TRANSCRANIAL ELECTROSTIMULATION OF THE BRAIN ENDORPHINERGIC SYSTEM AS AN EXAMPLE OF THE UNINVASIVE FUNCTIONAL ELECTROSTIMULATION OF THE BRAIN HOMEOSTATIC MECHANISMS: ACTIVATION OF TISSUE REPAIR
Lebedev V.P. 1, Illinsky O.B.1,
Savchenko A.B.1, Kolosova
L.I.1, Kovalevski A.V.1,
Tsirulnikov E.M.2, Rychkova S.V.3,
Melikhova M.V.4, Gerasimova
L.I.5
1Pavlov Institute of Physilology, 2Research Institute of Hearing, Throat and Nose Diseases, 3Medical Academy for Continuos Physicians’ Education, 4Institute of Toxicology, Saint Petersburg, Russia; 5Sklifassovski Research Institute of Emergency, Moscow, Russia
e-mail: lebedev@lvp.infran.ru
Abstract. Special electrical regimen and devices were developed for non-invasive transcranial stimulation of the brain antinociceptive endorphinergic structures. It was revealed in experiments and in clinical observations that stimulation of endorphin release effectively accelerates the repair processes in damaged tissues of different types.
INTRODUCTION
It is well known that opioid peptides injected systemically or introcerebroventricularly are able to produce homeostatic effects on regulation of the several physiological mechanisms including the acceleration the growth and repair of damaged tissues of different types [1, 2]. The same effects can be reproduced by invasive direct electrical stimulation of the endorphinergic antinociceptive structures located in medial part of the brain stem [3, 4]. To increase of brain b-endorphin release we elaborate the uninvasive method of transcranial electrostimulation (TES) with special regimen for activation the brain endorphinergic structures according their quasiresonance characteristics [5, 6].
The aim of present paper is to review the possibilities and pecuilarities of the TES effects on the regeneration processes of damage tissues of different types (skin and gastroduodenal epithelium, liver cells, connective tissue, peripheral nerve fibres) in experimental animal pathological models and in treatment of respective diseases in patients (P).
MATERIALS
AND METHODS
Animal experiments. All
experiments were carried out in four groups of
rats (R). The pathological models used are included in table I. In R of
I and IV groups all surgery was done under deep pentobarbital anesthesia. In each group TES was produced by rectangular pulses (70 Hz –
optimal for R, 3.5 msec, average current 0.8-1.2 mA,
three 1 h daily sessions in a day) and delivered through subcutaneous needle
electrodes on the forehead (cathode) and
behind the ears (anodes). R were semirestrained
(light ketamine anesthesia). As it was demonstrated previously these
impulse parameters are optimal to elicit
analgesia and the b-endorphin release in R [7, 8].
Clinical observations. The groups of P pathology for TES treatment were selected mainly in
accordance with positive results obtained in experimental pathological models
(Table II). In P TES was delivered through the surface Ti electrodes ( diameter
2.0 cm) applied on the skin of the
forehead and both mastoids with thick
wet cotton pads. Electrodes were fixed on the head of P by Velcro belts. TES in P was produced by rectangular pulses
(77 Hz – optimal for humans [9], 3.5 msec,
average current 1.0 - 5.0 mA, and session duration 30 – 45 min). In pilot
studies the optimal protocol of treatment was estimated for different groups of P. For P of groups A and C there were about 15
daily sessions produced with
current 2.5 - 5.0 mA. P of group B were
treated twice a day during 7 – 10 days with current 1.5 – 3.0 mA. For P of
group D the number of daily sessions and current were lower than for group C –
5 - 7 sessions and 1.0 -1.5 mA respectively.
|
Group of rats |
Type of model |
Damaging factor or intervention |
Methods used for estimation of the repair processes |
|
I |
Standard skin wounds |
Dissection of full layer skin flap on the back |
Measurement of squares, light microscopy |
|
II |
Gastrodoudenal ulcers |
Immobilization and cold stress, intoxication by alcohol and cisteamine hydrochloride |
Measurement of squares, counting of number,
calculation of the severity indexes |
|
III |
Toxic damage of liver cells |
Poisoning by dichlorethane |
Blood and liver biochemistry, light
microscopy, micromorphometry |
|
IV |
Peripheral nerve trauma |
Dissection and suturing of the sciatic nerve |
Registration of single nerve fibers
discharges |
In P
of A, B, and C groups the blood b-endorphin level was estimated by
radioimmunoassay before and after the
course of treatment and before and just after of 3-5 first sessions.
Table II. Groups of patients treated by TES
|
Group of
patients |
Diagnosis |
Respective
experimental model |
|
A |
Thermal
burns, postoperative wounds |
I |
|
B |
Gastric
and duodenal ulcers |
II |
|
C |
Acute
myocardial infarction |
No
experimental model |
|
D |
Sensorineural
hearing loss |
IV |
During
sessions all P were conscious and had no
unpleasant sensation, only light tingling
especially under cathode which was reduced in some minutes in process of
skin receptors adaptation . No side effects during or after sessions were observed. As a rule, after sessions P
reported the improvement of self-filling , mood, reduction of stress, fatigue
and pain relief. In follow-up and
psycho-physiological evaluations no any long term negative aftereffects were
found. In all experiments and clinical observations the match controls were
always used.
Devices.
