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. As 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 functional magnetic resonance imaging 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: Nonsignificant 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 were 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.

A cross-modal component of alexithymia and its relationship with performance in a social cognition task battery.

BACKGROUND: The personality trait alexithymia describes an altered emotional awareness that is associated with a range of social impairments and constitutes a transdiagnostic risk factor for various psychopathologies. Despite the characteristic interoceptive deficits in alexithymia, it is predominantly assessed via self-reports. This can result in unreliable measurements and arguably contributes to the prevailing uncertainty regarding its components, including constricted imaginal processes and emotional reactivity. METHODS: The current study employed an interview and two validated questionnaires to derive a shared component of multi-modally assessed alexithymia in a German non-clinical sample (n = 78) via prinicipal component analysis. This component was used as a predictor for performance in four behavioural social cognition tasks. The relative importance of this predictor against related variables was assessed via dominance analysis. RESULTS: The identified component reflected cognitive alexithymia. Higher cognitive alexithymia scores were associated with less affective distress in an ostracizing task. Dominance analysis revealed the dominance of competing autism traits relative to cognitive alexithymia and competing predictors empathy, depression, and anxiety, in predicting affective distress. LIMITATIONS: Emotional reactivity was only assessed via self-report and no implicit measures of alexithymia were employed. Due to the low reliability of the self-report measure, no measure of emotional reactivity could be included in the principal component analysis. CONCLUSIONS: Our results provide compelling evidence that cognitive interoceptive deficits are at the core of alexithymia across assessment modalities. Behavioural data suggest that these deficits result in diminished emotional sensitivity to high-pressure social situations, which may cause a lack of behavioural adaptation.

Medication-Enhanced Psychotherapy for Posttraumatic Stress Disorder: Recent Findings on Oxytocin's Involvement in the Neurobiology and Treatment of Posttraumatic Stress Disorder.

Background: Traumatic experiences may result in Posttraumatic Stress Disorder (PTSD), which is characterized as an exaggerated fear response that cannot be extinguished over time or in safe environments. What are beneficial psychotherapeutic treatment options for PTSD patients? Can oxytocin (OXT), which is involved in the stress response, and safety learning, ameliorate PTSD symptomatology and enhance psychotherapeutic effects? Here, we will review recent studies regarding OXT's potential to enhance psychotherapeutic therapies for PTSD treatment. Method: We conducted a literature review on the neurobiological underpinnings of PTSD especially focusing on OXT's involvement in the biology and memory formation of PTSD. Furthermore, we researched successful psychotherapeutic treatments for PTSD patients and discuss how OXT may facilitate observed psychotherapeutic effects. Results: For a relevant proportion of PTSD patients, existing psychotherapies are not beneficial. OXT may be a promising candidate to enhance psychotherapeutic effects, because it dampens responses to stressful events and allows for a faster recovery after stress. On a neural basis, OXT modulates processes that are involved in stress, arousal and memory. OXT effectively counteracts memory impairments caused by stress and facilitates social support seeking which is a key resilience factor for PTSD and which is beneficial in psychotherapeutic settings. Conclusion: OXT has many characteristics that are promising to positively influence psychotherapy for PTSD patients. It potentially reduces intrusions, but preserves memory of the event itself. Introducing OXT into psychotherapeutic settings may result in better treatment outcomes for PTSD patients. Future research should directly investigate OXT's effects on PTSD, especially in psychotherapeutic settings.

Neural mechanisms of affective matching across faces and scenes.

The emotional matching paradigm, introduced by Hariri and colleagues in 2000, is a widely used neuroimaging experiment that reliably activates the amygdala. In the classic version of the experiment faces with negative emotional expression and scenes depicting distressing events are compared with geometric shapes instead of neutral stimuli of the same category (i.e. faces or scenes). This makes it difficult to clearly attribute amygdala activation to the emotional valence and not to the social content. To improve this paradigm, we conducted a functional magnetic resonance imaging study in which emotionally neutral and, additionally, positive stimuli within each stimulus category (i.e. faces, social and non-social scenes) were included. These categories enabled us to differentiate the exact nature of observed effects in the amygdala. First, the main findings of the original paradigm were replicated. Second, we observed amygdala activation when comparing negative to neutral stimuli of the same category. However, for negative faces, the amygdala response habituated rapidly. Third, positive stimuli were associated with widespread activation including the insula and the caudate. This validated adaption study enables more precise statements on the neural activation underlying emotional processing. These advances may benefit future studies on identifying selective impairments in emotional and social stimulus processing.

