J. Physiol. (1984), 355, pp. 85-97 85With 4 text-figures

Printed in Great Britain

THE ROLE OF SPINAL CORD TRANSMISSION IN THE VENTILATORYRESPONSE TO EXERCISE IN MAN

BY L. ADAMS, H. FRANKEL, J. GARLICK*, A. GUZ, K. MURPHYAND S. J. G. SEMPLE

From the Department of Medicine, Charing Cross Hospital Medical School,the Department of Medicine, Middlesex Hospital Medical School

and The Spinal Injuries Unit, Stoke Mandeville Hospital

(Received 30 November 1983)

SUMMARY

1. The ventilatory response to electrically induced exercise was studied in thirteenpatients with traumatic spinal cord transaction at or about the level of T6. Thesteady-state and on-transient responses to this exercise were compared with thoseobtained in eighteen normal subjects (Adams, Garlick, Guz, Murphy & Semple, 1984).

2. Exercise was produced by surface electrode stimulation of the quadriceps andhamstring muscles so as to produce a pushing movement at 1 Hz against a springload.

3. At rest there was no significant difference between normals and patients, exceptthat the patients had a lower CO2 elimination (Pco2) and end-tidal Pco, (PET,Co2) anda higher heart rate.

4. On exercise the mean rise in Vco2 for the patients was 172 ml min- (S.D. 72),and for the normals was 287 ml min- (S.D. 143). The corresponding mean changesin ventilation (14) were 4-4 1 min- (S.D. 2 2) and 7-6 1 min- (S.D. 3-2). However,the ventilatory equivalent for CO2 (A 1I/A 1Co2) in the steady state was not significantlydifferent between patients (26-0, S.D. 5 9) and normals (28-5, S.D. 7 4).

5. In the steady state there was a mean rise in PETCO, of 0-9 mmHg (S.D. 1-4) inthe normals, and 3-2 mmHg (S.D. 2 7) in the patients, but there was overlap betweenthe two groups. In many experimental runs in both groups, PET,Co2 did not rise, andsometimes fell. Where PCO2 did rise, the ventilatory response to exercise could notbe accounted for on the basis of the ventilatory sensitivity to CO2 inhalation. Fromarterial sampling in three of the patients it was found that when PETC02 rose, thecorresponding change in Paco2 was less.

6. During the on transient, there was a significant rise in both Vco. and 14 by thesecond breath in both groups. At the end of the on transient the normal subjects hadachieved 84% (S.D. 40) of the steady-state increase in Vco2 and 88% (S.D. 24) of theincrease in 14. The corresponding values for the patients were 67% (S.D. 17) and 77%(S.D. 16) respectively; these differences between normals and patients are significant.The increase of 14 during the on transient in the patients was achieved almost entirely

* Present address: Department of Physiology, Chelsea College, London.

L. ADAMS AND OTHERS

by an increase in tidal volume whereas in normals, an increase in respiratory ratewas a more important component.

7. We conclude therefore that in man, spinal cord transaction with a presumedloss of muscle afferents allows a ventilatory response to electrically induced exercisethat cannot be explained by classical chemoreception. This suggests an, as yet,undetermined chemical stimulus.

INTRODUCTION

The experiments described in the previous paper (Adams, Garlick, Guz, Murphy& Semple, 1984) suggest that neither the cortex, nor other higher centres within thecentral nervous system are necessary for the normal matching of ventilation to CO2elimination in man exercising below the anaerobic threshold. However, it is possiblethat some afferent information from the exercising muscles associated with theirmovement or the development of tension, could still play an important role in makingventilation appropriate to the amount of exercise. Examination of this problem inanimals over the last 20 years (Kao, 1963; Kao & Suckling, 1963; Lamb, 1968; Tibes,1977; Levine, 1979; Weissman, Whipp, Huntsman & Wasserman, 1980; Phillipson,Bowes, Townsend, Duffin & Cooper, 1981; Phillipson, Duffin & Cooper, 1981) hasgiven conflicting results. Our own experiments in dogs with spinal cord transactionand electrically induced 'exercise' of the paralysed muscles (Cross, Davey, Guz,Katona, Maclean, Murphy, Semple & Stidwell, 1982) could not confirm a role forspinal cord transmission of afferent information from the moving legs, at least in thesteady state. Asmussen, Nielsen & Wieth-Pedersen (1943) came to a similar conclusionas a result of a study on a single patient with tabes dorsalis, who could move his legsbut could not feel them.The present study investigates the ventilatory response in man with cord tran-

