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Anodal Transcranial Direct Current Stimulation of the Motor Cortex Ameliorates Chronic Pain and Reduces Short Intracortical Inhibition
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Journal of Pain and Symptom Management
Vol. 39 No. 5 May 2010
Original Article
Anodal Transcranial Direct Current Stimulation of the Motor Cortex Ameliorates Chronic Pain and Reduces Short Intracortical Inhibition Andrea Antal, PhD, Daniella Terney, MD, Stefanie Ku¨hnl, and Walter Paulus, MD Department of Clinical Neurophysiology, Georg-August University, Go¨ttingen, Germany
Abstract Context. Consecutive sessions of transcranial direct current stimulation (tDCS) over the primary motor cortex (M1) may be a suitable therapy to treat chronic pain, as it can modulate neural activities in the stimulated and interconnected regions. Objectives. The present study investigated the analgesic effect of five consecutive days of anodal/sham tDCS using subjective (visual analog scale [VAS]) and objective (cortical excitability measured by transcranial magnetic stimulation [TMS]) measurements. Methods. Patients with therapy-resistant chronic pain syndromes (trigeminal neuralgia, poststroke pain syndrome, back pain, fibromyalgia) participated. As this clinical trial was an exploratory study, statistical analyses implemented exploratory methods. Twelve patients, who underwent both anodal and sham tDCS, were analyzed using a crossover design. An additional nine patients had only anodal or sham stimulation. tDCS was applied over the hand area of the M1 for 20 minutes, at 1 mA for five consecutive days, using a randomized, doubleblind design. Pain was assessed daily using a VAS rating for one month before, during, and one month post-stimulation. M1 excitability was determined using paired-pulse TMS. Results. Anodal tDCS led to a greater improvement in VAS ratings than sham tDCS, evident even three to four weeks post-treatment. Decreased intracortical inhibition was demonstrated after anodal stimulation, indicating changes in cortico-cortical excitability. No patient experienced severe adverse effects; seven patients suffered from light headache after anodal and six after sham stimulation. Conclusion. Results confirm that five daily sessions of tDCS over the hand area of the M1 can produce long-lasting pain relief in patients with chronic pain. J Pain Symptom Manage 2010;39:890e903. Ó 2010 U.S. Cancer Pain Relief Committee. Published by Elsevier Inc. All rights reserved.
This study was supported by the German Ministry for Research and Education (BMBF-01EM 0513). Address correspondence to: Andrea Antal, PhD, Department of Clinical Neurophysiology, Georg-August Ó 2010 U.S. Cancer Pain Relief Committee Published by Elsevier Inc. All rights reserved.
University, Robert Koch Strasse 40, 37075 Go¨ttingen, Germany. E-mail: [email protected] Accepted for publication: October 16, 2009.
0885-3924/$esee front matter doi:10.1016/j.jpainsymman.2009.09.023
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Key Words Chronic pain, tDCS, TMS, motor cortex stimulation, intracortical inhibition
Introduction Despite the availability of multiple pharmacological approaches concerning chronic pain, it is not uncommon that patients fail to experience sufficient pain relief. This dilemma establishes the need for new therapeutic interventions and has prompted a renewed interest in neuromodulatory approaches with brain stimulation. Stimulation of the primary motor cortex (M1) for the treatment of certain forms of refractory neuropathic pain has attracted much interest in recent years. Tsubokawa et al.1 first showed that central poststroke pain could be reduced by means of chronic motor cortex stimulation (MCS) through implanted epidural electrodes. Further studies proved that MCS could also relieve trigeminal neuropathic pain.2 Deep brain stimulation has shown promising results,3 but less invasive forms of stimulation also might be effective. Indeed, a number of studies have shown that both a single session and repeated sessions of repetitive transcranial magnetic stimulation (rTMS) can relieve pain transiently in some patients with chronic neuropathic pain,4e6 although others have found the effect to be small and not significant.7 Recent studies have demonstrated the effectiveness of transcranial direct current stimulation (tDCS) on pain symptoms in patients with central pain because of traumatic spinal cord injury8 and fibromyalgia.9 Several studies have shown that this technique modulates cortical excitability in the M1 (for a review, see Ref. 10), and its modulatory effect endures after stimulation. tDCS not only shifts the activity of cortical areas situated directly under the electrodes but also of distant areas, probably through interconnections between the principal stimulated area and these structures.11 The primary effect of tDCS is a neuronal de- or hyperpolarization of membrane potentials,12,13 whereby the induced aftereffects depend on N-methyl-D-aspartate receptorefficacy changes.14 In a recent study,8 patients were randomized to receive sham or active tDCS over the left or
right motor cortex (2 mA, 20 minutes for five consecutive days). There was a significant pain perception improvement after anodal stimulation of the M1 but not after sham stimulation. A follow-up study reported a similar decrease in pain perception in a patient group with fibromyalgia.9 Compared with the aforementioned studies,8,9 we changed three parameters related to the stimulation: 1) the intensity of stimulation was 1 mA (2 mA in the study8); 2) related electrode size was 4 4 cm to increase the focality of the stimulation (5 7 cm in the studies8,9); and 3) a crossover design was used in 13 participants, who received both types of stimulations. Furthermore, we examined the possible intracortical effects of repeated tDCS over M1 using paired-pulse stimulation. Pairedpulse TMS techniques include several protocols to study the modulation of motor cortex excitability by local circuits of afferent inputs from other cortical areas of the brain.15,16 Finally, the possible side effects of the stimulation were evaluated by a questionnaire developed by our research group.17
Methods Subjects All participants (patients with trigeminal neuralgia, poststroke pain syndrome, back pain, fibromyalgia) (Table 1) were outpatients at the Department of Clinical Neurophysiology, Go¨ttingen, Germany. They were regarded as suitable to participate if they fulfilled the following criteria: 1) stable chronic pain for at least the preceding six months; 2) score greater than or equal to 3 (0 ¼ no pain and 10 ¼ worst possible pain) on the visual analog scale (VAS) for pain perception during the last month before baseline/start of the stimulation; and 3) refractoriness to drugs for pain relief, such as nonopioid analgesics, tricyclic antidepressants, antiepileptic drugs, and/or opioids (pain resistance to at least two of these drugs supplied in adequate dosages for six months). The diagnoses were made by trained
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Table 1 Clinical and Demographic Characteristics of the Patients With Regard to the Different Stimulation Conditions Number (n) Gender (male) Age range (years) Etiology and side of the pain Fibromyalgia Chronic back pain Trigeminal neuralgia Atypical face pain Arthrosis (finger, foot) Phantom pain (leg) Poststroke pain (arm) Polyneuropathy Duration of chronic pain More than 5 years Between 2 and 5 years Less than 2 years Baseline VAS scores (SD) Present medication Pregabalin Nonsteroidal anti-inflammatory drug Morphine Amitriptyline No medication
Only Anodal tDCS
Only Sham tDCS
Active and Sham tDCS
6 (1 patient in the follow-up) 2 28e70
4
13 (1 patient in the follow-up) 3 41e70
2 (both sides) 2 (right side) 1 (both sides) 1 (left side)
1 50e70 2 (both sides) 1 (both sides) 1 (both sides)
1 5 1 2 2
(both sides) (both sides) (1 right side) (both sides) (both sides)
1 (right side) 1 (both sides) 4 1 1 7.11 (1.2)
2 2
3 1 7.0 (1.5) 1 2
6 5 2 5.8 (2.1); 5.95 (2.2) 2 2 2
1 2
neurologists at least two years before the study started. We excluded patients with any clinically significant or unstable medical or psychiatric disorder, history of substance abuse, or neuropsychiatric comorbidity. In addition, we excluded patients with metallic implants/implanted electric devices. As carbamazepine might decrease the effects of anodal stimulation after a single session of tDCS,14 patients taking carbamazepine also were excluded. Finally, 23 patients (age range 28e70 years; six males) participated in the study. The general clinical characteristics of the patients are summarized in Table 1. Table 2 shows the individual demographic and clinical parameters of the patients. Patients with lumber pain had not undergone surgery. Facial pains were continuous in all cases. The patients were aware of the fact that they could get sham or real stimulation. The study was a randomized, doubleblinded, placebo-controlled, single-center trial that was designed to evaluate the efficacy of five daily sessions of anodal tDCS in patients with chronic pain. The study conformed to the ethical standards of the 1964 Helsinki Declaration and was approved by the institutional ethics committee. All patients provided written, informed consent. Two of 23 patients
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were not included among the follow-up analyses (one from the crossover design and one who had received only anodal stimulation; see Table 1), because they did not provide us with their pain diaries in the follow-up period. In the case of 13 patients, a crossover design was applied; they had a second session of stimulation with at least a six-week break after the first one and only if the VAS values returned to the previous baseline values for at least 10 days’ prior stimulation. For the remaining 10 patients, six had anodal and four had sham stimulations.
Experimental Design The study had three phases: 1) baseline evaluation consisting of a four-week period of the daily registration of subjective, baseline pain; 2) one-week treatment, which consisted of daily treatment sessions with sham or active tDCS (20 minutes) for five consecutive days; and 3) a follow-up period of four weeks. Before the first stimulation and two to three days after the last stimulation, the patient underwent several measurements related to cortical excitability (see below). During the baseline period, patients were randomized to receive sham or active tDCS. Randomization was performed using the order of entrance into the study.
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Table 2 Individual Patient Parameters With Regard to the Different Stimulation Conditions Patient 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23
Stimulation Anodal-sham Anodal-sham Anodal-sham Anodal-sham Anodal-sham Anodal-sham Anodal-sham Anodal-sham Anodal-sham Anodal-sham Anodal-sham Anodal-sham Anodal-sham Anodal Anodal Anodal Anodal Anodal Anodal Sham Sham Sham Sham
Gender F F F F F M F F M M F F F F F F M F M F M F F
Age (Years)
Diagnosis
Duration of Pain (years)
Medication
58 63 70 68 63 70 51 56 53 61 41 54 55 70 42 65 28 57 59 56 70 50 52
Chronic back pain Arthrosis Fibromyalgia Chronic back pain Arthrosis (foot, finger) Chronic back pain Polyneuropathy Atypical face pain Trigeminal neuralgia Poststroke pain Atypical face pain Chronic back pain Chronic back pain Chronic back pain Arthrosis Trigeminal neuralgia Phantom pain (leg) Trigeminal neuralgia Chronic back pain Fibromyalgia Arthrosis Chronic back pain Fibromyalgia
19 5 20 4 3 1.5 5 12 6 8 1.5 6 25 8 2 3 7 3 6 6 2 8 10
Nonsteroidal Morphine Nonsteroidal Morphine d d Pregabalin d d d d Pregabalin d Nonsteroidal d Nonsteroidal Morphine Morphine d Nonsteroidal Nonsteroidal Pregabalin Amitriptyline
F ¼ female; M ¼ male.
