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Anesth Analg 2004;98:730-737
© 2004 International Anesthesia Research Society
doi: 10.1213/01.ANE.0000096007.12845.70

PAIN MEDICINE

The Antinociceptive Effect of Transcranial Electrostimulation with Combined Direct and Alternating Current in Freely Moving Rats

Vladimir Nekhendzy, MD*, Christo P. Fender, BA*, M. Frances Davies, PhD*, Hendrikus J. M. Lemmens, MD, PhD*, Michael S. Kim, MD*, Donna M. Bouley, DVM, PhD{dagger}, and Mervyn Maze, MBChB, FRCP, FRCA{ddagger}

Departments of *Anesthesiology and {dagger}Comparative Medicine, Stanford University School of Medicine, Stanford, California, and the {ddagger}Department of Anaesthetics and Intensive Care, Imperial College, London and Chelsea and Westminster NHS Hospital Trust, London, UK

Address correspondence and reprint requests to Vladimir Nekhendzy, MD, Assistant Professor of Anesthesia, Stanford University Medical Center, Department of Anesthesia, Route 2, 300 Pasteur Drive Stanford, CA 94305–5640. Address email to nek{at}.stanford.edu


   Abstract
Top
 Abstract
Introduction
 Methods
 Results
 Discussion
 References
 
Transcranial electrostimulation (TES) has been reported to elicit significant analgesia, allowing a substantial reduction of intraoperative opioids. Acceptance of TES into clinical practice is hampered by lack of controlled clinical trials and inconclusive animal data regarding the TES antinociceptive action. This inconclusive data may be explained, in part, by failure in rat experiments to simulate the variables used in humans when TES electrodes are positioned on the skin. In this study we validated the TES antinociceptive effect in a novel animal model of cutaneously administered TES, when the stimulating conditions mimic the ones used in clinical practice. The antinociceptive effect was assessed by measuring nociceptive thresholds in the tail-flick and hot-plate latency tests in awake, unrestrained male rats. Data were analyzed by analysis of variance and mixed-effects population modeling. The administration of TES at 2.25 mA produced an almost immediate, sustained, frequency-dependent (40–60 Hz) antinociceptive effect, reaching approximately 50% of the maximal possible value. We conclude that an antinociceptive effect of cutaneously administered TES can be demonstrated in the rat. Some characteristics of the effect suggest an important role of the sensory nerves of the rat’s scalp in mediating the TES antinociceptive response.

IMPLICATIONS: Transcranial electrostimulation produces a significant, frequency-dependent antinociceptive effect that may be mediated by cutaneous nerves of the scalp.


   Introduction
Top
 Abstract
 Introduction
Methods
 Results
 Discussion
 References
 
A method of administering electrical currents through the skin of the subject’s head, transcranial electrostimulation (TES), for producing narcosis or analgesia was pioneered by Leduc in 1902 (1). Different types of TES are suggested, described by a wide variety of titles, including transcutaneous cranial electrical stimulation (2,3), cranial electrotherapy stimulation, low current electrostimulation, and others (4). However, only the TES currents developed by French (Limoge) (1) and Russian (Lebedev) (5–7) investigators are thought to produce clinically significant effects. Limoge current delivers high-frequency (166 kHz) intermittent bursts of bidirectional balanced pulses, "packed" into trains, that are delivered at 100 Hz for 4 ms at 6-ms intervals (8,9). Lebedev current uses a combination of direct (DC) and a pulse train alternating (AC) current, with the ratio of the DC to the average AC value in the output current 2(3):1 (5–7). The major reported advantage of the TES technique with Limoge and Lebedev currents is the ability to potentiate intraoperative pharmacological analgesia (2,3,6,7) and provide benefit in chronic pain states (6). However, lack of randomized, double-blinded, placebo-controlled TES clinical studies (4,10) and an unclear scientific basis to explain the observed analgesia preclude widespread use of this technique in routine anesthesia practice.

