Medial frontal hyperactivity to sad faces in generalized social anxiety disorder and modulation by oxytocin

Abstract

Generalized social anxiety disorder (GSAD) is associated with heightened limbic and prefrontal activation to negative social cues conveying threat (e.g. fearful faces), but less is known about brain response to negative non-threatening social stimuli. The neuropeptide oxytocin (Oxt) has been shown to attenuate (and normalize) fear-related brain activation and reactivity to emotionally negative cues. Here, we examined the effects of intranasal Oxt on cortical activation to non-threatening sad faces in patients with GSAD and matched controls (Con). In a double-blind placebo-controlled within-subjects design, the cortical activation to sad and happy (vs. neutral) faces was examined using functional magnetic resonance imaging following acute intranasal administration of 24 IU Oxt and placebo. Relative to the Con group, GSAD patients exhibited heightened activity to sad faces in the medial prefrontal cortex (mPFC/BA 10) extending into anterior cingulate cortex (ACC/BA 32). Oxt significantly reduced this heightened activation in the mPFC/ACC regions to levels similar to that of controls. These findings suggest that GSAD is associated with cortical hyperactivity to non-threatening negative but not positive social cues and that Oxt attenuates this exaggerated cortical activity. The modulation of cortical activity by Oxt highlights a broader mechanistic role of this neuropeptide in modulating socially negative cues in GSAD.

Neurophysiological effects of acute oxytocin administration: systematic review and meta-analysis of placebo-controlled imaging studies

“…Labuschagne and colleagues 28 used explicit and implicit processing tasks in men to show a main effect of OXT administration on the activation within the left MTG and bilateral STG when implicitly processing a range of emotional faces, although the direction of this effect was not reported. In a follow-up report, 29 they showed increased activation within the right STG after OXT administration while explicitly processing happy faces. Wittfoth-Schardt and colleagues 39 also showed that in men activation is attenuated in the bilateral MTG and left STG after OXT administration when implicitly processing the faces of an unfamiliar child versus a familiar child.…”

“…66-68 Eight of the 12 studies reporting whole brain findings found differential activation in the temporal lobe after OXT administration, most of which used faces as social stimuli 24,25,[29][30][31][32][33]39 (Table 3). In addition, another study found that connectivity to the temporal lobe from the amygdala was increased after OXT administration.…”

“…A similar increase in activation within the STG was reported in women administered OXT before auditory stimuli of crying infants in a study by Riem and colleagues. 33 It is important to note that all of these studies in women (except the study by Riem and colleagues 33 ) used explicit emotional processing, whereas the studies in men used tasks with implicit facial processing (except the study by Labuschagne and colleagues, 29 who also showed increased activation in the temporal lobes after OXT administration, contrary to other studies in men). Thus, task type and sex may play a large role in how OXT administration affects neur al activity in the temporal lobes.…”

“…All of the fMRI studies presented in this review have investigated some aspect of the limbic system. [23][24][25][26][27][28][29][30][31][32][33][35][36][37][38][39] Its role has been one of the focuses of neuroendocrine research, most notably research on OXT, and has mainly revolved around the role of the amygdala, which is explored in greater detail below. This systematic review explores the role of other areas in the limbic system in addition to the amygdala relative to OXT.…”

“…Most of the imaging studies involving men have shown that OXT administration attenuates activation in both of these regions during the processing of social stimuli. 23,29,31,36 Overall, the studies show that, at least in men, the involvement of the orbitofrontal cortex (OFC) and ACC are minimized after OXT administration. Furthermore, attenuated activity in the dorsolateral (dlPFC) and ventrolateral PFC (vlPFC) after OXT administration may indicate an attenuated need for emotion regulation and cognitive control.…”