Identifying brain activity specifically related to the maintenance and perceptual consequence of central sensitization in humans

Abstract

Central sensitization (CS) refers to an increase in the excitability of spinal dorsal horn neurons that results from, and far outlasts the initiating nociceptive input. Here, functional magnetic resonance imaging was used to examine whether supraspinal activity might contribute to the maintenance of CS in humans. A crossover parametric design was used to distinguish and control for brain activity that is related to the consequence of increased pain experienced during CS. When the intensity of pain during CS and normal states were matched, only activity within the brainstem, including the mesencephalic pontine reticular formation, and the anterior thalami remained increased during CS. Further analyses revealed that activity in the isolated brainstem area correlated positively with the force of noxious stimulation only during CS, whereas activity in the isolated thalamic area was not modulated parametrically in either CS or normal states. Additionally, the mean activity in the isolated brainstem area was increased only during CS, whereas the mean activity in the isolated thalamic area was increased in both states, albeit less so in the normal state. Together, these findings suggest a specific role of the brainstem for the maintenance of CS in humans. Regarding brain areas related to the consequence of increased pain perception during CS, we found that only cortical activity, mainly in the primary somatosensory area, was significantly correlated with intensity of pain that was attributable to both the force of noxious stimulation used and state in which noxious stimulation was applied.

Figure 1.

Top, Mean (SD) numeral rating scale (NRS) pain intensity scores over time after intradermal capsaicin. Bottom, Psychophysical stimulus response functions for punctate stimulation of the control (gray) and capsaicin-injected (black) sites for 12 subjects. Each subject is represented by a different symbol. The mean (SD) VAS scores of pain intensity that was associated with each force are plotted. There was a significant effect of force and capsaicin in all subjects (p < 0.01). The pair of forces adjoined by the black line had means that were least different.

Figure 2.

Top, Group-averaged activation maps for punctate forces [(in mN) 64, 128, 256, 512] for control (con) and hyperalgesic state (cap). Maps are displayed as axial slices (MNI Z-coordinates) along a vertical strip. Activity in brainstem and thalamus were significant only in the hyperalgesic state. Bottom, Group mean (SD) VAS scores of pain intensity associated with punctate forces [(in mN) 64, 128, 256, 512] in the control (blue) and capsaicin-treated (red) areas. There was a significant effect of force and capsaicin on the group mean VAS scores of pain intensity (repeated-measures ANOVA; main effects p < 0.01; no interaction).

Figure 3.

Top row, left, VAS scores of pain intensity (averaged across all forces) for each subject (represented by different symbols) during punctate stimulation in control (con) and capsaicin-treated areas (cap). Right, Paired comparison showing increased activity in the hyperalgesic state compared with the normal state for the overall effect of force. Bottom row, left, Punctate forces (represented by color) with the least different VAS scores during control and capsaicin sessions for each subject. Each subject is represented by the symbol previously used in Figure 1. Right, Paired comparison of the corresponding activation maps showing increased activity in the hyperalgesic state compared with the normal state. The MNI coordinates for each brain slice are indicated between the top and bottom rows.

Figure 4.

Localization of the clusters showing increased activity in the hyperalgesic state compared with the normal state. The right, top-most image shows where activity is increased in the midsaggital section of the brainstem and thalamic areas. Blue lines indicate where the axial slices are positioned. The MNI Z-coordinate for each axial slice is indicated in blue. Annotated diagrams (Duvernoy, 1995) that correspond to each axial slice are included to guide anatomical localization in the brainstem. VTA, Ventral tegmentum area; SN, substantia nigra; RN, red nucleus; mRF, mesencephalic reticular formation; pRF, pontine reticular formation; PN, pontine nuclei.

Figure 5.

Top, The percentage of BOLD signal change in the brainstem increased significantly with increasing force in the hyperalgesic state only (p = 0.03; 95% confidence intervals shown). Bottom, The mean percentage of BOLD signal change in the brainstem during punctate stimulation across all forces was not significantly different (p = 0.1) from zero in the normal state. Two-tailed, one sample t tests were performed. Means and SDs are shown. ns, Nonsignificant. **p < 0.0001.

Figure 6.

The brain areas in which activity correlated positively with the perception of pain intensity across the normal and CS states are shown in green. Within these areas, activity in the contralateral primary somatosensory correlated with perception of pain intensity associated with punctate stimulation during CS (shown in red) and in the normal state (shown in blue).