Neuroscience Letters 589 (2015) 153–158
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Research article
Transcutaneous spinal DC stimulation reduces pain sensitivity in humans C.H. Meyer-Frießem a,1 , L.M. Haag b,1 , T. Schmidt-Wilcke b , W. Magerl c , E.M. Pogatzki-Zahn d , M. Tegenthoff b , P.K. Zahn a,∗ a Department of Anaesthesiology, Intensive Care Medicine, Palliative Care Medicine and Pain Management, Medical Faculty of Ruhr-University Bochum, Berufsgenossenschaftliches Universitätsklinikum Bergmannsheil GmbH Bochum, Bürkle-de-la-Camp-Platz 1, 44789 Bochum, Germany b Department of Neurology, Berufsgenossenschaftliches Universitätsklinikum Bergmannsheil GmbH Bochum, Ruhr University Bochum, Bürkle-de-la-Camp-Platz 1, 44789 Bochum, Germany c Department of Neurophysiology, Center of Biomedicine and Medical Technology, Medical Faculty Mannheim, Ruprecht-Karls-University Heidelberg, Ludolf-Krehl-Str. 13, 68167 Mannheim, Germany d Department of Anaesthesiology, Intensive Care and Pain Medicine, University Hospital of Muenster, Albert-Schweitzer-Campus 1 (Building A1), 48149 Münster, Germany
h i g h l i g h t s • Anodal tsDCS reduces pain sensitivity to painful mechanical pinprick stimuli. • This is the first evidence that tsDCS sensory effects last longer than 30 min. • Anodal tsDCS had no effect on pain sensitivity to single electrical pulses.
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Article history: Received 17 November 2014 Received in revised form 2 January 2015 Accepted 9 January 2015 Available online 14 January 2015 Keywords: tsDCS Transcutaneous stimulation Perception Pain Direct current stimulation Sensitivity
a b s t r a c t Non-invasive approaches to pain management are needed to manage patient pain escalation and to providing sufficient pain relief. Here, we evaluate the potential of transcutaneous spinal direct current stimulation (tsDCS) to modulate pain sensitivity to electrical stimuli and mechanical pinpricks in 24 healthy subjects in a sham-controlled, single-blind study. Pain ratings to mechanical pinpricks and electrical stimuli were recorded prior to and at three time points (0, 30, and 60 min) following 15 min of anodal tsDCS (2.5 mA, “active” electrode centered over the T11 spinous process, return electrode on the left posterior shoulder). Pain ratings to the pinpricks of the highest forces tested (128, 256, 512 mN) were reduced at 30 min and 60 min following anodal tsDCS. These findings demonstrate that pain sensitivity in healthy subjects can be suppressed by anodal tsDCS and suggest that tsDCS may provide a non-invasive tool to manage mechanically-induced pain. © 2015 Published by Elsevier Ireland Ltd.
1. Introduction Neuromodulation by means of direct currents has offered a non-invasive way to alter neural excitability [1–3]. Recently, noninvasive application of direct currents to the spinal cord, termed transcutaneous spinal direct current stimulation (tsDCS), has been
Abbreviations: EPS, electrical pain sensitivity; EDT, electrical detection threshold; MPS, mechanical pain sensitivity; MPT, mechanical pain thresholds; NRS, numerical rating scale; tsDCS, transcutaneous spinal direct current stimulation. ∗ Corresponding author. Tel.: +49 234302/6825. E-mail address: [email protected] (P.K. Zahn). 1 Both authors contributed equally. http://dx.doi.org/10.1016/j.neulet.2015.01.029 0304-3940/© 2015 Published by Elsevier Ireland Ltd.
employed with promising effects on neurophysiological processing [4,5]. In tsDCS, direct current is applied transcutaneously via one ‘active’ electrode placed over the spine and a second return electrode over a neutral body part (i.e., where no neuromodulatory effects are expected that could influence the outcome measures). Effects of tsDCS applied at the lower thoracic vertebral level have been described for the motor [6–8], somatosensory [9], and nociceptive [10,11] systems with encouraging clinical translation in recovering motor function in spinal cord injury patients [12] and reducing pain in restless leg syndrome (RLS [13]). In particular, anodal tsDCS anodal tsDCS amplified the motor component of the H-reflex in healthy subjects by reducing post-activation depression [6] and also shifted the H-reflex stimulus-response curve to
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the left, indicating increased excitability [7]. For nociception and pain, anodal tsDCS suppressed both the nociceptive component of the lower limb flexion reflex [10] and the N1 and N2 component amplitudes of foot-laser evoked potentials (LEPs [11]), as well as reduced pain sensitivity to cold stimuli [11]. Thus, anodal tsDCS has been shown to affect the pain system on a spinal, cortical, and perceptual level. (Please see [5] for tsDCS review.) Perceptual effects following anodal tsDCS have, however, been limited to cold pain, where anodal tsDCS proved beneficial in healthy subjects [11], and to symptom ratings in RLS patients, where it reduced their subjective rating of their instantaneous symptom severity [13]. In an effort to further investigate the potential of anodal tsDCS to modulate pain in particular, we therefore, tested the effects of 15 min of thoracically-applied anodal tsDCS on subjective pain ratings given to mechanical and electrical stimuli particularly focused on small-diameter, thinly-myelinated A-delta fibers, associated with “first pain”. Since LEPs and cold pain, A-delta fiber-dependent measures, were suppressed by anodal tsDCS, we expected that anodal tsDCS would likewise reduce pain ratings to pinpricks and electrical stimuli, corresponding to a suppression of pain sensitivity. 2. Material and methods 2.1. Subjects and study design The study was conducted on 24 healthy right-handed male subjects aged 20–33 years (mean 25 ± 3) after approval from the local Ethics Committee of Ruhr-University Bochum (No. 4549-12). Each subject provided written informed consent according to the Declaration of Helsinki and was introduced to the procedures before the baseline measurement. Subjects with relevant medical conditions (e.g., diabetes, seizure, migraine, pacemaker, obesity) or use of medication were excluded. All subjects participated in one session, were assigned to either Group A (anodal tsDCS, n = 12) or Group S (sham tsDCS, n = 12), and were blind to the stimulation group and polarity. The session consisted of 5 blocks: B (Baseline), tsDCS, T0, T30, and T60 (at 0, 30, and 60 min following tsDCS offset, respectively, (Supplementary Fig. 1). Each test block lasted 15 min and tested electrical detection threshold (EDT), mechanical pain threshold (MPT), mechanical pain sensitivity (MPS) and electrical pain sensitivity (EPS), in that order. MPS and EPS measurements were interleaved with one another. Details for each test and for tsDCS are provided below. No formal sample size analysis was performed on the basis of this study being an investigative analysis. Rather, we based our recruitment on comparable tsDCS study sample sizes, which are typically below fifteen subjects. 2.2. tsDCS TsDCS was applied using a constant current battery-driven stimulator (neuroConn GmbH, Ilmenau, Germany) through a pair of saline-soaked sponge electrodes (7 × 5 cm) while the subject was lying comfortably on his right side. Subjects were instructed to rest quietly and limit movement for the stimulation period. One electrode was centered over the spinous processes of the eleventh thoracic vertebra (T10–T12) and the other on the left dorsal shoulder, as has been described previously [9]. Polarity of stimulation refers to the electrode over the spinal process. During the tsDCS block of the experimental session, one 15min period of either anodal or sham tsDCS was applied. For anodal stimulation, +2.5 mA was applied for 15 min [6,7,9], resulting in a current density of 0.071 mA/cm2 and a total charge of 63.9 mC/cm2 , both of which are below the threshold for tissue damage [14].
