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Attenuation of pain reactivity by caudate nucleus stimulation in monkeys
Brain Research, 98 (1975) 110-134 © Elsevier Scientific Publishing Company, Amsterdam - Printed in The Netherlands
119
A T T E N U A T I O N OF P A I N R E A C T I V I T Y BY C A U D A T E N U C L E U S STIMULATION IN MONKEYS
C. G. LINEBERRY* ANDC. J. VIERCK Department of Neuroscience, College of Medicine, University of Florida, Gainesville, Fla. 32601 (U.S.A.)
(Accepted April 21st, 1975)
SUMMARY
The effect of caudate nucleus stimulation on reactivity to painful stimuli was investigated in Macaca speciosa monkeys chronically implanted with electrodes in the right caudate nucleus. The force with which subjects escaped from electrocutaneous leg shock was used as a measure of pain reactivity and was decreased by caudate stimulation. Escape thresholds and latencies were not influenced by the brain stimulation. Decreased escape force was obtained only when 50 msec trains of caudate stimulation preceded 20 msec trains of leg shock by 0-100 msec. Pain reactivity was not affected if brain stimulation followed leg shock or if leg shock followed brain stimulation by more than 100 msec. Intershock response distributions indicated that direct motor inhibition was not responsible for the depression of escape force, and the effectiveness of a restricted range of caudate-leg stimulation intervals ruled out generalized effects on arousal. The results indicate that the effect of caudate stimulation is to reduce the affective components of pain elicited by noxious electrocutaneous stimuli. The time course of this caudate effect parallels that previously reported for the caudate-induced depression of evoked activity in the non-specific somatosensory projections of the reticular formation and thalamus.
INTRODUCTION
Stimulation of the caudate nucleus has been shown to have significant effects on sensory evoked electrophysiological responses in the visual 12,19,z5, auditory az and somesthetic systems al. A number of recent investigations in the chloralose anesthetized cat have shown that stimulation of the caudate nucleus produces inhibition of somatosensory evoked neural activity in nucleus medialis dorsalis, in the * Present address: Department of Pharmacology, School of Medicine, University of Pittsburgh, Pittsburgh, Pa. 15261, U.S.A.
120 centromedian parafascicular complex and in other structures in the non-specific, extralemniscal somatosensory systeml,~6-19,29-3',4'~, 43. In addition, Lineberry and Siegel 3s have shown that caudate-induced neural inhibition occurs in unanesthetized cats, and that a single electrical pulse to the caudate nucleus produces a 150-300 msec period of inhibition in the spontaneous activity of 60~o of the cells in the mesencephalic tegmentum. The effects of this neural inhibition on the perception of sensory events are unknown, but one possibility is that caudate stimulation reduces pain, since the inhibitory effects of caudate stimulation are exerted on neural structures which appear to be important in the perception of pain9,1°,l~, 53. In addition, the caudate nucleus has been shown to have a relatively high density of opiate receptors24, 45 and therefore may be involved in the production of opiate analgesia. Ervin et al. t4 have reported that stimulation of the caudate nucleus through chronically implanted electrodes effectively reduced pain in a human patient, and more recently Schmidek et al. ~9 have shown that caudate stimulation in monkeys elevated escape thresholds. However, it has not been determined whether this effect reflects a direct reduction in the perceived painfulness of the stimuli. To demonstrate this, it will be necessary to control for other consequences of repetitive caudate stimulation such as inhibition of motor activity4-6,2v,28,36-38,48, '54,56, amnesia 6~-63, and synchronization of electroencephalographic activity 7,~s. The present study investigated the effects of caudate stimulation on pain reactivity of monkeys. The experimental paradigm was designed to minimize and yet evaluate the non-sensory effects of caudate stimulation. Also, it was possible to relate the time course of the behavioral results to the duration of neurophysiological modulations that have been produced by caudate stimulation. The results of this investigation have appeared previously in abstract form29 METHODS
The behavioral assessment of pain reactivity used in the present study has been described previously40, .~s. Three female M a c a e a s p e c i o s a monkeys were trained to escape electrocutaneous shock administered to the shaved, lateral calf of the left leg by pressing with a force of at least 2.25 kg on a rectangular plexiglass manipulandum. The manipulandum was attached to a Statham force transducer, the voltage output of which was led to a Grass Model 5 polygraph and a Schmitt trigger circuit which was used to set the force requirement for the termination of trials. Shock was delivered to the skin through l cm diameter, stainless steel hemispheres, separated by 1 cm. Twenty msec duration trains of 0.5 msec square wave constant current pulses were delivered at a frequency of 250 pulses/sec. These trains of pulses were repeated at either 1 or 2 trains/sec until the subject terminated a trial or until 15 sec had elapsed. The inter-trial interval was 30 sec. In order to prevent startle responses from terminating trials, subjects were prevented from escaping until they had received two trains of cutaneous shocks. On each trial, the number of trains of shock taken by the subject and the peak force exerted in trial termination were measured
121 from the polygraph record. Current levels used for the cutaneous stimulation were 4, 13, 22, 31, and 40 mA, and each intensity was delivered 16 times in a preset random order in daily sessions of 80 trials. Each monkey was implanted under aseptic conditions with 4 pairs of concentric bipolar stimulating electrodes in different regions in the vicinity of the right caudate nucleus. Each concentric electrode consisted of an outer barrel of 24-gauge stainless steel tubing which was insulated except for 0.5 mm at the tip. Inside the barrel was a length of 0.1 in. stainless steel wire which extended 2 mm beyond the end of the barrel and was insulated except for 0.5 mm at the tip. Brain stimulation consisted of square wave constant current pulses passed between the barrel (anode) and the stainless steel wire (cathode). Brain stimulation was delivered in a preset random order on one-half of the trials at each intensity of cutaneous stimulation delivered within a session. On brain stimulation trials, each train of cutaneous pulses to the leg was accompanied by a 50 msec duration train of brain stimuli consisting of 0.5 msec pulses at a frequency of 200 pulses/sec. The cutaneous and brain stimulation trains were temporally paired in a conditioning-test (C-T) sequence in which the cutaneous train was either preceded (positive conditioning-test delay) or followed (negative conditioningtest delay) by a train of brain stimuli. For each brain stimulation site, stimulation intensity and C - T delay were systematically varied to determine their effects on pain reactivity. However, only one brain stimulation site and one set of parameters for brain stimulation intensity and C - T delay were used in a particular session. Each set of parameters was used on at least two different sessions. Following the determinations described above, each brain stimulation site was tested for self-stimulation effects. During these testing periods various parameters of brain stimulation were used in addition to those used in the pain reactivity trials in order to maximize chances for obtaining self-stimulation behavior. After completion of all behavioral testing, the animals received an anesthetic dose of Nembutal and electrolytic marking lesions were made at each stimulation site. An overdose of Nembutal was then given and the subjects were perfused through the heart with normal saline followed by 10 ~ formalin containing potassium ferrocyanide. Electrode tips were identified in histological sections by following the electrode tracks to the blue spot formed at the lesion. RESULTS
The locations of the 4 electrodes in or near the right caudate nucleus of each animal are presented in Fig. l, along with the lowest intensities of current that produced significant pain reduction with stimulation at each locus, using the 50 msec C - T interval. All electrodes intended to lie within the anterior tip of the caudate head (1A, 2A, and 3A in Fig. 1) were found to be located in the white matter anterior to the nucleus. In the middle region of the caudate head, the electrode tips were lined up along the medial (MM) and lateral (ML) borders of the caudate, with two of the tips located ventral to the caudate nucleus (3MM and 2ML). Low intensity stimula-
122 I
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P
2.0
N p
2,0
#3 A
Fig. 1. Location of concentric, bipolar electrodes in the right hemispheres of monkeys Nos. I (top row), 2 (middle row) and 3 (bottom row). Abbreviations: A, anterior electrode placement; MM, mid-medial electrode; ML, mid-lateral placement; P, posterior tract; and V, ventricle. The ventral extents of the electrode barrels were discernable on the histological sections and are indicated near the bottom of each tract. If stimulation through an electrode was effective in attenuating pain reactivity, the lowest effective current intensity is indicated (eg., 3.5 mA for the anterior electrode of animal No. 1). tion of the mid-lateral electrode o f m o n k e y No. 3 produced attenuation of pain reactions, and therefore this site was chosen for evaluation of different C - T intervals. At posterior levels o f the caudate head, electrodes IP and 2P were located clearly within the nucleus, and pain reactivity was modulated with stimulation o f 2 m A or less. These loci were chosen for detailed C - T analysis for monkeys No. 1 and No. 2 in preference to electrodes I A and 2MM, where pain reactivity was depressed only with stimulation of 3.5 mA or more. Fig. 2 is a composite of graphs showing the average forces exerted on the manipulandum in escaping leg shock alone, as compared with leg shock plus caudate stimulation (3.0 mA), at different C - T delays. On control trials (solid circles-leg shock alone) the force o f escape responses was a monotonically increasing function o f leg stimulus intensity, as previously reported ~8. The average force exerted in terminating control trials at 40 m A o f leg stimulation was about 4 times the force exerted on trials at 4 mA. Stimulation o f the caudate nucleus at certain sites and parameters appeared to be effective in reducing pain reactivity as revealed by a lowering of force curves. In order to graphically represent the relationship between the effectiveness of
