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Modulatory Effects of Transcranial Direct Current Stimulation on Laser-Evoked Potentials

Gabor Csifcsak MD, Andrea Antal PhD, Ferdinand Hillers, Maik Levold, Cornelius G. Bachmann MD, Svenja Happe MD, Michael A. Nitsche MD, Jens Ellrich MD, Walter Paulus MD
DOI: http://dx.doi.org/10.1111/j.1526-4637.2008.00508.x 122-132 First published online: 1 January 2009

ABSTRACT

Objective. Invasive stimulation of the motor cortex has been used for years to alleviate chronic intractable pain in humans. In our study, we have investigated the effect of transcranial direct current stimulation (tDCS), a noninvasive stimulation method, for manipulating the excitability of cortical motor areas on laser evoked potentials (LEP) and acute pain perception.

Designs and Settings. The amplitude of the N1, N2, and P2 LEP components of 10 healthy volunteers were evaluated prior to and following anodal, cathodal, and sham stimulation of the primary motor cortex. In a separate experiment subjective, pain rating scores of 16 healthy subjects in two perceptual categories (warm sensation, mild pain) were also analyzed.

Results. Cathodal tDCS significantly reduced the amplitude of N2 and P2 components compared with anodal or sham stimulation. However, neither of the tDCS types modified significantly the laser energy values necessary to induce moderate pain. In a separate experiment, cathodal stimulation significantly diminished mild pain sensation only when laser-stimulating the hand contralateral to the side of tDCS, while anodal stimulation modified warm sensation.

Conclusions. The possible underlying mechanisms of our findings in view of recent neuroimaging studies are discussed. To our knowledge this study is the first to demonstrate the mild antinociceptive effect of tDCS over the primary motor cortex in healthy volunteers.

  • tDCS
  • Pain
  • Primary Motor Cortex
  • LEP

Introduction

The notion that the motor cortex is involved in modulating nociceptive processing was postulated more than 50 years ago by Penfield and colleagues [1]. He reoperated patients on whom he had previously resected a portion of the postcentral gyrus for epilepsy, and observed that stimulation of the corresponding primary motor cortex elicited sensory responses. Epidural electrical motor cortex stimulation (MCS) is a relatively safe clinical method for alleviating neuropathic pain [2]. In spite of its efficacy, MCS still remains an invasive procedure [3]. In recent years, several novel noninvasive techniques have been used in experimental and clinical neuroscience for manipulating brain function. In the field of pain research, repetitive transcranial magnetic stimulation (rTMS) of the motor cortex is the most promising method (for a review see: [4]).

Transcranial direct current stimulation (tDCS) has recently been reintroduced as a tool for inducing changes to cortical excitability in focal brain regions in a reversible, relatively selective, painless, and safe manner [5,6]. Motor cortex excitability is enhanced by anodal and decreased by cathodal stimulation when monitored with single-pulse TMS [7,8]. The primary effect of tDCS is a neuronal inhibition or excitation [9,10]: cathodal stimulation hyperpolarizes, while anodal stimulation depolarizes the resting membrane potential, whereby the induced after-effects depend on the polarity, the duration, and intensity of the stimulation. Even though in humans the effects of tDCS were first demonstrated on the motor system, it also influences visual, somatosensory, and cognitive functions [11,12]. In the field of pain perception, only two recently published tDCS studies have been performed. In a randomized, double-blind, parallel-group trial Fregni and colleagues demonstrated that a treatment of anodal tDCS over the primary motor cortex for five consecutive days significantly reduces the subjective pain rating scores of patients suffering from chronic, central, pharmacoresistant pain caused by spinal cord injury [13]. In a second study the same authors evaluated the effect of anodal stimulation vs sham stimulation in patient with fibromyalgia [14]. Despite the robust analgesic effect of anodal tDCS when compared with sham stimulation observed in both studies, the authors did not examine the efficacy of inhibitory, cathodal tDCS, which would have been very useful to understand the overall contribution of primary motor cortex to pain perception.

