why wet feels wet? a neurophysiological model of human cutaneous wetness sensitivity

doi:10.1152/jn.00120.2014 112:1457-1469, 2014. First published 18 June 2014;J NeurophysiolDavide Filingeri, Damien Fournet, Simon Hodder and George Havenithhuman cutaneous wetness sensitivityWhy wet feels wet? A neurophysiological model of

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Why wet feels wet? A neurophysiological model of human cutaneouswetness sensitivity

Davide Filingeri,1 Damien Fournet,2 Simon Hodder,1 and George Havenith1

1Environmental Ergonomics Research Centre, Loughborough Design School, Loughborough University, Loughborough,United Kingdom; and 2Thermal Sciences Laboratory, Oxylane Research, Villeneuve d’Ascq, France

Submitted 11 February 2014; accepted in final form 18 June 2014

Filingeri D, Fournet D, Hodder S, Havenith G. Why wet feelswet? A neurophysiological model of human cutaneous wetness sen-sitivity. J Neurophysiol 112: 1457–1469, 2014. First published June18, 2014; doi:10.1152/jn.00120.2014.—Although the ability to senseskin wetness and humidity is critical for behavioral and autonomicadaptations, humans are not provided with specific skin receptors forsensing wetness. It has been proposed that we “learn” to perceive thewetness experienced when the skin is in contact with a wet surface orwhen sweat is produced through a multisensory integration of thermaland tactile inputs generated by the interaction between skin andmoisture. However, the individual roles of thermal and tactile cuesand how these are integrated peripherally and centrally by our nervoussystem is still poorly understood. Here we tested the hypothesis thatthe central integration of coldness and mechanosensation, as sub-served by peripheral A-nerve afferents, might be the primary neuralprocess underpinning human wetness sensitivity. During a quantita-tive sensory test, we found that individuals perceived warm-wet andneutral-wet stimuli as significantly less wet than cold-wet stimuli,although these were characterized by the same moisture content. Also,when cutaneous cold and tactile sensitivity was diminished by aselective reduction in the activity of A-nerve afferents, wetnessperception was significantly reduced. Based on a concept of percep-tual learning and Bayesian perceptual inference, we developed thefirst neurophysiological model of cutaneous wetness sensitivity cen-tered on the multisensory integration of cold-sensitive and mechano-sensitive skin afferents. Our results provide evidence for the existenceof a specific information processing model that underpins the neuralrepresentation of a typical wet stimulus. These findings contribute toexplaining how humans sense warm, neutral, and cold skin wetness.

skin; wetness; thermoreceptors; mechanoreceptors; A-nerve fibers

THE ABILITY TO SENSE HUMIDITY and wetness is an importantattribute in the animal kingdom. For many insects, discrimi-nating between dryness and wetness is vital for procreation andsurvival (Liu et al. 2007). Sensing wetness is also critical forhumans, for both behavioral and autonomic adaptations. Per-ceiving changes in ambient humidity and skin wetness hasbeen shown to impact thermal comfort (Fukazawa and Have-nith 2009), and thus thermoregulatory behavior (Schlader et al.2010), in both healthy and clinical populations (e.g., individ-uals suffering from rheumatic pain) (Strusberg et al. 2002).From an autonomic perspective, decreases in ocular wetnessseem to initiate the lacrimation reflex in order to maintain a tearfilm to protect the ocular surface (Hirata and Oshinsky 2012).Also, tactile roughness and wetness discrimination is criticalfor precision grip (Augurelle et al. 2003) and object manipu-lation (André et al. 2010). However, although the ability to

sense wetness plays an important role in many physiologicaland behavioral functions, the neurophysiological mechanismsunderlying this complex sensory experience are still poorlyunderstood (Montell 2008).

In contrast with insects, in which humidity receptors sub-serving hygrosensation have been identified and widely de-scribed (Tichy and Kallina 2010), humans’ largest sensoryorgan, i.e., the skin, seems not to be provided with specificreceptors for the sensation of wetness (Clark and Edholm1985). Thus, as human beings, we seem to “learn” to perceivethe wetness experienced when the skin is in contact with a wetsurface or when sweat is produced (Bergmann Tiest et al.2012) through a complex multisensory integration (Driver andSpence 2000) of thermal (i.e., heat transfer) and tactile (i.e.,mechanical pressure and friction) inputs generated by theinteraction between skin, moisture, and (if donned) clothing(Fukazawa and Havenith 2009). The hypothesis of wetness asa “perceptual illusion” shaped by sensory experience has beensupported by our previous findings. We have recently shownthat exposing the skin to cold-dry stimuli (resulting in coolingrates similar to those occurring during the evaporation of waterfrom the skin) can evoke an illusion of local skin wetness(Filingeri et al. 2013, 2014a, 2014b). This could be due to thefact that we seem to interpret the coldness experienced duringthe evaporation of moisture from the skin as a signal of thepresence of moisture (and thus wetness) on the skin surface. Inline with this hypothesis, we have also observed that duringstatic contact with a warm-wet surface (with a temperaturewarmer than the skin) no local skin wetness was perceived, as noskin cooling, and thus no cold sensations, occurred (Filingeri et al.2014c).

These preliminary findings appeared to be in line with theBayesian concept of perceptual inference (Knill and Richards1996). According to this framework, sensory systems (such asthe somatosensory system) incorporate implicit knowledge ofthe environment and use this knowledge (i.e., sensory experi-ences) to infer about the properties of specific stimuli (Geislerand Kersten 2002). As the sensory feedback received from thesurrounding environment is by nature multimodal (i.e., involv-ing different sensory cues), as well as noisy and ambiguous,perceptual systems are thought to perform online tasks aimingto predict the underlying causes for a sensory observation in afashion that is considered as near optimal (Lochmann andDeneve 2011). In this context, humans have been shown tointegrate the different sensory cues associated with an externalstimulus and to infer the most probable multimodal estimate(i.e., perception) by taking into account the reliability of each

Address for reprint requests and other correspondence: G. Havenith, Environ-mental Ergonomics Research Centre, Loughborough Design School, Loughbor-ough Univ., Loughborough, LE11 3TU, UK (e-mail: [email protected]).

J Neurophysiol 112: 1457–1469, 2014.First published June 18, 2014; doi:10.1152/jn.00120.2014.

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sensory modality involved in the perceptual process (Ernst andBanks 2002; Weiss et al. 2002).

The potential ability of our neural systems to solve theinherent uncertainty associated with sensory interpretation in aprobabilistic and predictive manner (Lochmann and Deneve2011) explains why many apparently idiosyncratic perceptualillusions (see, e.g., the effects of luminance contrast on theperception of motion velocity; Weiss et al. 2002) are insteadwhat one would expect from a rational perceptual system(Geisler and Kersten 2002). Thus sensory illusions, such as theperception of wetness, can be used as a powerful method togain conceptual and functional understanding of the sensoryprocessing operated by specific sensory systems such as thesomatosensory system (Lochmann et al. 2012).

