Reduced vmPFC-insula functional connectivity in generalized anxiety disorder: a Bayesian confirmation study

Abstract

Differences in the correlated activity of networked brain regions have been reported in individuals with generalized anxiety disorder (GAD) but an overreliance on null-hypothesis significance testing (NHST) limits the identification of disorder-relevant relationships. In this preregistered study, we applied both a Bayesian statistical framework and NHST to the analysis of resting-state fMRI scans from females with GAD and matched healthy comparison females. Eleven a-priori hypotheses about functional connectivity (FC) were evaluated using Bayesian (multilevel model) and frequentist (t-test) inference. Reduced FC between the ventromedial prefrontal cortex (vmPFC) and the posterior-mid insula (PMI) was confirmed by both statistical approaches and was associated with anxiety sensitivity. FC between the vmPFC-anterior insula, the amygdala-PMI, and the amygdala-dorsolateral prefrontal cortex (dlPFC) region pairs did not survive multiple comparison correction using the frequentist approach. However, the Bayesian model provided evidence for these region pairs having decreased FC in the GAD group. Leveraging Bayesian modeling, we demonstrate decreased FC of the vmPFC, insula, amygdala, and dlPFC in females with GAD. Exploiting the Bayesian framework revealed FC abnormalities between region pairs excluded by the frequentist analysis and other previously undescribed regions in GAD, demonstrating the value of applying this approach to resting-state FC data in clinical investigations.

Figure 1

Posterior density distributions of the difference in region-pair effect magnitudes between the two study groups as revealed by the Bayesian multilevel analysis. The value at the right end of each curve indicates the posterior probability P₊ for the group difference of the effect being greater than 0 (indicated by the vertical green line). The posterior probability P₊ is additionally color-coded in the plane under each posterior density. The vertical black line in each distribution represents the mean effect difference between the two groups for each region pair. Bold font indicates region pairs included in the NHST analysis, with single daggers (^†) indicating significance in the NHST analysis before, and two daggers (^††) after, Bonferroni-correction for multiple comparisons. vmPFC ventromedial prefrontal cortex, PMI posterior-mid insula, dlPFC dorsolateral prefrontal cortex, dACC dorsal anterior cingulate cortex, dmPFC dorsomedial prefrontal cortex, TP temporal pole, PCC posterior cingulate cortex, AI anterior insula.

Figure 2

Bayesian multilevel analysis reveals the vmPFC and PMI to have strong evidence for a difference in region effects between the study groups. Posterior density distributions of the difference in region effects in the HC minus GAD contrast of the Bayesian multilevel model. The value at the right end of each curve indicates the posterior probability P₊ for the group difference of the effect being greater than 0 (indicated by the vertical green line). The posterior probability P₊ is additionally color-coded in the plane under each posterior density. The vertical black line in each distribution represents the mean difference in region effects (as Fishers’s z-score) between the two groups for each region in the model. vmPFC ventromedial prefrontal cortex, PMI posterior-mid insula, dlPFC dorsolateral prefrontal cortex, dACC dorsal anterior cingulate cortex, dmPFC dorsomedial prefrontal cortex, TP temporal pole, PCC posterior cingulate cortex, AI anterior insula.

Figure 3

Differences in resting-state FC between GAD and HC revealed by the frequentist analysis. (A) The solid line indicates a significantly decreased FC between the PMI and vmPFC in GAD participants after multiple comparison correction using the Bonferroni method. Dotted lines indicate differences in FC between the PMI and amygdala, AI and vmPFC, and dlPFC and amygdala that did not remain statistically significant after Bonferroni correction. Each brain region, indicated by different colors, reflects the selected labels drawn from the Brainnetome atlas. (B) Raincloud plots of Fisher r-to-z transformed correlation coefficients between the PMI and the vmPFC BOLD-signal time series. FC functional connectivity, GAD generalized anxiety disorder, HC healthy comparison, vmPFC ventromedial prefrontal cortex, PMI posterior-mid insula, AI anterior insula, dlPFC dorsolateral prefrontal cortex.