Responses evoked from the thalamic centrum medianum by painful input: Suppression by dorsal funiculus conditioning

EXPERIMENTAL

NEUROLOGY

39,

215-222 (1973)

Responses Evoked From The Thalamic Centrum Painful Input: Suppression by Dorsal Funiculus JUDITH

Division Drive,

of Neurosurgery,

K.

NYQUIST

AND

Veterans

JERRY

Administration

H.

Medianum Conditioning

by

GREENHOOT

Hospital,

3350 LaJolla

Village

San Diego, Califorfzia 92161, and University of Califamia at San Diego, G&ran Drive and LaJolla Village Drive, LaJolla, California 92037 Received

September

23, 1972;

revised

November

8, 1972

Prior stimulation of either dorsal funiculus of the spinal cord in cats produces a suppression of cutaneous evoked activity recorded in the thalamic nucleus centrum medianum. The dorsal funicular influence is exerted bilaterally on activity arising from all four limbs. These data are presented as evidence that suppression of cutaneous information occurs rostra1 to the spinal cord, and that there may be central, as well as spinal, “gate control” mechanisms important in the transmission of painful information.

INTRODUCTION The Melzack-Wall “gate control” hypothesis of pain transmission (13) states that pain is not a modality pev se, but rather results from a particular pattern of afferent input to the spinal cord at the dorsal horn and is based upon the interaction between large and small peripheral fibers which are activated by a painful stimulus. The small fibers enter the dorsal root, many terminating directly or via interneurons on dorsal horn neurons whose axons project rostrally and contralaterally as the ventrolateral quadrant fibers. Large peripheral nerve fibers bifurcate upon entering the cord, sending a short branch among the neurons of the dorsal horn and a long branch to ascend the ipsilateral dorsal funiculus. According to the hypothesis, small A-delta and C fiber-mediated information is suppressed at the spinal cord level by activity in large A fibers. Small fiber activity has been correlated with painful experience in man (5). On the basis of anatomical and clinical information, the thalamic intralaminar nucleus centrum medianurn-parafascicularis complex (CM-Pf) has been implicated as having a role in pain perception (1, 6). A large number 1 The technical assistance of Mr. Gary L. White and the support of Dr. John F. Alksnc are gratefully acknowledged. 215 Copyright All rights

@I 1973 by Academic Press, of reproduction in any form

Inc. reserved.

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of spinal cord vertrolateral quadrant fibers, the classical “pain pathway” arising from neurons in the spinal cord dorsal horn, do not terminate in specific thalamic nuclei, but project to the brain stem reticular formation (IO), which then projects primarily to the ipsilateral CM (4). Evoked potential and single unit studies suggest that the centrum medianum is involved in the reception of high threshold, often painful, cutaneous information (1,3,6,8, 14). In order to study the nature and site of large and small fiber interaction, we have investigated the influence of spinal cord dorsal funicular stimulation on activity in centrum medianum evoked by high intensity peripheral electrical stimulation. Our results show that stimulation of the spinal cord dorsal funiculus alters subsequent evoked activity recorded in centrum medianum and suggest that this interaction may occur in sites rostra1 to the spinal cord, not only in the dorsal horn, as suggested by Melzack and Wall (13). METHODS Experiments were performed on 18 cats (2.5-3.0 kg) anesthetized with an alpha-chloralose (50 mg/kg) and urethan mixture. Thalamic evoked potentials were recorded through 2.7 M NaCl-filled glass micropipettes or Insulex-coated stainless steel electrodes, led through conventional preamplifiers to a signal averager, and displayed on a Tektronix 565 dual-beam oscilloscope. The signals were simultaneously recorded on magnetic tape for subsequent analysis. A laminectomy was performed at the thoracolumbar junction and the dura mater removed to permit placement of a bipolar stimulating electrode (electrode tips separated by 0.5 mm) on each dorsal funiculus (Fig. 1). Stimulation was accomplished through bipolar electrodes, either on dissected peripheral nerves, or through needles thrust into the central foot pads. The thalamic evoked potential was observed to be independent of the type of stimulating electrodes. Electrical stimuli were delivered by an isolated Grass S88 stimulator at a rate of 0.3/set, with pulse widths of 0.20.5 msec, and intensities of 60 v. Sixty volt peripheral stimulation was used in these experiments to insure that all A-delta and unmyelinated C fibers were activated (15, 16). Using the contralateral forelimb input, the CM-Pf complex was searched for evoked potentials having the appropriate configuration and latency as seen previously by Kruger and AlbeLFessard (S). The response to each peripheral input and both dorsal funiculi was determined. Once a reliable evoked potential elicited by electrical stimulation of the estremity was obtained, a condition-test (C-T) series was performed. The peripheral test shock to each of the extremities was preceded by a single shock to either