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Fig. 2. Kilograms of force on escape responses is plotted against leg shock intensity in mA for trials without brain stimulation (solid circles) and with stimulation of the right caudate nucleus (open squares). The C-T interval between trains of caudate and leg stimulation is indicated in the lower R corner of each panel. Caudate stimulation was delivered to the posterior electrodes of monkeys Nos. 1 (top row), and 2 (middle row) and to the mid-lateral electrode of No. 3 (bottom row). Leg stimulation was delivered to the L leg of each animal during all sessions except those generating the data shown in the extreme R panel of each row. Each point represents an average of 16 trials over 2 sessions of testing. the caudate stimulation and the C - T delay, the forces exerted on 31 and 40 mA trials with brain stimulation were averaged together for each C - T delay and represented as a percentage of the average force exerted on 31 and 40 mA control trials. This percentage of control force was determined for each C - T delay and plotted as shown in Fig. 3. Notice that the pattern is essentially the same for all 3 animals. The statistical analyses of brain stimulation effects on escape force at each electrode, C - T delay and brain stimulation intensity are presented in Table I. Standard two way analysis of variance was computed with two treated conditions (control v s . brain stimulation), 4 leg shock intensities and 16 observations within each cell. The data from 4 mA leg shock trials were omitted from the analysis because this low level of stimulation was not always terminated by the animals. Inspection of Table I shows that the direct relationship between leg shock intensity and escape force was consistently significant for all animals (40 significant effects in 45 analyses). Stimulation through 5 of the 12 caudate electrodes produced a significant decrease in escape force (see Fig. 1), and these effects were rarely accompanied by a significant interaction F; only 3 of 24 significant main effects included significant interaction effects. Thus, although the stimulation-induced changes in escape force appeared to be great-
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PROPERTIES OF CAUDATE STIMULATION
lnterval (msec) Brain stim. Fa
STATISTICAL ANALYSIS OF FORCE DATA AND INTRINSIC REWARDING
TABLE I
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1.6
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3.6 1.0 0.9 1.7 1.5 1.6
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yes yes
yes yes
S e l f stimulation rate e
( T 0.4)
9.9
(~4.6) 1.6 (--7.9)
4.9
(+O.7) 16.8 (--6.2)
9.1 (--13.9) 23.7
7.2 (--15.8)
Escapes o f caudate alone
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3.0 3.0
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37.1 ( + 22.4)
14.2 (--0.5) 10.0 (--4.7) 31.1 ( ÷ 16.4)
10.8 ( ÷ 1.3)
Degrees o f f r e e d o m = 1/120. Degrees o f f r e e d o m = 3/120. Stimulation p a r a m e t e r s - 100 msec trains o f 0.5 msec pulses at 1 - 2 m A . Significance b e y o n d the 0.01 probability level. Significance b e y o n d the 0.001 probabilitylevel. Elevation o f t h e force curve on b r a i n s t i m u l a t i o n trials. All o t h e r differences were in the opposite direction - - depression of escape force by brain stimulation.
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Fig. 3. Average force exerted on brain stimulation trials at various C-T intervals, represented as the percentage of average force exerted on control trials. Each point represents combined data from 31 and 40 mA leg shock trials and is based on 32 brain stimulation and 32 control trials collected in 2 sessions of testing. Monkey No. 1 is represented by open circles, No. 2 by closed circles and No. 3 by X's. est at the high intensities of leg shock, the effect was similarly expressed throughout the range of intensities used. Stimulation through electrodes that significantly reduced escape force with low intensities at the 50 msec C - T interval also produced statistically significant force reductions at the 25 and 100 msec C - T intervals for all animals, using 3 mA brain stimulation. Simultaneous presentation of leg and brain stimulation was effective only for monkey No. 1. If the stimulus train to the caudate nucleus preceded leg shock by 200-500 msec or followed the onset of leg shock, the force curves from control and brain stimulation trials were either congruent (monkey No. I) or the brain stimulation significantly elevated escape forces (monkeys Nos. 2 and 3). At the optimum C - T delay of 50 msec, pain reactivity to stimulation of either leg was significantly decreased by stimulation through the posterior electrode in the right caudate nucleus of animals Nos. 1 and 2. Only a contralateral effect was obtained with stimulation through the mid-lateral electrode of monkey No. 3. The percentages of escape responses emitted at each leg shock intensity on control and on brain stimulation trials are shown in Table I[. There were no appreciable effects on the percentage of escape responses at any intensity of leg shock, even when the sessions with significant depressions of escape force were considered separately. In addition, escape latencies were not reliably modified by stimulation of any caudate site in any of the animals. Thus, the effects of caudate stimulation on response force were not accompanied by alterations of the amount of shock tolerated at any intensity. The force measure is intended to reflect the emotional impact of noxious stimuli, so that in determining the nature of the caudate effects it is essential to show
127 TABLE II PER CENT ESCAPE RESPONSES UNDER CONTROL AND BRAIN STIMULATION CONDITIONS
Intensity of leg shock ( mA ) 4
No brain stimulation* (n ~ 720 trials at each intensity) 88 Brain stimulation that reduced escape force** (n = 320 trials at each intensity) 89 Brain stimulation that elevated or did not affect escape force*** (n = 400 trials at each intensity) 88
13
22
31
40
97
99
100
100
97
96
100
100
94
96
100
100
* Obtained from control trials in 90 sessions, 36 from monkey No. 1, 32 from No. 2 and 22 from No. 3. ** Obtained from brain stimulation trials in 40 sessions in which escape force was significantly reduced by brain stimulation (16 from No. 1, 16 from No. 2 and 8 from No. 3.) *** Obtained from the remaining brain stimulation trials in 50 sessions not showing a reduction in escape force. that reductions in force are not due to reductions in the animal's capacity to push forcefully on the panel. Analysis o f response latencies was used for this purpose. F o r monkeys Nos. 1 and 2 the distributions o f response latencies relative to the last train o f cutaneous shock on each trial were determined for each C - T interval. As shown in Fig. 4, these animals adopted similar temporal patterns o f responding, with most responses occurring late in the interval between the leg shock train that directly preceded the response and the leg shock train that was avoided. This same pattern was observed regardless o f C - T interval, the presence or absence o f brain stimulation, or the n u m b e r o f cutaneous shocks that occurred prior to the response. In order for the depression o f escape force to be explained as m o t o r inhibition, the response distributions would have to have been differentially time-locked to caudate stimulation at effective C - T intervals as opposed to C - T intervals that did not reduce force. However, the extensive overlap o f response latency distributions, regardless o f C - T interval, suggests that direct m o t o r inhibition could not have been a major determinant o f escape force. This conclusion is particularly strengthened by comparing the results from one/sec stimulation (monkey No. 1) with those o f 2/sec stimulation (monkey No. 2). In the former case, most o f the responses were distributed more than 500 msec after leg shock, while all responses in the 2/sec condition were forced within 500 msec o f leg shock. Despite these substantial differences in latency distributions, moving the caudate stimulation by as little as 25 msec relative to leg stimulation produced significant changes in escape force for both animals. It is unreasonable to assume that such a small change in the temporal position o f caudate stimulation would bring a significant n u m b e r o f responses into critical m o t o r inhibitory periods in both cases. As a further check on the response inhibition hypothesis, analysis o f covariance was utilized to take into account the variability in the force data that was related to
128
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MILLISECONDS
Fig. 4. Distribution of response latencies in msec relative to the most recent leg shock received on brain stimulation trials with different C-T intervals for monkeys No. I (left column) and No. 2 (right column). The onset of the 20 msec leg trains is indicated by the vertical dashed lines. The temporal location and duration of posterior caudate stimulation is indicated by the dark bars underneath each histogram. The C-T intervals marked with an asterisk produced significant changes in escape force. Usually force was decreased by caudate stimulation, but in one case it was increased relative to control trials (No. 2, --25 delay). The analysis time is different for the two animals because No. 1 received leg shocks at 1/sec and No. 2 was tested at 2/sec leg stimulation. the latency variable (the covariate). The force and latency data were obtained from trials with stimulation through the posterior caudate electrodes of animals Nos. 1 and 2, during sessions with C - T intervals o f - - 2 5 - 5 0 msec. Control trials, without brain stimulation, and all trials o f 4 m A leg stimulation were omitted from the analysis. For 5 of the 6 possible comparisons between inhibitory vs. ineffective or facilitatory C - T intervals, the covariance procedure did not reduce the significance o f differences in force. Thus, it is concluded that latency o f response (and therefore response inhibition) was not a major factor in the modification o f escape force by caudate stimulation (see Table II1). At the end o f each pain testing session, the animals received 5 trials o f brain stimulation alone, at the parameters used during the immediately preceding session, in order to determine whether caudate stimulation alone would generate escape responses. This was o f interest since on 3 occasions, caudate stimulation produced statistically significant elevations in pain reactivity (see Table I). One possible explanation for this could be that caudate stimulation had intrinsically aversive properties which added to the aversiveness of leg shock and produced elevated force curves at negative or long positive C - T intervals when the brain stimulus appeared not to directly inhibit input from the leg shock. However, caudate stimulation that significantly increased escape force for monkeys Nos. 2 and 3 was not aversive when presented alone. Thus, when caudate and leg stimulation occurred together during a trial but outside o f the 0-100 msec range o f positive C - T intervals, there appeared
129 TABLE III F-RATIOS FOR ESCAPE FORCE COMPARISONSADJUSTEDFOR THE LATENCY COVARIATE Animal
C - T Comparison
df
1
- - 2 5 vs. 0 msec - - 2 5 vs. 25 msec
1/179 1/179
2.1 16.9"
2
- - 2 5 vs. - - 2 5 vs. 0 vs. 0 vs.
