Intranasal oxytocin selectively modulates large-scale brain networks in humans

© Katja Brodmann et al. 2017; Published by Mary Ann Liebert, Inc. This is an Open Access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.A growing body of evidence indicates that the neuropeptide oxytocin (OT) alters the neural correlates of socioemotional and salience processing. Yet the effects of OT over important large-scale networks involved in these processes, such as the default mode (DM), ventral attention (VA), and cingulo-opercular (CO) networks, remain unknown. Therefore, we conducted a placebo-controlled crossover study with intranasal 24 IU OT in 38 healthy male subjects using a resting-state functional magnetic resonance imaging paradigm to investigate its impact over these three networks candidates. To understand the underlying mechanisms of the neuropeptide, we compared the intranetwork connectivity for each network candidate and also the internetwork connectivity across all networks between both treatment conditions. Based on the relevance of interindividual factors for OT effects, we correlated individual network changes with behavioral performance in a decision-making task and with impulsivity scores. Our results show that OT mainly alters connectivity in the VA, on one side reducing the coupling to regions that typically form the nodes of DM, an introspective and self-referential network, and on the other side increasing the coupling to the edges of the CO, which is involved in salience processing. The results of the internetwork analyses confirmed the specificity of the OT effects. Indeed, we observed significant correlations with the erroneous performance during decision-making but not with the obtained impulsivity scores. Overall, our data support that the modulation of functional connectivity within the VA is a basic mechanism by which OT directs attentional resources from internal to external cues, preparing the brain for context-dependent salience processing.info:eu-repo/semantics/publishedVersio

Implications from social and non-social task-based and task-free neuroimaging studies

