The anatomy of the mesolimbic reward system: a link between personality and the placebo analgesic response.

The anticipation of clinical benefit, a crucial component of placebo analgesia, has been suggested to be a special case of reward anticipation. Since reward processing is closely linked to the ventral striatum and the neurotransmitter dopamine, we examined the relationships between brain gray matter, placebo analgesic response, and personality traits associated with dopaminergic neurotransmission. We report that dopamine-related traits predict a substantial portion of the pain relief an individual gains from a sham treatment. Voxel-based morphometry of magnetic resonance images shows that the magnitude of placebo analgesia is related to gray matter density (GMD) in several brain regions, including the ventral striatum, insula, and prefrontal cortex. Similarly, GMD in ventral striatum and prefrontal cortex is related to dopamine-related personality traits. Our findings highlight the relationship between placebo and reward and potentially offer ways of identifying subjects who are likely to show large placebo analgesic responses.

Response competition in the primary motor cortex: corticospinal excitability reflects response replacement during simple decisions.

It has been suggested that, during decisions about actions, multiple options are initially specified in parallel and then gradually eliminated in a competition for overt execution. To further test this hypothesis, we studied the modulation of human corticospinal excitability during the reaction time of the Eriksen flanker task. In the task, subjects responded with finger flexion or extension to a central arrow while ignoring congruent or incongruent flanker arrows. Single-pulse transcranial magnetic stimulation (TMS) was applied over primary motor cortex (M1) at one of five different latencies after stimulus onset, and motor-evoked potentials (MEPs) were measured in the contralateral index finger. During the control (no flankers) and congruent conditions, MEP size in the agonist increased gradually over the course of reaction time, indicating an increase in corticospinal excitability. Conversely, when the same muscle acted as an antagonist, MEP size decreased, suggesting inhibition. Critically, in the incongruent condition, MEPs briefly increased in the muscle corresponding to an initial default response to the flanker arrows and were later replaced by MEPs corresponding to the correct response to the central arrow. Finally, we found that the gradually growing MEPs for the three conditions reached a constant maximum level just before movement initiation. We propose that this dynamic modulation in corticospinal excitability reflects the competition process, leading to the selection of one response and the rejection of the other. Our results suggest that response competition influences activity in primary motor cortex and that its timing directly influences motor output latency.

Memory traces of pain in human cortex.

Distinct brain regions process sensory discriminative and affective components of pain; however, the role of these areas in pain memory is unknown. This event-related study investigated the short-term memory for sensory features of cutaneous heat pain using a delayed-discrimination paradigm and functional magnetic resonance imaging. During memory trials, subjects discriminated the location and intensity of two painful stimuli presented sequentially to the right hand. Control trials comprised the same sequence of stimuli and motor responses but required no delayed discrimination. Stimulus-evoked activity for memory and control trials was generally indistinguishable within the network of regions normally responsive to experimental pain [i.e., the primary somatosensory cortex/posterior parietal cortex (SI/PPC), secondary somatosensory cortex (SII), and anterior insular cortex (aIC)]; these data confirm the painful nature of the stimuli and the similar levels of attention and stimulus encoding engaged during the two randomly presented trial types. Memory-specific activity, assessed by contrasting the interstimulus interval in memory and control trials, was observed in SI/PPC and aIC but not in SII. We propose that SI/PPC plays a role in the short-term retention of spatial and intensity aspects of noxious stimuli and that aIC activation during memory trials is consistent with the integration of sensory and cognitive (attention, awareness, salience, and memory) components of pain perception. The absence of memory-specific anterior cingulate cortex activation, generally associated with pain unpleasantness, suggests that remembering affective aspects of the stimuli was not required during performance of the sensory delayed-discrimination task.

The effects of racemic ketamine on painful stimulation of skin and viscera in human subjects.

