Good vibrations: Itch induction by whole body vibration exercise without the need of a pruritogen

Abstract

Mechanically induced itch is an important cofactor in many patients with chronic itch. However, studying mechanical itch in a controlled environment is challenging because it is difficult to evoke. We investigated the use of whole body vibration (WBV) exercise, a training method used for musculoskeletal rehabilitation, to experimentally evoke mechanical itch. Mild to severe itch ascending from the soles to the groins was evoked in 16 of 20 healthy participants. We observed a characteristic on/off itch crescendo pattern reflecting the alternating intervals of vibration and no vibration. Wheals or an angioedema was absent, and serum mast cell tryptase was not increased by the exercise. Participants described the evoked sensation primarily as “itching” with some nociceptive components. Itch intensity correlated with the intensity of a concomitant erythema (R = 0.45, P = 0.043) and with the rise in skin temperature (R = 0.54, P = 0.017). Hence, WBV can be used as an easily applicable, noninvasive, investigator‐ and user‐friendly framework for studying mechanical itch. Moreover, WBV allows to “switch itch on and off” rapidly and to simultaneously study interactions between itch, skin blood flow and skin temperature.

Full text

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Good vibrations: itch induction by whole body vibration exercise without the
need of a pruritogen
Simon Müller1 0000-0002-0200-4254
Marilena Fischer1,2 (shared first authorship)
Simon Herger2
Corina Nüesch2,3, 0000-0002-7526-9536
Christian Egloff2 0000-0001-6867-0527
Peter Itin1
Lucian Cajacob1
Oliver Brandt1
Annegret Mündermann2,3, 0000-0002-6472-1689
1Department of Dermatology, University Hospital Basel, Basel, Switzerland
2Clinic of Orthopaedics and Traumatology, University Hospital Basel, Basel,
Switzerland
3Department of Biomedical Engineering, University of Basel, Basel, Switzerland
Original Article
DOI: 10.1111/exd.13776
August 2018
Accepted for publication in: Experimental Dermatology
Corresponding author: Simon M. Mueller, MD
Department of Dermatology
University Hospital Basel
Spitalstrasse 21
4031 Basel, Switzerland
Tel. +41 61 328 69 64
Email: simon.mueller@usb.ch
Short title: Itch induction by whole body vibration exercise
Word count: 3516 words
Abstract word count: 174 words
Key words: Itch; models; mast cells; vibration; erythema

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Abstract
Mechanically induced itch is an important cofactor in many patients with chronic itch.
However, studying mechanical itch in a controlled environment is challenging
because it is difficult to evoke. We investigated the use of whole body vibration
exercise (WBV) exercise, a training method used for musculoskeletal rehabilitation,
to experimentally evoke mechanical itch. Mild to severe itch ascending from the
soles to the groins was evoked in 16 of 20 healthy participants. We observed a
characteristic on/off itch crescendo pattern reflecting the alternating intervals of
vibration and no vibration. Wheals or an angioedema were absent, and serum mast
cell tryptase was not increased by the exercise. Participants described the evoked
sensation primarily as “itching” with some nociceptive components. Itch intensity
correlated with the intensity of a concomitant erythema (R=0.45, P=0.043) and with
the rise in skin temperature (R=0.54, P=0.017). Hence, WBV can be used as an
easily applicable, non-invasive, investigator- and user-friendly framework for
studying mechanical itch. Moreover, WBV allows to “switch itch on and off” rapidly
and to simultaneously study interactions between itch, skin blood flow and skin
temperature.

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INTRODUCTION
Commonly used human surrogate itch models require a pruritogen (e.g. histamine,
cowhage/mucunain, or serotonin) applied by skin pricking, intradermal injection or
iontophoresis.1,2 Once initiated, the itch response in these models lasts
approximately 10 to 30 minutes, which may be longer than desired in experimental
protocols.3-5 Moreover, while these models greatly contributed to the understanding
of the chemically induced histaminergic and non-histaminergic itch, they may not be
suitable for studying mechanically induced itch. To our knowledge, only one human
model for evoking mechanical itch by vellus hair vibration has been described.6
Consequently, little is known about the pathways of mechanical itch even though
mechanical stimuli are considered to be important but often overlooked co-factors in
chronic itch.6-11
According to the literature12-15, our own observations and numerous posts in non-
professional online-blogs, intense itch on the legs associated with “redness” often
occurs during whole body vibration (WBV) exercise. WBV is a training method that
improves physical function attributable to improvements in muscle and bone
strength.16,17 The effects of WBV are thought to not be a direct consequence of bone
tissue deformation but rather mediated by by-products of the high-frequency strain
signal, such as shear stress caused by fluid flow.18 WBV is widely used in medical
musculoskeletal rehabilitation, professional sports and recreational fitness training
and applied by plates vibrating side-to-side around the posterior-anterior axis or up
and down along the vertical axis, or rotationally oscillatiing around a central axis at 5
to 60 Hz. Rittweger et al.12 were the first to describe an “itching erythma” during WBV
and stated that—considering the high prevalence of this phenomenon—it clearly

