Veterinary Medicine and the tCardiovascular-Pulmonary Division

J. Physiol. (1987), 391, pp. 289-298 289With 3 text-ftguresPrinted in Great Britain

ROLE OF MEDULLARY INSPIRATORY NEURONES IN THE CONTROLOF THE DIAPHRAGM DURING OESOPHAGEAL STIMULATION

IN CATS

BY S. M. ALTSCHULER*, R. 0. DAVIESt AND A. I. PACKtFrom the *Division of Gastroenterology and Nutrition, Department of Pediatrics,

Children's Hospital of Philadelphia, the tDepartment of Animal Biology, School ofVeterinary Medicine and the tCardiovascular-Pulmonary Division, School of

Medicine, University of Pennsylvania, Philadelphia, PA 19104, U.S.A.

(Received 12 December 1986)

SUMMARY

1. The effect of oesophageal distension and swallowing on the activity of medullaryrespiratory neurones was recorded in decerebrate, spontaneously breathing cats. Thedistension, produced by inflating a balloon in the thoracic portion of the oesophagus,was of sufficient magnitude to induce inhibition of the peri-oesophageal part of thecrural diaphragm, with little effect on the respiratory function of the diaphragm asmeasured by the activity in the C5 branch of the phrenic nerve.

2. 424 neurones were tested. They were located bilaterally, in the region of thenucleus tractus solitarius (dorsal respiratory group) or the ambiguus complex (ven-tral respiratory group). No cell exhibited a change in activity during periods ofstrong inhibition of crural electrical activity induced by distension or swallowing.The activity of all cells paralleled that of the C5 phrenic neurogram, which wasunaffected by the tests.

3. We conclude that the reflex inhibition of the crural diaphragm during oeso-phageal distension does not result from an inhibition of medullary premotor inspira-tory neurones of the dorsal and ventral groups. Additional central pathways mustexist that inhibit motoneurones to the crural diaphragm during gastrointestinalreflexes.

INTRODUCTION

The diaphragm is now considered to consist of two distinct parts, the costal andcrural, whose muscles differ in embryonic origin (Langman, 1975), velocity of short-ening (Newman, Road, Bellemare, Clozel, Lavigne & Grassino, 1984), fibre com-position (Riley & Berger, 1979; Sieck, Roy, Powell, Blanco, Edgerton & Harper,1983) and mechanical action on the rib cage (De Troyer, Sampson, Sigrist & Macklem,1982). For respiratory function, the two parts of the diaphragm contract as a unit(Boyd & Basmajian, 1963; Pollard, Megirian & Sherry, 1985) and their phrenicmotoneurones are driven by inspiratory premotor neurones of the dorsal and ventralrespiratory groups (see Feldman, 1986; Long & Duffin, 1986, for reviews). Thediaphragm also plays an important role in many gastrointestinal functions and

10 PHY 391

S. M. ALTSCHULER, R. 0. DAVIES AND A. I. PACK

during these activities the two parts of the diaphragm may be dissociated (Duron,1975; Monges, Salducci & Naudy, 1978; Titchen, 1979; Harding & Titchen, 1981),the action of the crural diaphragm being integrated with that of the gastrointestinalsystem. During the complex behaviours of swallowing (Monges et al. 1978; Titchen,1979; Altschuler, Boyle, Nixon, Pack & Cohen, 1985), eructation (Monges et al.1978), vomiting (Monges et al. 1978; Tan & Miller, 1986) and regurgitation duringrumination (Titchen, 1979), inhibition of the crural diaphragm occurs while costalactivity is unaffected or increased. In addition, these functions are characterized bya relaxation of the lower oesophageal sphincter (Ingelfinger, 1958).While the central neural pathways that subserve the respiratory function of the

