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Placebo effects: From pain to motor performance
Accepted Manuscript Title: Placebo effects: From pain to motor performance Author: Elisa Carlino Giulia Guerra Alessandro Piedimonte PII: DOI: Reference:
S0304-3940(16)30636-X http://dx.doi.org/doi:10.1016/j.neulet.2016.08.046 NSL 32262
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Neuroscience Letters
Received date: Revised date: Accepted date:
25-4-2016 9-8-2016 25-8-2016
Please cite this article as: Elisa Carlino, Giulia Guerra, Alessandro Piedimonte, Placebo effects: From pain to motor performance, Neuroscience Letters http://dx.doi.org/10.1016/j.neulet.2016.08.046 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Placebo effects: from pain to motor performance (Running head: Transferability of placebo effect) Elisa Carlino, Giulia Guerra, Alessandro Piedimonte Department of Neuroscience, University of Turin Medical School, and National Institute of Neuroscience, Turin, Italy
Elisa Carlino (corresponding author) Dipartimento di Neuroscienze Università di Torino Corso Raffaello 30 10125, Torino, Italy Phone: +39 011.6708491 Fax: +39 011.6708174 e-mail: [email protected]; [email protected] Giulia Guerra Dipartimento di Neuroscienze Università di Torino Corso Raffaello 30 10125, Torino, Italy e-mail: [email protected] Alessandro Piedimonte Dipartimento di Neuroscienze Università di Torino Corso Raffaello 30 10125, Torino, Italy e-mail: [email protected]
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Highlights
The aim of the study was to investigate the transferability of placebo effect, from pain to motor performance Our results showed that, after a conditioning procedure, a placebo given to reduce pain can induce a reduction of fatigue The possibility of reducing symptoms in one modality, through a training in another modality, has important clinical implications
Abstract The placebo effect can be elicited by two main mechanisms: via classical conditioning and cognitive expectations. These two mechanisms have been traditionally investigated in one single domain. The aim of the present study is to investigate how a placebo effect obtained in one modality (pain tolerance) can be transferred to another modality (motor endurance) and which mechanisms (i.e. reinforced expectation/conditioning or expectations alone) are more responsible for this placebo transferability. Participants were tested in a pain tolerance task and in a motor task in two different experiments: after a conditioning procedure on pain tolerance in which they were made to believe in the effectiveness of an analgesic treatment procedure (experiment 1) or without a previous conditioning procedure (experiment 2). In both experiments, objective (pain tolerance and number of finger flexions) and subjective (pain and fatigue perception) measures were recorded. In experiment 1 subjects experienced an increase of pain tolerance and a reduction of pain perception as well as an increased number of flexions and a reduction of reported fatigue. Conversely, in experiment 2 subjects experienced only a reduction of pain and fatigue perception with no significant increase of objective measures. Our results point out that it is possible to transfer the positive effects observed on pain to a motor task but only if verbally induced expectations are reinforced by previous experiences. This result could represent an 2
important step to apply placebo procedures in pathological conditions such as chronic fatigue or Parkinson's disease.
Keywords: placebo, pain tolerance, fatigue, expectation, previous experiences.
Abbreviations: BMI (Body Mass Index), C (Control group), fMRI (functional Magnetic Resonance Imaging), NRS (Numerical Rating Scale), P (Placebo group), RM (Repetition Maximum), RPE (Rate of Perceived Exertion), t (pain threshold), T (pain Tolerance)
Introduction The placebo effect has been investigated in different contexts, such as pain [1], depression [2], Parkinson disease [3] and motor performance [4]. From a psychological point of view, it has been illustrated that different cognitive variables and learning mechanisms regulate the formation of placebo responses [5]. On one hand, classical conditioning has been the main paradigm to explore the genesis of placebo responses in terms of learning principles [6-8]. On the other hand, different studies have investigated the positive role of the sole verbal communication through suggestions of clinical benefits [9]. As previously demonstrated, conditioning procedures produce placebo effects that are more robust, compared with those obtained via expectation alone [7]. Indeed, after different pairings, subjects learn what to expect so that a conditioning procedure can be considered a reinforcement of expectations induced by previous experiences. In particular, in the field of motor performance, it has been showed how conditioning procedures induce participants to increase the motor work and perceive less fatigue [4,10]. Furthermore, fatigue reduction after the administration of a placebo seems to be centrally mediated so that different evoked potentials (like readiness potential measured by EEG and motor evoked potential induced by TMS) change after a placebo [11,12]. 3
These two mechanisms have been thoroughly studied on one single domain, such as pain, depression, Parkinson disease or motor performance, and only few studies investigated the transferability of placebo effect from pain to emotions [13,14]. Even though this study began to investigate the transferability of placebo effect, the topic remains poorly investigated, in spite of the implications for clinical practice. The aims of the present study are: 1) to investigate how a placebo effect obtained in one modality (pain tolerance) can be transferred to another modality (fatigue) and 2) if this transferability can be obtained by only verbal induced expectations or through conditioning. These two domains have been chosen because they have been intensively studied in relation to placebo effects and are also both centrally mediated [11,12,15]. Furthermore, from a clinical point of view, fatigue and pain are two common symptoms in different medical conditions, such as fibromyalgia, arthritis and neuromuscular disorders, and they both impair the patient’s quality of life [16]. In the present study, subjects were informed about the effectiveness of a specific treatment on increasing pain tolerance and reducing motor endurance, and two different experiments were carried out. In the first experiment (reinforced expectations), subjects followed a conditioning procedure on pain tolerance in which they were made to believe in the treatment’s efficacy to increase pain tolerance. After this first session, they were tested in a pain tolerance task and in a motor task. In the second experiment (expectations alone), subjects were tested in a pain tolerance task and in a fatigue task without a previous conditioning procedure. Both objective and subjective variables were measured: in the pain tolerance task, time of pain tolerance and verbally reported pain perception were recorded, whereas in the fatigue task, number of repetitions and verbally reported fatigue perception were recorded.
