ORIGINAL RESEARCH published: 01 October 2021 doi: 10.3389/fnins.2021.748188 Effects of a Green Oat Herb Extract on Cognitive Performance and Neurophysiological Activity: A Randomized Double-Blind Placebo-Controlled Study Saul Martinez-Horta 1,2,3* , Eran Ivanir 4 , Tania Perrinjaquet-Moccetti 5* , Matthias Heinrich Keuter 5 and Jaime Kulisevsky 1,2,3 Edited by: Jong-Min Kim, 1 Movement Disorders Unit, Neurology Department, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain, 2 Biomedical Seoul National University Bundang Research Institute (IIB-Sant Pau), Barcelona, Spain, 3 Centro de Investigación en Red-Enfermedades Neurodegenerativas Hospital, South Korea (CIBERNED), Madrid, Spain, 4 Frutarom Ltd., Migdal Haemeq, Israel, 5 Frutarom Switzerland Ltd., Wädenswil, Switzerland Reviewed by: Anna Pokryszko-Dragan, Green oat extracts have been used for centuries in traditional medicine in view Wrocław Medical University, Poland Binosha Fernando, of their supposed beneficial effects on cognition and mood. Recently, a specific Edith Cowan University, Australia green oat formulation (Neuravena ) showed to have significant bioactive compounds R *Correspondence: potentially associated with the enhancement of processing speed, working memory Saul Martinez-Horta smartinezho@santpau.cat and attention. The main aim of the current study was to compare the potential Tania Perrinjaquet-Moccetti effect of acute administration of 800 mg of Neuravena with placebo on a set of R TPerrinjaquet-Moccetti@ neurophysiological correlates of processing speed, attention, performance-monitoring frutarom.com and inhibitory control. Twenty healthy participants were randomized to receive either Specialty section: Neuravena or placebo. Electroencephalographic (EEG) signal acquisition was obtained R This article was submitted to Neuroenergetics, Nutrition and Brain while participants carried out the modified Eriksen flanker and oddball tasks. Both Health, groups were compared on measures of behavioral task performance, and a set of a section of the journal event-related potentials (ERPs) components related to performance monitoring (the Frontiers in Neuroscience error-related negativity; ERN and the N2), target detection, and attention (P3a/P3b). Received: 27 July 2021 Accepted: 10 September 2021 Following active-intervention N2, ERN, and P3a/P3b were significantly reduced and Published: 01 October 2021 performance was faster, with no loss of accuracy. Conversely, no neurophysiological Citation: differences were found in the placebo group before and after treatment and performance Martinez-Horta S, Ivanir E, Perrinjaquet-Moccetti T, Keuter MH worsened significantly in terms of reaction time and accuracy. Acute administration of and Kulisevsky J (2021) Effects of a 800 mg of Neuravena appears to enhance the optimization of neural resources and R Green Oat Herb Extract on Cognitive positively influences cognitive performance in tasks associated with executive functions, Performance and Neurophysiological Activity: A Randomized Double-Blind processing speed and attention. Moreover, Neuravena prevents the deleterious effects R Placebo-Controlled Study. of tiredness during task performance. Front. Neurosci. 15:748188. doi: 10.3389/fnins.2021.748188 Keywords: cognition, ERP, avena, green-oat herb, p300, ERN, EEG, N2 Frontiers in Neuroscience | www.frontiersin.org 1 October 2021 | Volume 15 | Article 748188 Martinez-Horta et al. Effects of Green Oat on Cognition and ERPs INTRODUCTION changes of the neurons projecting from the mesencephalon to the anterior cingulate cortex (ACC) (Gehring and Knight, 2000; Various forms and preparations of oat (Avena sativa L.) – also Luu and Tucker, 2001). Similarly, in conflict priming, it has commonly known by names such as green oat and common oat been suggested that the frontal-central N2 component reflects - have been used for centuries to treat physical and psychological cognitive control (Kopp et al., 1996; Nieuwenhuis et al., 2003; conditions (Blumenthal et al., 2000; Abascal and Yarnell, 2004). Kok et al., 2004; Ramautar et al., 2006; Folstein and Van Petten, However, as with many other formulations used in traditional 2008). The morphology of these ERPs has been found to be medicine, scientific evidence on the specific effects of this herb sensitive to changes caused by several conditions affecting the and on its mechanisms of action is lacking. central nervous system (CNS), and also to changes induced by Previously, however, several studies have reported that pharmacological agents (Aron et al., 2003; Fitzgerald et al., 2005; the ingestion of a specific green oat preparation in healthy Riba et al., 2005; Lopez-Gongora et al., 2015; Hedges et al., 2016; subjects has acute positive effects on cognitive functions Rabella et al., 2016; Seer et al., 2017). and neurophysiological parameters. Positive effects have been Considering the previously reported findings from studies observed in measures of speed of performance (global), addressing the effects of Neuravena , and taking into account R executive function, working and episodic memory, attention, and the proposed mechanisms of action of this compound, we quantitative electroencephalography (qEEG) (Berry et al., 2011; aimed to examine the relationship between indices of attention, Dimpfel et al., 2011; Kennedy et al., 2017). In all these studies, performance-monitoring and inhibitory control abilities, such a specific oat extract (Neuravena ) was used. Neuravena is R R as the P3a, P3b, ERN, and N2 amplitudes and cognitive green oat herb extract containing a range of potentially bioactive performance, as