TES treatment was
produced by device named as TRANSAIR-011[1].The
output parameters (constant amperage) of the
portable battery operated or plug-in generator was preprogramed
according the experimentally estimated sharp quasiresonance
characteristics of brain endorphinergic system which
were rather different in frequencies for R, humans and other animal species (
mice, rabbits). The clinical
application of TES with regimen elaborated and devices were approved by Russian
Ministry of Health. Now the devices of TRANSAIR-01 type are broadly used in
Hospitals and Outpatient Clinics in
RESULTS AND DISCUSSION
Experimental data. In all groups of animals the significant
acceleration of damaged tissue repair was observed. The opioid
nature of effects was proved by naloxone reversibility and potentiation
by enkephalinase inhibitors (D-leucine,
D-phenylalanine).
The wound healing in R
(group I) was accelerated up to
20-30% with active granulation at the bottom of wounds and very mild scars. The
healing effect could be elicited by one TES sessions produced even a day before
surgery. TES sessions with other
frequencies (50, 90 Hz) were completely
ineffective.
In R of group II after TES sessions reduction of ulcer number up to 20-40% was observed and the severity indexes were
decreased at about 2-5 times. The most prominent TES effect was found in cases
of gastroduodenal
ulcers elicited by pure ethyl alcohol. Prophylactic effect of TES sessions was
also observed especially in R with
stress induced ulcers.
In R with liver damage (group III) normalization or improvement of detoxification (thymol and
bromsulfalein tests) function, synthetic (proteins, lipids, glucose, glycogen,
cholinesterase) abilities and cytolysis
events (alanine and aspartate aminotranspherases, alkaline and acid
phosphatases, lactate dehydrogenase, ceruloplasmin). By means of light microscopy it was
revealed that in the liver of treated animal fat degeneration of hepatocytes were found very rarely in comparison with
control R. Necrotic areas were never
observed. In the R with chronic poisoning and one month TES treatment no events
of liver cirrhosis were found.
The
first afferent single nerve fiber discharges in sciatic nerve (group IV)
proximal to dissection level (focal mechanical hindpaw
stimulation) were registered in treated
R at the 12th day after surgery in comparison with same events at
15-20th days in control group. The same time difference of repair
was found in reflexly activated efferent nerve
fibers. It is important that in treated
R even after 9 months after surgery the duration of action potentials in
afferent fibres
was significantly shorter in comparison with control.
Thus,
experimental data demonstrated that TES
treatment accelerates the repair processes in skin and
gastroduodenal epithelium, connective
tissue, hepatocytes (originated from duodenal
epithelium) and peripheral nerve fibers.
These effects could be elicited when
some TES treatment was produced 1-2 days before damages (groups I and
II). It means that TES treatment has a long term effects, as it was also
demonstrated in group IV.
Surplus
regeneration may be dangerous in successive
malignancy. In connection with this possibility it was demonstrated in
additional group experiments in R that TES treatment (with the optimal
parameters for regeneration only) inhibited
the growth of implanted tumor
originated from the epithelium and connective tissue (carcinoma-256,
sarcoma-45, hepatoma-27). This TES effect was also naloxone
reversible.
Clinical data. In P with thermal burns (group A) II-III AB levels of severity (up to
60% of body surface) the acceleration of healing during TES treatment was
estimated as 20-30%. An important
observation that in all P the significant analgesic and antistress
effect was observed with increase of
blood b-endorphin and somatotrophin and decrease of
catecholamine levels. T-helpers and NK-lymhocytes
were also activated.
Adult
and children with gastric and duodenal ulcers (group B) were treated without
any antihelicobacter medications. The velocities of
gastric and duodenal ulcers healing (fibrogastroscopy)
was about 4.15±0.28 mm2/day and 3.7±0.37 (two daily TES sessions, 10 days) in
comparison respectively with 1.17±0.23 mm2/day and 1.76±0.58 mm2/day in control group. The
increase of blood b-endorphin level and normalization of gastrin level were constantly observed. In a two-three days
of treatment all pain events and dyspeptic disorders were abolished. In follow
the long term remission was found up of 81%
P.
The
TES treatment of acute myocardial infarction (group C) was started as usual in a 3-6 h after the beginning of heart
attack. According the precordial polytopic
ECG mapping the myocardial necrotic area was obviously
smaller in TES treated P. More rapid scar formation was supported, as a
demonstration of increased blood level
of oxyproline – a collagen repair marker. TES treatment
increased the heart contractility (with compensatory myocardial
hypertrophy) and reduction up to 2 times of the cardiovascular insufficiency
events at the end of observations. The increase of b-endorphin
baseline level was found at the 3rd day of TES treatment and
then each next TES sessions elicited
more b-endorphin release. In control group of P no elevations of b-endorphin or oxyproline
level were observed. TES treated P followed up to one year demonstrated
significantly higher myocardial contractility than control group ones.
Sensorineural
hearing loss (SNHL) based on impairment of neural structures of inner ear was
effectively treated by TES (group D). The first effect in 50% of P with
chronic SNHL (who were ineffectivly treated by medications by the years) was the reduction or abolishment of
subjective tinnitus. After the 5-7
sessions the positive results (25-35 dB increase of hearing ability) was
observed in 45% of P with chronic SNHL of different etiology. The prediction of
positive TES effect with probability about 95% could be done in chronic SNHL by
evaluation of of the presence of acoustic nerve
excitability with focused ultrasound. The duration of remission was about 4
months. In cases of sudden SNHL the full restoration of hearing ability was found in 90% P just
after two-three TES sessions.
CONCLUSIONS
TES
of the brain endorphinergic structures is a new
simple effective uninvasive scientifically based and clinicaly approved method for activation of endogenous
homeostatic mechanisms involved in improvement of several functional and structural body disturbances
e.g. by acceleration of repair processes in damaged tissues. The clinical study
of TES treatment efficacy of liver pathology is in progress now.
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