section, using electrical stimulation of the paralysed muscles as described in theprevious paper (Adams et al. 1984). We wished to know whether and how ventilationincreases as limbs are exercised without any sensory information from the exercisinglimb. We thought that such patients would provide a means of studying the chemicalcontrol of breathing during exercise without afferent neural input to and from theexercising limbs.

METHODS

Electrically induced exercise (EEL) was studied in patients with traumatic spinal cord transactionwhich was judged on clinical grounds to be complete. Informed consent was obtained from eachpatient and ethical approval for the experiment was given by the Ethical Committee of the StokeMandeville Hospital.The level of cord transaction ranged between T4 and T9 (skin dermatome); the commonest level

was T6. The experimental set-up and stimulating techniques used are described in the precedingpaper (Adams et al. 1984); the only differences were in allowances made for patients' incapacities.Consequently, the patients' feet were tied firmly to the pedals and their knees tied loosely together.These measures helped in maintaining the correct posture and preventing the limbs spreading apart,which would have altered the direction of the force produced by the muscle stimulation. The levelof stimulation was set initially at that used in normals, and then adjusted, if necessary, to givea good pattern of vigorous exercise.The level of exercise that could be produced in these paraplegic limbs was dependent on the

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ROLE OF SPINAL CORD IN EXERCISE VENTILATION

amount of wasting and this was variable, being less the higher the lesion. Some patients with highlesions who had 'spasms' in the legs were particularly free of wasting. Patients with lesions belowT9 had gross wasting and no exercise capability; this was presumably due to injury to the vascularsupply of the lower cord segment with resulting loss of function of the anterior horn cells. Patientswith such low lesions could not be used in this study.

Respiratory and circulatory measurements were made of expiratory duration (te)' respiratoryrate (RR), tidal volume (VT), ventilation (PI), 02 consumption (02), CO2 production (co'2), gasexchange ratio (R), end-tidal PCO, (PET,Co.), electrocardiogram (e.c.g.) and systolic and diastolicblood pressure as described in the preceding paper (Adams et al. 1984). The 'integration' methodof calculating Vco2 per breath (Cross et al. 1982) was validated, resulting in the followingrelationship:

TcoI (steady-state) ml min' = 0-738 V7Co2 (integration) + 35 4, r = 0O89.

In three patients catheters (Abocath) were inserted percutaneously into the radial artery formeasurements of Pco,, PO2, and pH (Radiometer ABLI).

Spirometry was used to measure vital capacity (VC), and its sub-divisions, the inspiratorycapacity (IC) and expiratory reserve volume (ER V), as well as the forced expiratory volume in1 second (FE V,). In addition a chest radiograph was taken.

Exercise protocolThe protocol followed was as in the preceding paper (Adams et al. 1984) with the exception that

no voluntary exercise could be performed. Sensitivity to inhaled CO2 was estimated after exercise,as previously described (Adams et al. 1984).

Statistical analysisThis was carried out as in the previous paper (Adams et al. 1984).

RESULTS

These studies were carried out in thirteen patients and compared with the resultsof electrically induced exercise (EEL) in eighteen normal subjects described in theprevious paper (Adams et al. 1984). Some of the patients were studied at two levelsof exercise on more than one occasion. This resulted in forty-one runs for the patientsbeing available for comparison with forty-six runs from the normal subjects.The patients had been through a full rehabilitation programme at the Spinal

Injuries Unit, Stoke Mandeville Hospital. None had symptoms of respiratory diseaseand the chest radiographs were all normal. The spirometric data expressed as thepercentage predicted for height, age, weight and sex were: VC 68-7 (S.D. 8 3); IC 68-4(S.D. 13.2); ERV 67-3 (S.D. 16-8) and FEV1 80-0 (S.D. 13-2).The patients found that electrically induced leg exercise caused no discomfort.

