Exp Brain Res DOI 10.1007/s00221-014-3878-0
Research Article
The effect of transcranial direct current stimulation on experimentally induced heat pain Per M. Aslaksen · Olena Vasylenko · Asbjørn J. Fagerlund
Received: 29 October 2013 / Accepted: 13 February 2014 © Springer-Verlag Berlin Heidelberg 2014
Abstract Transcranial direct current stimulation (tDCS) is a non-invasive neuromodulatory technique that can affect human pain perception. Placebo effects are present in most treatments and could therefore also interact with treatment effects in tDCS. The present study investigated whether short-term tDCS reduced heat pain intensity, stress, blood pressure and increased heat pain thresholds in healthy volunteers when controlling for placebo effects. Seventyfive (37 females) participants were randomized into three groups: (1) active tDCS group receiving anodal tDCS (2 mA) for 7 min to the primary motor cortex (M1), (2) placebo group receiving the tDCS electrode montage but only active tDCS stimulation for 30 s and (3) natural history group that got no tDCS montage but the same pain stimulation as the active tDCS and the placebo group. Heat pain was induced by a PC-controlled thermode attached to the left forearm. Pain intensity was significantly lower in the active tDCS group when examining change scores (pretest– posttest) for the 47 °C condition. The placebo group displayed lower pain compared with the natural history group, displaying a significant placebo effect. In the 43 and 45 °C conditions, the effect of tDCS could not be separated from placebo effects. The results revealed no effects on pain thresholds. There was a tendency that active tDCS reduced stress and systolic blood pressure, however, not significant. In sum, tDCS had an analgesic effect on high-intensity P. M. Aslaksen (*) · O. Vasylenko · A. J. Fagerlund Department of Psychology, Faculty of Health Sciences, University of Tromsø, 9037 Tromsö, Norway e-mail: [email protected] URL: http://www.uit.no A. J. Fagerlund Department of Surgery and Anaesthesia, University Hospital North Norway, Tromsö, Norway
pain, but the effect of tDCS could not be separated from placebo effects for medium and low pain. Keywords tDCS · Pain · Placebo effect · Emotions · Experimental pain
Introduction Transcranial direct current stimulation (tDCS) is a noninvasive method for brain stimulation and a promising tool for treatment of chronic pain. The technique relies on electrical modulation of resting membrane potentials in cerebral neurons (Nitsche and Paulus 2000, 2001), thus changing the endogenous excitability of neural circuits (Mylius et al. 2012a). The exact mechanism of analgesic effect is, however, not yet completely understood (Fregni and Pascual-Leone 2007). The number of tDCS studies on chronic pain is still limited, but existing evidence suggests that tDCS has a therapeutic analgesic potential (O’Connell et al. 2010). However, the methodological quality and the small number of studies make it difficult to be conclusive about the analgesic effects of tDCS (O’Connell et al. 2010). Additionally, studies on the effect of tDCS on experimentally induced pain have shown conflicting results. In several studies, beneficial effects on experimental pain have been found with both anodal (Boggio et al. 2008; Mylius et al. 2012b) and cathodal (Csifcsak et al. 2009) tDCS, whereas one study found no effects of either anodal or cathodal stimulation (Jurgens et al. 2012). The divergence in effect across studies might be due to differences in factors such as electrode placement, electrode size, current intensity, duration of tDCS stimulation and methods used for pain induction and pain assessment.
13
Interestingly, so far no tDCS study has included a natural history condition or a no-treatment group to control for placebo effects in tDCS treatment. Placebo effects are present in almost all medical treatments (Enck et al. 2008), and tDCS procedures are probably not an exception. All published tDCS studies on experimental pain have employed a sham/placebo control group/condition, but this is not sufficient for the estimation of placebo effects (Benedetti et al. 2003). The difference between the placebo group and the no-treatment/natural history group represents the real psychobiological placebo response (Fields and Levine 1984). Thus, the inclusion of a group receiving no tDCS montage, but the same pain stimulation as the treatment and sham/placebo groups is necessary to investigate the placebo effect in tDCS treatment. Furthermore, so far no experimental tDCS study has tested whether emotional factors affect the outcome of tDCS procedures. Similarly to other pain treatments, it can be expected that emotional activation can influence the effect of tDCS. Specifically, negative emotions might reduce the efficacy of analgesic treatments and procedures, e.g. Rhudy and Meagher (2000), Varelmann et al. (2010) and Lyby et al. (2011), but it is still uncertain how such factors might influence the tDCS analgesic effects. The present experiment tested whether anodal tDCS delivered to the primary motor cortex (M1) reduced heat pain intensity and increased heat pain thresholds in healthy volunteers. We hypothesized that active tDCS would reduce heat pain intensity and increase heat pain thresholds, and we expected that the group receiving placebo tDCS would display a significant placebo effect compared with the natural history group receiving the same pain stimulation, but no tDCS montage or stimulation.