Research on the effects of oxytocin on social cognition and behavior is constantly growing. Moreover, oxytocin is already discussed to be used as a drug supporting common therapies for a range of disorders displaying deficits in social cognition. Although, the knowledge about its neurophysiological mechanisms lacks in particular regarding its functioning in the non-social domain of behavior, cognition and related brain responses. Therefore, the present thesis had the aim to explore whether the neuropeptide oxytocin has an effect on non-social cognitive processes and their underlying neural correlates, how the neural mechanisms of oxytocin are modulated by additional social input and which basal changes are driven by the effects of oxytocin. I addressed these questions by the use of functional magnetic resonance imaging (fMRI) with task-based and resting-state designs and with a neuroimaging genetics approach. Oxytocin is synthesized in subnuclei of the hypothalamus and was originally known for its involvement in inducing labor. The oxytocin receptor is distributed largely across the brain, covering areas of the mesolimbic system such as the ventral striatum (vStr), the ventral tegmental area (VTA) and the amygdala, but also frontal areas and regions which are not prominently involved in social cognition. Generally, oxytocin is thought to affect social behavior and cognition, including parenting, affiliative behavior, but also emotion-regulation. It is also assumed to be sensitive for context, gender and personality characteristics. Whereas many studies explored the impact of oxytocin on socio-emotional actions such as on emotion-processing in the amygdala, only very few studies focused on the non-socioemotional domain, as for example memory processing or reward-related decision-making. With regard to the aims of this thesis, two of the three experiments employed a non-social decision making paradigm to reveal effects of oxytocin on non-social behavior and related brain activity. Indeed, oxytocin also modulated neural circuits during non-social tasks and even during the resting-state paradigm in the third experiment. This indicates that a social context might not be required to observe changes in neural activity and connectivity by oxytocin. Several theories have been proposed to explain the mechanisms by which oxytocin might function. The social cognition theory suggests that oxytocin might modulate prosocial affiliative behaviors and self-referential processing, the fear/stress approach emphasized its anxiolytic and stress reducing effects, the general approach-avoidance hypothesis of oxytocin assumes that oxytocin acts on approach and avoidance motivation and the social salience hypothesis implies that oxytocin regulates the salience of social stimuli. In conclusion, currently there is no general theory accounting for all the social and non-social effects of oxytocin as described in the literature. In the same perspective, the overall results from the current thesis contradict aspects of each theory, while specific patterns of effects may be best reconciliated with the framework of the approach-avoidance theory and the social salience hypothesis. In the first study a neuroimaging genetics approach was applied to investigate whether common variants of the oxytocin receptor gene influenced behavior and neural responses in a non-social reward-based decision-making paradigm. Specifically, due to dopaminergic-oxytocinergic interactions oxytocin-induced changes were expected in bottom-up reward-related and in top-down cognitive control-related activity. Two of the three candidate single-nucleotide-polymorphism (SNP) of the oxytocin receptor gene (OXTR) were associated with a modulation of reward-related activity during desire and reason situations in the paradigm used. The desire context was formed by allowing to obtain a presented reward, whereas in the reason context the same reward had to be rejected. Participants who were homozygous for the major allele of the OXTR SNP rs1042778 expressed more bottom-up related activity in the vStr in the desire context. In contrast to this, minor allele carriers showed a greater suppression of the reward-related activity in the reason context. This might have led to better cognitive control and therefore to significantly better performance in the rejection of reward stimuli in reason situations. According to this, major allele carriers had a stronger coupling between the vStr and the VTA in desire contexts. Moreover, minor allele carriers displayed an enhanced connectivity between the vStr and the anteroventral prefrontal cortex (avPFC) in reason situations. For the OXTR SNP rs237897 an interaction of gender with the activity in the VTA could be detected. Female participants, homozygous for the major genotype, presented more activation in the left VTA compared to males. Altogether, this study could show that OXTR polymorphisms are able to modulate reward-related as well as control-related activity even in a non-social decision-making paradigm. In study 2 a neuroimaging experiment was performed with the application of intranasal oxytocin and a modified reward-based decision-making paradigm including non-social as well as social stimuli. The main question was whether exogenous oxytocin alters behavioral and neural processes during the non-social condition in this task. Additionally, I was interested in possible changes of oxytocin effects by the presentation of emotional stimuli. Furthermore, by the additional use of both positive and fearful stimuli, I wanted to shed light on the ongoing discussion whether oxytocin acts valence-dependent or irrespective of valence on the activity of the amygdala. An opposite modulation of activity and functional connectivity regarding non-social compared with social context was shown after oxytocin treatment. In the non-social desire situation oxytocin reduced bottom-up activity within the vStr, probably by enhancing top-down control due to strengthening the negative coupling to a frontal region. In contrast, in non-social reason contexts the vStr was less deactivated, maybe due to decreased top-down control. By presenting fearful faces in the social condition, the pattern of neural responses and functional connectivity reversed. In this condition, oxytocin increased the activation in the vStr in desire situations, while it reduced the activation in reason situations. This change in activity was paralleled by stronger positive coupling in the desire context and less coupling as well as negative coupling in the reason context. Furthermore, depending on valence oxytocin decreased amygdala activation for fearful faces and increased amygdala activation for positive faces. The altered activity within the reward system by oxytocin might be the reason for an impaired performance during both desire and reason trials. After oxytocin treatment participants were less accurate in selecting target stimuli than in rejecting the reward stimulus and vice versa for the placebo. This suggests rather an impaired working memory than disturbed stimulus-association learning. To sum up, the comparison between the effects of oxytocin in the non-social and social condition yielded that oxytocin influences corticomesolimbic regions in a context-sensitive manner. The last study used a resting-state fMRI technique with additional administration of intranasal oxytocin. Of particular interest was the possible alteration of functional connectivity within and between large-scale networks by oxytocin. The analysis focused on functional networks indicated to play a major role in salience processing (the salience network - CO), social cognition and self-referential processing (the default mode network - DM) and attention processing (the ventral attentional network - VA). Thereby, basal changes by which oxytocin might influence neuronal responses were shown providing results for the ongoing debate on the underlying function of oxytocin. Although, I expected significant changes of functional connectivity within the DM network. The modulation of the CO and the VA networks were seen. Indeed, oxytocin changed the functional connectivity within and between large-scale networks even without engagement in a task. Oxytocin mainly influenced the VA by decreasing the cross-talk to regions typically part of the DM nodes; and oxytocin strengthened the functional connectivity to the edges of the CO, involving regions linked to salience processing. Additionally, oxytocin directly impacted the functional connectivity within the CO. Therefore, one basic effect of oxytocin might be to redirect attention (VA) from self-referential processing (DM) to the external environment, preparing for reception of salient information (CO). Taken together, the purpose of the present thesis was to extend the knowledge about the effects of oxytocin as well as basic mechanisms of oxytocin’s influence on cognition, behavior and neural activation and connectivity in non-social, social and task-free conditions. The results clearly demonstrated effects on neural activation, functional connectivity and on behavior in all three studies; supporting the claim that oxytocin does not only play an important role in socio-emotional processing

Association between oxytocin receptor gene polymorphisms and self-rated 'empathic concern' in schizophrenia