1/217 1/217 1/217 1/217
137.2" 141.5" 24.3* 24.7*
25 msec 50 msec 25 msec 50 msec
F-Ratio
* significance beyond the 0.001 probability level.
to be a potentiation of pain reactivity that could not be ascribed to a summation of individual aversive properties of the skin and brain stimulations. Also, the results from monkeys Nos. l and 2 show that caudate stimulation could be aversive when tested alone, and yet escape force was not significantly elevated during the preceding sessions. In the case of animal No. l, the caudate stimulation was escaped only after the sessions with negative C-T intervals, suggesting that the brain stimulus acquired aversive properties when consistently preceded by leg shock. Tests for positively reinforcing properties of brain stimulation were conducted to determine whether pain inhibition was correlated with the tendency of an electrode site to support self stimulation. The stimulation parameters that were found to generate the highest bar pressing rates were 100 msec of 0.5 msec square waves at 100 Hz and 1-2 mA. The rates of self stimulation were uniformly low and near the baseline rates of bar pressing without brain stimulation. The average rate of bar pressing for stimulation through each electrode is listed in Table I, and the numbers in parentheses are the self stimulation rates minus the mean baseline rates. Only the mid-lateral and posterior electrodes of animal No. 3 supported self stimulation, and these rates were not particularly high. Also, stimulation through the posterior electrode of this animal did not suppress pain reactivity. Thus, there appeared to be no relationship between the intrinsically rewarding properties of caudate stimulation and its effectiveness in decreasing escape force. DISCUSSION
Stimulation of the caudate nucleus has been shown in the present study to reduce reactivity to noxious electrocutaneous stimulation. Localization of the particular region or regions in the vicinity of the caudate nucleus that are responsible for the effects reported in the present study will require a more comprehensive mapping of stimulation sites. We did find however, that stimulation sites with the lowest threshold were located within the head of the caudate, and ventromediaily located sites were ineffective in reducing force. This indicates that an effect due to spread of current to ventromedial structures that have been shown to be involved in modulation
130 of pain2,3,1t,21,23, 49 can probably be ruled out. In addition, the effectiveness of stimulation sites in the present study was not related to their reward value, so that it is unlikely that involvement of reward systems within the septal region was critical for the results obtained. A major consideration in the interpretation of this and similar studies must concern the degree to which the reductions in pain reactivity produced by caudate stimulation reflect changes in pain sensitivity as opposed to other factors that could affect performance on behavioral tasks involving pain stimulation. Caudate stimulation has been shown in other studies to produce amnesia 61 63, interruption of motor activity and drowsiness associated with synchronization of electroencephalographic activity 6,v,3v,3s, and decreased incidence of emotional behavior 46. It could therefore be argued that the reduced escape force on caudate stimulation trials was due to reductions in overall levels of arousal or motor activity produced by brain stimulation. However, several findings in the present study effectively rule out this possibility. First, any generalized changes in the state of the organism induced by repetitive trains of caudate stimulation would necessarily require that the effectiveness of the stimulation be independent of the temporal relationship between the brain stimulus and the leg shock and this was cIearly not the case. In addition, none of the 3 monkeys showed evidence of drowsiness or inactivity during testing, and caudate stimulation did not elicit observable motor responses that might have modified the nature of escape responses. Finally, if generalized motor inhibition were responsible for the reduced force, it would be expected that the number of escape responses would have been reduced and escape latencies increased, but neither was observed in the present study. While generalized changes in the organism induced by caudate stimulation appear unlikely, another possible explanation for the reduced force is that each train of caudate stimuli produced a time-locked, motor inhibitory period following that train. If this were the case, then responses falling within the inhibitory period would be reduced in force. However, in order to account for the differential effectiveness of the C-T intervals, the latency distributions would have to have been differentially time-locked to caudate stimulation at effective C-T intervals as opposed to C-T intervals that did not reduce force. As we have shown, there was extensive overlap of the latency distributions for different C-T intervals, indicating that motor inhibition was not responsible for the reduced force. This argument does not assume that direct effects on response force would necessarily be accompanied by alterations of response latency or ,'ice versa; these measures could theoretically be affected quite independently. However, if the caudate stimulation did produce direct attenuation of response force, then this effect should have been independent of C-T interval, unless the effective intervals were accompanied by a shift of a significant number of responses within a critical caudate-motor response interval. Since C-T interval was the major determinant of response force and did not significantly affect the distribution of caudate-response intervals, it is concluded that the caudate effect was related to an alteration of sensory transmission. This conclusion is supported by the results of the covariance analysis.
131 On the basis of the discussion in the preceding two paragraphs, we conclude that caudate stimulation produced reductions in escape force which were not the result of either changes in levels of arousal or direct motor inhibition. The nature of the caudate effect therefore appear to be a reduction in the tendency of noxious stimuli to elicit intense emotional responses. The most obvious explanation for this effect would be that the reduced emotional responses to noxious stimuli simply reflect a reduction in the perceived painfulness of those stimuli. However, another possible explanation is related to the dissociation that can be made in humans between pain detection and pain tolerance. At low levels of painful stimulation, near pain detection threshold, intense emotional reactions are not elicited as they are at higher levels, near the pain tolerance threshold. Thus, a distinction can be made between pain detection or discrimination and pain reaction. The detection and tolerance limits of the pain continuum are associated with activity in different calibre nerve fibers in the peripheral nervous system8,22,3~-~5,47,5~,55,57, and there have also been suggestions of separate central conduction systems for the discriminative and reactive aspects of pain perception1, 9, lO,13,44,53,60. According to this scheme, the non-specific somatosensory pathways through reticular formation and intralaminar thalamus may be essential for the expression of emotional reactivity to intensely painful stimuli. On the other hand, direct spinothalamic conduction of pain input may mediate distinct sensations of pain without direct evocation of intense emotional reactivity. Since neurophysiological investigations have shown that inhibition of evoked activity in non-specific somatosensory pathwaysl,18,19,z0, 31 can be produced by caudate stimulation that appears not to inhibit evoked potentials in the lemniscal somatosensory pathway31,41, the effects of caudate stimulation could attenuate emotional reactivity without eliminating the discriminative aspects of pain. Thus, it is possible that the phasic effects of caudate stimulation mimic the chronic effects of frontal lobotomy, which results in attenuation of affective responses to pain without a concomitant alteration of pain thresholds20,~6,59. The monkeys in the present study behaved as if this were the case. Escape thresholds were not affected by caudate stimulation that substantially reduced the force exerted in terminating intense leg shock, and escape force appears to reflect the intensity of emotional reactions to pain stimuli. The time-course of the caudate-induced inhibition of pain reactivity closely parallels the time-course of the inhibition of non-specific thalamic and reticular neurons produced by caudate stimulation. Feltz et al. 18 found, in chloralose anesthetized cats, that the onset of the caudate-induced inhibition of the somatosensory responses of medial diencephalic neurons occurred at C - T delay intervals of from 0 to 26 msec. The upper limit of the duration of the inhibitory effect had a range that extended from 50 to 800 msec and a median duration of 183 msec. In addition, Lineberry and Siegel 38 and Siegel and Lineberry 50 have shown in awake cats that the spontaneous activity of mesencephalic tegmental cells is inhibited by caudate stimulation for periods of from 160 to 200 msec after the stimulus. These data are in close agreement with the time-course of the behavioral effects reported in the present study in which pain reactivity was found to be significantly reduced at C - T intervals of
132 25, 50 and 100 msec, but minimal attenuation was observed at the 200 msec delay. This correspondence between the neurophysiological and the behavioral effects ot caudate stimulation raises the possibility that the neurophysiological mechanisms by which caudate stimulation reduces pain reactivity are related to the inhibition o f mesencephalic and diencephalic neurons. it is important to note that caudate stimulation does not produce only inhibition. Facilitatory influences have also been demonstrated, and the most c o m m o n pattern o f unit activity is facilitation, followed by the inhibitory period, which is succeeded by a second facilitatory interval 38,51. In this context, it is interesting that escape force was significantly increased by caudate stimulation on 3 occasions - - at C - T delays o f - - 2 5 and 400 msec (electrodes Nos. 2P and 3 M L ; see Table 1). Since the latency o f initial facilitation is usually less than 5 msec St, and the intralaminar evoked potential from leg stimulation is well developed at 25-30 msec, the time relationships are appropriate for the observed increase in pain reactivity when caudate stimulation closely follows leg shock. Similarly a C - T delay of 400 msec could superimpose the rebound period o f facilitation with activity evoked by leg stimulation. Further direct comparisons o f these neurophysiological and behavioral effects are required to determine with more certainty the relationships between them. ACKNOWLEDGEMENIS
This research was supported by G r a n t NS 07261 from the National Institute of Neurological Diseases and Stroke. Dr. Lineberry was supported by a post-doctoral fellowship from the Center for Neurobiological Sciences (Training G r a n t M H 10320 from the National Institutes of Mental Health). The animal care was provided in part by N I H G r a n t 00421. The research described involved animals maintained in animal-care facilities fully accredited by the American Association for Accreditation o f Laboratory Animal Care.
