Placebo-Induced Somatic Sensations: A Multi-Modal Study of Three Different Placebo Interventions

Somatic sensations induced by placebos are a frequent phenomenon whose etiology and clinical relevance remains unknown. In this study, we have evaluated the quantitative, qualitative, spatial, and temporal characteristics of placebo-induced somatic sensations in response to three different placebo interventions: (1) placebo irritant solution, (2) placebo laser stimulation, and (3) imagined laser stimulation. The quality and intensity of evoked sensations were assessed using the McGill pain questionnaire and visual analogue scales (VAS), while subjects’ sensation drawings processed by a geographic information system (GIS) were used to measure their spatial characteristics. We found that all three interventions are capable of producing robust sensations most frequently described as “tingling” and “warm” that can reach consider-able spatial extent (≤ 205mm^²) and intensity (≤ 80/100 VAS). Sensations from placebo stimulation were often referred to areas remote from the stimulation site and exhibit considerable similarity with referred pain. Interestingly, there was considerable similarity of qualitative features as well as spatial patterns across subjects and placebos. However, placebo laser stimulation elicited significantly stronger and more widespread sensations than placebo irritant solution. Finally, novelty seeking, a character trait assessed by the Temperament and Character Inventory and associated with basal dopaminergic activity, was less pronounced in subjects susceptible to report placebo-induced sensations. Our study has shown that placebo-induced sensations are frequent and can reach considerable intensity and extent. As multiple somatosensory subsystems are involved despite the lack of peripheral stimulus, we propose a central etiology for this phenomenon.     

Comparison of hyperalgesia induced by capsaicin injection and controlled heat injury: effect on temporal summation

The relationship between induction of central sensitization and facilitation of temporal summation to repetitive stimulation is still unclear. The aim of this study was to investigate temporal summation before and after the induction of secondary hyperalgesia by two different experimental methods: capsaicin injection and controlled heat injury. The effect of each injury model was assessed on a separate day with an interval of at least 5 days. Twelve healthy volunteers participated. Each experiment was performed using electrical, radiant heat, mechanical impact, and punctuate stimuli consecutively. The pain threshold (PT) to a single stimulus and the summation threshold to five repetitive stimuli for electrical (2?Hz) and radiant heat (0.83?Hz) were assessed within the secondary hyperalgesic area. The degree of temporal summation for stimulus intensities of 0.8, 1.0, and 1.2 times the baseline pain thresholds were evaluated by the increase in visual analogue scale (VAS) scores from the first to the fifth stimulus of the train. Further, the degrees of temporal summation were assessed for mechanical impact and punctuate stimuli within the primary and secondary hyperalgesic areas. The contra-lateral forearm served as control (no injury). The pain threshold and the summation threshold to electrical and heat stimuli decreased significantly within the secondary hyperalgesic area after the injury induced by both heat injury or capsaicin injection. However, there was no temporal summation for heat and electrical stimuli in either model. In contrast, for the mechanical impact and punctuate mechanical stimuli the degree of temporal summation was significantly facilitated in the secondary hyperalgesic areas compared with the baseline and the control arm in both models. In the primary hyperalgesic area, the degree of temporal summation was facilitated to mechanical impact and punctuate stimuli but only following the capsaicin injection. In conclusion, the temporal summation mechanism for mechanical stimuli was facilitated in the secondary hyperalgesic area.     

Comparison of hyperalgesia induced by capsaicin injection and controlled heat injury: effect on temporal summation

