Effectiveness of Herbal Drugs on the Brain

Objective Classification of Natural Compounds and Extracts in
Rats and Humans Using Electrophysiological Methods

(Electropharmacograms)

Natural compounds and plant-derived products play an ever-increasing role not only in medical therapy but also in medical prophylaxis using food supplements and functional food. This presentation bridges the gap between animal studies and clinical trials using an electrophysiological approach validated for years in testing pharmaceutical preparations of chemically synthesized compounds. Common parameter in rat and humans is the local field potential as it is recorded from the depth of the rat brain and from the scalp of the human brain as electroencephalogram (EEG). These potentials - when recorded in the presence of drugs - lead to “electropharmacograms” representing the change of spectral frequency content in the presence of drugs. Feeding the results of the frequency analysis of these signals into discriminant analysis results in a 3-D projection as shown in Fig. 1 for rats and Fig. 2 for humans.

In the rat field potentials are recorded from implanted steel electrodes and transmitted via a telemetric system wirelessly to the secondary amplifiers and further transmitted to evaluation units by means of a glass fiber. The experimental design consists in recording a pre-drug base line for 45 minutes before administration of the natural ingredients or plant extracts. Recording continues for the next 5 hours. Effects are described in % change from pre-drug values with respect to 6 frequency ranges for each of the four brain areas: frontal cortex, hippocampus, striatum and reticular formation = 24 variables. Extracts from decaffeinated Green Tea, Schisandra, Ginkgo, Ginseng, St. John`s Wort, Rhodiola, Valeriana, Camilla, Guarana, Passiflora, Kava Kava were compared to the actions of caffeine, quercetin, theanine and theogalline. All extracts and single ingredients produced electrical changes, which could be differentiated from each other by feeding the data into a discriminant analysis, where the first three discriminant axes were coded into an additive colour mixture of the colours green, red and blue.  The next three discriminant axes were coded into spatial x, y and z axes. Using this method, products with a similar effect on the brain produve similar colours and are situated at a similar spatial location like seen for theanine, quercetin, St. John`s Wort. 

Fig. 1 Projection of results of discriminant analysis based on electropharmacograms of mean data from healthy rats. Similar colour (RGB mode) represents a similar clinical indication. Similar position of neighbours (x, y and z axes) signalizes similar mechanism of action.

In humans a similar approach is performed with data derived from EEG recordings. Data from a lozenge containing four plant derived extracts (lemon balm, oat, lavender and hops), a drink containing ginkgo and ginseng as well as a decaffeinated green tea extract and a tablet containing passiflora were tested within a similar experimental design in comparison to placebo. After base line recording, administration of the extracts was followed by hourly recordings of  5 minute duration under conditions of “eyes open”. The data from the electropharmacograms (17 electrode positions times 6 frequency ranges = 102 variables) were fed into a linear discriminant analysis. It could be shown, that the actions of the four preparations were entirely different from placebo. However, the hourly recordings within one trial showed the same colour. This proved the extremely high sensitivity of the method and the consistency of the observed effects. 

Fig. 2 Discriminant analysis of human EEG in the presence of Green Tea (deaffeineated theanine and theogallin enriched green tea extract), Lozenge (lozenge containing lavendula, oat, hops and lemon balm), Ginkgo (drink containing extract of ginkgo and ginseng), Neurexan^® (homeopathic tablet containing passiflora and avena sativa), Hypericum (St. John`s Wort), Ethanol, Melissengeist (Klosterfrau Melissengeist^®), Placebo. Numbers represent hours after administration. Recording during eyes open (a).

The data document, that field potentials from rats and EEG from humans are valid parameters for the description of effects of natural compounds and plant derived extracts on the brain.

Dimpfel W, Pischel I, Lehnfeld R (2004) Effects of lozenge containing Lavender oil, extracts from Hops, Lemon balm and Oat on electrical brain activity of volunteers. Eur. J. Med. Res Sep 29; 9 (9):423-431

Dimpfel W, Kler A, Kriesl E, Lehnfeld R and Keplinger-Dimpfel I.K (2006) Neurophysiological characterization of functionally active drink containing extracts of ginkgo and ginseng by source density analysis of the human EEG (Nutritional Neuroscience Vol 9, 213-224.

