Neuromagnetic SII responses do not fully reflect pain scale

doi:10.1016/j.neuroimage.2005.12.015

NeuroImage

Volume 31, Issue 2, June 2006, Pages 670-676

https://doi.org/10.1016/j.neuroimage.2005.12.015 Get rights and content

Abstract

To elucidate the role of somatosensory cortices in coding pain magnitude, we recorded the neuromagnetic responses of ten subjects to mild, moderate, and severe pain stimulation by delivering thulium-laser pulses on the dorsum of the left hand. The stimulus intensities for producing different pain levels were determined individually, and the mean values across subjects were 255, 365, and 490 mJ for mild, moderate, and severe pain, respectively. We obtained 40 responses for each intensity condition, and analyzed the averaged cortical signals by multi-dipole modeling. All subjects showed consistent activation over the bilateral secondary somatosensory (SII) cortices for each intensity level, peaking around 150–230 ms, with 15-ms earlier on the contralateral hemisphere. The SII dipole strength was significantly larger for the moderate than for the mild pain stimulation, but lacked further increase as the pain magnitude elevated to the severe level. In contrast, the primary somatosensory cortical response was detected in only half of our subjects, and thus it seemed difficult to evaluate its role in pain intensity coding. Our results suggest that activation strength in human SII cortices reflects the magnitude of peripheral noxious inputs only up to the moderate level, and some other cerebral correlates may get involved in sensing a further increment of pain magnitude.

Introduction

Pain perception is an essential function for humans, and the awareness of pain magnitude ensures the individual take immediate aversive behavior to avoid harm. Earlier functional imaging and electrophysiological studies on human pain processing have already shown consistent activations around the secondary somatosensory (SII) cortex (see Kakigi et al., 2005, Peyron et al., 2000 for a review). Additional responses from the primary somatosensory (SI) cortex, insula, anterior cingulate, and prefrontal cortices are otherwise inconsistently demonstrated (Kakigi et al., 2005, Peyron et al., 2000). The extent to which these pain-relevant brain responses correlate with pain intensity is not yet settled.

Cutaneous noxious laser pulses activate exclusively Aδ and C nociceptive receptors without eliciting responses from Aβ mechanoreceptors (Bromm and Treede, 1984). The recording of laser-evoked potentials (LEP) has been therefore used as a powerful method to study cortical processing of pain information. Early studies have observed that the late LEP component correlates with subjective pain magnitude and, to a lesser degree, with the stimulus intensity (Bromm et al., 1983, Carmon et al., 1978, Carmon et al., 1980, Kakigi et al., 1989). Recent studies were further devoted to the relationship between laser evoked responses and noxious stimulus intensities in isolated cerebral regions. For example, using subdural electrode recordings, Ohara et al. (2004) have shown that LEP over the SI, parasylvian, and frontal cortices correlate with the intensity of noxious stimuli perceived as mild to moderate pain. Timmermann et al. (2001) demonstrated a significant positive correlation of SI and SII amplitudes with mild pain intensity (rated as less than 20 with a visual analogue scale (VAS) of 0–100), but interestingly a sharp increase in SII activation was already obtained well above pain threshold. However, it is not clear whether somatosensory cortical responses would increase further as the subject receives even stronger painful stimulation.

In the present study, we investigated how the human brain responses reflected pain magnitude using a wide range of laser stimulus intensities, starting from a mild level and increasing up to a severely painful level. By comparing the cortical activations in varying pain conditions, we evaluated the functional roles of the activated cortices in coding perceived pain magnitude. Based on the differential coding of pain intensity in SI and SII cortices as well as the S-shaped stimulus–response function in bilateral SII in response to low levels of pain stimuli (Timmermann et al., 2001), we hypothesized that the neuronal correlate of perceiving severe pain might not necessarily be reflected by the amplitude of somatosensory cortical activations.

Section snippets

Materials and methods

Ten healthy right-handed volunteers (2 women and 8 men; age 27–39 years, mean 32.1 ± 4.3 years) gave their informed consent and participated in this study. This research adhered to the tenets of the Declaration of Helsinki, and the experimental protocol had a prior acceptance by the institutional review board of Taipei Veterans General Hospital.