Neither muscle spasms, nor emptying of the bladder and bowels was ever inducedby the stimulation. The patients sometimes sensed a rhythmic whole-body motion,but often had no idea that exercise had started until they looked at their legs. Nosensation of 'electricity' was felt above the level of the lesion except on one occasionwhen the stimulation voltage was excessively raised.

Control measurements

There were no significant differences between normals and patients for any of themean values of the respiratory and circulatory variables except that in the patientsTCO2 and PET, C02 were significantly lower and heart rate was significantly higher(Table 1).

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88 L. ADAMS AND OTHERS

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ROLE OF SPINAL CORD IN EXERCISE VENTILATION

Exercise: steady stateIn normals all the mean changes in the measured variables on exercise were

significant, except for PETCO2 and diastolic blood pressure (Table 1). The meanchanges in the patients that were significant on exercise were the same as in normalsexcept in three respects, namely that there was a significant rise in PETC02' and no

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change in heart rate, or systolic blood pressure. The final column of Table 1 recordswhether there is any significant difference in the changes in circulation and ventilationbetween the normals and the patients. The mean increase in PCo2 in the normals wasgreater than in the patients, the percentage increases being 125% and 81 %respectively. The mean increase in V02 was also less in the patients than the normals.The mean increase in PI was proportional to that of PCo2 in the normals and patients,so that the ventilatory equivalent for CO2 (A 1I/A VC02) was not significantly differentbetween the two. This is illustrated graphically in Fig. 1 where PC02 is plotted againstPI. It can be seen that all the measurements on the patients, both for rest and exercise,lie close to or on the regression line derived from the normals.Although the mean increase in V4 in the patients was less than in the normals, the

mean increase in VT was not significantly different, whilst the increase in RR wassignificantly less in the patients. This shows that the contribution of VT to the increasein VI was proportionally greater in the patients than the normals.The mean increase in PET, C02 for the patients was significantly greater than for the

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90 L. ADAMS AND OTHERS

normals. On examination of the individual responses (Fig. 2) a large degree of overlapbetween the patients and normals was seen. In four runs PET,C2 fell, whilst in afurther twenty-one runs it can be seen from Fig. 2 that the rises in PETCO0 were smalland fell within the range of change of the normals, which cluster round the zero pointof the X-axis. In the remaining sixteen runs a rise in PET, C0, of4-9 mmHg was seen;this did not occur in the normals except on one occasion.

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The circulatory response of the patients differed from the normals in that therewas no significant change in heart rate and systolic blood pressure on exercise.

Blood gas and acid-base changes in arterial bloodIn three patients (two runs per patient) arterial blood samples were taken before,

and during the last minute of, exercise. There was no hypoxaemia at rest and Pa °2always rose on exercise. pH always fell (mean -0-028, S.D. 0G015, range -0-013 to-0 053 units) and Pa co, always rose (mean + 17, S.D. 1P5, range +0 3 to+3-8 mmHg), whilst base excess fell (mean -1-4, S.D. 1.1, range -0-2 to-33 mmol 1-1). Thus the fall in pH on exercise in the patients was due to acombination of respiratory and metabolic changes, the proportional contribution ofeach component varying from one exercise run to another. The PaC02-PETCO2gradient increased on exercise, except in one run, the mean change being - 29 mmHg(S.D. 2-5, range - 6-8 to + 0 6). In normal subjects (Adams et al. 1984) this gradientalso increased on exercise, the mean change being - 1P mmHg (S.D. 1P3), but this

ROLE OF SPINAL CORD IN EXERCISE VENTILATION

56 7 8 9101 2 3 4 5 6 7 8 9 10On transient

Breath numberFig. 3. Mean values for breaths during control period and on transient of 1R and rco, andPET,CO. for patients ( x; n = 32) and normals EEL (*; n = 31). The vertical line indicatesthe breath (during expiration) in which exercise began. During the on transient there are

no significant differences between patients and normals for breaths 1 and 2. Thereafterboth I and TIco0 rise more slowly in the patients and are shown to be significantly less,in Table 4, for the last phase of the on transient.

increase is significantly less than in the patients (Mann-Whitney U test; U = 4.5,0-002 < P< 0-02). The rises in PETC02 seen in the patients (Fig. 2) will thereforeover-estimate rises in Pa co, more than in the normals.

