Yang et al The Journal of Headache and Pain 2014 1571httpwwwthejournalofheadacheandpaincomcontent15171

RESEARCH ARTICLE Open Access

Effect of negative emotions evoked by lightnoise and taste on trigeminal thermal sensitivityGuangju Yang1 Lene Baad-Hansen2 Kelun Wang3 Qiu-Fei Xie1 and Peter Svensson24

Abstract

Background Patients with migraine often have impaired somatosensory function and experience headache attackstriggered by exogenous stimulus such as light sound or taste This study aimed to assess the influence of threecontrolled conditioning stimuli (visual auditory and gustatory stimuli and combined stimuli) on affective state andthermal sensitivity in healthy human participants

Methods All participants attended four experimental sessions with visual auditory and gustatory conditioningstimuli and combination of all stimuli in a randomized sequence In each session the somatosensory sensitivitywas tested in the perioral region with use of thermal stimuli with and without the conditioning stimuli Positive andNegative Affect States (PANAS) were assessed before and after the tests Subject based ratings of the conditioningand test stimuli in addition to skin temperature and heart rate as indicators of arousal responses were collected inreal time during the tests

Results The three conditioning stimuli all induced significant increases in negative PANAS scores (paired t-testP le0016) Compared with baseline the increases were in a near dose-dependent manner during visual and auditoryconditioning stimulation No significant effects of any single conditioning stimuli were observed on trigeminal thermalsensitivity (P ge0051) or arousal parameters (P ge0057) The effects of combined conditioning stimuli on subjectiveratings (P le0038) and negative affect (P = 0011) were stronger than those of single stimuli

Conclusions All three conditioning stimuli provided a simple way to evoke a negative affective state without physicalarousal or influence on trigeminal thermal sensitivity Multisensory conditioning had stronger effects but also failed tomodulate thermal sensitivity suggesting that so-called exogenous trigger stimuli eg bright light noise unpleasanttaste in patients with migraine may require a predisposed or sensitized nervous system

Keywords Quantitative sensory testing Affective state Thermal sensitivity Light Noise Taste

BackgroundMigraine is an inherited episodic disorder involvingchanges in responsivity of the sensory systems Forexample migraine patients complain of headache attackswith increased sensitivity to eg light or sound Somepatients mention that otherwise pleasant odors areunpleasant during the attacks The disorder is consideredas a disturbance in the brain of the subcortical aminergicsensory modulatory systems [1] Overall these observationscould indicate that the migrainous brain does not habituateto signals in a normal way [2-4]

Correspondence xieqiuf163com1Department of Prosthodontics and Center for Oral Functional DiagnosisTreatment and Research Peking University School and hospital ofStomatology Zhongguancun Nandajie 22 100081 Beijing ChinaFull list of author information is available at the end of the article

copy 2014 Yang et al licensee Springer This is anAttribution License (httpcreativecommonsorin any medium provided the original work is p

For a biological system perception often requiresinformation emanating from sensors of multiple modalities[5] For instance human perception of food flavor andtexture during consumption involves taste intraoralsomatosensory function (thermal and mechanical) visionolfaction and auditory signals that contribute to the overallappreciation of food Different sensory modalities mayinteract in a non-linear way as multi-modal sensoryintegration (MSI) [6] Moreover observations that thesomatosensory system may modulate activity in auditorybrain regions become clinically relevant [7] The perceptionof migraine headache is uniquely exacerbated duringexposure to ambient light as compared with the pain levelperceived in the dark [8]

Open Access article distributed under the terms of the Creative Commonsglicensesby40) which permits unrestricted use distribution and reproductionroperly credited

Yang et al The Journal of Headache and Pain 2014 1571 Page 2 of 12httpwwwthejournalofheadacheandpaincomcontent15171

There are several theories to explain MSI One ofthem is the motivational priming model which sug-gested the affective state as a mediator [9] The painsensitivity may be enhanced by evoked unpleasantaffective states while attenuated by pleasant affectivestates and high arousal augments both effects [9]Visual stimuli used in previous studies examiningemotional processes have been either Pictures of FacialAffect or the International Affective Picture System(IAPS) [1011] Music may also evoke comparable emo-tional responses across different musical categories[1112] However the individual background such asculture and education is important for the results ofsuch tests [13] Therefore for example bright light anda chainsaw noise to which responses are less ethniccultural or education-dependent could be useful insome studies Sucrose has been reported to reduce painin children while the effect of unpleasant bitter gusta-tory stimulation on pain has not been systematicallystudied [1415]Another possible effect of cross-modality sensory

regulation could be simply a distraction effect reducingthe perceived stimulus intensity by diverting attentionaway from pain processing [16-18] However one studyindicated that distraction tasks that demand greaterattention processing do not produce greater reductionsin pain [19]It is obvious that real life experiences mostly rely on

the presence of combined stimuli coming from differentmodalities For example music is often used to enhancethe emotion impact of movies The enhancing effect ofcombined presentation of different modalities is how-ever intuitive and understudied [11]Quantitative sensory testing (QST) provides a reliable

and accurate tool for examination of somatosensory func-tion [2021] One study which evaluated the effect of emo-tion on sensory-discriminative parameters indicated thatchanges in pain sensitivity are more often observed for painthreshold measures than for pain tolerance measures [22]The present study aimed to assess the effect of and

possible interactions among different unpleasant con-ditioning stimulus modalities ie visual (light) auditory(noise) gustatory (bitter taste) on affective state physio-logical arousal and thermal somatosensory sensitivity inthe trigeminal system of young healthy human parti-cipants The following hypotheses were tested a thethermal sensitivity of the participants is increased duringexposure to conditioning stimuli compared with no con-ditioning stimuli b the unpleasant stimuli evoke negativeaffective states and physiological arousal compared withbaseline c combination of conditioning stimuli into amulti-sensory conditioning stimulus exerts larger changesin outcome parameters compared with single conditioningstimuli

MethodsParticipantsYoung healthy participants in this study were recruitedfrom university students through the webpage [23] andadvertisements at Aarhus University Denmark Inclusioncriteria were age between 20 to 30 years old physicallyand mentally healthy Exclusion criteria were Opticalauditory gustatory functional disorders infection in thetested area (perioral region) ongoing orofacial pain orreported chronic pain in last 6 months serious systemicdiseases medicine intake with effect on the centralnervous system in the last 2 weeks former experiencewith similar experiments Twenty-five people respondedto the advertisements Finally 20 participants agedbetween 20 to 30 years old (266 plusmn 32) 10 females and10 males met the criteria and were included in this studyThe study adhered to the Helsinki declaration II and was

approved by the local ethics committee (NO 1-10-72-31-13)and all participants gave written informed consent

Study procedureThe twenty participants each attended four experimentalsessions In each session the participants received one offour conditions A visual stimulation with bright lightalone B auditory stimulation with recorded chainsawnoise alone C gustatory stimulation with bitter tastealone and D multisensory stimulation with gustatorystimulation combined with bright light and chainsawnoise The four conditions were applied in a randomizedsequence produced by Microsoft Excel There was aninterval of about one week between sessions A B and CSession D was performed on the same day as session Cafter a 30 min rest period A total of six thermal sensorytests were performed over perioral region in eachparticipant in the A visual or B auditory sessions I base-line 1 II with conditioning stimulus 1 III baseline 2 IVwith conditioning stimulus 2 V baseline 3 VI with condi-tioning stimulus 3 Conditioning stimuli 1ndash3 (visual audi-tory depending on group) were of different intensity (seebelow) In the CD gustatory and multisensory sessionfour thermal sensory tests were performed over perioralregion in each participant I baseline 1 II with gustatoryconditioning stimulus III baseline 2 IV with multisensoryconditioning stimulus (see below) There was a 2 minadaption period before each test and an interval of 5 minbetween tests [2425] Each session lasted approximately60 min for each participant (Figure 1 shows the time lineof 1 thermal test including the conditioning stimulus)The tests were performed in a quiet room with tem

perature at 20ndash22degC All participants were required torefrain from ingestion of all food beverages and oralcare products for a minimum of 2 hour before arrivalThe participants were free from head colds and allergieson the test days

Figure 1 One thermal somatosensory test consists of before stimuli (05 min) stimulus habituation period (2 min) thermal test(~35 min) recovery period (5 min) lsquoHRrsquo = Heart Rate record lsquoTrsquo = face skin temperature record Cold Detection Threshold (CDT) WarmthDetection Threshold (WDT) Cold Pain Threshold (CPT) Heat Pain Threshold (HPT)

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Conditioning stimuliVisual stimuliVisual stimuli were created using three levels of bright lightshined directly at the participantsrsquo eyes in a randomized se-quence produced by Microsoft Excel (i) 1000 lux brightlight (ii) 3000 lux bright light (iii) 9000 lux bright light[2627] The bright light was generated using dental chairlamp with an area of 14 times 9 cm (ESTETICA E80 KaVoGermany) and calibrated by a Luxmeter (LX1010B+Malmbergs Sweden) There was a control test before eachtest without visual stimuli to eliminate timing effect inwhich the participants wore eyeshades and closed theireyes to make sure they did not see any light

Auditory stimuliParticipants were instructed to remain awake with eyescovered by eyeshades and were exposed to recordedsounds of an electric chainsaw at three different intensities(60 dB 75 dB 90 dB) in randomized sequence producedby Microsoft Excel [628] The noise was generated by acomputer through loud-speakers and measured by SoundPressure Lever Meter (RadioShack 33ndash2055 USA) A con-trol test was performed before each test without soundstimulus to eliminate the effect of timing

Gustatory stimulusParticipants were instructed to rinse with distilled waterat least four times over a 1 min period prior to testingGelatin was the vehicle for gustatory stimuli The partic-ipants were asked to hold 20 ml gelatin (2 bovine skingelatin Sigma-Aldrich St Louis USA) in their mouthwith either bitter (01 quinine Sigma-Aldrich adulttoxic dose 25 ndash 4 g) or neutral taste (2 gelatin) [29]The gustatory stimuli were presented at roomtemperature (~21degC) with an at least four times distilledwater rinse after each test for 5 min until the taste hasbeen washed out [30]

Multisensory stimuliThe three conditioning stimulus modalities (visual 9000lux light auditory 90 dB noise and gustatory 01 quininegelatin) were presented simultaneously to each participantwith a control test (no visual no auditory amp neutral taste)

All the conditioning stimuli were given in repeated trials3 trials for the visual or auditory tests and 1 trial for thegustatory or combination tests The stimuli were started2 min before each thermal test and ended after the emo-tion evaluations thus each episode of stimulus lastedabout 7 min (Figure 1)

Thermal sensitivity measuresParticipants were positioned in a comfortable dental chairThe measures were performed in the right perioral regionwith the thermode placed on the right angle of the mouthThe thermal tests were performed using a Medoc Pathwaywith ATS thermode (30 mm times 30 mm square surfaceMEDOC Israel) Care was taken throughout the sessionto keep the test sites during the repeated testing the sameCold and warmth detection thresholds (CDT WDT) weremeasured first Then cold pain and heat pain thresholds(CPT HPT) were determined [2021] The mean thresholdtemperature of three consecutive measurements was cal-culated All thresholds were obtained with ramped stimuli(1degCs) that were terminated when the participantspressed a button For thermal detection thresholds theramp back to baseline was 1degCs while for thermal painthresholds this ramp was chosen at 5degCs The baselinetemperature was 32degC Cut-off temperatures were set at 0degCand 50degC respectively [2021] A standardized verbal instruction was read to the participants and a training test wasperformed before the actual tests to make sure that theparticipants understood the thermal test program [20]

Psychometrical and physiological measuresThe perceived intensity of the conditioning stimuli wasassessed using a numerical scale from ldquo0 = no stimuluscould be detectedrdquo to ldquo100 = the strongest stimulus im-aginablerdquo The intensity rating was measured three timesfor each test 3 seconds after the stimulus and at thebeginning and ending of the thermal test The mean valuewas calculated for statistics analysis To determinewhether the conditioning stimuli induced affectivechanges participants rated their emotional reactions usingthe Positive and Negative Affect Schedule (PANAS)which composes of a list of 20 adjectives used to describe10 positive emotions (the global Positive Affect Score) and10 negative emotions (the global Negative Affect Score)

Yang et al The Journal of Headache and Pain 2014 1571 Page 4 of 12httpwwwthejournalofheadacheandpaincomcontent15171

after each thermal sensory test [3132] Respondents wererequired to indicate the extent to which they felt the emo-tions included on the schedule ldquoduring the thermal testrdquoon a five-point scale (where 1 = very slightly or not at allto 5 = extremely) [3132]Heart rate (HR) and skin temperature of contralateral

orofacial region were measured using a Patient Monitor(NPB-4000 US) and an infrared thermometer (THER-MOFOCUS 01500 serien Italy) continuously HR andskin temperature were recorded seven times in each test(Figure 1) and the mean was used for further analysis [28]

Statistical analysisAll statistical calculations were performed using SPSS 170software for windows (IBM inc USA) The assumption ofnormal distribution of all data was investigated by theShapiro-Wilk method Paired t-test was used to comparethe difference between baselines and stimuli tests Differ-ences between genders were evaluated by unpaired t-testThe changes under conditioning stimuli compared to base-line tests were calculated as delta values value = value(stimuli) ndash value (baseline) which was used in results andfigures as ldquorelative changesrdquo Differences between deltavalues within one session (dose dependent effect) were an-alyzed using two-way repeated measures ANOVA with thestimulus intensity as within-participant factor and genderas between-participant factor To evaluate the multisensoryeffect the delta values (ldquochangesrdquo) in multisensory stimula-tion test gustatory test 9000 lux light visual test and90 dB noise auditory test were compared using two-wayrepeated ANOVA with conditioning stimuli as within-participant factor gender as between-participant factorPost-hoc comparisons were estimated using Bonferronipost-hoc test with correction for multiple comparisonsP lt005 was taken as an indication of a statistically signifi-cant difference

ResultsParticipantsThere was no significant age difference between female(254 plusmn 29 years mean plusmn SD) and male (277 plusmn 32 years)participants (unpaired t-test age P = 0110)

Psychometrical measuresAll the subjective intensity rating scores to different condi-tioning stimuli were normally distributed (Shapiro-WilkP ge0066) Compared with baseline subjective stimulus in-tensity rating during conditioning stimuli tests was signifi-cantly higher in visual (paired t-test P lt0001) auditory(P lt0001) gustatory (P lt0001) and multisensory test(P lt0001) (Table 1) The participantsrsquo subjective ratingdifferences between the condition with stimulus andcorresponding baseline (ldquorelative changesrdquo in the text andfigures) was higher when participants were exposed to

stronger stimuli significant intensity effect on subjectiverating ldquorelative changesrdquo F = 8804 P lt0001 for visual test(Figure 2-A) F = 8825 P lt0001 for auditory test(Figure 2-B) Post-hoc test for multiple contrasts indicatedsignificant increases with increased intensity of light andnoise (Figure 2-AB) There were no gender differences invisual auditory gustatory and multisensory tests (un-paired t-test t le0266 P gt0791)Most of the affective scores to different conditioning

stimuli were normally distributed (Shapiro-Wilk P gt005)The conditioning stimuli induced statistically significantlyhigher negative affective states compared with baseline vis-ual test (baseline 116 plusmn 21 mean plusmn SD stimulus 136 plusmn45 paired t-test t = minus3742 P lt0001) auditory test (base-line 120 plusmn 30 stimulus 146 plusmn 45 t = minus5182 P lt0001)gustatory test (baseline 136 plusmn 45 stimulus 168 plusmn 41t = minus2656 P =0016) multisensory test (baseline 132 plusmn44 stimulus 196 plusmn 62 t = minus6719 P lt0001) (Figure 3)The negative affective score differences between the condi-tion with stimuli and corresponding baseline (as ldquodeltavaluerdquo or ldquochangesrdquo in the text and figures) were higherwhen the participants were exposed to more intense stim-uli significant intensity effects on negative affective scoresfor visual test (F = 7484 P =0006 Figure 4-A) auditorytest (F = 11335 P lt0001 Figure 4-B) The Post-hoc testfor multiple comparisons indicated a statistically significantincrease in negative affective scores with increasing inten-sities in the light and noise tests (Figure 4-AB) Besidesthere were statistically significant gender differences withmales having higher negative affective scores when exposedto the same stimuli compared to females in auditory test(unpaired t-test gender differences t = minus3308 P = 0004for 75 dB noise t = minus3519 P =0002 for 90 dB noiseFigure 4-B) and gustatory test (t = minus2694 P = 0015Figure 4-C) As could be expected all the stimuli failed toinduce positive affective changes of the participants com-pared with baseline visual test (paired t-test P = 0117)auditory test (P = 0091) gustatory test (P = 0169) andmultisensory test (P = 0080)

Physiological measuresThe heart rate and skin temperature data for differentconditioning stimuli were normally distributed (Shapiro-Wilk P ge0069) The conditioning stimuli did not changethe two indices of physical arousal heart rate and skintemperature in comparison with the corresponding base-line values pared t-test P value for differences (heart ratetemperature) in visual test (0408 0162) auditory test(0059 0574) gustatory test (0195 0639) and multi-sensory test (0137 0057)

Thermal somatosensory sensitivityMost of the QST data in different conditioning stimuli werenormally distributed only after logarithmic transformation

Table 1 Subjective intensity rating to conditioning stimuli (minus100)

Conditions Baseline (mean plusmn SD) With stimuli (mean plusmn SD) P

Visual 0 plusmn 0 590 plusmn 241 lt 0001

Auditory 188 plusmn 150 656 plusmn 241 lt 0001

Gustatory 66 plusmn 44 403 plusmn 173 lt 0001

Multisensory 75 plusmn 49 473 plusmn 228 lt 0001

Subjective rating to conditioning stimuli was assessed by numerical scale in which ldquo0 = no stimulus could be detectedrdquo to ldquo100 = the strongest stimulusimaginablerdquo The comparisons between the conditions with stimuli and corresponding baseline were investigated by paired t-test

Figure 2 Subjective rating (changes) to different conditioning stimuli The differences between test with conditioning stimuli andcorresponding baseline were calculated as delta values value = value (conditioned) ndash value (baseline) which was used in figures (A visual andB auditory test) as ldquorelative changesrdquo Compared with baseline subjective stimulus intensity rating during gustatory and multisensory tests wassignificantly higher The participantsrsquo subjective rating changes were higher when they were exposed to stronger stimuli in visual and auditorytests (C) gustatory test (D) multisensory test = P lt0001

Yang et al The Journal of Headache and Pain 2014 1571 Page 5 of 12httpwwwthejournalofheadacheandpaincomcontent15171

Figure 3 Negative affective state differences between testswith conditioning stimuli (grizzle bars) and correspondingbaselines (white bars) The results are presented as means plusmn SDs ofthe negative affective scores form Positive and Negative AffectSchedule The conditioning stimuli induced statistically significantlyhigher negative affective states compared with baseline = P lt0001 = P lt005

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(Shapiro-Wilk P gt005) Compared with baseline the sensi-tivity to thermal stimuli did not change when the partici-pants were exposed to conditioning stimuli visual test(paired t-test P value for CDT WDT CPT HPT were0074 0641 0165 0095 respectively Figure 5-A) auditorytest (paired t-test P value for CDT WDT CPT HPT were0055 0922 0515 0418 respectively Figure 5-B) gustatorytest (paired t-test P value for CDT WDT CPT HPT were0347 0207 0202 0729 respectively Figure 5-C) multi-sensory stimulation (paired t-test P value for CDT WDTCPT HPT were 0526 0051 0737 0331 respectivelyFigure 5-D)

Multisensory stimulation effectWhen the participants were exposed to multisensory(combined) conditioning stimuli they subjectively ratedhigher ldquodelta valuesrdquo to the same bitter taste comparedwith in the condition of taste stimulus alone (whole groupF = 5017 P = 0038 male F = 8980 P = 0015 femaleF = 1304 P gt005 Figure 6-A) The female participantspresented higher ldquodelta valuesrdquo for the negative affectivescores during the multisensory stimuli condition than dur-ing noise stimulation alone (noise 20 plusmn 24 mean plusmn SDtaste 15 plusmn 63 combination 68 plusmn 58 Post-hoc testbetween combination test and noise test P = 0011Figure 6-C) The participants presented a statistically sig-nificant decrease in WDT (ldquodeltardquo WDT decreasing) dur-ing multisensory conditioning stimuli compared with lightstimulus alone (male Post-hoc test P = 0019 Figure 6-GTable 2) or taste alone (whole group P =0004 maleP = 0003 female P = 0438 Figure 6-G Table 2)

DiscussionsThis study investigated for the first time the effects ofthree unpleasant conditioning stimuli (bright light chain-saw noise and bitter taste) on negative affective statephysiological arousal and skin thermal sensitivity Thethree conditioning stimuli as expected all induced statis-tically significant increases in negative affective scorescompared with baseline Additionally a dose dependentphenomenon was demonstrated in the visual and auditorytests (only one intensity gustatory stimulus was applied inthis study) There were no significant changes in positiveaffective scores physiological arousal (heart rate or skintemperature) between tests with and without conditioningstimuli The skin thermal sensitivity (via CDT WDTCPT HPT) in the perioral region did not change signifi-cantly during conditioning stimuli tests compared withbaseline Combining the individual conditioning stimuliinto a multisensory conditioning stimulus led to a strengthened effect compared with single conditioning stimulifor several outcome parameters ie subjective ratingsnegative affective scores and warmth detection threshold(WDT)

Influence of conditioning stimuli on affective stateThe experimental visual stimuli used in previous studies toexamine the affective processes were composed of emo-tional videos [3334] or photos [3536] Viewing faces withsad or happy expressions specifically evoked the expressedfeelings in the viewer defined as ldquoemotional contagionrdquo[35] This emotional contagion was considered as a ldquopre-wiredrdquo decoding instrument which was considered a fastrepeatable and stable process [35] These visual stimuliactivate an emotion perception process characterized byfocusing attention to external events and accurately under-standing the information conducted which need the fullco-operation of the investigated individuals [11] Addition-ally some studies concluded that the experimentallyinduced changes in the affective state were obtained onlyafter repeated stimuli presentation accompanied withspecified verbal inductions [37] Furthermore in anotherElectroencephalography (EEG) study emotional reactionscould not be evoked by presenting emotional picturesalone [11] In migraineurs bright light often exacerbate theheadache which could be accounted for a pathophysio-logical hypothesis of a disturbance of the subcortical sen-sory modulation system [18] Although the trigeminalautonomic reflex acts as a feed-forward system to facilitatethe acute attack the fundamental problem was thought tobe in the brain [1] The possible effect of bright light toexperimentally evoke an affective state and somatosensorysensitivity changes has not been assessed before Thehypothesis of the present study was that bright light couldevoke a negative affective state and change the somatosen-sory sensitivity In the present experimental study bright

Figure 4 Effects of conditioning stimuli on negative affective (changes) between genders The negative affective score differencesbetween the condition with stimuli and corresponding baseline (as ldquochangesrdquo in the figure) were higher when the participants were exposed tomore intense stimuli in visual (A) and auditory (B) tests Besides there were statistically significant gender differences in auditory test (B) andgustatory test (C) (D) indicates multisensory test = P lt0001 = P lt001 = P lt005

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light successfully evoked a negative affective state in adose-dependent manner according to the intensity of thelight (Figure 4-A) Bright light may be a simple andeffecient way to induce a negative affective state in humanstudies However bright light did not significantly changesomatosensory sensitivity to thermal stimuli This indicatesthat the light regulation of thermal somatosensory sensi-tivity may not exist in healthy humans without priorsensitization or predispositionSeveral studies have demonstrated that music is a power-

ful mediator of changes in affective state [3839] Func-tional neuro-imaging and lesion studies have shown thatmusic-evoked affective state changes can modulate activityin virtually all limbic and paralimbic brain structures suchas amygdala parahippocampal gyrus and hippocampus[1240-42] These structures are crucially involved in theinitiation generation detection maintenance regulation

and termination of changes in affective state [13] Musicmay affect trained musicians and non-musicians differentlyand different individuals have different musical preferencesand experiences which may be important in studies ofinfluence of music on different outcome parameters [13]In contrast to most people a chainsaw noise as used in thepresent study can be considered an unpleasant auditorystimulus The participants in this study rated moderate tostrong unpleasantness to the noise (Figure 2-B) Thehypothesis of the present study was that an unpleasantauditory stimulus could increase negative affect and changesomatosensoty sensitivity The chainsaw noise successfullyevoked a negative affective state in a dose-dependentmanner as the intensity of the auditory stimulus increased(Figure 4-B) Again chainsaw noise may be a simple andeffective way to induce a negative affective state in humanstudies However the chainsaw noise did not significantly

Figure 5 Thermal sensitivity differences between tests with conditioning stimuli (grizzle bars) and corresponding baselines (white bars)The results are presented as means plusmn SDs of the threshold values from visual test (A) auditory test (B) gustatory test (C) and multisensory test (D)Compared with baseline (white bars) the sensitivity to thermal stimulus did not change when the participants were exposed to conditioning stimuli(grizzle bars) CDT = cold detection threshold WDT =warmth detection threshold CPT = cold pain threshold HPT = heat pain threshold

Yang et al The Journal of Headache and Pain 2014 1571 Page 8 of 12httpwwwthejournalofheadacheandpaincomcontent15171

change somatosensory sensitivity to thermal stimuli Thisindicates that auditory stimulus regulation of thermal som-atosensory is not significant in healthy volunteers How-ever in some pathological conditions such as tension-typeand cervicogenic headache phonophobia is a commonsymptom [43] Again this may require a sensitized orpredisposed somatosensory systemIt has been reported that sucrose reduces pain during the

Cold Pressor Test (CPT) in 5- to 10-year-old children andthis kind of analgesia is dependent on the sweet taste pref-erence [14] However sucrose was not an effective analgesiain adult women in the same study The age-related declinein the analgesic efficacy of sucrose mirrors the age-relateddecline in the hedonic value of sweet tastes [44] In a recentstudy the taste of quinine gelatin (01) failed to producerobust affective state changes [45] However in the presentstudy the same stimulus evoked a significant change in

negative affective state These contradictory results maypossibly been explained by the ldquopreference theoryrdquo sincethe subjective rating to the bitter taste in this study (403 plusmn173 mean plusmn SD in a 0ndash100 numerical scale) was muchhigher than the study by Horjales-Aaujo (297 plusmn 197)[1445] Despite the negative affective state there were nochanges in somatosensory sensitivity in healthy volunteers

Multisensory conditioning stimulus effectsThere were several statistically significant effects of themultisensory conditioning stimulus which indicated thatthe multisensory stimulation enhanced the effect of indi-vidual stimuli with regard to subjective rating changesaffective score changes and induced slight thermal sensi-tivity changes This is in line with a neurophysiologicalstudy which demonstrates a strong emotion enhancementeffect by simultaneous presentation of congruent emotional

Figure 6 Multisensory effects between genders To diminish the effect of timing the delta values between test with stimuli and correspondingbaseline defined as ldquochangesrdquo in the figure was used Multisensory conditioning stimulus led to a strengthened effect compared with singleconditioning stimuli for several outcome parameters ie subjective ratings to gustatory stimulus (A) negative affective scores (C) and warmthdetection threshold (G) CDT = cold detection threshold WDT =warmth detection threshold CPT = cold pain threshold HPT = heat pain thresholdPositive affective changes (B) heat rate changes (D) skin temperature changes (E) cold detection threshold changes (F) cold pain threshold changes(H) and heat pain threshold changes (I) in different tests were also presented = P lt001 = P lt005

Yang et al The Journal of Headache and Pain 2014 1571 Page 9 of 12httpwwwthejournalofheadacheandpaincomcontent15171

pictures and music regarding subjective ratings peripheraland central physiological measures [11] The findings alsofit with a study which shows that when either positive (joy-ful) or negative (fearful) music is played simultaneouslywith an emotionally neutral film clip it evokes strongersignal changes in the amygdala and in areas of the ventro-lateral frontal cortex compared with when only music oronly film clips are presented [46] The activation increase

may be due to the cross modal integration of three sensorystimuli and this stronger activation possibly suggests en-hanced activation in a distributed neuronal network whichneeds to be confirmed in functional imaging studies [6]

Physiological arousal changesIt has been proposed that most affective changes are asso-ciated with undifferentiated physiological activity changes

Table 2 Impact of gender on warmth detection threshold (WDT degC) changes with different stimuli

Gender Visual (1) Auditory (2) Gustatory (3) Multisensory (4) F P 1 vs 4 2 vs 4 3 vs 4

Female Mean minus008 minus012 minus002 minus0150098 NS 0784 0938 0438

SD 076 064 035 060

Male Mean 017 minus003 027 minus0336036 0003 0019 NS 0003

SD 029 021 050 033

Sum Mean 004 minus008 013 minus0242241 NS 0058 0387 0004

SD 057 046 045 048

To evaluate the multisensory effect the delta values (ldquochangesrdquo) in 9000 lux light visual test 90 dB noise auditory test gustatory test and multisensory stimulationtest were compared using two-way repeated ANOVA with conditioning stimuli as within-participant factor gender as between-participant factor The male participantspresented a statistically significant decrease in ldquodeltardquo WDT during multisensory conditioning stimuli compared with light stimulus alone (P = 0019) or taste alone(P = 0003) Italics values indicate statistically significant P values (P lt 005)

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[47] Thus it seems reasonable to examine physiologicalarousal measurements related to affective reactions Skintemperature and heart rate are the most frequently usedphysiological expressions of affective state [47] Howeverin the present study these two parameters did not changesignificantly in response to changes in negative affectivestate by the different conditioning stimuli This is in linewith another study where it was demonstrated that theverbally reported affective experiences are not alwaysconsistent with the physiological parameters especially forunpleasant stimuli [47] On the other hand it may bebecause of the limited number of participants or that theapplied stimulus was inadequate for induction of a signifi-cant physiological change in arousal