Adequate validation of the TES is also hindered by inconclusive animal data and absence of an experimental animal model that uses the stimulating conditions used in humans (electrodes positioned on the skin). Previous rat studies with Limoge or Lebedev TES used bone-affixed or subcutaneous electrodes in lieu of skin electrodes and failed either to demonstrate prolongation of the tail-flick latency (TFL) responses (8) or to rigorously study these responses (5). TES evokes the central release of endorphins, serotonin and norepinephrine involved in nociceptive processing pathways (6,7,9,11), but applicability of these data to humans is questionable because the cutaneous stimulation was not used (9).

Earlier reports (12) suggest that cutaneous positioning of electrodes may be essential for the TES action: TES analgesia in primates is lost when the peripheral sensory nerves of the scalp are cut. This leads one to speculate that activation of these nerves, and not the brain, by the electrical current is the initiating mechanism for TES analgesia.

In this study we tested the hypothesis that the TES antinociceptive effect can be demonstrated in a novel rat model of cutaneously administered TES, by closely simulating the stimulating conditions used in humans. We investigated whether an antinociceptive effect can be produced in an awake unrestrained rat when TES with combined DC:AC current is delivered through the skin electrodes at different AC frequencies, and we have explored the possible mode of the TES antinociceptive action.


   Methods
Top
 Abstract
 Introduction
 Methods
Results
 Discussion
 References
 
The subjects were three groups (total 31 animals) of male Sprague-Dawley rats (Bantin and Kingman, Fremont, CA) weighing 390–553 g at the beginning of the experiments. Rats were housed individually at a constant ambient room temperature and a 12-h light-dark cycle, and had an unrestricted access to food and water. All experiments were performed during the light part of a day-night cycle. The study was conducted according to the experimental protocol approved by the Palo Alto VA Hospital Animal Care Committee.

Rats’ responses to noxious stimulation were assessed by measuring nociceptive thresholds in the tail-flick latency (TFL) and hot-plate (HP) latency tests. The TFL test was performed by placing the awake rat, briefly and loosely restrained in a surgical towel ("unrestrained, unstressed" rat) (13,14) on a tail-flick device (Tail Flick Analgesia Meter; Columbus Instruments, Columbus, OH) and focusing a light beam on the ventral surface of the middle third of the rat’s tail until a flick response was obtained. The intensity of a light beam was adjusted to produce baseline TFL in the 2.3–3.7 s range. During the TES procedure TFL cutoff time of 10 s was used to minimize tissue damage. The HP test was performed by placing the rat on a rectangular plate preheated to 52°C and enclosed in the container with the clear plexiglas walls (Hot Plate Analgesia Meter, Columbus Instruments, Columbus, OH) and recording the time when an animal started licking a hind paw or jumped (15,16). HP cutoff time of 60 s was used to minimize tissue damage. The antinociceptive effect of TES in the TFL and HP test was calculated similarly, as a percentage of the maximum possible effect (%MPE), according to the following formula (14):


After adequate conditioning, rats were entered into a selection process, to ensure stability of the nociceptive threshold. A series of 5 baseline TFL and HP latency measurements were taken for each rat, spaced at least 5 min apart to minimize the possibility of altering the sensitivity of cutaneous nociceptors (17). Rats whose individual baseline TFL measurements deviated more than 15% from their individual mean were excluded from further study. The greater variability of the baseline HP latencies was not used as an exclusion criterion because of the complexity of the HP response and its possible influence by factors such as coordination, learning, attention, and interference from other behaviors (15).

Nociceptive testing was performed at 5, 15, 30, and 45 min during the TES procedure and at 15, 30, 60, and 90 min after the TES stimulation was concluded. The HP test was always performed immediately after completion of the TFL test.

The constant-current TES apparatus was designed and built for our experiments (A. Volchegursky, MSEE), and it includes controls for manual adjustment of pulse duration, DC:AC ratio, TES frequency, and the current value. Frequency and current values used are continuously displayed on the front panel of the TES device.