Sham stimulation was applied using −1.5 mA for 45 s to mimic the initial tingling sensation while avoiding any stimulation-induced effects. Both groups were told that tsDCS stimulation would last for 15 min. Two trained investigators (CMF, LMH) performed the measurements. 2.3. Mechanical testing A selection of quantitative sensory testing (QST) measurements from a standardized test battery [15] was used for mechanical testing. To avoid interactions between subsequent test stimuli, mechanical probing of a 1 cm area surrounding the electrode was applied in a circular manner. All subjects closed their eyes during the assessment and rated each stimulus immediately following its presentation to maintain focus on the presented stimuli. MPS - Mechanical pain sensitivity was assessed using standardized punctuate probes (PinPrick, MRC-Systems, Heidelberg, Germany) with 0.25 mm-diameter tip to stimulate cutaneous nociceptors [15–19]. Forces of 8, 16, 32, 64, 128, 256 and 512 mN were presented once per run in a pseudo-randomized order, as provided by the QST protocol [15]. Each run is pseudo-randomized separately and a total of 10 runs (i.e., a total of 5 runs to the right leg, 5 runs to the left leg, alternating between runs) make up a block. All blocks used the same pseudo-randomization. Each subject received 5 runs per leg, alternating between the right and left leg, and was asked to rate pain associated with each stimulus using the numerical rating scale (NRS; 0–100). A rating of “0” indicated no pain; a rating of “100” indicated the worst pain imaginable. MPT - Mechanical pain threshold was tested using the seven previously described pinprick stimuli. Forces were presented in ascending and descending order (up-and-down rule) to identify suprathreshold and subthreshold stimulus intensities. The final threshold was determined by the geometric mean of five just suprathreshold and five just subthreshold stimulus intensities [15,19–21]. Reference data from the foot of 180 healthy subjects defined 73 mN to be the average pain threshold to pinpricks in young healthy males [22], i.e., on average, young healthy males rate pinpricks at or above 73 mN as painful, and those pinpricks below 73 mN as non-painful. Since we were specifically interested in anodal tsDCS’s effects on explicitly painful stimuli, pinpricks were categorized based on this population data as either suprathreshold (128, 256, 512 mN) or subthreshold (8, 16, 32, 64 mN), here defined as MPS128–512 mN and MPS8–64 mN , respectively. 2.4. Electrical testing Bilateral electrical test stimuli were applied 5 cm proximal to the knee using a custom-built multi-pin electrode following a previously-established paradigm (DS7A, Digitimer, UK) [21,23]. To achieve spatial summation within the receptive field of spinal cord neurons, 12 of these electrodes were mounted in a small circular plastic frame (attached to the skin by double-adhesive tape) and were stimulated simultaneously, which delivers a very high local current density at very low stimulus currents. Owing to the high impedance of the skin surface and rapid breakdown of current density in deeper tissue layers, this electrode has a high selectivity for nociceptive primary afferents located in superficial epidermal layers and avoids excitation of mechanoreceptive axons in subepidermal skin layers [24,25]. Accordingly, electrical stimuli delivered through this electrode have a predominantly “pricking” pain character already at threshold and over a high dynamic range of suprathreshold stimuli [23,25,26]. This “prickling” sensation has been attributed to activation of A-delta fibers such that pinpricks are thought to particularly test mechanosensitive A-delta fiber-mediated percept [27]. A strap electrode attached around the
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ipsilateral upper leg served as the anode. Two different measures of electro-cutaneous sensitivity were used: EPS – Single electrical pulses (3.0 mA, 2 ms pulse width) were given, which were rated on the NRS scale (0–100). Subjects were warned shortly before (≤1 s) the presentation of an EPS pulse. EDT – Electrical detection threshold was determined using single 2 ms electrical pulses in an ascending and descending order of stimulus intensity to determine three just-suprathreshold and three just-subthreshold stimulus intensities (up-and-down rule; [20]).
2.5. Statistical analysis All ratings and thresholds were transformed logarithmically (base 10) in order to achieve secondary normal distribution [15]. A small constant of 0.1 was added to all pain ratings (MPS, EPS) to avoid a loss of zero-values [18] whereas no constant was added to thresholds (MPT, EDT) before log-transformation. Logtransformed scores (both pain ratings and thresholds) were then normalized to baseline via subtraction to assess the overall effect of tsDCS. The average of scores for left and right legs was entered into a two-way ANOVA with main factors “stimulation” (independent measures, 2 levels: anodal and sham), and “post time point” (repeated measures, 3 levels: T0, T30, T60). Group differences at specific time points were further assessed using independent t-tests. All data analyses were carried out using STATISTICA (StatSoft, Inc. v10), and statistical significance was set at p < .05. Log
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differences (mean ± SEM) were re-transformed for the results and figures. 3. Results There were no differences in age, weight or clinical conditions of subjects between the sham and anodal groups. TsDCS procedures were well-tolerated by all participants; all reported an initial tingling sensation under the electrode placed over the spine. None complained of painful sensations during tsDCS. All subjects in Group A and 11 of 12 in Group S reported that they felt the stimulation and 11 of 12 from both Group A and Group S guessed they received ‘real’ and not placebo stimulation. 3.1. Heavy mechanical stimuli All subjects in the study rated the 256 mN and 512 mN pinprick as painful in more than 50% of the 5 stimulus presentations prior to tsDCS. Anodal tsDCS group’s pain incidence shown in (Supplementary Fig. 2). A main effect of stimulation was seen for pain ratings to heavy mechanical stimuli (MPS128–512 mN ) following anodal tsDCS (F1,22 = 5.83, p = .02; Fig. 1b). Further investigation of individual pinpricks identified a significant stimulation effect on pain ratings to the 512 mN pinprick (F1,22 = 6.01, p = .02; Fig. 1c) and strong trends toward a stimulation effect on pain ratings to the 128 mN pinprick (F1,22 = 3.37, p = .08) and 256 mN (F1,22 = 4.16, p = .05). There was
Fig. 1. Long-lasting effects of tsDCS on heavy pinpricks. Average pain ratings to light pinpricks (8–64 mN) increased over time but were unaffected by anodal stimulation (a) whereas pain ratings to heavy pinpricks (128–512 mN, (b) were significantly decreased following anodal tsDCS (black) as compared to sham tsDCS (gray). (c) Average changes in pain ratings for individual pinpricks for anodal (black bars) and sham (white bars) groups with the individual ratings for the 512 mN pinpricks. Graphs show re-transformed normalized means ± SEM. *p < .05.
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no interaction between stimulation and time (F2,44 = 0.03, p = ns). Specifically, pain ratings to heavy pinpricks (MPS128–512 mN ) following anodal tsDCS were 8% below baseline at T0 (−0.038 ± 0.035 log10 units), 13% at T30 (−0.061 ± 0.036 log10 units), and 13% at T60 (−0.062 ± 0.047 log10 units). This was 21% (p = .06), 28% (p = .03), and 34% (p = .04) below the changes in pain ratings following sham stimulation at T0, T30 and T60, respectively. For the 512 mN pinprick, t-tests revealed significantly reduced pain ratings in the anodal group compared to the sham group to the 512 mN pinprick at all time points (T0: t = −2.23, p < .05; T30: t = −2.23, p < .05; T60: t = −2.10, p < .05). 3.2. Light mechanical stimuli No main effect of stimulation was shown for pain ratings to lighter mechanical stimuli (MPS8–64 mN ; F1,22 = 0.63, p = ns; Fig. 1a); however, there was a significant main effect of time (F2,44 = 4.86, p = .01). Further investigation identified pain ratings to 16 mN and 32 mN pinpricks to be significantly increased over time (F2,44 = 5.07, p = .01 and F2,44 = 3.86, p = .03, respectively). Changes in pain ratings to MPS8–64 mN were as follows: anodal change: 0.017 ± 0.033 log10 units at T0, 0.056 ± 0.033 log10 units at T30, 0.096 ± 0.044 log10 units at T60; sham change: 0.062 ± 0.033 log10 units at T0, 0.094 ± 0.046 log10 units at T30, 0.128 ± 0.041 log10 units at T60. Mechanical pain thresholds were not significantly affected by stimulation (F1,22 < 0.01, p = ns) or by time (F2,44 = 1.48, p = ns). Changes in pain ratings to MPT were as follows: anodal change: −0.045 ± 0.049 log10 units at T0, −0.056 ± 0.073 log10 units at T30, −0.043 ± 0.089 log10 units at T60; sham change: −0.051 ± 0.033 log10 units at T0, −0.082 ± 0.043 log10 units at T30, −0.079 ± 0.039 log10 units at T60; (Supplementary Fig. 3c) 3.3. Electrical stimuli All participants rated the 3.0 mA stimulus as painful both prior to and following tsDCS. A significant main effect of time was shown for EDT (F2,44 = 4.60, p = .02) and EPS (F2,44 = 6.37, p = .004) but there was no main effect of stimulation for either EDT (F1,22 = 0.36, p = ns) or EPS (F1,22 = 1.56, p = ns). EDT decreased over the measurement period as follows: anodal change: −0.077 ± 0.056 log10 units at T0, 0.142 ± 0.045 log10 units at T30, 0.184 ± 0.056 log10 units at T60; sham change: −0.145 ± 0.049 log10 units at T0, 0.190 ± 0.047 log10 units at T30, 0.184 ± 0.045 log10 units at T60; (Supplementary Fig. 3b). Pain ratings to EPS were decreased 12% at T0 (Anodal: −0.072 ± 0.025 log10 units; Sham: −0.015 ± 0.019 log10 units; p = .09), 10% at T30 (anodal: −0.115 ± 0.047 log10 units; Sham: −0.060 ± 0.035 log10 units; p = ns), and 12% at T60 (anodal: −0.135 ± 0.045 log10 units; Sham: −0.067 ± 0.040 log10 units; p = ns) more following anodal stimulation than following sham stimulation (Supplementary Fig. 3a). 