Abstract
Introduction: Neurexan®, a natural pharmaceutical product sold over the counter (OTC), is composed of four diluted plant and mineral components: Passiflora incarnata (passionflower), Avena sativa (oats), Coffea arabica (coffee) and Zincum isovalerianicum (zinc valerianate). Neurexan® has been so far investigated in patients with symptoms related to acute stress, nervousness or restlessness and insomnia. Acute stress response is modulated via hypothalamic–pituitary–adrenal (HPA) axis, which interacts both with limbic and cortical areas in the brain. One of the prominent regions affect by stress is amygdala. The amygdala is involved in the development of fear and emotional behavior and acute stress sensitizes the amygdala. It increases vigilance and anxiety levels, which in turn further promote the stress response [1]. Amygdala reactivity to negative stimuli is considered a reliable phenotype that closely associates with the stress regulation [2] and can be assessed with the Hariri paradigm, a task measuring response to emotional facial expression of fear, happiness or anger [3]. A linkage between an increased level of stress hormones and increased emotional response to angry faces has been shown in patients with social phobia [4], further associating stress and emotion processing via amygdala. Previous investigation suggested an attenuated neuroendocrine stress response in healthy volunteers induced by Neurexan® [5]. Thus, the aim of this study was to explore possible effects of Neurexan® on lower emotional brain response to negative faces in the amygdala.
Methods: Thirty-nine healthy male subjects (age = 43.7 ± 9.8) participated in a randomized, placebo- controlled, double- blind, two- period crossover trial study. Participants were scanned in a 3 Tesla functional magnetic resonance (fMR). After a single dose of Neurexan® or placebo, to challenge their stress response, subjects firstly underwent a moderate stress task, after which an emotional Hariri paradigm was measured. Data were preprocessed and analyzed in SPM12. Amygdala was anatomically defined by the AAL (Automated Anatomical Labelling Atlas) and a difference between responses of placebo and Neurexan® for negative faces was calculated with a paired t-test, peak level FWE corrected for multiple comparisons within the search volume.
Results: Hariri task was firstly validated for emotional negative faces response. Significant (peak level FWE corrected) bilateral activations of fusiform gyri, amygdalae and prefrontal cortex as well as unilateral activation in right thalamus were confirmed as previously reported [3]. Additionally, significant activations in visual area and cerebellum were observed. Paired t-test showed a drug effect (p < 0.05) in the left amygdala, with stronger activations in placebo than in Neurexan® condition. Right amygdala did not show significant effect.
Conclusion: We found a significant reduction of BOLD response to negative faces in the left amygdala during the Neurexan® session compared to the placebo session. Neurexan® reduced the emotional brain response to negative stimuli, possibly interacting with the HPA axis.
