Sniffing oxytocin: Nose to brain or nose to blood?

In recent years ample studies have reported that intranasal administration of the neuropeptide oxytocin can facilitate social motivation and cognition in healthy and clinical populations. However, it is still unclear how effects are mediated since intranasally administered oxytocin can both directly enter the brain (nose to brain) and increase peripheral vascular concentrations (nose to blood). The relative functional contributions of these routes are not established and have received insufficient attention in the field. The current study used vasoconstrictor pretreatment to prevent intranasal oxytocin (24 IU) from increasing peripheral concentrations and measured effects on both resting-state neural (electroencephalography) and physiological responses (electrocardiogram, electrogastrogram and skin conductance). Results demonstrated that intranasal oxytocin alone produced robust and widespread increases of delta-beta cross-frequency coupling (CFC) from 30 min post-treatment but did not influence peripheral physiological measures. As predicted, vasoconstrictor pretreatment greatly reduced the normal increase in peripheral oxytocin concentrations and, importantly, abolished the majority of intranasal oxytocin effects on delta-beta CFC. Furthermore, time-dependent positive correlations were found between increases in plasma oxytocin concentrations and corresponding increases in delta-beta CFC following oxytocin treatment alone. Our findings suggest a critical role of peripheral vasculature-mediated routes on neural effects of exogenous oxytocin administration with important translational implications for its use as an intervention in psychiatric disorders.

Angiotensin blockade enhances motivational reward learning via enhancing striatal prediction error signaling and frontostriatal communication.

Adaptive human learning utilizes reward prediction errors (RPEs) that scale the differences between expected and actual outcomes to optimize future choices. Depression has been linked with biased RPE signaling and an exaggerated impact of negative outcomes on learning which may promote amotivation and anhedonia. The present proof-of-concept study combined computational modeling and multivariate decoding with neuroimaging to determine the influence of the selective competitive angiotensin II type 1 receptor antagonist losartan on learning from positive or negative outcomes and the underlying neural mechanisms in healthy humans. In a double-blind, between-subjects, placebo-controlled pharmaco-fMRI experiment, 61 healthy male participants (losartan, n = 30; placebo, n = 31) underwent a probabilistic selection reinforcement learning task incorporating a learning and transfer phase. Losartan improved choice accuracy for the hardest stimulus pair via increasing expected value sensitivity towards the rewarding stimulus relative to the placebo group during learning. Computational modeling revealed that losartan reduced the learning rate for negative outcomes and increased exploitatory choice behaviors while preserving learning for positive outcomes. These behavioral patterns were paralleled on the neural level by increased RPE signaling in orbitofrontal-striatal regions and enhanced positive outcome representations in the ventral striatum (VS) following losartan. In the transfer phase, losartan accelerated response times and enhanced VS functional connectivity with left dorsolateral prefrontal cortex when approaching maximum rewards. These findings elucidate the potential of losartan to reduce the impact of negative outcomes during learning and subsequently facilitate motivational approach towards maximum rewards in the transfer of learning. This may indicate a promising therapeutic mechanism to normalize distorted reward learning and fronto-striatal functioning in depression.

"Listen to your heart": A novel interoceptive strategy for real-time fMRI neurofeedback training of anterior insula activity.

Real-time fMRI (rt-fMRI) neurofeedback (NF) training is a novel non-invasive technique for volitional brain modulation. Given the important role of the anterior insula (AI) in human cognitive and affective processes, it has become one of the most investigated regions in rt-fMRI studies. Most rt-fMRI insula studies employed emotional recall/imagery as the regulation strategy, which may be less effective for psychiatric disorders characterized by altered emotional processing. The present study thus aimed to examine the feasibility of a novel interoceptive strategy based on heartbeat detection in rt-fMRI guided AI regulation and its associated behavioral changes using a randomized double-blind, sham feedback-controlled between-subject design. 66 participants were recruited and randomly assigned to receive either NF from the left AI (LAI) or sham feedback from a control region while using the interoceptive strategy. N = 57 participants were included in the final data analyses. Empathic and interoceptive pre-post training changes were collected as behavioral measures of NF training effects. Results showed that participants in the NF group exhibited stronger LAI activity than the control group with LAI activity being positively correlated with interoceptive accuracy following NF training, although there were no significant increases of LAI activity over training sessions. Importantly, ability of LAI regulation could be maintained in a transfer session without feedback. Successful LAI regulation was associated with strengthened functional connectivity of the LAI with cognitive control, memory and learning, and salience/interoceptive networks. The present study demonstrated for the first time the efficacy of a novel regulation strategy based on interoceptive processing in up-regulating LAI activity. Our findings also provide proof of concept for the translational potential of this strategy in rt-fMRI AI regulation of psychiatric disorders characterized by altered emotional processing.