4. Discussion This study investigated the effect of tsDCS on pain sensitivity to cutaneous stimuli. We were able to show that anodal tsDCS significantly decreased sensitivity to painful mechanical stimuli and moreover that the effect was present throughout the one hour post-tsDCS measurement period. Additionally, we could show that anodal effects were limited to pain evoked by heavy mechanical pinpricks (128–512 mN). This represents the first presentation of a long-lasting pain reduction following anodal tsDCS. Mechanical pain in healthy subjects is mediated by smalldiameter A-delta and C fiber nociceptive afferents that respond to mechanical stimuli. While the pinpricks tested (i.e., 8–512 mN) have all been shown to evoke responses in both types of nociceptive fibers [28–31], pain to these pinpricks is typically felt to pinpricks
over 73 mN [22]. As in the population data, all but two participants in this study rated the 128, 256, and 512 mN as painful. Since sensitivity to only these painful pinpricks was altered by anodal tsDCS, we postulate that the effects of tsDCS on high but not low-threshold pain are likely due to differential effects on high-threshold but not low-threshold nociceptive afferents contributing to pain. This is consistent with previous reports on anodal tsDCS and pain perception. Truini et al. [11], for example, found that anodal stimulation increased cold pain tolerance (i.e., a strong pain stimulus) without affecting cold pain thresholds (i.e., a weak pain stimulus). Thus, it seems that anodal tsDCS may require a certain threshold of stimulus strength, i.e., a certain percentage of activated fibers, to show a sensory effects. Further support for this comes from Cogiamanian et al. [9], who report that anodal tsDCS suppressed SEPs likely via an incomplete anodal block. Here, the authors suggest that tsDCS blocked a portion of the fibers, reducing the SSEP amplitude but not latency, and thereby affected only a portion of the fibers. As in our study, it is unclear by what mechanism the afferents were affected, and moreover which specific fiber sub-type(s) were affected. In this study, we specifically targeted the sharp “pinprick-like” sensation evoked by the pinprick stimuli, which is thought to be mediated by A-delta fibers [27]. Consequently, our results suggest that DC stimulation most likely affected the A-delta fiber-mediated pain percept. Previous studies also support an effect of tsDCS on A-delta fiber-mediated measures, showing that anodal tsDCS suppresses both the RIII component of the lower limb flexion reflex [10] and also laser evoked potentials [11], both of which are mediated by A-delta fibers [32]. Furthermore, anodal tsDCS reduced symptoms of RLS patients [13], who, as the authors note, involves mechanical hyperalgesia [33] (i.e., patients rated pinpricks more painful than controls). Taken together with anodal tsDCS’s suppression of cold pain [11] and to heavy mechanical pinpricks shown here, anodal tsDCS seems to affect pain on the spinal, cortical, and perceptual levels. In order to clarify the specific targets of anodal tsDCS, however, further studies using, for example microneurography or pharmacological targeting, will be needed. Notably, there was no significant reduction in pain sensitivity to high intensity electrical stimuli following anodal tsDCS. This is consistent with the finding that, while anodal tsDCS suppresses a nociceptive reflex, it does not alter pain ratings to the high frequency electrical pulses used to evoke the reflex [10]. Similarly, we find no anodal-induced suppression of sensitivity to painful electrical stimuli, despite the 3.0 mA pulse evoking pain in all subjects. We suspect, that the lack of a significant effect on EPS in our study is, in part, due to the unspecific targeting of electrical stimuli, where the pain evoked by an electrical pulse would consist of a mixture of both mechanosensitive and mechanoinsensitive A-delta fibers. Although it remains possible that C- and A-beta fibers contributed to EPS, it has been shown that A-delta fibers are preferentiallytargeted by the multi-pin electrode [24,25]. Nonetheless, our study, does confirm that anodal tsDCS modulates pain on the perceptual level with a particular effect on mechanical pain. Recently it has been shown that cathodal tsDCS affects motor unit recruitment for up to one hour following tsDCS offset [34]. Our results extend these relatively long-lasting effects to anodal tsDCS, and specifically to pain perception. Up until now, tsDCS effects on sensory measures have been shown to last for up to 30 min. Here we show that anodal tsDCS modulated pain for over one hour, supporting previous findings and encouraging further investigation into longer-lasting effects of tsDCS. 4.1. Limitations While our data show psychophysical effects of anodal tsDCS on pain sensitivity, we cannot identify the level on which and through which mechanism tsDCS acts. Our data support the notion that
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small-diameter fiber pathways were affected by DC stimulation; however, it is unclear whether this was of direct or indirect nature. Recent modeling of tsDCS suggests that current density is highest at and rostral to the level of stimulation [35], and since tsDCS was applied over the T10–T12 vertebral spinous processes, which correspond to the spinal L1–L4 region where afferents of the anterior thigh would enter the spinal cord, the highest current density was most likely around the entry level of the nociceptive afferents. It has been shown using other models of spinal electrical stimulation, that the current that reaches the spinal cord likely first stimulates the posterior roots, followed by the anterior roots, and then the posterior column fibers [36,37]. Thus, the mechanism of the reduction in pain sensitivity seen in our study may be similar to that proposed by these models. Namely, that current reaching the spinal cord may activate dorsal roots, and their subsequent activation of local inhibitory circuits in the superficial layers of the dorsal horn, reduced the pain afferent transmission. Supraspinal effects of tsDCS, however, cannot be excluded. Pain is notably susceptible to cognitive influences [38], and it has been shown that thoracic tsDCS indeed affects cortical potentials [10,11] and even affects distant motor unit recruitment [34]. Thus, it remains likely that supra-spinal effects of anodal tsDCS played a role in the modulation of pain ratings seen here, but it is unlikely this is due to attentional changes since we ensured that subjects actively attended to the presented stimuli with minimal distraction, or due to placebo effects, since almost all subjects from both groups similarly felt the stimulation and guessed that they received real stimulation. Future studies with brain imaging and further advances in computational models will likely shed light on the underlying mechanisms of the DC effects seen thus far. Nonetheless, our data support the notion that anodal tsDCS may be useful in reducing mechanical pain sensitivity. Finally, since our study was single rather than double-blinded, experimenter bias cannot completely be excluded. Nonetheless, the use of scripted directions, calibrated stimuli, and repetitive applications likely minimized any biases, such that it is unlikely that this was the cause of the anodal tsDCS effects. Follow-up studies are strongly encouraged to employ a double-blinded experimental design with a larger cohort. 5. Conclusion This study on healthy subjects shows that anodal tsDCS modulates pain sensitivity. Compared to sham tsDCS, anodal stimulation decreased sensitivity to heavy mechanical pinprick stimuli for at least an hour following stimulation offset. While these results confirm modulatory effects of tsDCS on pain perception in healthy subjects, further testing should be done on sensitized healthy volunteers to determine whether tsDCS should be considered for clinical translation. Authors contribution All authors have read and approved the final manuscript. CMF, LMH – acquired and analyzed data, drafted ethics proposal and manuscript. WM – made critical revisions, assisted in statistical analyses. TSW, EMPZ – made critical revisions. MT, PKZ – made critical revisions, responsible for concept. Acknowledgments None of the authors have potential conflicts of interest to be disclosed. MT and TSW currently receive funding from DFG (SFB874 TP A1, A8). LMH receives a stipend from the International Graduate School of Neuroscience, Ruhr-University Bochum (BoNeuroMed).
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Appendix A. Supplementary data Supplementary data associated with this article can be found, in the online version, at http://dx.doi.org/10.1016/j.neulet. 2015.01.029.
