Noninvasive Selective Transcranial Electrostimulation1

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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:[email protected]; 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 describedmethods 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.
mailto:[email protected]:[email protected]:[email protected]


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Table 1

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

Task Way of solution Result

Finding of optimal

position of electrodes on

the head surface for

approaching current to

structures of brain

protective mechanisms

Determination of ways of current

in the brain by nuclear magnetic

resonance tomography

Activation of protective brain

mechanisms can be performed

only if the current runs in

sagittal direction (fronto-

retromastoidal position of

electrodes)

Selection of optimal

electric TES parameters

Screening on experimental models

(pain, reflexes, wounds, tumors,

etc.)

Quasi-resonance regularities

frequencyeffect and

durationeffect have been

revealed to serve the ground for

construction of therapeutic TES

apparatuses

Proofs of activation of

endorphinergic and

serotoninergic structures

of protective brain

mechanisms

1. Mapping of activated neurons

by immunocytochemical and

autoradiographic methods.

2. Determination of levels of -

endorphin in the brain,

cerebrospinal fluid and blood

plasma by radiochemical and of

serotonin in the cerebrospinal

fluid and blood plasma by

biochemical methods.

3. Use of agonists and antagonists

of opioid and serotoninergic

receptors

The selected TES regimes have

been proved to activate

selectively endorphinergic and

serotoninergic structures of

protective brain mechanisms

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


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system. These correlations were further used to design equipment realizing the method of TES-

therapy (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).

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

B

C1 C2 60 65 70 75 80 Hz

pM/L

30

20

10

0

-en

dorphi

n

A


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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 asubjectively 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.


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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 omeo s ta t i c character their normalizing action is manifested only for disturbed

functions;

are manifested only as a co mp le x during treatment of the main pathology, positive

actions are observed on manifestations of accompanying disturbances (for instance, analgesiais accompanied by stimulation of reparation);

Fig. 3. The main effects of the TES therapy

Normalizationof autonomic and hormonal regulation

Improvement of the psychophysiological statusand quality of life

Analgesia

Vasomotorregulation

Antiaddicteffects

Activationof tissue repair

Stimulationof immunity

Inhibitionof tumor growth

TES

Brain

-endorphin

Blood

-endorphin

Central effects Peripheral effects

effects


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are manifested s ys t emic 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 eg e ne r a t io n me d i c in 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 Objective tests

Non-verbal

- Visual analogue scale

- Lushers visual test

Verbal

- (??) test

- Spielberger (?) test

- Life quality test

- 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.


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Table 3

Normalizing effects of TES-therapy during psychophysiological disturbances of various nature

Groups of observationsDirections of the normalizing action of TES-

therapy

Practically healthy people after a routine

work Elimination of fatigue

Rescuers after work Elimination of fatigue

Recruit soldiers and military students Military professional adaptation

Highly specialized military staff Preparation to fighting use and recovery after it

Relatives of victims lost in massive

catastrophesElimination of the syndrome of loss

Patients with syndrome of chronic fatigue Elimination of syndrome of chronic fatigue

Wounded people, refuges 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).


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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 anti-

inflammatory 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

Orofacial pains

trigeminitis, glossalgia

Fibromyalgia

Pains at deforming arthroses

Pains at endometriosis

Postoperational and posttraumatic pains

Oncological pains

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.

Table 5

Examples of stimulating effects of TES-therapy on processes of regeneration
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Search&term=%22Kahn+A%22%5BAuthor%5Dhttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Search&term=%22Kahn+A%22%5BAuthor%5D


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Types of tissues Experimental models Therapeutic application

Skin epithelium and

connective tissueSkin wounds Burns, wounds, trophic ulcers

GIT epithelium and

connective tissue

Stressor and toxic gastric

ulcers

Ulcerative disease of stomach and

duodenum

Hepatocytes Toxic and mechanical injuries Hepatoses, hepatitides, alcoholcirrhosis

cells of Langerhansislands

Toxic injuriesType 2 diabetes mellitus, metabolic

syndrome

Nerve fibers Section of nerves Neurosensory hypoacusis

Connective tissue Legation of the descending

branch of coronary artery

Acute myocardial infarct

Our obtained experimental-clinical data are presented in Table 5. Apart from use of TES-

therapy 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. References1. Transcranial Electrostimulation. Experimental-clinical investigations. Ed. by V.P.

Lebedev, St.-Petersburg, 2001, Vol. 1, 528 pp.


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


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


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Noninvasive Selective Transcranial Electrostimulation1