The mirror neuron system compensates for amygdala dysfunction - associated social deficits in individuals with higher autistic traits.

The amygdala is a core node in the social brain which exhibits structural and functional abnormalities in Autism spectrum disorder and there is evidence that the mirror neuron system (MNS) can functionally compensate for impaired emotion processing following amygdala lesions. In the current study, we employed an fMRI paradigm in 241 subjects investigating MNS and amygdala responses to observation, imagination and imitation of dynamic facial expressions and whether these differed in individuals with higher (n = 77) as opposed to lower (n = 79) autistic traits. Results indicated that individuals with higher compared to lower autistic traits showed worse recognition memory for fearful faces, smaller real-life social networks, and decreased left basolateral amygdala (BLA) responses to imitation. Additionally, functional connectivity between the left BLA and the left inferior frontal gyrus (IFG) as well as some other MNS regions was increased in individuals with higher autistic traits, especially during imitation of fearful expressions. The left BLA-IFG connectivity significantly moderated the autistic group differences on recognition memory for fearful faces, indicating that increased amygdala-MNS connectivity could diminish the social behavioral differences between higher and lower autistic trait groups. Overall, findings demonstrate decreased imitation-related amygdala activity in individuals with higher autistic traits in the context of increased amygdala-MNS connectivity which may functionally compensate for amygdala dysfunction and social deficits. Training targeting the MNS may capitalize on this compensatory mechanism for therapeutic benefits in Autism spectrum disorder.

Dysregulated anterior insula reactivity as robust functional biomarker for chronic pain-Meta-analytic evidence from neuroimaging studies.

Neurobiological pain models propose that chronic pain is accompanied by neurofunctional changes that mediate pain processing dysfunctions. In contrast, meta-analyses of neuroimaging studies in chronic pain conditions have not revealed convergent evidence for robust alterations during experimental pain induction. Against this background, the present neuroimaging meta-analysis combined three different meta-analytic approaches with stringent study selection criteria for case-control functional magnetic resonance imaging experiments during acute pain processing with a focus on chronic pain disorders. Convergent neurofunctional dysregulations in chronic pain patients were observed in the left anterior insula cortex. Seed-based resting-state functional connectivity based on a large publicly available dataset combined with a meta-analytic task-based approach identified the anterior insular region as a key node of an extended bilateral insula-fronto-cingular network, resembling the salience network. Moreover, the meta-analytic decoding showed that this region presents a high probability to be specifically activated during pain-related processes, although we cannot exclude an involvement in autonomic processes. Together, the present findings indicate that dysregulated left anterior insular activity represents a robust neurofunctional maladaptation and potential treatment target in chronic pain disorders.

Oral Administration of Oxytocin, Like Intranasal Administration, Decreases Top-Down Social Attention.

BACKGROUND: The neuropeptide oxytocin (OXT) modulates social cognition by increasing attention to social cues and may have therapeutic potential for impaired social attention in conditions such as autism spectrum disorder. Intranasal administration of OXT is widely used to examine the drug's functional effects in both adults and children and is assumed to enter the brain directly via this route. However, OXT can also influence brain function through increased blood concentrations, and we have recently shown that orally (lingual) administered OXT also modulates neural responses to emotional faces and may be better tolerated for therapeutic use. Here, we examine whether 24 IU OXT administered orally can facilitate social attention. METHODS: In a randomized, placebo-controlled pharmacologic study, we used a validated emotional antisaccade eye-tracking paradigm to explore the effects of oral OXT on bottom-up and top-down attention processing in 80 healthy male participants. RESULTS: Our findings showed that in terms of top-down attention, oral OXT increased errors for both social (angry, fearful, happy, sad, and neutral emotion faces) and nonsocial stimuli (oval shapes) in the antisaccade condition but increased response latencies only in the social condition. It also significantly reduced post-task state anxiety, but this reduction was not correlated with task performance. A comparison with our previous intranasal OXT study using the same task revealed that both routes have a similar effect on increasing antisaccade errors and response latencies and on reducing state anxiety. CONCLUSIONS: Overall, our findings suggest that oral administration of OXT produces similar effects on top-down social attention control and anxiety to intranasal administration and may therefore have therapeutic utility.

