An inhibitory interaction of human cortical responses to stimuli preferentially exciting Adelta or C fibers.

Finely myelinated (type Adelta) and unmyelinated (type C) fibers are the major afferent inputs to spinothalamic tract neurons mediating sensory and reflex responses to noxious and thermal stimuli. These two fiber types differ in their sensory and biophysical properties, raising questions about the interaction of their supraspinal responses. Therefore, we investigated the interaction of cortical responses to stimuli that preferentially excite these fibers in human subjects using evoked potential recordings in a paired conditioning stimulation (CS) and test stimulation (TS) paradigm. There were two experiments, one with Adelta as CS and C as TS (Adelta-C) and another with these stimuli reversed (C-Adelta). We used intra-epidermal electrical pulses applied to the dorsal left hand at 2x and 1x pinprick threshold (pp) for the preferential stimulation of Adelta fibers and 37-50 degrees C contact heat pulses applied to the left or right thenar and left hypothenar eminences for the preferential stimulation of C fibers. We found that the cortical response to preferential Adelta or C fiber stimulation was attenuated whenever either cortical response preceded the other. Standardized values of peak and integrated amplitudes were <1 in all pairing conditions and in all subjects in both experiments. The suppressive effect varied in magnitude with the intensity of the conditioning stimulus in both Adelta-C and C-Adelta experiments. Furthermore, intra-segmental interaction was differentially effective for Adelta conditioning (peak amplitude, P<0.008; analysis of variance). Our experiments provide the first neurophysiological evidence for a somatotopically distributed, mutually suppressive interaction between cortical responses to preferentially activated Adelta and C afferents in humans. This suppressive interaction of cortical responses suggests contrasting and possibly mutually exclusive sensorimotor functions mediated through the Adelta and C fiber afferent channels.

Imaging of acute versus pathological pain in humans.

Pain subserves different functions. Acute pain from the intact body alerts the victim to immediately react and withdraw from the bodily threat, ideally before an injury happens. However, during manifest injury and tissue inflammation, withdrawal and flight are no longer adaptive. Instead, sparing the affected body part to promote healing requires heightened awareness and avoidance behaviour over longer periods of time. Quality and time scales of behavioural adaptations are therefore substantially different between pain during normal compared to abnormal tissue states. Given these functional differences we postulated that the two phenomena also recruit different forebrain systems. We used positron emission tomography (PET) and subtracted scans obtained during painful heating of normal skin from scans during equally intense but normally non-painful heating of capsaicin-treated skin. This comparison reveals the specific activation of a medial thalamic pathway to limbic forebrain structures such as anterior insula, perigenual anterior cingulate, ventral striatum, and prefrontal cortex during pain originating in the chemically sensitised skin. It is possible that the unique forebrain recruitment by pain under a patho-physiological tissue status is caused by a significantly greater facilitation of the multi-synaptic projections from the spino-parabrachial tract of the superficial dorsal horn to the medial thalamus compared to deeper and direct lateral thalamic projections from the spino-thalamic tract.

Keeping pain out of mind: the role of the dorsolateral prefrontal cortex in pain modulation.

Frontal lobe activity during pain is generally linked to attentional processing. We addressed the question of whether 'bottom-up' processing and 'top-down' modulation of nociceptive information dissociate anatomically within the frontal lobe by using PET scanning during painful thermal stimulation of normal and capsaicin-treated skin. We showed recently that pain following normally non-painful heat stimuli on chemically irritated skin (heat allodynia) uniquely engages extensive areas of the bilateral dorsolateral prefrontal (DLPFC), ventral/orbitofrontal (VOFC) and perigenual anterior cingulate (ACC) cortices. Here, we applied principal component analysis (PCA) and multiple regression analysis to study the covariance structure of the volumes of interest (VOI) activated specifically during heat allodynia in 14 male healthy subjects and evaluated the relationship of these VOI to ratings of pain intensity and affect. Results yielded a primary principal component (PC) that correlated positively with intensity and unpleasantness and accounted for activity in the medial thalamus, bilateral anterior insula, ventral striatum, perigenual ACC and bilateral VOFC. Activities in the right and left DLPFC loaded on separate PC and correlated negatively with perceived intensity and unpleasantness. The inter-regional correlation of midbrain and medial thalamic activity was significantly reduced during high left DLPFC activity, suggesting that its negative correlation with pain affect may result from dampening of the effective connectivity of the midbrain-medial thalamic pathway. In contrast, right DLPFC activity was associated with a weakened relationship of the anterior insula with both pain intensity and affect. We propose that the DLPFC exerts active control on pain perception by modulating corticosubcortical and corticocortical pathways.

