Brain functional connectivity correlates of response in the 7.5% CO2 inhalational model of generalized anxiety disorder: a pilot study

Abstract

The 7.5% CO2 inhalational model ( CO2 challenge) can be used to explore potential treatments for generalized anxiety disorder. However, it remains unknown how inter-individual variability in the functional architecture of negative affective valence systems might relate to the anxiogenic response to CO2 challenge. In this pilot study, we explored how connectivity in systems associated with processing potential threat (\"anxiety\") correlated with behavioural measures of anxiety following prolonged CO2 inhalation.\n\nThe negative affective valence system was identified using a passive emotional face perception task. Spherical regions of interest were created from peak voxels of significant brain activation when 100 young adult participants viewed emotional faces compared with black and white concentric circles during a functional MRI scan. Using these regions of interest, generalized psychophysiological interaction (gPPI) analysis was undertaken to explore task-evoked functional connectivity in a separate group of 13 healthy volunteers. Within 7 days of the scan, these participants underwent CO2 challenge and results from the gPPI analysis were correlated with CO2 outcome measures.\n\nExposure to CO2 challenge significantly increased subjective anxiety, negative affect, systolic blood pressure and heart rate. Functional connectivity between the ventromedial prefrontal cortex and right amygdala was positively correlated with heart rate. Increased connectivity between the vmPFC and the right amygdala, and decreased connectivity between the midcingulate cortex (MCC) and the left amygdala, correlated with subjective anxiety during CO2 challenge.\n\nResponse to CO2 challenge was related to task-evoked functional connectivity between regions known to be important in processing potential threat. Further studies are required to assess whether this translates into clinical populations. Measures of functional connectivity within emotional processing networks could be potential biomarkers to enable stratification of healthy volunteers, and to examine correlates of response, in trials using experimental medicine models.