Regional cerebral blood flow (RCBF) in man during perception of radiant warmth and heat pain

353

Pain, 22 (1985) 353-362 Elsevier

PA1 00778

Regional Cerebral Blood Flow (rCBF) in Man during Perception of Radiant Warmth and Heat Pain ’ Erik Ryding, Margareta B.E. Eriksson, Ingmar Rosh Departmentof Clinical

Neurophysioiogv,

(Received

and David H. Ingvar

Uniuersity Hospitui, S- 221 85 Lund (Sweden)

13 March 1985, accepted

14 March 1985)

Summary

The present study concerns the effects of experimental pain (radiant warmth and heat pain) on regional cerebral blood flow (rCBF) in pretrained subjects. The radiant warmth caused a general rCBF increase. However, if anxiety was avoided, heat pain caused the general rCBF level to return towards the level at rest. Thus, pain sensation per se may not cause a larger rCBF (and metabolic) response than that of the localized tactile stimulation, provided that the element of psychic apprehension and anxiety is eliminated or controlled.

Perception of pain in man is influenced by the context in which pain is produced [1,11,12]. Factors like anxiety, apprehension and aggressiveness, may influence the results of experimental pain studies in man [2,22,23]. Similar factors are also known to influence brain metabolism and blood flow [7,8,23], which mainly are determined by nerve cell activity [5,18]. Only a few attempts have been made to study the effects of pain on regional cerebral blood flow (rCBF) [3,9]. In a previous study from this laboratory ]9] mild pain elicited by electrical finger stimulation had variable effects upon the individual mean hemisphere CBF, but for the whole group of subjects a significant average increase of the mean hemisphere flow was found (Fig. 1). The flow increase was most pronounced in frontal areas. These studies were performed in

’ Supported

by the Swedish

03~-3959/8~/$03.30

Medical

Research

6 1985 Elsevier Science

Council,

Publishers

Stockholm

(Project

B.V. (Biomedi~l

No. B84-04X-00084-20

Division)

C).

3.54

untrained subjects, and it is likely that factors like apprehension and anxiotv may have influenced the results. The present study concerns the effects of experimental pain on rCBF in pretrained subjects. Furthermore a radiant heat pain stimulation was used in order to avoid concomitant effects of cutaneous afferent stimulation [cf., 131.

Materials and Methods Subjects Five healthy male physicians, aged 27.--43 (mean 36) years, ~,olunteered for the study. They were all well informed about the experimental procedures and the object of the study. During the week preceding the actual rCBF recordings a sham rCBF measurement was made. The subjects were also exposed to the radiant heat stimulation of the thenar region with determination of the individual stimulation level that produced a sensation of pleasant warmth and an almost unbearable local heat pain. respectively. Thermal stimulus A halogen lamp was focused on a 5 mm X 5 mm area of the right volar thenar region. To improve heat absorption. the exposed area was blackened with India ink. A small thermistor (time constant I set) was placed in contact with the exposed skin but shielded from direct irradiation by a reflecting cover. The heat stimulus was applied in pulses with a duration of 3 set randomly spaced with intervals ranging from I to 7 sec. After the initial phase of increasing temperature for 1.5 set the stimulation level was kept constant during the following 1.5 set at the preset stimulation level by a negative feedback circuit. rCB F recording At each rCBF measurement 17 mCi (0.5 GBq) ‘32Xenon was given intravenously through a plastic cannula placed in the left cubitai vein. Clearance curves were recorded by 2 x 31 detectors placed at right angle lateral to each hemisphere. Regional cerebral blood flow was determined by monoexponential analysis of the l-2 min segment of the clearance curves. This gave a flow index (initial flow index or IFI), that is closely related to the grey matter flow [14,20,26]. The rCBF measurements were made with the subject lying comfortably with eyes closed and ears plugged. He was instructed to remain awake.. The lights were dimmed and the laboratory was kept silent. In each subject 3 rCBF measurements were made. The interval between the recordings was 30 min. The first measurement was made at rest. The second rCBF measurement was made under identical conditions, except for the addition of thermal stimulation to the thenar region of the right hand at the intensity that gave the sensation of pleasant warmth. The stimulation started 2 min before the rCBF recording and it was continued for IO min. At the end of the rCBF measurement which took 11.5 min the subjects were immediately asked to describe what he had