In this respect, our previous work has shown that the coldsensations resulting from the afferent activity of the cutaneouscold-sensitive, myelinated A�-nerve fibers (with conductionvelocities ranging from 5 to 30 m/s) (Campero et al. 2001) playa critical role in the ability to perceive skin wetness (Filingeriet al. 2013, 2014a, 2014b, 2014c). Furthermore, we haverecently demonstrated that tactile inputs, which are likely to beencoded by cutaneous mechanosensory A�-nerve fibers (withconduction velocities ranging from 16 to 100 m/s) (Tsunozakiand Bautista 2009), could have a role in modulating theperception of skin wetness (Filingeri et al. 2014a). Thus theseobservations have led us to hypothesize that the central inte-gration of coldness and mechanosensation, as subserved byperipheral myelinated A-nerve fibers, might be the primaryneural process underpinning humans’ ability to sense wetness.However, what remains unclear is the individual roles ofthermal and tactile cues and how these are integrated periph-erally as well as centrally. If the multimodal integration ofcoldness and mechanosensation was the main neural processfor sensing wetness, it would be reasonable to hypothesize thatduring the contact with a wet surface the absence of anycoldness and mechanosensation, if either naturally (i.e., contactwith a warm-wet or neutral-wet surface) or artificially (i.e.,during a selective reduction in the activity of A-nerve fibers)induced, would result in a reduced cutaneous sensitivity towetness. Hence, in the present study we used psychophysicalmethods to investigate the role of thermal and tactile afferentsand their central integration in the perception of skin wetnessunder normal fiber function and under a selective reduction inthe activity of A-nerve afferents.

We tested the hypothesis that under normal nerve fiberfunction wetness perception is primarily driven by the integra-tion of cold and tactile inputs as subserved by A-nerve fibers.Furthermore, we hypothesized that during a selective reductionin the activity of A-nerve fibers the artificially induced reduc-tion in cutaneous cold sensitivity and mechanosensitivitywould translate in a significant reduction in the extent ofperceived wetness. Finally, given the anatomical and func-tional differences in cutaneous thermal sensitivity and mecha-nosensitivity between hairy and glabrous skin (Abraira andGinty 2013; Haggard et al. 2013; Pleger and Villringer 2013),here we investigated whether the proposed neurophysiologicalmodel of wetness sensitivity applies similarly to the forearm(i.e., hairy) as well as to the index finger pad (i.e., glabrous). Ashairy and glabrous skin sites have been shown to differ in termsof innervation and particularly in terms of density of thermo-sensory and mechanosensory afferents as well as in their

biophysical properties (e.g., thickness and thermal conduc-tance) (Abraira and Ginty 2013), it was hypothesized that,because of the primary role of thermal cues in sensing wetness(Filingeri et al. 2013, 2014a, 2014b, 2014c), the higher thermalsensitivity of the hairy skin (due to its larger density ofthermoreceptors and to its lower thermal conductance) (Norr-sell et al. 1999) would translate in wetness being perceived inlarger magnitude on this skin site as opposed to the glabrousskin, despite the fact that latter presents a larger density ofslowly adapting type 1 mechanosensory afferents, also knownas Merkel cells (low-threshold mechanoreceptors transmittingacute spatial images of tactile stimuli with remarkably highspatial resolution) (Abraira and Ginty 2013), which couldpotentially contribute to an increase in the haptic perception ofwetness on this type of skin.

METHODS

Participants

Thirteen healthy male university students (mean age 21 yr, SD 2;mean height 185 cm, SD 9; mean body mass 86 kg, SD 12) with nohistory of sensory-related disorders volunteered to participate in thisstudy. All participants gave their informed consent for participation.The test procedure and the conditions were explained to each partic-ipant. The study design was approved by the Loughborough Univer-sity Ethics Committee, and testing procedures were in accordancewith the tenets of the Declaration of Helsinki.

A sample size calculation was performed in order to determine theminimum number of participants required to be able to detect asignificant change in thermal sensitivity and mechanosensitivity as aresult of the selective block protocol. Pilot tests data indicated that thedifference in the thermal sensations of matched pairs (block vs.no-block trials) was normally distributed with a standard deviation of�10 arbitrary units (a.u.). As we set the true difference in the meanthermal sensation of matched pairs at a value of 15 a.u., it wascalculated that a minimum number of 12 participants was needed to beable to reject the null hypothesis that this response difference is zerowith probability (power) 0.8. The type I error probability associatedwith this test of this null hypothesis (�) was 0.05. Sample sizecalculations were performed with Power and Sample Size Calculationversion 3.0 2009 (Vanderbilt University).

Experimental Design

Participants took part in three experimental trials, during which thesame quantitative sensory test was administered. The hairy skin of theventral side of the left forearm (i.e., middistance between elbow andwrist) and the glabrous skin of the left index finger pad were exposedto contact with a warm-wet (35°C), a neutral-wet (30°C), and acold-wet (25°C) stimulus during three phases: static, dynamic, andevaporation (i.e., after contact). During contact with the stimuli,participants reported their local thermal and wetness perceptions on ahand-scored 100-mm visual analog scale for thermal (anchor points:hot and cold) and wetness (anchor points: completely dry and com-pletely wet) perception, while skin temperature at the contact site wascontinuously monitored. The three experimental trials differed withregard to the presence or absence of a selective reduction in theactivity of A-nerve fibers and to the skin site stimulated. All 13participants performed one trial during which no nerve block wasperformed (NO-BLOCK) and the skin of the forearm and finger padwere exposed to the wet stimuli and two separate trials during whicha selective reduction in the activity of A-nerve fibers was performedthrough local compression ischemia and the skin of the forearm(FA-BLOCK) or finger pad (FI-BLOCK) was exposed to contact with

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the wet stimuli. Trials were performed in a balanced order, on separatedays, with at least 72 h in between.

The thermal stimuli were delivered by a thermal probe (PhysitempInstruments) with a contact surface of 25 cm2 and a weight of 269 g.To make the contact with the probe’s surface wet, test fabrics (100%cotton) with a surface of 100 cm2 were placed on the thermal probeand fixed by an elastic band. These were wetted with 2,000 �l ofwater at ambient temperature (�23°C) with a variable-volume pi-pettor (SciQuip, Newtown, UK). To ensure that the wet fabric wouldreach the required temperature (i.e., 35°C, 30°C, or 25°C), the contacttemperature between the probe and the test fabric was monitored witha thin thermocouple (0.08-mm wire diameter, 40 gauge; 5SRTC-TT-TI-40-2M, Omega, Manchester, UK) placed on the thermal probesurface. Also, local skin temperature (Tsk) at the contact site ofstimulation was measured continuously through the application of athermocouple on the ventral side of the forearm or index finger padwith Transpore tape (3M, Loughborough, UK), with the sensor tiptouching the skin but not covered by tape. Probe-fabric temperature aswell as Tsk were monitored with a Grant Squirrel SQ2010 data logger(Grant Instruments, Cambridge, UK).

During all the trials, participants rested in a seated position in athermoneutral environment (air temperature: �23°C; relative humid-ity: �50%). Participants were informed only about the skin sitesubjected to the stimulation and the trial to be performed (block vs. noblock). No information was made available on the type and magnitudeof the stimulation, to limit any expectation effects. To make thispossible, an S-shaped wooden panel (width: 81 cm; length: 74 cm;height: 60 cm) was placed on a table. A hole (width: 12 cm; height:13 cm) in the panel allowed participants to insert their left forearmthrough the panel. This experimental setup did not allow the partici-pants to see the stimulated area.

