Journal of Pain and Symptom Management
Volume 36, Issue 1 , Pages 79-91, July 2008

Pergolide Increases the Efficacy of Cathodal Direct Current Stimulation to Reduce the Amplitude of Laser-Evoked Potentials in Humans

Department of Clinical Neurophysiology (D.T., I.B., C.P, L.C. K.B., M.A.N., W.P., A.A.), Georg-August University, Göttingen, Germany; and Department of Neurology (D.T.), University of Szeged, Szeged, Hungary

Accepted 8 August 2007. published online 25 March 2008.

Article Outline

Abstract 

Transcranial direct current stimulation (tDCS) was recently reintroduced as a tool for inducing relatively long-lasting changes in cortical excitability in focal brain regions. Anodal stimulation over the primary motor cortex enhances cortical excitability, whereas cathodal stimulation decreases it. Prior studies have shown that enhancement of D2 receptor activity by pergolide consolidates tDCS-generated excitability diminution for up to 24 hours and that cathodal stimulation of the primary motor cortex diminishes experimentally induced pain sensation and reduces the N2–P2 amplitude of laser-evoked potentials immediately poststimulation. In the present study, we investigated the effect of pergolide and cathodal tDCS over the primary motor cortex on laser-evoked potentials and acute pain perception induced with a Tm:YAG laser in a double-blind, randomized, placebo-controlled, crossover study. The amplitude changes of laser-evoked potentials and subjective pain rating scores of 12 healthy subjects were analyzed prior to and following 15 minutes cathodal tDCS combined with pergolide or placebo intake at five different time points. Our results indicate that the amplitude of the N2 component was significantly reduced following cathodal tDCS for up to two hours. Additionally, pergolide prolonged the effect of the cathodal tDCS for up to 24 hours, and a significantly lowered pain sensation was observed for up to 40minutes. Our study is a further step toward clinical application of cathodal tDCS over the primary motor cortex using pharmacological intervention to prolong the excitability-diminishing effect on pain perception for up to 24 hours poststimulation. Furthermore, it demonstrates the potential for repetitive daily stimulation therapy for pain patients.

Key Words: Pain, tDCS, pergolide, LEP, motor cortex, human

 

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Introduction 

In recent years, invasive stimulation of the primary motor cortex (M1) for the treatment of certain kinds of pain has attracted much interest. The first widely accepted clinical method for alleviating pain using cortical stimulation was epidural electrical motor cortex stimulation.1, 2 Recently, the most frequently investigated noninvasive method so far is repetitive transcranial magnetic stimulation (rTMS). Studies of transcranial magnetic stimulation in experimental and acute pain sensations have produced encouraging outcomes.3, 4 In spite of the beneficial effects of rTMS, a new method, transcranial direct current stimulation (tDCS) has been favored in recent editorials.5, 6

Major advantages of tDCS as a tool for inducing long-lasting changes of cortical excitability and activity in focal brain regions is that it acts reversibly, painlessly, and safely.7, 8, 9, 10 Primarily, it causes polarity-dependent shifts of the resting membrane potentials and consequently changes the firing rates of neurons under the electrodes, neuronal projections and subsequent connected cortical areas.11, 12, 13 Generally, anodal stimulation over the M1 has been found to enhance cortical excitability, whereas cathodal stimulation decreases it.7, 8 Although in humans the modulatory effect of tDCS had first been demonstrated on the motor system, it influences visual, somatosensory and prefrontal functions as well.14, 15, 16 In a recent study, it was shown that enhancement of D2, and to a much lesser degree, of D1 receptor activity by pergolide consolidated cathodal tDCS-generated excitability diminution for up to 24 hours.17

Our first sham-controlled studies demonstrated that cathodal stimulation of the M1 diminishes experimentally induced pain sensation, and in parallel reduces the N2–P2 amplitude of laser-evoked potentials (LEPs) immediately after the end of stimulation.18 The aim of the present study was to investigate the effect of combined cathodal stimulation and pergolide treatment on LEPs and related pain perception in a double-blind, randomized, placebo-controlled, crossover study, with the clear intention of proving the already known inhibitory prolonging effect of pergolide17 on pain perception. Here, amplitude changes of the N1, N2, and P2 of LEPs and subjective pain rating scores of 12 healthy subjects were analyzed prior to and following 15 minutes of cathodal tDCS, and following pergolide or placebo treatment at five different time points (before, 0min, 40min, two hours, 24 hours).

