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Respiratory Physiology & Neurobiology 171 (2010) 1–16

Contents lists available at ScienceDirect

Respiratory Physiology & Neurobiology

journa l homepage: www.e lsev ier .com/ locate / resphys io l

rontiers review

he evolutionary origin of the mammalian diaphragm

teven F. Perrya, Thomas Similowskib, Wilfried Kleinc, Jonathan R. Coddd,∗

Institute for Zoology, Bonn University, Poppelsdorfer Schloss, Bonn 53115, GermanyAssistance Publique - Hôpitaux de Paris, Pitié-Salpêtrière Hospital, Department of Respiratory and Critical Care Medicine, and University Paris 6, ER10 UPMC, FranceInstitute for Biology, Federal University of Bahia, Rua Barão de Geremoabo, 147 - Campus de Ondina CEP 40170-290 Salvador, BrazilFaculty of Life Sciences, University of Manchester, Manchester M13 9PT, UK

r t i c l e i n f o

rticle history:ccepted 6 January 2010

eywords:

a b s t r a c t

The comparatively low compliance of the mammalian lung results in an evolutionary dilemma: the originand evolution of this bronchoalveolar lung into a high-performance gas-exchange organ results in a highwork of breathing that cannot be achieved without the coupled evolution of a muscular diaphragm. How-

iaphragmammal

reathing mechanicsung

ever, despite over 400 years of research into respiratory biology, the origin of this exclusively mammalianstructure remains elusive. Here we examine the basic structure of the body wall muscles in vertebratesand discuss the mechanics of costal breathing and functional significance of accessory breathing mus-cles in non-mammalian amniotes. We then critically examine the mammalian diaphragm and comparehypotheses on its ontogenetic and phylogenetic origin. A closer look at the structure and function across

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. Introduction

All extant amniotes are aspiration breathers that draw airnto the lungs by expansion of their body cavity. The primaryeterminant of this expansion is the motion of the ribs gener-ted by intercostal muscles. Although numerous tetrapod groupsave evolved accessory muscles that assist (crocodilians, teiid andaranid lizards, birds) or replace (turtles) rib movement as thective ventilatory pump, it is only the mammals that possess annspiratory muscular post-pulmonary diaphragm. The diaphragmelongs to a set of class defining characters, together with the pres-nce of mammary glands, body hair etc, of the Mammalia. Despitelong history of comparative, embryological and more recently,olecular and developmental studies, the phylogenetic origin of

he diaphragm remains speculative. Here we present a review ofhe structure and evolution of the body wall and the functionalnatomy of the diaphragm, including one possible scenario for itsvolution.

.1. Body wall structure

Aspiration breathing almost exclusively involves the musclesf the body wall and their derivatives that once constituted theocomotor apparatus in ancestral fish. In jawed vertebrates theseegmentally arranged and innervated muscles form two groups:

∗ Corresponding author.E-mail address: jonathan.codd@manchester.ac.uk (J.R. Codd).

569-9048/$ – see front matter © 2010 Elsevier B.V. All rights reserved.oi:10.1016/j.resp.2010.01.004

eals the evolutionary significance of collateral functions of the diaphragmole in producing high intra-abdominal pressure.

© 2010 Elsevier B.V. All rights reserved.

the dorsal “epaxial” and the ventral “hypaxial” muscles. Of these,the hypaxial muscles, which encase the body cavity, are primarilyinvolved in the evolution of aspiration breathing.

In chondrichthyans (sharks, rays and chimaeras) and basal ray-finned fishes (bichirs, sturgeons, gars and the bowfin), the hypaxialmuscles consist of a dorsal superior oblique and a ventral infe-rior oblique group (Fig. 1A) (Perry, 1989). In teleosts and lungfishthe superior oblique group extends ventrally over the inferioroblique group (Fig. 1B) (Perry, 1989). The muscle groups are thenrenamed: inferior oblique becomes the internal oblique or inter-nal intercostal; superior oblique becomes the external oblique orexternal intercostal. Where the internal and external oblique mus-cles meet ventrally they form the rectus group. The fibres of theinternal layer are oriented from cranio-ventral to caudo-dorsal andthose of the external layers, cranio-dorsal to caudo-ventral, the rec-tus muscles run directly in a cranio-caudal direction (Fig. 1A andB).