Transcranial Direct Current Stimulation Subjects were seated in a comfortable reclining chair with a mounted headrest throughout the experiments. The stimulations with regard to one given patient were always done by the same investigator. Direct current was transferred by a saline-soaked pair of surface sponge electrodes (4 4 cm over the M1 and 5 10 cm over the contralateral orbit) and delivered by a specially developed, battery-driven, constant current stimulator (NeuroConn, Ilmenau, Germany) with a maximum output of 5 mA. Patients received either anodal stimulation or sham stimulation of M1. First, the hand area over the left hemisphere was determined by single-pulse TMS. For anodal stimulation, the active electrode was placed over the hand representation field of M1 at the left side and the reference (cathode) electrode over the contralateral supraorbital area, independently from the lateralization of the pain. This electrode position has been shown to be effective to enhance the excitability of the M1.18 Furthermore, most of the patients had pain at the right side or both sides of the body. It was observed that M1 stimulation with tDCS induces widespread changes in the activity of cortical areas and can indeed change the activity of the contralateral hemisphere.11 This suggests that unilateral tDCS treatment might be sufficient for patients with
bilateral pain. In addition, because the electrode for tDCS is large, the stimulation encompassed a broad area of the motor cortex (upper limb and face). A constant current of 1-mA intensity was applied for 20 minutes. The maximal current density was 62.5 mA/cm2 over the M1 and 12 mA/cm2 at the reference electrode. Subjects felt the current as an itching sensation at both electrodes at the beginning of the stimulation. For sham stimulation, the electrodes were placed in the same positions as for anodal M1 stimulation; however, the stimulator was turned off automatically after 30 seconds of stimulation. Therefore, the subjects felt the initial itching sensation but received no current for the rest of the stimulation period. The stimulators were coded using a five-letter code, preprogrammed by one of the department members, who otherwise did not participate in the study. Therefore, neither the investigator nor the patient knew the type (anodal or sham) of the stimulation. After the five-day stimulation period, patients were asked if they could guess the type of stimulation they received.
Single-Pulse Transcranial Magnetic Stimulation The patients who participated in the crossover study (n ¼ 13) were included in this experiment. To detect current-driven changes
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of excitability, motor-evoked potentials (MEPs) of the right first dorsal interosseus (FDI) muscle were recorded before and after the stimulation of its motor-cortical representation field by single-pulse TMS. TMS was performed by using a Magstim standard double (‘‘figure eight’’) 70 mm coil (2.2 T; average inductance, 16.35 mH) connected to two monophasic Magstim 200 stimulators by means of a bistim module (Magstim Co., Whiteland, Dyfed, UK). Surface electromyogram (EMG) was recorded from the right FDI through a pair of Ag-AgCl surface electrodes in a belly-tendon montage. Raw signals were amplified, band-pass filtered (2 Hz to 3 kHz; sampling rate, 5 kHz), digitized with a micro 1401 AD converter (Cambridge Electronic Design, Cambridge, UK) controlled by Signal Software (version 2.13; Cambridge Electronic Design), and stored on a personal computer for offline analysis. Whenever necessary, complete relaxation was controlled through auditory and visual feedback of EMG activity. The coil was held tangentially to the skull, with the handle pointing backward and laterally at 45 from the midline, resulting in a posterior-anterior direction of current flow in the brain. This orientation of the induced electrical field is thought to be optimal for predominantly transsynaptic mode of activation of the corticospinal system. The optimum position was defined as the site where TMS resulted consistently in the largest MEP in the resting muscle. The site was marked with a skin marker to ensure that the coil was held in the correct position throughout the experiment.
Paired-Pulse Transcranial Magnetic Stimulation TMS measurements included resting motor threshold (RMT), active motor threshold (AMT), the intensity to evoke an MEP of w1mV peak-to-peak amplitude (SI1 mV), shortinterval intracortical inhibition/intracortical facilitation (SICI/ICF), long-interval intracortical inhibition (LICI), short-interval intracortical facilitation (SICF), recruitment curves and cortical silent period (CSP). Patients participated in four experimental conditions (before and after sham and anodal tDCS). Stimulus intensities (in percentage of maximal stimulator output) of TMS were determined at the beginning of each
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experiment. SI1 mV was determined with single-pulse TMS first. RMT was defined as the minimal output of the stimulator that induced a reliable MEP (w50 mV in amplitude) in at least three of six consecutive trials when the FDI muscle was completely relaxed. AMT was defined as the lowest stimulus intensity at which three of six consecutive stimuli elicited reliable MEP (w200 mV in amplitude) in the tonically contracting FDI muscle.19 SICI/ICF, LICI, and SICF were measured with three different protocols of single- and paired-pulse TMS applied in random order at 0.25 Hz. For SICI/ICF, two magnetic stimuli were given through the same stimulating coil, and the effect of the first (conditioning) stimulus on the second (test) stimulus was investigated.15 To avoid any floor or ceiling effect, the intensity of the conditioning stimulus was set to a relatively low value of 80% of AMT. The test-stimulus intensity was adjusted to SI1 mV. SICI was measured with interstimulus intervals (ISI) of two and four milliseconds, and ICF with ISIs of 9 and 12 milliseconds. The control condition (test pulse alone) was tested 40 times, and each of the conditioning-test stimuli was tested 20 times. The mean peak-to-peak amplitude of the conditioned MEP at each ISI was expressed as a percentage of the mean peak-to-peak size of the unconditioned test pulse. SICI was taken as the mean percentage inhibition at ISIs of two and four milliseconds, whereas ICF was taken as the mean facilitation at ISIs of 9 and 12 milliseconds. The second protocol tested LICI with two suprathreshold stimuli applied with ISIs of 50, 100, 150, and 200 milliseconds.16 The intensities of both stimuli were set to 110% of RMT. Here also, the intensity was set to this relatively low value to avoid any floor or ceiling effect. The control condition (first pulse alone) was tested 40 times, whereas each of the paired stimuli was tested 20 times. LICI was taken as the mean percentage inhibition of conditioned MEP at ISIs of 50, 100, 150, and 200 milliseconds. SICF also was measured in a paired-pulse TMS protocol, but here, the first pulse was suprathreshold, and the second pulse was subthreshold.20,21 The intensity of the first (test) pulse was set to SI1 mV, and the intensity of the second (conditioning) pulse to 90% of RMT. In this protocol, the
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control condition (test pulse alone) was given 40 times, and each of the conditioning-test stimuli with the ISIs 1.3, 2.1, 2.5, 3.5, and 4.1 milliseconds, was tested 20 times. The mean peak-to-peak amplitude of the conditioned MEP at each ISI was expressed as a percentage of the mean peak-to-peak size of the unconditioned test pulse. Recruitment curves (RECR) were measured with four different and increasing stimulus intensities (100%, 110%, 130%, and 150% of RMT), each with 10 pulses. Mean amplitude was calculated for each intensity. Finally, 10 pulses with SI1 mV and 10 pulses with 120% RMT were applied under tonic contraction of the right FDI muscle. CSPs were separately determined in rectified and averaged EMG traces with a prestimulus period of 100 milliseconds. CSP (in milliseconds) was measured from the TMS stimulus to the point where the signal reached the amplitude of the mean prestimulus EMG activity again for more than 5 milliseconds.
Pain Measurement: Visual Analog Scale for Pain This self-evaluation scale ranges from 0 to 10 as visually described in centimeter units: 0 cm indicates no pain and 10 cm means the worst pain possible. This scale has been widely used in studies that evaluate pain as an outcome; both validity and reproducibility have been demonstrated.22 Participants were asked to rate their pains three times a day at the same time point at least 30 days before, during, and 30 days after the end of the stimulation. These values were averaged, giving one VAS value per day. We instructed the participants to continue their routine medication regimen. Herbal remedies and alternative therapies, such as massage or acupuncture, were allowed if they had been used for at least four weeks before randomization, and the regimen was maintained constant throughout the study.
Adverse Effects of Transcranial Direct Current Stimulation The electric current was applied continuously for 20 minutes/day in this protocol. Because potential adverse effects of this technique are not fully known yet, the patients completed a questionnaire17 after anodal and sham stimulation, separately. The questionnaire
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contained rating scales for the presence and severity of headache; difficulties in concentrating; acute mood changes; visual perceptual changes; fatigue; and discomforting sensations, such as pain, tingling, itching, or burning under the electrodes during and after tDCS.
Statistical Analysis Pain Perception. Two kinds of analyses were done: 1) all of the patients (n ¼ 21) were included, and the anodal and sham conditions were compared (17 anodal vs. 16 sham stimulations); and 2) the data from 12 patients were analyzed, using a crossover analysis (12 anodal vs. 12 sham stimulations). We normalized the post-stimulation VAS values to baseline (mean of the last 10 days prestimulation). The data were treated using a betweensubject design because of the partly different groups. Additionally, we compared the prestimulation VAS values with Student’s t-test for both groups of patients to rule out that differences between sham and active stimulation might have been because of a priori differences between these two stimulation groups. For the analysis for VAS scores, we used repeated-measures analysis of variance (ANOVA), in which the dependent variable was the VAS score and the factors were STIMULATION (sham and anodal) and TIME of treatment (baseline: mean of the last 10 days before stimulation, during stimulation,1e5 and after stimulation [Days 7, 14, 21, and 28]). When appropriate, post hoc comparisons (between sham and anodal stimulation and between post-treatment evaluations and baseline evaluations) were carried out using Bonferroni correction for multiple comparisons. In addition, for all endpoints, we also ran a Student’s t-test, including only the time factor as a repeated measurement. Transcranial Magnetic Stimulation Measurements. For each measurement (SI1 mV, RMT, AMT, SICI, ICF, SICF, LICI, CSP), we performed separate ANOVAs for repeated measurements by using the mean values from each subject as the dependent variable to compare the parameters of cortical excitability. In addition to the factor ‘‘STIMULATION type’’ (anodal vs. sham) and factor ‘‘TIME’’ (baseline, post-stimulation), the ANOVA model included the factor ‘‘ISI’’ (2, 4,
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7, 9, and 12 milliseconds) when SICI and ICF were analyzed or the factor ‘‘intensity’’ (100%, 110%, 130%, and 150% of RMT) for recruitment curves, or the factor ‘‘INTENSITY’’ (120% RMT and SI1 mV) for CSP. Here, only the data of the patients who participated in the crossover design were included. Unless stated otherwise, all results are presented as means and standard errors, and statistical significance refers to a two-tailed Pvalue less than 0.05. Adverse Effects of Transcranial Direct Current Stimulation. The incidences of side effects were coded using a binary system (no ¼ 0, yes ¼ 1), and the severities of the side effects were rated using a numerical analog scale from 1 to 5; 1 being very mild and 5 indicating an extremely strong intensity of any given side effect. From these values, a mean intensity was calculated. The incidences and severities of the adverse effects were separately calculated during and after stimulation. The percent of affected patients in the sham and anodal conditions was calculated independently.