Evidence suggests that NMDA receptors may have a differential role in the modulation of visceral and somatic pain. Specifically, animal data indicate an analgesic role of NMDA-R antagonists in acute visceral but not acute somatic pain. In humans analgesic effects are documented in acute somatic pain, while the role of NMDA-R antagonists in acute visceral pain is still questionable. We, therefore, conducted a study in humans comparing the analgesic effects of ketamine in an experimental model of visceral and cutaneous pain. In a double-blind, randomized, cross-over study, 11 healthy volunteers (3M, 8F) participated in two experimental sessions in which they evaluated perceptions induced by balloon distention of the distal esophagus and contact heat on the upper chest during continuous computer-controlled i.v. infusion of either ketamine (60 and 120 ng/mL) or saline. Two stimulus intensities producing non-painful and painful sensation were used for each stimulus modality. Subjects reported maximum pain intensity and unpleasantness on visual analog scales (VAS). For noxious visceral stimulation, low dose ketamine produced significant attenuation of both pain intensity and unpleasantness. In contrast, for noxious cutaneous stimulation, ketamine reduced pain unpleasantness, but not perceived intensity. In addition, ketamine did not alter the perception of innocuous stimuli in either modality. Our results confirm the analgesic effects of low-dose ketamine, with minimal side effects, on acute visceral pain and indicate a similar but smaller effect on acute cutaneous pain. A decrease in the unpleasantness but not in the intensity of cutaneous pain may reflect the differential effect of NMDA-R antagonists for the two pain states observed in animal models.

Visceral and cutaneous pain representation in parasylvian cortex.

The ability to localize both touch and pain has been attributed mainly to the primary somatosensory cortex (S1), based on its fine somatotopic mapping of tactile inputs. Recently, S1 has also been implicated in the differentiation of noxious stimulation, such as distinguishing between pain arising from viscera and skin. Recent MEG and fMRI studies show that there is at least a rudimentary tactile topographic representation in the supra-sylvian cortex [encompassing secondary somatosensory area (S2)], suggesting that this area may contribute to touch localization. Nevertheless, the role of this region in pain localization or its role in the differentiation of various types of pain has not been clearly established. Healthy subjects (four males, three females) underwent fMRI-scanning (1.5 T, standard head coil, BOLD analysis) during painful balloon distention of the distal esophagus and painful heat on the midline chest in the zone of referred pain for the esophageal stimulation. Five of the seven subjects exhibited significant activation of the parasylvian region in both experimental conditions, and in each of these five subjects activation related to esophageal pain was represented more laterally within the parasylvian cortex than that associated with cutaneous trunk pain (paired t-test, p's < 0.01). Our results suggest segregation of visceral esophageal and cutaneous chest afferents within parasylvian cortex, possibly implicating this region in the perceptual differentiation of visceral and cutaneous pain.

Deep brain stimulation: a review of basic research and clinical studies.

Deep brain stimulation for pain control in humans was first used almost 30 years ago and has continued to receive considerable attention. Despite the large number of clinical reports describing pain relief, numerous studies have indicated that the results of these procedures vary considerably. In addition, many neurosurgeons find the procedures unpredictable, and considerable disagreement still exists regarding important issues related to the technique itself. This review gives an historical overview of the relevant basic and clinical literature and provides a critical examination of the clinical efficacy, choice of stimulation sites, parameters of stimulation, and effects on experimental pain. Finally, we give suggestions for future research that could more definitively determine the usefulness of deep brain stimulation for pain control.

Effects of attention on the intensity and unpleasantness of thermal pain.

Both experimental and clinical studies have shown that psychological manipulations, such as hypnosis, behavioral modification and cognitive-behavioral therapy, can reduce reports of pain. Although these are complex procedures, one important variable common to each is direction of attention. We have previously demonstrated in both humans and monkeys a method for monitoring and manipulating attention toward or away from a painful stimulus and have shown that changes in the direction of attention alter the ability to discriminate noxious heat stimuli. The present study assessed whether these changes in discrimination were accompanied by changes in the perception of pain intensity and/or unpleasantness. These data confirm that both the speed and accuracy of detecting changes in noxious heat stimuli are decreased when the subject attends to another stimulus modality. In addition, they show that direction of attention affects the perceived intensity and unpleasantness of painful stimuli in a similar manner. Our previous findings of attention-related modulation of nociceptive neuronal activity in the medullary dorsal horn suggest that these attention-dependent changes in sensory-discriminative and affective components of pain are mediated at early stages of sensory processing.

Psychophysical analysis of visceral and cutaneous pain in human subjects.