Age (years)

27 35 36 40 40 43 36.2 2.1

Subject

A B C Dl D2 E Mean S.E. of mean

53.6 51.8 43.6 5’7.8 46.9 51.0 51.6 2.3

51.7 49.1 43.3 57.9 46.6 47.6 49.9 2.4

41 34 36 37 36 41 37.6 1.4

pC0,

115/75

120/80

(mm Hg)

BP

51.2 52.1 50.5 51.4 50.1 51.1 0.4

51.9 52.8 53.3 51.2 52.1 52.3 0.4

40 37.6 1.3

41 34 37 36

(mm Hg)

pC0,

110,‘85

46.6 50.8 44.9 54.5 41.3 48.8 1.7

46.8 52.5 44.8 52.9 49.7 49.9 1.6

CBF CBF R L (ml/100 g/min)

40 35.5 1.7

38 34 36 30

pC0,

115/80

125/80

(mm Hg)

BP

AND ‘HEAT PAIN’ STIMULA-

Heat pain

STIMULATION

120/80

BP

REST, ‘WARMTH’

CBF CBF R L (ml/100 g/min)

Warmth

AT THE 3 STIMULUS CONDITIONS:

CBF CBF R L (ml/100 g/min)

Rest

RESULTS OF ALL MEASUREMENTS TION

TABLE I

experienced and to rate the experience on a scale ranging from warmth to heat pain [cf., 61. The third rCBF measurement was made during thermal stimulation which produced a local pain. Immediately after the rCBF measurement the subject was asked to rate the sensation on a continuous scaie ranging from threshold for heat pain to a presumed threshold for involuntary hand withdrawa1. During each rCBF measurement the partial CO1 pressure in the respiratory air was recorded continuously by means of a capnograph. The normal reactivity for the monoexponential rCBF flow index (IFI) to changes in pC0, was determined for a separate group of 14 normal male volunteers aged 25552 (mean 34) years. The statistical significance of the rCBF changes was determined by two-tailed Student’s t test.

Results The mean hemisphere CBF values obtained for each of the subjects are listed in Table I. One of the subjects, D, spontaneously admitted after the completion of the measurements that he had been concerned during the rCBF procedure, mainly due to discomfort from the intravenous cannula in his left arm. In contrast to the other volunteers, the pC0, recording showed that this subject hyperventilated during the pain stimulation. Because of these signs of anxiety during the rCBF measurements, the measurement at rest was repeated a few days later. The lower rCBF values found at this second rest measurement (Table I) supported the notion that the first rCBF results in subject D were influenced by anxiety. For this reason subject D was not included in the subsequent analysis of the rCBF results. The other 4 subjects showed no objective signs of uneasiness and they all denied any experience of anxiety during

TABLE

II

RESULTS OF EACH INDIVIDUAL’S RATING OF THE THE ‘WARMTH’ AND THE ‘HEAT PAIN’ STIMULATIONS

PERCEIVED

SENSATION

DURING

The subject’s rating was given on a continuous scale ranging O-1006. The extreme values of the scale were for the warmth stimulus: no warmth - threshold for heat pain. and for the heat pain stimulus: threshold for heat pain -- presumed threshold for hand withdrawal. Subject

Heat pain

Warmth Heat pain threshold (100%~

No warmth (OS) A B C D E

55 70 50-65 65 55

Heat pain threshold

Flexor reflex (withdrawal)

(0%)

(100%) 60 65 50 65 65

357

percent of flow

value

at

rest

t

Fig. 1. Mean hemisphere CBF results for each subject at the earlier CBF study (1976) on rCBF effects of electrical stimulation of the contralateral hand on a non-painful (Sens 1) and a painful (Sens 2) level.