On transient of exerciseAll the variables studied in the steady state were recorded for the first ten breaths

of exercise. Thirty-one exercise runs were available for analysis in the normals andthirty-two for the patients. The number of runs are less than in the steady state

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L. ADAMS AND OTHERS

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Fig. 4. Mean values for breaths during control period and on transient of ten RR and VTfor patients (x; n = 32) and normals EEL (*; n = 31). The vertical line indicates thebreath (during expiration) in which exercise began. In the patients, te changes more slowly,the rise in RR is slower and much less and VT changes more quickly.

because in some instances it was found when analysing the record that exercise hadbeen inadvertently started in inspiration and not expiration; as it was important todetermine the precise breath number in which each variable had changed in the twoforms of exercise, it was essential that exercise always started in the same phase ofthe respiratory cycle. Runs started in inspiration were therefore not included in theanalysis.

Fig. 3 shows the mean values for PETCo,, VCo, and PI for the ten breaths beforeand after the start of exercise for both normals and patients; Fig. 4 shows thecorresponding values for te, RR and VT. Mean PI and Pco2 had both increasedsignificantly by the second breath of exercise in normals and patients, though the

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changes were less for patients. There was little change in VI and Vco, throughout theon transient after the second breath. The increase in VI was achieved in the normalsubjects by an increase in VT and RR; te had changed significantly by the secondbreath and VT by the third. In contrast, there was little change in RR in the patientsand the increase in VI was mainly due to an increase in VT. The consistent fall in tein the normals was not found in the patients, a decrease in mean te in the patientsbeing significant on the fourth breath only. Even in late exercise, the increase in VIin the patients was due more to an increase in VT than RR, when compared to thenormals. For example, although the mean increase in ventilation was 11 min' lessin the patients than in normals, the mean increase in tidal volume was 100 ml greater.There was no significant change in mean PETCO2 in either the normals or the

patients. Heart rate rose immediately in the normals, whereas in these patients itfell and this fall was significant by the third breath.

Comparison of the on transient of exercise between patients and normalsThis comparison has been carried out, as in the preceding paper (Adams et al. 1984),

for the first two breaths of the on transient using an unpaired t test. There were nosignificant differences for PI and PCO2 between normals and patients for these breaths;nor for te on the first breath. Although the mean changes in te on the second breathappear different, this is not significant.

TABLE 2. Mean Pco, and TI of breaths 7 and 8 after onset of exercise derived fromsmoothed data

PCo02 ,

Normal P Patient Normal P Patient

Percentage increase 48 (35) < 0 001 18 (34) 44 (22) < 0 001 20 (33)from controlPercentage of late 84 (40) < 0 05 67 (17) 88 (24) < 0 05 77 (16)exercise

Values are means with S.D. in parentheses (n = 32, patients; n = 31, normals).

The same method of a five-point running average, described in the preceding paper(Adams et al. 1984), was used to determine if the mean level of CO2 production andventilation reached by the end of the on transient was the same or different betweennormals and patients. Table 2 shows that the levels of both VI and VC02 achieved wereless for the patients, whether the increase was expressed as a percentage of the controlvalues or as a percentage of the values in late exercise. These differences werestatistically significant

CO2 sensitivityEstimation of inhaled CO2 sensitivity in patients produced a mean value of

0-77 1 min- mmHg-' (S.D. 0 37, n = 13). On exercise, PET C02 fell in four out offorty-one runs, thus, in these four runs the 'apparent sensitivity' to CO2 (Crosset al. 1982) was infinite. Where PETC02 rose, the mean apparent sensitivity to CO2

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during exercise was 1-61 1 min- mmHg-' (S.D. 1-44, n = 37) which is significantlyhigher than that obtained from CO2 inhalation.

In the three patients in whom the arterial samples were taken, two had apparentsensitivities 2-20 times greater than their inhaled sensitivity, whereas in the thirdsubject both were similar.

DISCUSSION

We conclude from these experiments that under steady-state conditions a venti-lation appropriate to CO2 elimination is possible in man in the absence of spinal cordtransmission to and from the exercising limbs. Nevertheless there were differencesin the pattern of the ventilatory response and in the response of the circulation inthe patients compared with the normal subjects. We therefore examine thesedifferences to see if they invalidate our conclusion.

