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.

Neuropharmacological Characterization of Extracts from Rhodiola rosea, Oenothera paradoxa and Paullinia cupana in Comparison to Caffeine

To find possible therapeutic applications involving the Central Nervous System (CNS) for herbals is a major challenge during functional food and drug discovery and development programmes. Despite the availability of numerous in vitro and in vivo tests, there is no single agreed screening procedure for pharmacological testing of herbal extracts with anticipated CNS activity. Experience gained from more than 25 years of testing has shown that two models give reasonably reliable orientation for future CNS applications: construction of an electropharmacogram based on wireless recording of field potentials from the depth of the brain of freely moving rats (Tele-Stereo-EEG) and recording of the population spike produced by pyramidal cells from hippocampal slices in vitro. A combination of these two methods has now been used to characterize the pharmacological profile of extracts from Rhodiola rosea root, Oenothera paradoxa seeds and Paullinia cupana seeds. Spectral analysis of field potentials revealed attenuation of alpha2 and beta1 waves was common for all extracts. According to previous studies, this is interpreted as activation of the dopaminergic and glutamatergic transmission. In addition, Oenothera and Rhodiola extracts attenuated delta and theta power, probably related to interference with the cholinergic and norepinephrinergic transmission, respectively. Using discriminant analysis for comparison with reference pharmaceutical and botanical drugs, Rhodiola projected near the position of Ginkgo extract, whereas Oenothera extract was projected near the position of Tramadol, an analgesic drug. Physical motion was increased only in the presence of Paullinia extract and caffeine. Increases of long-term potentiation were observed in the presence of Rhodiola extract, Paullinia extract and caffeine. The combined information predicts stimulant and cognitive function-enhancing activities in humans for the Rhodiola extract, which could also be used as a possible caffeine-replacement, and antidepressant and analgesic activity for the Oenothera extract.

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.

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.

Opposite Neurophysiological Findings Induced by Sideritis scardica and Sideritis euboa Extract in the Rat

Psychophysiological effects of Sideritis herba extracts depend on biologically active ingredients, which might be different for several botanical types of this plant. The present investigation aimed at the characterization of extracts from Sideritis scardica and Sideritis euboa in vivo and in vitro. Construction of electropharmacograms on the base of recording of electrical field potentials from four different brain regions was used to compare the possible pharmacological effects to a database of reference drugs with known clinical indications. Whereas Sideritis scardica produced decreases of spectral power in line with stimulatory frequency patterns as observed in the presence of Ginkgo biloba extract, administration of Sideritis euboa produced opposite effects. Electrical stimulation of the Schaffer Collaterals was used to elicit a pyramidal cell response called population spike in vitro. The amplitude of this spike was determined in the presence of single as well as theta burst stimuli. Direct exposure of brain matter to Sideritis scardica extract led to concentration dependent increases of the population spike amplitude under both stimulation patterns in the range from 12.5 to 100 mg/L. On the opposite, extract from Sideritis euboa did not change the electric response up to 50 mg/L. Higher concentrations of this extract attenuated the signal amplitude. A 1:1 blend of both gave intermediate results. The in vitro results are in line with the in vivo EEG recordings, where both extracts induced opposite changes of the electric power with respect to electric frequency patterns. The results from both models suggest a stimulatory and/or memory-enhancing action for the extract from Sideritis scardica but not for Sideritis euboa extract, where a more tranquillizing effect like that observed in the presence of Humulus cone extract may be expected.

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®.

Ex Vivo Characterization of the Action of Sideritis Extract Using Electrical Activity in the Rat Hippocampus Slice Preparation

A hydroethanolic extract (20% V/V) from Herba Sideritis scardica has been recognized to positively influence cognition. The present investigation aimed at the question if this extract would be able to modify intra-hippocampal communication after oral administration of 100 mg/kg daily for one week. The glutamatergic synapse between Schaffer Collaterals and pyramidal cells can be tested by electric stimulation using single pulses or theta burst stimulation. The resulting population spike is modulated by compounds acting at the central nervous system or other preparations directly or as ex vivo approach. In this case the effect of the special extract was tested in vitro the next day after repetitive in vitro administration. Conventional recording technique in the in vitro hippocampus slice revealed an increase of the population spike in the presence of single stimuli and theta burst stimuli resulting in increased long-term potentiation. This effect was tried to modulate by several glutamate receptor antagonists, among them compounds targeting at the ionic NMDA receptor (CGS19755), AMPA receptor (NBQX), Kainate receptor (UBP301) and targeting at three metabotropic glutamate receptors (mGluR I (YM298198), mGluRII ((RS)-APICA)) and mGluRIII (MSOP). Only NBQX was able to prevent the action of the Sideritis scardica extract. Since the AMPA receptor has been related to cognition in several reports in the literature, it is concluded from this result that the positive action of Sideritis scardica extract on brain function involves a modulation of AMPA receptor dependent neurotransmission.

