Separating brain processing of pain from that of stimulus intensity

Abstract

Regions of the brain network activated by painful stimuli are also activated by nonpainful and even nonsomatosensory stimuli. We therefore analyzed where the qualitative change from nonpainful to painful perception at the pain thresholds is coded. Noxious stimuli of gaseous carbon dioxide (n = 50) were applied to the nasal mucosa of 24 healthy volunteers at various concentrations from 10% below to 10% above the individual pain threshold. Functional magnetic resonance images showed that these trigeminal stimuli activated brain regions regarded as the "pain matrix." However, most of these activations, including the posterior insula, the primary and secondary somatosensory cortex, the amygdala, and the middle cingulate cortex, were associated with quantitative changes in stimulus intensity and did not exclusively reflect the qualitative change from nonpainful to pain. After subtracting brain activations associated with quantitative changes in the stimuli, the qualitative change, reflecting pain-exclusive activations, could be localized mainly in the posterior insular cortex. This shows that cerebral processing of noxious stimuli focuses predominately on the quantitative properties of stimulus intensity in both their sensory and affective dimensions, whereas the integration of this information into the perception of pain is restricted to a small part of the pain matrix.

Figure 1

Brain regions activated by painful CO₂ stimuli. The painful CO₂ stimuli activated brain regions typically attributed to the pain matrix, including the insula lobe (Ins), secondary somatosensory cortex (SII), middle cingulate cortex (MCC), postcentral gyrus (PoG), precentral gyrus (PreG), inferior frontal gyrus, and the supplementary motor area (SMA). Statistically significantly activated voxels (P < 0.05 familywise error corrected) of the painful stimuli t‐contrast (contrast weight: 1) are presented overlaid (red) on 3D surface renderings of a standard Montreal Neurological Institute brain (Panel A) and as colored overlay on the three orthogonal views of a structural standard T ₁‐weighted MRI template (Panel B; L, Left hemisphere, contralateral to the presentation of the painful stimuli; R, Right hemisphere). The color depth of the displayed voxels reflects the respective t value of the voxel. Results reflect a 24‐subject group analysis.

Figure 2

CO₂‐stimulus related activation. Brain regions that were activated by the CO₂‐stimulus irrespective of its intensity and perception (cyan areas; “CO₂‐stimulus” regressor, t‐contrast weight: 1) included the anterior insula (Ins) and the supplementary motor area (SMA). Regions coding for stimulus intensity irrespective of its perception (yellow areas; “stimulus intensity” regressor, t‐contrast weight: 1) included the posterior insula, secondary somatosensory cortex (SII), amygdala (Amyg), postcentral gyrus (PoG), superior temporal gyrus (STG), middle cingulate cortex (MCC). Regions displaying exclusively pain perception related activation (red areas; “painful perception” regressor, t‐contrast weight: 1) included the postcentral gyrus, precentral gyrus (PreG), parts of the mid to posterior insula and the putamen (Put). In contrast, non‐painful stimulus perception was not associated with any specific brain activation (“non‐painful perception” regressor, t‐contrast weight: 1). Statistically significantly activated voxels (P < 0.05 familywise error corrected) are displayed as colored overlay on the three orthogonal views of a structural standard T ₁‐weighted MRI template (Panel A; L, Left hemisphere, contralateral to the presentation of the painful stimuli; R, Right hemisphere). The color depth of the displayed voxels reflects the respective t value of the voxel. For each regressor, stimulus related brain activations corresponding to the different CO₂‐concentrations are reported as mean percent signal change in a 5‐mm spherical search volume around selected familywise error‐corrected peak coordinates (Panel B; PSC: Colored bars; 90% CI: white error bars). Results reflect a 24‐subject group analysis.

Figure 3

CO₂‐stimulus‐related brain deactivation. Brain regions were deactivated irrespective of the stimulus intensity and perception (“CO₂ stimulus” regressor, t‐contrast weight: −1). Deactivated regions included the fusiform gyrus (FuG), hippocampus (HipC), inferior occipital lobe (IOL), precuneus (Prec), posterior cingulate cortex (PCC), rectal gyrus (RG), mid orbital gyrus (MOG), thalamus (Thal), middle temporal gyrus (MTG), and middle frontal gyrus (MFG). Statistically significant deactivated voxels (P < 0.05 familywise error corrected) are presented overlaid (blue) on 3D surface renderings of a standard Montreal Neurological Institute brain (Panel A) and as colored overlay on the horizontal and sagittal plane of a structural standard T ₁‐weighted MRI template (Panel B; L, Left hemisphere, contralateral to the presentation of the painful stimuli; R, Right hemisphere). The color depth of the displayed voxels reflects the respective t value of the voxel. Furthermore, stimulus related brain activations corresponding to the different CO₂ concentrations are reported as mean percent signal change in a 5‐mm spherical search volume around a selected familywise error‐corrected peak coordinate (Panel C; PSC: Colored bars; 90% CI: white error bars). Results reflect a 24‐subject group analysis.