Experimental Protocols

NO-BLOCK trial. In the NO-BLOCK trial, no compression isch-emia was performed and participants interacted actively with thewarm-wet, neutral-wet, and cold-wet stimuli. Forearm and indexfinger pad skin sites were tested separately within this trial, allowinga 5-min interval between them.

The thermal probe was secured with surgical tape on the side of thetable that was not visible to the participants, with the thermallycontrolled surface facing upward. Prior to interacting with each wetstimulus, and in order to set a baseline Tsk of 30°C, participants wereasked to insert their left arm through the hole in the panel and placethe forearm or index finger pad for 30 s on the dry thermal probe,which was set at 30°C. Participants then removed the arm from thethermal probe, placed it on the side of the table visible to them, andwaited 1 min for the first stimulus to be prepared. During this time, theprobe was set to the required temperature (i.e., 35°C, 30°C, or 25°C)and the test fabric was secured to the probe and then wetted with thepipettor. Pilot tests indicated 1 min as the time required for the wet testfabric to reach the selected temperature. Once the stimulus preparationwas completed, the interaction with the wet stimulus was initiated.This consisted of three phases (each lasting 10 s): static, dynamic, andevaporation (i.e., after contact). First, participants were instructed toinsert their left arm through the hole in the panel and to lower it untilthe forearm or index finger pad was in full contact with the thermalprobe. As soon as they were in static contact, they were encouraged torate their local thermal and wetness perceptions by marking a point onthe thermal and wetness scales they were provided with on the side ofthe table that was visible to them (response time �5 s). Thenparticipants were asked to move the forearm or index finger padforward (�2.5 cm) and backward (�2.5 cm) twice while maintainingfull contact with the thermal probe. At the end of this dynamicinteraction they were asked again to rate their local thermal andwetness perceptions (response time �5 s). Finally, they were asked tolift the forearm or index finger pad up from the thermal probe, thus

allowing evaporation of any residual moisture on the skin, and as soonas they were not in contact with the probe, to rate their local thermaland wetness perceptions for the last time (response time �5 s). Thissequence (i.e., setting the baseline skin temperature, preparing, andthen interacting with the wet stimulus) was repeated for each of thethree wet stimuli in a balanced order, with at least 1 min betweenthem.

As no visual feedback was available during the stimulation, toensure consistency in the interaction with the stimuli (i.e., pressureapplied to the probe and horizontal displacement during the dynamicphase), the investigator gently guided the participant’s arm throughoutthe interaction with each stimulus and provided verbal instructions onwhen to change the interaction (e.g., from static to dynamic). Allparticipants were familiarized with the experimental protocol prior totesting. Participants were also familiarized with the rating scales priorto testing. When reporting thermal sensations, they were instructed toassociate the anchor point “Hot” (on the left of the scale) with the ideaof a burning hot pan and the anchor point “Cold” (on the right of thescale) with the idea of an ice cube and to mark a point on the scale thatcorresponded to the level of warmness or coldness experienced. Themidpoint of the scale was suggested as a neutral point (to be markedif neither hot nor cold sensations were experienced). When reportingwetness perceptions, they were instructed to associate the anchor point“Completely dry” (on the left of the scale) with the absence of anywetness. Thus any marked point that was not on the left edge of thescale was to be considered to correspond to the perception of wetness;the closer this was to the anchor point “Completely wet” (on the rightof the scale), the greater the level of wetness experienced. The visualanalog scales used in this study were hand-scored on laminated paper.Washable markers were used by the participants to mark their sensa-tion so that the same scale could be reused within the same test afterparticipants’ ratings were recorded and cleaned off with a wet cottonpad.

FA-BLOCK and FI-BLOCK trials. In the FA-BLOCK and FI-BLOCK trials, participants underwent an initial selective reduction inthe activity of A-nerve fibers and then were passively exposed to thewarm-wet, neutral-wet, and cold-wet stimuli. The aim of this proce-dure was to reduce cutaneous cold sensitivity and mechanosensitivity,and it was performed through a modified local compression ischemiaprotocol. This method has been previously shown to induce a disso-ciated reduction in A-fiber afferent activity (Davis 1998; Yarnitskyand Ochoa 1990), as the compression ischemia impacts transmissionin myelinated A fibers before C fibers (i.e., primarily subservingconscious warmth and pain sensitivity) are affected (Torebjörk andHallin 1973). Compression ischemia was induced by inflating asphygmomanometer cuff on the upper arm to a suprasystolic pressure(i.e., 140 mmHg) for a maximum duration of 25 min. During thecompression ischemia protocol, thermal sensitivity to warm (i.e.,35°C) and cold (i.e., 25°C) dry stimuli as well as mechanical sensi-tivity to light brush were checked every 5 min. It deserves mentionthat, despite changes in mechanosensitivity and cold sensitivity, themaximal duration of the compression ischemia was set to 25 min inorder to limit the discomfort and pain the participants could experi-ence underneath the cuff (Note: this duration does not include thesubsequent stimulation with the wet stimuli, whose approximateduration was �8 min). Although the literature reports compressionblocks lasting between 27 and 60 min and performed with pressuresup to 100 mmHg above systolic pressure (see, e.g., Davis 1998;Yarnitsky and Ochoa 1990;), our pilot studies indicated that theduration chosen as well as the pressure used were sufficient to inducea gradual reduction in cold sensitivity and mechanosensitivity, whilekeeping participants’ overall discomfort at a minimum. Indeed, duringour preliminary testing, participants could not bear the 140-mmHgcuff pressure for longer than 35–40 min because of the excessivediscomfort experienced underneath the cuff.

Prior to the application of the compression ischemia protocol,instrumentation and baseline measurements were performed. Partici-

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pants were asked to sit on a chair for 15 min, at the end of whichresting blood pressure was measured from the left wrist with a digitalwrist blood pressure monitor (Speidel and Keller, Jungingen, Ger-many) while the arm was supported at heart level. Participants theninserted their left arm through the hole in the panel and laid it downwith the palm facing upward while a 13-cm-wide sphygmomanometercuff (Hokanson, Bellevue, WA) was placed around the arm (i.e.,middistance between shoulder and elbow). The sphygmomanometercuff was connected to a custom-made cuff inflator. According to theexperimental trial, a thermocouple was then taped to the ventral sideof the forearm or to the index finger pad to record Tsk throughout thetest. An 8-mm optic probe was taped to the ventral side of the forearm(proximal to the elbow joint) and connected to a laser Dopplermonitor (Moor Instruments, Axminster, UK) to record skin bloodflow. Finally, to allow thermal stimulation of the skin, the thermalprobe, set at 30°C, was secured with tape on the forearm or indexfinger pad (with the thermally controlled surface in full contact withthe skin), where it rested during the first part of the test.