Differences in the resting conditions of normal subjects and patientsAt rest the patients had a higher mean heart rate and lower mean PET, CO2 and PCo2

than the normal subjects. The difference in mean 1co2 at rest is small and probablycan be accounted for by a smaller muscle mass in the limbs of the patients. Whilstthe increased muscle tone associated with upper motoneurone lesions prevents thegross muscle wasting of lower motoneurone lesions, it is likely that there was somemuscle wasting in the patients due to disuse atrophy.The difference in heart rate and PETCO2 at rest could possibly reflect a higher level

of anxiety in patients compared to normals. We feel however that such aninterpretation is unlikely since in general patients appeared equally relaxed and ifanything were less apprehensive about the prospect of being 'electrically stimulated'.The difference in heart rate at rest is probably due to a failure in the patients to

reduce the capacity of the blood vessels in the lower extremities in the upright seatedposture. The sympathetic outflow from the cord below the transaction would not beunder baroreceptor control; therefore the normal circulatory adjustments in the lowerlimbs resulting from sitting upright in the patients would be absent leading to anincrease in baroreceptor stimulation and hence a higher heart rate than in normalsubjects.The lower PETCO2 in patients must imply that for a given VC02 there is a higher

alveolar ventilation compared to normals. This presumably results from the tendencyof the patients to breathe more deeply for any given ventilation (Table 1). We donot know why this should be so.The differences in sensitivity to inhaled CO2 between the patients, 0 77 (S.D. 0 37)

1 min- mmHg-' and normals, 1-56 (S.D. 0-64) 1 min' mmHg-1 was surprising. Onemechanism may be that a loss of neural tone to the abdominal musculature mightresult in a flattening of the diaphragm so that it was no longer operating within thenormal range of its length-tension curve, particularly when ventilation was stimu-lated. This is a feature of chest wall and abdominal interaction observed in normalsubjects (Grimley, Goldman & Mead, 1976). If this is so, it is unlikely to mean that theresponse of the central nervous system to the demand for increased ventilation is inany way different from normal subjects; the implication is that the response of the

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respiratory system to a normal neural drive is impaired because the system isoperating at a mechanical disadvantage in the patients. An alternative explanationfor the low sensitivity may result from the relatively low resting PCO2 in patientscompared to normals; the test for sensitivity might then have been confined to therelatively insensitive portion ('dog-leg') of the ventilation-CO2 response curve.The absence of voluntary neural control of the abdominal musculature presumably

accounts for the reduction in lung volumes. However it was surprising to find howsmall these reductions were: eight of ten measurements of ERV were within 2 S.D.of prediction. The least affected measurement was the FEV1 and no obviousabnormality was seen in the flow-volume curves; there is therefore no evidence ofan increase in airway resistance. We presume that expiratory intercostals above thelevel of the lesion and the latissimus dorsi play an increased role in enabling thepatients to expire below their functional residual capacity. In the three patients inwhom arterial blood was sampled Pa °2 was well within the normal range and the meanalveolar-to-arterial Po2 gradients in the three were 4-0, 13-1 and 1-2 mmHg; thecorresponding values on exercise were 1-8, 9-1 and -O04 mmHg respectively.

Differences in the response between normal subjects and patients to electrically inducedexercise

Steady state. The mean changes in "'02' Sco2' PET C02 and heart rate in exercise werenot the same in the normal subjects as in the patients (Table 1). As stated earlierit is likely that the muscle mass of the legs in the patients was less than in the normalsubjects so that it was not possible to obtain as high an increase in mean g0, andgc02 in the patients. Nevertheless the difference was not large and there was overlapin the range of increases in V between patients and normal subjects.The larger increase in mean PETC02 in the patients than in the normals might be

interpreted as resulting from the absence of a stimulus to ventilation from theexercising limbs in the patients. Furthermore, such a rise in PCO2 might be thoughtof as responsible in part, for the increase in ventilation on exercise in the patients.The mean rise in PETC02 of 3-2 mmHg in the patients brings the value in late exerciseto 39-0 mmHg which is virtually the same as the mean PET, C02 found in the normalsubjects, i.e. 38-9 mmHg (see Table 1).

