Where pain meets action in the human brain

Abstract

Pain's complex influence on behavior implies that it involves an action component, although little is known about how the human brain adaptively translates painful sensations into actions. The consistent activation of premotor and motor-related regions during pain, including the midcingulate cortex (MCC), raises the question of whether these areas contribute to an action component. In this fMRI experiment, we controlled for voluntary action-related processing during pain by introducing a motor task during painful or nonpainful stimulation. The MCC (particularly the caudal cingulate motor zone [CCZ]), motor cortex, thalamus, and cerebellum responded during action regardless of pain. Crucially, however, these regions did not respond to pain unless an action was performed. Reaction times were fastest during painful stimulation and correlated with CCZ activation. These findings are consistent with the results of an activation likelihood estimate meta-analysis in which activation across experiments involving pain, action execution, or action preparation (with a total of 4929 subjects) converged in a similar network. These findings suggest that specific motor-related areas, including the CCZ, play a vital role in the control and execution of context-sensitive behavioral responses to pain. In contrast, bilateral insular cortex responded to pain stimulation regardless of action.

Figure 1.

Design and task. Diagram shows schematic structure of thermal stimulus application (pain or nonpain) and task (press or refrain from pressing a button). Rectangles represent duration of stimulation from onset to offset; the thermode was at target temperature for the entire period in each trial. During stimulation, the task cue (black fixation dot) appeared 1 s before stimulus offset and remained on for 2 s (until 1 s poststimulus offset). On cue appearance participants pressed a button when stimulation was painful (for 2 of the 4 runs) or nonpainful (for the other 2 runs). The intersection of the voluntary button-press task with any pain-related motor potentiation processes was designed to capture behavioral and neural relationships between voluntary action and acute pain processing.

Figure 2.

Behavioral results. A, Mean RTs across painful and nonpainful thermal stimulation for heat and cold, with a significant main effect of pain (p = 0.006) reflecting faster responses during painful stimulation (n = 18). Error bars indicate SEM. B, Continuous ratings of an “urge to move” the hand away from the stimulus and stimulus intensity ratings, across painful and nonpainful thermal stimulation for heat and cold (n = 15). Mean slopes were significantly faster for painful compared with neutral conditions for both movement urge and stimulus intensity ratings (p < 0.001), with sharper rises for heat pain compared with cold pain (p = 0.01). HOT, Painful heat; COLD, painful cold; Warm, nonpainful heat; Cool, nonpainful cold.

Figure 3.

BOLD signal changes regardless of action (left) and driven by action (right) during pain. Top left, Activation map shows bilateral insular activation for the main effect of pain (pain > nonpain, regardless of task). Left bottom, BOLD in anterior insula contralateral to the response hand showed no significant correlation with RTs. Right top, CCZ and cerebellum respond during action regardless of painful stimulation in a conjunction between painful (pain press > pain no-press) and nonpainful (nonpain press > nonpain no-press) action conditions. Right bottom, Trial-by-trial correlation of BOLD and RTs in the CCZ. All activation maps were thresholded at p < 0.005 at a whole-brain–corrected familywise error of p < 0.05 on the cluster level for all voxels in the brain volume. Images are presented in radiological convention, with the left hemisphere shown on the right side.

Figure 4.

Left, BOLD activation contingent on the motor response factor. A, Activation maps for motor responses during painful stimulation (orange) and during nonpainful stimulation (blue), and their overlap (magenta). B, Clusters in the CCZ, thalamus, and cerebellum for action during both painful and nonpainful stimulation (conjunction contrast). C, ALE meta-analysis for intersection of activations reported for cutaneous pain (n = 814), action execution (n = 4019), and action preparation (n = 92). The resulting midcingulate cluster coincides with the CCZ activation in the fMRI experiment. All activation maps were thresholded at p < 0.001 at a whole-brain–corrected familywise error of p < 0.05 on the cluster level for all voxels in the brain volume. ALE maps were thresholded at a false discovery rate of q < 0.05; intersection map thresholded at p < 0.05, corrected. The left hemisphere is shown in all figures. Right, CMZ clusters in single- and double-sulcus variants for pain press contrast. D, Peak pain press activation for the whole group (n = 18) appears in the sulcus. E, Peak activation for single-sulcus variants (n = 12) fell on the dorsal bank of the cingulate sulcus (−2, 16, 35). F, Peak activation for double-sulcus variants (n = 6) fell within the depth of the cingulate sulcus (−5, 4, 39). Activation was thresholded at 20% below the cluster's peak voxel value for each group (t = 5.53 for single, t = 3.72 for double).