The nonapeptide oxytocin (OXT) and its receptor (OXTR) have been implicated in social cognition, empathy, emotion and stress regulation in humans. Previous studies reported associations between OXT and OXTR genetic polymorphisms and risk for disorders characterized by impaired socio-emotional functioning, such as schizophrenia and autism. Here we investigate the influence of two single nucleotide polymorphisms (SNPs) within the OXTR gene on a measure of socio-emotional functioning in schizophrenic patients. OXTR SNPs that were previously investigated in other studies were genotyped in 145 patients diagnosed with schizophrenia according to DSM-IV and 145 healthy controls matched for age and gender. The Interpersonal Reactivity Index (IRI) was used to assess cognitive ('perspective taking'), affective ('empathic concern') and self-related ('personal distress') dimensions of empathy. No group differences in genotype frequencies were observed. MANCOVA revealed a significant main (F [1,282] = 10.464; pGG) with 'empathic concern'. Within the schizophrenia group, linear regression analysis determined OXTR rs2254298 genotype, PANSS negative and general symptom score, and age of disease onset as being significantly associated with 'empathic concern'. OXTR rs2254298 significantly impacted PANSS general psychopathology scores. No associations were found for OXTR rs53576, IRI 'perspective taking' or 'personal distress' ratings. Our preliminary findings support hypotheses about an involvement of OXTR rs2254298 in emotional empathy in schizophrenic and healthy individuals, warranting independent replication

The effects of oxytocin on self-related processing and cognition

The neuropeptide oxytocin (OT) has been suggested to facilitate social cognition and behavior. Therefore, published literature mainly focuses on the study of OT in a social context or in relation to others. But how we think, act and feel in social situations might strongly depend on our own state of being – the self. Thus, the present three studies examine the effects of OT on self-related processing and cognition. The first study explores the idea that OT might decrease self-related information processing, even when individuals are specifically exposed to being self-aware. We could show that public self-awareness was increased when participants were placed in front of a mirror. Moreover, in the placebo group, lower scores in self-esteem were associated with increased self-awareness. This was not the case in the OT group in which self-esteem was unrelated to self-awareness. The results suggest that OT might function as a buffer against the negative consequences of enhanced self-related processing. The second study of this dissertation explores OT’s effects on self-related processing in a more physiological approach. Participants were to conduct a heartbeat perception task in front of a mirror (vs. no mirror) and we hypothesized OT to inhibit interoceptive awareness. Usually, people become more attuned to bodily responses in front of a mirror due to increased self-awareness. In line with the concept of de-individuation under OT, we could show that heartbeat accuracy, and thus interoceptive accuracy, was increased among participants under placebo who were placed in front of the mirror, but no such effect occurred after treatment with OT. The third study provides empirical evidence testing OT’s effect on situational self-awareness when attentional focus is shifted, either to external sensory perception or explicit self-related cognition, using a categorization vs. introspection task. The results suggest that situational self-awareness was reduced after OT treatment compared to placebo, when participants had previously been instructed to introspect about their feelings. In sum, all findings support the idea of OT being significantly involved in self-related processing and cognition by enhancing de-individuation

The effects of oxytocin on self-related processing and cognition

The neuropeptide oxytocin (OT) has been suggested to facilitate social cognition and behavior. Therefore, published literature mainly focuses on the study of OT in a social context or in relation to others. But how we think, act and feel in social situations might strongly depend on our own state of being – the self. Thus, the present three studies examine the effects of OT on self-related processing and cognition. The first study explores the idea that OT might decrease self-related information processing, even when individuals are specifically exposed to being self-aware. We could show that public self-awareness was increased when participants were placed in front of a mirror. Moreover, in the placebo group, lower scores in self-esteem were associated with increased self-awareness. This was not the case in the OT group in which self-esteem was unrelated to self-awareness. The results suggest that OT might function as a buffer against the negative consequences of enhanced self-related processing. The second study of this dissertation explores OT’s effects on self-related processing in a more physiological approach. Participants were to conduct a heartbeat perception task in front of a mirror (vs. no mirror) and we hypothesized OT to inhibit interoceptive awareness. Usually, people become more attuned to bodily responses in front of a mirror due to increased self-awareness. In line with the concept of de-individuation under OT, we could show that heartbeat accuracy, and thus interoceptive accuracy, was increased among participants under placebo who were placed in front of the mirror, but no such effect occurred after treatment with OT. The third study provides empirical evidence testing OT’s effect on situational self-awareness when attentional focus is shifted, either to external sensory perception or explicit self-related cognition, using a categorization vs. introspection task. The results suggest that situational self-awareness was reduced after OT treatment compared to placebo, when participants had previously been instructed to introspect about their feelings. In sum, all findings support the idea of OT being significantly involved in self-related processing and cognition by enhancing de-individuation

From autism to eating disorders and more: the role of oxytocin in neuropsychiatric disorders

