NONINVASIVE SELECTIVE TRANSCRANIAL ELECTROSTIMULATION OF THE BRAIN ENDORPHINERGIC STRUCTURES (TES-THERAPY) AS AN EFFECTIVE TOOL OF REVITALIZATIONE MEDICINE Professor Lebedev

V.P., MD, PhD, Dr. of Sci Center of Transcranial Electrostimulation, Pavlov Institute of Physiology, Russian Academy of Sciences, St.- Petersburg, Russia e-mail: lebedev@infran.ru; www.tes.spb.ru Endorphins are known to have many properties that allow considering them homeostatic regulators, which is manifested during their systemic and intracerebral injections. It has been shown that they have a pronounced anti-nociceptive effect, are anti-stressor hormones, help improve memory, activate immune system, promote elimination of age-related alterations of vascular walls, prevent aging by removing peroxide compounds. It is an appearing complex of such effects, which is important for use in revitalization medicine. Endorphins are produced predominantly by brain nerve cells and, to a lesser degree, by adrenal medullary cells and neurons of intestinal plexuses. Subcortical brain structures containing endorphinergic and closely related serotoninergic neurons are combined by the common term protective brain mechanisms as their direct electrostimulation produced the above homeostatic effects. This work presents data on development of the transcranial (through the skull) electrostimulation (TES) for noninvasive selective activation of protective (anti-nociceptive) mechanisms of brain subcortical mechanisms, which allows using activation of the brain protective mechanisms as an efficient tool of revitalization medicine. I. Development of the method of TES-therapy The present procedure and its application in clinical practice, unlike the earlier described methods of transcranial electrostimulation (electroanesthesia, electrosleep, electroanalgesia) was carried out with use of rules of GLP (good laboratory practice) and GCP (good clinical practice) accepted in international practice. In compliance with these rules, to study mechanisms of the effects, it seemed necessary to use the most current methods of study of mechanisms, screening to reveal optimal regime of action, use of experimental-pathological models in preclinical studies and double blind control in clinical observations. Taking into account these rules, we formulated tasks of the investigation and directed ways of their solution, presented in Table 1. This table also presents principal results of solution of these tasks.

Table 1 Setting of tasks and ways of their solution in the course of development of the TES method

Task Finding the head of optimal for brain

Way of solution

Result Activation of protective brain

position of electrodes on surface of approaching current to structures protective mechanisms

Determination of ways of current in the brain by nuclear magnetic resonance tomography

mechanisms can be performed only if the current runs in sagittal direction (frontoof retromastoidal electrodes) Quasi-resonance position

regularities and

Screening on experimental models frequencyeffect Selection of optimal electric TES parameters etc.)

(pain, reflexes, wounds, tumors, durationeffect have been revealed to serve the ground for construction of therapeutic TES apparatuses 1. Mapping of activated neurons by immunocytochemical and autoradiographic methods. 2. Determination of levels of endorphin in the brain, The selected TES regimes have proved to activate of cerebrospinal fluid and blood been

Proofs of activation of endorphinergic and serotoninergic structures of protective brain mechanisms

plasma by radiochemical and of selectively endorphinergic and serotonin in the cerebrospinal serotoninergic fluid and blood plasma biochemical methods. 3. Use of agonists and antagonists of opioid and serotoninergic structures by protective brain mechanisms

receptors Using a modified NMR-tomography, it was shown that only the sagittally directed current (the foreheadmastoids position of electrodes) could reach the anti-nociceptive system by running through two intracranial ways (cerebrospinal fluid of basal cisterns and brain ventricles). In screening experiments there were revealed quasi-resonance correlations frequency of impulseseffect and duration of impulseseffect of activation of the anti-nociceptive

system. These correlations were further used to design equipment realizing the method of TEStherapy (Fig. 1, A). By the above type of the brain electrostimulation, indeed, the anti-nociceptive system structures were activated. Thus, incorporation of [3H]-deoxyglucose (autoradiography) indicating activation of neurons increased in the periaqueductal gray substance and decreased in the brainstem relay nuclei involved in transmission of ascending nociceptive impulsation as well as in somatosensory brain cortex. The elaborated TES-regime activated predominantly endorphinergic and serotoninergic mechanisms of the anti-nociceptive system. There also was observed an essential rise of endorphin concentration in brainstem structures, spinal cord dorsal horns, cerebrospinal fluid and blood as well as of metenkephalin in the cerebrospinal fluid (radioimmunochemical studies). A

pM/L 30

Fig. 1. Dependence of TES-effects (A, analgesia) and of blood -endorphin level (B) on frequency of transcranial electrostimulation Maximal increase of -endorphin concentration was observed during actions with parameters coinciding with point of TES quasi-resonance (Fig. 1, B). The level of serotonin (5-HT) in the cerebrospinal fluid also increased. In parallel with the increase of the opioid peptide

