Brain evoked potentials are functional correlates of induced pain in man

Pain; 6(1979) 365--374 © Elsevier/North,Holland Biomedical Press

365

BR~N EVOKED POTENT~S OF INDUCED P~ IN M A N

ARE FUN~IONAL

ANDREW

CHAPMAN

C.N, C H E N *, C, R I C H A R D

CORRELATES

and S T E P H E N W. H A R K I N S

(A.C;N.C) Department o f Anesthesiology, (CR.C.) Departmerts of Anesthesiology, Psychia~ and Behavioml Sciences, and Psychology, University of Washington, Seattle, Wash. 98195 and (8. W,H.) Departments of Psychiatry and Behavioral Sciences, Anesthesiology, University o f Washington, and Veteran "sAdministration Medical Center, Seattle Wash. (U.S.A,) (Accepted February 23rd, 1979)

SUMMARY

Electrical potentials evoked by 5 intensitiesof painful dental stimulation were recorded at the scalp. During testing, volunteers indicated subjective painfulness b y verbal pain ratings and visual analogue scales. Evoked potentials (EPs) to each intensity, observed between 50 and 400 msec, were characterized by 4 waveform components. The peak-to-peak amplitudes, but not the peak latencies,of all 4 EP components systematically increased with increased stimulation. The amplitudes of the two earliercomponents correlated with stimulus intensity when the effect of subjective painfulnes~ was controlled, but this was not the case for the later components. In contrast, the amplitudes of the two later components were a~sociated with subjective painfulness but not with stimulus intensity. A strong linear relationship was observed between subjective painfulness and peak-to-peak amplitude for the EP componen1~ observed between 175 and 260 msec. The data suggest that the earlierEP cumponents may reflectsensory transmission processes while the later components indicate brain activity when pain is perceived. INTRODUCTION

Quantification of laboratory induced pain has been hindered by a lack of objective measures of the pain experience, and attempts to measure pain by recording physiologic variables have been considered unsuccessful. Hilgvxd a n d Hilgard [16], after reviewing measures of autonomic nervous system responses:to painful stimulation, concluded that no single, physiological measure provides an lemd 0fpain. ~*:Address!:~¢orrespbndence; to:- Andrew: C.N.:Chen, Department of Anesthesiology, BB1411, HSB RN:10~ Universityof Washington, Seattle, Wash. 9S 195, U.S.A.

366

Recently, brain electrical potentials evok.~l by noxious laboratory stimulation have been explored as possible correlates of human pain. Evoked I

stimulation [4]. Because the EP to dental electrical shock is absent when there is congenital insensitivity to pain [ 8], and because it can be eliminated in nozrnal volunteers b y local nerve ~block [13], the d e n ~ EP appears to reflect p ~ experience. Observed alterations~ insomatosensory and dental EP waveform amplitudes as a function of variousanalgesiC t r e a t m e n t s [2,5,10,20, 21,26,29] suggest t h a t E P s may provide sensitive measures of central nervous system reactivitytolaboratory induced noxious ewvts, Following an overview of the literature from several laboratories on EPs to painful stimulation, Chapman et al. [7] noted that there were: (1) similarities in the gross general EP morphologies despite differences in stimulation modality, recording procedure, and other methodological detail, (2) substantial similaritiesin the latencies of major peaks in all of the EP components observed by different laboratories, and (3) changes in amplitude but not in latency across laboratories when stimulus intensity level was varied. In all labolatories a large positive,component observed a~; approximately 160 ..... 260 msec has appeared consistently in response to noxious stimulation, and this component has been reduced in amplitude by a variety of pain modulating treatments that have been introduced in experiments. If measures of EP amplitude beyond 80 msec are to be ur~ful as correlates of pain, the relationship of these measures to subjective report indices must be more clearly specified. ~he purpose of this paper m to examine changes in EP waveform component amplitudes when the intensitiesof painful stimuli are varied and to determine the reiationships among stimulus intensity, subjectivejudgments of pain, and measures of the EP. METHOD

Subjects Ten male students, aged 24--28 years, served as paid volunteers. Before testing, subjects were given a training session involving familiarization with the stimulation procedure, the dental stimuli and the recording equipment. Subjects were informed of the general goal of the study and all signed institutionally approved informed consent agreements,

Testing and recordingprocedure For each voltun~eer, a healthy, unfilled central incisor was stimulated electrically to produce pain. This procedvre has beenused extensively by ourselves and oth~.rs fnr ]Ahnr~tnrvi rl~ln~dm ~trv: r:l Ig~.9.9. ~:~~: •Th~ ~,-hlp~t ~~s~ seate~ relax via a