Oxytocinergic Modulation of Stress-Associated Amygdala-Hippocampus Pathways in Humans Is Mediated by Serotonergic Mechanisms.

BACKGROUND: The hypothalamic neuropeptide oxytocin (OXT) may exert anxiolytic and stress-reducing actions via modulatory effects on amygdala circuits. Animal models and initial findings in humans suggest that some of these effects are mediated by interactions with other neurotransmitter systems, in particular the serotonin (5-HT) system. Against this background, the present pharmacological resting-state functional magnetic resonance imaging study aimed to determine whether effects of OXT on stress-associated amygdala intrinsic networks are mediated by 5-HT. METHODS: We employed a randomized, placebo-controlled, double-blind parallel-group, pharmacological functional magnetic resonance imaging resting-state experiment with 4 treatment groups in n = 112 healthy male participants. Participants underwent a transient decrease in 5-HT signaling via acute tryptophan depletion (ATD) or a corresponding placebo-control protocol before the administration of intranasal OXT (24 IU) or placebo intranasal spray. RESULTS: OXT and 5-HT modulation exerted interactive effects on the coupling of the left amygdala with the ipsilateral hippocampus and adjacent midbrain. OXT increased intrinsic coupling in this pathway, whereas this effect of OXT was significantly attenuated during transiently decreased central serotonergic signaling induced via acute tryptophan depletion. In the absence of OXT or 5-HT modulation, this pathway showed a trend for an association with self-reported stress perception in everyday life. No interactive effects were observed for the right amygdala. CONCLUSIONS: Together, the findings provide the first evidence, to our knowledge, that the effects of OXT on stress-associated amygdala-hippocampal-midbrain pathways are critically mediated by the 5-HT system in humans.

Anxiolytic Effects of Chronic Intranasal Oxytocin on Neural Responses to Threat Are Dose-Frequency Dependent.

INTRODUCTION: Anxiety disorders are prevalent mental conditions characterized by exaggerated anxious arousal and threat reactivity. Animal and human studies suggest an anxiolytic potential of the neuropeptide oxytocin (OT), yet, while a clinical application will require chronic administration protocols, previous human studies have exclusively focused on single-dose (acute) intranasal OT effects. OBJECTIVE: To facilitate the translation of the potential anxiolytic mechanism of OT into clinical application, we determined whether the anxiolytic effects of OT are maintained with repeated (chronic) administration or are influenced by dose frequency and trait anxiety. METHODS: In a pre-registered double-blind randomized placebo-controlled pharmaco-fMRI trial the acute (single dose) as well as chronic effects of two different dose frequencies of OT (OT administered daily for 5 days or every other day) on emotional reactivity were assessed in n = 147 individuals with high versus low trait anxiety (ClinicalTrials.gov ID: NCT03085654). RESULTS: OT produced valence, dose frequency, and trait anxiety-specific effects, such that the low-frequency (intermittent) chronic dosage specifically attenuated a neural reactivity increase in amygdala-insula-prefrontal circuits observed in the high anxious placebo-treated subjects in response to threatening but not positive stimuli. CONCLUSIONS: The present trial provides the first evidence that low-dose frequency chronic intranasal OT has the potential to alleviate exaggerated neural threat reactivity in subjects with elevated anxiety levels, suggesting a treatment potential for anxiety disorders.

Oxytocin Modulates the Intrinsic Dynamics Between Attention-Related Large-Scale Networks.

