Non-painful and painful stimulation of human skin and muscle: analysis of cerebral evoked potentials

The present study compared the cerebral processing of non-painful and painful cutaneous CO₂ laser stimulation and intramuscular electrical stimulation in 11 normal subjects. The overall wave form morphology of the long-latency evoked potentials (EPs) at the central vertex (Cz) was identical and surface topographic mappings of the 21-channel recordings showed similar distributions, suggesting involvement of common neural generators. However, the EPs caused by intramuscular stimulation differed from cutaneous stimulation in several distinct ways. First, the latency of the major positive and negative components were significantly shorter with intramuscular stimulation (N 128–145 ms; P 274–298 ms) compared to cutaneous stimulation (N 235–286 ms; P 371–383 ms) (P<0.001). Second, the peak-to-peak amplitude and root-mean-square values of intramuscular EPs recorded at Cz showed a ceiling effect in the painful range, whereas the laser EPs continued to increase in this range. Third, painful intramuscular, but not non-painful, stimulation caused a frontal activity which not was observed with cutaneous laser stimulation at any intensity. Conduction velocity measurements indicated activation of nociceptive A-delta afferents with cutaneous laser stimulation (10.2±0.2 m/s) and activation of a mixed nerve fiber population with intramuscular electrical stimulation (65.8±25.8 m/s). Differences between laser and intramuscular EPs may be due to different types and origins of activated afferent fibers. Laser EPs can be used specifically to assess cutaneous A-delta fiber function, whereas intramuscular EPs reflect the cerebral processing of a mixed afferent input from muscle tissue.     

Identification of pain,intensity and P300 components in the pain evoked potential

This study examined the relationships among 3 components of the somatosensory evoked potential (SEP) to painful stimuli. Painful stimuli were produced using intracutaneous electrical stimulation of a fingertip and two levels of non-painful stimuli were produced by superficial electrical stimulation of a neighboring fingertip. SEPs were recorded from Cz-A1 and Pz-A1, and difference waves were computed for 3 components: (1) a pain component (the difference between SEPs to painful vs. strong but non-painful stimuli); (2) an intensity component that is not related to pain (the difference between SEPs to strong non-painful vs. mild non-painful stimuli); and (3) a P300 component (the difference between SEPs to the same stimuli under Target instructions vs. Standard instructions).The positive peaks in the 3 types of difference waves differed in both latency and topography, although with latency and topography overlap. The intensity component had an earlier positive peak than the pain component, and the pain component had an earlier positive peak than the P300 component. The pain and intensity components were larger at Cz than Pz, whereas the P300 component was larger at Pz than Cz. Under certain conditions, the pain evoked SEP consists of a weighted combination of the 3 components, complicating interpretation of the positive peaks in the recorded wave forms.     

Changes in late components of somatosensory evoked potentials in humans during repetitive stimulation

Human evoked potentials to somatosensory stimuli of non-painful and painful intensity recorded from the vertex have been studied. The indices of variability of N150 and P250 components registered in the same subject as well as indices of interrelationship between spontaneous changes of these components decreased when stimulus intensity increased. A supposition is advanced that the role of general source responsible for generations N150 and P250 components diminished when stimulus intensity increased, accordingly participation of autonomic sources became more prominent.     

Modulation of perception and neurophysiological correlates of brief CO2 laser stimuli in humans using concurrent large fiber stimulation

It has been postulated that peripheral large fiber stimulation could modulate pain perception, probably by gating the input from AS-and C-fibers. The present study examined the effects of concurrent large fiber stimulation on the perception and neurophysiological correlates of brief CO2 laser stimuli known to activate A- and C-nociceptor endings selectively. Four test stimuli of brief non-painful and painful CO2 laser pulses (duration 50 ms; diameter 5 mm; intensity range 0.116-0.212J) were delivered at random every 5-10s on the dorsum of the left forearm of ten healthy subjects. Large fiber stimulation was performed by a dynamic soft brush applied either adjacently to test stimuli (segmental brush condition) or on the dorsum of the contra-lateral foot (extrasegmental brush condition). Perception, reaction time (RT) and laser-evoked potentials (EPs) were examined for conditions with brush and without brush (control condition). The signal detection theory (SDT) was used to evaluate the discrimination performance and the decision criterion. During extrasegmental brushing, these variables were unaffected as compared with control conditions. During segmental brushing, the absolute detection threshold increased, the probability of detection decreased and the RT increased. Interestingly, the stimulus-response curve of detected stimuli and late LTPs did not change significantly. SDT analysis showed that segmental brushing did not change the discrimination performance or sensitivity but increased significantly the subject's decision criterion for reporting sensation. It was concluded that segmental brushing acted primarily at supra-spinal levels and not by gating the input from small primary afferents activated selectively by brief CO2 laser stimuli.     