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Methods 

Subjects 

Fifteen healthy volunteers (aged between 20 and 31 years) were informed about all aspects of the experiments and all gave informed consent. Two participants chose not to continue the experiment after the first trials, and one subject was excluded as LEPs could not be identified reliably; 12 of the subjects (five male, seven female) were included in the study. All of the subjects underwent pergolide and placebo medication treatment. Additionally, seven subjects (three male, four female) participated in a control session in which no tDCS and drug treatment were introduced. We conform to the Declaration of Helsinki and the experimental protocol was approved by the Ethics Committee of the University of Göttingen. None of the subjects suffered from any neurological and psychological disorders, and none had metallic implants/implanted electric devices, nor took any medication regularly.

Pharmacological Interventions 

Pergolide 0.025mg combined with 10mg domperidone to avoid side effects (e.g., vomiting induced by the medication) or equivalent placebo (glucose) was taken by the subjects orally two hours prior to the start of the experiments. By this means, the drug induces a stable plasma level19 and produces prominent effects in the central nervous system.17, 20, 21 To avoid cumulative drug effects, each experimental session was separated by at least one week. Subjects and the investigator conducting the experiment were blinded as to the respective pharmacological condition.

tDCS 

tDCS was delivered by a battery-driven constant current stimulator (Eldith NeuroConn GmbH, Ilmenau, Germany) using a pair of rubber electrodes in a 5×7cm water-soaked synthetic sponge. The cathode was placed over the representational field of the right abductor digiti minimi as identified by transcranial magnetic stimulation (Dantec S.A., Skovlunde, Denmark), whereas the other electrode (reference) was situated contralaterally above the right eyebrow. The electrodes were oriented approximately parallel to the central sulcus and the eyebrow. This montage has been proven to be the most effective for modulating motor cortex excitability.7 The cathodal stimulation refers to the polarity of the electrode above the M1. The current was applied for 15 minutes with an intensity of 1.0mA.

Laser Stimulation 

A Tm:YAG laser system (WaveLight Laser Technologie AG, Erlangen, Germany) was used for the pain stimulation. The thulium laser emits near-infrared radiation (wavelength 2,000nm, pulse duration 1 millisecond, laser beam diameter 7mm) with a penetration depth of 360μm into the human skin and allows a precise restriction of the emitted heat energy to the termination area of primary nociceptive afferents without affecting the subcutaneous tissue22, 23 The distal handpiece of the laser was positioned 30cm from the radial part of the dorsal surface of the hand. Skin temperature of the stimulated area was checked prior to every switch between hands, and corrected with a heating lamp if it fell below 35°C. We stimulated slightly different spots in a square (5×5cm) for each measurement to reduce receptor fatigue or sensitization by skin overheating.23 In both experiments, the right hand was stimulated first in half of the cases and the left hand was stimulated first in the other half. This approach, used as increased response toward novel stimuli, has been described in evoked potential studies of other sensory modalities.24, 25, 26, 27

At the beginning of each condition the pain threshold of both hands was determined by applying laser stimuli from 200mJ in 50mJ steps. During EEG recording, we delivered 40 laser pulses to each hand before and after tDCS with 1.5–1.6 times of threshold intensity. The interstimulus interval of the stimulation ranged from eight to 15 seconds. During each condition, the intensity of the laser stimulation was kept constant as determined prior to tDCS, enabling a clear comparison between results.

Psychophysical Evaluation 

We used the numeric analog score to assess the subjective intensity of pain. The subjects were instructed to pay attention to the laser stimuli and to rate the perceived pain verbally (warm: 1, painful: from 2 (smallest) to 10 (most intense pain)) about 2–3 seconds after each stimulation.28 The ears of the subjects were plugged during the measurements to avoid auditory artifacts produced by the laser stimulation.