Amygdala and oxytocin functioning as keys to understanding and treating autism: Commentary on an RDoC based approach.

The recent review by Hennessey, Andari and Rainnie (2018) utilizes the proposed Research Domain Criteria (RDoC) to classify amygdala functions and relate them to autism symptomatology. This approach has the potential to challenge the overarching autism diagnosis by furthering our knowledge of the mechanisms giving rise to autism psychopathology and generate novel treatment options. The purpose of this commentary is to provide additional information on a number of points raised in the review. Thus, (1) we discuss the issue of amygdala and brain overgrowth in children with autism and relate it to developmental oxytocin changes, (2) examine potential mechanisms that underlie amygdala overgrowth and dysfunction of the oxytocin system, (3) zoom in on the sexually dimorphic characteristics of the amygdala and potential parallels with the oxytocin system and (4) discuss how the interplay of oxytocin and vasopressin may explain the partially inconsistent findings of their effects on amygdala functioning.

Clinical trial of modulatory effects of oxytocin treatment on higher-order social cognition in autism spectrum disorder: a randomized, placebo-controlled, double-blind and crossover trial.

BACKGROUND: Autism spectrum disorders are neurodevelopmental conditions with severe impairments in social communication and interaction. Pioneering research suggests that oxytocin can improve motivation, cognition and attention to social cues in patients with autism spectrum disorder. The aim of this clinical trial is to characterize basic mechanisms of action of acute oxytocin treatment on neural levels and to relate these to changes in different levels of socio-affective and -cognitive functioning. METHODS: This clinical study is a randomized, double-blind, cross-over, placebo-controlled, multicenter functional magnetic resonance imaging study with two arms. A sample of 102 male autism spectrum disorder patients, diagnosed with Infantile Autistic Disorder (F84.0 according to ICD-10), Asperger Syndrome (F84.5 according to ICD-10), or Atypical Autism (F84.1 according to ICD-10) will be recruited and will receive oxytocin and placebo nasal spray on two different days. Autism spectrum disorder patients will be randomized to determine who receives oxytocin on the first and who on the second visit. Healthy control participants will be recruited and case-control matched to the autism spectrum disorder patients. The primary outcome will be neural network activity, measured with functional magnetic resonance imaging while participants perform socio-affective and -cognitive tasks. Behavioral markers such as theory of mind accuracy ratings and response times will be assessed as secondary outcomes in addition to physiological measures such as skin conductance. Trait measures for alexithymia, interpersonal reactivity, and social anxiety will also be evaluated. Additionally, we will analyze the effect of oxytocin receptor gene variants and how these potentially influence the primary and secondary outcome measures. Functional magnetic resonance imaging assessments will take place at two time points which will be scheduled at least two weeks apart to ensure a sufficient wash-out time after oxytocin treatment. The study has been approved by an ethical review board and the competent authority. DISCUSSION: Revealing the mechanisms of acute oxytocin administration, especially on the socio-affective and -cognitive domains at hand, will be a further step towards novel therapeutic interventions regarding autism. TRIAL REGISTRATION: German Clinical Trial Register DRKS00010053 . The trial was registered on the 8th of April 2016.

Oxytocin Facilitates Pavlovian Fear Learning in Males.

In human evolution, social group living and Pavlovian fear conditioning have evolved as adaptive mechanisms promoting survival and reproductive success. The evolutionarily conserved hypothalamic peptide oxytocin is a key modulator of human sociality, but its effects on fear conditioning are still elusive. In the present randomized controlled study involving 97 healthy male subjects, we therefore employed functional magnetic resonance imaging and simultaneous skin conductance response (SCR) measures to characterize the modulatory influence of intranasal oxytocin (24 IU) on Pavlovian fear conditioning. We found that the peptide strengthened conditioning on both the behavioral and neural levels. Specifically, subjects exhibited faster task-related responses and enhanced SCRs to fear-associated stimuli in the late phase of conditioning, which was paralleled by heightened activity in cingulate cortex subregions in the absence of changes in amygdala function. This speaks against amygdalocentric views of oxytocin having pure anxiolytic-like effects. Instead, it suggests that the peptide enables extremely rapid and flexible adaptation to fear signals in social contexts, which may confer clear evolutionary advantages but could also elevate vulnerability for the pathological sequelae of interpersonal trauma.