Pain additivity, diffuse noxious inhibitory controls, and attention: a functional measurement analysis

This study utilized the methodology of Functional Measurement theory to investigate the additivity of painful and non-painful thermally induced experiences at one body site with those produced by brief noxious and innocuous electrical stimuli at another. Forty healthy young subjects were tested, using a Peltier thermode to induce tonic pain and an electrocutaneous stimulator for presenting phasic pain, under conditions of either full attention or visual/cognitive distraction (counting numerous light signals) in order to evaluate whether the summed effects are attributable to refocused attention. Six levels of intensity were combined in a factorial design for both tonic and phasic pain. Subjects indicated the overall strength of their dual perception on a visual analog scale. Stimuli showed complex patterns of interaction. Two stimuli were generally rated as greater than one, but the summation was far from additive and greatly influenced by the intensity of the stronger stimulus, suggesting inhibitory action. In general, tonic heat pain strongly affected the perception of phasic electrocutaneous pain whereas the reverse was only partly true. Distraction had a very small effect, suggesting that the "pain inhibits pain" phenomenon attributable to diffuse noxious inhibitory controls (DNIC) is not due to attentional processes. Our data also relate to issues regarding spatial summation across dermatomes and to adaptation level effects in pain, in which a strong painful experience serves as an anchor or comparison point by which others are judged. The psychophysical findings provide a perceptual foundation for clinical phenomena in which patients face with comorbid pain disorders.     

Pain additivity,diffuse noxious inhibitory controls,and attention: A functional measurement analysis

This study utilized the methodology of Functional Measurement theory to investigate the additivity of painful and non-painful thermally induced experiences at one body site with those produced by brief noxious and innocuous electrical stimuli at another. Forty healthy young subjects were tested, using a Peltier thermode to induce tonic pain and an electrocutaneous stimulator for presenting phasic pain, under conditions of either full attention or visual/cognitive distraction (counting numerous light signals) in order to evaluate whether the summed effects are attributable to refocused attention. Six levels of intensity were combined in a factorial design for both tonic and phasic pain. Subjects indicated the overall strength of their dual perception on a visual analog scale. Stimuli showed complex patterns of interaction. Two stimuli were generally rated as greater than one, but the summation was far from additive and greatly influenced by the intensity of the stronger stimulus, suggesting inhibitory action. In general, tonic heat pain strongly affected the perception of phasic electrocutaneous pain whereas the reverse was only partly true. Distraction had a very small effect, suggesting that the “pain inhibits pain” phenomenon attributable to diffuse noxious inhibitory controls (DNIC) is not due to attentional processes. Our data also relate to issues regarding spatial summation across dermatomes and to adaptation level effects in pain, in which a strong painful experience serves as an anchor or comparison point by which others are judged. The psychophysical findings provide a perceptual foundation for clinical phenomena in which patients face with comorbid pain disorders.     

Thermosensory intensity and affect throughout the perceptible range

The thermosensory system was evaluated psychophysically in 12 healthy volunteers, spanning the full range of tolerable temperatures. Subjects provided ratings of (1) perceived thermal intensity, (2) perceived pleasantness or unpleasantness, and (3) perceived pain intensity after placing either one hand or foot in a temperature controlled water bath. Of particular interest were the interrelationships among the three perceptual measures, and differences between heat and cold. The relationship between perceived intensity and (un)pleasantness was different for hot vs cold stimuli. Specifically, for a given perceived thermal intensity, cold stimuli were rated as less pleasant or more unpleasant than hot stimuli. Similarly, for a given pain intensity, cold stimuli were rated as more unpleasant than hot stimuli. As warm temperatures increased and as cold temperatures decreased, stimuli were perceived as being unpleasant before they were perceived as being painful. The difference in transition temperatures for unpleasantness vs pain for heat averaged 1.4 degrees C, while the same difference for cold averaged 5.6 degrees C. Thus, there was a fourfold difference in the range of unpleasant but non-painful cold vs hot temperatures. Pain intensity and unpleasantness ratings were significantly higher for heat stimuli applied to the foot vs hand. In contrast, there was no significant body site difference for pain intensity or unpleasantness ratings of cold stimuli. All of these results reveal important differences in the processing of cold vs hot stimuli. These differences could be exploited to differentiate processing relevant to discriminative vs affective components of somesthetic perception, in both the innocuous and noxious ranges.     