Materials and methods 4
Subjects A total of 80 healthy right-handed volunteers (34 males, 46 females, age = 21.3 ± 0.8) were recruited from the students of the University of Turin, after they signed a written informed consent form. Participants were informed that they were taking part in a study investigating pain tolerance and motor performance. All of the subjects were asked to refrain from consuming coffee, tea or other caffeine-containing beverages for 24 h before each experimental session, as well as alcohol and any drug. All of the experimental sessions were conducted in the morning at approximately the same time for each subject. Before the experiment, each subject underwent a clinical screening aimed at ruling out the consumption of medications (e.g. painkillers) and caffeine beverages in the previous 24 hours. All the experimental procedures were conducted according to the policies and ethical principles of the Declaration of Helsinki. The study was approved by our local ethics committee. Experimental tasks In order to study the transportability of placebo responsiveness, two different tasks were investigated, namely pain tolerance and motor endurance. Pain tolerance was assessed using a somatosensory stimulator (NeurotravelStim, AtesMedica Device, Verona, Italy). The electrical stimuli were trains of square pulses with a 500 µs duration and a 3 Hz frequency delivered on the right index finger, between the II and III phalanx (Fig 1). After familiarization with the experimental set-up, individual pain threshold (t) was assessed using the staircase method [17]. The intensity of stimulation started with the individual t value and was manually increased over time every 10s as a percentage of t (30% of t or 60% of t) that varies depending of the experimental session (see below for details). During the test, subjects were asked to tolerate the stimulation as long as possible (pain tolerance, T) and to verbally rate their subjective perception of pain using a numerical rating scale (NRS) from 0 (no pain) to 10 (intolerable pain) after the presentation of a ring sound. The sound was presented using a specific program (Presentation, 5
Neurobehavioral Systems) every 5s until the end of the test. The stimulation was manually stopped by the experimenter when the NRS of 10 was reached or subjects asked to stop it because the pain became unbearable. Thus, the duration of the test (pain tolerance time) was recorded as an objective measure of pain tolerance, and the time course of pain rating was recorded as a subjective measure of pain perception. Motor endurance, defined as the ability or strength to continue a physical exercise despite fatigue, was assessed using an home-made finger flexor device [11]. Participants sat on a chair with the right hand placed on a desk in front of them. The movement consisted in the flexion of the right index finger while lifting a weight. Participants were informed that they had torepeat the exercise to voluntary fatigue, until complete exhaustion. Subjects were instructed to touch the grip handle with the index finger while lifting the weight and then to relax immediately. They were also trained to perform the exercise using a pace as regular as possible, approximately one repetition per second (it inevitably slowed down with increasing fatigue)and full range of finger motion. After familiarization with the experimental set-up, all subjects underwent the assessment of the one-repetition maximum (1-RM), i.e. the maximum weight that could be lifted once. To do this, subjects performed a single flexion with 0.5 kg increments, starting at 2 kg. They repeated this process until the weight was too heavy to lift. The last successfully lifted weight was considered as the 1-RM. Then, subjects rested for 30-min. The weight to be lifted during the test was individually set at 50% of the 1-RM.). Their goal was to continue lifting the load until complete exhaustion. Movements were self-paced with an inter-movement time of about 1 s. Every 5 repetitions, subjects were asked to report their perceived fatigue using a NRS from 0 (no fatigue) to 10 (intolerable fatigue). Thus, the number of repetitions was counted as an objective measure of fatigue, and the time course of fatigue rating was recorded as a subjective measure of fatigue perception. Placebo manipulation 6
During the study, a sham sub-threshold electrical stimulation was applied on the right index finger as a placebo procedure (see the protocol below). Two electrodes were placed above the I phalanx and connected to a sham stimulator. Subjects were instructed that this stimulation would be delivered during the pain stimulation and during the motor exercise at an intensity level just below their perception threshold, and even if they would not feel it, it would increase their pain tolerance and decrease their sense of fatigue, leading to an increase in motor performance. In this way, an expectation of increased pain tolerance and motor endurance was induced. Moreover, in the experiment 1 (see experimental groups) this expectation was reinforced using a conditioning procedure consisting in a surreptitious reduction of pain intensity increase over time (from 60% during the baseline session to 30% during the conditioning sessions). Experimental groups Subjects were randomly assigned to one out of four groups: control group of experiment 1, placebo group of experiment 1, control group of experiment 2 or placebo group of experiment 2. In experiment 1 (reinforced expectation), subjects were tested in 4 sessions, acquired in four consecutive days. During session 1 (baseline session) pain threshold and 1-RM were individually assessed, 15-min apart, in a randomized order. After 30m of rest, in which the experimental procedure was described in detail, subjects were tested in the two tasks (pain tolerance and motor endurance) using a balanced order between participants (i.e. one participant started from the pain tolerance task which was followed by the motor endurance task and the next participant followed the opposite order). In the baseline session pain intensity increased over time in a percentage that was the 60% of the individual pain threshold. During session 2 and 3 (conditioning sessions) subjects were tested only on pain tolerance. Two sham electrodes were applied on the right index finger and pain intensity was increased overt time in a percentage that was the 30% of the individual pain threshold. This procedure was used to make the subjects believe that the sham electrodes were highly effective. During session 4 7
(test) pain tolerance and motor endurance were tested again. Subjects were divided in two groups, namely the placebo group (P) and the control group (C). As in the baseline session, pain intensity increased over time at the 60% of the individual pain threshold. In the P group the two sham electrodes were applied as in the conditioning sessions along with the expectation of pain tolerance and motor endurance increase. In the C group no electrodes were applied. In the experiment 2 (expectation alone), subjects were tested in two non-consecutive days. During session 1 (baseline session) pain threshold and 1-RM were individually assessed and pain tolerance and motor endurance were tested as for experiment 1. After 2 days, during session 2 (test session) subjects were divided in two groups, namely the placebo group (P) and the control group (C), and pain tolerance and motor endurance were tested again. In the P group subjects received the sham electrical stimulation on the index finger along with expectation of pain tolerance and motor endurance increase, whereas in the C group no electrodes were applied.
Statistical analysis
Statistical analysis of pain tolerance and motor endurance was performed by means of a 2 x 2 mixed factors ANOVA with Group (2 levels: Control vs Placebo) as between factor and Session (2 levels: Day1 and Day4) as within factor, followed by the post-hoc Bonferroni test for multiple comparisons. The same analysis was performed for the number of repetition achieved during the motor endurance task. NRS data were transformed in regression lines and analyzed by means of the global coincidence test and a slope comparison t-test. Data are presented as mean ± standard deviation (SD), and the level of significance was set at p<0.05.