It is unlikely that the rise in PCo2, exemplified by the rise in PETCOp, could accountfor the increase in VI on exercise. In four exercise runs on the patients PETC02 actuallyfell, while in twenty-one of the runs the changes in PET, C02 were within the range ofthe normal subjects. In the runs where PET, C02 rose the apparent sensitivity to CO2was on average greater than the sensitivity to inhaled CO2. Furthermore, the use ofPETC02 to determine apparent sensitivity will underestimate that sensitivity, forchanges in Paco2 were less than the corresponding rises in PETC02* This underestimateis even greater for the patients than the normal subjects, for the increase in thePa C02-PET, C02 on exercise is greater in the patients. Further, if a rise in Pco2 wasrequired, in these patients, to stimulate the ventilatory response to exercise, such arise in PETC02 should have occurred during the on transient; this it did not do(Fig. 3).Reasons were given for assuming that baroreceptor stimulation at rest was higher

in patients than in normal subjects. The increase in cardiac output on exercise in

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the patients would decrease this stimulation, leading to a fall in heart rate and thisis what was observed during the on transient. However, heart rate did not drop toa normal resting level, presumably because the effect of baroreceptor stimulation wasgradually replaced by the tachycardia associated with exercise, so that by lateexercise there was no difference in heart rate from that observed during the controlperiod. The mean heart rate in late exercise was lower in the patients than in thenormal subjects; this is probably a consequence of less work being achieved by thepatients as judged by the smaller increase in mean VO2.On transient. The slower increase in CO2 elimination in patients at the start of

exercise (Table 2) might be explained by a delayed transport of metabolicallyproduced CO2 from the lower limbs to the lungs. This may well result from a slowervenous return consequent upon both an abnormal muscle pump and the loss ofautonomic control to the vasculature of the lower limbs. If the level of ventilationis coupled to CO2 delivery to the lungs (Wasserman, Whipp & Davis, 1981) then theslowness of CO2 delivery would explain the correspondingly slower increase in PI inthe patients.

The mechanisms controlling pulmonary ventilation on exerciseIn the previous paper we argued that when exercise was induced electrically, and

not voluntarily, then the ventilatory response could not be accounted for by'irradiation' from the cortex to other centres within the central nervous system thatcould affect breathing. The validity of this argument depended on the assumptionthat there was no voluntary assistance to exercise when it was induced electrically. Inthe present experiments no voluntary assistance was possible and on occasions, thepatients were not even aware that exercise had started. Eldridge, Milhorn & Waldrop(1981) have proposed that the hyperpnoea of exercise results from the activation ofa sub-hypothalamic locomotor centre, by neural impulses from the motor cortex. Ourresults in man, show that this hyperpnoea can occur in the absence of activation ofthis system.

Finally, our results provide no support for the concept that neural signals fromthe exercising limbs are responsible for the major part of the ventilatory responseto exercise, unless those signals reach the central nervous system by some route otherthan the spinal cord. The rise in mean PCO, in the patients may imply a smallcontribution from the exercising limbs to the ventilatory response. The mechanismsproposed by Kao (1956) in the dog and Spode (1980) in the cat, quoted recently byLoescheke (1982) do not appear to be necessary for an appropriate ventilatoryresponse to exercise in man.We conclude therefore that in patients with spinal cord transaction the normal

relationship between Vj and PCO2 (Fig. 1) is preserved despite the loss of muscleafferents. This relationship is maintained despite circulatory differences and reducedsensitivity to CO2. Therefore, this relationship cannot be explained by classicalchemoreception and there must be a chemical stimulus to account for this hyperpnoeaof exercise, the nature of which remains to be determined.

We would like to thank Dr K. McCrae, Senior Lecturer in Medical Statistics, Charing CrossHospital Medical School, for his invaluable advice. Brenda A. Cross and R. Stidwell are thankedfor critical discussions and technical help.

ROLE OF SPINAL CORD IN EXERCISE VENTILATION

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WEISSMAN, M. L., WHIPP, B. J., HUNTSMAN, D. J. & WASSERMAN, K. (1980). Role of neuralafferents from working limbs in exercise hyperpnoea. Journal of Applied Physiology 49(2),239-248.

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