Clinical evidence suggests that cutaneous and visceral pain differ in sensory, affective, and motivational realms, yet there has been little comparative characterization of these types of pain. This study uses psychophysical measures to compare directly visceral and cutaneous pain and sensitivity. Healthy subjects (10 males, seven females, age 19-29) evaluated perceptions evoked by balloon distention of the distal esophagus and contact heat on the upper chest. Subjects gave continuous ratings of pain intensity using an on-line visual analog scale (VAS), reported maximum pain intensity and unpleasantness on printed VASs, chose phrases from the McGill Pain Questionnaire and Spielberger State-Trait Anxiety Inventory, and drew the area of perceived sensation. For esophageal distention, the threshold for pain intensity was higher than that observed for unpleasantness, whereas for contact heat, pain and unpleasantness thresholds did not differ for either phasic (10s) or tonic (36s) stimulus application. The relative unpleasantness, calculated as the difference between the unpleasantness and the intensity ratings, was higher during esophageal distention than during either phasic or tonic cutaneous heat; this difference in relative unpleasantness was seen at all intensities of esophageal stimulation. Subjects chose significantly more affective words and reported more anxiety during visceral pain than during phasic cutaneous heat pain. A similar tendency was observed when visceral pain was compared to tonic cutaneous heat pain. Subjects also chose a wider range of words to describe visceral than cutaneous pain. On-line VAS ratings revealed greater pain sensation after stimulus termination during visceral than during phasic cutaneous pain; likewise, a similar tendency was observed between visceral and tonic cutaneous pain. Finally, visceral pain led to a more spatially diffuse sensation and was referred to the entire chest and sometimes to the back. Our results show that visceral pain is more unpleasant, diffuse, and variable than cutaneous pain of similar intensity, independent of the duration of the presented stimuli. The data suggest the likelihood of both similarities and differences in the neural substrates underlying visceral and cutaneous pain.

Sex differences in the perception of noxious heat stimuli.

This study compared pain perception in young male and female subjects, using experimental noxious heat stimuli. During 2 sessions, each of 40 subjects rated the magnitude of 120 heat stimuli, ranging from 45 degrees C to 50 degrees C. The study included a comparison of visual analogue and magnitude matching rating procedures, as well as a test of simulated analgesia, in which the range of stimuli presented during the 2 experimental sessions was shifted by 1 degree C. We found that females rated noxious heat stimuli as more intense than did males, independent of the gender of the experimenter or the type of rating scale. In addition, the data suggest that females discriminate among the painful heat intensities better than males. For example, female subjects showed significant between-session discrimination of noxious heat stimuli, while male subjects did not, and females produced steeper within-session stimulus-response functions than did males. These observed differences in nociceptive discrimination between males and females indicate that the sex-related variation in pain perception is probably related to sensory factors rather than differences in attitude or emotional response.

Diffuse noxious inhibitory controls (DNICs): psychophysical evidence in man for intersegmental suppression of noxious heat perception by cold pressor pain.

Counterirritation, the phenomenon of one painful stimulus reducing pain caused by a second noxious stimulus, has been recognized clinically for decades. Recently a physiological mechanism to explain counterirritation was described and termed diffuse noxious inhibitory controls (DNICs). Nevertheless, few psychophysical studies have examined systematically the effects of a noxious conditioning stimulus on pain perception. The present study examined the perception of painful heat stimuli on the face before, during and after the subject submerged a hand in painfully cold water (5 degrees C) for 5 min (cold pressor pain). We found that the subjects' ratings of the heat stimuli were significantly, although not completely, reduced during the cold pressor pain; this attenuation of pain perception continued after the noxious conditioning stimulus was withdrawn. Similarly, the pain threshold was significantly increased from 45.7 degrees C to 47.3 degrees C while the hand was in cold water and this threshold remained elevated after the cold water was terminated. Since DNICs have been found to completely and selectively inhibit the activity of only one type of pain transmission neuron (wide dynamic range), our data suggest that these neurons are involved in the perception of pain intensity. However, the persistence of residual pain perception in the presence of noxious conditioning stimuli indicates the importance of other nociceptive pathways.

Rapid deterioration of pain sensory-discriminative information in short-term memory.

