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 .