measured by neuropsychological tests in constituents. In bio-assay guided approaches, it has been shown healthy individuals. to have a significant inhibitory effect on the monoamine oxidase B (MAO-B) and phosphodiesterase 4 (PDE-4) enzymes (Moccetti et al., 2006). Based on this finding, it has been proposed that MATERIALS AND METHODS increased dopaminergic availability and cerebral vasodilation underlie its reported acute positive effects (Moccetti et al., Design 2006; Kennedy et al., 2017). Chronic intake of the extract has This study had a single-session, randomized, double-blind, also shown to improve vasodilator function in peripheral and placebo-controlled design with two parallel study arms: Active cerebral arteries (Wong et al., 2013), suggesting a broad effect intervention or placebo. Assessments were performed at baseline on brain function. and 60 min after administering either the active intervention Dopamine plays a cardinal role in movement, cognition, or placebo. The total running time of the experimental session and motivation. Proper functioning of the structures conveyed was the same for all participants and consisted of a 60 min along basal ganglia-thalamo-cortical dopaminergic pathways session of neurophysiological acquisition and task performance is crucial for the optimal performance of several cognitive (baseline), a 60 min resting period at the beginning of which the processes ascribed to frontal-executive functions. These include active intervention or placebo was administered, and a 60 min action and conflict monitoring, inhibitory control, attention, session of neurophysiological acquisition and task performance target detection, and processing speed (Goldman-Rakic, 1998; after active intervention or placebo. The experimental session Nieoullon, 2002; Remy and Samson, 2003; Grahn et al., was conducted in the facilities of the Laboratory of Cognitive 2009). Event-related brain potentials (ERPs) derived from EEG Neurophysiology and Human Neuropsychopharmacology at recordings enable the study of neurophysiological activity and the Biomedical Research Institute Sant Pau, in an isolated behavioral parameters in relation to these cognitive processes room specifically prepared for conducting neurophysiological (Luck, 2005). The P3a and P3b components obtained during studies. As per protocol, before the experimental session was auditory oddball paradigms selectively reflect the automatic conducted, all participants were interviewed regarding adherence orientation of attention to novel stimuli (frontal P3a), target to the instructions provided in relation to the evening meal detection, and contextual update of information (parietal P3b) and breakfast as well as the quality of sleep and rest during (Sutton et al., 1965; Courchesne et al., 1975; Escera et al., 2000; the previous night. Friedman et al., 2001; Polich, 2007). Dopaminergic activity has To explore the acute effects of the studied compound, the been strongly associated with both P3a and P3b. Specifically, it experimental session was conducted on a single day, in the appears to play a cardinal role in the frontal-central P3a and morning. Participants were requested to have their standard related frontal functions such as working memory and focal evening meal on the previous day but to avoid alcohol. In order attention, but it also plays a partial role in the amplitude of P3b to get a relative homogeneity on evening meal, participants (Courchesne et al., 1975; Comerchero and Polich, 1999; Polich, were provided by a set of recommendations the amounts to 2007; Grahn et al., 2009). Error-related negativity (ERN) is a be consumed and the types of foods that were recommended negative deflection that occurs after error responses, and it is or should preferably be avoided. At breakfast, calorie intake part of the action monitoring system (Holroyd and Coles, 2002; was restricted to 200 kcal, and participants were required to Yeung et al., 2004; Gehring et al., 2018). It has been the subject of take their normal amount of coffee to prevent potential caffeine intensive research and has been interpreted as a neural correlate withdrawal effects. Similar to what was done with evening of error detection, originated due to the phasic dopaminergic meal, a list with possible breakfasts to consume and avoid was Frontiers in Neuroscience | www.frontiersin.org 2 October 2021 | Volume 15 | Article 748188 Martinez-Horta et al. Effects of Green Oat on Cognition and ERPs provided to participants. After the baseline assessment, during and 50% of incompatible trials. In the remaining 17% of trials the resting period, participants received a 200kcal snack followed we included “stop” trials. In these trials the central green arrow by the intervention. changed to red (for instance: ) after a delay of 150ms and participants had to inhibit response in these trials. Duration Participants of the stimuli was 300 ms. A random Stimulus-Onset Asynchrony Participants were pre-selected from a database of healthy (SOA) between 900 ms and 1100 ms was used. The experiment volunteers. Inclusion criteria were males or females aged 20 to consisted of 3 blocks of 4 min, each with 200 stimuli. A 30-s 50 years and able to freely decide to participate in the study rest period was allowed between blocks. Subjects were required by signing the proper informed consent. Exclusion criteria were to respond to the stimuli as fast and as accurate as possible any history of alcohol and/or other substance abuse, major and to inhibit their responses whenever a stop trial appeared. psychiatric events that required pharmacological management, The percentage