Fig 1.
(A) VASs for rating heat (left) and sound (right) stimuli. The midpoint signifies the pain threshold, corresponding to a score of 0 in a conventional VAS. (B) Thermode arrangement on a subject’s forearm. Patch C was used for calibration, patches 1|2 were used in counterbalanced fashion for experimental sessions 1 and 2. (C) Protocol by time. A visual cue (white fixation cross turning red) announced the upcoming stimulus (either heat or sound) and stayed visible throughout stimulation, which was 8 seconds at plateau (roughly 9.5 seconds all in all, depending on calibration). Subjects were then prompted to rate the stimulus. After rating, the white fixation cross reappeared, to turn red again for the next cue. Stimulus modalities were always alternating. ITI, intertrial interval; VAS, visual analogue scale.
Fig 2.
SCRs following heat (A) and sound (B) stimuli. The pain and unpleasantness thresholds were located between intensities 3 and 4, as per calibration. Individual data are shown in S1 Fig and S2 Fig. Data used to produce the figure can be found at https://www.doi.org/10.17605/OSF.IO/QXCNW within the component “Rating and SCR data.” SCR, skin conductance response.
Fig 3.
Behavioral ratings following heat (A) and sound (B) stimuli. The pain and unpleasantness thresholds were located between intensities 3 and 4, as per calibration. Individual data are shown in S3 Fig. Data used to produce the figure can be found at https://www.doi.org/10.17605/OSF.IO/QXCNW within the component “Rating and SCR data.” VAS, visual analogue scale.
Fig 4.
Differential effects of heat (orange) and sound (blue).
Significant differences were found in PO1 (and the more anterior PO2) and dpIns1 for heat and in the STG1 and Heschl’s gyri for sound. (A) Activations are thresholded at p(uncorrected) < 0.001 and overlaid on an average brain surface for display purposes. The black line delineates the region of interest used for correction for multiple comparisons. See S5 Fig for peak locations in brain volume slices. (B) Poststimulus plots of fMRI activation over all stimulus intensities (mean ± SE). Subplots PO1, PO2, and dpIns1 show that heat-related activation (orange) dominates in the analyzed time frames (seconds 2.2 through 10.8, see Materials and methods), while subplot STG1 shows increased sound activation (blue). Data used to produce the figure can be found at https://www.doi.org/10.17605/OSF.IO/QXCNW. BOLD, blood-oxygen-level–dependent; dpIns1, dorsal posterior insula cluster 1; fMRI, functional magnetic resonance imaging; PO1, parietal operculum cluster 1; PO2, parietal operculum cluster 2; STG1, superior temporal gyrus cluster 1.
Fig 5.
Differential modulation by stimulus intensity for heat (orange) and sound (blue). Significant differences were found in PO1 for heat. (A) Activations are thresholded at p(uncorrected) < 0.001 and overlaid on an average brain surface for display purposes. The black line delineates the region of interest used for correction for multiple comparisons. See S6 Fig for peak positions in brain volume slices. (B) Poststimulus plots of fMRI activation in vertex PO1 during heat (orange) and sound (blue). The colored patches at the right axes show the stimulus duration. The lower left (y-)axes show the parametric modulation affecting the main effect (average size of the effect along the lower right [x-]axes): a straight line parallel to the y-axis indicates no change of the BOLD response depending on stimulus intensity, whereas the sloped main effect along the y-axis indicates parametric modulation. In this area, the main effect of heat is mostly positively modulated by stimulus intensity, that is, higher stimulus intensities induce a higher extent of BOLD. The highest main effect activation occurs around second 10.8 (corresponding to scan 6), coinciding with the steepest slope of parametric modulation by intensity (y-axis). Data used to produce the figure can be found at https://www.doi.org/10.17605/OSF.IO/QXCNW. BOLD, blood-oxygen-level–dependent; fMRI, functional magnetic resonance imaging; PO1, parietal operculum cluster 1.
Fig 6.
Differential modulation by ratings for heat (orange). Significant differences were found in PO3 and PO4 as well as in daIns1 and the more ventral daIns2. (A) Activations are thresholded at p(uncorrected) < 0.001 and overlaid on an average brain surface for display purposes. The black line delineates the region of interest used for correction for multiple comparisons. See S7 Fig for peak positions in brain volume slices. (B) Poststimulus plots of fMRI activation in vertices PO3, PO4, daIns1 and daIns2 during heat (orange) and sound (blue). The colored patches at the right axes show the stimulus duration. The lower left (y-)axes show the parametric modulation by ratings that are affecting the main effect. Data used to produce the figure can be found at https://www.doi.org/10.17605/OSF.IO/QXCNW. BOLD, blood-oxygen-level–dependent; daIns1, dorsal anterior insula cluster 1; daIns2, dorsal anterior insula cluster 2; fMRI, functional magnetic resonance imaging; PO3, parietal operculum cluster 3; PO4, parietal operculum cluster 4.
Fig 7.
Areas fulfilling the axiomatic requirements of differential activation during pain compared to heat and sound.
These axioms were (1) a larger effect of suprathreshold heat compared to subthreshold heat, (2) a larger effect of suprathreshold heat compared to suprathreshold sound, (3) a stronger relationship of BOLD with pain ratings than with heat ratings, (4) a stronger relationship of BOLD with pain ratings than with unpleasantness ratings. Significant activation was found in PO3. (A) Activations are thresholded at p(uncorrected) < 0.001 and overlaid on an average brain surface for display purposes. The black line delineates the SVC mask. See S10 Fig for peak positions in brain volume slices. (B) Poststimulus plots of fMRI activation in vertex PO3 during heat (orange) and sound (blue). The shaded patch in the center signifies the pain threshold (for heat) and unpleasantness threshold (for sound). The colored patches at the right axes show the stimulus duration. Data used to produce the figure can be found at https://www.doi.org/10.17605/OSF.IO/QXCNW. BOLD, blood-oxygen-level–dependent; fMRI, functional magnetic resonance imaging; PO3, parietal operculum cluster 3; SVC, small-volume correction.
Fig 8.
Distinction of areas with SRFs corresponding to the axioms, or not (heat only).
(A) The slopes of subthreshold (heat) versus suprathreshold (pain) activation as described in Fig 7, corresponding to PO3. Heat slopes are shallower than pain slopes. (B) Slopes of heat and pain activation in an opercular vertex slightly anterior to A (corresponding to PO2), as determined per conjunction of heat and pain parametric modulation. Slopes are more aligned, preventing the contrasted activation (pain > heat) of reaching significance. Note that this is not a formal comparison to panel A. (C) Location of the vertices described in panels A and B. Panel B is in an adjacent area about 1 cm surface distance rostral from panel A. Data used to produce the figure can be found at https://www.doi.org/10.17605/OSF.IO/QXCNW. a.u., arbitrary units; BOLD, blood-oxygen-level–dependent; PO2, parietal operculum cluster 2; PO3, parietal operculum cluster 3; SRF, stimulus-response function.