The hypothalamic peptide oxytocin (OT) is crucial in social adaptation and used to treat emotional and social deficits. Here, we conducted a systematic, quantitative meta-analysis of functional-MRI studies intranasally administering OT (IN-OT) to uncover neural substrates underlying the IN-OT effects and to elucidate differential IN-OT effects between healthy and clinical populations. Meta-analyses were conducted on 66 IN-OT fMRI studies, stratified by psychopathology, valence and sex. IN-OT increased bilateral amygdala, caudate head, and superior temporal activity in healthy individuals and increased dorsal anterior cingulate activity in patients. Moreover, IN-OT decreased amygdala activity in both patients and healthy individuals but did so to a greater degree in patients than healthy individuals. The OT-increased amygdala activity was only found on the negative social and affective processes, whereas the OT-decreased amygdala activity was mainly contributed by contrasts on negative-valenced processes. IN-OT increased parahippocampal activity and decreased amygdala activity during negative socio-affective processing. During positive socio-affective processes, IN-OT increased caudate head activity. This study indicates convergent neural substrates and the underlying neuropsychological mechanisms for IN-OT effects on social and affective processes. The common and different effects of IN-OT on patients and healthy individuals and the modulation of OT effects by valence have critical implications.

Humans update their beliefs upon feedback and, accordingly, modify their behaviors to adapt to the complex, changing social environment. However, people tend to incorporate desirable (better than expected) feedback into their beliefs but to discount undesirable (worse than expected) feedback. Such optimistic updating has evolved as an advantageous mechanism for social adaptation. Here, we examine the role of oxytocin (OT)―an evolutionary ancient neuropeptide pivotal for social adaptation―in belief updating upon desirable and undesirable feedback in three studies (n = 320). Using a double-blind, placebo-controlled between-subjects design, we show that intranasally administered OT (IN-OT) augments optimistic belief updating by facilitating updates of desirable feedback but impairing updates of undesirable feedback. The IN-OT–induced impairment in belief updating upon undesirable feedback is more salient in individuals with high, rather than with low, depression or anxiety traits. IN-OT selectively enhances learning rate (the strength of association between estimation error and subsequent update) of desirable feedback. IN-OT also increases participants’ confidence in their estimates after receiving desirable but not undesirable feedback, and the OT effect on confidence updating upon desirable feedback mediates the effect of IN-OT on optimistic belief updating. Our findings reveal distinct functional roles of OT in updating the first-order estimation and second-order confidence judgment in response to desirable and undesirable feedback, suggesting a molecular substrate for optimistic belief updating. Significance People tend to incorporate desirable feedback into their beliefs but discount undesirable ones. Such optimistic updating has evolved as an advantageous mechanism for social adaptation and physical/mental health. Here, in three independent studies, we show that intranasally administered oxytocin (OT), an evolutionary ancient neuropeptide pivotal to social adaptation, augments optimistic belief updating by increasing updates and learning of desirable feedback but impairing updates of undesirable feedback. Moreover, the OT-impaired updating of undesirable feedback is more salient in individuals with high, rather than with low, depression or anxiety traits. OT also increases second-order confidence judgment after desirable feedback. These findings reveal a molecular substrate underlying the formation of optimistic beliefs about the future.

Significance: The World Health Organization defines health as a state of physical, mental, and social well-being. Although placebo treatment has been widely shown to improve physical and mental well-being, it remains unknown whether placebo treatment facilitates social well-being. Here, we provide evidence that placebo treatment facilitates social approach by increasing trust in others and preference for being physically closer to others. The social placebo effects (SPEs) resemble the effect of intranasal administration of oxytocin, an important neuropeptide for social cognition, on social trust and approach behavior, but the SPE is more sensitive to motivational state. Our findings extend the understanding of placebo effects on improving physical, mental, and social well-being and suggest clinical potentials in the treatment of social dysfunction.

Decision-making in uncertain environments can lead to varied outcomes, and how we process those outcomes may depend on our emotional state. Understanding how individuals interpret the sources of uncertainty is crucial for understanding adaptive behavior and mental well-being. Uncertainty can be broadly categorized into two components: volatility and stochasticity. Volatility describes how quickly conditions change. Stochasticity, on the other hand, refers to outcome randomness. We investigated how anxiety and apathy influenced people's perceptions of uncertainty, and how uncertainty perception shaped explore-exploit decisions. Participants (N = 1001, non-clinical sample) completed a restless three-armed bandit task that was analyzed using both latent state and process models. Anxious individuals perceived uncertainty as resulting more from volatility, leading to increased exploration and learning rates, especially after reward omission. Conversely, apathetic individuals viewed uncertainty as more stochastic, resulting in decreased exploration and learning rates. The perceived volatility-to-stochasticity ratio mediated the anxiety-exploration relationship post-adverse outcomes. Dimensionality reduction showed exploration and uncertainty estimation to be distinct but related latent factors shaping a manifold of adaptive behavior that is modulated by anxiety and apathy. These findings reveal distinct computational mechanisms for how anxiety and apathy influence decision-making, providing a framework for understanding cognitive and affective processes in neuropsychiatric disorders.