Psychophysiological Effects of Sideritis and Bacopa Extract and Three Combinations Thereof—A Quantitative EEG Study in Subjects Suffering from Mild Cognitive Impairment (MCI)

Mild cognitive impairment (MCI) is regarded as a transitional stage during the development of Alzheimer’s disease. Diagnosis of MCI can be obtained by the questionnaire “DemTect” in German speaking countries. Quantitative assessment has been successfully performed using psychometric testing concomitantly with quantitative EEG recording. The present investigation aimed at the possible treatment of MCI with two botanicals, namely extracts from Sideritis scardica (500 mg) or Bacopa monnieri (320 mg) and three combinations thereof using this method in order to find a new treatment. The performance of the d2-test, an arithmetic calculation test (CPT) and a memory-test revealed better performance for the d2-test only in the presence of Sideritis extract or the combinations with Bacopa extract. Quantitative EEG assessment during the different experimental conditions showed massive differences between both extracts. Whereas Sideritis extract and its combination with a low amount of Bacopa extract (160 mg) induced increases of spectral power in fronto-temporal brain areas, Bacopa and the combination of Sideritis with high amounts of Bacopa extract produced attenuation of all waves except for delta in fronto-temporal brain areas. These differences were also documented by quantitative EEG maps in comparison to Placebo. A different action of both extracts was confirmed by discriminant analysis, where Sideritis extract and its combination with low Bacopa grouped together quite at distance to Bacopa and the combination of Sideritis with high Bacopa. A combination of Sideritis extract with a low amount of Bacopa should be tested with daily repetitive dosing for at least 4 weeks as a consequence.

EnkephaloVision: Anatomical Functionality Indicated by Ultrashort Transient Regional EEG Spectral Power Changes during Cognitive and Emotional Challenges

Anatomical functionality is a major topic in brain research. Numerous investigations have shown task dependent activation of focal brain areas, with most information based on time-averaged data due to methodological limitations. Ultra-fast quantitative EEG, especially in the newly developed combination with eye tracking (EnkephaloVision), is very suitable to follow activities of local electric circuits. This investigation in 57 subjects revealed transient focal frequency changes reaching up to more than 6000% of global median spectra power during cognitive and emotional challenges at frontal electrode positions. Recording epochs of 364 ms uncovered coherences with respect to focal brain areas and single frequencies, which are typically lost during averaged calculations. When averaging data over a whole scene, a least demanding challenge like viewing a boring animal video only activated the lateral frontal lobe, whereas solving brain-teasers and performance of mathematical calculations led to delta (modulated by acetylcholine) and theta (modulated by norepinephrine) increases in all brain regions in a statistically significant manner. In addition to delta and theta increases, performance of the Stroop test led to beta2 (related to GABA-ergic transmission) increases in the temporal lobe. The higher the mental demand the more brain regions were involved during 10 different challenges. There was no challenge which did not activate the lateral frontal brain in terms of increases of delta and theta spectral power. The results are in line with the view that the lateral frontal lobe is involved primarily during cognitive and emotional behavior related to activity changes of acetylcholine and norepinephrine.

Psychophysiological Effects of a Combination of Sideritis and Bacopa Extract (memoLoges®) in 32 Subjects Suffering from Mild Cognitive Impairment. A Double-Blind, Randomized, Placebo-Controlled, 2-Armed Study with Parallel Design