Attention and salience processing have been linked to the intrinsic between- and within-network dynamics of large-scale networks engaged in internal (default network [DN]) and external attention allocation (dorsal attention network [DAN] and salience network [SN]). The central oxytocin (OXT) system appears ideally organized to modulate widely distributed neural systems and to regulate the switch between internal attention and salient stimuli in the environment. The current randomized placebo (PLC)-controlled between-subject pharmacological resting-state fMRI study in N = 187 (OXT, n = 94; PLC, n = 93; single-dose intranasal administration) healthy male and female participants employed an independent component analysis approach to determine the modulatory effects of OXT on the within- and between-network dynamics of the DAN-SN-DN triple network system. OXT increased the functional integration between subsystems within SN and DN and increased functional segregation of the DN with both attentional control networks (SN and DAN). Whereas no sex differences were observed, OXT effects on the DN-SN interaction were modulated by autistic traits. Together, the findings suggest that OXT may facilitate efficient attention allocation by modulating the intrinsic functional dynamics between DN components and large-scale networks involved in external attentional demands (SN and DAN).

Intrinsic, dynamic and effective connectivity among large-scale brain networks modulated by oxytocin.

The neuropeptide oxytocin is a key modulator of social-emotional behavior and its intranasal administration can influence the functional connectivity of brain networks involved in the control of attention, emotion and reward reported in humans. However, no studies have systematically investigated the effects of oxytocin on dynamic or directional aspects of functional connectivity. The present study employed a novel computational framework to investigate these latter aspects in 15 oxytocin-sensitive regions using data from randomized placebo-controlled between-subject resting state functional MRI studies incorporating 200 healthy subjects. In order to characterize the temporal dynamics, the 'temporal state' was defined as a temporal segment of the whole functional MRI signal which exhibited a similar functional interaction pattern among brain regions of interest. Results showed that while no significant effects of oxytocin were found on brain temporal state related characteristics (including temporal state switching frequency, probability of transitions between neighboring states, and averaged dwell time on each state) oxytocin extensively (n = 54 links) modulated effective connectivity among the 15 regions. The effects of oxytocin were primarily characterized by increased effective connectivity both between and within emotion, reward, salience, attention and social cognition processing networks and their interactions with the default mode network. Top-down control over emotional processing regions such as the amygdala was particularly affected. Oxytocin also increased effective homotopic interhemispheric connectivity in almost all these regions. Additionally, the effects of oxytocin on effective connectivity were sex-dependent, being more extensive in males. Overall, these findings suggest that modulatory effects of oxytocin on both within- and between-network interactions may underlie its functional influence on social-emotional behaviors, although in a sex-dependent manner. These findings may be of particular relevance to potential therapeutic use of oxytocin in psychiatric disorders associated with social dysfunction, such as autism spectrum disorder and schizophrenia, where directionality of treatment effects on causal interactions between networks may be of key importance .

Segregating domain-general from emotional context-specific inhibitory control systems - ventral striatum and orbitofrontal cortex serve as emotion-cognition integration hubs.

Inhibitory control hierarchically regulates cognitive and emotional systems in the service of adaptive goal-directed behavior across changing task demands and environments. While previous studies convergently determined the contribution of prefrontal-striatal systems to general inhibitory control, findings on the specific circuits that mediate emotional context-specific impact on inhibitory control remained inconclusive. Against this background we combined an evaluated emotional Go/No Go task with fMRI in a large cohort of subjects (N=250) to segregate brain systems and circuits that mediate domain-general from emotion-specific inhibitory control. Particularly during a positive emotional context, behavioral results showed a lower accuracy for No Go trials and a faster response time for Go trials. While the dorsal striatum and lateral frontal regions were involved in inhibitory control irrespective of emotional context, activity in the ventral striatum (VS) and medial orbitofrontal cortex (mOFC) varied as a function of emotional context. On the voxel-wise whole-brain network level, limbic and striatal systems generally exhibited highest changes in global brain connectivity during inhibitory control, while global brain connectivity of the left mOFC was less decreased during emotional contexts. Functional connectivity analyses moreover revealed that negative coupling between the VS with inferior frontal gyrus (IFG)/insula and mOFC varied as a function of emotional context. Together these findings indicate separable domain- general as well as emotional context-specific inhibitory brain systems which specifically encompass the VS and its connections with frontal regions.

Predictors of real-time fMRI neurofeedback performance and improvement - A machine learning mega-analysis.