The aim of our study was to evaluate the effect of tDCS overt the motor cortex on laser evoked potentials (LEPs) and on acute pain and warm perception in healthy control subjects. LEPs are electrophysiological measures that represent the activation of distributed neural populations [15] and are quantitative neuronal correlates of pain processing [16–18]. We stimulated the dorsum of both hands of healthy subjects with a Tm : YAG laser (WaveLight Laser Technologie AG, Erlangen, Germany) [19] and recorded and analyzed LEPs prior to and following anodal, cathodal, and sham tDCS. Currently, early and late LEP components are considered to be differentially sensitive to the subjective variability of pain perception: the early N1 component is thought to be a pre-perceptual sensory response, whereas the late N2-P2 complex strongly correlates with perceived pain and can be modulated by either exogenous or endogenous factors [20,21]. Two separate experiments were conducted: an electrophysiological study evaluating changes of LEP amplitudes always induced by medium intensity pain and a psychophysical study where we focused on alterations in laser intensities in both sub-threshold (warm sensation) and supra-threshold (mild pain) perceptual categories.

Materials and Methods

Subjects

There were 10 (5 male and 5 female) volunteers who participated in the electrophysiological experiment and 16 (5 male and 11 female) subjects took part in the psychophysical experiment. All subjects were aged between 20 and 30 and none suffered from chronic pain syndrome or were taking medication regularly. They had no current or previous neurological or psychiatric diseases. Written informed consent was obtained from all participants. The study protocol conformed to the Declaration of Helsinki and was approved by the Ethics Committee of the University of Göttingen.

tDCS

tDCS was provided by a battery driven constant-current stimulator (NeuroConn, Ilmenau, Germany) using a pair of rubber electrodes placed in a 5 × 7 cm synthetic water-soaked sponge. One electrode was placed at position C3 (according to the international 10–20 system), while the other was situated above the right eyebrow. We chose this position as it is situated over motor areas [22,23], and recent studies found that the stimulation of this area is not only effective in reducing chronic pain [13,14], but also improved muscle endurance in patients with neuromuscular fatigue [24]. The electrodes were orientated approximately parallel to the central sulcus and the eyebrow. This montage had been already proven to be the most effective in modulating motor cortex excitability [7]. The type of stimulation (anodal or cathodal) refers to the polarity of the electrode above motor cortex. The current was applied for 10 minutes with an intensity of 1.0 mA, while for sham stimulation it was turned on only for a few seconds to provide the slightly itchy sensation at the beginning of the stimulation. Subjects were not aware of the polarity and type of tDCS. We randomized the order of the sessions and separated them by at least 1 week in order to avoid the effect of interference.

Laser Stimulation and Psychophysical Evaluation

Pain was elicited using a Tm:YAG laser system. The thulium laser emits near-infrared radiation (wavelength 2,000 nm, pulse duration 1 ms, laser beam diameter 7 mm) with a penetration depth of 360 µm into the human skin [25]. It also allows the emitted heat energy to be precisely restricted to the termination area of primary nociceptive afferents without affecting the subcutaneous tissue [18]. The distal handpiece of the laser was positioned 30 cm from the radial part of the dorsal surface of the hand. The skin temperature of the stimulated area was checked prior to every switch of hands and corrected with a heating lamp when below 35°C. We stimulated slightly different spots in a square (5 × 5 cm) for each measurement to reduce receptor fatigue or sensitization through skin overheating [18]. In both experiments the right hand was stimulated first in half of the cases; in the other half we started with the left hand. This was done because increased response toward novel stimuli had already been described in evoked potential studies related to other sensory modalities [26]. Since in each case the left motor cortex was stimulated with tDCS, we anticipated that it would affect pain threshold dominantly on the contralateral right hand, which could have been masked by this initial orienting response.

We used a numeric analog score (NAS) to assess the subjective intensity of pain. We instructed the subjects to pay attention to the laser stimuli and to rate the perceived pain verbally with numbers (1 for warm, from 1.1 [for mildest] to 1.9 [most intensive] for painful sensation) about 2–3 seconds after each stimulation.

In order to obtain reliable pain rating scores, the subjects were trained to get accustomed to the NAS. Prior to the experimental stimulation sessions they were presented a series of laser stimuli from 200 mJ to 800 mJ and back during which they had to evaluate the intensity of pain.

In the electrophysiological experiment, at the beginning the pain threshold of both hands was determined by applying laser stimuli from 200 mJ in 50 mJ steps. We determined the pain threshold at a laser energy level, where subjects consistently perceived painful sensation between NAS scores 1.1–1.3. However, in order to get reliable LEP waveforms, we aimed to induce medium intensity pain by adapting the bioadaptive approach designed by Weiss and colleagues [27]. During the electroencephalographic (EEG) recording, we started with a laser intensity of 1.5–1.6 times of the threshold level and adjusted laser energy manually in order to keep the magnitude of pain between NAS scores 1.4–1.6. We delivered 40 laser pulses to each hand before and after tDCS, with an interstimulus interval between 8–15 seconds. The ears of the subjects were always plugged and white noise was presented during the measurements to avoid auditory artifacts due to laser stimulation.

