The International Journal of Neuropsychopharmacology

Research Article

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

Izelle Labuschagnea1 c2*, K. Luan Phana2a3, Amanda Wooda4, Mike Angstadta2, Phyllis Chuaa1, Markus Heinrichsa5, Julie C. Stouta1 and Pradeep J. Nathana1a6a7 c1*

a1 School of Psychology and Psychiatry, Monash University, Melbourne, Australia

a2 Department of Psychiatry, University of Michigan, Ann Arbor, MI, USA

a3 Mental Health Service, VA Ann Arbor Healthcare System, Ann Arbor, MI, USA

a4 Department of Critical Care and Neurosciences, Murdoch Childrens Research Institute, The Royal Children's Hospital, Melbourne, Australia

a5 Department of Psychology, University of Freiburg, Germany

a6 Brain Mapping Unit, Department of Psychiatry, University of Cambridge, UK

a7 Experimental Medicine, Clinical Unit Cambridge, GlaxoSmithKline Pharmaceuticals, UK


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.

(Received January 30 2011)

(Reviewed March 23 2011)

(Revised July 28 2011)

(Accepted September 10 2011)

(Online publication October 14 2011)


c1 Address for correspondence: Professor P. J. Nathan, Brain Mapping Unit, Department of Psychiatry, GSK Clinical Unit Cambridge, Addenbrooke's Hospital, Hills Road, Cambridge CB2 2GG, UK. Tel.: +44 1223 296081 Fax: +44 1223 296108 Email: [P.J.N.]

c2 Email: [I.L.]


* These authors contributed equally to this work.