1、Contact heat evoked potentials as a valid means to studynociceptive pathways in human subjectsAndrew C.N. Chen*, David M. Niddam, Lars Arendt-NielsenHumanBrainMappingandCorticalImagingLaboratory,TheInternationalDoctoralSchoolinBiomedicalSciencesandEngineering,CentreforSensoryMotorInteraction,Aalborg
2、University,FredrikBajerVej7,D-3,Aalborg9220,DenmarkReceived 9 August 2001; received in revised form 10 October 2001; accepted 10 October 2001AbstractContact heat evoked potentials (CHEPs) have been difficult to elicit due to slow temperature rise times. A recentlydeveloped heat-foil technology was u
3、sed to elicit pain and CHEPs. Two groups of subjects were separately stimulated atthe left arm with contact heat via one fast-acting (708C/s) heat-foil thermode. A set of CHEPs was recorded, each at threesubjective intensities: warm; slight; and moderate pain. In CHEPs, the 3D topography exhibited f
4、our components: T3T4/N450; Cz/N550; Cz/P750; and Pz/P1000. A vertex topography map was observed in the late Cz/N550Cz/P750 and parietaltopography in the very-late Pz/P1000 components. Consistent statistical values in the peak latencies and amplitudeswere noted between consecutive investigations. The
5、 correlation between the pain intensity ratings and the major Cz/P750 amplitudes was highly significant in each study. Our validity tests suggested CHEPs to be useful for research andclinical applications in studying human pain activation related to thermal and nociceptive pathways. q 2001 ElsevierS
6、cience Ireland Ltd. All rights reserved.Keywords: Contact heat evoked potentials; Pain perception; Late/very-late components; Consistency; Thin-fibre afferentAlthough heat pain examined by laser evoked potentials(LEPs) has been studied for 25 years 2,6, the coherentbeam and its small stimulation are
7、a (,5 mm diameter)may not constitute a natural activation as in contact heat.In addition, laser stimuli are too brief to simulate real lifeexperience of thermal pain, especially the nagging quality ofdeep pain associated with natural thermal injury. LEPs oftenconsist of late 3, and even ultra-late,
8、vertex potentials 1.Ultra-late LEPs, first found in a nerve block study 4, canbe obtained by a specially designed apparatus of tiny beam1, rectified cohesive beam 13 and a thin hole in metalfilm 16. Nevertheless, it is quite difficult to directly recordthe brain potentials of C-fibre thin afferents
9、by the availablelaser stimulation unless specific adjustment is implemented.One further drawback is that lasers often cause superficialburns lasting several days with hyper-pigmented spots. Thelaser apparatus is also expensive, and difficult to calibrateand operate.Contact heat can generally evoke b
10、oth fast and slow pain.However, due to its slow rising and falling times, the aver-aged evoked potentials to contact heat have rarely beenstudied. Here, we report a newly developed heat-foil witha rapid rising time at 708C/s to elicit contact heat evokedpotentials (CHEPs). The aims of this study wer
11、e to: (a),examine the 3D spatio-temporal dynamic topography ofCHEPs; (b), extract the major components in CHEPs; (c),relate these components to heat pain perception; and finally(d), investigate the consistency of CHEPs for potential usein clinical applications.CHEPs were recorded from two separate g
12、roups of 13(Study-I: age, 25.5 4.1) and ten (Study-II: age,26.8 5.2) males studied independently 2 months apart;informed consent was obtained from each subject. Contactheat was delivered via one 2 cm circular (3.14 cm2), fast-acting (708C/s), heat-foil thermode (Minco Products, Inc.,USA), which is a
13、 resistive heating element. Pulsed thermalstimuli were delivered by a computer-controlled stimulatorvia one thermode 12. Heat pulses were sent from the base-line (adaptive temperature, 31.58C) using an adjustablepower for 300 ms at three intensity levels (Fig. 1).The stimuli were applied within the
14、volar surface of theforearm in the left hand. The subject could withdraw hishand if the stimulus was intolerable. The subject wasinstructed to move the arm and area of thermode contactNeuroscience Letters 316 (2001) 79820304-3940/01/$ - see front matter q 2001 Elsevier Science Ireland Ltd. All right
15、s reserved.PII: S0304-3940(01)02374- Corresponding author. Tel.: 145-9635-9826; fax: 145-9815-4008.E-mailaddress: acsmi.auc.dk (A.C.N. Chen).slightly between stimuli to avoid potential sensitization ofthe skin or receptor fatigue. In five ascending and descend-ing trials, each of three pre-fixed sti
16、mulus levels was ratedon a 010 point scale (defined below). These thermal levels(temperatures: 41.0, 49.5 and 54.58C) were then used forrecording of CHEPs. Between each series of CHEP record-ings at a constant stimulus temperature, the subject had a 5min break. Forty repeated trials of thermal stimu
