J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.36.4.674 on 1 August 1973. Downloaded from

Journal ofNeurology, Neurosurgery, and Psychiatry, 1973, 36, 674-683

Renshaw cell activity in man1

J. L. VEALE2 AND SANDRA REES From the Van CleefFoundation Laboratory, Alfred Hospital, and Department ofPhysiology, Monash University, Clayton, Victoria, Australia

SUMMARY The H-reflex elicited in triceps surae by percutaneous stimulation of the posterior tibial nerve was conditioned by stimuli applied through the same electrode. The differential sensitivity of motor and sensory fibres to duration of the stimulus pulse made it possible to condition the H-reflex with either a motor or a sensory stimulus. With both types of conditioning, the H-reflex was in- hibited at conditioning-test intervals of 2-3 msec and was then facilitated, the peak of facilitation occurring at 5-8 msec with motor conditioning and 6-10 msec with sensory conditioning. The phase of facilitation was followed by further inhibition. We have concluded (1) that the effects of motor conditioning on the H-reflex result from the discharge of Renshaw cells activated by the volley in the motor , and (2) that the effects of sensory conditioning (at the times used in these experiments) are largely due to the activation of Renshaw cells secondary to the discharge of

alpha motoneurones by the conditioning volley. Protected by copyright.

Renshaw (1946) first described the changes which Experimental work to date has been largely occur in the excitability of spinal motoneurones on the cat and monkey, and there have been no as a result of stimulation of ventral roots in the accounts of Renshaw-like recurrent effects after of the cat. Since then considerable the stimulation of motor axons in man. We have information has accumulated concerning the previously demonstrated (Veale, Mark, and Rees, pharmacology and electrophysiology of the re- 1972) that there is a differential sensitivity of current effects of motoneurone discharge. These motor and sensory fibres to stimulus pulse dura- effects are thought to be due to the synaptic tion. With long duration pulses (1 msec or more) excitation of interneurones (Renshaw cells) sensory fibres have a lower threshold than motor which are activated by cholinergic recurrent col- fibres, whereas with short duration pulses (less laterals of spinal motoneurones. They exert an than 200 tsec) the motor fibres have the lower ipsilateral post-synaptic inhibition upon moto- threshold. With this technique, a Hoffman (H) neurones, interneurones, and also other Ren- test reflex can be conditioned by stimuli delivered http://jnnp.bmj.com/ shaw cells (Ryall, 1970; Ryall, Piercey, and to motor axons. These will conduct action poten- Polosa, 1971). The inhibition of motoneurones tials centrally leading to antidromic invasion of which results from ventral root stimulation is the spinal cord via the ventral roots. Thus a con- brought about by the direct action of Renshaw ditioning and test situation comparable with cells on motoneurones, while the facilitation that used by Renshaw can be investigated. In this which can also occur is a result of the inhibition way we have demonstrated both inhibitory and

of inhibitory interneurones-that is, disinhibi- facilitatory effects in man, and believe these to on September 28, 2021 by guest. tion (Wilson and Burgess, 1962: Hultborn, be secondary to the excitation of Renshaw cells. Jankowska, and Lindstrom, 1971a, b, c). Aspects of this work have been reported previ- ously (Veale, Rees, and Mark, 1972). 1 This work was funded by the Van Cleef Foundation and grant 71/308 from the National Health and Medical Research Council of Australia. METHODS 2 Van Cleef Foundation Research Fellow. Address for reprints: Professor J. L. Veale, Department of Human Physiology and Pharma- cology, University of Adelaide, Adelaide, South Australia, 5001, The subjects were 14 normal adults, with ages rang- Australia. ing from 20 to 40 years. They lay supine on a couch 674 J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.36.4.674 on 1 August 1973. Downloaded from