Methods Subjects A total of 75 healthy volunteers (37 females) with mean age of 23.52 years (standard deviation = 5.71) were included in the study. Subjects were recruited at the campus of the University of Tromsø, Norway. All participants signed an informed consent form that stated that they had no medical history of any serious diseases or injuries. Participants were told that they would take part in an experiment that tested the physiological and subjective effects of tDCS on heat pain. All participants received a gift card (worth 200 NOK, approx. 26 Eur). The study was approved by the Regional Committee for Medical Research Ethics, North Norway, project number 2010-2256.
13
Exp Brain Res
Design Participants were randomized into three different groups: (1) active tDCS where subjects received active anodal tDCS for 7 min, (2) placebo tDCS where subjects received the tDCS montage of the same duration as the active group, but stimulation was terminated after 30 s and (3) natural history group receiving the same pain procedure as the other groups, but no montage of the tDCS equipment. All groups received the same pain stimulation procedure in three blocks: pretest, treatment and posttest. Each stimulation block consisted of three pain stimuli of different temperatures that were presented in the same order for each block: 43, 45 and 47 °C. Thus, the design of the study was a mixed 3 group (between subjects) by 3 test (within subjects) design. In order to minimize the novelty effect of pain stimulation, a familiarization block consisting of three pain stimuli was administered before the experimental procedure. The experiment was run double-blind in the two groups receiving the tDCS electrode montage. Blinding was possible due to a built-in software feature in the tDCS stimulator that allows preprogramming of active or sham stimulation, stimulus intensity, duration and onset. The sample size was chosen on the basis on the few previous published studies employing heat pain in combination with tDCS. To ensure satisfactory statistical power, we included a higher number of subjects compared with studies that found both beneficial (Antal et al. 2008; Csifcsak et al. 2009; Mylius et al. 2012b) and limited/no effects (Borckardt et al. 2012; Jurgens et al. 2012) of tDCS on experimentally induced heat pain. Pain stimuli PC-controlled pain and sensory evaluation system (Pathway; Medoc Ltd., Ramat Yishai, Israel) with a 30 × 30 mm aluminium thermode was used. The thermode has a heating rate of 10 °C/s and is cooled by a Peltier device at the rate of 10 °C/s. When applied to the arm, the thermode had a baseline temperature of 32 °C. The duration of pain stimulation was 20 s at the intended temperature for each stimulus. During the familiarization block, the first stimulus was 42 °C, the second 45 °C and the third 47 °C. Interstimulus intervals during familiarization block were 60 s after the first stimulus (42 °C) and 120 s after the second stimulus (45 °C). Interstimulus intervals during pretest and treatment were 240 s after the first stimulus (43 °C) and 300 s after the second stimulus (45 °C). Interstimulus intervals during posttest were 60 s after the first stimulus (43 °C) and 120 s after the second stimulus (45 °C). The intensity of each stimulus was rated continuously as the stimulus was being delivered. In the pain threshold measures, the thermode heated from baseline of 32 °C at the rate of 0.5 °C/s and until the
Exp Brain Res
participant reported pain sensation by clicking on a computer mouse. After this, the temperature returned to baseline at the rate of 6 °C/s. Each threshold measurement consisted of six trials.
Participants were asked to rate their current state on an 11-point NRS for each adjective pair, and responses were recorded by the experimenter. Blood pressure was measured by an automatic blood pressure monitor (BP A100 Plus, Microlife, Switzerland).
