Intrinsic functional connectivity in families genetically enriched for social anxiety disorder – an endophenotype study

Abstract

Background Social anxiety disorder (SAD) is a serious psychiatric condition with a high prevalence, and a typical onset during childhood/adolescence. The condition runs in families, but it is largely unknown which neurobiological characteristics transfer this genetic vulnerability (‘endophenotypes’). Using data from the Leiden Family Lab study on SAD, including two generations of families genetically enriched for SAD, we investigated whether social anxiety (SA) co-segregated with changes in intrinsic functional connectivity (iFC), and examined heritability. Methods Functional MRI data were acquired during resting-state in 109 individuals (56 males; mean age: 31·5, range 9·2-61·5 years). FSL's tool MELODIC was used to perform independent component analysis. Six networks of interest (default mode, dorsal attention, executive control, frontoparietal, limbic and salience) were identified at the group-level and used to generate subject-specific spatial maps. Voxel-wise regression models, with SA-level as predictor and voxel-wise iFC as candidate endophenotypes, were performed to investigate the association with SA, within masks of the networks of interest. Subsequently, heritability was estimated. Findings SA co-segregated with iFC within the dorsal attention network (positive association in left middle frontal gyrus and right postcentral gyrus) and frontoparietal network (positive association within left middle temporal gyrus) (cluster-forming-threshold z >2·3, cluster-corrected extent-threshold p <0·05). Furthermore, iFC of multiple voxels within these clusters was at least moderately heritable. Interpretation These findings provide initial evidence for increased iFC as candidate endophenotype of SAD, particularly within networks involved in attention. These changes might underlie attentional biases commonly present in SAD. Funding Leiden University Research Profile ‘Health, Prevention and the Human Lifecycle’.

Large-scale brain functional network abnormalities in social anxiety disorder

“…Hence, characterizing intra- and inter-network functional network connectivity (FNC) using ICA is a powerful tool to probe macroscale functional integration/dissociation in the normal and abnormal brain (Cai et al, 2021 ; Fox & Raichle, 2007 ; Houck et al, 2017 ; Huang et al, 2018 ). However, to the best of our knowledge, only three studies have used ICA and rs-fMRI in SAD; one investigated the intrinsic FNC as candidate endophenotype in families genetically enriched for SAD, in which most (22/39) subjects were diagnosed with subclinical SAD, and had psychiatric comorbidity (Bas-Hoogendam, van Steenbergen, Cohen Kadosh, Westenberg, & van der Wee, 2021 ); the other two studies had relatively small sample size (18 and 20 SAD patients) (Geiger et al, 2016 ; Liao et al, 2010 ).…”

“…Lastly, we used machine learning to investigate the potential diagnostic efficacy of those FNC signatures. We hypothesized that: (i) SAD patients, compared with healthy controls (HC), would show FNC impairments mainly in default mode network (DMN), frontal parietal network (FPN), salience network (SN) and subcortical network (SCN), previously shown to be abnormal in SAD (Bas-Hoogendam et al, 2021 ; Geiger et al, 2016 ; Liao et al, 2010 ; Mizzi et al, 2022 ; Xu et al, 2019 ; Yang et al, 2019 ); (ii) altered FNC would be related to clinical features (e.g. symptom severity); and (iii) intrinsic FNC markers would have good sensitivity and specificity for SAD diagnosis.…”