Results Pain ControldVisual Analog Scale There was no significant difference concerning the baseline VAS values (t ¼ 1.8, df ¼ 32, P ¼ 0.1). To analyze whether tDCS treatment was associated with pain improvement, we performed a repeated-measures ANOVA, in which the dependent variable was change of normalized VAS pain scores, and the independent variable was TIME of evaluation (baseline; Days 1, 2, 3, 4, 5; and follow-up) and type of STIMULATION (anodal vs. sham tDCS). Concerning the whole group, this analysis revealed a significant main effect of STIMULATION (F(1,32) ¼ 5.32, P < 0.05) and TIME (F(8,256) ¼ 2.14, P < 0.03); however, the interaction between them was not significant: F(8,256) ¼ 0.28 and P ¼ 0.9 (Fig. 1a). Student’s t-test revealed a significant difference on Days 3 and 7 between anodal and sham stimulations (P < 0.05; VAS change: 27.3% decrease [anodal] vs. 2.7% [sham] and 8.9% decrease vs. 11% increase, respectively). Concerning the 12 patients who participated in both stimulation sessions, the ANOVA revealed a significant main effect of the group of STIMULATION (F(1,22) ¼ 14.3, P < 0.005). However, the TIME
Fig. 1. Pain scores as indexed by VAS throughout and after the stimulation (a) with regard to all of the patients and (b) the patients who participated in the crossover stimulation study. The VAS scores for each time point were normalized to the before-stimulation values (10 days’ mean VAS before the first day of stimulation). Bars show standard error of mean.
(F(8,176) ¼ 1.24, P ¼ 0.27) and the interaction between TIME and STIMULATION (F(8,176) ¼ 0.35; P ¼ 0.9) were not significant (Fig. 1b). Student’s t-test revealed a significant difference on Days 3, 4, 5, 7, 14, and 28 between anodal and sham stimulations (P < 0.05; VAS change: 36.5% decrease vs. 9% increase, 33.5% decrease vs. 7% increase, 35% decrease vs. 1% decrease, 11% decrease vs. 23% increase, 27.5% decrease vs. 5% increase, 26.5% decrease vs. 6% increase, respectively). Finally, we compared the baseline VAS values with all of the time points (the factor TIME was significant using ANOVA) for each condition separately, using Student’s t-test. Concerning the full group, this analysis showed a significant difference during the anodal stimulation (baseline comparison with first stimulation [P ¼ 0.03], second stimulation
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[P ¼ 0.03], third stimulation [P ¼ 0.003], fourth stimulation [P ¼ 0.001], fifth stimulation [P ¼ 0.0006]) and after the stimulation (Day 14 [P ¼ 0.03] and Day 28 [P ¼ 0.03]). The largest pain reduction was achieved after the fifth session of stimulation (30%; mean VAS pain scores: 4.22 [2.23]). Applying sham stimulation, there was no significant difference between baseline and during/poststimulation VAS values. Concerning the 12 patients, the analysis showed a similar tendency: significant difference was found during the anodal stimulation (baseline comparison with first stimulation [P ¼ 0.02], second stimulation [P ¼ 0.05], third stimulation [P ¼ 0.004], fourth stimulation [P ¼ 0.01], fifth stimulation [P ¼ 0.008]), and after the stimulation (Day 14 [P ¼ 0.03] and Day 28 [P ¼ 0.02]). The largest pain reduction was achieved after the third session of stimulation (37%; mean VAS pain scores: 3.54 [2.29]). Applying sham stimulation, there was no significant decrease with regard to baseline and during/post-stimulation VAS values except the first-day values (P ¼ 0.05). There were eight responders (reduction of 30% or more in the VAS after five-day stimulation) in the anodal tDCS group (63% of patients) and only four responders in the sham tDCS group (16%). In the follow-up evaluation, four patients in the active tDCS group were still considered as responders, and three responders in the sham tDCS group reported no more pain improvement. Importantly, active tDCS did not worsen pain in any of the patients who received this treatment. Because we had a small sample size and a heterogeneous group with regard to the origin of the chronic pain, we did not perform any correlation analysis for the characteristics of the disease. However, larger pain improvement was observed among patients with arthrosis than back pain. None of the patients with fibromyalgia showed a different pattern of pain reduction after the five-day treatment compared with sham stimulation.
Single- and Paired-Pulse Transcranial Magnetic Stimulation For two subjects, the experimental sessions were interrupted because of headache that
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started during the stimulation. In these cases, only threshold measurements were done. First, RMT, AMT, and SI1 mV baseline values were compared between active and sham stimulation conditions. There was no significant difference between anodal and sham stimulation in any of the measurements (Table 3). Anodal stimulation had no effect on SICF, ICF, LICI, CSP, or motor-evoked recruitment curves, as revealed by repeated-measures ANOVA (Table 3). However, Student’s t-tests showed a significant difference in the case of SICI (P < 0.05), showing decreased intracortical inhibition after anodal stimulation (Fig. 2). Eight of the patients showed a clear trend: the increase in SICI correlated with the decrease in VAS after anodal but not after sham stimulation. However, because of the low number of subjects, this was not significant.
Adverse Effects of Transcranial Direct Current Stimulation Neither of the subjects terminated the stimulation or needed any medical intervention during or after the end of tDCS. Tables 4 and 5 summarize the adverse effects during and after tDCS, including all of the sham and anodal stimulation conditions. During the stimulation, mild tingling sensation was the most common adverse effect; it was reported by 66.6% of the subjects during anodal and 52.9% during sham stimulation. Moderate fatigue was the second most frequent consequence; it was reported by 44.4% of the participants during anodal stimulation and, interestingly, 64.7% of the subjects during sham stimulation. Similarly, after the stimulation, 33.3% of the patients felt tired in the anodal group, and 70.6% reported this symptom in the sham group. Headache occurred in 38.9% in the anodal group and 35.3% in the sham group. Four patients in the anodal and two in the sham groups reported acute sleeping disturbances for two to five days after tDCS. Concerning the patients who participated in the crossover study, only one reported that there was a difference between the two types of stimulations when it was explicitly asked. There were two dropouts in the follow-up period (one anodal and one sham). Both the patients showed no improvement that could have contributed to their decision to abandon
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Table 3 Statistical Analysis of the Single- and Paired-Pulse TMS Experiments TMS measurement ANOVA
SI1 mV AMT RMT RECR
CSP
SICI/ICF
LICI
Factor
df
F
P
Stimulation Time Stimulation time Stimulation Time Stimulation time Stimulation Time Stimulation time Stimulation Time Stimulation time Intensity Stimulation intensity Time intensity Stimulation time intensity Stimulation Time Stimulation time Intensity Stimulation intensity Time intensity Stimulation time intensity Stimulation Time Stimulation time ISI Stimulation ISI Time ISI Stimulation time ISI Stimulation Time Stimulation time ISI Stimulation ISI Time ISI Stimulation time ISI
1 1 25 1 1 25 1 1 25 1 1 22 3 3 3 66 1 1 22 1 1 1 22 1 1 20 4 4 4 80 1 1 23 3 3 3 69
0.08 0.0 0.03 0.2 0.68 0.98 0.22 0.33 0.09 0.36 1.67 0.08 39.26 0.18 1.52 0.17 0.25 0.43 0.002 2.66 0.76 0.002 0.26 0.01 3.32 0.69 88.96 0.39 0.56 3.68 0.05 4.19 0.08 2.84 0.33 4.77 0.6
0.77 0.99 0.85 0.66 0.42 0.20 0.56 0.57 0.77 0.55 0.21 0.78 <0.01 0.90 0.22 0.92 0.61 0.52 0.95 0.11 0.39 0.96 0.61 0.9 0.08 0.41 <0.001 0.81 0.69 0.05 0.99 0.05 0.77 0.04 0.80 0.004 0.59
Student’s t-test
Stimulation Type
df
t
P
ICI 7 milliseconds ICF ICI 7 milliseconds ICF
Anodal
10 10 10 10 10 10
3.53 1.5 0.29 0.044 0.13 2.0
<0.005 0.16 0.77 0.96 0.89 0.07
Sham
their participation in the remainder of the study.
Discussion Our results demonstrate that five daily sessions of anodal tDCS using a relatively small (4 4 cm) stimulation electrode over the hand area of the M1 can produce longlasting pain relief in patients experiencing different types of chronic pain, probably by decreasing the level of intracortical inhibition. However, there was a higher incidence of
adverse events in both treatment groups, as in previous studies including patients with chronic pain8,9 or healthy subjects.17 These adverse events consisted of mild headache, fatigue, and itching under the electrodes. Compared with previous studies that used anodal tDCS for the treatment of chronic pain, the magnitude of our results (mean pain decrease of 37%) is somewhat lower (58% in the study by Fregni et al.,8 which included patients with low back pain), possibly because of our heterogeneous patient group and may be a result of the different criteria used to designate pain responders. Nevertheless, our result is similar to
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Fig. 2. The main results of the TMS experiment. After anodal stimulation decreased, intracortical inhibition (ISIs: 2, 4 milliseconds) was observed. Bars show standard error of mean.
those of high-frequency rTMS studies that report mean pain relief that ranges from 20% to 45%.4,5 Furthermore, the reduced tDCS intensity here may be better suited for blinding. As reported by Furubayashi et al.,23 an intensity of 3 mA starts to be painful, 1 mA certainly has a higher chance of going unnoticed compared with placebo conditions than 2 mA. Because there was no difference with regard to the occurrence of itching/tingling/burning sensations and headache between patients after sham and verum stimulation, and fatigue was experienced by an even higher percentage of sham patients compared with anodally stimulated patients, we are quite sure at having provided an optimal placebo condition. An interesting question to be solved in the near future is the optimal duration and repetition rate of tDCS sessions. In the present study, the effects built up during the first three stimulation sessions, being mild in many patients immediately after the initial stimulation but quite clear after the fourth or fifth days. Effects were also separated from the placebo effect of sham stimulation after this duration. According to the original observation by Lefaucheur et al.,5 pain relief after a single session was optimal two to four days after rTMS. Regarding
the long-lasting effect of anodal stimulation, our results are similar to those published by Fregni et al.8,9 However, compared with epidural stimulation, tDCS may result in a smaller treatment effect: the surgical approach resulted in a 28%e70% mean pain reduction in 50%e80% of responders;1,24e27 nevertheless, this may include a substantially stronger placebo effect. The mean pain relief varied from 28% to 47% in the largest series,27,28 and between 50% and 70% in the smallest series25,26 of patients. Nevertheless, the effects of five daily sessions of anodal tDCS are likely to have a shorter impact on brain activity than what can be achieved using MCS with epidural electrodes for several months. The magnitude of the placebo effect was lower in our study (varied from 18.9% to þ9.8% during and after treatment) compared with rTMS studies. Here, we expect a higher placebo response to rTMS, simply because of the higher technical effort and the remote risk of seizure induction, for which patients obtaining tDCS do not have to be informed. Furthermore, it has been documented that the severity and therapeutic refractoriness of symptoms can correlate negatively with placebo response.29 Therefore, a lower placebo
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Table 4 Adverse Effects of tDCS During Stimulation Pain
Tingling
Itching
Type of Stimulation
n
%
MI
n
%
MI
n
%
MI
Sham Anodal
2 2
11.8 11.1
10 21
9 12
52.9 66.6
1.1 0.11 1.5 0.15
0 6
0 33.3
0 2.0 0.15
Burning
Sham Anodal
Fatigue
n
%
MI
n
%
MI
n
%
MI
4 2
23.5 11.1
10 10
11 8
64.7 44.4
1.7 0.27 1.8 0.46
1 0
5.9 0
10 0
Trouble in Concentrating
Sham Anodal
Nervousness
Changes in Visual Perception
n
%
MI
n
%
1 1
5.9 5.5
20 20
0 2
0 11.1
MI 0 10
Unpleasantness
Sham Anodal
n
%
0 2
0 11.1
Headache n
%
MI
5 5
29.4 27.8
1.4 0.24 1.8 0.75
Other MI
n
0 21
1 1 1
Tingling in the tongue Warm tingling with regard to the leg Involuntary muscle contraction
MI ¼ mean intensity (0e5).