diaphragm have been studied extensively (Feldman, 1986; Long & Duffin, 1986), thelocation and role of the central neurones that mediate its gastrointestinal functionhave received little attention. De Troyer & Rosso (1982) and Cherniack, Haxhiu,Mitra, Strohl & van Lunteren (1984) suggested that the vagally mediated, reflexdecrease in the activity of the crural diaphragm observed during swallowing andoesophageal distension involves the inspiratory premotor neurones of the medullaoblongata. Alternatively, the modulation of crural diaphragmatic activity duringgastrointestinal function may be mediated by a central pathway independent of thatfor respiratory function, with convergence taking place at the spinal segmentallevel. To test this, we recorded the responses of medullary inspiratory neuronesto oesophageal distension of sufficient magnitude to induce crural inhibition. Ourfindings indicate that the reflex decrease in activity of the crural diaphragm does notresult from an inhibition of inspiratory neurones and that separate bulbospinalpathways control the gastointestinal function of the diaphragm. A brief reportdescribing similar results has recently been published (Marlot & Duron, 1986).

Preliminary reports have been published elsewhere (Altschuler, Davies & Pack,1986; Altschuler, Davies, Boyle & Pack, 1987).

METHODSAnimal preparationThe results reported are from experiments on thirteen cats of either sex weighing 2-5-4-0 kg. The

cats were pre-anaesthetized with ketamine (75 mg, I.M.) and given dexamethasone (2 mg, I.M.) tominimize brain oedema. Following intubation, the animals were anaesthetized with halothane anddecerebrated (Kirsten & St. John, 1978). Anaesthesia was then discontinued.A femoral artery and vein were catheterized for blood pressure recording and drug adminis-

tration, respectively. The C5 branch of one phrenic nerve was exposed, cut distally, and desheathedfor whole-nerve recording. The right cervical vagus was exposed by a lateral approach, dissectedfree from the surrounding connective tissue, and left uncut. A mid-line laparotomy was performedand the crural diaphragm visualized by retracting the liver. To record the electromyograms (e.m.g.),a bipolar electrode, consisting of two platinum hook needles spaced 0 5 cm apart, was anchored inthe right crural diaphragm within 1 cm of the oesophagus. The attached wires were led through theincision and the abdomen sutured closed. A Foley catheter (14 French) was inserted through themouth so that the balloon end was situated in the distal oesophagus. The cat was then placed ina stereotaxic frame with the head ventroflexed at 45 deg and a vertebral clamp at T2. After a posteriorfossa craniotomy and opening the dura, the cerebellar vermis was reflected rostrad to uncover theobex and the pia over the recording sites removed.

Tracheal C02 concentrations were continuously monitored using an infra-red gas analyser(Capnograh, Godart N. V., De Bilt, Netherlands). Systemic arterial blood pressure and trachealpressure were measured with Statham P23Gb transducers (Statham Laboratories, Hato Rey,

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OESOPHAGEAL ACTIVITY AND INSPIRATORY NEURONES 291

Puerto Rico) and the oesophageal balloon pressure with a Validyne MP 45-22 transducer(Validyne Engineering Corp., Northridge, CA, U.S.A.). The rectal temperature was maintainedat 37-5-38-5 °C by a servo-controlled heating pad.

Neural recordings and vagal stimulationThe phrenic neural activity was recorded by placing the desheathed nerve across a bipolar,

platinum electrode suspended in a pool of mineral oil. The signals were amplified with conventionaltechniques (30 Hz-10 kHz band width). The phrenic signal and the diaphragmatic e.m.g. wererectified and processed by low-pass, third-order Paynter filters with 100 ms time constants tocompute the moving averages of the electrical activities.