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MEDIANUM

a ipsi

contra

DC

contralateral superficial ‘radial nerve

DC

XL

.

contralateral sural nerve

FIG. 1. Evoked potentials were recorded through an electrode stereotaxically placed in the left centrum medianurn nucleus. Test stimuli were applied to all four extremities. Conditioning stimuli were applied independently to each of the spinal cord dorsal funiculi (DC) at the level of the thoracolumbar junction, between hind paw and fore paw inputs. IFP and IHP refer to ipsilateral forepaw and hind paw.

the contralateral or ipsilateral dorsal funiculus, at intervals ranging from 50-1000 msec. Recording sites were confirmed histologically by locating an electrolytic lesion produced at the electrode tip. RESULTS Although the results reported were obtained with high intensity stimulation, evoked potentials were also elicited at lower stimulus intensities. Potentials of maximum amplitude were achieved from all stimulation sites at intensities between 20 and 30 v. At these maximal stimulus intensities, evoked potentials were essentially identical, whether evoked by peripheral nerve or by paw stimulation of the samelimb. The configuration of the evoked potential from experiment to experiment differed somewhat in the relative amplitude and polarity of the various peaks, but the time relationships and latencies to peaks were very consistent. In the majority of experiments (SO%), the evoked potentials from all four extremities were virtually identical; in the remainder (ZOO/o), the forelimb and hindlimb potentials differed in amplitude. We attribute the amplitude and polarity differences to different recording loci within the CM-Pf complex (2).

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100

msec

FIG. 2. Records show averaged centrum medianum evoked activity, derived from the sum of 16 consecutive traces. Positivity downward deflection in this and subsequent records. Vertical markers represent stimulus shock artifacts. (A) CM evoked potential following test shock to ipsilateral hind paw (i = 60 v). (B) CM evoked potential following test shock to same site preceded at interval of 150 msec by single shock to the contralateral dorsal funiculus. Large amplitude positive-negative components of the evoked potential are abolished, whereas early short latency components are relatively unchanged. Note that the dorsal funicular conditioning shock evokes activity which has returned to baseline by the time the test shock occurs. (C) CM evoked potential following test shock to contralateral hind paw (; = 60 v). (D) CM evoked potential following test shock to the same site preceded at C-T interval of 150 msec by single shock to the contralateral dorsal funiculus. Large-amplitude components of test evoked potential are reduced, leaving early short latency waves unchanged. This experiment shows a suppressive effect of unilateral dorsal funicular conditioning shock on CM activity evoked from either side of the body.

Conditioning pulses of 3-5 v intensity, 0.3 msec duration, were applied to the dorsal funicular surface of either side at the thoracolumbar level, below the entrance to the cord of forelimb afferents (Fig. 1). Interaction between dorsal funicular and peripheral evoked activity was seen in the form of suppression or abolition of the late waves of the peripheral evoked potential (Fig. 2). The interaction occurred for as long as 400 msec after the dorsal funicular shock, but at the shorter C-T intervals (SO-ZOOmsec), interpretation of this interaction was sometimes complicated by the fact that the test-evoked potential occurred on the waning phases of activity evoked by the conditioning dorsal funicular shock itself. In all instances, the conditioning influence was one of suppression or abolition of the late components of the peripherally-evoked CM potential. Prior CM activity elicited

