Resting-state Functional Connectivity in Anxiety Disorders: A Multicenter fMRI Study

Abstract

Abstract Anxiety disorders (AD) are associated with altered connectivity in large-scale intrinsic brain networks. The extent to which these signatures are shared across different phenotypes remains unclear, as well-powered transdiagnostic comparisons are still largely missing. We used resting-state functional magnetic resonance imaging (rsfMRI) to investigate differences in functional connectivity (FC) in a transdiagnostic sample of AD patients and healthy controls (HC). Before treatment, 439 patients from two German multicenter clinical trials at eight different sites fulfilling a primary diagnosis of panic disorder and/or agoraphobia (PD/AG, n=154), social anxiety disorder (SAD, n=95), or specific phobia (SP, n=190) and 105 HC underwent an 8-minute rsfMRI assessment. We performed categorical and dimensional regions of interest (ROI)-to-ROI analyses focusing on connectivity between regions of the defensive system and prefrontal regulation areas. AD patients showed increased connectivity between the insula and the thalamus compared to controls. This was mainly driven by PD/AG patients who showed increased (insula/hippocampus/amygdala - thalamus) and decreased (dorsomedial prefrontal cortex/periaqueductal gray - anterior cingulate cortex) positive connectivity between subcortical and cortical areas. In contrast, SAD patients showed decreased negative connectivity exclusively in cortical areas (insula - orbitofrontal cortex), whereas no differences were found in SP patients. State anxiety associated with the scanner environment did not explain the FC between these regions. Only PD/AG patients showed pronounced connectivity changes along a widespread subcortical-cortical network, including the midbrain. The relative specificity of findings contradicts a strong overarching factor and thus challenges the predominance of shared transdiagnostic dysfunctions in intrinsic connectivity. Trial Registration: PROTECT-AD’s registration at NIMH Protocol Registration System: 01EE1402A and German Register of Clinical Studies: DRKS00008743. SpiderVR’s registration at ClinicalTrials.gov: NCT03208400.