Relative reinforcing strength of three N-methyl-D-aspartate antagonists with different onsets of action.

The potential contribution of onset and duration of pharmacological action to the reinforcing strength of three intravenously delivered N-methyl-D-aspartate antagonists was evaluated in this study. The onsets and durations of action of ketamine, phencyclidine, and dizocilpine were evaluated by observation and tabulation of their behavioral effects in rhesus monkeys after i.v. administration. The reinforcing effects of each drug were tested in a paradigm in which the fixed ratio requirements for i.v. drug injection were increased systematically. The peak observable effect of ketamine occurred immediately after its administration. There were some immediately observable effects of phencyclidine, although the peak effect of phencyclidine was delayed for 3 to 10 min. Dizocilpine had few immediate effects and a peak effect 32 min after administration. Ketamine had the shortest duration of action, followed by phencyclidine and dizocilpine. Analysis of demand curves and response output curves that were normalized to account for potency differences among the drugs revealed that ketamine and phencyclidine were equally effective as reinforcers, and they were both much stronger reinforcers than was dizocilpine. The data therefore suggest that a fast onset of action increases the reinforcing strength of drugs, although duration of action may play a role as well.

Temporal and spatial dynamics of human forebrain activity during heat pain: analysis by positron emission tomography.

To learn about the sequence of brain activation patterns during heat pain, we acquired positron emission tomographic (PET) brain scans at different times during repetitive heat stimulation (40 or 50 degrees C; 5-s contact) of each subject's left forearm. Early scans began at the onset of 60 s of stimulation; late scans began after 40 s of stimulation, which continued throughout the 60-s scan period (total stimulus duration 100 s). Each subject (14 normal, right-handed subjects; 10 male, 4 female; ages 18-42) used a visual analog scale to rate the perceived stimulus intensity (0 = no heat, 7 = pain threshold, 10 = barely tolerable pain) after each scan. The 40 degrees C stimulation received an average intensity rating of 2.19 +/- 1.22 (mean +/- SD) and the 50 degrees C an average rating of 8.93 +/- 1.33. During the scan sessions, subjects did not report a difference between early and late scans. To examine the effect of the duration of stimulation specifically, 8 of these subjects rated the perceived intensity of each of 20 sequential 5-s duration contact heat stimuli (40 or 50 degrees C; 100 s of stimulation). We used a graphical method to detect changes in perceived unpleasantness. There was no difference in perceived intensity or unpleasantness during the 40 degrees C stimulation. However, during 50 degrees C stimulation, perceived unpleasantness increased and subjects perceived the last five, but not the second five, stimuli as more intense than the first five stimuli. These psychophysical changes could be mediated by brain structures with increasing activity from early to late PET scans or that are active only during late scans. These structures include the contralateral M1/S1 cortex, bilateral S2 and mid-insular cortex, contralateral VP thalamus, medial ipsilateral thalamus, and the vermis and paravermis of the cerebellum. Structures that are equally active throughout stimulation (contralateral mid-anterior cingulate and premotor cortex) are less likely to mediate these psychophysical changes. Some cortical, but not subcortical, structures showed significant or borderline activation only during the early scans (ipsilateral premotor cortex, contralateral perigenual anterior cingulate, lateral prefrontal, and anterior insular cortex); they may mediate pain-related attentive or anticipatory functions. Overall, the results reveal that 1) the pattern of brain activation and the perception of heat pain both change during repetitive noxious heat stimulation, 2) cortical activity can be detected before subcortical responses appear, and 3) timing the stimulation with respect to the scan period can, together with psychophysical measurements, identify brain structures that are likely to participate in the perception of pain.

