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Prefrontal cortex modulates placebo analgesia
PAINÒ 148 (2010) 368–374
www.elsevier.com/locate/pain
Research papers
Prefrontal cortex modulates placebo analgesia Peter Krummenacher a,*, Victor Candia a, Gerd Folkers a, Manfred Schedlowski b, Georg Schönbächler a,c a
Collegium Helveticum, Schmelzbergstrasse 25, CH-8092 Zurich, Switzerland Institute of Medical Psychology and Behavioral Immunobiology, University Clinic Essen, 45122 Duisburg-Essen, Germany c Department of Psychology, University of Cape Town, Rondebosch 7701, South Africa b
a r t i c l e
i n f o
Article history: Received 22 July 2009 Received in revised form 10 September 2009 Accepted 30 September 2009
Keywords: Placebo analgesia Expectation Transcranial magnetic stimulation Dorsolateral prefrontal cortex
a b s t r a c t Expectations and beliefs modulate the experience of pain, which is particularly evident in placebo analgesia. The dorsolateral prefrontal cortex (DLPFC) has been associated with pain regulation and with the generation, maintenance and manipulation of cognitive representations, consistent with its role in expectation. In a heat-pain paradigm, we employed non-invasive low-frequency repetitive transcranial magnetic stimulation (rTMS) to transiently disrupt left and right DLPFC function or used the TMS device itself as a placebo, before applying an expectation-induced placebo analgesia. The results demonstrated that placebo significantly increased pain threshold and pain tolerance. While rTMS did not affect pain experience, it completely blocked placebo analgesia. These findings suggest that expectation-induced placebo analgesia is mediated by symmetric prefrontal cortex function. Ó 2009 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved.
1. Introduction Expectations and beliefs shape reality by affecting our perception and influencing our behavior. They influence behavior by modulating the neural processes that mediate the actual sensory experience [22], and affect perception by directing attention to and guiding interpretation of both internal and external sensations [14,22]. The role of expectations in sensory experiences is especially relevant in the context of pain processing [48], and research addressing the mechanisms mediating placebo analgesia have increasingly attracted scientific interest in recent years. The placebo response is a widespread, heterogeneous [2] and multidimensional learning phenomenon [7] which involves both subcortical (unconscious) conditioning and cortical (conscious) expectation mechanisms [11,21]. Over time, the concept of the placebo has shifted from that of an inert sugar pill to the implicit or explicit psychosocial stimulation of a therapeutic procedure [2]. A wide range of neurobiological mechanisms of placebo analgesia have been described. For example, both, expectation mediated and opioid conditioned placebo analgesia has been shown to activate endogenous opioids as it can be reversed by the mu-opioid antagonist naloxone [1]. In addition, placebo analgesia is reportedly dependent on reward-related dopaminergic activity [40], shares a common neural network with opioid analgesia [34], and reduces neural transmission in pain pathways [47].
* Corresponding author. Address: University of Zurich and ETH Zurich, Collegium Helveticum, Schmelzbergstrasse 25, CH-8092 Zurich, Switzerland. Tel.: +41(0) 44 632 54 35; fax: +41(0) 44 632 12 04. E-mail address: [email protected] (P. Krummenacher).
A growing body of evidence from lesion [3] and neuroimaging studies [12,25] highlights the critical role of the prefrontal cortex (PFC) in placebo analgesia. For example, in Alzheimer patients, the loss of communication between the prefrontal lobes and the rest of the brain results in a disruption of expectancy-related mechanisms, which has been correlated with reduced placebo analgesia [3]. However, patient studies are limited by confounding factors such as diffuse lesions, chronic medication, side effects and secondary brain plasticity processes. The dorsolateral PFC in particular has repeatedly been shown to be involved in expectation-related placebo analgesia [31,47,49] as well as in cognitive and attention-related pain regulation [15,27,29,32,36]. Pain processing has been associated with a predominant right hemisphere involvement [15]. Indirect evidence in favor of asymmetric cortical processing comes from functional imaging studies with acupuncture treatment [31], patients with depression [24] and irritable bowel syndrome [26], and suggests a right PFC preponderance in the general modulation of the placebo response. However, a possible lateralization of the neural underpinnings of placebo analgesia has never been directly tested. To enhance our understanding of left and right DLPFC contribution to placebo analgesia, we employed repetitive transcranial magnetic stimulation (rTMS) to transiently disrupt left and right PFC function. We thereby aimed to investigate whether the sensory components of placebo analgesia can be modified in healthy participants with high placebo analgesia-expectation. Employing a heat-pain paradigm, we tested three hypotheses. First, we predicted that placebo analgesia would affect pain threshold and tolerance after the deceptive induction of specific analgesia-expectation. Second, we hypothesized that placebo analgesia would be
0304-3959/$36.00 Ó 2009 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved. doi:10.1016/j.pain.2009.09.033
P. Krummenacher et al. / PAINÒ 148 (2010) 368–374
suppressed following inhibition of the PFC by means of low frequency rTMS. Finally, we predicted a predominantly right PFC involvement in the placebo response and concomitant peripheral pain asymmetry as evidenced by a higher pain threshold and tolerance on the left arm after placebo treatment.
2. Methods 2.1. Subjects Forty healthy right-handed men (mean Chapman score = 13.9, SD = 1.3, range = 13–18), age 20–43 years (mean = 25.3, SD = 6.5)] gave written informed consent for the study, which was approved by the Local Ethics Committee. All participants were naïve to TMS, guaranteeing a non-confounded sham condition. Participants were screened using the transcranial magnetic stimulation adult safety screening protocol [19] and a neuropsychiatric assessment questionnaire [6]. Exclusion criteria were the presence of acute or chronic pain, sensory abnormalities affecting the thermal perception modality, a history of neurological disorder, mental illness, drug or alcohol consumption, current use of central nervous system medication or any other factor contraindicated for TMS [28] or heat pain measurements. All participants were paid 80 Swiss francs for their participation in the study. Half of the participants were assigned to an analgesia-expectation condition (‘‘analgesia-expectation”) and the other half to a control expectation condition (‘‘false-expectation”) (Fig. 1). At the time of recruitment, participants in the ‘‘analgesia-expectation” condition were informed that the effectiveness of a new powerful device (i.e. the TMS device) to reduce pain experience was being evaluated (i.e. TMS as a painkiller). Twenty other volunteers were assigned to the ‘‘false-expectation” condition and individually matched with the ‘‘analgesia-expectation” for age and educational background. These volunteers had responded to the same recruitment procedure, which used a similar advertisement. However, the passage referring to pain reduction and rTMS now had the heading ‘‘Does rTMS have an impact on autonomous physiological reactions like skin conductance during painful and non-painful heat stimulation?” (i.e. that TMS would influence, if anything, only autonomous parameter but not pain experience). All participants in both conditions were told they would receive real-TMS, but this was true for only half of them. The participants in both conditions were randomly assigned to either ‘‘sham-TMS” or ‘‘real-TMS” treatment over the left and right DLPFC (see Fig. 1). This unconditioned deceptive design has been shown to produce much more powerful placebo responses than conditioned instructions [30,33,44,45]. After study completion, participants were fully informed about the real aims of the experiment. All participants were tested individually and did not see the investigator during the pain measurements. They were seated in a comfortable reclining chair in front of a 19-in. computer screen, head and arms stabilized by means of VelcroÒ straps and restraints. Room lighting, screen contrast and ambient temperature (19.5 °C) were all kept constant. Presentation of all instructions was carried out via a computer display and automatically controlled by ‘‘Superlab Pro 4” (by CedrusÓ) running on an Apple G4 PowerbookÓ, . Distance between each participant’s head and the computer screen was adjusted to permit undisturbed view and was kept at approximately 1.2 m for all participants. TM
2.2. Heat pain stimuli and measurement Heat pain measurements were performed three times per participant, at baseline and after each experimental condition (‘‘sham-TMS” or ‘‘real-TMS”) over the left and right DLPFC (see
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Fig. 1). Heat stimuli were administered in counterbalanced order to the left and right volar forearm using a 30 30-mm Peltier device (Medoc, Ramat-Yishai, Israel; TSA-II) placed at 2/3 of the distance from wrist to elbow. Individual pain threshold was measured using the search method starting at 42 °C: participants were asked to increase or decrease the magnitude of the heat stimulus to the transition point were they felt it changing from ‘‘hot” to ‘‘painful”. Participants were instructed to determine the transition point as precisely as possible (see [23] for detailed method references) and to use equally long response intervals (i.e. mouse click intervals) for altering temperature, and also to apply combined bottom-up (increasing temperature) and top-down (decreasing temperature) search strategies. Pain tolerance was determined by the method of limits: participants were asked to stop the increasing noxious heat stimulus at the moment they could no longer stand it. Three measurements starting at 35 °C, with a rise of 0.8 °C/s, were averaged. To avoid physical injury, the pain tolerance measurement stopped automatically at 52 °C. Prior to the actual measurements, participants were familiarized with the heat stimuli and the controlling device. Pain threshold was always measured prior to pain tolerance in order to minimize interactions between pain threshold and pain tolerance. All participants started with a practice trial for threshold and tolerance, counterbalanced for left and right forearm sites. 2.3. Expectation induction and placebo administration In the present study, the TMS device served as placebo [44]. Effective induction of pain treatment expectations can be achieved by lowering noxious stimulation levels (after an initial stimulus exposure), without informing participants about the real procedure [37,46]. Prior to rTMS treatment, misleading advertisement-induced expectations about TMS efficiency in reduction of pain experience were boosted in a multi-sensory learning procedure implemented with self-developed software. Following the message ‘‘The TMS apparatus is inhibiting pain perception”, sham visual feedback was provided by means of two color-coded intensity level bars (see SM Fig. 1). The bars represented rTMS- and heat level intensities, respectively (for both device intensity range 0–100%), and suggested a real association between increasing rTMS intensity and decreasing pain perception. The display heat level was set at a constant 60% for all participants and pain application trials, but participants were made to believe that this heat level corresponded exactly to their individual heat pain threshold. In both ‘‘analgesia-expectation” groups, participants experienced their real heat pain threshold first in order to credibly indicate that perceived pain level was congruent with the visual feedback on heat level (set at 60%) and TMS intensity (set at 0%, i.e. turned off). In the two consecutive trials, preceding a sham stimulation of 75 s, heat stimulus level was truly reduced by two intensity levels (conditioning level 1 = threshold minus 1 °C; conditioning level 2 = threshold minus 2 °C) while the display showed a constant heat (set at 60%) and increasing TMS intensity level (level 1: set at 20%; level 2: set at 60%). Conditioning-level pain stimuli were administered for 4 s. The occurrence of robust placebo and nocebo responses highly depends on the expectations induced by the experimental instruction [45]. The ‘‘analgesia-expectation” instruction preceding both sham and real magnetic stimulation was as follows: ‘‘During this stimulation period you will receive a 15 min TMS treatment of higher intensity than in the previous training run. The long stimulation period, paired with higher stimulation intensity, strengthens the experience of reduced pain even more. Please note that after magnetic stimulation you will perceive the increasing heat as much less painful
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Fig. 1. Experimental design. After the expectation induction procedure (10 min segment) participants in the ‘‘analgesia-expectation” (‘‘TMS as painkiller”, upper panel) and the ‘‘false-expectation” condition (‘‘TMS as measurement device”, lower panel) received 15 min of sham or real 1 Hz rTMS treatment over the right and left DLPFC (first 15 min segment). Stimulation side was counterbalanced. Participants’ heat pain threshold (H; green–yellow color bar) and tolerance (green–yellow–red color bar) were measured on both forearms (counterbalanced and homologous sites) at baseline (12 min segment) and after either sham or real rTMS treatments (two 7 min segments; see middle panel for a detailed description of the pain measurement time course). Participants rated their mood before and immediately after the rTMS trains (yellow bars and face symbols). Perceived treatment efficacy on pain experience was assessed at the end of the last pain measurement. Analgesia-expectation was rated before the experimental break (7 min segment) and at the end of the experiment (last 15 min segment). See methods section for details. Note: Time interval representations do not correspond to real time proportions.