367

in a plastic holder which was hand-held by the subject. Quality of contact between the stimulating cathode and the tooth was ensured by monitoring the stimulus waveform on an oscilloscope. The anodal electrode was taped on the left zygomat~c arch. The intensities of stimuli were determined by displayingthem on a calibrated oscilloscope. The recording ~leads for the ~electroencephalogram (EEG) were fixed with collodion at vertex (Cz) and at inion (Or)according to the International 1020 System [18]. A ground electrode was placed on the right zygomatic arch. Electrode resistances were maintained below 3 k~. • T h e electrical stimulus w a s produced by a Grass S-44 stimulator with modified constant current and isolation units. A fail-safe circuit was built into the apparatus to protect the subject from any possibility of excessive stimulation. The E E G was amplified using an isolation pre-amplifier (Model 227J), which was fed directly into a Nicolet 1072 signal averager (system gain 103). Input range on the signal digitizer (Nicolet SD-72/4A) was at +1 V with a filter time constant of 20 msec, resulting in an effective bandwidth of 0.5--15 Hz. The E E G was monitored on an oscilloscope and EPs were edited if artifacts were present. EPs were recorded via an X-Y plotter for subsequent analysis. The dental electrical stimuli consisted of single square wave pulses of 5 msec duration, delivered manually by the experimenter w h o pressed a hand-held trigger for each stimulus. Stimulus deliver#, was intentionally irregular so that expectancy could not contaminate measurement. The interstimulus interval was in the range of 2--6 sec with a mean of approximately 4 sec. Pauses of several seconds were occasion~ly introduced to allow subjects to blink. Shock levels in microamps necessary to elicit the judgments of "very faint sensation" and "strong pain" were recorded from 2G ascending trials (method of limits). Pain range was determined by subtracting the value of the stimulus judged to be a "very faint sensation" from the value of that judged to be "strong pain". The pain range interval was then used to determine 5 stimulus intensity values which were used for elicitingthe EPs. The 5 intensities consisted of "very faint sensation" and "strong pain" dental shock levels as the extreme values with 3 other experimenter~hosen values selected to be equi
368

EP:waveform for each of the 5 stimulus intensities was plotted ~ d quart, tiffed, ::Thus, 5 recordings were o b t ~ n e d from each s u b j ~ t , o n e for each of the stimulus intensities. Subjects received the 5 intensi~ies in an order determined, by a pseudorandom schedule.: .... ~ t w e e n sets of 6 4 trials, :as welt as ::~n: intensity: ~ d pain aversiveness ~estimates: u s i n g : ~ u a l ~ ~ e scales. : ...... Data analysis • A single group randomized block design with repeated measures was used for data analyses. T h e category ratings for each of the 5 stimuli were analyzed by Kendall's Coefficient of Concordance [ 19] in order to assess the internal consistency of pain ratings given by the subjects to the different stimuli. Visual analogue scales were scored in millimeters and subjected to an-,dysis of variance as were the amplitude and latency of each major waveform component. RESULTS

Subjective assessment o f painful tooth shocks There was a significant rank order correlation between stimulus intensity level and subjective category judgment of reported sensations (Kendall Coefficient of Concordance = 1.00, P < 0.001). All subjects were able to discriminate the, stimuh~ levels from one another perfectly, but as Table I indicates, labeling of the 5 intensities by the different subjects was variable. There was somewhat less agreement in grading the subjective sensations at lower levels of stimulation as compared to intensities above 34 #A where the sensory judgments were always moderate pain and strong pain for all subjects. A strong linear relationship was observed between mean visual analogue scale values of judged pain intensity and those of pain aversiveness (r = 0.90).

TABLE I U S E O F R A T I N G S C A L E CA"P~GORIES B Y S U B J E C T S (N = I0) Stimulus inter.aity(~A) (mean +-S.D.) 9 . 6 +- 5 . 4 4

1 7 . 5 +- 6 . 6 7

26.0 + 10.37

3 4 . 0 +- 1 3 . 7 7

4 2 . 0 +- 1 7 . 1 7

8 Mi.P 2 Mo.P

i0 Mo.P~

10 SP

Number of subjects using each category

7 VFS 3 VFP

4 VFP 5 FP 1 Mi.P

369 |00

N|75 STIMULATION /'~

cJs~

! I

N=~^

40 20 0

9.6 IZ.5 26D 34.0 42.0

DENTAL STIMUIJ./$ (#A)

i/

l:.,v

PL:~O .__b__ +

Fig. 7, Relation,'hip between subjective painfulness and dental stimulus intensity. Fig. 2. A typica! brain potential evoked by painful dental stimulation. Negative polarity is upward and positive polarity is downward. Each peak is identified by its r, olarity and latency (in rose,- after the stimulus onset).