17、li, with amean inter-stimulus interval of 10 s (random 812 s), at thesame stimulus intensity were presented to the subjects forrecording of CHEPs. The subject rated each stimulationverbally 5 s after each trial of the stimulation on a 010scale. The corresponding intensities were: 0, no pain; 1,sligh
18、t intense; 2, mild intense; 3, moderate intense; 4, slightpain (pain threshold); 5, mild pain; 6, moderate pain; 7,moderatestrong pain; 8, strong pain; 9, severe pain; 10,unbearable pain.Electrodes were placed in accordance with the extended1020 International System, and two extra electrodes (C30and
19、 C40) were placed about 1 cm posterior to C3 and C4,respectively. The EEGs were recorded from 32 surface elec-trodes (including one electro-oculogram) mounted on thescalp using a standard EEG-cap and referenced to bilateralearlobes (A1/A2). The impedance of the electrodes was keptbelow 5 kV. The EEG
20、 signals were sampled at 250 Hz withbandpass (0.1550 Hz). EEG activity was sampled for 512ms before and 2048 ms following the onset of each series ofstimuli. Baselines were computed for the time interval 50ms before stimulation and subtracted prior to averaging.However, the CHEPs were triggered by s
21、timulus offset toexclude the occasional stimulus artefacts generated fromamplifier saturation. Also, the use of stimulus offset wasdeemed necessary due to the 300 ms stimulus pulse durationrequired to induce noxious sensation. Nevertheless, peaklatencies were adjusted to the stimulus onset for repor
22、ting.Each epoch was checked for eye-movement and blink arte-facts, and rejected if any were found. Valid epochs of the 40repeated sweeps were averaged within each stimulus inten-sity before grand mean averaging.For each averaged CHEP, global field power 10 analysiswas conducted to measure the time w
23、indow where signifi-cant brain activation could be isolated. The electrode siteclosest to the identified peak extreme was selected for peakdetection within each of the isolated windows. CHEPs fromall 31 electrodes were displayed as topographic maps usinga double-spline interpolation (ASA Software, A
24、NT A/S, theNetherlands). Peak latencies and amplitudes were subjectedto repeated measure analysis of variance (ANOVA) withinthe group and mixed measure ANOVA for between groupcomparison.A systematic effect between stimulus intensities and painratings was observed. The two groups showed nearly iden-t
25、ical rating patterns (Table 1). In CHEPs, the prominentactivation resided at the vertex and its vicinity. Similarvertex waveforms were observed across both groups fornon-painful and painful intensities (Fig. 2).At the low stimulus intensity, only a shallow, very-latepositive wave was observed at the
26、 vertex Cz site. In contrast,four clear peaks were identified and isolated at painfullevels. These were T3/N450, Cz/N550, Cz/P750 and Pz/P1000. There were no statistical differences betweenStudy-I and Study-II in peak latencies and amplitudes forthe isolated components (Table 1). The mean and deviat
27、ionvalues were very similar between these two independentgroups.For the grand averages in Study-I and Study-II, Fig. 3illustrates the 3D topographic maps at the moderate pain(I-6) intensity. Comparing these two independent groups,A.C.N.Chenetal./NeuroscienceLetters316(2001)798280Fig. 1. Dynamics of
28、the temperature ramp measured in the ther-mode at three intensities corresponding to pain levels at: I-2,non-painful, warm; I-4, slight pain; and I-6, moderate pain. Thepeak temperature was reached 360 ms after the offset of stimu-lus pulse (300 ms duration). A fast-acting temperature ramp at708C/s
29、is the unique feature in inducing synchronized neuralactivation for recording sharp CHEPs.Table 1Pain ratings and peak CHEP amplitudes: consistency in twogroupsaI-2 I-4 I-6PainratingbStudy-I 0.8 0.5 2.7 0.9 5.9 1.0Study-II 2.2 0.2 2.7 1.5 5.5 1.3CHEPpeakamplitudescT3/N450Study-I 2 0.2 1.4 2 0.4 1.9
30、2 0.2 1.5Study-II 2 0.3 2.2 2 0.1 2.1 2 1.2 2.3Cz/N550Study-I 2 0.4 2.3 2 0.5 2.1 2 6.0 5.1Study-II 2 0.5 2.1 2 1.4 1.1 2 7.4 3.2Cz/P750Study-I 1.3 2.7 3.2 2.9 13.3 4.5Study-II 0.7 2.2 2.1 2.0 15.1 6.2Pz/P1000Study-I 2.6 2.7 4.1 3.2 6.2 3.8Study-II 1.7 2.8 3.6 2.2 7.0 4.1aStimulus: I-2, non-pain, wa
31、rm; I-4, slight pain; I-6, moderatepain.bPain rating (010 scale): mean SD.cAmplitude (mV): mean SD.similar 3D topographic maps were observed in these lateand very-late components (Fig. 3). The correlation betweenthe pain ratings and the Cz/P750 amplitudes over threeintensities were found to be highl
32、y significant (P , 0:001)in both groups (r 0:71; r 0:80), as were the pain ratingsand Cz/N550 amplitudes (negative correlation, r 20:83;r 20:81), but not others. In addition, similar rate effects(slopes) were noted for the amplitude/pain relations.Contact heat exhibits several characteristics of uni
33、quequality for pain research. It activates thin-fibre noxious ther-mal afferents, in the C-fibre range, in addition to mechano-thermal A-delta fibres. It elicits diffused nagging pain at asufficient intensity. Sometimes, it can produce double painsensations: first, pain of sharp quality; and second,
