High frequency electrical stimulation induces a long-lasting enhancement of event-related potentials but does not change the perception elicited by intra-epidermal electrical stimuli delivered to the area of increased mechanical pinprick sensitivity

Abstract

High frequency electrical stimulation (HFS) of the skin induces increased pinprick sensitivity in the surrounding unconditioned skin. The aim of the present study was to investigate the contribution of A-fiber nociceptors to this increased pinprick sensitivity. For this we assessed if the perception and brain responses elicited by low-intensity intra-epidermal electrical stimulation (IES), a method preferentially activating Aδ-fiber nociceptors, are increased in the area of HFS-induced increased pinprick sensitivity. HFS was delivered to one of the two forearms of seventeen healthy volunteers. Mechanical pinprick stimulation and IES were delivered at both arms before HFS (T0), 20 minutes after HFS (T1) and 45 minutes after HFS (T2). In all participants, HFS induced an increase in pinprick perception at the HFS-treated arm, adjacent to the site of HFS. This increase was significant at both T1 and T2. HFS did not affect the percept elicited by IES, but did enhance the magnitude of the N2 wave of IES-evoked brain potentials, both at T1 and at T2. Our results show that HFS induces a long-lasting enhancement of the N2 wave elicited by IES in the area of secondary hyperalgesia, indicating that HFS enhances the responsiveness of the central nervous system to nociceptive A-fiber input. However, we found no evidence that HFS affects the perception elicited by IES, which may suggest that the population of nociceptors that mediate the perception elicited by IES do not contribute to HFS-induced increased pinprick sensitivity.

Fig 1

A. Experimental set up. High frequency electrical stimulation of the skin (HFS) was applied on either the left or right volar forearm. Intra-epidermal electrical stimuli (IES) were delivered to the left and right volar forearm using a concentric pin electrode, placed adjacent to the HFS electrode. Mechanical pinprick stimuli were applied to the skin surrounding the IES electrode. B. Time-line of the experiment. The effects of HFS on the perception to mechanical pinprick stimuli and the perception and brain responses elicited by IES were assessed at 3 different time points: before HFS (T0), 20 min after HFS (T1), and 45 min after HFS (T2).

Fig 2

A. Distribution of reaction times to intra-epidermal electrical stimuli delivered at all time-points (T0, T1 and T2) and arms (control and HFS). Note that the distribution peaks at latencies compatible with the conduction velocity of Aδ fibers. B. Individual and group-level median (± interquartile ranges) reaction times for each time-point and arm. C. Number of detected trials for each participant at each time-point and arm. Horizontal bar shows the group-level average number of detected trials.

Fig 3

A. Group-level average (± SD) intensity of perception elicited by mechanical pinprick stimuli. B. Individual difference ratings (post-pre) at time point T1 and T2 for control and HFS arm. Asterisks show the significant enhancement of pinprick perception after HFS at the HFS treated arm. *** = p < .001. C. Individual ratings for both arms (control and HFS) at all time points (T0, T1 and T2).

Fig 4

A. Group-level average (± SD) intensity of perception elicited by intra-epidermal electrical stimuli. B. Individual difference ratings (post-pre) at time point T1 and T2 for control and HFS arm. Note that the distribution of the data points at the HFS arm is not bimodal which argues against the existence of two different subgroups (“responders” vs “non-responders”). C. Individual ratings for both arms (control and HFS) at all time points (T0, T1 and T2).

Fig 5

A. Increase in pinprick perception after HFS (respective to baseline and control site) for each participant and ordered according to size, from large to small. B. Increase or decrease in the perception elicited by intra-epidermal electrical stimulation after HFS (respective to baseline and control site) for every participant and according to the order in A. C. Lack of correlation between the increase in pinprick perception and the increase/decrease in the perception to intra-epidermal electrical stimulation.

Fig 6

A. Grand-average global field power of the event-related potentials elicited by intra-epidermal electrical stimulation. The global field power is calculated across all electrodes, conditions and participants. Two ERP peaks can be identified. First, a negative peak appearing between 130 and 230 ms, labelled N2. Second, a positive peak appearing between 280 and 500 ms, labelled P2. The grey squares represent the time window that was used for identifying the N2 and P2 peaks in individual waveforms. B. Group-level average event-related potentials (Cz) elicited by intra-epidermal electrical stimulation before and after applying HFS from both arms.

Fig 7

A. Group-level average (± SD) magnitude of the N2 wave elicited by intra-epidermal electrical stimuli before and after HFS at the two arms. B. Group-level average (± SD) magnitude of the N2 wave for the 9 participants that detected the stimulus in more than half of the trials for each condition. C. Individual difference ratings (post-pre) at time point T1 and T2 for control and HFS arm. Black dots represent the participants that detected at least half of the stimuli in every condition, whereas the grey dots represent the participants that detected less than half of the stimuli. A negative or positive value indicates an enhancement or decrease of the N2 wave, respectively. Asterisks show the significant enhancement of the N2 wave after HFS at the HFS treated arm. ** = p < .01. Grey line refers to the main analysis (all participants) whereas the black lines refer to the additional analysis (participants that detected at least half of the stimuli). D. Individual magnitudes of the N2 wave for both arms (control and HFS) at all time points (T0, T1 and T2).

Fig 8

A. Increase or decrease in magnitude of the N2 wave of IES-evoked brain potentials after HFS (respective to baseline and control site) for every participant. B. Lack of correlation between the increase in pinprick perception and the change in magnitude of the N2 wave of IES-evoked brain potentials.