of total correct responses, and the reaction times symptoms suggestive of cognitive impairment, traumatic brain (RT) to correct responses, and to error responses were recorded. injury with loss of consciousness or any other disease of the CNS Same measures were separately obtained for the compatible and (i.e., epilepsy, migraine), neurosurgical intervention in the CNS, incompatible trials. systemic disease – compensated or not- (i.e., diabetes), use of any dietary supplement, food allergies, body mass index (BMI) Auditory Oddball Task >35 or <18, or being pregnant at the time of screening. From A standard auditory oddball task with a set of frequent, the pre-selected volunteers, twenty participants were included in infrequent, and novel stimuli was used. Frequent stimuli the study and randomly allocated to receive the placebo or the (1500 Hz, 60 ms duration) occurred with a probability of 0.8, active compound. Although the final sample was relatively small, infrequent stimuli (1620 Hz; 60 ms duration) occurred with a the total number of trials during EEG/ERPs acquisition was in probability of 0.1, and novel sounds (such as the sound of a key, accordance with the recommendations regarding sample size for or a door closing) occurred with a probability of 0.1 at 60 dB ERPs studies (Larson and Carbine, 2017). The study included two for 60 ms duration. Over a period of 15 min, participants were groups of ten participants matched for main sociodemographic requested to respond as fast as possible to infrequent (target) variables (age, gender, years of education, and BMI, summarized sounds with the right index finger, and to ignore all other sounds. in Table 1). Percentage of correct responses to target and percentage or responses to non-target novel stimuli were recorded. Interventions Both the placebo and encapsulated active intervention were Electroencephalogram Recording and provided by Frutarom Switzerland Ltd. The active intervention Analysis consisted of an extract (Neuravena ) manufactured from the R An electroencephalogram (EEG) was recorded using the dried above-ground parts of a selected variety of Avena sativa BrainAmp system and Brain Vision Recorder Software (Brain L., treated with aqueous ethanol (30% m/m) solution, filtered Products GmbH, Germany) from 19 standard scalp sites according to a proprietary filtration process and spray-dried. according to the international 10/20 system (Fp1/2, F3/4, C3/4, Twenty-eight per cent (m/m) Maltodextrin Ph. Eur. was added T3/4, T5/6, P3/4, O1/2, F7/8, Fz, Cz, Pz) referenced to the two as a carrier together with 2% (m/m) of Silica, colloidal anhydrous mastoid leads. Vertical eye movements were recorded using a Ph. Eur. Characteristics of the extract are drug-to-extract- ratio bipolar montage with two electrodes linked together and placed (DER) 3.5:1, and a flavonoid content (calculated as isovitexin) below each eye referenced to a third electrode placed centrally of ≥0.3% (w/w). The dosage form consisted of two hard-gelatin above the eyes. Horizontal eye movements were monitored using capsules, each containing 400 mg of extract or maltodextrin as two electrodes placed on the external canthi of each eye. Electrode placebo for a total of 800 mg. The reason for choosing 800 mg in impedances were kept below 5 kOhm. The electrophysiological the current study relies on a previous study (Kennedy et al., 2017), signals were filtered with a bandpass of 0.1–35 Hz and digitized where the results suggested that the optimal dose of Neuravena R at a rate of 250 Hz. in relation to improving cognitive performance lies at this level. To maximize the information available for the subsequent event-related potential analysis (ERPs), raw EEG signals Assessments were subjected to an ocular artifact minimization algorithm. Stop-Signal Task This algorithm is based on an eigenvalue decomposition We used a modified version of the Eriksen flanker task (Lopez- of time-delayed covariance matrices. After identifying the Gongora et al., 2015). Participants were required to respond source signals associated with eye movements, we obtained to the orientation of a central green arrow (target) with two corrected EEG signals from the remaining components. The additional green arrows on either side. To do so, they were algorithm was implemented using Brain Vision Analyzer (Brain instructed to signal with the right hand after a right-pointed Products GmbH; Germany). target arrow and with the left hand after a left-directed target arrow. The four surrounding arrows either primed the target P3a and P3b response (compatible trials, or ) or In the auditory oddball task, the continuous EEG recording was primed the opposite direction (incompatible trials, segmented in epochs of 1000 ms starting 100 ms before the or ). The task included 33% of compatible trials stimulus presentation and until 900 ms post-stimulus. Epochs Frontiers in Neuroscience | www.frontiersin.org 3 October 2021 | Volume 15 | Article 748188 Martinez-Horta et al. Effects of Green Oat on Cognition and ERPs TABLE 1 | Sociodemographic and baseline characteristics of the sample. Total (n = 20) Placebo (n = 10) Active intervention (n = 10) p Mean ± SD (range) Age (years) 25.5 ± 3.6 (19–34) 26.0 ± 3.8 (23–34) 24.9 ± 3.4 (19–30) 0.510 Gender (f/m) 9/11 6/4 3/7 0.370 Education (years) 13.0 ± 2.1 (8–18) 13.0 ± 1.3 (12–15) 13.0 ± 2.7 (8–18) 0.999 Weight (kg) 68.3 ± 7.1 (58–80) 68.0 ± 6.4 (58–76) 68.5 ± 8.1 (58–80) 0.880 BMI (kg/m2 ) 22.7 ± 1.7 (20–27) 22.1 ± 1.3 (20–23) 23.2 ± 1.8 (21–27) 0.148 P value is based on independent t-test for continuous variables and Pearson’s χ2 for categorical