The relationship between induction of central sensitization and facilitation of temporal summation to repetitive stimulation is still unclear. The aim of this study was to investigate temporal summation before and after the induction of secondary hyperalgesia by two different experimental methods: capsaicin injection and controlled heat injury. The effect of each injury model was assessed on a separate day with an interval of at least 5 days. Twelve healthy volunteers participated. Each experiment was performed using electrical, radiant heat, mechanical impact, and punctuate stimuli consecutively. The pain threshold (PT) to a single stimulus and the summation threshold to five repetitive stimuli for electrical (2 Hz) and radiant heat (0.83 Hz) were assessed within the secondary hyperalgesic area. The degree of temporal summation for stimulus intensities of 0.8, 1.0, and 1.2 times the baseline pain thresholds were evaluated by the increase in visual analogue scale (VAS) scores from the first to the fifth stimulus of the train. Further, the degrees of temporal summation were assessed for mechanical impact and punctuate stimuli within the primary and secondary hyperalgesic areas. The contra-lateral forearm served as control (no injury). The pain threshold and the summation threshold to electrical and heat stimuli decreased significantly within the secondary hyperalgesic area after the injury induced by both heat injury or capsaicin injection. However, there was no temporal summation for heat and electrical stimuli in either model. In contrast, for the mechanical impact and punctuate mechanical stimuli the degree of temporal summation was significantly facilitated in the secondary hyperalgesic areas compared with the baseline and the control arm in both models. In the primary hyperalgesic area, the degree of temporal summation was facilitated to mechanical impact and punctuate stimuli but only following the capsaicin injection. In conclusion, the temporal summation mechanism for mechanical stimuli was facilitated in the secondary hyperalgesic area.     

Influence of segmental and extra-segmental conditioning stimuli on cortical potentials evoked by painful electrical stimulation

This study evaluated the effects of two different types of segmental/extra-segmental conditioning stimuli (tonic muscle pain and non-painful vibration) on the subjective experience (perceived pain intensity) and on the cortical evoked potentials to standardized test stimuli (cutaneous electrical stimuli). Twelve subjects participated in two separate sessions to investigate the effects of tonic muscle pain or cutaneous vibration on experimental test stimuli. The experimental protocol contained a baseline registration (test stimuli only), a registration with the test stimuli in combination with the conditioning stimuli, followed by a registration with the test stimuli only. In addition, the effects of the conditioning stimuli were examined at two anatomically separated locations (segmental and extra-segmental). Compared with the test stimulus alone, the perceived pain intensity and peak-to-peak amplitudes of the evoked potentials were unchanged in the presence of non-painful conditioning stimuli at either location. In contrast, a significant decrease of the perceived pain intensity and peak-to-peak amplitudes was found in the presence of painful conditioning stimuli at the extra-segmental sites. Moreover, the topographic maps of the 32-channel recordings suggested that the distribution of the scalp evoked potentials was almost symmetrical around the vertex Cz in the baseline registration. The evoked potentials were generally decreased during hypertonic saline infusion at the extra-segmental sites, but the distribution of the topographic maps did not appear to change. Vibration has previously been shown to inhibit pain, but in the present study the perceived intensity of phasic painful electrical stimuli was unchanged. The reduced perceived pain intensity and the smaller peak-to-peak amplitude of the evoked potential in the presence of extra-segmental conditioning pain are in accordance with the concept of diffuse noxious inhibitory control.     

Augmented Pain Processing in Primary and Secondary Somatosensory Cortex in Fibromyalgia: A Magnetoencephalography Study Using Intra-Epidermal Electrical Stimulation

The aim of this study was to investigate augmented pain processing in the cortical somatosensory system in patients with fibromyalgia (FM). Cortical evoked responses were recorded in FM (n = 19) and healthy subjects (n = 21) using magnetoencephalography after noxious intra-epidermal electrical stimulation (IES) of the hand dorsum (pain rating 6 on a numeric rating scale, perceptually-equivalent). In addition, healthy subjects were stimulated using the amplitude corresponding to the average stimulus intensity rated 6 in patients with FM (intensity-equivalent). Quantitative sensory testing was performed on the hand dorsum or thenar muscle (neutral site) and over the trapezius muscle (tender point), using IES (thresholds, ratings, temporal summation of pain, stimulus-response curve) and mechanical stimuli (threshold, ratings). Increased amplitude of cortical responses was found in patients with FM as compared to healthy subjects. These included the contralateral primary (S1) and bilateral secondary somatosensory cortices (S2) in response to intensity-equivalent stimuli and the contralateral S1 and S2 in response to perceptually-equivalent stimuli. The amplitude of the contralateral S2 response in patients with FM was positively correlated with average pain intensity over the last week. Quantitative sensory testing results showed that patients with FM were more sensitive to painful IES as well as to mechanical stimulation, regardless of whether the stimulation site was the hand or the trapezius muscle. Interestingly, the slope of the stimulus-response relationship as well as temporal summation of pain in response to IES was not different between groups. Together, these results suggest that the observed pain augmentation in response to IES in patients with FM could be due to sensitization or disinhibition of the cortical somatosensory system. Since the S2 has been shown to play a role in higher-order functions, further studies are needed to clarify the role of augmented S2 response in clinical characteristics of FM.     

