Dissociable neural responses related to pain intensity, stimulus intensity, and stimulus awareness within the anterior cingulate cortex: a parametric single-trial laser functional magnetic resonance imaging study

Abstract

Neuroimaging studies have demonstrated activations in the anterior cingulate cortex (ACC) related to the affective component of pain, but not to stimulus intensity. However, it is possible that the low spatial resolution of positron emission tomography, as used in the majority of these studies, obscured areas coding stimulus intensity. We revisited this issue, using a parametric single-trial functional magnetic resonance imaging design, and investigated pain, stimulus intensity, and stimulus awareness (i.e., pain unrelated) responses within the ACC in nine healthy volunteers. Four different stimulus intensities ranging from warm to painful (300-600 mJ) were applied with a thulium yttrium-aluminum granite infrared laser in a randomized order and rated by the subjects on a five point scale (P0-P4). Pain-related regions in the ventral posterior ACC showed a response that did not distinguish between innocuous trials (P0 and P1) but showed a positive linear relationship with the blood oxygenation level-dependent contrast signal for painful trials (P2-P4). Regions in the dorsal anterior ACC along the cingulate sulcus differentiated between P0 (not perceived) and P1 but exhibited no additional signal increase with P2; these regions are related to stimulus awareness and probably to cognitive processing. Most importantly, we identified a region in the dorsal posterior ACC showing a response that discriminated between nonpainful trials (P0 and P1); therefore, this region was simply related to basic sensory processing and not to pain intensity. Stimulus-related activations were all located adjacent to the cingulate motor area, highlighting the strategic link of stimulus processing and response generation in the posterior ACC.

Fig. 1.

Relationship between applied stimulus energy (x-axis) and average rating (P0–P4;y-axis). Each plotted data point refers to the mean rating for each energy level and each subject (i.e., nine data points for each energy level). The average pain rating was linearly related to laser energy (average pain rating = laser energy × 0.84–0.15), where laser energy is 300, 400, 500, and 600 mJ.

Fig. 2.

Different SRFs. The SRF in a shows a higher BOLD signal for P1 (stimulus perceived, but not painful) compared with P0 (stimulus not perceived), but no additional signal increase with P2–P4 (low level, mid-level, and high level of pain). This step function discriminates between perceived and unperceived stimuli without any additional pain or intensity discrimination and seems to be linked to stimulus awareness and possibly to cognitive processing (e.g., working memory or attention). The SRF inb shows a linear relationship beginning at P0 and differentiates well between stimulus intensities, although some (P0 and P1) were perceived as nonpainful. This SRF is related to stimulus intensity. The SRF depicted in c shows an initial plateau (i.e., does not differentiate between P0 and P1 but shows a linear relationship for P2–P4). According to our pain-rating scale, in which P2 was defined as clearly painful and P0 and P1 were not painful, this SRF is related to pain intensity.

Fig. 3.

Activations in the ACC (p < 0.001) overlaid on a structural T₁-weighted MRI used for spatial normalization. Laser-evoked responses and their locations are depicted ina. Three sagittal slices through the ACC are shown from x = −3 mm to x = 3 mm. The dashed white lineindicates the vertical line through the anterior commissure (VAC). Regions showing different SRFs are color-coded. Stimulus intensity-related areas are shown in red, pain intensity-related areas are shown in green, and cognitive processing-related areas are shown in blue. The top row shows an area in the dorsal pACC with a stimulus intensity-related (red) SRF. The middle row shows the cognitive processing-related step function response of a region in the cingulate sulcus of the aACC (blue). The bottom row shows the SRF of a pain intensity-related area in the ventral pACC (green). (Figure legend continues.)(Figure legend continued.) Themiddle column shows the individual SRF for each region. Fitting canonical HRFs (see Materials and Methods for details) to the data yields a regression coefficient indicating the magnitude of the response for each trial type (P0–P4). This magnitude (±SEM) plotted as a function of rating is the SRF. In the right column, adjusted data in each region are plotted in bins of 2 sec as a function of peristimulus time separately for P0–P4. In b, the motor-evoked hemodynamic response in the CMA is plotted. Additional motor-evoked responses were observed in the SMA.