Interactions between somatosensory sensitivity andconditioning stimuliThe perception of migraine headache which is mediatedby nociceptive signals is exacerbated by exposure to en-vironment stimuli ie light or noise which are mediatedby optical and acoustic signals Prolonged neuronal activa-tion during a migraine attack is thought to induce periph-eral and central sensitization along the trigeminovascularpathway which stands to explain the throbbing headache[48] accompanying scalp and neck-muscle tenderness[49] and whole-body cutaneous allodynia [50] Severaltheories exist which predict the relationship betweenconditioning stimuli and somatosensory sensitivity Todevelop a more comprehensive model of somatosensorymodulation by conditioning stimuli it may be useful toconsider a theory of ldquomotivational primingrdquo [9] It is pro-posed that affective state processing evoked by stimulicould be viewed as two opposing motivational systemsOne system is appetitive and produces approach behav-iors and the other system is aversive and promotes avoid-ance behaviors [9] Considerable evidence indicates thatprior activation of these systems modulates defensive be-haviors which facilitates somatosensory capability [51]These defensive behaviors increase in magnitude whenthe aversive system is primed by a negative affective stateie anticipation of shock [52] Conversely this defensive

response is inhibited when the appetitive system is primedby a positive affective state [53] According to the motiv-ational priming theory participants exposed to negativeaffective loading whose aversive systems are activatedshould get their perception facilitated [922] Howeversomatosensory sensitivity to thermal stimuli was not chan-ged during induction of negative affective states in thepresent study Another perspective on somatosensory andaffective processing is provided by the four-region neuro-biological model which indicates a complex relationshipbetween acute pain and simple emotion [54] For instancefear and pain sites overlap in the anterior midcingulatecortex (aMCC) and this region is involved in avoidancebehaviors posterior midcingulate cortex (pMCC) has noconsistent emotion activations yet has robust nociceptiveresponses subgenual anterior cingulate cortex (sACC) acti-vation during noxious stimulation of the skin and viscerain a person-specific manner the cingulate cortex is notuniformly involved in emotion and not all pain-activationsites are associated with affect or emotion [54]

ConclusionsThe three conditioning stimuli induced significantincreases in subjective rating and negative effectivescores accompanied with no physiological arousalchanges These stimuli did not however modulate skinthermal sensitivity The multisensory conditioning stimuliinduced stronger effects on subjective rating and negativeaffect than individual conditioning stimuli alone Theoften observed trigger or exacerbation of migraine byvisual auditory or gustatory stimuli may require a pre-disposed or sensitized nervous system

AbbreviationsMSI Multi-modal sensory integration IAPS Pictures of facial affect or theinternational affective picture system QST Quantitative sensory testingCDT Cold detection threshold WDT Warmth detection threshold CPT Coldpain threshold HPT Heat pain threshold PANAS Positive and negative affectschedule HR Heart rate EEG Electroencephalography aMCC AnteriorMidCingulate cortex pMCC Posterior MidCingulate cortex sACC Subgenualanterior cingulate cortex

Competing interestsThe authors declare that they have no competing interests

Yang et al The Journal of Headache and Pain 2014 1571 Page 11 of 12httpwwwthejournalofheadacheandpaincomcontent15171

Authorsrsquo contributionsYG recruited the participants carried out the study performed the statisticalanalysis and drafted the manuscript SP and BHL participated in the designof the study statistical analysis and revision of the draft XQ and WK helpedto draft and revise the manuscript All authors read and approved the finalmanuscript

AcknowledgementsWe are indebted to the subjects who participated in the study for theirconsent and co-operation This study was made possible by the supportsof Danish Dental Association

Author details1Department of Prosthodontics and Center for Oral Functional DiagnosisTreatment and Research Peking University School and hospital ofStomatology Zhongguancun Nandajie 22 100081 Beijing China 2Section ofClinical Oral Physiology Department of Dentistry Aarhus University AarhusDenmark 3Center for Sensory-Motor Interaction (SMI) Department of HealthScience and Technology Aalborg University Aalborg Denmark 4Departmentof Dental Medicine Karolinska Institute Huddinge Sweden

Received 28 August 2014 Accepted 28 October 2014Published 7 November 2014

References1 Goadsby PJ (2009) Pathophysiology of migraine Neurol Clin 27(2)335ndash360

httpdxdoiorg101016jncl2008110122 Judit A Saacutendor PS Schoenen J (2000) Habituation of visual and intensity

dependence of cortical auditory evoked potentials tends to normalize justbefore and during migraine attack Cephalalgia 20(8)714ndash719httponlinelibrarywileycomdoi101111j1468-2982200000122xfull

3 Schoenen J Wang W Albert A Delwaide PJ (1995) Potentiation instead ofhabituation characterizes visual evoked potentials in migraine patientsbetween attacks Eur J Neurol 2(2)115ndash122 doi101111j1468-1331

4 Wang W Schoenen J (1998) Interictal potentiation of passive ldquooddballrdquoauditory event-related potentials in migraine Cephalalgia 18(5)261ndash265doi101111j1468-298219981805261x

5 Stein BE Stanford TR (2008) Multisensory integration current issues fromthe perspective of the single neuron Nat Rev Neurosci 9(4)255ndash266doi101038nrn2331

6 Basura GJ Koehler SD Shore SE (2012) Multi-sensory integration inbrainstem and auditory cortex Brain Res 148595ndash107 httpdxdoiorg101016jbrainres201208037

7 Jain R Shore S (2006) External inferior colliculus integrates trigeminal andacoustic information unit response to trigeminal nucleus and acousticstimulation in the guinea pig Neurosci Lett 395(1)71ndash75 httpdxdoiorg101016jneulet200510077

8 Kawasaki A Purvin VA (2002) Photophobia as the presenting visual symptom ofchiasmal compression J Neuroophthalmol 22(1)3ndash8httpovidsptxovidcomsp-3131aovidwebcgiT=JSampPAGE=fulltextampD=ovftampAN=00041327-200203000-00002ampNEWS=NampCSC=YampCHANNEL=PubMed

9 Lang PJ (1995) The emotion probe Studies of motivation and attentionAm Psychol 50(5)372ndash385 doi1010370003-066X505372

10 Esslen M Pascual-Marqui RD Hell D Kochi K Lehmann D (2004) Brain areasand time course of emotional processing Neuroimage 21(4)1189ndash1203httpdxdoiorg101016jneuroimage200310001

11 Baumgartner T Esslen M Jaumlncke L (2006) From emotion perception toemotion experience emotions evoked by pictures and classical music Int JPsychophysiol 60(1)34ndash43 httpdxdoiorg101016jijpsycho200504007

12 Mitterschiffthaler MT Fu CH Dalton JA Andrew CM Williams SC (2007) Afunctional MRI study of happy and sad affective states induced by classicalmusic Hum Brain Mapp 28(11)1150ndash1162 DOI 101002hbm20337

13 Koelsch S (2010) Towards a neural basis of music-evoked emotions TrendsCogn Sci 14(3)131ndash137 httpdxdoiorg101016jtics201001002

14 Pepino MY Mennella JA (2005) Sucrose-induced analgesia is related tosweet preference in children but not adults Pain 119(1ndash3)210ndash218httpdxdoiorg101016jpain200509029

15 Horjales-Araujo E Demontis D Lund EK Vase L Finnerup NB Boslashrglum ADJensen TS Svensson P (2013) Emotional modulation of muscle pain isassociated with polymorphisms in the serotonin transporter gene Pain154(8)1469ndash1476 doi101016jpain201305011

16 Bushnell EW Baxt C (1999) Childrenrsquos haptic and cross-modal recognitionwith familiar and unfamiliar objects J Exp Psychol Hum Percept Perform25(6)1867ndash1881 doi1010370096-1523256

17 Longe SE Wise R Bantick S Lloyd D Johansen-Berg H McGlone F Tracey I(2001) Counter-stimulatory effects on pain perception and processing aresignificantly altered by attention an fMRI study Neuroreport 12(9)2021ndash2025httpovidsptxovidcomsp-3131aovidwebcgiT=JSampPAGE=fulltextampD=ovf-tampAN=00001756-200107030-00047ampNEWS=NampCSC=YampCHANNEL=PubMed

18 Rode S Salkovskis PM Jack T (2001) An experimental study of attentionlabeling and memory in people suffering from chronic pain Pain 94(2)193ndash203httpdxdoiorg101016S0304-3959(01)00356-6

19 McCaul KD Monson N Maki RH (1992) Does distraction reduce pain-produced distress among college students Health Psychol 11(4)210ndash217doi1010370278-6133114210

20 Rolke R Baron R Maier C Toumllle TR Treede RD Beyer A Binder A Birbaumer NBirklein F Boumltefuumlr IC Braune S Flor H Huge V Klug R Landwehrmeyer GBMagerl W Maihoumlfner C Rolko C Schaub C Scherens A Sprenger T Valet MWasserka B (2006) Quantitative sensory testing in the German ResearchNetwork on Neuropathic Pain (DFNS) Standardized protocol and referencevalue Pain 123(3)231ndash243 httpdxdoiorg101016jpain200601041

21 Yang G Luo Y Baad-Hansen L Wang K Arendt-Nielsen L Xie QF SvenssonP (2013) Ethnic differences in oro-facial somatosensory profiles-quantitativesensory testing in Chinese and Danes J Oral Rehabil 40(11)844ndash853doi101111joor12091

22 Meagher MW Arnau RC Rhudy JL (2001) Pain and emotion Effect ofAffective Picture Modulation Psychosom Med 63(1)79ndash90 httpwwwpsychosomaticmedicineorgcontent63179short

23 Danish volunteers recruit website for clinical research [wwwforsoegspersondk]24 Okamoto K Tashiro A Thompson R Nishida Y Bereiter DA (2012) Trigeminal

interpolariscaudalis transition neurons mediate reflex lacrimation evoked bybright light in the rat Eur J Neurosci 36(11)3492ndash3499 doi101111j1460-9568201208272x

25 Noseda R Kainz V Jakubowski M Gooley JJ Saper CB Digre K Burstein R(2010) A neural mechanism for exacerbation of headache by light NatNeurosci 13(2)239ndash245 doi101038nn2475

26 Sliney DH (1983) Standards for use of visible and nonvisible radiation on theeye Am J Optom Physiol Opt 60(4)278ndash286 httpovidsptxovidcomsp-3131aovidwebcgiWebLinkFrameset=1ampS=GDKPFPEIMNDDLJBJNCLKDFIBGENOAA00ampreturnUrl=ovidwebcgi3fMain2bSearch2bPage3d126S3dGDKPFPEIMNDDLJBJNCLKDFIBGENOAA00ampdirectlink=http3a2f2fgraphicstxovidcom2fovftpdfs2fFPDDNCIBDFBJMN002ffs0462fovft2flive2fgv0232f000004512f00000451-198304000-00003pdfampfilename=Standards+for+Use+of+Visible+and+Nonvisible+Radiation+on+the+Eyeampnavigation_links=NavLinksSsh421amplink_from=Ssh427c1amppdf_key=FPDDNCIBDFBJMN00amppdf_index=fs046ovftlivegv0230000045100000451-198304000-00003ampD=ovftamplink_set=Ssh42|1|sl_10|resultSet|Ssh4243|0

27 Rappaport SM (1993) Threshold limit values permissible exposure limitsand feasibility the bases for exposure limits in the United States Am J IndMed 23(5)683ndash694 doi101002ajim4700230502

28 Rhudy JL Meagher MW (2001) Noise stress and human pain thresholdsdivergent effects in men and women J Pain 2(1)64 httpdxdoiorg101054jpai200019947

29 Goldenberg AM Wexler LF (1988) Quinine overdose review of toxicity andtreatment Clin Cardiol 11(10)716ndash718 doi101002clc4960111012

30 Cardesiacuten A Alobid I Beniacutetez P Sierra E de Haro J Bernal-Sprekelsen MPicado C Mullol J (2006) Barcelona Smell Test - 24 (BAST-24) validation andsmell characteristics in the healthy Spanish population Rhinology 44(1)83ndash89httpwwwrhinologyjournalcomabstractphpid=556

31 Watson D Clark LA Tellegen A (1988) Development and validation of briefmeasures of positive and negative affect the PANAS scale J Pers SocPsychol 54(6)1063ndash1070 doi1010370022-35145461063

32 Crawford JR Herry JD (2004) The positive and negative affect schedule(PANAS) construct validity measurement properties and normative data ina large non-clinical sample Br J Clin Psychol 43(3)245ndash265 httpovidsptxovidcomsp-3131aovidwebcgiT=JSampPAGE=fulltextampD=ovftampAN=00002604-200409000-00003ampNEWS=NampCSC=YampCHANNEL=PubMed

33 Hsee CK Hatfield E Carlson JG Chemtob C (1990) The effect of power onsusceptibility to emotional contagion Cogn Emot 4327ndash340 doi10108002699939008408081

34 Doherty RW (1998) Emotional contagion and social judgment Motiv Emot22187ndash209 doi101023A1022368805803

Figure 1 One thermal somatosensory test consists of before stimuli (05 min) stimulus habituation period (2 min) thermal test(~35 min) recovery period (5 min) lsquoHRrsquo = Heart Rate record lsquoTrsquo = face skin temperature record Cold Detection Threshold (CDT) WarmthDetection Threshold (WDT) Cold Pain Threshold (CPT) Heat Pain Threshold (HPT)

Yang et al The Journal of Headache and Pain 2014 1571 Page 3 of 12httpwwwthejournalofheadacheandpaincomcontent15171

Conditioning stimuliVisual stimuliVisual stimuli were created using three levels of bright lightshined directly at the participantsrsquo eyes in a randomized se-quence produced by Microsoft Excel (i) 1000 lux brightlight (ii) 3000 lux bright light (iii) 9000 lux bright light[2627] The bright light was generated using dental chairlamp with an area of 14 times 9 cm (ESTETICA E80 KaVoGermany) and calibrated by a Luxmeter (LX1010B+Malmbergs Sweden) There was a control test before eachtest without visual stimuli to eliminate timing effect inwhich the participants wore eyeshades and closed theireyes to make sure they did not see any light

Auditory stimuliParticipants were instructed to remain awake with eyescovered by eyeshades and were exposed to recordedsounds of an electric chainsaw at three different intensities(60 dB 75 dB 90 dB) in randomized sequence producedby Microsoft Excel [628] The noise was generated by acomputer through loud-speakers and measured by SoundPressure Lever Meter (RadioShack 33ndash2055 USA) A con-trol test was performed before each test without soundstimulus to eliminate the effect of timing

Gustatory stimulusParticipants were instructed to rinse with distilled waterat least four times over a 1 min period prior to testingGelatin was the vehicle for gustatory stimuli The partic-ipants were asked to hold 20 ml gelatin (2 bovine skingelatin Sigma-Aldrich St Louis USA) in their mouthwith either bitter (01 quinine Sigma-Aldrich adulttoxic dose 25 ndash 4 g) or neutral taste (2 gelatin) [29]The gustatory stimuli were presented at roomtemperature (~21degC) with an at least four times distilledwater rinse after each test for 5 min until the taste hasbeen washed out [30]

Multisensory stimuliThe three conditioning stimulus modalities (visual 9000lux light auditory 90 dB noise and gustatory 01 quininegelatin) were presented simultaneously to each participantwith a control test (no visual no auditory amp neutral taste)

All the conditioning stimuli were given in repeated trials3 trials for the visual or auditory tests and 1 trial for thegustatory or combination tests The stimuli were started2 min before each thermal test and ended after the emo-tion evaluations thus each episode of stimulus lastedabout 7 min (Figure 1)

Thermal sensitivity measuresParticipants were positioned in a comfortable dental chairThe measures were performed in the right perioral regionwith the thermode placed on the right angle of the mouthThe thermal tests were performed using a Medoc Pathwaywith ATS thermode (30 mm times 30 mm square surfaceMEDOC Israel) Care was taken throughout the sessionto keep the test sites during the repeated testing the sameCold and warmth detection thresholds (CDT WDT) weremeasured first Then cold pain and heat pain thresholds(CPT HPT) were determined [2021] The mean thresholdtemperature of three consecutive measurements was cal-culated All thresholds were obtained with ramped stimuli(1degCs) that were terminated when the participantspressed a button For thermal detection thresholds theramp back to baseline was 1degCs while for thermal painthresholds this ramp was chosen at 5degCs The baselinetemperature was 32degC Cut-off temperatures were set at 0degCand 50degC respectively [2021] A standardized verbal instruction was read to the participants and a training test wasperformed before the actual tests to make sure that theparticipants understood the thermal test program [20]

Psychometrical and physiological measuresThe perceived intensity of the conditioning stimuli wasassessed using a numerical scale from ldquo0 = no stimuluscould be detectedrdquo to ldquo100 = the strongest stimulus im-aginablerdquo The intensity rating was measured three timesfor each test 3 seconds after the stimulus and at thebeginning and ending of the thermal test The mean valuewas calculated for statistics analysis To determinewhether the conditioning stimuli induced affectivechanges participants rated their emotional reactions usingthe Positive and Negative Affect Schedule (PANAS)which composes of a list of 20 adjectives used to describe10 positive emotions (the global Positive Affect Score) and10 negative emotions (the global Negative Affect Score)

Yang et al The Journal of Headache and Pain 2014 1571 Page 4 of 12httpwwwthejournalofheadacheandpaincomcontent15171

after each thermal sensory test [3132] Respondents wererequired to indicate the extent to which they felt the emo-tions included on the schedule ldquoduring the thermal testrdquoon a five-point scale (where 1 = very slightly or not at allto 5 = extremely) [3132]Heart rate (HR) and skin temperature of contralateral

orofacial region were measured using a Patient Monitor(NPB-4000 US) and an infrared thermometer (THER-MOFOCUS 01500 serien Italy) continuously HR andskin temperature were recorded seven times in each test(Figure 1) and the mean was used for further analysis [28]

Statistical analysisAll statistical calculations were performed using SPSS 170software for windows (IBM inc USA) The assumption ofnormal distribution of all data was investigated by theShapiro-Wilk method Paired t-test was used to comparethe difference between baselines and stimuli tests Differ-ences between genders were evaluated by unpaired t-testThe changes under conditioning stimuli compared to base-line tests were calculated as delta values value = value(stimuli) ndash value (baseline) which was used in results andfigures as ldquorelative changesrdquo Differences between deltavalues within one session (dose dependent effect) were an-alyzed using two-way repeated measures ANOVA with thestimulus intensity as within-participant factor and genderas between-participant factor To evaluate the multisensoryeffect the delta values (ldquochangesrdquo) in multisensory stimula-tion test gustatory test 9000 lux light visual test and90 dB noise auditory test were compared using two-wayrepeated ANOVA with conditioning stimuli as within-participant factor gender as between-participant factorPost-hoc comparisons were estimated using Bonferronipost-hoc test with correction for multiple comparisonsP lt005 was taken as an indication of a statistically signifi-cant difference

ResultsParticipantsThere was no significant age difference between female(254 plusmn 29 years mean plusmn SD) and male (277 plusmn 32 years)participants (unpaired t-test age P = 0110)

Psychometrical measuresAll the subjective intensity rating scores to different condi-tioning stimuli were normally distributed (Shapiro-WilkP ge0066) Compared with baseline subjective stimulus in-tensity rating during conditioning stimuli tests was signifi-cantly higher in visual (paired t-test P lt0001) auditory(P lt0001) gustatory (P lt0001) and multisensory test(P lt0001) (Table 1) The participantsrsquo subjective ratingdifferences between the condition with stimulus andcorresponding baseline (ldquorelative changesrdquo in the text andfigures) was higher when participants were exposed to

stronger stimuli significant intensity effect on subjectiverating ldquorelative changesrdquo F = 8804 P lt0001 for visual test(Figure 2-A) F = 8825 P lt0001 for auditory test(Figure 2-B) Post-hoc test for multiple contrasts indicatedsignificant increases with increased intensity of light andnoise (Figure 2-AB) There were no gender differences invisual auditory gustatory and multisensory tests (un-paired t-test t le0266 P gt0791)Most of the affective scores to different conditioning

stimuli were normally distributed (Shapiro-Wilk P gt005)The conditioning stimuli induced statistically significantlyhigher negative affective states compared with baseline vis-ual test (baseline 116 plusmn 21 mean plusmn SD stimulus 136 plusmn45 paired t-test t = minus3742 P lt0001) auditory test (base-line 120 plusmn 30 stimulus 146 plusmn 45 t = minus5182 P lt0001)gustatory test (baseline 136 plusmn 45 stimulus 168 plusmn 41t = minus2656 P =0016) multisensory test (baseline 132 plusmn44 stimulus 196 plusmn 62 t = minus6719 P lt0001) (Figure 3)The negative affective score differences between the condi-tion with stimuli and corresponding baseline (as ldquodeltavaluerdquo or ldquochangesrdquo in the text and figures) were higherwhen the participants were exposed to more intense stim-uli significant intensity effects on negative affective scoresfor visual test (F = 7484 P =0006 Figure 4-A) auditorytest (F = 11335 P lt0001 Figure 4-B) The Post-hoc testfor multiple comparisons indicated a statistically significantincrease in negative affective scores with increasing inten-sities in the light and noise tests (Figure 4-AB) Besidesthere were statistically significant gender differences withmales having higher negative affective scores when exposedto the same stimuli compared to females in auditory test(unpaired t-test gender differences t = minus3308 P = 0004for 75 dB noise t = minus3519 P =0002 for 90 dB noiseFigure 4-B) and gustatory test (t = minus2694 P = 0015Figure 4-C) As could be expected all the stimuli failed toinduce positive affective changes of the participants com-pared with baseline visual test (paired t-test P = 0117)auditory test (P = 0091) gustatory test (P = 0169) andmultisensory test (P = 0080)

Physiological measuresThe heart rate and skin temperature data for differentconditioning stimuli were normally distributed (Shapiro-Wilk P ge0069) The conditioning stimuli did not changethe two indices of physical arousal heart rate and skintemperature in comparison with the corresponding base-line values pared t-test P value for differences (heart ratetemperature) in visual test (0408 0162) auditory test(0059 0574) gustatory test (0195 0639) and multi-sensory test (0137 0057)

Thermal somatosensory sensitivityMost of the QST data in different conditioning stimuli werenormally distributed only after logarithmic transformation

Table 1 Subjective intensity rating to conditioning stimuli (minus100)

Conditions Baseline (mean plusmn SD) With stimuli (mean plusmn SD) P

Visual 0 plusmn 0 590 plusmn 241 lt 0001

Auditory 188 plusmn 150 656 plusmn 241 lt 0001

Gustatory 66 plusmn 44 403 plusmn 173 lt 0001

Multisensory 75 plusmn 49 473 plusmn 228 lt 0001

Subjective rating to conditioning stimuli was assessed by numerical scale in which ldquo0 = no stimulus could be detectedrdquo to ldquo100 = the strongest stimulusimaginablerdquo The comparisons between the conditions with stimuli and corresponding baseline were investigated by paired t-test

Figure 2 Subjective rating (changes) to different conditioning stimuli The differences between test with conditioning stimuli andcorresponding baseline were calculated as delta values value = value (conditioned) ndash value (baseline) which was used in figures (A visual andB auditory test) as ldquorelative changesrdquo Compared with baseline subjective stimulus intensity rating during gustatory and multisensory tests wassignificantly higher The participantsrsquo subjective rating changes were higher when they were exposed to stronger stimuli in visual and auditorytests (C) gustatory test (D) multisensory test = P lt0001

Yang et al The Journal of Headache and Pain 2014 1571 Page 5 of 12httpwwwthejournalofheadacheandpaincomcontent15171

Figure 3 Negative affective state differences between testswith conditioning stimuli (grizzle bars) and correspondingbaselines (white bars) The results are presented as means plusmn SDs ofthe negative affective scores form Positive and Negative AffectSchedule The conditioning stimuli induced statistically significantlyhigher negative affective states compared with baseline = P lt0001 = P lt005

Yang et al The Journal of Headache and Pain 2014 1571 Page 6 of 12httpwwwthejournalofheadacheandpaincomcontent15171

(Shapiro-Wilk P gt005) Compared with baseline the sensi-tivity to thermal stimuli did not change when the partici-pants were exposed to conditioning stimuli visual test(paired t-test P value for CDT WDT CPT HPT were0074 0641 0165 0095 respectively Figure 5-A) auditorytest (paired t-test P value for CDT WDT CPT HPT were0055 0922 0515 0418 respectively Figure 5-B) gustatorytest (paired t-test P value for CDT WDT CPT HPT were0347 0207 0202 0729 respectively Figure 5-C) multi-sensory stimulation (paired t-test P value for CDT WDTCPT HPT were 0526 0051 0737 0331 respectivelyFigure 5-D)

Multisensory stimulation effectWhen the participants were exposed to multisensory(combined) conditioning stimuli they subjectively ratedhigher ldquodelta valuesrdquo to the same bitter taste comparedwith in the condition of taste stimulus alone (whole groupF = 5017 P = 0038 male F = 8980 P = 0015 femaleF = 1304 P gt005 Figure 6-A) The female participantspresented higher ldquodelta valuesrdquo for the negative affectivescores during the multisensory stimuli condition than dur-ing noise stimulation alone (noise 20 plusmn 24 mean plusmn SDtaste 15 plusmn 63 combination 68 plusmn 58 Post-hoc testbetween combination test and noise test P = 0011Figure 6-C) The participants presented a statistically sig-nificant decrease in WDT (ldquodeltardquo WDT decreasing) dur-ing multisensory conditioning stimuli compared with lightstimulus alone (male Post-hoc test P = 0019 Figure 6-GTable 2) or taste alone (whole group P =0004 maleP = 0003 female P = 0438 Figure 6-G Table 2)

DiscussionsThis study investigated for the first time the effects ofthree unpleasant conditioning stimuli (bright light chain-saw noise and bitter taste) on negative affective statephysiological arousal and skin thermal sensitivity Thethree conditioning stimuli as expected all induced statis-tically significant increases in negative affective scorescompared with baseline Additionally a dose dependentphenomenon was demonstrated in the visual and auditorytests (only one intensity gustatory stimulus was applied inthis study) There were no significant changes in positiveaffective scores physiological arousal (heart rate or skintemperature) between tests with and without conditioningstimuli The skin thermal sensitivity (via CDT WDTCPT HPT) in the perioral region did not change signifi-cantly during conditioning stimuli tests compared withbaseline Combining the individual conditioning stimuliinto a multisensory conditioning stimulus led to a strengthened effect compared with single conditioning stimulifor several outcome parameters ie subjective ratingsnegative affective scores and warmth detection threshold(WDT)

Influence of conditioning stimuli on affective stateThe experimental visual stimuli used in previous studies toexamine the affective processes were composed of emo-tional videos [3334] or photos [3536] Viewing faces withsad or happy expressions specifically evoked the expressedfeelings in the viewer defined as ldquoemotional contagionrdquo[35] This emotional contagion was considered as a ldquopre-wiredrdquo decoding instrument which was considered a fastrepeatable and stable process [35] These visual stimuliactivate an emotion perception process characterized byfocusing attention to external events and accurately under-standing the information conducted which need the fullco-operation of the investigated individuals [11] Addition-ally some studies concluded that the experimentallyinduced changes in the affective state were obtained onlyafter repeated stimuli presentation accompanied withspecified verbal inductions [37] Furthermore in anotherElectroencephalography (EEG) study emotional reactionscould not be evoked by presenting emotional picturesalone [11] In migraineurs bright light often exacerbate theheadache which could be accounted for a pathophysio-logical hypothesis of a disturbance of the subcortical sen-sory modulation system [18] Although the trigeminalautonomic reflex acts as a feed-forward system to facilitatethe acute attack the fundamental problem was thought tobe in the brain [1] The possible effect of bright light toexperimentally evoke an affective state and somatosensorysensitivity changes has not been assessed before Thehypothesis of the present study was that bright light couldevoke a negative affective state and change the somatosen-sory sensitivity In the present experimental study bright

Figure 4 Effects of conditioning stimuli on negative affective (changes) between genders The negative affective score differencesbetween the condition with stimuli and corresponding baseline (as ldquochangesrdquo in the figure) were higher when the participants were exposed tomore intense stimuli in visual (A) and auditory (B) tests Besides there were statistically significant gender differences in auditory test (B) andgustatory test (C) (D) indicates multisensory test = P lt0001 = P lt001 = P lt005

Yang et al The Journal of Headache and Pain 2014 1571 Page 7 of 12httpwwwthejournalofheadacheandpaincomcontent15171

light successfully evoked a negative affective state in adose-dependent manner according to the intensity of thelight (Figure 4-A) Bright light may be a simple andeffecient way to induce a negative affective state in humanstudies However bright light did not significantly changesomatosensory sensitivity to thermal stimuli This indicatesthat the light regulation of thermal somatosensory sensi-tivity may not exist in healthy humans without priorsensitization or predispositionSeveral studies have demonstrated that music is a power-

ful mediator of changes in affective state [3839] Func-tional neuro-imaging and lesion studies have shown thatmusic-evoked affective state changes can modulate activityin virtually all limbic and paralimbic brain structures suchas amygdala parahippocampal gyrus and hippocampus[1240-42] These structures are crucially involved in theinitiation generation detection maintenance regulation

and termination of changes in affective state [13] Musicmay affect trained musicians and non-musicians differentlyand different individuals have different musical preferencesand experiences which may be important in studies ofinfluence of music on different outcome parameters [13]In contrast to most people a chainsaw noise as used in thepresent study can be considered an unpleasant auditorystimulus The participants in this study rated moderate tostrong unpleasantness to the noise (Figure 2-B) Thehypothesis of the present study was that an unpleasantauditory stimulus could increase negative affect and changesomatosensoty sensitivity The chainsaw noise successfullyevoked a negative affective state in a dose-dependentmanner as the intensity of the auditory stimulus increased(Figure 4-B) Again chainsaw noise may be a simple andeffective way to induce a negative affective state in humanstudies However the chainsaw noise did not significantly

Figure 5 Thermal sensitivity differences between tests with conditioning stimuli (grizzle bars) and corresponding baselines (white bars)The results are presented as means plusmn SDs of the threshold values from visual test (A) auditory test (B) gustatory test (C) and multisensory test (D)Compared with baseline (white bars) the sensitivity to thermal stimulus did not change when the participants were exposed to conditioning stimuli(grizzle bars) CDT = cold detection threshold WDT =warmth detection threshold CPT = cold pain threshold HPT = heat pain threshold

Yang et al The Journal of Headache and Pain 2014 1571 Page 8 of 12httpwwwthejournalofheadacheandpaincomcontent15171

change somatosensory sensitivity to thermal stimuli Thisindicates that auditory stimulus regulation of thermal som-atosensory is not significant in healthy volunteers How-ever in some pathological conditions such as tension-typeand cervicogenic headache phonophobia is a commonsymptom [43] Again this may require a sensitized orpredisposed somatosensory systemIt has been reported that sucrose reduces pain during the