than before. Moreover, you will be able to endure strong pain for a prolonged period of time”. During the entire treatment, the sentence ‘‘your pain matrix is now being inhibited; maximal pain resistance will be achieved in X (remaining) minutes” was presented on the screen. Participants in the ‘‘false-expectation” condition were only told that their skin conductance would be measured during the 15 min rTMS run and during the subsequent pain measurement as well, and that rTMS would influence, if anything, only autonomous parameters (but not pain experience). In all four groups sham skin conductance electrodes were attached to the right and left palm of the hand. As for the ‘‘analgesia-expectation” procedure, remaining stimulation time until rTMS-completion was displayed on the screen. 2.4. Transcranial magnetic stimulation Following instruction, rTMS was delivered using a MagPro X100 stimulator (Medtronic-DantecÒ, Skovlunde, Denmark) with an 8-shaped cooled coil (Cool-B65; inner radius = 2 17.5 mm, outer radius = 2 37.5 mm, winding high = 12 mm, 2 10 windings, maximum magnetic field = 2.5 T). Current waveform was biphasic. The magnetic coil was positioned over the scalp of participants using
the 10–20 EEG international system as a reference, where on a larger scale level C3 approximately corresponds to left primary motor cortex, F3 to the left and F4 to the right Brodmann areas (BA) 8/9 within the DLPFC [16]. Positions were marked on participants’ scalps using individual EEG-Caps [16,39]. Albeit this procedure does not take into account possible interindividual neuronanatomical differences, it has been shown to reach desired cortex regions reliably on a large scale level and to be an acceptable compromise between precision and head shape individuality on the one hand and costs on the other [16]. Coil angle, contact surface and coil position were kept constant by using a coil stand (MagPro X100) and a thin (0.1 mm) plastic template, which was directly fixed on the EEG-Cap (see SM Fig. 2). The magnetic coil was positioned tangentially to the scalp with its handle pointing in an antero-medial direction, 45° from the mid-sagittal axis of the subject’s head. To determine experimental stimulation intensity, individual resting motor threshold (RMT) was measured first. RMT was defined as the minimum stimulator output sufficient to elicit a motor evoked potential (MEP) greater than 50 lV, base-to-peak amplitude, in the relaxed abductor pollicis brevis in at least 4 of 7 successive trials. Experimental stimulation intensity was set at 100% of the individual resting motor threshold (RMT).
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*
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Half of the participants in the ‘‘false-expectation” and ‘‘analgesia-expectation” condition received two real, 1 Hz rTMS trains of 15 min each (2 900 pulses) over the left and right DLPFC while the other half received sham stimulation (placebo coil: Medtronic MCF-B65). Stimulation side was counterbalanced. The inter-traininterval was 35 min (see Fig. 1). Such a stimulation protocol results in depression of cortical excitability of the targeted cortical region for approximately half the duration of the stimulation train itself, being maximal beneath the midline of the coil [10,38].
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2.5. Questionnaires
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sham-TMS real-TMS
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Threshold difference score (°C)
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false-expectation 0.6
analgesia-expectation
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Tolerance difference score (°C)
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0.0
-0.2
**
-0.4
-0.6
100
Perceived treatment efficiency (pain reduction)
371
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2.6. Statistical analyses false-expectation
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analgesia-expectation
* *
*
80
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20
0
Measurement of participants’ mood: Participants rated their mood four times, once immediately before and once immediately after the two rTMS trains (see Fig. 1). Ratings were assessed with 24 adjectives from the German Multidimensional Mood questionnaire (MDBF) [43]. The MDBF questionnaire is a short, multidimensional, self-evaluative questionnaire that describes the current mood state of an individual on three dimensions ‘‘good vs. bad mood”, ‘‘wakefulness vs. sleepiness”, and ‘‘calmness vs. restlessness”. Subjective treatment evaluation: At the end of the experiment, participants retrospectively evaluated the generally – arm side unspecific – perceived effect of rTMS for both hemispheres on their pain experience in a two-step procedure. First, they indicated the direction of perceived altered pain experience (i.e. increased, decreased or no effect). Thereafter, they judged the magnitude of this effect using a 10-cm visual analog scale (VAS), where 0 indicated ‘‘no effect at all” and 10 a ‘‘very strong effect”. Measurement of expectation: Participants retrospectively rated the magnitude of their expectation regarding rTMS and pain modulation on a 10-cm VAS. The left end of the scale indicated ‘‘no expectation at all” while the right end indicated a ‘‘very high expectation”. Ratings were given twice, once after each treatment in order to prevent participants from becoming skeptic about the analgesia procedure.
false-expectation
analgesia-expectation
Fig. 2. Difference score (treatment condition baseline condition) of heat pain threshold (A) and tolerance (B) (mean ± SEM) for subjects receiving real rTMS (‘‘real-TMS”; gray bars) or sham rTMS (‘‘sham-TMS”; white bars) in both expectation conditions (‘‘analgesia-expectation” or ‘‘false-expectation”). Baseline level = 0; placebo analgesia = positive values. Asterisks (*,**) indicate significant post-hoc and baseline comparisons (*p < 0.05; **p < 0.01). Data are averaged over application side (left and right hemisphere) and side of pain application (left and right forearm). (C) Retrospectively assessed perceived treatment efficiency on pain experience (mean ± SEM), indicated on a VAS (0–100 mm). 100 mm = maximal perceived TMS-related pain reduction. Data are averaged over application side (left and right hemisphere).
Initially, three separate two-way ANOVAs on age, educational level and strength of right-handedness were computed. They included the factors expectation condition (analgesia vs. false) and treatment group (sham vs. real-TMS). Main measures were the within-subject difference scores (in °C) of heat pain threshold and tolerance between treatment and baseline. Negative values reflected lower threshold and tolerance compared to baseline. Positive values indicated placebo analgesia. These two main measures were subjected to two separate fourway repeated-measures ANOVAs with expectation condition (analgesia vs. false) and treatment group (sham vs. real-TMS) as between-subject factors and application side (left vs. right DLPFC) and side of pain application (left vs. right forearm) as within-subject factors. To assess the effect of treatment on mood, we computed a difference score for test session by subtracting pre- from post-treatment sessions. Negative values indicated lower mood scores after treatment. A four-way repeated measure ANOVA was then computed on this difference score comprising the between-subject factors expectation condition (analgesia vs. false) and treatment group (sham vs. real rTMS), and the within-subject factors application side (left vs. right DLPFC) and mood dimension (valence, wakefulness, calmness). Perceived treatment analgesia efficiency was subjected to a three-way repeated measure ANOVA with expectation condition (analgesia vs. false) and treatment group (sham vs. real-TMS) as between-subject factors, and application side (left vs. right DLPFC) as within-subject factor.