tDCS Procedure A Neuroconn DC stimulator Plus (Neuroconn, Germany) was used for transcranial DC stimulation. Current was transferred from the stimulator to the scalp by a pair of surface sponge electrodes (35 cm2) soaked in saline. Conductive paste (Ten20 Conductive EEG Paste, USA) was applied to the sponges and to the electrode sites on the scalp. Impedance was continuously monitored and kept below 5 Ω. Participants received either anodal or placebo stimulation of M1. In both the active and the placebo conditions, the anode electrode was placed over C4 according to EEG 10–20 system and the cathode electrode over the contralateral supraorbital area. This electrode position has been shown to modulate excitability of M1 (Nitsche and Paulus 2001). For anodal stimulation, a constant current of 2 mA intensity was applied for 420 s (7 min). The duration of the tDCS stimulation was based on previous studies that have found excitability changes after 5 min (Nitsche and Paulus 2001; Boggio et al. 2008), and to maximize the intervention, the duration was set to 7 min. At the beginning and end of stimulation, current was ramped up and down, respectively, for 20 s in order to minimize discomfort. In the placebo group, stimulation stopped automatically after 30 s. As neither the experimenter nor the participants knew whether the applied code was active or placebo tDCS, and the nature of stimulation was not revealed in the apparatus display, a double-blind procedure was ensured. Impedance was monitored in the stimulator display through the session. During active tDCS, the true impedance was displayed. During placebo tDCS stimulation, a nominal value not related to the stimulation was displayed, thus making the visual output in the apparatus similar in both conditions. Most participants in the placebo group reported the same initial itching as did participants in the active group, but stimulation for 30 s was not considered sufficiently prolonged for excitability changes to occur (Nitsche and Paulus 2000). Measurements Pain intensity was measured by a computerized visual analogue scale (COVAS). Recorded pain intensity ranges from 0 (no pain) to 100 (most intense pain imaginable). Subjective stress was measured by two adjective pairs from the Stress/Arousal Adjective Check List (SACL) (Mackay et al. 1978), similarly to previous studies (Aslaksen and Flaten 2008; Aslaksen et al. 2011).
Upon meeting in the laboratory, participants were informed about the purpose and nature of the study and given the opportunity to ask questions about the study. Written consent was obtained from the participants. Participants were seated in a comfortable reclining chair inside a steel cubicle shielded for electromagnetic disturbances. After the initial measurement of blood pressure and subjective stress, the thermode was attached to the participant’s left volar forearm and the familiarization block began. After this, the thermode was moved to a different site of the arm. Then, following a 3-min break, participants received the next block of stimuli, the pretest. After the pretest, there was a 6-min break for the natural history group. For the active and placebo groups, tDCS apparatus was set up and the electrodes were attached to the participant’s scalp. For the active and placebo groups, the experimenter started the tDCS apparatus 3 min before the first stimulus in the treatment block was given. Thus, during this block, participants in the active group received tDCS, while participants in the natural history group received painful stimulation only, and for the placebo group, tDCS ended 2.5 min before the first stimulus in the treatment block was given. Blood pressure and subjective stress were measured again following the treatment block after these measurements ended, the tDCS apparatus was removed. Then, the last block of stimuli, the posttest, was delivered. After the posttest, the final blood pressure and subjective stress measurements were obtained. At the end of the session, participants were asked to report any side effects or discomfort during the treatment and received a gift card as compensation for their participation (see Fig. 1 for an overview of the procedure). The total duration of the session was approximately 60 min. Statistical analyses Statistical analyses were performed with IBM SPSS v. 21 (IBM SPSS, USA). The normal distribution of data was tested with the Kolmogorov–Smirnov test in SPSS. There was no significant deviation from a normal distribution in any of the reported outcome data. Repeated-measures general linear ANOVAs with 3 Group (tDCS, placebo tDCS and natural history) by 3 trial (pretest, treatment and posttest) as within-subject factors and participant sex as between-groups factors were employed for pain, blood pressure and stress measures. All significant interactions
13
Exp Brain Res
Fig. 1 Overview of the procedure. *Blood pressure and subjective stress measurement. NH natural history group, An anodal tDCS group, Pa placebo tDCS group. /// tDCS
Table 1 Pain intensity, heat pain threshold, stress and blood pressure (BP) data for pretest, treatment and posttest in all groups
Total n = 75 SEM standard error of mean
Natural history
Placebo tDCS
tDCS
Mean
SEM
Mean
SEM
Mean
SEM
Pain intensity pretest at 43 °C Pain intensity treatment at 43 °C Pain intensity posttest at 43 °C Pain intensity pretest at 45 °C Pain intensity treatment at 45 °C Pain intensity posttest at 45 °C Pain intensity pretest at 47 °C Pain intensity treatment at 47 °C
25.04 25.95 23.17 38.58 39.71 38.38 66.79 68.88
4.09 3.65 2.92 3.50 4.40 5.01 3.90 4.51
22.73 16.42 18.19 34.62 31.31 26.81 62.81 55.00
3.25 2.68 3.97 4.16 3.89 4.76 4.43 5.16
23.68 15.24 17.72 34.56 27.92 21.88 63.52 56.36
3.35 2.46 3.29 3.69 3.43 4.05 3.97 4.53
Pain intensity posttest at 47 °C Pain threshold pretest Pain threshold posttest Stress pretest Stress treatment Stress posttest BP pretest BP treatment BP posttest Female/male
71.04 44.74 °C 46.17 °C 3.15 2.29 2.21 133/82 126/79 128/78 11/13
4.29 .55 .32 .19 .22 .23 1.16/1.74 1.98/1.19 1.62/1.49
56.89 44.81 °C 45.86 °C 3.04 2.33 1.78 130/82 121/78 122/77 15/11
5.66 .50 .19 .26 .46 .38 3.24/1.66 2.36/1.58 2.45/1.41
49.64 44.84 °C 45.60 °C 2.44 1.52 1.19 127/78 119/75 121/75 11/14
4.87 .57 .38 .31 .33 .27 2.25/1.82 2.27/1.76 2.11/1.58
Age
21.04
.30
23.11
.72
23.20
1.12
were followed up with contrast analyses employing Fisher’s LSD statistics. Univariate general linear ANOVAs were used to examine predictors for treatment effect of tDCS on pain, stress and systolic blood pressure. Measures of effect sizes (η2) with 95 % confidence intervals (CI) are presented for significant results in treatment effect data. A significance level of 0.05 was employed for all analyses.