Electrophysiological Recordings 

The electroencephalogram was recorded using a five-channel montage as described by Treede et al.23 This montage has been used in numerous experimental and clinical LEP studies as it enables the easy identification of late LEP components. Electroencephalogram was recorded with gold disc electrodes from the Fz, Cz, Pz, T3, T4 (vs. linked mastoids) according to the international 10/20 system. The ground electrode was positioned on the forehead. The impedance was kept below 5 kOhm. Data were collected with a sampling rate of 1,000Hz by the BrainAmp system (Brain Products GmbH, Munich, Germany) and were analyzed offline. A 0.5Hz low cutoff and a 30Hz high cutoff filter were used. After semiautomatic artifact detection (150 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 millisecond prestimulus interval. Using semiautomatic peak detection, we investigated different LEP components. The earliest component is a negativity N1 (peaking around 140–170 milliseconds), using T3 and T4 channels vs. Fz. The N1 component is followed by the late N2–P2 complex (N2: peaking around 160–220 milliseconds, P2: peaking around 300–360 milliseconds) in the midline (Fz, Cz, Pz) leads, using linked mastoid reference.

Experimental Procedures 

The experiments were conducted in a repeated measurement design using a randomized order, with a break of at least one week between each session. Pergolide 0.025mg or equivalent placebo (glucose) was taken by the subjects orally two hours before the start of the experiments. The subjects were seated in a reclining chair. First, the left motor-cortical representational field of the right abductor digiti minimi was identified using transcranial magnetic stimulation. At the beginning of each condition, the pain threshold of both hands was determined by applying laser stimuli from 200mJ in 50mJ steps. During electroencephalogram recording, we delivered 40 laser pulses to each hand before tDCS with 1.5–1.6 times of threshold intensity. Afterward, cathodal tDCS was performed for 15 minutes, followed by 40 laser pulses to each hand immediately after the stimulation, 40minutes, two hours, and 24 hours later (Fig. 1).

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  • Fig. 1 

    Experimental procedure: Pergolide or an equivalent placebo drug was taken by all subjects orally two hours before the start of the experiments (2.5 hours before tDCS). First, the left motor-cortical representational field of the right abductor digiti minimi was identified using TMS. During electroencephalogram recording, we delivered 40 laser pulses to each hand before tDCS. Afterward, cathodal tDCS was performed for 15 minutes, followed by 40 laser pulses to each hand immediately after the stimulation, 40minutes, two hours, and 24 hours later.

Because our previous study has shown that sham stimulation has no significant effect on pain sensation,18 no sham stimulation was used as an additional condition. However, we aimed to examine the normal habituation process. Seven subjects, chosen among the ones participating in the previous experiment, underwent the same protocol described previously, in which no tDCS and drug condition were introduced.

Data Analysis 

Because the size of the amplitudes differed across subjects, normalization of the data was necessary. We divided the “after” tDCS-conditions by the value of the “before” condition. As a consequence of the bilateral representation of pain29, 30 and the lack of significant differences (P>0.05) between the LEP amplitudes of the two sides, the data were not analyzed separately. Averaged numeric analog score values for N1, N2, and P2 amplitudes from each set of 40 trials were individually averaged and entered into a repeated-measures analysis of variance (ANOVA) (2 medications CONDITION [pergolide, placebo]×4 TIME [after 0min/before, after 40min/before, after 2 hours/before, after 24 hours/before]). To compare the control results with the under medication conditions, all results of the seven subjects (3 CONDITION [pergolide, placebo, control]×4 TIME) were also individually averaged and entered into a repeated-measures ANOVA. In addition, a one-way ANOVA was performed separately for each condition to show the effectiveness of direct current (DC) stimulation. We considered a psychophysical or an electrophysiological change if the CONDITION×TIME interaction was significant or if the one-way ANOVA revealed significant difference between time points. Post-hoc analysis was done using a Fischer LSD test.

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Results 

Psychophysics 

The intensity of the laser stimulation was 21.32mJ/mm2 for pergolide medication (range, 19.5–23.4mJ/mm2), 21.177 mJ/mm2 for placebo medication (range, 19.5–23.4mJ/mm2), and 21.32mJ/mm2 (range, 19.5–22.1 mJ/mm2) for the control measurements (without tDCS and medication).