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Post-hoc single comparisons were corrected for multiple comparisons by means of false discovery ratio (FDR 6 0.05) procedure [9]. In order to assess effects of repeated pain measurement (e.g. altered sensitivity or fatigue), deviations from baseline were tested by means of one-sample t-tests and were compared against a value of zero (i.e. baseline). All hypotheses were tested one-tailed with an alpha-level of p 6 0.05. One participant in the ‘‘analgesia-expectation/sham-TMS” group was identified as an outlier by the Grubbs-Test and by the Dixon-Test (two-tailed, p = .05; i.e. 2.2 SD). In addition, at the end of the experiment this individual explicitly stated that he was extremely scared of the TMS device. For this reason, this participant was excluded from further analyses. 3. Results 3.1. Subjects The four groups (expectation condition treatment group) did not differ in age (F(1, 35) 6 2.281, p P .140), education (F(1, 35) 6 2.881, p P .099) and strength of right-handedness (F(1, 35) 6 1.519, p P .226) (Table 1). In addition, participants’ analgesia-expectations in both treatment groups (‘‘sham-” and ‘‘real-TMS”, respectively) were comparable (‘‘sham-TMS” group: mean = 37.0, SD = 27.07; ‘‘real-TMS” group: mean = 36.9, SD = 27.72) (p = .764). 3.1.1. rTMS Individual resting motor threshold (RMT) in the groups treated with ‘‘real-TMS” ranged from 39% to 54% of maximum stimulator output in the ‘‘analgesia-expectation” (mean = 47.2, SD = 4.3%), and from 41% to 52% in the ‘‘false-expectation” condition (mean 48.3, SD = 3.2%) and did not significantly differ between groups (p = .524). 3.1.2. Mood ANOVA on mood difference scores revealed a significant main effect for mood dimension (F(1, 35) = 19.932, p < .000). One-sample t-tests showed that this effect was mainly due to the dimension wakefulness/sleepiness. After the treatment, irrespective of TMS application side, ‘‘real-” or ‘‘sham-TMS” or ‘‘false” or ‘‘analgesiaexpectation”, participants felt more tired (p < .000), and slightly less happy (p = .078). 3.2. Pain threshold ANOVA for pain threshold revealed a significant main effect for the expectation condition (F(1, 35) = 8.390, p = .006; analgesia > false) as well as a main effect for treatment (F(1, 35) = 6.679, p = .014; ‘‘real-TMS” < ‘‘sham-TMS”). Most importantly, these two factors interacted significantly with each other (F(1, 35) = 6.434, p = .016) (Fig. 2A). Corrected post-hoc t-test comparisons revealed that rTMS per se did not affect pain threshold in the false-expectation condition (p = .961). In participants deliberately misled to expect analgesia, pain threshold in the
‘‘sham-TMS” group was significantly higher compared to the ‘‘real-TMS” group (p < .033). In addition, pain threshold in the ‘‘sham-TMS” treated groups, were higher in the ‘‘analgesia-expectation” than in the ‘‘false-expectation” condition (p < .017). In contrast, the groups in the ‘‘analgesia-” and ‘‘false-expectation” condition, both treated with the ‘‘real-TMS”, did not significantly differ in their pain threshold score (p = .784) (Fig. 2A). These pain threshold data indicate a clear placebo analgesia in the ‘‘analgesia-expectation” condition which was completely blocked by TMS-induced disruption of DLPFC function. 3.3. Pain tolerance ANOVA for heat pain tolerance revealed a significant main effect for the expectation condition (analgesia > false) (F(1, 35) = 7.929, p = .008) and a significant interaction between expectation condition and treatment group (F(1, 35) = 4.304, p = .045) (Fig. 2B). Corrected post-hoc t-test comparisons revealed similar pain tolerance scores between the ‘‘sham-” and ‘‘real-TMS” groups in the ‘‘falseexpectation” condition (p = .635), indicating that rTMS alone did not affect pain tolerance. In contrast, for participants expecting analgesia, pain tolerance in the ‘‘real-TMS” group was significantly lower than in the ‘‘sham-TMS” group (p < .033). In addition, subjects in the ‘‘sham-TMS” group in the ‘‘analgesia-expectation” condition revealed significantly higher pain tolerance scores compared to the ‘‘sham-TMS” group in the ‘‘false-expectation” condition (p < .017). In parallel with the pain threshold results, these data in pain tolerance document a significant placebo analgesia which was thoroughly abrogated by TMS treatment. 3.4. Subjective reports Subjective evaluation for treatment analgesia efficiency revealed a significant main effect for the expectation condition (analgesia > false) (F(1, 35) = 62.116, p < .001). Moreover, a significant interaction between expectation condition and treatment group (‘‘real-/sham-TMS”) was revealed (F(1, 35) = 4.574, p = .040; see Fig. 2C). In contrast, no other main (F(1, 35) 6 1.190, p P .283) or interaction effects (F(1, 35) 6 .402, p P .530) were statistical significant. Corrected post-hoc t-test comparisons showed that participants with a deceptively induced analgesia-expectation in the ‘‘sham-TMS” group perceived pain reduction as more effective than those subjects in the ‘‘real-TMS” group (p < .038). In addition, in the ‘‘analgesia-expectation” condition, both treatment groups (‘‘shamTMS” and ‘‘real-TMS”) rated the pain reduction as more effective than did participants in the ‘‘false-expectation” condition (‘‘sham-TMS” group: p < .013; ‘‘real-TMS” group: p < .025). 4. Discussion Cognitive factors such as expectations and beliefs modulate the experience of pain and in particular placebo analgesia. Until now, studies addressing the mechanisms underlying the placebo process have only provided correlative associations between brain struc-
Table 1 Descriptive data of the study sample. Data correspond to the two expectation conditions (‘‘analgesia-expectation” or ‘‘false-expectation”) and the two corresponding treatment subgroups (‘‘sham-TMS” and ‘‘real-TMS”). Analgesia-expectation Sham-TMS (n = 9)
Age (year) Education (year) Handedness
False-expectation Real-TMS (n = 10)
Sham-TMS (n = 10)
Real-TMS (n = 10)
Mean (SD)
Range
Mean (SD)
Range
Mean (SD)
Range
Mean (SD)
Range
26.0 (7.2) 14.1 (3.1) 13.8 (1.7)
20–43 10–20 13–18
27.9 (7.7) 15.8 (2.8) 14.0 (1.1)
20–43 10–20 13–18
24.6 (7.0) 13.1 (2.1) 13.3 (0.7)
20–41 9–16 13–15
23.0 (3.3) 13.8 (2.9) 14.0 (1.1)
20–31 10–20 13–16
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tures and function. In order to analyze the critical contribution of prefrontal cortex structures, we employed a heat-pain paradigm. We implemented a parallel matched group design including an interventional approach with real or sham non-invasive low-frequency repetitive transcranial magnetic stimulation (rTMS) in healthy subjects and analyzed both, heat pain tolerance and pain threshold. In line with our hypothesis, placebo analgesia reflected by a significantly increased pain threshold and pain tolerance was observed in those subjects who received the ‘‘analgesiaexpectation” and who were treated with ‘‘sham-TMS”. In contrast, subjects with the ‘‘false-expectation” did not show placebo analgesia. These results clearly indicate that heat pain tolerance and pain threshold are rather dynamic variables that can be modified not only by pharmacological or physiological but also by psychological factors [13]. Placebo analgesia is thought to be mediated by prefrontal neural mechanisms involving the release of opioids in subcortical regions, e.g. midbrain, which subsequently reduce pain transmission [3,5,47]. In order to analyze the role of prefrontal neural mechanisms in placebo analgesia, subjects in the ‘‘falseexpectation” as well in the ‘‘analgesia-expectation” condition were treated with rTMS. These results show that the rTMS treatment did not affect pain perception at all. More importantly, disruption of prefrontal cortex function with TMS completely blocked expectation-induced placebo analgesia. Since the TMS treatment groups did not differ in self-reported analgesia-expectations, the reported placebo analgesia can neither simply be attributed to compliance with the investigator’s suggestions nor to the result of biases in the suggestion used. In addition, these data are further supported by an analog pattern of results in participants’ self-reported and retrospectively perceived treatment efficacy on pain experience. Both groups in the ‘‘analgesia-expectation” condition reported more effective pain reduction than participants in the ‘‘falseexpectation” condition. Furthermore, analgesia expecting participants in the ‘‘real-TMS” group perceived the ‘‘pain-treatment” as less effective than those in the ‘‘sham-TMS” group. Several peripheral and central nervous mechanisms may explain the rTMS blockade of placebo analgesia over the PFC. First, peripheral effects such as auditory clicks, stimulation of nearby nerves and muscle twitches may non-specifically interfere with task performance [17]. However, this appears to be an unlikely explanation for the present results since reports on qualitative and quantitative effects after the treatments were neither condition nor treatment dependent, and there were no indications of adverse responses to rTMS. Second, emotional factors are known to play a role in the placebo response [33], and rTMS may affect mood either indirectly due to discomfort during the stimulation and/or directly by modulating emotional processes in both hemispheres. However, this is also not a likely factor in the present findings given that participants’ mood interacted neither with stimulated brain hemisphere nor with the treatment in all four groups [18]. It has been proposed that the right hemisphere is more involved in pain processing compared to the left hemisphere, consistent with a role of the right hemisphere in negative emotional perception and withdrawal-related behaviors [8]. For example, in a recent rTMS study [15], 15 min of 1 Hz rTMS (100%) over the right DLPFC increased cold pressure pain tolerance for the right and left hand during, but not after, the rTMS treatment. However, as stated by the authors, the study sample was highly heterogeneous in age, education level and handedness. Beside this, we used a rather long verbal instruction that participants had to read and this process of left hemisphere-related verbal-monitoring may have led to a relative inhibition of the right hemisphere, compensating a possible laterality effect. In this experiment, we investigated the laterality
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hypothesis within the context of placebo responses but found no evidence in favor of a lateralized placebo effect when using heat pain; placebo responses for heat pain threshold and tolerance did not differ between left and right forearms. Most importantly, both pain indexes were suppressed following rTMS over the left and right DLPFC. This finding is especially interesting since several correlative imaging studies suggested a more right ventrolateral PFC and orbitofrontal cortex involvement [4,26,31,34] in the placebo analgesia process. The DLPFC has been related to the generation, maintenance and manipulation of cognitive representations within a high degree of executive control demanding working memory [29,32]. It has also been implicated in general attentional processes [29]. Thus, the absence of a placebo response in expectation-induced subjects following rTMS over the PFC seems to be a consequence of a transiently disrupted cognitive representation of pain analgesia and the result of redirected attention away from pain [35]. Given that the PFC is considered to be one of the most complex and interconnected structures in the human brain [29], possible remote effects of rTMS and functional disinhibition processes cannot be completely ruled out in the present experimental design. TMS can have either a direct effect on the stimulation side and/or an indirect effect through trans-synaptic connections to distal networks [10]. For example, functional brain imaging studies combined with 1 Hz rTMS over the DLPFC have shown metabolic [20] and regional blood flow changes in the anterior cingulate cortex (ACC) and midbrain [42]. The ACC has repeatedly been shown to play a crucial role in cortical control of brainstem during placebo analgesia [12,34]. In addition, the dorsolateral and ventrolateral PFC are closely interconnected [48], and stimulation of one leads to ipsilateral co-activation of the other [10]. The ventrolateral PFC has been hypothesized to be involved in the cognitive modulation of pain, reflecting context-dependent reappraisal of the emotional significance of a pain stimulus [48]. Furthermore, the ventrolateral and orbitofrontal have both been implicated in processing reward expectations and aversive prediction of error signals [41] which have repeatedly been shown to be important in the placebo response. Our present data do not allow a disentangling of differential roles for the two prefrontal areas in the observed placebo analgesia. Therefore, a combination of brain imaging, in particular diffusion tensor techniques and other interventional approaches, as well as improved rTMS double-blind control methodologies [17] may shed more light on these issues. In addition, the specificity of the DLPFC for the expectation effect needs to be consolidated in further studies, which should include control sites over other cortical regions in order to completely rule out a generalized rTMS effect. Viewed from a broader perspective, our results may also have indirect as well as direct clinical implications. We used low frequency rTMS according to current safety guidelines [28]. However, with increasing knowledge, high frequency rTMS or alternatively transcranial direct current stimulation (tDCS) might be used to facilitate prefrontal cortical excitability, which might result in an amplification of expectations and consequently enhance the placebo response. In summary, our data provide evidence supporting an expectation-related placebo effect on pain threshold and tolerance that was suppressed after rTMS over the PFC. Based on these results, we suggest that the contribution of expectancy to placebo analgesia depends on the activity level of the prefrontal cortex. Our approach complements previous pharmacological and imaging approaches, helping to better differentiate between associative learning and expectation mechanisms in placebo analgesia in the context of neurocognitive pain research [48].