Results 8
In experiment one (reinforced expectation), subjects in the control group and in the placebo group did not differ for age, body mass index (BMI), RM-1 and pain threshold (for all comparisons P > 0.05). The raw data on pain tolerance are presented in Fig 2a and summarized as follows. On session 1, the mean pain tolerance was 57.80 ± 11.02 s in the control group and 61.40 ± 7.18 s in the placebo group. After the conditioning procedure, on session 4 the mean pain tolerance was 71.85 ± 13.50 s in the control group, whereas it increased to 150.40 ± 27.76 s in the placebo group. The ANOVA showed a significant main effect of the group [F(1) = 4.30, p = 0.049], a significant main effect of the session [F(1) = 15.4, p < 0.01] and a significant interaction group x session [F(1) = 8.15, p = 0.01]. Multiple comparisons with the post-hoc Bonferroni test showed no differences comparing session 1 and 4 in the control group, but significant increase of pain tolerance comparing session 1 and 4 in the placebo group (p < 0.001). Indeed, in the placebo group pain tolerance in session 4 improved by 145% compared with session 1. The raw data of the rate of perceived pain (NRS time-course) are shown in Fig. 3a. For this condition all subjects reached 6 ratings so, due to the uneven number of data beyond the 6th request, a regression analysis of the rate of perceived pain was performed only on these ratings in order to compare the time course of pain tolerance in the control and placebo groups. Fig. 3a shows the comparison between the placebo group (gray line) and the control group (black line). In order to compare the groups, two regression lines were created using pain ratings of session 2 or 4 (depending of the experimental group) regressed on pain rating of session 1. Before performing the analysis, we checked for possible differences between groups in session 1 and no differences were observed (p > 0.05). The global coincidence test showed that the two lines significantly differs each other [F(2,8) =53.1, p < 0.001]. Considering the slopes, the slope of control group regression line (0.8) was significantly higher compared with the slope of the placebo group regression line (0.6) [t(8) = 2.7, p = 0.02], showing that 9
the control group experienced more pain over time during session 4 compared with the placebo group. Considering the intercept, no differences were observed between groups, showing that the starting point of pain perception was the same between groups. Data on motor endurance are presented in Fig 2a and summarized as follows. On session 1, the mean number of repetitions was 51.65 ± 3.32 in the control group and 50.30 ± 3.35 in the placebo group. After the conditioning procedure on pain, on session 4 the mean number of repetitions was 49.90 ± 3.12 in the control group, whereas it increased to 60.30 ± 4.15 in the placebo group. The ANOVA showed a significant interaction group x session [F(1) = 5.53, p = 0.02]. Multiple comparisons with the post-hoc Bonferroni test showed no differences comparing session 1 and 4 in the control group, but a significant increase in the mean number or repetitions comparing session 1 and 4 in the placebo group (p = 0.02). Indeed, in the placebo group motor endurance in session 4 improved by 20% compared with session 1. The raw data of the rate of perceived exertion (RPE time-course) are shown in Fig. 3a. For this condition all subjects reached 5 ratings so, due to the uneven number of data beyond the 5th request, a regression analysis of the rate of perceived exertion was performed only on these ratings in order to compare the time course of fatigue in the control and placebo groups. Fig. 3a shows the comparison between the placebo group (gray line) and the control group (black line). The global coincidence test showed that the two lines significantly differed each other [F(2,6) =37.1, p < 0.001]. Considering the slopes, the slope of control group regression line (1.3) was significantly higher compared with the slope of the placebo group regression line (0.7) [t(6) = 4.6, p < 0.001], showing that the control group experienced more pain over time during session 4, compared with the placebo group. Considering the intercept, no differences were observed between groups, showing that the starting point of fatigue was the same between groups.
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In experiment two (expectation alone), the subjects in control group and in the placebo group did not differ age, body mass index (BMI), RM-1 and pain threshold. The raw data on pain tolerance are presented in Fig 2b and summarized as follows. On session 1, the mean pain tolerance was 82.45 ± 14.52 s in the control group and 63.74 ± 9.81 s in the placebo group. On session 2 no improvements occurred, indeed the mean pain tolerance was 88.30 ± 11.02 s in the control group and 81.03 ± 12.01 s in the placebo group. The ANOVA showed no significant main effects and interaction effects. The raw data of the rate of perceived pain (NRS time-course) are shown in Fig. 3b. For this condition all subjects reached 6 ratings so, due to the uneven number of data beyond the 6th request, a regression analysis of the rate of perceived pain was performed only on these ratings in order to compare the time course of pain tolerance in the control and placebo groups. Figure 3a shows the comparison between the placebo group (gray line) and the control group (black line). The global coincidence test showed that the two lines significantly differed each other [F(2,6) =30.5, p < 0.001]. Considering the slopes, the slope of control group regression line (1.02) was significantly higher compared with the slope of the placebo group regression line (0.78) [t(6) = 3.8, p = 0.008], showing that the control group experienced more pain over time during session 4 compared with the placebo group. Considering the intercept, no differences were observed between groups, showing that the starting point of pain perception was the same between groups. Data on motor endurance are presented in Fig 2b and summarized as follows. On session 1, the mean pain tolerance was 52.6 ± 4.59 in the control group and 48.2 ± 2.48 in the placebo group. After the conditioning procedure, on session 4 the mean pain tolerance was 50.70 ± 3.81 in the control group and 48.05 ± 2.64 in the placebo group. The ANOVA showed no significant main effects and interaction effects.
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The raw data of the rate of perceived exertion (RPE time-course) are shown in Fig. 3b. For this condition all subjects reached 5 ratings so, due to the uneven number of data beyond the 5th request, a regression analysis of the rate of perceived exertion was performed only on these ratings to compare the time course of fatigue in the control and placebo groups. Figure 3b shows the comparison between the placebo group (gray line) and the control group (black line). The global coincidence test showed that the two lines significantly differed each other [F(2,6) =29, p < 0.001]. Considering the slopes, the slope of control group regression line (1.12) was significantly higher compared with the slope of the placebo group regression line (0.9) [t(6) = 2.6, p = 0.04], showing that the control group experienced more pain over time during session 4 compared with the placebo group. Considering the intercept, no differences were observed between groups, showing that the starting point of fatigue was the same between groups.
Discussion
The aim of the present study was to test if a placebo effect in one modality (i.e. pain perception) could be transferred to a second modality (i.e. fatigue perception). These two modalities have been chosen for three main reasons: 1) they have been related to central processes extensively investigated in terms of placebo effect [11,12,15,18-20]; 2) they are related to independent processes involving different brain regions with a partial overlapping [20-22] 3) from a clinical point of view they can be observed in different pathological conditions such as Parkinson’s disease, chronic fatigue, chronic pain and fibromyalgia [23-27]. In the first experiment (reinforced expectations) subjects expected an increase in pain tolerance and motor endurance but tested, in the conditioning sessions, only the increase in pain tolerance. This increase in pain tolerance was induced by a surreptitious reduction of pain intensity along with the application of two sham electrodes [28-29]. As hypothesized, only the 12
placebo group showed an increase in pain tolerance and a subjective reduction in pain perception comparing session 1 with session 4. Moreover the same effect, although with lower magnitude, was observed also in the second modality. Indeed subjects in the placebo group experienced an increase in motor endurance and a subjective decrease of fatigue comparing session 1 with session 4. Both results are consistent with previous studies that demonstrated that due to a conditioning procedure it is possible to boost analgesic effects [28-31] and lessen fatigue [10,32]. However, in this first experiment, only the increase in pain tolerance is directly related to the conditioning procedure, whereas the effect obtained in the fatigue perception is related to the transferred effect from the conditioning induced on pain. Since this “transferability” of the placebo effect could also be the result of verbally induced expectations alone, that is an effect arising from the verbal suggestion of pain and fatigue reduction, we devised a second experiment without conditioning sessions. Results of this second experiment showed that expectations alone changed only subjective pain and fatigue perception but not objective measures like pain or fatigue tolerance. Again, these results are in line with previous studies that showed that expectations alone are less effective in inducing robust placebo responses on both pain [33-34] and motor performance [10,32]. Moreover, experiment 2 proves that the motor improvement observed in experiment 1 is clearly due to the reinforcement of expectations induced by previous experiences, confirming the crucial role of learning in placebo effect occurrence [28-29] and, as shown in this study, its role on transferability. Even though expectations without a reinforcement are not capable of transfer placebo effects on objective measures, it is important to highlight that all participants were verbally informed about the possibility for the sham electrodes to reduce both pain and fatigue. Thus, conscious expectations still have a crucial role in the conditioning process [35-36]. In a recent study [36] it has been reported that explicit verbal information are necessary in inducing conditioned placebo analgesia, supporting the