Correlation between stimulus intensity and pain magnitude

All subjects identified the stabbing-like pain to laser pulse stimulation. No tactile sensation was reported. Fig. 1 shows the linear correlation between the subjective pain magnitude and the applied stimulus intensity (R² = 0.91, P < 0.001). The mean (± SEM) PT was 205 ± 9 mJ (range 150–250 mJ). The intensities for producing mild (VAS = 2–3; intensity range 200–300 mJ) and moderate pain (VAS 5–6; intensity range 300–450 mJ) were 255 ± 12 mJ and 365 ± 19 mJ, respectively (P < 0.001). Pain

Discussion

In this study, we identified SI activation in only about half of our subjects, in contrast to the consistent SI responses reported by Timmermann et al. (2001). The detection yield of the SI signal and its role in pain processing is currently under debate. The neuromagnetic SI activation has been either indiscernible (Forss et al., 2005, Kakigi et al., 1995) or inconsistently elicited (Kanda et al., 2000). The anatomical variability in the extension of the postcentral gyrus may be one of the

Conclusion

The human SII cortex is abundantly activated by moderate noxious stimuli (∼ 2 PT), and its activation size reflects the pain magnitude only up to the moderate level. The cerebral correlates for sensing further increments of noxious inputs may involve activation in more distributed brain regions that may be not reliably recorded with MEG.

Acknowledgments

This study was supported by research grants VGH-94-323, V95C1-043, and V95ER3-006 from Taipei Veterans General Hospital, NSC-94-2314-B-010-065 (YY Lin) from the National Science Council, and GH0401 (WT Chen) from Taipei Medical University Hospital, Taipei, Taiwan. We highly appreciated the comments from anonymous reviewers that strengthened our present work.