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response to natural and electrical stimulation, J. Neurophysiol., 25 0962) l 20. 2 BLACK, P., CIANCI, S. N., AND MARKOWITZ, R. S., Alleviation of pain by hypothalamic stimulation in the monkey, Con]in. neurol. (Basel), 34 (1972) 374-381. 3 BREGLIO, V., ANDERSON, D. C., AND MERRILL, H. K., Alteration in footshock threshold by low-
level septal brain stimulation, Physiol. Behav., 5 (1970) 715-719. 4 BUCHWALD, N. A., AND HULL, C. D., Some problems associated with interpretation of physiologic-
al and behavioral responses to stimulation of caudate and thalamic nuclei, Brain Research, 6 (1967) l-l I. 5 BUCHWALD, N. A., HULL,C. O., AND TRACHTENBERG, M. C., Concomitant behavioral and neural inhibition and disinhibition in response to subcortical stimulation, Exp. Brain Res., 4 (1967) 58-72. 6 BUCHWALO,N. A., WVERS, E. J., LAUPRECHT, C. W., AND HEUSER, G., The ~caudate spindle'. IV. A behavioral index of caudate-induced inhibition, Electroenceph. clin. Neurophysiol., 13 (1961) 531-537. 7 BtJCHWALD,N. A., WVERS,E. J., OKtJMA,T., AND HEUSER,G., The ~caudate spindle'. 1. Electrophysiological properties, Electroenceph. olin. Neurophysiol., 13 (1961) 509-518.
133 8 COLLINS, W. F., NULSEN, F. E., AND RANDT, C. T., Relation of peripheral nerve fiber size and sensation in man, Arch. Neurol. (Chic.), 3 (1960) 381-385. 9 COLLINS, W. F., AND RANDT, C. T., Evoked central nervous system activity relating to peripheral unmyelinated or 'C' fibers in cat, J. Neurophysiol., 21 (1958) 345-352. 10 COLLINS, W. F., AND RANDT, C. T., Midbrain evoked responses relating to peripheral unmyelinated or C fibers in cat, J. NeurophysioL, 23 (1960) 47-53. 11 Cox, V. C., AND VALENSTEIN, E. S., Attenuation of aversive properties of peripheral shock by hypothalamic stimulation, Science, 149 (1965) 323-325. 12 DEMETRESCU, M., AND DEMETRESCU, M., The inhibitory action of the caudate nucleus in cortical primary receiving areas in the cat, Electroenceph. clin. Neurophysiol., 14 (1962) 37-52. 13 DRAKE, C. G., AND MACKENZIE, K. G., Mesencephalic tractotomy for pain, J. Neurosurg., 10 (1953) 457-462. 14 ERVIN, F. R., BROWN, C. E., AND MARK, V. H., Striatal influence on facial pain, Confin. neurol. (Basel), 27 (1966) 75-86. 15 FAIRMAN, n . , Stereotactic treatment for the alleviation of intractable pain, reassessments and limitations, Confin. neurol. (Basel), 32 (1970) 341-344. 16 FELDMAN, S., Striatal connections and influences on somatosensory and photic projections to the hypothalamus, Electroenceph. clin. Neurophysiol., 21 (1966) 249-260. 17 FELDMAN, S., AND DAFNY, N., Modification of single cell responses in the posterior hypothalamus to sensory stimuli by caudate and globus pallidus stimulation and lesions, Brain Research, 10 (1968) 402-417. 18 FELTZ, P., KRAUTHAMER, G., AND ALBE-FESSARD, D., Neurons of the medial diencephalon. I. Somatosensory responses and caudate inhibition, d. NeurophysioL, 30 (1967) 55-80. 19 Fox, S. S., AND O'BRIEN, J. H., Inhibition and facilitation of afferent information by the caudate nucleus, Science, 137 (1962) 423-425. 20 FREEMAN, W., AND WATTS, J. W., Pain mechanisms and the frontal lobes: a study of pre-frontal lobotomy for intractable pain, Ann. intern. Ned., 28 (1948) 747-754. 21 GARDNER, L., AND MALMO, R. B., Effects of low-level septal stimulation on escape: significance for limbic-midbrain interactions in pain, J. cutup, physiol. Psychol., 68 (1969) 65-73. 22 HALLIN, R. G., AND TOREBJORK, H. E., Electrically induced A and C fibre responses in intact h u m a n skin nerves, Exp. Brain Res., 16 (1973) 309-320. 23 HARVEY, J. A., AND LINTS, C. E., Lesions in the medial forebrain bundle: relationship between pain sensitivity and telencephalic content of serotonin, J. cutup, physiol. Psychol., 74 (1971) 28-36. 24 JACQUET,Y. F., AND LAJTHA, A., Morphine action at central nervous system sites in rat: analgesia or hypalgesia depending on site and dose, Science, 132 (1973) 4902,92. 25 KADOBAYASHI, I., AND UKIDA, G., Effects of lenticular stimulation on unitary responses of the lateral geniculate body to light, Exp. Neurol., 33 (1971) 518-527. 26 KING, H. E., CLAUSEN, J., AND SCARFF, J. E., Cutaneous thresholds for pain before and after unilateral prefrontal Iobotomy, J. nerv. merit. Dis., 112 (1950) 93-96. 27 KITSIKIS, A., The suppression of arm movements in monkeys: threshold variations of caudate nucleus stimulation, Brain Research, l0 (1968) 460-462. 28 KITSlKIS, A., AND ROUGEUL, A., The effect of caudate stimulation on conditioned motor behavior in monkeys, Physiol. Behav., 3 (1968) 831-837. 29 KRAUTHAMER, G. M., Inhibition of evoked potentials by striatal stimulation and its blockage by strychnine, Science, 142 (1963) 1175-1176. 30 KRAUTHAMER,G. M., AND ALBE-FESSARD, D., Electrophysiologic studies of the basal ganglia and striopallidal inhibition of non-specific afferent activity, Neuropsychologia (Bed.), 2 (1964) 73-83. 31 KRAUTHAMER, G., AND ALBE-FESSARD, D., Inhibition of non-specific sensory activities following striopallidal and capsular stimulation, J. Neurophysiol., 28 (1965) 100-124. 32 LA GRUTTA, A., AMATO, G., AND MILITELLO, L., The responsiveness of acoustic area after stimulation of the caudate nucleus, Experientia (Basel), 26 (1970) 259-260. 33 LANDAU, W., AND BISHOP, G. H., Pain from dermal, periosteal, and facial endings and from inflammation, Arch. Neurol. Psychiat. (Chic.), 69 (1953) 490-504. 34 LEWIS, T., AND POCHIN, E. E., The double response of the human skin to a single stimulus, Clin. Sci., 3 (1937) 67-76. 35 LEwis, T., AND POCH1N, E. E., Effects of asphyxia and pressure on sensory nerves of man, Clin. Sci., 3 (1938) 141-155.
