Elsevier

Neuropsychologia

Volume 79, Part A, December 2015, Pages 53-69
Neuropsychologia

Oxytocin enhances orienting to social information in a selective group of high-functioning male adults with autism spectrum disorder

https://doi.org/10.1016/j.neuropsychologia.2015.10.025Get rights and content

Highlights

  • High-functioning males with ASD show intact orienting to affective social pictures.

  • Oxytocin enhances social orienting in male adults with high avoidance tendencies.

  • Both avoidance and approach tendencies may influence the effects of oxytocin.

Abstract

Objective

The study investigated the effects of nasally administered oxytocin on neurophysiological orienting to empathy-evoking pictures in normally intelligent male adults with and without an autism spectrum disorder (ASD). It further investigated whether these effects might be moderated by the individual's approach and avoidance tendencies.

Methods

All subjects participated in a randomised double-blind placebo controlled crossover trial where either oxytocin (OXT) or placebo was administered preceding the viewing of affective pictures.The pictures, selected from the International Affective Picture System (IAPS), represented a systematic variation of pleasant, unpleasant and neutral scenes with and without humans. Both cardiac (ECR) and cortical (LPP) evoked orienting responses were measured and both were enhanced for the pictures with humans, in particular for the unpleasant ones.

Results

No significant group differences were found, nor were there any treatment effects. Moderator analysis, however, demonstrated that OXT did enhance orienting to affective pictures with humansin male adults with ASD who are easily distressed when seeing others in stressful situations and in healthy males who are highly sensitive to anticipated punishment and criticism or have a low drive for goal achievement.

Conclusion

Individual differences in stress-related avoidance tendencies should be taken into account when considering OXT as a treatment of social deficiencies in autism.

Introduction

Many studies have investigated the effects of nasally administered oxytocin (OXT) on social cognition and prosocial behavior (see Bartz et al., 2011a; Guastella and MacLeod, 2012; Bakermans-Kranenburg and van I Jzendoorn, 2013; Cochran et al., 2013 for extensive reviews). In general, OXT has been proposed to alter behavior along different mechanisms leading to three main hypotheses, the (1) fear reduction, (2) affiliative motivation, and (3) perceptual selectivity/social salience hypothesis ().

Fear reduction after OXT administration has been shown in both animals (e.g., Febo et al., 2009) and humans (e.g., Heinrichs et al., 2003; Heinrichs and Domes, 2008; Ditzen et al., 2009), with OXT leading to diminished reactivity of both the HPA axis and the amygdala when responding to fearful and threatening stimuli (e.g., Neumann, 2002; Kirsch et al., 2005; Domes et al., 2007). This has led to the hypothesis that OXT may increase prosocial behavior by its anxiolytic effects in potentially frightening social situations, thereby promoting approach behavior.

There are studies, however, that did not report any decreased anxiety or increased calmness following OXT treatment (Domes et al., 2007) while, for example, trust did improve (e.g. Kosfeld et al., 2005) suggesting a rather direct effect of OXT on affiliative behavior. Involved in these direct effects of OXT on affiliation-related motivational states might be brain systems that are activated when experiencing empathy. When observing or communicating with an attached person the dopaminergic reward system including the orbitofrontal cortex and midbrain-striatal structures is activated. The pathways related to pro-social motivation and reward processing contain high levels of OXT receptors (Insel, 2003), while furthermore OXT has been shown to facilitate dopamine release in particularly the midbrain striatal nucleus accumbens (Liu and Wang, 2003).

OXT may also activate affiliative motives or goals by increasing the individual's attention to socially relevant information in general, through altering the perceptual salience of social cues independent of their emotional valence. The social salience hypothesis has been considered by Bartz et al. (2011a) to be the one that may account for most of the findings so far.

