Alexander Bystritsky (2008) provided an excellent technical overview of the current state of knowledge in regard to CES’ mechanism of action. Readers are encouraged to read his paper. Dr. Bystrisky states that,

“Some of the signals from these afferent nerves eventually reach the ventral posteromedial nucleus of the thalamus. Animal studies indicate that 42% to 46% of CES current enters the brain, with the highest levels of current recorded in the thalamus. The thalamus is a region that seems to be important in the pathophysiology of anxiety. Evidence of this comes from positron emission tomography (PET) and functional magnetic resonance imaging (fMRI) studies in GAD patients, which show changes in thalamic activity (as well as in other regions) with medication treatments. A single photon emission computed tomography (SPECT) study in other anxiety disorders including obsessive-compulsive disorder, post-traumatic stress disorder, and social anxiety disorder also found decreases in thalamic activity with treatment with the medication citalopram. Therefore, CES could hypothetically exert anxiolytic effects by affecting the thalamus and/or its afferent pathways. Future neuroimaging studies examining the brain regions and circuits associated with CES treatment will be needed to understand its mechanism of action” (pgs. 415-416).

Dr. Bystritsky went on to hypothesize that CES may also reset the brain to prestress homeostasis levels – this has important treatment implications for post-traumatic stress disorder (PTSD) and substance dependence, which may explain the current research interest in these areas.

CES And QEEG
Kennerly (2006) found that persons treated with CES for 20 minutes exhibited significant changes in the EEG, including increased alpha (8-12Hz) relative power and decreased relative power in the delta (0–3.5Hz) and beta (12.5-30Hz) frequencies. Increased alpha typically correlates with improved relaxation and possibly increased mental alertness or clarity (Thompson & Thompson, 2003), while decreased delta suggests reduced drowsiness. Beta reductions were exhibited mostly between 20-30Hz and this frequency band correlates with reductions in anxiety, ruminative thought, and obsessive/compulsive-like behaviors (Demos, 2005). Kennerly further reported that quantitative electroencephalography (qEEG) and low resolution electromagnetic tomography (LORETA) analyses showed that the electrical pulses generated by the Alpha-Stim reached all cortical and subcortical areas of the brain.

Kabalak AA, Senel OO, Gogus N.
Department of Anaesthesiology and Reanimation, Ankara Numune Research and Training Hospital, Turkey. drayla2002@yahoo.com
BACKGROUND AND OBJECTIVES: Recent experiments have shown that transcranial electrical stimulation significantly increases the potency and duration of the analgesic effects of opioids in humans and rats. In the present study, the influence of transcranial electrical stimulation (TCES) on the analgesic effect of remifentanil hydrochloride (HCl) in rats was determined. METHODS: Experiments were performed on 80 albino male Wistar rats. Rats were randomly assigned to four groups: remifentanil HCl, remifentanil HCl and TCES, TCES, and control (n=20/group). Remifentanil HCl was injected on the 55th minute. Analgesia was assessed using the wet tail-flick latency test. RESULTS: In the remifentanil HCl group, analgesia (10.85+/-1.04 s) was reached at the fifth minute, and the analgesia was high for the first 10 min. In the remifentanil HCl and TCES group, the latency time peaked (16.60+/-1.19 s) at the fifth minute. This peak was 150% higher than that for the remifentanil HCl group, and 251% higher than the control or TCES groups. Analgesia in the remifentanil HCl and TCES group was sustained for 20 min at a statistically higher rate than the other treatment groups (P<0.001). CONCLUSIONS: TCES markedly increased the duration and analgesic potency of remifentanil HCl in rats. This effect appeared to be related to the release of enkephalins from brain structures, thus enhancing opioid analgesia.