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5. Competing interest statement The authors declare that they have no competing financial interests. Acknowledgements We thank G. Thut for helpful advice regarding rTMS and P.C. Cattin for programming the sham display. We further thank N. Schaffner, A. Wittwer, E. Kut, J. Stern, V. Pliska and A. Borg for help during the preparation of the study and P. Brugger for critical reading of the manuscript. This research was supported by a grant from the OPO Foundation and the Cogito Foundation. Appendix A. Supplementary data Supplementary data associated with this article can be found, in the online version, at doi:10.1016/j.pain.2009.09.033. References [1] Amanzio M, Benedetti F. Neuropharmacological dissection of placebo analgesia: expectation-activated opioid systems versus conditioningactivated specific subsystems. J Neurosci 1999;19:484–94. [2] Benedetti F. Mechanisms of placebo and placebo-related effects across diseases and treatments. Annu Rev Pharmacol Toxicol 2008;48:33–60. [3] Benedetti F, Arduino C, Costa S, Vighetti S, Tarenzi L, Rainero I, Asteggiano G. Loss of expectation-related mechanisms in Alzheimer’s disease makes analgesic therapies less effective. Pain 2006;121:133–44. [4] Benedetti F, Mayberg HS, Wager TD, Stohler CS, Zubieta JK. Neurobiological mechanisms of the placebo effect. J Neurosci 2005;25:10390–402. [5] Bingel U, Schoell E, Buchel C. Imaging pain modulation in health and disease. Curr Opin Neurol 2007;20:424–31. [6] Campbell JJ. Neuropsychiatric assessment. In: Coffey C, Cummings E, editors. Textbook of geriatric neuropsychiatry. Washington, DC: American Psychiatric Press; 2000. p. 109–24. [7] Colloca L, Benedetti F. How prior experience shapes placebo analgesia. Pain 2006;124:126–33. [8] Craig AD. Forebrain emotional asymmetry: a neuroanatomical basis? Trends Cogn Sci 2005;9:566–71. [9] Curran-Everett D. Multiple comparisons: philosophies and illustrations. Am J Physiol Regul Integr Comp Physiol 2000;279:R1–8. [10] Eisenegger C, Treyer V, Fehr E, Knoch D. Time-course of ‘‘off-line” prefrontal rTMS effects – a PET study. Neuroimage 2008;42:379–84. [11] Enck P, Benedetti F, Schedlowski M. New insights into the placebo and nocebo responses. Neuron 2008;59:195–206. [12] Faria V, Fredrikson M, Furmark T. Imaging the placebo response: a neurofunctional review. Eur Neuropsychopharmacol 2008;18:473–85. [13] Gardner E, Martin J. Coding of sensory information. In: Kandel E, Schwartz J, Jessell T, editors. Principles of neural science. New York: McGraw-Hill; 2000. p. 411–29. [14] Geers AL, Helfer SG, Weiland PE, Kosbab K. Expectations and placebo response: a laboratory investigation into the role of somatic focus. J Behav Med 2006;29:171–8. [15] Graff-Guerrero A, Gonzalez-Olvera J, Fresan A, Gomez-Martin D, MendezNunez JC, Pellicer F. Repetitive transcranial magnetic stimulation of dorsolateral prefrontal cortex increases tolerance to human experimental pain. Brain Res Cogn Brain Res 2005;25:153–60. [16] Herwig U, Satrapi P, Schonfeldt-Lecuona C. Using the international 10–20 EEG system for positioning of transcranial magnetic stimulation. Brain Topogr 2003;16:95–9. [17] Hoeft F, Wu DA, Hernandez A, Glover GH, Shimojo S. Electronically switchable sham transcranial magnetic stimulation (TMS) system. PLoS One 2008;3:e1923. [18] Jenkins J, Shajahan PM, Lappin JM, Ebmeier KP. Right and left prefrontal transcranial magnetic stimulation at 1 Hz does not affect mood in healthy volunteers. BMC Psychiatry 2002;2:1. [19] Keel JC, Smith MJ, Wassermann EM. A safety screening questionnaire for transcranial magnetic stimulation. Clin Neurophysiol 2000;112:720. [20] Kimbrell TA, Dunn RT, George MS, Danielson AL, Willis MW, Repella JD, Benson BE, Herscovitch P, Post RM, Wassermann EM. Left prefrontal-repetitive transcranial magnetic stimulation (rTMS) and regional cerebral glucose metabolism in normal volunteers. Psychiatry Res 2002;115:101–13. [21] Koshi EB, Short CA. Placebo theory and its implications for research and clinical practice: a review of the recent literature. Pain Pract 2007;7:4–20.
[22] Koyama T, McHaffie JG, Laurienti PJ, Coghill RC. The subjective experience of pain: where expectations become reality. Proc Natl Acad Sci USA 2005;102:12950–5. [23] Kut E, Schaffner N, Wittwer A, Candia V, Brockmann M, Storck C, Folkers G. Changes in self-perceived role identity modulate pain perception. Pain 2007;131:191–201. [24] Leuchter AF, Cook IA, Witte EA, Morgan M, Abrams M. Changes in brain function of depressed subjects during treatment with placebo. Am J Psychiatry 2002;159:122–9. [25] Lidstone SC, Stoessl AJ. Understanding the placebo effect: contributions from neuroimaging. Mol Imaging Biol 2007;9:176–85. [26] Lieberman MD, Jarcho JM, Berman S, Naliboff BD, Suyenobu BY, Mandelkern M, Mayer EA. The neural correlates of placebo effects: a disruption account. Neuroimage 2004;22:447–55. [27] Lorenz J, Minoshima S, Casey KL. Keeping pain out of mind: the role of the dorsolateral prefrontal cortex in pain modulation. Brain 2003;126:1079–91. [28] Machii K, Cohen D, Ramos-Estebanez C, Pascual-Leone A. Safety of rTMS to non-motor cortical areas in healthy participants and patients. Clin Neurophysiol 2006;117:455–71. [29] Miller EK, Cohen JD. An integrative theory of prefrontal cortex function. Annu Rev Neurosci 2001;24:167–202. [30] Pacheco-Lopez G, Engler H, Niemi MB, Schedlowski M. Expectations and associations that heal: immunomodulatory placebo effects and its neurobiology. Brain Behav Immun 2006;20:430–46. [31] Pariente J, White P, Frackowiak RS, Lewith G. Expectancy and belief modulate the neuronal substrates of pain treated by acupuncture. Neuroimage 2005;25:1161–7. [32] Petrides M, Pandya DN. Dorsolateral prefrontal cortex: comparative cytoarchitectonic analysis in the human and the macaque brain and corticocortical connection patterns. Eur J Neurosci 1999;11:1011–36. [33] Petrovic P, Dietrich T, Fransson P, Andersson J, Carlsson K, Ingvar M. Placebo in emotional processing-induced expectations of anxiety relief activate a generalized modulatory network. Neuron 2005;46:957–69. [34] Petrovic P, Kalso E, Petersson KM, Ingvar M. Placebo and opioid analgesia – imaging a shared neuronal network. Science 2002;295:1737–40. [35] Peyron R, Garcia-Larrea L, Gregoire MC, Costes N, Convers P, Lavenne F, Mauguiere F, Michel D, Laurent B. Haemodynamic brain responses to acute pain in humans: sensory and attentional networks. Brain 1999;122:1765–80. [36] Peyron R, Laurent B, Garcia-Larrea L. Functional imaging of brain responses to pain. A review and meta-analysis (2000). Neurophysiol Clin 2000;30: 263–88. [37] Price DD, Milling LS, Kirsch I, Duff A, Montgomery GH, Nicholls SS. An analysis of factors that contribute to the magnitude of placebo analgesia in an experimental paradigm. Pain 1999;83:147–56. [38] Robertson EM, Theoret H, Pascual-Leone A. Studies in cognition: the problems solved and created by transcranial magnetic stimulation. J Cogn Neurosci 2003;15:948–60. [39] Rossi S, Cappa SF, Babiloni C, Pasqualetti P, Miniussi C, Carducci F, Babiloni F, Rossini PM. Prefrontal [correction of Prefontal] cortex in long-term memory: an ‘‘interference” approach using magnetic stimulation. Nat Neurosci 2001;4:948–52. [40] Scott DJ, Stohler CS, Egnatuk CM, Wang H, Koeppe RA, Zubieta JK. Individual differences in reward responding explain placebo-induced expectations and effects. Neuron 2007;55:325–36. [41] Seymour B, O’Doherty JP, Koltzenburg M, Wiech K, Frackowiak R, Friston K, Dolan R. Opponent appetitive–aversive neural processes underlie predictive learning of pain relief. Nat Neurosci 2005;8:1234–40. [42] Speer AM, Willis MW, Herscovitch P, Daube-Witherspoon M, Shelton JR, Benson BE, Post RM, Wassermann EM. Intensity-dependent regional cerebral blood flow during 1-Hz repetitive transcranial magnetic stimulation (rTMS) in healthy volunteers studied with H215O positron emission tomography: II. Effects of prefrontal cortex rTMS. Biol Psychiatry 2003;54:826–32. [43] Steyer R, Schwenkmezger P, Notz P, Eid M. MDBF – Mehrdimensionaler Befindlichkeitsfragebogen [Multidimensional mood questionnaire]. Goettingen, Germany: Hogrefe Verlag; 1997. [44] Strafella AP, Ko JH, Monchi O. Therapeutic application of transcranial magnetic stimulation in Parkinson’s disease: the contribution of expectation. Neuroimage 2006;31:1666–72. [45] Vase L, Riley 3rd JL, Price DD. A comparison of placebo effects in clinical analgesic trials versus studies of placebo analgesia. Pain 2002;99:443–52. [46] Voudouris NJ, Peck CL, Coleman G. The role of conditioning and verbal expectancy in the placebo response. Pain 1990;43:121–8. [47] Wager TD, Rilling JK, Smith EE, Sokolik A, Casey KL, Davidson RJ, Kosslyn SM, Rose RM, Cohen JD. Placebo-induced changes in FMRI in the anticipation and experience of pain. Science 2004;303:1162–7. [48] Wiech K, Ploner M, Tracey I. Neurocognitive aspects of pain perception. Trends Cogn Sci 2008;12:306–13. [49] Zubieta JK, Bueller JA, Jackson LR, Scott DJ, Xu Y, Koeppe RA, Nichols TE, Stohler CS. Placebo effects mediated by endogenous opioid activity on mu-opioid receptors. J Neurosci 2005;25:7754–62.