References [1] M.A. Nitsche, W. Paulus, Excitability changes induced in the human motor cortex by weak transcranial direct current stimulation, J. Physiol. 527 (2000) 633–639. [2] M.A. Nitsche, D. Liebetanz, A. Antal, N. Lang, F. Tergau, W. Paulus, Modulation of cortical excitability by weak direct current stimulation-technical safety and functional aspects, Suppl. Clin. Neurophysiol. 56 (2003) 255–276. [3] G. Ardolino, B. Bossi, S. Barbieri, A. Priori, Non-synaptic mechanisms underlie the after-effects of cathodal transcutaneous direct current stimulation of the human brain, J. Physiol. 568 (Pt2) (2005) 653–663. [4] F. Cogiamanian, G. Ardolino, M. Vergari, R. Ferrucci, M. Ciocca, E. Scelzo, S. Barbieri, A. Priori, Transcutaneous spinal direct current stimulation, Front. Psychiatry 3 (2012), http://dx.doi.org/10.3389/fpsyt.2012.00063. [5] A. Priori, M. Ciocca, M. Parazzini, M. Vergari, R. Ferrucci, Transcranial cerebellar direct current stimulation and transcutaneous spinal cord direct current stimulation as innovative tools for neuroscientists, J. Physiol. 592 (Pt16) (2014) 3345–3369. [6] T. Winkler, P. Hering, A. Straube, Spinal DC stimulation in humans modulates post-activation depression of the H-reflex depending on current polarity, Clin. Neurophysiol. 121 (6) (2010) 957–961. [7] J.C. Lamy, C. Ho, A. Badel, R.T. Arrigo, M. Boakye, Modulation of soleus H reflex by spinal DC stimulation in humans, J. Neurophys. 108 (3) (2012) 906–914. [8] J.C. Lamy, M. Boakye, BDNF Val66Met polymorphism alters spinal DC stimulation-induced plasticity in humans, J. Neurophys. 110 (1) (2013) 109–116. [9] F. Cogiamanian, M. Vergari, F. Pulecchi, S. Marceglia, A. Priori, Effect of spinal transcutaneous direct current stimulation on somatosensory evoked potentials in humans, Clin. Neurophysiol. 119 (11) (2008) 2636–2640. [10] F. Cogiamanian, M. Vergari, E. Schiaffi, S. Marceglia, G. Ardolino, S. Barbieri, A. Priori, Transcutaneous spinal cord direct current stimulation inhibits the lower limb nociceptive flexion reflex in human beings, Pain 152 (2) (2011) 370–375. [11] A. Truini, M. Vergari, A. Biasiotta, S. La Cesa, M. Gabriele, G. Di Stefano, C. Cambieri, G. Cruccu, M. Inghilleri, A. Priori, Transcutaneous spinal direct current stimulation inhibits nociceptive spinal pathway conduction and increases pain tolerance in humans, Eur. J. Pain 15 (10) (2011) 1023–1027. [12] M. Hubli, V. Dietz, M. Schrafl-Altermatt, M. Bolliger, Modulation of spinal neuronal excitability by spinal direct currents and locomotion after spinal cord injury, Clin. Neurophysiol. 124 (6) (2013) 1187–1195. [13] A.C. Heide, T. Winkler, H.J. Helms, M.A. Nitsche, C. Trenkwalder, W. Paulus, C.G. Bachmann, Effects of transcutaneous spinal direct current stimulation in idiopathic restless legs patients, Brain Stimul. 7 (5) (2014) 636–642. [14] M.A. Nitsche, L.G. Cohen, E.M. Wassermann, A. Priori, N. Lang, A. Antal, W. Paulus, F. Hummel, P.S. Boggio, F. Fregni, A. Pascual-Leone, Transcranial direct current stimulation: state of the art 2008, Brain Stimul. 1 (3) (2008) 206–223. [15] R. Rolke, W. Magerl, K.A. Campbell, C. Schalber, S. Caspari, F. Birklein, R.D. Treede, Quantitative sensory testing: a comprehensive protocol for clinical trials, Eur. J. Pain 10 (1) (2006) 77–88. [16] J.D. Greenspan, S.L. McGillis, Stimulus features relevant to the perception of sharpness and mechanically evoked cutaneous pain, Somatosens. Mot. Res. 8 (2) (1991) 137–147. [17] W. Chan, D. Bowsher, Weighted needle pinprick sensory thresholds: a simple test of sensory function in diabetic peripheral neuropathy, J. Neurol. Neurosurg. Psychiatry 55 (1) (1991) 56–59. [18] W. Mager, S.H. Wilk, R.D. Treede, Secondary hyperalgesia and perceptual wind-up following intradermal injection of capsaicin in humans, Pain 74 (1998) 257–268. [19] E.A. Ziegler, W. Magerl, R.A. Meyer, R.D. Treede, Secondary hyperalgesia to punctate mechanical stimuli: central sensitization to A-fibre nociceptor input, Brain 122 (1999) 2245–2257. [20] S. Lang, T. Klein, W. Magerl, R.D. Treede, Modality-specific sensory changes in humans after the induction of long-term potentiation (LTP) in cutaneous nociceptive pathways, Pain 128 (3) (2007) 254–263. [21] T. Klein, S. Stahn, W. Magerl, R.D. Treede, The role of heterosynaptic facilitation in long-term potentiation (LTP) of human pain sensation, Pain 139 (3) (2008) 507–519. [22] W. Magerl, E.K. Krumova, R. Baron, T. Tölle, R.D. Treede, C. Maier, Reference data for quantitative sensory testing (QST): refined stratification for age and a novel method for statistical comparison of group data, Pain 151 (3) (2010) 598–605. [23] T. Klein, W. Magerl, H.C. Hopf, J. Sandkühler, R.D. Treede, Perceptual correlates of nociceptive long-term potentiation and long-term depression in humans, J. Neurosci. 24 (2004) 964–971. [24] N. Sha, L.P. Kenney, B.W. Heller, A.T. Barker, D. Howard, M. Moatamedi, A finite element model to identify electrode influence on current distribution in the skin, Artif. Organs 32 (8) (2008) 639–643.
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[25] C.D. Mørch, K. Hennings, O.K. Andersen, Estimating nerve excitation thresholds to cutaneous electrical stimulation by finite element modeling combined with a stochastic branching nerve fiber model, Med. Biol. Eng. Comput. 49 (4) (2001) 385–395. [26] N. Hansen, T. Klein, W. Magerl, R.D. Treede, Psychophysical evidence for long-term potentiation of C-fiber and Adelta-fiber pathways in humans by analysis of pain descriptors, J. Neurophysiol. 97 (3) (2007) 2559–2563. [27] W. Magerl, P.N. Fuchs, R.A. Meyer, R.D. Treede, Roles of capsaicin-insensitive nociceptors in cutaneous pain and secondary hyperalgesia, Brain 124 (2001) 1754–1764. [28] H. Adriaensen, J. Gybels, H.O. Handwerker, J. van Hees, Response properties of thin myelinated (A-delta) fibers in human skin nerves, J. Neurophysiol. 49 (1) (1983) 111–122. [29] R. Schmidt, M. Schmelz, C. Forster, M. Ringkamp, E. Torebjörk, H. Hermann, Novel classes of responsive and unresponsive C nociceptors in human skin, J. Neurosci. 15 (1995) 333–341. [30] R. Schmidt, M. Schmelz, C. Weidner, H.O. Handwerker, H.E. Torebjörk, Innervation territories of mechano-insensitive C nociceptors in human skin, J. Neurophysiol. 88 (4) (2002) 1859–1866. [31] C. Weidner, M. Schmelz, R. Schmidt, B. Hansson, H.O. Handwerker, H.E. Torebjörk, Functional attributes discriminating mechano-insensitive and mechano-responsive C nociceptors in human skin, J. Neurosci. 19 (22) (1999) 10184–10190.
[32] G. Sandrini, M. Serrao, P. Rossi, A. Romaniello, G. Cruccu, J.C. Willer, The lower limb flexion reflex in humans, Prog. Neurobiol. 77 (6) (2005) 353–395. [33] C.G. Bachmann, R. Rolke, U. Scheidt, C. Stadelmann, M. Sommer, G. Pavlakovic, S. Happe, R.D. Treede, W. Paulus, Thermal hypoaesthesia differentiates secondary restless legs syndrome associated with small fibre neuropathy from primary restless legs syndrome, Brain 133 (Pt 3) (2010) 762–770. [34] T. Bocci, B. Vannini, A. Torzini, A. Mazzatenta, M. Vergari, F. Cogiamanian, A. Priori, F. Sartucci, Cathodal transcutaneous spinal driect current stimulation (tsDCS) improves motor unit recruitment in healthy subjects, Neurosci. Lett. 578 (2014) 75–79. [35] M. Parazzini, S. Fiocchi, I. Liorni, E. Rossi, M. Vergari, A. Priori, P. Ravazzani, Modeling the current density generated by transcutaneous spinal direct current stimulation (tsDCS), Clin. Neurophysiol. 125 (11) (2014) 2260–2270, http://dx.doi.org/10.1016/j.clinph.2014.02.027. [36] J. Ladenbauer, K. Minassian, U.S. Hofstoetter, M.R. Dimitrijevic, F. Rattay, Stimulation of the human lumbar spinal cord with implanted and surface electrodes: a computer simulation study, IEEE Trans. Neural. Syst. Rehabil. Eng. 18 (6) (2010) 637–645. [37] S.M. Danner, U.S. Hofstoetter, J. Ladenbauer, F. Rattay, K. Minassian, Can the human lumbar posterior columns be stimulated by transcutaneous spinal cord stimulation? A modeling study, Artif. Organs 35 (3) (2011) 257–262. [38] T.D. Wager, L.Y. Atlas, How is pain influenced by cognition? Neuroimaging weighs in, Perspect. Psychol. Sci. 8 (1) (2013) 91–97.