Transcranial electrical stimulation with high frequency intermittent current (Limoge's) potentiates opiate-induced analgesia: blind studies.
Author: Stinus, L : Auriacombe, M : Tignol, J : Limoge, A : Le Moal, M
Citation: Pain. 1990 Sep; 42(3): 351-63
Abstract: Transcutaneous cranial electrical stimulation (TCES) with high frequency (166 kHz) intermittent current (100 Hz: Limoge current) has been used for several years in cardiac, thoracic, abdominal, urological and micro-surgery. The main benefits are a reduced requirement for analgesic drugs, especially opiates, and a long-lasting postoperative analgesia. We have confirmed these clinical observations in rats using the tail-flick latency (TFL) test to measure pain threshold. TCES was not found to modify the pain threshold in drug-free rats, but it potentiated morphine-induced analgesia (systemic injection). To obtain a maximal effect, the stimulation must be initiated 3 h before the drug injection and be maintained throughout the duration of its pharmacological action. TCES potentitation was found to depend on the dose of the drug, the intensity of the current and the polarity of electrodes. These findings were confirmed by blind tests of the efficiency of TCES on several opiate analgesic drugs currently used in human surgery (morphine, fentanyl, alfentanil and dextromoramide). The analgesic effect of these 4 opiates (TFL as % of baseline without or with TCES) were respectively: 174%, 306%; 176%, 336%; 160%, 215%; and 267%, 392%. The results were obtained not only after systemic opiate treatment, but also after intracerebroventricular injection of morphine (10 micrograms; analgesic effect 152%, 207% with TCES) suggesting that TCES potentiation of opiate-induced analgesia is centrally mediated.

Potentiation of fentanyl suppression of the jaw-opening reflex by transcranial electrical stimulation.

Alantar A, Azerad J, Limoge A, Robert C, Rokyta R, Pollin B.
Laboratoire de Physiologie de la Manducation, Université Denis Diderot, Paris, France.
Stinus et al. [L. Stinus, M. Auriacombe, J. Tignol, A. Limoge, M. Le Moal, Transcranial electrical stimulation with high frequency intermittent current (Limoge's) potentiates opiate-induced analgesia: blind studies, Pain, 42 (1990) 351-363.] observed that transcranial electrical stimulation (TCES) with high-frequency intermittent current potentiated opiate-induced analgesia using the tail-flick test. In unanesthetized, chronic preparations, electrical stimulation (0.5 Hz) of the lower incisor pulp of rats elicits a short-(6 ms) and a long-latency (12-18 ms) jaw-opening reflex (JOR) without any evidence of aversive behavior [J. Azerad, F. Fuentes, I. Lendais, A. Limoge, B. Pollin, Methods for selective tooth pulp stimulation in acute and chronic preparations in rats, J. Physiol., 406 (1988) 3P.]. Fentanyl increases thresholds of both reflexes and transiently suppresses the long-latency JOR. We then decided to look at the influence of TCES on both drug-induced mean of maximal threshold variation (MMTV) and duration of JOR suppression period. These parameters have been investigated in 43 Wistar rats with or without TCES administered for 3 h before the drug injection and throughout the testing period. TCES alone has no effect. In contrast, it significantly increases the duration of the reflex suppression period (149 +/- 5% vs. control, P < 0.001) while fentanyl-increased reflex thresholds remain unchanged. The fentanyl-induced JOR suppression period returns to the control values 2 days later. When a second 3-h TCES session is delivered 2 or 4 days after the first TCES session, a similar increase of this suppression period is observed. Moreover, 2 days after a second TCES session, an increase of the duration of the fentanyl-induced JOR suppression period is systematically observed. In contrast, a 6-h TCES session never induces such effects. These results confirm a potentiating effect of TCES on opioid action and demonstrate the value of repeated TCES sessions.


Transcranial electrical stimulation with high frequency intermittent current (Limoge's) potentiates opiate-induced analgesia: blind studies.

Stinus L, Auriacombe M, Tignol J, Limoge A, Le Moal M.
INSERM U259, Université de Bordeaux II, France.
Transcutaneous cranial electrical stimulation (TCES) with high frequency (166 kHz) intermittent current (100 Hz: Limoge current) has been used for several years in cardiac, thoracic, abdominal, urological and micro-surgery. The main benefits are a reduced requirement for analgesic drugs, especially opiates, and a long-lasting postoperative analgesia. We have confirmed these clinical observations in rats using the tail-flick latency (TFL) test to measure pain threshold. TCES was not found to modify the pain threshold in drug-free rats, but it potentiated morphine-induced analgesia (systemic injection). To obtain a maximal effect, the stimulation must be initiated 3 h before the drug injection and be maintained throughout the duration of its pharmacological action. TCES potentitation was found to depend on the dose of the drug, the intensity of the current and the polarity of electrodes. These findings were confirmed by blind tests of the efficiency of TCES on several opiate analgesic drugs currently used in human surgery (morphine, fentanyl, alfentanil and dextromoramide). The analgesic effect of these 4 opiates (TFL as % of baseline without or with TCES) were respectively: 174%, 306%; 176%, 336%; 160%, 215%; and 267%, 392%. The results were obtained not only after systemic opiate treatment, but also after intracerebroventricular injection of morphine (10 micrograms; analgesic effect 152%, 207% with TCES) suggesting that TCES potentiation of opiate-induced analgesia is centrally mediated.