Transcutaneous nerve stimulation. Frequency and waveform specificity in humans

The effects of transcutaneous electrical nerve stimulation (TNS) of a constant alternating current administered at various frequencies and waveforms to volunteer human subjects were investigated. The TNS was found to evoke noncutaneous subjective sensations in all the subjects. Only with a sinusoid waveform of TNS were distinct frequency ranges of the stimulation associated with specific noncutaneous subjective sensations. Our findings suggest that nervous tissue is capable of discriminating the waveform parameters of an electrical stimulus.     

The influence of rate of temperature change and peak stimulus duration on pain intensity and quality

An important aspect of experimental pain research is that the assessment methods can investigate the different aspects of pain perception. The aim of the present study was to investigate the influence of rate of temperature change and peak stimulus duration on heat evoked pain intensity and quality. All stimuli were applied within the medial aspect of the anterior forearm. The rate of temperature change was varied from 1 to 16 C/s without any effect on the pain threshold. The pain threshold decreased with an increasing peak stimulus duration from 0.1 to 2 s, but not from 2 to 3 s. The pain intensity for suprathreshold stimuli (46 C, 48 C, 50 C) increased for decreasing rates and increasing duration. The pain intensity was highly correlated with the energy of the stimulus. When the rates of temperature change (1-16 C/s) are varied, no differences between pricking and burning pain were present at either low stimulus intensity (46 C) or high stimulus intensity (50 C). At low stimulus intensity (46 C), the pricking pain was not influenced by the duration (0.1-3 s), but the burning pain was intensified when the duration was increased from 1.5 to 3 s. At high intensity stimuli (50 C), the pricking pain intensified with an increased duration, whereas burning pain did not. The heat pain threshold is influenced by the peak stimulus duration, and not by the rate of temperature change. If suprathreshold stimuli are used, both the rate of temperature change and the peak stimulus duration can strongly affect the pain intensity and the pain quality. Therefore, the same stimulus modality can be used to assess the modulation of different pain intensities and of the pricking and burning pain qualities simply by varying the stimulus configuration.     

A Psychophysical Comparison of Sensory and Affective Responses to Four Modalities of Experimental Pain

It is generally accepted that the sensory and affective components of pain may be differentially associated with various acute and chronic diseases, and that some treatment regimens are best directed toward certain aspects of the pain experience. In addition, experimental animal models have been described that presume to assess either the sensory-discriminative aspects of phasic pain or the affective responses associated with tonic pain. The present psychophysical experiment directly compares the perceived intensity and unpleasantness of sensations evoked by four types of experimental noxious stimuli: contact heat, electric shock, ischemic exercise, and cold-pressor pain. A novel pain measurement technique is described that incorporates unbounded magnitude-estimation/category scales; this technique allows precise ratio responses, while minimizing within- and between- subject variability. We observe that, relative to the perceived intensity of the individual stimuli, subjects consistently differentiate among the degrees of unpleasantness evoked by the four stimulus modalities. Ischemic exercise and cold-pressor pain evoke higher estimates of unpleasantness, and thus may better mimic the pain of chronic disease. The relative unpleasantness produced by contact heat is significantly less than that of the other modalities tested, and therefore contact heat stimuli may be ideally suited for assessing sensory-discriminative aspects of pain perception. Possible neurophysiological mechanisms underlying the observed differences in perceived unpleasantness are discussed in relation to the growing body of literature concerning tonic and phasic pain stimuli.     