en dor phi n

20

10

0 C1 C2 60
65 70 75 80 Hz

concentration in the cerebrospinal fluid there occurred a decrease of the P substance level, especially on the background of a nociceptive stimulation. The TES effects were eliminated by an antagonist of opioid receptors, naloxon, and by antagonists of serotonin receptors, 5,7-dihydrotryptamine and mergolin, and were absent on the background of morphine tolerance. Potentiation of the TES effects was produced by enkephalinase inhibitors (D-leucine, D-phenylalanine), 5-HT precursors, inhibitors of monoamine oxidase and tryptophan pyrrolase (a decrease of leakage of the 5-HT precursors by the kinurenin pathway). Changes of the TES effects under action of cholinergic and GABA-ergic agonists-antagonists were poorly expressed. The presented data demonstrate essential differences in substantiation of the present development of the TES method from the earlier offered kinds of transcranial actions (electroanesthesia, electrosleep, and electroanalgesia), of which development was based on a subjectively justified wish to get a clinically important effect without medications; however, unfortunately, their development was not substantiated by experimental methods. On the basis of this results several models of devices for transcranial electrostimulation (TES-therapy) were developed (Fig.2)

Fig. 2. Models of Transair for hospital, outpatient clinic and domestic usage, and position of electrodes on the head.

II. The main effects of the TES-therapy general characteristics Fig. 3 presents the main types of the TES effects considered in detail by collections of papers published by the TES Centers [1, 2]. All these effects have been proved to be due the central or peripheral action of endorphins. It is to be emphasized that the scheme (Fig. 3) merely demonstrates our analytical approach to the TES effects, but does not fully characterize their clinical peculiarities. In reality the therapeutic TES effects have the following most important peculiarities: have a h o m e o s t a t i c character their normalizing action is manifested only for disturbed functions; are manifested only as a c o m p l e x during treatment of the main pathology, positive actions are observed on manifestations of accompanying disturbances (for instance, analgesia is accompanied by stimulation of reparation);

TES

Central effects
Brain -endorphin

Blood -endorphin

Peripheral effects effects

Improvement of the psychophysiological status and quality of life Activation of tissue repair Stimulation of immunity Inhibition of tumor growth

Analgesia Vasomotor regulation Antiaddict effects

Normalization of autonomic and hormonal regulation

Fig. 3. The main effects of the TES therapy

 are manifested s ys t e m i c a l l y on one hand, during treatment of different pathologies with similar syndromes (for instance, pain or depression), on the other hand, during treatment of different disorders produced by the same factor or of different pathologies connected with disturbances of the single functional system. III. TES-therapy in revitalization medicine According to the current concepts put forward by Academician A.N. Razumov, the main contents of the revitalization medicine are preservation and restoration of health of healthy and practically healthy people as well as of the people who have functional disturbances or premorbid disorders, medical rehabilitation of patients and disabled people. In our opinion, the revitalization medicine is to include a new important part r e g e n e r a t i o n m e d i c i n e . . TES-therapy for preservation and rehabilitation of health of healthy and practically healthy people. From the determination of the revitalization medicine according to Acad. A.N. Razumov, it follows that one of its basic scientific platforms is the theory of stress and adaptation. Our investigations carried out with use of psychophysiological methods (Table 2) have shown that TES-therapy has a pronounced normalizing and anti-stressor effects in disorders of the psychophysiological status of various degrees of severity. Table 2 Methods of evaluation of psychophysiological effects of TES-therapy

Subjective tests Non-verbal - Visual analogue scale - Lushers visual test Verbal - (??) test - Spielberger (?) test - Life quality test

Objective tests - Correction test with Landolts rings - Critical frequency of fusion of flashings - Response to moving object - Cardiovascular tests - Respiratory tests - Variational pulsometry

Table 3 indicates the main cases of application of TES-therapy for elimination of fatigue, tiredness, stress, and stressor disorders. Efficiency of TES-therapy during fatigue has been confirmed by blind control studies with use of active and passive placebo. These effects are beyond any doubt to be due to the endorphinergic mechanism of TES-therapy.

Table 3 Normalizing effects of TES-therapy during psychophysiological disturbances of various nature Groups of observations Practically healthy people after a routine work Rescuers after work Recruit soldiers and military students Highly specialized military staff Relatives of victims lost in massive catastrophes Patients with syndrome of chronic fatigue Wounded people, refuges Directions of the normalizing action of TEStherapy Elimination of fatigue Elimination of fatigue Military professional adaptation Preparation to fighting use and recovery after it Elimination of the syndrome of loss Elimination of syndrome of chronic fatigue Treatment of posttraumatic stressor disorders