4
differs from vibratory urticaria or angioedema. This assumption was supported by
results of few subsequent experimental studies that did not report urticarial lesions,
angioedema or systemic symptoms associated with WBV exercise.13-15 However, to
date the mechanisms underlying the itch induction in response to WBV has not been
further explored. Specifically, it is unknown if and how itch and erythema are
connected and whether WBV may lead to degranulation of mast cells. While it has
been hypothesised that an increased perfusion pressure of the arteries may lead to
vasodilation and erythema12, another study suggested that the blood is rather
extruded from venous muscle veins.19
According to unpublished observations, WBV-induced itch on the legs usually starts
and disappears within seconds upon switching the vibration plate on or off,
respectively. We therefore theorised that WBV may be a suitable for rapidly inducing
and terminating experimental itch non-invasively without the need of a chemical
pruritogen. The primary purpose of this study was to describe the WBV-induced itch
and erythema and to evaluate whether WBV could be a suitable framework for
studying mechanical itch. Because WBV generates warmth from muscle activity19
and warmth is known to increase itch20,21, we also investigated the association of
skin temperature and itch using infrared thermography. Furthermore, we addressed
the question of WBV-induced mast cell degranulation by comparing pre-exercise and
1-h post-exercise mast cell tryptase. The role of vellus hair in WBV-induced itch was
investigated by intra-individually comparing itch between the shaved and the
unshaven leg.

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MATERIAL & METHODS
Design
The study was designed as a single-centre cross-sectional single-arm interventional
study.
Participants
Female participants were recruited from the community surrounding the University of
Basel by posting flyers and from our own database of healthy volunteers. We only
included female participants in this study to eliminate potential sex differences.
Inclusion criteria were: age between 18 and 35 years with a negative urine beta-
HCG pregnancy test and a body mass index (BMI) between 17 and 35 kg/m2.
Exclusion criteria were: Erlanger Atopy Score22 ≥ 10; itchy skin diseases; asthma;
chronic venous insufficiency; peripheral artery disease; and musculoskeletal
diseases or injuries affecting the legs, hips and pelvis. To determine a potential
effect by vellus hair on itch development, participants were instructed not to shave
their legs for 1 week before the intervention day and to shave the left leg on the day
prior to the intervention day. The study was approved by the regional ethics board
(Ethikkommission Nordwestschweiz EKNZ 2017-02009). All participants provided
written informed consent prior to participation.
Procedure
Participants were instructed to stand on the vibration plate (Galileo 900; Novotec
Medical GmbH, Pforzheim, Germany) in a slightly crouched position (knee and hip
angle 30°) with their hands loosely resting on the rail. The following settings for the
WBV-exercise were used: 20 Hz vibration frequency, 3 mm amplitude, ten 1-minute

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repetitions with intermittent 1-minute breaks without WBV.23 After the last WBV
repetition, participants remained on the plate for another 5 minutes without WBV.
Throughout the exercise and rest periods, itch intensity was assessed as described
below.24 Blood samples were drawn immediately before the first exercise bout and
60 minutes after the last WBV repetition.
Blood sampling
Blood samples were collected and allowed to clot for 30 minutes. Serum was
separated and frozen in aliquots to -20°C within 1 hour of collection and
subsequently transferred for storage at -80°C until assayed. Serum biomarker
concentrations were determined using commercial ELISAs (ImmunoCAP Tryptase;
Thermo Fisher Scientific – Phadia GmbH, Freiburg, Germany). Serum mast cell
tryptase levels were assessed immediately before and 1 hour after the termination of
the WBV. This time point was chosen because serum tryptase usually peaks 1 hour
after mast cells degranulation.25-27
Assessment of study variables
Itch intensity
Participants rated the itch intensity using a numerical rating scale (NRS) from 0 (no
itch at all) to 10 (most intense itch imaginable)28 immediately and 30 and 60 s after
each WBV interval. To assess the quality of itch, participants completed the first 80
items of the Eppendorf itch questionnaire24 after the WBV exercise.