variables. were baseline-corrected, subtracting the mean amplitude in the appearing between 200 and 350 ms following the presentation 100 ms before the presentation of the stimulus. A two-step of compatible and incompatible trials with correct responses. artifact rejection procedure was then used. First epochs were The mean amplitude was calculated at the defined time-window. rejected if the signal in any of the 19 channels showed amplitude As with the ERN, given the frontocentral distribution of the values greater than ± 300 µV. Subsequently, additional epochs N2, it was quantified at Fz and Cz. The obtained average mean were excluded if amplitude values were greater than ± 40 µV amplitudes for each subject were introduced into the statistical in Fz, Cz or Pz channels. After these preprocessing steps, analysis described below. For depicting purposes, the signals three types of trials were averaged separately: epochs containing obtained for each participant were averaged together providing frequent stimuli, epochs containing infrequent stimuli, and a single grand average. epochs containing novel stimuli. These averages were obtained for each study participant and the ERP components were Statistical Analysis identified and quantified. The P3b was identified as the most Sociodemographic and baseline characteristics were subjected positive deflection in the ERP between 300 and 700 ms post- to independent t-test comparisons between the two groups stimulus in the infrequent trials. The P3a was identified as the of interest for continuous variables and χ2 for categorical most positive deflection in the ERP between 250 and 500 ms post- variables. Intervention effect on cognitive performance variable stimulus in the novel trials. The mean amplitude was calculated was analyzed using repeated-measures analyses of variance in the time-window defining each ERP and was introduced into (ANOVA). Within each intervention arm, the effect was the statistical analysis. tested using paired t-test analysis. ERP effects were quantified for the three midline electrodes (Fz, Cz, and Pz), and the Error-Related Negativity and N2 resulting data were subjected to repeated-measures ANOVAs In the stop task, ERPs were obtained following response and with the Greenhouse-Geisser correction applied when necessary. stimuli-locked average procedure. For the response-locked ERPs, Post hoc comparisons were performed using paired t-test the continuous EEG was segmented in epochs of 1000 ms, comparisons. The statistical analysis was conducted using SPSS starting 200 ms before the commission of stop errors and v25 software package. before the correct responses until 800 ms thereafter. The 0-time point thus corresponded to a button press when the participant should withhold the response, and to the emission of a correct RESULTS response. Baseline correction was performed subtracting the mean amplitude in the 100 ms before button press. Subsequently, Twenty healthy adults participated in this study (9 females and we used the same two-step artifact rejection and procedure 11 males). Sociodemographic and baseline characteristics of the described above for P3a/P3b. For the stimulus-locked ERPs, we participants are shown in Table 1. Participants had a mean performed the same procedure as described for the acquisition age of 25.5 years, mean weight of 68.3 and mean body mass and averaging of P3a or P3b, but on these occasions, we created index of 22.7 kg/m2 . The two groups were matched for all the two types of epochs: epochs containing trials compatible with sociodemographic and baseline characteristics. correct responses and epochs containing trials incompatible with correct responses. Stop-Signal Task Following preprocessing, the epochs of the response-locked T-test comparisons showed equivalent performance at baseline condition were averaged in order to obtain the ERN wave in the percentage of total correct responses [t = 0.179; p = 0.860)], following commission errors. The ERN was identified as the in the percentage of correct responses in compatible trials negative deflection in the ERP appearing between 0 and 160 ms [t = −0.377; p = 0.710] and in the percentage of correct responses following a stop error. Quantification methods were used at Fz incompatible trials [t = −0.178; p = 0.861]. Similarly, equivalent and Cz, because the ERN shows a frontocentral distribution. reaction times (RT) were found for all the conditions at baseline Accordingly, the average mean voltage was calculated between (p > 0.05; Table 2). Repeated measures ANOVA using the factors 0 and 160 ms following stop errors and correct responses. “intervention group” (placebo; active intervention) and “time” The N2 was identified as the negative deflection in the ERP (baseline; post-intervention) showed a trend to interaction [F Frontiers in Neuroscience | www.frontiersin.org 4 October 2021 | Volume 15 | Article 748188 Martinez-Horta et al. Effects of Green Oat on Cognition and ERPs TABLE 2 | Behavioral performance in the Stop-signal task and in the Auditory oddball task at baseline and endpoint. Placebo Active P value Baseline Mean ± SD Change Mean ± SD Baseline Mean ± SD Change Mean ± SD Baseline Change Stop signal Total trials Correct responses (%) 88.54 ± 5.96 −5.05 ± 9.31 89.08 ± 7.5 1.21 ± 4.21 0.860 0.068 RT in correct responses (ms) 357.02 ± 21.83 5.45 ± 12.2 376.84 ± 32.1 −17.72 ± 12.54b 0.124 < 0.001 RT in errors (ms) 302.37 ± 24.41 11.67 ± 20.24 308.94 ± 13.40 −2.19 ± 8.33 0.465 0.060 Compatible trials Correct compatible responses (%) 95.13 ± 5.32 −2.54 ± 3.3 94.23 ± 5.33 0.44 ± 4.23 0.710 0.096 RT in correct responses (ms) 335.27 ± 15.59 2.33 ± 17.25 354.17 ± 33.13 −12.13 ± 2.33b 0.120 0.017 RT in errors (ms) 289.30 ± 44.06 14.13 ± 39.27 294.43 ± 21.17 1.13 ± 28.44 0.744 0.407 Incompatible trials Correct incompatible responses (%) 95.93 ± 4.26 −4.22 ± 6.33a 95.60 ± 4.01 −1.48 ± 5.34 0.861 0.309 RT in correct responses (ms) 370.17 ± 21.25 4.37 ± 20.68 393.82 ± 32.73 −18.21 ± 12.49b 0.071 0.008 RT in errors (ms) 305.19 ± 21.62 10.19 ± 18.55a 312.86 ± 13.87 −4.17 ± 9.32 0.360 0.042 Auditory oddball task Correct responses to target (%) 89.53 ± 9.84 −1.41 ± 6.51 88.27 ± 8.71 0.82 ± 4.23 0.765 0.375 Responses to novel stimuli (%) 3.23 ± 3.52 4.44 ± 8.68 4.12 ± 2.31 3.98 ± 7.52 0.512 0.900 ap ≤ 0.05 significance based on paired t-test (baseline and post-treatment in the placebo group). b p ≤ 0.05 significance based on paired t-test (baseline and post-treatment in the active group). P value: Based on two-sided t-test for independent samples (placebo vs. active). (1,18) = 3.71; p = 0.068] for the percentage of total correct averaged from the incompatible condition (Figure 1, part A). In responses, a trend to interaction [F (1,18) = 4.01; p = 0.060] for the the response-locked analysis, repeated measures ANOVA with RT to error responses, and a significant interaction for the RT to the factors “electrode” (Fz and Cz) and “response” (correct, error) correct responses [F (1,18) = 11.80; p < 0.001], RT to compatible showed a significant effect at Fz [F (1,19) = 90.91; p < 0.001] correct responses [F (1,18) = 5.09; p < 0.05], RT to incompatible and at Cz [F (1,19) = 133.45; p < 0.001], driven by a significantly correct responses [F (1,18) = 8.74; p < 0.01], and RT to increased amplitude at Fz [t = 7.96; p < 0.001] and at Cz [t = 9.54; incompatible error responses [F (1,18) = 4.78; p < 0.05] (Table 2). p < 0.001] of the frontal-central negativity following an error Post hoc paired t-test comparisons using the difference score response (ERN) (Figure 1, part B). between pre- and post-intervention administration showed that No significant differences were found at baseline between these effects were driven by significant decreases in several groups in the mean amplitude of N2 and ERN. Repeated measures of RT in the active intervention group (Table 2). These measures ANOVA for the N2 using the factors “intervention effects were found for the RT to correct responses [t = −3.43; group” (placebo; active intervention) and “time” (baseline; post- p < 0.005], the RT to compatible correct responses [t = −2.25; intervention) showed a significant group x time interaction at p < 0.05], and the RT to incompatible correct responses Fz [F(1,19) = 15.2; p < 0.001] and at Cz [F(1,19) = 19.3; [t = −2.95; p < 0.01]. Effects were also seen in the placebo <0.001], characterized by a decreased negativity of the N2 for group in terms of increased RT to incompatible error responses the active-intervention arm (Figure 2). Bivariate correlation [t = 2.18; p < 0.05) and in post-effects in terms of accuracy in analysis showed that the reduction in the N2 amplitude was the form of decreased performance “in the incompatible trials associated with an increase in the percentage of correct responses [t = −2.66; p < 0.05] (Table 2). (r = −0.483; p < 0.05) and with a reduction in the RT to correct Bivariate correlation analysis showed significant negative responses (r = 0.590; p < 0.01). Regarding the ERN, repeated effects after intervention in the placebo group (data not shown). measures ANOVA showed a significant group x time interaction Thus, the observed change in RT to incompatible error responses at Fz [F (1,19) = 4.69; p < 0.05] (Figure 3). Post hoc comparisons was significantly associated with worse performance in the showed that this effect was driven by a significant reduction of placebo group in terms of percentage of correct responses the ERN at Fz in the active-intervention arm after intervention (r = −0.458; p < 0.05). [t = 2.23; p < 0.05]. In the stimulus-locked ERPs analysis, repeated measures ANOVA with the factors “electrode” (Fz and Cz) and condition Auditory Oddball Task (compatible/incompatible) showed a significant effect at Fz [F No differences were found between groups at baseline neither (1,19) = 19.8; p < 0.001] and Cz [F (1,19) = 13.52; p < 0.005] post-intervention in the percentage of correct responses to driven by a significant increased amplitude of the N2 at Fz target and to non-target novel stimuli. Repeated measures [t = 4.45; p < 0.001], and Cz [t = 3.67; p < 0.005] in the signal ANOVA using the factors “electrode” (Fz, Cz, Pz) and Frontiers in Neuroscience | www.frontiersin.org 5 October 2021 | Volume 15 | Article 748188 Martinez-Horta et al. Effects of Green Oat on Cognition and ERPs FIGURE 1 | Stimulus-locked and response-locked (ERN) grand average ERPs for the whole sample in the stop-signal task. (A) Stimulus-locked grand average ERP at Fz electrode for compatible (grey line) and incompatible (black line) trials. The N2 is identified as the negative deflection in the ERP appearing between 200 and 350 ms (grey area). The topographical map shows the increased frontocentral negativity for incompatible trials. (B) Response-locked grand average ERPs at Fz electrode for correct (grey line) and error (black line) responses. The ERN is identified as the negative deflection in the ERP appearing between 0 and 160 ms (grey area). The topographical map shows the frontal-central ERN. (C) ERPs associated with frequent, infrequent and novel stimuli in auditory oddball task. Grand average stimulus-locked ERPs at Fz and Pz electrodes for the whole sample. The P3a was identified as the most positive deflection in