Temporal and spatial dynamics of human forebrain activity during heat pain: analysis by positron emission tomography

To learn about the sequence of brain activation patterns during heat pain, we acquired positron emission tomographic (PET) brain scans at different times during repetitive heat stimulation (40 or 50 degrees C; 5-s contact) of each subject's left forearm. Early scans began at the onset of 60 s of stimulation; late scans began after 40 s of stimulation, which continued throughout the 60-s scan period (total stimulus duration 100 s). Each subject (14 normal, right-handed subjects; 10 male, 4 female; ages 18-42) used a visual analog scale to rate the perceived stimulus intensity (0 = no heat, 7 = pain threshold, 10 = barely tolerable pain) after each scan. The 40 degrees C stimulation received an average intensity rating of 2.19 +/- 1.22 (mean +/- SD) and the 50 degrees C an average rating of 8.93 +/- 1.33. During the scan sessions, subjects did not report a difference between early and late scans. To examine the effect of the duration of stimulation specifically, 8 of these subjects rated the perceived intensity of each of 20 sequential 5-s duration contact heat stimuli (40 or 50 degrees C; 100 s of stimulation). We used a graphical method to detect changes in perceived unpleasantness. There was no difference in perceived intensity or unpleasantness during the 40 degrees C stimulation. However, during 50 degrees C stimulation, perceived unpleasantness increased and subjects perceived the last five, but not the second five, stimuli as more intense than the first five stimuli. These psychophysical changes could be mediated by brain structures with increasing activity from early to late PET scans or that are active only during late scans. These structures include the contralateral M1/S1 cortex, bilateral S2 and mid-insular cortex, contralateral VP thalamus, medial ipsilateral thalamus, and the vermis and paravermis of the cerebellum. Structures that are equally active throughout stimulation (contralateral mid-anterior cingulate and premotor cortex) are less likely to mediate these psychophysical changes. Some cortical, but not subcortical, structures showed significant or borderline activation only during the early scans (ipsilateral premotor cortex, contralateral perigenual anterior cingulate, lateral prefrontal, and anterior insular cortex); they may mediate pain-related attentive or anticipatory functions. Overall, the results reveal that 1) the pattern of brain activation and the perception of heat pain both change during repetitive noxious heat stimulation, 2) cortical activity can be detected before subcortical responses appear, and 3) timing the stimulation with respect to the scan period can, together with psychophysical measurements, identify brain structures that are likely to participate in the perception of pain.