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).

Neurocode-Tracking Based on Quantitative Fast Dynamic EEG Recording in Combination with Eye-Tracking

Information processing within the brain relies on electro-chemical features. Electric events are accessible by recording of the EEG. These electric oscillations might be regarded as a neuronal code carrying information on important motor, cognitive and emotional events. A new approach of quantitative assessment of very short time epochs of 364 ms has been developed on the base of particularly defined frequency ranges and called “Neurocode-Tracking”. The new method was technically validated by the use of a signal generator and was found to correspond to classical quantitative EEG analysis except for some smudging during the transition from one frequency range to the next. Real data from a subject were obtained during relaxation and performance of three mental tasks. Data were time averaged for 180 s using the classical method and compared to data averaging during 16.4 s. Results were nearly identical with respect to spectral signatures showing the expected midline frontal theta increases during performance of three cognitive tests but not during relaxation. Collection of very short time epochs of 728 ms duration confirmed task dependent frontal theta increases, most prominent during calculation performance test (CPT), less during d2-concentration and memory test, none during relaxation. Finally, the new technique was combined with eye-tracking. Capture of the EEG mapping video of Neurocode-Tracking and synchronization with the gaze overlay video by starting recording with an audio signal (gong) allowed a match of gazes precisely with the corresponding electric events. Use of this technical combination in research will hopefully lead to a new understanding of spectral signatures of electric activity called enkephaloglyphs.

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.

Mechanism of Action of Low Dose Preparations from <i>Coffea arabica</i>, <i>Gelsemium</i>and <i>Veratrum</i>Based on <i>in Vivo</i>and <i>in Vitro</i>Neurophysiological Findings

Low dose remedies are widely administered in medicine. We used Tele-Stereo-EEG and the hippocampal slice preparation to measure physiological effects of orally given Coffea D6 (40 mg/kg), Gelsemium D4 (10 mg/kg) and Veratrum D6 (30 mg/kg) in rats. Adult rats were implanted with electrodes positioned stereotactically into four brain regions. Changes in field potentials were transmitted wirelessly. After frequency analysis data from 6 - 8 animals were averaged. For in vitro testing, preparations were superfused directly on hippocampal slices. Stimulation of Schaffer Collaterals by single stimuli (SS) or theta burst stimulation (TBS) resulted in stable population spike amplitudes. All three low dose preparations produced decreases of spectral power. Statistically significant changes were observed in delta, theta and alpha2 spectral power. In the hippocampal slice preparation Coffea facilitated signal transfer presumably by enhancing glutamate AMPA receptor transmission. Gelsemium showed a similar effect, but only after single shock stimulation. Opposite to this, attenuation of the electric pathway was recognized after theta burst stimulation due to AMPA receptor and glutamate metabotropic II receptor mediated transmission. Veratrum was able to attenuate glutamatergic due to receptor-mediated signalling sensitive to AMPA and NMDA. The results strongly speak in favour of the existence of biologically active molecules in these low dose preparations.

Slow Gamma Activity of Local Field Potentials (LFP) in the Freely Moving Rat Relates to Movement

Quantitative assessment of local field potentials by means of Fast Fourier Transformation (FFT) results in the so-called power density spectrum. Within this spectrum particular frequency ranges are defined in order to relate these to behavior. Frequencies above 35 Hz are generally labeled as gamma oscillations, especially as low gamma (40 - 55 Hz) or high gamma (70 - 100 Hz). In order to learn more about this feature, we implanted a set of 4 bipolar concentric steel electrodes in frontal cortex, hippocampus, striatum and midbrain reticular formation of 10 rats. After recovery, field potentials were recorded and wirelessly transmitted to our computer for frequency analysis. At the same time, motion was registered during the whole experimental period of 5.75 hours. Results revealed that low gamma activity only emerged when the animal moved—at least his head. FFT of the data showed—besides other frequencies—a slow gamma activity peaking around 47 Hz pre-dominantly within the striatum, less in frontal cortex and reticular formation and nearly none in the hippocampus. Spectral analysis was performed for single epochs of 4 seconds and all 15 minutes intervals. Correlation analysis of these intervals was done to motion data. All rats showed a highly significant correlation between gamma activity and movement. We therefore conclude from these experiments that this slow gamma activity of the field potentials is not only related to movement, but possibly part of the general neuronal coding of movement.