Concepts of pain mechanisms: the contribution of functional imaging of the human brain.

Functional imaging of the conscious human brain has a solid physiological basis in synaptically induced rCBF responses. We still do not know how these responses are generated, but recent studies have shown that the rCBF response is parametrically positively correlated with functional measures of neuronal activity. Technical advances in both fMRI and PET imaging have improved the spatial and temporal resolution of imaging methods. Further advances may be expected in the near future. Consequently, we now have an important tool to apply to the study of normal and, most importantly, pathological pain. There is a tendency to expect too much of this exciting technique, but the problems we wish to address are complex and will require considerable time, effort, and patience. We now know that the CNS adapts to both peripheral and central nervous system injury, sometimes in beneficial ways, but sometimes with reorganization that is maladaptive. An understanding of the pathophysiology of neuropathic pain is further complicated by the new knowledge, emphasized by functional brain imaging, that pain and pain modulation is mediated, not by a simple pathway with one or a few central targets, but by a network of multiple interacting modules of neuronal activity. Simplified phrenological thinking, with complete psychological functions separate and localized, is appealing, but wildly misleading. It is far more realistic and productive to apply qualitative and quantitative spatial and temporal analyses to the distributed activity of the conscious, communicating human brain. This will not be quick and easy, but there is every reason for optimism in our search for a thorough and useful understanding of both normal and pathological pain.

Selective opiate modulation of nociceptive processing in the human brain.

Fentanyl, a mu-opioid receptor agonist, produces analgesia while leaving vibrotactile sensation intact. We used positron emission tomography (PET) to study the mechanisms mediating this specific effect in healthy, right-handed human males (ages 18-28 yr). Subjects received either painful cold (n = 11) or painless vibratory (n = 9) stimulation before and after the intravenous injection of fentanyl (1.5 microgram/kg) or placebo (saline). Compared with cool water (29 degrees C), immersion of the hand in ice water (1 degrees C) is painful and produces highly significant increases in regional cerebral blood flow (rCBF) within the contralateral second somatosensory (S2) and insular cortex, bilaterally in the thalamus and cerebellum, and medially in the cerebellar vermis. Responses just below the statistical threshold (3.5 < Z < 4.0) are seen in the contralateral anterior cingulate, ipsilateral insular cortex, and dorsal medial midbrain. The contralateral primary sensory cortex (S1) shows a trend of activation. Except for slight changes in intensity, this pattern is unchanged following a saline placebo injection. Fentanyl reduces the average visual analogue scale ratings of perceived pain intensity (47%) and unpleasantness (50%), reduces pain-related cardioacceleration, and has positive hedonic effects. After fentanyl, but not placebo, all cortical and subcortical responses to noxious cold are greatly reduced. Subtraction analysis [(innocuous water + fentanyl) - (innocuous water + no injection)] shows that fentanyl alone increases rCBF in the anterior cingulate cortex, particularly in the perigenual region. Vibration (compared with mock vibration) evokes highly significant rCBF responses in the contralateral S1 cortex in the baseline (no injection) and placebo conditions; borderline responses (3.5 < Z < 4. 0) are detected also in the contralateral thalamus. Fentanyl has no effect on the perceived intensity or unpleasantness of vibratory stimulation, which continues to activate contralateral S1. Fentanyl alone [(mock vibration + fentanyl) - (mock vibration + no injection)] again produces highly significant activation of the perigenual and mid-anterior cingulate cortex. A specific comparison of volumes of interest, developed from activation peaks in the baseline condition (no injection), shows that fentanyl strongly attenuates both the contralateral thalamic and S1 cortical responses to noxious cold stimulation (P < 0.048 and 0.007, respectively) but fails to affect significantly these responses to vibrotactile stimulation (P > 0.26 and 0.91, respectively). In addition, fentanyl, compared with placebo, produces a unique activation of the mid-anterior cingulate cortex during fentanyl analgesia, suggesting that this region of the cingulate cortex participates actively in mediating opioid analgesia. The results are consistent with a selective, fentanyl-mediated suppression of nociceptive spinothalamic transmission to the forebrain. This effect could be implemented directly at the spinal level, indirectly through cingulate corticofugal pathways, or by a combination of both mechanisms.