Renshaw cell activity in man 675

and averaged. It was considered that more reliable TO ANODE results were obtained in this way, since random variations could be expected to affect all procedures in the single run equally. In previous work (Veale, Mark, and Rees, 1972) we demonstrated that there is a differential sensitivity of motor and sensory fibres to stimulus pulse dura- tion. The popliteal fossa was explored with the stimu- DIFFERENTIAL lating electrode to find a spot where test stimuli (1 E -M.G. msec duration) yielded an H-reflex without any direct FIG. 1. Diagram of arrangement of stitnulating and motor (M) response, and motor conditioning stimuli recording electrodes. (20-50 ,usec duration) yielded a small M response with no H-reflex. Typical records are shown in Fig. 2. It was required furthermore that no H-reflex resulted with the relaxed left leg supported undler the thigh and ankle (Fig. 1). Surface recording ele(ctrodes were applied over triceps surae (gastrocnemiuIs and soleus mostly), and a copper sheet, about 3 cm square, was applied to the knee cap as the stimulatting anodal electrode. The cathodal electrode was a iround metal dome about 1 cm in diameter, covered by a saline- 1 msec. 22 volts soaked cloth, and mounted on an insulated rod whose position could be freely adjusted and then Protected by copyright. clamped. This electrode was applied oNver the pos- terior tibial nerve in the popliteal fossa. The relevant skin areas for stimulating and recordinig were first prepared by mild abrasion, washing, anid swabbing with methanol. Electrode resistances cf less than 10 kQ were obtained and Cambridge el(ectrode jelly / was employed at all stimulating and rec ording sites. 100#sec 62 volts Stimuli were generated by two Devices Mark IV stimulators connected in series. One gave square- Am wave electrical pulses of 1 msec duratic)n, and this was always used for eliciting the test H[-reflex. The other stimulator was modified to produce pulses down to 5 ,usec duration, with a rise tinne of about 20 msec 1 ,usec. This stimulator was used for the csonditioning l _I pulse, and generally was set at 50 ,usec. The maximum voltage used was 90 V. A Devices digitimer con- N.H.(24) http://jnnp.bmj.com/ trolled the of the timing stimuli and the gating of the FIG. 2. Two myograms, each an averaging device. average of 20 repe- elicited stimulation the The potentials were recorded differentiially, ampli- titions, by of posterior tibial la.lly, ampli- nerve. The upper trace shows an H-reflex with no M fled and displayed on a 565 Tektronix o response, the lower an M response with no Averaging of responses was done usiIns oithes H-reflex. sgeite CAT The duration and strength of the stimuli applied are Mnemotron Computer of Average Trans ( shown above the stimulus artefacts, model 400B), or a Radiation Instrumer tients Al which have been teD truncated for clarity. Calibrations apply to both on September 28, 2021 by guest. ment Laboratory (RIDL) analyser syst em(model(odvel ams 34-27), and outputs recorded on either a Moseley myograms. X-Y plotter or a Heath Servorecorder. By gating trains of pulses that advance the memiory of the averaging device, one sweep of the devi(ce could be from motor stimulation during a medium to strong split into four or five segments with significant voluntary contraction of the triceps surae. In some pauses between them. In a single run, thlis sequence experiments a sensory conditioning stimulus (1 msec of procedures could be repeated up to 5(0 times, the duration) was used. In this case the stimulus strength result of each procedure being consistebntly stored was adjusted to elicit a small H-reflex without a J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.36.4.674 on 1 August 1973. Downloaded from 676 J. L. Veale and Sandra Rees direct motor response. Care was taken to ensure that ditioning. Frequently two of the conditioning time the contractions after the test or conditioning stimuli intervals were kept constant throughout many runs, were occurring in triceps surae, and not in the lateral while the remaining two were changed. In this way peronei or the deep toe flexor muscles. one had a check on the overall stability of the results. When undertaking repeated sequences with test The test stimulus alone gave the standard against and conditioning stimuli, the interval between suc- which the conditioned responses were expressed. cessive test (H) reflexes was between one and two 2. In this sequence, the first, second, and fourth seconds. This interval is obviously a compromise segments were the test stimulus alone, and the third between having it so short that the H-reflex is extin- and fifth were test stimuli conditioned at some guished, and having it so long that the experiment selected time interval (the same for both). The first is impossibly tedious for the subject. and second segments gave a check that the stimulus repetition rate was not significantly altering the size Two sequences of five stimulating procedures were of the H-reflex. Each of the conditioned responses commonly employed: (in the third and fifth segments) was preceded and 1. A test stimulus alone in the first segment, then, followed by a test alone segment. (The first segment for the remaining four segments, a test stimulus con- follows the fifth, of course.) Thus any prolonged ditioned at four different time intervals. These con- after-effects following the conditioning of a response ditioning intervals could be negative as well as posi- could be discovered. The average of the preceding tive. This sequence was commonly employed when and following test responses gave the standard building up the graphs for motor and sensory con- against which the conditioned responses were ex-