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Research papers
Prefrontal cortex modulates placebo analgesia Peter Krummenacher a,*, Victor Candia a, Gerd Folkers a, Manfred Schedlowski b, Georg Schönbächler a,c a
Collegium Helveticum, Schmelzbergstrasse 25, CH-8092 Zurich, Switzerland Institute of Medical Psychology and Behavioral Immunobiology, University Clinic Essen, 45122 Duisburg-Essen, Germany c Department of Psychology, University of Cape Town, Rondebosch 7701, South Africa b
a r t i c l e
i n f o
Article history: Received 22 July 2009 Received in revised form 10 September 2009 Accepted 30 September 2009
Keywords: Placebo analgesia Expectation Transcranial magnetic stimulation Dorsolateral prefrontal cortex
a b s t r a c t Expectations and beliefs modulate the experience of pain, which is particularly evident in placebo analgesia. The dorsolateral prefrontal cortex (DLPFC) has been associated with pain regulation and with the generation, maintenance and manipulation of cognitive representations, consistent with its role in expectation. In a heat-pain paradigm, we employed non-invasive low-frequency repetitive transcranial magnetic stimulation (rTMS) to transiently disrupt left and right DLPFC function or used the TMS device itself as a placebo, before applying an expectation-induced placebo analgesia. The results demonstrated that placebo significantly increased pain threshold and pain tolerance. While rTMS did not affect pain experience, it completely blocked placebo analgesia. These findings suggest that expectation-induced placebo analgesia is mediated by symmetric prefrontal cortex function. Ó 2009 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved.
1. Introduction Expectations and beliefs shape reality by affecting our perception and influencing our behavior. They influence behavior by modulating the neural processes that mediate the actual sensory experience [22], and affect perception by directing attention to and guiding interpretation of both internal and external sensations [14,22]. The role of expectations in sensory experiences is especially relevant in the context of pain processing [48], and research addressing the mechanisms mediating placebo analgesia have increasingly attracted scientific interest in recent years. The placebo response is a widespread, heterogeneous [2] and multidimensional learning phenomenon [7] which involves both subcortical (unconscious) conditioning and cortical (conscious) expectation mechanisms [11,21]. Over time, the concept of the placebo has shifted from that of an inert sugar pill to the implicit or explicit psychosocial stimulation of a therapeutic procedure [2]. A wide range of neurobiological mechanisms of placebo analgesia have been described. For example, both, expectation mediated and opioid conditioned placebo analgesia has been shown to activate endogenous opioids as it can be reversed by the mu-opioid antagonist naloxone [1]. In addition, placebo analgesia is reportedly dependent on reward-related dopaminergic activity [40], shares a common neural network with opioid analgesia [34], and reduces neural transmission in pain pathways [47].
* Corresponding author. Address: University of Zurich and ETH Zurich, Collegium Helveticum, Schmelzbergstrasse 25, CH-8092 Zurich, Switzerland. Tel.: +41(0) 44 632 54 35; fax: +41(0) 44 632 12 04. E-mail address: [email protected] (P. Krummenacher).
A growing body of evidence from lesion [3] and neuroimaging studies [12,25] highlights the critical role of the prefrontal cortex (PFC) in placebo analgesia. For example, in Alzheimer patients, the loss of communication between the prefrontal lobes and the rest of the brain results in a disruption of expectancy-related mechanisms, which has been correlated with reduced placebo analgesia [3]. However, patient studies are limited by confounding factors such as diffuse lesions, chronic medication, side effects and secondary brain plasticity processes. The dorsolateral PFC in particular has repeatedly been shown to be involved in expectation-related placebo analgesia [31,47,49] as well as in cognitive and attention-related pain regulation [15,27,29,32,36]. Pain processing has been associated with a predominant right hemisphere involvement [15]. Indirect evidence in favor of asymmetric cortical processing comes from functional imaging studies with acupuncture treatment [31], patients with depression [24] and irritable bowel syndrome [26], and suggests a right PFC preponderance in the general modulation of the placebo response. However, a possible lateralization of the neural underpinnings of placebo analgesia has never been directly tested. To enhance our understanding of left and right DLPFC contribution to placebo analgesia, we employed repetitive transcranial magnetic stimulation (rTMS) to transiently disrupt left and right PFC function. We thereby aimed to investigate whether the sensory components of placebo analgesia can be modified in healthy participants with high placebo analgesia-expectation. Employing a heat-pain paradigm, we tested three hypotheses. First, we predicted that placebo analgesia would affect pain threshold and tolerance after the deceptive induction of specific analgesia-expectation. Second, we hypothesized that placebo analgesia would be
0304-3959/$36.00 Ó 2009 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved. doi:10.1016/j.pain.2009.09.033
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suppressed following inhibition of the PFC by means of low frequency rTMS. Finally, we predicted a predominantly right PFC involvement in the placebo response and concomitant peripheral pain asymmetry as evidenced by a higher pain threshold and tolerance on the left arm after placebo treatment.
2. Methods 2.1. Subjects Forty healthy right-handed men (mean Chapman score = 13.9, SD = 1.3, range = 13–18), age 20–43 years (mean = 25.3, SD = 6.5)] gave written informed consent for the study, which was approved by the Local Ethics Committee. All participants were naïve to TMS, guaranteeing a non-confounded sham condition. Participants were screened using the transcranial magnetic stimulation adult safety screening protocol [19] and a neuropsychiatric assessment questionnaire [6]. Exclusion criteria were the presence of acute or chronic pain, sensory abnormalities affecting the thermal perception modality, a history of neurological disorder, mental illness, drug or alcohol consumption, current use of central nervous system medication or any other factor contraindicated for TMS [28] or heat pain measurements. All participants were paid 80 Swiss francs for their participation in the study. Half of the participants were assigned to an analgesia-expectation condition (‘‘analgesia-expectation”) and the other half to a control expectation condition (‘‘false-expectation”) (Fig. 1). At the time of recruitment, participants in the ‘‘analgesia-expectation” condition were informed that the effectiveness of a new powerful device (i.e. the TMS device) to reduce pain experience was being evaluated (i.e. TMS as a painkiller). Twenty other volunteers were assigned to the ‘‘false-expectation” condition and individually matched with the ‘‘analgesia-expectation” for age and educational background. These volunteers had responded to the same recruitment procedure, which used a similar advertisement. However, the passage referring to pain reduction and rTMS now had the heading ‘‘Does rTMS have an impact on autonomous physiological reactions like skin conductance during painful and non-painful heat stimulation?” (i.e. that TMS would influence, if anything, only autonomous parameter but not pain experience). All participants in both conditions were told they would receive real-TMS, but this was true for only half of them. The participants in both conditions were randomly assigned to either ‘‘sham-TMS” or ‘‘real-TMS” treatment over the left and right DLPFC (see Fig. 1). This unconditioned deceptive design has been shown to produce much more powerful placebo responses than conditioned instructions [30,33,44,45]. After study completion, participants were fully informed about the real aims of the experiment. All participants were tested individually and did not see the investigator during the pain measurements. They were seated in a comfortable reclining chair in front of a 19-in. computer screen, head and arms stabilized by means of VelcroÒ straps and restraints. Room lighting, screen contrast and ambient temperature (19.5 °C) were all kept constant. Presentation of all instructions was carried out via a computer display and automatically controlled by ‘‘Superlab Pro 4” (by CedrusÓ) running on an Apple G4 PowerbookÓ, . Distance between each participant’s head and the computer screen was adjusted to permit undisturbed view and was kept at approximately 1.2 m for all participants. TM
2.2. Heat pain stimuli and measurement Heat pain measurements were performed three times per participant, at baseline and after each experimental condition (‘‘sham-TMS” or ‘‘real-TMS”) over the left and right DLPFC (see
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Fig. 1). Heat stimuli were administered in counterbalanced order to the left and right volar forearm using a 30 30-mm Peltier device (Medoc, Ramat-Yishai, Israel; TSA-II) placed at 2/3 of the distance from wrist to elbow. Individual pain threshold was measured using the search method starting at 42 °C: participants were asked to increase or decrease the magnitude of the heat stimulus to the transition point were they felt it changing from ‘‘hot” to ‘‘painful”. Participants were instructed to determine the transition point as precisely as possible (see [23] for detailed method references) and to use equally long response intervals (i.e. mouse click intervals) for altering temperature, and also to apply combined bottom-up (increasing temperature) and top-down (decreasing temperature) search strategies. Pain tolerance was determined by the method of limits: participants were asked to stop the increasing noxious heat stimulus at the moment they could no longer stand it. Three measurements starting at 35 °C, with a rise of 0.8 °C/s, were averaged. To avoid physical injury, the pain tolerance measurement stopped automatically at 52 °C. Prior to the actual measurements, participants were familiarized with the heat stimuli and the controlling device. Pain threshold was always measured prior to pain tolerance in order to minimize interactions between pain threshold and pain tolerance. All participants started with a practice trial for threshold and tolerance, counterbalanced for left and right forearm sites. 2.3. Expectation induction and placebo administration In the present study, the TMS device served as placebo [44]. Effective induction of pain treatment expectations can be achieved by lowering noxious stimulation levels (after an initial stimulus exposure), without informing participants about the real procedure [37,46]. Prior to rTMS treatment, misleading advertisement-induced expectations about TMS efficiency in reduction of pain experience were boosted in a multi-sensory learning procedure implemented with self-developed software. Following the message ‘‘The TMS apparatus is inhibiting pain perception”, sham visual feedback was provided by means of two color-coded intensity level bars (see SM Fig. 1). The bars represented rTMS- and heat level intensities, respectively (for both device intensity range 0–100%), and suggested a real association between increasing rTMS intensity and decreasing pain perception. The display heat level was set at a constant 60% for all participants and pain application trials, but participants were made to believe that this heat level corresponded exactly to their individual heat pain threshold. In both ‘‘analgesia-expectation” groups, participants experienced their real heat pain threshold first in order to credibly indicate that perceived pain level was congruent with the visual feedback on heat level (set at 60%) and TMS intensity (set at 0%, i.e. turned off). In the two consecutive trials, preceding a sham stimulation of 75 s, heat stimulus level was truly reduced by two intensity levels (conditioning level 1 = threshold minus 1 °C; conditioning level 2 = threshold minus 2 °C) while the display showed a constant heat (set at 60%) and increasing TMS intensity level (level 1: set at 20%; level 2: set at 60%). Conditioning-level pain stimuli were administered for 4 s. The occurrence of robust placebo and nocebo responses highly depends on the expectations induced by the experimental instruction [45]. The ‘‘analgesia-expectation” instruction preceding both sham and real magnetic stimulation was as follows: ‘‘During this stimulation period you will receive a 15 min TMS treatment of higher intensity than in the previous training run. The long stimulation period, paired with higher stimulation intensity, strengthens the experience of reduced pain even more. Please note that after magnetic stimulation you will perceive the increasing heat as much less painful
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Fig. 1. Experimental design. After the expectation induction procedure (10 min segment) participants in the ‘‘analgesia-expectation” (‘‘TMS as painkiller”, upper panel) and the ‘‘false-expectation” condition (‘‘TMS as measurement device”, lower panel) received 15 min of sham or real 1 Hz rTMS treatment over the right and left DLPFC (first 15 min segment). Stimulation side was counterbalanced. Participants’ heat pain threshold (H; green–yellow color bar) and tolerance (green–yellow–red color bar) were measured on both forearms (counterbalanced and homologous sites) at baseline (12 min segment) and after either sham or real rTMS treatments (two 7 min segments; see middle panel for a detailed description of the pain measurement time course). Participants rated their mood before and immediately after the rTMS trains (yellow bars and face symbols). Perceived treatment efficacy on pain experience was assessed at the end of the last pain measurement. Analgesia-expectation was rated before the experimental break (7 min segment) and at the end of the experiment (last 15 min segment). See methods section for details. Note: Time interval representations do not correspond to real time proportions.