In the psychophysical experiment we applied two series of stimuli for each hand before and after tDCS. We systematically increased laser intensity from 200 mJ (5.2 mJ/mm2) in 50 mJ steps until subjects reported moderate pain. Then the laser energy was decreased from that intensity again in 50 mJ steps. This stimulation protocol was repeated twice. Hence we obtained four pain rating scores for each laser intensity prior to and following tDCS for each hand and simulation type.

Electrophysiological Recordings

The EEG was recorded using a five channel montage as described by Treede and colleagues [18]. This montage has been used in numerous experimental and clinical LEP studies as it enables the easy identification of both late LEP components. We placed three electrodes in the midline (Fz, Cz, and Pz) and two laterally above the temporal region (T3 and T4) in accordance with the international 10/20 system. The impedance was kept below 5 kOhm. We used the connected mastoids as reference (RLm) and the ground electrode was positioned on the forehead. Data were collected with a sampling rate of 1,000 Hz by the BrainAmp system (Brain Products GmbH, Munich, Germany) and were analyzed offline. A 0.5 Hz low cutoff and a 30 Hz high cutoff filter were used. After automatic artifact detection (200 µV amplitude criterion) all epochs were visually inspected as well, and those containing eye blinks or muscle movement artifacts were excluded. All recordings consisted of at least 35 artifact-free epochs. Baseline correction was performed on the basis of the 100 ms prestimulus interval. The amplitudes of N1 (referring to Fz) and N2-P2 (referring to RLm) components were measured offline.

Data Analysis

Concerning electrophysiological data, N1, N2, and P2 baseline amplitudes were entered into a repeated-measures anova for both hands separately. For each LEP component, pre- and post-stimulation values (timefactor), tDCS condition pairs (type factor) and electrodes (electrode factor) were entered into the statistical analyses. Here, we considered an amplitude change dependent on the tDCS condition only if the time × type interaction was significant. Furthermore we investigated whether this effect was dependent on the electrode positions by calculating the time × type × electrode interaction. Student's t-test was used to compare the baseline amplitudes between different conditions.

In the electrophysiological study, we did not get any significant difference between the different conditions with regard to the laser intensities necessary to induce moderate pain. Therefore in the psychophysical experiment, we divided the obtained pain rating scores into two perceptual categories: warm sensation (NAS = 1), mild (NAS between 1.1–1.3). We used this kind of classification because pain perception shows high inter-individual variability even among healthy subjects [28] and therefore subjective ratings do not necessarily correlate linearly with the laser energy applied.

Given that there were different numbers of laser stimuli belonging to the same perceptual category before and after tDCS, we applied a 2-way anova for each hand and perceptual category in order to determine whether there was a significantly different change in laser energies (mJ) before and after cathodal vs sham, anodal vs sham, and cathodal vs anodal tDCS. Always two tDCS conditions were entered into anova; hence, we could examine the efficacy of one stimulation type over another and avoid the masking effect of the third one. Since we were interested whether the change in laser energies was dependent on the tDCS conditions that had been used, we always examined the interaction of the time (before and after tDCS) and type (tDCS comparison pairs) factors.

Results

Electrophysiology

The laser stimulation induced a pricking pain in all subjects and a N1 and a biphasic N2-P2 component was clearly identified in all LEP measures (Figure 1).

Figure 1

Grand averages of LEPs obtained by right hand laser stimulation for five scalp electrodes. The solid line shows LEPs before and the intermittent line after cathodal (A), sham (B) and anodal (C) tDCS. Please note that a greater amplitude reduction of the N2 and P2 components for cathodal tDCS is observed when compared with sham tDCS. LEP = laser evoked potentials; tDCS = transcranial direct current stimulation.

In case of the N1 component the amplitudes recorded at T3 and T4 channels (referring to Fz) were analyzed separately for each hand. There was no significant main effect of type of stimulation on channel T3 (right hand: F = 2.07, P = 0.12; left hand: F = 1.18, P = 0.3) and on channel T4 (right hand: F = 1.18, P = 0.21; left hand: F = 0.2, P = 0.8). The time factor was also not significant on channel T3 (right hand: F = 0.9, P = 0.4; left hand: F = 0.03, P = 0.9) and on channel T4 (right hand: F = 1.47, P = 0.3; left hand: F = 1.82, P = 0.2). Similarly, there was no significant time × type interaction on T3 (right hand: F = 0.21, P = 0.8; left hand: F = 0.21, P = 0.8) and on channel T4 (right hand: F = 0.7, P = 0.6; left hand: F = 0.5, P = 0.6).