Rats were anesthetized with isoflurane (Abbott Laboratories, North Chicago, IL) in oxygen, and the hair of the skull was completely depilated by clippers and NAIR® lotion (Carter-Wallace, Inc., New York, NY). The recessed cavity of the stimulating electrodes (E220A-LP and E220X-LP; In Vivo Metric, Inc., Healdsburg, CA) was filled with the conductive cream (SYNAPSE®; Med-Tek Corporation, Joliet, IL), which caused no irritation to the skin during current administration. The electrodes were affixed to the skin of the rat’s head using an industrial adhesive (Loctite 426 Black Max® Gel; Loctite Corporation, Rocky Hill, CT) in the following configuration: one E220A-LP electrode was applied to the skin overlying the anterior pole of the frontal lobe, and two E220X-LP were applied symmetrically to the skin over the mastoid areas. The electrode placement was held constant based on the corresponding bony landmarks identified during pilot experiments, and mimicked electrode positioning for administration of TES with either Limoge or Lebedev current in humans (6–8). To avoid electrode drift resulting from skin movement, mastoid electrodes were additionally stabilized by enclosing them into the skin fold, which was held in place by adhesive and silk intracutaneous sutures.

Each rat was subjected to TES only once on each particular day. Each rat’s recovery from anesthesia and readiness for TES procedure was documented by normalization of behavioral tests: return of the TFL within the 15% range of the individual baseline mean and HP latency within the 15% range of the individual baseline highest or lowest value.

The frontal electrode was attached to the cathode and the mastoid electrodes were attached to the paired anode of the TES apparatus. The ability of rats to tolerate the amount of current decreased with the decreasing frequency of stimulation, and therefore a "physiological calibration procedure" described by Woolf et al. (18) was performed for each rat to standardize the stimulation intensity. For any given TES frequency, the current was adjusted to the maximal value that would not elicit aversion responses or escape behavior (e.g., jumping, struggling, vocalizations) and maintained at that level during the TES procedure. Maintaining constant intensity of the behavioral response during TES preserved the optimal current-frequency relationship for all the frequencies tested (19). During the stimulation, the polarity of the electrodes was reversed automatically every 5 min (over a 2-min interval) to prevent the formation of electrolytic skin burns (20,21).

In the first set of experiments, we studied the presence of the TES-induced antinociceptive effect and its frequency-dependence in a randomized fashion in each of the 3 groups of rats (11, 12, and 8 animals). The assessor of the antinociceptive response was blinded to the frequencies (10–100 Hz) used. Reproducibility of the TES antinociceptive effect in all three groups of rats was assessed at 60 Hz TES because the preliminary analysis established 60 Hz as the effective antinociceptive frequency.

Other experiments were randomized but not blinded. The second set of experiments (rats of the first and second group) sought to determine whether a combination of the DC and AC currents was essential for producing an antinociceptive effect. Individual DC and AC current values (TESDC only and TESAC only) were set according to the 2:1 DC:AC ratio, from the maximal tolerated current value of 2.25 mA at the 60 Hz TES. The third set of experiments (rats of the second group) investigated whether administration of the current transcranially was essential for the observed prolongation of the TFL and HP latency: the antinociceptive effect of the 60 Hz TES was compared with that of the 60 Hz TES applied across the rat’s lower spine (TESback). During TESback administration, we followed Woolf et al.’s (18) technique of achieving the maximal amount of current that would induce only slight fibrillation of the tail and back muscles, without sustained contractions. This approach avoids false-positive results in the TFL test and causes no escape behavior. With this technique, the maximal current value achieved on the rat’s back was similar to that on the head (2.25 mA). The fourth set of experiments (rats of the second group) explored whether the 60 Hz TES antinociceptive effect depends on the amount of current used. As a control, rats of all groups also randomly received no current TES, when the stimulating electrodes were applied in a usual manner but no TES was administered during nociceptive testing.

Nonparametric data are reported as median (interquartile range) and parametric data as mean±SEM. For each rat group, the effects of the stimulation time and TES frequency on %MPE were analyzed by two-way analysis of variance on ranks. The Tukey procedure was used for multiple comparisons. In addition, TES frequency versus %MPE data from all 3 groups of rats were analyzed with a mixed effects population modeling approach (NONMEM V). All other data were analyzed by one-way analysis of variance followed by Dunnett’s test. A value of P<0.05 was regarded statistically significant.