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Research article
Transcutaneous spinal DC stimulation reduces pain sensitivity in humans C.H. Meyer-Frießem a,1 , L.M. Haag b,1 , T. Schmidt-Wilcke b , W. Magerl c , E.M. Pogatzki-Zahn d , M. Tegenthoff b , P.K. Zahn a,∗ a Department of Anaesthesiology, Intensive Care Medicine, Palliative Care Medicine and Pain Management, Medical Faculty of Ruhr-University Bochum, Berufsgenossenschaftliches Universitätsklinikum Bergmannsheil GmbH Bochum, Bürkle-de-la-Camp-Platz 1, 44789 Bochum, Germany b Department of Neurology, Berufsgenossenschaftliches Universitätsklinikum Bergmannsheil GmbH Bochum, Ruhr University Bochum, Bürkle-de-la-Camp-Platz 1, 44789 Bochum, Germany c Department of Neurophysiology, Center of Biomedicine and Medical Technology, Medical Faculty Mannheim, Ruprecht-Karls-University Heidelberg, Ludolf-Krehl-Str. 13, 68167 Mannheim, Germany d Department of Anaesthesiology, Intensive Care and Pain Medicine, University Hospital of Muenster, Albert-Schweitzer-Campus 1 (Building A1), 48149 Münster, Germany
h i g h l i g h t s • Anodal tsDCS reduces pain sensitivity to painful mechanical pinprick stimuli. • This is the first evidence that tsDCS sensory effects last longer than 30 min. • Anodal tsDCS had no effect on pain sensitivity to single electrical pulses.
a r t i c l e
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Article history: Received 17 November 2014 Received in revised form 2 January 2015 Accepted 9 January 2015 Available online 14 January 2015 Keywords: tsDCS Transcutaneous stimulation Perception Pain Direct current stimulation Sensitivity
a b s t r a c t Non-invasive approaches to pain management are needed to manage patient pain escalation and to providing sufficient pain relief. Here, we evaluate the potential of transcutaneous spinal direct current stimulation (tsDCS) to modulate pain sensitivity to electrical stimuli and mechanical pinpricks in 24 healthy subjects in a sham-controlled, single-blind study. Pain ratings to mechanical pinpricks and electrical stimuli were recorded prior to and at three time points (0, 30, and 60 min) following 15 min of anodal tsDCS (2.5 mA, “active” electrode centered over the T11 spinous process, return electrode on the left posterior shoulder). Pain ratings to the pinpricks of the highest forces tested (128, 256, 512 mN) were reduced at 30 min and 60 min following anodal tsDCS. These findings demonstrate that pain sensitivity in healthy subjects can be suppressed by anodal tsDCS and suggest that tsDCS may provide a non-invasive tool to manage mechanically-induced pain. © 2015 Published by Elsevier Ireland Ltd.
1. Introduction Neuromodulation by means of direct currents has offered a non-invasive way to alter neural excitability [1–3]. Recently, noninvasive application of direct currents to the spinal cord, termed transcutaneous spinal direct current stimulation (tsDCS), has been
Abbreviations: EPS, electrical pain sensitivity; EDT, electrical detection threshold; MPS, mechanical pain sensitivity; MPT, mechanical pain thresholds; NRS, numerical rating scale; tsDCS, transcutaneous spinal direct current stimulation. ∗ Corresponding author. Tel.: +49 234302/6825. E-mail address: [email protected] (P.K. Zahn). 1 Both authors contributed equally. http://dx.doi.org/10.1016/j.neulet.2015.01.029 0304-3940/© 2015 Published by Elsevier Ireland Ltd.
employed with promising effects on neurophysiological processing [4,5]. In tsDCS, direct current is applied transcutaneously via one ‘active’ electrode placed over the spine and a second return electrode over a neutral body part (i.e., where no neuromodulatory effects are expected that could influence the outcome measures). Effects of tsDCS applied at the lower thoracic vertebral level have been described for the motor [6–8], somatosensory [9], and nociceptive [10,11] systems with encouraging clinical translation in recovering motor function in spinal cord injury patients [12] and reducing pain in restless leg syndrome (RLS [13]). In particular, anodal tsDCS anodal tsDCS amplified the motor component of the H-reflex in healthy subjects by reducing post-activation depression [6] and also shifted the H-reflex stimulus-response curve to
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the left, indicating increased excitability [7]. For nociception and pain, anodal tsDCS suppressed both the nociceptive component of the lower limb flexion reflex [10] and the N1 and N2 component amplitudes of foot-laser evoked potentials (LEPs [11]), as well as reduced pain sensitivity to cold stimuli [11]. Thus, anodal tsDCS has been shown to affect the pain system on a spinal, cortical, and perceptual level. (Please see [5] for tsDCS review.) Perceptual effects following anodal tsDCS have, however, been limited to cold pain, where anodal tsDCS proved beneficial in healthy subjects [11], and to symptom ratings in RLS patients, where it reduced their subjective rating of their instantaneous symptom severity [13]. In an effort to further investigate the potential of anodal tsDCS to modulate pain in particular, we therefore, tested the effects of 15 min of thoracically-applied anodal tsDCS on subjective pain ratings given to mechanical and electrical stimuli particularly focused on small-diameter, thinly-myelinated A-delta fibers, associated with “first pain”. Since LEPs and cold pain, A-delta fiber-dependent measures, were suppressed by anodal tsDCS, we expected that anodal tsDCS would likewise reduce pain ratings to pinpricks and electrical stimuli, corresponding to a suppression of pain sensitivity. 2. Material and methods 2.1. Subjects and study design The study was conducted on 24 healthy right-handed male subjects aged 20–33 years (mean 25 ± 3) after approval from the local Ethics Committee of Ruhr-University Bochum (No. 4549-12). Each subject provided written informed consent according to the Declaration of Helsinki and was introduced to the procedures before the baseline measurement. Subjects with relevant medical conditions (e.g., diabetes, seizure, migraine, pacemaker, obesity) or use of medication were excluded. All subjects participated in one session, were assigned to either Group A (anodal tsDCS, n = 12) or Group S (sham tsDCS, n = 12), and were blind to the stimulation group and polarity. The session consisted of 5 blocks: B (Baseline), tsDCS, T0, T30, and T60 (at 0, 30, and 60 min following tsDCS offset, respectively, (Supplementary Fig. 1). Each test block lasted 15 min and tested electrical detection threshold (EDT), mechanical pain threshold (MPT), mechanical pain sensitivity (MPS) and electrical pain sensitivity (EPS), in that order. MPS and EPS measurements were interleaved with one another. Details for each test and for tsDCS are provided below. No formal sample size analysis was performed on the basis of this study being an investigative analysis. Rather, we based our recruitment on comparable tsDCS study sample sizes, which are typically below fifteen subjects. 2.2. tsDCS TsDCS was applied using a constant current battery-driven stimulator (neuroConn GmbH, Ilmenau, Germany) through a pair of saline-soaked sponge electrodes (7 × 5 cm) while the subject was lying comfortably on his right side. Subjects were instructed to rest quietly and limit movement for the stimulation period. One electrode was centered over the spinous processes of the eleventh thoracic vertebra (T10–T12) and the other on the left dorsal shoulder, as has been described previously [9]. Polarity of stimulation refers to the electrode over the spinal process. During the tsDCS block of the experimental session, one 15min period of either anodal or sham tsDCS was applied. For anodal stimulation, +2.5 mA was applied for 15 min [6,7,9], resulting in a current density of 0.071 mA/cm2 and a total charge of 63.9 mC/cm2 , both of which are below the threshold for tissue damage [14].