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Erythema
Erythema were bilaterally quantified using a Mexameter® MX 1829 in an area located
about 10 cm below the popliteal line (Appendix 1).30 The intensity of the erythema
was measured by reflection and absorption of two wavelengths (568 and 660 nm).
The wavelength of 568 nm is absorbed by haemoglobin, the wavelength of 660 nm is
reflected by haemoglobin, the result is a ratio ranging from 0 to 999
(intensity(568nm)/intensity(660nm)*1000). Measurements were performed on and 2
cm medial and lateral to the midline, respectively, immediately after each WBV
interval.
Thermography of lower extremities
Quantitative and topographical changes in skin surface temperature were assessed
using a thermal imaging camera (VarioCAM® HR INSPECT 700 SERIES; InfraTec
GmbH Infrarotsensorik und Messtechnik, Dresden, Germany; 1.280 x 960 pixels).31
Images were analysed with IRBIS® remote version 3 (InfraTec GmbH
Infrarotsensorik und Messtechnik, Dresden, Germany), exported and post-processed
using project-specific generated masks of areas of interest (about 10 cm below the
popliteal line on both legs corresponding to the site of the Mexameter®
measurements; 10 cm proximal of the malleoli; and 10 cm above the popliteal line)
written in MATLAB (The MathWorks Inc., Natick, MA, USA). The average
temperature for these regions was calculated on each image and used for further
analyses.

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Statistical analysis
Statistical computations were performed using SPSS 21 software (IBM Corporation;
Amonk NY, USA). Parameters were checked for normal distribution using
Kolmogorov-Smirnov tests. Changes in itch intensity, erythema and temperature
during the WBV exercise were analysed using a linear mixed model with time as
within-subject factor and group membership as between-subject factor. Because
erythema did not differ between locations (medial, central, lateral), values for these
regions were averaged for each leg and used for further analyses. Relationships
among parameters were assessed using Pearson’s correlation coefficients. The
significance level for all statistical tests was set a priori to α=0.05.

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RESULTS
Participant characteristics
Twenty healthy women participated in the study (mean ± 1 standard deviation, age:
24.9 ± 3.5 years; height: 168 ± 4 cm; body mass: 62.3 ± 6.3 kg; body mass index
(BMI): 22.1 ± 2.5 kg/m2). Five participants had previously used WBV exercise, and
four of these had experienced itch and erythema while one had been asymptomatic.
None of the 20 participants suffered from itchy skin diseases or had indications of an
atopic disease (Erlanger Atopy Score < 11).
Itch prevalence, pattern, perception and localization of WBV-induced itch
Sixteen (80%) participants developed itch: nine reported mild (NRS≤5) and seven
reported moderate/intense (NRS>5) itch. These participants had a characteristic
on/off or jugged crescendo pattern (Figure 1). Mean duration until itch onset was 2.4
± 1.5 min, the intensity peaked at 6.6 ± 2.0 min, and values returned to baseline
levels 3.0 ± 1.9 min after the end of the exercise. Of all items of the sEIQ describing
itch perception, “itching” was rated highest (mean 2.35 ± 1.50), followed by “biting”
(1.75 ± 1.48), “tingling” (1.75 ± 1.55), “unpleasant” (1.75 ± 1.55), “tickling” (1.55 ±
1.47), “ant-like” (1.55 ± 1.54), “pricking” (1.50 ± 1.47), “bothersome” (1.50 ± 1.40)
and “tiresome” (1.50 ± 1.57). “Vibrating” (1.40 ± 1.39) was ranked only 10th, and
“painful” (0.5 ± 0.76) only 32nd of 80 items (investigated items are presented as
Supplement).
In 11 of the 16 participants experiencing itch (68.7%), itch started on the feet, in four
(25.0%) on the lower legs and in one (6.3%) in the popliteal fossae. In 14
participants (87.5%), itch ascended to the groin without spreading to proximal body

10
parts. Twelve participants (75.0%) reported no difference in itch between the shaved
and unshaven legs, two participants (16.0%) perceived itch more intense in the
shaved and two (16.0%) in the unshaven leg. Thirteen participants were re-exposed
to WBV 3 months after the first WBV session: 11 previously symptomatic participants
experienced symptoms again, 2 previously asymptomatic participants remained
asymptomatic indicating that the WBV effects are highly reproducible.
Erythema, prevalence, localisation, correlation with itch intensity
Although all participants developed at least a slight erythema during WBV, those with
higher itch intensities also appeared to experience more intense erythema. The
erythema became visible after 4 to 6 WBV bouts (i.e. a few minutes after the onset of
itch) and became more intense towards the end of the exercise. In all participants,
the erythema was limited to the legs and best visible on the lower legs with a patchy
appearance in some participants (Figure 2). Measurements of erythema intensity
revealed an initial decrease in skin redness that was not visible to the naked eye.
Erythema intensity did not differ significantly between the shaved and unshaven legs
(P=0.296; 95% confidence interval of the difference between sides, [-21.1;6.4]) and
no interaction between itch-group and time were found (P=0.121; without itch (n=4),
with mild itch (n=8) and with moderate/intense itch (n=7)). Erythema intensity
correlated with itch intensity at 7 minutes when itch was most intense (R=0.45,
P=0.043).
Topographical changes in skin temperature, correlation with erythema and itch
intensity
Average skin temperature increased in all regions (Figure 3). This increase was

