Oxytocin Attenuates Amygdala Reactivity to Fear in Generalized Social Anxiety Disorder

Abstract

Patients with generalized social anxiety disorder (GSAD) exhibit heightened activation of the amygdala in response to social cues conveying threat (eg, fearful/angry faces). The neuropeptide oxytocin (OXT) decreases anxiety and stress, facilitates social encounters, and attenuates amygdala reactivity to threatening faces in healthy subjects. The goal of this study was to examine the effects of OXT on fear-related amygdala reactivity in GSAD and matched healthy control (CON) subjects. In a functional magnetic resonance imaging study utilizing a double-blind placebo-controlled within-subjects design, we measured amygdala activation to an emotional face matching task of fearful, angry, and happy faces following acute intranasal administration of OXT (24 IU or 40.32 μg) and placebo in 18 GSAD and 18 CON subjects. 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 (ie, normalization). These findings suggest that OXT has a specific effect on fear-related amygdala activity, particularly when the amygdala is hyperactive, such as in GSAD, thereby providing a brain-based mechanism of the impact of OXT in modulating the exaggerated processing of social signals of threat in patients with pathological anxiety.

Intranasal Oxytocin Administration Dampens Amygdala Reactivity towards Emotional Faces in Male and Female PTSD Patients

“…Notably, OT administration dampened left amygdala reactivity toward all emotional faces in PTSD patients, independent of stimulus valence and participants' sex. This finding corresponds with previous intranasal OT administration studies in healthy individuals (Kirsch et al, 2005) and psychiatric patients with GSAD and BPD (Bertsch et al, 2013;Labuschagne et al, 2010). Our findings extend accumulating evidence that OT may have anxiolytic properties, possibly by inhibiting fear-associated output of the central amygdala to the brainstem and hypothalamus (Huber et al, 2005).…”

“…An anatomical scan was first acquired, followed by an emotional face-matching task, which began on average 44.68 (±3.74) minutes after intranasal spray application. This is in line with previous intranasal fMRI studies (Kirsch et al, 2005;Labuschagne et al, 2010), and coincides with the pharmacodynamic peak response of intranasal OT in healthy individuals (Paloyelis et al, 2014).…”

“…Notably, we found opposite OT administration effects on amygdala reactivity in PTSD patients versus trauma-exposed controls (ie, dampening versus enhancing effects). This fits with the hypothesis that OT administration effects may be especially beneficial in those who lack proficiency in fear regulation (Labuschagne et al, 2010) or social functioning (Olff et al, 2013;Weisman and Feldman, 2013). We included highly trauma-exposed, but apparently resilient control participants, who did not have any current psychopathology or history of PTSD and MDD, despite having experienced numerous traumatic events in their lives.…”

“…Behaviorally, OT administration resulted in decreased subjective anxiety during a public speaking stressor in healthy individuals (de Oliveira et al, 2012) and increased (recall of) extinction learning in both rodents (Zoicas et al, 2014) and healthy males (Acheson et al, 2013). In addition, functional MRI (fMRI) studies have shown that OT administration dampened amygdala reactivity toward emotional stimuli in healthy males (Kirsch et al, 2005), males with generalized social anxiety disorder (GSAD; Labuschagne et al, 2010) and females with borderline personality disorder (BPD; Bertsch et al, 2013), although findings for females have been mixed (Domes et al, 2010). Furthermore, OT administration resulted in increased resting-state functional connectivity between the amygdala and vmPFC in healthy males (Sripada et al, 2013) and in patients with GSAD (Dodhia et al, 2014), possibly enhancing top-down control over the fear response.…”

“…For both PTSD patients and trauma-exposed controls, we hypothesized that OT would dampen amygdala reactivity. We expected that OT administration would have greater effects in PTSD patients than in trauma-exposed controls, as OT administration effects may be more beneficial in those who have something to gain regarding fear regulation (Labuschagne et al, 2010) or social functioning (Olff et al, 2013).…”