Because of this high correlation, the intensity and the aversiveness visual analogue scales were combined to yield a single sc~e of subjective painfulness. Fig. 1 presents mean subjective painfulness changes over stimulus levels. Analysis o f variance revealed significant differences in the mean subjective painfulness scores across stimulus intensities F (4,36) = 133.88, P < 0.001. A test for linear trend [12] also yielded significance F (4,36) = 493.13, P < 0.001.

Relationship of EP amplitudes to subjective painfulness An example of the dental EP is illustrated in Fig. 2. This waveform represents 192 trials for a single subject delivered at a level judged to be strong pain. The EP is comprised of a series of positive and negative components labeled in this figure according to polarity and peak latency [11]. For subsequent data analyses peak latencies were computed at the point where the individual waveforms began a sharp, smooth change in polarity. Amplitude was quantified by peak-to-peak measurement. Peak latencies of the EP components were not affected by the dental shock intensities. Table II list~ the mean EP latencies across stimulus levels. Peak-to-peak vmplitude increased with stimulus intensity for all components as shown h~ Table HI. Trend analysis revealed significant linearity in peak-to-peak amplitude over stimulus levels for each component, except P26o-'N34o.

Correlation analyses were used to explore the relationships among stimuhis intensity level, peak-to-peak amplitudes of the 4 EP components and subjective painfulness scores. The goal was to determine whether stimulus inLensity level, subjective painfulness values, or a combination of both, could b e s t a c c o u n t for. the various EP amplitudes. Table IV lists the Pearson product m o m e n t correlations. The correlation of subjective painfulness and stimulus intensity was r = 0.68.

370 TABLE II MEAN PEAK EP LATENCIES (msec) OVER 5 SHOCK INTENSITIES Stimulus (/JA)

Peak ',.... :'~: ~:~'

N6s~

P I~o

NiTs

P26o

N34o 324,8 338.2 349.2 • 346.2 351.2

9.6 17.5 26.0 34.0 42.0

59.6 64.0 63.4 63.4 65.4

113,9 131;5 119,3 116.9 112.6

179.7 180.2 176.2 171.2 176.2

259,6 252.2 258.1 265.8 265.0

S.D.

6.4.6 24 6

120.8 23.2

176.6 25.0

260.2 26.1

~

341.8 31.3

T a b l e IV s h o w s t h a t s u b j e c t i v e p a i n f u l n e s s v a l u e s c o r r e l a t e d p o s i t i v e l y a n d significantly with peak-to-peak amplitudes of EP components. Stimulus i n t e n s i t y levels also: :c o r r e l a t e d p o s i t i v e l y a n d s i g n i f i c a n t l y w i t h c o m p o n e n t a m p l i t u d e s a t all s t i m u l u s levels e x c e p t t h e a m p l i t u d e o f P~20--Nlvs c o m p o nent, In order to determine whether the4 EP amplitude measures reflected p r i n c i p a l l y s u b j e c t i v e p a i n f u l n e s s o r t h e s t i m u l u s i n t e n s i t y level, w e a p p l i e d p a r t i a l c o r r e l a t i o n a n a l y s e s [ 2 5 ], T h e s e t e c h n i q u e s c a n b e u s e d t o a r r i v e a t a correlation between two variables when the influence of a third variable that c o r r e l a t e s w i t h b o t h is h e l d c o n s t a n t ( p a r t i a l e d o u t ) . P a r t i a l i n g o u t s u b j e c t i v e painfulness, we observed significant positive correlations between stimulus

TABLE III PEAK-TO-PEAK AMPLITUDE (pA) OVER 5 SHOCK INTENSITIES Stimulus (pA)

9.6 17.5 26.0 34.0 42.0

(VFS) (FP) (Mi.P) (Mo.P} (SP)