Sham stimulation was applied using −1.5 mA for 45 s to mimic the initial tingling sensation while avoiding any stimulation-induced effects. Both groups were told that tsDCS stimulation would last for 15 min. Two trained investigators (CMF, LMH) performed the measurements. 2.3. Mechanical testing A selection of quantitative sensory testing (QST) measurements from a standardized test battery [15] was used for mechanical testing. To avoid interactions between subsequent test stimuli, mechanical probing of a 1 cm area surrounding the electrode was applied in a circular manner. All subjects closed their eyes during the assessment and rated each stimulus immediately following its presentation to maintain focus on the presented stimuli. MPS - Mechanical pain sensitivity was assessed using standardized punctuate probes (PinPrick, MRC-Systems, Heidelberg, Germany) with 0.25 mm-diameter tip to stimulate cutaneous nociceptors [15–19]. Forces of 8, 16, 32, 64, 128, 256 and 512 mN were presented once per run in a pseudo-randomized order, as provided by the QST protocol [15]. Each run is pseudo-randomized separately and a total of 10 runs (i.e., a total of 5 runs to the right leg, 5 runs to the left leg, alternating between runs) make up a block. All blocks used the same pseudo-randomization. Each subject received 5 runs per leg, alternating between the right and left leg, and was asked to rate pain associated with each stimulus using the numerical rating scale (NRS; 0–100). A rating of “0” indicated no pain; a rating of “100” indicated the worst pain imaginable. MPT - Mechanical pain threshold was tested using the seven previously described pinprick stimuli. Forces were presented in ascending and descending order (up-and-down rule) to identify suprathreshold and subthreshold stimulus intensities. The final threshold was determined by the geometric mean of five just suprathreshold and five just subthreshold stimulus intensities [15,19–21]. Reference data from the foot of 180 healthy subjects defined 73 mN to be the average pain threshold to pinpricks in young healthy males [22], i.e., on average, young healthy males rate pinpricks at or above 73 mN as painful, and those pinpricks below 73 mN as non-painful. Since we were specifically interested in anodal tsDCS’s effects on explicitly painful stimuli, pinpricks were categorized based on this population data as either suprathreshold (128, 256, 512 mN) or subthreshold (8, 16, 32, 64 mN), here defined as MPS128–512 mN and MPS8–64 mN , respectively. 2.4. Electrical testing Bilateral electrical test stimuli were applied 5 cm proximal to the knee using a custom-built multi-pin electrode following a previously-established paradigm (DS7A, Digitimer, UK) [21,23]. To achieve spatial summation within the receptive field of spinal cord neurons, 12 of these electrodes were mounted in a small circular plastic frame (attached to the skin by double-adhesive tape) and were stimulated simultaneously, which delivers a very high local current density at very low stimulus currents. Owing to the high impedance of the skin surface and rapid breakdown of current density in deeper tissue layers, this electrode has a high selectivity for nociceptive primary afferents located in superficial epidermal layers and avoids excitation of mechanoreceptive axons in subepidermal skin layers [24,25]. Accordingly, electrical stimuli delivered through this electrode have a predominantly “pricking” pain character already at threshold and over a high dynamic range of suprathreshold stimuli [23,25,26]. This “prickling” sensation has been attributed to activation of A-delta fibers such that pinpricks are thought to particularly test mechanosensitive A-delta fiber-mediated percept [27]. A strap electrode attached around the
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ipsilateral upper leg served as the anode. Two different measures of electro-cutaneous sensitivity were used: EPS – Single electrical pulses (3.0 mA, 2 ms pulse width) were given, which were rated on the NRS scale (0–100). Subjects were warned shortly before (≤1 s) the presentation of an EPS pulse. EDT – Electrical detection threshold was determined using single 2 ms electrical pulses in an ascending and descending order of stimulus intensity to determine three just-suprathreshold and three just-subthreshold stimulus intensities (up-and-down rule; [20]).
2.5. Statistical analysis All ratings and thresholds were transformed logarithmically (base 10) in order to achieve secondary normal distribution [15]. A small constant of 0.1 was added to all pain ratings (MPS, EPS) to avoid a loss of zero-values [18] whereas no constant was added to thresholds (MPT, EDT) before log-transformation. Logtransformed scores (both pain ratings and thresholds) were then normalized to baseline via subtraction to assess the overall effect of tsDCS. The average of scores for left and right legs was entered into a two-way ANOVA with main factors “stimulation” (independent measures, 2 levels: anodal and sham), and “post time point” (repeated measures, 3 levels: T0, T30, T60). Group differences at specific time points were further assessed using independent t-tests. All data analyses were carried out using STATISTICA (StatSoft, Inc. v10), and statistical significance was set at p < .05. Log
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differences (mean ± SEM) were re-transformed for the results and figures. 3. Results There were no differences in age, weight or clinical conditions of subjects between the sham and anodal groups. TsDCS procedures were well-tolerated by all participants; all reported an initial tingling sensation under the electrode placed over the spine. None complained of painful sensations during tsDCS. All subjects in Group A and 11 of 12 in Group S reported that they felt the stimulation and 11 of 12 from both Group A and Group S guessed they received ‘real’ and not placebo stimulation. 3.1. Heavy mechanical stimuli All subjects in the study rated the 256 mN and 512 mN pinprick as painful in more than 50% of the 5 stimulus presentations prior to tsDCS. Anodal tsDCS group’s pain incidence shown in (Supplementary Fig. 2). A main effect of stimulation was seen for pain ratings to heavy mechanical stimuli (MPS128–512 mN ) following anodal tsDCS (F1,22 = 5.83, p = .02; Fig. 1b). Further investigation of individual pinpricks identified a significant stimulation effect on pain ratings to the 512 mN pinprick (F1,22 = 6.01, p = .02; Fig. 1c) and strong trends toward a stimulation effect on pain ratings to the 128 mN pinprick (F1,22 = 3.37, p = .08) and 256 mN (F1,22 = 4.16, p = .05). There was
Fig. 1. Long-lasting effects of tsDCS on heavy pinpricks. Average pain ratings to light pinpricks (8–64 mN) increased over time but were unaffected by anodal stimulation (a) whereas pain ratings to heavy pinpricks (128–512 mN, (b) were significantly decreased following anodal tsDCS (black) as compared to sham tsDCS (gray). (c) Average changes in pain ratings for individual pinpricks for anodal (black bars) and sham (white bars) groups with the individual ratings for the 512 mN pinpricks. Graphs show re-transformed normalized means ± SEM. *p < .05.
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no interaction between stimulation and time (F2,44 = 0.03, p = ns). Specifically, pain ratings to heavy pinpricks (MPS128–512 mN ) following anodal tsDCS were 8% below baseline at T0 (−0.038 ± 0.035 log10 units), 13% at T30 (−0.061 ± 0.036 log10 units), and 13% at T60 (−0.062 ± 0.047 log10 units). This was 21% (p = .06), 28% (p = .03), and 34% (p = .04) below the changes in pain ratings following sham stimulation at T0, T30 and T60, respectively. For the 512 mN pinprick, t-tests revealed significantly reduced pain ratings in the anodal group compared to the sham group to the 512 mN pinprick at all time points (T0: t = −2.23, p < .05; T30: t = −2.23, p < .05; T60: t = −2.10, p < .05). 3.2. Light mechanical stimuli No main effect of stimulation was shown for pain ratings to lighter mechanical stimuli (MPS8–64 mN ; F1,22 = 0.63, p = ns; Fig. 1a); however, there was a significant main effect of time (F2,44 = 4.86, p = .01). Further investigation identified pain ratings to 16 mN and 32 mN pinpricks to be significantly increased over time (F2,44 = 5.07, p = .01 and F2,44 = 3.86, p = .03, respectively). Changes in pain ratings to MPS8–64 mN were as follows: anodal change: 0.017 ± 0.033 log10 units at T0, 0.056 ± 0.033 log10 units at T30, 0.096 ± 0.044 log10 units at T60; sham change: 0.062 ± 0.033 log10 units at T0, 0.094 ± 0.046 log10 units at T30, 0.128 ± 0.041 log10 units at T60. Mechanical pain thresholds were not significantly affected by stimulation (F1,22 < 0.01, p = ns) or by time (F2,44 = 1.48, p = ns). Changes in pain ratings to MPT were as follows: anodal change: −0.045 ± 0.049 log10 units at T0, −0.056 ± 0.073 log10 units at T30, −0.043 ± 0.089 log10 units at T60; sham change: −0.051 ± 0.033 log10 units at T0, −0.082 ± 0.043 log10 units at T30, −0.079 ± 0.039 log10 units at T60; (Supplementary Fig. 3c) 3.3. Electrical stimuli All participants rated the 3.0 mA stimulus as painful both prior to and following tsDCS. A significant main effect of time was shown for EDT (F2,44 = 4.60, p = .02) and EPS (F2,44 = 6.37, p = .004) but there was no main effect of stimulation for either EDT (F1,22 = 0.36, p = ns) or EPS (F1,22 = 1.56, p = ns). EDT decreased over the measurement period as follows: anodal change: −0.077 ± 0.056 log10 units at T0, 0.142 ± 0.045 log10 units at T30, 0.184 ± 0.056 log10 units at T60; sham change: −0.145 ± 0.049 log10 units at T0, 0.190 ± 0.047 log10 units at T30, 0.184 ± 0.045 log10 units at T60; (Supplementary Fig. 3b). Pain ratings to EPS were decreased 12% at T0 (Anodal: −0.072 ± 0.025 log10 units; Sham: −0.015 ± 0.019 log10 units; p = .09), 10% at T30 (anodal: −0.115 ± 0.047 log10 units; Sham: −0.060 ± 0.035 log10 units; p = ns), and 12% at T60 (anodal: −0.135 ± 0.045 log10 units; Sham: −0.067 ± 0.040 log10 units; p = ns) more following anodal stimulation than following sham stimulation (Supplementary Fig. 3a). 