Brain activation during input from mechanoinsensitive versus polymodal C-nociceptors

Abstract

C-nociceptors mediating cutaneous pain in humans can be distinguished in mechano-heat-responsive units (CMH) and mechano-insensitive units (CMi). However, if sensitized in damaged tissue, CMi play an important role in inflammatory pain. CMi differ from CMH by higher electrical thresholds and by mediating the axon reflex. Using these properties, we established two stimulation paradigms: (1) transcutaneous stimulation (TCS) of low current density below the CMi threshold and (2) intracutaneous stimulation (ICS) of high current density that excites CMi. This was proven by the quantification of the axon-reflex flare. Applying these stimulation paradigms during functional magnetic resonance imaging, we investigated whether nociceptor stimulation that recruits CMi leads to different cerebral activation than stimuli that do not recruit CMi. Brain activation by CMi was inferred by subtraction. Both stimuli recruited multiple afferents other than CMi, and we expected a common network of regions involved in different aspects of pain perception and motor nocifensive reactions in both stimuli. ICS that additionally recruited CMi should activate regions with low acuity that are involved in pain memory and emotional attribution. Besides a common network of pain in both stimuli, TCS activated the supplementary motor area, motor thalamic nuclei, the ipsilateral insula, and the medial cingulate cortex. These regions contribute to a pain processing loop that coordinates the nocifensive motor reaction. CMi nociceptor activation did not cause relevant activation in this loop and does not seem to play a role in withdrawal. The posterior cingulate cortex was selectively activated by ICS and is apparently important for the processing of inflammatory pain.

Figure 1.

Positioning of the EPI slices for the collection of the functional data. The block consisted of 16 slices, each with a thickness of 4 mm. The scan time was a repetition time of 2.5 s per block.

Figure 2.

Flare reactions in the skin of the dorsum of the foot. a, Baseline-subtracted LDIs from one representative subject for ICS (top block of records) and TCS (bottom block of records). Recording of each scan started at the time in seconds indicated in the white boxes. The ROI and electrode positions are depicted in the first image (baseline). A stimulus that lasted 20 s (ICS, 8 mA; TCS, 25 mA; rating 7) was applied during the second picture. Pictures 3–7are poststimulus scans. Altogether, a time frame of 210 s after stimulation is covered. Flux values are encoded by the pixel color. The corresponding flux values are displayed in the scale on the right. After ICS, a pronounced flux increase could be observed, whereas TCS did not provoke changes in the LDF signal. b, Mean flux time courses of all subjects (n = 10) at rating 7 (squares) and rating 3 (triangles) for ICS (filled symbols) and TCS (open symbol). SEs are displayed. The black box marks the stimulus application time. ICS provokes a significant increase of flux with a maximum at 90–120 s after the onset of stimulation. The increase is significantly larger at rating 7 than at rating 3. TCS does not provoke flux increase at any level of stimulation. Thus, only flux at rating 7 is displayed. c, Map of the electrode positions for the LDI trial: needle electrodes for ICS are exemplary displayed on the dorsum of the left foot, and surface electrodes for TCS exemplary displayed on the dorsum of the right foot. Scanned fields are plotted in blue. These scanned fields correspond to the displayed area in a.

Figure 3.

Multi Studies of activations by both stimuli in a standardized Talairach brain. Activation by ICS is plotted in red; activation by TCS is plotted in green. Common activation by ICS and TCS is shown in yellow. This sagittal slice shows activation in the cingulate cortex, thalamus, and cerebellar vermis. Only ICS activates the PCC, whereas TCS dominates in the MCC. The mean relative changes of the BOLD signals in the MCC and PCC during the stimuli are plotted on the left: the time courses over the five stimulation periods are averaged for all subjects. They include 15 s before the 20 s stimulation period and 20 s after stimulation. TCS (green frame) and ICS (red frame) activations are linked to the corresponding clusters. The BOLD signal of the left hemisphere is plotted in black, and the BOLD signal of the right side is plotted in blue. Stimulation periods are indicated by the gray bars on the x-axis.

Figure 4.

Multi Studies as in Figure 3. Activation by ICS and by TCS is in red and green, respectively, and common activation is in yellow. BOLD signals of the left hemisphere are plotted on the right side and are contralateral to the stimulus. a, This axial slice shows that insular activation by ICS is strictly contralateral, whereas TCS activates the MIC in both hemispheres. S2 activation is found bilaterally during both types of stimulation. b, This axial slice shows bilateral thalamus activation in both stimuli. Thalamus activation by TCS activation is rostral to ICS activation. Activation over time is plotted for the medial and PIC (a) and the thalamus (b). The time courses over the five stimulation periods are averaged for all subjects. They include 15 s before the 20 s stimulation period and 20 s after stimulation. TCS (green frame) and ICS (red frame) activations are linked to the corresponding clusters. The BOLD signal of the left hemisphere is plotted in black, and the BOLD signal of the right side is plotted in blue. Stimulation periods are indicated by the gray bars on the x-axis.

Figure 5.

Multi Studies as in Figure 3. Activation by ICS and TCS is in red and green, respectively, and common activation is in yellow. a, This axial slice shows activation in the contralateral brainstem and the cerebellar vermis. b, This axial slice shows bilateral activation in the AC during both types of stimulation. Activation over time in is plotted for brainstem (a) and cerebellum (b). The time courses over the five stimulation periods are averaged for all subjects. They include 15 s before the 20 s stimulation period and 20 s after stimulation. TCS (green frame) and ICS (red frame) activations are linked to the corresponding clusters. The BOLD signal of the left hemisphere is plotted in black, and the BOLD signal of the right side is plotted in blue. Stimulation periods are indicated by the gray bars on the x-axis.