IO sec ' 1 sec 1 2 sec 3 sec Protected by copyright.

I 1 m\/I H Ll I I ~~H | H

I/V III F I I I I 100 msec r, I I I I

I Test alone Test, 0 msec Conditioning. 0 msec, Conditioning. 0 msec http://jnnp.bmj.com/ I Conditioning, 2 msec, Test. 4 msec Test, 8 msec (negative I I conditioning) I 50 Sweeps, motor conditioning L. K. (19) FIG. 3. Averages of myograms with 50 sweeps of the CAT, with each sweep split into four segments,

separated by the vertical dashed lines. Each segment of averaging lasts 100 msec, and begins 1 sec after on September 28, 2021 by guest. the start of the previous segment, as shown by the timings marked at the top of the dashed lines. In the first segment, a test stimulus only was delivered at the start of the segment. In the second segment the test stimulus was delivered at the start of the segment and the motor conditioning stimulus 2 msec later (negative conditioning). The direct M response can be seen, as well as the absence ofsignificant effect on the test reflex. In the third andfourth segmsnts the motor stimulus was given a few milliseconds after the start of the segment, and the test stimulus follows by 4 and 8 msec respectively. The inhibition at + 4 msec andfacilitation at + 8 msec can be clearly seen. Stimulus artefacts have been truncated for clarity. Calibrations apply to all segments. J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.36.4.674 on 1 August 1973. Downloaded from Renshaw cell activity in man 677

0 sec :1-5 sec 3 sec :4 5 sec 6 sec

[1 A 11

CONDITIONED. CONDITIONED, 4m[- TEST ALONE TEST ALONE + 2 msec TEST ALONE +2 msec 0I4mV l

I B .1a ----- 11- c Protected by copyright.

:CONDITIONED. CONDITIONED, 80 msec i + 10 msec + 10 msec

10 SWEEPS, MOTOR CONDITIONING D.H. (33) FIG. 4. Two averages ofmyograms, each with 10 sweeps ofthe RIDL, and each with sweep split into five segments, separated by vertical dashed lines. Each segment ofaveraging lasts 80 msec, and begins 15 sec after the start of the previous segment, as shown by the timings marked at the top ofthe dashed lines. In all segments a test stimulus was delivered 30 msec after the start of the segment. In segments three and five it was preceded by a conditioning stimulus, 2 msec