than before. Moreover, you will be able to endure strong pain for a prolonged period of time”. During the entire treatment, the sentence ‘‘your pain matrix is now being inhibited; maximal pain resistance will be achieved in X (remaining) minutes” was presented on the screen. Participants in the ‘‘false-expectation” condition were only told that their skin conductance would be measured during the 15 min rTMS run and during the subsequent pain measurement as well, and that rTMS would influence, if anything, only autonomous parameters (but not pain experience). In all four groups sham skin conductance electrodes were attached to the right and left palm of the hand. As for the ‘‘analgesia-expectation” procedure, remaining stimulation time until rTMS-completion was displayed on the screen. 2.4. Transcranial magnetic stimulation Following instruction, rTMS was delivered using a MagPro X100 stimulator (Medtronic-DantecÒ, Skovlunde, Denmark) with an 8-shaped cooled coil (Cool-B65; inner radius = 2 17.5 mm, outer radius = 2 37.5 mm, winding high = 12 mm, 2 10 windings, maximum magnetic field = 2.5 T). Current waveform was biphasic. The magnetic coil was positioned over the scalp of participants using
the 10–20 EEG international system as a reference, where on a larger scale level C3 approximately corresponds to left primary motor cortex, F3 to the left and F4 to the right Brodmann areas (BA) 8/9 within the DLPFC [16]. Positions were marked on participants’ scalps using individual EEG-Caps [16,39]. Albeit this procedure does not take into account possible interindividual neuronanatomical differences, it has been shown to reach desired cortex regions reliably on a large scale level and to be an acceptable compromise between precision and head shape individuality on the one hand and costs on the other [16]. Coil angle, contact surface and coil position were kept constant by using a coil stand (MagPro X100) and a thin (0.1 mm) plastic template, which was directly fixed on the EEG-Cap (see SM Fig. 2). The magnetic coil was positioned tangentially to the scalp with its handle pointing in an antero-medial direction, 45° from the mid-sagittal axis of the subject’s head. To determine experimental stimulation intensity, individual resting motor threshold (RMT) was measured first. RMT was defined as the minimum stimulator output sufficient to elicit a motor evoked potential (MEP) greater than 50 lV, base-to-peak amplitude, in the relaxed abductor pollicis brevis in at least 4 of 7 successive trials. Experimental stimulation intensity was set at 100% of the individual resting motor threshold (RMT).
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*
0.2
Half of the participants in the ‘‘false-expectation” and ‘‘analgesia-expectation” condition received two real, 1 Hz rTMS trains of 15 min each (2 900 pulses) over the left and right DLPFC while the other half received sham stimulation (placebo coil: Medtronic MCF-B65). Stimulation side was counterbalanced. The inter-traininterval was 35 min (see Fig. 1). Such a stimulation protocol results in depression of cortical excitability of the targeted cortical region for approximately half the duration of the stimulation train itself, being maximal beneath the midline of the coil [10,38].
0.0
2.5. Questionnaires
1.0
A
0.8
sham-TMS real-TMS
0.6
Threshold difference score (°C)
*
0.4
-0.2
-0.4
**
-0.6
**
false-expectation 0.6
analgesia-expectation
*
B
*
Tolerance difference score (°C)
0.4
0.2
0.0
-0.2
**
-0.4
-0.6
100
Perceived treatment efficiency (pain reduction)
371
*
2.6. Statistical analyses false-expectation
C
analgesia-expectation
* *
*
80
60
40
20
0
Measurement of participants’ mood: Participants rated their mood four times, once immediately before and once immediately after the two rTMS trains (see Fig. 1). Ratings were assessed with 24 adjectives from the German Multidimensional Mood questionnaire (MDBF) [43]. The MDBF questionnaire is a short, multidimensional, self-evaluative questionnaire that describes the current mood state of an individual on three dimensions ‘‘good vs. bad mood”, ‘‘wakefulness vs. sleepiness”, and ‘‘calmness vs. restlessness”. Subjective treatment evaluation: At the end of the experiment, participants retrospectively evaluated the generally – arm side unspecific – perceived effect of rTMS for both hemispheres on their pain experience in a two-step procedure. First, they indicated the direction of perceived altered pain experience (i.e. increased, decreased or no effect). Thereafter, they judged the magnitude of this effect using a 10-cm visual analog scale (VAS), where 0 indicated ‘‘no effect at all” and 10 a ‘‘very strong effect”. Measurement of expectation: Participants retrospectively rated the magnitude of their expectation regarding rTMS and pain modulation on a 10-cm VAS. The left end of the scale indicated ‘‘no expectation at all” while the right end indicated a ‘‘very high expectation”. Ratings were given twice, once after each treatment in order to prevent participants from becoming skeptic about the analgesia procedure.
false-expectation
analgesia-expectation
Fig. 2. Difference score (treatment condition baseline condition) of heat pain threshold (A) and tolerance (B) (mean ± SEM) for subjects receiving real rTMS (‘‘real-TMS”; gray bars) or sham rTMS (‘‘sham-TMS”; white bars) in both expectation conditions (‘‘analgesia-expectation” or ‘‘false-expectation”). Baseline level = 0; placebo analgesia = positive values. Asterisks (*,**) indicate significant post-hoc and baseline comparisons (*p < 0.05; **p < 0.01). Data are averaged over application side (left and right hemisphere) and side of pain application (left and right forearm). (C) Retrospectively assessed perceived treatment efficiency on pain experience (mean ± SEM), indicated on a VAS (0–100 mm). 100 mm = maximal perceived TMS-related pain reduction. Data are averaged over application side (left and right hemisphere).
Initially, three separate two-way ANOVAs on age, educational level and strength of right-handedness were computed. They included the factors expectation condition (analgesia vs. false) and treatment group (sham vs. real-TMS). Main measures were the within-subject difference scores (in °C) of heat pain threshold and tolerance between treatment and baseline. Negative values reflected lower threshold and tolerance compared to baseline. Positive values indicated placebo analgesia. These two main measures were subjected to two separate fourway repeated-measures ANOVAs with expectation condition (analgesia vs. false) and treatment group (sham vs. real-TMS) as between-subject factors and application side (left vs. right DLPFC) and side of pain application (left vs. right forearm) as within-subject factors. To assess the effect of treatment on mood, we computed a difference score for test session by subtracting pre- from post-treatment sessions. Negative values indicated lower mood scores after treatment. A four-way repeated measure ANOVA was then computed on this difference score comprising the between-subject factors expectation condition (analgesia vs. false) and treatment group (sham vs. real rTMS), and the within-subject factors application side (left vs. right DLPFC) and mood dimension (valence, wakefulness, calmness). Perceived treatment analgesia efficiency was subjected to a three-way repeated measure ANOVA with expectation condition (analgesia vs. false) and treatment group (sham vs. real-TMS) as between-subject factors, and application side (left vs. right DLPFC) as within-subject factor.