the ERP between 250 and 500 ms (grey area) post-stimulus in the novel trials. The P3b was identified as the most positive deflection in the ERP between 300 and 700 ms post-stimulus in the infrequent trials. The topographical map shows the P3a and P3b. “condition” (frequent/infrequent) showed significant effects at significant reduction after the administration of intervention in Cz [F (1,19) = 21.5; p < 0.001] and Pz [F (1,19) = 42.2; the active-intervention arm of the P3a at Cz [t = 3.18; p < 0.05] p < 0.001] driven by significant increased positivity at Cz and at Pz [t = 4.48; p < 0.005], and the P3b at Pz [t = 2.8; [t = 4.63; p < 0.001] and at Pz [t = 6.5; p < 0.001] around 300 ms – p < 0.05] (Figure 4). Bivariate correlation analysis showed that 700 ms following an infrequent stimulus (P3b). Similarly, adding this reduction in the P3a component was significantly associated novel stimuli to the factor “condition,” significant effects were with the percentage of correct responses post-intervention in found at Fz [F (1,19) = 53.4; p < 0.001], and Cz [F (1,19) = 81.5; both compatible (r = −0.480; p < 0.05) and incompatible p < 0.001] driven by a significantly increased positivity at (r = −0.488; p < 0.05) trials (data not shown). Fz [t = 7.3; p < 0.001], and at Cz [t = 9; p < 0.001] around 250 ms – 500 ms following a novel stimulus (P3a) (Figure 1, part C). No significant differences were found between DISCUSSION groups at baseline on the mean amplitude of the P3a and P3b components. Repeated measures ANOVA using the factors In the present study we explored the acute effects of ingestion “intervention group” (placebo; active intervention) and “time” of 800 mg of a green-oat herb extract (Neuravena ) on a set of R (baseline; post-intervention) showed a significant group x time behavioral and neurophysiological parameters. While previous interaction both for the P3a at Cz [F (1,19) = 3.30; p < 0.05] studies have shown a potential modulatory effect of Neuravena R and for the P3b at Pz [F (1,19) = 4.68; p < 0.05]. Post on neurophysiological activity as measured by EEG in the fronto- hoc comparisons showed that these effects were driven by a temporal brain region, and successive improvements in several Frontiers in Neuroscience | www.frontiersin.org 6 October 2021 | Volume 15 | Article 748188 Martinez-Horta et al. Effects of Green Oat on Cognition and ERPs FIGURE 2 | Stimulus-locked (grand average) ERPs for the N2 in the two groups. (A) ERPs after correct compatible (thin line) and incompatible (thick line) trials in each group, pre (blue/gray) and post (red/black) intervention. (B) The topographical map shows the pre-post effect on the mean amplitude of the N2 for incompatible condition. (C) Mean percentage of N2 change (in mV) for incompatible condition between study groups. *** significantly different (p < 0.05). measures of cognitive function (Berry et al., 2011; Dimpfel et al., resources and cognitive performance in participants receiving the 2011; Kennedy et al., 2017), the current investigation provides active intervention. These effects likely influence the maintenance evidence of an improvement in cognitive performance related of optimal performance in the task, as obvious signatures of to a concomitant neurophysiological effect. We specifically tiredness were found in the placebo group. looked at potential effects on a set of neurophysiological In previous studies focusing on neurological disorders, signatures of action and conflict monitoring (ERN/N2), target compensatory mechanisms were observed during performance detection, and attention (P3a/P3b). We also looked at the in the same tasks as those we used in the present study association between these neurophysiological measures and (Lopez-Gongora et al., 2015; Kropotov et al., 2016). Specifically, several behavioral variables. in ERP studies, the engagement of efficient compensatory Our results show that the two groups were strictly matched mechanisms has been seen as a significant increase in ERP for the main variables of interest and that before the intervention amplitude in association with the normalization of related there were no differences in any of the studied variables. behavior (Lopez-Gongora et al., 2015). This suggests that However, in the active-intervention group, we found a set in these cases, participants use additional neural resources of post-intervention differences with respect to baseline and to perform tasks with no apparent difficulties. Similarly, with respect to the placebo group in several neurophysiological throughout neurodevelopment, a progressive reduction in and related behavioral parameters. Specifically, after active- the amplitude of several ERPs is found in association with intervention administration, we found significant reductions in better performance in related tasks (Abdul Rahman et al., several ERPs, and a significantly faster performance in several 2017). This progressive reduction may reflect progressive task components. Importantly, this faster performance was specialization along neurodevelopment of the neural resources not associated with a worsening in accuracy. In contrast, in needed to overcome task performance (Davis et al., 2003; the placebo group, we found worsening effects both in RT Cragg and Nation, 2008; Abdul Rahman et al., 2017). and in accuracy. Taken together, it is reasonable to assume in the present We interpret the reduction in the mean amplitude of several study that the reductions found in the ERPs in the group ERPs as signatures of an acute effect of optimization of neural receiving the active intervention and the related positive