Intranasal Oxytocin Enhances Connectivity in the Neural Circuitry Supporting Social Motivation and Social Perception in Children with Autism

Abstract

Oxytocin (OT) has become a focus in investigations of autism spectrum disorder (ASD). The social deficits that characterize ASD may relate to reduced connectivity between brain sites on the mesolimbic reward pathway (nucleus accumbens; amygdala) that receive OT projections and contribute to social motivation, and cortical sites involved in social perception. Using functional magnetic resonance imaging and a randomized, double blind, placebo-controlled crossover design, we show that OT administration in ASD increases activity in brain regions important for perceiving social-emotional information. Further, OT enhances connectivity between nodes of the brain's reward and socioemotional processing systems, and does so preferentially for social (versus nonsocial) stimuli. This effect is observed both while viewing coherent versus scrambled biological motion, and while listening to happy versus angry voices. Our findings suggest a mechanism by which intranasal OT may bolster social motivation-one that could, in future, be harnessed to augment behavioral treatments for ASD.

Figure 1. Schematic representation of oxytocinergic (OT; solid black) and mesocorticolimbic dopaminergic (DA; dashed blue) pathways.

DA is synthesized in ventral tegmental area (VTA) and projects to nucleus accumbens (NAcc) and amygdala (Amyg) as well as prefrontal cortex (PFC). OT, which is synthesized in paraventricular nucleus (PVN), projects to key limbic sites on the DA pathway (VTA, NAcc, and Amyg), thus potentially allowing it to modulate DA activity. We note that while only neurotransmitter effects of OT are illustrated here, neuromodulatory effects via OT diffusion through extracellular space may also play a role in these processes. Via PFC, which is densely interconnected with many other regions of the brain (dark red solid lines), motivational factors may be able to influence attention and perception (see for review79). Brain art adapted from illustrations created by Patrick Lynch, medical illustrator, and C. Carl Jaffe, MD, cardiologist (available at https://commons.wikimedia.org/wiki/File:Brain_human_lateral_view.svg and https://commons.wikimedia.org/wiki/File:Brain_human_sagittal_section.svg) and licensed under a Creative Commons Attribution 2.5 Generic License, 2006 (CC BY 2.5).

Figure 2. Brain regions in which activation to the experimental contrast of interest was significantly greater under oxytocin (OT) than placebo (PLC).

Main effects of OT administration on brain response to (A) coherent (BIO) versus scrambled (SCRAM) biological motion and (B) angry (ANG) versus happy (HAP) voices are depicted. Results are displayed on the MNI standard brain template, cluster-corrected at p < 0.05 and Z = 2.3. Bar graphs depict group mean percent signal change to each experimental condition, with standard errors.

Figure 3. Oxytocin (OT)-induced increases in effective connectivity as assessed via whole-brain psychophysiological interaction (PPI) analysis.

Results of PPI analysis, indicating regions with significantly greater connectivity to the seed of interest for (A) happy greater than angry voices and (B) coherent versus scrambled biological motion, under OT versus placebo (PLC), are displayed on the MNI standard brain template, cluster-corrected at p < 0.05 and Z = 2.3. (C) Segmentation of seed regions from one representative participant’s T1-weighted anatomical image.

Figure 4. Brain regions for which oxytocin (OT)-induced connectivity changes (OT > placebo) for Happy versus Angry voices were associated with levels of social functioning, as assessed via the Social Responsiveness Scale (SRS) total t-score and the Autism Diagnostic Interview-Revised (ADI-R) diagnostic algorithm A: “Qualitative Abnormalities in Reciprocal Social Interaction”.

Higher scores on the ADI-R or SRS indicate greater symptom severity. Results are depicted in MNI space, with regions displaying negative correlations (lower symptomaticity associated with a higher PPI value) in cyan and regions displaying positive correlations (greater symptomaticity associated with a higher PPI value) in red. Brain outline images at top were adapted in part from an illustration by Patrick Lynch, medical illustrator, and C. Carl Jaffe, MD, cardiologist (available at https://commons.wikimedia.org/wiki/File:Cranial_nerve_VII.svg), licensed under CC BY 2.5, 2006.