functional connectivity analyses. Relative to controls, the ASD group demonstrated decreased phasic dopamine release to incentives in the bilateral putamen and left caudate, as well as increased functional connectivity between a PET-derived right putamen seed and the precuneus and insula. Within the ASD group, decreased phasic dopamine release in the putamen was related to poorer theory-of-mind skills. Our findings that ASD is characterized by impaired striatal phasic dopamine release to incentives provide support for the social motivation hypothesis of autism. PET-fMRI may be a suitable tool to evaluate novel ASD therapeutics targeting the striatal dopamine system.

Dynamic Eye Tracking as a Predictor and Outcome Measure of Social Skills Intervention in Adolescents and Adults with Autism Spectrum Disorder.

To evaluate an eye tracking task as a predictor and outcome measure of treatment response for autism spectrum disorder (ASD) social skills interventions, adolescents and young adults with ASD completed the eye tracking task before, immediately after, and two months after completing Social Cognition and Interaction Training for Autism (SCIT-A). The study compared SCIT-A participants (n = 20) to participants with ASD who received treatment as usual (TAU; n = 21). Overall, increased visual attention to faces and background objects and decreased attention to hands playing with toys at baseline were associated with improved social functioning immediately following intervention, suggesting this eye tracking task may reliably predict ASD social intervention outcomes.

Corneal thinning and cornea guttata in patients with mutations in TGFB2.

OBJECTIVE: Human genome-wide association studies and animal models suggest a role for TGFB2 in contributing to the corneal thickness phenotype. No specific mutations, however, have been reported in this gene that affect corneal thickness. We sought to determine if haploinsufficiency of TGFB2 in humans associated with Loeys-Dietz syndrome type 4 is associated with corneal thinning. DESIGN: Observational cohort study of families with Loeys-Dietz syndrome type 4, caused specifically by TGFB2 mutations, in a tertiary care setting. PARTICIPANTS: Three probands with pathogenic mutations in TGFB2 and family members underwent comprehensive ophthalmic examination. METHODS: Clinical assessment included Scheimpflug imaging, specular microscopy, and slit-lamp biomicroscopy. We measured visual acuity, axial length, refractive error, and central corneal thickness. RESULTS: Clinical evaluation of 2 probands identified corneal thinning and cornea guttata, despite a young age and distinct mutations in TGFB2 (c.905G>A, p.Arg302His; c.988C>A, p.Arg330Ser). In the third family, corneal thinning co-segregated with a TGFB2 mutation (c.1103G>A, p.Gly368Glu), although without apparent guttae. CONCLUSIONS: In this series, participants with TGFB2 mutations associated with Loeys-Dietz syndrome type 4 demonstrated decreased corneal thickness, and in 2 cases with splice site mutations, also demonstrated cornea guttata. The data demonstrate the importance of considering distinct phenotype-genotype correlations within this condition.

Neural Mechanisms of Social and Nonsocial Reward Prediction Errors in Adolescents with Autism Spectrum Disorder.

Autism spectrum disorder (ASD) is characterized by impaired predictive abilities; however, the neural mechanisms subsuming reward prediction errors in ASD are poorly understood. In the current study, we investigated neural responses during social and nonsocial reward prediction errors in 22 adolescents with ASD (ages 12-17) and 20 typically developing control adolescents (ages 12-18). Participants performed a reward prediction error task using both social (i.e., faces) and nonsocial (i.e., objects) rewards during a functional magnetic resonance imaging scan. Reward prediction errors were defined in two ways: (a) the signed prediction error, the difference between the experienced and expected reward; and (b) the thresholded unsigned prediction error, the difference between expected and unexpected outcomes regardless of magnitude. During social reward prediction errors, the ASD group demonstrated the following differences relative to the TD group: (a) signed prediction error: decreased activation in the right precentral gyrus and increased activation in the right frontal pole; and (b) thresholded unsigned prediction error: increased activation in the right anterior cingulate gyrus and bilateral precentral gyrus. Groups did not differ in brain activation during nonsocial reward prediction errors. Within the ASD group, exploratory analyses revealed that reaction times and social-communication impairments were related to precentral gyrus activation during social prediction errors. These findings elucidate the neural mechanisms of social reward prediction errors in ASD and suggest that ASD is characterized by greater neural atypicalities during social, relative to nonsocial, reward prediction errors in ASD. Autism Res 2020, 13: 715-728. © 2020 International Society for Autism Research, Wiley Periodicals, Inc. LAY SUMMARY: We used brain imaging to evaluate differences in brain activation in adolescents with autism while they performed tasks that involved learning about social and nonsocial information. We found no differences in brain responses during the nonsocial condition, but differences during the social condition of the learning task. This study provides evidence that autism may involve different patterns of brain activation when learning about social information.