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Post-hoc single comparisons were corrected for multiple comparisons by means of false discovery ratio (FDR 6 0.05) procedure [9]. In order to assess effects of repeated pain measurement (e.g. altered sensitivity or fatigue), deviations from baseline were tested by means of one-sample t-tests and were compared against a value of zero (i.e. baseline). All hypotheses were tested one-tailed with an alpha-level of p 6 0.05. One participant in the ‘‘analgesia-expectation/sham-TMS” group was identified as an outlier by the Grubbs-Test and by the Dixon-Test (two-tailed, p = .05; i.e. 2.2 SD). In addition, at the end of the experiment this individual explicitly stated that he was extremely scared of the TMS device. For this reason, this participant was excluded from further analyses. 3. Results 3.1. Subjects The four groups (expectation condition treatment group) did not differ in age (F(1, 35) 6 2.281, p P .140), education (F(1, 35) 6 2.881, p P .099) and strength of right-handedness (F(1, 35) 6 1.519, p P .226) (Table 1). In addition, participants’ analgesia-expectations in both treatment groups (‘‘sham-” and ‘‘real-TMS”, respectively) were comparable (‘‘sham-TMS” group: mean = 37.0, SD = 27.07; ‘‘real-TMS” group: mean = 36.9, SD = 27.72) (p = .764). 3.1.1. rTMS Individual resting motor threshold (RMT) in the groups treated with ‘‘real-TMS” ranged from 39% to 54% of maximum stimulator output in the ‘‘analgesia-expectation” (mean = 47.2, SD = 4.3%), and from 41% to 52% in the ‘‘false-expectation” condition (mean 48.3, SD = 3.2%) and did not significantly differ between groups (p = .524). 3.1.2. Mood ANOVA on mood difference scores revealed a significant main effect for mood dimension (F(1, 35) = 19.932, p < .000). One-sample t-tests showed that this effect was mainly due to the dimension wakefulness/sleepiness. After the treatment, irrespective of TMS application side, ‘‘real-” or ‘‘sham-TMS” or ‘‘false” or ‘‘analgesiaexpectation”, participants felt more tired (p < .000), and slightly less happy (p = .078). 3.2. Pain threshold ANOVA for pain threshold revealed a significant main effect for the expectation condition (F(1, 35) = 8.390, p = .006; analgesia > false) as well as a main effect for treatment (F(1, 35) = 6.679, p = .014; ‘‘real-TMS” < ‘‘sham-TMS”). Most importantly, these two factors interacted significantly with each other (F(1, 35) = 6.434, p = .016) (Fig. 2A). Corrected post-hoc t-test comparisons revealed that rTMS per se did not affect pain threshold in the false-expectation condition (p = .961). In participants deliberately misled to expect analgesia, pain threshold in the
‘‘sham-TMS” group was significantly higher compared to the ‘‘real-TMS” group (p < .033). In addition, pain threshold in the ‘‘sham-TMS” treated groups, were higher in the ‘‘analgesia-expectation” than in the ‘‘false-expectation” condition (p < .017). In contrast, the groups in the ‘‘analgesia-” and ‘‘false-expectation” condition, both treated with the ‘‘real-TMS”, did not significantly differ in their pain threshold score (p = .784) (Fig. 2A). These pain threshold data indicate a clear placebo analgesia in the ‘‘analgesia-expectation” condition which was completely blocked by TMS-induced disruption of DLPFC function. 3.3. Pain tolerance ANOVA for heat pain tolerance revealed a significant main effect for the expectation condition (analgesia > false) (F(1, 35) = 7.929, p = .008) and a significant interaction between expectation condition and treatment group (F(1, 35) = 4.304, p = .045) (Fig. 2B). Corrected post-hoc t-test comparisons revealed similar pain tolerance scores between the ‘‘sham-” and ‘‘real-TMS” groups in the ‘‘falseexpectation” condition (p = .635), indicating that rTMS alone did not affect pain tolerance. In contrast, for participants expecting analgesia, pain tolerance in the ‘‘real-TMS” group was significantly lower than in the ‘‘sham-TMS” group (p < .033). In addition, subjects in the ‘‘sham-TMS” group in the ‘‘analgesia-expectation” condition revealed significantly higher pain tolerance scores compared to the ‘‘sham-TMS” group in the ‘‘false-expectation” condition (p < .017). In parallel with the pain threshold results, these data in pain tolerance document a significant placebo analgesia which was thoroughly abrogated by TMS treatment. 3.4. Subjective reports Subjective evaluation for treatment analgesia efficiency revealed a significant main effect for the expectation condition (analgesia > false) (F(1, 35) = 62.116, p < .001). Moreover, a significant interaction between expectation condition and treatment group (‘‘real-/sham-TMS”) was revealed (F(1, 35) = 4.574, p = .040; see Fig. 2C). In contrast, no other main (F(1, 35) 6 1.190, p P .283) or interaction effects (F(1, 35) 6 .402, p P .530) were statistical significant. Corrected post-hoc t-test comparisons showed that participants with a deceptively induced analgesia-expectation in the ‘‘sham-TMS” group perceived pain reduction as more effective than those subjects in the ‘‘real-TMS” group (p < .038). In addition, in the ‘‘analgesia-expectation” condition, both treatment groups (‘‘shamTMS” and ‘‘real-TMS”) rated the pain reduction as more effective than did participants in the ‘‘false-expectation” condition (‘‘sham-TMS” group: p < .013; ‘‘real-TMS” group: p < .025). 4. Discussion Cognitive factors such as expectations and beliefs modulate the experience of pain and in particular placebo analgesia. Until now, studies addressing the mechanisms underlying the placebo process have only provided correlative associations between brain struc-
Table 1 Descriptive data of the study sample. Data correspond to the two expectation conditions (‘‘analgesia-expectation” or ‘‘false-expectation”) and the two corresponding treatment subgroups (‘‘sham-TMS” and ‘‘real-TMS”). Analgesia-expectation Sham-TMS (n = 9)
Age (year) Education (year) Handedness
False-expectation Real-TMS (n = 10)
Sham-TMS (n = 10)
Real-TMS (n = 10)
Mean (SD)
Range
Mean (SD)
Range
Mean (SD)
Range
Mean (SD)
Range
26.0 (7.2) 14.1 (3.1) 13.8 (1.7)
20–43 10–20 13–18
27.9 (7.7) 15.8 (2.8) 14.0 (1.1)
20–43 10–20 13–18
24.6 (7.0) 13.1 (2.1) 13.3 (0.7)
20–41 9–16 13–15
23.0 (3.3) 13.8 (2.9) 14.0 (1.1)
20–31 10–20 13–16
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tures and function. In order to analyze the critical contribution of prefrontal cortex structures, we employed a heat-pain paradigm. We implemented a parallel matched group design including an interventional approach with real or sham non-invasive low-frequency repetitive transcranial magnetic stimulation (rTMS) in healthy subjects and analyzed both, heat pain tolerance and pain threshold. In line with our hypothesis, placebo analgesia reflected by a significantly increased pain threshold and pain tolerance was observed in those subjects who received the ‘‘analgesiaexpectation” and who were treated with ‘‘sham-TMS”. In contrast, subjects with the ‘‘false-expectation” did not show placebo analgesia. These results clearly indicate that heat pain tolerance and pain threshold are rather dynamic variables that can be modified not only by pharmacological or physiological but also by psychological factors [13]. Placebo analgesia is thought to be mediated by prefrontal neural mechanisms involving the release of opioids in subcortical regions, e.g. midbrain, which subsequently reduce pain transmission [3,5,47]. In order to analyze the role of prefrontal neural mechanisms in placebo analgesia, subjects in the ‘‘falseexpectation” as well in the ‘‘analgesia-expectation” condition were treated with rTMS. These results show that the rTMS treatment did not affect pain perception at all. More importantly, disruption of prefrontal cortex function with TMS completely blocked expectation-induced placebo analgesia. Since the TMS treatment groups did not differ in self-reported analgesia-expectations, the reported placebo analgesia can neither simply be attributed to compliance with the investigator’s suggestions nor to the result of biases in the suggestion used. In addition, these data are further supported by an analog pattern of results in participants’ self-reported and retrospectively perceived treatment efficacy on pain experience. Both groups in the ‘‘analgesia-expectation” condition reported more effective pain reduction than participants in the ‘‘falseexpectation” condition. Furthermore, analgesia expecting participants in the ‘‘real-TMS” group perceived the ‘‘pain-treatment” as less effective than those in the ‘‘sham-TMS” group. Several peripheral and central nervous mechanisms may explain the rTMS blockade of placebo analgesia over the PFC. First, peripheral effects such as auditory clicks, stimulation of nearby nerves and muscle twitches may non-specifically interfere with task performance [17]. However, this appears to be an unlikely explanation for the present results since reports on qualitative and quantitative effects after the treatments were neither condition nor treatment dependent, and there were no indications of adverse responses to rTMS. Second, emotional factors are known to play a role in the placebo response [33], and rTMS may affect mood either indirectly due to discomfort during the stimulation and/or directly by modulating emotional processes in both hemispheres. However, this is also not a likely factor in the present findings given that participants’ mood interacted neither with stimulated brain hemisphere nor with the treatment in all four groups [18]. It has been proposed that the right hemisphere is more involved in pain processing compared to the left hemisphere, consistent with a role of the right hemisphere in negative emotional perception and withdrawal-related behaviors [8]. For example, in a recent rTMS study [15], 15 min of 1 Hz rTMS (100%) over the right DLPFC increased cold pressure pain tolerance for the right and left hand during, but not after, the rTMS treatment. However, as stated by the authors, the study sample was highly heterogeneous in age, education level and handedness. Beside this, we used a rather long verbal instruction that participants had to read and this process of left hemisphere-related verbal-monitoring may have led to a relative inhibition of the right hemisphere, compensating a possible laterality effect. In this experiment, we investigated the laterality
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hypothesis within the context of placebo responses but found no evidence in favor of a lateralized placebo effect when using heat pain; placebo responses for heat pain threshold and tolerance did not differ between left and right forearms. Most importantly, both pain indexes were suppressed following rTMS over the left and right DLPFC. This finding is especially interesting since several correlative imaging studies suggested a more right ventrolateral PFC and orbitofrontal cortex involvement [4,26,31,34] in the placebo analgesia process. The DLPFC has been related to the generation, maintenance and manipulation of cognitive representations within a high degree of executive control demanding working memory [29,32]. It has also been implicated in general attentional processes [29]. Thus, the absence of a placebo response in expectation-induced subjects following rTMS over the PFC seems to be a consequence of a transiently disrupted cognitive representation of pain analgesia and the result of redirected attention away from pain [35]. Given that the PFC is considered to be one of the most complex and interconnected structures in the human brain [29], possible remote effects of rTMS and functional disinhibition processes cannot be completely ruled out in the present experimental design. TMS can have either a direct effect on the stimulation side and/or an indirect effect through trans-synaptic connections to distal networks [10]. For example, functional brain imaging studies combined with 1 Hz rTMS over the DLPFC have shown metabolic [20] and regional blood flow changes in the anterior cingulate cortex (ACC) and midbrain [42]. The ACC has repeatedly been shown to play a crucial role in cortical control of brainstem during placebo analgesia [12,34]. In addition, the dorsolateral and ventrolateral PFC are closely interconnected [48], and stimulation of one leads to ipsilateral co-activation of the other [10]. The ventrolateral PFC has been hypothesized to be involved in the cognitive modulation of pain, reflecting context-dependent reappraisal of the emotional significance of a pain stimulus [48]. Furthermore, the ventrolateral and orbitofrontal have both been implicated in processing reward expectations and aversive prediction of error signals [41] which have repeatedly been shown to be important in the placebo response. Our present data do not allow a disentangling of differential roles for the two prefrontal areas in the observed placebo analgesia. Therefore, a combination of brain imaging, in particular diffusion tensor techniques and other interventional approaches, as well as improved rTMS double-blind control methodologies [17] may shed more light on these issues. In addition, the specificity of the DLPFC for the expectation effect needs to be consolidated in further studies, which should include control sites over other cortical regions in order to completely rule out a generalized rTMS effect. Viewed from a broader perspective, our results may also have indirect as well as direct clinical implications. We used low frequency rTMS according to current safety guidelines [28]. However, with increasing knowledge, high frequency rTMS or alternatively transcranial direct current stimulation (tDCS) might be used to facilitate prefrontal cortical excitability, which might result in an amplification of expectations and consequently enhance the placebo response. In summary, our data provide evidence supporting an expectation-related placebo effect on pain threshold and tolerance that was suppressed after rTMS over the PFC. Based on these results, we suggest that the contribution of expectancy to placebo analgesia depends on the activity level of the prefrontal cortex. Our approach complements previous pharmacological and imaging approaches, helping to better differentiate between associative learning and expectation mechanisms in placebo analgesia in the context of neurocognitive pain research [48].