Cold Pressor Test (CPT) in 5- to 10-year-old children andthis kind of analgesia is dependent on the sweet taste pref-erence [14] However sucrose was not an effective analgesiain adult women in the same study The age-related declinein the analgesic efficacy of sucrose mirrors the age-relateddecline in the hedonic value of sweet tastes [44] In a recentstudy the taste of quinine gelatin (01) failed to producerobust affective state changes [45] However in the presentstudy the same stimulus evoked a significant change in

negative affective state These contradictory results maypossibly been explained by the ldquopreference theoryrdquo sincethe subjective rating to the bitter taste in this study (403 plusmn173 mean plusmn SD in a 0ndash100 numerical scale) was muchhigher than the study by Horjales-Aaujo (297 plusmn 197)[1445] Despite the negative affective state there were nochanges in somatosensory sensitivity in healthy volunteers

Multisensory conditioning stimulus effectsThere were several statistically significant effects of themultisensory conditioning stimulus which indicated thatthe multisensory stimulation enhanced the effect of indi-vidual stimuli with regard to subjective rating changesaffective score changes and induced slight thermal sensi-tivity changes This is in line with a neurophysiologicalstudy which demonstrates a strong emotion enhancementeffect by simultaneous presentation of congruent emotional

Figure 6 Multisensory effects between genders To diminish the effect of timing the delta values between test with stimuli and correspondingbaseline defined as ldquochangesrdquo in the figure was used Multisensory conditioning stimulus led to a strengthened effect compared with singleconditioning stimuli for several outcome parameters ie subjective ratings to gustatory stimulus (A) negative affective scores (C) and warmthdetection threshold (G) CDT = cold detection threshold WDT =warmth detection threshold CPT = cold pain threshold HPT = heat pain thresholdPositive affective changes (B) heat rate changes (D) skin temperature changes (E) cold detection threshold changes (F) cold pain threshold changes(H) and heat pain threshold changes (I) in different tests were also presented = P lt001 = P lt005

Yang et al The Journal of Headache and Pain 2014 1571 Page 9 of 12httpwwwthejournalofheadacheandpaincomcontent15171

pictures and music regarding subjective ratings peripheraland central physiological measures [11] The findings alsofit with a study which shows that when either positive (joy-ful) or negative (fearful) music is played simultaneouslywith an emotionally neutral film clip it evokes strongersignal changes in the amygdala and in areas of the ventro-lateral frontal cortex compared with when only music oronly film clips are presented [46] The activation increase

may be due to the cross modal integration of three sensorystimuli and this stronger activation possibly suggests en-hanced activation in a distributed neuronal network whichneeds to be confirmed in functional imaging studies [6]

Physiological arousal changesIt has been proposed that most affective changes are asso-ciated with undifferentiated physiological activity changes

Table 2 Impact of gender on warmth detection threshold (WDT degC) changes with different stimuli

Gender Visual (1) Auditory (2) Gustatory (3) Multisensory (4) F P 1 vs 4 2 vs 4 3 vs 4

Female Mean minus008 minus012 minus002 minus0150098 NS 0784 0938 0438

SD 076 064 035 060

Male Mean 017 minus003 027 minus0336036 0003 0019 NS 0003

SD 029 021 050 033

Sum Mean 004 minus008 013 minus0242241 NS 0058 0387 0004

SD 057 046 045 048

To evaluate the multisensory effect the delta values (ldquochangesrdquo) in 9000 lux light visual test 90 dB noise auditory test gustatory test and multisensory stimulationtest were compared using two-way repeated ANOVA with conditioning stimuli as within-participant factor gender as between-participant factor The male participantspresented a statistically significant decrease in ldquodeltardquo WDT during multisensory conditioning stimuli compared with light stimulus alone (P = 0019) or taste alone(P = 0003) Italics values indicate statistically significant P values (P lt 005)

Yang et al The Journal of Headache and Pain 2014 1571 Page 10 of 12httpwwwthejournalofheadacheandpaincomcontent15171

[47] Thus it seems reasonable to examine physiologicalarousal measurements related to affective reactions Skintemperature and heart rate are the most frequently usedphysiological expressions of affective state [47] Howeverin the present study these two parameters did not changesignificantly in response to changes in negative affectivestate by the different conditioning stimuli This is in linewith another study where it was demonstrated that theverbally reported affective experiences are not alwaysconsistent with the physiological parameters especially forunpleasant stimuli [47] On the other hand it may bebecause of the limited number of participants or that theapplied stimulus was inadequate for induction of a signifi-cant physiological change in arousal

Interactions between somatosensory sensitivity andconditioning stimuliThe perception of migraine headache which is mediatedby nociceptive signals is exacerbated by exposure to en-vironment stimuli ie light or noise which are mediatedby optical and acoustic signals Prolonged neuronal activa-tion during a migraine attack is thought to induce periph-eral and central sensitization along the trigeminovascularpathway which stands to explain the throbbing headache[48] accompanying scalp and neck-muscle tenderness[49] and whole-body cutaneous allodynia [50] Severaltheories exist which predict the relationship betweenconditioning stimuli and somatosensory sensitivity Todevelop a more comprehensive model of somatosensorymodulation by conditioning stimuli it may be useful toconsider a theory of ldquomotivational primingrdquo [9] It is pro-posed that affective state processing evoked by stimulicould be viewed as two opposing motivational systemsOne system is appetitive and produces approach behav-iors and the other system is aversive and promotes avoid-ance behaviors [9] Considerable evidence indicates thatprior activation of these systems modulates defensive be-haviors which facilitates somatosensory capability [51]These defensive behaviors increase in magnitude whenthe aversive system is primed by a negative affective stateie anticipation of shock [52] Conversely this defensive

response is inhibited when the appetitive system is primedby a positive affective state [53] According to the motiv-ational priming theory participants exposed to negativeaffective loading whose aversive systems are activatedshould get their perception facilitated [922] Howeversomatosensory sensitivity to thermal stimuli was not chan-ged during induction of negative affective states in thepresent study Another perspective on somatosensory andaffective processing is provided by the four-region neuro-biological model which indicates a complex relationshipbetween acute pain and simple emotion [54] For instancefear and pain sites overlap in the anterior midcingulatecortex (aMCC) and this region is involved in avoidancebehaviors posterior midcingulate cortex (pMCC) has noconsistent emotion activations yet has robust nociceptiveresponses subgenual anterior cingulate cortex (sACC) acti-vation during noxious stimulation of the skin and viscerain a person-specific manner the cingulate cortex is notuniformly involved in emotion and not all pain-activationsites are associated with affect or emotion [54]

ConclusionsThe three conditioning stimuli induced significantincreases in subjective rating and negative effectivescores accompanied with no physiological arousalchanges These stimuli did not however modulate skinthermal sensitivity The multisensory conditioning stimuliinduced stronger effects on subjective rating and negativeaffect than individual conditioning stimuli alone Theoften observed trigger or exacerbation of migraine byvisual auditory or gustatory stimuli may require a pre-disposed or sensitized nervous system

AbbreviationsMSI Multi-modal sensory integration IAPS Pictures of facial affect or theinternational affective picture system QST Quantitative sensory testingCDT Cold detection threshold WDT Warmth detection threshold CPT Coldpain threshold HPT Heat pain threshold PANAS Positive and negative affectschedule HR Heart rate EEG Electroencephalography aMCC AnteriorMidCingulate cortex pMCC Posterior MidCingulate cortex sACC Subgenualanterior cingulate cortex

Competing interestsThe authors declare that they have no competing interests

Yang et al The Journal of Headache and Pain 2014 1571 Page 11 of 12httpwwwthejournalofheadacheandpaincomcontent15171

Authorsrsquo contributionsYG recruited the participants carried out the study performed the statisticalanalysis and drafted the manuscript SP and BHL participated in the designof the study statistical analysis and revision of the draft XQ and WK helpedto draft and revise the manuscript All authors read and approved the finalmanuscript

AcknowledgementsWe are indebted to the subjects who participated in the study for theirconsent and co-operation This study was made possible by the supportsof Danish Dental Association

Author details1Department of Prosthodontics and Center for Oral Functional DiagnosisTreatment and Research Peking University School and hospital ofStomatology Zhongguancun Nandajie 22 100081 Beijing China 2Section ofClinical Oral Physiology Department of Dentistry Aarhus University AarhusDenmark 3Center for Sensory-Motor Interaction (SMI) Department of HealthScience and Technology Aalborg University Aalborg Denmark 4Departmentof Dental Medicine Karolinska Institute Huddinge Sweden

Received 28 August 2014 Accepted 28 October 2014Published 7 November 2014

References1 Goadsby PJ (2009) Pathophysiology of migraine Neurol Clin 27(2)335ndash360

httpdxdoiorg101016jncl2008110122 Judit A Saacutendor PS Schoenen J (2000) Habituation of visual and intensity

dependence of cortical auditory evoked potentials tends to normalize justbefore and during migraine attack Cephalalgia 20(8)714ndash719httponlinelibrarywileycomdoi101111j1468-2982200000122xfull

3 Schoenen J Wang W Albert A Delwaide PJ (1995) Potentiation instead ofhabituation characterizes visual evoked potentials in migraine patientsbetween attacks Eur J Neurol 2(2)115ndash122 doi101111j1468-1331

4 Wang W Schoenen J (1998) Interictal potentiation of passive ldquooddballrdquoauditory event-related potentials in migraine Cephalalgia 18(5)261ndash265doi101111j1468-298219981805261x

5 Stein BE Stanford TR (2008) Multisensory integration current issues fromthe perspective of the single neuron Nat Rev Neurosci 9(4)255ndash266doi101038nrn2331

6 Basura GJ Koehler SD Shore SE (2012) Multi-sensory integration inbrainstem and auditory cortex Brain Res 148595ndash107 httpdxdoiorg101016jbrainres201208037

7 Jain R Shore S (2006) External inferior colliculus integrates trigeminal andacoustic information unit response to trigeminal nucleus and acousticstimulation in the guinea pig Neurosci Lett 395(1)71ndash75 httpdxdoiorg101016jneulet200510077

8 Kawasaki A Purvin VA (2002) Photophobia as the presenting visual symptom ofchiasmal compression J Neuroophthalmol 22(1)3ndash8httpovidsptxovidcomsp-3131aovidwebcgiT=JSampPAGE=fulltextampD=ovftampAN=00041327-200203000-00002ampNEWS=NampCSC=YampCHANNEL=PubMed

9 Lang PJ (1995) The emotion probe Studies of motivation and attentionAm Psychol 50(5)372ndash385 doi1010370003-066X505372

10 Esslen M Pascual-Marqui RD Hell D Kochi K Lehmann D (2004) Brain areasand time course of emotional processing Neuroimage 21(4)1189ndash1203httpdxdoiorg101016jneuroimage200310001

11 Baumgartner T Esslen M Jaumlncke L (2006) From emotion perception toemotion experience emotions evoked by pictures and classical music Int JPsychophysiol 60(1)34ndash43 httpdxdoiorg101016jijpsycho200504007

12 Mitterschiffthaler MT Fu CH Dalton JA Andrew CM Williams SC (2007) Afunctional MRI study of happy and sad affective states induced by classicalmusic Hum Brain Mapp 28(11)1150ndash1162 DOI 101002hbm20337

13 Koelsch S (2010) Towards a neural basis of music-evoked emotions TrendsCogn Sci 14(3)131ndash137 httpdxdoiorg101016jtics201001002

14 Pepino MY Mennella JA (2005) Sucrose-induced analgesia is related tosweet preference in children but not adults Pain 119(1ndash3)210ndash218httpdxdoiorg101016jpain200509029

15 Horjales-Araujo E Demontis D Lund EK Vase L Finnerup NB Boslashrglum ADJensen TS Svensson P (2013) Emotional modulation of muscle pain isassociated with polymorphisms in the serotonin transporter gene Pain154(8)1469ndash1476 doi101016jpain201305011

16 Bushnell EW Baxt C (1999) Childrenrsquos haptic and cross-modal recognitionwith familiar and unfamiliar objects J Exp Psychol Hum Percept Perform25(6)1867ndash1881 doi1010370096-1523256

17 Longe SE Wise R Bantick S Lloyd D Johansen-Berg H McGlone F Tracey I(2001) Counter-stimulatory effects on pain perception and processing aresignificantly altered by attention an fMRI study Neuroreport 12(9)2021ndash2025httpovidsptxovidcomsp-3131aovidwebcgiT=JSampPAGE=fulltextampD=ovf-tampAN=00001756-200107030-00047ampNEWS=NampCSC=YampCHANNEL=PubMed

18 Rode S Salkovskis PM Jack T (2001) An experimental study of attentionlabeling and memory in people suffering from chronic pain Pain 94(2)193ndash203httpdxdoiorg101016S0304-3959(01)00356-6

19 McCaul KD Monson N Maki RH (1992) Does distraction reduce pain-produced distress among college students Health Psychol 11(4)210ndash217doi1010370278-6133114210

20 Rolke R Baron R Maier C Toumllle TR Treede RD Beyer A Binder A Birbaumer NBirklein F Boumltefuumlr IC Braune S Flor H Huge V Klug R Landwehrmeyer GBMagerl W Maihoumlfner C Rolko C Schaub C Scherens A Sprenger T Valet MWasserka B (2006) Quantitative sensory testing in the German ResearchNetwork on Neuropathic Pain (DFNS) Standardized protocol and referencevalue Pain 123(3)231ndash243 httpdxdoiorg101016jpain200601041

21 Yang G Luo Y Baad-Hansen L Wang K Arendt-Nielsen L Xie QF SvenssonP (2013) Ethnic differences in oro-facial somatosensory profiles-quantitativesensory testing in Chinese and Danes J Oral Rehabil 40(11)844ndash853doi101111joor12091

22 Meagher MW Arnau RC Rhudy JL (2001) Pain and emotion Effect ofAffective Picture Modulation Psychosom Med 63(1)79ndash90 httpwwwpsychosomaticmedicineorgcontent63179short

23 Danish volunteers recruit website for clinical research [wwwforsoegspersondk]24 Okamoto K Tashiro A Thompson R Nishida Y Bereiter DA (2012) Trigeminal

interpolariscaudalis transition neurons mediate reflex lacrimation evoked bybright light in the rat Eur J Neurosci 36(11)3492ndash3499 doi101111j1460-9568201208272x

25 Noseda R Kainz V Jakubowski M Gooley JJ Saper CB Digre K Burstein R(2010) A neural mechanism for exacerbation of headache by light NatNeurosci 13(2)239ndash245 doi101038nn2475

26 Sliney DH (1983) Standards for use of visible and nonvisible radiation on theeye Am J Optom Physiol Opt 60(4)278ndash286 httpovidsptxovidcomsp-3131aovidwebcgiWebLinkFrameset=1ampS=GDKPFPEIMNDDLJBJNCLKDFIBGENOAA00ampreturnUrl=ovidwebcgi3fMain2bSearch2bPage3d126S3dGDKPFPEIMNDDLJBJNCLKDFIBGENOAA00ampdirectlink=http3a2f2fgraphicstxovidcom2fovftpdfs2fFPDDNCIBDFBJMN002ffs0462fovft2flive2fgv0232f000004512f00000451-198304000-00003pdfampfilename=Standards+for+Use+of+Visible+and+Nonvisible+Radiation+on+the+Eyeampnavigation_links=NavLinksSsh421amplink_from=Ssh427c1amppdf_key=FPDDNCIBDFBJMN00amppdf_index=fs046ovftlivegv0230000045100000451-198304000-00003ampD=ovftamplink_set=Ssh42|1|sl_10|resultSet|Ssh4243|0

27 Rappaport SM (1993) Threshold limit values permissible exposure limitsand feasibility the bases for exposure limits in the United States Am J IndMed 23(5)683ndash694 doi101002ajim4700230502

28 Rhudy JL Meagher MW (2001) Noise stress and human pain thresholdsdivergent effects in men and women J Pain 2(1)64 httpdxdoiorg101054jpai200019947

29 Goldenberg AM Wexler LF (1988) Quinine overdose review of toxicity andtreatment Clin Cardiol 11(10)716ndash718 doi101002clc4960111012

30 Cardesiacuten A Alobid I Beniacutetez P Sierra E de Haro J Bernal-Sprekelsen MPicado C Mullol J (2006) Barcelona Smell Test - 24 (BAST-24) validation andsmell characteristics in the healthy Spanish population Rhinology 44(1)83ndash89httpwwwrhinologyjournalcomabstractphpid=556

31 Watson D Clark LA Tellegen A (1988) Development and validation of briefmeasures of positive and negative affect the PANAS scale J Pers SocPsychol 54(6)1063ndash1070 doi1010370022-35145461063

32 Crawford JR Herry JD (2004) The positive and negative affect schedule(PANAS) construct validity measurement properties and normative data ina large non-clinical sample Br J Clin Psychol 43(3)245ndash265 httpovidsptxovidcomsp-3131aovidwebcgiT=JSampPAGE=fulltextampD=ovftampAN=00002604-200409000-00003ampNEWS=NampCSC=YampCHANNEL=PubMed

33 Hsee CK Hatfield E Carlson JG Chemtob C (1990) The effect of power onsusceptibility to emotional contagion Cogn Emot 4327ndash340 doi10108002699939008408081

34 Doherty RW (1998) Emotional contagion and social judgment Motiv Emot22187ndash209 doi101023A1022368805803

Yang et al The Journal of Headache and Pain 2014 1571 Page 4 of 12httpwwwthejournalofheadacheandpaincomcontent15171

after each thermal sensory test [3132] Respondents wererequired to indicate the extent to which they felt the emo-tions included on the schedule ldquoduring the thermal testrdquoon a five-point scale (where 1 = very slightly or not at allto 5 = extremely) [3132]Heart rate (HR) and skin temperature of contralateral

orofacial region were measured using a Patient Monitor(NPB-4000 US) and an infrared thermometer (THER-MOFOCUS 01500 serien Italy) continuously HR andskin temperature were recorded seven times in each test(Figure 1) and the mean was used for further analysis [28]

Statistical analysisAll statistical calculations were performed using SPSS 170software for windows (IBM inc USA) The assumption ofnormal distribution of all data was investigated by theShapiro-Wilk method Paired t-test was used to comparethe difference between baselines and stimuli tests Differ-ences between genders were evaluated by unpaired t-testThe changes under conditioning stimuli compared to base-line tests were calculated as delta values value = value(stimuli) ndash value (baseline) which was used in results andfigures as ldquorelative changesrdquo Differences between deltavalues within one session (dose dependent effect) were an-alyzed using two-way repeated measures ANOVA with thestimulus intensity as within-participant factor and genderas between-participant factor To evaluate the multisensoryeffect the delta values (ldquochangesrdquo) in multisensory stimula-tion test gustatory test 9000 lux light visual test and90 dB noise auditory test were compared using two-wayrepeated ANOVA with conditioning stimuli as within-participant factor gender as between-participant factorPost-hoc comparisons were estimated using Bonferronipost-hoc test with correction for multiple comparisonsP lt005 was taken as an indication of a statistically signifi-cant difference

ResultsParticipantsThere was no significant age difference between female(254 plusmn 29 years mean plusmn SD) and male (277 plusmn 32 years)participants (unpaired t-test age P = 0110)

Psychometrical measuresAll the subjective intensity rating scores to different condi-tioning stimuli were normally distributed (Shapiro-WilkP ge0066) Compared with baseline subjective stimulus in-tensity rating during conditioning stimuli tests was signifi-cantly higher in visual (paired t-test P lt0001) auditory(P lt0001) gustatory (P lt0001) and multisensory test(P lt0001) (Table 1) The participantsrsquo subjective ratingdifferences between the condition with stimulus andcorresponding baseline (ldquorelative changesrdquo in the text andfigures) was higher when participants were exposed to

stronger stimuli significant intensity effect on subjectiverating ldquorelative changesrdquo F = 8804 P lt0001 for visual test(Figure 2-A) F = 8825 P lt0001 for auditory test(Figure 2-B) Post-hoc test for multiple contrasts indicatedsignificant increases with increased intensity of light andnoise (Figure 2-AB) There were no gender differences invisual auditory gustatory and multisensory tests (un-paired t-test t le0266 P gt0791)Most of the affective scores to different conditioning

stimuli were normally distributed (Shapiro-Wilk P gt005)The conditioning stimuli induced statistically significantlyhigher negative affective states compared with baseline vis-ual test (baseline 116 plusmn 21 mean plusmn SD stimulus 136 plusmn45 paired t-test t = minus3742 P lt0001) auditory test (base-line 120 plusmn 30 stimulus 146 plusmn 45 t = minus5182 P lt0001)gustatory test (baseline 136 plusmn 45 stimulus 168 plusmn 41t = minus2656 P =0016) multisensory test (baseline 132 plusmn44 stimulus 196 plusmn 62 t = minus6719 P lt0001) (Figure 3)The negative affective score differences between the condi-tion with stimuli and corresponding baseline (as ldquodeltavaluerdquo or ldquochangesrdquo in the text and figures) were higherwhen the participants were exposed to more intense stim-uli significant intensity effects on negative affective scoresfor visual test (F = 7484 P =0006 Figure 4-A) auditorytest (F = 11335 P lt0001 Figure 4-B) The Post-hoc testfor multiple comparisons indicated a statistically significantincrease in negative affective scores with increasing inten-sities in the light and noise tests (Figure 4-AB) Besidesthere were statistically significant gender differences withmales having higher negative affective scores when exposedto the same stimuli compared to females in auditory test(unpaired t-test gender differences t = minus3308 P = 0004for 75 dB noise t = minus3519 P =0002 for 90 dB noiseFigure 4-B) and gustatory test (t = minus2694 P = 0015Figure 4-C) As could be expected all the stimuli failed toinduce positive affective changes of the participants com-pared with baseline visual test (paired t-test P = 0117)auditory test (P = 0091) gustatory test (P = 0169) andmultisensory test (P = 0080)

Physiological measuresThe heart rate and skin temperature data for differentconditioning stimuli were normally distributed (Shapiro-Wilk P ge0069) The conditioning stimuli did not changethe two indices of physical arousal heart rate and skintemperature in comparison with the corresponding base-line values pared t-test P value for differences (heart ratetemperature) in visual test (0408 0162) auditory test(0059 0574) gustatory test (0195 0639) and multi-sensory test (0137 0057)

Thermal somatosensory sensitivityMost of the QST data in different conditioning stimuli werenormally distributed only after logarithmic transformation

Table 1 Subjective intensity rating to conditioning stimuli (minus100)

Conditions Baseline (mean plusmn SD) With stimuli (mean plusmn SD) P

Visual 0 plusmn 0 590 plusmn 241 lt 0001

Auditory 188 plusmn 150 656 plusmn 241 lt 0001

Gustatory 66 plusmn 44 403 plusmn 173 lt 0001

Multisensory 75 plusmn 49 473 plusmn 228 lt 0001

Subjective rating to conditioning stimuli was assessed by numerical scale in which ldquo0 = no stimulus could be detectedrdquo to ldquo100 = the strongest stimulusimaginablerdquo The comparisons between the conditions with stimuli and corresponding baseline were investigated by paired t-test

Figure 2 Subjective rating (changes) to different conditioning stimuli The differences between test with conditioning stimuli andcorresponding baseline were calculated as delta values value = value (conditioned) ndash value (baseline) which was used in figures (A visual andB auditory test) as ldquorelative changesrdquo Compared with baseline subjective stimulus intensity rating during gustatory and multisensory tests wassignificantly higher The participantsrsquo subjective rating changes were higher when they were exposed to stronger stimuli in visual and auditorytests (C) gustatory test (D) multisensory test = P lt0001

Yang et al The Journal of Headache and Pain 2014 1571 Page 5 of 12httpwwwthejournalofheadacheandpaincomcontent15171

Figure 3 Negative affective state differences between testswith conditioning stimuli (grizzle bars) and correspondingbaselines (white bars) The results are presented as means plusmn SDs ofthe negative affective scores form Positive and Negative AffectSchedule The conditioning stimuli induced statistically significantlyhigher negative affective states compared with baseline = P lt0001 = P lt005

Yang et al The Journal of Headache and Pain 2014 1571 Page 6 of 12httpwwwthejournalofheadacheandpaincomcontent15171

(Shapiro-Wilk P gt005) Compared with baseline the sensi-tivity to thermal stimuli did not change when the partici-pants were exposed to conditioning stimuli visual test(paired t-test P value for CDT WDT CPT HPT were0074 0641 0165 0095 respectively Figure 5-A) auditorytest (paired t-test P value for CDT WDT CPT HPT were0055 0922 0515 0418 respectively Figure 5-B) gustatorytest (paired t-test P value for CDT WDT CPT HPT were0347 0207 0202 0729 respectively Figure 5-C) multi-sensory stimulation (paired t-test P value for CDT WDTCPT HPT were 0526 0051 0737 0331 respectivelyFigure 5-D)

Multisensory stimulation effectWhen the participants were exposed to multisensory(combined) conditioning stimuli they subjectively ratedhigher ldquodelta valuesrdquo to the same bitter taste comparedwith in the condition of taste stimulus alone (whole groupF = 5017 P = 0038 male F = 8980 P = 0015 femaleF = 1304 P gt005 Figure 6-A) The female participantspresented higher ldquodelta valuesrdquo for the negative affectivescores during the multisensory stimuli condition than dur-ing noise stimulation alone (noise 20 plusmn 24 mean plusmn SDtaste 15 plusmn 63 combination 68 plusmn 58 Post-hoc testbetween combination test and noise test P = 0011Figure 6-C) The participants presented a statistically sig-nificant decrease in WDT (ldquodeltardquo WDT decreasing) dur-ing multisensory conditioning stimuli compared with lightstimulus alone (male Post-hoc test P = 0019 Figure 6-GTable 2) or taste alone (whole group P =0004 maleP = 0003 female P = 0438 Figure 6-G Table 2)

DiscussionsThis study investigated for the first time the effects ofthree unpleasant conditioning stimuli (bright light chain-saw noise and bitter taste) on negative affective statephysiological arousal and skin thermal sensitivity Thethree conditioning stimuli as expected all induced statis-tically significant increases in negative affective scorescompared with baseline Additionally a dose dependentphenomenon was demonstrated in the visual and auditorytests (only one intensity gustatory stimulus was applied inthis study) There were no significant changes in positiveaffective scores physiological arousal (heart rate or skintemperature) between tests with and without conditioningstimuli The skin thermal sensitivity (via CDT WDTCPT HPT) in the perioral region did not change signifi-cantly during conditioning stimuli tests compared withbaseline Combining the individual conditioning stimuliinto a multisensory conditioning stimulus led to a strengthened effect compared with single conditioning stimulifor several outcome parameters ie subjective ratingsnegative affective scores and warmth detection threshold(WDT)

Influence of conditioning stimuli on affective stateThe experimental visual stimuli used in previous studies toexamine the affective processes were composed of emo-tional videos [3334] or photos [3536] Viewing faces withsad or happy expressions specifically evoked the expressedfeelings in the viewer defined as ldquoemotional contagionrdquo[35] This emotional contagion was considered as a ldquopre-wiredrdquo decoding instrument which was considered a fastrepeatable and stable process [35] These visual stimuliactivate an emotion perception process characterized byfocusing attention to external events and accurately under-standing the information conducted which need the fullco-operation of the investigated individuals [11] Addition-ally some studies concluded that the experimentallyinduced changes in the affective state were obtained onlyafter repeated stimuli presentation accompanied withspecified verbal inductions [37] Furthermore in anotherElectroencephalography (EEG) study emotional reactionscould not be evoked by presenting emotional picturesalone [11] In migraineurs bright light often exacerbate theheadache which could be accounted for a pathophysio-logical hypothesis of a disturbance of the subcortical sen-sory modulation system [18] Although the trigeminalautonomic reflex acts as a feed-forward system to facilitatethe acute attack the fundamental problem was thought tobe in the brain [1] The possible effect of bright light toexperimentally evoke an affective state and somatosensorysensitivity changes has not been assessed before Thehypothesis of the present study was that bright light couldevoke a negative affective state and change the somatosen-sory sensitivity In the present experimental study bright

Figure 4 Effects of conditioning stimuli on negative affective (changes) between genders The negative affective score differencesbetween the condition with stimuli and corresponding baseline (as ldquochangesrdquo in the figure) were higher when the participants were exposed tomore intense stimuli in visual (A) and auditory (B) tests Besides there were statistically significant gender differences in auditory test (B) andgustatory test (C) (D) indicates multisensory test = P lt0001 = P lt001 = P lt005

Yang et al The Journal of Headache and Pain 2014 1571 Page 7 of 12httpwwwthejournalofheadacheandpaincomcontent15171

light successfully evoked a negative affective state in adose-dependent manner according to the intensity of thelight (Figure 4-A) Bright light may be a simple andeffecient way to induce a negative affective state in humanstudies However bright light did not significantly changesomatosensory sensitivity to thermal stimuli This indicatesthat the light regulation of thermal somatosensory sensi-tivity may not exist in healthy humans without priorsensitization or predispositionSeveral studies have demonstrated that music is a power-

ful mediator of changes in affective state [3839] Func-tional neuro-imaging and lesion studies have shown thatmusic-evoked affective state changes can modulate activityin virtually all limbic and paralimbic brain structures suchas amygdala parahippocampal gyrus and hippocampus[1240-42] These structures are crucially involved in theinitiation generation detection maintenance regulation

and termination of changes in affective state [13] Musicmay affect trained musicians and non-musicians differentlyand different individuals have different musical preferencesand experiences which may be important in studies ofinfluence of music on different outcome parameters [13]In contrast to most people a chainsaw noise as used in thepresent study can be considered an unpleasant auditorystimulus The participants in this study rated moderate tostrong unpleasantness to the noise (Figure 2-B) Thehypothesis of the present study was that an unpleasantauditory stimulus could increase negative affect and changesomatosensoty sensitivity The chainsaw noise successfullyevoked a negative affective state in a dose-dependentmanner as the intensity of the auditory stimulus increased(Figure 4-B) Again chainsaw noise may be a simple andeffective way to induce a negative affective state in humanstudies However the chainsaw noise did not significantly

Figure 5 Thermal sensitivity differences between tests with conditioning stimuli (grizzle bars) and corresponding baselines (white bars)The results are presented as means plusmn SDs of the threshold values from visual test (A) auditory test (B) gustatory test (C) and multisensory test (D)Compared with baseline (white bars) the sensitivity to thermal stimulus did not change when the participants were exposed to conditioning stimuli(grizzle bars) CDT = cold detection threshold WDT =warmth detection threshold CPT = cold pain threshold HPT = heat pain threshold