Attention-related, cross-modality modulation of somatosensory neurons in primate ventrobasal (VB) thalamus.

Attention-related modulation (AM) of the somatosensory responses of single neurons has been demonstrated in the cerebral cortex and medullary dorsal horn, but not in the ventrobasal thalamus. The somatically evoked activity was recorded of single units in the ventral posterior lateral thalamus (VPL) of awake monkeys while they detected the termination of task-relevant somatic or visual stimuli. Eighteen of 56 somatically responsive VPL neurons are reported that were recorded for enough time for a complete analysis of their responses during both the visual and somatic attention tasks. All neurons were spontaneously active and responded either to innocuous cutaneous (13/18) or deep (5/18) stimuli. Seven neurons (7/18, 38.8%) showed AM of somatosensory responsiveness. Two cells (2/7, 28.6%) showed AM only during the visual task, two others (2/7, 28.6%) only during the somatosensory task, and three cells (3/7, 42.8%) showed AM during both tasks. All five cells showing AM during the somatosensory task had enhanced responses to the task-relevant somatic stimulus. In contrast, the somatosensory responses of all five cells showing AM during the visual task were reduced. It is concluded that selective attention is associated with a modality specific modulation of the somatosensory responses of a sub-population of neurons within the primate VPL nucleus.

Bilateral behavioral and regional cerebral blood flow changes during painful peripheral mononeuropathy in the rat.

A unilateral chronic constriction injury (CCI) of the sciatic nerve produced bilateral effects in both pain related behaviors and in the pattern of forebrain activation. All CCI animals exhibited spontaneous pain-related behaviors as well as bilateral hyperalgesia and allodynia after CCI. Further, we identified changes in baseline (unstimulated) forebrain activation patterns 2 weeks following CCI by measuring regional cerebral blood flow (rCBF). Compared to controls, CCI consistently produced detectable, well-localized and typically bilateral increases in rCBF within multiple forebrain structures in unstimulated animals. For example, the hindlimb region of somatosensory cortex was significantly activated (22%) as well as multiple thalamc nuclei, including the ventral medial (8%), ventral posterior lateral (10%) and the posterior (9%) nuclear groups. In addition, several forebrain regions considered to be part of the limbic system showed pain-induced changes in rCBF, including the anterior dorsal nucleus of the thalamus (23%), cingulate cortex (18%), retrosplenial cortex (30%), habenular complex (53%), interpeduncular nucleus (45%) and the paraventricular nucleus of the hypothalamus (30%). Our results suggest that bilateral somatosensory and limbic forebrain structures participate in the neural mechanisms of prolonged persistent pain produced by a unilateral injury.

Chronic, selective forebrain responses to excitotoxic dorsal horn injury.

Intraspinal injection of the AMPA/metabotropic receptor agonist quisqualic acid (QUIS) results in excitotoxic injury which develops pathological characteristics similar to those associated with ischemic and traumatic spinal cord injury (SCI) (R. P. Yezierski et al., 1998, Pain 75: 141-155; R. P. Yezierski et al., 1993, J. Neurotrauma 10: 445-456). Since spinal injury can lead to partial or complete deafferentation of ascending supraspinal structures, it is likely that secondary to the disruption of spinal pathways these regions could undergo significant reorganization. Recently, T. J. Morrow et al. (Pain 75: 355-365) showed that autoradiographic estimates of regional cerebral blood flow (rCBF) can be used to simultaneously identify alterations in the activation of multiple forebrain structures responsive to noxious formalin stimulation. Accordingly, we examined whether excitotoxic SCI produced alterations in the activation of supraspinal structures using rCBF as a marker of neuronal activity. Twenty-four to 41 days after unilateral injection of QUIS into the T12 to L3 spinal segments, we found significant increases in the activation of 7 of 22 supraspinal structures examined. As compared to controls, unstimulated SCI rats exhibited a significant bilateral increase in rCBF within the arcuate nucleus (ARC), the hindlimb region of S1 cortex (HL), parietal cortex (PAR), and the thalamic posterior (PO), ventral lateral (VL), ventral posterior lateral (VPL), and ventral posterior medial (VPM) nuclei. All structures showing significantly altered rCBF are associated with the processing of somatosensory information. These changes constitute remote responses to injury and suggest that widespread functional changes occur within cortical and subcortical regions following injury to the spinal cord.