Mild cognitive impairment (MCI) can be regarded as a non-demented transitional stage during the development of Alzheimer’s disease. Early recognition of this stage might increase the chance of prevention by early treatment. Within a pilot study, two plant-derived preparations and mixtures thereof were tested successfully in subjects suffering from MCI. A combination of Sideritis scardica and Bacopa monnieri extract (memoLoges®) was chosen now for a repetitive dosing during 4 weeks. Thirty-two subjects aged 50 to 80 years and suffering from MCI (having a DemTect questionnaire score between 8 and 13) were recruited for intake of 2 capsules of the preparation per day. Quantitative EEG recording during relaxation and concomitant performance of three 5 minutes lasting psychometric tests (d2-concentration test, arithmetic calculation test and memory test) was achieved at the first day and one day after the last repetitive intake. Seventeen channels of EEG and one channel EOG (for artefact rejection) were recorded. After frequency analysis (FFT) current source density was calculated as reported earlier. One, two and three hours after intake of the herbal extract or placebo the whole procedure was repeated. Brain imaging was achieved by conversion of numerical values of spectral EEG power into spectral colors and additive color mixture according to RGB as used in TV settings. Intake of memoLoges® induced a trend of improvement of performance in psychometric testing (all three tests). During relaxation quantitative assessment of EEG data revealed attenuation of delta and theta spectral power in frontal brain as likewise reported in the presence of the Alzheimer drug rivastigmine, bringing the spectrum back to “normality”. During mental work memoLoges® induced statistically significant increases of beta power. Since MCI subjects produce less beta power in comparison to healthy subjects, this increase must likewise be seen as a positive effect pointing to a healthier spectrum.

Psychophysiological Effects of Zembrin®Using Quantitative EEG Source Density in Combination with Eye-Tracking in 60 Healthy Subjects. A Double-Blind, Randomized, Placebo-Controlled, 3-Armed Study with Parallel Design

The endemic South African succulent plant Sceletium tortuosum (L.) N.E. Br., family Mesembryathemaceae, is known as kanna in Nama, kougoed in Afrikaans, and sceletium in English. The plant has been used as a tea and as a masticatory for millennia by indigenous San hunter-gatherers and Nama pastoralists for endurance and well-being. It has been reported that the plant “gives strength to their limbs, and takes away pain, and makes their memory strong”. The current investigation aimed at the psychophysiological characterization of 25.0 and 50.0 mg of a special extract marketed as Zembrin® in comparison to placebo using a new methodology called “EnkephaloVision”. This combination of EEG Neurocode-Tracking and Eye-Tracking allows for concomitant analysis of time epochs of only 364 ms duration. Spectral EEG analysis during cognitive and emotional challenges revealed statistically significant increases of delta (p < 0.01 during arithmetic calculation and watching a boring animal video) and theta spectral power (p < 0.10 during these same challenges) in the presence of Zembrin® within the frontal brain. It is these same increases of slow waves in the frontal brain that are described in the literature during performance of mental tests. This indicates a positive effect of Zembrin® on the electrical activity of the brain during cognitive processing. In addition, alpha1 and alpha2 spectral power in the frontal brain was increased during several challenges including brain teasing, arithmetic calculations and performance of a memory test. From the literature, increases of spectral alpha1 power indicate a greater degree of calmness and may represent decreased depressive symptoms, while increases in alpha2 waves have been related to memory. Beta2 waves increased during mental performance in the presence of the higher dosage of Zembrin® in parietal, occipital and temporal brain regions. In comparison to placebo, Zembrin® induced frequency changes in the brain, which have been related to enhanced attention and memory. These results may represent a positive action of Zembrin® on cognitive and emotional processes in the brain.

Neuromarketing: Neurocode-Tracking in Combination with Eye-Tracking for Quantitative Objective Assessment of TV Commercials

The term “neuromarketing” suggests a combination of marketing research and brain research. Within marketing research, objective assessment of TV commercials is performed by use of Eye-Tracking devices. Brain research has been dominated by NMRI technologies during the last years. However, information content and time resolution are much better when monitoring electric activity by spectral analysis. The current experimental approach was initiated in order to test the combination of a newly developed EEG technology (Neurocode-Tracking) with commercially available Eye-Tracking. Ten male subjects were exposed to a reference recording condition (watching a fixed cross on the screen) followed by 5 TV commercials representing 5 different banks. Video films obtained from Eye-Tracking (so-called heat maps) were synchronized with the results of Neurocode-Tracking in form of a second video with a time resolution of 364 ms per image. Spectral power analysis of the EEG in different brain regions allowed for assessment of single scenes for cognitive and emotional responses. Averaging of data over the whole time course gave information on mental activation, attention, visual perception, memory, pleasure and tension. Comparison of the 5 commercials to reference recording revealed the clip of the Targo-Bank having the highest values with respect to mental activation and attention.These experiments have proven that the combination of Neurocode-Tracking with Eye-Tracking can be successfully used in advertisement research and gives valid information on individual as well as group dependent cognitive and emotional responses leading to objective assessment of TV commercials.

