Central sensitization of nociceptive pathways demonstrated by robot-controlled pinprick-evoked brain potentials
Introduction
Cutaneous tissue injury can be accompanied by increased pain sensitivity in the area of tissue damage (“primary hyperalgesia”) and in surrounding uninjured skin (“secondary hyperalgesia”). Secondary hyperalgesia is most pronounced for mechanical pinprick stimuli (van den Broeke et al., 2016a, Ali et al., 1996) and is the result of an increased responsiveness of nociceptive neurons in the central nervous system (central sensitization) (Baumann et al., 1991, Simone et al., 1991).
To explore the changes in brain activity related to secondary hyperalgesia we previously recorded pinprick-evoked brain potentials (PEPs) before and after intradermal capsaicin injection (van den Broeke et al., 2015). Intradermal capsaicin injection mimics injury and is a well-established method for inducing secondary hyperalgesia (Magerl et al., 1998). In that study, different pinprick intensities, ranging from 16 to 512 mN, were used to characterize the effect of stimulation intensity on PEPs. We found that when pinprick stimuli were applied to the area of increased pinprick sensitivity around the site of injection (i.e. area of secondary hyperalgesia), a late positive peak of the PEP waveform (between 0.2 s and 0.5 s after stimulus onset) was increased. The magnitude of this increase was dependent on the intensity of pinprick stimulation, with the strongest and only significant increase observed for 64 mN pinprick stimuli.
In two follow-up studies we then recorded PEPs before and after transcutaneous high frequency electrical stimulation of the skin (HFS) (van den Broeke et al., 2017, van den Broeke et al., 2016b). Such as capsaicin, HFS also induces a clear increase in mechanical pinprick sensitivity of the skin surrounding the site at which HFS is applied (Klein et al., 2004). Similarly to the results with capsaicin, we observed in both studies an increase in the magnitude of a late positive peak of PEPs when elicited by 64 mN pinprick stimuli delivered to the area of increased pinprick sensitivity. The increase in amplitude was maximal at central-posterior scalp regions (van den Broeke et al., 2016b, van den Broeke et al., 2017).
In these previous studies the signal-to-noise ratio of PEPs was relatively low, and no clear negative peak could be observed before the late positive peak. This could be due to the fact that the pinprick stimuli were delivered to the skin manually, which may affect the reproducibility of the pinprick stimulation. To overcome this, we ran a third follow-up study using a robot-controlled mechanical pinprick stimulator to elicit PEPs before and after HFS at the volar forearm (van den Broeke et al., 2019b). In that study, in addition to a late positive peak which was maximal approximately 320 ms after stimulation onset, we observed an earlier negative peak, which was maximal approximately 120 ms after stimulation onset. Both peaks were prominent at the scalp vertex. Although this negative peak was, on average, increased after HFS, this increase was not significant. A similar negative peak had also been reported by Iannetti et al. (2013). In that study, the magnitude of this negative peak was significantly increased after intradermal injection of capsaicin. One important difference between our study that did not show a significant increase of PEPs after HFS (van den Broeke et al., 2019b) and studies that showed a significant increase after HFS or capsaicin (van den Broeke et al., 2015, van den Broeke et al., 2016b, van den Broeke et al., 2017, Iannetti et al., 2013) was task relevance of the pinprick stimuli. In van den Broeke et al. (2019b), participants were asked to provide an average rating of the pinprick stimuli at the end of the stimulation block, while in the other studies, participants had to provide a rating of the perceived intensity and/or had to indicate the quality of perception after individual pinprick stimuli. Engaging participants in a task requiring to evaluate the perceived intensity and/or quality of the sensation elicited by individual pinprick stimuli increases the task relevance of the stimuli.
The aim of the present study was to assess the effect of HFS on the negative and positive peaks of PEPs elicited by a robot-controlled mechanical pinprick stimulator in conditions where pinprick stimuli are made task relevant by asking participants to evaluate their quality of perception and perceived intensity.
Section snippets
Participants
Sixteen healthy volunteers took part in the experiment. In two subjects, technical problems led to a loss of stimulation triggers or loss of EEG data in one of the two recording sessions. Data from these two subjects was discarded. Therefore, the data presented here consists of the remaining fourteen subjects (9 men and 5 women; aged 18 – 27 years; 21.9 ± 2.3 years [mean ± sd]). “The experiment was conducted according to the declaration of Helsinki (except preregistration of the trial).
Perceived pinprick intensity
In agreement with previous studies, HFS induced an increase in pinprick sensitivity of the skin surrounding the site at which HFS was applied (Fig. 2). This was confirmed by a paired-t-test between the individual NRS scores elicited by the pinprick stimuli before versus after HFS (t (13) = 3.778, p = .0012, Cohens dz = 1.010).
Quality of perception
Before applying HFS, pinprick stimuli were qualified as ‘pinprick’ in approximately 50% of the trials, and as ‘touch’ in the remaining 50% of the trials (Fig. 2C and
Discussion
The present study shows that robot-controlled mechanical pinprick stimuli elicit both an early-latency negative peak maximal at the scalp vertex (Cz) and a later-latency positive peak maximal at the more posterior electrode (CPz). Both peaks were significantly enhanced after HFS.
Whereas we did not observe a significant increase in PEPs in our previous study (van den Broeke et al., 2019b) we do here. In both studies we used robot-controlled pinprick stimuli to elicit PEPs before and after HFS.
Declaration of Competing Interest
The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
Acknowledgements
EvdB is supported by the Fonds de Recherche Cliniques (FRC) of the Université catholique de Louvain (UCL), Brussels, Belgium.
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Authors contributed equally.