4. Discussion This study investigated the effect of tsDCS on pain sensitivity to cutaneous stimuli. We were able to show that anodal tsDCS significantly decreased sensitivity to painful mechanical stimuli and moreover that the effect was present throughout the one hour post-tsDCS measurement period. Additionally, we could show that anodal effects were limited to pain evoked by heavy mechanical pinpricks (128–512 mN). This represents the first presentation of a long-lasting pain reduction following anodal tsDCS. Mechanical pain in healthy subjects is mediated by smalldiameter A-delta and C fiber nociceptive afferents that respond to mechanical stimuli. While the pinpricks tested (i.e., 8–512 mN) have all been shown to evoke responses in both types of nociceptive fibers [28–31], pain to these pinpricks is typically felt to pinpricks
over 73 mN [22]. As in the population data, all but two participants in this study rated the 128, 256, and 512 mN as painful. Since sensitivity to only these painful pinpricks was altered by anodal tsDCS, we postulate that the effects of tsDCS on high but not low-threshold pain are likely due to differential effects on high-threshold but not low-threshold nociceptive afferents contributing to pain. This is consistent with previous reports on anodal tsDCS and pain perception. Truini et al. [11], for example, found that anodal stimulation increased cold pain tolerance (i.e., a strong pain stimulus) without affecting cold pain thresholds (i.e., a weak pain stimulus). Thus, it seems that anodal tsDCS may require a certain threshold of stimulus strength, i.e., a certain percentage of activated fibers, to show a sensory effects. Further support for this comes from Cogiamanian et al. [9], who report that anodal tsDCS suppressed SEPs likely via an incomplete anodal block. Here, the authors suggest that tsDCS blocked a portion of the fibers, reducing the SSEP amplitude but not latency, and thereby affected only a portion of the fibers. As in our study, it is unclear by what mechanism the afferents were affected, and moreover which specific fiber sub-type(s) were affected. In this study, we specifically targeted the sharp “pinprick-like” sensation evoked by the pinprick stimuli, which is thought to be mediated by A-delta fibers [27]. Consequently, our results suggest that DC stimulation most likely affected the A-delta fiber-mediated pain percept. Previous studies also support an effect of tsDCS on A-delta fiber-mediated measures, showing that anodal tsDCS suppresses both the RIII component of the lower limb flexion reflex [10] and also laser evoked potentials [11], both of which are mediated by A-delta fibers [32]. Furthermore, anodal tsDCS reduced symptoms of RLS patients [13], who, as the authors note, involves mechanical hyperalgesia [33] (i.e., patients rated pinpricks more painful than controls). Taken together with anodal tsDCS’s suppression of cold pain [11] and to heavy mechanical pinpricks shown here, anodal tsDCS seems to affect pain on the spinal, cortical, and perceptual levels. In order to clarify the specific targets of anodal tsDCS, however, further studies using, for example microneurography or pharmacological targeting, will be needed. Notably, there was no significant reduction in pain sensitivity to high intensity electrical stimuli following anodal tsDCS. This is consistent with the finding that, while anodal tsDCS suppresses a nociceptive reflex, it does not alter pain ratings to the high frequency electrical pulses used to evoke the reflex [10]. Similarly, we find no anodal-induced suppression of sensitivity to painful electrical stimuli, despite the 3.0 mA pulse evoking pain in all subjects. We suspect, that the lack of a significant effect on EPS in our study is, in part, due to the unspecific targeting of electrical stimuli, where the pain evoked by an electrical pulse would consist of a mixture of both mechanosensitive and mechanoinsensitive A-delta fibers. Although it remains possible that C- and A-beta fibers contributed to EPS, it has been shown that A-delta fibers are preferentiallytargeted by the multi-pin electrode [24,25]. Nonetheless, our study, does confirm that anodal tsDCS modulates pain on the perceptual level with a particular effect on mechanical pain. Recently it has been shown that cathodal tsDCS affects motor unit recruitment for up to one hour following tsDCS offset [34]. Our results extend these relatively long-lasting effects to anodal tsDCS, and specifically to pain perception. Up until now, tsDCS effects on sensory measures have been shown to last for up to 30 min. Here we show that anodal tsDCS modulated pain for over one hour, supporting previous findings and encouraging further investigation into longer-lasting effects of tsDCS. 4.1. Limitations While our data show psychophysical effects of anodal tsDCS on pain sensitivity, we cannot identify the level on which and through which mechanism tsDCS acts. Our data support the notion that
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small-diameter fiber pathways were affected by DC stimulation; however, it is unclear whether this was of direct or indirect nature. Recent modeling of tsDCS suggests that current density is highest at and rostral to the level of stimulation [35], and since tsDCS was applied over the T10–T12 vertebral spinous processes, which correspond to the spinal L1–L4 region where afferents of the anterior thigh would enter the spinal cord, the highest current density was most likely around the entry level of the nociceptive afferents. It has been shown using other models of spinal electrical stimulation, that the current that reaches the spinal cord likely first stimulates the posterior roots, followed by the anterior roots, and then the posterior column fibers [36,37]. Thus, the mechanism of the reduction in pain sensitivity seen in our study may be similar to that proposed by these models. Namely, that current reaching the spinal cord may activate dorsal roots, and their subsequent activation of local inhibitory circuits in the superficial layers of the dorsal horn, reduced the pain afferent transmission. Supraspinal effects of tsDCS, however, cannot be excluded. Pain is notably susceptible to cognitive influences [38], and it has been shown that thoracic tsDCS indeed affects cortical potentials [10,11] and even affects distant motor unit recruitment [34]. Thus, it remains likely that supra-spinal effects of anodal tsDCS played a role in the modulation of pain ratings seen here, but it is unlikely this is due to attentional changes since we ensured that subjects actively attended to the presented stimuli with minimal distraction, or due to placebo effects, since almost all subjects from both groups similarly felt the stimulation and guessed that they received real stimulation. Future studies with brain imaging and further advances in computational models will likely shed light on the underlying mechanisms of the DC effects seen thus far. Nonetheless, our data support the notion that anodal tsDCS may be useful in reducing mechanical pain sensitivity. Finally, since our study was single rather than double-blinded, experimenter bias cannot completely be excluded. Nonetheless, the use of scripted directions, calibrated stimuli, and repetitive applications likely minimized any biases, such that it is unlikely that this was the cause of the anodal tsDCS effects. Follow-up studies are strongly encouraged to employ a double-blinded experimental design with a larger cohort. 5. Conclusion This study on healthy subjects shows that anodal tsDCS modulates pain sensitivity. Compared to sham tsDCS, anodal stimulation decreased sensitivity to heavy mechanical pinprick stimuli for at least an hour following stimulation offset. While these results confirm modulatory effects of tsDCS on pain perception in healthy subjects, further testing should be done on sensitized healthy volunteers to determine whether tsDCS should be considered for clinical translation. Authors contribution All authors have read and approved the final manuscript. CMF, LMH – acquired and analyzed data, drafted ethics proposal and manuscript. WM – made critical revisions, assisted in statistical analyses. TSW, EMPZ – made critical revisions. MT, PKZ – made critical revisions, responsible for concept. Acknowledgments None of the authors have potential conflicts of interest to be disclosed. MT and TSW currently receive funding from DFG (SFB874 TP A1, A8). LMH receives a stipend from the International Graduate School of Neuroscience, Ruhr-University Bochum (BoNeuroMed).
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Appendix A. Supplementary data Supplementary data associated with this article can be found, in the online version, at http://dx.doi.org/10.1016/j.neulet. 2015.01.029.