Table 3 summarizes cases of efficient TES application which are arranged according to an increase of the degree of severity of stress and of disorders of the psychophysiological status. It is seen that TES-therapy can be used both in everyday life at a routine work and in a stressed work possibly connected with a danger (divers). TES-therapy has turned out to be efficient in chronic stress at deadaptation at military service initial stages as well as under conditions of real fighting actions and in wounded people. B. TES-therapy for elimination of premorbid disorders and for rehabilitation. Elimination of premorbid disorders and rehabilitation are the most important tasks of revitalization medicine; their solution is in a close contact with medicine of labor. Efficiency of use of TES therapy to solve these tasks can be demonstrated by the example of a number of examples. 1. TES-therapy promotes statistically significantly normalization of arterial pressure (AP) at arterial hypertension of I degree (APsyst = 140-159 mm Hg) and hypotension. There are certain perspectives of use of TES-therapy for prevention of development of hypertension at prehypertension (APsyst = 130-139 mm Hg). This state has recently been identified in the 7-th report (2004) of the USA United National Committee on detection, evaluation, and treatment of high AP, as risk of cardiovascular complications, according to data of the Framingham study, increases twice. Our experimental studies have shown that normalization of AP is based on endorphin action on vasomotor center. 2. TES-therapy is highly efficient for elimination of disturbances of the psychophysiological status in women at various stages of their life. We mean elimination of typical complication of the first half of pregnancy (especially vomiting) and manifestation of climacteric disorders (vegetovascular dystonia, depression).

3. Extensive experimental-clinical studies have shown TES-therapy to be highly efficient during elimination of pain syndromes of various geneses and various localizations (Table 4). The latter is accounted for by that endorphins, apart from their analgesic action, also have an antiinflammatory effect. 4. TES-therapy has been used successfully for rehabilitation of chronic alcoholics and opium drug abusers for elimination and for elimination of postabstinence affective disorders, which eventually leads to a decrease or elimination of pathological thrive for repeated use of alcohol and narcotics. Table 4. Types of nociceptive syndromes cupped up with use of TES-therapy Spondylogenic pains Pains connected with lesion of nerves neurites, neurinomas, phantom pains Headaches pains of tension, arachnoiditis, postcommotion syndrome, migraine The presented examples show that use of TES-therapy is an efficient tool of rehabilitative action. It is important to be emphasized that this instrument is applicable under conditions of the usual life of the working-capacity population. . TES therapy in revitalization medicine A new direction, revitalization medicine, has recently been formed. The revitalization medicine is determined as a possibility of replacing aging/damaged cells by genetically similar young and functioning cells. This can be achieved by use of embryonic stem cells of human cloned embryos or pluripotent stem cells of adults (Kahn A., 2001). TES-therapy does not use stem cells, but owing to activation of the endorphinergic system and released endorphins it can stimulate considerably processes of reparative regeneration. From this, it follows that use of TES-therapy is a new direction of revitalization medicine. Orofacial pains trigeminitis, glossalgia Fibromyalgia Pains at deforming arthroses Pains at endometriosis Postoperational and posttraumatic pains Oncological pains

Table 5 Examples of stimulating effects of TES-therapy on processes of regeneration

Types of tissues Skin epithelium and connective tissue GIT epithelium and connective tissue Hepatocytes cells of Langerhans islands Nerve fibers Connective tissue

Experimental models Skin wounds

Therapeutic application Burns, wounds, trophic ulcers

Stressor and toxic gastric Ulcerative disease of stomach and ulcers duodenum Toxic and mechanical injuries Hepatoses, hepatitides, alcohol cirrhosis Type 2 diabetes mellitus, metabolic Toxic injuries syndrome Section of nerves Legation of the descending branch of coronary artery Neurosensory hypoacusis Acute myocardial infarct

Our obtained experimental-clinical data are presented in Table 5. Apart from use of TEStherapy under conditions of hospitals, a part of such therapeutic effects can be for rehabilitation and maintenance of a state after medication therapy as well as for prevention. One of examples is an efficient use of TES-therapy for stimulation of regeneration of gastric mucosa in ulcerative disease and prevention of spring-autumn exacerbations. This reparative effect is combined with analgesia and normalization of life quality parameters. Another important example is a pronounced improvement of hearing in sensoneural hypoacusis under effect of TES-therapy. Remarkably, this effect is also found in people suffering from professional sensoneural hypoacusis caused by a long work under conditions of intensive noise (for instance, in helicopter workers or in workers of atomic ship building). IV. Conclusion The presented data have shown that TES-therapy can be an important component of the set of actions of revitalization medicine by promoting maintenance and recovery of the health of healthy and practically healthy people suffering from functional disturbances or premorbid disorders as well as of medical rehabilitation of patients and invalids. It is to be particularly emphasized that TES- therapy has the ability to activate reparative regeneration. An important peculiarity of TES-therapy is that this non-medication method of treatment has a rather limited circle of contraindications, with practically no side effects. From economical point of view this method of revitalization medicine is highly profitable, as the TRANSAIR apparatuses realizing it are simple and convenient for use.

V. References 1. Transcranial Electrostimulation. Experimental-clinical investigations. Ed. by V.P. Lebedev, St.-Petersburg, 2001, Vol. 1, 528 pp.

2.

Transcranial Electrostimulation. Experimental-clinical investigations. Ed. by V.P.

Lebedev, St.-Petersburg, 2003, Vol. 2, 524 pp. 3. Transcranial Electrostimulation. Experimental-clinical investigations. Ed. by V.P. Lebedev, St.-Petersburg, 2009, Vol. 3, 392 pp.