Abstract
Background: Stress initiates intricate changes in functional connectivity (FC) between amygdala and cortical regions that are associated with vigilance monitoring, salience processing and executive control [1,2]. The functional integrity of these stress regulation circuitries can be assessed via amygdala-centered resting state functional connectivity (rs-FC). Resting state measures spontaneous fluctuations in BOLD signal without an explicit task, thereby investigating regional associations and underlying brain architecture. Previous studies have associated changes in the amygdala rs-FC with state, trait and pathological anxiety [3,4]. Neurexan®, a medicinal product sold over the counter (OTC), is composed of four ingredients: Passiflora incarnata (passionflower), Avena sativa (oats), Coffea arabica (coffee) and Zincum isovalerianicum (zinc valerianate). Recent study suggested that Neurexan® attenuates neuroendocrine stress response in healthy volunteers [5]. Thus, in the present study, we aimed to explore the effect of Neurexan® on the amygdala-centered rs-FC. We dissociated between the amygdala subregions, given their differential role in stress activation, adaptation and behavioral regulation [2].
Methods: Thirty-nine healthy male subjects (age = 43.7 ± 9.8) participated in an functional magnetic resonance imaging study of Neurexan® effects using a double- blind, randomized, placebo- controlled, within- subject crossover design. In each scanning session, an 11 min resting state measurement was performed at baseline and after the intake of a single dose of Neurexan® or placebo. Data were preprocessed and analyzed in SPM12 and DPABI. Using a seed- based approach, resting state functional connectivity maps of bilateral centromedial (CeA) and basolateral (BLA) subregions of amygdala were analyzed. Regions were created according to the probabilistic cytoarchitectonic maps provided by the Anatomy Toolbox. Firstly, a whole– brain within– subject ANOVA, with focus on the time by pharmaceutical interaction (FWE cluster level corrected) was conducted. To dissect the drug by time interaction on the rs- FC, post- hoc analyses were afterwards ran for significant regions.
Results: Significant effect of Neurexan® was found on rs-FC between the left centromedial amygdala and cortical regions including posterior cingulate cortex (PCC), dorsomedial prefrontal cortex (dmPFC) and bilateral inferior parietal lobule. Post- hoc tests showed that rs- FC between the left CeA and PCC did not differ between placebo and of Neurexan® at baseline, but the CeA- PCC rs- FC strength after the medicinal intake, was significantly weaker in the Neurexan® compared with the placebo condition (t(20) = 2.89, p < 0.01). Similarly, the drug by time interaction on the rs- FC between the left CeA and dmPFC was also driven by significantly weaker connectivity strength after medicinal intake in the Neurexan® compared with the placebo condition (t(20) = 3.48, p < 0.01). For seed regions in right CeA and bilateral BLA, the drug by time interaction effect did not survive FWE correction for multiple comparisons.
Conclusions: Our finding suggest that Neurexan® influences resting state functional connectivity of the centromedial amygdala towards cortical regions involved in emotion regulation and higher cognitive processes.