The influence of oxytocin on volitional and emotional ambivalence.

Moral decisions and social relationships are often characterized by strong feelings of ambivalence which can be a catalyst for emotional distress and several health-related problems. The anterior cingulate cortex (ACC) has been identified as a key brain region in monitoring conflicting information, but the neurobiological substrates of ambivalence processing are still widely unknown. We have conducted two randomized, double-blind, placebo-controlled, functional magnetic resonance imaging experiments involving 70 healthy male volunteers to investigate the effects of the neuropeptide oxytocin (OXT) on neural and behavioral correlates of ambivalence. We chose moral decision-making and the imagery of partner infidelity as examples to probe volitional and emotional ambivalence. In both experiments, intranasal OXT diminished neural responses in the ACC to ambivalence. Under OXT, moral dilemma vignettes also elicited a reduced activation in the orbitofrontal cortex, and the imagery of partner infidelity was rated as less arousing. Interestingly, the OXT-induced differential activation in the ACC predicted the magnitude of arousal reduction. Taken together, our findings reveal an unprecedented role of OXT in causing a domain-general decrease of neural responses to ambivalence. By alleviating emotional distress, OXT may qualify as a treatment option for psychiatric disorders with heightened ambivalence sensitivity such as schizophrenia or obsessive-compulsive disorder.

Oxytocin facilitates the extinction of conditioned fear in humans.

BACKGROUND: Current neurocircuitry models of anxiety disorders posit a lack of inhibitory tone in the amygdala during acquisition of Pavlovian fear responses and deficient encoding of extinction responses in amygdala-medial prefrontal cortex circuits. Competition between these two responses often results in a return of fear, limiting control over anxiety. However, one hypothesis holds that a pharmacologic strategy aimed at reducing amygdala activity while simultaneously augmenting medial prefrontal cortex function could facilitate the extinction of conditioned fear. METHODS: Key among the endogenous inhibitors of amygdala activity in response to social fear signals is the hypothalamic peptide oxytocin. To address the question whether oxytocin can strengthen Pavlovian extinction beyond its role in controlling social fear, we conducted a functional magnetic resonance imaging experiment with 62 healthy male participants in a randomized, double-blind, parallel-group, placebo-controlled design. Specifically, subjects were exposed to a Pavlovian fear conditioning paradigm before receiving an intranasal dose (24 IU) of synthetic oxytocin or placebo. RESULTS: Oxytocin, when administered intranasally after Pavlovian fear conditioning, was found to increase electrodermal responses and prefrontal cortex signals to conditioned fear in the early phase of extinction and to enhance the decline of skin conductance responses in the late phase of extinction. Oxytocin also evoked an unspecific inhibition of amygdalar responses in both phases. CONCLUSIONS: Collectively, our findings identify oxytocin as a differentially acting modulator of neural hubs involved in Pavlovian extinction. This specific profile of oxytocin action may open up new avenues for enhancing extinction-based therapies for anxiety disorders.

Oxytocin facilitates social approach behavior in women.

In challenging environments including both numerous threats and scarce resources, the survival of an organism depends on its ability to quickly escape from dangers and to seize opportunities to gain rewards. The phylogenetically ancient neurohormonal oxytocin (OXT) system has been shown to influence both approach and avoidance (AA) behavior in men, but evidence for comparable effects in women is still lacking. We thus conducted a series of pharmacological behavioral experiments in a randomized double-blind study involving 76 healthy heterosexual women treated with either OXT (24 IU) or placebo intranasally. In Experiment 1, we tested how OXT influenced the social distance subjects maintained between themselves and either a female or male experimenter. In Experiment 2, we applied a reaction time based AA task. In Experiment 3 we investigated effects on peri-personal space by measuring the lateral attentional bias in a line bisection task. We found that OXT specifically decreased the distance maintained between subjects and the male but not the female experimenter and also accelerated approach toward pleasant social stimuli in the AA task. However, OXT did not influence the size of peri-personal space, suggesting that it does not alter perception of personal space per se, but rather that a social element is necessary for OXT's effects on AA behavior to become evident. Taken together, our results point to an evolutionarily adaptive mechanism by which OXT in women selectively promotes approach behavior in positive social contexts.