Exploration of the effects of high frequency stimulation induced secondary hyperalgesia on the NDT-EP method.

Chronic pain often is results from disturbed processes in the central nervous
system. Once chronic pain is established, treatment is relatively ineffective,
with * at best * one patient in three or four achieving 50% pain intensity
reduction. Early detection and therapeutic action would mean better treatment
outcome and less clinical efforts per patient, but appropriate diagnostic tools
are lacking. An increased sensitivity to noxious stimuli is widely recognized
as a key factor in chronic pain development. Noxious stimuli are processed by
neural mechanisms at several stages in the ascending pathway from periphery to
brain, into a conscious pain experience. As a response to injury or disease,
maladaptive changes in this pathway may result in an increased pain
sensitivity. Clinical observation of the specific malfunctioning of peripheral
and central components of this pathway is limited at present, but would permit
a better understanding and early selection of interventions for treatment or
prevention of chronic pain. Recently, we developed a new method for observing
the properties of nociceptive processing utilizing subjective detection of
electrocutaneous stimuli in combination with objective neurophysiological brain
responses (NDT-EP). In this method, nociceptive afferents are activated by
temporally defined current stimuli with varying number of pulses and varying
inter pulse intervals. As these different temporal stimulus properties result
in different excitation of nociceptive processing mechanisms of the ascending
system, subsequent processing of stimulus-response pairs (SRPs) into estimated
nociceptive detection thresholds (NDTs) and Evoked brain Potentials (EPs) of
multiple stimulus types may provide information about the properties of these
mechanisms.

A crucial step in exploring whether the above method could serve as a
diagnostic tool is the assessment of the observability of changes in
nociceptive function which are relevant for the development or maintenance of
chronic pain. This can be achieved by measuring the effect of a well
characterized and demonstrated alteration in nociceptive processing mechanisms
on the NDTs and EPs. Other research groups have demonstrated that high
frequency electrocutaneous stimulation (HFS) of sufficient duration and
intensity can be used for prolonged activation of central sensitization
mechanisms. These central sensitization effects are observed as a post-HFS
secondary hyperalgesia to pin-prick stimuli and considered to play a key role
in the development of chronic pain. Other results show that HFS also modulates
the EPs obtained by electrocutaneous stimulation on the site of induced
secondary hyperalgesia. Recently during a pilot study here at the University of
Twente, we have assessed that HFS is technically feasible to implement in our
lab. Therefore, the next step is to use HFS in an experiment together with the
NDT-EP method.

The primary objective of this study is to investigate the quality and content
of the MTT-EP model in response to electrocutaneous stimuli by determining
stimulus-related and/or physiological-related components, before and after the
occurrence of HFS-induced central sensitization onto the skin of healthy
subjects.

The current study is a mono-center, cross-sectional study. Each subject will
undergo a single measurement session.
Each Measurement Session (155 minutes) consists of:
* Introduction (10 minutes): The subject will be provided with information
about the experiment and asked for consent to participate in the experiment.

* Preparation (20 minutes): The subject will be connected to the EEG equipment
and the nociceptive stimulation device.

* Familiarization (10 minutes): The subject will be familiarized with the
stimuli. In this phase, the subject can get used to determining whether a
stimulus exceeds the stimulation threshold, and learn how to behave during the
experiment.

* 1st punctate mechanical stimulation (2 minutes): The target for the
mechanical pinpricks are marked and the first mechanical stimulation is
performed.

* Experiment (103 minutes): The actual experiment, in which nociceptive
stimulus-response pairs will be measured for a variety of nociceptive stimuli.
- 35 minutes: first NDTs acquisition
(both arm and hand)
- +2 minutes: 2nd punctate mechanical
stimulation
- +5 minutes: HFS and assessment of
perceived pain
- +2 minutes: right after HFS for 3rd
pinprick stimulation
20
minutes break
- +2 minutes: 4th pinprick stimulation
- +35 minutes: second and final NDTs
acquisition (both arm and hand)
- +2 minutes: 5th and final punctate
mechanical stimulation

* Round-Up (10 minutes): Disconnection and debriefing of the subject.

The healthy participants will be asked to come to the Human Physiology Lab of
the BSS Group at the University of Twente for one session. First, the
participant is familiarized with the stimuli by stepwise application of
increasing stimuli until stimulus detection. During the experiment, the
participant will receive randomized stimuli around the detection threshold
according to the multiple threshold tracking paradigm. Afterwards, HFS is
applied to induce secondary hyperalgesia. Lastly, the subjects will receive a
second series of randomized stimuli around the detection threshold according to
the MTT paradigm. During the entire duration of the experimental session,
cortical activity of the subject will be recorded using an EEG cap. All
participants will be compensated for their participation. The participants will
obtain no direct personal benefit.