Extracellular recordings of single-unit activity were made using tungsten micro-electrodeshaving resistances of 0-2-1-6 MQl. The position of the recording electrode was determined withrespect to the obex and the sulcus intermediolateralis. To record from inspiratory neurones of thedorsal respiratory group, associated with the nucleus tractus solitarius, penetrations were made ina region extending from the obex to 2-0 mm rostral to the obex, 1-02-5 mm lateral to the mid-line,and at a depth of 1-02-5 mm from the dorsal surface. To record from inspiratory neurones of theventral respiratory group, associated with the nucleus ambiguus complex, penetrations weremade in a region extending from 0 5 to 2-0 mm rostral to the obex, from 3 0 to 5-0 mm lateral tothe mid-line, and at a depth of 30-50 mm from the dorsal surface. The micro-electrode wasadvanced with a stepping-motor, hydraulic microdrive (Frederick Haer, Brunswick, ME, U.S.A.).The medullary unit activity was amplified (P511, Grass Instrument Co., Quincy, MA, U.S.A.),filtered (30 Hz-10 kHz), displayed on an oscilloscope, and fed to a window discriminator. Thestandard pulses from the discriminator were processed by a microprocessor-based rate-meter toprovide a moving average of the cell 's firing rate (window width: 200 ms; advanced in time every5 ms) (Marino, Davies & Pack, 1981).

Electrical stimulation of the vagus was performed with a bipolar hook electrode placed low inthe neck. The current pulses were 100 #ss in duration and the stimulus current adjusted formaximum prolongation of expiration, an intensity sufficient to recruit most of the pulmonarystretch receptor fibres (Zuperku, Hopp & Kampine, 1982). The pulses were delivered from a GrassS48 stimulator and PSIU6 stimulus isolation unit.The medullary unit activity, cell firing rate, integrated phrenic activity, integrated crural e.m.g.,

tracheal pressure, and oesophageal balloon pressure were recorded on a chart recorder (ES 1000,Gould, Inc., Cleveland, OH, U.S.A.) and tape recorder (HP 3968A, Hewlett-Packard, Palo Alto,CA, U.S.A.)

ProtocolAll recordings were made from spontaneously breathing animals. Inspiratory neurones were

identified by their having a bursting pattern of discharge activity confined to the period of phrenicactivity and lung inflation. Cells of the dorsal respiratory group were further characterized as beingRa or Rfl subtypes (Baumgarten & Kanzow, 1958); R.l neurones receive inputs from a centralpattern generator of inspiratory activity and from vagal pulmonary stretch receptors whereasthe firing of R. cells is determined principally by the central pattern generator. Initially, cells wereclassified as Rfl solely on the basis of their displaying a decreased rate of firing, or delayed onsetof firing, when lung inflation was prevented by occluding the tracheal tube just before inspiration(Cohen & Feldman, 1977; Bowden & Duffin, 1980). However, due to movement artifacts it wasdifficult to make a secure distinction for many cells; therefore, in addition we classified the cells onthe basis of R. having an excitatory response to electrical stimulation of the cervical vagus nerve.Inspiratory neurones of the ventral respiratory group were tested to determine whether they werevagal motoneurones by electrical stimulation of the cervical vagus nerve and testing for antidromicresponses. Vagal motoneurones were not studied further. Due to the fact that the animals were notparalysed, no attempt was made to determine whether a particular inspiratory cell had spinalprojections by testing for antidromic invasion after intraspinal electrical stimulation.Once a cell was characterized, oesophageal distension was performed by the rapid injection of

20-30 ml of air into the balloon portion of the Foley catheter. The balloon typically was about5 cm rostral to the gastro-oesophageal high-pressure zone. This position was ascertained before theonset of the medullary recording by determining the place where oesophageal distension caused alarge decrease in the activity of the crural diaphragm (Altschuler et al. 1985) and often had to be

10-2

S. M. ALTSCHULER, R. 0. DA VIES AND A. I. PACK

adjusted somewhat during the course of the experiment. Distension was maintained for severalbreaths and then quickly released. Following balloon deflation, the animal was observed forspontaneous swallowing activity that, in some animals, followed closely thereafter.

