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Neural modulation of social reinforcement learning by intranasal oxytocin in male adults with high-functioning autism spectrum disorder: a randomized trial.

ABSTRACT: Reduced social motivation is a hallmark of individuals with autism spectrum disorders (ASDs). Although the exact neural mechanisms are unclear, oxytocin has been shown to enhance motivation and attention to social stimuli, suggesting a potential to augment social reinforcement learning as the central mechanism of behavioral interventions in ASD. We tested how reinforcement learning in social contexts and associated reward prediction error (RPE) signals in the nucleus accumbens (NAcc) were modulated by intranasal oxytocin. Male adults with a childhood diagnosis of ASD (n?=?15) and healthy controls (n?=?24; aged 18-26 years) performed a probabilistic reinforcement learning task during functional magnetic resonance imaging in a single-center (research center in Germany), randomized double-blind, placebo-controlled cross-over trial. The interventions were intranasal oxytocin (Syntocinon®, Novartis; 10 puffs?=?20 international units (IUs) per treatment) and placebo spray. Using computational modeling of behavioral data, trial-by-trial RPE signals were assessed and related to brain activation in NAcc during reinforcing feedback in social and non-social contexts. The order of oxytocin/placebo was randomized for 60 participants. Twenty-one participants were excluded from analyses, leaving 39 for the final analysis. Behaviorally, individuals with ASD showed enhanced learning under oxytocin when the learning target as well as feedback was social as compared to non-social (social vs. non-social target: 87.09% vs. 71.29%, 95% confidence interval (CI): 7.28-24.33, p?=?.003; social vs. non-social feedback: 81.00% vs. 71.29%, 95% CI: 2.81-16.61, p?=?.027). Correspondingly, oxytocin enhanced the correlation of the RPE signal with NAcc activation during social (vs. non-social) feedback in ASD (3.48 vs. -1.12, respectively, 95% CI: 2.98-6.22, p?=?.000), whereas in controls, this effect was found in the placebo condition (2.90 vs. -1.14, respectively, 95% CI: 1.07-7.01, p?=?.010). In ASD, a similar pattern emerged when the learning target was social (3.00 vs. -0.64, respectively, 95% CI: -0.13 to 7.41, p?=?.057), whereas controls showed a reduced correlation for social learning targets under oxytocin (-0.70 vs. 2.72, respectively, 95% CI: -5.86 to 0.98, p?=?.008). The current data suggest that intranasal oxytocin has the potential to enhance social reinforcement learning in ASD. Future studies are warranted that investigate whether oxytocin can potentiate social learning when combined with behavioral therapies, resulting in greater treatment benefits than traditional behavior-only approaches.

SUBMITTER: Kruppa JA

PROVIDER: S-EPMC6372686 | biostudies-literature | 2019 Mar

REPOSITORIES: biostudies-literature

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Neural modulation of social reinforcement learning by intranasal oxytocin in male adults with high-functioning autism spectrum disorder: a randomized trial.

Kruppa Jana A JA Gossen Anna A Oberwelland Weiß Eileen E Kohls Gregor G Großheinrich Nicola N Cholemkery Hannah H Freitag Christine M CM Karges Wolfram W Wölfle Elke E Sinzig Judith J Fink Gereon R GR Herpertz-Dahlmann Beate B Konrad Kerstin K Schulte-Rüther Martin M

Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology 20181102 4

Reduced social motivation is a hallmark of individuals with autism spectrum disorders (ASDs). Although the exact neural mechanisms are unclear, oxytocin has been shown to enhance motivation and attention to social stimuli, suggesting a potential to augment social reinforcement learning as the central mechanism of behavioral interventions in ASD. We tested how reinforcement learning in social contexts and associated reward prediction error (RPE) signals in the nucleus accumbens (NAcc) were modula ...[more]

PMID: 30390065

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Project description:Impairments in social communication (coupled with intact nonsocial language skills) are common in autism spectrum disorder (ASD). However, the neural correlates of these social communication deficits in adolescents and young adults with ASD are not fully understood. The communication checklist self-report (CC-SR) was administered to adolescents and young adults with ASD (n?=?52) and typically developing (TD) controls (n?=?64) to assess structural-language, pragmatic-language, and social-engagement. One high-resolution T1-weighted structural image was obtained from each participant. FreeSurfer was used to quantify cortical thickness. A main effect of diagnosis, with the ASD group performing worse than the TD group on all three CC-SR scales, and a diagnosis by scale interaction, driven by low social-engagement self-ratings in the ASD group, were found. There were also group differences in the relationship between scores on two of the three CC-SR scales and cortical thickness in multiple regions (pragmatic-language: left rostral frontal; social-engagement: left medial prefrontal). These interactions were driven by poorer self-ratings of language/social skills associated with decreased cortical thickness in the ASD group, while in the TD group worse self-ratings were associated with thicker cortex. Self-ratings of language/social-communication were lower in the ASD than the TD group. Moreover, language/social-communication self-ratings showed a different relationship with cortical thickness for the ASD and TD groups in the left inferior frontal region for pragmatic language ratings and the left medial prefrontal cortex for social engagement ratings. These findings suggest thinner cortex is associated with more impaired pragmatic language and social communication abilities in ASD. Autism Res 2018, 11: 1175-1186. © 2018 International Society for Autism Research, Wiley Periodicals, Inc. LAY SUMMARY: The present study examines the associations between brain structure and language/social communication ability in adolescents and young adults with autism spectrum disorder (ASD) as compared to neurotypical adolescents and young adults. We utilized thickness of the cerebral cortex as a measure of brain structure, and we found different correlations between language or social communication ability and cortical thickness in distinct regions for the ASD and TD groups. These findings suggest that for regions implicated in language/social communication ability, decreased cortical thickness is associated with more impaired pragmatic language and social communication abilities in ASD.