In the case of the N2 component, we found a significant time × type interaction only when the right hand was stimulated. When compared with sham and anodal tDCS, cathodal stimulation significantly diminished the N2 amplitude (F = 6.02, P = 0.018 for cathodal-sham and F = 4.58, P = 0.038 for cathodal-anodal comparison). The interaction with electrode position (time × type × electrode) was not significant though (F = 0.39, P = 0.81 and F = 0.42, P = 0.79). In contrast to cathodal stimulation, anodal stimulation, did not affect the N2 amplitude when compared with sham tDCS (F = 0.08, P = 0.77). The amplitude differences of the N2 component for all three tDCS conditions and both hands are shown in Figure 2a.

Figure 2

LEP component amplitude differences (before tDCS—after tDCS) in the three tDCS conditions for the N2 (A) and P2 (B) waveforms at the Cz electrode for both hands. The stars mark significant differences for the N2 component in the case of the right hand laser stimulation between cathodal-sham and cathodal-anodal tDCS conditions (P < 0.03). They also mark significant differences for the P2 component in the case of the contralateral hand between cathodal-sham tDCS conditions (P < 0.01). Please note, that in the case of the N2 wave a negative difference represents a decrease in the amplitude, while in the case of the P2 component the more positive the value is, the greater the amplitude reduction was caused by tDCS. LEP = laser evoked potentials; tDCS = transcranial direct current stimulation.

With regard to the P2 amplitude in comparison with the sham condition, we found a greater reduction after cathodal tDCS when the left hand was laser stimulated (from 18.31 µV to 15.62 µV and from 16.26 µV to 15.95 µV); however, the time × type interaction was not significant (F = 0.01, P = 0.07). In the case of the contralateral right hand, the repeated-measures anova revealed a significant modulatory effect of tDCS. The interaction of time and type was significant for the cathodal-sham (F = 9.86, P < 0.01), marked but not significant for the anodal-sham (F = 3.00, P = 0.09) and not significant for the anodal-cathodal (F = 0.78, P = 0.37) comparison (Fig. 2). There was no significant interaction with electrode position (F = 1.08, P = 0.37; F = 0.56, P = 0.69 and F = 0.06, P = 0.99). The amplitude differences of the P2 component for all three tDCS conditions and both hands are shown in Figure 2b.

The means and standard deviations for both hands, LEP components and tDCS pairs are presented in Table 1.

View this table:
Table 1

Changes of LEP amplitudes at the Cz electrode

HandLaser evoked potentials componentCathodalAnodalSham
BeforeAfterBeforeAfterBeforeAfter
Right HandN2 (µV)(Cz)Mean ± SD −13.9 ± 7.2 −8.2 ± 6.2 −13.3 ± 6.8 −10.6 ± 6.4−12.24 ± 8.7 −9.1 ± 6.2
P2 (µV)(Cz)Mean ± SD 20.04 ± 9.2515.56 ± 7.55 19.38 ± 8.11 15.87 ± 6.82 16.03 ± 6.44 15.23 ± 5.80
Left HandN2 (µV)(Cz)Mean ± SD−11.06 ± 6.77−8.99 ± 5.89−13.16 ± 8.00−10.16 ± 6.40−10.93 ± 7.86−9.13 ± 7.06
P2 (µV)(Cz)Mean ± SD 18.31 ± 9.9615.62 ± 6.85 18.01 ± 10.17 16.17 ± 7.62 16.26 ± 5.1115.95 ± 5.27

Psychophysics

In the electrophysiological experiment, moderate pain was always induced in order to get reliable LEP components. However, we did not get any significant difference among the different conditions with regard to the laser intensities necessary to induce moderate pain. For the left and right hand stimulations the two-way anova revealed no significant change in laser intensities before and after tDCS in either pain categories or any of the tDCS-type comparisons (F < 0.38, P > 0.37 for all conditions, respectively). Therefore we implemented a new psychophysical experiment in order to see if tDCS has an effect for less intensive sensations.

In the case of the right hand, after anodal stimulation significantly lower laser energy values were necessary to induce warm sensation than before tDCS, when they were compared with sham tDCS (F = 4.34, P = 0.038; Figure 3a). On the contrary, cathodal stimulation significantly increased laser intensities that were needed to induce mild pain when compared with sham or anodal stimulation as shown in Figure 3b (F = 4.83, P = 0.028 for cathodal-anodal and F = 7.63, P < 0.01 for cathodal-sham comparison).