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Pain was considered to be integrated subcortically during most of the 20^th century, and it was not until 1956 that focal injury to the parietal opercular-insular cortex was shown to produce selective loss of pain senses. The parietal operculum and adjacent posterior insula are the main recipients of spinothalamic afferents in primates. The innermost operculum appears functionally associated with the posterior insula and can be segregated histologically, somatotopically and neurochemically from the more lateral S2 areas. The Posterior Insula and Medial Operculum (PIMO) encompass functional networks essential to initiate cortical nociceptive processing. Destruction of this region selectively abates pain sensations; direct stimulation generates acute pain, and epileptic foci trigger painful seizures. Lesions of the PIMO have also high potential to develop central pain with dissociated loss of pain and temperature. The PIMO region behaves as a somatosensory area on its own, which handles phylogenetically old somesthetic capabilities based on thinly myelinated or unmyelinated inputs. It integrates spinothalamic-driven information – not only nociceptive but also innocuous heat and cold, crude touch, itch, and possibly viscero-somatic interoception. Conversely, proprioception, graphesthesia or stereognosis are not processed in this area but in S1 cortices. Given its anatomo-functional properties, thalamic connections, and tight relations with limbic and multisensory cortices, the region comprising the inner parietal operculum and posterior insula appears to contain a third somatosensory cortex contributing to the spinothalamic attributes of the final perceptual experience.
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Noteworthy, stimuli evoking non-painful warm and cold tended to concentrate in the medial operculum, while those yielding pain predominated in the posterior dorsal insula (Fig. 2, and see [117,119]). This is in accordance with studies of evoked potentials to thermal laser stimuli, where the inner opercular region was able to encode low levels of thermal change, [28,64] whereas the posterior insula tended to respond only when thermal stimuli almost had reached the subjective pain threshold [64]. The PIMO region is involved in different types of mechano-sensation too.
To be considered specific for nociception, a cortical region should: (a) have plausible connections with ascending nociceptive pathways; (b) be activated by noxious stimuli; (c) trigger nociceptive sensations if directly stimulated; and (d) tone down nociception when injured. In addition, lesions in this area should have a potential to develop neuropathic pain, as is the case of all lesions in nociceptive pathways. The single cortical region approaching these requirements in humans encompasses the suprasylvian posterior insula and its adjoining medial operculum (referred to as “PIMO” in this review). This region does not contain, however, solely nociceptive networks, but represents in primates the main sensory receiving area of the spinothalamic system, and as such contributes to the processing of thermo-sensory, nociceptive, C-fibre tactile, and visceral input. Nociception (and, a fortiori, pain) should therefore not be considered as a separate sensory modality, like vision or audition, but rather as one component of a global system subtending the most primitive forms of somatosensation. Although a clear functional segregation of PIMO sub-areas has not yet been achieved, some preferential distribution has been described in humans: pain-related networks appear preferentially distributed within the posterior insula, and non-noxious thermal processing in the adjacent medial operculum. Thus, spinothalamic sub-modalities may be partially segregated in the PIMO, in analogy with the separate representation of dorsal column input from joint, muscle spindle and tactile afferents in S1. Specificity, however, may not wholly depend on ascending ‘labelled lines’ but also on cortical network properties driven by intrinsic and extrinsic circuitry. Given its particular anatomo-functional properties, thalamic connections, and tight relations with limbic and multisensory cortices, the PIMO region deserves to be considered as a third somatosensory region (S3) devoted to the processing of spinothalamic inputs.
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This is not without precedent. Chen et al. (2006) found that the activation strength in the S2 significantly increased with the perceived pain intensity from a mild pain level (ratings as 2–3 on a 0–10 visual analogue scale (VAS)) up to a moderate level (VAS: 5–6), but lacked further increase as the pain magnitude elevated to the severe level (VAS: 8–9). A particular concern associated with the present study is the residual muscle artifact which could confound the EEG analysis in the high frequency band (18–30 Hz).
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Scalp EEG data were recorded from 26 healthy subjects under tonic cold pain (CP) and no-pain control (NP) conditions. EEG power spectra and the standardized low-resolution brain electromagnetic tomography (sLORETA) localized EEG cortical sources were compared between the two conditions in five frequency bands: 1–4 Hz, 4–8 Hz, 8–12 Hz, 12–18 Hz and 18–30 Hz.
In line with the EEG power spectral results, the source power significantly differed between the CP and NP conditions in 8–12 Hz (CP < NP) and 18–30 Hz (CP > NP) in extensive brain regions. Besides, there were also significantly different 4–8 Hz and 12–18 Hz source activities between the two conditions. Among the significant source activities, the left medial frontal and left superior frontal 4–8 Hz activities, the anterior cingulate 8–12 Hz activity and the posterior cingulate 12–18 Hz activity showed significant negative correlations with subjective pain ratings.
The brain’s perception of tonic cold pain was characterized by cortical source power changes across different frequency bands in multiple brain regions. Oscillatory activities that significantly correlated with subjective pain ratings were found in the prefrontal and cingulate regions.
These findings may offer useful measures for objective pain assessment and provide a basis for pain treatment by modulation of neural oscillations at specific frequencies in specific brain regions.