Pain intensity ratings at 43 °C
Results
Pain intensity ratings at 45 °C
Descriptive data are presented in Table 1. There were no significant group differences in the pretest data for any measure, all p values >0.10.
The significant main effect of group (F(2, 69) = 3.25, p = 0.04) revealed that pain reports were lower in the active tDCS group (p = 0.02) compared with the natural
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There was a main effect of trial (F(2, 138) = 3.63, p = 0.029), as pain decreased from the pretest to the posttest regardless of group. Males reported lower pain compared with females, as shown by the main effect of sex (F(1, 69) = 7.86, p = 0.006). No other main effects or interactions reached significance.
Exp Brain Res
history group, whereas the difference between the active tDCS group and the placebo group (p = 0.56), and the difference between the placebo group and the natural history group (p = 0.10) were nonsignificant. Pain decreased from the pretest to the posttest, as shown by the main effect of trial (F(2, 138) = 6.35, p = 0.002). There was a sex difference, with males reporting lower pain compared with females (F(1, 69) = 9.84, p = 0.002). No other main effects or interactions reached significance. Pain intensity ratings at 47 °C Males reported lower pain compared with females, as shown by the main effect of sex (F(1, 69) = 5.06, p = 0.03). The main effect of trial was significant (F(2, 138) = 6.96, p = 0.001), with lower pain reports from the pretest to the posttest. The interaction trial by group was significant (F(4, 138) = 7.19, p = 0.0003). Fisher’s LSD test revealed lower pain reports in the placebo tDCS group compared with the natural history group (p = 0.02) and lower pain reports in the active tDCS group compared with the natural history group (p = 0.049) during treatment. In the posttest, pain reports in the natural history group were higher compared with the active tDCS group (p = 0.002) and higher compared with the placebo tDCS group (p = 0.027). No other contrast for the interaction trial by group reached significance, and no other main effect or interaction was significant in the 47 °C condition. See Fig. 2 for pain data in each temperature condition. Pain thresholds Pain thresholds increased from the pretest to the posttest regardless of group (F(1, 69) = 15.40, p = 0.0002). No other main effects or interactions were significant. Treatment effects on pain intensity Treatment effects were calculated as pretest–posttest pain ratings for each pain condition (43, 45 and 47 °C). For each temperature condition, a univariate GLM with treatment effect as the dependent variable was performed to display significant predictors for the pain change due to the experimental procedure. Group and sex of the participant were entered as factors. The results showed no significant effects in the treatment effect data for 43 °C. In the 45 °C condition, there was a main effect of group (F(2, 71) = 3.69, η2 = 0.10 95 % CI 0.01–0.22, p = 0.029), with larger treatment effect in the tDCS group compared with the natural history group (η2 = 0.10 95 % CI 0.01–0.26, p = 0.009). In the treatment effect data for the 47 °C condition, there was a main effect of group (F(2, 71) = 10.21, η2 = 0.22 95 % CI 0.07–0.37, p = 0.001), with higher pain reduction in the tDCS group compared with both the natural history group
Fig. 2 Pain intensity ratings (0–100) obtained at COVAS for a 43 °C, b 45 °C and c 47 °C. Error bars denote standard error of the mean (SEM)
(η2 = 0.33 95 % CI 0.12–0.50, p
Research Article
The effect of transcranial direct current stimulation on experimentally induced heat pain Per M. Aslaksen · Olena Vasylenko · Asbjørn J. Fagerlund
Received: 29 October 2013 / Accepted: 13 February 2014 © Springer-Verlag Berlin Heidelberg 2014
Abstract Transcranial direct current stimulation (tDCS) is a non-invasive neuromodulatory technique that can affect human pain perception. Placebo effects are present in most treatments and could therefore also interact with treatment effects in tDCS. The present study investigated whether short-term tDCS reduced heat pain intensity, stress, blood pressure and increased heat pain thresholds in healthy volunteers when controlling for placebo effects. Seventyfive (37 females) participants were randomized into three groups: (1) active tDCS group receiving anodal tDCS (2 mA) for 7 min to the primary motor cortex (M1), (2) placebo group receiving the tDCS electrode montage but only active tDCS