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.     

The Effect of Opioid Receptor Blockade on the Neural Processing of Thermal Stimuli

The endogenous opioid system represents one of the principal systems in the modulation of pain. This has been demonstrated in studies of placebo analgesia and stress-induced analgesia, where anti-nociceptive activity triggered by pain itself or by cognitive states is blocked by opioid antagonists. The aim of this study was to characterize the effect of opioid receptor blockade on the physiological processing of painful thermal stimulation in the absence of cognitive manipulation. We therefore measured BOLD (blood oxygen level dependent) signal responses and intensity ratings to non-painful and painful thermal stimuli in a double-blind, cross-over design using the opioid receptor antagonist naloxone. On the behavioral level, we observed an increase in intensity ratings under naloxone due mainly to a difference in the non-painful stimuli. On the neural level, painful thermal stimulation was associated with a negative BOLD signal within the pregenual anterior cingulate cortex, and this deactivation was abolished by naloxone.     

Reaction times to painless and painful CO2 and argon laser stimulation

The introduction of lasers in pain research has made it possible to activate the nociceptive system without activating mechanosensitive afferents. In the present study the reaction times to painless and painful laser stimuli were studied to investigate if the reaction time to experimental pain is reproduceable. CO2 and argon lasers were used for stimulation, and the influence of stimulus (intensity and duration) and skin parameters (temperature, thickness, and reflectance) on reaction time were investigated. When these parameters were controlled the reaction times to painful CO2 and argon laser stimulation were within the same range (350-450 ms), and the intra-individual variability minimal (6.9%). The reaction time was used to estimate peripheral conduction velocity (10 m.s-1) for the activated fibre population when distinct pain was perceived. Determination of reaction times to non-painful and painful stimuli may be suitable ways to assess the functioning of thermal and nociceptive pathways.     

Segmental inhibition of laser-evoked brain potentials by ipsi- and contralaterally applied cold pressor pain.

An experiment was designed to quantify the inhibitory effect of cold pressor pain (ice water immersion) on brain potentials evoked by acute laser-induced pain. One hand (including the C7 dermatome) was immersed into ice water and simultaneously the laser-evoked brain potentials were elicited consecutively from the right and left lower forearms within the C7 dermatomes. The cold pressor pain was continuously rated on a visual analogue scale (VAS). The size of the averaged brain potentials evoked from the ipsi- and contralateral C7 dermatomes were reduced significantly during cold pressor pain. The largest decrease was obtained for the potentials evoked within the C7 dermatome ipsilateral to the cold pressor pain. The size (power) of the brain potentials to individual stimuli could be measured and was correlated to the intensity of the cold pressor pain (VAS score). During the onset phase of cold pressor pain, there was a decrease in power of the individual brain potentials evoked from the C7 dermatome contralateral to the cold pressor pain but the potentials, evoked from the C7 dermatome ipsilateral to cold pressor pain, were decreased more. The overall rating of the laser-induced pain intensity showed that the perceived intensity was lowest when evoked from the dermatome concurrently exposed to cold pressor pain.     

Cortical correlates of perception and suppression of electrically induced pain

Two neuroimaging studies using fMRI were conducted in order to assess the cortical processes involved in the perception and suppression of pain. In the first study, 15 healthy subjects were stimulated with variable intensities of electrical pulses during a discrimination task. In the second study, the same subjects had to try to suppress the feeling of pain during tonic stimulation. The discrimination task resulted in cortical activation of contralateral SI, corresponding in extent to the intensity of the stimulus. Activation of contralateral operculum/posterior insula (SII) and non-dominant dorsolateral prefrontal cortex (DLPFC) with non-painful stimuli changed to activations of non-dominant anterior insula upon painful stimulation. In the second study, all subjects succeeded in suppressing the feeling of pain during previously painful levels of stimulation. During this suppression task, activations changed from anterior to posterior insula; also there was a suppression of activity in the anterior cingulated cortex (ACC) and caudate nucleus. Subjects seem to be able to suppress to a certain degree the feeling of pain under constant (and previously painful) stimulation. The cortical correlate seems to be a shift of cerebral activation from anterior to posterior right insula and a suppression of activity in the ACC and caudate nucleus.     