Yang et al The Journal of Headache and Pain 2014 1571 Page 8 of 12httpwwwthejournalofheadacheandpaincomcontent15171

change somatosensory sensitivity to thermal stimuli Thisindicates that auditory stimulus regulation of thermal som-atosensory is not significant in healthy volunteers How-ever in some pathological conditions such as tension-typeand cervicogenic headache phonophobia is a commonsymptom [43] Again this may require a sensitized orpredisposed somatosensory systemIt has been reported that sucrose reduces pain during the

Cold Pressor Test (CPT) in 5- to 10-year-old children andthis kind of analgesia is dependent on the sweet taste pref-erence [14] However sucrose was not an effective analgesiain adult women in the same study The age-related declinein the analgesic efficacy of sucrose mirrors the age-relateddecline in the hedonic value of sweet tastes [44] In a recentstudy the taste of quinine gelatin (01) failed to producerobust affective state changes [45] However in the presentstudy the same stimulus evoked a significant change in

negative affective state These contradictory results maypossibly been explained by the ldquopreference theoryrdquo sincethe subjective rating to the bitter taste in this study (403 plusmn173 mean plusmn SD in a 0ndash100 numerical scale) was muchhigher than the study by Horjales-Aaujo (297 plusmn 197)[1445] Despite the negative affective state there were nochanges in somatosensory sensitivity in healthy volunteers

Multisensory conditioning stimulus effectsThere were several statistically significant effects of themultisensory conditioning stimulus which indicated thatthe multisensory stimulation enhanced the effect of indi-vidual stimuli with regard to subjective rating changesaffective score changes and induced slight thermal sensi-tivity changes This is in line with a neurophysiologicalstudy which demonstrates a strong emotion enhancementeffect by simultaneous presentation of congruent emotional

Figure 6 Multisensory effects between genders To diminish the effect of timing the delta values between test with stimuli and correspondingbaseline defined as ldquochangesrdquo in the figure was used Multisensory conditioning stimulus led to a strengthened effect compared with singleconditioning stimuli for several outcome parameters ie subjective ratings to gustatory stimulus (A) negative affective scores (C) and warmthdetection threshold (G) CDT = cold detection threshold WDT =warmth detection threshold CPT = cold pain threshold HPT = heat pain thresholdPositive affective changes (B) heat rate changes (D) skin temperature changes (E) cold detection threshold changes (F) cold pain threshold changes(H) and heat pain threshold changes (I) in different tests were also presented = P lt001 = P lt005

Yang et al The Journal of Headache and Pain 2014 1571 Page 9 of 12httpwwwthejournalofheadacheandpaincomcontent15171

pictures and music regarding subjective ratings peripheraland central physiological measures [11] The findings alsofit with a study which shows that when either positive (joy-ful) or negative (fearful) music is played simultaneouslywith an emotionally neutral film clip it evokes strongersignal changes in the amygdala and in areas of the ventro-lateral frontal cortex compared with when only music oronly film clips are presented [46] The activation increase

may be due to the cross modal integration of three sensorystimuli and this stronger activation possibly suggests en-hanced activation in a distributed neuronal network whichneeds to be confirmed in functional imaging studies [6]

Physiological arousal changesIt has been proposed that most affective changes are asso-ciated with undifferentiated physiological activity changes

Table 2 Impact of gender on warmth detection threshold (WDT degC) changes with different stimuli

Gender Visual (1) Auditory (2) Gustatory (3) Multisensory (4) F P 1 vs 4 2 vs 4 3 vs 4

Female Mean minus008 minus012 minus002 minus0150098 NS 0784 0938 0438

SD 076 064 035 060

Male Mean 017 minus003 027 minus0336036 0003 0019 NS 0003

SD 029 021 050 033

Sum Mean 004 minus008 013 minus0242241 NS 0058 0387 0004

SD 057 046 045 048

To evaluate the multisensory effect the delta values (ldquochangesrdquo) in 9000 lux light visual test 90 dB noise auditory test gustatory test and multisensory stimulationtest were compared using two-way repeated ANOVA with conditioning stimuli as within-participant factor gender as between-participant factor The male participantspresented a statistically significant decrease in ldquodeltardquo WDT during multisensory conditioning stimuli compared with light stimulus alone (P = 0019) or taste alone(P = 0003) Italics values indicate statistically significant P values (P lt 005)

Yang et al The Journal of Headache and Pain 2014 1571 Page 10 of 12httpwwwthejournalofheadacheandpaincomcontent15171

[47] Thus it seems reasonable to examine physiologicalarousal measurements related to affective reactions Skintemperature and heart rate are the most frequently usedphysiological expressions of affective state [47] Howeverin the present study these two parameters did not changesignificantly in response to changes in negative affectivestate by the different conditioning stimuli This is in linewith another study where it was demonstrated that theverbally reported affective experiences are not alwaysconsistent with the physiological parameters especially forunpleasant stimuli [47] On the other hand it may bebecause of the limited number of participants or that theapplied stimulus was inadequate for induction of a signifi-cant physiological change in arousal

Interactions between somatosensory sensitivity andconditioning stimuliThe perception of migraine headache which is mediatedby nociceptive signals is exacerbated by exposure to en-vironment stimuli ie light or noise which are mediatedby optical and acoustic signals Prolonged neuronal activa-tion during a migraine attack is thought to induce periph-eral and central sensitization along the trigeminovascularpathway which stands to explain the throbbing headache[48] accompanying scalp and neck-muscle tenderness[49] and whole-body cutaneous allodynia [50] Severaltheories exist which predict the relationship betweenconditioning stimuli and somatosensory sensitivity Todevelop a more comprehensive model of somatosensorymodulation by conditioning stimuli it may be useful toconsider a theory of ldquomotivational primingrdquo [9] It is pro-posed that affective state processing evoked by stimulicould be viewed as two opposing motivational systemsOne system is appetitive and produces approach behav-iors and the other system is aversive and promotes avoid-ance behaviors [9] Considerable evidence indicates thatprior activation of these systems modulates defensive be-haviors which facilitates somatosensory capability [51]These defensive behaviors increase in magnitude whenthe aversive system is primed by a negative affective stateie anticipation of shock [52] Conversely this defensive

response is inhibited when the appetitive system is primedby a positive affective state [53] According to the motiv-ational priming theory participants exposed to negativeaffective loading whose aversive systems are activatedshould get their perception facilitated [922] Howeversomatosensory sensitivity to thermal stimuli was not chan-ged during induction of negative affective states in thepresent study Another perspective on somatosensory andaffective processing is provided by the four-region neuro-biological model which indicates a complex relationshipbetween acute pain and simple emotion [54] For instancefear and pain sites overlap in the anterior midcingulatecortex (aMCC) and this region is involved in avoidancebehaviors posterior midcingulate cortex (pMCC) has noconsistent emotion activations yet has robust nociceptiveresponses subgenual anterior cingulate cortex (sACC) acti-vation during noxious stimulation of the skin and viscerain a person-specific manner the cingulate cortex is notuniformly involved in emotion and not all pain-activationsites are associated with affect or emotion [54]

ConclusionsThe three conditioning stimuli induced significantincreases in subjective rating and negative effectivescores accompanied with no physiological arousalchanges These stimuli did not however modulate skinthermal sensitivity The multisensory conditioning stimuliinduced stronger effects on subjective rating and negativeaffect than individual conditioning stimuli alone Theoften observed trigger or exacerbation of migraine byvisual auditory or gustatory stimuli may require a pre-disposed or sensitized nervous system

AbbreviationsMSI Multi-modal sensory integration IAPS Pictures of facial affect or theinternational affective picture system QST Quantitative sensory testingCDT Cold detection threshold WDT Warmth detection threshold CPT Coldpain threshold HPT Heat pain threshold PANAS Positive and negative affectschedule HR Heart rate EEG Electroencephalography aMCC AnteriorMidCingulate cortex pMCC Posterior MidCingulate cortex sACC Subgenualanterior cingulate cortex

Competing interestsThe authors declare that they have no competing interests

Yang et al The Journal of Headache and Pain 2014 1571 Page 11 of 12httpwwwthejournalofheadacheandpaincomcontent15171

Authorsrsquo contributionsYG recruited the participants carried out the study performed the statisticalanalysis and drafted the manuscript SP and BHL participated in the designof the study statistical analysis and revision of the draft XQ and WK helpedto draft and revise the manuscript All authors read and approved the finalmanuscript

AcknowledgementsWe are indebted to the subjects who participated in the study for theirconsent and co-operation This study was made possible by the supportsof Danish Dental Association

Author details1Department of Prosthodontics and Center for Oral Functional DiagnosisTreatment and Research Peking University School and hospital ofStomatology Zhongguancun Nandajie 22 100081 Beijing China 2Section ofClinical Oral Physiology Department of Dentistry Aarhus University AarhusDenmark 3Center for Sensory-Motor Interaction (SMI) Department of HealthScience and Technology Aalborg University Aalborg Denmark 4Departmentof Dental Medicine Karolinska Institute Huddinge Sweden

Received 28 August 2014 Accepted 28 October 2014Published 7 November 2014

References1 Goadsby PJ (2009) Pathophysiology of migraine Neurol Clin 27(2)335ndash360

httpdxdoiorg101016jncl2008110122 Judit A Saacutendor PS Schoenen J (2000) Habituation of visual and intensity

dependence of cortical auditory evoked potentials tends to normalize justbefore and during migraine attack Cephalalgia 20(8)714ndash719httponlinelibrarywileycomdoi101111j1468-2982200000122xfull

3 Schoenen J Wang W Albert A Delwaide PJ (1995) Potentiation instead ofhabituation characterizes visual evoked potentials in migraine patientsbetween attacks Eur J Neurol 2(2)115ndash122 doi101111j1468-1331

4 Wang W Schoenen J (1998) Interictal potentiation of passive ldquooddballrdquoauditory event-related potentials in migraine Cephalalgia 18(5)261ndash265doi101111j1468-298219981805261x

5 Stein BE Stanford TR (2008) Multisensory integration current issues fromthe perspective of the single neuron Nat Rev Neurosci 9(4)255ndash266doi101038nrn2331

6 Basura GJ Koehler SD Shore SE (2012) Multi-sensory integration inbrainstem and auditory cortex Brain Res 148595ndash107 httpdxdoiorg101016jbrainres201208037

7 Jain R Shore S (2006) External inferior colliculus integrates trigeminal andacoustic information unit response to trigeminal nucleus and acousticstimulation in the guinea pig Neurosci Lett 395(1)71ndash75 httpdxdoiorg101016jneulet200510077

8 Kawasaki A Purvin VA (2002) Photophobia as the presenting visual symptom ofchiasmal compression J Neuroophthalmol 22(1)3ndash8httpovidsptxovidcomsp-3131aovidwebcgiT=JSampPAGE=fulltextampD=ovftampAN=00041327-200203000-00002ampNEWS=NampCSC=YampCHANNEL=PubMed

9 Lang PJ (1995) The emotion probe Studies of motivation and attentionAm Psychol 50(5)372ndash385 doi1010370003-066X505372

10 Esslen M Pascual-Marqui RD Hell D Kochi K Lehmann D (2004) Brain areasand time course of emotional processing Neuroimage 21(4)1189ndash1203httpdxdoiorg101016jneuroimage200310001

11 Baumgartner T Esslen M Jaumlncke L (2006) From emotion perception toemotion experience emotions evoked by pictures and classical music Int JPsychophysiol 60(1)34ndash43 httpdxdoiorg101016jijpsycho200504007

12 Mitterschiffthaler MT Fu CH Dalton JA Andrew CM Williams SC (2007) Afunctional MRI study of happy and sad affective states induced by classicalmusic Hum Brain Mapp 28(11)1150ndash1162 DOI 101002hbm20337

13 Koelsch S (2010) Towards a neural basis of music-evoked emotions TrendsCogn Sci 14(3)131ndash137 httpdxdoiorg101016jtics201001002

14 Pepino MY Mennella JA (2005) Sucrose-induced analgesia is related tosweet preference in children but not adults Pain 119(1ndash3)210ndash218httpdxdoiorg101016jpain200509029

15 Horjales-Araujo E Demontis D Lund EK Vase L Finnerup NB Boslashrglum ADJensen TS Svensson P (2013) Emotional modulation of muscle pain isassociated with polymorphisms in the serotonin transporter gene Pain154(8)1469ndash1476 doi101016jpain201305011

16 Bushnell EW Baxt C (1999) Childrenrsquos haptic and cross-modal recognitionwith familiar and unfamiliar objects J Exp Psychol Hum Percept Perform25(6)1867ndash1881 doi1010370096-1523256

17 Longe SE Wise R Bantick S Lloyd D Johansen-Berg H McGlone F Tracey I(2001) Counter-stimulatory effects on pain perception and processing aresignificantly altered by attention an fMRI study Neuroreport 12(9)2021ndash2025httpovidsptxovidcomsp-3131aovidwebcgiT=JSampPAGE=fulltextampD=ovf-tampAN=00001756-200107030-00047ampNEWS=NampCSC=YampCHANNEL=PubMed

18 Rode S Salkovskis PM Jack T (2001) An experimental study of attentionlabeling and memory in people suffering from chronic pain Pain 94(2)193ndash203httpdxdoiorg101016S0304-3959(01)00356-6

19 McCaul KD Monson N Maki RH (1992) Does distraction reduce pain-produced distress among college students Health Psychol 11(4)210ndash217doi1010370278-6133114210

20 Rolke R Baron R Maier C Toumllle TR Treede RD Beyer A Binder A Birbaumer NBirklein F Boumltefuumlr IC Braune S Flor H Huge V Klug R Landwehrmeyer GBMagerl W Maihoumlfner C Rolko C Schaub C Scherens A Sprenger T Valet MWasserka B (2006) Quantitative sensory testing in the German ResearchNetwork on Neuropathic Pain (DFNS) Standardized protocol and referencevalue Pain 123(3)231ndash243 httpdxdoiorg101016jpain200601041

21 Yang G Luo Y Baad-Hansen L Wang K Arendt-Nielsen L Xie QF SvenssonP (2013) Ethnic differences in oro-facial somatosensory profiles-quantitativesensory testing in Chinese and Danes J Oral Rehabil 40(11)844ndash853doi101111joor12091

22 Meagher MW Arnau RC Rhudy JL (2001) Pain and emotion Effect ofAffective Picture Modulation Psychosom Med 63(1)79ndash90 httpwwwpsychosomaticmedicineorgcontent63179short

23 Danish volunteers recruit website for clinical research [wwwforsoegspersondk]24 Okamoto K Tashiro A Thompson R Nishida Y Bereiter DA (2012) Trigeminal

interpolariscaudalis transition neurons mediate reflex lacrimation evoked bybright light in the rat Eur J Neurosci 36(11)3492ndash3499 doi101111j1460-9568201208272x

25 Noseda R Kainz V Jakubowski M Gooley JJ Saper CB Digre K Burstein R(2010) A neural mechanism for exacerbation of headache by light NatNeurosci 13(2)239ndash245 doi101038nn2475

26 Sliney DH (1983) Standards for use of visible and nonvisible radiation on theeye Am J Optom Physiol Opt 60(4)278ndash286 httpovidsptxovidcomsp-3131aovidwebcgiWebLinkFrameset=1ampS=GDKPFPEIMNDDLJBJNCLKDFIBGENOAA00ampreturnUrl=ovidwebcgi3fMain2bSearch2bPage3d126S3dGDKPFPEIMNDDLJBJNCLKDFIBGENOAA00ampdirectlink=http3a2f2fgraphicstxovidcom2fovftpdfs2fFPDDNCIBDFBJMN002ffs0462fovft2flive2fgv0232f000004512f00000451-198304000-00003pdfampfilename=Standards+for+Use+of+Visible+and+Nonvisible+Radiation+on+the+Eyeampnavigation_links=NavLinksSsh421amplink_from=Ssh427c1amppdf_key=FPDDNCIBDFBJMN00amppdf_index=fs046ovftlivegv0230000045100000451-198304000-00003ampD=ovftamplink_set=Ssh42|1|sl_10|resultSet|Ssh4243|0

27 Rappaport SM (1993) Threshold limit values permissible exposure limitsand feasibility the bases for exposure limits in the United States Am J IndMed 23(5)683ndash694 doi101002ajim4700230502

28 Rhudy JL Meagher MW (2001) Noise stress and human pain thresholdsdivergent effects in men and women J Pain 2(1)64 httpdxdoiorg101054jpai200019947

29 Goldenberg AM Wexler LF (1988) Quinine overdose review of toxicity andtreatment Clin Cardiol 11(10)716ndash718 doi101002clc4960111012

30 Cardesiacuten A Alobid I Beniacutetez P Sierra E de Haro J Bernal-Sprekelsen MPicado C Mullol J (2006) Barcelona Smell Test - 24 (BAST-24) validation andsmell characteristics in the healthy Spanish population Rhinology 44(1)83ndash89httpwwwrhinologyjournalcomabstractphpid=556

31 Watson D Clark LA Tellegen A (1988) Development and validation of briefmeasures of positive and negative affect the PANAS scale J Pers SocPsychol 54(6)1063ndash1070 doi1010370022-35145461063

32 Crawford JR Herry JD (2004) The positive and negative affect schedule(PANAS) construct validity measurement properties and normative data ina large non-clinical sample Br J Clin Psychol 43(3)245ndash265 httpovidsptxovidcomsp-3131aovidwebcgiT=JSampPAGE=fulltextampD=ovftampAN=00002604-200409000-00003ampNEWS=NampCSC=YampCHANNEL=PubMed

33 Hsee CK Hatfield E Carlson JG Chemtob C (1990) The effect of power onsusceptibility to emotional contagion Cogn Emot 4327ndash340 doi10108002699939008408081

34 Doherty RW (1998) Emotional contagion and social judgment Motiv Emot22187ndash209 doi101023A1022368805803

Table 1 Subjective intensity rating to conditioning stimuli (minus100)

Conditions Baseline (mean plusmn SD) With stimuli (mean plusmn SD) P

Visual 0 plusmn 0 590 plusmn 241 lt 0001

Auditory 188 plusmn 150 656 plusmn 241 lt 0001

Gustatory 66 plusmn 44 403 plusmn 173 lt 0001

Multisensory 75 plusmn 49 473 plusmn 228 lt 0001

Subjective rating to conditioning stimuli was assessed by numerical scale in which ldquo0 = no stimulus could be detectedrdquo to ldquo100 = the strongest stimulusimaginablerdquo The comparisons between the conditions with stimuli and corresponding baseline were investigated by paired t-test

Figure 2 Subjective rating (changes) to different conditioning stimuli The differences between test with conditioning stimuli andcorresponding baseline were calculated as delta values value = value (conditioned) ndash value (baseline) which was used in figures (A visual andB auditory test) as ldquorelative changesrdquo Compared with baseline subjective stimulus intensity rating during gustatory and multisensory tests wassignificantly higher The participantsrsquo subjective rating changes were higher when they were exposed to stronger stimuli in visual and auditorytests (C) gustatory test (D) multisensory test = P lt0001

Yang et al The Journal of Headache and Pain 2014 1571 Page 5 of 12httpwwwthejournalofheadacheandpaincomcontent15171

Figure 3 Negative affective state differences between testswith conditioning stimuli (grizzle bars) and correspondingbaselines (white bars) The results are presented as means plusmn SDs ofthe negative affective scores form Positive and Negative AffectSchedule The conditioning stimuli induced statistically significantlyhigher negative affective states compared with baseline = P lt0001 = P lt005

Yang et al The Journal of Headache and Pain 2014 1571 Page 6 of 12httpwwwthejournalofheadacheandpaincomcontent15171

(Shapiro-Wilk P gt005) Compared with baseline the sensi-tivity to thermal stimuli did not change when the partici-pants were exposed to conditioning stimuli visual test(paired t-test P value for CDT WDT CPT HPT were0074 0641 0165 0095 respectively Figure 5-A) auditorytest (paired t-test P value for CDT WDT CPT HPT were0055 0922 0515 0418 respectively Figure 5-B) gustatorytest (paired t-test P value for CDT WDT CPT HPT were0347 0207 0202 0729 respectively Figure 5-C) multi-sensory stimulation (paired t-test P value for CDT WDTCPT HPT were 0526 0051 0737 0331 respectivelyFigure 5-D)

Multisensory stimulation effectWhen the participants were exposed to multisensory(combined) conditioning stimuli they subjectively ratedhigher ldquodelta valuesrdquo to the same bitter taste comparedwith in the condition of taste stimulus alone (whole groupF = 5017 P = 0038 male F = 8980 P = 0015 femaleF = 1304 P gt005 Figure 6-A) The female participantspresented higher ldquodelta valuesrdquo for the negative affectivescores during the multisensory stimuli condition than dur-ing noise stimulation alone (noise 20 plusmn 24 mean plusmn SDtaste 15 plusmn 63 combination 68 plusmn 58 Post-hoc testbetween combination test and noise test P = 0011Figure 6-C) The participants presented a statistically sig-nificant decrease in WDT (ldquodeltardquo WDT decreasing) dur-ing multisensory conditioning stimuli compared with lightstimulus alone (male Post-hoc test P = 0019 Figure 6-GTable 2) or taste alone (whole group P =0004 maleP = 0003 female P = 0438 Figure 6-G Table 2)

DiscussionsThis study investigated for the first time the effects ofthree unpleasant conditioning stimuli (bright light chain-saw noise and bitter taste) on negative affective statephysiological arousal and skin thermal sensitivity Thethree conditioning stimuli as expected all induced statis-tically significant increases in negative affective scorescompared with baseline Additionally a dose dependentphenomenon was demonstrated in the visual and auditorytests (only one intensity gustatory stimulus was applied inthis study) There were no significant changes in positiveaffective scores physiological arousal (heart rate or skintemperature) between tests with and without conditioningstimuli The skin thermal sensitivity (via CDT WDTCPT HPT) in the perioral region did not change signifi-cantly during conditioning stimuli tests compared withbaseline Combining the individual conditioning stimuliinto a multisensory conditioning stimulus led to a strengthened effect compared with single conditioning stimulifor several outcome parameters ie subjective ratingsnegative affective scores and warmth detection threshold(WDT)

Influence of conditioning stimuli on affective stateThe experimental visual stimuli used in previous studies toexamine the affective processes were composed of emo-tional videos [3334] or photos [3536] Viewing faces withsad or happy expressions specifically evoked the expressedfeelings in the viewer defined as ldquoemotional contagionrdquo[35] This emotional contagion was considered as a ldquopre-wiredrdquo decoding instrument which was considered a fastrepeatable and stable process [35] These visual stimuliactivate an emotion perception process characterized byfocusing attention to external events and accurately under-standing the information conducted which need the fullco-operation of the investigated individuals [11] Addition-ally some studies concluded that the experimentallyinduced changes in the affective state were obtained onlyafter repeated stimuli presentation accompanied withspecified verbal inductions [37] Furthermore in anotherElectroencephalography (EEG) study emotional reactionscould not be evoked by presenting emotional picturesalone [11] In migraineurs bright light often exacerbate theheadache which could be accounted for a pathophysio-logical hypothesis of a disturbance of the subcortical sen-sory modulation system [18] Although the trigeminalautonomic reflex acts as a feed-forward system to facilitatethe acute attack the fundamental problem was thought tobe in the brain [1] The possible effect of bright light toexperimentally evoke an affective state and somatosensorysensitivity changes has not been assessed before Thehypothesis of the present study was that bright light couldevoke a negative affective state and change the somatosen-sory sensitivity In the present experimental study bright

Figure 4 Effects of conditioning stimuli on negative affective (changes) between genders The negative affective score differencesbetween the condition with stimuli and corresponding baseline (as ldquochangesrdquo in the figure) were higher when the participants were exposed tomore intense stimuli in visual (A) and auditory (B) tests Besides there were statistically significant gender differences in auditory test (B) andgustatory test (C) (D) indicates multisensory test = P lt0001 = P lt001 = P lt005

Yang et al The Journal of Headache and Pain 2014 1571 Page 7 of 12httpwwwthejournalofheadacheandpaincomcontent15171

light successfully evoked a negative affective state in adose-dependent manner according to the intensity of thelight (Figure 4-A) Bright light may be a simple andeffecient way to induce a negative affective state in humanstudies However bright light did not significantly changesomatosensory sensitivity to thermal stimuli This indicatesthat the light regulation of thermal somatosensory sensi-tivity may not exist in healthy humans without priorsensitization or predispositionSeveral studies have demonstrated that music is a power-

ful mediator of changes in affective state [3839] Func-tional neuro-imaging and lesion studies have shown thatmusic-evoked affective state changes can modulate activityin virtually all limbic and paralimbic brain structures suchas amygdala parahippocampal gyrus and hippocampus[1240-42] These structures are crucially involved in theinitiation generation detection maintenance regulation

and termination of changes in affective state [13] Musicmay affect trained musicians and non-musicians differentlyand different individuals have different musical preferencesand experiences which may be important in studies ofinfluence of music on different outcome parameters [13]In contrast to most people a chainsaw noise as used in thepresent study can be considered an unpleasant auditorystimulus The participants in this study rated moderate tostrong unpleasantness to the noise (Figure 2-B) Thehypothesis of the present study was that an unpleasantauditory stimulus could increase negative affect and changesomatosensoty sensitivity The chainsaw noise successfullyevoked a negative affective state in a dose-dependentmanner as the intensity of the auditory stimulus increased(Figure 4-B) Again chainsaw noise may be a simple andeffective way to induce a negative affective state in humanstudies However the chainsaw noise did not significantly

Figure 5 Thermal sensitivity differences between tests with conditioning stimuli (grizzle bars) and corresponding baselines (white bars)The results are presented as means plusmn SDs of the threshold values from visual test (A) auditory test (B) gustatory test (C) and multisensory test (D)Compared with baseline (white bars) the sensitivity to thermal stimulus did not change when the participants were exposed to conditioning stimuli(grizzle bars) CDT = cold detection threshold WDT =warmth detection threshold CPT = cold pain threshold HPT = heat pain threshold

Yang et al The Journal of Headache and Pain 2014 1571 Page 8 of 12httpwwwthejournalofheadacheandpaincomcontent15171

change somatosensory sensitivity to thermal stimuli Thisindicates that auditory stimulus regulation of thermal som-atosensory is not significant in healthy volunteers How-ever in some pathological conditions such as tension-typeand cervicogenic headache phonophobia is a commonsymptom [43] Again this may require a sensitized orpredisposed somatosensory systemIt has been reported that sucrose reduces pain during the

Cold Pressor Test (CPT) in 5- to 10-year-old children andthis kind of analgesia is dependent on the sweet taste pref-erence [14] However sucrose was not an effective analgesiain adult women in the same study The age-related declinein the analgesic efficacy of sucrose mirrors the age-relateddecline in the hedonic value of sweet tastes [44] In a recentstudy the taste of quinine gelatin (01) failed to producerobust affective state changes [45] However in the presentstudy the same stimulus evoked a significant change in

negative affective state These contradictory results maypossibly been explained by the ldquopreference theoryrdquo sincethe subjective rating to the bitter taste in this study (403 plusmn173 mean plusmn SD in a 0ndash100 numerical scale) was muchhigher than the study by Horjales-Aaujo (297 plusmn 197)[1445] Despite the negative affective state there were nochanges in somatosensory sensitivity in healthy volunteers

Multisensory conditioning stimulus effectsThere were several statistically significant effects of themultisensory conditioning stimulus which indicated thatthe multisensory stimulation enhanced the effect of indi-vidual stimuli with regard to subjective rating changesaffective score changes and induced slight thermal sensi-tivity changes This is in line with a neurophysiologicalstudy which demonstrates a strong emotion enhancementeffect by simultaneous presentation of congruent emotional

Figure 6 Multisensory effects between genders To diminish the effect of timing the delta values between test with stimuli and correspondingbaseline defined as ldquochangesrdquo in the figure was used Multisensory conditioning stimulus led to a strengthened effect compared with singleconditioning stimuli for several outcome parameters ie subjective ratings to gustatory stimulus (A) negative affective scores (C) and warmthdetection threshold (G) CDT = cold detection threshold WDT =warmth detection threshold CPT = cold pain threshold HPT = heat pain thresholdPositive affective changes (B) heat rate changes (D) skin temperature changes (E) cold detection threshold changes (F) cold pain threshold changes(H) and heat pain threshold changes (I) in different tests were also presented = P lt001 = P lt005

Yang et al The Journal of Headache and Pain 2014 1571 Page 9 of 12httpwwwthejournalofheadacheandpaincomcontent15171

pictures and music regarding subjective ratings peripheraland central physiological measures [11] The findings alsofit with a study which shows that when either positive (joy-ful) or negative (fearful) music is played simultaneouslywith an emotionally neutral film clip it evokes strongersignal changes in the amygdala and in areas of the ventro-lateral frontal cortex compared with when only music oronly film clips are presented [46] The activation increase

may be due to the cross modal integration of three sensorystimuli and this stronger activation possibly suggests en-hanced activation in a distributed neuronal network whichneeds to be confirmed in functional imaging studies [6]

Physiological arousal changesIt has been proposed that most affective changes are asso-ciated with undifferentiated physiological activity changes

Table 2 Impact of gender on warmth detection threshold (WDT degC) changes with different stimuli

Gender Visual (1) Auditory (2) Gustatory (3) Multisensory (4) F P 1 vs 4 2 vs 4 3 vs 4

Female Mean minus008 minus012 minus002 minus0150098 NS 0784 0938 0438

SD 076 064 035 060

Male Mean 017 minus003 027 minus0336036 0003 0019 NS 0003

SD 029 021 050 033

Sum Mean 004 minus008 013 minus0242241 NS 0058 0387 0004

SD 057 046 045 048

To evaluate the multisensory effect the delta values (ldquochangesrdquo) in 9000 lux light visual test 90 dB noise auditory test gustatory test and multisensory stimulationtest were compared using two-way repeated ANOVA with conditioning stimuli as within-participant factor gender as between-participant factor The male participantspresented a statistically significant decrease in ldquodeltardquo WDT during multisensory conditioning stimuli compared with light stimulus alone (P = 0019) or taste alone(P = 0003) Italics values indicate statistically significant P values (P lt 005)

Yang et al The Journal of Headache and Pain 2014 1571 Page 10 of 12httpwwwthejournalofheadacheandpaincomcontent15171

