Abstract
Background: 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). Neurexan® has been investigated in patients with symptoms related to acute stress, nervousness/restlessness, and insomnia. The underlying neuronal mechanisms that lead to the reduction of those symptoms are less clear. Two areas of importance in stress reactivity are the anterior cingulated cortex (ACC) as well as the amygdala [1]. Previous studies showed that especially the dorsal part of the ACC (dACC) influences the generation of autonomic arousal [2]. Similarly, it was reported that electrical stimulation of the ACC leads to changed physiological processes like heart rate and blood pressure [3]. Additionally, it was found that the dACC is activated under cognitive stress [4]. Thus, previous studies indicated the importance of the dACC in controlling stress reactivity. Therefore, we hypothesized that Neurexan® induces changes in the activation of dACC and associated areas during a stress task.
Method: The drug effect of a single dose of Neurexan® or placebo was investigated using a randomized, placebo-controlled, double-blind, two-period crossover design. 36 male subjects between the ages of 31–59 (mean age 43.1 years, SD = 9.9) took part in the experiment and completed various fMRI tasks. The stress response was induced using the ScanSTRESS [5] which uses arithmetic tasks as well as mental rotation tasks. Data were preprocessed and analyzed in SPM12. fMRI analysis was conducted assuming a block design. The investigated contrasts of interest were stress > control, rotation stress > rotation control, and arithmethics stress > arithmetics control. The drug effect was assessed using paired t-test with day sequence as a covariate. dACC and amygdala were considered as regions of interest, and FWE cluster level corrections were made within the search volumes.
Results: In the main effect of task, as expected, we found higher activation during psychosocial stress (contrast stress > control; rotation and arithmetics together) in the anterior insula and premotor area (PMA) bilaterally, as well as in the angular gyrus, occipital lobe, and the cerebellum (p < 0.05, FWE cluster level corrected). Additionally, we observed increased activation of the supplementary motor area (SMA). Significant deactivations were found in regions of the default mode network, namely vmPFC, PCC, and temporal pole/hippocampus (p < 0.05, FWE cluster level corrected). In the contrast placebo > Neurexan®, paired t-test analysis showed a significant cluster in the region of interest of the right dACC in rotation stress > rotation control (p < 0.05, FWE). Stress-induced activity in the right dACC was reduced in the Neurexan® condition. No effects of condition were found in amygdalae.
Conclusion: The intake of a single dose of Neurexan® significantly reduces right dACC activation during psychosocial stress compared to the intake of placebo. This suggests that the mechanism through which Neurexan® reduces symptoms related to acute stress may involve a reduction of autonomic arousal.
