Electrical Brain Responses During Processing of Nociceptive Stimuli Around Detection Threshold: an Explorative Study in Pain Patients

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 , CRPS, certain types of DPN,
sarcoidosis, arthrosis in healthy BMI and (morbid) obesity and CIPN 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, and of adequate diagnostic means for the presumed
causes of chronic pain (such as small fibre neuropathy, or SFN, in painful
diabetic neuropathy) . 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 to changes 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.

However, we did not yet investigate the NDT and EPs 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 when compared to healthy subjects.

[Amendment *test-retest*]
Preliminary results from this study show values of NDTs and EPs, habituation
and paired-pulse facilitation, which are in line with results from the
University of Twente. Again, EPs are modulated by stimulus detection and
amplitudes. Strikingly, we found higher NDTs in FBSS patients and EPs appeared
modulated by stimulus detection, but not by amplitudes. Since similar phenomena
in NDTs and EPs were observed during nociceptive stimulation in pain-free
subjects at St. Antonius hospital, it can be concluded that results of MTT-EP
method can be replicated in a hospital environment. Secondly, the observed
altered behavior of NDTs and EPs in FBSS patients showing signs of central
sensitization allows further hypotheses regarding responsiveness to mechanisms
underlying chronic pain.

However, the reproducibility of the MTT-EP method is never assessed within the
same subject. Therefore, it would be interesting to investigate the effects of
a test-retest in the same pain-free subjects, because it yields unique results
on the reliability of this MTT-EP experiment. Second, future work should be
performed in the same FBSS patient as well, but then when they are just treated
by neuromodulation. This chain of results would facilitate new insights into
the underlying mechanisms of the CNS and reveal possibly a new approach to
current treatment.

However, it is unknown if EPs can be seen using this MTT-EP experiment in FBSS
patients who are treated by neuromodulation. Therefore, it is also recommended
to measure the same FBSS patients again. But then, when the neuromodulator is
turned off and on. This is relevant, because then we should measure the
efficacy of the treatment in chronic pain patients in future.

[Amendment *Uitbreiding groep diabeten lidocaïne model']
Additionally, the MTT-EP approach could play a role in (early and more
objective) neurophysiological, nociceptive characterization of diabetes
patients with chronic painful DPN and without neuropathic pain complaints. To
find out, exploration and evaluation of (the results of) the MTT-EP method in a
lidocaine model of SFN is also necessary. Outcomes, compared to those of other
research groups (e.g. healthy subjects and other chronic pain patient
populations), will expectedly grant insight in potential applicability within a
broader clinical perspective.

[Amendement 'Uitbreiding gezonde controlegroep']
Subject characteristics, such as age and gender, may affect the detection
threshold and stimilus-related response. However, this is unknown yet. It is
important to know their relationship, so that we can match the healthy controls
in a good way to the characteristics of the pain syndromes.

[Amendement *Pijn bij sarcoïdose en (morbide) obesitas*]:
The group will be expanded further to examine the influence of BMI on the
measurements. This is done by adding (morbid) obesity patients with and without
chronic arthrogenic pain. The effect of BMI on the measurements will become
more visible if morbidly obese patients with / without chronic pain are
measured before and after bariatric surgery. Moreover, the MTT-EP approach
could play a role in neurophysiological characterization of sarcoidosis
patients with chronic pain and symptoms of SFN. These results can be compared
with other research groups and are expected to provide insight into the
possible applicability.

[Amendement 'Toevoeging onderzoeksgroep: CIPN']:
The MTT-EP approach could play a role in neurophysiological characterization of
CIPN patients with chronic pain and symptoms of SFN. These results can be
compared with other research groups and are expected to provide insight into
the possible applicability.

[Amendment *FBSS-SCS*]
It is essential to explore the reproducibility and feasibility of the MTT-EP
method to be able to investigate whether the MTT-EP method can be used to
determine the effect of spinal cord stimulation in patients with FBSS.