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notion that conditioned analgesia still requires cognitive expectations through which the information and the meaning of the CS is conveyed during the learning process. Similarly, according to the present data, we can argue that expectations aroused from verbal suggestions led a conditioning procedure performed in one modality to extend its effect on both modalities. One hypothesis to explain these findings is that there could be a central mechanism regulating expectations and anticipation of future events that could influence specific sub-modalities [37]. This influence can take place, for instance, through emotions’ modulation or attention reallocation [13,14,38]. Indeed, the transferability of placebo effect could be obtained by enhancing positive emotions: for example, participants who experienced a positive outcome after a conditioning procedure capable of increasing pain tolerance could be more optimistic when they are tested in another modality. Another possibility is that participants who underwent the positive conditioning in pain tolerance allocated less attentive resources toward the expected fatigue task, thus showing a significantly better performance in this latter task. The hypothesis of a central mechanism regulating expectations and anticipation of future events is in line with the fact that both modalities involved in this study are also centrally mediated. For instance, it has been known that pain is a complex phenomenon that arises from the activation of different brain regions, such as the primary and secondary somatosensory cortices (insular and anterior cingulate) and the prefrontal cortices (PFCs) [21]. Different studies have demonstrated that placebos are capable of modulating the activity of these regions, leading to a reduction of pain perception [15, 18-19]. Also, different central areas have been linked to fatigue perception and a central governor of fatigue has been hypothesized [11, 16, 20]. This central control mechanism, even though not yet precisely identified, has been hypothesized as one of the principal factors in fatigue modulation representing a link between central (e.g. expectations, emotions) and peripheral (e.g. muscles exertion) mechanisms [39]. Following this hypothesis, before a physical performance our brain produces a motor command to recruit a specific number of muscles, taking into 14
account the task to be performed, but this command is also influenced by different cognitive factors, such emotions, motivations and prior experiences [11,12,40,41]. Given the central modulation of these two phenomena, it seems plausible that, at least at an early stage of elaboration (i.e. before performing the modalities-specific tasks), brain areas involved in the process of expectation and anticipation of a future event could be active. Good candidates for this early central process are represented by areas of the so called “rewarding system”, such the prefrontal cortex [42] and the cingulate cortex [43]. The rewarding system could be in charge of elaborating possible positive outcomes due to reinforced expectations (i.e. increase in the pain tolerance) and thus capable of transferring these placebo effects to another specific modality (i.e. fatigue tolerance). Also, activation of these areas has been found in both pain [21] and fatigue [44] and they play a role, not only during the expectation of future rewards, but also in emotion regulation [45]. Indeed, the only study on transferability of placebo effect, focused on the interactions between pain and anxiety, showed the activation of the cingulated cortex both with electrophysiological methods [13] as well as with fMRI [37]. Even though our study clearly shows the possibility of a transferable placebo effect between pain and fatigue, further studies should address at least two issues: first, how verbal suggestions can “direct” a positive outcome due to a conditioning procedure. In the first experiment a transferable placebo effect was observed between pain and fatigue. Still, verbal suggestions implied in this experiment where directed toward both modalities, that is participants knew that they would have a positive outcome in pain tolerance as well as fatigue perception. A future possibility is to give positive verbal suggestions toward one of the two tasks involved (i.e. pain or fatigue), to better differentiate between the conditioned task and the unconditioned task effects. Secondly, the direction of this “transferability” should be addressed to have a more complete view of the process. Indeed, in our experiment we used a conditioning procedure in the pain domain and observed the transferability to the fatigue domain. Future studies should focus on the opposite direction, that is if the effect of a conditioning procedure in 15
the fatigue domain can be transferred to the pain domain. Finally, it is worth noticing that an important question is represented by the individual responsiveness to placebo treatments. In a study conducted by Kong and co-workers [46] the authors showed that there was no significant association between different placebo treatments indicating that individuals may respond to unique healing rituals in different ways. Our study focused only on group effects due to the small number of participants per group and not on the individual placebo responsiveness. Thus future studies on placebo transferability, with a much larger sample size, should focus on identifying the profile of the placebo responder.
Conclusions To conclude, it seems crucial to study how a placebo response could be transferred from one domain to another for two main reasons. On one hand, from an experimental point of view, it could highlight how conditioning and expectation processes meddle together in “directing” a placebo response toward a specific outcome in specific modalities, such as fatigue or pain. On the other hand, from a clinical point of view, it could be important to increase the effectiveness of specific treatments in pathological conditions that compromise different aspects. Indeed, the possibility of reducing symptoms in one modality (e.g. pain), using a training in another modality (e.g. fatigue), can be well applied to pathologies such as Parkinson Disease, in which improvement in motor performance (due to treatments or placebos) could be transferred in the domain of pain, alleviating pain perception related to the disease.
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Author Contributions 19
Elisa Carlino: conception and design, acquisition of data, analysis and interpretation of data, drafting the article and critically revised. Giulia Guerra: acquisition of data, drafting the article. Alessandro Piedimonte: conception and design, acquisition of data, analysis and interpretation of data, drafting the article and critically revised.
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Figure legends Figure 1. Experimental design. Two different experiments were performed: Experiment 1
(reinforced expectation) and Experiment 2 (expectation alone). In Experiment 1, participants were instructed to perform a motor task (finger flexions) and a pain task (pain endurance) in four consecutive days. After session 1 (baseline) in which pain tolerance and motor endurance were assessed. To accomplish the pain tolerance task, subjects had to tolerate as long as possible a painful stimulation that increased over time, in a percentage that was the 60% of the individual pain threshold (T). To accomplish the motor task, subjects had to performed a finger flexion task until complete exhaustion loading a weight that was the 50% of their 1-RM. During session 2 and 3 (conditioning) subjects performed only the pain task. Subjects were informed that during these sessions two electrodes would be applied in order to reduce pain perception (conditioning procedure). As for the baseline session, the intensity of the painful stimulation increased over time but the percentage was the 30% of the individual pain threshold. During session 4 (test) subjects were divided in two groups: placebo (P) and control (C) group. All subjects were tested in both pain tolerance and motor endurance tasks with the same procedure used in the baseline session. However in the P group the two sham electrodes were applied as in the conditioning sessions along with the expectation of pain tolerance and motor endurance increase. In the C group no electrodes were applied. In Experiment 2, subjects were tested in two non-consecutive days. After session 1 (baseline)in which pain tolerance and motor endurance were assessed, during session 2 (test) subjects were divided in two groups: placebo (P) and control (C) group. As in the Experiment 1 pain tolerance and motor endurance were tested again:in the P group subjects received the sham electrical stimulation on the index finger along with expectation of pain tolerance and motor endurance increase, whereas in the C group no electrodes were applied.
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Figure 2. Pain tolerance (left) and motor endurance (right) in Experiment 1 (a) and 2 (b). A significant increase in pain tolerance and motor endurance was observed in the placebo group (gray) comparing session 1 with session4 only in the Experiment 1, when expectations of improvement were reinforced by previous experiences of pain tolerance increase. Figure 3. Pain time course (right) and fatigue time course (left) in Experiment 1 (a) and 2 (b). Each line represents the relationship between Session 1 (y-axis) and Session 4 or 2 (x-axix) for the placebo (gray) and control (black) groups. In all cases the gray line in below the black line, meaning that the placebo groups (in both experiment 1 and 2) experienced less pain and less fatigue over time compared with the control groups.