11
significant after the last vibration bout in the proximal lower leg (0.7 ± 1.2°C;
P=0.018). The highest increase (1.4 ± 1.0°C; P<0.001) was observed in the thigh
where the increase in temperature was statistically significant after the first vibration
bout and throughout the remainder of the experiment. The highest temperatures
were observed on the proximal lower legs (Appendix 2). The temporal and
topographical changes in skin temperature matched well with the visible erythema
intensity. Itch (R=0.541, P=0.017; Figure 4) but not erythema intensity (R=0.175,
P=0.470) correlated with the change in temperature from baseline to 7 min when itch
was most intense.
Mast cell tryptase
Serum mast cell tryptase decreased significantly from pre-WBV to 1h post-WBV
(3.49 ± 1.57 ng/m versus 3.27 ± 1.38 ng/m; P=0.004). The analytical variation for
tryptase at the levels measured in our patients (around 3 ng/ml; 1-8 ng/ml) was
approximately 5%, the biological variation for tryptase is estimated as at least 10%,
and the pre-analytical variation is assumed to be minimal. Hence, although the
observed differences were statistically significant, these differences fall within the
levels of normal biological and analytical variation.

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DISCUSSION
In recent years, itch models using pruritogens greatly contributed to the
understanding of histaminergic and non-histaminergic itch. However, presumably
because of a lack of suitable itch models, much less is known about mechanically
induced itch that is still a neglected but important cofactor in many patients with
chronic itch.9-11 We investigated the use of standard WBV-exercise to experimentally
study mechanically induced itch. WBV indeed allowed us to rapidly “switch itch on
and off” in 16 of 20 healthy participants without the need of a chemical pruritogen
and its antagonist. We observed a characteristic on/off itch crescendo pattern
reflecting the alternating intervals with and without WBV. The evoked sensation was
primarily described as “itching” in the sEIQ. Interestingly, while pain-related
components such as “biting”, “tingling”, “pricking” and “ant-like” were among the top
10 ratings, “hurting” and “painful” were not among the top 30 ratings. These pain-
related components have repeatedly been described in both histaminergic and non-
histaminergic (cowhage32-34, bradykinin11, serotonin11) and electrically evoked itch.8
In contrast to our findings, Fukuoka et al.6 were able to evoke itch by horizontal
vibration of vellus hair in the face (but not on the arm) and reported that mechanically
evoked itch does not include pain-related components. We found no difference in
itch manifestation and perception between the shaved and unshaven legs indicating
that vellus hair do not play a relevant role in WBV-induced itch. This result is a
possible explanation why our participants perceived the quality of vibratory itch
differently than those in the study by Fukuoka et al.
To date, we can only speculate about the mechanisms responsible for the WBV-
induced itch. Fukuoka et al.6 hypothesised that C-tactile neurons (CT, low threshold

13
mechanosensitive C-afferents) are involved in mechanically evoked itch. However,
our findings do not support this hypothesis because of two observations: first, itch
mostly started on the soles of their feet, which are devoid of CT; second, we
observed a crescendo pattern of itch but CT fatigue during mechanical stimulation at
short intervals.35 Although to date the response of CT to vibratory stimulation has not
been investigated36, CT are responsive to slow gentle touch at amplitudes and
frequencies that are much lower than those of WBV in our study.36 The pain-related
components of itch observed in our study suggest an involvement of
mechanosensitive C- or Aδ-afferents. For example, polymodal C-fibres transduce
cowhage-induced itch, mechanical stimuli and heat1,37 and could potentially link the
WBV-induced itch to the non-histaminergic pathway. Considering that WBV-induced
itch instantly changed depending on whether the plate was vibrating or not, the
histamine-sensitive neurons do not seem to be relevant role because they are
insensitive to mechanical stimuli.6,37 This on/off pattern rather indicates an
involvement of encapsulated low-threshold mechanoreceptors. Fast-adapting
Meissner corpuscules connected to myelinated Aβ-fibres are best responsive to
vibrations below 50Hz38 and located exclusively in glabrous skin, which may explain
why itch onset in most of our participants started on the soles of their feet. However,
involvement of Meissner corpuscules would not explain the spreading of the itch to
non-glabrous (hairy) skin. Moreover, a diminished vibration sensitivity to 30 Hz on
the soles for more than 1 hour after 10-minute continuous WBV has been reported38
indicating that stimulation of the Meissner corpuscules alone may not explain our
findings. It is conceivable that microneurography could help to characterise the
conducting fibres involved. Unfortunately, microneurography during WBV in vivo is