stimulation for 30 s and (3) natural history group that got no tDCS montage but the same pain stimulation as the active tDCS and the placebo group. Heat pain was induced by a PC-controlled thermode attached to the left forearm. Pain intensity was significantly lower in the active tDCS group when examining change scores (pretest– posttest) for the 47 °C condition. The placebo group displayed lower pain compared with the natural history group, displaying a significant placebo effect. In the 43 and 45 °C conditions, the effect of tDCS could not be separated from placebo effects. The results revealed no effects on pain thresholds. There was a tendency that active tDCS reduced stress and systolic blood pressure, however, not significant. In sum, tDCS had an analgesic effect on high-intensity P. M. Aslaksen (*) · O. Vasylenko · A. J. Fagerlund Department of Psychology, Faculty of Health Sciences, University of Tromsø, 9037 Tromsö, Norway e-mail: [email protected] URL: http://www.uit.no A. J. Fagerlund Department of Surgery and Anaesthesia, University Hospital North Norway, Tromsö, Norway
pain, but the effect of tDCS could not be separated from placebo effects for medium and low pain. Keywords tDCS · Pain · Placebo effect · Emotions · Experimental pain
Introduction Transcranial direct current stimulation (tDCS) is a noninvasive method for brain stimulation and a promising tool for treatment of chronic pain. The technique relies on electrical modulation of resting membrane potentials in cerebral neurons (Nitsche and Paulus 2000, 2001), thus changing the endogenous excitability of neural circuits (Mylius et al. 2012a). The exact mechanism of analgesic effect is, however, not yet completely understood (Fregni and Pascual-Leone 2007). The number of tDCS studies on chronic pain is still limited, but existing evidence suggests that tDCS has a therapeutic analgesic potential (O’Connell et al. 2010). However, the methodological quality and the small number of studies make it difficult to be conclusive about the analgesic effects of tDCS (O’Connell et al. 2010). Additionally, studies on the effect of tDCS on experimentally induced pain have shown conflicting results. In several studies, beneficial effects on experimental pain have been found with both anodal (Boggio et al. 2008; Mylius et al. 2012b) and cathodal (Csifcsak et al. 2009) tDCS, whereas one study found no effects of either anodal or cathodal stimulation (Jurgens et al. 2012). The divergence in effect across studies might be due to differences in factors such as electrode placement, electrode size, current intensity, duration of tDCS stimulation and methods used for pain induction and pain assessment.
13
Interestingly, so far no tDCS study has included a natural history condition or a no-treatment group to control for placebo effects in tDCS treatment. Placebo effects are present in almost all medical treatments (Enck et al. 2008), and tDCS procedures are probably not an exception. All published tDCS studies on experimental pain have employed a sham/placebo control group/condition, but this is not sufficient for the estimation of placebo effects (Benedetti et al. 2003). The difference between the placebo group and the no-treatment/natural history group represents the real psychobiological placebo response (Fields and Levine 1984). Thus, the inclusion of a group receiving no tDCS montage, but the same pain stimulation as the treatment and sham/placebo groups is necessary to investigate the placebo effect in tDCS treatment. Furthermore, so far no experimental tDCS study has tested whether emotional factors affect the outcome of tDCS procedures. Similarly to other pain treatments, it can be expected that emotional activation can influence the effect of tDCS. Specifically, negative emotions might reduce the efficacy of analgesic treatments and procedures, e.g. Rhudy and Meagher (2000), Varelmann et al. (2010) and Lyby et al. (2011), but it is still uncertain how such factors might influence the tDCS analgesic effects. The present experiment tested whether anodal tDCS delivered to the primary motor cortex (M1) reduced heat pain intensity and increased heat pain thresholds in healthy volunteers. We hypothesized that active tDCS would reduce heat pain intensity and increase heat pain thresholds, and we expected that the group receiving placebo tDCS would display a significant placebo effect compared with the natural history group receiving the same pain stimulation, but no tDCS montage or stimulation.
