Association between resting-state connectivity patterns in the defensive system network and treatment response in spider phobia-a replication approach

Abstract

Although highly effective on average, exposure-based treatments do not work equally well for all patients with anxiety disorders. The identification of pre-treatment response-predicting patient characteristics may enable patient stratification. Preliminary research highlights the relevance of inhibitory fronto-limbic networks as such. We aimed to identify pre-treatment neural signatures differing between exposure treatment responders and non-responders in spider phobia and to validate results through rigorous replication. Data of a bi-centric intervention study comprised clinical phenotyping and pre-treatment resting-state functional connectivity (rsFC) data of n = 79 patients with spider phobia (discovery sample) and n = 69 patients (replication sample). RsFC data analyses were accomplished using the Matlab-based CONN-toolbox with harmonized analyses protocols at both sites. Treatment response was defined by a reduction of >30% symptom severity from pre- to post-treatment (Spider Phobia Questionnaire Score, primary outcome). Secondary outcome was defined by a reduction of >50% in a Behavioral Avoidance Test (BAT). Mean within-session fear reduction functioned as a process measure for exposure. Compared to non-responders and pre-treatment, results in the discovery sample seemed to indicate that responders exhibited stronger negative connectivity between frontal and limbic structures and were characterized by heightened connectivity between the amygdala and ventral visual pathway regions. Patients exhibiting high within-session fear reduction showed stronger excitatory connectivity within the prefrontal cortex than patients with low within-session fear reduction. Whereas these results could be replicated by another team using the same data (cross-team replication), cross-site replication of the discovery sample findings in the independent replication sample was unsuccessful. Results seem to support negative fronto-limbic connectivity as promising ingredient to enhance response rates in specific phobia but lack sufficient replication. Further research is needed to obtain a valid basis for clinical decision-making and the development of individually tailored treatment options. Notably, future studies should regularly include replication approaches in their protocols.

Fig. 1. Differential functional connectivity in SPQ- and BAT-responders vs. non-responders and high vs. low WS-ext groups as identified by ROI-to-ROI and Seed-to-Voxel analyses in the Würzburg sample.

Clusters/Edges in red indicate responders to exhibit stronger positive connectivity compared to non-responders. Clusters/Edges in blue indicate stronger negative connectivity in responders. The corresponding bar graphs show connectivity values (Pearson’s correlation coefficients extracted from the respective cluster(s)/edges. ROI-to-ROI: Spheres indicate ROIs. Edges indicate significant connectivity between ROIs. Seed-to-Voxel: Green spheres indicate seeds. SPQ Spider Phobia Questionnaire, BAT Behavior Avoidance Test, WS-ext within-session fear reduction, L left, R right, ROI Region of Interest, MFG_orb middle frontal gyrus pars orbitalis, HC Hippocampus, SFG superior frontal gyrus, MFG middle frontal gyrus, cluster threshold: p < 0.05 (FDR); height-threshold: p < 0.001 (uncorr.); *p < 0.05; **p < 0.01; ***p < 0.001.