Concerning the pain perception scale, the ANOVA revealed no main effect of CONDITION [F(1,23)=2.38, P=0.136], but the effect of TIME was significant [F(3,69)=10.89, P<0.005]. The CONDITION×TIME interaction was not significant [F(3,69)=0.50, P=0.680]. If we compared the control results with the medication conditions, there was no main effect of CONDITION [F(2,26)=1.56, P=0.229], but the effect of TIME [F(3,39)=7.47, P<0.005] was significant (Fig. 2). There was no significant difference in the CONDITION×TIME interaction [F(6,78)=0.80, P=0.570].

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  • Fig. 2 

    The differences between numeric analog score results at four time points (standardized data by calculating the after 1–4/before ratio), for the two medication conditions (pergolide, placebo) and control experiment for both hands with laser stimulation. The standardized numeric analog score results show either an increase in pain sensation or a decline, relative to one. Following cathodal tDCS, the pain sensation was lowered up to 40minutes. The asterisks indicate significant differences between the different time points.

One-way ANOVA revealed significant effect of TIME in the case of pergolide medication [F(4,92)=6.06, P<0.005]. The post-hoc analysis showed a significant difference between the before and after conditions (P<0.05). In the case of placebo medication, the effect of TIME was significant [F(4,92)=4.54, P=0.002] and a significant difference was revealed between the after and all the other time points (P<0.05). In the case of the control experiment, one-way ANOVA revealed no significant effect of TIME [F(4,52)=0.94, P=0.446].

The means and standard deviations of numeric analog score values for both hands and for all conditions are shown in Table 1.

Table 1. Averaged Numeric Analog Score Values and Standard Deviations from Each Set of 40 Trials
ConditionSideBeforeAfter1After2After3After4
Pergolide+tDCS, n=12Left4.91±2.024.37±1.984.06±2.044.25±2.274.89±2.09
Right5.05±1.774.30±2.033.66±2.094.50±2.324.65±1.79

Placebo+tDCS, n=12Left4.05±1.344.14±1.413.55±1.374.14±1.724.36±1.48
Right4.39±1.393.98±1.663.46±1.344.41±1.914.27±1.32

Control, n=7Left3.69±1.763.31±1.563.43±2.153.61±1.794.02±1.40
Right3.28±1.153.19±1.323.59±1.883.35±1.903.49±1.55

Averaged numeric analog score values from each set of 40 trials for the left and right sides separately and all conditions before and after tDCS.

Electrophysiology 

The laser stimulation induced a pricking pain and a biphasic N2–P2 component was clearly identified in all LEP measures of all 12 subjects (Fig. 3).

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  • Fig. 3 

    Grand averages of LEPs obtained by both hand laser stimulation for the Cz recording electrode. The solid line shows LEPs for placebo medication combined with tDCS and the intermittent line for pergolide medication combined with tDCS at five different time points (before, after tDCS 0min, after tDCS 40min, after tDCS two hours, after tDCS 24 hours). Note that 24 hours following tDCS a greater amplitude reduction of the N2 component and N2P2 peak-to-peak amplitude for pergolide medication is observed when compared to placebo medication. The asterisk indicates a significant difference between the pergolide and placebo conditions.

N1 Component 

In the case of the N1 component, there was no main effect of CONDITION [F(1,23)=0.437, P=0.515] or TIME [F(3,69)=0.14, P=0.937] at the T3 electrode position. There was no significant CONDITION×TIME interaction [F(3,69)=0.28, P=0.840]. At the T4 electrode position, there was no main effect of CONDITION [F(1,23)=0.116, P=0.325] or TIME [F(3,69)=0.24, P=0.654]. There was no significant CONDITION×TIME interaction [F(3,69)=0.38, P=0.213]. In the control experiment, there was no main effect of CONDITION, or TIME. There was no significant difference in the CONDITION×TIME interaction (P>0.005).