beforehand in A, 10 msec in B. The contrasting effects on the H-reflex can be clearly seen. Stimu- http://jnnp.bmj.com/ lus artefacts have been truncated for clarity. Calibrations apply to all records. pressed. Control of the pulses for the various se- RESULTS quences was aided by a Ledex stepping switch. Stimulation was begun 10 to 20 seconds before MOTOR CONDITIONING OF H-REFLEX Condition- averaging of the responses was started. This elimin- ing stimuli applied to motor axons will cause ated some of the early changes in an H-reflex that action potentials to travel in both directions away on September 28, 2021 by guest. occur after a rest period and improved the stability from the stimulating electrode. Those travelling of the results. Subjects were encouraged to relax antidromically will enter the spinal cord via the fully throughout the recording session of one to two hours, but were not permitted to sleep. ventral roots and will exert effects on the test Measurements of the greatest peak-to-peak ampli- reflex, which reach the spinal cord in spindle tude of the triphasic H-reflexes were made, and afferent nerve fibres via the dorsal nerve roots. conditioned responses expressed as a percentage of An example of the experimental records, unconditioned responses. shown in Fig. 3, illustrates the effects exerted on J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.36.4.674 on 1 August 1973. Downloaded from 678 J. L. Veale and Sandra Rees the H-reflex by motor conditioning stimuli ap- and conditioning volleys, although we did not plied at -2, + 4, and + 8 msec. The complete test this systematically and the relationship is results from four of the 14 experiments are pre- complex. sented graphically in Fig. 6 below. The graphs The use of negative conditioning times enabled show the percentage changes in H-reflex ampli- us to determine whether or not the conditioning tude (in terms of the unconditioned reflex re- and test stimuli were exciting two separate frac- sponse) with various intervals between motor tions of the triceps surae motoneurone pool. conditioning and test stimuli. The afferent volley giving rise to the test reflex Motor conditioning at 0 msec could not be was initiated 2-10 msec before the conditioning investigated since the two stimuli were applied stimulus to the motor axons (negative condition- through the same electrode. Inhibition of the H- ing). The test reflex would therefore have en- reflex was evident at 1 msec and a point of maxi- gaged the spinal motoneurones and would be mal inhibition was reached at 2-3 msec. Occa- descending in the ventral root axons before the sionally the H-reflex fell to 10% of the uncon- antidromic volley had reached the spinal cord. ditioned response but was more usually 3050%O. If a reduction in the size of the recorded H-reflex This inhibitory period was immediately followed had occurred it would have indicated that the by a return of the response back to near the con- antidromic motor action potentials evoked by trol level (80-120%) or into a phase of facilita- tion-that is, up to 200-250%. This is clearly the conditioning stimulus had collided with the seen in Fig. 4. The peak of facilitation occurred orthodromic motor action potentials elicited by at 5-8 msec. This was followed by further in- the test stimulus (occlusion, Fig. 5). As there was hibition which persisted in varying degrees for no significant reduction in the H-reflex with Protected by copyright. up to 30 msec, this being the limit of our testing negative conditioning (Figs 3 and 6) there was no period. The actual extent of inhibition and facili- collision in motor axons. Motor (conditioning) tation could vary quite widely between subjects and sensory (test) stimuli were therefore exciting and in the same subject on different days (see separate portions of the triceps surae moto- subject LK in Fig. 6), although the pattern of neurone pool. This conclusion is consistent with the response as described remained the same. It is the visual observation that the test and con- our impression that this variation partly depends ditioning volleys elicited contractions in different upon the relative and absolute size of the test parts of the triceps surae muscle.

FIG. 5. Diagram to illustrate collision in motor axons with negative conditioning intervals (motor stimulus later than

sensory stimulus). In the http://jnnp.bmj.com/ example illustrated, one of the motor axons carrying an orthodromic that otherwise would elicit an H-reflex is also carrying an = antidromic action potential from the motor conditioning

stimulus: the H-reflex in this on September 28, 2021 by guest. case will be halved. If negative conditioning is without effect on the H-reflex, then there is no commonality between motor axons carrying action poten- tials for the H-reflex response and those stimulated by the motor conditioning stimulus. J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.36.4.674 on 1 August 1973. Downloaded from

Renshaw cell activity in man 679

MOTOR CONDITIONING a SENSORY CONDITIONING w z 300 I 0 - LK(21) DH (33) TS(34) Z 200- - 0 a z _ 100 ---i U. 11 0 _ i

- u, 0- I I 1 I I I I I1 _ _ 2 I§I-I I I ,U) 300-0 Ln z _ 0 a. LKz (14) NHt23) _ JV(28) > 200- C I' U' I' __- 0 l'1 z 100-i 1il _1 F _ I i oz n.