response may indicate the therapeutic refractoriness of our patient population. It was suggested by previous studies that the best stimulation site using rTMS for pain control is not the area corresponding to the painful zone but the adjacent one.6 However, with regard to epidural stimulation, another study showed that the most efficacious position of the stimulating electrodes was the one corresponding to the cortical somatotopic representation of pain perception.27 We have used a smaller stimulation electrode (4 4 cm) compared with those of previous clinical studies8,9 to increase the focality of the stimulation. However, because of the still large electrode size applied in our study, it is likely that the stimulation induced a modulatory effect over a large area of M1 that encompassed both the area corresponding to the pain and the adjacent areas. Further studies are needed to explore whether somatotopically guided stimulation might increase the analgesic effect of tDCS and to pursue the concept of Lefaucheur et al.6 The mechanisms responsible for the longlasting effect of anodal tDCS on pain are still unknown. Upregulation of M1 excitability could modulate pain perception through indirect effects on pain-modulating areas, such as
the thalamic and subthalamic nuclei. In fact, a change in the activity of these nuclei is associated with rTMS30 and tDCS.11 Sequentially, the activation of thalamic nuclei can modify the activity of other pain-related structures (e.g., anterior cingulate, periaqueductal gray) and can also inhibit pain of spinal origin. The higher incidence of adverse effects (mainly headache and fatigue) during and after tDCS compared with those reported among healthy subjects in a previous study17 might be related to the type of disorder investigated in our study. Similarly, a higher proportion of migraineurs (55.6%) reported headache after tDCS compared with healthy subjects (7.8%).17 Therefore, it is not astonishing that 35%e39% of the subjects reported headache in our study. However, we have not observed any serious complications, such as seizures, in connection with the application of tDCS. As tDCS has been tested only recently for clinical applications, the impact of consecutive sessions of cortical stimulations on different cognitive, motor, and other functions in different patient populations is not yet fully known. Therefore, our data concerning the side effects of the stimulation could be interpreted as preliminary safety evidence with regard to tDCS in chronic pain.
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Table 5 Adverse Effects of tDCS After Stimulation Pain
Tingling
Itching
Type of Stimulation
n
%
MI
n
%
MI
n
%
MI
Sham Anodal
1 1
5.9 5.5
10 10
1 1
5.9 5.5
10 10
1 1
5.9 5.5
10 10
Burning
Sham Anodal
Fatigue
n
%
MI
n
%
MI
n
%
MI
1 1
5.9 5.5
10 10
12 6
70.6 33.3
2.25 0.30 2.4 0.51
1 1
5.9 5.5
10 20
Trouble in Concentrating
Sham Anodal
n
%
2 0
11.8 0
Changes in Visual Perception
MI 2.5 0.5 0
n
%
0 2
0 11.1
Nausea
Sham Anodal
Headache
MI 0 1.0 0
Vomiting
n
%
MI
6 7
35.3 38.9
2.2 0.54 2 0.38
Acute Sleeping Problems
n
%
MI (h)
n
%
MI
n
%
MI (d)
1 0
5.9 0
20 0
0 0
0 0
0 0
2 4
11.8 22.2
21 3 0.71
Elevated Mood
Sham Anodal
Nervousness
Feeling Cold
Feeling Warm
n
%
MI (h)
n
%
MI
n
%
MI
2 3
11.8 16.6
3.5 1.5 1.3 0.33
1 1
5.9 5.5
0.25 0 10
2 1
11.8 5.5
1.5 0.5 20
Others n 1
Increment in the subjective good feeling
MI ¼ mean intensity (0e5); h ¼ post-tDCS hours; d ¼ post-tDCS days.
In terms of commonly used noninvasive excitability parameters, we have found a decreased SICI after anodal tDCS compared with sham tDCS over M1 using the paired-pulse paradigm. TDCS application had no significant effect on SICF, ICF, LICI, CSP, or motor-evoked recruitment curves (for an overview of methods used to study the modulation of human motor cortex excitability in local circuits, see Refs. 21,31). SICI is a low-threshold inhibition that can be elicited using paired-pulse TMS delivered with short ISIs.12 Because the conditioning subthreshold stimulus during paired-pulse TMS neither recruits descending volleys in the corticospinal tract32 nor alters spinal reflexes,15 it is suggested that the inhibitory phenomena are produced by mechanisms acting only at the cortical level. SICI can be mediated by gamma aminobutyric acid (GABAA) receptors. It was found that tiagabine (a GABA-reuptake inhibitor) decreases SICI.33 In a previous study, a single session of anodal tDCS over the M1 reduced
intracortical inhibition and enhanced facilitation.34 However, this effect was explained by the fact that the aftereffects of tDCS, as well as intracortical inhibition and facilitation, are at least partly modulated by NMDA receptor activity.35 Interestingly, a previous study36 in which 1or 10-Hz rTMS was applied over the M1 corresponding to the painful hand of patients with chronic neuropathic pain showed a significant increase in ICI after 10-Hz rTMS, which was correlated with pain relief. However, in these patients, ICI was reduced at baseline compared with the measurements of healthy subjects. The authors concluded that chronic neuropathic pain was associated with M1 disinhibition, suggesting impaired GABAergic neurotransmission related to underlying sensory or motor disturbances. From our present study, it is difficult to conclude which neurotransmitter system was involved in the reduction of the SICI in our patient population; hence, further studies are necessary to clarify this point.
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The limitations of this study need to be discussed. First, this clinical trial was an exploratory study; we had a heterogeneous patient group, the symptoms and the etiology of the chronic pain syndromes differed across patients, and our sample size might not have been large enough to detect some characteristics associated with a positive effect of anodal tDCS. Nonetheless, many of the previous rTMS studies have investigated patients with different types of chronic pain.5,6 Furthermore, in practice, it is the general pain symptoms of the patients that are targeted and treated, and not specific symptoms of pain, which are dependent upon the selected groups of patients themselves, with symptoms often varying within a wide range with regard to the intensity, quality and localization. Second, our patients were allowed to adhere to their medication regimens throughout the trial; nevertheless, none of the patients requested to increase the dosage of their medication. Furthermore, the patients were taking different types of medications in varying dosages. Therefore, we have to conclude that medication might confound our results. Because of the exploratory nature of the study, the statistical analysis used also implemented exploratory methods. In summary, previous studies showed that high-frequency rTMS is associated with a significant pain improvement compared with sham rTMS.4e6,36 TDCS is a relatively new technology that appears to stimulate the M1 in a way similar to that of rTMS and epidural stimulation and can transiently reduce pain in some groups of patients with neuropathic pain.8,9 Although the basic neuronal mechanisms of tDCS are probably different from those of rTMS, both techniques might lead to a similar indirect change of activity in connected areas and, thus, result in similar effects on chronic pain.
Acknowledgment The authors thank Leila Chaieb for her assistance with the English translation of this article.
References 1. Tsubokawa T, Katayama Y, Yamamoto T, Hirayama T, Koyama S. Chronic motor cortex
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stimulation in patients with thalamic pain. J Neurosurg 1993;78:393e401. 2. Meyerson BA, Lindblom U, Linderoth B, Lind G, Herregodts P. Motor cortex stimulation as treatment of trigeminal neuropathic pain. Acta Neurochir Suppl (Wien) 1993;58:150e153. 3. Wallace BA, Ashkan K, Benabid AL. Deep brain stimulation for the treatment of chronic, intractable pain. Neurosurg Clin N Am 2004;15:343e357. 4. Khedr EM, Kotb H, Kamel NF, et al. Long lasting antalgic effects of daily sessions of repetitive transcranial magnetic stimulation in central and peripheral neuropathic pain. J Neurol Neurosurg Psychiatr 2005;76:833e838. 5. Lefaucheur JP, Drouot X, Keravel Y, Nguyen JP. Pain relief induced by repetitive transcranial magnetic stimulation of precentral cortex. Neuroreport 2001;12:2963e2965. 6. Lefaucheur JP, Drouot X, Menard-Lefaucheur I, et al. Neurogenic pain relief by repetitive transcranial magnetic cortical stimulation depends on the origin and the site of pain. J Neurol Neurosurg Psychiatr 2004;75:612e616. 7. Rollnik JD, Wu¨stefeld S, Da¨uper J, et al. Repetitive transcranial magnetic stimulation for the treatment of chronic painda pilot study. Eur Neurol 2002;48:6e10. 8. Fregni F, Boggio PS, Lima MC, et al. A sham-controlled, phase II trial of transcranial direct current stimulation for the treatment of central pain in traumatic spinal cord injury. Pain 2006; 122:197e209. 9. Fregni F, Gimenes R, Valle AC, et al. A randomized sham-controlled proof-of principle study of transcranial direct current stimulation for the treatment of pain in fibromyalgia. Arthritis Rheum 2006; 54:3988e3998. 10. Nitsche MA, Cohen LG, Wassermann EM, et al. Transcranial direct current stimulation: state of the art 2008. Brain Stimulat 2008;1:206e223. 11. Lang N, Siebner HR, Ward NS, et al. How does transcranial DC stimulation of the primary motor cortex alter regional neuronal activity in the human brain? Eur J Neurosci 2005;22:495e504. 12. Bindman LJ, Lippold OCJ, Redfearn JWT. The action of brief polarizing currents on the cerebral cortex of the rat (1) during current flow and (2) in the production of long-lasting after-effects. J Physiol 1964;172:369e382. 13. Creutzfeldt OD, From GH, Kapp H. Influence of transcortical DC currents on cortical neuronal activity. Exp Neurol 1962;5:436e452. 14. Liebetanz D, Nitsche MA, Tergau F, Paulus W. Pharmacological approach to the mechanisms of transcranial DC-stimulation-induced after-effects of human motor cortex excitability. Brain 2002;125: 2238e2247.
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15. Kujirai T, Caramia MD, Rotwell JC, et al. Corticocortical inhibition in human motor cortex. J Physiol (Lond) 1993;471:501e519.
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of the motor cortex. Acta Neurochir Suppl 1995;64: 132e135.
16. Valls-Sole J, Pascual-Leone A, Wassermann EM, Hallet M. Human motor evoked responses to paired transcranial magnetic stimuli. Electroencephalogr Clin Neurophysiol 1992;85:355e364.
27. Nguyen JP, Lefaucheur JP, Decq P, et al. Chronic motor cortex stimulation in the treatment of central and neuropathic pain. Correlations between clinical, electrophysiological and anatomical data. Pain 1999;82:245e251.