134 36 L1LES, S. L., AND DAVIS, G. D., Interrelation of caudate nucleus and thalamus in alteration of cortically induced movement, J. Neurophysiol., 32 (1969) 564-573. 37 LILES, S. L., AND DAVIS, G. D., Electrocortical effects ofcaudate stimulations which alter cortically induced movement, J. Neurophysiol., 32 (1969) 574-582. 38 LINEBERRY,C. G., AND SIEGEL, J., LEG synchronization, behavioral inhibition, and mesencephalic unit effects produced by stimulation of orbital cortex, basal forebrain and caudate nucleus, Brain Research, 34 (1971) 143-161. 39 LINEBERRY, C. G., AND VIERCK, C. J., JR., Effects of caudate nucleus stimulation on reactivity to noxious electrocutaneous stimulation, Proc. Soc. Neurosci., 2 (1972) 87. 40 MANNING, A. A., AND VIERCK, C. J., JR., Behavioral assessment of pain detection and tolerance in monkeys, J. exp. Anal. Behav., 19 (1973) 125-132. 41 MARCO, L. A., BROWN, T. S., BUSSE, J. M., AND WEINER, W . J . , Effects of caudate-capsular stimulation on thalamic ventrolateral unitary activity in the cat, Arch. ital. Biol., 105 (1967) 399~12. 42 MCKENZIE, J. S., AND GILBERT, D. M., Hippocampal and neostriatal inhibition of medial thalamic unit responses to somatic and brain stem stimulation, Brain Research, 38 (1972) 202-205. 43 MCKENZIE, J. S., AND ROGERS, O. K., Hippocampal suppression evoked from the caudate nucleus, Brain Research, 64 (1973) 1-15. 44 MELZACK, R., AND CASEY, K. L., Sensory, motivational, and central control determinants of pain. In D. R. KENSHALO (Ed.), The Skin Senses, Thomas, Springfield, Ill., 1968, pp. 423~143. 45 PERT, C. B., AND SNYDER, S. H., Opiate receptor: demonstration in nervous tissue, Science, 179 (1973) 1011-1014. 46 PLOTNIK, R., AND DELGADO, J. M. R., Emotional responses in monkeys inhibited with electrical stimulation, Psychon. Sci., 18 (1970) 129-130. 47 PRICE, O. O., Characteristics of second pain and flexion reflexes indicative of prolonged central summation, Exp. Neurol., 37 (1972) 371-387. 48 RUBINSTEIN, E. H., AND DELGAOO, J. M. R., Inhibition induced by forebrain stimulation in the monkey, Amer. J. PhysioL, 205 (1963) 941-948. 49 SCHMIDEK, H. H., FOHANNO, O., ERVIN, F. R., AND SWEET, W. H., Pain threshold alterations by brain stimulation in the monkey, J. Neurosurg., 35 (1971) 715-722. 50 SIEGEL, J., AND LINEBERRY, C. G., Caudate-eapsular induced modulation of single unit activity in mesencephalic reticular formation, Exp. Neurol., 22 (1968) 444 463. 51 SIEGEL, J., AND WANG, R. Y., Electroencephalographic, behavioral and single-unit effects produced by stimulation of forebrain inhibitory structures in cats, Exp. Neurol., 42 (1974) 28-50. 52 SINCLAIR, D. C., AND STOKES, B. A. R., The production and characteristics of 'second pain', Brain, 87 (1964) 609-618. 53 SPIEGEL,E. A., AND WYCIS, H. T., Present status of stereoencephalotomies for pain relief, Confin. neurol. (Basel), 27 (1966) 7-17. 54 STEVENS, J. R., KIM, C., AND MACLEAN, P. D., Stimulation of caudate nucleus, Arch. Neurol. (Chic.), 4 (1961) 47-54. 55 TOREBJORK, H. E., AND HALLIN, R. G., Perceptual changes accompanying controlled preferential blocking of A and C fibre responses in intact human skin nerves, Exp. Brain Res., 16 (1973) 321-332. 56 VAN BUREN, J. M., LI, C. L., AND OJEMANN, G. A., The fronto-striatal arrest response in man, Electroenceph. clin. NeurophysioL, 21 (1966) 114-130. 57 VAN HEES, J., AND GYBELS, J. M., Pain related to single afferent C fibers from human skin, Brain Research, 48 (1972) 397~,00. 58 VIERCK, C. J., HAMILTON, D. M., AND THORNBY, J. 1., Pain reactivity of monkeys after lesions to the dorsal and lateral columns of the spinal cord, Exp. Brain Res., 13 (1971) 140-158. 59 WHITE, J. C., AND SWEET, W. H., Pain and the Neurosurgeon: A Forty- Year Experience, Thomas, Springfield, I11., 1969. 60 WHITLOCK, D. G., AND PERL, E. R., Thalamic projections of spinothalamic pathways in monkey, Exp. NeuroL, 3 (1961) 240-255. 61 WILBtJRN, M. W., AND KESNER, R. P., Differential amnestic effects produced by electrical stimulation of the caudate nucleus and nonspeciflc thalamic system, Exp. Neurol., 34 (1972) 45-50. 62 WVERS, E. J., AND DEADWVLER, S. A., Duration and nature of retrograde amnesia produced by stimulation of the eaudate nucleus, Physiol. Behav., 6 (1971) 97-103. 63 WYERS, E. J., PEEKE, H. V. S., WILLISTON, J. S., AND HERZ, M. J., Retroactive impairment of passive avoidance learning by stimulation of the caudate nucleus, Exp. Neurol., 22 (1968) 350366.
119
A T T E N U A T I O N OF P A I N R E A C T I V I T Y BY C A U D A T E N U C L E U S STIMULATION IN MONKEYS
C. G. LINEBERRY* ANDC. J. VIERCK Department of Neuroscience, College of Medicine, University of Florida, Gainesville, Fla. 32601 (U.S.A.)
(Accepted April 21st, 1975)
SUMMARY
The effect of caudate nucleus stimulation on reactivity to painful stimuli was investigated in Macaca speciosa monkeys chronically implanted with electrodes in the right caudate nucleus. The force with which subjects escaped from electrocutaneous leg shock was used as a measure of pain reactivity and was decreased by caudate stimulation. Escape thresholds and latencies were not influenced by the brain stimulation. Decreased escape force was obtained only when 50 msec trains of caudate stimulation preceded 20 msec trains of leg shock by 0-100 msec. Pain reactivity was not affected if brain stimulation followed leg shock or if leg shock followed brain stimulation by more than 100 msec. Intershock response distributions indicated that direct motor inhibition was not responsible for the depression of escape force, and the effectiveness of a restricted range of caudate-leg stimulation intervals ruled out generalized effects on arousal. The results indicate that the effect of caudate stimulation is to reduce the affective components of pain elicited by noxious electrocutaneous stimuli. The time course of this caudate effect parallels that previously reported for the caudate-induced depression of evoked activity in the non-specific somatosensory projections of the reticular formation and thalamus.
INTRODUCTION
Stimulation of the caudate nucleus has been shown to have significant effects on sensory evoked electrophysiological responses in the visual 12,19,z5, auditory az and somesthetic systems al. A number of recent investigations in the chloralose anesthetized cat have shown that stimulation of the caudate nucleus produces inhibition of somatosensory evoked neural activity in nucleus medialis dorsalis, in the * Present address: Department of Pharmacology, School of Medicine, University of Pittsburgh, Pittsburgh, Pa. 15261, U.S.A.