After instrumentation, baseline Tsk and skin blood flow wererecorded for 5 min while participants were asked to maintain acomfortable seated position, having their left arm lying on the left-hand side of the table (which was not visible to them) and their rightarm on the right-hand side, where the rating scale and washablemarker were positioned to allow ratings of sensation when required.This position was maintained throughout the whole test. At this pointbefore compression ischemia cutaneous thermal sensitivity andmechanosensitivity were tested as follows: the thermal probe’s tem-perature was first set to 35°C (i.e., warm-dry stimulus), and as soonthis temperature was reached (response time �4 s) participants wereimmediately asked to rate their thermal sensation only, by marking apoint on the thermal sensation scale. The thermal probe was then resetto 30°C. As soon as the Tsk returned to 30°C (this was monitoredonline on the data logger recording from the thermocouple placed onthe skin site stimulated) the thermal probe’s temperature was changedto 25°C (i.e., cold-dry stimulus), and as soon this temperature wasreached participants were asked again to rate their thermal sensationonly. The thermal probe was then reset to 30°C. Finally, the skin nearthe stimulated site was gently touched with a cotton pad and partic-ipants were asked to report verbally whether they could sense thetouch. As soon as the baseline measurements were completed, thecustom-made cuff inflator was started, the sphygmomanometer cuff wasinflated with the required pressure (time to reach the pressure: �5 s),and the compression ischemia protocol was initiated. The cutaneoussensitivity test was then repeated as above every 5 min. When theinability to perceive the light brush was observed, along with areduction in thermal sensitivity to the cold stimulus, the thermal probewas removed from the skin site, and the warm-wet, neutral-wet, andcold-wet stimuli were prepared and then applied according to aprotocol identical to that performed during the NO-BLOCK trial (i.e.,static, dynamic, and evaporation phases), with the only differencebeing that the investigator applied the thermal probe instead of theparticipants placing their forearm or finger pad on it.

Statistical Analysis

In the present study, the independent variables were the tempera-ture of the stimuli (i.e., 35°C, 30°C, and 25°C), the different phases ofstimulation (i.e., static, dynamic, and evaporation), the skin sitestimulated (i.e., forearm and index finger pad), and the condition (i.e.,presence or absence of a selective reduction in A-fiber activity). Thedependent variables were local Tsk, thermal sensation, and wetnessperception. All data were first tested for normality of distribution andhomogeneity of variance with Shapiro-Wilk and Levene’s tests, re-spectively. To investigate the role of thermal and mechanical cues oncutaneous thermal and wetness sensitivity, and whether differencesexist between hairy and glabrous skin, data from the NO-BLOCK trialwere analyzed by a three-way repeated-measures ANOVA, with

temperature of the stimuli (3 levels), phase of stimulation (3 levels),and skin site (2 levels) as repeated-measures variables. To investigatewhether the compression ischemia protocol was effective in selec-tively reducing A-nerve fiber function in both forearm and indexfinger pad skin sites, thermal ratings recorded prior to and at the endof the protocol (i.e., just before the wet stimuli were applied) werecompared for both warm and cold stimulations by using paired t-tests.To investigate whether a reduction in cutaneous cold sensitivity andmechanosensitivity decreased the ability to perceive skin wetness,data from the NO-BLOCK and BLOCK trials were analyzed sepa-rately for the forearm and index finger pad by a three-way repeated-measures ANOVA, with condition (2 levels), temperature of thestimuli (3 levels), and phase of stimulation (3 levels) as repeated-measures variables. Data were tested for sphericity, and if the assump-tion of sphericity was violated Huynh-Feldt or Greenhouse-Geissercorrections were undertaken to adjust the degrees of freedom for theaveraged tests of significance. Estimated marginal means and 95%confidence intervals (CIs) were used to investigate the main effectsand interactions of the variables. When a significant main effect wasfound, Tukey’s post hoc analyses were performed. To quantify thepower associated with the statistically nonsignificant results, observedpower was computed with � � 0.05 and reported. In all analyses, P �0.05 was used to establish significant differences. Furthermore, ac-cording to Curran-Everett and Benos (2004), precise P values wereinterpreted as follows: P � 0.1 data are consistent with a true zeroeffect; 0.05 � P � 0.1 data suggest that there may be a true effect thatdiffers from zero; 0.01 � P � 0.05 data provide good evidence thatthe true effect differs from zero; and P � 0.01 data provide strongevidence that the true effect differs from zero. Data were analyzedwith SPSS Statistics 19 (IBM, Armonk, NY) and are reported asmeans and SD and 95% CI.

RESULTS

Cutaneous Sensitivity to Wetness Under Normal A-NerveFiber Function (NO-BLOCK Trial)

During the initial static contact with the warm-wet, neutral-wet, and cold-wet stimuli, forearm skin and index finger padTsk respectively increased, remained unchanged, or decreased(Fig. 1, A and C). These variations in Tsk remained stableduring the following dynamic phase. During the evaporationphase Tsk started to return to prestimulation values after thewarm-wet and cold-wet stimulations, whereas it started todecrease after the neutral-wet stimulation.

As a result, participants reported thermal sensations thatvaried significantly according to the temperature [F �28.8(1.2,12.9), P � 0.0001] and phase of interaction [F �6.3(2,22), P � 0.007] with the wet stimuli. A trend was ob-served, with the forearm being more thermally sensitive thanthe finger pad [F � 3.6(1,11), P � 0.085, observed power �0.4]. Overall, thermal sensations matched the variations ob-served in local Tsk, with the warm-wet stimulus resulting inwarmer sensations, the neutral-wet stimulus in neutral sensa-tions, and the cold-wet stimulus in colder sensations (Fig. 1, Eand G).

With regard to wetness sensitivity, although all the stimulipresented the same level of physical wetness (i.e., 20 �l/cm2),participants reported wetness perceptions that increased signifi-cantly with decreasing contact temperatures [F � 5.3(2,24), P �0.012] (Fig. 2A). Also, wetness perception increased signifi-cantly during the dynamic as opposed to the static contact [F �11.5(2,24), P � 0.0001] (Fig. 2B). Overall, a trend was observedin the interaction between temperature and phase of stimulation



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[F � 2.38(4,48), P � 0.064, observed power � 0.6]. Thisindicated that during the static phase the cold-wet stimulus wasperceived as “wetter” than the warm-wet and neutral-wetstimuli and that during the dynamic and evaporation phases,wetness perceptions increased for all stimuli (Fig. 1, I and K).Finally, a trend of the effect of skin site on wetness perceptionwas observed [F � 3.5(1,12), P � 0.086, observed power �0.4], with the forearm showing a tendency in having a highersensitivity to wetness (mean � 30.4 a.u.; CI � 21.8, 39 a.u.) thanthe index finger pad (mean � 18.2 a.u.; CI � 8.3, 28.1 a.u.).

Overall these results indicate that the perception of skinwetness was driven by the coldness experienced, and that whenno coldness was perceived (e.g., warm-wet and neutral-wetstimulations), participants’ ability to sense wetness relied onthe mechanical inputs generated during the dynamic interactionwith the wet surface.

