A functional magnetic resonance imaging investigation of the effects of oxytocin on brain responses to social emotional cues in generalised social anxiety disorder

Abstract

Generalised social anxiety disorder (GSAD) is an anxiety disorder characterised by intense fear in social situations causing considerable distress and impaired ability to function in at least some parts of daily life. Individuals with GSAD exhibit heightened brain activation in response to social emotional cues conveying threat (e.g., fearful/angry faces) in brain areas critical for emotion processing including the amygdala. Very little is known about brain response to negative, but not ‘threatening’, cues which may involve a wider brain network including the cortex. Oxytocin (OXT) is a neuropeptide synthesised in the hypothalamus and exerts its physiological effects by binding to oxytocin receptors (OXT-R) found to limbic and cortical areas. In humans, OXT decreases anxiety and stress, facilitates social encounters, and attenuates brain reactivity (i.e., including the amygdala) to threatening cues in healthy controls. This thesis examined the effects of OXT on fear-related amygdala and non-threat related cortical reactivity to social cues in patients with GSAD and matched healthy control (CON) participants in two experimental studies. Eighteen GSAD and 18 CON individuals participated in the study. The study utilised a double-blind placebo-controlled within-subjects design, with two acute treatment conditions including intranasal OXT and placebo administrations. Functional magnetic resonance imaging (fMRI) was used to examine brain activation in response to processing social facial cues using an emotional face matching task (study 1) and emotional face recognition task (study 2) following OXT or placebo administration. In study 1, both the CON and GSAD groups activated bilateral amygdala to all emotional faces during placebo, with the GSAD group exhibiting hyperactivity specifically to fearful faces in bilateral amygdala compared with the CON group. OXT had no effect on amygdala activity to emotional faces in the CON group, but attenuated the heightened amygdala reactivity to fearful faces in the GSAD group, such that the hyperactivity observed during the placebo session was no longer evident following OXT (i.e., normalisation). In study 2, the GSAD group relative to the CON group, exhibited heightened activity to sad faces in the medial prefrontal cortex (MPFC), i.e., brodmann area (BA) 10, extending into anterior cingulate cortex (ACC), i.e., BA32, during placebo. Oxytocin suppressed the heightened activation in the MPFC/ACC regions in the GSAD group to levels similar to that of the CON group. The findings of this thesis suggest that OXT has specific effect on fear-related amygdala activity, and non-threat (i.e., sad) related cortical activity, particularly when these areas are hyperactive as observed in individuals with GSAD. The modulation by OXT was specific to negative threat and non-threat related social cues as no effects were observed on brain response to processing happy social cues. These findings provide a brain-based mechanism of the impact of OXT in modulating the exaggerated processing of negative social signals in individuals with pathological anxiety, thereby justifying future long-term treatment studies to investigate the effects of OXT on clinical symptoms of social anxiety.