120 a http://jnnp.bmj.com/ U) Z 100 0 z O -4 FIG. 7. Graph (filled circles) 0~ -), ofpercentage change in the UO 0 80 Z 0 conditioned H-reflex at + 2 lY o msec conditioning interval, plotted against the strength (in oZ 0 volts) of the conditioning z z O IL motor stimulus. Also plotted z in open circles is the size of on September 28, 2021 by guest. the direct M wave generated 0Z $ C) o by the conditioning stimulus, 4)tlE and its magnitude is indicated by the vertical scale on the right. 52 56 60 64 68 72 76 80 m STIMULUS VOLTAGE J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.36.4.674 on 1 August 1973. Downloaded from

680 J. L. Veale and Sandra Rees

EFFECT OF VARIATION IN STRENGTH OF MOTOR although it occurred as early as 10 msec in one CONDITIONING STIMULUS In this type of experi- experiment. ment a conditioning interval of +2 msec was selected and the effect of changing the strength OTHER ASPECTS Tetanic stinulations In three of the motor conditioning stimulus investigated. experiments trains of four motor or four At this time interval there is significant inhibition sensory conditioning stimuli were applied, in- of the H-reflex. As the strength of the condition- stead of the usual single stimulus. With such ing stimulus was reduced, the extent of the in- tetanic motor conditioning, various levels of hibition of the H-reflex was correspondingly re- inhibition were evident at test intervals of up to duced, eventually reaching the control level of 30 msec. With tetanic sensory conditioning the 100%. At this point there was still a significant H-reflex was completely extinguished for inter- recordable M wave. Presumably, some central vals of up to 30 msec. In neither case was post- summation is necessary before inhibitory effects tetanic facilitation evident. occur. The results of one such investigation are shown in Fig. 7. Over the range of 56 to 78 V, Absence of inhibition In a few subjects it was the conditioning stimulus elicited only an M noted that motor conditioning stimuli failed to wave whose magnitudes are plotted in the Figure. produce initial inhibition of the H-reflex. On Strengths of conditioning stimuli immediately visual examination of the muscle groups con- higher than 78 V also generated an M wave and tracting in these subjects, it was evident that the no H-reflex, but could generate an H-reflex when motor conditioning stimuli were stimulating (in- the subject voluntarily contracted triceps surae. advertently) the deep toe flexor muscles rather

At such stimulus levels stimulation of type Ia than the gastrocnemius/soleus muscles. Correc- Protected by copyright. nerve fibres is obviously occurring. However, tion of this error by repositioning the electrode below this level of 78 V it is unlikely that any yielded typical results. significant stimulation of la fibres is taking place. Motor conditioning stimuli in peroneal nerve In two experiments the motor conditioning stimuli SENSORY CONDITIONING OF H-REFLEX Condition- were applied to the peroneal nerve, while the ing stimuli applied to sensory fibres will cause the test stimuli were applied through a second elec- action potentials to travel orthodromically to trode to the posterior tibial nerve, both electrodes spinal cord in the Ia afferent fibres and to exert being positioned over the popliteal fossa. For on the test reflex which will follow their effects test intervals of up to 30 msec the H-reflex was two the seven in the same fibres. Results from of usually inhibited to 50-75o of the uncondi- experiments are presented in Fig. 6. tioned response. Facilitation of the H-reflex did Sensory conditioning at 0-1 msec could not not occur at any of the test intervals. be investigated, since the duration of the con- ditioning stimulus was 1 msec and test and con- Possible interactions at stimulating site It is http://jnnp.bmj.com/ ditioning stimuli were applied through the same possible that the demonstrated effects of motor electrode. conditioning arise because the conditioning In all of the experiments, complete extinction stimulus has partially depolarized some sensory of the H-reflex was evident at 2-3 msec and in fibres. It could then be envisaged that this effect two experiments lasted until 4 msec. Rapid re- persists at the stimulating site sufficiently long covery of the H-reflex followed this period of for the excitability to be different when the test extinction and there was usually a period of stimulus is delivered. Thus the change in size on September 28, 2021 by guest. facilitation of the response to 200-250%, al- of the conditioned reflex may reflect change in though in two of the experiments the response size of the test volley travelling to the cord. It is returned to only 65% and 85%. The peak of this technically difficult to record neurograms from facilitation, which occurred at 6-10 msec, was the posterior tibial nerve, so we undertook an followed quite abruptly by further inhibition of investigation using the ulnar nerve, selected for the response. In six of the experiments marked ease of recording. Identical paired stimuli were suppression had occurred by about 20-30 msec, applied at the wrist, and the evoked neurograms J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.36.4.674 on 1 August 1973. Downloaded from