17. Poreisz C, Boros K, Antal A, Paulus W. Safety aspects of transcranial direct current stimulation concerning healthy subjects and patients. Brain Res Bull 2007;72:208e214.
28. Nuti C, Peyron R, Garcia-Larrea L, et al. Motor cortex stimulation for refractory neuropathic pain: four year outcome and predictors of efficacy. Pain 2005;118:43e52.
18. Nitsche MA, Paulus W. Sustained excitability elevations induced by transcranial DC motor cortex stimulation in humans. Neurology 2001;57: 1899e1901.
29. Ruck A, Sylven C. ‘‘Improvement’’ in the placebo group could be due to regression to the mean as well as to sociobiologic factors. Am J Cardiol 2006;97:152e153.
19. Rothwell JC, Hallett M, Berardelli A, et al. Magnetic stimulation: motor evoked potentials: the International Federation of Clinical Neurophysiology. Electroencephalogr Clin Neurophysiol Suppl 1999;52:97e103.
30. Strafella AP, Vanderwerf Y, Sadikot AF. Transcranial magnetic stimulation of the human motor cortex influences the neuronal activity of subthalamic nucleus. Eur J Neurosci 2004;20:2245e2249.
20. Ziemann U, Tergau F, Wassermann EM, et al. Demonstration of facilitatory I wave interaction in the human motor cortex by paired transcranial magnetic stimulation. J Physiol 1998;511:181e190.
31. Paulus W, Classen J, Cohen LG, et al. State of the art: pharmacologic effects on cortical excitability measures tested by transcranial magnetic stimulation. Brain Stimulat 2008;1:151e163.
21. Ziemann U, Paulus W, Nitsche MA, et al. Consensus: motor cortex plasticity protocols. Brain Stimulat 2008;1:164e182.
32. Di Lazzaro V, Rothwell JC, Oliviero A, et al. Intracortical origin of the short latency facilitation produced by pairs of threshold magnetic stimuli applied to human motor cortex. Exp Brain Res 1999; 129:494e499.
22. Bolton JE, Wilkinson RC. Responsiveness of pain scales: a comparison of three pain intensity measures in chiropractic patients. J Manipulative Physiol Ther 1998;21:1e7. 23. Furubayashi T, Terao Y, Arai N, et al. Short and long duration transcranial direct current stimulation (tDCS) over the human hand motor area. Exp Brain Res 2008;185:279e286. 24. Carroll D, Joint C, Maartens N, et al. Motor cortex stimulation for chronic neuropathic pain: a preliminary study of 10 cases. Pain 2000;84:431e437. 25. Ebel H, Rust D, Tronnier V, Boker D, Kunze S. Chronic precentral stimulation in trigeminal neuropathic pain. Acta Neurochir 1996;138:1300e1306. 26. Herregodts P, Stadnik T, De Ridder F, D’Haens J. Cortical stimulation for central neuropathic pain: 3-D surface MRI for easy determination
33. Werhahn KJ, Kunesch E, Noachtar S, Benecke R, Classen J. Differential effects on motorcortical inhibition induced by blockade of GABA uptake in humans. J Physiol 1999;517:591e597. 34. Nitsche MA, Seeber A, Frommann K, et al. Modulating parameters of excitability during and after transcranial direct current stimulation of the human motor cortex. J Physiol 2005;568:291e303. 35. Ziemann U, Chen R, Cohen LG, Hallett M. Dextromethorphan decreases the excitability of the human motor cortex. Neurology 1998;51:1320e1324. 36. Lefaucheur JP, Drouot X, Me´nard-Lefaucheur I, Keravel Y, Nguyen JP. Motor cortex rTMS restores defective intracortical inhibition in chronic neuropathic pain. Neurology 2006;67:1568e1574.
Journal of Pain and Symptom Management
Vol. 39 No. 5 May 2010
Original Article
Anodal Transcranial Direct Current Stimulation of the Motor Cortex Ameliorates Chronic Pain and Reduces Short Intracortical Inhibition Andrea Antal, PhD, Daniella Terney, MD, Stefanie Ku¨hnl, and Walter Paulus, MD Department of Clinical Neurophysiology, Georg-August University, Go¨ttingen, Germany
Abstract Context. Consecutive sessions of transcranial direct current stimulation (tDCS) over the primary motor cortex (M1) may be a suitable therapy to treat chronic pain, as it can modulate neural activities in the stimulated and interconnected regions. Objectives. The present study investigated the analgesic effect of five consecutive days of anodal/sham tDCS using subjective (visual analog scale [VAS]) and objective (cortical excitability measured by transcranial magnetic stimulation [TMS]) measurements. Methods. Patients with therapy-resistant chronic pain syndromes (trigeminal neuralgia, poststroke pain syndrome, back pain, fibromyalgia) participated. As this clinical trial was an exploratory study, statistical analyses implemented exploratory methods. Twelve patients, who underwent both anodal and sham tDCS, were analyzed using a crossover design. An additional nine patients had only anodal or sham stimulation. tDCS was applied over the hand area of the M1 for 20 minutes, at 1 mA for five consecutive days, using a randomized, doubleblind design. Pain was assessed daily using a VAS rating for one month before, during, and one month post-stimulation. M1 excitability was determined using paired-pulse TMS. Results. Anodal tDCS led to a greater improvement in VAS ratings than sham tDCS, evident even three to four weeks post-treatment. Decreased intracortical inhibition was demonstrated after anodal stimulation, indicating changes in cortico-cortical excitability. No patient experienced severe adverse effects; seven patients suffered from light headache after anodal and six after sham stimulation. Conclusion. Results confirm that five daily sessions of tDCS over the hand area of the M1 can produce long-lasting pain relief in patients with chronic pain. J Pain Symptom Manage 2010;39:890e903. Ó 2010 U.S. Cancer Pain Relief Committee. Published by Elsevier Inc. All rights reserved.
This study was supported by the German Ministry for Research and Education (BMBF-01EM 0513). Address correspondence to: Andrea Antal, PhD, Department of Clinical Neurophysiology, Georg-August Ó 2010 U.S. Cancer Pain Relief Committee Published by Elsevier Inc. All rights reserved.
University, Robert Koch Strasse 40, 37075 Go¨ttingen, Germany. E-mail: [email protected] Accepted for publication: October 16, 2009.
0885-3924/$esee front matter doi:10.1016/j.jpainsymman.2009.09.023
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Key Words Chronic pain, tDCS, TMS, motor cortex stimulation, intracortical inhibition
Introduction Despite the availability of multiple pharmacological approaches concerning chronic pain, it is not uncommon that patients fail to experience sufficient pain relief. This dilemma establishes the need for new therapeutic interventions and has prompted a renewed interest in neuromodulatory approaches with brain stimulation. Stimulation of the primary motor cortex (M1) for the treatment of certain forms of refractory neuropathic pain has attracted much interest in recent years. Tsubokawa et al.1 first showed that central poststroke pain could be reduced by means of chronic motor cortex stimulation (MCS) through implanted epidural electrodes. Further studies proved that MCS could also relieve trigeminal neuropathic pain.2 Deep brain stimulation has shown promising results,3 but less invasive forms of stimulation also might be effective. Indeed, a number of studies have shown that both a single session and repeated sessions of repetitive transcranial magnetic stimulation (rTMS) can relieve pain transiently in some patients with chronic neuropathic pain,4e6 although others have found the effect to be small and not significant.7 Recent studies have demonstrated the effectiveness of transcranial direct current stimulation (tDCS) on pain symptoms in patients with central pain because of traumatic spinal cord injury8 and fibromyalgia.9 Several studies have shown that this technique modulates cortical excitability in the M1 (for a review, see Ref. 10), and its modulatory effect endures after stimulation. tDCS not only shifts the activity of cortical areas situated directly under the electrodes but also of distant areas, probably through interconnections between the principal stimulated area and these structures.11 The primary effect of tDCS is a neuronal de- or hyperpolarization of membrane potentials,12,13 whereby the induced aftereffects depend on N-methyl-D-aspartate receptorefficacy changes.14 In a recent study,8 patients were randomized to receive sham or active tDCS over the left or
right motor cortex (2 mA, 20 minutes for five consecutive days). There was a significant pain perception improvement after anodal stimulation of the M1 but not after sham stimulation. A follow-up study reported a similar decrease in pain perception in a patient group with fibromyalgia.9 Compared with the aforementioned studies,8,9 we changed three parameters related to the stimulation: 1) the intensity of stimulation was 1 mA (2 mA in the study8); 2) related electrode size was 4 4 cm to increase the focality of the stimulation (5 7 cm in the studies8,9); and 3) a crossover design was used in 13 participants, who received both types of stimulations. Furthermore, we examined the possible intracortical effects of repeated tDCS over M1 using paired-pulse stimulation. Pairedpulse TMS techniques include several protocols to study the modulation of motor cortex excitability by local circuits of afferent inputs from other cortical areas of the brain.15,16 Finally, the possible side effects of the stimulation were evaluated by a questionnaire developed by our research group.17
Methods Subjects All participants (patients with trigeminal neuralgia, poststroke pain syndrome, back pain, fibromyalgia) (Table 1) were outpatients at the Department of Clinical Neurophysiology, Go¨ttingen, Germany. They were regarded as suitable to participate if they fulfilled the following criteria: 1) stable chronic pain for at least the preceding six months; 2) score greater than or equal to 3 (0 ¼ no pain and 10 ¼ worst possible pain) on the visual analog scale (VAS) for pain perception during the last month before baseline/start of the stimulation; and 3) refractoriness to drugs for pain relief, such as nonopioid analgesics, tricyclic antidepressants, antiepileptic drugs, and/or opioids (pain resistance to at least two of these drugs supplied in adequate dosages for six months). The diagnoses were made by trained
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Table 1 Clinical and Demographic Characteristics of the Patients With Regard to the Different Stimulation Conditions Number (n) Gender (male) Age range (years) Etiology and side of the pain Fibromyalgia Chronic back pain Trigeminal neuralgia Atypical face pain Arthrosis (finger, foot) Phantom pain (leg) Poststroke pain (arm) Polyneuropathy Duration of chronic pain More than 5 years Between 2 and 5 years Less than 2 years Baseline VAS scores (SD) Present medication Pregabalin Nonsteroidal anti-inflammatory drug Morphine Amitriptyline No medication
Only Anodal tDCS
Only Sham tDCS
Active and Sham tDCS
6 (1 patient in the follow-up) 2 28e70
4
13 (1 patient in the follow-up) 3 41e70
2 (both sides) 2 (right side) 1 (both sides) 1 (left side)
1 50e70 2 (both sides) 1 (both sides) 1 (both sides)
1 5 1 2 2
(both sides) (both sides) (1 right side) (both sides) (both sides)
1 (right side) 1 (both sides) 4 1 1 7.11 (1.2)
2 2
3 1 7.0 (1.5) 1 2
6 5 2 5.8 (2.1); 5.95 (2.2) 2 2 2
1 2
neurologists at least two years before the study started. We excluded patients with any clinically significant or unstable medical or psychiatric disorder, history of substance abuse, or neuropsychiatric comorbidity. In addition, we excluded patients with metallic implants/implanted electric devices. As carbamazepine might decrease the effects of anodal stimulation after a single session of tDCS,14 patients taking carbamazepine also were excluded. Finally, 23 patients (age range 28e70 years; six males) participated in the study. The general clinical characteristics of the patients are summarized in Table 1. Table 2 shows the individual demographic and clinical parameters of the patients. Patients with lumber pain had not undergone surgery. Facial pains were continuous in all cases. The patients were aware of the fact that they could get sham or real stimulation. The study was a randomized, doubleblinded, placebo-controlled, single-center trial that was designed to evaluate the efficacy of five daily sessions of anodal tDCS in patients with chronic pain. The study conformed to the ethical standards of the 1964 Helsinki Declaration and was approved by the institutional ethics committee. All patients provided written, informed consent. Two of 23 patients
7
were not included among the follow-up analyses (one from the crossover design and one who had received only anodal stimulation; see Table 1), because they did not provide us with their pain diaries in the follow-up period. In the case of 13 patients, a crossover design was applied; they had a second session of stimulation with at least a six-week break after the first one and only if the VAS values returned to the previous baseline values for at least 10 days’ prior stimulation. For the remaining 10 patients, six had anodal and four had sham stimulations.