Cortical correlates of perception and suppression of electrically induced pain

Two neuroimaging studies using fMRI were conducted in order to assess the cortical processes involved in the perception and suppression of pain. In the first study, 15 healthy subjects were stimulated with variable intensities of electrical pulses during a discrimination task. In the second study, the same subjects had to try to suppress the feeling of pain during tonic stimulation. The discrimination task resulted in cortical activation of contralateral SI, corresponding in extent to the intensity of the stimulus. Activation of contralateral operculum/posterior insula (SII) and non-dominant dorsolateral prefrontal cortex (DLPFC) with non-painful stimuli changed to activations of non-dominant anterior insula upon painful stimulation. In the second study, all subjects succeeded in suppressing the feeling of pain during previously painful levels of stimulation. During this suppression task, activations changed from anterior to posterior insula; also there was a suppression of activity in the anterior cingulated cortex (ACC) and caudate nucleus. Subjects seem to be able to suppress to a certain degree the feeling of pain under constant (and previously painful) stimulation. The cortical correlate seems to be a shift of cerebral activation from anterior to posterior right insula and a suppression of activity in the ACC and caudate nucleus.     

Afferent Modulation of Warmth Sensation and Heat Pain in the Human Hand

The hands of 14 normal humans were used to determine the somatotopic organization of the modulation of warmth sensation and heat pain by different forms of cutaneous stimuli. Test stimuli were 5-sec heat pulses ranging from 36° to 51°C, delivered to the fingerpads of digits 1, 2, 4, and 5 with a contact thermode. Conditioning stimuli (15 sec) bracketed the test stimuli and included vibration, noxious and innocuous heat, cold, and electrical pulses delivered to the fingerpads of digits that were adjacent or nonadjacent to the tested digits. Noxious (48° ± 1.3°C), but not innocuous (43°C), heat stimuli increased the perceived magnitude estimation of innocuous test stimuli (36–43°C) by 20–37% when delivered to adjacent, but not to nonadjacent, digits. No other conditioning stimuli had any effect on the intensity of warmth perception. In contrast, both noxious and innocuous heat or electrical conditioning reduced the magnitude estimation of noxious (50–5°C), but not innocuous, test pulses by 12–22% when delivered to adjacent digits. Conditioning of nonadjacent digits was significantly less effective. The analgesic effects of noxious and innocuous conditioning were approximately equal. Vibratory (120 Hz, 3.5 μm) and cold (15°C) conditioning stimuli were ineffective. The results are consistent with a dermatomal somatotopic organization of tactile and heat modulatory influences on warmth sensation and heat pain. The results further suggest that the neural mechanisms subserving warmth mediate a negative feedback influence on heat pain intensity.     

Conditioned modification of viscerosensory evoked potentials during sleep and wakefulness in cats

The effects of classic conditioning on the viscerosensory evoked potentials (EPs) were studied in twenty cats during wakefulness (W), slow-wave-sleep (SWS) and paradoxical sleep (PS). Four types of the experiment were performed on four groups of animals. Weak, non-painful stimulation of the small intestine or of the left splanchnic nerve was used as conditional stimulus (CS) in all experiments. A painful or non-painful shock on the left radial nerve served as unconditional stimulus (US) which followed the CS with a delay of 500 ms. In the first and second series of experiments, the CS was paired with non-painful or painful CS during W. In the third and fourth types of experiment, weak US was used and conditioning was done during SWS or PS. The evoked responses were recorded from the primary (SI) and secondary (SII) somatosensory and associative (AS) cortex, the thalamus (VPL), hypothalamus (HPT) and dorsal hippocampus (HPC). In each experiment, the stimulus pairings resulted in a complex electrographic conditional response (CR) which included an amplitude increase of the late components of EP's (early CR) and the development of a wave of 500 ms latency (delayed CR). In the second experiment, however, a behavioural CR (limb flexion) also appeared. All these CRs proved to be extinguishable. The recall of CR established during W was successful in SWS. The traces of CS-US pairings during SWS could, however, be elicited only in SWS. Both establishment and recall of CR were unsuccessful during PS. The possible mechanism of the effects originating from an interaction of conditioning and sleep on the viscerosensory inputs of the brain are discussed.     

Pain-evoked potentials: what do they really measure?

Cerebral evoked potentials (EPs) in response to painful stimuli have been recorded since the 1970s. Based on the apparent relationship of the response amplitude to intensity of stimulation, these potentials are conventionally interpreted as reflecting the sensory-discriminative aspects of pain. As such, pain-EPs provide an objective measure for sensation of pain. An alternative interpretation regards the pain-EP as comprised of at least two overlapping components, one pain-specific, the other, a P300 wave. In the case of pain, the P300 may reflect the degree of discomfort or unpleasantness, thus reflecting the emotional-motivational aspect. To establish the nature of the pain-EP, mini doses of a benzodiazepine, counterbalanced with placebo, were given to 6 normal volunteers. Benzodiazepines decrease anxiety, and so diminish the emotional response to pain, but they have no analgesic effect. In all subjects, pain perception was unchanged, while the EP wave was almost completely obliterated. We conclude that the pain-EP reflects the emotional-motivational response to pain rather than the sensory-discriminative. Thus, it provides a useful neurophysiological tool for studying the emotions associated with pain.     