Transcutaneous cranial electrical stimulation (TCES): a review 1998.
Limoge A, Robert C, Stanley TH.
Laboratoire d'Electrophysiologie, Universite Rene Descartes de Paris,
Montrouge, France.

The Transcutaneous Cranial Electrical Stimulation (TCES) technique
appeared at the beginning of the 1960s and is aimed to act at the
level of the central nervous system. The current, composed of high
frequency pulses interrupted with a repetitive low frequency, is
delivered through three electrodes (a negative electrode placed
between the eyebrows while two positive electrodes are located in the
retro-mastoid region). Due to the characteristics of the current
delivered, shortcomings encountered with previous electrical
stimulation techniques are avoided. The main property of TCES is to
potentiate some drug effects, especially opiates and neuroleptics,
during anesthetic clinical procedures. This potentiation effect
permits drastic reduction of pharmacological anesthetic agent and
reduces post-operative complications. Animal studies performed with
TCES demonstrated that this stimulation releases 5-hydroxy-indol-
acetic acid and enkephalins. Despite numerous clinical and animal
studies performed with this technique for several decades, TCES
mechanisms are not completely elucidated but results obtained without
undesirable effect are encouraging signs to continue investigations
of this particular technique.
TCES and opiates
A study evaluating the effects of TCES used in combi-
nation with subcutaneous administration of morphine or
morphinomimetic drugs have shown that TCES poten-
tiated the analgesic effects of morphine [5, 102]. Blind
studies have also shown that in order to obtain the maxi-
mum potentiation, certain conditions must be followed:
the drug dose, the intensity of the current, the duration of
the stimulation both before and after the injection of the
drug, the polarity of electrodes. Thus, in the rat, the
minimum dose of morphine must be no less than 3 mg/
kg, a minimum intensity of electric current, peak to peak,
must be of 50 mA, a duration of stimulation before injec-
tion of the drug must not be less than 1 h, and stimula-
tion must be continued after the injection during the
pharmacokinetic activity. Moreover, an active electrode
and an asymmetrical biphasic current must be used. As
the dental pulp of the incisor of the rat mainly contains
unmyelinated nerve fibers [10], the long latency jaw
opening reflex (LLJOR) elicited from electrical discharge
delivered in the dental pulp of the rat seemed to be a
suitable model for studying the effects of TCES
combined with pharmacological treatments. In the study
presented by Alan tar et al. [1], the potentiation of fenta-
nyl effect by TCES was studied using this model. The
major results of this study were (a) a 3-h TCES session
applied before subcutaneous fentanyl injection (130 |xg/
kg) significantly increased (about 150%) the duration of
the reflex suppression period (compared with non-TCES
group values), (b) in contrast, TCES alone had no effect
on the LLJOR. These two observations confirm the
results observed in rats using the tail-flick latency test
to measure pain threshold [102].
TCES and ß-endorphin
A double blind study was conducted during the course of
childbirth in order to evaluate Limoge currents effects on
maternal plasma ß-endorphin concentrations [100]. Prior to
evaluating the level of ß-endorphin, blood was drawn from
two groups of voluntary patients in labor (a control group
and a group to be stimulated) at four precise stages: (a) at the
moment the TCES device was attached, (b) after 1 h of
current application, (c) when the cervix reached 5 cm dila-
tation, (d) at the time of complete dilatation when birth was
to occur. All measurements of ß-endorphin were made
using the radio-immuno-enzymatic method. In the absence
of stimulation, the plasma levels of ß-endorphin during
labor were not significantly changed and were similar to
levels described in the literature [38]. Under the influence
of TCES however, ß-endorphin rates increased progres-
sively in a significant fashion during the course of the
study. It is certainly more useful to measure endorphins in
cerebral structures known for their abundance of opiate
sensitive receptors as compared to measuring them in
plasma. Following authorization of the ethics committee it
was possible to conduct such studies at the Vishnevski Insti-
tute of Moscow (USSR). Thus, endorphin measurements
were made in cerebral spinal fluid (CSF) as well as blood
plasma prior to and during cardiac surgical procedures with
and without TCES. This study demonstrated that electrosti-
mulation significantly increased the level of endorphins in
the CSF and in the plasma when compared to the control
group [85, 51]. Naloxone antagonized the effects of TCES.
TCES and morphinomimetic drugs
Coeytaux [18] and Kunegel [49] observed a significant
decrease of phenoperidine or pethidine requirements in
patients under TCES relative to patients under classical
anesthesia. These observations were confirmed by all
teams [6, 24,65]. In an experiment conducted on 50 patients
undergoing urologie operations, the potentiation of analge-
sic effects by TCES was studied [97]. In the TCES group,
fentanyl requirements during anesthesia were significantly
lower than doses required in non-stimulated patients. These
results were confirmed by Naveau et al. [75] who observed a
significant reduction (about 30%) of fentanyl requirements
in stimulated patients suffering from rectal cancer surgery
and treated by Nd:YAG laser. This reduction of fentanyl
requirements when TCES was applied is found: in observa-
tions of Coeytaux et al. [19] obtained in patients undergoing
transvesical prostatectomy, in results presented by Debras et
al. [24] in more than 700 major surgical operations, and in
the work of Le Guillou et al. [57] on cardiac operation, and
by Graftieaux et al. [40] when performing cranial or spinal
surgery.
Many studies showed that pure electroanesthesia was
impossible, whereas utilization of pharmacodynamic drugs
is well documented [35, 41, 43, 108]. Conversely in studies
previously reported, investigators noted that drug potentia-
tion significantly prolonged intra- and post-operative
opioid-induced analgesia. Of prime interest with TCES is
the advantage provided in major operations of long duration
and in micro-surgery [20, 58] as the degree of intoxication
elicited by classical anesthesia is proportional to the dura-
tion of anesthesia. The potentiation effect obtained with
TCES represents an undeniable advantage for long-lasting
surgical interventions. For these interventions, results are
encouraging as TCES permits a reduction of anxiolytics
and neuroleptics by 45% and reduction of morphinomi-
metics by 90% and demonstrate the possibilities of drag
potentiation in prolonged anesthesia while at the same
time providing a less depressive general anesthetic [12,
40, 58, 75]. Early results have improved thanks to animal
research and protocol revision [56, 71, 102, 105]. In 1972,
clinicians did not know to begin electrostimulation 3 h prior
to medicinal induction [15]. According to the results
presented in this review, TCES appears to have its principle
effects on the rhinencephalo-hypothalamo-pituitary axis and
allows liberation of several neurotransmitters and
neurohormones.
For all clinical applications, it must be borne in mind that
the currents of Limoge are able to provoke endogenous
neurosecretions [51, 59, 71, 85, 99] which require a certain
amount of time. It is also important to note that the effects of
TCES are not immediate nor short-lived. It must also be
remembered that these currents have a potentiation effect
on opioid and non-opioid analgesics, hypnotics, psycho-
tropes and psycholeptics, [5, 34, 56, 97, 101-103, 105]
and the fact that the application of TCES allows use of
reduced doses means less toxicity.