14
not feasible because the strong vibrations in WBV would immediately dislocate the
needle electrodes.
Erythema appeared in all participants but seemed to be more intense in those with
itch. This association was supported by a moderate positive correlation indicating
that itch and erythema are somehow linked. The following arguments refute the
hypothesis that a WBV-induced mast cell degranulation could lead to a histamine-
induced flare response and to itch. First, participants who did not perceive itch still
developed an erythema. Second, we did not observe any clinical evidence of mast
cell degranulation (e.g. urticarial dermographism, angioedema, flushing). Third,
levocetirizine—a 2nd generation H1-antihistamine—did not prevent an erythema
during WBV (tested in one participant, data not shown). Therefore, our results
support the interpretation of Rittweger et al. that WBV-induced itch and erythema are
distinct from histamine-induced vibratory angioedema/urticarial.12 We assume that
WBV-induced increase in skin blood flow is responsible for the development of
erythema. Several studies using Doppler imaging techniques have shown that WBV
increases skin blood flow12,15,39-41, yet the physiological mechanism for this
phenomenon remains unclear. It was hypothesised that mechanically induced
endothelial stress increase nitric oxide (NO) release leading to vasodilation and thus
erythema.15,41,42 However, Johnson et al. were unable to detect elevated NO-
concentrations in whole blood samples during or after WBV.15
Surprisingly, erythema intensity in all participants dropped initially and was not
paralleled by visible skin paling. We interpret this decrease in erythema intensity as a
sign of an initial vasoconstriction. Although the exact mechanism leading to WBV-

15
induced vasoconstriction is unknown, several factors such as a somatosympathetic
reflex, smooth muscle membrane depolarisation or endothelium-derived factors have
been suggested.43 Vibration-induced vasoconstriction has also been reported in
patients with Raynaud’s phenomenon44 and is thought to be caused by
hyperreactivity of the sympathetic nervous system and a dysfunction of sensory
nerve fibres.45,46 In this condition, the subsequent transition to reactive hyperemia is
often perceived as (painful) pins and needles paraesthesia.47 This sequence
resembles our observations. However, the relationship between itch and erythema
observed by us needs further investigation, and micro dialysis may be useful for
studying mediators potentially released by immune- and skin cells.
Itch intensity correlated not only positively with erythema intensity but also with skin
temperature on the lower legs. We observed the most pronounced absolute increase
in temperatures on the proximal lower legs where itch was most intense.
Interestingly, itch ascended during WBV-exercise towards the thighs—the site with
the largest relative increase in temperature. It is known that WBV results in an
increase in skin temperature.48-52 Although our results cannot be directly compared
with the literature because of different WBV set-ups, they are in agreement with
previous studies that reported a mean increase in skin temperature of approximately
0.3-1.0°C on the lower legs after 5 minutes of WBV.48,52,53 Visually, the maxima of
erythema intensity and temperature on the lower legs occurred at similar times
during the WBV, yet they did not statistically coincide. A possible explanation for this
finding is that the increase in skin temperature may be caused by warmth generated
by muscle activity rather than by vasodilation (i.e. an increased skin blood flow).19,49

16
Nonetheless, it is possible that WBV itself increases skin temperature as
demonstrated in a study with passive vibration in supine position.53
A rise in temperature is a well-known itch-aggravating factor and experienced by
most patients with pruritic conditions.20,21 Our data confirmed the association of sub-
noxious warmth with higher itch intensities. However, to date only little is known
about the underlying mechanisms of this phenomenon.20 It has been hypothesised
that the transient receptor potential vanilloid type 1 (TRPV1) protein might play a role
in heat provoked itch as it is involved both in the induction of histaminergic itch
responses and the perception of heat above 42°C.20,54 The mechanosensitive
polymodal C-fibres transduce heat and cowhage-induced stimuli, and are thus
another possible link between warmth and itch. Interestingly, Harazin et al.55
demonstrated that the vibrotactile perception threshold at 25 Hz in women is lower
on warm than on cold hands (<29°C). Whether the increase in temperature lowered
the vibrotactile perception threshold and thus correlates with the WBV-induced itch in
our set-up needs further exploration.
While warmth appears to intensify itch, heat inhibits itch. Yosipovitch et al.21 reported
that similar to scratching, heat-induced pain (49°C) inhibits itch and histamine-
induced skin perfusion suggesting neurogenic inhibition by mechanosensitive
thermal nociceptors. In recent years, the understanding of the “gate control” of
chemically and mechanically induced itch by spinal cord interneurons has continually
increased.9,56,57 Due to the relatively small number of asymptomatic participants, we
could not perform a group comparison between participants with and without itch.
However, it is possible that differences in the gate control mechanisms (e.g. spinal

17
inhibitory mechanisms) may influence whether and how WBV-induced itch is
perceived. Appendix 3 summarises our results and suggests a working hypothesis
based on our observations and the literature on how WBV-induced itch, erythema
and temperature increase could be related.
To the best of our knowledge, this is only the second study to report mechanically
induced itch with an intensity and quality that is comparable to histamine- or
cowhage-induced itch.6 Moreover, our results indicate that WBV indeed could be a
practical, non-invasive, investigator- and user-friendly framework for studying
experimental itch. WBV allows to quickly switch itch on and off and to simultaneously
study the interaction between itch, skin blood flow and skin temperature in healthy
participants and patients without the need for a chemical pruritogen. Given the intra-
individual reproducibility of itch, asymptomatic participants could be excluded based
on results a selective WBV exercise before study inclusion. Moreover, comparing
symptomatic and asymptomatic participants may provide further insights into the
pathomechanism of WBV-induced itch. The set-up used in our study may also be
suitable for exploring the effect of different systemic and topical drugs on WBV-
induced itch and the role of muscle contraction and vibration characteristics including
frequency, amplitude, and exercise duration. Thus, we believe that the used WBV
set-up provides several aspects required to develop a mechanical itch model.

