Differentiation of visceral and cutaneous pain in the human brain

The widespread convergence of information from visceral, cutaneous, and muscle tissues onto CNS neurons invites the question of how to identify pain as being from the viscera. Despite referral of visceral pain to cutaneous areas, individuals regularly distinguish cutaneous and visceral pain and commonly have contrasting behavioral reactions to each. Our study addresses this dilemma by directly comparing human neural processing of intensity-equated visceral and cutaneous pain. Seven subjects underwent fMRI scanning during visceral and cutaneous pain produced by balloon distention of the distal esophagus and contact heat on the midline chest. Stimulus intensities producing nonpainful and painful sensations, interleaved with rest periods, were presented in each functional run. Analyses compared painful to nonpainful conditions. A similar neural network, including secondary somatosensory and parietal cortices, thalamus, basal ganglia, and cerebellum, was activated by visceral and cutaneous painful stimuli. However, cutaneous pain evoked higher activation bilaterally in the anterior insular cortex. Further, cutaneous but not esophageal pain activated ventrolateral prefrontal cortex, despite higher affective scores for visceral pain. Visceral but not cutaneous pain activated bilateral inferior primary somatosensory cortex, bilateral primary motor cortex, and a more anterior locus within anterior cingulate cortex. Our results reveal a common cortical network subserving cutaneous and visceral pain that could underlie similarities in the pain experience. However, we also observed differential activation patterns within insular, primary somatosensory, motor, and prefrontal cortices that may account for the ability to distinguish visceral and cutaneous pain as well as the differential emotional, autonomic and motor responses associated with these different sensations.     

Cortical neuroplastic changes to painful colon stimulation in patients with irritable bowel syndrome

The aim of this study was to model the cerebral generators following painful electrical stimulation of the sigmoid colon in 10 healthy controls and 10 patients with visceral pain due to the irritable bowel syndrome. The evoked brain potentials to 30 painful electrical stimuli from the sigmoid colon were recorded from 31 surface electrodes and subjected to electrical dipole source modelling. Two dipoles in the bilateral insular cortex, one dipole in the anterior cingulate gyrus and two dipoles in the bilateral second somatosensory area were found. The anterior cingulate dipole showed a more posterior position in patients than in control subjects. This finding suggests that the cortical representation of painful stimuli can be modified in presence of chronic visceral pain and that this change involves the anterior cingulate gyrus.     

Regional intensive and temporal patterns of functional MRI activation distinguishing noxious and innocuous contact heat

Cortical responses to painful and nonpainful heat were measured using functional magnetic resonance imaging (fMRI) region of interest analysis (ROI) of primary somatosensory cortex (S1), secondary somatosensory cortex (S2), anterior cingulate (ACC), supplementary motor area (SMA), insula, and inferior frontal gyrus (IFG). Previous studies indicated that innocuous and noxious stimuli of different modalities produce responses with different time courses in S1 and S2. The aim of this study was to 1) determine whether temporally distinct nociceptive blood oxygen level-dependent (BOLD) responses are evoked in multiple somatosensory processing cortical areas and 2) whether these responses discriminate small noxious stimulus intensity differences. Thirty-three subjects underwent fMRI scanning while receiving three intensities of thermal stimuli, ranging from innocuous warm (41 degrees C) to 1 degrees C below tolerance, applied to the dorsum of the left foot. Innocuous and noxious responses were distinguishable in contralateral S1, the mid-ACC, and SMA. The peak of the nociceptive response was temporally delayed from the innocuous response peak by 6-8 s. Responses to noxious but not to innocuous stimuli were observed in contralateral posterior insula. Responses to innocuous and noxious stimuli were not statistically different in contralateral S2. In contralateral S1 only, the nociceptive response could differentiate heat stimuli separated by 1 degrees C. These results show that 1) multiple cortical areas have temporally distinguishable innocuous and noxious responses evoked by a painfully hot thermode, 2) the nociceptive processing properties vary across cortical regions, and 3) nociceptive responses in S1 discriminate between painful temperatures at a level unmatched in other cortical areas.     

