Nx4 Reduced Susceptibility to Distraction in an Attention Modulation Task

Abstract

Background: Stress adversely affects the attentional focus, the active concentration on stimuli, and increases susceptibility to distraction. To experimentally explore the susceptibility to distraction, the Attention Modulation by Salience Task (AMST) is a validated paradigm measuring reaction times (RT) for processing auditory information while presenting task-irrelevant visual distractors of high or low salience. We extended the AMST by an emotional dimension of distractors and an EEG-based evaluation. We then investigated the effect of the stress-relieving medication Neurexan (Nx4) on the participants' susceptibility to distraction. Methods: Data from a randomized, placebo-controlled, crossover trial (NEURIM study; ClinicalTrials.gov: NCT02602275) were exploratively reanalyzed post-hoc. In this trial, 39 participants received a single dose of placebo or Nx4 immediately before the AMST. Participants had to discriminate two different tone modulations (ascending or descending) while simultaneously perceiving task-irrelevant pictures of different salience (high or low) or valence (negative or positive) as distractors. Using EEG recordings, RT and the event-related potential (ERP) components N1, N2, and N3 were analyzed as markers for susceptibility to distraction. Results: In the placebo condition, we could replicate the previously reported task effects of salient distractors with longer RT for high salient distractors on the behavioral level. On the electrophysiological level, we observed significantly increased amplitudes of the N2 and N3 ERP components for positive emotional pictures. In terms of drug effect, we found evidence that Nx4 reduced distractibility by emotional distractors. The effect was shown by significantly reduced amplitudes of N2 and N3 ERP components and reduced RT for the positive valence domain under Nx4 compared to placebo. The Nx4 effects on RT and ERP components also showed a significant correlation. Conclusion: Emotional distractors in addition to the previously used salience distractors and the EEG based evaluation of ERPs valuably complement the AMST. Salient distractors were affecting attentional processes earlier, while valent distractors show modulatory effects later. Our results suggest that Nx4 has beneficial effects on attention by inhibiting the effect of task-irrelevant information and reducing susceptibility to emotionally distracting stimuli. The observation of a beneficial impact of Nx4 on attention regulation is supportive of Nx4's claim as a stress-relieving medication.

Keywords: EEG; ERP; Neurexan; attention modulation; natural medicine; reaction time; stress.

Conflict of interest statement

BN and MS were employed by Biologische Heilmittel Heel GmbH. MW received institutional research support from Heel paid to his institution for this study, and from BrainWaveBank, H. Lundbeck A/S and LivaNova Belgium N.V., LivaNova PLC outside the submitted work. The University of Tübingen received institutional fees for advisory services by MW from Heel GmbH, Servier Deutschland GmbH, Bayer AG and Janssen-Cilag GmbH. The University of Tübingen received financial support for conference attendance of KM, MK, SA, and HJ from Heel for presenting data of this study not reported in this article for this study. JV is a senior biometric consultant of idv Datenanalyse & Versuchsplanung (conceptualization, methodology, formal analysis, writing–original draft, writing–review, and editing) and received personal fees for biometric services from the Foundation of the Society for the Study of Neuroprotection and Neuroplasticity (SSNN) outside the submitted work, and idv Datenanalyse & Versuchsplanung received payments for biometric services from Heel, University Medical Center Göttigen, IgNova GmbH, Abnoba GmbH, AOP Orphan Pharmaceuticals AG, IDEA AG, PBB Entrepreneur Ltd., Tillots Pharma AG, STORZ Medical AG, EVER Neuro Pharma GmbH, MUCOS Pharma GmbH & Co. KG, Steigerwald Arzneimittelwerk GmbH outside the submitted work. MS and BN are employed by Heel (conceptualization, project administration, methodology, validation, writing–review, editing, and supervision). KM, MK, SA, HJ, and JM were part of MW team for this study and declare no other conflict of interest outside the submitted work. All investigators followed the institutional guidelines for COI management in full compliance with the regulations of the Otto v. Guericke University, Magdeburg.