Selective Reduction in Activity of A-Nerve Fibers

To test the effectiveness of the selective reduction in theactivity of A-nerve fibers, during the compression ischemiaprotocol thermal sensitivity to warm (i.e., 35°C) and cold (i.e.,25°C) dry stimuli as well as mechanical sensitivity to light

brush were checked every 5 min. As a result of the protocol, astatistically significant reduction in thermal sensitivity to coldwas observed, both in the forearm (mean difference � �17.3a.u.; CI � �2.9, �31.7 a.u.; t � �2.6; 2-tailed P � 0.022;Fig. 3A) and index finger pad (mean difference � �16.8 a.u.;CI � �7.7, �25.9 a.u.; t � �1.5; 2-tailed P � 0.002; Fig. 3B).No significant differences in thermal sensitivity to warmthwere observed at the end of the selective block protocol, eitherin the forearm (mean difference � �5.1 a.u.; CI � �5.6, 15.9a.u.; t � 1.04; 2-tailed P � 0.32; Fig. 3C) or in the index fingerpad (mean difference � �5.9 a.u.; CI � �14.4, 2.6 a.u.; t ��1.5; 2-tailed P � 0.15; Fig. 3D). As the warm and cold drystimuli produced the same relative variations in local Tsk

throughout the compression ischemia protocol (Fig. 4), theseresults indicate that this procedure was effective in selectivelyreducing cutaneous cold sensitivity of both forearm and fingerpad, while keeping warmth sensitivity intact. With regard tomechanosensitivity, at the end of the compression ischemiaprotocol 2 of 13 participants were not able to sense the lightbrush on the forearm (FA-BLOCK trial), whereas during theFI-BLOCK trial 12 of 13 participants were not able to sense thelight brush on the finger pad.

Fig. 1. Forearm and finger pad skin temperature and corresponding ratings for thermal sensation and wetness perception [arbitrary units (a.u.)] during the static(STAT), dynamic (DYN), and evaporation (EVAP) phases of contact with the warm-wet (35°C), neutral-wet (30°C), and cold-wet (25°C) stimuli. A and C, Eand G, and I and K show skin temperature, thermal sensation, and wetness perception data, respectively, as recorded during the NO-BLOCK trial for the forearmand finger pad. B and D, F and H, and J and L show skin temperature, thermal sensation, and wetness perception data, respectively, as recorded during theBLOCK trial for the forearm and finger pad. Two tendencies are illustrated. In the NO-BLOCK trials, thermal sensations matched the variation in skintemperature and wetness perceptions increased with decreasing contact temperatures (static phase) and from static to dynamic to after contact (evaporation). Inthe BLOCK trials, cold sensitivity was reduced in the forearm, and both warmth and cold sensitivity were reduced on the finger pad. This resulted in a significantdecrease in wetness perceptions during all temperature stimulations (and particularly during the cold stimulation) and during all phases of interaction. Data arereported as means (group average n � 13) and SD (vertical lines).



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Changes in cold sensitivity and mechanosensitivity oc-curred earlier for the finger pad than for the forearm. For 11of 13 participants, the selective block lasted 20 min duringthe FI-BLOCK trial and 25 min during the FA-BLOCK trial.It deserves mention that the selective block resulted inparadoxical heat sensations during cold stimulation in fourparticipants in the FA-BLOCK trial and six participants inthe FI-BLOCK trial. Before the application of the selectiveblock, average values for resting systolic and diastolicpressure were 135 mmHg (SD 8) and 66 mmHg (SD 6),respectively.

Cutaneous Sensitivity to Wetness Under Selective Reductionof A-Nerve Fiber Function

As soon as the compression ischemia protocol proved effec-tive, the quantitative sensory test was initiated. The results ofthe sensory test are presented individually for the forearm andthen for the finger pad. Similar outcomes were observed forboth forearm and finger pad during contact with the wetstimuli, after cold sensitivity and mechanosensitivity werereduced with the selective block protocol.

With regard to the forearm, during the initial static contactwith the warm-wet, neutral-wet, and cold-wet stimuli forearmTsk showed variations similar to those recorded during theNO-BLOCK trial (Fig. 1B). However, a significant effect ofthe compression protocol [F � 10.6(1,11), P � 0.008] wasfound on thermal sensation. During the contact with the warm-wet and neutral-wet stimuli, participants’ thermal sensationsdid not differ significantly between NO-BLOCK and FA-BLOCK trials. However, as a result of the same cold-wetstimulus applied to the forearm, significantly “less cold” thermalsensations were reported during the FA-BLOCK trial (CI � 39.7,65.5 a.u.) than during the NO-BLOCK trial (CI � 61.3, 82.5 a.u.)(Fig. 1F). These results confirmed that at the time of applicationof the wet stimuli the forearm presented a reduced thermalsensitivity to cold.

This artificially induced reduction in cold sensitivity trans-lated into a reduced perception of wetness of the forearm (Fig.1J). Overall, the magnitude of perceived wetness was sig-nificantly reduced during the FA-BLOCK trial (CI � 4.9,18.8 a.u.) compared with the NO-BLOCK trial (CI � 21.8,39 a.u.) [F � 13.7(1,12), P � 0.003] (Fig. 5A). A trend in the

Fig. 2. A and B: ratings for wetness perception grouped forforearm and finger pad and averaged over temperature of thestimuli (35°C, 30°C, and 25°C; A) and phase of stimulation(static, dynamic, and evaporation; B) as recorded during theNO-BLOCK trial. C and D show data as recorded for theforearm during the FA-BLOCK trial, whereas E and F showdata as recorded for the finger pad during the FI-BLOCK trial.Two tendencies are illustrated. During the NO-BLOCK trial,wetness perception increased with decreasing contact temper-atures and from static to dynamic and evaporation phases.During the BLOCK trials, wetness perception was reduced atany temperature for both forearm and finger pad, and nochanges occurred from static to dynamic phase. Data arereported as means (group average n � 13) and 95% confidenceinterval (CI; vertical lines).



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interaction between the effect of the block and the temper-ature of the stimuli was observed [F � 3(2,24), P � 0.07,observed power � 0.5], with the greatest reduction inperceived wetness occurring during the cold-wet stimulation(see comparison between Fig. 1, I and J). Finally, a signif-icant interaction between condition and phase of stimulationwas found [F � 11.7(2,24), P � 0.0001]. As opposed to theNO-BLOCK trial, during which wetness perception in-creased from static to dynamic and evaporation, during theFA-BLOCK trial no changes in the forearm wetness percep-tion from static to dynamic and a decrease from dynamic toevaporation occurred (Fig. 2D). Overall these results indi-cate that the significant reduction in the magnitude ofperceived wetness observed during the FA-BLOCK trialwas mainly due to the reduced cutaneous cold sensitivityand mechanosensitivity of the forearm.

Similar results were observed during the index finger padcontact with the wet stimuli (i.e., FI-BLOCK trial). Duringthe initial static contact with the warm-wet, neutral-wet, andcold-wet stimuli, finger pad Tsk respectively increased (i.e.,warm-wet and neutral-wet) or decreased (i.e., cold-wet)(Fig. 1D). As a result of the contact with the warm-wet andcold-wet stimuli, “less warm” and “less cold” thermal sen-sations were reported during the FI-BLOCK trial than dur-ing the NO-BLOCK trial (Fig. 1H). This interaction be-

tween condition (i.e., block vs. no block) and temperature ofthe stimuli was found to be statistically significant [F �13.1(1.5,17.6), P � 0.001]. These results indicated that at thetime of application of the wet stimuli the index finger padpresented a reduced thermal sensitivity to warmth and cold.This translated into a reduced sensitivity to wetness (Fig.1L). A significant effect of condition [F � 13.9(1,12), P �0.003], a trend in temperature of the stimuli [F � 2.9(2,24),P � 0.072, observed power � 0.5], and a significant effectof phase of stimulation [F � 5.9(2,24), P � 0.008] werefound on wetness perception (Fig. 2E).