Oxytocin (oxy) is a pituitary neuropeptide hormone synthesized from the paraventricular and supraoptic nuclei within the hypothalamus. Like other neuropeptides, oxy can modulate a wide range of neurotransmitter and neuromodulator activities. Additionally, through the neurohypophysis, oxy is secreted into the systemic circulation to act as a hormone, thereby influencing several body functions. Oxy plays a pivotal role in parturition, milk let-down and maternal behavior and has been demonstrated to be important in the formation of pair bonding between mother and infants as well as in mating pairs. Furthermore, oxy has been proven to play a key role in the regulation of several behaviors associated with neuropsychiatric disorders, including social interactions, social memory response to social stimuli, decision-making in the context of social interactions, feeding behavior, emotional reactivity, etc. An increasing body of evidence suggests that deregulations of the oxytocinergic system might be involved in the pathophysiology of certain neuropsychiatric disorders such as autism, eating disorders, schizophrenia, mood, and anxiety disorders. The potential use of oxy in these mental health disorders is attracting growing interest since numerous beneficial properties are ascribed to this neuropeptide. The present manuscript will review the existing findings on the role played by oxy in a variety of distinct physiological and behavioral functions (Figure 1) and on its role and impact in different psychiatric disorders. The aim of this review is to highlight the need of further investigations on this target that might contribute to the development of novel more efficacious therapies. Figure 1Oxytocin regulatory control of different and complex processes

Oxytocin alters patterns of brain activity and amygdalar connectivity by age during dynamic facial emotion identification

Aging is associated with increased difficulty in facial emotion identification, possibly due to age-related network change. The neuropeptide oxytocin (OT) facilitates emotion identification, but this is understudied in aging. To determine the effects of OT on dynamic facial emotion identification across adulthood, 46 young and 48 older participants self-administered intranasal OT or a placebo in a randomized, double-blind procedure. Older participants were slower and less accurate in identifying emotions. Although there was no behavioral treatment effect, partial least squares analysis supported treatment effects on brain patterns during emotion identification that varied by age and emotion. For young participants, OT altered the processing of sadness and happiness, whereas for older participants, OT only affected the processing of sadness (15.3% covariance, p\ua0= 0.004). Furthermore, seed partial least squares analysis showed that older participants in the OT group recruited a large-scale amygdalar network that was positively correlated for anger, fear, and happiness, whereas older participants in the placebo group recruited a smaller, negatively correlated network (7% covariance, p\ua0= 0.002). Advancing the literature, these findings show that OT alters brain activity and amygdalar connectivity by age and emotion

The Role Of Oxytocin In Modulating Neural Oscillations In Nulliparous Women

The hormone oxytocin (OT) has been implicated in social cognition and behavior as well as in modulating important affiliative relationships such as parenting; meanwhile, intranasal OT administration is gaining popularity as a means to modulate neural activity in brain regions during experimental tasks. However, the neural mechanisms underscoring the changes associated with OT administration have yet to be fully elucidated. Using electroencephalography (EEG), this thesis project aims to further our understanding of how OT affects brain activity and response to infant cues. In a double-blind placebo controlled design, OT’s effect on resting-state neural oscillations and event-related potentials (ERPs) to face stimuli were examined in a cohort of nulliparous women of childbearing age. Specifically, we examined the effects of intranasal OT on delta, beta, and delta-beta coupling during the resting state, and the amplitudes of the ERP components N170, P300, and the Late Positive Potential (LPP) to infant and adult faces. Prior work has suggested that cross-frequency coupling may be a useful way to study cognitive processing, whereas the N170, P300 and LPP are all components involved in the processing of facial and emotional stimuli. We found that OT, relative to placebo, decreased delta-beta coupling across multiple brain regions; ERP data showed that OT administration led to an increased amplitude of the P300 component to infant faces compared with adult faces. Taken together, these findings demonstrate that OT administration may lead nulliparous women to allocate greater attentional resources to infant faces than adult faces via a neural mechanism captured by delta-beta coupling

Assessment of reward-related brain function after a single-dose of oxytocin in autism: A randomized controlled trial

Background Autism spectrum disorder (ASD) is characterized by difficulties in social communication and interaction, which have been related to atypical neural processing of rewards, especially in the social domain. Since intranasal oxytocin has been shown to modulate activation of the brain’s reward circuit, oxytocin might ameliorate the processing of social rewards in ASD and thus improve social difficulties. Methods In this randomized, double-blind, placebo-controlled, crossover fMRI study, we examined effects of a 24 IU dose of intranasal oxytocin on reward-related brain function in 37 men with ASD without intellectual impairment and 37 age- and IQ-matched control participants. Participants performed an incentive delay task that allows the investigation of neural activity associated with the anticipation and receipt of monetary and social rewards. Results Non-significant tests suggested that oxytocin did not influence neural processes related to the anticipation of social or monetary rewards in either group. Complementary Bayesian analyses indicated moderate evidence for a null model, relative to an alternative model. Our results are inconclusive regarding possible oxytocin effects on amygdala responsiveness to social rewards during reward consumption. There were no significant differences in reward-related brain function between the two groups under placebo. Conclusions Our results do not support the hypothesis that intranasal oxytocin generally enhances activation of reward-related neural circuits in men with and without ASD