Social anxiety disorder (SAD) is a prevalent and disabling condition whose neurobiology remains poorly understood. The goal of this study is to identify a novel endophenotype associated with SAD and a biomarker of its response to treatment that could be used for further research in animal models and humans to improve understanding of the causes of SAD and to advance its treatment. Fear of eye gaze is a core symptom of SAD that appears related to evolutionarily-conserved submissive behaviors, such as avoidance of direct gaze and vigilance for social threat. Threatening facial expressions (especially if implicitly processed), activate neural circuits in SAD involved with perceiving social visual cues, but eye gaze stimuli have been little studied. Also, gaze and facial expression stimuli have not yet been used to identify SAD treatment-related changes in neural activation. This study will assess neural circuitry activation in SAD, before and after treatment, using fMRI with two sets of stimuli: 1) a novel set of face photos that realistically simulate eye motion into direct or indirect gaze; and 2) emotional facial expression photos. We hypothesize that in SAD patients, processing of faces with direct eye gaze and processing of angry facial expressions will preferentially activate fear circuitry structures such as the amygdala and insula, associated frontal regions (rostral anterior cingulate and medial prefrontal cortex), and core areas of visual face processing (fusiform gyrus). We further hypothesize that activation of these regions will be correlated with severity of SAD in these patients, and that after treatment with serotonin reuptake inhibitor (SSRI) medication, these regional activations will normalize, and the extent of normalization will be correlated with the extent of symptomatic improvement. Twenty subjects with generalized SAD and 20 matched healthy comparison (HC) subjects will be assessed with fMRI for activation of neurocircuitry in response to direct vs. indirect gaze, and to implicit vs. explicit processing of angry and neutral facial expressions. Gaze avoidance during fMRI will be assessed using an eye tracking device and utilized as a covariate in fMRI analyses. Subjects will repeat the same procedures 12 weeks later, after SAD subjects have completed acute treatment with SSRI medication. If threat neurocircuitry activation is associated with direct eye gaze in SAD and decreased activation is associated with treatment response, this would support the response to dynamic direct gaze stimuli as an endophenotype suitable for further study in animal models and humans with SAD and other disorders. 7. Project Narrative Social anxiety disorder is a prevalent and disabling condition whose neurobiology remains poorly understood. The goal of this study is to identify a biological marker of this disorder and its response to treatment that could be used for further research in animal models and humans, and ultimately to improve the diagnosis and treatment of social anxiety disorder. ? ? ?