Overall wetness sensitivity was significantly reduced dur-ing the FI-BLOCK trial (CI � 0, 2.5 a.u.) compared with theNO-BLOCK trial (CI � 8.3, 28.1 a.u.) (Fig. 5B). A signif-icant interaction between condition and phase of stimulationwas found [F � 5.7(2,24), P � 0.001]. As opposed to theNO-BLOCK trial, during which wetness perceptions in-creased from static to dynamic, during the FI-BLOCK trialno changes were observed from static to dynamic to evap-oration (Fig. 2F). Overall these results reflect those ob-served with the forearm during the FA-BLOCK trial andindicate that the significant reduction in wetness sensitivityobserved on the finger pad during the FI-BLOCK trial wasmainly due to the reduced cutaneous thermal sensitivity andmechanosensitivity of this skin site.

Fig. 3. Ratings for thermal sensation as a resultof the cold (25°C) and warm (35°C) stimuli asrecorded before (Pre-BLOCK) and at the endof (i.e., just before application of wet stimuli,Post-BLOCK) the compression ischemia pro-tocol. A and C show average and individualratings for thermal sensation for the forearm.B and D show average and individual ratingsfor thermal sensation for the finger pad. Meandifference (group average n � 13) and 95% CIbetween Pre and Post-BLOCK are also shown.One main tendency is illustrated. At the end ofthe BLOCK trials, thermal sensitivity on thecold side was significantly reduced while nosignificant changes in sensitivity on the warmside occurred, both for forearm and finger pad.Data are reported as means (group average n �13) and 95% CI (vertical lines).



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DISCUSSION

The present study focused on the role of cutaneous thermaland tactile afferents and their central integration in the abilityto sense wetness. By exposing hairy and glabrous skin sites tostatic and dynamic contact with warm-wet, neutral-wet, andcold-wet stimuli characterized by the same moisture content(i.e., 20 �l/cm2), we demonstrated that during a static contactwetness perception increases with decreasing contact temper-atures and that during a subsequent dynamic interaction wet-ness perception increases regardless of the thermal inputsavailable. Also, we demonstrated that when cutaneous cold

sensitivity and mechanosensitivity were significantly dimin-ished through a selective reduction in the activity of A-nerveafferents, the extent of perceived wetness was also significantlyreduced, on both the forearm and index finger pad. Finally, atrend was observed, with the extent of perceived wetness beinghigher on the hairy than on the glabrous skin.

In summary, our results indicate that the central integrationof conscious coldness and mechanosensation, as subserved byperipheral myelinated A-nerve fibers, could be the primaryneural process underpinning humans’ ability to sense wetness.To our knowledge the present study is the first to provideevidence in support of the hypothesis that a specific informa-tion processing model for cutaneous wetness sensitivity existsand that this is based on A-type somatosensory afferents.Given these outcomes, we developed the first neurophysiolog-ical model of human cutaneous wetness sensitivity (Fig. 6).

A Neurophysiological Model of Cutaneous WetnessSensitivity

The proposed neurophysiological model is based on theconcept of Bayesian perceptual inference for which sensoryprocessing is considered an inference problem (Knill andRichards 1996). Given noisy and ambiguous sensory inputs(such as thermal and mechanical stimuli on the skin), the brainis thought to estimate which events caused these inputs (e.g.,the presence or absence of physical wetness on the skin), on thebasis of prior knowledge that is acquired and shaped by

Fig. 4. Representative skin blood flow (A) and forearm (B) and finger pad (C)skin temperature as recorded for participant 4 during the cutaneous thermalsensitivity test performed during the BLOCK trials. Cutaneous thermal sensi-tivity was tested as follows: the thermal probe’s temperature was first set to35°C, and as soon this temperature was reached (response time � 4 s)participants were asked to rate their thermal sensation only. The thermal probewas then reset to 30°C. As soon as the skin temperature returned to 30°C, thethermal probe’s temperature was changed to 25°C (i.e., cold stimulus) andparticipants were asked again to rate their thermal sensation only. The thermalprobe was then reset to 30°C. Throughout the compression ischemia protocol,the cold and warm dry stimuli always resulted in the same variation in skintemperature.

Fig. 5. Ratings for wetness perception averaged over condition (NO-BLOCKvs. BLOCK) for the forearm (A) and finger pad (B). A significant reduction inwetness sensitivity was recorded during the BLOCK trials compared with theNO-BLOCK trial, both for the forearm and finger pad. Data are reported asmeans (group average n � 13) and 95% CI (vertical lines).



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sensory experience (Lochmann et al. 2012). In our proposedinformation processing model, two main neural pathways aresuggested to subserve cutaneous wetness sensitivity: one re-ferring to the afferent activity of cold-sensitive A�-nerve fibers(projecting through the spinothalamic tract) and one referringto the afferent activity of mechanosensitive A� fibers (project-ing through the dorsal-column medial lemniscal pathway). Theoutcomes of this study have indeed indicated that in order tosense cutaneous wetness a multimodal integration of thermal(i.e., cold) and mechanical sensory inputs had to take place(Fig. 6A). From a functional point of view, this was confirmedby the fact that when the activity of A-nerve fibers was

selectively reduced the extent of perceived wetness was alsosignificantly reduced (Fig. 6B). From a central processing pointof view, this was confirmed by the fact that, although all thestimuli had the same moisture levels, warm-wet and neutral-wet stimuli were sensed as significantly less wet than thecold-wet stimulus.

Perceptual learning and somatosensory decision makingcould contribute to explaining why the central nervous systemprocesses sensory information about the perception of wetnessin such a fashion (Pleger and Villringer 2013). As the skinseems not to be provided with hygroreceptors (Clark andEdholm 1985), we hypothesized that the primary and second-

Fig. 6. Neurophysiological model of cutaneous wetness sensitivity. Mechanosensitive (A�), cold-sensitive (A�), and warm sensitive (C) nerve fibers and theirprojections from the skin, through peripheral nerve, spinal cord (via dorsal-column medial lemniscal pathway and spinothalamic tract), thalamus, andsomatosensory cerebral cortex (including primary and secondary somatosensory cortices SI and SII, insular cortex, and posterior parietal lobe) are shown. A andB show the neural model of wetness sensitivity (consisting of A� and A� afferents) under normal and selective reduction conditions, respectively, in the activityof A-nerve fibers. C, E, and G show the pathways for wetness sensitivity during static contact with warm, neutral, and cold moisture. D, F, and H show thepathways for wetness sensitivity during dynamic contact with moisture. Tsk, skin temperature.