References [1] M.A. Nitsche, W. Paulus, Excitability changes induced in the human motor cortex by weak transcranial direct current stimulation, J. Physiol. 527 (2000) 633–639. [2] M.A. Nitsche, D. Liebetanz, A. Antal, N. Lang, F. Tergau, W. Paulus, Modulation of cortical excitability by weak direct current stimulation-technical safety and functional aspects, Suppl. Clin. Neurophysiol. 56 (2003) 255–276. [3] G. Ardolino, B. Bossi, S. Barbieri, A. Priori, Non-synaptic mechanisms underlie the after-effects of cathodal transcutaneous direct current stimulation of the human brain, J. Physiol. 568 (Pt2) (2005) 653–663. [4] F. Cogiamanian, G. Ardolino, M. Vergari, R. Ferrucci, M. Ciocca, E. Scelzo, S. Barbieri, A. Priori, Transcutaneous spinal direct current stimulation, Front. Psychiatry 3 (2012), http://dx.doi.org/10.3389/fpsyt.2012.00063. [5] A. Priori, M. Ciocca, M. Parazzini, M. Vergari, R. Ferrucci, Transcranial cerebellar direct current stimulation and transcutaneous spinal cord direct current stimulation as innovative tools for neuroscientists, J. Physiol. 592 (Pt16) (2014) 3345–3369. [6] T. Winkler, P. Hering, A. Straube, Spinal DC stimulation in humans modulates post-activation depression of the H-reflex depending on current polarity, Clin. Neurophysiol. 121 (6) (2010) 957–961. [7] J.C. Lamy, C. Ho, A. Badel, R.T. Arrigo, M. Boakye, Modulation of soleus H reflex by spinal DC stimulation in humans, J. Neurophys. 108 (3) (2012) 906–914. [8] J.C. Lamy, M. Boakye, BDNF Val66Met polymorphism alters spinal DC stimulation-induced plasticity in humans, J. Neurophys. 110 (1) (2013) 109–116. [9] F. Cogiamanian, M. Vergari, F. Pulecchi, S. Marceglia, A. Priori, Effect of spinal transcutaneous direct current stimulation on somatosensory evoked potentials in humans, Clin. Neurophysiol. 119 (11) (2008) 2636–2640. [10] F. Cogiamanian, M. Vergari, E. Schiaffi, S. Marceglia, G. Ardolino, S. Barbieri, A. Priori, Transcutaneous spinal cord direct current stimulation inhibits the lower limb nociceptive flexion reflex in human beings, Pain 152 (2) (2011) 370–375. [11] A. Truini, M. Vergari, A. Biasiotta, S. La Cesa, M. Gabriele, G. Di Stefano, C. Cambieri, G. Cruccu, M. Inghilleri, A. Priori, Transcutaneous spinal direct current stimulation inhibits nociceptive spinal pathway conduction and increases pain tolerance in humans, Eur. J. Pain 15 (10) (2011) 1023–1027. [12] M. Hubli, V. Dietz, M. Schrafl-Altermatt, M. Bolliger, Modulation of spinal neuronal excitability by spinal direct currents and locomotion after spinal cord injury, Clin. Neurophysiol. 124 (6) (2013) 1187–1195. [13] A.C. Heide, T. Winkler, H.J. Helms, M.A. Nitsche, C. Trenkwalder, W. Paulus, C.G. Bachmann, Effects of transcutaneous spinal direct current stimulation in idiopathic restless legs patients, Brain Stimul. 7 (5) (2014) 636–642. [14] M.A. Nitsche, L.G. Cohen, E.M. Wassermann, A. Priori, N. Lang, A. Antal, W. Paulus, F. Hummel, P.S. Boggio, F. Fregni, A. Pascual-Leone, Transcranial direct current stimulation: state of the art 2008, Brain Stimul. 1 (3) (2008) 206–223. [15] R. Rolke, W. Magerl, K.A. Campbell, C. Schalber, S. Caspari, F. Birklein, R.D. Treede, Quantitative sensory testing: a comprehensive protocol for clinical trials, Eur. J. Pain 10 (1) (2006) 77–88. [16] J.D. Greenspan, S.L. McGillis, Stimulus features relevant to the perception of sharpness and mechanically evoked cutaneous pain, Somatosens. Mot. Res. 8 (2) (1991) 137–147. [17] W. Chan, D. Bowsher, Weighted needle pinprick sensory thresholds: a simple test of sensory function in diabetic peripheral neuropathy, J. Neurol. Neurosurg. Psychiatry 55 (1) (1991) 56–59. [18] W. Mager, S.H. Wilk, R.D. Treede, Secondary hyperalgesia and perceptual wind-up following intradermal injection of capsaicin in humans, Pain 74 (1998) 257–268. [19] E.A. Ziegler, W. Magerl, R.A. Meyer, R.D. Treede, Secondary hyperalgesia to punctate mechanical stimuli: central sensitization to A-fibre nociceptor input, Brain 122 (1999) 2245–2257. [20] S. Lang, T. Klein, W. Magerl, R.D. Treede, Modality-specific sensory changes in humans after the induction of long-term potentiation (LTP) in cutaneous nociceptive pathways, Pain 128 (3) (2007) 254–263. [21] T. Klein, S. Stahn, W. Magerl, R.D. Treede, The role of heterosynaptic facilitation in long-term potentiation (LTP) of human pain sensation, Pain 139 (3) (2008) 507–519. [22] W. Magerl, E.K. Krumova, R. Baron, T. Tölle, R.D. Treede, C. Maier, Reference data for quantitative sensory testing (QST): refined stratification for age and a novel method for statistical comparison of group data, Pain 151 (3) (2010) 598–605. [23] T. Klein, W. Magerl, H.C. Hopf, J. Sandkühler, R.D. Treede, Perceptual correlates of nociceptive long-term potentiation and long-term depression in humans, J. Neurosci. 24 (2004) 964–971. [24] N. Sha, L.P. Kenney, B.W. Heller, A.T. Barker, D. Howard, M. Moatamedi, A finite element model to identify electrode influence on current distribution in the skin, Artif. Organs 32 (8) (2008) 639–643.
158
C.H. Meyer-Frießem et al. / Neuroscience Letters 589 (2015) 153–158
[25] C.D. Mørch, K. Hennings, O.K. Andersen, Estimating nerve excitation thresholds to cutaneous electrical stimulation by finite element modeling combined with a stochastic branching nerve fiber model, Med. Biol. Eng. Comput. 49 (4) (2001) 385–395. [26] N. Hansen, T. Klein, W. Magerl, R.D. Treede, Psychophysical evidence for long-term potentiation of C-fiber and Adelta-fiber pathways in humans by analysis of pain descriptors, J. Neurophysiol. 97 (3) (2007) 2559–2563. [27] W. Magerl, P.N. Fuchs, R.A. Meyer, R.D. Treede, Roles of capsaicin-insensitive nociceptors in cutaneous pain and secondary hyperalgesia, Brain 124 (2001) 1754–1764. [28] H. Adriaensen, J. Gybels, H.O. Handwerker, J. van Hees, Response properties of thin myelinated (A-delta) fibers in human skin nerves, J. Neurophysiol. 49 (1) (1983) 111–122. [29] R. Schmidt, M. Schmelz, C. Forster, M. Ringkamp, E. Torebjörk, H. Hermann, Novel classes of responsive and unresponsive C nociceptors in human skin, J. Neurosci. 15 (1995) 333–341. [30] R. Schmidt, M. Schmelz, C. Weidner, H.O. Handwerker, H.E. Torebjörk, Innervation territories of mechano-insensitive C nociceptors in human skin, J. Neurophysiol. 88 (4) (2002) 1859–1866. [31] C. Weidner, M. Schmelz, R. Schmidt, B. Hansson, H.O. Handwerker, H.E. Torebjörk, Functional attributes discriminating mechano-insensitive and mechano-responsive C nociceptors in human skin, J. Neurosci. 19 (22) (1999) 10184–10190.
[32] G. Sandrini, M. Serrao, P. Rossi, A. Romaniello, G. Cruccu, J.C. Willer, The lower limb flexion reflex in humans, Prog. Neurobiol. 77 (6) (2005) 353–395. [33] C.G. Bachmann, R. Rolke, U. Scheidt, C. Stadelmann, M. Sommer, G. Pavlakovic, S. Happe, R.D. Treede, W. Paulus, Thermal hypoaesthesia differentiates secondary restless legs syndrome associated with small fibre neuropathy from primary restless legs syndrome, Brain 133 (Pt 3) (2010) 762–770. [34] T. Bocci, B. Vannini, A. Torzini, A. Mazzatenta, M. Vergari, F. Cogiamanian, A. Priori, F. Sartucci, Cathodal transcutaneous spinal driect current stimulation (tsDCS) improves motor unit recruitment in healthy subjects, Neurosci. Lett. 578 (2014) 75–79. [35] M. Parazzini, S. Fiocchi, I. Liorni, E. Rossi, M. Vergari, A. Priori, P. Ravazzani, Modeling the current density generated by transcutaneous spinal direct current stimulation (tsDCS), Clin. Neurophysiol. 125 (11) (2014) 2260–2270, http://dx.doi.org/10.1016/j.clinph.2014.02.027. [36] J. Ladenbauer, K. Minassian, U.S. Hofstoetter, M.R. Dimitrijevic, F. Rattay, Stimulation of the human lumbar spinal cord with implanted and surface electrodes: a computer simulation study, IEEE Trans. Neural. Syst. Rehabil. Eng. 18 (6) (2010) 637–645. [37] S.M. Danner, U.S. Hofstoetter, J. Ladenbauer, F. Rattay, K. Minassian, Can the human lumbar posterior columns be stimulated by transcutaneous spinal cord stimulation? A modeling study, Artif. Organs 35 (3) (2011) 257–262. [38] T.D. Wager, L.Y. Atlas, How is pain influenced by cognition? Neuroimaging weighs in, Perspect. Psychol. Sci. 8 (1) (2013) 91–97.