Experimental Design The study had three phases: 1) baseline evaluation consisting of a four-week period of the daily registration of subjective, baseline pain; 2) one-week treatment, which consisted of daily treatment sessions with sham or active tDCS (20 minutes) for five consecutive days; and 3) a follow-up period of four weeks. Before the first stimulation and two to three days after the last stimulation, the patient underwent several measurements related to cortical excitability (see below). During the baseline period, patients were randomized to receive sham or active tDCS. Randomization was performed using the order of entrance into the study.
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Table 2 Individual Patient Parameters With Regard to the Different Stimulation Conditions Patient 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23
Stimulation Anodal-sham Anodal-sham Anodal-sham Anodal-sham Anodal-sham Anodal-sham Anodal-sham Anodal-sham Anodal-sham Anodal-sham Anodal-sham Anodal-sham Anodal-sham Anodal Anodal Anodal Anodal Anodal Anodal Sham Sham Sham Sham
Gender F F F F F M F F M M F F F F F F M F M F M F F
Age (Years)
Diagnosis
Duration of Pain (years)
Medication
58 63 70 68 63 70 51 56 53 61 41 54 55 70 42 65 28 57 59 56 70 50 52
Chronic back pain Arthrosis Fibromyalgia Chronic back pain Arthrosis (foot, finger) Chronic back pain Polyneuropathy Atypical face pain Trigeminal neuralgia Poststroke pain Atypical face pain Chronic back pain Chronic back pain Chronic back pain Arthrosis Trigeminal neuralgia Phantom pain (leg) Trigeminal neuralgia Chronic back pain Fibromyalgia Arthrosis Chronic back pain Fibromyalgia
19 5 20 4 3 1.5 5 12 6 8 1.5 6 25 8 2 3 7 3 6 6 2 8 10
Nonsteroidal Morphine Nonsteroidal Morphine d d Pregabalin d d d d Pregabalin d Nonsteroidal d Nonsteroidal Morphine Morphine d Nonsteroidal Nonsteroidal Pregabalin Amitriptyline
F ¼ female; M ¼ male.
Transcranial Direct Current Stimulation Subjects were seated in a comfortable reclining chair with a mounted headrest throughout the experiments. The stimulations with regard to one given patient were always done by the same investigator. Direct current was transferred by a saline-soaked pair of surface sponge electrodes (4 4 cm over the M1 and 5 10 cm over the contralateral orbit) and delivered by a specially developed, battery-driven, constant current stimulator (NeuroConn, Ilmenau, Germany) with a maximum output of 5 mA. Patients received either anodal stimulation or sham stimulation of M1. First, the hand area over the left hemisphere was determined by single-pulse TMS. For anodal stimulation, the active electrode was placed over the hand representation field of M1 at the left side and the reference (cathode) electrode over the contralateral supraorbital area, independently from the lateralization of the pain. This electrode position has been shown to be effective to enhance the excitability of the M1.18 Furthermore, most of the patients had pain at the right side or both sides of the body. It was observed that M1 stimulation with tDCS induces widespread changes in the activity of cortical areas and can indeed change the activity of the contralateral hemisphere.11 This suggests that unilateral tDCS treatment might be sufficient for patients with
bilateral pain. In addition, because the electrode for tDCS is large, the stimulation encompassed a broad area of the motor cortex (upper limb and face). A constant current of 1-mA intensity was applied for 20 minutes. The maximal current density was 62.5 mA/cm2 over the M1 and 12 mA/cm2 at the reference electrode. Subjects felt the current as an itching sensation at both electrodes at the beginning of the stimulation. For sham stimulation, the electrodes were placed in the same positions as for anodal M1 stimulation; however, the stimulator was turned off automatically after 30 seconds of stimulation. Therefore, the subjects felt the initial itching sensation but received no current for the rest of the stimulation period. The stimulators were coded using a five-letter code, preprogrammed by one of the department members, who otherwise did not participate in the study. Therefore, neither the investigator nor the patient knew the type (anodal or sham) of the stimulation. After the five-day stimulation period, patients were asked if they could guess the type of stimulation they received.
Single-Pulse Transcranial Magnetic Stimulation The patients who participated in the crossover study (n ¼ 13) were included in this experiment. To detect current-driven changes
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of excitability, motor-evoked potentials (MEPs) of the right first dorsal interosseus (FDI) muscle were recorded before and after the stimulation of its motor-cortical representation field by single-pulse TMS. TMS was performed by using a Magstim standard double (‘‘figure eight’’) 70 mm coil (2.2 T; average inductance, 16.35 mH) connected to two monophasic Magstim 200 stimulators by means of a bistim module (Magstim Co., Whiteland, Dyfed, UK). Surface electromyogram (EMG) was recorded from the right FDI through a pair of Ag-AgCl surface electrodes in a belly-tendon montage. Raw signals were amplified, band-pass filtered (2 Hz to 3 kHz; sampling rate, 5 kHz), digitized with a micro 1401 AD converter (Cambridge Electronic Design, Cambridge, UK) controlled by Signal Software (version 2.13; Cambridge Electronic Design), and stored on a personal computer for offline analysis. Whenever necessary, complete relaxation was controlled through auditory and visual feedback of EMG activity. The coil was held tangentially to the skull, with the handle pointing backward and laterally at 45 from the midline, resulting in a posterior-anterior direction of current flow in the brain. This orientation of the induced electrical field is thought to be optimal for predominantly transsynaptic mode of activation of the corticospinal system. The optimum position was defined as the site where TMS resulted consistently in the largest MEP in the resting muscle. The site was marked with a skin marker to ensure that the coil was held in the correct position throughout the experiment.
Paired-Pulse Transcranial Magnetic Stimulation TMS measurements included resting motor threshold (RMT), active motor threshold (AMT), the intensity to evoke an MEP of w1mV peak-to-peak amplitude (SI1 mV), shortinterval intracortical inhibition/intracortical facilitation (SICI/ICF), long-interval intracortical inhibition (LICI), short-interval intracortical facilitation (SICF), recruitment curves and cortical silent period (CSP). Patients participated in four experimental conditions (before and after sham and anodal tDCS). Stimulus intensities (in percentage of maximal stimulator output) of TMS were determined at the beginning of each
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experiment. SI1 mV was determined with single-pulse TMS first. RMT was defined as the minimal output of the stimulator that induced a reliable MEP (w50 mV in amplitude) in at least three of six consecutive trials when the FDI muscle was completely relaxed. AMT was defined as the lowest stimulus intensity at which three of six consecutive stimuli elicited reliable MEP (w200 mV in amplitude) in the tonically contracting FDI muscle.19 SICI/ICF, LICI, and SICF were measured with three different protocols of single- and paired-pulse TMS applied in random order at 0.25 Hz. For SICI/ICF, two magnetic stimuli were given through the same stimulating coil, and the effect of the first (conditioning) stimulus on the second (test) stimulus was investigated.15 To avoid any floor or ceiling effect, the intensity of the conditioning stimulus was set to a relatively low value of 80% of AMT. The test-stimulus intensity was adjusted to SI1 mV. SICI was measured with interstimulus intervals (ISI) of two and four milliseconds, and ICF with ISIs of 9 and 12 milliseconds. The control condition (test pulse alone) was tested 40 times, and each of the conditioning-test stimuli was tested 20 times. The mean peak-to-peak amplitude of the conditioned MEP at each ISI was expressed as a percentage of the mean peak-to-peak size of the unconditioned test pulse. SICI was taken as the mean percentage inhibition at ISIs of two and four milliseconds, whereas ICF was taken as the mean facilitation at ISIs of 9 and 12 milliseconds. The second protocol tested LICI with two suprathreshold stimuli applied with ISIs of 50, 100, 150, and 200 milliseconds.16 The intensities of both stimuli were set to 110% of RMT. Here also, the intensity was set to this relatively low value to avoid any floor or ceiling effect. The control condition (first pulse alone) was tested 40 times, whereas each of the paired stimuli was tested 20 times. LICI was taken as the mean percentage inhibition of conditioned MEP at ISIs of 50, 100, 150, and 200 milliseconds. SICF also was measured in a paired-pulse TMS protocol, but here, the first pulse was suprathreshold, and the second pulse was subthreshold.20,21 The intensity of the first (test) pulse was set to SI1 mV, and the intensity of the second (conditioning) pulse to 90% of RMT. In this protocol, the
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control condition (test pulse alone) was given 40 times, and each of the conditioning-test stimuli with the ISIs 1.3, 2.1, 2.5, 3.5, and 4.1 milliseconds, was tested 20 times. The mean peak-to-peak amplitude of the conditioned MEP at each ISI was expressed as a percentage of the mean peak-to-peak size of the unconditioned test pulse. Recruitment curves (RECR) were measured with four different and increasing stimulus intensities (100%, 110%, 130%, and 150% of RMT), each with 10 pulses. Mean amplitude was calculated for each intensity. Finally, 10 pulses with SI1 mV and 10 pulses with 120% RMT were applied under tonic contraction of the right FDI muscle. CSPs were separately determined in rectified and averaged EMG traces with a prestimulus period of 100 milliseconds. CSP (in milliseconds) was measured from the TMS stimulus to the point where the signal reached the amplitude of the mean prestimulus EMG activity again for more than 5 milliseconds.
Pain Measurement: Visual Analog Scale for Pain This self-evaluation scale ranges from 0 to 10 as visually described in centimeter units: 0 cm indicates no pain and 10 cm means the worst pain possible. This scale has been widely used in studies that evaluate pain as an outcome; both validity and reproducibility have been demonstrated.22 Participants were asked to rate their pains three times a day at the same time point at least 30 days before, during, and 30 days after the end of the stimulation. These values were averaged, giving one VAS value per day. We instructed the participants to continue their routine medication regimen. Herbal remedies and alternative therapies, such as massage or acupuncture, were allowed if they had been used for at least four weeks before randomization, and the regimen was maintained constant throughout the study.