Neural Mechanisms of Reward Prediction Error in Autism Spectrum Disorder.

Few studies have explored neural mechanisms of reward learning in ASD despite evidence of behavioral impairments of predictive abilities in ASD. To investigate the neural correlates of reward prediction errors in ASD, 16 adults with ASD and 14 typically developing controls performed a prediction error task during fMRI scanning. Results revealed greater activation in the ASD group in the left paracingulate gyrus during signed prediction errors and the left insula and right frontal pole during thresholded unsigned prediction errors. Findings support atypical neural processing of reward prediction errors in ASD in frontostriatal regions critical for prediction coding and reward learning. Results provide a neural basis for impairments in reward learning that may contribute to traits common in ASD (e.g., intolerance of unpredictability).

Rates of Co-occurring Psychiatric Disorders in Autism Spectrum Disorder Using the Mini International Neuropsychiatric Interview.

Individuals with autism spectrum disorder (ASD) often meet criteria for at least one additional psychiatric disorder. The present study evaluated the utility of the Mini International Neuropsychiatric Interview (MINI) in assessing co-occurring psychiatric disorders in children, adolescents, and young adults with ASD. Ninety-one percent of children/adolescents and thirty-one percent of young adults were diagnosed with one or more co-occurring diagnoses using the MINI. MINI diagnostic rates were comparable to those found in the literature on children/adolescents with ASD; however, in young adults, MINI diagnostic rates were lower relative to rates found in the literature on young adults with ASD. Implications for treatment, transitioning to adulthood, and the need for instruments developed specifically to diagnose co-occurring disorders in ASD are discussed.

Social and nonsocial visual prediction errors in autism spectrum disorder.

Impaired predictive coding has been proposed as a framework to explain discrepancies between expectations and outcomes in autism spectrum disorder (ASD) that may contribute to core symptoms of the disorder. However, no eye tracking study has directly addressed this framework in the context of visual predictions of social and nonsocial stimuli. The current study used eye tracking to examine violations of learned visual associations of both social and nonsocial stimuli. Twenty-six adolescents with ASD and 18 typically developing control (TDC) adolescents completed an outcome expectation eye tracking task in which predictive cues correctly (80% of trials) or incorrectly (20% of trials) indicated the location (left or right) of forthcoming social or nonsocial stimuli. During violation trials, individuals with ASD focused their gaze relatively more often on stimuli presented on locations that violated the learned association and less often on locations that corresponded with the learned association. This finding was not moderated by stimulus type (i.e., social vs. nonsocial). Additionally, participants who looked at incorrectly predicted locations more often had significantly greater ASD symptom severity. These results are consistent with theories that characterize ASD as a disorder of prediction and have potential implications for understanding symptoms related to prediction errors in individuals with ASD. Autism Res 2019, 12: 878-883. © 2019 International Society for Autism Research, Wiley Periodicals, Inc. LAY SUMMARY: Individuals with autism spectrum disorder (ASD) exhibit impairments making predictions that may impact learning. In this study, we used eye tracking methodology and found that individuals with ASD were less likely to look at the predicted location when a visual routine was violated. This pattern was evident for both social and nonsocial images and was associated with greater ASD symptom severity. These findings provide additional support for predictive challenges in ASD.

Parent-Mediated Intervention for One-Year-Olds Screened as At-Risk for Autism Spectrum Disorder: A Randomized Controlled Trial.