Real-time fMRI neurofeedback is an increasingly popular neuroimaging technique that allows an individual to gain control over his/her own brain signals, which can lead to improvements in behavior in healthy participants as well as to improvements of clinical symptoms in patient populations. However, a considerably large ratio of participants undergoing neurofeedback training do not learn to control their own brain signals and, consequently, do not benefit from neurofeedback interventions, which limits clinical efficacy of neurofeedback interventions. As neurofeedback success varies between studies and participants, it is important to identify factors that might influence neurofeedback success. Here, for the first time, we employed a big data machine learning approach to investigate the influence of 20 different design-specific (e.g. activity vs. connectivity feedback), region of interest-specific (e.g. cortical vs. subcortical) and subject-specific factors (e.g. age) on neurofeedback performance and improvement in 608 participants from 28 independent experiments. With a classification accuracy of 60% (considerably different from chance level), we identified two factors that significantly influenced neurofeedback performance: Both the inclusion of a pre-training no-feedback run before neurofeedback training and neurofeedback training of patients as compared to healthy participants were associated with better neurofeedback performance. The positive effect of pre-training no-feedback runs on neurofeedback performance might be due to the familiarization of participants with the neurofeedback setup and the mental imagery task before neurofeedback training runs. Better performance of patients as compared to healthy participants might be driven by higher motivation of patients, higher ranges for the regulation of dysfunctional brain signals, or a more extensive piloting of clinical experimental paradigms. Due to the large heterogeneity of our dataset, these findings likely generalize across neurofeedback studies, thus providing guidance for designing more efficient neurofeedback studies specifically for improving clinical neurofeedback-based interventions. To facilitate the development of data-driven recommendations for specific design details and subpopulations the field would benefit from stronger engagement in open science research practices and data sharing.

Putamen volume predicts real-time fMRI neurofeedback learning success across paradigms and neurofeedback target regions.

Real-time fMRI guided neurofeedback training has gained increasing interest as a noninvasive brain regulation technique with the potential to modulate functional brain alterations in therapeutic contexts. Individual variations in learning success and treatment response have been observed, yet the neural substrates underlying the learning of self-regulation remain unclear. Against this background, we explored potential brain structural predictors for learning success with pooled data from three real-time fMRI data sets. Our analysis revealed that gray matter volume of the right putamen could predict neurofeedback learning success across the three data sets (n = 66 in total). Importantly, the original studies employed different neurofeedback paradigms during which different brain regions were trained pointing to a general association with learning success independent of specific aspects of the experimental design. Given the role of the putamen in associative learning this finding may reflect an important role of instrumental learning processes and brain structural variations in associated brain regions for successful acquisition of fMRI neurofeedback-guided self-regulation.

Serotonin and early life stress interact to shape brain architecture and anxious avoidant behavior - a TPH2 imaging genetics approach.

BACKGROUND: Early life stress has been associated with emotional dysregulations and altered architecture of limbic-prefrontal brain systems engaged in emotional processing. Serotonin regulates both, developmental and experience-dependent neuroplasticity in these circuits. Central serotonergic biosynthesis rates are regulated by Tryptophan hydroxylase 2 (TPH2) and transgenic animal models suggest that TPH2-gene associated differences in serotonergic signaling mediate the impact of aversive early life experiences on a phenotype characterized by anxious avoidance. METHODS: The present study employed an imaging genetics approach that capitalized on individual differences in a TPH2 polymorphism (703G/T; rs4570625) to determine whether differences in serotonergic signaling modulate the effects of early life stress on brain structure and function and punishment sensitivity in humans (n = 252). RESULTS: Higher maltreatment exposure before the age of 16 was associated with increased gray matter volumes in a circuitry spanning thalamic-limbic-prefrontal regions and decreased intrinsic communication in limbic-prefrontal circuits selectively in TT carriers. In an independent replication sample, associations between higher early life stress and increased frontal volumes in TT carriers were confirmed. On the phenotype level, the genotype moderated the association between higher early life stress exposure and higher punishment sensitivity. In TT carriers, the association between higher early life stress exposure and punishment sensitivity was critically mediated by increased thalamic-limbic-prefrontal volumes. CONCLUSIONS: The present findings suggest that early life stress shapes the neural organization of the limbic-prefrontal circuits in interaction with individual variations in the TPH2 gene to promote a phenotype characterized by facilitated threat avoidance, thus promoting early adaptation to an adverse environment.