120 centromedian parafascicular complex and in other structures in the non-specific, extralemniscal somatosensory systeml,~6-19,29-3',4'~, 43. In addition, Lineberry and Siegel 3s have shown that caudate-induced neural inhibition occurs in unanesthetized cats, and that a single electrical pulse to the caudate nucleus produces a 150-300 msec period of inhibition in the spontaneous activity of 60~o of the cells in the mesencephalic tegmentum. The effects of this neural inhibition on the perception of sensory events are unknown, but one possibility is that caudate stimulation reduces pain, since the inhibitory effects of caudate stimulation are exerted on neural structures which appear to be important in the perception of pain9,1°,l~, 53. In addition, the caudate nucleus has been shown to have a relatively high density of opiate receptors24, 45 and therefore may be involved in the production of opiate analgesia. Ervin et al. t4 have reported that stimulation of the caudate nucleus through chronically implanted electrodes effectively reduced pain in a human patient, and more recently Schmidek et al. ~9 have shown that caudate stimulation in monkeys elevated escape thresholds. However, it has not been determined whether this effect reflects a direct reduction in the perceived painfulness of the stimuli. To demonstrate this, it will be necessary to control for other consequences of repetitive caudate stimulation such as inhibition of motor activity4-6,2v,28,36-38,48, '54,56, amnesia 6~-63, and synchronization of electroencephalographic activity 7,~s. The present study investigated the effects of caudate stimulation on pain reactivity of monkeys. The experimental paradigm was designed to minimize and yet evaluate the non-sensory effects of caudate stimulation. Also, it was possible to relate the time course of the behavioral results to the duration of neurophysiological modulations that have been produced by caudate stimulation. The results of this investigation have appeared previously in abstract form29 METHODS
The behavioral assessment of pain reactivity used in the present study has been described previously40, .~s. Three female M a c a e a s p e c i o s a monkeys were trained to escape electrocutaneous shock administered to the shaved, lateral calf of the left leg by pressing with a force of at least 2.25 kg on a rectangular plexiglass manipulandum. The manipulandum was attached to a Statham force transducer, the voltage output of which was led to a Grass Model 5 polygraph and a Schmitt trigger circuit which was used to set the force requirement for the termination of trials. Shock was delivered to the skin through l cm diameter, stainless steel hemispheres, separated by 1 cm. Twenty msec duration trains of 0.5 msec square wave constant current pulses were delivered at a frequency of 250 pulses/sec. These trains of pulses were repeated at either 1 or 2 trains/sec until the subject terminated a trial or until 15 sec had elapsed. The inter-trial interval was 30 sec. In order to prevent startle responses from terminating trials, subjects were prevented from escaping until they had received two trains of cutaneous shocks. On each trial, the number of trains of shock taken by the subject and the peak force exerted in trial termination were measured
121 from the polygraph record. Current levels used for the cutaneous stimulation were 4, 13, 22, 31, and 40 mA, and each intensity was delivered 16 times in a preset random order in daily sessions of 80 trials. Each monkey was implanted under aseptic conditions with 4 pairs of concentric bipolar stimulating electrodes in different regions in the vicinity of the right caudate nucleus. Each concentric electrode consisted of an outer barrel of 24-gauge stainless steel tubing which was insulated except for 0.5 mm at the tip. Inside the barrel was a length of 0.1 in. stainless steel wire which extended 2 mm beyond the end of the barrel and was insulated except for 0.5 mm at the tip. Brain stimulation consisted of square wave constant current pulses passed between the barrel (anode) and the stainless steel wire (cathode). Brain stimulation was delivered in a preset random order on one-half of the trials at each intensity of cutaneous stimulation delivered within a session. On brain stimulation trials, each train of cutaneous pulses to the leg was accompanied by a 50 msec duration train of brain stimuli consisting of 0.5 msec pulses at a frequency of 200 pulses/sec. The cutaneous and brain stimulation trains were temporally paired in a conditioning-test (C-T) sequence in which the cutaneous train was either preceded (positive conditioning-test delay) or followed (negative conditioningtest delay) by a train of brain stimuli. For each brain stimulation site, stimulation intensity and C - T delay were systematically varied to determine their effects on pain reactivity. However, only one brain stimulation site and one set of parameters for brain stimulation intensity and C - T delay were used in a particular session. Each set of parameters was used on at least two different sessions. Following the determinations described above, each brain stimulation site was tested for self-stimulation effects. During these testing periods various parameters of brain stimulation were used in addition to those used in the pain reactivity trials in order to maximize chances for obtaining self-stimulation behavior. After completion of all behavioral testing, the animals received an anesthetic dose of Nembutal and electrolytic marking lesions were made at each stimulation site. An overdose of Nembutal was then given and the subjects were perfused through the heart with normal saline followed by 10 ~ formalin containing potassium ferrocyanide. Electrode tips were identified in histological sections by following the electrode tracks to the blue spot formed at the lesion. RESULTS
The locations of the 4 electrodes in or near the right caudate nucleus of each animal are presented in Fig. l, along with the lowest intensities of current that produced significant pain reduction with stimulation at each locus, using the 50 msec C - T interval. All electrodes intended to lie within the anterior tip of the caudate head (1A, 2A, and 3A in Fig. 1) were found to be located in the white matter anterior to the nucleus. In the middle region of the caudate head, the electrode tips were lined up along the medial (MM) and lateral (ML) borders of the caudate, with two of the tips located ventral to the caudate nucleus (3MM and 2ML). Low intensity stimula-
122 I
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Fig. 1. Location of concentric, bipolar electrodes in the right hemispheres of monkeys Nos. I (top row), 2 (middle row) and 3 (bottom row). Abbreviations: A, anterior electrode placement; MM, mid-medial electrode; ML, mid-lateral placement; P, posterior tract; and V, ventricle. The ventral extents of the electrode barrels were discernable on the histological sections and are indicated near the bottom of each tract. If stimulation through an electrode was effective in attenuating pain reactivity, the lowest effective current intensity is indicated (eg., 3.5 mA for the anterior electrode of animal No. 1). tion of the mid-lateral electrode o f m o n k e y No. 3 produced attenuation of pain reactions, and therefore this site was chosen for evaluation of different C - T intervals. At posterior levels o f the caudate head, electrodes IP and 2P were located clearly within the nucleus, and pain reactivity was modulated with stimulation o f 2 m A or less. These loci were chosen for detailed C - T analysis for monkeys No. 1 and No. 2 in preference to electrodes I A and 2MM, where pain reactivity was depressed only with stimulation of 3.5 mA or more. Fig. 2 is a composite of graphs showing the average forces exerted on the manipulandum in escaping leg shock alone, as compared with leg shock plus caudate stimulation (3.0 mA), at different C - T delays. On control trials (solid circles-leg shock alone) the force o f escape responses was a monotonically increasing function o f leg stimulus intensity, as previously reported ~8. The average force exerted in terminating control trials at 40 m A o f leg stimulation was about 4 times the force exerted on trials at 4 mA. Stimulation o f the caudate nucleus at certain sites and parameters appeared to be effective in reducing pain reactivity as revealed by a lowering of force curves. In order to graphically represent the relationship between the effectiveness of
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Fig. 2. Kilograms of force on escape responses is plotted against leg shock intensity in mA for trials without brain stimulation (solid circles) and with stimulation of the right caudate nucleus (open squares). The C-T interval between trains of caudate and leg stimulation is indicated in the lower R corner of each panel. Caudate stimulation was delivered to the posterior electrodes of monkeys Nos. 1 (top row), and 2 (middle row) and to the mid-lateral electrode of No. 3 (bottom row). Leg stimulation was delivered to the L leg of each animal during all sessions except those generating the data shown in the extreme R panel of each row. Each point represents an average of 16 trials over 2 sessions of testing. the caudate stimulation and the C - T delay, the forces exerted on 31 and 40 mA trials with brain stimulation were averaged together for each C - T delay and represented as a percentage of the average force exerted on 31 and 40 mA control trials. This percentage of control force was determined for each C - T delay and plotted as shown in Fig. 3. Notice that the pattern is essentially the same for all 3 animals. The statistical analyses of brain stimulation effects on escape force at each electrode, C - T delay and brain stimulation intensity are presented in Table I. Standard two way analysis of variance was computed with two treated conditions (control v s . brain stimulation), 4 leg shock intensities and 16 observations within each cell. The data from 4 mA leg shock trials were omitted from the analysis because this low level of stimulation was not always terminated by the animals. Inspection of Table I shows that the direct relationship between leg shock intensity and escape force was consistently significant for all animals (40 significant effects in 45 analyses). Stimulation through 5 of the 12 caudate electrodes produced a significant decrease in escape force (see Fig. 1), and these effects were rarely accompanied by a significant interaction F; only 3 of 24 significant main effects included significant interaction effects. Thus, although the stimulation-induced changes in escape force appeared to be great-
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PROPERTIES OF CAUDATE STIMULATION
lnterval (msec) Brain stim. Fa
STATISTICAL ANALYSIS OF FORCE DATA AND INTRINSIC REWARDING
TABLE I
1.2 1.0 0.3 0.8
1.6
2.2 4.5* 1.2 0.6 0.4 2.6 1.6 3.1 5.2* 1.7 0.9 3.6
3.6 1.0 0.9 1.7 1.5 1.6
Interaction F I'
yes yes
yes yes
S e l f stimulation rate e
( T 0.4)
9.9
(~4.6) 1.6 (--7.9)
4.9
(+O.7) 16.8 (--6.2)
9.1 (--13.9) 23.7
7.2 (--15.8)
Escapes o f caudate alone
4.0 4.0 4.0 3.0 2.0 1.0 3.0
3.0 3.0
Anterior
Mid.-med.
Mid.-lat.
