Lower functional connectivity in vestibular-limbic networks in individuals with subclinical agoraphobia

Background: Agoraphobia was described in 1871 as a condition of fear-related alterations in spatial orientation and locomotor control triggered by places or situations that might cause a patient to panic and feel trapped. In contemporary nosology, however, this original concept of agoraphobia was split into two diagnostic entities, i.e., the modern anxiety disorder of agoraphobia, consisting solely of phobic/avoidant symptoms in public spaces, and the recently defined vestibular disorder of persistent postural perceptual dizziness (PPPD), characterized by dizziness, and unsteadiness exacerbated by visual motion stimuli. Previous neuroimaging studies found altered brain activity and connectivity in visual-vestibular networks of patients with PPPD vs. healthy controls. Neuroticism and introversion, which pre-dispose to both agoraphobia and PPPD, influenced brain responses to vestibular and visual motion stimuli in patients with PPPD. Similar neuroimaging studies have not been undertaken in patients with agoraphobia in its current definition. Given their shared history and pre-disposing factors, we sought to test the hypotheses that individuals with agoraphobic symptoms have alterations in visual-vestibular networks similar to those of patients with PPPD, and that these alterations are influenced by neuroticism and introversion. Methods: Drawing from the Human Connectome Project (HCP) database, we matched 52 participants with sub-clinical agoraphobia and 52 control subjects without agoraphobic symptoms on 19 demographic and psychological/psychiatric variables. We then employed a graph-theoretical framework to compare resting-state functional magnetic resonance images between groups and evaluated the interactive effects of neuroticism and introversion on the brain signatures of agoraphobia. Results: Individuals with subclinical agoraphobia had lower global clustering, efficiency and transitivity relative to controls. They also had lower connectivity metrics in two brain networks, one positioned to process incoming visual space-motion information, assess threat, and initiate/inhibit behavioral responses (visuospatial-emotional network) and one positioned to control and monitor locomotion (vestibular-navigational network). Introversion interacted with agoraphobic symptoms to lower the connectivity of the visuospatial-emotional network. This contrasted with previous findings describing neuroticism-associated higher connectivity in a narrower visual-spatial-frontal network in patients with PPPD. Conclusion: Functional connectivity was lower in two brain networks in subclinical agoraphobia as compared to healthy controls. These networks integrate visual vestibular and emotional response to guide movement in space.