   Results
Top
 Abstract
 Introduction
 Methods
 Results
Discussion
 References
 
The antinociceptive effect of TES was significantly affected by the TES frequency, but not by the stimulation time. Figure 1 shows frequency-dependence of the antinociceptive response in each of the three groups of rats. It appears that most frequencies tested in the range 40–60 Hz in the TFL test and 40–65 Hz in the HP latency test elicited a substantial antinociceptive effect. The antinociceptive effect was reproducible in all three groups of rats at 60 Hz TES. No antinociceptive effect was observed in the control group (no current TES).



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  		Figure 1. Frequency-dependence of the transcranial electrostimulation (TES) antinociceptive effect in the tail-flick latency (TFL) and hot plate (HP) tests. Box plots show the distribution of maximum possible effect (%MPE) stratified by TES (Hz) in each group of rats. The horizontal line in the interior of each box is the median. The height of the box is the interquartile distance, which is the difference between the third quartile and first quartile. The whiskers extend to a distance of 1.5 times the interquartile distance. Horizontal lines indicate outliers. An asterisk indicates a median value statistically different from the control group (0 Hz, no current TES). 78 Hz is substituted for (tested) 77.75 Hz [suggested by Lebedev et al. (6,7) as the preferred antinociceptive frequency in humans] for convenience purposes only.

 
The combined TES (Hz) versus %MPE data from all groups of rats could be best described by a biphasic sigmoid Emax model (Table 1). In contrast to traditional statistics, mixed effect population modeling offers the advantage of combining unbalanced data from different groups to model a "typical" response within the population. This model demonstrates that for a "typical" rat the antinociceptive response increases gradually between 30 and 60 Hz in the TFL test and between 40 and 65 Hz in the HP latency test. At higher frequencies a steep decrease in effect is observed in both paradigms. In both instances the maximum response reaches approximately 50% MPE.


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  		Table 1. The Biphasic Sigmoid Emax Model Equation and Parameters
 
Stimulation time had no effect on %MPE at all the tested frequencies: the antinociceptive effect is evoked almost immediately and is sustained throughout 45 min of stimulation. No statistically significant antinociceptive aftereffect was observed (data not shown).

A comparison of the antinociceptive effect of the 60 Hz TES and other different stimulating modalities is presented in Figure 2 and Figure 3. Data reveal that administration of the DC and AC in combination, but not individually, is capable of inducing the antinociceptive response. The data also show that the antinociceptive effect is site (head)-specific, and cannot be elicited peripherally, in a transcutaneous electrical nerve stimulation (TENS)-like fashion.



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  		Figure 2. Comparison of the antinociceptive effects of the 60 Hz transcranial electrostimulation (TES) and TES with direct current (DC) only, in the tail-flick latency (TFL) and hot plate (HP) latency tests. Data are presented as mean ± SEM *P < 0.05 compared with no current (control) TES.

 


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  		Figure 3. Comparison of the antinociceptive effect of the 60 Hz transcranial electrostimulation (TES), 60 Hz TES with alternating current (AC) only, and 60 Hz TES administered on the rats’ back, in the tail-flick latency (TFL) and hot plate (HP) latency tests. Data are presented as mean ± SEM *P < 0.05 compared with no current (control) TES. The achieved maximal tolerable current intensity on the back and on the head is identical (2.25 mA).

 
Figure 4 displays the antinociceptive effect of the 60 Hz TES at different current values, demonstrating that the antinociceptive effect increases progressively with the increased intensity of stimulation.



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  		Figure 4. Comparison of the antinociceptive effect of the 60 Hz transcranial electrostimulation (TES) at different current values in the tail-flick latency (TFL) and hot plate (HP) latency tests. Data presented as mean ± SEM. *P < 0.05 compared with no current (control) TES.

 

   Discussion
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
References
 
The principal finding of the current study is that, when administered under the stimulating conditions used in humans, TES with combined DC:AC current is capable of producing a significant and reproducible antinociceptive effect in the rat.

The pivotal effect of frequency is observed in several electro-analgesic procedures in different electrical stimulation modalities, such as TENS, electroacupuncture, percutaneous neuromodulation therapy (22), and TES (1,7,11).