Frontiers in Neuroscience | www.frontiersin.org 7 October 2021 | Volume 15 | Article 748188 Martinez-Horta et al. Effects of Green Oat on Cognition and ERPs FIGURE 3 | Response-locked (ERN) grand average ERPs after correct (thin line) and error (thick line) responses in the stop-signal task for each group, pre (blue/gray) and post (red/black) intervention. (A) ERPs comparison in the placebo and in the active intervention group. (B) The topographical map shows the pre-post effect on the mean amplitude of the ERN. (C) Mean percentage of ERN change (in mV) between study groups. *** significantly different (p < 0.05). behavioral consequences of these effects reflect better was found in the placebo group, affecting specific trials and optimization of the neural resources required to perform thus suggesting a loss of performance efficiency along the the tasks, and better capacity to maintain optimal levels experimental session. of performance, avoiding the tiredness effects found in the During the auditory oddball task, both P3a and P3b placebo group. were lower in the active-intervention group after intervention Taking into account the functional meaning of the studied administration. The P3b is one of the most frequently studied ERPs and the related behavioral parameters, our results are ERPs in the history of cognitive neurophysiology. Although its consistent with previous data suggesting that Neuravena R specific functional meaning is only partially understood, it is induces positive acute effects in processing speed and measures of clear that it is associated with processing speed and integration attention and executive function (Berry et al., 2011; Dimpfel et al., of information. Participants in the active-intervention group 2011; Kennedy et al., 2017). More specifically, our data supports showed a significant decrease in the P3b component, with no significant effects of Neuravena in terms of improving efficiency R deleterious effects on performance. Again, this finding supports in action monitoring, cognitive control over interference and the idea that more efficient neural resources are deployed by those attention. Here, we demonstrate that in participants receiving using 800 mg of Neuravena , promoting better performance. R a single dose of 800mg of Neuravena , a reduction in the R Equivalent findings were found for P3a component. The frontal amplitude of the ERN is found with no deleterious effects P3a is specifically associated with automatic orientation of on performance. Similarly, in the present study, participants attention to novelty. Here, participants in the active-intervention in the active-intervention arm showed a reduction in the N2 group showed a significant reduction in the P3a component component that was associated with faster performance both in association with a better performance in terms of accuracy. in compatible and incompatible trials. Specifically, incompatible Again, more efficient neural resources and performance appear to trials are usually associated with greater RT than compatible be enhanced after the administration of 800 mg of Neuravena . R trials. This greater RT is assumed to reflect the higher processing The main strengths of the present study are the inclusion of demands of the conflict monitoring system when participants are a carefully matched sample of healthy individuals in each study faced with incompatible trials. Thus, the significant reduction in arm and the use of several behavioral and neurophysiological RT in the active-intervention arm suggests increased efficiency of metrics to assess the effects pre and post intervention. The study the conflict monitoring system to solve the processing demands is not free of limitations that must be taken into consideration. driven by incompatibility. Conversely, increased latency of RT The sample size is relatively small and does not allow large Frontiers in Neuroscience | www.frontiersin.org 8 October 2021 | Volume 15 | Article 748188 Martinez-Horta et al. Effects of Green Oat on Cognition and ERPs FIGURE 4 | Stimulus-locked (grand average) ERPs for the P3a/P3b. (A) ERPs after infrequent (gray/blue line) and novel (black/red line) stimuli in each group. (B) Topographical maps showing the pre-post intervention effects on the P3a and P3b. (C) Mean percentage of P3a and P3b change (in mV) between study groups. *** significantly different (p < 0.05). extrapolations of the results. Despite this, taking into account two consecutive sessions could also play a role that must be taken these results and the results obtained in previous studies, the into account. Similarly, the effects of inter and intraindividual current findings add evidence about the pro-cognitive effects of variability in the ERPs between sessions could also play a role the studied compound. In this sense, although it is true that in the observed effects. In any case, since it is a study where a larger sample would have favored the extrapolation of these the two groups were subjected to exactly the same experiment, findings, the effects observed in the different measures can be we can consider that to a large extent, the effects mediated by considered consistent. Unquestionably, however, more specific fatigue and/or inter and intraindividual variability should be studies and clinical trials using larger samples will be necessary similar in both groups and that, therefore, the differences found to help us to better understand the mechanisms involved in the would not be explained as a consequence of this factors. Finally, reported findings and to allow the extrapolation of the results. taking into account that the