Exploration of the effects of HFS-induced secondary hyperalgesia on the NDT-EP method with paired probing stimuli

In Europe, pain is considered the major cause of disability and disease burden
affecting 20.27% of the population over 18 years of age. A class of syndromes
characterized by a persistent pain lasting over normal healing times is defined
as Chronic Pain Syndromes. Central sensitivity is a phenomenon associated to
chronic pain and is defined by the occurrence of unpleasant sensations in
response to normally-innocuous stimuli. The increased sensitivity over an
injured area is known as primary hyperalgesia, whereas the spreading of
sensitization to an uninjured, adjacent region is called secondary
hyperalgesia. The underlying mechanism of secondary hyperalgesia is also
addressed as central sensitization, since sensitized neurons are located in the
central nervous system (i.e. dorsal horn of the spinal cord) and contribute to
neurogenic hyperalgesia. Thus, investigating the alteration of nociceptive
processing might yield to an understanding of the mechanisms generated by
central sensitization and resulting in secondary hyperalgesia. However, further
investigation of underlying mechanisms occurring in central sensitization has
been challenging due to the lack of an objective measure of peripheral and
central sensitivity.

In general it is difficult to measure how much pain one is experiencing as
numerical scores are dependent on personal experiences and thus subjective.
Over the past few years, the BSS group of University of Twente has developed
the NDT-EP a new method for combined observation of Nociceptive Detection
Thresholds (NDT) and Evoked Potentials (EP) to investigate brain activation in
response to nociceptive stimuli via intra-epidermal electrocutaneous
stimulation (IES). Several studies with the NDT-EP methods have demonstrated
differences between patients and pain-free subjects and treatment effects. A
next step is to link these findings to well-known mechanisms underlying changes
in the nociceptive function, like central sensitization, which can be studied
using experimentally induced secondary hyperalgesia. The High Frequency
Stimulation (HFS) paradigm is an established and well characterized
experimental model for induction of secondary hyperalgesia. Therefore, the goal
of this study is to explore HFS induced changes in NDT-EP measurement results
in pain-free subjects. For this purpose, the NDT-EP method is extended with a
paired probing feature to also capture the coding of well-defined
suprathreshold stimuli simultaneously in the evoked potentials.

The primary objectives are to describe NDTs from double pulse IES stimuli
before and 20 minutes after HFS induced secondary hyperalgesia, as verified by
responses to mechanical pinprick stimuli, and describe EPs of detected double
pulse IES stimuli and of paired quadruple pulse IES stimuli of equal amplitude.

The secondary objective is to evaluate the effects of HFS on nociceptive gating
(threshold) and coding (EP) by comparing pre- and post-HFS NDT and EPs, and EPs
from double and quadruple pulse stimuli.

Mono-center, cross-sectional study

All participants will be asked to come to the Human Physiology Lab of the BSS
Group at the University of Twente for one session that is split up in two
parts. In the first part, the participant is familiarized with the stimuli of
the IES electrode during the NDT-EP measurement by stepwise application of
increasing stimuli until the sensation is clearly felt and with one train of
HFS. HFS trains induce a painful but short sensation and are generally
experienced as the most unpleasant part of the experiment. After the first part
of the experiment, the subject is invited to proceed with the second part of
the experiment.

In the second part of the NDT-EP method will be performed. The participant will
receive randomized stimuli around the detection threshold and suprathreshold
according to the paired probing paradigm. The sensations of these stimuli are
best described as brief pinpricks. Next five trains of HFS are administered
after which a second series of the NDT-EP and paired probing stimuli are given.
During the entire duration of the experimental session cortical activity of the
subject will be recorded using an EEG cap. The participants will obtain no
direct personal benefit for their personal health but will be compensated for
their participation.