[47] Thus it seems reasonable to examine physiologicalarousal measurements related to affective reactions Skintemperature and heart rate are the most frequently usedphysiological expressions of affective state [47] Howeverin the present study these two parameters did not changesignificantly in response to changes in negative affectivestate by the different conditioning stimuli This is in linewith another study where it was demonstrated that theverbally reported affective experiences are not alwaysconsistent with the physiological parameters especially forunpleasant stimuli [47] On the other hand it may bebecause of the limited number of participants or that theapplied stimulus was inadequate for induction of a signifi-cant physiological change in arousal

Interactions between somatosensory sensitivity andconditioning stimuliThe perception of migraine headache which is mediatedby nociceptive signals is exacerbated by exposure to en-vironment stimuli ie light or noise which are mediatedby optical and acoustic signals Prolonged neuronal activa-tion during a migraine attack is thought to induce periph-eral and central sensitization along the trigeminovascularpathway which stands to explain the throbbing headache[48] accompanying scalp and neck-muscle tenderness[49] and whole-body cutaneous allodynia [50] Severaltheories exist which predict the relationship betweenconditioning stimuli and somatosensory sensitivity Todevelop a more comprehensive model of somatosensorymodulation by conditioning stimuli it may be useful toconsider a theory of ldquomotivational primingrdquo [9] It is pro-posed that affective state processing evoked by stimulicould be viewed as two opposing motivational systemsOne system is appetitive and produces approach behav-iors and the other system is aversive and promotes avoid-ance behaviors [9] Considerable evidence indicates thatprior activation of these systems modulates defensive be-haviors which facilitates somatosensory capability [51]These defensive behaviors increase in magnitude whenthe aversive system is primed by a negative affective stateie anticipation of shock [52] Conversely this defensive

response is inhibited when the appetitive system is primedby a positive affective state [53] According to the motiv-ational priming theory participants exposed to negativeaffective loading whose aversive systems are activatedshould get their perception facilitated [922] Howeversomatosensory sensitivity to thermal stimuli was not chan-ged during induction of negative affective states in thepresent study Another perspective on somatosensory andaffective processing is provided by the four-region neuro-biological model which indicates a complex relationshipbetween acute pain and simple emotion [54] For instancefear and pain sites overlap in the anterior midcingulatecortex (aMCC) and this region is involved in avoidancebehaviors posterior midcingulate cortex (pMCC) has noconsistent emotion activations yet has robust nociceptiveresponses subgenual anterior cingulate cortex (sACC) acti-vation during noxious stimulation of the skin and viscerain a person-specific manner the cingulate cortex is notuniformly involved in emotion and not all pain-activationsites are associated with affect or emotion [54]

ConclusionsThe three conditioning stimuli induced significantincreases in subjective rating and negative effectivescores accompanied with no physiological arousalchanges These stimuli did not however modulate skinthermal sensitivity The multisensory conditioning stimuliinduced stronger effects on subjective rating and negativeaffect than individual conditioning stimuli alone Theoften observed trigger or exacerbation of migraine byvisual auditory or gustatory stimuli may require a pre-disposed or sensitized nervous system

AbbreviationsMSI Multi-modal sensory integration IAPS Pictures of facial affect or theinternational affective picture system QST Quantitative sensory testingCDT Cold detection threshold WDT Warmth detection threshold CPT Coldpain threshold HPT Heat pain threshold PANAS Positive and negative affectschedule HR Heart rate EEG Electroencephalography aMCC AnteriorMidCingulate cortex pMCC Posterior MidCingulate cortex sACC Subgenualanterior cingulate cortex

Competing interestsThe authors declare that they have no competing interests

Yang et al The Journal of Headache and Pain 2014 1571 Page 11 of 12httpwwwthejournalofheadacheandpaincomcontent15171

Authorsrsquo contributionsYG recruited the participants carried out the study performed the statisticalanalysis and drafted the manuscript SP and BHL participated in the designof the study statistical analysis and revision of the draft XQ and WK helpedto draft and revise the manuscript All authors read and approved the finalmanuscript

AcknowledgementsWe are indebted to the subjects who participated in the study for theirconsent and co-operation This study was made possible by the supportsof Danish Dental Association

Author details1Department of Prosthodontics and Center for Oral Functional DiagnosisTreatment and Research Peking University School and hospital ofStomatology Zhongguancun Nandajie 22 100081 Beijing China 2Section ofClinical Oral Physiology Department of Dentistry Aarhus University AarhusDenmark 3Center for Sensory-Motor Interaction (SMI) Department of HealthScience and Technology Aalborg University Aalborg Denmark 4Departmentof Dental Medicine Karolinska Institute Huddinge Sweden

Received 28 August 2014 Accepted 28 October 2014Published 7 November 2014

References1 Goadsby PJ (2009) Pathophysiology of migraine Neurol Clin 27(2)335ndash360

httpdxdoiorg101016jncl2008110122 Judit A Saacutendor PS Schoenen J (2000) Habituation of visual and intensity

dependence of cortical auditory evoked potentials tends to normalize justbefore and during migraine attack Cephalalgia 20(8)714ndash719httponlinelibrarywileycomdoi101111j1468-2982200000122xfull

3 Schoenen J Wang W Albert A Delwaide PJ (1995) Potentiation instead ofhabituation characterizes visual evoked potentials in migraine patientsbetween attacks Eur J Neurol 2(2)115ndash122 doi101111j1468-1331

4 Wang W Schoenen J (1998) Interictal potentiation of passive ldquooddballrdquoauditory event-related potentials in migraine Cephalalgia 18(5)261ndash265doi101111j1468-298219981805261x

5 Stein BE Stanford TR (2008) Multisensory integration current issues fromthe perspective of the single neuron Nat Rev Neurosci 9(4)255ndash266doi101038nrn2331

6 Basura GJ Koehler SD Shore SE (2012) Multi-sensory integration inbrainstem and auditory cortex Brain Res 148595ndash107 httpdxdoiorg101016jbrainres201208037

7 Jain R Shore S (2006) External inferior colliculus integrates trigeminal andacoustic information unit response to trigeminal nucleus and acousticstimulation in the guinea pig Neurosci Lett 395(1)71ndash75 httpdxdoiorg101016jneulet200510077

8 Kawasaki A Purvin VA (2002) Photophobia as the presenting visual symptom ofchiasmal compression J Neuroophthalmol 22(1)3ndash8httpovidsptxovidcomsp-3131aovidwebcgiT=JSampPAGE=fulltextampD=ovftampAN=00041327-200203000-00002ampNEWS=NampCSC=YampCHANNEL=PubMed

9 Lang PJ (1995) The emotion probe Studies of motivation and attentionAm Psychol 50(5)372ndash385 doi1010370003-066X505372

10 Esslen M Pascual-Marqui RD Hell D Kochi K Lehmann D (2004) Brain areasand time course of emotional processing Neuroimage 21(4)1189ndash1203httpdxdoiorg101016jneuroimage200310001

11 Baumgartner T Esslen M Jaumlncke L (2006) From emotion perception toemotion experience emotions evoked by pictures and classical music Int JPsychophysiol 60(1)34ndash43 httpdxdoiorg101016jijpsycho200504007

12 Mitterschiffthaler MT Fu CH Dalton JA Andrew CM Williams SC (2007) Afunctional MRI study of happy and sad affective states induced by classicalmusic Hum Brain Mapp 28(11)1150ndash1162 DOI 101002hbm20337

13 Koelsch S (2010) Towards a neural basis of music-evoked emotions TrendsCogn Sci 14(3)131ndash137 httpdxdoiorg101016jtics201001002

14 Pepino MY Mennella JA (2005) Sucrose-induced analgesia is related tosweet preference in children but not adults Pain 119(1ndash3)210ndash218httpdxdoiorg101016jpain200509029

15 Horjales-Araujo E Demontis D Lund EK Vase L Finnerup NB Boslashrglum ADJensen TS Svensson P (2013) Emotional modulation of muscle pain isassociated with polymorphisms in the serotonin transporter gene Pain154(8)1469ndash1476 doi101016jpain201305011

16 Bushnell EW Baxt C (1999) Childrenrsquos haptic and cross-modal recognitionwith familiar and unfamiliar objects J Exp Psychol Hum Percept Perform25(6)1867ndash1881 doi1010370096-1523256

17 Longe SE Wise R Bantick S Lloyd D Johansen-Berg H McGlone F Tracey I(2001) Counter-stimulatory effects on pain perception and processing aresignificantly altered by attention an fMRI study Neuroreport 12(9)2021ndash2025httpovidsptxovidcomsp-3131aovidwebcgiT=JSampPAGE=fulltextampD=ovf-tampAN=00001756-200107030-00047ampNEWS=NampCSC=YampCHANNEL=PubMed

18 Rode S Salkovskis PM Jack T (2001) An experimental study of attentionlabeling and memory in people suffering from chronic pain Pain 94(2)193ndash203httpdxdoiorg101016S0304-3959(01)00356-6

19 McCaul KD Monson N Maki RH (1992) Does distraction reduce pain-produced distress among college students Health Psychol 11(4)210ndash217doi1010370278-6133114210

20 Rolke R Baron R Maier C Toumllle TR Treede RD Beyer A Binder A Birbaumer NBirklein F Boumltefuumlr IC Braune S Flor H Huge V Klug R Landwehrmeyer GBMagerl W Maihoumlfner C Rolko C Schaub C Scherens A Sprenger T Valet MWasserka B (2006) Quantitative sensory testing in the German ResearchNetwork on Neuropathic Pain (DFNS) Standardized protocol and referencevalue Pain 123(3)231ndash243 httpdxdoiorg101016jpain200601041

21 Yang G Luo Y Baad-Hansen L Wang K Arendt-Nielsen L Xie QF SvenssonP (2013) Ethnic differences in oro-facial somatosensory profiles-quantitativesensory testing in Chinese and Danes J Oral Rehabil 40(11)844ndash853doi101111joor12091

22 Meagher MW Arnau RC Rhudy JL (2001) Pain and emotion Effect ofAffective Picture Modulation Psychosom Med 63(1)79ndash90 httpwwwpsychosomaticmedicineorgcontent63179short

23 Danish volunteers recruit website for clinical research [wwwforsoegspersondk]24 Okamoto K Tashiro A Thompson R Nishida Y Bereiter DA (2012) Trigeminal

interpolariscaudalis transition neurons mediate reflex lacrimation evoked bybright light in the rat Eur J Neurosci 36(11)3492ndash3499 doi101111j1460-9568201208272x

25 Noseda R Kainz V Jakubowski M Gooley JJ Saper CB Digre K Burstein R(2010) A neural mechanism for exacerbation of headache by light NatNeurosci 13(2)239ndash245 doi101038nn2475

26 Sliney DH (1983) Standards for use of visible and nonvisible radiation on theeye Am J Optom Physiol Opt 60(4)278ndash286 httpovidsptxovidcomsp-3131aovidwebcgiWebLinkFrameset=1ampS=GDKPFPEIMNDDLJBJNCLKDFIBGENOAA00ampreturnUrl=ovidwebcgi3fMain2bSearch2bPage3d126S3dGDKPFPEIMNDDLJBJNCLKDFIBGENOAA00ampdirectlink=http3a2f2fgraphicstxovidcom2fovftpdfs2fFPDDNCIBDFBJMN002ffs0462fovft2flive2fgv0232f000004512f00000451-198304000-00003pdfampfilename=Standards+for+Use+of+Visible+and+Nonvisible+Radiation+on+the+Eyeampnavigation_links=NavLinksSsh421amplink_from=Ssh427c1amppdf_key=FPDDNCIBDFBJMN00amppdf_index=fs046ovftlivegv0230000045100000451-198304000-00003ampD=ovftamplink_set=Ssh42|1|sl_10|resultSet|Ssh4243|0

27 Rappaport SM (1993) Threshold limit values permissible exposure limitsand feasibility the bases for exposure limits in the United States Am J IndMed 23(5)683ndash694 doi101002ajim4700230502

28 Rhudy JL Meagher MW (2001) Noise stress and human pain thresholdsdivergent effects in men and women J Pain 2(1)64 httpdxdoiorg101054jpai200019947

29 Goldenberg AM Wexler LF (1988) Quinine overdose review of toxicity andtreatment Clin Cardiol 11(10)716ndash718 doi101002clc4960111012

30 Cardesiacuten A Alobid I Beniacutetez P Sierra E de Haro J Bernal-Sprekelsen MPicado C Mullol J (2006) Barcelona Smell Test - 24 (BAST-24) validation andsmell characteristics in the healthy Spanish population Rhinology 44(1)83ndash89httpwwwrhinologyjournalcomabstractphpid=556

31 Watson D Clark LA Tellegen A (1988) Development and validation of briefmeasures of positive and negative affect the PANAS scale J Pers SocPsychol 54(6)1063ndash1070 doi1010370022-35145461063

32 Crawford JR Herry JD (2004) The positive and negative affect schedule(PANAS) construct validity measurement properties and normative data ina large non-clinical sample Br J Clin Psychol 43(3)245ndash265 httpovidsptxovidcomsp-3131aovidwebcgiT=JSampPAGE=fulltextampD=ovftampAN=00002604-200409000-00003ampNEWS=NampCSC=YampCHANNEL=PubMed

33 Hsee CK Hatfield E Carlson JG Chemtob C (1990) The effect of power onsusceptibility to emotional contagion Cogn Emot 4327ndash340 doi10108002699939008408081

34 Doherty RW (1998) Emotional contagion and social judgment Motiv Emot22187ndash209 doi101023A1022368805803

Figure 3 Negative affective state differences between testswith conditioning stimuli (grizzle bars) and correspondingbaselines (white bars) The results are presented as means plusmn SDs ofthe negative affective scores form Positive and Negative AffectSchedule The conditioning stimuli induced statistically significantlyhigher negative affective states compared with baseline = P lt0001 = P lt005

Yang et al The Journal of Headache and Pain 2014 1571 Page 6 of 12httpwwwthejournalofheadacheandpaincomcontent15171

(Shapiro-Wilk P gt005) Compared with baseline the sensi-tivity to thermal stimuli did not change when the partici-pants were exposed to conditioning stimuli visual test(paired t-test P value for CDT WDT CPT HPT were0074 0641 0165 0095 respectively Figure 5-A) auditorytest (paired t-test P value for CDT WDT CPT HPT were0055 0922 0515 0418 respectively Figure 5-B) gustatorytest (paired t-test P value for CDT WDT CPT HPT were0347 0207 0202 0729 respectively Figure 5-C) multi-sensory stimulation (paired t-test P value for CDT WDTCPT HPT were 0526 0051 0737 0331 respectivelyFigure 5-D)

Multisensory stimulation effectWhen the participants were exposed to multisensory(combined) conditioning stimuli they subjectively ratedhigher ldquodelta valuesrdquo to the same bitter taste comparedwith in the condition of taste stimulus alone (whole groupF = 5017 P = 0038 male F = 8980 P = 0015 femaleF = 1304 P gt005 Figure 6-A) The female participantspresented higher ldquodelta valuesrdquo for the negative affectivescores during the multisensory stimuli condition than dur-ing noise stimulation alone (noise 20 plusmn 24 mean plusmn SDtaste 15 plusmn 63 combination 68 plusmn 58 Post-hoc testbetween combination test and noise test P = 0011Figure 6-C) The participants presented a statistically sig-nificant decrease in WDT (ldquodeltardquo WDT decreasing) dur-ing multisensory conditioning stimuli compared with lightstimulus alone (male Post-hoc test P = 0019 Figure 6-GTable 2) or taste alone (whole group P =0004 maleP = 0003 female P = 0438 Figure 6-G Table 2)

DiscussionsThis study investigated for the first time the effects ofthree unpleasant conditioning stimuli (bright light chain-saw noise and bitter taste) on negative affective statephysiological arousal and skin thermal sensitivity Thethree conditioning stimuli as expected all induced statis-tically significant increases in negative affective scorescompared with baseline Additionally a dose dependentphenomenon was demonstrated in the visual and auditorytests (only one intensity gustatory stimulus was applied inthis study) There were no significant changes in positiveaffective scores physiological arousal (heart rate or skintemperature) between tests with and without conditioningstimuli The skin thermal sensitivity (via CDT WDTCPT HPT) in the perioral region did not change signifi-cantly during conditioning stimuli tests compared withbaseline Combining the individual conditioning stimuliinto a multisensory conditioning stimulus led to a strengthened effect compared with single conditioning stimulifor several outcome parameters ie subjective ratingsnegative affective scores and warmth detection threshold(WDT)

Influence of conditioning stimuli on affective stateThe experimental visual stimuli used in previous studies toexamine the affective processes were composed of emo-tional videos [3334] or photos [3536] Viewing faces withsad or happy expressions specifically evoked the expressedfeelings in the viewer defined as ldquoemotional contagionrdquo[35] This emotional contagion was considered as a ldquopre-wiredrdquo decoding instrument which was considered a fastrepeatable and stable process [35] These visual stimuliactivate an emotion perception process characterized byfocusing attention to external events and accurately under-standing the information conducted which need the fullco-operation of the investigated individuals [11] Addition-ally some studies concluded that the experimentallyinduced changes in the affective state were obtained onlyafter repeated stimuli presentation accompanied withspecified verbal inductions [37] Furthermore in anotherElectroencephalography (EEG) study emotional reactionscould not be evoked by presenting emotional picturesalone [11] In migraineurs bright light often exacerbate theheadache which could be accounted for a pathophysio-logical hypothesis of a disturbance of the subcortical sen-sory modulation system [18] Although the trigeminalautonomic reflex acts as a feed-forward system to facilitatethe acute attack the fundamental problem was thought tobe in the brain [1] The possible effect of bright light toexperimentally evoke an affective state and somatosensorysensitivity changes has not been assessed before Thehypothesis of the present study was that bright light couldevoke a negative affective state and change the somatosen-sory sensitivity In the present experimental study bright

Figure 4 Effects of conditioning stimuli on negative affective (changes) between genders The negative affective score differencesbetween the condition with stimuli and corresponding baseline (as ldquochangesrdquo in the figure) were higher when the participants were exposed tomore intense stimuli in visual (A) and auditory (B) tests Besides there were statistically significant gender differences in auditory test (B) andgustatory test (C) (D) indicates multisensory test = P lt0001 = P lt001 = P lt005

Yang et al The Journal of Headache and Pain 2014 1571 Page 7 of 12httpwwwthejournalofheadacheandpaincomcontent15171

light successfully evoked a negative affective state in adose-dependent manner according to the intensity of thelight (Figure 4-A) Bright light may be a simple andeffecient way to induce a negative affective state in humanstudies However bright light did not significantly changesomatosensory sensitivity to thermal stimuli This indicatesthat the light regulation of thermal somatosensory sensi-tivity may not exist in healthy humans without priorsensitization or predispositionSeveral studies have demonstrated that music is a power-

ful mediator of changes in affective state [3839] Func-tional neuro-imaging and lesion studies have shown thatmusic-evoked affective state changes can modulate activityin virtually all limbic and paralimbic brain structures suchas amygdala parahippocampal gyrus and hippocampus[1240-42] These structures are crucially involved in theinitiation generation detection maintenance regulation

and termination of changes in affective state [13] Musicmay affect trained musicians and non-musicians differentlyand different individuals have different musical preferencesand experiences which may be important in studies ofinfluence of music on different outcome parameters [13]In contrast to most people a chainsaw noise as used in thepresent study can be considered an unpleasant auditorystimulus The participants in this study rated moderate tostrong unpleasantness to the noise (Figure 2-B) Thehypothesis of the present study was that an unpleasantauditory stimulus could increase negative affect and changesomatosensoty sensitivity The chainsaw noise successfullyevoked a negative affective state in a dose-dependentmanner as the intensity of the auditory stimulus increased(Figure 4-B) Again chainsaw noise may be a simple andeffective way to induce a negative affective state in humanstudies However the chainsaw noise did not significantly

Figure 5 Thermal sensitivity differences between tests with conditioning stimuli (grizzle bars) and corresponding baselines (white bars)The results are presented as means plusmn SDs of the threshold values from visual test (A) auditory test (B) gustatory test (C) and multisensory test (D)Compared with baseline (white bars) the sensitivity to thermal stimulus did not change when the participants were exposed to conditioning stimuli(grizzle bars) CDT = cold detection threshold WDT =warmth detection threshold CPT = cold pain threshold HPT = heat pain threshold

Yang et al The Journal of Headache and Pain 2014 1571 Page 8 of 12httpwwwthejournalofheadacheandpaincomcontent15171

change somatosensory sensitivity to thermal stimuli Thisindicates that auditory stimulus regulation of thermal som-atosensory is not significant in healthy volunteers How-ever in some pathological conditions such as tension-typeand cervicogenic headache phonophobia is a commonsymptom [43] Again this may require a sensitized orpredisposed somatosensory systemIt has been reported that sucrose reduces pain during the

Cold Pressor Test (CPT) in 5- to 10-year-old children andthis kind of analgesia is dependent on the sweet taste pref-erence [14] However sucrose was not an effective analgesiain adult women in the same study The age-related declinein the analgesic efficacy of sucrose mirrors the age-relateddecline in the hedonic value of sweet tastes [44] In a recentstudy the taste of quinine gelatin (01) failed to producerobust affective state changes [45] However in the presentstudy the same stimulus evoked a significant change in

negative affective state These contradictory results maypossibly been explained by the ldquopreference theoryrdquo sincethe subjective rating to the bitter taste in this study (403 plusmn173 mean plusmn SD in a 0ndash100 numerical scale) was muchhigher than the study by Horjales-Aaujo (297 plusmn 197)[1445] Despite the negative affective state there were nochanges in somatosensory sensitivity in healthy volunteers

Multisensory conditioning stimulus effectsThere were several statistically significant effects of themultisensory conditioning stimulus which indicated thatthe multisensory stimulation enhanced the effect of indi-vidual stimuli with regard to subjective rating changesaffective score changes and induced slight thermal sensi-tivity changes This is in line with a neurophysiologicalstudy which demonstrates a strong emotion enhancementeffect by simultaneous presentation of congruent emotional

Figure 6 Multisensory effects between genders To diminish the effect of timing the delta values between test with stimuli and correspondingbaseline defined as ldquochangesrdquo in the figure was used Multisensory conditioning stimulus led to a strengthened effect compared with singleconditioning stimuli for several outcome parameters ie subjective ratings to gustatory stimulus (A) negative affective scores (C) and warmthdetection threshold (G) CDT = cold detection threshold WDT =warmth detection threshold CPT = cold pain threshold HPT = heat pain thresholdPositive affective changes (B) heat rate changes (D) skin temperature changes (E) cold detection threshold changes (F) cold pain threshold changes(H) and heat pain threshold changes (I) in different tests were also presented = P lt001 = P lt005

Yang et al The Journal of Headache and Pain 2014 1571 Page 9 of 12httpwwwthejournalofheadacheandpaincomcontent15171

pictures and music regarding subjective ratings peripheraland central physiological measures [11] The findings alsofit with a study which shows that when either positive (joy-ful) or negative (fearful) music is played simultaneouslywith an emotionally neutral film clip it evokes strongersignal changes in the amygdala and in areas of the ventro-lateral frontal cortex compared with when only music oronly film clips are presented [46] The activation increase

may be due to the cross modal integration of three sensorystimuli and this stronger activation possibly suggests en-hanced activation in a distributed neuronal network whichneeds to be confirmed in functional imaging studies [6]

Physiological arousal changesIt has been proposed that most affective changes are asso-ciated with undifferentiated physiological activity changes

Table 2 Impact of gender on warmth detection threshold (WDT degC) changes with different stimuli

Gender Visual (1) Auditory (2) Gustatory (3) Multisensory (4) F P 1 vs 4 2 vs 4 3 vs 4

Female Mean minus008 minus012 minus002 minus0150098 NS 0784 0938 0438

SD 076 064 035 060

Male Mean 017 minus003 027 minus0336036 0003 0019 NS 0003

SD 029 021 050 033

Sum Mean 004 minus008 013 minus0242241 NS 0058 0387 0004

SD 057 046 045 048

To evaluate the multisensory effect the delta values (ldquochangesrdquo) in 9000 lux light visual test 90 dB noise auditory test gustatory test and multisensory stimulationtest were compared using two-way repeated ANOVA with conditioning stimuli as within-participant factor gender as between-participant factor The male participantspresented a statistically significant decrease in ldquodeltardquo WDT during multisensory conditioning stimuli compared with light stimulus alone (P = 0019) or taste alone(P = 0003) Italics values indicate statistically significant P values (P lt 005)

Yang et al The Journal of Headache and Pain 2014 1571 Page 10 of 12httpwwwthejournalofheadacheandpaincomcontent15171

[47] Thus it seems reasonable to examine physiologicalarousal measurements related to affective reactions Skintemperature and heart rate are the most frequently usedphysiological expressions of affective state [47] Howeverin the present study these two parameters did not changesignificantly in response to changes in negative affectivestate by the different conditioning stimuli This is in linewith another study where it was demonstrated that theverbally reported affective experiences are not alwaysconsistent with the physiological parameters especially forunpleasant stimuli [47] On the other hand it may bebecause of the limited number of participants or that theapplied stimulus was inadequate for induction of a signifi-cant physiological change in arousal

Interactions between somatosensory sensitivity andconditioning stimuliThe perception of migraine headache which is mediatedby nociceptive signals is exacerbated by exposure to en-vironment stimuli ie light or noise which are mediatedby optical and acoustic signals Prolonged neuronal activa-tion during a migraine attack is thought to induce periph-eral and central sensitization along the trigeminovascularpathway which stands to explain the throbbing headache[48] accompanying scalp and neck-muscle tenderness[49] and whole-body cutaneous allodynia [50] Severaltheories exist which predict the relationship betweenconditioning stimuli and somatosensory sensitivity Todevelop a more comprehensive model of somatosensorymodulation by conditioning stimuli it may be useful toconsider a theory of ldquomotivational primingrdquo [9] It is pro-posed that affective state processing evoked by stimulicould be viewed as two opposing motivational systemsOne system is appetitive and produces approach behav-iors and the other system is aversive and promotes avoid-ance behaviors [9] Considerable evidence indicates thatprior activation of these systems modulates defensive be-haviors which facilitates somatosensory capability [51]These defensive behaviors increase in magnitude whenthe aversive system is primed by a negative affective stateie anticipation of shock [52] Conversely this defensive

response is inhibited when the appetitive system is primedby a positive affective state [53] According to the motiv-ational priming theory participants exposed to negativeaffective loading whose aversive systems are activatedshould get their perception facilitated [922] Howeversomatosensory sensitivity to thermal stimuli was not chan-ged during induction of negative affective states in thepresent study Another perspective on somatosensory andaffective processing is provided by the four-region neuro-biological model which indicates a complex relationshipbetween acute pain and simple emotion [54] For instancefear and pain sites overlap in the anterior midcingulatecortex (aMCC) and this region is involved in avoidancebehaviors posterior midcingulate cortex (pMCC) has noconsistent emotion activations yet has robust nociceptiveresponses subgenual anterior cingulate cortex (sACC) acti-vation during noxious stimulation of the skin and viscerain a person-specific manner the cingulate cortex is notuniformly involved in emotion and not all pain-activationsites are associated with affect or emotion [54]

ConclusionsThe three conditioning stimuli induced significantincreases in subjective rating and negative effectivescores accompanied with no physiological arousalchanges These stimuli did not however modulate skinthermal sensitivity The multisensory conditioning stimuliinduced stronger effects on subjective rating and negativeaffect than individual conditioning stimuli alone Theoften observed trigger or exacerbation of migraine byvisual auditory or gustatory stimuli may require a pre-disposed or sensitized nervous system

AbbreviationsMSI Multi-modal sensory integration IAPS Pictures of facial affect or theinternational affective picture system QST Quantitative sensory testingCDT Cold detection threshold WDT Warmth detection threshold CPT Coldpain threshold HPT Heat pain threshold PANAS Positive and negative affectschedule HR Heart rate EEG Electroencephalography aMCC AnteriorMidCingulate cortex pMCC Posterior MidCingulate cortex sACC Subgenualanterior cingulate cortex

Competing interestsThe authors declare that they have no competing interests

Yang et al The Journal of Headache and Pain 2014 1571 Page 11 of 12httpwwwthejournalofheadacheandpaincomcontent15171

Authorsrsquo contributionsYG recruited the participants carried out the study performed the statisticalanalysis and drafted the manuscript SP and BHL participated in the designof the study statistical analysis and revision of the draft XQ and WK helpedto draft and revise the manuscript All authors read and approved the finalmanuscript

AcknowledgementsWe are indebted to the subjects who participated in the study for theirconsent and co-operation This study was made possible by the supportsof Danish Dental Association

Author details1Department of Prosthodontics and Center for Oral Functional DiagnosisTreatment and Research Peking University School and hospital ofStomatology Zhongguancun Nandajie 22 100081 Beijing China 2Section ofClinical Oral Physiology Department of Dentistry Aarhus University AarhusDenmark 3Center for Sensory-Motor Interaction (SMI) Department of HealthScience and Technology Aalborg University Aalborg Denmark 4Departmentof Dental Medicine Karolinska Institute Huddinge Sweden

Received 28 August 2014 Accepted 28 October 2014Published 7 November 2014

References1 Goadsby PJ (2009) Pathophysiology of migraine Neurol Clin 27(2)335ndash360

httpdxdoiorg101016jncl2008110122 Judit A Saacutendor PS Schoenen J (2000) Habituation of visual and intensity

dependence of cortical auditory evoked potentials tends to normalize justbefore and during migraine attack Cephalalgia 20(8)714ndash719httponlinelibrarywileycomdoi101111j1468-2982200000122xfull

3 Schoenen J Wang W Albert A Delwaide PJ (1995) Potentiation instead ofhabituation characterizes visual evoked potentials in migraine patientsbetween attacks Eur J Neurol 2(2)115ndash122 doi101111j1468-1331

4 Wang W Schoenen J (1998) Interictal potentiation of passive ldquooddballrdquoauditory event-related potentials in migraine Cephalalgia 18(5)261ndash265doi101111j1468-298219981805261x

5 Stein BE Stanford TR (2008) Multisensory integration current issues fromthe perspective of the single neuron Nat Rev Neurosci 9(4)255ndash266doi101038nrn2331

6 Basura GJ Koehler SD Shore SE (2012) Multi-sensory integration inbrainstem and auditory cortex Brain Res 148595ndash107 httpdxdoiorg101016jbrainres201208037