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ACKNOWLEDGEMENTS
We thank Pia Steinger und Annet Tiemessen for assisting in data collection, Dr.
Ingmar Heijnen for performing the ELISA tests, the Institute of Physiotherapy at the
University Hospital Basel for providing the pressure plate and the University of
Applied Sciences Northwest for providing the thermal camera and technical support.
This study was funded by the Department of Dermatology and the Department of
Orthopaedics and Traumatology of the University Hospital Basel, Switzerland.
Conflict of Interest
The authors declare no conflict of interest.
Author Contributions
SM, MF and AM conceived the study; SM coordinated data collection, analysed and
interpreted the data and prepared the manuscript; MF recruited subjects, managed
data collection, processed and analysed the data, and prepared the manuscript; SM
was involved in coordination of data collection and collected data; CN as involved in
data collection and processed and analysed image data; CE was involved in data
collection. PI and LC were involved in data interpretation; OB was involved in data
interpretation and prepared the manuscript; AM performed the statistical analysis,
interpreted the data and prepared the manuscript; all authors critically revised the
manuscript.

19
References
1. Hoeck EA, Marker JB, Gazerani P, H HA, Arendt-Nielsen L. Preclinical and
human surrogate models of itch. Exp Dermatol. 2016;25(10):750-757.
2. Falcone D, Uzunbajakava N, Richters R, van de Kerkhof PCM, van Erp PEJ.
Histamine Iontophoresis as in vivo Model to Study Human Skin Inflammation
with Minimal Barrier Impairment: Pilot Study Results of Application of the
Model to a Sensitive Skin Panel. Skin Pharmacol Physiol. 2017;30(5):246-
259.
3. Brull SJ, Atanassoff PG, Silverman DG, Zhang J, Lamotte RH. Attenuation of
experimental pruritus and mechanically evoked dysesthesiae in an area of
cutaneous allodynia. Somatosens Mot Res. 1999;16(4):299-303.
4. Hartmann EM, Handwerker HO, Forster C. Gender differences in itch and
pain-related sensations provoked by histamine, cowhage and capsaicin. Acta
Derm Venereol. 2015;95(1):25-30.
5. Papoiu AD, Tey HL, Coghill RC, Wang H, Yosipovitch G. Cowhage-induced
itch as an experimental model for pruritus. A comparative study with
histamine-induced itch. PLoS One. 2011;6(3):e17786.
6. Fukuoka M, Miyachi Y, Ikoma A. Mechanically evoked itch in humans. Pain.
2013;154(6):897-904.
7. Davidson S. A Spinal Circuit for Mechanically-Evoked Itch. Trends Neurosci.
2016;39(1):1-2.
8. Ikoma A, Handwerker H, Miyachi Y, Schmelz M. Electrically evoked itch in
humans. Pain. 2005;113(1-2):148-154.
9. Bourane S, Duan B, Koch SC, et al. Gate control of mechanical itch by a
subpopulation of spinal cord interneurons. Science. 2015;350(6260):550-554.
10. Wahlgren CF, Hagermark O, Bergstrom R. Patients' perception of itch
induced by histamine, compound 48/80 and wool fibres in atopic dermatitis.
Acta Derm Venereol. 1991;71(6):488-494.
11. Hosogi M, Schmelz M, Miyachi Y, Ikoma A. Bradykinin is a potent pruritogen
in atopic dermatitis: a switch from pain to itch. Pain. 2006;126(1-3):16-23.
12. Rittweger J, Beller G, Felsenberg D. Acute physiological effects of exhaustive
whole-body vibration exercise in man. Clin Physiol. 2000;20(2):134-142.