The results of the original studies (5), performed in restrained animals with subcutaneous needle electrodes, suggested 70 Hz as an optimal antinociceptive frequency of the TES with DC:AC current in rats, and described disappearance of the antinociceptive effect if the frequency deviation exceeded ± 4 Hz from that critical value (5–7). This provided the basis for excluding an individual frequency adjustment during application of Lebedev TES in humans (7). These data may be questioned: the experiments were nonrandomized and not controlled, and it is not clear whether the antinociceptive effects in the rats were produced by the stress of restraint or by intervention (23–25).

The results of our study demonstrate that when the TES stimulating conditions mimic the ones used in clinical practice, frequency response is lower than that observed previously (5). Presence of a narrow range (40–60 Hz) of the most effective TES frequencies, rather than a single "best" frequency, suggests that individual frequency adjustment may be necessary in clinical settings.

Our data (Fig. 3) also dispute the recent claim (7) that the AC component of the combined DC:AC current may be by itself equally effective in producing analgesia. TES technique of combining AC pulse trains with the DC offset was first suggested by Anan’ev et al. in 1960 (26) and over the years has gained its strong proponents, as well as critics (1,20). Though pulse train administration is associated with the possibility of occurrence of skin burns resulting from the charge transfer (1,20,21), unipolar rectangular pulses are considered the most promising for producing analgesia in humans (27). Skin burns can usually be prevented with proper technique of electrode application (20) and intermittent change in the stimulation polarity (21), as in our study. No skin burns were observed in our experiments.

Quick onset of the TES antinociceptive effect and its persistence during the period of stimulation are of major importance. Earlier studies reported "fading," or attenuation of the "electroanesthetic state" that may develop within several minutes of stimulation, especially in animals at the higher end of the phylogenetic tree (28). Fading is not observed uniformly (27), and it can be counteracted by increasing the intensity of current or changing the current frequency (8,28). The fact that fading was not observed in our experiments may be explained by the gradual decrease and reestablishment of current every 5 min during the change in polarity.

In our study, the antinociceptive effect of TES in rats disappeared within 15 min after cessation of electrical stimulation (data not shown), corroborating the effect noted by both Lebedev and Limoge in rats and other animal species (1,10). Although Lebedev reported that in humans the analgesic effect may extend into the immediate postoperative period for as long as 12 hours (6), those studies were neither randomized nor blinded. TES with Limoge current has been shown in a randomized, double-blinded, placebo-controlled study to significantly reduce narcotic requirements in the early postoperative period (29). At present, the reason for this discrepancy between the duration of the antinociceptive effect in animals and poststimulation analgesia in humans is unclear, but may relate to decrease in sensitization or "wind-up."

The data obtained demonstrate that transcranial application of current is necessary for the TES antinociceptive effect to occur (Fig. 3). Whether this effect is mediated by direct action of the electrical current on the brain or the sensory nerves of the rat’s scalp, remains to be determined. Though it is generally believed that the former is responsible for observed effects, no experimental evidence has been produced to identify the neural substrates for the putative antinociceptive action of TES. To the contrary, striking similarities between the current-frequency and current-pulse duration curves obtained during application of the pulse train AC transcranially and on the peripheral nerves (30), suggest a role of primary sensory afferents in mediating the antinociceptive response to TES. Some of the characteristics of the antinociceptive effect observed in our study lead us to speculate that the response could indeed be mediated, at least in part, by stimulation of the sensory nerves of the rat’s scalp.

In particular, the TES antinociceptive effect bears some similarities with the diffuse noxious inhibitory controls (DNIC) phenomena, described by Le Bars et al. (31,32). DNIC refers to the largely supraspinally mediated widespread inhibitory processes that occur in the convergent neurons of the spinal dorsal horns and trigeminal nucleus caudalis in response to heterotopic noxious cutaneous and visceral stimuli (32,33). Whether DNIC can be triggered by the noxious stimulation of the rat’s scalp is unknown, though it can be evoked with the noxious mechanical stimulation of the rat’s ear (31). DNIC has been most extensively studied in rats, but it has also been demonstrated in humans (34).