Quantitative Objective Assessment of Websites by Neurocode-Tracking in Combination with Eye-Tracking

Assessment of websites remains a definite challenge within advertisement research. In order to gather objective information, one possibility exists in using Eye-Tracking. This method allows for determination of where and how long particular areas of a website are fixed. However, longer fixation values do not necessarily reflect higher attention or even memorizing of the content. It could also mean that the content is too complicated. Therefore more information can be obtained by addition of quantitative analysis of brain electricity. Following the changes of the frequency content of electric brain activity has been recently introduced as “Neurocode-Tracking”. In the present study, quantitative assessment of websites has been performed by the combination of Neuro-code-Tracking with Eye-Tracking. Fast dynamic quantitative EEG recording with a time resolution of nearly 3 images/second provided electric power values according to frequency analysis in 17 brain regions (electrode positions). Particular values represented changes of electric brain activity, which were interpreted to represent visual perception, mental activation, concentration, stimulation, memory and tension according to earlier experience. Eye-Tracking was performed in a conventional manner by defining special areas of interest for detection of fixation lengths and time to first awareness. Ten male subjects (aged 36 ± 4.4 years) entered the study. They were asked to view Internet landing pages of five bank institutions: ComDirect, DKB, INGDiBa, Postbank and Targo-Bank. According to Eye-Track analysis, ComDirect was recognized to have the shortest time-to-awareness with respect to conditions, bonus, faces and application or address form. With respect to region of interest “service”, INGDiBa showed the shortest time-to-awareness. Neurocode-Tracking provided best results for INGDiBa with respect to mental activation and concentration. Stimulation and memory values were headed by Targo-Bank. Lowest tension was observed by the landing page of the Postbank. In summary, the combination of Neurocode-Tracking and Eye-Tracking provided much more information than any one of the methods used in separate. We therefore recommend this combination for the assessment and optimizing of Internet websites.

Neurophysiological Biomarker of Mild Cognitive Impairment

Mild cognitive impairment is sometimes regarded as related to aging. However, statistically every second case turns into full dementia, which still is resistant to any treatment. It is therefore desir-able to recognize deviations from normality as early as possible. This might be feasible by using quantitative EEG analysis in the presence of mental work. The present retrospective data analysis revealed a new quantitative biomarker indicating the degree of impairment. Current source density was calculated from 16 channel EEG using CATEEM?? software. Four different conditions were analyzed: relaxed state, performing a d2-concentration test, a calculation performance test and a memory test for 5 min each. Subjects older than 40 years were divided into two groups according to their DemTect score: 13 - 18 (HC;n = 44) or 8 - 12 (MCI;n = 45). Spectral power was chopped into six frequency ranges (delta, theta, alpha 1, alpha 2, beta 1 and beta 2). Average spectral power was enhanced in the MCI group in comparison to healthy subjects with respect to delta (p = 0.05) during relaxed state when all electrode positions were regarded. With respect to EEG recording during performance of three different psychometric tests it was recognized that mainly spectral changes during performance of the d2-concentration test were related to mild cognitive impairment. With regard to all electrode positions statistically significantly lower spectral power values were reached during the d2-test for delta (p = 0.001), theta (p = 0.0001) and alpha 1 waves (p = 0.08) in impaired subjects in comparison to healthy subjects. Regarding regions of interest increases of delta and theta power were seen in the fronto-temporal brain during performance of the d2-concentration test. These increases disappeared when looking at MCI data. In the centro-parietal region decreases of alpha and beta 1 power emerged, which were even larger in MCI subjects. No MCI-dependent changes were observed in the other two tests. A correlation was found between psychometric performance of the d2-test and the DemTect score (r = 0.51). MCI subjects had statistically significant worse performance in all three mental challenges in comparison to healthy volunteers. It is concluded that MCI can be characterized at an early stage by EEG recording in the relaxed state. High spectral delta and theta power in general and specifically at fronto- temporal electrode positions (especially at T3) was recognized as a biomarker for MCI. A DemTect score of 8-12 was validated as indicative for MCI.

