Resting-state functional connectivity in anxiety disorders: a multicenter fMRI study

Abstract

Anxiety disorders (AD) are associated with altered connectivity in large-scale intrinsic brain networks. It remains uncertain how much these signatures overlap across different phenotypes due to a lack of well-powered cross-disorder comparisons. We used resting-state functional magnetic resonance imaging (rsfMRI) to investigate differences in functional connectivity (FC) in a cross-disorder 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 min 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. Dimensional analyses yielded no significant results. The results highlighting categorical differences between ADs at a systems neuroscience level are discussed within the context of personalized neuroscience-informed treatments. PROTECT-AD's registration at NIMH Protocol Registration System: 01EE1402A and German Register of Clinical Studies: DRKS00008743. SpiderVR's registration at ClinicalTrials.gov: NCT03208400.

Fig. 1. Participant flowchart.

¹for pilot patients (n = 31) in PROTECT-AD inclusion criteria were different with either SIGH-A or CGI being above cut-off. For details see Supplemental Material.

Fig. 2. Differences in connectivity as a function of primary diagnosis.

a Glass brain with increased connectivity in red and decreased connectivity in blue compared to HC and connectome rings with increased connectivity in red and decreased connectivity in blue compared to HC. b Functional connectivity values. FISHERS-Z transformed correlations as connectivity measures. * for significant connection-level FDR-corrected differences compared to healthy controls. (r) = right hemisphere; (l) = left hemisphere; p INS posterior insula; THAL Thalamus; pre ACC pregenual anterior cingulate cortex; AMY amygdala; HIP hippocampus; PAG periaqueductal gray; dmPFC dorsolateral medial prefrontal cortex; sub ACC subgenual anterior cingulate cortex; OFC orbitofrontal cortex.