7 Jain R Shore S (2006) External inferior colliculus integrates trigeminal andacoustic information unit response to trigeminal nucleus and acousticstimulation in the guinea pig Neurosci Lett 395(1)71ndash75 httpdxdoiorg101016jneulet200510077

8 Kawasaki A Purvin VA (2002) Photophobia as the presenting visual symptom ofchiasmal compression J Neuroophthalmol 22(1)3ndash8httpovidsptxovidcomsp-3131aovidwebcgiT=JSampPAGE=fulltextampD=ovftampAN=00041327-200203000-00002ampNEWS=NampCSC=YampCHANNEL=PubMed

9 Lang PJ (1995) The emotion probe Studies of motivation and attentionAm Psychol 50(5)372ndash385 doi1010370003-066X505372

10 Esslen M Pascual-Marqui RD Hell D Kochi K Lehmann D (2004) Brain areasand time course of emotional processing Neuroimage 21(4)1189ndash1203httpdxdoiorg101016jneuroimage200310001

11 Baumgartner T Esslen M Jaumlncke L (2006) From emotion perception toemotion experience emotions evoked by pictures and classical music Int JPsychophysiol 60(1)34ndash43 httpdxdoiorg101016jijpsycho200504007

12 Mitterschiffthaler MT Fu CH Dalton JA Andrew CM Williams SC (2007) Afunctional MRI study of happy and sad affective states induced by classicalmusic Hum Brain Mapp 28(11)1150ndash1162 DOI 101002hbm20337

13 Koelsch S (2010) Towards a neural basis of music-evoked emotions TrendsCogn Sci 14(3)131ndash137 httpdxdoiorg101016jtics201001002

14 Pepino MY Mennella JA (2005) Sucrose-induced analgesia is related tosweet preference in children but not adults Pain 119(1ndash3)210ndash218httpdxdoiorg101016jpain200509029

15 Horjales-Araujo E Demontis D Lund EK Vase L Finnerup NB Boslashrglum ADJensen TS Svensson P (2013) Emotional modulation of muscle pain isassociated with polymorphisms in the serotonin transporter gene Pain154(8)1469ndash1476 doi101016jpain201305011

16 Bushnell EW Baxt C (1999) Childrenrsquos haptic and cross-modal recognitionwith familiar and unfamiliar objects J Exp Psychol Hum Percept Perform25(6)1867ndash1881 doi1010370096-1523256

17 Longe SE Wise R Bantick S Lloyd D Johansen-Berg H McGlone F Tracey I(2001) Counter-stimulatory effects on pain perception and processing aresignificantly altered by attention an fMRI study Neuroreport 12(9)2021ndash2025httpovidsptxovidcomsp-3131aovidwebcgiT=JSampPAGE=fulltextampD=ovf-tampAN=00001756-200107030-00047ampNEWS=NampCSC=YampCHANNEL=PubMed

18 Rode S Salkovskis PM Jack T (2001) An experimental study of attentionlabeling and memory in people suffering from chronic pain Pain 94(2)193ndash203httpdxdoiorg101016S0304-3959(01)00356-6

19 McCaul KD Monson N Maki RH (1992) Does distraction reduce pain-produced distress among college students Health Psychol 11(4)210ndash217doi1010370278-6133114210

20 Rolke R Baron R Maier C Toumllle TR Treede RD Beyer A Binder A Birbaumer NBirklein F Boumltefuumlr IC Braune S Flor H Huge V Klug R Landwehrmeyer GBMagerl W Maihoumlfner C Rolko C Schaub C Scherens A Sprenger T Valet MWasserka B (2006) Quantitative sensory testing in the German ResearchNetwork on Neuropathic Pain (DFNS) Standardized protocol and referencevalue Pain 123(3)231ndash243 httpdxdoiorg101016jpain200601041

21 Yang G Luo Y Baad-Hansen L Wang K Arendt-Nielsen L Xie QF SvenssonP (2013) Ethnic differences in oro-facial somatosensory profiles-quantitativesensory testing in Chinese and Danes J Oral Rehabil 40(11)844ndash853doi101111joor12091

22 Meagher MW Arnau RC Rhudy JL (2001) Pain and emotion Effect ofAffective Picture Modulation Psychosom Med 63(1)79ndash90 httpwwwpsychosomaticmedicineorgcontent63179short

23 Danish volunteers recruit website for clinical research [wwwforsoegspersondk]24 Okamoto K Tashiro A Thompson R Nishida Y Bereiter DA (2012) Trigeminal

interpolariscaudalis transition neurons mediate reflex lacrimation evoked bybright light in the rat Eur J Neurosci 36(11)3492ndash3499 doi101111j1460-9568201208272x

25 Noseda R Kainz V Jakubowski M Gooley JJ Saper CB Digre K Burstein R(2010) A neural mechanism for exacerbation of headache by light NatNeurosci 13(2)239ndash245 doi101038nn2475

26 Sliney DH (1983) Standards for use of visible and nonvisible radiation on theeye Am J Optom Physiol Opt 60(4)278ndash286 httpovidsptxovidcomsp-3131aovidwebcgiWebLinkFrameset=1ampS=GDKPFPEIMNDDLJBJNCLKDFIBGENOAA00ampreturnUrl=ovidwebcgi3fMain2bSearch2bPage3d126S3dGDKPFPEIMNDDLJBJNCLKDFIBGENOAA00ampdirectlink=http3a2f2fgraphicstxovidcom2fovftpdfs2fFPDDNCIBDFBJMN002ffs0462fovft2flive2fgv0232f000004512f00000451-198304000-00003pdfampfilename=Standards+for+Use+of+Visible+and+Nonvisible+Radiation+on+the+Eyeampnavigation_links=NavLinksSsh421amplink_from=Ssh427c1amppdf_key=FPDDNCIBDFBJMN00amppdf_index=fs046ovftlivegv0230000045100000451-198304000-00003ampD=ovftamplink_set=Ssh42|1|sl_10|resultSet|Ssh4243|0

27 Rappaport SM (1993) Threshold limit values permissible exposure limitsand feasibility the bases for exposure limits in the United States Am J IndMed 23(5)683ndash694 doi101002ajim4700230502

28 Rhudy JL Meagher MW (2001) Noise stress and human pain thresholdsdivergent effects in men and women J Pain 2(1)64 httpdxdoiorg101054jpai200019947

29 Goldenberg AM Wexler LF (1988) Quinine overdose review of toxicity andtreatment Clin Cardiol 11(10)716ndash718 doi101002clc4960111012

30 Cardesiacuten A Alobid I Beniacutetez P Sierra E de Haro J Bernal-Sprekelsen MPicado C Mullol J (2006) Barcelona Smell Test - 24 (BAST-24) validation andsmell characteristics in the healthy Spanish population Rhinology 44(1)83ndash89httpwwwrhinologyjournalcomabstractphpid=556

31 Watson D Clark LA Tellegen A (1988) Development and validation of briefmeasures of positive and negative affect the PANAS scale J Pers SocPsychol 54(6)1063ndash1070 doi1010370022-35145461063

32 Crawford JR Herry JD (2004) The positive and negative affect schedule(PANAS) construct validity measurement properties and normative data ina large non-clinical sample Br J Clin Psychol 43(3)245ndash265 httpovidsptxovidcomsp-3131aovidwebcgiT=JSampPAGE=fulltextampD=ovftampAN=00002604-200409000-00003ampNEWS=NampCSC=YampCHANNEL=PubMed

33 Hsee CK Hatfield E Carlson JG Chemtob C (1990) The effect of power onsusceptibility to emotional contagion Cogn Emot 4327ndash340 doi10108002699939008408081

34 Doherty RW (1998) Emotional contagion and social judgment Motiv Emot22187ndash209 doi101023A1022368805803

Figure 4 Effects of conditioning stimuli on negative affective (changes) between genders The negative affective score differencesbetween the condition with stimuli and corresponding baseline (as ldquochangesrdquo in the figure) were higher when the participants were exposed tomore intense stimuli in visual (A) and auditory (B) tests Besides there were statistically significant gender differences in auditory test (B) andgustatory test (C) (D) indicates multisensory test = P lt0001 = P lt001 = P lt005

Yang et al The Journal of Headache and Pain 2014 1571 Page 7 of 12httpwwwthejournalofheadacheandpaincomcontent15171

light successfully evoked a negative affective state in adose-dependent manner according to the intensity of thelight (Figure 4-A) Bright light may be a simple andeffecient way to induce a negative affective state in humanstudies However bright light did not significantly changesomatosensory sensitivity to thermal stimuli This indicatesthat the light regulation of thermal somatosensory sensi-tivity may not exist in healthy humans without priorsensitization or predispositionSeveral studies have demonstrated that music is a power-

ful mediator of changes in affective state [3839] Func-tional neuro-imaging and lesion studies have shown thatmusic-evoked affective state changes can modulate activityin virtually all limbic and paralimbic brain structures suchas amygdala parahippocampal gyrus and hippocampus[1240-42] These structures are crucially involved in theinitiation generation detection maintenance regulation

and termination of changes in affective state [13] Musicmay affect trained musicians and non-musicians differentlyand different individuals have different musical preferencesand experiences which may be important in studies ofinfluence of music on different outcome parameters [13]In contrast to most people a chainsaw noise as used in thepresent study can be considered an unpleasant auditorystimulus The participants in this study rated moderate tostrong unpleasantness to the noise (Figure 2-B) Thehypothesis of the present study was that an unpleasantauditory stimulus could increase negative affect and changesomatosensoty sensitivity The chainsaw noise successfullyevoked a negative affective state in a dose-dependentmanner as the intensity of the auditory stimulus increased(Figure 4-B) Again chainsaw noise may be a simple andeffective way to induce a negative affective state in humanstudies However the chainsaw noise did not significantly

Figure 5 Thermal sensitivity differences between tests with conditioning stimuli (grizzle bars) and corresponding baselines (white bars)The results are presented as means plusmn SDs of the threshold values from visual test (A) auditory test (B) gustatory test (C) and multisensory test (D)Compared with baseline (white bars) the sensitivity to thermal stimulus did not change when the participants were exposed to conditioning stimuli(grizzle bars) CDT = cold detection threshold WDT =warmth detection threshold CPT = cold pain threshold HPT = heat pain threshold

Yang et al The Journal of Headache and Pain 2014 1571 Page 8 of 12httpwwwthejournalofheadacheandpaincomcontent15171

change somatosensory sensitivity to thermal stimuli Thisindicates that auditory stimulus regulation of thermal som-atosensory is not significant in healthy volunteers How-ever in some pathological conditions such as tension-typeand cervicogenic headache phonophobia is a commonsymptom [43] Again this may require a sensitized orpredisposed somatosensory systemIt has been reported that sucrose reduces pain during the

Cold Pressor Test (CPT) in 5- to 10-year-old children andthis kind of analgesia is dependent on the sweet taste pref-erence [14] However sucrose was not an effective analgesiain adult women in the same study The age-related declinein the analgesic efficacy of sucrose mirrors the age-relateddecline in the hedonic value of sweet tastes [44] In a recentstudy the taste of quinine gelatin (01) failed to producerobust affective state changes [45] However in the presentstudy the same stimulus evoked a significant change in

negative affective state These contradictory results maypossibly been explained by the ldquopreference theoryrdquo sincethe subjective rating to the bitter taste in this study (403 plusmn173 mean plusmn SD in a 0ndash100 numerical scale) was muchhigher than the study by Horjales-Aaujo (297 plusmn 197)[1445] Despite the negative affective state there were nochanges in somatosensory sensitivity in healthy volunteers

Multisensory conditioning stimulus effectsThere were several statistically significant effects of themultisensory conditioning stimulus which indicated thatthe multisensory stimulation enhanced the effect of indi-vidual stimuli with regard to subjective rating changesaffective score changes and induced slight thermal sensi-tivity changes This is in line with a neurophysiologicalstudy which demonstrates a strong emotion enhancementeffect by simultaneous presentation of congruent emotional

Figure 6 Multisensory effects between genders To diminish the effect of timing the delta values between test with stimuli and correspondingbaseline defined as ldquochangesrdquo in the figure was used Multisensory conditioning stimulus led to a strengthened effect compared with singleconditioning stimuli for several outcome parameters ie subjective ratings to gustatory stimulus (A) negative affective scores (C) and warmthdetection threshold (G) CDT = cold detection threshold WDT =warmth detection threshold CPT = cold pain threshold HPT = heat pain thresholdPositive affective changes (B) heat rate changes (D) skin temperature changes (E) cold detection threshold changes (F) cold pain threshold changes(H) and heat pain threshold changes (I) in different tests were also presented = P lt001 = P lt005

Yang et al The Journal of Headache and Pain 2014 1571 Page 9 of 12httpwwwthejournalofheadacheandpaincomcontent15171

pictures and music regarding subjective ratings peripheraland central physiological measures [11] The findings alsofit with a study which shows that when either positive (joy-ful) or negative (fearful) music is played simultaneouslywith an emotionally neutral film clip it evokes strongersignal changes in the amygdala and in areas of the ventro-lateral frontal cortex compared with when only music oronly film clips are presented [46] The activation increase

may be due to the cross modal integration of three sensorystimuli and this stronger activation possibly suggests en-hanced activation in a distributed neuronal network whichneeds to be confirmed in functional imaging studies [6]

Physiological arousal changesIt has been proposed that most affective changes are asso-ciated with undifferentiated physiological activity changes

Table 2 Impact of gender on warmth detection threshold (WDT degC) changes with different stimuli

Gender Visual (1) Auditory (2) Gustatory (3) Multisensory (4) F P 1 vs 4 2 vs 4 3 vs 4

Female Mean minus008 minus012 minus002 minus0150098 NS 0784 0938 0438

SD 076 064 035 060

Male Mean 017 minus003 027 minus0336036 0003 0019 NS 0003

SD 029 021 050 033

Sum Mean 004 minus008 013 minus0242241 NS 0058 0387 0004

SD 057 046 045 048

To evaluate the multisensory effect the delta values (ldquochangesrdquo) in 9000 lux light visual test 90 dB noise auditory test gustatory test and multisensory stimulationtest were compared using two-way repeated ANOVA with conditioning stimuli as within-participant factor gender as between-participant factor The male participantspresented a statistically significant decrease in ldquodeltardquo WDT during multisensory conditioning stimuli compared with light stimulus alone (P = 0019) or taste alone(P = 0003) Italics values indicate statistically significant P values (P lt 005)

Yang et al The Journal of Headache and Pain 2014 1571 Page 10 of 12httpwwwthejournalofheadacheandpaincomcontent15171

[47] Thus it seems reasonable to examine physiologicalarousal measurements related to affective reactions Skintemperature and heart rate are the most frequently usedphysiological expressions of affective state [47] Howeverin the present study these two parameters did not changesignificantly in response to changes in negative affectivestate by the different conditioning stimuli This is in linewith another study where it was demonstrated that theverbally reported affective experiences are not alwaysconsistent with the physiological parameters especially forunpleasant stimuli [47] On the other hand it may bebecause of the limited number of participants or that theapplied stimulus was inadequate for induction of a signifi-cant physiological change in arousal

Interactions between somatosensory sensitivity andconditioning stimuliThe perception of migraine headache which is mediatedby nociceptive signals is exacerbated by exposure to en-vironment stimuli ie light or noise which are mediatedby optical and acoustic signals Prolonged neuronal activa-tion during a migraine attack is thought to induce periph-eral and central sensitization along the trigeminovascularpathway which stands to explain the throbbing headache[48] accompanying scalp and neck-muscle tenderness[49] and whole-body cutaneous allodynia [50] Severaltheories exist which predict the relationship betweenconditioning stimuli and somatosensory sensitivity Todevelop a more comprehensive model of somatosensorymodulation by conditioning stimuli it may be useful toconsider a theory of ldquomotivational primingrdquo [9] It is pro-posed that affective state processing evoked by stimulicould be viewed as two opposing motivational systemsOne system is appetitive and produces approach behav-iors and the other system is aversive and promotes avoid-ance behaviors [9] Considerable evidence indicates thatprior activation of these systems modulates defensive be-haviors which facilitates somatosensory capability [51]These defensive behaviors increase in magnitude whenthe aversive system is primed by a negative affective stateie anticipation of shock [52] Conversely this defensive

response is inhibited when the appetitive system is primedby a positive affective state [53] According to the motiv-ational priming theory participants exposed to negativeaffective loading whose aversive systems are activatedshould get their perception facilitated [922] Howeversomatosensory sensitivity to thermal stimuli was not chan-ged during induction of negative affective states in thepresent study Another perspective on somatosensory andaffective processing is provided by the four-region neuro-biological model which indicates a complex relationshipbetween acute pain and simple emotion [54] For instancefear and pain sites overlap in the anterior midcingulatecortex (aMCC) and this region is involved in avoidancebehaviors posterior midcingulate cortex (pMCC) has noconsistent emotion activations yet has robust nociceptiveresponses subgenual anterior cingulate cortex (sACC) acti-vation during noxious stimulation of the skin and viscerain a person-specific manner the cingulate cortex is notuniformly involved in emotion and not all pain-activationsites are associated with affect or emotion [54]

ConclusionsThe three conditioning stimuli induced significantincreases in subjective rating and negative effectivescores accompanied with no physiological arousalchanges These stimuli did not however modulate skinthermal sensitivity The multisensory conditioning stimuliinduced stronger effects on subjective rating and negativeaffect than individual conditioning stimuli alone Theoften observed trigger or exacerbation of migraine byvisual auditory or gustatory stimuli may require a pre-disposed or sensitized nervous system

AbbreviationsMSI Multi-modal sensory integration IAPS Pictures of facial affect or theinternational affective picture system QST Quantitative sensory testingCDT Cold detection threshold WDT Warmth detection threshold CPT Coldpain threshold HPT Heat pain threshold PANAS Positive and negative affectschedule HR Heart rate EEG Electroencephalography aMCC AnteriorMidCingulate cortex pMCC Posterior MidCingulate cortex sACC Subgenualanterior cingulate cortex

Competing interestsThe authors declare that they have no competing interests

Yang et al The Journal of Headache and Pain 2014 1571 Page 11 of 12httpwwwthejournalofheadacheandpaincomcontent15171

Authorsrsquo contributionsYG recruited the participants carried out the study performed the statisticalanalysis and drafted the manuscript SP and BHL participated in the designof the study statistical analysis and revision of the draft XQ and WK helpedto draft and revise the manuscript All authors read and approved the finalmanuscript

AcknowledgementsWe are indebted to the subjects who participated in the study for theirconsent and co-operation This study was made possible by the supportsof Danish Dental Association

Author details1Department of Prosthodontics and Center for Oral Functional DiagnosisTreatment and Research Peking University School and hospital ofStomatology Zhongguancun Nandajie 22 100081 Beijing China 2Section ofClinical Oral Physiology Department of Dentistry Aarhus University AarhusDenmark 3Center for Sensory-Motor Interaction (SMI) Department of HealthScience and Technology Aalborg University Aalborg Denmark 4Departmentof Dental Medicine Karolinska Institute Huddinge Sweden

Received 28 August 2014 Accepted 28 October 2014Published 7 November 2014

References1 Goadsby PJ (2009) Pathophysiology of migraine Neurol Clin 27(2)335ndash360

httpdxdoiorg101016jncl2008110122 Judit A Saacutendor PS Schoenen J (2000) Habituation of visual and intensity

dependence of cortical auditory evoked potentials tends to normalize justbefore and during migraine attack Cephalalgia 20(8)714ndash719httponlinelibrarywileycomdoi101111j1468-2982200000122xfull

3 Schoenen J Wang W Albert A Delwaide PJ (1995) Potentiation instead ofhabituation characterizes visual evoked potentials in migraine patientsbetween attacks Eur J Neurol 2(2)115ndash122 doi101111j1468-1331

4 Wang W Schoenen J (1998) Interictal potentiation of passive ldquooddballrdquoauditory event-related potentials in migraine Cephalalgia 18(5)261ndash265doi101111j1468-298219981805261x

5 Stein BE Stanford TR (2008) Multisensory integration current issues fromthe perspective of the single neuron Nat Rev Neurosci 9(4)255ndash266doi101038nrn2331

6 Basura GJ Koehler SD Shore SE (2012) Multi-sensory integration inbrainstem and auditory cortex Brain Res 148595ndash107 httpdxdoiorg101016jbrainres201208037

7 Jain R Shore S (2006) External inferior colliculus integrates trigeminal andacoustic information unit response to trigeminal nucleus and acousticstimulation in the guinea pig Neurosci Lett 395(1)71ndash75 httpdxdoiorg101016jneulet200510077

8 Kawasaki A Purvin VA (2002) Photophobia as the presenting visual symptom ofchiasmal compression J Neuroophthalmol 22(1)3ndash8httpovidsptxovidcomsp-3131aovidwebcgiT=JSampPAGE=fulltextampD=ovftampAN=00041327-200203000-00002ampNEWS=NampCSC=YampCHANNEL=PubMed

9 Lang PJ (1995) The emotion probe Studies of motivation and attentionAm Psychol 50(5)372ndash385 doi1010370003-066X505372

10 Esslen M Pascual-Marqui RD Hell D Kochi K Lehmann D (2004) Brain areasand time course of emotional processing Neuroimage 21(4)1189ndash1203httpdxdoiorg101016jneuroimage200310001

11 Baumgartner T Esslen M Jaumlncke L (2006) From emotion perception toemotion experience emotions evoked by pictures and classical music Int JPsychophysiol 60(1)34ndash43 httpdxdoiorg101016jijpsycho200504007

12 Mitterschiffthaler MT Fu CH Dalton JA Andrew CM Williams SC (2007) Afunctional MRI study of happy and sad affective states induced by classicalmusic Hum Brain Mapp 28(11)1150ndash1162 DOI 101002hbm20337

13 Koelsch S (2010) Towards a neural basis of music-evoked emotions TrendsCogn Sci 14(3)131ndash137 httpdxdoiorg101016jtics201001002

14 Pepino MY Mennella JA (2005) Sucrose-induced analgesia is related tosweet preference in children but not adults Pain 119(1ndash3)210ndash218httpdxdoiorg101016jpain200509029

15 Horjales-Araujo E Demontis D Lund EK Vase L Finnerup NB Boslashrglum ADJensen TS Svensson P (2013) Emotional modulation of muscle pain isassociated with polymorphisms in the serotonin transporter gene Pain154(8)1469ndash1476 doi101016jpain201305011

16 Bushnell EW Baxt C (1999) Childrenrsquos haptic and cross-modal recognitionwith familiar and unfamiliar objects J Exp Psychol Hum Percept Perform25(6)1867ndash1881 doi1010370096-1523256

17 Longe SE Wise R Bantick S Lloyd D Johansen-Berg H McGlone F Tracey I(2001) Counter-stimulatory effects on pain perception and processing aresignificantly altered by attention an fMRI study Neuroreport 12(9)2021ndash2025httpovidsptxovidcomsp-3131aovidwebcgiT=JSampPAGE=fulltextampD=ovf-tampAN=00001756-200107030-00047ampNEWS=NampCSC=YampCHANNEL=PubMed

18 Rode S Salkovskis PM Jack T (2001) An experimental study of attentionlabeling and memory in people suffering from chronic pain Pain 94(2)193ndash203httpdxdoiorg101016S0304-3959(01)00356-6

19 McCaul KD Monson N Maki RH (1992) Does distraction reduce pain-produced distress among college students Health Psychol 11(4)210ndash217doi1010370278-6133114210

20 Rolke R Baron R Maier C Toumllle TR Treede RD Beyer A Binder A Birbaumer NBirklein F Boumltefuumlr IC Braune S Flor H Huge V Klug R Landwehrmeyer GBMagerl W Maihoumlfner C Rolko C Schaub C Scherens A Sprenger T Valet MWasserka B (2006) Quantitative sensory testing in the German ResearchNetwork on Neuropathic Pain (DFNS) Standardized protocol and referencevalue Pain 123(3)231ndash243 httpdxdoiorg101016jpain200601041

21 Yang G Luo Y Baad-Hansen L Wang K Arendt-Nielsen L Xie QF SvenssonP (2013) Ethnic differences in oro-facial somatosensory profiles-quantitativesensory testing in Chinese and Danes J Oral Rehabil 40(11)844ndash853doi101111joor12091

22 Meagher MW Arnau RC Rhudy JL (2001) Pain and emotion Effect ofAffective Picture Modulation Psychosom Med 63(1)79ndash90 httpwwwpsychosomaticmedicineorgcontent63179short

23 Danish volunteers recruit website for clinical research [wwwforsoegspersondk]24 Okamoto K Tashiro A Thompson R Nishida Y Bereiter DA (2012) Trigeminal

interpolariscaudalis transition neurons mediate reflex lacrimation evoked bybright light in the rat Eur J Neurosci 36(11)3492ndash3499 doi101111j1460-9568201208272x

25 Noseda R Kainz V Jakubowski M Gooley JJ Saper CB Digre K Burstein R(2010) A neural mechanism for exacerbation of headache by light NatNeurosci 13(2)239ndash245 doi101038nn2475

26 Sliney DH (1983) Standards for use of visible and nonvisible radiation on theeye Am J Optom Physiol Opt 60(4)278ndash286 httpovidsptxovidcomsp-3131aovidwebcgiWebLinkFrameset=1ampS=GDKPFPEIMNDDLJBJNCLKDFIBGENOAA00ampreturnUrl=ovidwebcgi3fMain2bSearch2bPage3d126S3dGDKPFPEIMNDDLJBJNCLKDFIBGENOAA00ampdirectlink=http3a2f2fgraphicstxovidcom2fovftpdfs2fFPDDNCIBDFBJMN002ffs0462fovft2flive2fgv0232f000004512f00000451-198304000-00003pdfampfilename=Standards+for+Use+of+Visible+and+Nonvisible+Radiation+on+the+Eyeampnavigation_links=NavLinksSsh421amplink_from=Ssh427c1amppdf_key=FPDDNCIBDFBJMN00amppdf_index=fs046ovftlivegv0230000045100000451-198304000-00003ampD=ovftamplink_set=Ssh42|1|sl_10|resultSet|Ssh4243|0

27 Rappaport SM (1993) Threshold limit values permissible exposure limitsand feasibility the bases for exposure limits in the United States Am J IndMed 23(5)683ndash694 doi101002ajim4700230502

28 Rhudy JL Meagher MW (2001) Noise stress and human pain thresholdsdivergent effects in men and women J Pain 2(1)64 httpdxdoiorg101054jpai200019947

29 Goldenberg AM Wexler LF (1988) Quinine overdose review of toxicity andtreatment Clin Cardiol 11(10)716ndash718 doi101002clc4960111012

30 Cardesiacuten A Alobid I Beniacutetez P Sierra E de Haro J Bernal-Sprekelsen MPicado C Mullol J (2006) Barcelona Smell Test - 24 (BAST-24) validation andsmell characteristics in the healthy Spanish population Rhinology 44(1)83ndash89httpwwwrhinologyjournalcomabstractphpid=556

31 Watson D Clark LA Tellegen A (1988) Development and validation of briefmeasures of positive and negative affect the PANAS scale J Pers SocPsychol 54(6)1063ndash1070 doi1010370022-35145461063

32 Crawford JR Herry JD (2004) The positive and negative affect schedule(PANAS) construct validity measurement properties and normative data ina large non-clinical sample Br J Clin Psychol 43(3)245ndash265 httpovidsptxovidcomsp-3131aovidwebcgiT=JSampPAGE=fulltextampD=ovftampAN=00002604-200409000-00003ampNEWS=NampCSC=YampCHANNEL=PubMed

33 Hsee CK Hatfield E Carlson JG Chemtob C (1990) The effect of power onsusceptibility to emotional contagion Cogn Emot 4327ndash340 doi10108002699939008408081

34 Doherty RW (1998) Emotional contagion and social judgment Motiv Emot22187ndash209 doi101023A1022368805803

Figure 5 Thermal sensitivity differences between tests with conditioning stimuli (grizzle bars) and corresponding baselines (white bars)The results are presented as means plusmn SDs of the threshold values from visual test (A) auditory test (B) gustatory test (C) and multisensory test (D)Compared with baseline (white bars) the sensitivity to thermal stimulus did not change when the participants were exposed to conditioning stimuli(grizzle bars) CDT = cold detection threshold WDT =warmth detection threshold CPT = cold pain threshold HPT = heat pain threshold

Yang et al The Journal of Headache and Pain 2014 1571 Page 8 of 12httpwwwthejournalofheadacheandpaincomcontent15171

change somatosensory sensitivity to thermal stimuli Thisindicates that auditory stimulus regulation of thermal som-atosensory is not significant in healthy volunteers How-ever in some pathological conditions such as tension-typeand cervicogenic headache phonophobia is a commonsymptom [43] Again this may require a sensitized orpredisposed somatosensory systemIt has been reported that sucrose reduces pain during the

Cold Pressor Test (CPT) in 5- to 10-year-old children andthis kind of analgesia is dependent on the sweet taste pref-erence [14] However sucrose was not an effective analgesiain adult women in the same study The age-related declinein the analgesic efficacy of sucrose mirrors the age-relateddecline in the hedonic value of sweet tastes [44] In a recentstudy the taste of quinine gelatin (01) failed to producerobust affective state changes [45] However in the presentstudy the same stimulus evoked a significant change in

negative affective state These contradictory results maypossibly been explained by the ldquopreference theoryrdquo sincethe subjective rating to the bitter taste in this study (403 plusmn173 mean plusmn SD in a 0ndash100 numerical scale) was muchhigher than the study by Horjales-Aaujo (297 plusmn 197)[1445] Despite the negative affective state there were nochanges in somatosensory sensitivity in healthy volunteers

Multisensory conditioning stimulus effectsThere were several statistically significant effects of themultisensory conditioning stimulus which indicated thatthe multisensory stimulation enhanced the effect of indi-vidual stimuli with regard to subjective rating changesaffective score changes and induced slight thermal sensi-tivity changes This is in line with a neurophysiologicalstudy which demonstrates a strong emotion enhancementeffect by simultaneous presentation of congruent emotional

Figure 6 Multisensory effects between genders To diminish the effect of timing the delta values between test with stimuli and correspondingbaseline defined as ldquochangesrdquo in the figure was used Multisensory conditioning stimulus led to a strengthened effect compared with singleconditioning stimuli for several outcome parameters ie subjective ratings to gustatory stimulus (A) negative affective scores (C) and warmthdetection threshold (G) CDT = cold detection threshold WDT =warmth detection threshold CPT = cold pain threshold HPT = heat pain thresholdPositive affective changes (B) heat rate changes (D) skin temperature changes (E) cold detection threshold changes (F) cold pain threshold changes(H) and heat pain threshold changes (I) in different tests were also presented = P lt001 = P lt005