Mid.-lat. Posterior
3L
a b e * ** *
--25 25 400 50 50
50
50
50
--25 0 25 100 200 400 50
50
21.4'* 37.1"* 18.8"* 0.1 7.5 ~ * 26.5** 3.3 I' 2.1 0.3
2.1 -I"
2.9
55.3** 65.6** 31.1'* 0.2 33.9 q ** 0.6 47.5** 88.0** 4.6 13.2 I' ** 46.1 **
11.3"* 10.3"* 19.9"* 13.1"* 11.6"* 3.2 2.6 18.3"* 7.3"*
12.3"*
10.I**
5.7* 1.7 15.2'* 4.2* 9.4** 13.5"* 8.5** 5.9** 10.8"* 12.9"* 8.2"*
0.7 1.1 2.9 1.3 2.8 1.3 3.5 1.8 1.0
0.1
2.7
1.3 0.2 4.0* 0.3 0.1 2.1 1.8 1.0 1.1 0.5 1.9
37.1 ( + 22.4)
14.2 (--0.5) 10.0 (--4.7) 31.1 ( ÷ 16.4)
10.8 ( ÷ 1.3)
Degrees o f f r e e d o m = 1/120. Degrees o f f r e e d o m = 3/120. Stimulation p a r a m e t e r s - 100 msec trains o f 0.5 msec pulses at 1 - 2 m A . Significance b e y o n d the 0.01 probability level. Significance b e y o n d the 0.001 probabilitylevel. Elevation o f t h e force curve on b r a i n s t i m u l a t i o n trials. All o t h e r differences were in the opposite direction - - depression of escape force by brain stimulation.
3.0
Posterior
2R
3R 3L
4.0 3.0 2.0 1.5 3.0
Posterior
tO
126
_J 0 I00 FF I-Z 0 0
Z w ~9 rr W o_
5O
I
-50-25
I I
0
i
i
25 5 0
I
I
2OO
~00
I
kO0
C-T
I
400
I
500
Interval (msec)
Fig. 3. Average force exerted on brain stimulation trials at various C-T intervals, represented as the percentage of average force exerted on control trials. Each point represents combined data from 31 and 40 mA leg shock trials and is based on 32 brain stimulation and 32 control trials collected in 2 sessions of testing. Monkey No. 1 is represented by open circles, No. 2 by closed circles and No. 3 by X's. est at the high intensities of leg shock, the effect was similarly expressed throughout the range of intensities used. Stimulation through electrodes that significantly reduced escape force with low intensities at the 50 msec C - T interval also produced statistically significant force reductions at the 25 and 100 msec C - T intervals for all animals, using 3 mA brain stimulation. Simultaneous presentation of leg and brain stimulation was effective only for monkey No. 1. If the stimulus train to the caudate nucleus preceded leg shock by 200-500 msec or followed the onset of leg shock, the force curves from control and brain stimulation trials were either congruent (monkey No. I) or the brain stimulation significantly elevated escape forces (monkeys Nos. 2 and 3). At the optimum C - T delay of 50 msec, pain reactivity to stimulation of either leg was significantly decreased by stimulation through the posterior electrode in the right caudate nucleus of animals Nos. 1 and 2. Only a contralateral effect was obtained with stimulation through the mid-lateral electrode of monkey No. 3. The percentages of escape responses emitted at each leg shock intensity on control and on brain stimulation trials are shown in Table I[. There were no appreciable effects on the percentage of escape responses at any intensity of leg shock, even when the sessions with significant depressions of escape force were considered separately. In addition, escape latencies were not reliably modified by stimulation of any caudate site in any of the animals. Thus, the effects of caudate stimulation on response force were not accompanied by alterations of the amount of shock tolerated at any intensity. The force measure is intended to reflect the emotional impact of noxious stimuli, so that in determining the nature of the caudate effects it is essential to show
127 TABLE II PER CENT ESCAPE RESPONSES UNDER CONTROL AND BRAIN STIMULATION CONDITIONS
Intensity of leg shock ( mA ) 4
No brain stimulation* (n ~ 720 trials at each intensity) 88 Brain stimulation that reduced escape force** (n = 320 trials at each intensity) 89 Brain stimulation that elevated or did not affect escape force*** (n = 400 trials at each intensity) 88
13
22
31
40
97
99
100
100
97
96
100
100
94
96
100
100
* Obtained from control trials in 90 sessions, 36 from monkey No. 1, 32 from No. 2 and 22 from No. 3. ** Obtained from brain stimulation trials in 40 sessions in which escape force was significantly reduced by brain stimulation (16 from No. 1, 16 from No. 2 and 8 from No. 3.) *** Obtained from the remaining brain stimulation trials in 50 sessions not showing a reduction in escape force. that reductions in force are not due to reductions in the animal's capacity to push forcefully on the panel. Analysis o f response latencies was used for this purpose. F o r monkeys Nos. 1 and 2 the distributions o f response latencies relative to the last train o f cutaneous shock on each trial were determined for each C - T interval. As shown in Fig. 4, these animals adopted similar temporal patterns o f responding, with most responses occurring late in the interval between the leg shock train that directly preceded the response and the leg shock train that was avoided. This same pattern was observed regardless o f C - T interval, the presence or absence o f brain stimulation, or the n u m b e r o f cutaneous shocks that occurred prior to the response. In order for the depression o f escape force to be explained as m o t o r inhibition, the response distributions would have to have been differentially time-locked to caudate stimulation at effective C - T intervals as opposed to C - T intervals that did not reduce force. However, the extensive overlap o f response latency distributions, regardless o f C - T interval, suggests that direct m o t o r inhibition could not have been a major determinant o f escape force. This conclusion is particularly strengthened by comparing the results from one/sec stimulation (monkey No. 1) with those o f 2/sec stimulation (monkey No. 2). In the former case, most o f the responses were distributed more than 500 msec after leg shock, while all responses in the 2/sec condition were forced within 500 msec o f leg shock. Despite these substantial differences in latency distributions, moving the caudate stimulation by as little as 25 msec relative to leg stimulation produced significant changes in escape force for both animals. It is unreasonable to assume that such a small change in the temporal position o f caudate stimulation would bring a significant n u m b e r o f responses into critical m o t o r inhibitory periods in both cases. As a further check on the response inhibition hypothesis, analysis o f covariance was utilized to take into account the variability in the force data that was related to
128
30-
#
20-
I J~-25
25"
#2
I0i
(1) I.iJ
m
I
30-
0
2o0
lO-
0
20-
o."
I0-
rI
30-
I
20-
I I
30-
Z I0-
L
F
w
,
h
_
_
~
i
/ 360 *oo 5~o
MILLISECONDS
Fig. 4. Distribution of response latencies in msec relative to the most recent leg shock received on brain stimulation trials with different C-T intervals for monkeys No. I (left column) and No. 2 (right column). The onset of the 20 msec leg trains is indicated by the vertical dashed lines. The temporal location and duration of posterior caudate stimulation is indicated by the dark bars underneath each histogram. The C-T intervals marked with an asterisk produced significant changes in escape force. Usually force was decreased by caudate stimulation, but in one case it was increased relative to control trials (No. 2, --25 delay). The analysis time is different for the two animals because No. 1 received leg shocks at 1/sec and No. 2 was tested at 2/sec leg stimulation. the latency variable (the covariate). The force and latency data were obtained from trials with stimulation through the posterior caudate electrodes of animals Nos. 1 and 2, during sessions with C - T intervals o f - - 2 5 - 5 0 msec. Control trials, without brain stimulation, and all trials o f 4 m A leg stimulation were omitted from the analysis. For 5 of the 6 possible comparisons between inhibitory vs. ineffective or facilitatory C - T intervals, the covariance procedure did not reduce the significance o f differences in force. Thus, it is concluded that latency o f response (and therefore response inhibition) was not a major factor in the modification o f escape force by caudate stimulation (see Table II1). At the end o f each pain testing session, the animals received 5 trials o f brain stimulation alone, at the parameters used during the immediately preceding session, in order to determine whether caudate stimulation alone would generate escape responses. This was o f interest since on 3 occasions, caudate stimulation produced statistically significant elevations in pain reactivity (see Table I). One possible explanation for this could be that caudate stimulation had intrinsically aversive properties which added to the aversiveness of leg shock and produced elevated force curves at negative or long positive C - T intervals when the brain stimulus appeared not to directly inhibit input from the leg shock. However, caudate stimulation that significantly increased escape force for monkeys Nos. 2 and 3 was not aversive when presented alone. Thus, when caudate and leg stimulation occurred together during a trial but outside o f the 0-100 msec range o f positive C - T intervals, there appeared
129 TABLE III F-RATIOS FOR ESCAPE FORCE COMPARISONSADJUSTEDFOR THE LATENCY COVARIATE Animal
C - T Comparison
df
1
- - 2 5 vs. 0 msec - - 2 5 vs. 25 msec
1/179 1/179
2.1 16.9"
2
- - 2 5 vs. - - 2 5 vs. 0 vs. 0 vs.