Cerebral Bioavailability of Silexan—A Quantitative EEG Study in Healthy Volunteers

Background: A quantitative EEG (qEEG) study was performed to investigate the cerebral bioavailability of Silexan. Method: Twenty-four male and female healthy volunteers between 20 and 62 years of age were eligible for participation and received 160 or 80 mg/day Silexan or placebo in randomised order according to a 3-way crossover design. Treatment phases of 14 days were separated by 14-day washout periods. qEEG recordings in conditions “eyes open”, “eyes closed”, as well as during performance of 3 different cognitive tasks, were performed at 0, 1, 2, 3, and 4 h after drug administration on the first (single-dose assessment) and last day of each treatment period (repetitive dose assessment). Result: Compared with placebo, qEEG analysis revealed a significant increase of spectral power within two hours in the alpha1 range (7.0 - 9.5 Hz), particularly in the fronto-temporal region, where it was more pronounced after administration of Silexan 160 mg/day than after the 80 mg/day dose. Changes in other frequency bands were mainly attributable to circadian rhythm. No EEG changes typically seen during the investigation of sedative drugs (general theta increase) were observed. Cognitive task performance under both doses of Silexan was not inferior compared with that in the placebo period. Conclusions: The study provides evidence that ingredients of the anxiolytic lavender oil preparation Silexan penetrate the blood-brain barrier and induce functional changes in the CNS. The types of changes observed in the qEEG are consistent with the anxiolytic clinical effect of the drug represented by increases of alpha1 spectral power. No sedative effects were observed. Silexan was well tolerated during repetitive administration of doses up to twice the marketed dose.

Classification of Herbal Drug Effects by Discriminant Analysis of Quantitative Human EEG Data

Clinical indications for herbal drugs very often only rely on traditional knowledge. Single plant-derived preparations are used for many purposes and cannot be classified to belong to a single category like calming or stimulating drugs. With respect to the brain a unique possibility exists to analyze drug effects by recording the EEG. It is common knowledge that many drugs change the frequency content of electric brain activity. Quantitative analysis of the EEG by Fast Fourier Transformation reveals parameters like spectral power, which can be processed further (CATEEM&#174;). Source density was determined from 17 channels of the quantitative EEG from 10 clinical studies recorded in a relaxed state with open eyes. Linear discriminant analysis was used to differentiate the effects of Placebo (circadian rhythm) from CNS-active herbal drugs in comparison to Valium&#174;. Calmvalera&#174;, L-Theanine, Lasea&#174;, Neurapas&#174;, Neuravena&#174;, Neurexan&#174;, Nutrifin Relax&#174;, Pascoflair&#174;(herbal calming drugs) as well as memoLoges&#174;, Zembrin&#174;(herbal stimulating drugs) induced different changes of the frequency content of brain electric activity. Discriminant analysis revealed that Nutrifin Relax&#174;, Pascoflair&#174;and Suntheanine&#174;could not be separated well from each other indicating a similar mechanism of action. The effect of Valium&#174;was projected at a very isolated position far away from the herbal preparations indicating a totally different mechanism of action. Zembrin&#174;and memoLoges&#174;grouped together with respect to the first three discriminant functions, but were different with respect to the 4th to 6th discriminant function. Lasea&#174;as anxiolytic drug and Neurapas&#174;as antidepressive drug were projected at isolated positions indicating their different clinical indications. The results indicate that discriminant analysis of human quantitative EEG data allows for unique pharmacological description of individual effect profiles of herbal drugs.