Copyright © 2021 Mayer, Krylova, Alizadeh, Jamalabadi, van der Meer, Vester, Naschold, Schultz and Walter.

Figures

Graphical Abstract

Nx4 reduced susceptibility to distraction by visual distractors in an auditory tone discrimination task.

Figure 1

Two sequence, two period cross-over Study design of NEURIM study. (A) Overall design with screening on day 0 and the two cross-over sessions on day 1 and 2 with a 7–35 days washout period in between. (B) Detailed procedures on each day, 1 and 2. During the first fMRI scan an anatomical scan and a baseline resting-state measurement were acquired, followed by the intake of the IMP. Afterwards, two EEG paradigms (AMST and Oddball) were recorded. The second fMRI scan consisted of three task measurements, the Hariri paradigm, the Expectancy paradigm, and the ScanSTRESS paradigm, and two resting-state sequences. Psychometrics were measured several times. AMST, Attention Modulation by Salience Task; EEG, Electroencephalography; IMP, Investigational Medicinal Product; MRI, Magnetic Resonance Imaging; PSY, psychometrics.

Figure 2

Design of the Attention Modulation by Salience Task. The task consistent of two runs of 80 trials each. Each trial consisted of presentation of a visual stimuli (high salient/low salient pictures in run 1 or negative/positive pictures in run 2) for 4 s followed by a presentation of fixation cross for another 4 s. Four tones (ascending or descending) were presented starting after 1,300 ms after picture offset with inter-tone interval of 2,000 ± 100 ms. Images for this illustration were taken from (https://zen.yandex.ru/) while the actual experiment used IAPS pictures.

Figure 3

Grand average event-related potentials (ERPs) of the Attention Modulation by Salience Task. (A) Grand average ERP responses averaged over 4 picture types and two tones (T1 and T2), for placebo (blue solid lines) and Nx4 (red dashed lines) conditions. Tone onset is indicated with vertical gray line. Electric field revealed three prominent peaks in N1 (92–124 ms), N2 (240–336 ms) and N3 (496–616 ms) time intervals, indicated with gray rectangles. Thick lines indicate mean ERP response in the selected channel group. (B) Scalp electrical field potential distributions of N1, N2, and N3 components for the placebo and Nx4 conditions. White dots indicate channels that were used for further ERP component analysis.

Figure 4

Number of participants in the two sequences of the cross-over trial, placebo first and Nx4 first.

Figure 5

Graph illustrating the effect of salient and valent visual stimuli on reaction time (A) and amplitudes of N2 and N3 ERP components (B) in the AMST for placebo condition. Data for high salient (HS) condition are shown in red, low salient (LS) in blue, negative valence (NE) in magenta, and positive valence (PE) in turquoise. Data are given as mean and standard error. Stars correspond to the significance levels (***p < 0.001, **p < 0.01, and *p < 0.05) after Bonferroni correction. We observed longer reaction times for tones presented during high salience pictures in the first tone position and shorter reaction times for tones presented during negative valence pictures in the second tone position. N2 and N3 amplitudes were greater for the tones presented during positive valence pictures in the second tone position.

Figure 6

Effect of Nx4 on reaction time (A) and amplitudes of the ERP components, N2 (B), and N3 (C). Data for high salient (HS) condition are shown in red, low salient (LS) in blue, negative valence (NE) in magenta, and positive valence (PE) in turquoise. Solid bars represent data for placebo condition, striped ones for Nx4. Data are given as mean and standard error. Stars correspond to the significance levels (**p < 0.01, and *p < 0.05) after Bonferroni correction. We observed an overall reduction of the RT and amplitudes of ERPs after Nx4 intake, that was more prominent for positive and negative emotional distractors (D) Correlation of the Nx4 effect on the reaction time and amplitude of N2 ERP component for positive emotional distractor at tone 2. Nx4 effect on the reaction time (x-axis) and amplitude of N2 ERP component (y-axis) was estimated by subtraction of the values under the Nx4 condition from the ones under placebo for each participant (i.e., Nx4 effect = placebo–Nx4). Each dot represents data for one participant; red lines indicate confidence interval of the linear model fit.