Methods Subjects A total of 75 healthy volunteers (37 females) with mean age of 23.52 years (standard deviation = 5.71) were included in the study. Subjects were recruited at the campus of the University of Tromsø, Norway. All participants signed an informed consent form that stated that they had no medical history of any serious diseases or injuries. Participants were told that they would take part in an experiment that tested the physiological and subjective effects of tDCS on heat pain. All participants received a gift card (worth 200 NOK, approx. 26 Eur). The study was approved by the Regional Committee for Medical Research Ethics, North Norway, project number 2010-2256.
13
Exp Brain Res
Design Participants were randomized into three different groups: (1) active tDCS where subjects received active anodal tDCS for 7 min, (2) placebo tDCS where subjects received the tDCS montage of the same duration as the active group, but stimulation was terminated after 30 s and (3) natural history group receiving the same pain procedure as the other groups, but no montage of the tDCS equipment. All groups received the same pain stimulation procedure in three blocks: pretest, treatment and posttest. Each stimulation block consisted of three pain stimuli of different temperatures that were presented in the same order for each block: 43, 45 and 47 °C. Thus, the design of the study was a mixed 3 group (between subjects) by 3 test (within subjects) design. In order to minimize the novelty effect of pain stimulation, a familiarization block consisting of three pain stimuli was administered before the experimental procedure. The experiment was run double-blind in the two groups receiving the tDCS electrode montage. Blinding was possible due to a built-in software feature in the tDCS stimulator that allows preprogramming of active or sham stimulation, stimulus intensity, duration and onset. The sample size was chosen on the basis on the few previous published studies employing heat pain in combination with tDCS. To ensure satisfactory statistical power, we included a higher number of subjects compared with studies that found both beneficial (Antal et al. 2008; Csifcsak et al. 2009; Mylius et al. 2012b) and limited/no effects (Borckardt et al. 2012; Jurgens et al. 2012) of tDCS on experimentally induced heat pain. Pain stimuli PC-controlled pain and sensory evaluation system (Pathway; Medoc Ltd., Ramat Yishai, Israel) with a 30 × 30 mm aluminium thermode was used. The thermode has a heating rate of 10 °C/s and is cooled by a Peltier device at the rate of 10 °C/s. When applied to the arm, the thermode had a baseline temperature of 32 °C. The duration of pain stimulation was 20 s at the intended temperature for each stimulus. During the familiarization block, the first stimulus was 42 °C, the second 45 °C and the third 47 °C. Interstimulus intervals during familiarization block were 60 s after the first stimulus (42 °C) and 120 s after the second stimulus (45 °C). Interstimulus intervals during pretest and treatment were 240 s after the first stimulus (43 °C) and 300 s after the second stimulus (45 °C). Interstimulus intervals during posttest were 60 s after the first stimulus (43 °C) and 120 s after the second stimulus (45 °C). The intensity of each stimulus was rated continuously as the stimulus was being delivered. In the pain threshold measures, the thermode heated from baseline of 32 °C at the rate of 0.5 °C/s and until the
Exp Brain Res
participant reported pain sensation by clicking on a computer mouse. After this, the temperature returned to baseline at the rate of 6 °C/s. Each threshold measurement consisted of six trials.
Participants were asked to rate their current state on an 11-point NRS for each adjective pair, and responses were recorded by the experimenter. Blood pressure was measured by an automatic blood pressure monitor (BP A100 Plus, Microlife, Switzerland).