Spatial localization of electrotactile stimuli on the fingertip in humans

This study was designed to determine the extent to which sensations elicited by discrete electrotactile stimulation can be spatially localized, with a qualitative comparison to mechanical stimulation, in a 2 x 2 electrode array on the fingertip. Electrotactile stimulation was delivered in two modes: (1) same current to all locations (constant) or (2) current adjusted to perceptual threshold of each location (varied). For each stimulus location, subjects were asked to identify the location of the stimulus. Mechanical stimulation of the same locations on the fingerpad was delivered through von Frey hairs (0.07, 0.2 and 0.4 g). The percentage of accurate responses was computed for all stimulation modes. We found that the accuracy of discrimination of stimulus location in both the constant (46%) and varied (40%) electrotactile stimulation modes was significantly higher than chance level (25%; p < 0.01). Furthermore, subjects were significantly more accurate in discriminating electrotactile stimuli in the constant than in the varied mode (p < 0.05). We also found that the accuracy of spatial discrimination was dependent on stimulation site for mechanical, but not electrotactile stimulation. Finally, we found a significant difference in accuracy over the duration of the experiment only for mechanical modes, which may indicate that electrotactile stimuli are less biased over time. These results suggest that, although low in accuracy, human subjects are able to extract spatial information from electrotactile stimuli. Further research is needed to optimize the amount of the information that can be delivered through electrotactile stimulation.     

Functional characteristics of the skin receptor structures in animals and man

Threshold electrical reactions of single fibers from the ischiadic nerve of rats to mechanical stimulation and rectangle impulses of focused ultrasound have been compared with respect to the parameters of stimulation to the effect of focused ultrasound on the skin of human fingers evoking different sensations. It was concluded that low-threshold fibers may be associated with tactile reception, mean-threshold ones--with tactile and thermal, whereas high-threshold fibers may be referred to reception of specific skin pain.     

Correlation of subjective assessments with somatosensory evoked potentials to electrical stimulation of the finger in man

The relationship between 5 positive components of somatosensory evoked potentials (EPs) and subjective response to electrical stimuli, which were recorded in the same human subjects, was assessed in the present study. Five levels of tactile stimuli and 6 levels of noxious stimuli were applied to the tip of the right index finger. The relationship between the magnitude of subjective response and stimulus intensity was well expressed by a power function. Of 5 major positive components in an EP, P30 and P50 were localized at contralateral primary somatic projection area, while P90, P190 and P270 were at the vertex area. The amplitude of the 5 components systematically increased as increasing stimulus intensity, and also increased with the magnitude of subjective response. A significant correlation between the amplitude of P30 or P50 and stimulus intensity was found when the effect of subjective response was partially out. By contrast, the amplitudes of P190 and P270 were associated with subjective response when the effect of stimulus intensity was partially out. These results suggest that the earlier EP components reflect sensory signal processing, while the latter ones concern the subjective evaluating system.     

Evoked Temporal Summation in Cats to Highlight Central Sensitization Related to Osteoarthritis-Associated Chronic Pain: A Preliminary Study

In cats, osteoarthritis causes significant chronic pain. Chronicity of pain is associated with changes in the central nervous system related to central sensitization, which have to be quantified. Our objectives were 1) to develop a quantitative sensory testing device in cats for applying repetitive mechanical stimuli that would evoke temporal summation; 2) to determine the sensitivity of this test to osteoarthritis-associated pain, and 3) to examine the possible correlation between the quantitative sensory testing and assessment using other pain evaluation methods. We hypothesized that mechanical sub-threshold repetitive stimuli would evoke temporal summation, and that cats with osteoarthritis would show a faster response. A blinded longitudinal study was performed in 4 non-osteoarthritis cats and 10 cats with naturally occurring osteoarthritis. Quantification of chronic osteoarthritis pain-related disability was performed over a two week period using peak vertical force kinetic measurement, motor activity intensity assessment and von Frey anesthesiometer-induced paw withdrawal threshold testing. The cats afflicted with osteoarthritis demonstrated characteristic findings consistent with osteoarthritis-associated chronic pain. After a 14-day acclimation period, repetitive mechanical sub-threshold stimuli were applied using a purpose-developed device. Four stimulation profiles of predetermined intensity, duration and time interval were applied randomly four times during a four-day period. The stimulation profiles were different (P<0.001): the higher the intensity of the stimulus, the sooner it produced a consistent painful response. The cats afflicted with osteoarthritis responded more rapidly than cats osteoarthritis free (P = 0.019). There was a positive correlation between the von Frey anesthesiometer-induced paw withdrawal threshold and the response to stimulation profiles #2 (2N/0.4 Hz) and #4 (2N/0.4 Hz): Rho_s = 0.64 (P = 0.01) and 0.63 (P = 0.02) respectively. This study is the first report of mechanical temporal summation in awake cats. Our results suggest that central sensitization develops in cats with naturally occurring osteoarthritis, providing an opportunity to improve translational research in osteoarthritis-associated chronic pain.     