Dimpfel W, Kler A, Kriesl E, Lehnfeld R and Keplinger-Dimpfel I.K (2007) Source density analysis of human EEG after ingestion of a drink containing decaffeinated extract of green tea enriched with L-theanine and Theogallin (Nutritional Neuroscience Vol 10, 169-180).

Dimpfel W (2007) Psychophysiological effects of Neurexan^® on stress-induced Electropsychograms (World Conference of Stress 2007 in Budapest).

Enkephaloglyphs

Spectral Signatures of Electric Brain Activity

Enkephaloglyphs represent spectral signatures of electric brain activity under various recording conditions. Start point is a 16 channel EEG recorded followed by quantitative frequency analysis based on Fast Fourier Transformation (FFT). A unique method for mapping frequency changes allows documentation of all changes within one map, which corresponds mathematically to a 64 channel EEG. Depending on the application field enkephaloglyphs are subdivided into four categories:

Category	Duration of Recording	Information on	Main Use	Software Package
Electropsychogram	364 ms	Advertisement Research	TV Commercials Internet Surfing	neo-CATEEM®
Electropathogram	3 min	Medical Diagnosis	Neurological Disease	neo-CATEEM®
Electropharmacogram	2 x 5 min	Drug Action	Drug Development	neo-CATEEM®
Electrohypnogram	8 h	Sleep	Characterization of Sleep Aids	neo-CATEEM®

For the purpose of advertisement research single sweeps of 364 ms duration are needed because of the processing time of the brain for acoustic or visual stimuli (300-400 ms). Exact synchronization with eye tracking allows for quantitative evaluation of the reaction of the brain to single gazes. Importantly, not only conscious but also subconscious processes are evaluated.

For the purpose of medical diagnosis a longer recording of at least 3 minutes is recommended in order to determine the averaged basic status of electric activity and to compare it to a norm data base of several hundred healthy brains. Any of 102 quantitative parameters (17 electrode positions x 6 frequency bands) are evaluated and given with statistical significance for deviation from normality.

For the purpose of drug development at least two periods of 5 minutes of recording (placebo and active drug) are recommended to see changes of basic activity related to drug action. Frequency changes can be interpreted in terms of neurotransmitter activity. Based on about 25 years of experience a rational pharmacotherapy can be initiated on the knowledge which frequencies can be modulated by particular drugs with known effects on neurotransmission.

For the purpose of quantitative, objective description of sleep and discovery of new sleep aids the spectral frequency index (SFx) - an algorithm patented 20 years ago - was developed and validated. The SFx continuously documents the depth of sleep even during anaesthesia in one minute intervals. The parameter is medication independent and displayed in line real time on the screen. Its use saves medication and prevents undetected awakening (muscle relaxation!).

More information: www.neurocode-ag.com  w.dimpfel@neurocode-ag.com Phone: +49 6441 2002033

Wilfried Dimpfel: Enkephaloglyphen, Spektrale Signaturen der elektrischen Hirntätigkeit als Spiegel der Psyche.

ISBN  978-3-8448-8208-7

Quantitative Assessment of Brain Disease by EEG

Like any other organ of our body the brain is also prone to a number of disturbances exerted by inner and external influences. Internal reasons might be disturbances of the blood flow and by it supplementation of oxygen. External influences might come from intrusion of bacteria and viruses. But also traumatic influences are of considerable meaning. As multifunctional disturbances can be, as heterogeneous are the consequences. This is a trivial statement, which shows special consequences, since we are dealing with a highly complex system. In many organs partial disturbance of a particular region only leads to quantitative diminution of total organ capacity. With respect to the brain one might suffer from a variety of different qualitative and quantitative failures. This is quite obvious in the case of stroke or tumors, where particular regions suffer from local disturbances, or even lack their function totally. This high complexity together with the network structure as mentioned above asks for evaluation of its total functionality. Traditionally, one discriminates between the so called “somatic” part of the brain and its “psychic” components. Breakdown of the former part is covered by the field of neurology, whereas breakdown or disturbances of the latter are covered by the field of psychiatry. Fortunately, both areas are very often covered by one and the same doctor, at least within Germany. Differences are also reflected by different diagnostic tools. Neurologists mainly use  methods based on the visualization of the brain`s “hardware”, but psychiatrists still depend on the verbal communication of subjectively experienced symptoms.