RESULTS

A total of 424 medullary inspiratory neurones were studied, 257 in the dorsalrespiratory group and 167 in the ventral respiratory group. In the dorsal respiratorygroup, 152 cells were located contralateral to the phrenic nerve from which recordings

C5 phrenic (

neurogram

Integratedcrural e.m.g. J.j

Tracheal 21pressure 30(cmH20) 2

60

Neurone

firing rate 30

0J

Neuroneactivity HHHHF

2sFig. 1. Response of the phrenic nerve (top trace), crural diaphragm (second trace),tracheal pressure (third trace) and an inspiratory neurone (bottom two traces) todistension of an oesophageal balloon with 30 ml air (approximate time given by signalmarker). Only the crural diaphragmatic e.m.g. was inhibited by the distension and theneuronal activity paralleled that of the phrenic nerve. The inhibition was not maintainedfor the entire duration of the distension.

were made and 105 ipsilateral. Of the contralateral dorsal group cells, 72 wereclassified as R., 31 as R,f, and for 49 an adequate determination could not be madewith certainty (due to mechanical difficulties such as movement artifacts). Of theipsilateral dorsal group cells, 48 were R., 11 were R,B and 46 were unclassified. In theventral respiratory group, 82 cells were contralateral to the phrenic and 85 ipsilateral.

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We found no cell that decreased its firing during oesophageal distension; rather, allmedullary inspiratory neurones maintained their firing in parallel with that of the C5branch of the phrenic nerve. This is seen for an R. neurone of the dorsal respiratorygroup in Fig. 1. It can be seen that during control breaths (the first two cycles ofphrenic activity) the phrenic nerve, the crural diaphragm and the neurone wereactivated in parallel. Upon balloon distension, the phasic inspiratory activity of the

05 phrenicneurogram

Integratedcrural e.m.g.

Balloon distension

Tracheal 21 A N k & Apressure 01(cmH2O) 2

25-

Neuronefiring rate

5sFig. 2. Response of the phrenic nerve, crural diaphragm and an inspiratory neurone toballoon distension. Note that upon distension the activity of the crural diaphragm wasstrongly inhibited; not only was the respiratory burst suppressed, but the base-line,interburst activity was also inhibited. The inhibition of the respiratory burst was notmaintained for the entire duration of the distension. Upon release from distension, therewas a second inhibition due to a reflex contraction of the oesophagus. The inspiratoryneurone was recorded in the dorsal respiratory group.

crural diaphragm was almost completely suppressed for two breaths, whereas therewas little change in the pattern of firing of the phrenic nerve and the neurone.Although not illustrated, blood pressure and tracheal CO2 concentrations were un-affected by the manoeuvres. The duration of the crural inhibition was variable amonganimals and among tests in the same animal. Partial or complete recovery of cruraldiaphragmatic activity often occurred during the inflation, as seen in the fifth breathin this Figure, as well as in Fig. 2.The basal activity of the crural diaphragm, that observed during the interval

between phrenic bursts, was usually unaffected by oesophageal stimulation; however,in five animals, it decreased during the distensions. A good example of this effect is

294 S. M. ALTSCHULER, R. 0. DA VIES AND A. I. PACK

shown in Fig. 2. In the test illustrated, the interburst activity of the crural diaphragmwas reduced to zero upon balloon distension, suggesting the presence of a tonicinhibition or disfacilitation, not merely suppression of the respiratory-related input.In this test, it can also be seen that deflation of the balloon was accompanied by a

C5phrenicneurogramI

Integrated IA

Spontaneous swallow

Tracheal 21pressure 0 - +j/$(cmH20) 2 -~

Neuronefiring rate 30

(Hz)

^~~~~ __p ___^^^Neuroneactivity 4

2 s

Fig. 3. The activity of the phrenic nerve, crural diaphragm and an inspiratory neuroneduring a spontaneous swallow (visual observation). The inspiratory neurone is the sameas that shown in Fig. 1. During the swallow, the activity of the crural diaphragm wasinhibited while the phrenic and neuronal activities were unchanged.

second inhibition of the crural diaphragm due to a reflex contraction of the oeso-phagus. This was observed in about half the animals.

In addition to the suppression of crural diaphragmatic activity observed uponinflation of the oesophageal balloon, a dissociation of crural diaphragmatic andphrenic activities also was seen during the spontaneous swallows (visual observation)that occurred in several of the cats. This is illustrated in Fig. 3. Again, the activityof the inspiratory neurones always paralleled that of the phrenic nerve, never thatof the crural diaphragm.