the rCBF measurements. The evaluation of the subjective sensations during the measurements is given in Table II. In all subjects the heat pain stimulus produced a local erythema and hyperestesia of the stimulated cutaneous region. In one case, A, this stimulus produced a small blister. Except for subject D, there were only minor (< 3 mm Hg) changes in respiratory pC0,. To prevent small pC0, changes from obscuring any effect on rCBF of the pain stimulation [21] the rCBF values were corrected for pC0, change from the value at warmth stimulation (correction factor 4% per mm Hg pCO,, Fig. 2). The blood pressure did not change in two subjects in which it was measured. The mean hemisphere CBF, after pC0, correction for the 4 subjects are shown in Fig. 3 as compared with the values obtained in subject D. The 4 subjects with no anxiety showed a significant (P < 0.01) increase of CBF during warmth stimulation and a significant (P < 0.01) decrease of CBF when pain was added to the warmth stimulation. The mean hemisphere CBF during pain was not significantly different from the level at rest.

III

52.6* 1.2 + 0.3

52.3 + 1.5 + 1.9 54.2 + 1.1 - 1.6

(C)

52.6 + 1 .O +0.7

51.9k1.5 + 3.2 55.2+ 1.0 - 2.6

24

R

Central

50.9 f 0.9 + 1.8

49.2il.l + 2.9 52.1 f 1.0 - 1.2

24

L

50.3+_1.2 + 3.1

47.1 * 1.4 + 3.0 50.1 f 1.2 +0.1 *

16

R

Parietal (P)

( P -c 0.05) difference from other regions in the same hemisphere. (P c 0.01) change from previous stimulus condition

54.8 + 1.3 - 1.6

Heat pain (P) P-R

l Significant ** Significant

56.4 + 1.4 f 1.3 57.7 * 1.0 - 2.9

20

20

Rest (R) W-R Warmth(W) P-W

detectors

L

(F)

g/min).

FOR THE SUBJECTS

(ml/100

CORRECTION

SE. of mean

R

Frontal

Region

pC0,

Meanf

AFTER

4 with no anxiety.

Stimulus condition Number of

n =

rCBF RESULTS

TABLE

48.1 i_ 1 .O + 2.1

46.Orf- 1.2 + 0.6 46.6k 1.4 i-1.5 *

16

L

(0)

45.5 + 1.1 0.0

45.5 * 2.0 +2.0 47.4* 1.2 - 1.8

19

R

Occipital

46.7i + 0.3

1.0

46.4 k 1.5 + 2.3 48.7&1.1 - 2.0

19

L

49.Ok1.5 +1.8

47.2? 1.8 + 3.3 50.4 f 1.5 -1.4

24

R

‘Temporal (T)

47.6k1.4 + 1.2

46.4+ 1.7 t4.8 ** 51.3* 1.5 - 3.7 **

24

L

359

n=14

l4O

R2=0.90

0

-40

I -10

I *lo

I 0

APCO2 (mmWg

)

Fig. 2. Normal relation between CBF, as determined by the IFl index, and changes in pCOz dete~ined by inhalation of 6% CO,/air mixture in 8 normal subjects and by hyperventilation in 6 normal subjects. A

Mean Hemisphere ml I lOOg_’

CBF ?: 2 SE of mean

* min-’

70 -

.’

Subject

D

60 -

Subjects with no anxiety (0=4)

__- ____--

40 -

R REST

I L

I

I

R L WARMTH

I R HEAT

I L PAIN

Fig. 3. Mean hemisphere CBF results, after pC0, correction, for the subjects with no anxiety (n = 4) as compared to subject D who aftenvards spont~wnsly admitted anxiety.

Regional values of CBF. after pc’0, c ‘I unifornl (‘RF: incrc:r\c from rest for all areas which was most pronounced in the left temporal region. Pain produced a uniform decrease of rCBF compared lo warmth stimulation in all regions except in the posterior parietal areas on both hide&. ivhich in contrast to the others (P < 0.05) showed ;I alight increase. rnmt pronounced cm rhc left side. contralateral to the stimulus. The changes in regional C‘BF valucx from re\t to heat pain are the sum of the effects of the warmth and the pain atimulua which tnainly altered the rCBF in opposite directions. Consequently the r(‘BF changes from rest to heat pain were small and not significant.