Figure 3

Laser energy changes in the perceptual categories (warm sensation [A], mild [B]) before and after cathodal, sham and anodal tDCS in the case of the right hand laser stimulation. The star on panel (A) marks significant difference between the changes of laser energy in the anodal and sham conditions necessary to induce warm sensation. The star on panel (B) represents significant difference between the changes of laser energy in the cathodal-sham, while the double cross shows significant difference between cathodal and anodal tDCS in the mild pain category. tDCS = transcranial direct current stimulation.

The F and P-values for all three tDCS comparison pairs, both hands and both perceptual categories are presented in Table 2.

View this table:
Table 2

Statistical results of the psychophysical experiment

HandtDCS comparisonWarmMild
Right handCathodal–ShamF = 0.75, P = 0.38F = 4.83, P = 0.02*
Anodal–ShamF = 4.34, P = 0.038*F = 0.30, P = 0.58
Cathodal–AnodalF = 1.65, P = 0.20F = 7.63, P < 0.01*
Left handCathodal–ShamF = 1.12, P = 0.29F = 1.60, P = 0.20
Anodal–ShamF = 0.30, P = 0.58F = 3.63, P = 0.057
Cathodal–AnodalF = 0.22, P = 0.63F = 0.41, P = 0.51
  • * Significant changes between the tDCS conditions.

  • tDCS = transcranial direct current stimulation.

Discussion

Several animal and human studies have shown that tDCS modifies the excitability of the stimulated cortical area in a polarity dependent way and as a result, causes perceptual changes (for a recent review see Antal et al. 2006 [11]). In our study, we explored the effects of this noninvasive technique on LEPs and acute pain perception. Cathodal stimulation significantly reduced the N2 and P2 components of LEPs when we induced pain in the contralateral hand. There was no effect on the N1 component observed. In the psychophysical experiment, cathodal stimulation of the motor cortex significantly diminished mild pain, whereas anodal stimulation facilitated warm sensation. Both effects were only present when the hand contralateral to the side of tDCS was stimulated with Tm:YAG laser.

The Effect of tDCS on LEPs and Pain Perception

Perhaps the most important finding of this study was the significantly decreased N2 and P2 amplitudes after cathodal tDCS on the contralateral hand. According to intracranial EEG and source localizing studies, the N2 component is generated mainly in the primary somatosensory cortex (SI) and in the operculoinsular region, while the P2 component mainly arises from the anterior cingulated cortex ([29–31], for a review see: [15]). Positron emission tomography (PET) and functional magnetic resonance imaging (fMRI) studies have also shown that the hemodynamic responses of these brain regions correlate with pain intensity [32–34]. It is likely that in our study, the observed diminution of both LEP components after cathodal tDCS reflects a modulation of the activation of at least some of these areas. Indeed, in a recent PET study, Lang and colleagues examined changes of regional cerebral blood flow (rCBF) in several brain regions while they used exactly the same stimulation protocol for modifying motor cortex excitability of 16 healthy subjects as we did in our study [35]. Concerning pain related regions, cathodal tDCS significantly changed rCBF in the right cingulate cortex and the right thalamus. As this area is situated on the medial surface of the brain, relatively far from the cortical convexity, it is not likely that tDCS could have directly modulated this structure. However, given that cingulate cortex is widely interconnected with primary and premotor areas [36], the secondary modification of its excitability could be a possible explanation of our results.

In the psychophysical experiment we found a significant reduction of mild pain perception after cathodal tDCS when the contralateral hand was stimulated with laser. In a recent study of Fregni and colleagues, anodal tDCS significantly reduced subjective pain perception in patients with intractable central pain [13], and this finding seems to contradict our results. One possible explanation for this discrepancy is that we examined experimentally induced acute pain in healthy subjects, while Fregni and colleagues have stimulated motor cortex in a chronic pain syndrome. Such chronic pathological states are characterized by both functional (i.e., reorganization of synaptic transmission [37–39] and structural (i.e., grey matter atrophy: see [40]) changes in cortical and subcortical areas, probably also leading to excitability changes [41,42].