Adverse Effects of Transcranial Direct Current Stimulation The electric current was applied continuously for 20 minutes/day in this protocol. Because potential adverse effects of this technique are not fully known yet, the patients completed a questionnaire17 after anodal and sham stimulation, separately. The questionnaire
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contained rating scales for the presence and severity of headache; difficulties in concentrating; acute mood changes; visual perceptual changes; fatigue; and discomforting sensations, such as pain, tingling, itching, or burning under the electrodes during and after tDCS.
Statistical Analysis Pain Perception. Two kinds of analyses were done: 1) all of the patients (n ¼ 21) were included, and the anodal and sham conditions were compared (17 anodal vs. 16 sham stimulations); and 2) the data from 12 patients were analyzed, using a crossover analysis (12 anodal vs. 12 sham stimulations). We normalized the post-stimulation VAS values to baseline (mean of the last 10 days prestimulation). The data were treated using a betweensubject design because of the partly different groups. Additionally, we compared the prestimulation VAS values with Student’s t-test for both groups of patients to rule out that differences between sham and active stimulation might have been because of a priori differences between these two stimulation groups. For the analysis for VAS scores, we used repeated-measures analysis of variance (ANOVA), in which the dependent variable was the VAS score and the factors were STIMULATION (sham and anodal) and TIME of treatment (baseline: mean of the last 10 days before stimulation, during stimulation,1e5 and after stimulation [Days 7, 14, 21, and 28]). When appropriate, post hoc comparisons (between sham and anodal stimulation and between post-treatment evaluations and baseline evaluations) were carried out using Bonferroni correction for multiple comparisons. In addition, for all endpoints, we also ran a Student’s t-test, including only the time factor as a repeated measurement. Transcranial Magnetic Stimulation Measurements. For each measurement (SI1 mV, RMT, AMT, SICI, ICF, SICF, LICI, CSP), we performed separate ANOVAs for repeated measurements by using the mean values from each subject as the dependent variable to compare the parameters of cortical excitability. In addition to the factor ‘‘STIMULATION type’’ (anodal vs. sham) and factor ‘‘TIME’’ (baseline, post-stimulation), the ANOVA model included the factor ‘‘ISI’’ (2, 4,
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7, 9, and 12 milliseconds) when SICI and ICF were analyzed or the factor ‘‘intensity’’ (100%, 110%, 130%, and 150% of RMT) for recruitment curves, or the factor ‘‘INTENSITY’’ (120% RMT and SI1 mV) for CSP. Here, only the data of the patients who participated in the crossover design were included. Unless stated otherwise, all results are presented as means and standard errors, and statistical significance refers to a two-tailed Pvalue less than 0.05. Adverse Effects of Transcranial Direct Current Stimulation. The incidences of side effects were coded using a binary system (no ¼ 0, yes ¼ 1), and the severities of the side effects were rated using a numerical analog scale from 1 to 5; 1 being very mild and 5 indicating an extremely strong intensity of any given side effect. From these values, a mean intensity was calculated. The incidences and severities of the adverse effects were separately calculated during and after stimulation. The percent of affected patients in the sham and anodal conditions was calculated independently.
Results Pain ControldVisual Analog Scale There was no significant difference concerning the baseline VAS values (t ¼ 1.8, df ¼ 32, P ¼ 0.1). To analyze whether tDCS treatment was associated with pain improvement, we performed a repeated-measures ANOVA, in which the dependent variable was change of normalized VAS pain scores, and the independent variable was TIME of evaluation (baseline; Days 1, 2, 3, 4, 5; and follow-up) and type of STIMULATION (anodal vs. sham tDCS). Concerning the whole group, this analysis revealed a significant main effect of STIMULATION (F(1,32) ¼ 5.32, P < 0.05) and TIME (F(8,256) ¼ 2.14, P < 0.03); however, the interaction between them was not significant: F(8,256) ¼ 0.28 and P ¼ 0.9 (Fig. 1a). Student’s t-test revealed a significant difference on Days 3 and 7 between anodal and sham stimulations (P < 0.05; VAS change: 27.3% decrease [anodal] vs. 2.7% [sham] and 8.9% decrease vs. 11% increase, respectively). Concerning the 12 patients who participated in both stimulation sessions, the ANOVA revealed a significant main effect of the group of STIMULATION (F(1,22) ¼ 14.3, P < 0.005). However, the TIME
Fig. 1. Pain scores as indexed by VAS throughout and after the stimulation (a) with regard to all of the patients and (b) the patients who participated in the crossover stimulation study. The VAS scores for each time point were normalized to the before-stimulation values (10 days’ mean VAS before the first day of stimulation). Bars show standard error of mean.
(F(8,176) ¼ 1.24, P ¼ 0.27) and the interaction between TIME and STIMULATION (F(8,176) ¼ 0.35; P ¼ 0.9) were not significant (Fig. 1b). Student’s t-test revealed a significant difference on Days 3, 4, 5, 7, 14, and 28 between anodal and sham stimulations (P < 0.05; VAS change: 36.5% decrease vs. 9% increase, 33.5% decrease vs. 7% increase, 35% decrease vs. 1% decrease, 11% decrease vs. 23% increase, 27.5% decrease vs. 5% increase, 26.5% decrease vs. 6% increase, respectively). Finally, we compared the baseline VAS values with all of the time points (the factor TIME was significant using ANOVA) for each condition separately, using Student’s t-test. Concerning the full group, this analysis showed a significant difference during the anodal stimulation (baseline comparison with first stimulation [P ¼ 0.03], second stimulation
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[P ¼ 0.03], third stimulation [P ¼ 0.003], fourth stimulation [P ¼ 0.001], fifth stimulation [P ¼ 0.0006]) and after the stimulation (Day 14 [P ¼ 0.03] and Day 28 [P ¼ 0.03]). The largest pain reduction was achieved after the fifth session of stimulation (30%; mean VAS pain scores: 4.22 [2.23]). Applying sham stimulation, there was no significant difference between baseline and during/poststimulation VAS values. Concerning the 12 patients, the analysis showed a similar tendency: significant difference was found during the anodal stimulation (baseline comparison with first stimulation [P ¼ 0.02], second stimulation [P ¼ 0.05], third stimulation [P ¼ 0.004], fourth stimulation [P ¼ 0.01], fifth stimulation [P ¼ 0.008]), and after the stimulation (Day 14 [P ¼ 0.03] and Day 28 [P ¼ 0.02]). The largest pain reduction was achieved after the third session of stimulation (37%; mean VAS pain scores: 3.54 [2.29]). Applying sham stimulation, there was no significant decrease with regard to baseline and during/post-stimulation VAS values except the first-day values (P ¼ 0.05). There were eight responders (reduction of 30% or more in the VAS after five-day stimulation) in the anodal tDCS group (63% of patients) and only four responders in the sham tDCS group (16%). In the follow-up evaluation, four patients in the active tDCS group were still considered as responders, and three responders in the sham tDCS group reported no more pain improvement. Importantly, active tDCS did not worsen pain in any of the patients who received this treatment. Because we had a small sample size and a heterogeneous group with regard to the origin of the chronic pain, we did not perform any correlation analysis for the characteristics of the disease. However, larger pain improvement was observed among patients with arthrosis than back pain. None of the patients with fibromyalgia showed a different pattern of pain reduction after the five-day treatment compared with sham stimulation.
Single- and Paired-Pulse Transcranial Magnetic Stimulation For two subjects, the experimental sessions were interrupted because of headache that
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started during the stimulation. In these cases, only threshold measurements were done. First, RMT, AMT, and SI1 mV baseline values were compared between active and sham stimulation conditions. There was no significant difference between anodal and sham stimulation in any of the measurements (Table 3). Anodal stimulation had no effect on SICF, ICF, LICI, CSP, or motor-evoked recruitment curves, as revealed by repeated-measures ANOVA (Table 3). However, Student’s t-tests showed a significant difference in the case of SICI (P < 0.05), showing decreased intracortical inhibition after anodal stimulation (Fig. 2). Eight of the patients showed a clear trend: the increase in SICI correlated with the decrease in VAS after anodal but not after sham stimulation. However, because of the low number of subjects, this was not significant.
Adverse Effects of Transcranial Direct Current Stimulation Neither of the subjects terminated the stimulation or needed any medical intervention during or after the end of tDCS. Tables 4 and 5 summarize the adverse effects during and after tDCS, including all of the sham and anodal stimulation conditions. During the stimulation, mild tingling sensation was the most common adverse effect; it was reported by 66.6% of the subjects during anodal and 52.9% during sham stimulation. Moderate fatigue was the second most frequent consequence; it was reported by 44.4% of the participants during anodal stimulation and, interestingly, 64.7% of the subjects during sham stimulation. Similarly, after the stimulation, 33.3% of the patients felt tired in the anodal group, and 70.6% reported this symptom in the sham group. Headache occurred in 38.9% in the anodal group and 35.3% in the sham group. Four patients in the anodal and two in the sham groups reported acute sleeping disturbances for two to five days after tDCS. Concerning the patients who participated in the crossover study, only one reported that there was a difference between the two types of stimulations when it was explicitly asked. There were two dropouts in the follow-up period (one anodal and one sham). Both the patients showed no improvement that could have contributed to their decision to abandon
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Table 3 Statistical Analysis of the Single- and Paired-Pulse TMS Experiments TMS measurement ANOVA
SI1 mV AMT RMT RECR
CSP
SICI/ICF
LICI
Factor
df
F
P
Stimulation Time Stimulation time Stimulation Time Stimulation time Stimulation Time Stimulation time Stimulation Time Stimulation time Intensity Stimulation intensity Time intensity Stimulation time intensity Stimulation Time Stimulation time Intensity Stimulation intensity Time intensity Stimulation time intensity Stimulation Time Stimulation time ISI Stimulation ISI Time ISI Stimulation time ISI Stimulation Time Stimulation time ISI Stimulation ISI Time ISI Stimulation time ISI
1 1 25 1 1 25 1 1 25 1 1 22 3 3 3 66 1 1 22 1 1 1 22 1 1 20 4 4 4 80 1 1 23 3 3 3 69
0.08 0.0 0.03 0.2 0.68 0.98 0.22 0.33 0.09 0.36 1.67 0.08 39.26 0.18 1.52 0.17 0.25 0.43 0.002 2.66 0.76 0.002 0.26 0.01 3.32 0.69 88.96 0.39 0.56 3.68 0.05 4.19 0.08 2.84 0.33 4.77 0.6
0.77 0.99 0.85 0.66 0.42 0.20 0.56 0.57 0.77 0.55 0.21 0.78 <0.01 0.90 0.22 0.92 0.61 0.52 0.95 0.11 0.39 0.96 0.61 0.9 0.08 0.41 <0.001 0.81 0.69 0.05 0.99 0.05 0.77 0.04 0.80 0.004 0.59
Student’s t-test
Stimulation Type
df
t
P
ICI 7 milliseconds ICF ICI 7 milliseconds ICF
Anodal
10 10 10 10 10 10
3.53 1.5 0.29 0.044 0.13 2.0
<0.005 0.16 0.77 0.96 0.89 0.07
Sham
their participation in the remainder of the study.