Low Current Electrostimulation Produces Naloxone-Reversible Analgesia in Rats
M.H. Skolnicka, O.B. Wilsona, R.F. Hamiltona, C.D. Collarda, L. Hudson-Howarda, C. Hymela, D.H. Malinb
a University of Texas Health Science Center, and
b University of Houston at Clear Lake, Houston, Tex., USA

Abstract A new form of transcranial electrostimulation (TE) has been shown to induce analgesia in rats, as measured by the wet tail flick test. Charge-balanced rectangular current pulses of very low amplitude were delivered bilaterally into low impedance regions of the rat pinnae. The resultant analgesia was studied as a function of systematic variations in stimulus frequency, amplitude and duration. The optimal current for inducing analgesia was found to be 10 µA, well below the startle threshold, and several orders of magnitude below effective stimulus current levels required for other treatment modalities. The optimal stimulation duration was 30 min, during which time a slow onset of analgesia was noted. Significant analgesia persisted for at least 200 min after stimulation ended, and no evidence was found of tolerance developing in the course of 5 daily stimulation sessions. Consistent with findings for other forms of electrostimulation, the analgesic effect of TE was abolished by subcutaneous injection of 3 mg/kg naloxone, suggesting that the mechanism of TE analgesia has an endogenous opioid component.

 

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