Yang et al The Journal of Headache and Pain 2014 1571 Page 9 of 12httpwwwthejournalofheadacheandpaincomcontent15171

pictures and music regarding subjective ratings peripheraland central physiological measures [11] The findings alsofit with a study which shows that when either positive (joy-ful) or negative (fearful) music is played simultaneouslywith an emotionally neutral film clip it evokes strongersignal changes in the amygdala and in areas of the ventro-lateral frontal cortex compared with when only music oronly film clips are presented [46] The activation increase

may be due to the cross modal integration of three sensorystimuli and this stronger activation possibly suggests en-hanced activation in a distributed neuronal network whichneeds to be confirmed in functional imaging studies [6]

Physiological arousal changesIt has been proposed that most affective changes are asso-ciated with undifferentiated physiological activity changes

Table 2 Impact of gender on warmth detection threshold (WDT degC) changes with different stimuli

Gender Visual (1) Auditory (2) Gustatory (3) Multisensory (4) F P 1 vs 4 2 vs 4 3 vs 4

Female Mean minus008 minus012 minus002 minus0150098 NS 0784 0938 0438

SD 076 064 035 060

Male Mean 017 minus003 027 minus0336036 0003 0019 NS 0003

SD 029 021 050 033

Sum Mean 004 minus008 013 minus0242241 NS 0058 0387 0004

SD 057 046 045 048

To evaluate the multisensory effect the delta values (ldquochangesrdquo) in 9000 lux light visual test 90 dB noise auditory test gustatory test and multisensory stimulationtest were compared using two-way repeated ANOVA with conditioning stimuli as within-participant factor gender as between-participant factor The male participantspresented a statistically significant decrease in ldquodeltardquo WDT during multisensory conditioning stimuli compared with light stimulus alone (P = 0019) or taste alone(P = 0003) Italics values indicate statistically significant P values (P lt 005)

Yang et al The Journal of Headache and Pain 2014 1571 Page 10 of 12httpwwwthejournalofheadacheandpaincomcontent15171

[47] Thus it seems reasonable to examine physiologicalarousal measurements related to affective reactions Skintemperature and heart rate are the most frequently usedphysiological expressions of affective state [47] Howeverin the present study these two parameters did not changesignificantly in response to changes in negative affectivestate by the different conditioning stimuli This is in linewith another study where it was demonstrated that theverbally reported affective experiences are not alwaysconsistent with the physiological parameters especially forunpleasant stimuli [47] On the other hand it may bebecause of the limited number of participants or that theapplied stimulus was inadequate for induction of a signifi-cant physiological change in arousal

Interactions between somatosensory sensitivity andconditioning stimuliThe perception of migraine headache which is mediatedby nociceptive signals is exacerbated by exposure to en-vironment stimuli ie light or noise which are mediatedby optical and acoustic signals Prolonged neuronal activa-tion during a migraine attack is thought to induce periph-eral and central sensitization along the trigeminovascularpathway which stands to explain the throbbing headache[48] accompanying scalp and neck-muscle tenderness[49] and whole-body cutaneous allodynia [50] Severaltheories exist which predict the relationship betweenconditioning stimuli and somatosensory sensitivity Todevelop a more comprehensive model of somatosensorymodulation by conditioning stimuli it may be useful toconsider a theory of ldquomotivational primingrdquo [9] It is pro-posed that affective state processing evoked by stimulicould be viewed as two opposing motivational systemsOne system is appetitive and produces approach behav-iors and the other system is aversive and promotes avoid-ance behaviors [9] Considerable evidence indicates thatprior activation of these systems modulates defensive be-haviors which facilitates somatosensory capability [51]These defensive behaviors increase in magnitude whenthe aversive system is primed by a negative affective stateie anticipation of shock [52] Conversely this defensive

response is inhibited when the appetitive system is primedby a positive affective state [53] According to the motiv-ational priming theory participants exposed to negativeaffective loading whose aversive systems are activatedshould get their perception facilitated [922] Howeversomatosensory sensitivity to thermal stimuli was not chan-ged during induction of negative affective states in thepresent study Another perspective on somatosensory andaffective processing is provided by the four-region neuro-biological model which indicates a complex relationshipbetween acute pain and simple emotion [54] For instancefear and pain sites overlap in the anterior midcingulatecortex (aMCC) and this region is involved in avoidancebehaviors posterior midcingulate cortex (pMCC) has noconsistent emotion activations yet has robust nociceptiveresponses subgenual anterior cingulate cortex (sACC) acti-vation during noxious stimulation of the skin and viscerain a person-specific manner the cingulate cortex is notuniformly involved in emotion and not all pain-activationsites are associated with affect or emotion [54]

ConclusionsThe three conditioning stimuli induced significantincreases in subjective rating and negative effectivescores accompanied with no physiological arousalchanges These stimuli did not however modulate skinthermal sensitivity The multisensory conditioning stimuliinduced stronger effects on subjective rating and negativeaffect than individual conditioning stimuli alone Theoften observed trigger or exacerbation of migraine byvisual auditory or gustatory stimuli may require a pre-disposed or sensitized nervous system

AbbreviationsMSI Multi-modal sensory integration IAPS Pictures of facial affect or theinternational affective picture system QST Quantitative sensory testingCDT Cold detection threshold WDT Warmth detection threshold CPT Coldpain threshold HPT Heat pain threshold PANAS Positive and negative affectschedule HR Heart rate EEG Electroencephalography aMCC AnteriorMidCingulate cortex pMCC Posterior MidCingulate cortex sACC Subgenualanterior cingulate cortex

Competing interestsThe authors declare that they have no competing interests

Yang et al The Journal of Headache and Pain 2014 1571 Page 11 of 12httpwwwthejournalofheadacheandpaincomcontent15171

Authorsrsquo contributionsYG recruited the participants carried out the study performed the statisticalanalysis and drafted the manuscript SP and BHL participated in the designof the study statistical analysis and revision of the draft XQ and WK helpedto draft and revise the manuscript All authors read and approved the finalmanuscript

AcknowledgementsWe are indebted to the subjects who participated in the study for theirconsent and co-operation This study was made possible by the supportsof Danish Dental Association

Author details1Department of Prosthodontics and Center for Oral Functional DiagnosisTreatment and Research Peking University School and hospital ofStomatology Zhongguancun Nandajie 22 100081 Beijing China 2Section ofClinical Oral Physiology Department of Dentistry Aarhus University AarhusDenmark 3Center for Sensory-Motor Interaction (SMI) Department of HealthScience and Technology Aalborg University Aalborg Denmark 4Departmentof Dental Medicine Karolinska Institute Huddinge Sweden

Received 28 August 2014 Accepted 28 October 2014Published 7 November 2014

References1 Goadsby PJ (2009) Pathophysiology of migraine Neurol Clin 27(2)335ndash360

httpdxdoiorg101016jncl2008110122 Judit A Saacutendor PS Schoenen J (2000) Habituation of visual and intensity

dependence of cortical auditory evoked potentials tends to normalize justbefore and during migraine attack Cephalalgia 20(8)714ndash719httponlinelibrarywileycomdoi101111j1468-2982200000122xfull

3 Schoenen J Wang W Albert A Delwaide PJ (1995) Potentiation instead ofhabituation characterizes visual evoked potentials in migraine patientsbetween attacks Eur J Neurol 2(2)115ndash122 doi101111j1468-1331

4 Wang W Schoenen J (1998) Interictal potentiation of passive ldquooddballrdquoauditory event-related potentials in migraine Cephalalgia 18(5)261ndash265doi101111j1468-298219981805261x

5 Stein BE Stanford TR (2008) Multisensory integration current issues fromthe perspective of the single neuron Nat Rev Neurosci 9(4)255ndash266doi101038nrn2331

6 Basura GJ Koehler SD Shore SE (2012) Multi-sensory integration inbrainstem and auditory cortex Brain Res 148595ndash107 httpdxdoiorg101016jbrainres201208037

7 Jain R Shore S (2006) External inferior colliculus integrates trigeminal andacoustic information unit response to trigeminal nucleus and acousticstimulation in the guinea pig Neurosci Lett 395(1)71ndash75 httpdxdoiorg101016jneulet200510077

8 Kawasaki A Purvin VA (2002) Photophobia as the presenting visual symptom ofchiasmal compression J Neuroophthalmol 22(1)3ndash8httpovidsptxovidcomsp-3131aovidwebcgiT=JSampPAGE=fulltextampD=ovftampAN=00041327-200203000-00002ampNEWS=NampCSC=YampCHANNEL=PubMed

9 Lang PJ (1995) The emotion probe Studies of motivation and attentionAm Psychol 50(5)372ndash385 doi1010370003-066X505372

10 Esslen M Pascual-Marqui RD Hell D Kochi K Lehmann D (2004) Brain areasand time course of emotional processing Neuroimage 21(4)1189ndash1203httpdxdoiorg101016jneuroimage200310001

11 Baumgartner T Esslen M Jaumlncke L (2006) From emotion perception toemotion experience emotions evoked by pictures and classical music Int JPsychophysiol 60(1)34ndash43 httpdxdoiorg101016jijpsycho200504007

12 Mitterschiffthaler MT Fu CH Dalton JA Andrew CM Williams SC (2007) Afunctional MRI study of happy and sad affective states induced by classicalmusic Hum Brain Mapp 28(11)1150ndash1162 DOI 101002hbm20337

13 Koelsch S (2010) Towards a neural basis of music-evoked emotions TrendsCogn Sci 14(3)131ndash137 httpdxdoiorg101016jtics201001002

14 Pepino MY Mennella JA (2005) Sucrose-induced analgesia is related tosweet preference in children but not adults Pain 119(1ndash3)210ndash218httpdxdoiorg101016jpain200509029

15 Horjales-Araujo E Demontis D Lund EK Vase L Finnerup NB Boslashrglum ADJensen TS Svensson P (2013) Emotional modulation of muscle pain isassociated with polymorphisms in the serotonin transporter gene Pain154(8)1469ndash1476 doi101016jpain201305011

16 Bushnell EW Baxt C (1999) Childrenrsquos haptic and cross-modal recognitionwith familiar and unfamiliar objects J Exp Psychol Hum Percept Perform25(6)1867ndash1881 doi1010370096-1523256

17 Longe SE Wise R Bantick S Lloyd D Johansen-Berg H McGlone F Tracey I(2001) Counter-stimulatory effects on pain perception and processing aresignificantly altered by attention an fMRI study Neuroreport 12(9)2021ndash2025httpovidsptxovidcomsp-3131aovidwebcgiT=JSampPAGE=fulltextampD=ovf-tampAN=00001756-200107030-00047ampNEWS=NampCSC=YampCHANNEL=PubMed

18 Rode S Salkovskis PM Jack T (2001) An experimental study of attentionlabeling and memory in people suffering from chronic pain Pain 94(2)193ndash203httpdxdoiorg101016S0304-3959(01)00356-6

19 McCaul KD Monson N Maki RH (1992) Does distraction reduce pain-produced distress among college students Health Psychol 11(4)210ndash217doi1010370278-6133114210

20 Rolke R Baron R Maier C Toumllle TR Treede RD Beyer A Binder A Birbaumer NBirklein F Boumltefuumlr IC Braune S Flor H Huge V Klug R Landwehrmeyer GBMagerl W Maihoumlfner C Rolko C Schaub C Scherens A Sprenger T Valet MWasserka B (2006) Quantitative sensory testing in the German ResearchNetwork on Neuropathic Pain (DFNS) Standardized protocol and referencevalue Pain 123(3)231ndash243 httpdxdoiorg101016jpain200601041

21 Yang G Luo Y Baad-Hansen L Wang K Arendt-Nielsen L Xie QF SvenssonP (2013) Ethnic differences in oro-facial somatosensory profiles-quantitativesensory testing in Chinese and Danes J Oral Rehabil 40(11)844ndash853doi101111joor12091

22 Meagher MW Arnau RC Rhudy JL (2001) Pain and emotion Effect ofAffective Picture Modulation Psychosom Med 63(1)79ndash90 httpwwwpsychosomaticmedicineorgcontent63179short

23 Danish volunteers recruit website for clinical research [wwwforsoegspersondk]24 Okamoto K Tashiro A Thompson R Nishida Y Bereiter DA (2012) Trigeminal

interpolariscaudalis transition neurons mediate reflex lacrimation evoked bybright light in the rat Eur J Neurosci 36(11)3492ndash3499 doi101111j1460-9568201208272x

25 Noseda R Kainz V Jakubowski M Gooley JJ Saper CB Digre K Burstein R(2010) A neural mechanism for exacerbation of headache by light NatNeurosci 13(2)239ndash245 doi101038nn2475

26 Sliney DH (1983) Standards for use of visible and nonvisible radiation on theeye Am J Optom Physiol Opt 60(4)278ndash286 httpovidsptxovidcomsp-3131aovidwebcgiWebLinkFrameset=1ampS=GDKPFPEIMNDDLJBJNCLKDFIBGENOAA00ampreturnUrl=ovidwebcgi3fMain2bSearch2bPage3d126S3dGDKPFPEIMNDDLJBJNCLKDFIBGENOAA00ampdirectlink=http3a2f2fgraphicstxovidcom2fovftpdfs2fFPDDNCIBDFBJMN002ffs0462fovft2flive2fgv0232f000004512f00000451-198304000-00003pdfampfilename=Standards+for+Use+of+Visible+and+Nonvisible+Radiation+on+the+Eyeampnavigation_links=NavLinksSsh421amplink_from=Ssh427c1amppdf_key=FPDDNCIBDFBJMN00amppdf_index=fs046ovftlivegv0230000045100000451-198304000-00003ampD=ovftamplink_set=Ssh42|1|sl_10|resultSet|Ssh4243|0

27 Rappaport SM (1993) Threshold limit values permissible exposure limitsand feasibility the bases for exposure limits in the United States Am J IndMed 23(5)683ndash694 doi101002ajim4700230502

28 Rhudy JL Meagher MW (2001) Noise stress and human pain thresholdsdivergent effects in men and women J Pain 2(1)64 httpdxdoiorg101054jpai200019947

29 Goldenberg AM Wexler LF (1988) Quinine overdose review of toxicity andtreatment Clin Cardiol 11(10)716ndash718 doi101002clc4960111012

30 Cardesiacuten A Alobid I Beniacutetez P Sierra E de Haro J Bernal-Sprekelsen MPicado C Mullol J (2006) Barcelona Smell Test - 24 (BAST-24) validation andsmell characteristics in the healthy Spanish population Rhinology 44(1)83ndash89httpwwwrhinologyjournalcomabstractphpid=556

31 Watson D Clark LA Tellegen A (1988) Development and validation of briefmeasures of positive and negative affect the PANAS scale J Pers SocPsychol 54(6)1063ndash1070 doi1010370022-35145461063

32 Crawford JR Herry JD (2004) The positive and negative affect schedule(PANAS) construct validity measurement properties and normative data ina large non-clinical sample Br J Clin Psychol 43(3)245ndash265 httpovidsptxovidcomsp-3131aovidwebcgiT=JSampPAGE=fulltextampD=ovftampAN=00002604-200409000-00003ampNEWS=NampCSC=YampCHANNEL=PubMed

33 Hsee CK Hatfield E Carlson JG Chemtob C (1990) The effect of power onsusceptibility to emotional contagion Cogn Emot 4327ndash340 doi10108002699939008408081

34 Doherty RW (1998) Emotional contagion and social judgment Motiv Emot22187ndash209 doi101023A1022368805803

Figure 6 Multisensory effects between genders To diminish the effect of timing the delta values between test with stimuli and correspondingbaseline defined as ldquochangesrdquo in the figure was used Multisensory conditioning stimulus led to a strengthened effect compared with singleconditioning stimuli for several outcome parameters ie subjective ratings to gustatory stimulus (A) negative affective scores (C) and warmthdetection threshold (G) CDT = cold detection threshold WDT =warmth detection threshold CPT = cold pain threshold HPT = heat pain thresholdPositive affective changes (B) heat rate changes (D) skin temperature changes (E) cold detection threshold changes (F) cold pain threshold changes(H) and heat pain threshold changes (I) in different tests were also presented = P lt001 = P lt005

Yang et al The Journal of Headache and Pain 2014 1571 Page 9 of 12httpwwwthejournalofheadacheandpaincomcontent15171

pictures and music regarding subjective ratings peripheraland central physiological measures [11] The findings alsofit with a study which shows that when either positive (joy-ful) or negative (fearful) music is played simultaneouslywith an emotionally neutral film clip it evokes strongersignal changes in the amygdala and in areas of the ventro-lateral frontal cortex compared with when only music oronly film clips are presented [46] The activation increase

may be due to the cross modal integration of three sensorystimuli and this stronger activation possibly suggests en-hanced activation in a distributed neuronal network whichneeds to be confirmed in functional imaging studies [6]

Physiological arousal changesIt has been proposed that most affective changes are asso-ciated with undifferentiated physiological activity changes

Table 2 Impact of gender on warmth detection threshold (WDT degC) changes with different stimuli

Gender Visual (1) Auditory (2) Gustatory (3) Multisensory (4) F P 1 vs 4 2 vs 4 3 vs 4

Female Mean minus008 minus012 minus002 minus0150098 NS 0784 0938 0438

SD 076 064 035 060

Male Mean 017 minus003 027 minus0336036 0003 0019 NS 0003

SD 029 021 050 033

Sum Mean 004 minus008 013 minus0242241 NS 0058 0387 0004

SD 057 046 045 048

To evaluate the multisensory effect the delta values (ldquochangesrdquo) in 9000 lux light visual test 90 dB noise auditory test gustatory test and multisensory stimulationtest were compared using two-way repeated ANOVA with conditioning stimuli as within-participant factor gender as between-participant factor The male participantspresented a statistically significant decrease in ldquodeltardquo WDT during multisensory conditioning stimuli compared with light stimulus alone (P = 0019) or taste alone(P = 0003) Italics values indicate statistically significant P values (P lt 005)

Yang et al The Journal of Headache and Pain 2014 1571 Page 10 of 12httpwwwthejournalofheadacheandpaincomcontent15171

[47] Thus it seems reasonable to examine physiologicalarousal measurements related to affective reactions Skintemperature and heart rate are the most frequently usedphysiological expressions of affective state [47] Howeverin the present study these two parameters did not changesignificantly in response to changes in negative affectivestate by the different conditioning stimuli This is in linewith another study where it was demonstrated that theverbally reported affective experiences are not alwaysconsistent with the physiological parameters especially forunpleasant stimuli [47] On the other hand it may bebecause of the limited number of participants or that theapplied stimulus was inadequate for induction of a signifi-cant physiological change in arousal

Interactions between somatosensory sensitivity andconditioning stimuliThe perception of migraine headache which is mediatedby nociceptive signals is exacerbated by exposure to en-vironment stimuli ie light or noise which are mediatedby optical and acoustic signals Prolonged neuronal activa-tion during a migraine attack is thought to induce periph-eral and central sensitization along the trigeminovascularpathway which stands to explain the throbbing headache[48] accompanying scalp and neck-muscle tenderness[49] and whole-body cutaneous allodynia [50] Severaltheories exist which predict the relationship betweenconditioning stimuli and somatosensory sensitivity Todevelop a more comprehensive model of somatosensorymodulation by conditioning stimuli it may be useful toconsider a theory of ldquomotivational primingrdquo [9] It is pro-posed that affective state processing evoked by stimulicould be viewed as two opposing motivational systemsOne system is appetitive and produces approach behav-iors and the other system is aversive and promotes avoid-ance behaviors [9] Considerable evidence indicates thatprior activation of these systems modulates defensive be-haviors which facilitates somatosensory capability [51]These defensive behaviors increase in magnitude whenthe aversive system is primed by a negative affective stateie anticipation of shock [52] Conversely this defensive

response is inhibited when the appetitive system is primedby a positive affective state [53] According to the motiv-ational priming theory participants exposed to negativeaffective loading whose aversive systems are activatedshould get their perception facilitated [922] Howeversomatosensory sensitivity to thermal stimuli was not chan-ged during induction of negative affective states in thepresent study Another perspective on somatosensory andaffective processing is provided by the four-region neuro-biological model which indicates a complex relationshipbetween acute pain and simple emotion [54] For instancefear and pain sites overlap in the anterior midcingulatecortex (aMCC) and this region is involved in avoidancebehaviors posterior midcingulate cortex (pMCC) has noconsistent emotion activations yet has robust nociceptiveresponses subgenual anterior cingulate cortex (sACC) acti-vation during noxious stimulation of the skin and viscerain a person-specific manner the cingulate cortex is notuniformly involved in emotion and not all pain-activationsites are associated with affect or emotion [54]

ConclusionsThe three conditioning stimuli induced significantincreases in subjective rating and negative effectivescores accompanied with no physiological arousalchanges These stimuli did not however modulate skinthermal sensitivity The multisensory conditioning stimuliinduced stronger effects on subjective rating and negativeaffect than individual conditioning stimuli alone Theoften observed trigger or exacerbation of migraine byvisual auditory or gustatory stimuli may require a pre-disposed or sensitized nervous system

AbbreviationsMSI Multi-modal sensory integration IAPS Pictures of facial affect or theinternational affective picture system QST Quantitative sensory testingCDT Cold detection threshold WDT Warmth detection threshold CPT Coldpain threshold HPT Heat pain threshold PANAS Positive and negative affectschedule HR Heart rate EEG Electroencephalography aMCC AnteriorMidCingulate cortex pMCC Posterior MidCingulate cortex sACC Subgenualanterior cingulate cortex

Competing interestsThe authors declare that they have no competing interests

Yang et al The Journal of Headache and Pain 2014 1571 Page 11 of 12httpwwwthejournalofheadacheandpaincomcontent15171

Authorsrsquo contributionsYG recruited the participants carried out the study performed the statisticalanalysis and drafted the manuscript SP and BHL participated in the designof the study statistical analysis and revision of the draft XQ and WK helpedto draft and revise the manuscript All authors read and approved the finalmanuscript

AcknowledgementsWe are indebted to the subjects who participated in the study for theirconsent and co-operation This study was made possible by the supportsof Danish Dental Association

Author details1Department of Prosthodontics and Center for Oral Functional DiagnosisTreatment and Research Peking University School and hospital ofStomatology Zhongguancun Nandajie 22 100081 Beijing China 2Section ofClinical Oral Physiology Department of Dentistry Aarhus University AarhusDenmark 3Center for Sensory-Motor Interaction (SMI) Department of HealthScience and Technology Aalborg University Aalborg Denmark 4Departmentof Dental Medicine Karolinska Institute Huddinge Sweden

Received 28 August 2014 Accepted 28 October 2014Published 7 November 2014

References1 Goadsby PJ (2009) Pathophysiology of migraine Neurol Clin 27(2)335ndash360

httpdxdoiorg101016jncl2008110122 Judit A Saacutendor PS Schoenen J (2000) Habituation of visual and intensity

dependence of cortical auditory evoked potentials tends to normalize justbefore and during migraine attack Cephalalgia 20(8)714ndash719httponlinelibrarywileycomdoi101111j1468-2982200000122xfull

3 Schoenen J Wang W Albert A Delwaide PJ (1995) Potentiation instead ofhabituation characterizes visual evoked potentials in migraine patientsbetween attacks Eur J Neurol 2(2)115ndash122 doi101111j1468-1331

4 Wang W Schoenen J (1998) Interictal potentiation of passive ldquooddballrdquoauditory event-related potentials in migraine Cephalalgia 18(5)261ndash265doi101111j1468-298219981805261x

5 Stein BE Stanford TR (2008) Multisensory integration current issues fromthe perspective of the single neuron Nat Rev Neurosci 9(4)255ndash266doi101038nrn2331

6 Basura GJ Koehler SD Shore SE (2012) Multi-sensory integration inbrainstem and auditory cortex Brain Res 148595ndash107 httpdxdoiorg101016jbrainres201208037

7 Jain R Shore S (2006) External inferior colliculus integrates trigeminal andacoustic information unit response to trigeminal nucleus and acousticstimulation in the guinea pig Neurosci Lett 395(1)71ndash75 httpdxdoiorg101016jneulet200510077

8 Kawasaki A Purvin VA (2002) Photophobia as the presenting visual symptom ofchiasmal compression J Neuroophthalmol 22(1)3ndash8httpovidsptxovidcomsp-3131aovidwebcgiT=JSampPAGE=fulltextampD=ovftampAN=00041327-200203000-00002ampNEWS=NampCSC=YampCHANNEL=PubMed

9 Lang PJ (1995) The emotion probe Studies of motivation and attentionAm Psychol 50(5)372ndash385 doi1010370003-066X505372

10 Esslen M Pascual-Marqui RD Hell D Kochi K Lehmann D (2004) Brain areasand time course of emotional processing Neuroimage 21(4)1189ndash1203httpdxdoiorg101016jneuroimage200310001

11 Baumgartner T Esslen M Jaumlncke L (2006) From emotion perception toemotion experience emotions evoked by pictures and classical music Int JPsychophysiol 60(1)34ndash43 httpdxdoiorg101016jijpsycho200504007

12 Mitterschiffthaler MT Fu CH Dalton JA Andrew CM Williams SC (2007) Afunctional MRI study of happy and sad affective states induced by classicalmusic Hum Brain Mapp 28(11)1150ndash1162 DOI 101002hbm20337

13 Koelsch S (2010) Towards a neural basis of music-evoked emotions TrendsCogn Sci 14(3)131ndash137 httpdxdoiorg101016jtics201001002

14 Pepino MY Mennella JA (2005) Sucrose-induced analgesia is related tosweet preference in children but not adults Pain 119(1ndash3)210ndash218httpdxdoiorg101016jpain200509029

15 Horjales-Araujo E Demontis D Lund EK Vase L Finnerup NB Boslashrglum ADJensen TS Svensson P (2013) Emotional modulation of muscle pain isassociated with polymorphisms in the serotonin transporter gene Pain154(8)1469ndash1476 doi101016jpain201305011

16 Bushnell EW Baxt C (1999) Childrenrsquos haptic and cross-modal recognitionwith familiar and unfamiliar objects J Exp Psychol Hum Percept Perform25(6)1867ndash1881 doi1010370096-1523256

17 Longe SE Wise R Bantick S Lloyd D Johansen-Berg H McGlone F Tracey I(2001) Counter-stimulatory effects on pain perception and processing aresignificantly altered by attention an fMRI study Neuroreport 12(9)2021ndash2025httpovidsptxovidcomsp-3131aovidwebcgiT=JSampPAGE=fulltextampD=ovf-tampAN=00001756-200107030-00047ampNEWS=NampCSC=YampCHANNEL=PubMed

18 Rode S Salkovskis PM Jack T (2001) An experimental study of attentionlabeling and memory in people suffering from chronic pain Pain 94(2)193ndash203httpdxdoiorg101016S0304-3959(01)00356-6

19 McCaul KD Monson N Maki RH (1992) Does distraction reduce pain-produced distress among college students Health Psychol 11(4)210ndash217doi1010370278-6133114210

20 Rolke R Baron R Maier C Toumllle TR Treede RD Beyer A Binder A Birbaumer NBirklein F Boumltefuumlr IC Braune S Flor H Huge V Klug R Landwehrmeyer GBMagerl W Maihoumlfner C Rolko C Schaub C Scherens A Sprenger T Valet MWasserka B (2006) Quantitative sensory testing in the German ResearchNetwork on Neuropathic Pain (DFNS) Standardized protocol and referencevalue Pain 123(3)231ndash243 httpdxdoiorg101016jpain200601041

21 Yang G Luo Y Baad-Hansen L Wang K Arendt-Nielsen L Xie QF SvenssonP (2013) Ethnic differences in oro-facial somatosensory profiles-quantitativesensory testing in Chinese and Danes J Oral Rehabil 40(11)844ndash853doi101111joor12091

22 Meagher MW Arnau RC Rhudy JL (2001) Pain and emotion Effect ofAffective Picture Modulation Psychosom Med 63(1)79ndash90 httpwwwpsychosomaticmedicineorgcontent63179short

23 Danish volunteers recruit website for clinical research [wwwforsoegspersondk]24 Okamoto K Tashiro A Thompson R Nishida Y Bereiter DA (2012) Trigeminal

interpolariscaudalis transition neurons mediate reflex lacrimation evoked bybright light in the rat Eur J Neurosci 36(11)3492ndash3499 doi101111j1460-9568201208272x

25 Noseda R Kainz V Jakubowski M Gooley JJ Saper CB Digre K Burstein R(2010) A neural mechanism for exacerbation of headache by light NatNeurosci 13(2)239ndash245 doi101038nn2475

26 Sliney DH (1983) Standards for use of visible and nonvisible radiation on theeye Am J Optom Physiol Opt 60(4)278ndash286 httpovidsptxovidcomsp-3131aovidwebcgiWebLinkFrameset=1ampS=GDKPFPEIMNDDLJBJNCLKDFIBGENOAA00ampreturnUrl=ovidwebcgi3fMain2bSearch2bPage3d126S3dGDKPFPEIMNDDLJBJNCLKDFIBGENOAA00ampdirectlink=http3a2f2fgraphicstxovidcom2fovftpdfs2fFPDDNCIBDFBJMN002ffs0462fovft2flive2fgv0232f000004512f00000451-198304000-00003pdfampfilename=Standards+for+Use+of+Visible+and+Nonvisible+Radiation+on+the+Eyeampnavigation_links=NavLinksSsh421amplink_from=Ssh427c1amppdf_key=FPDDNCIBDFBJMN00amppdf_index=fs046ovftlivegv0230000045100000451-198304000-00003ampD=ovftamplink_set=Ssh42|1|sl_10|resultSet|Ssh4243|0

27 Rappaport SM (1993) Threshold limit values permissible exposure limitsand feasibility the bases for exposure limits in the United States Am J IndMed 23(5)683ndash694 doi101002ajim4700230502

28 Rhudy JL Meagher MW (2001) Noise stress and human pain thresholdsdivergent effects in men and women J Pain 2(1)64 httpdxdoiorg101054jpai200019947

29 Goldenberg AM Wexler LF (1988) Quinine overdose review of toxicity andtreatment Clin Cardiol 11(10)716ndash718 doi101002clc4960111012