Renshaw cell activity in man 681 recorded at the elbow. The time interval between In order to justify the first conclusion, it is the stimuli was varied, and the effect upon the necessary to exclude several important possi- second response observed. No change in the bilities: height of the second response occurred, even 1. The conditioning pulse has stimulated when the separation between stimuli was as motor axons, and caused a direct motor con- short as 1 msec. It was accordingly considered traction. This in turn has caused an afferent unlikely that such a mechanism would be in discharge responsible for the changes in the test operation when stimulating the posterior tibial reflex. After delivery of a stimulus to . axons in the popliteal fossa, it would take about 6 msec for conduction and initiation of the direct Possible cutaneous stimulation It is possible that motor (M) contraction, and another 6 msec the demonstrated conditioning effects arise be- for the afferent discharge to travel back to the cause of stimulation of skin afferent nerve fibres popliteal fossa, taking a total of approximately by the conditioning stimulus. This was elimin- 12 msec. It is obvious then that such a mechan- ated by using two stimulating electrodes in the ism could not explain any reflex changes that popliteal fossa. One was adjusted to produce a occur earlier than this. Our testing intervals were small test H-reflex. The other was made to pro- taken to 30 msec, but there were no sudden duce an easily perceptible stimulation of the skin effects occurring in the 12-30 msec range, only close to the test electrode, but no muscular con- a steady decline from the early peak of facilita- traction (direct or reflex). Using this latter stimu- tion. lus as a conditioning stimulus, it was demon- 2. The conditioning M contraction has altered strated that it was without effect on the test some peripheral aspect of the nerve-muscle Protected by copyright. H-reflex. mechanism, rendering it more sensitive to the H volley. This is excluded by the double M ex- Possible muscular influences Although the con- periments, and also is most unlikely, since the ditioning and test volleys are exciting substan- M and H waves were exciting different regions tially different regions of triceps surae, it may be of the muscle. argued that there is enough commonality for the 3. The antidromic action potentials have in- conditioning effects to be explicable in terms of vaded the cell bodies of the motoneurones, and facilitation of the contractile mechanism itself. induced complex excitability changes respon- Since the direct M wave occurs some 5-6 msec sible for the changes in the test reflex. This is after the conditioning stimulus is given, and the effectively excluded by the demonstration, using test H response some 35 msec or more after the negative conditioning, that the conditioning and test stimulus, the region of interest is from 30 test stimuli are exciting different fractions of the msec and later. Double stimuli, each eliciting motoneurone pool of triceps surae. The anti- direct M waves were delivered over a range of dromically activated motoneurones are not those http://jnnp.bmj.com/ 10-40 msec separation, and the second (con- excited by the testing H-reflex. ditioned) response compared with the first. No 4. There is a remote possibility of the effects variations in amplitude occurred. being based upon some dendro-dendritic inter- action. That is, the conditioning volley leads to an antidromic depolarization of the of DISCUSSION some of the motoneurones. This gives rise to a We have concluded that the effects of motor change in the excitability of dendrites of other