Somatosensory mu activity reflects imagined pain intensity of others

In accordance with simulation theories of empathy, the somatosensory cortex is involved in the perception of pain of others. Cognitive processes, like perspective taking, can alter empathy‐related activity within the somatosensory cortex. The current study investigates whether this modulation is caused by the imagined sensation of pain or by the cognitive load of a perspective‐taking task. Applying a within‐subject design, participants (N = 30) watched pictures of painful and nonpainful actions, while imagining reduced, normal, or increased pain perception of the observed individual. Mu activity (8–13 Hz), which is inversely correlated with sensorimotor‐cortex activity, was measured via EEG. To calculate mu activity (central electrodes) and alpha activity (occipital electrodes), which served as a control for effects of cognitive load, a fast Fourier transform was applied. Mu suppression linearly increased from reduced to normal to increased imagined pain (p < .05), while alpha activity was unaffected by the imagined pain (p > .80). Suppression of the 8–13 Hz band at central and occipital electrodes was stronger in response to painful actions compared to nonpainful actions (p < .01). These results indicate that modulation of mu activity through perspective taking reflects the imagined pain intensity and not the cognitive load induced by the task.     

Hemispheric lateralization of somatosensory processing

Processing of both painful and nonpainful somatosensory information is generally thought to be subserved by brain regions predominantly contralateral to the stimulated body region. However, lesions to right, but not left, posterior parietal cortex have been reported to produce a unilateral tactile neglect syndrome, suggesting that components of somatosensory information are preferentially processed in the right half of the brain. To better characterize right hemispheric lateralization of somatosensory processing, H(2)(15)O positron emission tomography (PET) of cerebral blood flow was used to map brain activation produced by contact thermal stimulation of both the left and right arms of right-handed subjects. To allow direct assessment of the lateralization of activation, left- and right-sided stimuli were delivered during separate PET scans. Both innocuous (35 degrees C) and painful (49 degrees C) stimuli were employed to determine whether lateralized processing occurred in a manner related to perceived pain intensity. Subjects were also scanned during a nonstimulated rest condition to characterize activation that was not related to perceived pain intensity. Pain intensity-dependent and -independent changes in activation were identified in separate multiple regression analyses. Regardless of the side of stimulation, pain intensity--dependent activation was localized to contralateral regions of the primary somatosensory cortex, secondary somatosensory cortex, insular cortex, and bilateral regions of the cerebellum, putamen, thalamus, anterior cingulate cortex, and frontal operculum. No hemispheric lateralization of pain intensity-dependent processing was detected. In sharp contrast, portions of the thalamus, inferior parietal cortex (BA 40), dorsolateral prefrontal cortex (BA 9/46), and dorsal frontal cortex (BA 6) exhibited right lateralized activation during both innocuous and painful stimulation, regardless of the side of stimulation. Thus components of information arising from the body surface are processed, in part, by right lateralized systems analogous to those that process auditory and visual spatial information arising from extrapersonal space. Such right lateralized processing can account for the left somatosensory neglect arising from injury to brain regions within the right cerebral hemisphere.     

Distinct effects of attention and affect on pain perception and somatosensory evoked potentials

The influence of affect and attention on sensory and affective pain as well as on somatosensory evoked potentials in response to painful and nonpainful electrical stimuli was investigated in a single experimental design. Affect was induced by pictures from the International Affective Picture System; attention was manipulated by asking participants to focus attention either on the pictures or on the electrical stimuli. Sensory and affective pain ratings were generally lower during exposure to positive compared to negative and neutral pictures. Attention modulated only sensory pain ratings with lower ratings with an attention focus on pictures than with an attention focus on sensory pain. The N150 was modulated by picture valence, the P260 by picture arousal. Furthermore, the P260 was modulated by attention with highest amplitudes with an attention focus on the stimulus intensity. This study provides neurophysiological evidence that attention and affect have distinct effects on pain processing.     