30 Cardesiacuten A Alobid I Beniacutetez P Sierra E de Haro J Bernal-Sprekelsen MPicado C Mullol J (2006) Barcelona Smell Test - 24 (BAST-24) validation andsmell characteristics in the healthy Spanish population Rhinology 44(1)83ndash89httpwwwrhinologyjournalcomabstractphpid=556

31 Watson D Clark LA Tellegen A (1988) Development and validation of briefmeasures of positive and negative affect the PANAS scale J Pers SocPsychol 54(6)1063ndash1070 doi1010370022-35145461063

32 Crawford JR Herry JD (2004) The positive and negative affect schedule(PANAS) construct validity measurement properties and normative data ina large non-clinical sample Br J Clin Psychol 43(3)245ndash265 httpovidsptxovidcomsp-3131aovidwebcgiT=JSampPAGE=fulltextampD=ovftampAN=00002604-200409000-00003ampNEWS=NampCSC=YampCHANNEL=PubMed

33 Hsee CK Hatfield E Carlson JG Chemtob C (1990) The effect of power onsusceptibility to emotional contagion Cogn Emot 4327ndash340 doi10108002699939008408081

34 Doherty RW (1998) Emotional contagion and social judgment Motiv Emot22187ndash209 doi101023A1022368805803

Table 2 Impact of gender on warmth detection threshold (WDT degC) changes with different stimuli

Gender Visual (1) Auditory (2) Gustatory (3) Multisensory (4) F P 1 vs 4 2 vs 4 3 vs 4

Female Mean minus008 minus012 minus002 minus0150098 NS 0784 0938 0438

SD 076 064 035 060

Male Mean 017 minus003 027 minus0336036 0003 0019 NS 0003

SD 029 021 050 033

Sum Mean 004 minus008 013 minus0242241 NS 0058 0387 0004

SD 057 046 045 048

To evaluate the multisensory effect the delta values (ldquochangesrdquo) in 9000 lux light visual test 90 dB noise auditory test gustatory test and multisensory stimulationtest were compared using two-way repeated ANOVA with conditioning stimuli as within-participant factor gender as between-participant factor The male participantspresented a statistically significant decrease in ldquodeltardquo WDT during multisensory conditioning stimuli compared with light stimulus alone (P = 0019) or taste alone(P = 0003) Italics values indicate statistically significant P values (P lt 005)

Yang et al The Journal of Headache and Pain 2014 1571 Page 10 of 12httpwwwthejournalofheadacheandpaincomcontent15171

[47] Thus it seems reasonable to examine physiologicalarousal measurements related to affective reactions Skintemperature and heart rate are the most frequently usedphysiological expressions of affective state [47] Howeverin the present study these two parameters did not changesignificantly in response to changes in negative affectivestate by the different conditioning stimuli This is in linewith another study where it was demonstrated that theverbally reported affective experiences are not alwaysconsistent with the physiological parameters especially forunpleasant stimuli [47] On the other hand it may bebecause of the limited number of participants or that theapplied stimulus was inadequate for induction of a signifi-cant physiological change in arousal

Interactions between somatosensory sensitivity andconditioning stimuliThe perception of migraine headache which is mediatedby nociceptive signals is exacerbated by exposure to en-vironment stimuli ie light or noise which are mediatedby optical and acoustic signals Prolonged neuronal activa-tion during a migraine attack is thought to induce periph-eral and central sensitization along the trigeminovascularpathway which stands to explain the throbbing headache[48] accompanying scalp and neck-muscle tenderness[49] and whole-body cutaneous allodynia [50] Severaltheories exist which predict the relationship betweenconditioning stimuli and somatosensory sensitivity Todevelop a more comprehensive model of somatosensorymodulation by conditioning stimuli it may be useful toconsider a theory of ldquomotivational primingrdquo [9] It is pro-posed that affective state processing evoked by stimulicould be viewed as two opposing motivational systemsOne system is appetitive and produces approach behav-iors and the other system is aversive and promotes avoid-ance behaviors [9] Considerable evidence indicates thatprior activation of these systems modulates defensive be-haviors which facilitates somatosensory capability [51]These defensive behaviors increase in magnitude whenthe aversive system is primed by a negative affective stateie anticipation of shock [52] Conversely this defensive

response is inhibited when the appetitive system is primedby a positive affective state [53] According to the motiv-ational priming theory participants exposed to negativeaffective loading whose aversive systems are activatedshould get their perception facilitated [922] Howeversomatosensory sensitivity to thermal stimuli was not chan-ged during induction of negative affective states in thepresent study Another perspective on somatosensory andaffective processing is provided by the four-region neuro-biological model which indicates a complex relationshipbetween acute pain and simple emotion [54] For instancefear and pain sites overlap in the anterior midcingulatecortex (aMCC) and this region is involved in avoidancebehaviors posterior midcingulate cortex (pMCC) has noconsistent emotion activations yet has robust nociceptiveresponses subgenual anterior cingulate cortex (sACC) acti-vation during noxious stimulation of the skin and viscerain a person-specific manner the cingulate cortex is notuniformly involved in emotion and not all pain-activationsites are associated with affect or emotion [54]

ConclusionsThe three conditioning stimuli induced significantincreases in subjective rating and negative effectivescores accompanied with no physiological arousalchanges These stimuli did not however modulate skinthermal sensitivity The multisensory conditioning stimuliinduced stronger effects on subjective rating and negativeaffect than individual conditioning stimuli alone Theoften observed trigger or exacerbation of migraine byvisual auditory or gustatory stimuli may require a pre-disposed or sensitized nervous system

AbbreviationsMSI Multi-modal sensory integration IAPS Pictures of facial affect or theinternational affective picture system QST Quantitative sensory testingCDT Cold detection threshold WDT Warmth detection threshold CPT Coldpain threshold HPT Heat pain threshold PANAS Positive and negative affectschedule HR Heart rate EEG Electroencephalography aMCC AnteriorMidCingulate cortex pMCC Posterior MidCingulate cortex sACC Subgenualanterior cingulate cortex

Competing interestsThe authors declare that they have no competing interests

Yang et al The Journal of Headache and Pain 2014 1571 Page 11 of 12httpwwwthejournalofheadacheandpaincomcontent15171

Authorsrsquo contributionsYG recruited the participants carried out the study performed the statisticalanalysis and drafted the manuscript SP and BHL participated in the designof the study statistical analysis and revision of the draft XQ and WK helpedto draft and revise the manuscript All authors read and approved the finalmanuscript

AcknowledgementsWe are indebted to the subjects who participated in the study for theirconsent and co-operation This study was made possible by the supportsof Danish Dental Association

Author details1Department of Prosthodontics and Center for Oral Functional DiagnosisTreatment and Research Peking University School and hospital ofStomatology Zhongguancun Nandajie 22 100081 Beijing China 2Section ofClinical Oral Physiology Department of Dentistry Aarhus University AarhusDenmark 3Center for Sensory-Motor Interaction (SMI) Department of HealthScience and Technology Aalborg University Aalborg Denmark 4Departmentof Dental Medicine Karolinska Institute Huddinge Sweden

Received 28 August 2014 Accepted 28 October 2014Published 7 November 2014

References1 Goadsby PJ (2009) Pathophysiology of migraine Neurol Clin 27(2)335ndash360

httpdxdoiorg101016jncl2008110122 Judit A Saacutendor PS Schoenen J (2000) Habituation of visual and intensity

dependence of cortical auditory evoked potentials tends to normalize justbefore and during migraine attack Cephalalgia 20(8)714ndash719httponlinelibrarywileycomdoi101111j1468-2982200000122xfull

3 Schoenen J Wang W Albert A Delwaide PJ (1995) Potentiation instead ofhabituation characterizes visual evoked potentials in migraine patientsbetween attacks Eur J Neurol 2(2)115ndash122 doi101111j1468-1331

4 Wang W Schoenen J (1998) Interictal potentiation of passive ldquooddballrdquoauditory event-related potentials in migraine Cephalalgia 18(5)261ndash265doi101111j1468-298219981805261x

5 Stein BE Stanford TR (2008) Multisensory integration current issues fromthe perspective of the single neuron Nat Rev Neurosci 9(4)255ndash266doi101038nrn2331

6 Basura GJ Koehler SD Shore SE (2012) Multi-sensory integration inbrainstem and auditory cortex Brain Res 148595ndash107 httpdxdoiorg101016jbrainres201208037

7 Jain R Shore S (2006) External inferior colliculus integrates trigeminal andacoustic information unit response to trigeminal nucleus and acousticstimulation in the guinea pig Neurosci Lett 395(1)71ndash75 httpdxdoiorg101016jneulet200510077

8 Kawasaki A Purvin VA (2002) Photophobia as the presenting visual symptom ofchiasmal compression J Neuroophthalmol 22(1)3ndash8httpovidsptxovidcomsp-3131aovidwebcgiT=JSampPAGE=fulltextampD=ovftampAN=00041327-200203000-00002ampNEWS=NampCSC=YampCHANNEL=PubMed

9 Lang PJ (1995) The emotion probe Studies of motivation and attentionAm Psychol 50(5)372ndash385 doi1010370003-066X505372

10 Esslen M Pascual-Marqui RD Hell D Kochi K Lehmann D (2004) Brain areasand time course of emotional processing Neuroimage 21(4)1189ndash1203httpdxdoiorg101016jneuroimage200310001

11 Baumgartner T Esslen M Jaumlncke L (2006) From emotion perception toemotion experience emotions evoked by pictures and classical music Int JPsychophysiol 60(1)34ndash43 httpdxdoiorg101016jijpsycho200504007

12 Mitterschiffthaler MT Fu CH Dalton JA Andrew CM Williams SC (2007) Afunctional MRI study of happy and sad affective states induced by classicalmusic Hum Brain Mapp 28(11)1150ndash1162 DOI 101002hbm20337

13 Koelsch S (2010) Towards a neural basis of music-evoked emotions TrendsCogn Sci 14(3)131ndash137 httpdxdoiorg101016jtics201001002

14 Pepino MY Mennella JA (2005) Sucrose-induced analgesia is related tosweet preference in children but not adults Pain 119(1ndash3)210ndash218httpdxdoiorg101016jpain200509029

15 Horjales-Araujo E Demontis D Lund EK Vase L Finnerup NB Boslashrglum ADJensen TS Svensson P (2013) Emotional modulation of muscle pain isassociated with polymorphisms in the serotonin transporter gene Pain154(8)1469ndash1476 doi101016jpain201305011

16 Bushnell EW Baxt C (1999) Childrenrsquos haptic and cross-modal recognitionwith familiar and unfamiliar objects J Exp Psychol Hum Percept Perform25(6)1867ndash1881 doi1010370096-1523256

17 Longe SE Wise R Bantick S Lloyd D Johansen-Berg H McGlone F Tracey I(2001) Counter-stimulatory effects on pain perception and processing aresignificantly altered by attention an fMRI study Neuroreport 12(9)2021ndash2025httpovidsptxovidcomsp-3131aovidwebcgiT=JSampPAGE=fulltextampD=ovf-tampAN=00001756-200107030-00047ampNEWS=NampCSC=YampCHANNEL=PubMed

18 Rode S Salkovskis PM Jack T (2001) An experimental study of attentionlabeling and memory in people suffering from chronic pain Pain 94(2)193ndash203httpdxdoiorg101016S0304-3959(01)00356-6

19 McCaul KD Monson N Maki RH (1992) Does distraction reduce pain-produced distress among college students Health Psychol 11(4)210ndash217doi1010370278-6133114210

20 Rolke R Baron R Maier C Toumllle TR Treede RD Beyer A Binder A Birbaumer NBirklein F Boumltefuumlr IC Braune S Flor H Huge V Klug R Landwehrmeyer GBMagerl W Maihoumlfner C Rolko C Schaub C Scherens A Sprenger T Valet MWasserka B (2006) Quantitative sensory testing in the German ResearchNetwork on Neuropathic Pain (DFNS) Standardized protocol and referencevalue Pain 123(3)231ndash243 httpdxdoiorg101016jpain200601041

21 Yang G Luo Y Baad-Hansen L Wang K Arendt-Nielsen L Xie QF SvenssonP (2013) Ethnic differences in oro-facial somatosensory profiles-quantitativesensory testing in Chinese and Danes J Oral Rehabil 40(11)844ndash853doi101111joor12091

22 Meagher MW Arnau RC Rhudy JL (2001) Pain and emotion Effect ofAffective Picture Modulation Psychosom Med 63(1)79ndash90 httpwwwpsychosomaticmedicineorgcontent63179short

23 Danish volunteers recruit website for clinical research [wwwforsoegspersondk]24 Okamoto K Tashiro A Thompson R Nishida Y Bereiter DA (2012) Trigeminal

interpolariscaudalis transition neurons mediate reflex lacrimation evoked bybright light in the rat Eur J Neurosci 36(11)3492ndash3499 doi101111j1460-9568201208272x

25 Noseda R Kainz V Jakubowski M Gooley JJ Saper CB Digre K Burstein R(2010) A neural mechanism for exacerbation of headache by light NatNeurosci 13(2)239ndash245 doi101038nn2475

26 Sliney DH (1983) Standards for use of visible and nonvisible radiation on theeye Am J Optom Physiol Opt 60(4)278ndash286 httpovidsptxovidcomsp-3131aovidwebcgiWebLinkFrameset=1ampS=GDKPFPEIMNDDLJBJNCLKDFIBGENOAA00ampreturnUrl=ovidwebcgi3fMain2bSearch2bPage3d126S3dGDKPFPEIMNDDLJBJNCLKDFIBGENOAA00ampdirectlink=http3a2f2fgraphicstxovidcom2fovftpdfs2fFPDDNCIBDFBJMN002ffs0462fovft2flive2fgv0232f000004512f00000451-198304000-00003pdfampfilename=Standards+for+Use+of+Visible+and+Nonvisible+Radiation+on+the+Eyeampnavigation_links=NavLinksSsh421amplink_from=Ssh427c1amppdf_key=FPDDNCIBDFBJMN00amppdf_index=fs046ovftlivegv0230000045100000451-198304000-00003ampD=ovftamplink_set=Ssh42|1|sl_10|resultSet|Ssh4243|0

27 Rappaport SM (1993) Threshold limit values permissible exposure limitsand feasibility the bases for exposure limits in the United States Am J IndMed 23(5)683ndash694 doi101002ajim4700230502

28 Rhudy JL Meagher MW (2001) Noise stress and human pain thresholdsdivergent effects in men and women J Pain 2(1)64 httpdxdoiorg101054jpai200019947

29 Goldenberg AM Wexler LF (1988) Quinine overdose review of toxicity andtreatment Clin Cardiol 11(10)716ndash718 doi101002clc4960111012

30 Cardesiacuten A Alobid I Beniacutetez P Sierra E de Haro J Bernal-Sprekelsen MPicado C Mullol J (2006) Barcelona Smell Test - 24 (BAST-24) validation andsmell characteristics in the healthy Spanish population Rhinology 44(1)83ndash89httpwwwrhinologyjournalcomabstractphpid=556

31 Watson D Clark LA Tellegen A (1988) Development and validation of briefmeasures of positive and negative affect the PANAS scale J Pers SocPsychol 54(6)1063ndash1070 doi1010370022-35145461063

32 Crawford JR Herry JD (2004) The positive and negative affect schedule(PANAS) construct validity measurement properties and normative data ina large non-clinical sample Br J Clin Psychol 43(3)245ndash265 httpovidsptxovidcomsp-3131aovidwebcgiT=JSampPAGE=fulltextampD=ovftampAN=00002604-200409000-00003ampNEWS=NampCSC=YampCHANNEL=PubMed

33 Hsee CK Hatfield E Carlson JG Chemtob C (1990) The effect of power onsusceptibility to emotional contagion Cogn Emot 4327ndash340 doi10108002699939008408081

34 Doherty RW (1998) Emotional contagion and social judgment Motiv Emot22187ndash209 doi101023A1022368805803

Yang et al The Journal of Headache and Pain 2014 1571 Page 11 of 12httpwwwthejournalofheadacheandpaincomcontent15171

Authorsrsquo contributionsYG recruited the participants carried out the study performed the statisticalanalysis and drafted the manuscript SP and BHL participated in the designof the study statistical analysis and revision of the draft XQ and WK helpedto draft and revise the manuscript All authors read and approved the finalmanuscript

AcknowledgementsWe are indebted to the subjects who participated in the study for theirconsent and co-operation This study was made possible by the supportsof Danish Dental Association

Author details1Department of Prosthodontics and Center for Oral Functional DiagnosisTreatment and Research Peking University School and hospital ofStomatology Zhongguancun Nandajie 22 100081 Beijing China 2Section ofClinical Oral Physiology Department of Dentistry Aarhus University AarhusDenmark 3Center for Sensory-Motor Interaction (SMI) Department of HealthScience and Technology Aalborg University Aalborg Denmark 4Departmentof Dental Medicine Karolinska Institute Huddinge Sweden

Received 28 August 2014 Accepted 28 October 2014Published 7 November 2014

References1 Goadsby PJ (2009) Pathophysiology of migraine Neurol Clin 27(2)335ndash360

httpdxdoiorg101016jncl2008110122 Judit A Saacutendor PS Schoenen J (2000) Habituation of visual and intensity

dependence of cortical auditory evoked potentials tends to normalize justbefore and during migraine attack Cephalalgia 20(8)714ndash719httponlinelibrarywileycomdoi101111j1468-2982200000122xfull

3 Schoenen J Wang W Albert A Delwaide PJ (1995) Potentiation instead ofhabituation characterizes visual evoked potentials in migraine patientsbetween attacks Eur J Neurol 2(2)115ndash122 doi101111j1468-1331

4 Wang W Schoenen J (1998) Interictal potentiation of passive ldquooddballrdquoauditory event-related potentials in migraine Cephalalgia 18(5)261ndash265doi101111j1468-298219981805261x

5 Stein BE Stanford TR (2008) Multisensory integration current issues fromthe perspective of the single neuron Nat Rev Neurosci 9(4)255ndash266doi101038nrn2331

6 Basura GJ Koehler SD Shore SE (2012) Multi-sensory integration inbrainstem and auditory cortex Brain Res 148595ndash107 httpdxdoiorg101016jbrainres201208037

7 Jain R Shore S (2006) External inferior colliculus integrates trigeminal andacoustic information unit response to trigeminal nucleus and acousticstimulation in the guinea pig Neurosci Lett 395(1)71ndash75 httpdxdoiorg101016jneulet200510077

8 Kawasaki A Purvin VA (2002) Photophobia as the presenting visual symptom ofchiasmal compression J Neuroophthalmol 22(1)3ndash8httpovidsptxovidcomsp-3131aovidwebcgiT=JSampPAGE=fulltextampD=ovftampAN=00041327-200203000-00002ampNEWS=NampCSC=YampCHANNEL=PubMed

9 Lang PJ (1995) The emotion probe Studies of motivation and attentionAm Psychol 50(5)372ndash385 doi1010370003-066X505372

10 Esslen M Pascual-Marqui RD Hell D Kochi K Lehmann D (2004) Brain areasand time course of emotional processing Neuroimage 21(4)1189ndash1203httpdxdoiorg101016jneuroimage200310001

11 Baumgartner T Esslen M Jaumlncke L (2006) From emotion perception toemotion experience emotions evoked by pictures and classical music Int JPsychophysiol 60(1)34ndash43 httpdxdoiorg101016jijpsycho200504007

12 Mitterschiffthaler MT Fu CH Dalton JA Andrew CM Williams SC (2007) Afunctional MRI study of happy and sad affective states induced by classicalmusic Hum Brain Mapp 28(11)1150ndash1162 DOI 101002hbm20337

13 Koelsch S (2010) Towards a neural basis of music-evoked emotions TrendsCogn Sci 14(3)131ndash137 httpdxdoiorg101016jtics201001002

14 Pepino MY Mennella JA (2005) Sucrose-induced analgesia is related tosweet preference in children but not adults Pain 119(1ndash3)210ndash218httpdxdoiorg101016jpain200509029

15 Horjales-Araujo E Demontis D Lund EK Vase L Finnerup NB Boslashrglum ADJensen TS Svensson P (2013) Emotional modulation of muscle pain isassociated with polymorphisms in the serotonin transporter gene Pain154(8)1469ndash1476 doi101016jpain201305011

16 Bushnell EW Baxt C (1999) Childrenrsquos haptic and cross-modal recognitionwith familiar and unfamiliar objects J Exp Psychol Hum Percept Perform25(6)1867ndash1881 doi1010370096-1523256

17 Longe SE Wise R Bantick S Lloyd D Johansen-Berg H McGlone F Tracey I(2001) Counter-stimulatory effects on pain perception and processing aresignificantly altered by attention an fMRI study Neuroreport 12(9)2021ndash2025httpovidsptxovidcomsp-3131aovidwebcgiT=JSampPAGE=fulltextampD=ovf-tampAN=00001756-200107030-00047ampNEWS=NampCSC=YampCHANNEL=PubMed

18 Rode S Salkovskis PM Jack T (2001) An experimental study of attentionlabeling and memory in people suffering from chronic pain Pain 94(2)193ndash203httpdxdoiorg101016S0304-3959(01)00356-6

19 McCaul KD Monson N Maki RH (1992) Does distraction reduce pain-produced distress among college students Health Psychol 11(4)210ndash217doi1010370278-6133114210

20 Rolke R Baron R Maier C Toumllle TR Treede RD Beyer A Binder A Birbaumer NBirklein F Boumltefuumlr IC Braune S Flor H Huge V Klug R Landwehrmeyer GBMagerl W Maihoumlfner C Rolko C Schaub C Scherens A Sprenger T Valet MWasserka B (2006) Quantitative sensory testing in the German ResearchNetwork on Neuropathic Pain (DFNS) Standardized protocol and referencevalue Pain 123(3)231ndash243 httpdxdoiorg101016jpain200601041

21 Yang G Luo Y Baad-Hansen L Wang K Arendt-Nielsen L Xie QF SvenssonP (2013) Ethnic differences in oro-facial somatosensory profiles-quantitativesensory testing in Chinese and Danes J Oral Rehabil 40(11)844ndash853doi101111joor12091

22 Meagher MW Arnau RC Rhudy JL (2001) Pain and emotion Effect ofAffective Picture Modulation Psychosom Med 63(1)79ndash90 httpwwwpsychosomaticmedicineorgcontent63179short

23 Danish volunteers recruit website for clinical research [wwwforsoegspersondk]24 Okamoto K Tashiro A Thompson R Nishida Y Bereiter DA (2012) Trigeminal

interpolariscaudalis transition neurons mediate reflex lacrimation evoked bybright light in the rat Eur J Neurosci 36(11)3492ndash3499 doi101111j1460-9568201208272x

25 Noseda R Kainz V Jakubowski M Gooley JJ Saper CB Digre K Burstein R(2010) A neural mechanism for exacerbation of headache by light NatNeurosci 13(2)239ndash245 doi101038nn2475

26 Sliney DH (1983) Standards for use of visible and nonvisible radiation on theeye Am J Optom Physiol Opt 60(4)278ndash286 httpovidsptxovidcomsp-3131aovidwebcgiWebLinkFrameset=1ampS=GDKPFPEIMNDDLJBJNCLKDFIBGENOAA00ampreturnUrl=ovidwebcgi3fMain2bSearch2bPage3d126S3dGDKPFPEIMNDDLJBJNCLKDFIBGENOAA00ampdirectlink=http3a2f2fgraphicstxovidcom2fovftpdfs2fFPDDNCIBDFBJMN002ffs0462fovft2flive2fgv0232f000004512f00000451-198304000-00003pdfampfilename=Standards+for+Use+of+Visible+and+Nonvisible+Radiation+on+the+Eyeampnavigation_links=NavLinksSsh421amplink_from=Ssh427c1amppdf_key=FPDDNCIBDFBJMN00amppdf_index=fs046ovftlivegv0230000045100000451-198304000-00003ampD=ovftamplink_set=Ssh42|1|sl_10|resultSet|Ssh4243|0

27 Rappaport SM (1993) Threshold limit values permissible exposure limitsand feasibility the bases for exposure limits in the United States Am J IndMed 23(5)683ndash694 doi101002ajim4700230502

28 Rhudy JL Meagher MW (2001) Noise stress and human pain thresholdsdivergent effects in men and women J Pain 2(1)64 httpdxdoiorg101054jpai200019947

29 Goldenberg AM Wexler LF (1988) Quinine overdose review of toxicity andtreatment Clin Cardiol 11(10)716ndash718 doi101002clc4960111012

30 Cardesiacuten A Alobid I Beniacutetez P Sierra E de Haro J Bernal-Sprekelsen MPicado C Mullol J (2006) Barcelona Smell Test - 24 (BAST-24) validation andsmell characteristics in the healthy Spanish population Rhinology 44(1)83ndash89httpwwwrhinologyjournalcomabstractphpid=556

31 Watson D Clark LA Tellegen A (1988) Development and validation of briefmeasures of positive and negative affect the PANAS scale J Pers SocPsychol 54(6)1063ndash1070 doi1010370022-35145461063

32 Crawford JR Herry JD (2004) The positive and negative affect schedule(PANAS) construct validity measurement properties and normative data ina large non-clinical sample Br J Clin Psychol 43(3)245ndash265 httpovidsptxovidcomsp-3131aovidwebcgiT=JSampPAGE=fulltextampD=ovftampAN=00002604-200409000-00003ampNEWS=NampCSC=YampCHANNEL=PubMed

33 Hsee CK Hatfield E Carlson JG Chemtob C (1990) The effect of power onsusceptibility to emotional contagion Cogn Emot 4327ndash340 doi10108002699939008408081

34 Doherty RW (1998) Emotional contagion and social judgment Motiv Emot22187ndash209 doi101023A1022368805803

Yang et al The Journal of Headache and Pain 2014 1571 Page 12 of 12httpwwwthejournalofheadacheandpaincomcontent15171

35 Wild B Erb M Bartels M (2001) Are emotions contagious Evoked emotionswhile viewing emotionally expressive faces quality quantity time courseand gender differences Psychiatry Res 102109ndash124 httpdxdoiorg101016S0165-1781(01)00225-6

36 Surakka V Hietanen JK (1998) Facial and emotional reactions to Duchenneand non-Duchenne smiles Int J Psychophysiol 29(1)23ndash33 httpdxdoiorg101016S0167-8760(97)00088-3

37 Dimberg U (1988) Facial electromyography and the experience of emotionJ Psychophysiol 2(4)277ndash282 httppsycnetapaorgpsycinfo1989-28675-001

38 Altenmuumlller E Schuumlrmann K Lim VK Parlitz D (2002) Hits to the left flops tothe right different emotions during listening to music are reflected incortical lateralisation patterns Neuropsychologia 40(13)2242ndash2256httpdxdoiorg101016S0028-3932(02)00107-0

39 Krumhansl CL (1997) An exploratory study of musical emotions andpsychophysiology Can J Exp Psychol 51(4)336ndash353 doi1010371196-1961514336

40 Koelsch S Fritz T Cramon DY V Muumlller K Friederici AD (2006) Investigatingemotion with music an fMRI study Hum Brain Mapp 27(3)239ndash250doi101002hbm20180

41 Tillmann B Koelsch S Escoffier N Bigand E Lalitte P Friederici AD vonCramon DY (2006) Cognitive priming in sung and instrumental musicactivation of inferior frontal cortex Neuroimage 31(4)1771ndash1782httpdxdoiorg101016jneuroimage200602028

42 Janata P (2009) The neural architecture of music-evoked autobiographicalmemories Cereb Cortex 19(11)2579ndash2594 doi101093cercorbhp008

43 Drummond PD (1998) Sensitivity to light and noise in tension-type andcervicogenic headache Cephalalgia 18(6)303 doi101046j1468-298219981806303-2x

44 Miller A Barr RG Young SN (1994) The cold pressor test in childrenmethodological aspects and the analgesic effect of intraoral sucrosePain 56(2)175ndash183 httpdxdoiorg1010160304-3959(94)90092-2

45 Horjales-Araujo E Finnerup NB Jensen TS Svensson P (2013) Differentialeffect of visual and gustatory stimuli on experimental jaw muscle painEur J Pain 17(6)811ndash819 doi101002j1532-2149201200253x

46 Eldar E Ganor O Admon R Bleich A Hendler T (2007) Feeling the realworld limbic response to music depends on related content Cereb Cortex17(12)2828ndash2840 doi101093cercorbhm011

47 Aloui-Ismaili O Robin O Rada H Dittmar A Vernet-Maury E (1997) Basicemotions evoked by odorants comparison between autonomic responsesand self-evaluation Physiol Bebav 62(4)713ndash720 httpdxdoiorg101016S0031-9384(97)90016-0

48 Strassman AM Raymond SA Burstein R (1996) Sensitization of meningealsensory neurons and the origin of headaches Nature 384(6609)560ndash564doi101038384560a0

49 Burstein R Yarnitsky D Goor-Aryeh I Ransil BJ Bajwa ZH (2000) An associationbetween migraine and cutaneous allodynia Ann Neurol 47(5)614ndash624httpwwwresearchgatenetpublication12513142_An_association_between_migraine_and_cutaneous_allodynia

50 Burstein R Cutrer MF Yarnitsky D (2000) The development of cutaneousallodynia during a migraine attack clinical evidence for the sequentialrecruitment of spinal and supraspinal nociceptive neurons in migraineBrain 123(8)1703ndash1709 DOI 101093brain12381703

51 Crown ED King TE Meagher MW Grau JW (2000) Shock-induced hyperalgesiaIII Role of the bed nucleus of the stria terminalis and amygdaloid nucleiBehav Neursosci 114(3)561ndash573 httpdxdoiorg1010370735-70441143561

52 Greenwald MK Bradley MM Cuthbert BN Lang PJ (1998) Startlepotentiation shock sensitization aversive learning and affective picturemodulation Behav Neurosci 112(5)1069ndash1079 doi1010370735-704411251069

53 Vogt BA (2005) Pain and emotion interactions in subregions of thecingulated gyrus Nat Rev Neurosci 6(7)533ndash544 doi101038nrn1704

54 Vrana SR Spence EL Lang PJ (1988) The startle probe response a newmeasure of emotion J Abnorm Psychol 97(4)487ndash491 doi1010370021-843X974487

doi1011861129-2377-15-71Cite this article as Yang et al Effect of negative emotions evoked bylight noise and taste on trigeminal thermal sensitivity The Journal ofHeadache and Pain 2014 1571

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