Theoretically, interventions initiated with at-risk infants prior to the point in time a definitive autism spectrum disorder (ASD) diagnosis can be made will improve outcomes. Pursuing this idea, we tested the efficacy of a parent-mediated early intervention called Adapted Responsive Teaching (ART) via a randomized controlled trial with 87 one-year-olds identified by community screening with the First Year Inventory as at-risk of later ASD diagnoses. We found minimal evidence for main effects of ART on child outcomes. However, ART group parents showed significantly greater increases in responsiveness to their infants than control group parents. Further, significant indirect (mediation) effects of assignment group on multiple child outcomes through changes in parent responsiveness supported our theory of change.

Vicarious Effort-Based Decision-Making in Autism Spectrum Disorders.

This study investigated vicarious effort-based decision-making in 50 adolescents with autism spectrum disorders (ASD) compared to 32 controls using the Effort Expenditure for Rewards Task. Participants made choices to win money for themselves or for another person. When choosing for themselves, the ASD group exhibited relatively similar patterns of effort-based decision-making across reward parameters. However, when choosing for another person, the ASD group demonstrated relatively decreased sensitivity to reward magnitude, particularly in the high magnitude condition. Finally, patterns of responding in the ASD group were related to individual differences in consummatory pleasure capacity. These findings indicate atypical vicarious effort-based decision-making in ASD and more broadly add to the growing body of literature addressing social reward processing deficits in ASD.

Predictors of Parent Responsiveness to 1-Year-Olds At-Risk for Autism Spectrum Disorder.

Parent responsiveness is critical for child development of cognition, social-communication, and self-regulation. Parents tend to respond more frequently when children at-risk for autism spectrum disorder (ASD) demonstrate stronger social-communication; however, it is unclear how responsiveness is associated with sensory characteristics of children at-risk for ASD. To address this issue, we examined the extent to which child social-communication and sensory reactivity patterns (i.e., hyper- and hypo-reactivity) predicted parent responsiveness to 1-year-olds at-risk for ASD in a community sample of 97 parent-infant pairs. A combination of child social-communication and sensory hypo-reactivity consistently predicted how parents played and talked with their 1-year-old at-risk for ASD. Parents tended to talk less and use more play actions when infants communicated less and demonstrated stronger hypo-reactivity.

Late Positive Potential ERP Responses to Social and Nonsocial Stimuli in Youth with Autism Spectrum Disorder.

We examined the late positive potential (LPP) event related potential in response to social and nonsocial stimuli from youths 9 to 19 years old with (n = 35) and without (n = 34) ASD. Social stimuli were faces with positive expressions and nonsocial stimuli were related to common restricted interests in ASD (e.g., electronics, vehicles, etc.). The ASD group demonstrated relatively smaller LPP amplitude to social stimuli and relatively larger LPP amplitude to nonsocial stimuli. There were no group differences in subjective ratings of images, and there were no significant correlations between LPP amplitude and ASD symptom severity within the ASD group. LPP results suggest blunted motivational responses to social stimuli and heightened motivational responses to nonsocial stimuli in youth with ASD.

Neural mechanisms of negative reinforcement in children and adolescents with autism spectrum disorders.

BACKGROUND: Previous research has found accumulating evidence for atypical reward processing in autism spectrum disorders (ASD), particularly in the context of social rewards. Yet, this line of research has focused largely on positive social reinforcement, while little is known about the processing of negative reinforcement in individuals with ASD. METHODS: The present study examined neural responses to social negative reinforcement (a face displaying negative affect) and non-social negative reinforcement (monetary loss) in children with ASD relative to typically developing children, using functional magnetic resonance imaging (fMRI). RESULTS: We found that children with ASD demonstrated hypoactivation of the right caudate nucleus while anticipating non-social negative reinforcement and hypoactivation of a network of frontostriatal regions (including the nucleus accumbens, caudate nucleus, and putamen) while anticipating social negative reinforcement. In addition, activation of the right caudate nucleus during non-social negative reinforcement was associated with individual differences in social motivation. CONCLUSIONS: These results suggest that atypical responding to negative reinforcement in children with ASD may contribute to social motivational deficits in this population.