The assessment of pain and analgesic efficacy sometimes relies on the retrospective evaluation of pain felt in the immediate, recent or distant past, yet we have a very limited understanding of the processes involved in the encoding, maintenance and intentional retrieval of pain. We examine the properties of the short-term memory of thermal and pain sensation intensity with a delayed-discrimination task using pairs of heat pain, warm and cool stimulation in healthy volunteers. Performance decreased as a function of the inter-stimulus interval (ISI), indicating a robust deterioration of sensory information over the test period of 4-14 s. As expected, performance also decreased with smaller temperature differences (Delta-T) and shorter stimulus durations (6-2 s). The relation between performance and Delta-T was adequately described by a power function, the exponent of which increased linearly with longer ISI. Importantly, performance declined steadily with increasing ISI (from 6 to 14 s)--but only for pairs of heat pain stimuli that were relatively difficult to discriminate (Delta-T < or = 1.0 degree C; perceptual difference < or = 32/100 pain rating units) while no deterioration in performance was observed for the largest temperature difference tested (Delta T = 1.5 degrees C; perceptual difference of 50 units). These results are consistent with the possibility that short-term memory for pain and temperature sensation intensity relies on a transient analog representation that is quickly degraded and transformed into a more resistant but less precise categorical format. This implies that retrospective pain ratings obtained even after very short delays may be rather inaccurate but relatively reliable.

Analgesic and placebo effects of thalamic stimulation.

Numerous clinical studies have reported successful relief of chronic pain with sensory thalamic stimulation. However, even with the extensive use of sensory thalamic stimulation as a clinical tool in the relief of chronic pain, the results are still inconsistent. This discrepancy could probably be explained by the fact that the majority of these studies are case reports or retrospective analyses, which have often used imprecise pain measurements that do not allow a rigorous statistical evaluation of pain relief. None of these studies measured the effect of stimulation on clinical pain for longer than a few hours per day, which is an important aspect considering that clinical pain can vary over time. Moreover, placebo controls are seldom included. In the current study, we measured patients' pain perception at home over a 2-week period, both during days of normal stimulation of the sensory thalamus and during days without stimulation. Patients also came to the laboratory to assess the effects of thalamic and placebo stimulation on clinical pain, experimental heat pain, innocuous air puff and visual stimulation. A potential relation between the perceived paresthesia and analgesic efficacy during thalamic and placebo stimulation was also explored. We found that thalamic stimulation significantly affected clinical and experimental pain perception, but that an important placebo component also exists. On the other hand, neither thalamic nor placebo stimulation affected air puff and visual ratings, suggesting that the effect applies specifically to pain and hence is not caused by a general change in attention. The level of paresthesia elicited during the placebo manipulation was also directly correlated with the degree of placebo pain relief. These results suggest that thalamic stimulation produces a small but significant reduction in pain perception, but that a significant placebo effect also exists.

The pain profile: a computerized system for assessment of chronic pain.

A computer-based system to assess and quantify three components of the chronic pain experience is described. The system produces a Pain Profile and classification for each patient based on a mathematical comparison of the pathophysiologic, psychological and behavioral aspects of chronic pain. This computer-based evaluation assists the researcher in analyzing the relative importance of the chronic pain components and helps direct the clinician to the appropriate emphasis of therapy.

Effects of diffuse noxious inhibitory controls (DNICs) on the sensory-discriminative dimension of pain perception.

We have recently demonstrated that humans report heat stimuli as less painful when presented concurrently with a second noxious stimulus applied to another part of the body. Previous neurophysiological studies have shown that similar heterotopically applied noxious stimuli selectively and completely inhibit the activity of wide-dynamic-range (WDR) neurons in the dorsal horn - a phenomenon termed diffuse noxious inhibitory controls (DNICs). Taken together, these 2 lines of evidence suggest that activation of WDR cells may be necessary for normal perception of pain. Recent studies in the behaving monkey have additionally shown that WDR neurons respond to small changes in noxious heat stimuli better than do high threshold neurons, thus indicating a more specific role for WDR neurons in sensory-discriminative aspects of pain perception. If DNICs do indeed selectively and completely inhibit the activity of WDR neurons, then a heterotopically applied noxious stimulus should selectively interfere with a subject's ability to discriminate noxious stimuli. This hypothesis was tested using a noxious heat discrimination task and a cold water (5 degrees C) diffuse noxious stimulus. We found that the ability to detect small changes (0.4-0.8 degrees C) in painful heat stimuli applied to the face decreases when the person's hand is submerged in painfully cold water (P = 0.005) and that this effect persists, to a lesser extent, after the hand is removed from water. Control tasks, using visual stimuli, demonstrated that the modulation of nociceptive discrimination was not a generalized effect on sensory perception; other control measures indicated that the results could not be attributed to distraction, fatigue or changes in response bias.(ABSTRACT TRUNCATED AT 250 WORDS)

Comparison of verbal and visual analogue scales for measuring the intensity and unpleasantness of experimental pain.