N2 Component 

In the case of the N2 component, there was no main effect of CONDITION [F(1,23)=0.12, P=0.737], but the effect of TIME was significant [F(3,69)=7.44, P<0.005] at the Fz electrode position. There was no significant difference in the CONDITION×TIME interaction [F(3,69)=1.369, P=0.259]. At the Cz electrode position, there was no main effect of CONDITION [F(1,23)=0.91, P=0.349], but the effect of TIME was significant [F(3,69)=5.65, P=0.001]. We also found a significant CONDITION×TIME interaction [F(3,69)=3.67, P=0.016]. According to the post hoc analysis, pergolide medication, significantly decreased the amplitudes of the N2 component, compared to the placebo medication, at the 24-hour time point (P=0.006). However, there were no significant differences between the other time points when compared with the pergolide and placebo medication (P>0.05). At the Pz electrode position, there was no main effect of CONDITION [F(1,23)=1.93, P=0.178], but the effect of TIME was significant [F(3,69)=6.82, P<0.005]. There was no significant CONDITION×TIME interaction [F(3,69)=2.16, P=0.101].

To compare the control results to the under medication conditions, the results of the seven subjects were also individually averaged and entered into a repeated-measures ANOVA for all electrode positions. Although the effect of TIME was significant at all electrode positions (P<0.05), neither the effect of CONDITION nor the CONDITION×TIME interaction were significant (P>0.05).

One-way ANOVA revealed significant effect of TIME in the case of pergolide medication [F(3,69)=3.65, P=0.017]. The post hoc analysis showed a significant difference between the before and after conditions (P=0.002). In the case of placebo medication, the effect of TIME was significant [F(3,69)=6.60, P<0.005] and a significant difference was revealed between the before and after, and after and after, conditions (P<0.05). In the case of the control experiment, one-way ANOVA revealed no significant effect of TIME [F(3,39)=1.57, P=0.211].

P2 Component 

Although the effect of TIME was significant (P<0.05) in the case of the P2 component, there was no main effect of CONDITION, nor a significant CONDITION×TIME interaction at all electrode positions (P>0.05). If we compared the control results with the under medication conditions, the effect of TIME was significant at all electrode positions, but neither the effect of CONDITION, nor the CONDITION×TIME interaction were significant (P>0.05).

The means and standard deviations for the right and left hand separately, and under all conditions, are shown in Table 2, Table 3.

Table 2. Mean Values and Standard Deviations of the LEP Parameters for the Right Hand
ConditionComponentBefore tDCSAfter1 tDCS (0min)After2 tDCS (40min)After3 tDCS (2 hours)After4 tDCS (24 hours)
Pergolide+tDCS, n=12N2 (μV)−11.42±6.40−10.09±5.55−7.23±4.49−7.32±5.97−9.33±5.33
P2 (μV)14.87±5.5412.82±6.1210.9±6.1411.68±7.5813.55±5.90

Placebo+tDCS, n=12N2 (μV)−11.04±5.82−9.36±6.59−6.78±4.23−7.38±3.66−11.39±5.32
P2 (μV)15.14±6.9612.27±7.119.07±5.4411.53±5.2314.76±5.49

Control, n=7N2 (μV)−13.12±7.52−11.83±7.92−10.31±6.44−8.67±5.42−12.45±7.75
P2 (μV)12.94±3.5110.06±3.218.79±5.259.57±3.8311.32±2.05

The table shows the mean values and standard deviations of the LEP parameters for all conditions at the Cz electrode positions obtained from all subjects for right hand before and after cathodal tDCS.

Table 3. Mean Values and Standard Deviations of the LEP Parameters for the Left Hand
ConditionComponentBefore tDCSAfter1 tDCS (0min)After2 tDCS (40min)After3 tDCS (2 hours)After4 tDCS (24 hours)
Pergolide+tDCS, n=12N2 (μV)−11.73±4.66−9.98±5.52−7.45±5.71−5.83±7.01−8.5±5.19
P2 (μV)15.22±6.2712.48±6.8710.38±6.4010.75±6.3914.22±7.03

Placebo+tDCS, n=12N2 (μV)−11.57±6.96−9.16±5.81−5.56±4.15−6.37±4.52−11.52±6.30
P2 (μV)15.55±8.6011.83±6.619.41±6.8911.61±8.0215.58±7.02

Control, n=7N2 (μV)−13.22±6.70−10.68±7.76−8.48±4.95−9.15±5.93−11.89±5.84
P2 (μV)11.95±3.528.67±3.919.46±3.859.61±4.4612.45±2.46

The table shows the mean values and standard deviations of the LEP parameters for all conditions at the Cz electrode positions obtained from all subjects for left hand before and after cathodal tDCS.