Convergent cross-sectional and longitudinal evidence for gaming-cue specific posterior parietal dysregulations in early stages of internet gaming disorder.

Exaggerated reactivity to drug-cues and emotional dysregulations represent key symptoms of early stages of substance use disorders. The diagnostic criteria for (Internet) gaming disorder strongly resemble symptoms for substance-related addictions. However, previous cross-sections studies revealed inconsistent results with respect to neural cue reactivity and emotional dysregulations in these populations. To this end, the present fMRI study applied a combined cross-sectional and longitudinal design in regular online gamers (n = 37) and gaming-naïve controls (n = 67). To separate gaming-associated changes from predisposing factors, gaming-naive subjects were randomly assigned to 6 weeks of daily Internet gaming or a non-gaming condition. At baseline and after the training, subjects underwent an fMRI paradigm presenting gaming-related cues and non-gaming-related emotional stimuli. Cross-sectional comparisons revealed gaming-cue specific enhanced valence attribution and neural reactivity in a parietal network, including the posterior cingulate in regular gamers as compared to gaming naïve-controls. Longitudinal analysis revealed that 6 weeks of gaming elevated valence ratings as well as neural cue-reactivity in a similar parietal network, specifically the posterior cingulate in previously gaming-naïve controls. Together, the longitudinal design did not reveal supporting evidence for altered emotional processing of non-gaming associated stimuli in regular gamers whereas convergent evidence for increased emotional and neural reactivity to gaming-associated stimuli was observed. Findings suggest that exaggerated neural reactivity in posterior parietal regions engaged in default mode and automated information processing already occur during early stages of regular gaming and probably promote continued engagement in gaming behavior.

Can we predict real-time fMRI neurofeedback learning success from pretraining brain activity?

Neurofeedback training has been shown to influence behavior in healthy participants as well as to alleviate clinical symptoms in neurological, psychosomatic, and psychiatric patient populations. However, many real-time fMRI neurofeedback studies report large inter-individual differences in learning success. The factors that cause this vast variability between participants remain unknown and their identification could enhance treatment success. Thus, here we employed a meta-analytic approach including data from 24 different neurofeedback studies with a total of 401 participants, including 140 patients, to determine whether levels of activity in target brain regions during pretraining functional localizer or no-feedback runs (i.e., self-regulation in the absence of neurofeedback) could predict neurofeedback learning success. We observed a slightly positive correlation between pretraining activity levels during a functional localizer run and neurofeedback learning success, but we were not able to identify common brain-based success predictors across our diverse cohort of studies. Therefore, advances need to be made in finding robust models and measures of general neurofeedback learning, and in increasing the current study database to allow for investigating further factors that might influence neurofeedback learning.

Real-Time Functional Connectivity-Informed Neurofeedback of Amygdala-Frontal Pathways Reduces Anxiety.

BACKGROUND: Deficient emotion regulation and exaggerated anxiety represent a major transdiagnostic psychopathological marker. On the neural level these deficits have been closely linked to impaired, yet treatment-sensitive, prefrontal regulatory control over the amygdala. Gaining direct control over these pathways could therefore provide an innovative and promising intervention to regulate exaggerated anxiety. To this end the current proof-of-concept study evaluated the feasibility, functional relevance and maintenance of a novel connectivity-informed real-time fMRI neurofeedback training. METHODS: In a randomized crossover sham-controlled design, 26 healthy subjects with high anxiety underwent real-time fMRI-guided neurofeedback training to enhance connectivity between the ventrolateral prefrontal cortex (vlPFC) and the amygdala (target pathway) during threat exposure. Maintenance of regulatory control was assessed after 3 days and in the absence of feedback. Training-induced changes in functional connectivity of the target pathway and anxiety ratings served as primary outcomes. RESULTS: Training of the target, yet not the sham control, pathway significantly increased amygdala-vlPFC connectivity and decreased levels of anxiety. Stronger connectivity increases were significantly associated with higher anxiety reduction on the group level. At the follow-up, volitional control over the target pathway was maintained in the absence of feedback. CONCLUSIONS: The present results demonstrate for the first time that successful self-regulation of amygdala-prefrontal top-down regulatory circuits may represent a novel intervention to control anxiety. As such, the present findings underscore both the critical contribution of amygdala-prefrontal circuits to emotion regulation and the therapeutic potential of connectivity-informed real-time neurofeedback.