Forebrain mechanisms of nociception and pain: analysis through imaging.

Pain is a unified experience composed of interacting discriminative, affective-motivational, and cognitive components, each of which is mediated and modulated through forebrain mechanisms acting at spinal, brainstem, and cerebral levels. The size of the human forebrain in relation to the spinal cord gives anatomical emphasis to forebrain control over nociceptive processing. Human forebrain pathology can cause pain without the activation of nociceptors. Functional imaging of the normal human brain with positron emission tomography (PET) shows synaptically induced increases in regional cerebral blood flow (rCBF) in several regions specifically during pain. We have examined the variables of gender, type of noxious stimulus, and the origin of nociceptive input as potential determinants of the pattern and intensity of rCBF responses. The structures most consistently activated across genders and during contact heat pain, cold pain, cutaneous laser pain or intramuscular pain were the contralateral insula and anterior cingulate cortex, the bilateral thalamus and premotor cortex, and the cerebellar vermis. These regions are commonly activated in PET studies of pain conducted by other investigators, and the intensity of the brain rCBF response correlates parametrically with perceived pain intensity. To complement the human studies, we developed an animal model for investigating stimulus-induced rCBF responses in the rat. In accord with behavioral measures and the results of human PET, there is a progressive and selective activation of somatosensory and limbic system structures in the brain and brainstem following the subcutaneous injection of formalin. The animal model and human PET studies should be mutually reinforcing and thus facilitate progress in understanding forebrain mechanisms of normal and pathological pain.

Central modulation of pain perception.

The information presented in this article provides a basis for individual variability in the sensation of pain and the behavioral correlates associated with pain. The knowledge of pain-inhibitory and pain-facilitating pathways linked to cognitive, emotional, and stress-response systems leads to a greater understanding of the complexities of the experience of pain. Appreciation of the influence of these higher centers should lead to improvements in the clinical management of pain.

Site- and modality-specific modulation of experimental muscle pain in humans.

The neurophysiological mechanisms involved in diffuse noxious inhibitory controls (DNIC) have been investigated extensively, but information is lacking about the effect of different stimulus modalities and somatic locations on the effectiveness of DNIC. This study is the first to examine the hypoalgesic effects on a deep, tonic and painful test stimulus (TS) of both painful and non-painful conditioning stimuli (CS) applied to different sites of the body. Two separate experiments were performed using painful electrical stimulation of the left anterior tibialis muscle as the TS. In the first experiment (n = 9), injection of 5% hypertonic saline was used as a painful CS into one of four muscles: anterior tibialis of each leg and brachioradialis of each arm. In the second experiment (n = 5), a non-painful vibratory stimulus was used as the CS at the same four sites. Compared with TS alone, the perceived pain intensity of the TS increased (4.5 +/- 1.8%; P = 0.019) in combination with the painful CS applied to the same muscle (ipsilateral homotopic site), but decreased (-25.3 +/- 1.4%; P < 0.001) in combination with non-painful CS at the same site. Both painful and non-painful CS applied at the three heterotopic sites caused significant and site-dependent decreases in the perceived pain intensity of the TS (range 15%-37%; P < 0.05). We conclude that a hypoalgesic DNIC-like effect on muscle pain is not produced exclusively by painful stimuli, and that the valence and magnitude of the modulation depend on the nature of the CS and its location relative to the applied TS.