The ribs of most fish slant caudally from their articulation onthe vertebral column, and contraction of the external intercostalsswings them forward; the internal intercostals do the opposite. If allhypaxial muscles were to contract simultaneously the effect wouldbe to increase the pressure in the body cavity and to flex the spineventrally. The latter is counteracted by contraction of the epaxialmuscles. In undulatory locomotion, the simultaneous contraction

of epaxial and hypaxial groups occurs segmentally and alternatelyon left and right sides of the body, in waves that move caudallydown the spine. The anterior segmental body wall musculaturemigrates during ontogeny around the gill apparatus (Perry, 1989).The part dorsal to the gills is called epibranchial; the part ventral

2 S.F. Perry et al. / Respiratory Physiology

Fig. 1. Body wall muscles in the basal bony fish Lepisosteus (A) and the lungfishProtopterus (B and C). Note the incomplete layering of hypaxial muscles in superiorand inferior oblique groups in Lepisosteus as opposed to Protopterus, with internalaTNi

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ing the lungs along the dorsomedial body wall even when they are

nd external intercostals, with the latter disposed in deep and superficial layers.he peritoneum shows transverse fiber orientation (arrow) but lacks musculature.ote also the broad connection between hypobranchial and rectus muscle groups

n Protopterus (part C) (after Perry, 1985).

o the gills, hypobranchial musculature. The hypobranchial mus-ulature connects the two halves of the jaws with one another orhe jaws with the ventral part of the shoulder girdle. In sharks iterves in opening the mouth, but in other vertebrates, in which theyomandibular arch forms the hyoid bone, hypobranchial musclesove the tongue and larynx (Johanson, 2003).In tetrapods we encounter a new muscle group, the M. transver-

us. The transverse muscle group has a dorso-ventral orientation,ies internal to the ribs and is usually not attached to them (Maurer,896). In all animals that possess it, the transversus serves to

ncrease intraperitoneal pressure during expiration (Brainerd etl., 1993). Tetrapods also possess a sub-vertebral muscle grouphat plays an important role in neck movement. Extant lissam-hibians (frogs and toads, salamanders, caecilians) lack functionalibs, however it is not possible to determine if the rib-bearingncient animals from which they evolved used costal breathingGans, 1970, 1971). Since aestivating African lungfish (Protopterusp.) have been observed to engage in non-buccopharyngeal breath-ng, (Lumholt et al., 1975; Lumholt, 1993), it is plausible thatostal breathing may have already existed long before the origin ofmniotes. Indeed, costal breathing is often considered as an ances-ral (plesiomorphic) trait in early tetrapods (Gans, 1970, 1971)

eaning it would represent the earliest modality in the evolution ofspiration breathing. The independent origin of uncinate processesr similar structures on well-developed ribs in several unrelatedines of early tetrapods (the basal genera Ichthyostega, Acanthostega,

reererpeton, the Batrachomorphs Whatcheeria, Eucritta, Eryops,issorophus, Baphetes and the Reptiliomorph Kotlassia) supports

his ancestral origin of costal breathing. These projections from theosterior margin of the ribs are the origin of inspiratory muscles inirds (Zimmer, 1935; Codd et al., 2005; Tickle et al., 2007) and may

& Neurobiology 171 (2010) 1–16

have had similar function in dinosaurs, early tetrapods and birds(Codd et al., 2008).

