Effects of exogenous testosterone application on network connectivity within emotion regulation systems

Abstract

Studies with steroid hormones underlined the vital role of testosterone on social-emotional processing. However, there is still a lack of studies investigating whether testosterone modulates network connectivity during resting-state. Here, we tested how the exogenous application of testosterone would affect functional connectivity between regions implicated in emotion regulation. In total, 96 male participants underwent resting-state fMRI scanning. Before the measurement, half of the subjects received 5 g Testim^TM gel (containing 50 mg testosterone) and the other half a corresponding amount of placebo gel. Seeds for the connectivity analysis were meta-analytically defined. First, all regions associated with emotion regulation were chosen via Neurosynth (data driven). Among those, specific seeds were selected and categorized based on the neural model of emotion regulation by Etkin and colleagues (Etkin et al., 2015) (theory-guided). Resting-state connectivity analysis revealed decreased connectivity between the right DLPFC and the right amygdala as well as between the VMPFC and the left IPL for the testosterone group compared to the placebo group. A complementary dynamic causal modeling (DCM) analysis on findings from the resting-state connectivity analysis underlined a bidirectional coupling which was decreased close to zero by testosterone administration. Our results demonstrate that testosterone administration disrupts resting-state connectivity within fronto-subcortical and fronto-parietal circuits. The findings suggest that even without a specific task (e.g. challenge, reward processing) testosterone modulates brain networks important for social-emotional processing.

Figure 1

Regions of interest were defined in a two-pass procedure. (A) Activation map (pink color) was obtained by conducting a neuroimaging meta-analysis for the term “emotion regulation” in Neurosynth (161 fMRI studies). (B) Only ROIs that were given by the Etkin model was selected as seed regions. Fourteen 5 mm sphere ROIs which matched with the three systems: blue color -perception (left and right amygdala, insula, and dACC), red color - valuation (VMPFC) and green color - action (DLPFC, inferior parietal lobule (IPL), SMA, VLPFC, PCC).

Figure 2

Hormone levels are presented separately for the testosterone (T) and placebo (PL) group. Mean raw levels and standard errors are indicated. Testosterone levels were significantly higher after applying the testosterone gel in the testosterone group (see time points T2, T3, and T4 indicated by *). Blue colored square represents time in the scanner.

Figure 3

Network resting-state connectivity revealed the significant difference between groups for two pairs of the region of interests. Left: Between right Amygdala and right Dorsolateral Prefrontal Cortex (DLPFC). Right: Between Ventromedial Prefrontal Cortex (VMPFC) and left Ipsilateral Parietal Lobule (IPL).

Figure 4

Results of the DCM analysis. Top: Directional connectivity between the right Dorsolateral Prefrontal Cortex (DLPFC) and the right amygdala was decreased in the testosterone group compared to the placebo group. Connectivity in the placebo group from the right amygdala to the right Dorsolateral Prefrontal Cortex (DLPFC) was stronger than for the reversed directionality. Bottom: Directional connectivity between Ventromedial Prefrontal Cortex. (VMPFC) and left ipsilateral parietal lobule (IPL) was decreased in the placebo group compared to the testosterone group.