tDCS Procedure A Neuroconn DC stimulator Plus (Neuroconn, Germany) was used for transcranial DC stimulation. Current was transferred from the stimulator to the scalp by a pair of surface sponge electrodes (35 cm2) soaked in saline. Conductive paste (Ten20 Conductive EEG Paste, USA) was applied to the sponges and to the electrode sites on the scalp. Impedance was continuously monitored and kept below 5 Ω. Participants received either anodal or placebo stimulation of M1. In both the active and the placebo conditions, the anode electrode was placed over C4 according to EEG 10–20 system and the cathode electrode over the contralateral supraorbital area. This electrode position has been shown to modulate excitability of M1 (Nitsche and Paulus 2001). For anodal stimulation, a constant current of 2 mA intensity was applied for 420 s (7 min). The duration of the tDCS stimulation was based on previous studies that have found excitability changes after 5 min (Nitsche and Paulus 2001; Boggio et al. 2008), and to maximize the intervention, the duration was set to 7 min. At the beginning and end of stimulation, current was ramped up and down, respectively, for 20 s in order to minimize discomfort. In the placebo group, stimulation stopped automatically after 30 s. As neither the experimenter nor the participants knew whether the applied code was active or placebo tDCS, and the nature of stimulation was not revealed in the apparatus display, a double-blind procedure was ensured. Impedance was monitored in the stimulator display through the session. During active tDCS, the true impedance was displayed. During placebo tDCS stimulation, a nominal value not related to the stimulation was displayed, thus making the visual output in the apparatus similar in both conditions. Most participants in the placebo group reported the same initial itching as did participants in the active group, but stimulation for 30 s was not considered sufficiently prolonged for excitability changes to occur (Nitsche and Paulus 2000). Measurements Pain intensity was measured by a computerized visual analogue scale (COVAS). Recorded pain intensity ranges from 0 (no pain) to 100 (most intense pain imaginable). Subjective stress was measured by two adjective pairs from the Stress/Arousal Adjective Check List (SACL) (Mackay et al. 1978), similarly to previous studies (Aslaksen and Flaten 2008; Aslaksen et al. 2011).
Upon meeting in the laboratory, participants were informed about the purpose and nature of the study and given the opportunity to ask questions about the study. Written consent was obtained from the participants. Participants were seated in a comfortable reclining chair inside a steel cubicle shielded for electromagnetic disturbances. After the initial measurement of blood pressure and subjective stress, the thermode was attached to the participant’s left volar forearm and the familiarization block began. After this, the thermode was moved to a different site of the arm. Then, following a 3-min break, participants received the next block of stimuli, the pretest. After the pretest, there was a 6-min break for the natural history group. For the active and placebo groups, tDCS apparatus was set up and the electrodes were attached to the participant’s scalp. For the active and placebo groups, the experimenter started the tDCS apparatus 3 min before the first stimulus in the treatment block was given. Thus, during this block, participants in the active group received tDCS, while participants in the natural history group received painful stimulation only, and for the placebo group, tDCS ended 2.5 min before the first stimulus in the treatment block was given. Blood pressure and subjective stress were measured again following the treatment block after these measurements ended, the tDCS apparatus was removed. Then, the last block of stimuli, the posttest, was delivered. After the posttest, the final blood pressure and subjective stress measurements were obtained. At the end of the session, participants were asked to report any side effects or discomfort during the treatment and received a gift card as compensation for their participation (see Fig. 1 for an overview of the procedure). The total duration of the session was approximately 60 min. Statistical analyses Statistical analyses were performed with IBM SPSS v. 21 (IBM SPSS, USA). The normal distribution of data was tested with the Kolmogorov–Smirnov test in SPSS. There was no significant deviation from a normal distribution in any of the reported outcome data. Repeated-measures general linear ANOVAs with 3 Group (tDCS, placebo tDCS and natural history) by 3 trial (pretest, treatment and posttest) as within-subject factors and participant sex as between-groups factors were employed for pain, blood pressure and stress measures. All significant interactions
13
Exp Brain Res
Fig. 1 Overview of the procedure. *Blood pressure and subjective stress measurement. NH natural history group, An anodal tDCS group, Pa placebo tDCS group. /// tDCS
Table 1 Pain intensity, heat pain threshold, stress and blood pressure (BP) data for pretest, treatment and posttest in all groups
Total n = 75 SEM standard error of mean
Natural history
Placebo tDCS
tDCS
Mean
SEM
Mean
SEM
Mean
SEM
Pain intensity pretest at 43 °C Pain intensity treatment at 43 °C Pain intensity posttest at 43 °C Pain intensity pretest at 45 °C Pain intensity treatment at 45 °C Pain intensity posttest at 45 °C Pain intensity pretest at 47 °C Pain intensity treatment at 47 °C
25.04 25.95 23.17 38.58 39.71 38.38 66.79 68.88
4.09 3.65 2.92 3.50 4.40 5.01 3.90 4.51
22.73 16.42 18.19 34.62 31.31 26.81 62.81 55.00
3.25 2.68 3.97 4.16 3.89 4.76 4.43 5.16
23.68 15.24 17.72 34.56 27.92 21.88 63.52 56.36
3.35 2.46 3.29 3.69 3.43 4.05 3.97 4.53
Pain intensity posttest at 47 °C Pain threshold pretest Pain threshold posttest Stress pretest Stress treatment Stress posttest BP pretest BP treatment BP posttest Female/male
71.04 44.74 °C 46.17 °C 3.15 2.29 2.21 133/82 126/79 128/78 11/13
4.29 .55 .32 .19 .22 .23 1.16/1.74 1.98/1.19 1.62/1.49
56.89 44.81 °C 45.86 °C 3.04 2.33 1.78 130/82 121/78 122/77 15/11
5.66 .50 .19 .26 .46 .38 3.24/1.66 2.36/1.58 2.45/1.41
49.64 44.84 °C 45.60 °C 2.44 1.52 1.19 127/78 119/75 121/75 11/14
4.87 .57 .38 .31 .33 .27 2.25/1.82 2.27/1.76 2.11/1.58
Age
21.04
.30
23.11
.72
23.20
1.12
were followed up with contrast analyses employing Fisher’s LSD statistics. Univariate general linear ANOVAs were used to examine predictors for treatment effect of tDCS on pain, stress and systolic blood pressure. Measures of effect sizes (η2) with 95 % confidence intervals (CI) are presented for significant results in treatment effect data. A significance level of 0.05 was employed for all analyses.