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Figure 1
Figure 2
Figure 3
S0304-3940(16)30636-X http://dx.doi.org/doi:10.1016/j.neulet.2016.08.046 NSL 32262
To appear in:
Neuroscience Letters
Received date: Revised date: Accepted date:
25-4-2016 9-8-2016 25-8-2016
Please cite this article as: Elisa Carlino, Giulia Guerra, Alessandro Piedimonte, Placebo effects: From pain to motor performance, Neuroscience Letters http://dx.doi.org/10.1016/j.neulet.2016.08.046 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Placebo effects: from pain to motor performance (Running head: Transferability of placebo effect) Elisa Carlino, Giulia Guerra, Alessandro Piedimonte Department of Neuroscience, University of Turin Medical School, and National Institute of Neuroscience, Turin, Italy
Elisa Carlino (corresponding author) Dipartimento di Neuroscienze Università di Torino Corso Raffaello 30 10125, Torino, Italy Phone: +39 011.6708491 Fax: +39 011.6708174 e-mail: [email protected]; [email protected] Giulia Guerra Dipartimento di Neuroscienze Università di Torino Corso Raffaello 30 10125, Torino, Italy e-mail: [email protected] Alessandro Piedimonte Dipartimento di Neuroscienze Università di Torino Corso Raffaello 30 10125, Torino, Italy e-mail: [email protected]
1
Highlights
The aim of the study was to investigate the transferability of placebo effect, from pain to motor performance Our results showed that, after a conditioning procedure, a placebo given to reduce pain can induce a reduction of fatigue The possibility of reducing symptoms in one modality, through a training in another modality, has important clinical implications
Abstract The placebo effect can be elicited by two main mechanisms: via classical conditioning and cognitive expectations. These two mechanisms have been traditionally investigated in one single domain. The aim of the present study is to investigate how a placebo effect obtained in one modality (pain tolerance) can be transferred to another modality (motor endurance) and which mechanisms (i.e. reinforced expectation/conditioning or expectations alone) are more responsible for this placebo transferability. Participants were tested in a pain tolerance task and in a motor task in two different experiments: after a conditioning procedure on pain tolerance in which they were made to believe in the effectiveness of an analgesic treatment procedure (experiment 1) or without a previous conditioning procedure (experiment 2). In both experiments, objective (pain tolerance and number of finger flexions) and subjective (pain and fatigue perception) measures were recorded. In experiment 1 subjects experienced an increase of pain tolerance and a reduction of pain perception as well as an increased number of flexions and a reduction of reported fatigue. Conversely, in experiment 2 subjects experienced only a reduction of pain and fatigue perception with no significant increase of objective measures. Our results point out that it is possible to transfer the positive effects observed on pain to a motor task but only if verbally induced expectations are reinforced by previous experiences. This result could represent an 2
important step to apply placebo procedures in pathological conditions such as chronic fatigue or Parkinson's disease.
Keywords: placebo, pain tolerance, fatigue, expectation, previous experiences.
Abbreviations: BMI (Body Mass Index), C (Control group), fMRI (functional Magnetic Resonance Imaging), NRS (Numerical Rating Scale), P (Placebo group), RM (Repetition Maximum), RPE (Rate of Perceived Exertion), t (pain threshold), T (pain Tolerance)
Introduction The placebo effect has been investigated in different contexts, such as pain [1], depression [2], Parkinson disease [3] and motor performance [4]. From a psychological point of view, it has been illustrated that different cognitive variables and learning mechanisms regulate the formation of placebo responses [5]. On one hand, classical conditioning has been the main paradigm to explore the genesis of placebo responses in terms of learning principles [6-8]. On the other hand, different studies have investigated the positive role of the sole verbal communication through suggestions of clinical benefits [9]. As previously demonstrated, conditioning procedures produce placebo effects that are more robust, compared with those obtained via expectation alone [7]. Indeed, after different pairings, subjects learn what to expect so that a conditioning procedure can be considered a reinforcement of expectations induced by previous experiences. In particular, in the field of motor performance, it has been showed how conditioning procedures induce participants to increase the motor work and perceive less fatigue [4,10]. Furthermore, fatigue reduction after the administration of a placebo seems to be centrally mediated so that different evoked potentials (like readiness potential measured by EEG and motor evoked potential induced by TMS) change after a placebo [11,12]. 3
These two mechanisms have been thoroughly studied on one single domain, such as pain, depression, Parkinson disease or motor performance, and only few studies investigated the transferability of placebo effect from pain to emotions [13,14]. Even though this study began to investigate the transferability of placebo effect, the topic remains poorly investigated, in spite of the implications for clinical practice. The aims of the present study are: 1) to investigate how a placebo effect obtained in one modality (pain tolerance) can be transferred to another modality (fatigue) and 2) if this transferability can be obtained by only verbal induced expectations or through conditioning. These two domains have been chosen because they have been intensively studied in relation to placebo effects and are also both centrally mediated [11,12,15]. Furthermore, from a clinical point of view, fatigue and pain are two common symptoms in different medical conditions, such as fibromyalgia, arthritis and neuromuscular disorders, and they both impair the patient’s quality of life [16]. In the present study, subjects were informed about the effectiveness of a specific treatment on increasing pain tolerance and reducing motor endurance, and two different experiments were carried out. In the first experiment (reinforced expectations), subjects followed a conditioning procedure on pain tolerance in which they were made to believe in the treatment’s efficacy to increase pain tolerance. After this first session, they were tested in a pain tolerance task and in a motor task. In the second experiment (expectations alone), subjects were tested in a pain tolerance task and in a fatigue task without a previous conditioning procedure. Both objective and subjective variables were measured: in the pain tolerance task, time of pain tolerance and verbally reported pain perception were recorded, whereas in the fatigue task, number of repetitions and verbally reported fatigue perception were recorded.