Spatial localization of electrotactile stimuli on the fingertip in humans

This study was designed to determine the extent to which sensations elicited by discrete electrotactile stimulation can be spatially localized, with a qualitative comparison to mechanical stimulation, in a 2 × 2 electrode array on the fingertip. Electrotactile stimulation was delivered in two modes: (1) same current to all locations (constant) or (2) current adjusted to perceptual threshold of each location (varied). For each stimulus location, subjects were asked to identify the location of the stimulus. Mechanical stimulation of the same locations on the fingerpad was delivered through von Frey hairs (0.07, 0.2 and 0.4 g). The percentage of accurate responses was computed for all stimulation modes. We found that the accuracy of discrimination of stimulus location in both the constant (46%%) and varied (40%%) electrotactile stimulation modes was significantly higher than chance level (25%%; p < 0.01). Furthermore, subjects were significantly more accurate in discriminating electrotactile stimuli in the constant than in the varied mode (p < 0.05). We also found that the accuracy of spatial discrimination was dependent on stimulation site for mechanical, but not electrotactile stimulation. Finally, we found a significant difference in accuracy over the duration of the experiment only for mechanical modes, which may indicate that electrotactile stimuli are less biased over time. These results suggest that, although low in accuracy, human subjects are able to extract spatial information from electrotactile stimuli. Further research is needed to optimize the amount of the information that can be delivered through electrotactile stimulation.     

Modification of Electrical Pain Threshold by Voluntary Breathing-Controlled Electrical Stimulation (BreEStim) in Healthy Subjects

Background

Pain has a distinct sensory and affective (i.e., unpleasantness) component. BreEStim, during which electrical stimulation is delivered during voluntary breathing, has been shown to selectively reduce the affective component of post-amputation phantom pain. The objective was to examine whether BreEStim increases pain threshold such that subjects could have improved tolerance of sensation of painful stimuli.

Methods

Eleven pain-free healthy subjects (7 males, 4 females) participated in the study. All subjects received BreEStim (100 stimuli) and conventional electrical stimulation (EStim, 100 stimuli) to two acupuncture points (Neiguan and Weiguan) of the dominant hand in a random order. The two different treatments were provided at least three days apart. Painful, but tolerable electrical stimuli were delivered randomly during EStim, but were triggered by effortful inhalation during BreEStim. Measurements of tactile sensation threshold, electrical sensation and electrical pain thresholds, thermal (cold sensation, warm sensation, cold pain and heat pain) thresholds were recorded from the thenar eminence of both hands. These measurements were taken pre-intervention and 10−min post-intervention.

Results

There was no difference in the pre-intervention baseline measurement of all thresholds between BreEStim and EStim. The electrical pain threshold significantly increased after BreEStim (27.5±6.7% for the dominant hand and 28.5±10.8% for the non-dominant hand, respectively). The electrical pain threshold significantly decreased after EStim (9.1±2.8% for the dominant hand and 10.2±4.6% for the non–dominant hand, respectively) (F_{[1, 10]} = 30.992, p = .00024). There was no statistically significant change in other thresholds after BreEStim and EStim. The intensity of electrical stimuli was progressively increased, but no difference was found between BreEStim and EStim.

Conclusion

Voluntary breathing controlled electrical stimulation selectively increases electrical pain threshold, while conventional electrical stimulation selectively decreases electrical pain threshold. This may translate into improved pain control.     

Pain-related somatosensory evoked potentials following CO2 laser stimulation in man

0ain-related somatosensory evoked potentials (SEPs) following CO₂ laser stimulation were analyzed in normal volunteers. Low power and long wavelength CO₂ laser stimuli to the hand induced a sharp pain which was associated with a large positive component, P320, recorded over the scalp. Amplitude decreased and latency increased with reduction in stimulus intensity and subjective pain feeling. P320 was maximal at the vertex but was distributed widely over the scalp. There were no topographic differences between left- and right-hand stimulation, or between hand and chest stimulation. Lidocaine injection to produce anesthetic nerve block resulted in loss of P320, but the potential was relatively preserved during ischemic nerve block. No potential corresponding to P320 could be recorded following electrical or mechanical tactile stimulation.We consider P320 to be generated by impulses arising from pain stimuli and ascending through Aδ fibers. We propose the thalamus as a generator source from considering its scalp topography, but pain-specific cognition or perception may also be involved in generating this potential.     

