C-fiber-related EEG-oscillations induced by laser radiant heat stimulation of capsaicin-treated skin

Abstract

Nociceptive input reaches the brain via two different types of nerve fibers, moderately fast A-delta and slowly conducting C-fibers, respectively. To explore their distinct roles in normal and inflammatory pain we used laser stimulation of normal and capsaicin treated skin at proximal and distal arm sites in combination with time frequency transformation of electroencephalography (EEG) data. Comparison of phase-locked (evoked) and non-phase-locked (total) EEG to laser stimuli revealed three significant pain-related oscillatory responses. First, an evoked response in the delta-theta band, mediated by A-fibers, was reduced by topical capsaicin treatment. Second, a decrease of total power in the alpha-to-gamma band reflected both an A- and C-nociceptor-mediated response with only the latter being reduced by capsaicin treatment. Finally, an enhancement of total power in the upper beta band was mediated exclusively by C-nociceptors and appeared strongly augmented by capsaicin treatment. These findings suggest that phase-locking of brain activity to stimulus onset is a critical feature of A-delta nociceptive input, allowing rapid orientation to salient and potentially threatening events. In contrast, the subsequent C-nociceptive input exhibits clearly less phase coupling to the stimulus. It may primarily signal the tissue status allowing more long-term behavioral adaptations during ongoing inflammatory events that accompany tissue damage.

Keywords: C-fibers; EEG; capsaicin; inflammatory pain; laser; oscillations.

Figure 1

The test procedure comprised eight blocks consisting of 40 laser stimuli of two intensities. Section A) indicates the trial design. The laser was given at time point zero of each trial. Three seconds after the pain stimulus a tone prompted the subjects to verbally rate the perceived pain. Section B) shows the experimental procedure of all eight blocks. One arm (left or right, counterbalanced across subjects) was treated proximally as well as distally with topical capsaicin (0.1% dissolved in 70% ethyl alcohol). The session started with stimulation of the proximal site of the control arm (Block 1) and proceeded with Block 2 at the distal control site (distance between proximal and distal sites = 30 cm). Laser stimuli of Block 3 were applied to the capsaicin treated distal forearm, followed by Block 4 at the capsaicin treated proximal upper arm. 1 repetition, the sites were stimulated in reverse block order, thus started at the proximal capsaicin-treated site and ended at the proximal control site. This procedure minimized confounding effects of site with habituation.

Figure 2

Overview of the data processing flow starting with two steps of artifact elimination procedures applied to the raw data followed by the indicated steps of time frequency transformations to achieve evoked and total TFR plots. The computation of the evoked TFR also included the averaging of the conventional LEP. Abbreviations: LEP, laser-evoked potentials; TFR, time frequency representation.

Figure 3

Evoked and total TFR plots illustrating the effects of topical capsaicin treatment at distal and proximal stimulus sites. For comparison, the LEP at central electrode Cz obtained from stimulation at distal treated and control sites is also shown top left. Time frequency data represent responses from central ROIs averaged across all subjects (N = 16). They are plotted as percentage change of signal amplitude relative to pre-stimulus baseline (−1000 to −200 ms). A) Phase-locked evoked response increase (ER I: 3–7 Hz, 0–500 ms) is diminished by skin sensitization as is the N2–P2 component of the LEP. B) Total TFR also reveals a stimulus-induced increase from 3 to 7 Hz (TR I), which was followed by an alpha-to-gamma decrease (TR II) around 1000 ms (distal). This decrease has two minima (TR IIa, TR IIb), the latter delayed as predicted by C-fiber conduction velocity between proximal and distal stimulus sites and suppressed by topical capsaicin treatment. A later upper beta increase (TR III: 15–30 Hz, 1400–2100 ms, distal) also shows a shift in latency between proximal and distal stimulation that is compatible with C-fiber conduction velocity. It exhibits an enhancement following capsaicin treatment. Abbreviations: LEP, laser-evoked potentials; ROI, region of interest; TFR, time frequency representation.

Figure 4

Summary diagram illustrating putative Aδ (solid circles) and C-nociceptor (broken circles) contributions to enhanced (red) and reduced (blue) oscillatory electroencephalography responses in the indicated frequency ranges and their capsaicin sensitivity.