Amplitudes

N6 s--P120

Pl 2o--Nt 7s

Ni ~s--P260

P260--P340

1.82 2.98 3.09 4.26 4.66

1.62 2.64 2.80 3.21 3.82

2.15 3.29 4.01 5:03 6.36

1.21 2.49 2.32 3.31 5.13

+- 1.88 ± 1.87 ± 1.84 +- 2.33 ± 3.58

+- 1.60 ~- 1.47 ± 2,08 +- 2.19 ± 2.46

Statistical significance across levels ( d r = 4, 36)

F = 4.24 P < 0.01

F = 5,07 P < 0.0]

Linearity ( d f = 4, 36)

F = 4.50 P < 0.01

± 0.96 -~i.15 +- 1.35 +: 2.03 ± 1.96

~ 0,57 ± 1.70 ± 1.61 ~- 2.01 ± 2.21

F = 18.82 P < 0.001

F = 14.31 P < 0.001

F = 4.55

F

F = 2.78

F < 0,01

P

371

T A B L E IV R E L A T I O N S H I P O F EP A M P L I T U D E T O S T I M U L U S I N T E N S I T Y A N D S U B J E C T I V E PAINFULNESS Component

Correlation of EP amplitude

N6$--PI20

Pl20--NlTs

NITs--P260

P260--N340

0.44 **

0.31 **

0.67 ***

0.63 ***

0.49 * * *

0.02

0 . 3 8 **

0.38 **

0.44 * *

0.55 * * *

with subjective painfulness Correlation of EP amplitude

with stimulus intensity Correlation of amplitude

--0.11

--0.15

with stimulus intensity w h e n subjective painfulness is p a r t i a l e d out Correlation of amplitude with ~=,bjective p~ in-

0.26

--0.39 **

0.61 * * *

0.81 * * *

fulness when stirr,ulus intensity is partia~ed out * * P < 0.01. *** P < 0.001.

intensity level and peak-to-peak amplitude for the earliest 2 of the 4 EP components. For the later 2 components there was no relationship between component amplitude and stimulus intensity when subjective painfulness was partialed out (Table IV, row 3). In contrast, the correlation between peak-to-peak amplitude and subjective painfulness with stimulus intensity partialed out was positive and significant for the latter 2 of the 4 components. No significant relationship between peak-to-peak amplitude and subjective painfulness was evident at N6s'-Pl20, but at Pl20- Nl~s a significant negative relationship was observed. That is, when the influence of stimulus intensity was removed, the data revealed a tendency for increases in subjective painfulness scores to be associated with smaller peak-to-peak amplitudes (Table IV, row 4). The surprising lack of correlation between P12o--NlTs and stimulus intensity evident in the second row of Table IV appears to be due to the influence of subjective painfulness which is negatively correlated with waveform amplitude. When this influence was removed a high positive correlation emerged, as is e v i d e n t i n r o w 3 , column 2, of Table IV. Fig. 3 describes the relationship between subjective painfulness values and peak,to-peak amplitudes f o r t h e two later components. It is evident that component amplitude is linearly related to subjective pain intensity and that the slope of the line of best fitis nearly the same for the two components. Thepartial~:c0~elati0n analyses clearly demonstrate that the two earliest components o f ~the E P : a r e closely related t o the physical intensity of the dentalstimulus while the latter two components are independent of stimulus

372 ~-.-A

NI75--~60 SP

~" s .S

6

.r. ~ .~'

5 ~.. j.o j o ~,A

"-

y

2

I0

20

~

40

50

60

70

SUBJECTIVE PA/NFULNESS

Fig. 3. Functional relationship between amplitude of brain evoked potential and subjective painfulness. For the two late components linear regression indicated that~ Ya = 1.08 + 0.05X and Yb = 2.33 + 0.05X. where Ya is the amplitude of N175--P260, Yb is the amplitude of N260--P340, and X is subjective painfulness assessed by visual pain analogues. Pearson product m o m e n t correlations demonstrated significant (P < 0.001) relationships between amplitudes and subjective painfulness (rya x = 0.63; ryb X = 0.65). The identical effective coefficient, i.e. 0.05, in both regression lines suggests that both amplitudes increased at an equal rate as a function of subjective painfulness.

intensity and are highly correlated with subjective painfulness, or subjective appreciation of pain. DISCUSSION