Contingent negative variation in the parasylvian cortex increases during expectancy of painful sensorimotor events: a magnetoencephalographic study

Previous evidence relating to somatosensory-evoked magnetic fields has shown that the human parasylvian cortex (PC) is affected by ongoing painful sensorimotor interactions. In the present magnetoencephalographic study, the activity of the PC was investigated to evaluate the hypothesis of anticipatory processes preceding painful sensorimotor interactions. Sensorimotor interactions were induced by warned painful electrical stimulations at the left hand concomitant with a motor task of the right hand. The anticipatory activity of the PC was probed via contingent negative variation. Compared with the control nonpainful condition, the anticipation of the painful sensorimotor interactions increased the PC activity over the hemisphere ipsilateral to the stimulation. Dipole modeling indicated that the center of gravity of the anticipatory activity in the PC was located in the secondary somatosensory cortex. These results suggest that anticipation of painful sensorimotor interactions engages the human PC, especially in the hemisphere ipsilateral to upcoming painful stimuli and contralateral to preparatory motor commands.     

Right-lateralized pain processing in the human cortex: an FMRI study

Neuroimaging studies of human pain have revealed a widespread "pain matrix" distributed across both hemispheres of the brain. It is not resolved whether the pain matrix is biased toward one hemisphere, although behavioral and clinical data suggest that pain is perceived differently on the two sides of the body, and several neuroimaging studies suggest that pain processing in some regions of cortex may be lateralized toward the right hemisphere. The current study used fMRI in nine subjects to determine whether acute pain is preferentially processed in one cortical hemisphere. All cortical areas that were activated during the painful simulation were investigated, and several analytic approaches were used to directly compare activated regions to similar regions in the opposite hemisphere. Results indicated that four regions of the cortical pain matrix were activated either contralaterally (somatosensory cortex) or bilaterally (mid/posterior insula, anterior insula, and posterior cingulate). In addition, activation in five cortical regions during acute pain stimulation was localized either exclusively in the right hemisphere or was strongly lateralized to the right. These five areas were in the middle frontal gyrus, anterior cingulate, inferior frontal gyrus, medial/superior frontal gyri, and inferior parietal lobule. The location of some of these regions is consistent with the idea that there may be a right-lateralized attentional system to alert an organism to an infrequent, but behaviorally relevant, stimulus such as pain.     

Affective modulation of brain potentials to painful and nonpainful stimuli

In accordance with the emotional priming hypothesis, emotions seem to modulate pain perception and pain tolerance thresholds. To further evaluate this association, event-related brain potentials (ERPs) elicited by painful and nonpainful electrical stimuli during processing of positive, neutral, and negative valenced pictures were recorded from 30 healthy volunteers. Valence of pictures affected pain ratings and the N150 elicited by painful stimuli, with lowest amplitudes for positive pictures and highest amplitudes for negative pictures. The P260 elicited by painful and nonpainful stimuli was modulated by arousal with reduced amplitudes with arousing (positive or negative) compared to neutral pictures. N150 amplitudes varying with picture valence seem to reflect an affective modulation of pain perception whereas P260 amplitudes varying with picture arousal rather reflect non-pain-specific attentional processes.     

Attentional set effects on spinal and supraspinal responses to pain

The effects of attentional set on subjective magnitude ratings, spinal reflexes, and somatosensory evoked potentials (SEP) elicited by innocuous and painful sural nerve stimulation were investigated in 24 subjects. Cuing stimuli informed subjects as to whether a visual identification or a somatosensory rating task would follow. Twenty percent of the trials were invalidly cued, where the subjects were expecting a visual stimulus but were given a sural nerve stimulus and vice versa. Subjective magnitude ratings were lower in the invalidly cued condition than the validly cued condition. Attentional set had no effect on innocuous-related spinal or early cortical responses, nor on the spinal nociceptive withdrawal reflex. The pain-related negative difference potential (NDP) and P2 component of the SEP were largest in the invalidly cued condition. These results provide further support for our hypothesis that the NDP is generated in part by the anterior cingulate, and suggest that the anterior cingulate response to pain reflects non-pain-specific cognitive processes (e.g., orienting attention towards important stimuli in the environment and/or response competition) and not some aspect of the pain experience. The effects of attentional set on the pain-related P2 suggests that it might correspond to the P3a event-related potential. If this is the case, the pain-related P2 could serve as a useful index of neural processes involved in the cognitive-evaluative aspect of pain.     

Does exercise induce hypoalgesia through conditioned pain modulation?