At the first sight, many OXT administration studies suggest therapeutic potentials in the treatment of psychiatric disorders characterized by social impairments such as autism spectrum disorders (ASD), schizophrenia and mood disorders. However, Bartz et al. (2011a) showed that there are studies revealing only weak and/or inconsistent effects. They explained these inconsistencies by referring to the context-and person dependency of effects. For example, with respect to context dependency, an OXT-induced increase of attention to social cues could explain both enhanced prosocial behavior when dealing with familiar or reliable others (Kosfeld et al., 2005) and diminished prosocial behavior when being in competition (Shamay-Tsoory et al., 2009) or when interacting with outgroup members (De Dreu et al., 2010). With respect to the dependency of OXT effects on person-related characteristics, OXT-induced increases of social attention might be helpful to some people yet harmful to others. Those who are characterized by a diminished interest in the social world, as may be the case in people with autistic traits (e.g. Bartz et al., 2009), may benefit from OXT-induced increases of social attention. However, individuals who are hypersensitive to social cues may not, as has been suggested for people with borderline personality disorder (Bartz et al., 2011b). Based on the inconsistencies found in the various treatment studies, Bartz et al. (2011a) proposed an interactionist approach in which effect moderating contextual factors, as well as personal characteristics of the treated individuals, should be systematically taken into account.

ASDs are characterized by impairments in social interaction and communication as well as by repetitive behavior and a restricted repertoire of interests (DSM-5). It has been proposed that social interactive and communicative problems can be accounted for by impairments in empathy while the non-social characteristics, such as narrow interests and extraordinary attention to detail can be explained by a strong inclination to systemize (Baron-Cohen, 2002). Systemizing is defined as having the drive to understand, derive, and consistently apply the rules of a system. These hypotheses have been tested in the frame of the so-called Empathizing–Systemizing (E–S) theory (Baron-Cohen, 2009, Baron-Cohen, 2010). Using self-report measures i.e., the Empathy Quotient (EQ) questionnaire (Baron-Cohen and Wheelwright, 2004) and the Systemizing Quotient (SQ) questionnaire (Baron-Cohen et al., 2003), numerous studies have demonstrated that females adopt on average a more empathizing style, while males adopt on average a more systemizing style of information processing (Groen et al., 2015). According to E–S theory, individuals with ASD have been shown to lie at the extreme end of the normally distributed difference between systemizing and empathizing. This led to the Extreme Male Brain hypothesis of autism (Baron-Cohen and Wheelwright, 2004).

Yet, empathy has long been defined as a multifactorial construct with a commonly made distinction between affective (emotional) and cognitive empathy (e.g., Davis, 1983; Shamay-Tsoory, 2011). Affective empathy refers to feeling what another person feels. It relies on emotional contagion or emotional sharing, which means sensing an emotion that is triggered when observing the emotion of someone else. Cognitive empathy refers to understanding and evaluating the feelings of others while attributing a mental state to the other person (affective mentalizing) (Baron-Cohen et al., 2007; Gonzales-Liencres et al., 2013). There is evidence for the two facets of empathy being mediated by different neurophysiological systems. A phylogenetically older system, including limbic structures such as the amygdala and the insula, is assumed to be at the basis of empathic arousal (Decety et al., 2012), emotional contagion, and affective empathy (De Waal, 2008). The cognitive empathic system, of which the medial prefrontal cortex (mPFC) forms part, is supposed to have developed later as it involves higher cognitive functions such as mental state attribution and perspective-taking (e.g. Shamay-Tsoory, 2011). Interestingly, although the interplay of neurotransmitters affecting empathic experiences is probably much more complex, OXT has been suggested to be involved in affective empathy but not in cognitive empathy (Hurlemann et al., 2010).

Although several studies on cognitive and affective empathy in individuals with ASD initially revealed only cognitive empathy to be affected in individuals with ASD (Dziobek et al., 2008, Jones et al., 2010, Schwenck et al., 2012), some more recent studies also suggested deficits in affective empathy (e.g., Mazza et al., 2014, Butean et al., 2014). A study demonstrating that the EQ questionnaire actually assesses three empathy components, i.e., cognitive empathy, emotional (affective) empathy and social skills moreover showed that all three components discriminated not only individuals with autism spectrum problems but also their parents from healthy controls (Grove et al., 2014). The authors concluded that autism is characterized by difficulties with multiple facets of empathy and that these may be manifested even in a “broader autism phenotype”.