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ary somatosensory cortices, the insular cortex (a cortical regioninvolved in cold temperature sensation) (Craig et al. 2000), aswell as the posterior parietal lobe (a cortical region concernedwith integrating the different somatic sensory modalities nec-essary for perception) (McGlone and Reilly 2010) could beinvolved in generating a neural representation of a “typical wetstimulus.” This could be based on the multimodal transforma-tion (i.e., information from one sensory submodality can betransformed into a map or reference frame defined by anothersubmodality) of the somatosensory inputs generated when theskin is physically wet (Haggard et al. 2013). As the sensoryinputs associated with the physical experience of wetness areoften generated by heat transfer in the form of evaporativecooling (Ackerley et al. 2012) and mechanical pressure in theform of friction and stickiness (Adams 2013), the typicalneural representation of a wet stimulus might rely on perceiv-ing coldness and stickiness. As for perceptual learning andsomatosensory decision making (Pleger and Villringer 2013),this neural representation could be transformed into a firingrate code, representing the wet stimulus, and then associated tothe perception of wetness. Hence, only if the memorizedcombination of stimuli (i.e., coldness and stickiness) as codedby the specific afferents (i.e., A-nerve fibers) is presented willwetness be sensed. In the occurrence of physical wetness onthe skin, the bottom-up processes (i.e., combination of thermaland mechanical sensory afferents) as well as the top-downprocesses (i.e., inference of the potential perception based onthe neural representation of a typical wet stimulus) mighttherefore interact in giving rise (or not) to the perception ofwetness (Lochmann and Deneve 2011).

At this point, however, although perceiving coldness andstickiness is likely to be determinant in the ability to processwetness at a central level, studies by Gerrett et al. (2013) andeveryday experience suggest that we are able to sense wetnesseven in the absence of coldness (e.g., during exposure to warm,humid environments or when in contact with warm water). Inthese particular conditions, the mechanical and pressure-re-lated sensations resulting from the afferent information gener-ated by cutaneous mechanosensitive fibers could therefore playa critical role in the ability to sense wetness. On the basis of theresults of this study, as well as the available literature, wehypothesized possible mechanisms through which wetness issensed, according to the sensory inputs available when the skinis in contact with warm, neutral, or cold moisture.

Cutaneous Sensitivity to Warm, Neutral, and Cold Wetness

Figure 6, C and D, shows the process through which warmmoisture could be sensed. When the skin is in static contactwith warm moisture (i.e., temperature above Tsk), no activationof cold-sensitive A�-nerve fibers occurs, and only C-fibers(subserving conscious warmth sensitivity) and A�-nerve fibers(subserving light touch) are involved in the somatosensation ofmoisture (Fig. 6C). In this scenario, as A�-nerve fibers are theonly nerve fibers available within the processing model, cuta-neous wetness will be sensed only if a higher level of mecha-nosensory afferents, i.e., a dynamic interaction between skinand warm moisture, occurs (Fig. 6D). A similar mechanismapplies if the skin is in contact with neutral moisture (i.e., witha temperature equal to Tsk) (Fig. 6, E and F). In support of this,Bergmann Tiest et al. (2012) have recently observed that

during the interaction with wet materials (i.e., cotton wool andviscose), Weber fractions for wetness discrimination thresh-olds decreased significantly when individuals were alloweddynamic as opposed to static touching. This indicated thatindividuals’ cutaneous sensitivity to wetness was increased bya higher availability of mechanosensory afferents, as occurringduring the dynamic exploration of the wet materials. Theauthors concluded that when thermal cues (e.g., thermal con-ductance of a wet material) provide insufficient sensory inputsindividuals seem to use mechanical cues (e.g., stickiness re-sulting from the adhesion of a wet material to the skin) to aidthem in the perception of wetness.

In line with Bergmann Tiest et al. (2012), in this study weobserved that the lack of thermal inputs (i.e., in the case ofneutral wetness) translated in a reduced sensitivity to wetness,until a dynamic interaction with the wet stimuli was allowedand a higher level of mechanosensory afferents was then madeavailable for central integration (Fig. 6, E and F). However,and in addition to the findings of Bergmann Tiest et al. (2012),in our proposed neural model we suggest that the extent ofperceived wetness is reduced, and mechanosensory afferentsare therefore more important, not only when thermal cues areinsufficient but also when these are the “incorrect” cues. Thisseems to happen when in contact with warm moisture (Fig. 6,C and D). Although in this case thermal cues in the form ofwarm sensations are available, as these are generated bysensory afferents (i.e., C-nerve fibers) that are “outside” theproposed model for wetness (i.e., relying on A-nerve fibers)and that are not associated with the neural representation of a“typical wet stimulus,” wetness sensitivity to warm moisture isreduced unless more mechanosensory afferents are activated(i.e., stickiness due to the skin friction with the wet stimulus)(Adams 2013; Gerhardt et al. 2008). In line with this, we haverecently shown that during static contact with a wet surfacewarm stimuli (i.e., temperature above Tsk) can suppress theperception of cutaneous wetness (Filingeri et al. 2014c).

Behavioral and learning components could contribute to theconcept of “incorrect” thermal cues. Psychophysical studieshave indeed shown that as humans we tend to associate theblend of warmth and light pressure more with the perception ofoiliness (Cobbey and Sullivan 1922) than with the perceptionof wetness (Bentley 1900). Everyday life further providesevidence in support of why, in the absence of stickiness, warmsensations only seem not to be associated with the perceptionof wetness. For example, a bleeding nose is an experience weusually become aware of only after this has been pointed out tous and the “wet area” has been haptically explored by touch.This could be due to the fact that blood temperature (�37°C)is usually higher than Tsk (�30°C) (Mekjavic and Eiken 2006).

A combination of anatomical, physiological, and learningfactors could also explain the trend observed with the forearm(i.e., hairy skin) being more sensitive to wetness than the fingerpad (i.e., glabrous skin). Hairy and glabrous skin sites differ interms of innervation and particularly in terms of density ofthermo- and mechanosensory afferents as well as in theirbiophysical properties. As observed in this study and as pre-viously shown (Norrsell et al. 1999), hairy skin seems indeedto be more sensitive to thermal stimuli than glabrous skin,which on the contrary presents higher spatial acuity. From thereceptor point of view, this could be due to the fact thatalthough both glabrous and hairy skin sites are innervated with



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slowly adapting type 1 mechanosensory afferents, also knownas Merkel cells (low-threshold mechanoreceptors transmittingacute spatial images of tactile stimuli with remarkably highspatial resolution), glabrous skin presents a higher density ofthese specialized organs for tactile discrimination, a fact thatcould explain the higher spatial acuity to mechanical stimuli ofthis type of skin (Abraira and Ginty 2013). From a biophysicalpoint of view, the presence of a thicker stratum corneum (i.e.,the outermost layer of the skin) on glabrous skin, resulting ina greater thermal insulation of this type of skin, contributes tothe reduced thermal conductance of the finger pad (Rushmer etal. 1966) and therefore to the lower thermosensitivity ofglabrous as opposed to hairy skin during short-contact coolingand/or heating, as a result of the longer time that is needed fora given change in temperature of glabrous skin superficiallayers to penetrate to the underlying tissues (e.g., stratumgranulosum) where the thermoreceptors lie (McGlone andReilly 2010). In this context, as thermal sensitivity seems toplay the key role in sensing wetness, it is therefore reasonableto hypothesize that, despite a larger content in highly spatiallysensitive mechanoreceptive afferents (Abraira and Ginty 2013)that could potentially contribute to an increase in the hapticperception of wetness, the lower thermal sensitivity of theglabrous skin might translate to the palms of the hands beinggenerally less sensitive to wetness than the rest of the body.From a thermoregulatory standpoint, this could be supportedby the fact that, as opposed to regions covered by hairy skin,human hands are indeed more of a specialized organ for heatexchange than a thermosensory organ (Romanowsky 2014).Finally, from a behavioral point of view, the fact that hairy skinpresents a higher sweat production than glabrous skin (forthermoregulatory reasons) (Smith and Havenith 2012) couldresult in individuals expecting to experience cutaneous wetnessin larger magnitude on hairy than on glabrous skin sites.