Pain sensitivity decreases with exercise. The mechanisms that underlie this exercise‐induced hypoalgesia (EIH) are unclear. Our purpose was to investigate conditioned pain modulation (CPM) as a potential mechanism of EIH. Sixteen women completed pain testing during three sessions: painful exercise, nonpainful exercise, and quiet rest. Intensity and unpleasantness ratings to noxious heat stimuli were assessed at baseline and during and following each session. Results showed that pain sensitivity decreased significantly during both exercise sessions (p < .05), but not during quiet rest. Effect size calculations showed that the size of the hypoalgesic response was greater following painful exercise than nonpainful exercise. Our results suggest that exercise‐induced muscle pain may contribute to the magnitude of EIH. However, as pain sensitivity also decreased following nonpainful exercise, CPM is not likely the primary mechanism of EIH.     

Differentiating noxious- and innocuous-related activation of human somatosensory cortices using temporal analysis of fMRI

The role of the somatosensory cortices (SI and SII) in pain perception has long been in dispute. Human imaging studies demonstrate activation of SI and SII associated with painful stimuli, but results have been variable, and the functional relevance of any such activation is uncertain. The present study addresses this issue by testing whether the time course of somatosensory activation, evoked by painful heat and nonpainful tactile stimuli, is sufficient to discriminate temporal differences that characterize the perception of these stimulus modalities. Four normal subjects each participated in three functional magnetic resonance imaging (fMRI) sessions, in which painful (noxious heat 45-46 degrees C) and nonpainful test stimuli (brushing at 2 Hz) were applied repeatedly (9-s stimulus duration) to the left leg in separate experiments. Activation maps were generated comparing painful to neutral heat (35 degrees C) and nonpainful brushing to rest. Directed searches were performed in SI and SII for sites reliably activated by noxious heat and brush stimuli, and stimulus-dependent regions of interest (ROI) were then constructed for each subject. The time course, per stimulus cycle, was extracted from these ROIs and compared across subjects, stimulus modalities, and cortical regions. Both innocuous brushing and noxious heat produced significant activation within contralateral SI and SII. The time course of brush-evoked responses revealed a consistent single peak of activity, approximately 10 s after the onset of the stimulus, which rapidly diminished upon stimulus withdrawal. In contrast, the response to heat pain in both SI and SII was characterized by a double-peaked time course in which the maximum response (the 2nd peak) was consistently observed approximately 17 s after the onset of the stimulus (8 s following termination of the stimulus). This prolonged period of activation paralleled the perception of increasing pain intensity that persists even after stimulus offset. On the other hand, the temporal profile of the initial minor peak in pain-related activation closely matched that of the brush-evoked activity, suggesting a possible relationship to tactile components of the thermal stimulation procedure. These data indicate that both SI and SII cortices are involved in the processing of nociceptive information and are consistent with a role for these structures in the perception of temporal aspects of pain intensity.     

Cortical responses to thermal pain depend on stimulus size: a functional MRI study

Cortical activity patterns to thermal painful stimuli of two different sizes were examined in normal volunteers using functional magnetic resonance imaging (fMRI). Seven right-handed subjects were studied when the painful stimulus applied to the right hand fingers covered either 1,074-mm(2)-area large stimulator or 21-mm(2)-area small stimulator. Stimulus temperatures were adjusted to give rise to equivalent moderately painful ratings. fMRI signal increases and decreases were determined for the contralateral parietal and motor areas. When the overall activity in these regions was compared across subjects, increased fMRI activity was observed over more brain volume with the larger stimulator, whereas decreased fMRI activity was seen in more brain volume for the smaller stimulator. The individual subject and group-averaged activity patterns indicated regional specific differences in increased and decreased fMRI activity. The small stimulator resulted in decreased fMRI responses throughout the upper body representation in both primary somatosensory and motor cortices. In contrast, no decreased fMRI signals were seen in the secondary somatosensory cortex and in the insula. In another seven volunteers, the effects of the size of the thermal painful stimulus on vibrotactile thresholds were examined psychophysically. Painful stimuli were delivered to the fingers and vibrotactile thresholds were measured on the arm just distal to the elbow. Consistent with the fMRI results in the primary somatosensory cortex, painful thermal stimuli using the small stimulator increased vibrotactile thresholds on the forearm, whereas similarly painful stimuli using the large stimulator had no effect on forearm vibrotactile thresholds. These results are discussed in relation to the cortical dynamics for pain perception and in relation to the center-surround organization of cortical neurons.     