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5. Competing interest statement The authors declare that they have no competing financial interests. Acknowledgements We thank G. Thut for helpful advice regarding rTMS and P.C. Cattin for programming the sham display. We further thank N. Schaffner, A. Wittwer, E. Kut, J. Stern, V. Pliska and A. Borg for help during the preparation of the study and P. Brugger for critical reading of the manuscript. This research was supported by a grant from the OPO Foundation and the Cogito Foundation. Appendix A. Supplementary data Supplementary data associated with this article can be found, in the online version, at doi:10.1016/j.pain.2009.09.033. References [1] Amanzio M, Benedetti F. Neuropharmacological dissection of placebo analgesia: expectation-activated opioid systems versus conditioningactivated specific subsystems. J Neurosci 1999;19:484–94. [2] Benedetti F. Mechanisms of placebo and placebo-related effects across diseases and treatments. Annu Rev Pharmacol Toxicol 2008;48:33–60. [3] Benedetti F, Arduino C, Costa S, Vighetti S, Tarenzi L, Rainero I, Asteggiano G. Loss of expectation-related mechanisms in Alzheimer’s disease makes analgesic therapies less effective. Pain 2006;121:133–44. [4] Benedetti F, Mayberg HS, Wager TD, Stohler CS, Zubieta JK. Neurobiological mechanisms of the placebo effect. J Neurosci 2005;25:10390–402. [5] Bingel U, Schoell E, Buchel C. Imaging pain modulation in health and disease. Curr Opin Neurol 2007;20:424–31. [6] Campbell JJ. Neuropsychiatric assessment. In: Coffey C, Cummings E, editors. Textbook of geriatric neuropsychiatry. Washington, DC: American Psychiatric Press; 2000. p. 109–24. [7] Colloca L, Benedetti F. How prior experience shapes placebo analgesia. Pain 2006;124:126–33. [8] Craig AD. Forebrain emotional asymmetry: a neuroanatomical basis? Trends Cogn Sci 2005;9:566–71. [9] Curran-Everett D. Multiple comparisons: philosophies and illustrations. Am J Physiol Regul Integr Comp Physiol 2000;279:R1–8. [10] Eisenegger C, Treyer V, Fehr E, Knoch D. Time-course of ‘‘off-line” prefrontal rTMS effects – a PET study. Neuroimage 2008;42:379–84. [11] Enck P, Benedetti F, Schedlowski M. New insights into the placebo and nocebo responses. Neuron 2008;59:195–206. [12] Faria V, Fredrikson M, Furmark T. Imaging the placebo response: a neurofunctional review. Eur Neuropsychopharmacol 2008;18:473–85. [13] Gardner E, Martin J. Coding of sensory information. In: Kandel E, Schwartz J, Jessell T, editors. Principles of neural science. New York: McGraw-Hill; 2000. p. 411–29. [14] Geers AL, Helfer SG, Weiland PE, Kosbab K. Expectations and placebo response: a laboratory investigation into the role of somatic focus. J Behav Med 2006;29:171–8. [15] Graff-Guerrero A, Gonzalez-Olvera J, Fresan A, Gomez-Martin D, MendezNunez JC, Pellicer F. Repetitive transcranial magnetic stimulation of dorsolateral prefrontal cortex increases tolerance to human experimental pain. Brain Res Cogn Brain Res 2005;25:153–60. [16] Herwig U, Satrapi P, Schonfeldt-Lecuona C. Using the international 10–20 EEG system for positioning of transcranial magnetic stimulation. Brain Topogr 2003;16:95–9. [17] Hoeft F, Wu DA, Hernandez A, Glover GH, Shimojo S. Electronically switchable sham transcranial magnetic stimulation (TMS) system. PLoS One 2008;3:e1923. [18] Jenkins J, Shajahan PM, Lappin JM, Ebmeier KP. Right and left prefrontal transcranial magnetic stimulation at 1 Hz does not affect mood in healthy volunteers. BMC Psychiatry 2002;2:1. [19] Keel JC, Smith MJ, Wassermann EM. A safety screening questionnaire for transcranial magnetic stimulation. Clin Neurophysiol 2000;112:720. [20] Kimbrell TA, Dunn RT, George MS, Danielson AL, Willis MW, Repella JD, Benson BE, Herscovitch P, Post RM, Wassermann EM. Left prefrontal-repetitive transcranial magnetic stimulation (rTMS) and regional cerebral glucose metabolism in normal volunteers. Psychiatry Res 2002;115:101–13. [21] Koshi EB, Short CA. Placebo theory and its implications for research and clinical practice: a review of the recent literature. Pain Pract 2007;7:4–20.
[22] Koyama T, McHaffie JG, Laurienti PJ, Coghill RC. The subjective experience of pain: where expectations become reality. Proc Natl Acad Sci USA 2005;102:12950–5. [23] Kut E, Schaffner N, Wittwer A, Candia V, Brockmann M, Storck C, Folkers G. Changes in self-perceived role identity modulate pain perception. Pain 2007;131:191–201. [24] Leuchter AF, Cook IA, Witte EA, Morgan M, Abrams M. Changes in brain function of depressed subjects during treatment with placebo. Am J Psychiatry 2002;159:122–9. [25] Lidstone SC, Stoessl AJ. Understanding the placebo effect: contributions from neuroimaging. Mol Imaging Biol 2007;9:176–85. [26] Lieberman MD, Jarcho JM, Berman S, Naliboff BD, Suyenobu BY, Mandelkern M, Mayer EA. The neural correlates of placebo effects: a disruption account. Neuroimage 2004;22:447–55. [27] Lorenz J, Minoshima S, Casey KL. Keeping pain out of mind: the role of the dorsolateral prefrontal cortex in pain modulation. Brain 2003;126:1079–91. [28] Machii K, Cohen D, Ramos-Estebanez C, Pascual-Leone A. Safety of rTMS to non-motor cortical areas in healthy participants and patients. Clin Neurophysiol 2006;117:455–71. [29] Miller EK, Cohen JD. An integrative theory of prefrontal cortex function. Annu Rev Neurosci 2001;24:167–202. [30] Pacheco-Lopez G, Engler H, Niemi MB, Schedlowski M. Expectations and associations that heal: immunomodulatory placebo effects and its neurobiology. Brain Behav Immun 2006;20:430–46. [31] Pariente J, White P, Frackowiak RS, Lewith G. Expectancy and belief modulate the neuronal substrates of pain treated by acupuncture. Neuroimage 2005;25:1161–7. [32] Petrides M, Pandya DN. Dorsolateral prefrontal cortex: comparative cytoarchitectonic analysis in the human and the macaque brain and corticocortical connection patterns. Eur J Neurosci 1999;11:1011–36. [33] Petrovic P, Dietrich T, Fransson P, Andersson J, Carlsson K, Ingvar M. Placebo in emotional processing-induced expectations of anxiety relief activate a generalized modulatory network. Neuron 2005;46:957–69. [34] Petrovic P, Kalso E, Petersson KM, Ingvar M. Placebo and opioid analgesia – imaging a shared neuronal network. Science 2002;295:1737–40. [35] Peyron R, Garcia-Larrea L, Gregoire MC, Costes N, Convers P, Lavenne F, Mauguiere F, Michel D, Laurent B. Haemodynamic brain responses to acute pain in humans: sensory and attentional networks. Brain 1999;122:1765–80. [36] Peyron R, Laurent B, Garcia-Larrea L. Functional imaging of brain responses to pain. A review and meta-analysis (2000). Neurophysiol Clin 2000;30: 263–88. [37] Price DD, Milling LS, Kirsch I, Duff A, Montgomery GH, Nicholls SS. An analysis of factors that contribute to the magnitude of placebo analgesia in an experimental paradigm. Pain 1999;83:147–56. [38] Robertson EM, Theoret H, Pascual-Leone A. Studies in cognition: the problems solved and created by transcranial magnetic stimulation. J Cogn Neurosci 2003;15:948–60. [39] Rossi S, Cappa SF, Babiloni C, Pasqualetti P, Miniussi C, Carducci F, Babiloni F, Rossini PM. Prefrontal [correction of Prefontal] cortex in long-term memory: an ‘‘interference” approach using magnetic stimulation. Nat Neurosci 2001;4:948–52. [40] Scott DJ, Stohler CS, Egnatuk CM, Wang H, Koeppe RA, Zubieta JK. Individual differences in reward responding explain placebo-induced expectations and effects. Neuron 2007;55:325–36. [41] Seymour B, O’Doherty JP, Koltzenburg M, Wiech K, Frackowiak R, Friston K, Dolan R. Opponent appetitive–aversive neural processes underlie predictive learning of pain relief. Nat Neurosci 2005;8:1234–40. [42] Speer AM, Willis MW, Herscovitch P, Daube-Witherspoon M, Shelton JR, Benson BE, Post RM, Wassermann EM. Intensity-dependent regional cerebral blood flow during 1-Hz repetitive transcranial magnetic stimulation (rTMS) in healthy volunteers studied with H215O positron emission tomography: II. Effects of prefrontal cortex rTMS. Biol Psychiatry 2003;54:826–32. [43] Steyer R, Schwenkmezger P, Notz P, Eid M. MDBF – Mehrdimensionaler Befindlichkeitsfragebogen [Multidimensional mood questionnaire]. Goettingen, Germany: Hogrefe Verlag; 1997. [44] Strafella AP, Ko JH, Monchi O. Therapeutic application of transcranial magnetic stimulation in Parkinson’s disease: the contribution of expectation. Neuroimage 2006;31:1666–72. [45] Vase L, Riley 3rd JL, Price DD. A comparison of placebo effects in clinical analgesic trials versus studies of placebo analgesia. Pain 2002;99:443–52. [46] Voudouris NJ, Peck CL, Coleman G. The role of conditioning and verbal expectancy in the placebo response. Pain 1990;43:121–8. [47] Wager TD, Rilling JK, Smith EE, Sokolik A, Casey KL, Davidson RJ, Kosslyn SM, Rose RM, Cohen JD. Placebo-induced changes in FMRI in the anticipation and experience of pain. Science 2004;303:1162–7. [48] Wiech K, Ploner M, Tracey I. Neurocognitive aspects of pain perception. Trends Cogn Sci 2008;12:306–13. [49] Zubieta JK, Bueller JA, Jackson LR, Scott DJ, Xu Y, Koeppe RA, Nichols TE, Stohler CS. Placebo effects mediated by endogenous opioid activity on mu-opioid receptors. J Neurosci 2005;25:7754–62.