Electrical taste stimulus: current intensity or current density?

In electrical taste stimulation, current intensity is usuallyconsidered to be a simple equivalent of the taste stimulus intensity,this being analogous to the concentration of a chemical solution.However, there are indications that current density might bea better correlate of the true electrical taste stimulus. Inthe present study the relationship between the size of the stimulatedhuman tongue area, the electrical current intensity, and themagnitude of elicited taste sensations was examined. Tests insix subjects showed that in order to achieve the standard sourtaste magnitude when using electrode sizes that increased insize, the current intensity also had to be increased, but currentdensity decreased. This might be attributed to spatial summationwhich is plausible only if current density was taken as a realelectrical taste stimulus. Summation degree was less than complete,indicating that the density might be a predominant, but notthe only factor in electrical stimulus efficacy.     

The effects of heat-induced pain on the detectability,discriminability, and sensation magnitude of vibrotactile stimuli

The effects of heat-induced pain on absolute thresholds, sensation magnitudes and amplitude-difference thresholds were measured at 10 and 100 Hz. Consistent with previous results, heat-induced pain elevated the absolute thresholds by approximately 8.0 dB and lessened the magnitudes of tactile sensations during pain as compared to the non-painful condition. In contrast to these effects, the discriminability of change in the intensity of the vibrotactile stimuli was unaffected by the presence of pain indicating that the effect of pain on tactile sensations is more likely due to sensory rather than cognitive processes (i.e., attention) and that the mechanisms underlying tactile sensitivity as compared to discriminability are different.     

The effects of heat-induced pain on the detectability, discriminability, and sensation magnitude of vibrotactile stimuli

The effects of heat-induced pain on absolute thresholds, sensation magnitudes and amplitude-difference thresholds were measured at 10 and 100 Hz. Consistent with previous results, heat-induced pain elevated the absolute thresholds by approximately 8.0 dB and lessened the magnitudes of tactile sensations during pain as compared to the non-painful condition. In contrast to these effects, the discriminability of change in the intensity of the vibrotactile stimuli was unaffected by the presence of pain indicating that the effect of pain on tactile sensations is more likely due to sensory rather than cognitive processes (i.e., attention) and that the mechanisms underlying tactile sensitivity as compared to discriminability are different.     

Electrotactile stimulation on the tongue: Intensity perception,discrimination, and cross-modality estimation

Due to its high sensitivity and conductivity, electrotactile stimulation (ETS) on the tongue has proven to be a useful and technically convenient tool to substitute and/or augment sensory capabilities. However, most of its applications have only provided spatial attributes and little is known about (a) the ability of the tongue's sensory system to process electrical stimuli of varying magnitudes and (b) how modulation of ETS intensity affects subjects’ ability to decode stimulus intensity. We addressed these questions by quantifying: (1) the magnitude of the dynamic range (DR; maximal comfortable intensity/perception threshold) and its sensitivity to prolonged exposure; (2) subjects’ ability to perceive intensity changes; and (3) subjects’ ability to associate intensity with angular excursions of a protractor's handle. We found that the average DR (17 dB) was generally large in comparison with other tactile loci and of a relatively constant magnitude among subjects, even after prolonged exposure, despite a slight but significant upward drift (p < 0.001). Additionally, our results showed that as stimulus intensity increased, subjects’ ability to discriminate ETS stimuli of different intensities improved (p < 0.05) while estimation accuracy, in general, slightly decreased (increasing underestimation). These results suggest that higher ETS intensity may increase recruitment of rapidly adapting mechanoreceptor fibers, as these are specialized for coding stimulus differences rather than absolute intensities. Furthermore, our study revealed that the tongue's sensory system can effectively convey electrical stimuli despite minimal practice and when information transfer is limited by memory and DR drift.