Gender differences in pain perception and patterns of cerebral activation during noxious heat stimulation in humans.

The purpose of the present study was to determine whether gender differences exist in the forebrain cerebral activation patterns of the brain during pain perception. Accordingly, positron emission tomography (PET) with intravenous injection of H2(15)O was used to detect increases in regional cerebral blood flow (rCBF) in normal right-handed male and female subjects as they discriminated differences in the intensity of innocuous and noxious heat stimuli applied to the left forearm. Each subject was instructed in magnitude estimation based on a scale for which 0 indicated 'no heat sensation'; 7, 'just barely painful' and 10, 'just barely tolerable'. Thermal stimuli were 40 degrees C or 50 degrees C heat, applied with a thermode as repetitive 5-s contacts to the volar forearm. Both male and female subjects rated the 40 degrees C stimuli as warm but not painful and the 50 degrees C stimuli as painful but females rated the 50 degrees C stimuli as significantly more intense than did the males (P=0.0052). Both genders showed a bilateral activation of premotor cortex in addition to the activation of a number of contralateral structures, including the posterior insula, anterior cingulate cortex and the cerebellar vermis, during heat pain. However, females had significantly greater activation of the contralateral prefrontal cortex when compared to the males by direct image subtraction. Volume of interest comparison (t-statistic) also suggested greater activation of the contralateral insula and thalamus in the females (P < 0.05). These pain-related differences in brain activation may be attributed to gender, perceived pain intensity, or to both factors.

Regional changes in forebrain activation during the early and late phase of formalin nociception: analysis using cerebral blood flow in the rat.

This is the first neural imaging study to use regional cerebral blood flow (rCBF) in an animal model to identify the patterns of forebrain nociceptive processing that occur during the early and late phase of the formalin test. We measured normalized rCBF increases by an autoradiographic method using the radiotracer [99mTc]exametazime. Noxious formalin consistently produced detectable, well-localized and typically bilateral increases in rCBF within multiple forebrain structures, as well as the interpeduncular nucleus (Activation Index, AI = 66) and the midbrain periaqueductal gray (AI = 20). Structures showing pain-induced changes in rCBF included several forebrain regions considered part of the limbic system. The hindlimb region of somatosensory cortex was significantly activated (AI = 31), and blood flow increases in VPL (AI = 8.7) and the medial thalamus (AI = 9.0) exhibited a tendency to be greater in the late phase as compared to the early phase of the formalin test. The spatial pattern and intensity of activation varied as a function of the time following the noxious formalin stimulus. The results highlight the important role of the limbic forebrain in the neural mechanisms of prolonged persistent pain and provide evidence for a forebrain network for pain.

Setters and samoyeds: the emergence of subordinate level categories as a basis for inductive inference in preschool-age children.

Basic level categories are a rich source of inductive inference for children and adults. These 3 experiments examine how preschool-age children partition their inductively rich basic level categories to form subordinate level categories and whether these have inductive potential. Children were taught a novel property about an individual member of a familiar basic level category (e.g., a collie). Then, children's extensions of that property to other objects from the same subordinate (e.g., other collies), basic (e.g., other dogs), and superordinate (e.g., other animals) level categories were examined. The results suggest (a) that contrastive information promotes the emergence of subordinate categories as a basis of inductive inference and (b) that newly established subordinate categories can retain their inductive potential in subsequent reasoning over a week's time.

Pain-related laser-evoked potentials in awake monkeys: identification of components, behavioral correlates and drug effects.