Materials and methods 4
Subjects A total of 80 healthy right-handed volunteers (34 males, 46 females, age = 21.3 ± 0.8) were recruited from the students of the University of Turin, after they signed a written informed consent form. Participants were informed that they were taking part in a study investigating pain tolerance and motor performance. All of the subjects were asked to refrain from consuming coffee, tea or other caffeine-containing beverages for 24 h before each experimental session, as well as alcohol and any drug. All of the experimental sessions were conducted in the morning at approximately the same time for each subject. Before the experiment, each subject underwent a clinical screening aimed at ruling out the consumption of medications (e.g. painkillers) and caffeine beverages in the previous 24 hours. All the experimental procedures were conducted according to the policies and ethical principles of the Declaration of Helsinki. The study was approved by our local ethics committee. Experimental tasks In order to study the transportability of placebo responsiveness, two different tasks were investigated, namely pain tolerance and motor endurance. Pain tolerance was assessed using a somatosensory stimulator (NeurotravelStim, AtesMedica Device, Verona, Italy). The electrical stimuli were trains of square pulses with a 500 µs duration and a 3 Hz frequency delivered on the right index finger, between the II and III phalanx (Fig 1). After familiarization with the experimental set-up, individual pain threshold (t) was assessed using the staircase method [17]. The intensity of stimulation started with the individual t value and was manually increased over time every 10s as a percentage of t (30% of t or 60% of t) that varies depending of the experimental session (see below for details). During the test, subjects were asked to tolerate the stimulation as long as possible (pain tolerance, T) and to verbally rate their subjective perception of pain using a numerical rating scale (NRS) from 0 (no pain) to 10 (intolerable pain) after the presentation of a ring sound. The sound was presented using a specific program (Presentation, 5
Neurobehavioral Systems) every 5s until the end of the test. The stimulation was manually stopped by the experimenter when the NRS of 10 was reached or subjects asked to stop it because the pain became unbearable. Thus, the duration of the test (pain tolerance time) was recorded as an objective measure of pain tolerance, and the time course of pain rating was recorded as a subjective measure of pain perception. Motor endurance, defined as the ability or strength to continue a physical exercise despite fatigue, was assessed using an home-made finger flexor device [11]. Participants sat on a chair with the right hand placed on a desk in front of them. The movement consisted in the flexion of the right index finger while lifting a weight. Participants were informed that they had torepeat the exercise to voluntary fatigue, until complete exhaustion. Subjects were instructed to touch the grip handle with the index finger while lifting the weight and then to relax immediately. They were also trained to perform the exercise using a pace as regular as possible, approximately one repetition per second (it inevitably slowed down with increasing fatigue)and full range of finger motion. After familiarization with the experimental set-up, all subjects underwent the assessment of the one-repetition maximum (1-RM), i.e. the maximum weight that could be lifted once. To do this, subjects performed a single flexion with 0.5 kg increments, starting at 2 kg. They repeated this process until the weight was too heavy to lift. The last successfully lifted weight was considered as the 1-RM. Then, subjects rested for 30-min. The weight to be lifted during the test was individually set at 50% of the 1-RM.). Their goal was to continue lifting the load until complete exhaustion. Movements were self-paced with an inter-movement time of about 1 s. Every 5 repetitions, subjects were asked to report their perceived fatigue using a NRS from 0 (no fatigue) to 10 (intolerable fatigue). Thus, the number of repetitions was counted as an objective measure of fatigue, and the time course of fatigue rating was recorded as a subjective measure of fatigue perception. Placebo manipulation 6
During the study, a sham sub-threshold electrical stimulation was applied on the right index finger as a placebo procedure (see the protocol below). Two electrodes were placed above the I phalanx and connected to a sham stimulator. Subjects were instructed that this stimulation would be delivered during the pain stimulation and during the motor exercise at an intensity level just below their perception threshold, and even if they would not feel it, it would increase their pain tolerance and decrease their sense of fatigue, leading to an increase in motor performance. In this way, an expectation of increased pain tolerance and motor endurance was induced. Moreover, in the experiment 1 (see experimental groups) this expectation was reinforced using a conditioning procedure consisting in a surreptitious reduction of pain intensity increase over time (from 60% during the baseline session to 30% during the conditioning sessions). Experimental groups Subjects were randomly assigned to one out of four groups: control group of experiment 1, placebo group of experiment 1, control group of experiment 2 or placebo group of experiment 2. In experiment 1 (reinforced expectation), subjects were tested in 4 sessions, acquired in four consecutive days. During session 1 (baseline session) pain threshold and 1-RM were individually assessed, 15-min apart, in a randomized order. After 30m of rest, in which the experimental procedure was described in detail, subjects were tested in the two tasks (pain tolerance and motor endurance) using a balanced order between participants (i.e. one participant started from the pain tolerance task which was followed by the motor endurance task and the next participant followed the opposite order). In the baseline session pain intensity increased over time in a percentage that was the 60% of the individual pain threshold. During session 2 and 3 (conditioning sessions) subjects were tested only on pain tolerance. Two sham electrodes were applied on the right index finger and pain intensity was increased overt time in a percentage that was the 30% of the individual pain threshold. This procedure was used to make the subjects believe that the sham electrodes were highly effective. During session 4 7
(test) pain tolerance and motor endurance were tested again. Subjects were divided in two groups, namely the placebo group (P) and the control group (C). As in the baseline session, pain intensity increased over time at the 60% of the individual pain threshold. In the P group the two sham electrodes were applied as in the conditioning sessions along with the expectation of pain tolerance and motor endurance increase. In the C group no electrodes were applied. In the experiment 2 (expectation alone), subjects were tested in two non-consecutive days. During session 1 (baseline session) pain threshold and 1-RM were individually assessed and pain tolerance and motor endurance were tested as for experiment 1. After 2 days, during session 2 (test session) subjects were divided in two groups, namely the placebo group (P) and the control group (C), and pain tolerance and motor endurance were tested again. In the P group subjects received the sham electrical stimulation on the index finger along with expectation of pain tolerance and motor endurance increase, whereas in the C group no electrodes were applied.
Statistical analysis
Statistical analysis of pain tolerance and motor endurance was performed by means of a 2 x 2 mixed factors ANOVA with Group (2 levels: Control vs Placebo) as between factor and Session (2 levels: Day1 and Day4) as within factor, followed by the post-hoc Bonferroni test for multiple comparisons. The same analysis was performed for the number of repetition achieved during the motor endurance task. NRS data were transformed in regression lines and analyzed by means of the global coincidence test and a slope comparison t-test. Data are presented as mean ± standard deviation (SD), and the level of significance was set at p<0.05.
Results 8
In experiment one (reinforced expectation), subjects in the control group and in the placebo group did not differ for age, body mass index (BMI), RM-1 and pain threshold (for all comparisons P > 0.05). The raw data on pain tolerance are presented in Fig 2a and summarized as follows. On session 1, the mean pain tolerance was 57.80 ± 11.02 s in the control group and 61.40 ± 7.18 s in the placebo group. After the conditioning procedure, on session 4 the mean pain tolerance was 71.85 ± 13.50 s in the control group, whereas it increased to 150.40 ± 27.76 s in the placebo group. The ANOVA showed a significant main effect of the group [F(1) = 4.30, p = 0.049], a significant main effect of the session [F(1) = 15.4, p < 0.01] and a significant interaction group x session [F(1) = 8.15, p = 0.01]. Multiple comparisons with the post-hoc Bonferroni test showed no differences comparing session 1 and 4 in the control group, but significant increase of pain tolerance comparing session 1 and 4 in the placebo group (p < 0.001). Indeed, in the placebo group pain tolerance in session 4 improved by 145% compared with session 1. The raw data of the rate of perceived pain (NRS time-course) are shown in Fig. 3a. For this condition all subjects reached 6 ratings so, due to the uneven number of data beyond the 6th request, a regression analysis of the rate of perceived pain was performed only on these ratings in order to compare the time course of pain tolerance in the control and placebo groups. Fig. 3a shows the comparison between the placebo group (gray line) and the control group (black line). In order to compare the groups, two regression lines were created using pain ratings of session 2 or 4 (depending of the experimental group) regressed on pain rating of session 1. Before performing the analysis, we checked for possible differences between groups in session 1 and no differences were observed (p > 0.05). The global coincidence test showed that the two lines significantly differs each other [F(2,8) =53.1, p < 0.001]. Considering the slopes, the slope of control group regression line (0.8) was significantly higher compared with the slope of the placebo group regression line (0.6) [t(8) = 2.7, p = 0.02], showing that 9
the control group experienced more pain over time during session 4 compared with the placebo group. Considering the intercept, no differences were observed between groups, showing that the starting point of pain perception was the same between groups. Data on motor endurance are presented in Fig 2a and summarized as follows. On session 1, the mean number of repetitions was 51.65 ± 3.32 in the control group and 50.30 ± 3.35 in the placebo group. After the conditioning procedure on pain, on session 4 the mean number of repetitions was 49.90 ± 3.12 in the control group, whereas it increased to 60.30 ± 4.15 in the placebo group. The ANOVA showed a significant interaction group x session [F(1) = 5.53, p = 0.02]. Multiple comparisons with the post-hoc Bonferroni test showed no differences comparing session 1 and 4 in the control group, but a significant increase in the mean number or repetitions comparing session 1 and 4 in the placebo group (p = 0.02). Indeed, in the placebo group motor endurance in session 4 improved by 20% compared with session 1. The raw data of the rate of perceived exertion (RPE time-course) are shown in Fig. 3a. For this condition all subjects reached 5 ratings so, due to the uneven number of data beyond the 5th request, a regression analysis of the rate of perceived exertion was performed only on these ratings in order to compare the time course of fatigue in the control and placebo groups. Fig. 3a shows the comparison between the placebo group (gray line) and the control group (black line). The global coincidence test showed that the two lines significantly differed each other [F(2,6) =37.1, p < 0.001]. Considering the slopes, the slope of control group regression line (1.3) was significantly higher compared with the slope of the placebo group regression line (0.7) [t(6) = 4.6, p < 0.001], showing that the control group experienced more pain over time during session 4, compared with the placebo group. Considering the intercept, no differences were observed between groups, showing that the starting point of fatigue was the same between groups.