Discussion Our results demonstrate that five daily sessions of anodal tDCS using a relatively small (4 4 cm) stimulation electrode over the hand area of the M1 can produce longlasting pain relief in patients experiencing different types of chronic pain, probably by decreasing the level of intracortical inhibition. However, there was a higher incidence of
adverse events in both treatment groups, as in previous studies including patients with chronic pain8,9 or healthy subjects.17 These adverse events consisted of mild headache, fatigue, and itching under the electrodes. Compared with previous studies that used anodal tDCS for the treatment of chronic pain, the magnitude of our results (mean pain decrease of 37%) is somewhat lower (58% in the study by Fregni et al.,8 which included patients with low back pain), possibly because of our heterogeneous patient group and may be a result of the different criteria used to designate pain responders. Nevertheless, our result is similar to
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Fig. 2. The main results of the TMS experiment. After anodal stimulation decreased, intracortical inhibition (ISIs: 2, 4 milliseconds) was observed. Bars show standard error of mean.
those of high-frequency rTMS studies that report mean pain relief that ranges from 20% to 45%.4,5 Furthermore, the reduced tDCS intensity here may be better suited for blinding. As reported by Furubayashi et al.,23 an intensity of 3 mA starts to be painful, 1 mA certainly has a higher chance of going unnoticed compared with placebo conditions than 2 mA. Because there was no difference with regard to the occurrence of itching/tingling/burning sensations and headache between patients after sham and verum stimulation, and fatigue was experienced by an even higher percentage of sham patients compared with anodally stimulated patients, we are quite sure at having provided an optimal placebo condition. An interesting question to be solved in the near future is the optimal duration and repetition rate of tDCS sessions. In the present study, the effects built up during the first three stimulation sessions, being mild in many patients immediately after the initial stimulation but quite clear after the fourth or fifth days. Effects were also separated from the placebo effect of sham stimulation after this duration. According to the original observation by Lefaucheur et al.,5 pain relief after a single session was optimal two to four days after rTMS. Regarding
the long-lasting effect of anodal stimulation, our results are similar to those published by Fregni et al.8,9 However, compared with epidural stimulation, tDCS may result in a smaller treatment effect: the surgical approach resulted in a 28%e70% mean pain reduction in 50%e80% of responders;1,24e27 nevertheless, this may include a substantially stronger placebo effect. The mean pain relief varied from 28% to 47% in the largest series,27,28 and between 50% and 70% in the smallest series25,26 of patients. Nevertheless, the effects of five daily sessions of anodal tDCS are likely to have a shorter impact on brain activity than what can be achieved using MCS with epidural electrodes for several months. The magnitude of the placebo effect was lower in our study (varied from 18.9% to þ9.8% during and after treatment) compared with rTMS studies. Here, we expect a higher placebo response to rTMS, simply because of the higher technical effort and the remote risk of seizure induction, for which patients obtaining tDCS do not have to be informed. Furthermore, it has been documented that the severity and therapeutic refractoriness of symptoms can correlate negatively with placebo response.29 Therefore, a lower placebo
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Table 4 Adverse Effects of tDCS During Stimulation Pain
Tingling
Itching
Type of Stimulation
n
%
MI
n
%
MI
n
%
MI
Sham Anodal
2 2
11.8 11.1
10 21
9 12
52.9 66.6
1.1 0.11 1.5 0.15
0 6
0 33.3
0 2.0 0.15
Burning
Sham Anodal
Fatigue
n
%
MI
n
%
MI
n
%
MI
4 2
23.5 11.1
10 10
11 8
64.7 44.4
1.7 0.27 1.8 0.46
1 0
5.9 0
10 0
Trouble in Concentrating
Sham Anodal
Nervousness
Changes in Visual Perception
n
%
MI
n
%
1 1
5.9 5.5
20 20
0 2
0 11.1
MI 0 10
Unpleasantness
Sham Anodal
n
%
0 2
0 11.1
Headache n
%
MI
5 5
29.4 27.8
1.4 0.24 1.8 0.75
Other MI
n
0 21
1 1 1
Tingling in the tongue Warm tingling with regard to the leg Involuntary muscle contraction
MI ¼ mean intensity (0e5).
response may indicate the therapeutic refractoriness of our patient population. It was suggested by previous studies that the best stimulation site using rTMS for pain control is not the area corresponding to the painful zone but the adjacent one.6 However, with regard to epidural stimulation, another study showed that the most efficacious position of the stimulating electrodes was the one corresponding to the cortical somatotopic representation of pain perception.27 We have used a smaller stimulation electrode (4 4 cm) compared with those of previous clinical studies8,9 to increase the focality of the stimulation. However, because of the still large electrode size applied in our study, it is likely that the stimulation induced a modulatory effect over a large area of M1 that encompassed both the area corresponding to the pain and the adjacent areas. Further studies are needed to explore whether somatotopically guided stimulation might increase the analgesic effect of tDCS and to pursue the concept of Lefaucheur et al.6 The mechanisms responsible for the longlasting effect of anodal tDCS on pain are still unknown. Upregulation of M1 excitability could modulate pain perception through indirect effects on pain-modulating areas, such as
the thalamic and subthalamic nuclei. In fact, a change in the activity of these nuclei is associated with rTMS30 and tDCS.11 Sequentially, the activation of thalamic nuclei can modify the activity of other pain-related structures (e.g., anterior cingulate, periaqueductal gray) and can also inhibit pain of spinal origin. The higher incidence of adverse effects (mainly headache and fatigue) during and after tDCS compared with those reported among healthy subjects in a previous study17 might be related to the type of disorder investigated in our study. Similarly, a higher proportion of migraineurs (55.6%) reported headache after tDCS compared with healthy subjects (7.8%).17 Therefore, it is not astonishing that 35%e39% of the subjects reported headache in our study. However, we have not observed any serious complications, such as seizures, in connection with the application of tDCS. As tDCS has been tested only recently for clinical applications, the impact of consecutive sessions of cortical stimulations on different cognitive, motor, and other functions in different patient populations is not yet fully known. Therefore, our data concerning the side effects of the stimulation could be interpreted as preliminary safety evidence with regard to tDCS in chronic pain.
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Table 5 Adverse Effects of tDCS After Stimulation Pain
Tingling
Itching
Type of Stimulation
n
%
MI
n
%
MI
n
%
MI
Sham Anodal
1 1
5.9 5.5
10 10
1 1
5.9 5.5
10 10
1 1
5.9 5.5
10 10
Burning
Sham Anodal
Fatigue
n
%
MI
n
%
MI
n
%
MI
1 1
5.9 5.5
10 10
12 6
70.6 33.3
2.25 0.30 2.4 0.51
1 1
5.9 5.5
10 20
Trouble in Concentrating
Sham Anodal
n
%
2 0
11.8 0
Changes in Visual Perception
MI 2.5 0.5 0
n
%
0 2
0 11.1
Nausea
Sham Anodal
Headache
MI 0 1.0 0
Vomiting
n
%
MI
6 7
35.3 38.9
2.2 0.54 2 0.38
Acute Sleeping Problems
n
%
MI (h)
n
%
MI
n
%
MI (d)
1 0
5.9 0
20 0
0 0
0 0
0 0
2 4
11.8 22.2
21 3 0.71
Elevated Mood
Sham Anodal
Nervousness
Feeling Cold
Feeling Warm
n
%
MI (h)
n
%
MI
n
%
MI
2 3
11.8 16.6
3.5 1.5 1.3 0.33
1 1
5.9 5.5
0.25 0 10
2 1
11.8 5.5
1.5 0.5 20
Others n 1
Increment in the subjective good feeling
MI ¼ mean intensity (0e5); h ¼ post-tDCS hours; d ¼ post-tDCS days.
In terms of commonly used noninvasive excitability parameters, we have found a decreased SICI after anodal tDCS compared with sham tDCS over M1 using the paired-pulse paradigm. TDCS application had no significant effect on SICF, ICF, LICI, CSP, or motor-evoked recruitment curves (for an overview of methods used to study the modulation of human motor cortex excitability in local circuits, see Refs. 21,31). SICI is a low-threshold inhibition that can be elicited using paired-pulse TMS delivered with short ISIs.12 Because the conditioning subthreshold stimulus during paired-pulse TMS neither recruits descending volleys in the corticospinal tract32 nor alters spinal reflexes,15 it is suggested that the inhibitory phenomena are produced by mechanisms acting only at the cortical level. SICI can be mediated by gamma aminobutyric acid (GABAA) receptors. It was found that tiagabine (a GABA-reuptake inhibitor) decreases SICI.33 In a previous study, a single session of anodal tDCS over the M1 reduced
intracortical inhibition and enhanced facilitation.34 However, this effect was explained by the fact that the aftereffects of tDCS, as well as intracortical inhibition and facilitation, are at least partly modulated by NMDA receptor activity.35 Interestingly, a previous study36 in which 1or 10-Hz rTMS was applied over the M1 corresponding to the painful hand of patients with chronic neuropathic pain showed a significant increase in ICI after 10-Hz rTMS, which was correlated with pain relief. However, in these patients, ICI was reduced at baseline compared with the measurements of healthy subjects. The authors concluded that chronic neuropathic pain was associated with M1 disinhibition, suggesting impaired GABAergic neurotransmission related to underlying sensory or motor disturbances. From our present study, it is difficult to conclude which neurotransmitter system was involved in the reduction of the SICI in our patient population; hence, further studies are necessary to clarify this point.
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The limitations of this study need to be discussed. First, this clinical trial was an exploratory study; we had a heterogeneous patient group, the symptoms and the etiology of the chronic pain syndromes differed across patients, and our sample size might not have been large enough to detect some characteristics associated with a positive effect of anodal tDCS. Nonetheless, many of the previous rTMS studies have investigated patients with different types of chronic pain.5,6 Furthermore, in practice, it is the general pain symptoms of the patients that are targeted and treated, and not specific symptoms of pain, which are dependent upon the selected groups of patients themselves, with symptoms often varying within a wide range with regard to the intensity, quality and localization. Second, our patients were allowed to adhere to their medication regimens throughout the trial; nevertheless, none of the patients requested to increase the dosage of their medication. Furthermore, the patients were taking different types of medications in varying dosages. Therefore, we have to conclude that medication might confound our results. Because of the exploratory nature of the study, the statistical analysis used also implemented exploratory methods. In summary, previous studies showed that high-frequency rTMS is associated with a significant pain improvement compared with sham rTMS.4e6,36 TDCS is a relatively new technology that appears to stimulate the M1 in a way similar to that of rTMS and epidural stimulation and can transiently reduce pain in some groups of patients with neuropathic pain.8,9 Although the basic neuronal mechanisms of tDCS are probably different from those of rTMS, both techniques might lead to a similar indirect change of activity in connected areas and, thus, result in similar effects on chronic pain.
Acknowledgment The authors thank Leila Chaieb for her assistance with the English translation of this article.
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