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Discussion 

tDCS modifies the excitability of the stimulated cortical area in a polarity-dependent way7, 8 and simultaneously causes perceptual changes.31, 32 In the present study, we explored the effects of this noninvasive brain stimulation technique on subjective acute pain perception and its electrophysiological correlates. Our results confirm that 15 minutes of cathodal tDCS over the primary motor cortex significantly reduced the amplitude of the N2 component, and the changes of the electrophysiological parameter remained stable for up to two hours after stimulation when compared to the control experiment (Fig. 4). Furthermore, the subjective pain sensation was lowered after cathodal tDCS for up to 40minutes (Fig. 2).

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  • Fig. 4 

    The differences between mean N2 amplitude values at four time points (standardized data by calculating the after 1–4/before ratio), for the two medication conditions (pergolide, placebo) and control experiment for both hands laser stimulation at the Cz electrode. The standardized peak amplitudes show either an increase in the amplitude of the N2 component or a decline, relative to a value of one. Our results confirm that cathodal tDCS significantly reduced the amplitude of the N2 component when compared to the control experiment. The pergolide medication prolonged this effect for up to 24 hours. The symbols indicate significant differences between the pergolide and placebo medications (0) or differences between time points (*).

Recording LEPs is a widely accepted method for examining the neuronal correlates of pain perception temporally and spatially in human subjects.22, 23 The earliest cortical LEP component is a negativity (N1, peaking around 140–170 milliseconds). According to its scalp topography (maximum near T3 and T4), it is probably generated near the secondary somatosensory cortex in the fronto-parietal operculum.23 We did not find any significant change concerning the N1 amplitudes. Probably, this area could not be stimulated directly or the intensity of stimulation used was not sufficient to reflect any significant change.

The N1 component is followed by the late negative–positive complex (N2–P2) that can be most accurately recorded in the midline (Fz, Cz, Pz) leads. According to source localizing studies, the N2 component (peaking around 160–220 milliseconds) is generated both bilaterally in the operculoinsular region and partly in the anterior cingulate cortex (ACC).2 This component contributes to sensory-discriminatory aspects of pain. The P2 component (peaking around 300–360 milliseconds) arises mainly from the ACC and reflects endogenous, attentional-cognitive,33 and affective factors.23, 34 The role of ACC in coding pain intensity is still under debate; however, there is increasing evidence to suggest that activity in some parts of the ACC significantly correlates with increasing pain sensation.35

In a recent study, the effect of tDCS has been investigated by PET.13 Concerning pain-related regions, cathodal tDCS significantly diminished regional cerebral blood flow in the right ACC and the right thalamus. As the ACC is widely interconnected with primary and premotor areas,36 it is likely that the stimulation of the M1 could result in a secondary inhibition of the ACC, and as a consequence, in N2 amplitude reduction. The antinociceptive effect as revealed by the psychophysical experiment could reflect the diminished involvement of the ACC in pain processing. DC stimulation of the left motor cortex resulted in several critical changes at the contralateral side.13 Relative increases in regional cerebral blood flow after cathodal tDCS compared to sham tDCS were found in the right M1, frontal pole, primary sensorimotor cortex, and parietal occipital cortex. Regional CBF increase in homologous contralateral M1 was also found after rTMS to left M1.37, 38 Our results suggest that the stimulation of the left motor cortex has an influence on LEP components and pain perception of both sides. However, a recent study from Le Pera et al.39 showed that the physiological activation of the motor cortex is able to reduce pain perception and LEP amplitude only when the motor area contralateral to painful stimuli is activated.

Relevant clinical studies show that repeatedly administering anodal tDCS over the M1 diminished pain sensation in patients with traumatic spinal cord injury40 and induced significantly greater pain reduction compared with sham stimulation in patients with fibromyalgia.41 However, comparing these results to our data, Fregni et al.40, 41 found pain reduction after anodal tDCS. The divergent results can be explained by the difference between acute and chronic pain processing. Pathological changes due to chronic pain are characterized by many functional and structural changes in the brain42, 43 and these cortical reorganizations probably lead to changes in cortical excitability.