Although the multidimensional nature of pain is now well recognized, there are, nevertheless, very few quantitative tests to measure the separate dimensions of pain and little data concerning their relative sensitivity. The present study compares 2 currently available methods, verbal descriptor and visual analogue scales. Eight subjects rated painful and near-painful heat stimuli by using visual analogue scales for intensity or unpleasantness and by choosing the most appropriate phrases from lists of intensity or unpleasantness descriptors. In the intensity dimension, the relationship between perception and stimulus temperature was essentially identical whether calculated from the visual analogue or verbal descriptor scales. However, data derived from the verbal descriptor scales revealed that subjects rated the painful temperatures as relatively more intense than unpleasant; this difference could not be detected using the visual analogue scales. These results confirm that both visual analogue and verbal descriptor techniques successfully quantify sensory intensity and affective aspects of pain, but that verbal descriptors may provide the more sensitive tool for separating intensity and unpleasantness.

High versus low intensity acupuncture analgesia for treatment of chronic pain: effects on platelet serotonin.

The 26 chronic pain patients were tested in a baseline plus cross-over design. Half of the subjects were first treated with high intensity acupuncture; then they were treated with low intensity acupuncture. For the other 13 subjects the treatment order was reversed. In the first treatment sequence subjects reported lower pain estimates and engaging in more activities of daily living during treatment with high intensity acupuncture--but not with low intensity acupuncture. In addition, under high intensity acupuncture (i.e. with low pain levels), subjects had higher levels of platelet serotonin; this last finding is consistent with recent research which implicates central serotonin in pain control. The results of the second treatment sequence were ambiguous.

Dissociation of sensory and affective dimensions of pain using hypnotic modulation.

Understanding the complex nature of pain perception requires the ability to separately analyze its psychological dimensions and their interaction, and relate them to specific variables and responses. The present study, therefore, attempted to selectively modulate the sensory and affective dimensions of pain, using a cognitive intervention, and to assess the possible relationship between these psychological dimensions of pain and changes in physiological responses to the noxious stimuli. In three experiments, normal subjects trained in hypnosis rated pain intensity and pain unpleasantness produced by a tonic heat-pain stimulus (1-min immersion of the hand in 45.0-47.5 degrees C water). Two experiments were designed to test hypnotic suggestions to decrease (Experiment one (Section 2.5.1)), or increase and decrease (Experiment two (Section 2.5.2)) pain affect. Suggestions in Experiment three (Section 2.5.3) were directed towards an increase or decrease in pain sensation. In Experiments one and two (Sections 2.5.1 and 2.5.2), the significant modulation in pain unpleasantness ratings was largely independent of variations in perceived pain intensity. Moreover, in Experiment two (Section 2.5.2), there was a significant correlation between the stimulus-evoked heart-rate increase and ratings of pain unpleasantness, but not of pain intensity, suggesting a direct functional interaction between pain affect and autonomic activation. In Experiment three (Section 2.5.3), suggestions to modulate the sensory aspect of pain produced significant modulation of pain intensity ratings, with secondary changes in pain unpleasantness ratings. Hypnotic susceptibility (Stanford Hypnotic Susceptibility Scale form A) was specifically correlated to pain unpleasantness modulation in Experiment two (Section 2.5.2) and to pain intensity modulation in Experiment three (Section 2.5.3), suggesting that this factor relates to the primary process toward which hypnotic suggestions are directed. The specific pain dimension on which hypnotic suggestions act depends on the content of the instructions and is not a characteristic of hypnosis itself. Results are consistent with a successive-stage model of pain perception (e.g. Wade JB, Dougherty LM, Archer CR, Price DD. Assessing the stages of pain processing: a multivariate analytical approach. Pain 1996;68:157-167) which provides a conceptual framework necessary to study the cerebral representation of pain perception.