Further support for the hypothesis of a possible neuralrepresentation of a “typical wet stimulus” being based primar-ily on cold and mechanosensory A-type afferents could befound when looking at the perceptions evoked by the skin’scontact with cold moisture (Fig. 6, G and H). In the case of theskin’s contact with cold moisture (i.e., temperature below Tsk),A�-nerve fibers (subserving cold sensitivity) and A�-nervefibers (subserving light touch) are involved in the somatosen-sation of moisture. In this scenario, as both A� and A�afferents are available within the processing pathway we sug-gest to subserve wetness, the extent of perceived wetness willbe greater compared with the wetness experienced when incontact with warm and neutral moisture. In this study weobserved that although all the stimuli had the same moisturelevels, cold-wet stimuli were sensed as significantly wetterthan warm-wet and neutral-wet stimuli, particularly during thestatic interaction, when only thermal cues were available (Fig.6G). Also, the selective block trials indicated that the extent ofperceived wetness was overall significantly decreased, mainlybecause of the reduced cutaneous cold sensitivity and mecha-nosensitivity.

The critical role of experiencing coldness in the ability tosense wetness is in line with our previous findings. We haverecently demonstrated that an illusion of local skin wetness canbe evoked during the skin’s contact with a cold-dry surfaceproducing skin cooling rates in a range of 0.14–0.41°C/s(Filingeri et al. 2013, 2014a, 2014b), a temperature course that

is similar to that suggested to occur when the skin is physicallywet (Daanen 2009). Evidence in support of the role played bythermal cold afferents in sensing wetness comes from studiesinvestigating the role of cold-sensitive neurons in ocular dry-ness and wetness (Belmonte and Gallar 2011; Hirata andOshinsky 2012). Hirata and Oshinsky (2012) have recentlysuggested that the sensation of “ocular wetness” could be basedon the afferent activity of corneal cold-sensitive neurons,carrying a sensation of gentle cooling via a transient receptorpotential (TRP) channel activation. The authors proposed thisas a potential explanation for why tears on the ocular surfacecould feel wet (Hirata and Oshinsky 2012). The possibility thatcold-sensitive neurons and TRP channels could be criticaldeterminants of the human ability to sense wetness representsan intriguing possibility (Montell 2008), particularly as TRPchannels have been shown previously to be required for hy-grosensation and detection of both dry and moist air in someinsects, such as the fruit fly Drosophila melanogaster (Liu etal. 2007). However, the speculative nature of this hypothesishighlights the need for further experimental evidence in orderto better understand the still little investigated neurophysiolog-ical mechanisms involved in such complex cognitive functionssuch as wetness sensitivity. For example, it must be stressedthat on the basis of the present results it cannot be concludedthat coldness alone (without tactile component) is sufficient forgenerating a perception of wetness. Although we believe that aperception of wetness always results from the combination ofthermal and tactile cues (and in this respect, our proposedprocessing model provides evidence in support of which cuesthe central nervous system relies on more in its prediction ofwetness) (Ernst and Banks 2002), further research should dealwith, e.g., whether wetness could be evoked without any tactilecomponent (e.g., through radiative cooling) or whether tactilestimuli only can evoke wetness, in order to further our under-standing of somatosensation in the context of perceptual infer-ence.

It deserves mention that C-nerve fibers (i.e., polymodalafferents responding to nociceptive, warm, cool, and lightmechanical stimulation with conduction velocities rangingfrom 0.2 to 2 m/s) (McGlone et al. 2014) have been shownpreviously to respond to innocuous cold temperatures (Camp-ero et al. 2001) as well as to touch (Lumpkin and Caterina2007). Therefore, it might be argued that these fibers could alsocontribute to the sensory processing of skin wetness. However,as their contribution to conscious cold sensations has not beenproven conclusively (Schepers and Ringkamp 2010) (thereforesuggesting an alternative autonomic thermoregulatory func-tion) and as their mechanical sensitivity seems to be specifi-cally tuned to affective as opposed to discriminative touch(Löken et al. 2009; Olausson et al. 2010), the contribution ofC-nerve fibers to the perception of wetness seemed not to becritical, at least not within the experimental conditions of thepresent study. Indeed, we observed that the reduction in A-nerve fiber afferent activity, when either naturally (i.e., staticcontact with warm and neutral moisture) or artificially (i.e.,during the compression ischemia protocol) induced, was suf-ficient to significantly change the dynamic of the perception ofwetness (i.e., significantly diminishing the extent of perceivedskin wetness). Nevertheless, because of the polymodal natureof these nerve fibers (McGlone et al. 2014) and because of theabsence of a direct measurement of peripheral neural activity in



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the present study (e.g., by microneurographic recording), thehypothesis of C fibers significantly contributing to the sensoryintegration of skin wetness cannot be ruled out conclusively.

In summary, a neurophysiological model of cutaneous wet-ness sensitivity, based on the multimodal transformation ofA-type somatosensory afferents, was developed in order toexplain how humans could sense warm, neutral, and coldcutaneous wetness. This model supports the hypothesis that thebrain infers about the perception of wetness in a rationalfashion, taking into account the variance associated with ther-mal afferents and mechanoafferents evoked by the contact withwet stimuli, and comparing this with a potential neural repre-sentation of a “typical wet stimulus,” which is based on priorsensory experience. In this respect, our findings have both afundamental and a clinical significance. They provide insightson the integration and processing of somatosensory informa-tion occurring between peripheral and central nervous systems.Also, they provide insights on the possible origin of symptomssuch as spontaneous sensations of cold wetness experiencedacross the body by individuals suffering from multiple sclero-sis or polyneuropathies (Hulse et al. 2010; Nolano et al. 2008;Rae-Grant et al. 1999; Susser et al. 1999). As these disordershave been shown to affect peripheral A-nerve fiber functionsand to alter somatic perception, the neurophysiological modelof cutaneous wetness sensitivity developed in this study couldbe used as a frame of reference for normal and altered somato-sensory function.

DISCLOSURES

The present research was done in the context of an industry-cofunded Ph.D.Loughborough University and Oxylane Research provided financial support.D. Fournet, member of the sponsoring industry (Oxylane Research), contrib-uted to the conception and design of the experiment and contributed to editingand revising the manuscript.

AUTHOR CONTRIBUTIONS

Author contributions: D. Filingeri, D. Fournet, S.H., and G.H. conception anddesign of research; D. Filingeri performed experiments; D. Filingeri analyzed data;D. Filingeri and G.H. interpreted results of experiments; D. Filingeri preparedfigures; D. Filingeri drafted manuscript; D. Filingeri, D. Fournet, S.H., and G.H.edited and revised manuscript; D. Filingeri, D. Fournet, S.H., and G.H. approvedfinal version of manuscript.

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