DISCUSSION

As a test of the hypothesis that medullary inspiratory neurones are involved in thevagally mediated inhibition of crural diaphragmatic activity seen upon oesophagealdistension or swallowing (De Troyer & Rosso, 1982; Cherniack et al. 1984), we


recorded the response of respiratory neurones during these reflexes. The activity ofall inspiratory neurones tested, those located in both the dorsal and ventral respir-atory groups, were unaltered during mechanical stimulation of the oesophagus andparalleled that of the phrenic nerve. Thus, additional central pathways must exist forthe control of crural diaphragmatic activity during gastrointestinal function.For respiratory function, the major excitatory inputs to the phrenic motoneurone

pool come from bulbospinal neurones of the dorsal and ventral respiratory groups ofthe medulla (Feldman, 1986; Long & Duffin, 1986), although there are direct pro-jections to this area of the spinal cord from other regions of the medulla and pons(Rikard-Bell, Bystrzycka & Nail, 1984). In the literature, no determination wasmade as to whether the bulbospinal cells projected to motoneurones innervating thecrural versus the costal part of the diaphragm. Since it is possible that some relativelysmall population of medullary inspiratory neurones project preferentially to moto-neurones of the crural diaphragm, we tested a large number of units, of differentsubtypes and located throughout the various groups concerned. (In addition to thecells reported, we also obtained many multi-unit recordings where good discrimi-nation of the several units was impossible; the mass activity of these groups of cellswas unaffected by oesophageal distension.) Thus, while it is possible that a small,discrete population of bulbospinal inspiratory units contained in the dorsal andventral respiratory groups was missed, we think it unlikely. Because the animal wasnot paralysed, we did not determine whether the inspiratory neurones that we testedhad bulbospinal projections. Rather, we relied on the fact that 50-90% of theinspiratory neurones in the dorsal and ventral respiratory groups have bulbospinalprojections, with most of the evidence indicating that they provide excitatory driveto phrenic or thoracic motoneurones, although not necessarily monosynaptic(Feldman, 1986; Long & Duffin, 1986). Thus it is highly probable that many of theunits we tested were bulbospinal neurones, excitatory to the diaphragm. Since theresponse of all inspiratory cells was the same, it seemed unnecessary to determinethe precise number having projections to the spinal cord.We used the moving average of the C5 phrenic activity for its convenience as a

measure of the central respiratory drive of the animal, since the peak of this activitycorrelates well with tidal volume (Eldridge, 1971); and to provide a good samplingof the activity of the costal part of the diaphragm, since the C5 branch of the phrenicinnervates all but the dorsal portion of the costal diaphragm (Duron, Marlot,Larnicol, Jung-Caillol & Macron, 1979; Fournier & Sieck, 1987). In contrast, we had torecord the e.m.g. activity of the hiatal region of the crural diaphragm because, in thecat, it does not receive its innervation from one particular phrenic root. Its moto-neurones lie throughout a large part of the rostro-caudal extent of the phrenicnucleus (Tan & Miller, 1986) and are not contained in just the C6 segment; nor is theC6 branch composed only of neurones innervating the crural diaphragm (Duron et al.1979; Fournier & Sieck, 1987). Even though axons from some motoneurones to thehiatal region travel in the C5 branch, we were unable to detect a decrease in C5activity during oesophageal distension and crural inhibition. This presumably wasdue to the fact that these neurones carry only a very small fraction of the total C5inspiratory activity.Our results indicating no effect on the C5 phrenic neurogram during mechanical