Pain intensity ratings at 43 °C
Results
Pain intensity ratings at 45 °C
Descriptive data are presented in Table 1. There were no significant group differences in the pretest data for any measure, all p values >0.10.
The significant main effect of group (F(2, 69) = 3.25, p = 0.04) revealed that pain reports were lower in the active tDCS group (p = 0.02) compared with the natural
13
There was a main effect of trial (F(2, 138) = 3.63, p = 0.029), as pain decreased from the pretest to the posttest regardless of group. Males reported lower pain compared with females, as shown by the main effect of sex (F(1, 69) = 7.86, p = 0.006). No other main effects or interactions reached significance.
Exp Brain Res
history group, whereas the difference between the active tDCS group and the placebo group (p = 0.56), and the difference between the placebo group and the natural history group (p = 0.10) were nonsignificant. Pain decreased from the pretest to the posttest, as shown by the main effect of trial (F(2, 138) = 6.35, p = 0.002). There was a sex difference, with males reporting lower pain compared with females (F(1, 69) = 9.84, p = 0.002). No other main effects or interactions reached significance. Pain intensity ratings at 47 °C Males reported lower pain compared with females, as shown by the main effect of sex (F(1, 69) = 5.06, p = 0.03). The main effect of trial was significant (F(2, 138) = 6.96, p = 0.001), with lower pain reports from the pretest to the posttest. The interaction trial by group was significant (F(4, 138) = 7.19, p = 0.0003). Fisher’s LSD test revealed lower pain reports in the placebo tDCS group compared with the natural history group (p = 0.02) and lower pain reports in the active tDCS group compared with the natural history group (p = 0.049) during treatment. In the posttest, pain reports in the natural history group were higher compared with the active tDCS group (p = 0.002) and higher compared with the placebo tDCS group (p = 0.027). No other contrast for the interaction trial by group reached significance, and no other main effect or interaction was significant in the 47 °C condition. See Fig. 2 for pain data in each temperature condition. Pain thresholds Pain thresholds increased from the pretest to the posttest regardless of group (F(1, 69) = 15.40, p = 0.0002). No other main effects or interactions were significant. Treatment effects on pain intensity Treatment effects were calculated as pretest–posttest pain ratings for each pain condition (43, 45 and 47 °C). For each temperature condition, a univariate GLM with treatment effect as the dependent variable was performed to display significant predictors for the pain change due to the experimental procedure. Group and sex of the participant were entered as factors. The results showed no significant effects in the treatment effect data for 43 °C. In the 45 °C condition, there was a main effect of group (F(2, 71) = 3.69, η2 = 0.10 95 % CI 0.01–0.22, p = 0.029), with larger treatment effect in the tDCS group compared with the natural history group (η2 = 0.10 95 % CI 0.01–0.26, p = 0.009). In the treatment effect data for the 47 °C condition, there was a main effect of group (F(2, 71) = 10.21, η2 = 0.22 95 % CI 0.07–0.37, p = 0.001), with higher pain reduction in the tDCS group compared with both the natural history group
Fig. 2 Pain intensity ratings (0–100) obtained at COVAS for a 43 °C, b 45 °C and c 47 °C. Error bars denote standard error of the mean (SEM)
(η2 = 0.33 95 % CI 0.12–0.50, p