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.

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.

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.

Effects of Neurexan on Stress-Induced Changes of Spectral EEG Power: A Double-Blind, Randomized, Placebo-Controlled, Crossover Exploratory Trial in Human Volunteers

Neurexan is a multicomponent natural medicinal product?used?for?stress-related?symptoms such as nervous restlessness and insomnia. The present study?investigated?the?efficacy?of Neurexan on stress-induced changes of brainwave frequencies?using quantitative analysis of spectral EEG power. Thirty healthy male and female volunteers were tested in a randomized, placebo controlled cross-over trial under conditions of relaxation and experimental stress-in-?duction. Recording of the EEG was performed over four hours after drug administration. Data was?analyzed using the proprietary fast dynamic EEG technology Neurocode-Tracking. Quantitative EEG revealed a task dependent increase of beta2 power as a surrogate parameter of stress induced anxiety. The elevated frontotemporal beta2 power was ameliorated by intake of Neurexan during the second and third hour after administration. This indicates that Neurexan is effectively helping subjects to better cope with task-related stress situations.

Modulation of Neurotransmission by a Specified Oregano Extract Alters Brain Electrical Potentials Indicative of Antidepressant-Like and Neuroprotective Activities

Different behavioral states are characterized by distinct patterns of global brain activity. Therefore, the biological effects of herbal extracts on brain functions can be assessed by analyzing the local field potentials, the so-called electropharmacogram analysis. Inspired by our recent findings that a specified oregano extract (OE) exhibited a triple-reuptake activity in vitro, this extract was tested in model of Tele-Stereo-electroencephalogram (EEG) to elucidate how OE affects the electrical brain activity in freely moving rats. Furthermore, discriminant analysis was performed to compare the electric brain activity of four standardized brain regions with those produced by several reference compounds, representing a whole variety of clinical indications. Oral intake of OE produced fast and robust dose and time dependent EEG alterations consisting of significant changes of spectral power in comparison to controls. Strongest effects were seen with respect to alpha1, alpha2 and beta1 waves representing an activation of serotonergic, dopaminergic and glutamatergic neurotransmission, respectively. Moreover, the discriminant analysis revealed that OE’s pattern of activity locates in close vicinity to antidepressant and neuroprotective compound. The presented data support the hypothesis suggesting the use of OE as a neuroprotective dietary supplement to promote mood, motivation and mental wellbeing.

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.

<i>In Vitro</i>Hippocampal Electrophysiology and <i>in Vivo</i>Quantitative EEG Revealed Robust Neurophysiological Effects of the Antivertigo-Agent Vertigoheel^&#174;in a Rat Study

Vertigo is a common symptom with impact on daily life. Vertigoheel&#174;(VH-04) has demonstrated to be effective for Vertigo in former studies. This paper aims to investigate the mode of action of the medicinal product VH-04 in the rat brain. In an in vitro study neurophysiological recording from hippocampal slices from adult male Sprague Dawley&#174;rats was performed in order to substantiate a possible direct effect on the brain of VH-04 in different concentrations. In an in vivo cross-over study with 11 Fischer 344&#174;?rats, a neurophysiological method was applied to systemically analyse VH-04’s activity in the rat brain. This method combines quantitative assessments of telemetrically transmitted field potentials after drug treatment with subsequent discriminant analysis to classify the compound. The database used for the analysis of classification contained numerous chemicals and medicinal products of different dosages, all tested in the same paradigm, which is continuous wireless monitoring of the EEG of freely moving rats before and after drug intake. Following single stimuli on the Schaffer collaterals in the presence of VH-04 in different concentrations, in vitro responses of pyramidal cells increased depending on the VH-04 concentration (0.25 - 4 ml/L). Results were statistically significant for concentrations above 2.5 ml/L. Long-term potentiation was only marginally affected. Out of several specific glutamate receptor antagonists the effect of VH-04 was only antagonized by AMPA and kainic acid receptor-mediated signalling. Their enhancement indicates better information processing in the hippocampus, a brain structure primarily involved in memory processes. The in vivo characterisation of VH-04-induced changes in EEG-signatures of four brain areas (the frontal cortex (FC), the hippocampus (HC), the striatum (ST) and the reticular formation (RF)) revealed a dose-dependent attenuation of delta, theta, alpha 2 and beta 1 waves. The subsequent discriminant function analysis classified the VH-04 EEG-signature into a subset of cognition-enhancing medicinal products.