Broadest use in neurology is made of x-ray, computer tomography and magnetic resonance tomography (MRT). In the second case electroencephalography (inclusive evoked potentials, see later) and functional MRT. In addition, ultra sound technologies are used currently more and more. I mention this because the development of technical methods for assessment of possible “somatic” causes of disease has made large progress, whereas for example electroencephalography as “software check” remained far behind its possibilities. The mathematical description of the electric brain activity by means of the Fast Fourier Transformation (FFT) as well as the definition of particular frequency ranges according to their physiological meanings, as realized in the CATEEM system, seem to be very promising.

After extensive use of the CATEEM system for characterization of drugs and after its successful use in sleep research it was decided to learn more about disturbances of electric brain activity during disease processes. Based on the assumption, that disease origins from disturbances of electrochemical communication within the brain, the goal emerged to describe the current state of the brain in terms of changed local frequency patterns. All what was needed now was a data base of healthy subjects characterized in the same manner giving median numbers of all six frequency ranges at each of the 17 locations. A total of 500 healthy volunteers of both sexes aged 18 to 80 participating in our medication studies were used to construct a “normal” database. The distribution of these 102 values (17 electrode positions times 6 frequency ranges) now serves for comparison of single patients to this data base. According to the distribution function, error probabilities for each single value are calculated and given as numbers from 1 to 4 representing error probabilities from 10:1 to 10000 to 1. Fig. 1 documents the mathematical base of the calculation. 

Fig. 1 Calculation of the aberration index

This value is called “aberration index”. In medicine “normal values” are based on averaged mean numbers collected from a larger population. Even if your blood pressure is not exactly 120 to 80, it can still be normal. But the larger the deviation of individual values, the higher the probability of having a pathological feature. For mapping the same type of color code is used as for depiction of the original data, but now they represent the statistical deviation from normality. Fig. 2 shows examples of the recorded electric disturbances during different diseases.

With this index an objective measure for the occurrence of a functional disturbance of the brain was developed, which not only can be used as a diagnostic aid, but also could serve as control for a therapeutic success. If the aberration index becomes smaller this is interpreted as an approach to normality. During the course of degenerative disease also a progressive development can be detected using this parameter. From this is becomes obvious that this parameter is useful for the evaluation of the effect of medications as could be shown recently in patients suffering from Parkinson`s disease (Dimpfel et. al. ,2014). 

 Consequently, a large number of patients have been recorded using the CATEEM technology in numerous hospitals. We always made the experience, that discoveries of “hardware” abnormalities were accompanied by disturbances of electric activity. Of special interest were disturbances of electric brain communication, which up to now have escaped objective quantitative measurements. I like to mention headache and especially migraine, since we – using the method developed by us – succeeded for the first time to record clear, statistically significant, reproducible changes of electric patterns of this disease. Recording from more than 600 patients suffering from migraine indicated that in about 90% of the cases a deviation from normality was detected. But results also revealed the heterogeneity of headache and migraine, since deviations form normality not only occurred within different brain areas but also with respect to different frequencies. These deviant electric patterns were recorded during the ache-free interval and support the neurogenic origin of the disease. However, many textbooks refer to the vascular origin of migraine, based on disturbance of the blood flow. Since higher nervous systems activity at the same time recommends higher oxygen demand, it is very difficult to see where the original disturbance comes from, the famous egg-hen problem. Thus, quantitative assessment of EEG recordings using neo-CATEEM (http://www.mewicon.at) provides an entirely new approach in objectifying pathological disturbances of the brain during disease. 

 

Examples of quantitative assessment of pathological electric brain activity using CATEEM.

Reference

Dimpfel W, Öhlwein C, Hoffmann JA, Müller T (2014) Parkinson`s Disease during Therapy with Rasagilin. Advances in Parkinson`s Diesease 3: 22-34