20
13. Russo CR, Lauretani F, Bandinelli S, et al. High-frequency vibration training
increases muscle power in postmenopausal women. Arch Phys Med Rehabil.
2003;84(12):1854-1857.
14. Hazell TJ, Thomas GW, Deguire JR, Lemon PW. Vertical whole-body
vibration does not increase cardiovascular stress to static semi-squat
exercise. Eur J Appl Physiol. 2008;104(5):903-908.
15. Johnson PK, Feland JB, Johnson AW, Mack GW, Mitchell UH. Effect of whole
body vibration on skin blood flow and nitric oxide production. J Diabetes Sci
Technol. 2014;8(4):889-894.
16. Games KE, Sefton JM, Wilson AE. Whole-body vibration and blood flow and
muscle oxygenation: a meta-analysis. J Athl Train. 2015;50(5):542-549.
17. Maeda N, Urabe Y, Sasadai J, Miyamoto A, Murakami M, Kato J. Effect of
Whole-Body-Vibration Training on Trunk-Muscle Strength and Physical
Performance in Healthy Adults: Preliminary Results of a Randomized
Controlled Trial. J Sport Rehabil. 2016;25(4):357-363.
18. Rubin C, Turner AS, Mallinckrodt C, Jerome C, McLeod K, Bain S.
Mechanical strain, induced noninvasively in the high-frequency domain, is
anabolic to cancellous bone, but not cortical bone. Bone. 2002;30(3):445-452.
19. Zange J, Molitor S, Illbruck A, et al. In the unloaded lower leg, vibration
extrudes venous blood out of the calf muscles probably by direct acceleration
and without arterial vasodilation. Eur J Appl Physiol. 2014;114(5):1005-1012.
20. Murota H, Katayama I. Evolving understanding on the aetiology of thermally
provoked itch. Eur J Pain. 2016;20(1):47-50.
21. Yosipovitch G, Fast K, Bernhard JD. Noxious heat and scratching decrease
histamine-induced itch and skin blood flow. J Invest Dermatol.
2005;125(6):1268-1272.
22. Diepgen TL, Fartasch M, Hornstein OP. Evaluation and relevance of atopic
basic and minor features in patients with atopic dermatitis and in the general
population. Acta Derm Venereol Suppl (Stockh). 1989;144:50-54.
23. Liphardt AM, Mündermann A, Koo S, et al. Vibration training intervention to
maintain cartilage thickness and serum concentrations of cartilage oligometric
matrix protein (COMP) during immobilization. Osteoarthritis and Cartilage.
2009;17(12):1598-1603.

21
24. Darsow U, Scharein E, Simon D, Walter G, Bromm B, Ring J. New aspects of
itch pathophysiology: component analysis of atopic itch using the 'Eppendorf
Itch Questionnaire'. Int Arch Allergy Immunol. 2001;124(1-3):326-331.
25. Walls AF, He S, Teran LM, et al. Granulocyte recruitment by human mast cell
tryptase. Int Arch Allergy Immunol. 1995;107(1-3):372-373.
26. Payne V, Kam PC. Mast cell tryptase: a review of its physiology and clinical
significance. Anaesthesia. 2004;59(7):695-703.
27. Dua S, Dowey J, Foley L, et al. Diagnostic Value of Tryptase in Food Allergic
Reactions: A Prospective Study of 160 Adult Peanut Challenges. J Allergy
Clin Immunol Pract. 2018.
28. Phan NQ, Blome C, Fritz F, et al. Assessment of pruritus intensity:
prospective study on validity and reliability of the visual analogue scale,
numerical rating scale and verbal rating scale in 471 patients with chronic
pruritus. Acta Derm Venereol. 2012;92(5):502-507.
29. Matias AR, Ferreira M, Costa P, Neto P. Skin colour, skin redness and
melanin biometric measurements: comparison study between Antera((R)) 3D,
Mexameter((R)) and Colorimeter((R)). Skin Res Technol. 2015;21(3):346-362.
30. Huggenberger R, Detmar M. The cutaneous vascular system in chronic skin
inflammation. J Investig Dermatol Symp Proc. 2011;15(1):24-32.
31. Tse J, Rand C, Carroll M, et al. Determining peripheral skin temperature:
subjective versus objective measurements. Acta Paediatr. 2016;105(3):e126-
131.
32. Kosteletzky F, Namer B, Forster C, Handwerker HO. Impact of scratching on
itch and sympathetic reflexes induced by cowhage (Mucuna pruriens) and
histamine. Acta Derm Venereol. 2009;89(3):271-277.
33. Reddy VB, Iuga AO, Shimada SG, LaMotte RH, Lerner EA. Cowhage-evoked
itch is mediated by a novel cysteine protease: a ligand of protease-activated
receptors. J Neurosci. 2008;28(17):4331-4335.
34. Sikand P, Shimada SG, Green BG, LaMotte RH. Similar itch and nociceptive
sensations evoked by punctate cutaneous application of capsaicin, histamine
and cowhage. Pain. 2009;144(1-2):66-75.
35. Nordin M. Low-threshold mechanoreceptive and nociceptive units with
unmyelinated (C) fibres in the human supraorbital nerve. J Physiol.
1990;426:229-240.