(1) on September 28, 2021 by guest. conditioning on the H-reflex result from the dis- motoneurones in the pool, explaining the facili- charge of Renshaw cells, activated by the anti- tation phase of the conditioned H-reflex. Nelson dromic volley in the motor axons, and (2) that (1966) has demonstrated that such an interaction the early excitability changes that follow sensory takes place between motoneurones in the mam- conditioning of an H-reflex are largely due to the malian spinal cord (cat). If the information given activation of Renshaw cells secondary to the by Nelson is applicable to humans, then this discharge of alpha motoneurones by the con- interaction is most unlikely to be the explanation ditioning volley. of our results. It required large antidromic vol- J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.36.4.674 on 1 August 1973. Downloaded from

682 J. L. Veale and Sandra Rees leys to a major part of a ventral root in order to the early excitability changes that follow sensory demonstrate slight facilitation of short duration, conditioning may be largely due to recurrent about 1 msec. Our conditioning volleys were effects-there are a number of factors to con- very much smaller, and the resulting facilitation sider. The early (2-3 msec) suppression and sub- larger and of longer duration. We conclude that sequent facilitation (5-15 msec) of the H-reflex dendrodendritic interaction is not a plausible have been previously described in man (Paillard, explanation for our phase of facilitation. 1955; McLeod, 1969). Paillard (1955) ascribed 5. The possibility of skin afferent fibres being the early suppression to refractoriness in nerve excited by the conditioning stimuli and causing fibres. Without direct monitoring of the con- the changes has been excluded. ditioning and test volleys at these short intervals, We therefore concluded that the conditioning one cannot be certain of the constancy of the motor action potentials invaded the collateral testing volley reaching the cord, but it is possible branches of the motor axons and stimulated that refractoriness of nerve fibres contributes. Renshaw cells, whose activity was responsible Furthermore, the absolute and relative refractory for the subsequent effects. periods of the muscle may influence the results. The phase of facilitation of the H-reflex is ex- The general pattern of recurrent inhibition and plicable in terms of activation of the subliminal facilitation resulting from antidromic motor con- fringe by the conditioning volley as well as by ditioning of motoneurones in man is similar to disinhibition of motoneurones via Renshaw the pattern found in experimental animals by cells. However, the pattern of inhibition and Renshaw (1946) and later elaborated upon by facilitation with sensory conditioning is so com- Eccles, Fatt, and Koketsu (1954), Wilson (1959) parable with that obtained with motor condition-Protected by copyright. and others. There was a period of inhibition of ing that we accordingly concluded that recurrent the motoneurones (as shown in our experiments effects subsequent to activation of the alpha by a depression of the H-reflex) at short condi- motoneurones with sensory conditioning con- tioning test intervals followed by a period of tributed significantly to the observed changes. facilitation at longer intervals. In both situations There has as yet been no anatomical demon- the motoneurones were found to be maximally stration in animals of cells in the spinal cord with inhibited at a conditioning-test interval of 2-3 the necessary location and connections to identi- msec but the peak of facilitation was reached fy them unequivocally as Renshaw cells. Scheibel much earlier and was of a shorter duration in and Scheibel (1971) have given a thorough ac- man than it was in the experimental animals count of the difficulties relating to their identifi- (Renshaw, 1946; Wilson, 1959). Wilson (1959) cation. They are careful to make it plain that did, in fact, mention that the onset of facilitation they are not disputing the demonstrated electro- occurred at a conditioning-test interval of physiological and effects that approximately 3 msec and this concurs with our pharmacological

