Central Sensitization of Mechanical Nociceptive Pathways Is Associated with a Long-Lasting Increase of Pinprick-Evoked Brain Potentials

Emanuel N van den Broeke, Julien Lambert, Gan Huang, André Mouraux, Emanuel N van den Broeke, Julien Lambert, Gan Huang, André Mouraux

Abstract

Intense or sustained nociceptor activation, occurring, for example, after skin injury, can induce "central sensitization," i.e., an increased responsiveness of nociceptive neurons in the central nervous system. A hallmark of central sensitization is increased mechanical pinprick sensitivity in the area surrounding the injured skin. The aim of the present study was to identify changes in brain activity related to this increased pinprick sensitivity. In 20 healthy volunteers, increased pinprick sensitivity was induced using high frequency electrical stimulation of the forearm skin (HFS). Mechanical pinprick stimulation (64 and 90 mN) was used to elicit event-related brain potentials (ERPs). The recordings were performed before, 20 min after and 45 min after applying HFS. The contralateral non-sensitized arm served as control. Pinprick stimulation of 64 mN, but not 90 mN, applied in the area of increased pinprick sensitivity elicited a significant increase of a late-latency positive wave, between 300 and 1100 ms after stimulus onset and was maximal at midline posterior electrodes. Most importantly, this increase in EEG activity followed the time course of the increase in pinprick perception, both being present 20 and 45 min after applying HFS. Our results show that the central sensitization of mechanical nociceptive pathways, manifested behaviorally as increased pinprick sensitivity, is associated with a long-lasting increase in pinprick-evoked brain potentials provided that a 64 mN stimulation intensity is used.

Keywords: brain; central sensitization; evoked potentials; hyperalgesia; mechanical; pinprick.

Figures

Figure 1
Figure 1
Experimental setup. (A) High frequency electrical stimulation of the skin (HFS) was applied to the left or right volar forearm. Two different intensities of pinprick stimulation (64 and 90 mN) were applied to the skin surrounding the area onto which HFS was applied as well as to the same skin area on the contralateral arm, which served as control. (B) The electrode used to deliver HFS consisted in 16 blunt stainless steel pins placed in a 10-mm diameter circle (cathode), surrounded by a concentrically-located stainless steel anode. (C) The effect of HFS on the responses elicited by the pinprick stimuli was assessed at three different time points: before HFS (T0), 20 min after HFS (T1) and 45 min after HFS (T2).
Figure 2
Figure 2
(A) Design of the custom-build mechanical pinprick stimulator used to record pinprick-evoked potentials. (B) Calibration protocol for the mechanical pinprick stimulus. Each trial started with a 200 ms baseline period. Subsequently, the probe, moved during 300 ms downwards to the force transducer. Then, the probe was maintained at this position for 1000 ms and withdrawn back to its initial position during 300 ms. A total of 30 trials were recorded. (C) Time course of the normal force generated against the force transducer with and without overlying soft tissue using the two different pinprick intensities (64 and 90 mN). The black line shows the average force across the thirty trials. The gray area shows the standard deviation.
Figure 3
Figure 3
Effect of HFS on intensity of perception elicited by the two pinprick intensities (64 and 90 mN). Shown are the group-level mean and standard deviation of the numeric rating scale (NRS) scores obtained at the three different time points: before HFS (T0), 20 min after HFS (T1) and 45 min after HFS (T2). Asterisks denote a statistically significant increase of the HFS treated arm compared to T0 (p < 0.001, post-hoc paired t-test).
Figure 4
Figure 4
The effect of HFS on PEPs elicited by 64 mN pinprick stimulation. (A) The first row of scalp topographies shows the temporal evolution of the group-level average topography of the difference between the subtracted waves (T1 minus T0) of both arms for T1. Red denotes an increase of the ERP amplitude at the HFS arm compared to the control arm whereas blue indicates a decrease of ERP amplitude at the HFS arm compared to the control arm. Each topographic plot corresponds to the average amplitude within successive segments of 200 ms. The second row of scalp topographies shows the same topographies, masked by the spatiotemporal pattern of the significant clusters identified using the spatiotemporal cluster-based permutation testing. Masked means that only the time-electrode samples included in the significant clusters are displayed. The third row of scalp topographies shows the temporal evolution of the group- level average topography of the difference between the subtracted waves (T2 minus T0) of both arms for T2. The fourth row of scalp topographies shows those topographies masked using the spatiotemporal pattern of the significant clusters. Scalp topographies were corrected (flipped) according to the side of HFS stimulation. (B) Group-level average ERP waveforms of the signals measured from Pz vs. M1M2, before HFS (T0), 20 min after HFS (T1) and 45 min after HFS treatment (T2) and group-level average difference waveforms (T1–T0 and T2–T0) for the control arm (blue) and the HFS-treated arm (red). Gray shadings indicate the time intervals of the significant clusters shown in (A).
Figure 5
Figure 5
Average (and SEM) group-level increase of the intensity of perception (A) and event-related potential amplitude, i.e., mean value of cluster 1 (B) respective to baseline and control site for both T1 and T2.
Figure 6
Figure 6
Group-level average ERP waveforms measured from Pz vs. M1M2, before HFS (T0), 20 min after HFS (T1) and 45 min after HFS treatment (T2), as well as the difference waveforms, for both the control arm (blue) and HFS-treated arm (red) for the 90 mN pinprick intensity.

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