1/217 1/217 1/217 1/217
137.2" 141.5" 24.3* 24.7*
25 msec 50 msec 25 msec 50 msec
F-Ratio
* significance beyond the 0.001 probability level.
to be a potentiation of pain reactivity that could not be ascribed to a summation of individual aversive properties of the skin and brain stimulations. Also, the results from monkeys Nos. l and 2 show that caudate stimulation could be aversive when tested alone, and yet escape force was not significantly elevated during the preceding sessions. In the case of animal No. l, the caudate stimulation was escaped only after the sessions with negative C-T intervals, suggesting that the brain stimulus acquired aversive properties when consistently preceded by leg shock. Tests for positively reinforcing properties of brain stimulation were conducted to determine whether pain inhibition was correlated with the tendency of an electrode site to support self stimulation. The stimulation parameters that were found to generate the highest bar pressing rates were 100 msec of 0.5 msec square waves at 100 Hz and 1-2 mA. The rates of self stimulation were uniformly low and near the baseline rates of bar pressing without brain stimulation. The average rate of bar pressing for stimulation through each electrode is listed in Table I, and the numbers in parentheses are the self stimulation rates minus the mean baseline rates. Only the mid-lateral and posterior electrodes of animal No. 3 supported self stimulation, and these rates were not particularly high. Also, stimulation through the posterior electrode of this animal did not suppress pain reactivity. Thus, there appeared to be no relationship between the intrinsically rewarding properties of caudate stimulation and its effectiveness in decreasing escape force. DISCUSSION
Stimulation of the caudate nucleus has been shown in the present study to reduce reactivity to noxious electrocutaneous stimulation. Localization of the particular region or regions in the vicinity of the caudate nucleus that are responsible for the effects reported in the present study will require a more comprehensive mapping of stimulation sites. We did find however, that stimulation sites with the lowest threshold were located within the head of the caudate, and ventromediaily located sites were ineffective in reducing force. This indicates that an effect due to spread of current to ventromedial structures that have been shown to be involved in modulation
130 of pain2,3,1t,21,23, 49 can probably be ruled out. In addition, the effectiveness of stimulation sites in the present study was not related to their reward value, so that it is unlikely that involvement of reward systems within the septal region was critical for the results obtained. A major consideration in the interpretation of this and similar studies must concern the degree to which the reductions in pain reactivity produced by caudate stimulation reflect changes in pain sensitivity as opposed to other factors that could affect performance on behavioral tasks involving pain stimulation. Caudate stimulation has been shown in other studies to produce amnesia 61 63, interruption of motor activity and drowsiness associated with synchronization of electroencephalographic activity 6,v,3v,3s, and decreased incidence of emotional behavior 46. It could therefore be argued that the reduced escape force on caudate stimulation trials was due to reductions in overall levels of arousal or motor activity produced by brain stimulation. However, several findings in the present study effectively rule out this possibility. First, any generalized changes in the state of the organism induced by repetitive trains of caudate stimulation would necessarily require that the effectiveness of the stimulation be independent of the temporal relationship between the brain stimulus and the leg shock and this was cIearly not the case. In addition, none of the 3 monkeys showed evidence of drowsiness or inactivity during testing, and caudate stimulation did not elicit observable motor responses that might have modified the nature of escape responses. Finally, if generalized motor inhibition were responsible for the reduced force, it would be expected that the number of escape responses would have been reduced and escape latencies increased, but neither was observed in the present study. While generalized changes in the organism induced by caudate stimulation appear unlikely, another possible explanation for the reduced force is that each train of caudate stimuli produced a time-locked, motor inhibitory period following that train. If this were the case, then responses falling within the inhibitory period would be reduced in force. However, in order to account for the differential effectiveness of the C-T intervals, the latency distributions would have to have been differentially time-locked to caudate stimulation at effective C-T intervals as opposed to C-T intervals that did not reduce force. As we have shown, there was extensive overlap of the latency distributions for different C-T intervals, indicating that motor inhibition was not responsible for the reduced force. This argument does not assume that direct effects on response force would necessarily be accompanied by alterations of response latency or ,'ice versa; these measures could theoretically be affected quite independently. However, if the caudate stimulation did produce direct attenuation of response force, then this effect should have been independent of C-T interval, unless the effective intervals were accompanied by a shift of a significant number of responses within a critical caudate-motor response interval. Since C-T interval was the major determinant of response force and did not significantly affect the distribution of caudate-response intervals, it is concluded that the caudate effect was related to an alteration of sensory transmission. This conclusion is supported by the results of the covariance analysis.
131 On the basis of the discussion in the preceding two paragraphs, we conclude that caudate stimulation produced reductions in escape force which were not the result of either changes in levels of arousal or direct motor inhibition. The nature of the caudate effect therefore appear to be a reduction in the tendency of noxious stimuli to elicit intense emotional responses. The most obvious explanation for this effect would be that the reduced emotional responses to noxious stimuli simply reflect a reduction in the perceived painfulness of those stimuli. However, another possible explanation is related to the dissociation that can be made in humans between pain detection and pain tolerance. At low levels of painful stimulation, near pain detection threshold, intense emotional reactions are not elicited as they are at higher levels, near the pain tolerance threshold. Thus, a distinction can be made between pain detection or discrimination and pain reaction. The detection and tolerance limits of the pain continuum are associated with activity in different calibre nerve fibers in the peripheral nervous system8,22,3~-~5,47,5~,55,57, and there have also been suggestions of separate central conduction systems for the discriminative and reactive aspects of pain perception1, 9, lO,13,44,53,60. According to this scheme, the non-specific somatosensory pathways through reticular formation and intralaminar thalamus may be essential for the expression of emotional reactivity to intensely painful stimuli. On the other hand, direct spinothalamic conduction of pain input may mediate distinct sensations of pain without direct evocation of intense emotional reactivity. Since neurophysiological investigations have shown that inhibition of evoked activity in non-specific somatosensory pathwaysl,18,19,z0, 31 can be produced by caudate stimulation that appears not to inhibit evoked potentials in the lemniscal somatosensory pathway31,41, the effects of caudate stimulation could attenuate emotional reactivity without eliminating the discriminative aspects of pain. Thus, it is possible that the phasic effects of caudate stimulation mimic the chronic effects of frontal lobotomy, which results in attenuation of affective responses to pain without a concomitant alteration of pain thresholds20,~6,59. The monkeys in the present study behaved as if this were the case. Escape thresholds were not affected by caudate stimulation that substantially reduced the force exerted in terminating intense leg shock, and escape force appears to reflect the intensity of emotional reactions to pain stimuli. The time-course of the caudate-induced inhibition of pain reactivity closely parallels the time-course of the inhibition of non-specific thalamic and reticular neurons produced by caudate stimulation. Feltz et al. 18 found, in chloralose anesthetized cats, that the onset of the caudate-induced inhibition of the somatosensory responses of medial diencephalic neurons occurred at C - T delay intervals of from 0 to 26 msec. The upper limit of the duration of the inhibitory effect had a range that extended from 50 to 800 msec and a median duration of 183 msec. In addition, Lineberry and Siegel 38 and Siegel and Lineberry 50 have shown in awake cats that the spontaneous activity of mesencephalic tegmental cells is inhibited by caudate stimulation for periods of from 160 to 200 msec after the stimulus. These data are in close agreement with the time-course of the behavioral effects reported in the present study in which pain reactivity was found to be significantly reduced at C - T intervals of
132 25, 50 and 100 msec, but minimal attenuation was observed at the 200 msec delay. This correspondence between the neurophysiological and the behavioral effects ot caudate stimulation raises the possibility that the neurophysiological mechanisms by which caudate stimulation reduces pain reactivity are related to the inhibition o f mesencephalic and diencephalic neurons. it is important to note that caudate stimulation does not produce only inhibition. Facilitatory influences have also been demonstrated, and the most c o m m o n pattern o f unit activity is facilitation, followed by the inhibitory period, which is succeeded by a second facilitatory interval 38,51. In this context, it is interesting that escape force was significantly increased by caudate stimulation on 3 occasions - - at C - T delays o f - - 2 5 and 400 msec (electrodes Nos. 2P and 3 M L ; see Table 1). Since the latency o f initial facilitation is usually less than 5 msec St, and the intralaminar evoked potential from leg stimulation is well developed at 25-30 msec, the time relationships are appropriate for the observed increase in pain reactivity when caudate stimulation closely follows leg shock. Similarly a C - T delay of 400 msec could superimpose the rebound period o f facilitation with activity evoked by leg stimulation. Further direct comparisons o f these neurophysiological and behavioral effects are required to determine with more certainty the relationships between them. ACKNOWLEDGEMENIS
This research was supported by G r a n t NS 07261 from the National Institute of Neurological Diseases and Stroke. Dr. Lineberry was supported by a post-doctoral fellowship from the Center for Neurobiological Sciences (Training G r a n t M H 10320 from the National Institutes of Mental Health). The animal care was provided in part by N I H G r a n t 00421. The research described involved animals maintained in animal-care facilities fully accredited by the American Association for Accreditation o f Laboratory Animal Care.
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