Differential changes of laser evoked potentials,late auditory evoked potentials and P300 under morphine in chronic pain patients

The present study investigates the differential behavior of laser evoked brain potentials (LEPs), late auditory evoked potentials (AEP) and the endogenous P300 in response to morphine treatment, examined in 6 chronic pain patients. The main result was that in parallel with marked clinical pain relief, amplitudes of the long latency LEP positivity (P400) were significantly reduced under morphine. One patient suffering from extremely painful osteoporosis for 20 years exhibited a large middle latency component (N170) which was prominently attenuated by morphine. In contrast to LEP amplitude reductions, auditory N1 and P2 potentials appeared either unchanged or even enlarged during morphine treatment. Also P300 amplitude was slightly increased under morphine. Reaction time and mood scales also failed to indicate any sedation. Obviously, LEPs reflected specifically the analgesic morphine effect in this study, while stability or enhancement of AEPs and P300 during morphine treatment indicated lack of sedation or even improved perception and concentration due to the removal of persistent pain as a disruptive perceptual-cognitive stressor.     

Comparative psychophysical characteristics of cutaneous CO2 laser and contact heat stimulation

Psychophysical visual analog scaling can be used to reveal critical determinants of the neural processing underlying non-painful and painful heat sensations produced by radiant and contact heat stimulation. This study determined the stimulus-response (S-R) functions of cutaneous non-painful and painful heat stimuli delivered by an infra-red CO2 laser or by a contact thermode in a series of experiments in healthy volunteers. In experiment 1 ( n = 12), with the rating scale anchored at pain threshold, the S-R curve for brief (60 ms) laser pulse stimulation with a beam diameter of 10 mm was a negatively accelerating function. Transformation of laser stimulus intensity (W) into temperatures ( C) did not change the form of the S-R curve. In experiment 2 ( n=9), using the same laser stimulus parameters as in experiment 1, but without an anchored rating scale, the form of the S-R relationship did not change. In experiment 3 ( n =9), increases of the laser pulse duration up to 5 s and the beam diameter up to 18 mm produced linear S-R curves. In contrast, in experiment 4 ( n =21), the S-R curve for cutaneous contact heat stimuli applied for 5 s with an 18 mm diameter probe was best described by a positively accelerating power function with an exponent greater than 2.0. These experiments have (1) characterized the S-R functions for different parameters of infra-red laser stimulation of the skin, and (2) have shown that the form of the S-R function for innocuous and noxious heat sensation is influenced strongly by the physical conditions of heat stimulus application, including mechanical contact with the skin.     

Habituation of evoked potentials in subjects with high, medium and low levels of anxiety

The habituation of the peak-to-peak amplitudes of N1P2 and P2N2 complexes of the evoked potentials as responses to series of the increasing number of visual and acoustic stimuli was investigated in 55 male and female volunteers aged 20-30. The size and speed of the habituation process were approximated by hyperbola. The shape and coefficients of the hyperbola were correlated with high, medium and low levels of the anxiety and probably reflected the balance between synchronization and desynchronization processes in the cortex.     

Variability of laser-evoked potentials: attention,arousal and lateralized differences

We recorded laser-evoked potentials (LEPs) from 20 normal subjects by stimulating the skin with pulses from an infrared CO₂ laser. The conduction velocity of the peripheral afferent fibers mediating the LEPs averaged 14.9 m/sec. The amplitude of the LEP components correlated significantly with perceived stimulus intensity. During repetitive constant intensity stimulation, the peak-to-peak LEP amplitude decreased 38% during a distraction task and 42% during drowsiness and was absent during stage 2 sleep, indicating a modulation of responsiveness to laser stimulation during distraction and decreased states of arousal. Normative data revealed considerable intersubject variability in LEP latencies and amplitudes. Analysis of intrasubject lateralized (side-to-side) differences revealed that the relative peak-to-peak amplitude was less variable than that of the N or P components. For clinical applications using 3 S.D.s to define the normal range, a lateral interpeak amplitude difference greater than 28% would suggest focal or lateralized sensory abnormality in an individual patient. Vigilance and attentiveness to the stimuli should be monitored during the acquisition of LEPs.