Cutaneous stimulation with CO2 laser pulses activates small diameter sensory afferents and evokes a pain-related potential best recorded from the vertex (Cz) of humans. We report here the first successful recording of pain-related laser evoked potentials (LEPs) from awake monkeys. Laser pulses with stimulus intensities adjusted to the lowest level giving reproducible cerebral responses were delivered to the shaved tail of three awake African green monkeys. The proximal and distal tail were stimulated to calculate the conduction velocity of the activated fibers. The effects of subcutaneous injections of morphine and cocaine on the LEPs were evaluated. The results indicate that reproducible LEPs, with a morphology similar to those obtained from humans, can be recorded from the awake monkey. The calculated conduction velocity of the activated fibers averaged 8.7 m/s, which is in the range of A delta fibers. Following subcutaneous morphine injections, the LEPs disappeared and were quickly restored to their baseline amplitude following administration of naloxone. Cocaine administered subcutaneously led to a significant attenuation of LEP amplitudes without producing behavioral sedation. These findings suggest that the LEPs recorded from monkeys represent analgesic-sensitive, nociceptive-related potentials similar to those recorded from humans.

Cerebral processing of acute skin and muscle pain in humans.

The human cerebral processing of noxious input from skin and muscle was compared with the use of positron emission tomography with intravenous H2(15)O to detect changes in regional cerebral blood flow (rCBF) as an indicator of neuronal activity. During each of eight scans, 11 normal subjects rated the intensity of stimuli delivered to the nondominant (left) forearm on a scale ranging from 0 to 100 with 70 as pain threshold. Cutaneous pain was produced with a high-energy CO2 laser stimulator. Muscle pain was elicited with high-intensity intramuscular electrical stimulation. The mean ratings of perceived intensity for innocuous and noxious stimulation were 32.6 +/- 4.5 (SE) and 78.4 +/- 1.7 for cutaneous stimulation and 15.4 +/- 4.2 and 73.5 +/- 1.4 for intramuscular stimulation. The pain intensity ratings and the differences between noxious and innocuous ratings were similar for cutaneous and intramuscular stimuli (P > 0.05). After stereotactic registration, statistical pixel-by-pixel summation (Z score) and volumes-of-interest (VOI) analyses of subtraction images were performed. Significant increases in rCBF to both noxious cutaneous and intramuscular stimulation were found in the contralateral secondary somatosensory cortex (SII) and inferior parietal lobule [Brodmann area (BA) 40]. Comparable levels of rCBF increase were found in the contralateral anterior insular cortex, thalamus, and ipsilateral cerebellum. Noxious cutaneous stimulation caused significant activation in the contralateral lateral prefrontal cortex (BA 10/46) and ipsilateral premotor cortex (BA 4/6). Noxious intramuscular stimulation evoked rCBF increases in the contralateral anterior cingulate cortex (BA 24) and subsignificant responses in the contralateral primary sensorimotor cortex (MI/SI) and lenticular nucleus. These activated cerebral structures may represent those recruited early in nociceptive processing because both forms of stimuli were near pain threshold. Correlation analyses showed a negative relationship between changes in rCBF for thalamus and MI/SI for cutaneous stimulation, and positive relationships between thalamus and anterior insula for both stimulus modalities. Direct statistical comparisons between innocuous cutaneous and intramuscular stimulation with the use of Z scores and VOI analyses showed no reliable differences between these two forms of noxious stimulation, indicating a substantial overlap in brain activation pattern. The comparison of noxious cutaneous and intramuscular stimulation indicated more activation in the premotor cortex, SII, and prefrontal cortex with cutaneous stimulation, but these differences did not reach statistical significance. The similar cerebral activation patterns suggest that the perceived differences between acute skin and muscle pain are mediated by differences in the intensity and temporospatial pattern of neuronal activity within similar sets of forebrain structures.

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.

Human intramuscular and cutaneous pain: psychophysical comparisons.

We used psychophysical methods to compare the central processing of nociceptive inputs from skin and muscle in ten normal humans. Both intramuscular electrical and infrared CO2 laser cutaneous stimulation showed increasing but decelerating (downward concave) stimulus-response curves and similar temporal summation characteristics. Intramuscular stimulation was rated significantly more unpleasant than cutaneous stimulation. The results are consistent with a common mode of central nociceptive processing for skin and muscle pain intensity but suggest a relatively larger activation of affective mechanisms by muscle afferents.