Inspiration by means of negative pressure generation requiresparticipation of skeletal elements. Active expiration, however, doesnot suffer the same constraints. Special inspiratory structures haverepeatedly evolved but expiratory specializations are rare. Mostgroups have retained transversus and external oblique muscles andactively expire by increasing abdominal pressure, pushing the liveragainst the lungs. The oldest surviving amniote group that has func-tional ribs, the Rhynchocephalia, is represented by a single genus,the tuatara Sphenodon (Fig. 2). Given its phylogenetic position atthe base of the Lepidosauriomorpha, the body wall musculature ofSphenodon probably represents a basal state for this group or pos-sibly even for all amniotes, and will be used here as a model toillustrate the hypaxial body wall musculature. The ribs have ossi-fied dorsal (vertebral) and cartilaginous ventral (sternal) parts. Thevertebral parts possess prominent cartilaginous uncinate processes(Fig. 2A), and the sternal parts also possess flattened plates thatserve as muscle attachment sites. In addition Sphenodon possessesa set of 22 gastralia in the ventral body wall caudal to the ster-num (Fig. 2B; Maurer, 1896). The general structural type is similarto that found in basal synapsids such as Varanops. Basal synapsidslack uncinate processes however, if these were cartilaginous as inSphenodon, they would not have been conserved in fossil speci-mens. The hypaxial body wall musculature in Sphenodon is complex(Maurer, 1896; Byerly, 1925). The external intercostal musculature(Fig. 2C and D) has four layers: the superficial short and long uncio-costal muscles, which connect the uncinate processes to the nextrib (short) or to the one following it (long), and the deeper externalintercostals, which also have short and long subdivisions. Ventralto the uncinate processes the most superficial muscle layer, theunsegmented external oblique, also has two sheets, that extend tothe rectus and have the same general orientation as the externalintercostals. The sternal parts of the ribs also possess two layers ofventral intercostal muscles, which link the broadened portions ofthe ribs to the rectus-gastralia system. Ventrally (Fig. 2E) the exter-nal and internal oblique muscles insert in the sheath of the rectusabdominis, which runs longitudinally beneath the gastralia, incor-porating them (Maurer, 1896), whereas the transversus inserts atthe linea alba (Fig. 2F).

1.2. Development of the lungs and their suspensory ligaments inamniotes

The mechanical properties of the lungs bear a close relation-ship to the anatomy of the ventilatory apparatus. The lungs mustbe “guided” during inflation to prevent folding. Furthermore, as thelungs become stiffer due to increased surface area, counterproduc-tive movement of the viscera becomes an increasingly importantproblem. The lungs of Amniotes form by branching of an unpairedlaryngotracheal tube into two lung buds. As they elongate, thedeveloping lungs become separated from the gut by a pocket thatinvades caudally. Finally each lung remains attached to the gut onlyalong its dorsomedial and ventromedial margin by two thin sheets:the dorsal and ventral pulmonary ligaments, also called “mesop-neumonia” (Broman, 1904; Duncker, 1978; Perry, 1985). In mostlizards the ventral pulmonary ligaments tend to become reduced,particularly on the left side, where the stomach is (Klein et al.,2005). The dorsal ones, however, play an important role in stretch-

empty. The pulmonary ligaments are therefore primarily involvedin reserving space for the lungs to inflate. In animals in which thelungs are broadly attached to the body wall (most lizards, snakes,turtles, birds) or are freely moveable in pleural cavities (juvenilecrocodiles, mammals), the pulmonary ligaments are often reduced.

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ig. 2. Body wall muscles of Sphendon punctatum in lateral view, showing sequentiuperficial layers (after Maurer, 1896).

. Costal breathing

Speculations on intercostal muscle function in tetrapods dateack over 250 years, when Hamberger (1749) postulated that con-raction of the internal intercostals reduces rib cage volume causingxpiration, whereas the external intercostals cause inspiration. Fick1898) cites an earlier report by Hamberger from 1727, which isased on similar observations by Bayle (1688). Although this dogmaay be correct in part (Fick, 1898) and is often repeated in text-

ooks, the whole truth appears much more complex (De Troyer etl., 1981; Wilson & De Troyer, 2004; Codd et al., 2005; De Troyer,005). In mammals, for example, both internal and external inter-ostals increase rib cage volume when the thoracic volume is lowut decrease rib cage volume at high lung volumes (De Troyer et al.,981). Furthermore when contraction of the neck muscles fixes therst two ribs, the lateral parts of the intercostals can increase ribage volume. If, however, abdominal muscles fix the most caudalib, contraction of the same muscles would have the opposite effect.hus, the intercostals may be more involved in postural control andocomotion than in respiratory movements. This is reminiscent ofheir ancestral functions; the evolution of ribs and the associated

usculature did not primarily provide a “respiratory” advantageut rather, most probably, improves the ability of the coelomic cav-

ty to withstand pressure (Romer, 1978). A locomotor function ofhe intercostals muscles has been described in lizards (Owerkowiczt al., 1999) and in resting dogs intercostal activity was associatedith breathing movements, but during locomotion, activity of the

nterosseous portions of the intercostals became uncoupled fromreathing and was correlated with leg movement (Carrier, 1996).he intercartilagenous (parasternal) internal intercostals, however,ere always associated with inspiration. In birds the separation isore complete: the external intercostal muscles only function dur-

ng locomotion, possibly to stabilise the thorax (Codd et al., 2005).nterestingly, costal breathing alone is mechanically suboptimalecause the negative intrathoracic pressure that it produces torive air towards the lungs also drive the abdominal content toward

oval of muscle layers from A to F. Note that most groups are disposed in deep and

the thorax. In mammals, the contraction of the diaphragm coun-teracts this phenomenon, thus enhancing the efficiency of costalbreathing.