Discussion The rCBF changes at warmth and at heat pain should be discussed in relation to the multiple factors influencing the cerebral blood flow. Experitnental evidence shows that temperature as well as nociceptive information is forwarded to sensory cortical areas [17,19]. On radiant warmth and at heat pain stimulation a localized rCBF increase would then be expected in those areas as a result of localized sensory cortical activation. Furthermore, the cortical neuronal activity is influenced by diffuse projecting systems which regulate the level of wakefulness and attention with subsequent effects on CBF and metabolism [7.10,27]. Thirdly, direct cerebrovascular effects of substances, circulating in the blood. released by painful stimulation will have to be considered. However. intracarotid injections of epinephrine, norepinephrine and angiotensin in man do not influence the cerebrovascular resistance [15]. Furthermore, animal experiments have shown that intravenous infusion of epinephrine causes a marked increase of cerebral bood flow and metabolism provided that the blood-brain barrier is transiently damaged by the accompanying blood pressure increase [4]. Variations in blood pressure do not influence rCBF due to cerebrovascular autoregulation in healthy humans (and animals). The blood flow is kept virtually constant within the normal physiological range for blood pressure [ 16,251. In the present series. localired cortical increases of rCBF were found in the left temporal region during warmth stimulation and in the parietal regions, mainly on the left side. during the heat pain stimulation. In agreement with the notion that these effects may he due to action of specific sensory pathways to the cortex, the effects were mainly contralateral to the stimulus. It is not easy to explain why the flow increases were seen in different cortical areas in the two stimulus conditions. Possibly perception of pleasant warmth mainly engages cortical regions related to the secondary sensory area [17,29] but any functional interpretation of this or of the shift of engaged cortical areas at a painful stimulus level remains speculative. Our results of an overall decrease of KBF during heat pain stimulation as compared with warmth stand in marked contrast to the overall increase of rCBF found with painful electrical stimulation of the thumb [9]. The difference cannot be explained by differences in effects on blood pressure or pC0,. The overall increase

361

of rCBF caused by painful stimulation of the thumb (at 15 mA) as compared with the stimulation producing touch sensation (at 5 mA) cannot be explained by the increase of tactile somatosensory input. The increase in stimulus strength required to produce a painful sensation may cause a slight stimulus spread but not to nerve fibres outside the thumb area which is specifically represented by a rather restricted cortical sensorimotor area [17]. The most likely explanation for the opposing effects of painful stimulation on rCBF relates to the completely different psychological setting of the two studies. The effects of electrical thumb stimulation were obtained in a group of patients unfamiliar with the rCBF recording and the electrical stimulation procedures. Although agreeing to the stimulation and reporting a moderate pain sensation during the test, it may very well have caused apprehension and some anxiety. In contrast the present subjects exposed to heat stimulation were pretrained to the rCBF measurements procedure and to the heat stimulation itself. They were highly motivated to comply also with the quite painful period of stimulation. This test situation is likely to produce a high degree of corticofugal inhibition of afferent pathways at different levels of the brain thereby reducing the afferent cortical influx towards the level that existed during the resting rCBF measurement. Very little is known about which cortical areas are responsible for such descending control of pain afferent pathways, although orbital frontal cortical areas presumably play an important role [22,28]. The cortical activation involved in these descending control mechanisms may be quite limited in space and localized in a region close to the airways, that is not visible in rCBF as measured in the present study. The differences found in the two experiments may therefore be attributed to the difference in apprehension and anxiety rather than the difference in pain sensation. The present study therefore supports the general conclusion reached by Sokoloff [23,24] that anxiety augments cerebral metabolism and rCBF. This interpretation is further corroborated by the observations from the fifth subject in our series in which apprehension and anxiety during the initial resting rCBF measurement caused a marked increase in the rCBF values. This subject also exhibited a higher degree of heat pain sensitivity as indicated by the marked CBF increase on heat pain stimulation and by the hyperventilation evoked by this stimulation. In conclusion, pain sensation per se may not cause a larger rCBF (and metabolic) response than that of the localized tactile stimulation provided that the element of psychic apprehension and anxiety is eliminated or controlled.

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