Oxytocin Facilitates Approach Behavior to Positive Social Stimuli via Decreasing Anterior Insula Activity.

Background: The neuropeptide oxytocin can extensively modulate human social behavior and affective processing, and its effects can be interpreted in terms of mediating approach-avoidance motivational processes. However, little is known about how oxytocin mediates approach-avoidance behavior and particularly the underlying neural mechanisms. Methods: In a randomized, double-blind, between-subject design, the present pharmaco-fMRI study used an approach-avoidance paradigm to investigate oxytocin's effects on approach-avoidance behavior and associated neural mechanisms. Results: Results revealed that oxytocin generally decreased activity in the right striatum irrespective of response (approach/avoidance) and social context, suggesting an inhibitory effect on motivational representation during both appetitive approach and aversive avoidance. Importantly, while on the behavioral level oxytocin selectively enhanced accuracy when approaching social positive stimuli, on the neural level it decreased left ventral and right dorsal anterior insula activity in response to social vs nonsocial positive stimuli compared with the placebo treatment. The left ventral anterior insula activity was negatively correlated with the corresponding accuracy difference scores in the oxytocin but not in the placebo group. Conclusion: Given the role of the ventral anterior insula in emotional processing and the dorsal anterior insula in salience processing, the oxytocin-induced suppression of activity in these regions may indicate that oxytocin is acting to reduce interference from hyper-activity in core regions of the emotional and salience networks when approaching salient positive social stimuli and thereby to promote social interaction. Thus, oxytocin may be of potential therapeutic benefit for psychiatric disorders exhibiting avoidance of social stimuli.

Sex-dependent neural effect of oxytocin during subliminal processing of negative emotion faces.

In line with animal models indicating sexually dimorphic effects of oxytocin (OXT) on social-emotional processing, a growing number of OXT-administration studies in humans have also reported sex-dependent effects during social information processing. To explore whether sex-dependent effects already occur during early, subliminal, processing stages the present pharmacological fMRI-study combined the intranasal-application of either OXT or placebo (n = 86-43 males) with a backward-masking emotional face paradigm. Results showed that while OXT suppressed inferior frontal gyrus, dorsal anterior cingulate and anterior insula responses to threatening face stimuli in men it increased them in women. In women increased anterior cingulate reactivity during subliminal threat processing was also positively associated with trait anxiety. On the network level, sex-dependent effects were observed on amygdala, anterior cingulate and inferior frontal gyrus functional connectivity that were mainly driven by reduced coupling in women following OXT. Our findings demonstrate that OXT produces sex-dependent effects even at the early stages of social-emotional processing, and suggest that while it attenuates neural responses to threatening social stimuli in men it increases them in women. Thus in a therapeutic context OXT may potentially produce different effects on anxiety disorders in men and women.

Enhanced conflict-driven cognitive control by emotional arousal, not by valence.

Emotion is widely agreed to have two dimensions, valence and arousal. Few studies have explored the effect of emotion on conflict adaptation by considering both of these, which could have dissociate influence. The present study aimed to fill the gap as to whether emotional valence and arousal would exert dissociable influence on conflict adaptation. In the experiments, we included positive, neutral, and negative conditions, with comparable arousal between positive and negative conditions. Both positive and negative conditions have higher arousal than neutral ones. In Experiment 1, by using a two-colour-word Flanker task, we found that conflict adaptation was enhanced in both positive and negative contexts compared to a neutral context. Furthermore, this effect still existed when controlling stimulus-response repetitions in Experiment 2, which used a four-colour-word Flanker task. The findings suggest emotional arousal enhances conflict adaptation, regardless of emotional valence. Thus, future studies should consider emotional arousal when studying the effect of emotion on conflict adaptation. Moreover, the unique role of the emotional context in conflict-driven cognitive control is emphasised.