In our study, the oral administration of pergolide prolonged the effect of cathodal tDCS for up to 24 hours on LEPs. The possible mechanisms of DC-induced after-effect were investigated by several previous studies. Pharmacological intervention suggests that the after-effect is N-methyl-d-aspartate (NMDA)-receptor dependent.44, 45, 46 Dextromethorphan (NMDA-receptor and intracellular sigma 1 receptor blocker) intake prevented both anodal and cathodal tDCS-induced after-effects, demonstrating that dextromethorphan critically interferes with the functionality of tDCS, irrespective of the polarity of DC stimulation.44 It is known that long-lasting NMDA-receptor dependent cortical excitability and activity shifts are involved in neuroplastic modification. Dopaminergic mechanisms stabilize these processes, as shown by animal experiments.47, 48, 49 Dopamine (DA) resident in the synapses could strongly influence the induction of long-term potentiation and/or long-term depression through specific changes in the initial levels of cAMP and Ca2+, which are key regulators of LTPs in the hippocampus, striatum, and prefrontal cortex.50, 51, 52, 53 One study showed that long-term potentiation dependent processes such as practice-dependent plasticity are enhanced by DA.54 DA acting on D1 receptors increases NMDA currents.55 In a recent study, the dopaminergic influence on NMDA receptor-dependent neuroplasticity was investigated using tDCS. The enhancement of D2, and to a lesser degree, of D1 receptors by pergolide consolidated tDCS-generated excitability diminution up until the morning poststimulation.17 Our results are in agreement with this study.

An antinociceptive effect of pergolide is implausible in the case of a single oral dose of 0.025mg. Pronociceptive or antinociceptive effects of pergolide have not yet been published. However, the administration of levodopa, an indirect DA agonist, has been reported to reduce pain ratings in painful diabetic neuropathy in humans.56 The DA reuptake inhibitor bupropion also has analgesic effects.57 Contrary to these results, the systematic administration of DA D2 receptor antagonist in humans has also been shown to reduce pain ratings in clinical trials.58, 59

The reduction of pain perception and the amplitudes of N2 and P2 components could also be due to a normal habituation observed by several studies.60, 61 Therefore, we have repeated the measurements in the absence of tDCS and medication. Although during the control experiment a normal habituation process was observed (the N2 and P2 amplitudes were reduced insignificantly), our results demonstrated that medication conditions with tDCS induced a significant amplitude reduction of the N2 peak. In addition to this, the psychophysical evaluation did not reveal significant changes in subjective pain perception during the control experiment.

To summarize, we observed that following cathodal tDCS, the N2 amplitude of the LEP components were significantly decreased when compared to the control experiment, and simultaneously, pain sensation was reduced. The changes in LEPs remained stable for up to two hours after 15 minutes of cathodal stimulation and pergolide prolonged the effect of the cathodal tDCS, causing a decrease in the amplitude of the N2 component for up to 24 hours. Our findings were based on experimentally induced pain using LEPs in a population of healthy subjects. The limitation of our investigation is that results from a study using healthy subjects cannot be directly transferable to clinical settings. However, on the way toward a clinical application of either rTMS or tDCS, to our knowledge, this is the first study observing plasticity-prolonging effects of drugs affecting the CNS on a clinically relevant behavioral range. Two principle effects may be relevant in further clinical studies: prolongation of excitability enhancing effects for diseases such as stroke and Parkinson's disease by, for example, amphetamine62, 63 or d-cycloserine;64 and prolongation of inhibitory after-effects, as shown here, on pain, epilepsy, or other diseases associated with cortical hyperexcitability.

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 This study was performed within the “Kompetenznetz Schmerz” (FKZ: 01EM0117), funded by the German Ministry of Research and Education.

PII: S0885-3924(08)00064-X

doi:10.1016/j.jpainsymman.2007.08.014

Journal of Pain and Symptom Management
Volume 36, Issue 1 , Pages 79-91, July 2008

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