[Amendment 'Meetlocatie voet']:
Exploring the feasibility of the MTT-EP method when stimuli are applied to the
foot in FBSS patients with implanted spinal cord stimulator is important to
further investigate whether the MTT-EP method can be used to determine the
effect of spinal cord stimulation. By changing the location where stimuli are
applied, the MTT-EP method could provide an objective evaluative measure of the
effectivity of spinal cord stimulation and may lead to more insight into
underlying mechanisms of FBSS and spinal cord stimulation.

Adding a healthy control group where stimuli will be applied to the foot,
provides the possibility to compare the FBSS-SCS-f group to a pain-free
population. Additionally, this control group could be used as a comparison for
other patient groups where the foot appears to be a more appropriate location
for stimulus application.

The aim of this study is to combine measurements of the NDT with EEG recording
and analysis to observe neurophysiological activity during nociceptive
processing in CRPS patients. In this explorative study, multiple types of
stimuli are delivered. The NDT and EEG are measured and analysed with respect
to the stimulus parameters.

The first primary objective is to compare NDTs and EPs of healthy subjects in a
hospital with the results of healthy subjects from previous study at the
University of Twente. Another primary objective is to describe how the NDTs for
electrical stimuli behave in healthy subjects, in chronic pain patients (FBSS,
CRPS-I, painful DPN, sarcoidosis, CIPN, (morbid) obesity with chronic
arthrogenic pain and arthrogenic pain patients with healthy BMI) and in
diabetes patients without neuropathic pain and pain-free (morbid) obese
patients, using a multiple threshold tracking paradigm, and how
neurophysiological responses (EPs) are related to the delivered
electrocutaneous stimuli properties in healthy subjects and these patients. A
third primary objective is exploration of the reproducibility of the MTT-EP
measurement in healthy subjects and FBSS patients (when spinal cord stimulator
is turned off) by a test-retest at the St. Antonius hospital Nieuwegein. Also,
the applicability of the MTT-EP method in FBSS patients who are treated by
neuromodulation (when the spinal cord stimulator is turned on) needs to be
explored by analyzing whether the evoked potentials can be induced during
spinal cord stimulation, and in FBSS patients treated by neuromodulation when
stimuli are applied to the foot. Furthermore, the primary objective is to
explore the influence of subject characteristics on the detection theshold and
stimulus-related responses in healthy subjects. A last primary objective is
exploration of the MTT-EP capabilities for neurophysiological mapping of
nociception in (pain-free) healthy subject with a lidocaine SFN model.

Secondary objectives are to confirm the hypothesis that FBSS patients, CRPS-I
patients, diabetes patients with painful DPN, sarcoidosis patients, CIPN
patients, (mobid) obese patients with chronic arthrogenic pain (retest for the
morbid obesity) and chronic arthrogenic pain patients with healthy BMI are
appropriate populations to study (chronification of) pain and pain physiology,
and to analyze how the NDT and EEG are related to sensitization in these
chronic pain patients (compared to matched healthy subjects).

Mono-center, cross-sectional study.

The participants are asked to come to the St. Antonius Hospital for one
session. Half of the FBSS patients with spinal cord stimulator (FBSS-SCS) will
be asked to turn of the stimulator 4 hours prior to the experiment, and half of
the FBSS-SCS-f patients will be asked to turn off the stimulator 12 hours prior
to the experiment. If this is not tolerated, patients can switch the stimulator
on again. 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. This is
followed by a short, orienting neurological examination (*pin-prick test* for
sharp sensations, *gauze test* for subtle sensations) of diabetes patients and
healthy subjects that will receive the lidocaine SFN model. Then, two patches
(active and placebo) will be applied on the back of both hands of participants
in the lidocaine SFN model group. As these participant are allowed to continue
their activities at the St. Antonius Hospital, the burden of this waiting time
is estimated to be minimal. 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, first on one hand and then on the other. The burden
during the session is minor, as the 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 one hour. For this, the
participants will be compensated with a voucher.. In healthy participants with
lidocaine SFN model, there is a chance (approximately 16%) of skin reactions,
such as redness or itch, directly under or around the patch. These normally do
not persist for more than a day. Risks of allergic reactions or systemic
adverse events are negligible, as are risks of the stimulation method for all
research groups.

*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 CRPS
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.