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Pain is a sensory and emotional experience that involves numerous brain areas. Among these areas the insular cortex has been shown to be involved in the expectation and processing of pain. Alpha power modulation has been associated with the experience of pain. The aim of this study was to test the hypothesis that the threat of a painful stimulus affects alpha rhythm oscillation in the insular cortex and to find the time intervals during which the insular cortex is most active. We used a beamforming method in the frequency domain to estimate alpha power associated with source activity during psychologically different conditions, namely a sequence of nonpainful somatosensory stimuli (non-threatening condition) and a sequence of nonpainful stimuli randomly intermixed with painful stimuli (threatening condition). The results revealed that the anterior insula alone was involved during the threat of painful stimuli. Conversely, the posterior insula – as well as other brain areas such as SII – was involved in the processing of somatosensory stimuli regardless their painfulness. Additionally, the involvement of the anterior insula should not be accounted for by fear, arousal, habituation effect or by the occurrence of randomly interleaved different stimuli, but it is likely to be related mainly to expectancy mechanisms enhancing activity of specific neuronal populations.
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One limitation shared by several intensity coding studies is their concentration on specific pain-related regions; using MEG and focused on SI and SII, Timmermann et al71 suggested SI represented the perceived stimulus intensity, while the activation pattern of SII pointed against a significant contribution to the sensory-discriminative aspect of pain perception. Chen et al16 characterized the temporal activation of the same regions using fMRI, and concluded both SI and SII encoded a temporal signature specific to the perceptual characteristics of both noxious and innocuous stimuli. However, neither study tested direct correlations between activation magnitudes and pain ratings.
Multiple studies have supported the usefulness of standardized low-resolution brain electromagnetic tomography (sLORETA) in localizing generators of scalp-recorded potentials. The current study implemented sLORETA on pain event-related potentials, primarily aiming at validating this technique for pain research by identifying well-known pain-related regions. Subsequently, we pointed at investigating the still-debated and ambiguous topic of pain intensity coding at these regions, focusing on their relative impact on subjective pain perception. sLORETA revealed significant activations of the bilateral primary somatosensory (SI) and anterior cingulate cortices and of the contralateral operculoinsular and dorsolateral prefrontal (DLPFC) cortices (P < .05 for each). Activity of these regions, excluding DLPFC, correlated with subjective numerical pain scores (P < .05 for each). However, a multivariate regression analysis (R = .80; P = .024) distinguished the contralateral SI as the only region whose activation magnitude significantly predicted the subjective perception of noxious stimuli (P = .020), further substantiated by a reduced regression model (R = .75, P = .008). Based on (1) correspondence of the pain-activated regions identified by sLORETA with the acknowledged imaging-based pain-network and (2) the contralateral SI proving to be the most contributing region in pain intensity coding, we found sLORETA to be an appropriate tool for relevant pain research and further substantiated the role of SI in pain perception.
Because the literature of pain intensity coding offers inconsistent findings, the current article used a novel tool for revisiting this controversial issue. Results suggest that it is the activation magnitude of SI, which solely establishes the significant correlation with subjective pain ratings, in accordance with the classical clinical thinking, relating SI lesions to diminished perception of pain. Although this study cannot support a causal relation between SI activation magnitude and pain perception, such relation might be insinuated.
Central processing of tactile and nociceptive stimuli in complex regional pain syndrome
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Patients with complex regional pain syndrome (CRPS) suffer from continuous regional limb pain and from hyperesthesia to touch and pain. To better understand the pathophysiological mechanisms underlying the hyperesthesia of CRPS patients, we investigated their cortical processing of touch and acute pain.
Cortical responses to tactile stimuli applied to the thumbs, index and little fingers (D1, D2, and D5) and nociceptive stimuli delivered to dorsa of the hands were recorded with a whole-scalp neuromagnetometer from eight chronic CRPS patients and from nine healthy control subjects.
In the patients, primary somatosensory (SI) cortex activation to tactile stimulation of D2 was significantly stronger, and the D1–D5 distance in SI was significantly smaller for the painful hand compared to the healthy hand. The PPC activation to tactile stimulation was significantly weaker in the patients than in the control subjects. To nociceptive stimulation with equal laser energy, the secondary somatosensory (SII) cortices and posterior parietal cortex (PPC) were similarly activated in both groups. The PPC source strength correlated with the pain rating in the control subjects, but not in the patients.
The enhanced SI activation in hyperesthetic CRPS patients may reflect central sensitization to touch. The decreased D1–D5 distance implies permanent changes in SI hand representations in chronic CRPS. The defective PPC activation could be associated with the neglect-like symptoms of the patients. As the SII and PPC responses were not enhanced in the CRPS patients, other brain areas are likely to contribute to the observed hyperesthesia to pain.
Our results indicate changes of somatosensory processing at cortical level in CRPS.

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Neuromagnetic SII responses do not fully reflect pain scale

Abstract

Introduction

Section snippets

Materials and methods

Correlation between stimulus intensity and pain magnitude

Discussion

Conclusion

Acknowledgments

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