34、 pain ofdull quality 11,14. Our consistent reports from two inde-pendent groups/studies strongly confirm the reliability inelicitation of quantitative CHEPs, and thus show applicabil-ity for routine clinical use. The reliability of the CHEPs iscomparable with that reported in repeated measures of LE
35、Ps9. In addition, the validity of CHEPs is strengthened byour findings of a close association between the pain ratingsand the brain responses at the vertex Cz/P750 componentand its proceeding Cz/N550 component. The high correla-tion of the late/very-late component and pain perception isreminiscent o
36、f that in LEP also 5.A recent publication on CHEPs using a 2000 ms durationof thermal pulse showed recognizable vertex brain poten-tials 7. Limited topographic waveform distribution wasshown in that paper. In our CHEPs to painful stimulation,we observed four major components in 3D topography: T3/N45
37、0; Cz/N550; Cz/P750; and Pz/P1000 (Fig. 3). OurCHEPs at the non-painful intensity produced no specificpeak component, which is similar to the absence of thefirst positive peak from the recent report 8. This was attrib-uted to a lack of synchronized activation of warm and/orlow threshold mechanotherm
38、al afferents at the adaptingtemperature intensity of 398C. At painful intensities, weobserved a temporal T3/N450 component, followed by avertex Cz/N550 component. This vertex N550 componentmay correspond to the reported first peak of 500 ms inA.C.N.Chenetal./NeuroscienceLetters316(2001)7982 81Fig. 3
39、. 3D topography of CHEPs at the moderate pain level (I-6)for both Study-I and Study-II. The head model is oriented in asuperioranterior view of the right hemisphere (nose down)perspectives. Discernible focal maxima identified are: T3/N450;Cz/N550; Cz/P750; and Pz/P1000. Similar topographies arelarge
40、ly demonstrated in both Study-I and Study-II. (Lowerpanel) EEG montage labels.Fig. 2. Vertex waveforms in relation to stimulus heat energylevels (I-2, I-4, I-6). Systematic increase in relation to increaseof energy levels was noted, and the results also demonstratedthe consistency between Study-I (d
41、ark) and Study-II (grey).Prominent vertex components are marked: Cz/N550; Cz/P750;and Cz/P1000 at I-6 (moderate pain level).CHEPs induced at a temperature of 458C 7. At a painfulintensity of 528C, a second peak was also reported around1000 ms 7, as seen in our Pz/P1000 component. Incontrast, only a
42、very-late component at 830 ms was reportedfollowing stimulus onset to arm stimulation for the contactheat evoked response 8. This very-late positive vertexpeak may correspond to our Cz/P750 component. Thesmall discrepancy of peak latencies observed might bedue to the difference in study apparatus an
43、d stimulus para-meters.Possibly due to a lack of synchronization from peripheralvolley in receptor activation or cortical responses, noprimary somatosensory activation would be noted. Thefirst discernible volley can be observed at the temporalarea, which is likely to reflect the initiation of the se
44、condarysomatosensory (SII) activation, and is then followed 100 mslater by a probable bilateral SII activation with a focalvertex maxima as the Cz/N550 component. A furtherprocessing, 200 ms later, reflected as the large vertex posi-tive wave may index the deep generator from the posteriorcingulus c
45、ortex as the scalp Cz/P750 component. Finally,the very-late component shown as the scalp Pz/P1000 wavemay reflect a late processing of the parietal cortex innoxious somatosensory information. The neuropsychologi-cal sequence in CHEPs is similar to that of LEPs 6.The late Cz/N550 component may be in
46、association withA-delta fibre activation since its conduction velocity hasbeen estimated at 10 m/s 7. The very-late Pz/N1000component at 8001000 ms may be in association with C-fibre activation with the conduction velocity estimated at 23 m/s for the ultra-late component at 10001500 ms 13,16.Thus, t
47、he isolation of late Cz/N550 and very-late Pz/P1000components may allow to infer the integrity of A-delta andC-fibre peripheral afferents and could be useful for furtherevaluation of the clinical pathophysiology associated withthin-fibre alteration in patients and neuropathic pain 15.This study was
48、supported by funding from the DanishNational Research Foundation.1 Bragard, D., Chen, A.C.N. and Plaghki, L., Direct isolation ofultra-late (C-fibre) evoked brain potentials by CO2laserstimulation of tiny cutaneous surface areas in man,Neurosci. Lett., 209 (1996) 8184.2 Bromm, B. and Lorenz, J., Neu
49、rophysiological evaluation ofpain, Electroenceph. clin. Neurophysiol., 107 (1998) 227253.3 Bromm, B. and Treede, R.D., Laser-evoked cerebral poten-tials in the assessment of cutaneous pain sensitivity innormal subjects and patients, Rev. Neurol., 147 (1991)625643.4 Bromm, B., Neitzel, H., Tecklenburg, A. and Treede, R.D.,Evoked cerebral potential correlates of C-fibre activity inman, Neurosci. Lett., 43 (1983) 1091
