Temporal summation of heat pain in humans: Evidence supporting thalamocortical modulation

Abstract

Noxious cutaneous contact heat stimuli (48 degrees C) are perceived as increasingly painful when the stimulus duration is extended from 5 to 10s, reflecting the temporal summation of central neuronal activity mediating heat pain. However, the sensation of increasing heat pain disappears, reaching a plateau as stimulus duration increases from 10 to 20s. We used functional magnetic resonance imaging (fMRI) in 10 healthy subjects to determine if active central mechanisms could contribute to this psychophysical plateau. During heat pain durations ranging from 5 to 20s, activation intensities in the bilateral orbitofrontal cortices and the activation volume in the left primary (S1) somatosensory cortex correlated only with perceived stimulus intensity and not with stimulus duration. Activation volumes increased with both stimulus duration and perceived intensity in the left lateral thalamus, posterior insula, inferior parietal cortex, and hippocampus. In contrast, during the psychophysical plateau, both the intensity and volume of thalamic and cortical activations in the right medial thalamus, right posterior insula, and left secondary (S2) somatosensory cortex continued to increase with stimulus duration but not with perceived stimulus intensity. Activation volumes in the left medial and right lateral thalamus, and the bilateral mid-anterior cingulate, left orbitofrontal, and right S2 cortices also increased only with stimulus duration. The increased activity of specific thalamic and cortical structures as stimulus duration, but not perceived intensity, increases is consistent with the recruitment of a thalamocortical mechanism that participates in the modulation of pain-related cortical responses and the temporal summation of heat pain.

Figure 1

Summary of data acquisition protocol during the fMRI experiment. The sequence of sessions was counterbalanced among subjects (N = 10). Each stimulus was applied to previously unstimulated skin in each session. Two 30s periods bracketed the 30s stimulation period during each epoch. See text for details.

Figure 2

A. The average COVAS curves of real-time stimulus intensity ratings during the psychophysical experiment. Designated pain threshold is 50. At 43°C (blue curves), the perceived sensation is warm and never painful regardless of stimulus duration. At 48°C, the perceived sensation is increasingly painful when the stimulus duration is extended from 5 to 10s (thin orange and red curves). However, as the duration increases beyond 10 to 20s, the peak perceived intensity does not increase further but remains nearly constant throughout the remainder of the 20s stimulus (thick red curve). The time of the stimulus plateau at 48°C begins ~ 2.5s after stimulus onset and is shown for the 5 (blue bar), 10 (blue + green bars), and 20 s (blue + green + red bars) duration stimuli. B. Normalized (to the rating of 5s duration stimuli) individual peak COVAS ratings of 48°C stimuli of each of the 14 subjects participating in the psychophysical experiment. C. Mean and SE of peak COVAS ratings of 48°C stimulation of all subjects at 5, 10, and 20s duration stimuli in the psychophysical experiment. D. Mean and SD of duration, peak, and area under the curve (AUC) of COVAS curves at 48°C. At 48°C, the COVAS peak of 10s and 20s durations are significantly different from that of the 5s duration stimulus (asterisk; P < 0.001); however, the ratings of 10s vs. 20s are not significantly different (P = 0.413). At 43°C, the COVAS peaks of 5, 10 and 20s stimulation (not shown) are not significantly different.

Figure 3

Activations (Z > 2.0; see color bar at lower right) during increasing durations of noxious contact heat stimulation at 48°C. Images in this and subsequent figures are shown in MNI space. As the stimulus duration increases from 5s to 20s, activations shift from the anterior and pregenual cingulate, anterior insular, orbitofrontal, medial prefrontal, and dorsal lateral prefrontal cortices to the posterior insular cortex and thalamus. In addition, an early activation of the right inferior parietal lobule (red circle; MNI coordinates: 54, −44, 40) is replaced by late activation of the leg area of S1 cortex (blue circle; MNI coordinates: −8, −38, 58). The time series at right shows the right medial thalamic average (and std.error) BOLD signals increasing in amplitude as stimulus duration increases. Although we used the same hemodynamic response function model to extract BOLD responses from all VOI, thalamic activity did not pass statistical threshold during the 5s stimulation (see Figure S2 in supplementary on-line material).

Figure 4

Activation contrasts (Z > 2.0) during contact heat stimulation at 48°C. Consistent with the main effects, the 5s-20s comparisons (top row) show greater activity in the ACC, OFC and DLPFC of the frontal cortex during the 5s, compared to the 20s stimulus duration. The 20s-5s contrast, however (lower row), shows greater activity in the bilateral posterior insular cortex and thalamic nuclei during the 20s stimulus compared to the 5s stimulus.

Figure 5

Average (+/− s.d.) percentage changes in COVAS ratings and in BOLD and voxel counts during changes in stimulus duration from 5s to 10s and from 10s to 20s (during the psychophysical plateau). A. COVAS ratings increase early but show no increase, and even a slight decrease, as stimulus duration increases from 10s to 20s. B. Changes in the peak BOLD signals in the right and left orbitofrontal cortices correlate with the COVAS changes but not with stimulus duration (see Table 2). C. Voxel count changes in the left S1 cortex also correlate with COVAS changes but not with stimulus duration (see Table 2). D. In contrast, both voxel count changes (not shown) and BOLD signal changes in the right medial thalamus, posterior insula, and left S2 cortex correlate with increases in stimulus duration but not with changes in COVAS rating (see Table 2).

Figure 6

Diagrammatic representation of the estimated 20 s time courses of neuronal action potential activity during prolonged (~30 s) cutaneous heat stimulation within the noxious range (47-53°C). The frequency of action potentials (Hz) is shown on the same ordinate scale as the real-time COVAS ratings obtained during the psychophysical experiment and shown in Figure 2A. Time courses of the stimulus plateaus in this study are shown above the COVAS curves as increasingly dark bars for the 5, 10, and 20 s duration stimuli (48°C). Peripheral primate nerve fiber activities shown are: dashed line, type 1 Aδ heat nociceptors; dash-dot line, type 2 Aδ and rapidly adapting C heat nociceptors; dotted line, slowly adapting C heat nociceptors (SCs); activity estimates are derived from text and Figure 3 of reference [ 71 ] and Figure 2 of reference [ 44 ]. The peaks of primate central pathway activities (colored ellipses) are shown at equal levels of 30 Hz (arbitrarily chosen for illustrative purposes) followed by the estimated time course of adaptation during the 20 s stimulus. Blue, spinothalamic tract (STT) neurons (activity estimates derived from text and Figure 7 of reference [ 32 ]); green, ventral posterior lateral thalamic neurons (THAL) (activity estimates derived from text and Figure 5 of reference [ 29 ]); red, primary somatosensory (S1) cortical neurons (CTX) (activity estimate is derived from text and Figures 4 and 5 of reference [ 30 ] showing the overall lack of negative adaptation in these neurons compared to STT and THAL). Note that, even if accounting for additional activity delays in humans, peripheral afferent activity, with the exception of the type 1 Aδ heat nociceptors, declines before continuing at a lower level during the early stimulation period while COVAS ratings are increasing. Similarly, the activity of spinothalamic and thalamic neurons declines during the 5 and 10 s duration stimulation and during the early phase of the 20 s stimulation before reaching a lower level throughout the remaining stimulation period. Cortical activity, however, declines very slowly or not at all during stimulation [ 30 , 31 ] .