Electrophysiological indices of orienting attention toward pain

This study examined the effects of orienting on two pain-related components of the sural nerve-evoked somatosensory evoked potential: the NDP (80-230 ms), which is generated in part by the anterior cingulate cortex (ACCc), and SP6 (280-340 ms). NDP and SP6 amplitudes were larger when subjects oriented their attention away from an invalidly cued location and toward the sural nerve pain than when their attention remained focused on the pain. These results and our earlier studies suggest that the ACCc activity generating the NDP is involved in detecting transient painful stimuli. This activity is enhanced when the pain occurs outside the focus of attention, and it may signal other brain areas that attention should be oriented away from its current focus and toward the pain. SP6 appears to be a pain-evoked P3a event-related potential, with an anterior component involved in orienting attention away from some other task and toward the pain, and an posterior component involved in evaluating the pain.     

Short-term cortical plasticity induced by conditioning pain modulation

To investigate the effects of homotopic and heterotopic conditioning pain modulation (CPM) on short-term cortical plasticity. Glutamate (tonic pain) or isotonic saline (sham) was injected in the upper trapezius (homotopic) and in the thenar (heterotopic) muscles. Intramuscular electrical stimulation was applied to the trapezius at pain threshold intensities, and somatosensory evoked potentials were recorded with 128 channel EEG. Pain ratings were obtained during glutamate and sham pain injection. Short-term cortical plasticity to electrical stimulation was investigated before, during, and after homotopic and heterotopic CPM versus control. Peak latencies at N100, P200, and P300 were extracted and the location/strength of corresponding dipole current sources and multiple dipoles were estimated. Homotopic CPM caused hypoalgesia (P = 0.032, 30.6% compared to baseline) to electrical stimulation. No cortical changes were found for homotopic CPM. A positive correlation at P200 between electrical pain threshold after tonic pain and the z coordinate after tonic pain (P = 0.032) was found for homotopic CPM. For heterotopic CPM, no significant hypoalgesia was found and a dipole shift of the P300 z coordinate (P = 0.001) was found between glutamate versus sham pain (P = 0.009). This generator was located in the cingulate. A positive correlation at P300 between pain ratings to glutamate injection and the x coordinate during tonic pain (P = 0.016) was found for heterotopic CPM. Heterotopic CPM caused short-term cortical plasticity within the cingulate that was correlated to subjective pain ratings. The degree of long-term depressive effect to homotopic CPM was correlated to the change in location of the P200 dipole.     

Cortical responses to noxious stimuli during sleep

We used magnetoencephalography to study effects of sleep on cortical responses to noxious stimuli and to clarify the mechanisms underlying pain perception. For a noxious stimulus, painful intra-epidermal electrical stimulation, which selectively activates A-delta fibers, was applied to the dorsum of the left hand. While awake, subjects were asked to count the number of stimuli silently (Attention) or ignore the stimuli (Control). During sleep, magnetic fields recorded in stage 1 sleep and stage 2 sleep were analyzed. One main component at a latency around 140-160 ms was identified in the awake condition. Multiple source analysis indicated that this main component was generated by activities in the contralateral primary somatosensory cortex (SI), bilateral secondary somatosensory cortex (SII) and insular cortex. The medial temporal area (MT) and cingulate cortex were activated later than the main component. Cortical responses in the contralateral SI, ipsilateral SII and MT, bilateral insula and cingulate cortex were significantly enhanced in Attention as compared with Control. The main component 1 M as well as later magnetic fields were markedly attenuated during sleep, suggesting that all these cortical areas are involved in pain cognition.     

Neural correlates of prickle sensation: a percept-related fMRI study

The painful sensations produced by a laceration, freeze, burn, muscle strain or internal injury are readily distinguishable because each is characterized by a particular sensory quality such as sharp, aching, burning or prickling. We propose that there are specific neural correlates of each pain quality, and here we used a new functional magnetic resonance imaging (fMRI) method to identify time-locked responses to prickle sensations that were evoked by noxious cold stimuli. With percept-related fMRI, we identified prickle-related brain activations in the anterior cingulate cortex (ACC), insula, secondary somatosensory cortex (S2), prefrontal cortex (PFC), premotor cortex (PMC), caudate nucleus and dorsomedial thalamus, indicating that multiple pain, sensory and motor areas act together to produce the prickle sensation.     