pro-cognitive effect of Neuravena R Another limitation is that the sample size does not allow us to constitutes the central element that have been studied in the explore the possible association between the effects found and present study, future studies should implement comprehensive specific sociodemographic and baseline characteristics that may neuropsychological assessment or additional tasks to more contribute to the magnitude of the effects. We also consider a exhaustively address the influence of Neuravena over cognitive R limitation to have not collected some data or to have controlled performance. Overall, some of the conclusions derived from the for other variables that could play a role in the observed results. present study may be considered preliminary and in need of Among these, we highlight that the type and amount of intake confirmation in future larger studies, but the set of results shed made the day before and during breakfast could have been light on the potential effects of Neuravena in certain aspects of R better controlled. These data were partially controlled by means cognitive functioning in healthy individuals. of a previous interview but in future studies they should be In summary, we found that a single dose of 800mg objectified more specifically. The effect of fatigue throughout the of the special green-oat herb preparation Neuravena was R Frontiers in Neuroscience | www.frontiersin.org 9 October 2021 | Volume 15 | Article 748188 Martinez-Horta et al. Effects of Green Oat on Cognition and ERPs associated with acute modulations on several neurophysiological ETHICS STATEMENT parameters associated with action monitoring, cognitive control, attention, and processing speed, and no negative effects were The studies involving human participants were reviewed and seen. The exact mechanisms subserving these effects are not approved by Ethics Review Board at Sant Pau Hospital. The totally understood. However, the suggested and demonstrated patients/participants provided their written informed consent to MAO-B inhibitory activity of Neuravena may play an essential R participate in this study. role in these findings. CONCLUSION AUTHOR CONTRIBUTIONS SM-H, TP-M, and JK: conception and design of the study. SM-H: Neuravena is associated with the optimization of neural R recruitment of participants and assessments. SM-H, TP-M, and resources and with increased efficiency in terms of performance EI: data analysis. SM-H, EI, TP-M, MHK, and JK: interpretation, and brain activity in healthy individuals. Further studies draft manuscript, and review. All authors contributed to the could help elucidate the effects of chronic administration article and approved the submitted version. of Neuravena on cognitive functions in health and in R disease population. ACKNOWLEDGMENTS DATA AVAILABILITY STATEMENT We would like to thank Frutarom Ltd. and Frutarom Switzerland The data that support the findings of this study are available on Ltd. for the support received during the study and to all request from the corresponding author. the participants. REFERENCES Folstein, J. R., and Van Petten, C. (2008). Influence of cognitive control and mismatch on the N2 component of the ERP: a review. Psychophysiology 45, Abascal, K., and Yarnell, E. (2004). Nervine Herbs for Treating Anxiety. Alternative 152–170. doi: 10.1111/j.1469-8986.2007.00602.x and Compl. 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The remaining authors declare that the research was conducted in the absence of Neurosci. 3, 17–26. doi: 10.3758/CABN.3.1.17 any commercial or financial relationships that could be construed as a potential Polich, J. (2007). Updating P300: an integrative theory of P3a and conflict of interest. P3b. Clin. Neurophysiol. 118, 2128–2148. doi: 10.1016/j.clinph.2007. 04.019 Publisher’s Note: All claims expressed in this article are solely those of the authors Rabella, M., Grasa, E., Corripio, I., Romero, S., Mananas, M. A., Antonijoan, and do not necessarily represent those of their affiliated organizations, or those of R. M., et al. (2016). Neurophysiological evidence of impaired self-monitoring in the publisher, the editors and the reviewers. Any product that may be evaluated in schizotypal personality disorder and its reversal by dopaminergic antagonism. this article, or claim that may be made by its manufacturer, is not guaranteed or Neuroimage Clin. 11, 770–779. doi: 10.1016/j.nicl.2016.05.019 endorsed by the publisher. Ramautar, J. R., Kok, A., and Ridderinkhof, K. R. (2006). Effects of stop-signal modality on the N2/P3 complex elicited in the stop-signal paradigm. Biol. Copyright © 2021 Martinez-Horta, Ivanir, Perrinjaquet-Moccetti, Keuter and Psychol. 72, 96–109. doi: 10.1016/j.biopsycho.2005.08.001 Kulisevsky. This is an open-access article distributed under the terms of the Creative Remy, P., and Samson, Y. (2003). The role of dopamine in cognition: evidence Commons Attribution License (CC BY). The use, distribution or reproduction in from functional imaging studies. Curr. Opin. Neurol. 16, S37–S41. doi: 10.1097/ other forums is permitted, provided the original author(s) and the copyright owner(s) 00019052-200312002-00007 are credited and that the original publication in this journal is cited, in accordance Riba, J., Rodriguez-Fornells, A., Munte, T. F., and Barbanoj, M. J. (2005). A with accepted academic practice. No use, distribution or reproduction is permitted neurophysiological study of the detrimental effects of alprazolam on human which does not comply with these terms. Frontiers in Neuroscience | www.frontiersin.org 11 October 2021 | Volume 15 | Article 748188