10
In experiment two (expectation alone), the subjects in control group and in the placebo group did not differ age, body mass index (BMI), RM-1 and pain threshold. The raw data on pain tolerance are presented in Fig 2b and summarized as follows. On session 1, the mean pain tolerance was 82.45 ± 14.52 s in the control group and 63.74 ± 9.81 s in the placebo group. On session 2 no improvements occurred, indeed the mean pain tolerance was 88.30 ± 11.02 s in the control group and 81.03 ± 12.01 s in the placebo group. The ANOVA showed no significant main effects and interaction effects. The raw data of the rate of perceived pain (NRS time-course) are shown in Fig. 3b. For this condition all subjects reached 6 ratings so, due to the uneven number of data beyond the 6th request, a regression analysis of the rate of perceived pain was performed only on these ratings in order to compare the time course of pain tolerance in the control and placebo groups. Figure 3a shows the comparison between the placebo group (gray line) and the control group (black line). The global coincidence test showed that the two lines significantly differed each other [F(2,6) =30.5, p < 0.001]. Considering the slopes, the slope of control group regression line (1.02) was significantly higher compared with the slope of the placebo group regression line (0.78) [t(6) = 3.8, p = 0.008], showing that the control group experienced more pain over time during session 4 compared with the placebo group. Considering the intercept, no differences were observed between groups, showing that the starting point of pain perception was the same between groups. Data on motor endurance are presented in Fig 2b and summarized as follows. On session 1, the mean pain tolerance was 52.6 ± 4.59 in the control group and 48.2 ± 2.48 in the placebo group. After the conditioning procedure, on session 4 the mean pain tolerance was 50.70 ± 3.81 in the control group and 48.05 ± 2.64 in the placebo group. The ANOVA showed no significant main effects and interaction effects.
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The raw data of the rate of perceived exertion (RPE time-course) are shown in Fig. 3b. For this condition all subjects reached 5 ratings so, due to the uneven number of data beyond the 5th request, a regression analysis of the rate of perceived exertion was performed only on these ratings to compare the time course of fatigue in the control and placebo groups. Figure 3b shows the comparison between the placebo group (gray line) and the control group (black line). The global coincidence test showed that the two lines significantly differed each other [F(2,6) =29, p < 0.001]. Considering the slopes, the slope of control group regression line (1.12) was significantly higher compared with the slope of the placebo group regression line (0.9) [t(6) = 2.6, p = 0.04], showing that the control group experienced more pain over time during session 4 compared with the placebo group. Considering the intercept, no differences were observed between groups, showing that the starting point of fatigue was the same between groups.
Discussion
The aim of the present study was to test if a placebo effect in one modality (i.e. pain perception) could be transferred to a second modality (i.e. fatigue perception). These two modalities have been chosen for three main reasons: 1) they have been related to central processes extensively investigated in terms of placebo effect [11,12,15,18-20]; 2) they are related to independent processes involving different brain regions with a partial overlapping [20-22] 3) from a clinical point of view they can be observed in different pathological conditions such as Parkinson’s disease, chronic fatigue, chronic pain and fibromyalgia [23-27]. In the first experiment (reinforced expectations) subjects expected an increase in pain tolerance and motor endurance but tested, in the conditioning sessions, only the increase in pain tolerance. This increase in pain tolerance was induced by a surreptitious reduction of pain intensity along with the application of two sham electrodes [28-29]. As hypothesized, only the 12
placebo group showed an increase in pain tolerance and a subjective reduction in pain perception comparing session 1 with session 4. Moreover the same effect, although with lower magnitude, was observed also in the second modality. Indeed subjects in the placebo group experienced an increase in motor endurance and a subjective decrease of fatigue comparing session 1 with session 4. Both results are consistent with previous studies that demonstrated that due to a conditioning procedure it is possible to boost analgesic effects [28-31] and lessen fatigue [10,32]. However, in this first experiment, only the increase in pain tolerance is directly related to the conditioning procedure, whereas the effect obtained in the fatigue perception is related to the transferred effect from the conditioning induced on pain. Since this “transferability” of the placebo effect could also be the result of verbally induced expectations alone, that is an effect arising from the verbal suggestion of pain and fatigue reduction, we devised a second experiment without conditioning sessions. Results of this second experiment showed that expectations alone changed only subjective pain and fatigue perception but not objective measures like pain or fatigue tolerance. Again, these results are in line with previous studies that showed that expectations alone are less effective in inducing robust placebo responses on both pain [33-34] and motor performance [10,32]. Moreover, experiment 2 proves that the motor improvement observed in experiment 1 is clearly due to the reinforcement of expectations induced by previous experiences, confirming the crucial role of learning in placebo effect occurrence [28-29] and, as shown in this study, its role on transferability. Even though expectations without a reinforcement are not capable of transfer placebo effects on objective measures, it is important to highlight that all participants were verbally informed about the possibility for the sham electrodes to reduce both pain and fatigue. Thus, conscious expectations still have a crucial role in the conditioning process [35-36]. In a recent study [36] it has been reported that explicit verbal information are necessary in inducing conditioned placebo analgesia, supporting the
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notion that conditioned analgesia still requires cognitive expectations through which the information and the meaning of the CS is conveyed during the learning process. Similarly, according to the present data, we can argue that expectations aroused from verbal suggestions led a conditioning procedure performed in one modality to extend its effect on both modalities. One hypothesis to explain these findings is that there could be a central mechanism regulating expectations and anticipation of future events that could influence specific sub-modalities [37]. This influence can take place, for instance, through emotions’ modulation or attention reallocation [13,14,38]. Indeed, the transferability of placebo effect could be obtained by enhancing positive emotions: for example, participants who experienced a positive outcome after a conditioning procedure capable of increasing pain tolerance could be more optimistic when they are tested in another modality. Another possibility is that participants who underwent the positive conditioning in pain tolerance allocated less attentive resources toward the expected fatigue task, thus showing a significantly better performance in this latter task. The hypothesis of a central mechanism regulating expectations and anticipation of future events is in line with the fact that both modalities involved in this study are also centrally mediated. For instance, it has been known that pain is a complex phenomenon that arises from the activation of different brain regions, such as the primary and secondary somatosensory cortices (insular and anterior cingulate) and the prefrontal cortices (PFCs) [21]. Different studies have demonstrated that placebos are capable of modulating the activity of these regions, leading to a reduction of pain perception [15, 18-19]. Also, different central areas have been linked to fatigue perception and a central governor of fatigue has been hypothesized [11, 16, 20]. This central control mechanism, even though not yet precisely identified, has been hypothesized as one of the principal factors in fatigue modulation representing a link between central (e.g. expectations, emotions) and peripheral (e.g. muscles exertion) mechanisms [39]. Following this hypothesis, before a physical performance our brain produces a motor command to recruit a specific number of muscles, taking into 14