Gray matter volume differences between lower,average, and higher pain resilience subgroups

Resilience refers to the capacity to function well despite adversity and facilitates adaptation to various stressors, including pain. Previous studies have operationalized resilience via questionnaires or task performance behaviors that do not always correlate with one another and tested extreme (lower vs. higher) resilience subgroup differences that do not permit the assessment of nonlinear associations between resilience and brain matter volume. To address these limitations, we identified high (HPR, N = 21), moderate (MPR, N = 20), and low (LPR, N = 16) pain resilience subgroups from a trait resilience questionnaire as well as behavioral performance on a laboratory pain task. Subsequently, resilience subgroup differences in gray matter volume (GMV) and behavior responses to a novel numerical interference task (NIT) were assessed. Behavioral results indicated the LPR subgroup was slower in responding to NIT trials accompanied by pain compared to MPR, and especially, HPR subgroups. Voxel-based morphology analyses indicated the LPR subgroup had more GMV in the left postcentral gyrus than did MPR and HPR subgroups. LPR and MPR subgroups displayed larger GMV in the right inferior temporal gyrus than did the HPR subgroup. Nonlinear relations reflecting less regional GMV in the right inferior frontal gyrus (IFG)/putamen, orbitofrontal cortex and left IFG/insula were also observed for the MPR subgroup compared to LPR and HPR subgroups. In sum, lower pain resilience is characterized, in part, by comparatively greater GMV in pain processing regions and reduced GMV in “resilience” regions, though regional GMV also has several nonlinear associations with resilience.     

Pain catastrophizing and cortical responses in amputees with varying levels of phantom limb pain: a high-density EEG brain-mapping study

Pain catastrophizing has been associated with phantom limb pain, but so far the cortical processes and the brain regions involved in this relationship have not been investigated. It was therefore tested whether catastrophizing was related to (1) spontaneous pain, (2) somatosensory activity and (3) cortical responses in phantom limb pain patients. The cortical responses were investigated via electroencephalography (EEG) as it has a high temporal resolution which may be ideal for investigating especially the attentional and hypervigilance aspect of catastrophizing to standardized acute stimuli. Eighteen upper limb amputees completed the pain catastrophizing scale. Patients’ spontaneous pain levels (worst and average pain, numerical rating scales) and thresholds to electrical stimulation (sensory detection and VRS2: intense but not painful) were determined. Non-painful electrical stimuli were applied to both the affected and non-affected arm, while high-resolution (128 channels) EEG signals were recorded. Catastrophizing accounted for significant amounts of the variance in relation to spontaneous pain, especially worst pain (64.1%), and it was significantly associated with thresholds. At the affected side, catastrophizing was significantly related to the power RMS of the N/P135 dipole located in the area around the secondary somatosensory cortex which has been shown to be associated with arousal and expectations. These findings corroborate the attentional model of pain catastrophizing by indicating that even non-painful stimuli are related to enhanced attention to and negative expectations of stimuli, and they suggest that memory processes may be central to understanding the link between catastrophizing and pain.     

Perspective taking modulates event-related potentials to perceived pain

Recent event-related brain potential (ERP) study disentangled an early automatic component and a late top-down controlled component of neural activities to perceived pain of others. This study assessed the hypothesis that perspective taking modulates the top-down controlled component but not the automatic component of empathy for pain by recording ERPs from 24 subjects who performed pain judgments of pictures of hands in painful or non-painful situations from either self-perspective or other-perspective. We found that, relative to non-painful stimuli, painful stimuli induced positive shifts of ERPs at frontal–central electrodes as early as 160 ms after sensory stimulation and this effect lasted until 700 ms. The amplitudes of ERPs at 230–250 ms elicited by painful stimuli negatively correlated with both subjective ratings of others’ pain and self-unpleasantness in both self-perspective and other-perspective conditions. Neural response to perceived pain over the central–parietal area was significantly reduced at 370–420 ms when performing the pain judgment task from other-perspective compared to self-perspective. The results suggest that shifting between self-perspectives and other-perspectives modulates the late controlled component but not the early automatic component of neural responses to perceived pain.