Another important issue is that Fregni and colleagues [13] observed long lasting antinociceptive effects of 20-minute daily sessions with 2 mA strong anodal tDCS; that is a stimulation condition twice as long and strong as the one applied in our study. Interestingly enough, even by using this protocol they did not observe significant changes immediately after tDCS, but only the following day; this indicates that the effect of tDCS developed much slower than one would expect it in any other modality among healthy subjects. Although with our stimulation protocol, the possibility of having induced subtle and slow-evolving effects of anodal tDCS on pain perception is less likely, taking into account the different subject population, it cannot be ruled out.

The Effect of tDCS on Warm Sensation

The effect of anodal stimulation on subjective warm assessment was to some extent opposite to cathodal tDCS as it facilitated warm sensation without influencing pain sensation or LEP amplitudes. Regarding the differential effect of anodal tDCS on warm and pain sensation there is some evidence that certain brain regions are differentially involved into processing of warm and painful stimuli. In a PET study, increased rCBF was found for mild painful stimulation but not for warm perception in the contralateral insular cortex, bilateral prefrontal cortex, bilateral inferior parietal cortex, and the ipsilateral premotor area [43]. Additionally, different blood oxygen level-dependent signal change in the contralateral operculoinsular region was reported for painful and warm stimulation as revealed by fMRI [44]. Thus, we might speculate that the modulation of all or some of these regions—namely the insular, motor/premotor cortex or the right frontopolar area (where the reference electrode was placed)—could contribute to the observed shift of pain threshold and manifest in thermal hyperaesthesia.

The discrepancy between the effect of anodal tDCS on warm and pain perception could also be explained by the different peripherial receptors involved in the two processes. Warm perception is mediated by C fiber nociceptors [45], while painful thermal stimuli trigger both A-delta and C-afferents [18]. The N2 and P2 late LEP components reflect A-delta activation, and albeit they remain unchanged after anodal tDCS, this might not be true for the so-called ultralate LEPs that reflect C-fiber firing. However, the analysis of ultralate LEP components requires special techniques. Moreover, warm sensation following laser skin stimulation is still controversial, as there is evidence that A-delta fiber activation suppresses C-fiber activation and consequent warm sensation [46,47].

Further Considerations

Since many imaging studies have reported that either MCS [17,48], TMS [49], or tDCS [35] over motor cortical areas are associated with altered activity in the thalamus and subthalamic nucleus, we cannot exclude the possibility of having modulated the involvement of these subcortical structures when interpreting our data. Indeed, in the case of MCS, Garcia-Larrea and colleagues proposed that the activation of the thalamus as a key structure would be the primary event that could trigger a cascade of synaptic events and reduce pain perception mainly by modulating activity of anterior cingulated cortex, orbitofrontal cortex, and the brainstem periaqueductal grey area [48].

tDCS is a relatively novel tool that causes focal and long lasting modulation of cortical excitability. It does not actively “stimulate” the cortex in the classic sense of the term, but rather it “modulates” cortical excitability. With regard to the increased use of tDCS in healthy subjects, the extent of cortical stimulation and the spatial distribution of the current density within the volume of the human brain for a given electrode montage is recently intensively investigated (for a recent article see: [50]). It was observed that approximately half of the current injected during tDCS is shunted through the scalp, depending on electrode dimension and position [51]. Using stimulating currents of 2.0 mA, the magnitude of the current density in relevant regions of the brain is of the order of 0.1 A/m2, corresponding to an electric field of 0.22 V/m. Concerning the spatial distribution of the stimulation, Lang et al. [35] observed that tDCS is an effective means of provoking sustained and widespread changes in regional neuronal activity.

With regard to neuronal mechanisms, tDCS is likely to induce intracellular protein-synthesis and alterations of cAMP and calcium-levels [52–54]. NMDA receptors also seem to play a pivotal role in its cellular mechanism, as dextromethorphan—a selective NMDA receptor antagonist—abolishes any after-effects of stimulation [55]. Recent studies suggest that tDCS applied to motor and nonmotor areas according to the present tDCS safety guidelines is associated with relatively minor adverse effects in healthy humans and in patients as well [56–58]. The efficacy of this method has already been proven in several sensory modalities, recently in chronic pain [13,14]. To our knowledge, its efficacy was revealed for the first time in experimentally induced acute pain in healthy volunteers by our study. In the future, the pharmacological prolongation of the excitability diminishing after-effects [59] combined with the antinociceptive effect of cathodal stimulation would render the method of tDCS applicable to different patient populations with chronic pain.

Acknowledgment

We thank Judit Karacsonyi and Laszlo Czako for the English corrections and Annegrete Ende for the technical help. This study was supported by the German Ministry of Research and Education within the “Kompetenznetz Schmerz” (FKZ Ø1EMØ519).

References

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