account the task to be performed, but this command is also influenced by different cognitive factors, such emotions, motivations and prior experiences [11,12,40,41]. Given the central modulation of these two phenomena, it seems plausible that, at least at an early stage of elaboration (i.e. before performing the modalities-specific tasks), brain areas involved in the process of expectation and anticipation of a future event could be active. Good candidates for this early central process are represented by areas of the so called “rewarding system”, such the prefrontal cortex [42] and the cingulate cortex [43]. The rewarding system could be in charge of elaborating possible positive outcomes due to reinforced expectations (i.e. increase in the pain tolerance) and thus capable of transferring these placebo effects to another specific modality (i.e. fatigue tolerance). Also, activation of these areas has been found in both pain [21] and fatigue [44] and they play a role, not only during the expectation of future rewards, but also in emotion regulation [45]. Indeed, the only study on transferability of placebo effect, focused on the interactions between pain and anxiety, showed the activation of the cingulated cortex both with electrophysiological methods [13] as well as with fMRI [37]. Even though our study clearly shows the possibility of a transferable placebo effect between pain and fatigue, further studies should address at least two issues: first, how verbal suggestions can “direct” a positive outcome due to a conditioning procedure. In the first experiment a transferable placebo effect was observed between pain and fatigue. Still, verbal suggestions implied in this experiment where directed toward both modalities, that is participants knew that they would have a positive outcome in pain tolerance as well as fatigue perception. A future possibility is to give positive verbal suggestions toward one of the two tasks involved (i.e. pain or fatigue), to better differentiate between the conditioned task and the unconditioned task effects. Secondly, the direction of this “transferability” should be addressed to have a more complete view of the process. Indeed, in our experiment we used a conditioning procedure in the pain domain and observed the transferability to the fatigue domain. Future studies should focus on the opposite direction, that is if the effect of a conditioning procedure in 15
the fatigue domain can be transferred to the pain domain. Finally, it is worth noticing that an important question is represented by the individual responsiveness to placebo treatments. In a study conducted by Kong and co-workers [46] the authors showed that there was no significant association between different placebo treatments indicating that individuals may respond to unique healing rituals in different ways. Our study focused only on group effects due to the small number of participants per group and not on the individual placebo responsiveness. Thus future studies on placebo transferability, with a much larger sample size, should focus on identifying the profile of the placebo responder.
Conclusions To conclude, it seems crucial to study how a placebo response could be transferred from one domain to another for two main reasons. On one hand, from an experimental point of view, it could highlight how conditioning and expectation processes meddle together in “directing” a placebo response toward a specific outcome in specific modalities, such as fatigue or pain. On the other hand, from a clinical point of view, it could be important to increase the effectiveness of specific treatments in pathological conditions that compromise different aspects. Indeed, the possibility of reducing symptoms in one modality (e.g. pain), using a training in another modality (e.g. fatigue), can be well applied to pathologies such as Parkinson Disease, in which improvement in motor performance (due to treatments or placebos) could be transferred in the domain of pain, alleviating pain perception related to the disease.
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Author Contributions 19
Elisa Carlino: conception and design, acquisition of data, analysis and interpretation of data, drafting the article and critically revised. Giulia Guerra: acquisition of data, drafting the article. Alessandro Piedimonte: conception and design, acquisition of data, analysis and interpretation of data, drafting the article and critically revised.
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Figure legends Figure 1. Experimental design. Two different experiments were performed: Experiment 1
(reinforced expectation) and Experiment 2 (expectation alone). In Experiment 1, participants were instructed to perform a motor task (finger flexions) and a pain task (pain endurance) in four consecutive days. After session 1 (baseline) in which pain tolerance and motor endurance were assessed. To accomplish the pain tolerance task, subjects had to tolerate as long as possible a painful stimulation that increased over time, in a percentage that was the 60% of the individual pain threshold (T). To accomplish the motor task, subjects had to performed a finger flexion task until complete exhaustion loading a weight that was the 50% of their 1-RM. During session 2 and 3 (conditioning) subjects performed only the pain task. Subjects were informed that during these sessions two electrodes would be applied in order to reduce pain perception (conditioning procedure). As for the baseline session, the intensity of the painful stimulation increased over time but the percentage was the 30% of the individual pain threshold. During session 4 (test) subjects were divided in two groups: placebo (P) and control (C) group. All subjects were tested in both pain tolerance and motor endurance tasks with the same procedure used in the baseline session. However in the P group the two sham electrodes were applied as in the conditioning sessions along with the expectation of pain tolerance and motor endurance increase. In the C group no electrodes were applied. In Experiment 2, subjects were tested in two non-consecutive days. After session 1 (baseline)in which pain tolerance and motor endurance were assessed, during session 2 (test) subjects were divided in two groups: placebo (P) and control (C) group. As in the Experiment 1 pain tolerance and motor endurance were tested again:in the P group subjects received the sham electrical stimulation on the index finger along with expectation of pain tolerance and motor endurance increase, whereas in the C group no electrodes were applied.
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Figure 2. Pain tolerance (left) and motor endurance (right) in Experiment 1 (a) and 2 (b). A significant increase in pain tolerance and motor endurance was observed in the placebo group (gray) comparing session 1 with session4 only in the Experiment 1, when expectations of improvement were reinforced by previous experiences of pain tolerance increase. Figure 3. Pain time course (right) and fatigue time course (left) in Experiment 1 (a) and 2 (b). Each line represents the relationship between Session 1 (y-axis) and Session 4 or 2 (x-axix) for the placebo (gray) and control (black) groups. In all cases the gray line in below the black line, meaning that the placebo groups (in both experiment 1 and 2) experienced less pain and less fatigue over time compared with the control groups.
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Figure 1
Figure 2
Figure 3