Considering that emotional contagion is an evolutionary precursor of affective empathy (Gonzalez-Liencres et al., 2013), and assuming that it is contingent upon enhanced neurophysiological responding to observing people in emotionally exciting situations (see also Althaus et al. (2014)), our study investigated the influence of extraneously administered OXT on neurophysiological correlates of affective empathy in male individuals with ASD. Specifically, it investigated whether nasally administered OXT would enhance neurophysiological orienting to affective pictures with humans as compared to affective pictures without humans. It further investigated whether this effect would discriminate young male adults with ASD from young healthy male adults. The pictures were pleasant, unpleasant and neutral pictures from the International Affective Picture System (IAPS, Lang et al., 2008) and the physiological responses were an evoked cardiac response (ECR) and an event-related potential (ERP) derived from the EEG. The ECR shows stimulus dependent heart rate slowing, and the ERP reflects a late long lasting parietal positivity, the LPP. Both types of responses have previously been shown to be larger in response to pictures when humans are portrayed. Moreover, responses to pictures with humans appeared to discriminate males from females, with females showing the larger responses (Proverbio et al., 2009, Groen et al., 2013, Althaus et al., 2014). They have further been shown to correlate positively with questionnaire measures of affective empathic traits such as empathic concern and experiencing personal distress when seeing others in stressful situations (Groen et al., 2013, Althaus et al., 2014). Moreover, and most interesting in this context, a recent study by Norman and colleagues revealed that nasally administered OXT selectively affected the subjective ratings for only IAPS pictures with humans portrayed while it had no effect on non-social IAPS pictures (Norman et al., 2011).

Finally, following the interactionist approach proposed by Bartz and colleagues (2011b), the study took into account individual differences in personal characteristics reflecting the behavior tendencies that are controlled by the two systems proposed to mediate the effects of OXT on prosocial behavior, i.e., the systems involved in fear-related avoidance behavior and affiliate approach behavior, respectively (e.g., Kirsch et al., 2005; Kosfeld et al., 2005; Heinrichs and Domes, 2008; Ditzen et al., 2009).

The present study was designed as a double-blind placebo-controlled cross-over trial with OXT being administered intranasally once. Participants, a group of healthy male adults and male adults with ASD, came to our laboratory twice with one week in between.

Since OXT has been suggested to have anxiolytic effects we first of all hypothesized (1) that subjective feelings of anxiety or discomfort as measured by self-report would have decreased after OXT administration. Moreover, in line with our previous findings on the neurophysiological orienting responses (Groen et al., 2013, Althaus et al., 2014), we expected (2) that, in the placebo situation, both the ECR and LPP would be larger to pictures with humans as compared to pictures without humans, (3) that this would hold in particular for the responses to the affective pictures, and (4) that, according to the Extreme Male Brain hypothesis, the male adults with ASD would differ in their orienting responses from the controls by showing smaller responses to pictures with humans in both the positive and negative context. According to the literature on OXT administration, we moreover expected (5) that nasally administered OXT would enhance these responses particularly in the males with ASD. Finally, we expected (6) that the effects of nasally administered OXT would be moderated by the individual's tendency to show fear-related avoidance behavior or his preference for exhibiting approach behavior.

Section snippets

Methods and material

The present study was conducted according to the guidelines for ethical conduct and report of research. The study had been approved by the Medical Ethics Committee of the University Medical Center Groningen, and written informed consent was obtained from all participants.

Treatment effects on state anxiety

There were no significant treatment effects on the STAI state anxiety scores; i.e., there were no significant Treatment*Time interactions [FTime*Treatment (1,60)=1.88; p=.18; η2=.03], nor did the two groups differ in this effect [FTime*Treatment*Group (1,59)=2.29; p=.14; η2=.04]. Adjusting for trait anxiety did not change these results. Yet, Time effects were found for both groups who did not significantly differ herein [FTime (1,60)=13.71; p<.001; η2=.19; FTime*Group (1,59)=1.94; p=.17; η2

Discussion

Our study tested whether a single dose (24 IE) of nasally administered oxytocin would alter self-reported feelings of state anxiety and neurophysiological orienting to affective pictures with humans in groups of healthy male adults and male adults with ASD.

There was no effect of OXT on state anxiety, neither in the group of males with ASD nor in the control group although the groups differed in their subjectively felt state anxiety (discomfort). The males with ASD reported more discomfort each

Acknowledgments

We give our special thanks to the Accare Foundation for the financial support of this investigation. We are further grateful for the kind support by the Autism Team of the North of the Netherlands and the Jonx Team of Lentis, Groningen, in recruiting our participants.

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