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by the conditioning shock was not a necessary condition for suppression. In all cases evoked potentials from all four extremities were influenced by both contralateral and ipsilateral dorsal funicular conditioning shocks. In ten experiments, the dorsal funiculi were sectioned bilaterally, and the C-T series repeated with stimulation of dorsal funiculi both above and below the section. Conditioning suppression was still evident with both rostra1 and caudal dorsal funicular electrode placement (Fig. 3). These results confirm those of Albe-Fessard (I), in that CM activity was evoked by dorsal funicular stimulation only below the transection. Following section of the dorsal funiculi, little or no activity was evoked by dorsal funicular stimulation above the transection. All suppressive effects, whether done in transected or intact preparations, were seen with stimulation of the spinal cord dorsal funiculi of either side of the midline. Although primary attention was paid to evoked potentials, eight single neurons were identified whose discharge pattern was altered by a conditionA T-- CHP

B C rostrdl VCHP

I

100

contrd

DC

- - -

mscc

Cor!r/lrmrle~l

Resporm

FIG. 3. Condition-test interactions after bilateral dorsal funicular section. Solid curve is test alone: dashed curve is C-T interaction. In this experiment, test shock is delivered to the contralateral hind paw. The conditioning shock to the contralateral dorsal funiculus occurs 200 msec prior to the test shock. Traces represent the average of 16 consecutive responses. (A) Superimposed traces of CM evoked potentials following bilateral dorsal funicular section. Dorsal funicular electrode placed caudal to section. The test evoked potential (T) is abolished by the prior dorsal funicular shock which itself evokes a potential in CM (C). (B) Superimposed traces of CM evoked potentials following bilateral dorsal funicular section. Dorsal funicular electrode placed rostra1 to section. The peripherally evoked CM potential is suppressed, as in A, but no potential is generated by the dorsal funicular stimulus itself.

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ing shock to either dorsal funiculus. The unit discharge to the peripheral shock in some cases was abolished by a dorsal funicular shock occurring 100-200 msec earlier. Other units responded to the high intensity peripheral input with a series of bursts. In these cases the conditioning shock effect was most profound on the later bursts, leaving the shortest latency burst unaltered. Still another discharge pattern was displayed by spontaneously discharging neurons, whose pattern consisted of a short latency (15 msec) burst followed by a long silent period (250 msec), with later resumption of the “spontaneous” discharge. Dorsal funicular shock had the effect of prolonging the silent period, but did not change the initial burst discharge. DISCUSSION This study implies a modulating role for the dorsal funicular system in the reception of high intensity peripheral cutaneous information as measured at a thalamic intralaminar nucleus, the CM-Pf complex. That dorsal funicular afferents evoke CM activity has previously been reported by AlbeFessard (1). On the basis of data obtained in transsected dorsal funiculus preparations, these investigators concluded that dorsal funicular aff erent fiber collaterals impinge upon neurons whose axons comprise the ventrolateral tract. Our findings confirm this and, in addition, suggest that there is a rostra1 site of interaction or convergence between the dorsal funiculuslemniscal system and pathways mediating high threshold cutaneous information. In experiments reported here, either ipsilateral or contralateral dorsal funicular stimulation suppressed late components of evoked potentials, regardless of location of the peripheral test stimulus. Since there are no known connections between dorsal funiculi of each half of the spinal cord, we propose a site of interaction rostra1 to the spinal cord, and independent of any spinal “gate.” In the cases where the conditioning dorsal funicular shock evoked CM activity, occlusion might explain the subsequent test evoked potential suppression. However, dorsal funiculus-evoked CM activity is not a necessary condition for producing the suppression (Figs. 2D and 3B). The bilateral and rostral-caudal patterns of interaction between limb afferents and dorsal funiculus fibers are also of interest. The system is nonspecific insofar as dorsal funicular large-fiber activity from either hind limb suppresses information arising from either forelimb. There are several possible explanations. The dorsal fmlcilus gracile fibers, during their rostra1 course to the ipsilateral nucleus gracilis, may give off collaterals in the cervical-upper thoracic spinal cord levels where forelimb afferents enter the cord and thus close a rostra1 spinal “gate” at that level. While this may explain interactions between stimuli on the same side, it does not account for