TES-induced antinociception shares the following features with DNIC:

  1. The effect appears rapidly and is sustained throughout a period of stimulation (32,35).
  2. The effect is relatively short-lived. Analysis of Le Bars et al.’s original data (31,32) reveals that electrophysiologically, in rats, DNIC-induced antinociceptive aftereffect disappears within 15 min after cessation of noxious stimulation. Behavioral response (prolongation of the TFL) in rats seemingly disappears within 3–6 min on withdrawal of noxious cutaneous stimulation (36).
  3. There is a correlation between the intensity of the noxious conditioning stimulus and the resultant strength of DNIC (33,34), similar to the current-dependency of the antinociceptive effect observed in our study (Fig. 4).

DNIC is triggered by activation of peripheral nociceptors whose signals are carried by A{delta} and C-fibers of the sensory nerves (33), and activation of these fibers during TES would have to be present to explain the observed similarities in the antinociceptive effects. The assumption that TES administration at a maximal tolerable intensity is associated with certain degree of noxious input and that some of the frequencies could be more "painful" than others may have some merit: A{delta} fibers play a key role in mediating the antinociceptive effect of high-intensity, high-frequency TENS in rats and primates (37–39). Moreover, Sjölund (37) has demonstrated that in the rat, for the recruitment of A{delta} fibers to occur, the stimulation frequency should be at least 40 Hz, which closely parallels the onset of the frequency-response curve obtained in our experiments (Fig. 1).

It is also conceivable that involvement of A{delta} fibers may not be essential. Onset of the maximal antinociceptive effect of TES and low-intensity, high-frequency TENS activating A{alpha}ß fibers only in the rat is similar; furthermore, isolated activation of A{alpha}ß fibers is capable of producing antinociception by suppressing the activity of the spinothalamic tract in primates (38). This entertains the possibility that the TENS-like mechanisms may be equally involved in TES-induced antinociception. A more complete study (in progress) should provide more detailed information regarding involvement of the sensory nerves of the rat’s scalp in the observed antinociceptive response.

We have demonstrated the antinociceptive effect of cutaneously administered TES with combined DC:AC current in two commonly used forms of acute nociceptive testing in rats. Although the rat TFL test correlates well with the analgesic potency of drugs in humans (14), continuous pain generated by injured tissue better approximates clinical conditions (40). The potential effectiveness of the determined TES antinociceptive frequency range in controlling surgical pain awaits further evaluation in additional rat studies on models for inflammatory (41) and incisional (42) nociception. The novel animal model of cutaneously administered TES validated in this study is likely be useful in future experiments aimed at optimizing TES stimulation parameters for humans, and investigating a possible mode of the TES antinociceptive action.


   Acknowledgments
 
Supported, in part, by Grant NIGMS 30232 from the National Institutes of Health, Bethesda, Maryland (to Dr. Maze) and a research grant from the Department of Anesthesia of Stanford University, Stanford, California (to Dr. Nekhendzy).

The authors thank Dr. I. S. Katsnelson for consulting help during the study; Dr. C. G. Burgar (VA Palo Alto Health Care System) for technical expertise in evaluating the TCES apparatus; Dr. D. R. Drover (Stanford University, Department of Anesthesia) for contribution to statistical analysis of the data; Drs. L. J. Saidman, D. C. Yeomans (Stanford University, Department of Anesthesia) and Dr. W. S. Kingery (VA Palo Alto Health Care System) for reviewing the manuscript and their critical comments.


   References
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 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 

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Accepted for publication August 21, 2003.




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V. Nekhendzy, M. F. Davies, H. J. M. Lemmens, and M. Maze
The role of the craniospinal nerves in mediating the antinociceptive effect of transcranial electrostimulation in the rat.
Anesth. Analg., June 1, 2006; 102(6): 1775 - 1780.
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Lippincott, Williams & Wilkins Anesthesia & Analgesia® is published for the International Anesthesia Research Society® by Lippincott Williams & Wilkins and Stanford University Libraries' HighWire Press®. Copyright 2004 by the International Anesthesia Research Society. Online ISSN: 1526-7598   Print ISSN: 0003-2999 HighWire Press