Proof of Effectiveness of PASCOFLAIR®in Subjects Suffering from Examination Anxiety Using Quantitative EEG in Combination with Eye-Tracking (EnkephaloVision). A Double-Blind, Randomized, Placebo Controlled, 2-Armed, Phase IV Study in Parallel Design

The pharmaco-dynamic action of plant-derived drugs still remains a big challenge in the field of pharmacology. This applies especially for the discovering of the possible mechanism of action. With respect to the brain, surrogate parameters may be very helpful. Non-invasive pharmaco-EEG has been proven to provide valid information on drug effects in general. Fast dynamic EEG recording with epoch length of 364 ms has now been achieved in combination with Eye-Tracking in order to elucidate single scenes during cognitive and emotional challenges (EnkephaloVision). The present investigation deals with the psychophysiological characterization of the effect of a plant-derived preparation marketed in Germany under the name of PASCOFLAIR® containing 425 mg of passionflower extract in subjects suffering from examination anxiety. Forty healthy volunteer subjects (17 men and 23 woman), with ages varying between 18 and 40 years (26 ± 6.726 for men and 25 ± 5.397 for women) were included into the study when having a score higher than 60 in the PAF (Pr&#220fungsangstfragebogen). Spectral power analysis of pre-drug data with respect to beta waves revealed a significant correlation to the score of the PAF. Increases of delta, theta and beta waves as induced by 4 cognitive and 4 emotional challenges were attenuated in the presence of 2 tablets of PASCOFLAIR® already 45 minutes after intake in a statistically significant manner in comparison to placebo. Regarding attenuation of beta1 and beta2 spectral power, effects on glutamatergic and GABAergic neurotransmission, respectively, can be suspected according to our knowledge of frequency—transmitter relations. Accordingly, this attenuation must be interpreted as ability to counteract examination induced stress symptoms. Results confirm and extend earlier experimental data showing a calming action of PASCOFLAIR®.

Quantitative EEG Changes in Patients with Parkinson’s Disease during Therapy with Rasagiline

It has been suggested that in patients with Parkinson’s disease (PD) metabolism of the MAO-B inhibitor selegiline to methamphetamine may contribute and/or exacerbate sleep problems, possibly leading to deficits of cognition. This open-label exploratory study included 30 PD patients currently being treated with selegiline (7.5 mg/day) and complaining of sleep disturbances. The aim of the study was to determine whether switching from selegiline to another MAO-B inhibitor without amphetamine-like metabolites, namely rasagiline, would improve sleep behaviour and cognitive function in PD patients. Pathologic aberrations as determined by comparison of the frequency pattern of patients to a database consisting of healthy subjects revealed an approximation of electric brain activity to normality. For verification of efficacy, a combination of questionnaires, quantitative source density EEG recording with CATEEMò and performance of two psychometric tasks (d2-test of attention and reading) during the EEG recording were done on the last day of selegiline treatment (7.5 mg/day) as well as 2 and 4 months later, during which the patients were treated with rasagiline (1 mg/day). In addition, performance of the mental tasks revealed a statistically significant (p < 0.05) increase of theta power (4.75 - 6.75 Hz) indicative of improved cognitive abilities at the end of the treatment period. At the same time evaluation of the psychometric test results indicated a statistical improvement with respect to the score of the d2-test (increase from 6.54 to 7.37;p < 0.05). Serum levels of methamphetamine were measured before and after intake of selegiline or rasagiline. They were correlated to alpha2 power, which is under dopaminergic control, within the temporal lobe. From these results it is concluded that the switch from selegiline to rasagiline not only improved sleep behaviour as reported separately but also had a positive effect on electric brain activity and on cognition in these patients.