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the dorsal funicular influence on contralateral inputs. Another possibility is that dorsal funicular stimulation activates cortical structures, with effects on spinal cord mediated by descending corticofugal path\vays capable of influencing activity at the slGna1 cortl tlorsal horn (7). Our data shed no light upon this speculation. ~1 third pussil&ty is that the dorsal funicular system interacts with the ventrolateral quadrant pathway at a site rostra1 to the spinal cord. This interaction may occur in the brain stem or the thalamus itself, where a suppressive effect could be activated from many peripheral sources, and which could exert its effect diffusely and bilaterally. Our data showing that effects of stimulation of either dorsal funiculus are exerted upon activity evoked by peripheral stimulation of either side are consistent with this view. The hypothesis does not exclude the possibility of descending influence on the cord as a subsequent event. Other investigators have advanced the idea of a central neural substrate which functions to reduce response to noxious inputs. Melzack (11, 12) has proposed that part of the brain stem reticular formation is tonically inhibitory at all levels of the somatic projection system. In the behavioral esperiments of Mayer ct al. (9), rats were rendered analgesic following stimulation in the mesencephalic tegmentum-central gray region. Our esperiments suggest that a supraspinal suppressive mechanism may also be activated by peripheral stimulation. Insofar as these data may relate to pain, they remain consistent with the gate control theory proposed bq Melzack and IVall ( 13) but modify it by predicting another “gate” above the spinal cord. REFERENCES 1.

D. 1966. Organization of somatic central projections. Confrib. Physiol. 3 : 101-167. 2. ALBE-FESSARD, D., and D. BOWSHER. 1965. Responses of monkey thalatnus to stimuli under chloralose anesthesia. Elm. Clin. Neurophysiol. 19: l-15. 3. ALBE-FESSARD, C., and L. KRUGER. 1962. Duality of unit discharges from cat centrum medianum in response to natural and electrical stimulation. J. Ncwophysiol. 25 : 3-20. 4. BOWSHER, D., A. MALLART, D. PETIT, and D. ALBE-FESSARD. 1968. A bulbar relay to the centre median. J. Nrrlvoplzysiol. 31: 288-300. ALBE-FESSARD,

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5. COLLINS, W. F., JR., F. E. NULSON, and C. T. RANDT. 1960. Relation of peripheral nerve fiber size and sensation in man. Arclc. Nrwol. (Chicago) 3 : 381385. 6. ERVIN, F. R., and V. H. MARK. 1961. Studies of the human thalamus: IV. evoked responses. AM. NY ‘Icad. Sci. 112: 81-92. 7. FETZ, E. E. 1968. Pyramidal tract effects on interneurons in the cat lumbar dorsal horn. J. Neuropkysiol. 31: 69-80. 8. KRUGER, L., and D. ALBE-FESSARD. 1960. Distribution of responses to somatic afferent stimuli in the diencephalon of the cat under chloralose anesthesia. Exptl. Neural. 2: 442-467.

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9. MAYER, D., T. WOLFLE, M. AKIL, B. CARDER, and J. LIEBESKIND. 1971. Analgesia from electrical stimulation in the brainstem of the rat. Scic~ccc 174: 1351-1354. 10. MEHLER, W. R., M. E. FEFERMAN, and W. J. H. NAUTA. 1960. Ascending axon degeneration following anterolateral cordotomy. An experimental study in the monkey. Bruin 83 : 718-750. 11. MELZACK, R. 1971. Phantom limb pain: concept of a central biasing mechanism, pp. 188-207. In “Clinical Neurosurgery.” [R. G. Ojemann, Ed.], Williams and Wilkins Co., Baltimore. 12. MELZACK, R. 1971. Phantom limb pain: implications for treatment of pathologic pain. Anesthesiology 35 : 409-419. 13. MELZACK, R., and P. D. WALL. 1965. Pain mechanisms: a new theory. Science 150: 971-979. 14. PERL, E. R., and D. G. WHITLOCK. 1961. Somatic stimuli exciting spinothalamic projections to thalamic neurons in cat and monkey. Exp. Neural. 3: 256-296. 15. PRICE, D. D., and I. H. WAGMAN. 1970. Physiological roles of A and C fiber inputs to the spinal dorsal horn of macaca mulatta. Exp. New-ok 29: 383-399. 16. WAGMAN, J. H., and D. D. PRICE. 1969. Responses of dorsal horn cells of M. Mulatta to cutaneous and sural nerve A and C fiber stimuli. J. Neurophysiol. 32: 803-817.