The E P to painful dental stimulation was observed to be a complex waveform characterizedby amajor negativepeak at175 msec anda positive~eak at 260 msec. W h e n stimulus intensity was varied,~the amplitudes of all 4 components of the waveform changed, but latenciesremained invariant. These observations replicate those previously reported by Harkins and Chapman [15] and are consistent with reports from several other laboratories [ 4,9,27 ]. Partial correlation analyses revealed that the EPwaveform reflects both information transmission and subjective appreciation of painful stimulation. The first two waveform components, N'2.- P120 and P120--N~Ts,correlate with stimulus intensity and appear t o code ir-~ormation about intensity of external st~ulation. The latter two components are closely related t o subjective estimation of pain intensity~ and see~\a t o reflect association processes • . ¥~ . . . . . . . . . revolved m e ~aluatlonof t h e n o m o u s stimulus, :~: O u r findings clearly:: suppo~:~ th m e a s u r e : o f the pain:experience problem :~_mpeding progress i n t h e development o f t h e EP for measurement

373 applications is t h e lack o f a clear definition for pain. C o n t e m p o r a r y theorists agTee t h a t pain is a c o m p l e x psychological experience involving n o t o n l y sensory i n f o r m a t i o n transmission b u t also e m o t i o n a l arousal a n d cognitive i n t e r p r e t a t i o n . EP c o m p o n e n t a m p l i t u d e s are a l m o s t certainly an oversimplification o f t h i s experience, bin: t h e y m a y provide valuable ways o f evaluating c e r t a i n a s p e c t s o f t h e p e r c e p t u a l processes associated with pain. Our findings suggest t h a t t h e NITs--P260 a n d P26o--N34o c o m p o n e n t s o f t h e EP waveform m a y reflect the cognitive aspects o f l a b o r a t o r y dental pain perception. The observation t h a t early EP c o m p o n e n t s reflect i n f o r m a t i o n transmission while later c o m p o n e n t s reflect psychological evaluation processes roughly parallels t h e distinction b e t w e e n p e r c e p t u a l capability (d') and decision criterion (beta) in sensory decision t h e o r y p s y c h o p h y s i c a l w o r k [ 14]. The relationship of EP changes t o p s y c h o p h y s i c a l p e r f o r m a n c e [17] clearly warrants f u r t h e r e x p l o r a t i o n . ACKNOWLEDGEMENTS We t h a n k Ms. Y o k o Hiraga for assistance in p r e p a r a t i o n of figures and in editorial support. T h i s research was s u p p o r t e d b y N I D R G r a n t D E 0 4 0 0 4 - 0 2 f r o m t h e National Institutes of Health. REFERENCES 1 Azerad, J. and Woda, A., Sensatmn evoked by bipolar intrapulpar stimulation in man, Pain, 4 (1977) 145--152. 2 Blair, R.D., Dorsal column stimulation: its effect on the somatosensory evoked response, Arch. Neurol. (Chic.), 32 (1975) 826--829. 3 Buchsbaum, M. and Silverman, J., Stimulus intensity control and the cortical evoked response, Psychosom. Med., 30 (1968) 12--22. 4 Cartoon, A., Mor, J. and Goldberg, J., Evoked cerebral responses to noxious thermal stimulation in humans, Exp. Brain Res., 25 (1976) 103--107. 5 Chapman, C.R., Benedetti, C. and Butler, S.H., Cerebral response measures of stimulation-induced and opiate-induced analgesia in man: attempted analgesia reversal with narcotic antagonist. In: D.J. Anderson and B. Matthews (Eds.), Pain in the Trigeminal Region, Elsevier, Amstei~dam, 1977, pp. 423--433. 6 Chapman, C.R, Chen, AC. and Bonica, J.J., Effects of intrasegmental electrical acupuncture on dental pain: evaluation by threshold estimation and sensory decision theory, Pain 3 (1977) 213--227. 7 Chapman, C.R., Chen, A.C. and Harkins, S., Brain evoked potentials as correlates of laboratory pain: a review and perspective. In: J.J. Bonica and D. Albe-Fessard (Eds.), Advances in Pain Research and Therapy, Vol. II, Raven Press, New York, 1979, in press. 8 Chatrian, G.E., Farrell, D.E., Canfield, R.C. and Lettich, E., Congenital insensitivity to noxious stimuli, Arch. Neurol. (Chic.), 32 (1975) 141--145. 9 Chatrian, G.E., Canfield, R.C., Knauss, J.A. and Lettich, E., Cerebral responses to electrical tooth pulp stimulation in man, Neurology (Minneap.), 25 (1975 ) 745-757. 10 Clark, D.L. and Rosner, B.S., Neurophysiologic effects of general anesthetics. I. The electroencephalogram and sensory evoked responses in man, Anesthesiology, 38 (1973) 564--582.

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