Effect of Zembrin^(█) on Brain Electrical Activity in 60 Older Subjects after 6 Weeks of Daily Intake.A Prospective,Randomized,Double-Blind,Placebo-Controlled,3-Armed Study in a Parallel Design

Zembrin? is a botanical functional food and dietary supplement ingredient sold in the USA, and Canada for enhancing mood, decreasing anxiety and stress and improving cognitive function under stress. It is a proprietary extract of a cultivated selection of Sceletium tortuosum. The present investigation aimed at the measurement of the effect of 25 or 50 mg of Zembrin? in comparison to placebo after daily repetitive intake for 6 weeks. Sixty healthy male (n = 32) and female (n = 28) right-handed subjects between 50 and 80 years old (59.7 ± 5.43 and 56.7 ± 5.88 years, respectively) were recruited. The EEG was recorded bipolarly from 17 surface electrodes (CATEEM?) before and 1 h after intake. Six cognitive tests were performed: d2-test, memory test, calculation performance test, reaction time test, number identifying test and number connection test. Three questionnaires were included: Profile of Mood States, Hamilton Anxiety Rating Scale and a sleep questionnaire. Quantitative EEG revealed increases of delta activity during performance of the d2-test, the number identification and number connection test in the fronto-temporal brain region. Higher theta activity was seen during relaxation and performance of the d2-test after intake of 50 mg of Zembrin?. Statistically conspicuous increases of alpha1 spectral power were seen in the relaxed state. With respect to alpha2 spectral power larger increases were observed in the centro- occipital region. Discriminant analysis revealed a projection of Zembrin? data into the vicinity of the calming preparation Calmvalera tablets and a Ginkgo-Ginseng mixture. Statistically significant improvement during performance of the arithmetic calculation test and number connection test was documented. The HAM-A anxiety score revealed a statistically significant decrease (p = 0.03) after six weeks. Zembrin? showed significant activity on three levels of evidence: questionnaires, psychometry and quantitative EEG. The results indicate that in healthy people Zembrin? improves some aspects of cognitive function, decreases anxiety, and may enhance mood.

Psychophysiological Effectiveness of Calmvalera Hevert Tablets as Measured by EnkephaloVision in Anxious Subjects during Audio-Visual Cognitive and Emotional Challenges: A Double-Blind, Randomized, Placebo-Controlled, 2-Armed, Phase IV Study in Parallel Design

Subjects suffering from anxiety during examinations often take drugs with considerable side effects. As alternative, homeopathic preparations virtually lack side effects in general. However, clinical efficacy has to be demonstrated. This experimental series was initiated to provide evidence, that Calmvalera Hevert tablets, marketed for treatment of nervous restlessness and better coping with stress, have an influence on brain electric activity. In order to test this, a new clinical design was used: “EnkephaloVision”. It consists of the combination of quantitative EEG recording with time epochs of 364 ms (Neurocode-Tracking) with conventional Eye-Tracking. Seventeen channels of EEG and one channel EOG were recorded. After frequency analysis (FFT) current source density was calculated. Recording was performed in the presence of a video clip, which contained several different cognitive and emotional challenges in series. Twenty-four male and female subjects having a score >60 in an anxiety questionnaire (Prüfungsangstfragebogen PAF-S) were recruited to participate. A correlation between the Hamilton anxiety score and spectral alpha1 power during the recording condition “eyes open” before drug intake was detected. Spectral power was averaged including Cz, F3 and F4 electrode positions. Audiovisual challenges induced spectral changes with respect to delta, theta and beta power, not in the alpha ranges, to a different but statistically significant degree. Intake of Calmvalera Hevert tablets resulted in statistically significant increases of alpha1 and alpha2 spectral power during most of the recording conditions within the left hemisphere. Increases of alpha activity have been related to relaxation and calmness as reported in the literature. Discriminant analysis of the whole data set revealed a clear difference between verum and placebo and a projection of the data into the vicinity of other plant-derived calming preparations. Performance of psychometric tasks was not disturbed. Efficacy of Calmvalera Hevert tablets points to active molecules contained due to low triturations (D2 - D8).