S. M. ALTSCHULER, R. 0. DAVIES AND A. I. PACK

stimulation of the oesophagus contrast with two previous reports; in the dog, balloondistensions sufficient to inhibit the crural diaphragm completely (100-200 ml) wereaccompanied by a decrease in costal e.m.g. activity by 50% or more (De Troyer &Rosso, 1982; Cherniack et al. 1984). (It was this simultaneous inhibition of both partsof the diaphragm that led to the hypothesis that this reflex is mediated through aninhibition of the inspiratory neurones of the medulla which provide the descendingrespiratory drive.) Both groups observed a compensatory increase in intercostalmuscle activity, allowing ventilation to remain unchanged. We can offer no goodexplanation for the differences observed other than that they may reflect speciesdifferences, anaesthetic differences (our cats were unanaesthetized and decerebrate) orthe relative magnitudes of the distensions. Our results clearly show that, in the cat,during balloon distensions of up to 30 ml and spontaneous swallows, inhibition of thecrural diaphragm can occur in the absence of a change in the amplitude of the C5phrenic neurogram or the activity of inspiratory neurones of the dorsal and ventralrespiratory groups. This is consistent with the results obtained during swallowing,eructation, vomiting and regurgitation during rumination in unanaesthetized ani-mals (Monges et al. 1978; Titchen, 1979).

Implicit in the hypothesis that medullary inspiratory neurones are involved in thedecreased crural diaphragmatic activity seen during oesophageal distension is thatthe decrease can be ascribed to an inhibition of brain-stem activity and thus a phasicdisfacilitation of phrenic and muscle activity. Our results, evident in Fig. 2, indicatethat the decrease is more easily explained by a strong tonic inhibition (or disfacili-tation) since not only is the inspiratory burst activity diminished but also theinterburst (expiratory) activity. One way to interpret our results is that the inhibi-tory and respiratory related drives come from separate sources in the brain stemand sum in the phrenic motoneurone pool, with the motoneurones to the cruraldiaphragm receiving a much larger inhibitory input. Thus, at the onset of distension,when the inhibition is strongest, the phrenic motoneurones to the crural diaphragmare inhibited and the e.m.g. is greatly decreased or silent. (It is possible that thedecreased activity could be a movement artifact. Although the balloon was placed inthe oesophagus several centimetres cranial to the diaphragm, its inflation could havedistorted the crural diaphragm in some unspecified manner, leading to a change inthe inter-electrode distance and a decrease in the magnitude of the recorded e.m.g.signal seen in Fig. 2. We think this unlikely because an equivalent decrease inactivity, lasting 2-3 s, was also seen following deflation; at this time, the interelec-trode distance presumably returned to its control position, or could even havechanged in the opposite direction due to a contraction of the oesophagus. In ad-dition, the decrease in base-line activity was sometimes observed during spontaneousswallows.) As distension is maintained, the inhibition adapts, possibly due to receptoradaptation (Clerc & Mei, 1983), and the inspiratory related input is evidenced by anincrease in the amplitude of the crural e.m.g. of variable magnitude. This 'break-through' of inspiratory related activity during the inhibitions can be seen in Figs.1 and 2 as an increase in crural diaphragmatic activity synchronous with the phrenicbursts. Such an interpretation of tonic inhibition adding to a descending inspiratorydrive would also explain the finding of Cherniack et al. (1984) that the 'onset ofdiaphragmatic activity was delayed' (relative to the activity of other respiratorymuscles and airflow) during oesophageal distension (see their Fig. 5) since it would

296


take longer for an augmenting inspiratory drive to reach the threshold for moto-neurone activation.

In summary, the inhibition of crural diaphragmatic activity seen during mech-anical stimulation of the oesophagus is mediated by brain-stem structures indepen-dent of those for respiratory function. The presence of separate control mechanismsallows the crural diaphragm to function as a muscle of respiration and as a componentof the sphincter at the gastro-oesophageal junction. The location, characteristics, andconnectivity of the neurones that subserve the gastrointestinal function of thediaphragm remain to be elucidated.

We are grateful to Dr A. P. Fishman for his encouragement and advice. We thank Dr Y. Hannafor technical assistance and Mr Daniel Barrett for secretarial support. This study was supported bygrants HL-08805, HL-36621, DK-01747 and S07 RR05506 from the National Institutes ofHealth.

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Veterinary Medicine and the tCardiovascular-Pulmonary Division