The effects of intranasal oxytocin on reward circuitry responses in children with autism spectrum disorder

Abstract

Background: 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.

Methods: 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.

Results: 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.

Conclusions: 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.

Keywords: Autism spectrum disorder; Oxytocin; Reward; fMRI.

Conflict of interest statement

Ethics approval and consent to participate

This protocol was approved by the Institutional Review Boards at Duke University Medical Center and the University of North Carolina at Chapel Hill, and informed consent was obtained from the parent or guardian of each participant before testing. Each participant 12 years old or above also provided verbal and written assent.

Consent for publication

Not applicable.

Competing interests

The authors declare that they have no competing interests.

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Figures

Fig. 1

Subjective ratings of faces. Average ratings of valence, arousal, and trust of faces. Valence = 0 (extremely unpleasant) to 8 (extremely pleasant); arousal = 0 (not at all aroused) to 8 (extremely aroused); trust = 0 (not at all trustworthy) to 8 (extremely trustworthy). *p < .05

Fig. 2

fMRI task reaction times. Mean reaction times of reward and non-reward trials during the social and nonsocial reward tasks. *p < .05

Fig. 3

Differential functional activation after OT relative to PLC administration during nonsocial reward anticipation. Brain areas with greater activation during nonsocial reward anticipation after intranasal OT administration relative to PLC administration include the right nucleus accumbens (left), the right orbital frontal cortex (center), and the left anterior cingulate cortex (right)

Fig. 4

Differences in functional activation after OT relative to PLC administration during nonsocial reward outcomes. Brain areas with greater activation during nonsocial reward outcome after intranasal OT administration relative to PLC administration include the left frontal pole (left) and the right orbital frontal cortex (right)

Fig. 5

Correlations between SRS and differences in functional activation after OT vs. PLC during nonsocial reward anticipation. The right frontal pole, left putamen, and left anterior cingulate cortex showed increased activation in individuals with greater ASD symptoms during nonsocial reward anticipation following OT relative to PLC administration

Fig. 6

Functional connectivity during nonsocial reward anticipation with the functionally defined right nucleus accumbens seed. The right frontal pole (red) shows greater functional connectivity with the right NAcc (white) during nonsocial reward anticipation after intranasal OT administration relative to PLC administration

Fig. 7

Salivary OT concentrations. Change in log-transformed salivary OT levels (pg/ml) for 24 participants (minutes between samples M = 85; SD = 9). Four participants were unable to provide adequate saliva samples and were not included in the salivary analyses. a Change in salivary OT following nasal OT administration. b Change in salivary OT following nasal-PLC administration. Because participant 10 was a significant outlier (change in OT concentration after PLC = − 723.59), their data are not included in the graph above. c *p < .05. Salivary samples collected after OT administration showed significantly greater OT concentrations compared to those following the PLC nasal spray, t = 3. 57; p = 0.0016

Fig. 8

Correlations between OT-related neural activation and OT salivary concentration changes following OT administration. Correlation between mean percent signal change in the right NAcc functional activation cluster during the anticipatory phase of the nonsocial reward condition and change in peripheral OT levels following OT administration