The submaximal effort tourniquet test: its use in evaluating experimental and chronic pain.

The submaximal effort tourniquet test has been widely used to evaluate experimental and chronic pain; however, there has been great variation in the manner in which the test has been applied. The present study systemitically evaluates how different levels of exercise duration and effort affect subjects' report of pain. The data indicate the following: (1) the manner in which the exercise is performed has an important effect on subjects' rating of pain, and (2) under all conditions studied, the pain ratings do not increase as a linear function of time. Both findings warrant precautions when using the submaximal effort tourniquet test to study experimental and chronic pain.

Is there a role for the parietal lobes in the perception of pain?

Converging lines of evidence confirm a role for the anterior parietal cortex in pain processing and extend the traditional view of SI to include discriminative aspects of somatic stimulation that is potentially tissue-damaging (e.g., painful). Recent studies more specifically implicate SI in the sensory aspect of pain perception by demonstrating that SI activation is modulated by cognitive manipulations that alter perceived pain intensity, but not by manipulations that alter unpleasantness, independent of pain intensity. Nevertheless, despite the probable role of SI in the encoding of the various sensory features of pain, considerable evidence suggests that nociceptive input to SI may also serve to modulate tactile perception. Thus, SI cortex may be involved in both the perception and modulation of both painful and nonpainful somatosensory sensations. Defining a role in pain processing for the parietal operculum is somewhat more problematic. The absence of a fine somatotopic organization of cutaneous (or visceral) receptors virtually eliminates a substantial role for this region in localizing noxious stimuli. Several studies suggest separate representations for pain and touch within the posterior parietal cortex and SII, respectively; however, inter-species differences in cortical anatomy and inconsistencies in the designation of SII proper preclude a clear reconciliation of the data. Likewise, suggestions that SII activation is predominantly related to processing the nociceptive quality of the stimulus (60,61) are inconsistent with many studies in both human and nonhuman subjects, which show a strong functional relationship between SII activity and innocuous (especially, vibrotactile) stimulation. Nevertheless, the numerous studies indicating pain-related activation within the parietal operculum (and/or SII) underscore the potential importance of this region in the perception of pain and the need for continued research. Finally, a possible role of posterior parietal cortex (BA 5/7, 39/40) in orientation and attention toward painful sensory stimuli is consistent with existing literature describing this region as a poly modal association area concerned with intrapersonal and extrapersonal space; however, results from studies that actually manipulate the subjects' level of attention relative to painful stimuli have not uniformly supported this hypothesis (75). Future studies assessing both attentional demand and direct manipulation or motor interactions involving noxious stimuli may help to resolve this issue. In spite of some discrepant results concerning specific details of the nociceptive process, the weight of human pain research now firmly establishes a role for the parietal lobes in the conscious appreciation of the sensation of pain.

Remembering the dynamic changes in pain intensity and unpleasantness: a psychophysical study.

This study investigated the short-term memory of dynamic changes in acute pain using psychophysical methods. Pain intensity or unpleasantness induced by painful contact-heat stimuli of 8, 9, or 10s was rated continuously during the stimulus or after a 14-s delay using an electronic visual analog scale in 10 healthy volunteers. Because the continuous visual analog scale time courses contained large amounts of redundant information, a principal component analysis was applied to characterize the main features inherent to both the concurrent rating and retrospective evaluations. Three components explained about 90% of the total variance across all trials and subjects, with the first component reflecting the global perceptual profile, and the second and third components explaining finer perceptual aspects (eg, changes in slope at onset and offset and shifts in peak latency). We postulate that these 3 principal components may provide some information about the structure of the mental representations of what one perceives, stores, and remembers during the course of few seconds. Analysis performed on the components confirmed significant memory distortions and revealed that the discriminative information about pain dimensions in concurrent ratings was partly or completely lost in retrospective ratings. Importantly, our results highlight individual differences affecting these memory processes. These results provide further evidence of the important transformations underlying the processing of pain in explicit memory and raise fundamental questions about the conversion of dynamic nociceptive signals into a mental representation of pain in perception and memory.