Observing Electrical Brain Responses during Processing of Nociceptive Stimuli around the Detection Threshold combined with a Cold Pressor Test: an Explorative Study

The development of treatments for chronic pain requires a more profound
understanding of the physiological and psychological aspects of chronic pain.
Several types of chronic pain, including FBSS, are linked to increased
sensitivity of the central nervous system. Therefore, it is important to study
the underlying mechanisms of this increased sensitivity. However, one major
obstacle is the lack of an objective measure of peripheral and central
sensitivity. Besides hampering the development of new treatments, this causes
inaccuracies in chronic pain diagnoses, resulting in delayed or unnecessary
treatments. Tracking detection thresholds of nociceptive specific
electrocutaneous stimuli can facilitate the investigation of the underlying
mechanisms of sensitization.

Recently, a subjective method was developed for tracking multiple
psychophysical thresholds over time, referred to as multiple threshold tracking
(MTT), which has been shown sensitive to central changes in nociception. An
objective measure of nociception related activity in the central nervous system
is the electroencephalographic (EEG) signal. Multiple-trial averages of this
signal, referred to as evoked potentials (EPs), have been shown to reflect
nociceptive sensitivity tochanges in stimulus parameters. Since MTT has been
shown to be effective in measuring the effect of stimulus parameters on
stimulus detection, while the EP has been shown to reflect neurophysiological
activity related to stimulus processing, a combination of both techniques might
provide insight into the relation between neurophysiological activity and
nociceptive stimuli. We have recently investigated this relationship in healthy
subjects in a study at Biomedical Signals and Systems at the University of
Twente (approved by the METC Twente numbered NL62721.044.17). In this research,
it was shown that components of the EP are closely related to the stimulus
detection.

Furthermore, research has shown that the descending pathways seem to show an
crucial role in the modulation of pain. In this study we try to activate these
pathways by applying a cold pressor test to see how this test will affect the
detection threshold and to what extent pain is modulated (Conditioned Pain
Modulation, CPM). Results from the MTT-EP method combined with CPT are needed
to validate the measurement technique in pain-free subjects. Next, it is
important to explore the feasibility in chronic pain patients. Subsequently,
results may contribute to provide insight into the underlying pathophysiology
of chronic pain.

A similar study has been performed at the University of Twente whereby a cold
pressor test was applied at one hand (see attached file K6, Doll et al.).
However, this study only comprises the nociceptive detection threshold
measurements (no EEG was recorded).

Additionally, we did not yet investigate the NDT and EPs combined with CPT in
patients with altered pain processing mechanisms. Measurements of NDTs and EPs
in chronic pain patients could aid the diagnosis and the development of new
treatments in these patients in the future. To enable this, it is necessary to
understand how the NDTs and EPs in these patients behave pre-, during and
post-CPT when compared to healthy subjects.

The aim of this study is to explore the feasibility to combine measurements of
the NDT and EEG recording with a cold pressor test (CPT) in a clinical
environment. In this explorative study, multiple types of stimuli are
delivered. The NDT and EEG are measured and analysed with respect to the
stimulus parameters.

A primary objective is to explore the feasibility of CPT with the MTT-EP method
in a clinical environment and to evaluate and explore NDTs and EPs pre-, during
and post-CPT-induced CPM activation of healthy subjects and FBSS patients.
Another primary objective is to describe how the NDTs for electrical stimuli
behave pre-, during and post-CPT in healthy controls and FBSS patients using a
multiple threshold tracking paradigm, and how neurophysiological responses
(EPs), measured pre-, during and post-CPT, are related to the delivered
electrocutaneous stimuli properties in healthy controls and FBSS patients.
Lastly, a primary objective is to explore the reproducibility of the MTT-EP
measurement in healthy subjects and FBSS patients by a test-retest in the St.
Antonius Hospital Nieuwegein.

Secondary objective is to analyze how the NDT and EEG pre-, during and post-CPT
are related to sensitization in FBSS patients. Furthermore, other secondary
objectives are to see if differences in NDTs and EPs pre-, during and post-CPT
can be found between FBSS patients and healthy controls and between different
age groups in healthy subjects and FBSS patients.

Mono-center, cross-sectional study.

The participants are asked to come to the St. Antonius Hospital for two
sessions. Participants are not allowed to consume alcohol or use drugs during
the 24 hours prior to the session (they are allowed to take medication). At the
start of the session, the participant fills in a questionnaire. Subsequently,
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 (MTT) paradigm at the dominant
hand. The burden during the session is minor, as the electrical stimuli are
expected to stay below the pain threshold* but participants will undergo the
experiment for two hours in total, of which they need to be very concentrated
for approximately 30 minutes. Furthermore, during the experiment the
participants are asked to immerse one foot into a container filled with cold
water. This could be experienced as painful, however, previous study has been
performed at the University of Twente resulting in good results (see attached
file K6, Doll et al.). For this, the subjects will be compensated with a
voucher. The risks are expected to be neglectible.

*The pain threshold in healthy subjects lays around 2 mA for intra-epidermal
stimulation, see the IMDD of the AmbuStim (D2). The pain threshold in FBSS
patients might be lower. However, using the MTT paradigm, stimuli are applied
around the detection threshold estimated during the experiment. Therefore, the
pain threshold will not be reached unless the subject fails to respond
adequately to the applied stimuli.