follow stimulation of ventral roots (see Willis, http://jnnp.bmj.com/ results. As similar experiments have not been 1971, for a review). This problem of anatomical performed on primates, it is impossible to know identification is not of direct importance to the whether differences in the results indicate a true present investigation. species difference or are merely a reflection of the different conditions. experimental We acknowledge the considerable contribution of It seems most likely that the brief period of in- Dr. R. F. Mark, who took a substantial part in the creased excitability is due to recurrent disinhibi- initial planning and development of this project. He tion of motoneurones. This would result from actively participated in several of the early experi- on September 28, 2021 by guest. Renshaw cells inhibiting interneurones which are ments, has contributed much to our discussions of tonically inhibitory to motoneurones. The evi- this work, and has read the manuscript. We thank dence from cats (Hultborn et al., 1971a, b, c) Miss Louise Keegan for her help in the laboratory, indicates that the inhibitory interneurones in- and for the preparation of the illustrations. We are clude those on the grateful to Professor A. K. McIntyre for the use of disynaptic inhibitory pathway the CAT, and to Dr. W. R. Webster (Department of from the muscle spindles of antagonist muscles. Psychology) for the use of the RIDL. We are grateful In considering the second conclusion-that to Professor R. Porter for reading the manuscript. J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.36.4.674 on 1 August 1973. Downloaded from Renshaw cell activity in man 683

REFERENCES axons of spinal ventral roots. Journal of Neurophysiology, 9, 190-204. Eccles, J. C., Fatt, P., and Koketsu, K. (1954). Cholinergic Ryall, R. W. (1970). Renshaw cell mediated inhibition of and inhibitory in a pathway from motor- Renshaw cells: patterns of excitation and inhibition from collaterals to motoneurones. Journal of Physiology, 126, impulses in motor axon collaterals. Journal of Neurophysi- 524-562. ology, 33, 257-270. Hultborn, H., Jankowska, E., and Lindstr6m, S. (1971a). Ryall, R. W., Piercey, M. F., and Polosa, C. (1971). Inter- Recurrent inhibition from motor axon collaterals of trans- segmental and intrasegmental distribution of mutual in- mission in the Ia inhibitory pathway to motoneurones. hibition of Renshaw cells. Journal of Neurophysiology, 34, Journal ofPhysiology, 215, 591-612. 700-707. Hultborn, H., Jankowska, E., and Lindstr6m, S. (1971b). Scheibel, M. E., and Scheibel, A. B. (1971). Inhibition and Recurrent inhibition of interneurones monosynaptically the Renshaw cell. A structural critique. Brain, Behavior activated from group Ia afferents. Journal of Physiology, and Evolution, 4, 53-93. 215, 613-636. Veale, J. L., Rees, S., and Mark, R. F. (1972). Renshaw cell Hultborn, H., Jankowska, E., and Lindstrbm, S. (1971c). activity in normal and spastic man. New Developments in Relative contribution from different nerves to recurrent Electromyography and Clinical Neurophysiology, 3, 250- depression of Ia IPSPs in motoneurones. Journal of 261. Physiology, 215, 637-664. Veale, J. L., Mark, R. F., and Rees, S. (1972). Differential sensitivity of motor and sensory fibres in human ulnar McLeod, J. G. (1969). H reflex studies in patients with cere- nerve. Journal of Neurology, Neurosurgery, and Psychiatry, bellar disorders. Journal of Neurology, Neurosurgery, and 36, 75-86. Psychiatry, 32, 21-27. Willis, W. D. (1971). The case for the Renshaw cell. Brain, Nelson, P. G. (1966). Interaction between spinal motoneu- Behavior and Evolution, 4, 5-52. rones of the cat. Journal of Neurophysiology, 29, 275-287. Wilson, V. J. (1959). Recurrent facilitation of spinal reflexes. Paillard, J. (1955). Reflexes et Regulations d'Origine Proprio- Journal of General Physiology, 42, 703-713. ceptive chez l'Homme. Arnette: Paris. Wilson, V. J., and Burgess, P. R. (1962). Disinhibition in the Renshaw, B. (1946). Central effects of centripetal impulses in cat spinal cord. Journal of Neurophysiology, 25, 392-404. Protected by copyright. http://jnnp.bmj.com/ on September 28, 2021 by guest.