Project description:Intranasal oxytocin (OT) has been shown to improve social communication functioning of individuals with autism spectrum disorder (ASD) and, thus, has received considerable interest as a potential ASD therapeutic agent. Although preclinical research indicates that OT modulates the functional output of the mesocorticolimbic dopamine system that processes rewards, no clinical brain imaging study to date has examined the effects of OT on this system using a reward processing paradigm. To address this, we used an incentive delay task to examine the effects of a single dose of intranasal OT, versus placebo (PLC), on neural responses to social and nonsocial rewards in children with ASD.In this placebo-controlled double-blind study, 28 children and adolescents with ASD (age: M?=?13.43 years, SD?=?2.36) completed two fMRI scans, one after intranasal OT administration and one after PLC administration. During both scanning sessions, participants completed social and nonsocial incentive delay tasks. Task-based neural activation and connectivity were examined to assess the impact of OT relative to PLC on mesocorticolimbic brain responses to social and nonsocial reward anticipation and outcomes.Central analyses compared the OT and PLC conditions. During nonsocial reward anticipation, there was greater activation in the right nucleus accumbens (NAcc), left anterior cingulate cortex (ACC), bilateral orbital frontal cortex (OFC), left superior frontal cortex, and right frontal pole (FP) during the OT condition relative to PLC. Alternatively, during social reward anticipation and outcomes, there were no significant increases in brain activation during the OT condition relative to PLC. A Treatment Group × Reward Condition interaction revealed relatively greater activation in the right NAcc, right caudate nucleus, left ACC, and right OFC during nonsocial relative to social reward anticipation during the OT condition relative to PLC. Additionally, these analyses revealed greater activation during nonsocial reward outcomes during the OT condition relative to PLC in the right OFC and left FP. Finally, functional connectivity analyses generally revealed changes in frontostriatal connections during the OT condition relative to PLC in response to nonsocial, but not social, rewards.The effects of intranasal OT administration on mesocorticolimbic brain systems that process rewards in ASD were observable primarily during the processing of nonsocial incentive salience stimuli. These findings have implications for understanding the effects of OT on neural systems that process rewards, as well as for experimental trials of novel ASD treatments developed to ameliorate social communication impairments in ASD.

Project description:There are no effective medications for the treatment of social cognition/function deficits in autism spectrum disorder (ASD), and adult intervention literature in this area is sparse. Emerging data from animal models and genetic association studies as well as early, single-dose intervention studies suggest that the oxytocin system may be a potential therapeutic target for social cognition/function deficits in ASD. The primary aim of this study was to examine the safety/therapeutic effects of intranasal oxytocin versus placebo in adults with ASD, with respect to the two core symptom domains of social cognition/functioning and repetitive behaviors.This was a pilot, randomized, double-blind, placebo-controlled, parallel design trial of intranasal oxytocin versus placebo in 19 adults with ASD (16 males; 33.20 ± 13.29 years). Subjects were randomized to 24 IU intranasal oxytocin or placebo in the morning and afternoon for 6 weeks. Measures of social function/cognition (the Diagnostic Analysis of Nonverbal Accuracy) and repetitive behaviors (Repetitive Behavior Scale Revised) were administered. Secondary measures included the Social Responsiveness Scale, Reading-the-Mind-in-the-Eyes Test and the Yale Brown Obsessive Compulsive Scale - compulsion subscale and quality of life (World Health Organization Quality of Life Questionnaire - emotional/social subscales). Full-information maximum-likelihood parameter estimates were obtained and tested using mixed-effects regression analyses.Although no significant changes were detected in the primary outcome measures after correcting for baseline differences, results suggested improvements after 6 weeks in measures of social cognition (Reading-the-Mind-in-the-Eyes Test, p = 0.002, d = 1.2), and quality of life (World Health Organization Quality of Life Questionnaire - emotion, p = 0.031, d = 0.84), both secondary measures. Oxytocin was well tolerated and no serious adverse effects were reported.This pilot study suggests that there is therapeutic potential to daily administration of intranasal oxytocin in adults with ASD and that larger and longer studies are warranted.NCT00490802.

Dataset Information

Neural modulation of social reinforcement learning by intranasal oxytocin in male adults with high-functioning autism spectrum disorder: a randomized trial.

Publications

Neural modulation of social reinforcement learning by intranasal oxytocin in male adults with high-functioning autism spectrum disorder: a randomized trial.

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