22
36. Nagi SS, Rubin TK, Chelvanayagam DK, Macefield VG, Mahns DA. Allodynia
mediated by C-tactile afferents in human hairy skin. J Physiol. 2011;589(Pt
16):4065-4075.
37. Namer B, Carr R, Johanek LM, Schmelz M, Handwerker HO, Ringkamp M.
Separate peripheral pathways for pruritus in man. J Neurophysiol.
2008;100(4):2062-2069.
38. Sonza A, Maurer C, Achaval M, Zaro MA, Nigg BM. Human cutaneous
sensors on the sole of the foot: altered sensitivity and recovery time after
whole body vibration. Neurosci Lett. 2013;533:81-85.
39. Sa-Caputo D, Paineiras-Domingos L, Carvalho-Lima R, et al. Potential Effects
of Whole-Body Vibration Exercises on Blood Flow Kinetics of Different
Populations: A Systematic Review with a Suitable Approach. Afr J Tradit
Complement Altern Med. 2017;14(4 Suppl):41-51.
40. Lythgo N, Eser P, de Groot P, Galea M. Whole-body vibration dosage alters
leg blood flow. Clin Physiol Funct Imaging. 2009;29(1):53-59.
41. Lohman EB, 3rd, Petrofsky JS, Maloney-Hinds C, Betts-Schwab H, Thorpe D.
The effect of whole body vibration on lower extremity skin blood flow in normal
subjects. Med Sci Monit. 2007;13(2):CR71-76.
42. Sackner MA, Gummels E, Adams JA. Nitric oxide is released into circulation
with whole-body, periodic acceleration. Chest. 2005;127(1):30-39.
43. Sonza A, Robinson CC, Achaval M, Zaro MA. Whole body vibration at
different exposure frequencies: infrared thermography and physiological
effects. ScientificWorldJournal. 2015;2015:452657.
44. Liapina M, Tzvetkov D, Vodenitcharov E. Pathophysiology of vibration-
induced white fingers--current opinion: a review. Cent Eur J Public Health.
2002;10(1-2):16-20.
45. Olsen N, Petring OU. Vibration elicited vasoconstrictor reflex in Raynaud's
phenomena. Br J Ind Med. 1988;45(6):415-419.
46. Olsen N. Hyperreactivity of the central sympathetic nervous system in
vibration-induced white finger. Kurume Med J. 1990;37 Suppl:S109-116.
47. Silman A, Holligan S, Brennan P, Maddison P. Prevalence of symptoms of
Raynaud's phenomenon in general practice. BMJ. 1990;301(6752):590-592.
48. Seixas A, Silva A, Gabriel J, Vardasca R. The Effect of Whole-body Vibration
in the Skin Temperature of Lower Extremities in Healthy Subjects. 2012.

23
49. Cochrane DJ, Stannard SR, Sargeant AJ, Rittweger J. The rate of muscle
temperature increase during acute whole-body vibration exercise. Eur J Appl
Physiol. 2008;103(4):441-448.
50. Oliveri DJ, Lynn K, Hong CZ. Increased skin temperature after vibratory
stimulation. Am J Phys Med Rehabil. 1989;68(2):81-85.
51. Kerschan-Schindl K, Grampp S, Henk C, et al. Whole-body vibration exercise
leads to alterations in muscle blood volume. Clin Physiol. 2001;21(3):377-382.
52. Games KE, Sefton JM. Whole-body vibration influences lower extremity
circulatory and neurological function. Scand J Med Sci Sports.
2013;23(4):516-523.
53. Lohman EB, 3rd, Sackiriyas KS, Bains GS, et al. A comparison of whole body
vibration and moist heat on lower extremity skin temperature and skin blood
flow in healthy older individuals. Med Sci Monit. 2012;18(7):CR415-424.
54. Tominaga M, Caterina MJ. Thermosensation and pain. J Neurobiol.
2004;61(1):3-12.
55. Harazin B, Harazin-Lechowska A, Kalamarz J. Effect of individual finger skin
temperature on vibrotactile perception threshold. Int J Occup Med Environ
Health. 2013;26(6):930-939.
56. Foster E, Wildner H, Tudeau L, et al. Targeted ablation, silencing, and
activation establish glycinergic dorsal horn neurons as key components of a
spinal gate for pain and itch. Neuron. 2015;85(6):1289-1304.
57. Ross SE, Mardinly AR, McCord AE, et al. Loss of inhibitory interneurons in
the dorsal spinal cord and elevated itch in Bhlhb5 mutant mice. Neuron.
2010;65(6):886-898.

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Figure legends
Figure 1. Itch rating over time for all participants. Grey bars indicate the time of
whole body vibration stimulus.
Figure 2. a) Erythema, best visible on the lower leg with a patchy appearance on the
upper leg. b) Blanching of erythema on finger pressing.
Figure 3. Average temperature (top) and average change (bottom) in temperature in
the areas of interest on the distal (red) and proximal (blue) lower leg and upper leg
(green). Error bars indicate 1 standard deviation. Grey bars indicate the time of
whole body vibration stimulus.
Figure 4. Relationship between itch intensity and rise in temperature at minute 7.

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Figure 1

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Figure 2

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Figure 3

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Figure 4

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Appendix 1
Appendix 2