In many amniotes the ancestral costal breathing mechanism issupported by changes in internal body septation or by the involve-ment of additional muscle groups. From the functional anatomicalviewpoint there appear to be three such mechanisms: (1) utiliza-tion of passive internal septation to prevent movement of the gutinto the pleural space during inspiration, (2) muscular movement ofsepta that can directly or indirectly change the body cavity volumeand (3) supporting or assuming ventilatory function by body wallmuscles other than those groups originally involved: intercostal,oblique abdominal and rectus. These possibilities are not mutuallyexclusive and are often combined. In mammals, for example, thediaphragm participates in mechanisms 1 and 2, while as many as15 other trunk, head and shoulder muscles are involved in the thirdcategory (Osmond, 1985).

Passive septation refers to the presence of an internal (intra-coelomic) membrane that prevents free movement of parts of thecontents of the body cavity but which is not actively moved itself.In addition to attachment of certain parts of the mensentery, as inlacertid lizards, for example (Klein et al., 2005), the most impor-tant intracoelomic membranes are the post-pulmonary (Fig. 3A,PPS) and post-hepatic septa (Fig. 3B, PHS). In addition to passivesepta, some septa possess musculature and can influence the infla-tion of the lungs directly. Monitor lizards possess large, flexible,multi-chambered lungs, which are separated from the remainingviscera by a PPS (Duncker, 1978). The PPS extends dorsally fromthe transverse septum, separating the lungs from the rest of theviscera (Fig. 3). A PPS is present in some turtles, varanoid lizards,chameleons, archosaurs (crocodilians, dinosaurs and birds) andmammals. It is possible that the PPS developed early in amniote his-

tory in connection with the origin of aspiration breathing (Perry andSander, 2004). However, if the PPS is ancestral for amniotes a com-pelling explanation for its repeated disappearance among turtlesand lepidosaurs is unclear.

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A second major internal body cavity partition is the post-hepaticeptum (PHS, Duncker, 1978). This structure (Fig. 3) separates theungs and liver from the rest of the viscera, and has evolved sepa-ately in archosaurs and in teiioid lizards (Broman, 1904; Klein etl., 2000). In Archosaurs it is derived from the capsula fibrosa of theiver and separates the gall bladder from the liver (Duncker, 1978),

hereas in teiioids it develops from the mesentery and includeshe gall bladder in the same compartment with the liver (Klein etl., 2000).

In the tegu lizard, the PHS is of great importance for the orga-ization of the viscera. Its surgical removal results in invasion ofhe pleuro-hepatic cavity by the intestine and stomach, and in sig-ificant reduction of space for the lungs (Klein et al., 2003a,b) in aimilar manner to a diaphragmatic hernia, rupture, or eventrationn mammals. Furthermore, the PHS is important for the mechan-cs of ventilation by reducing lung compliance (Klein et al., 2003b).hus, during moderate exercise the PHS allows tegus to increaseidal volume and overcome an axial constraint. Interestingly theHS in the tegu is perforated in locations analogous to those presentn the mammalian diaphragm during ontogeny (Goodrich, 1930;abiuk et al., 2003) and that it also possesses copious smooth mus-le (Hochstetter, 1906; Klein et al., 2003a). This combination ofeatures was predicted by Brink (1956) as typical of a precursor

o the mammalian diaphragm.

Crocodilians are the only other tetrapods to possess non-ntercostal muscles that increase the volume of the chest cavity,hereby supporting the activity of the intercostals. During inspira-ion, the ribs are rotated forward and outwards by the intercostal

ig. 3. Generalized amniote embryo showing the position of primordia from whichost-pulmonary and post-hepatic septa develop. The gall bladder is shown lying inhe peritoneal cavity. Since the post-hepatic septum in teiid lizards develops fromfold in the mesentery rather than from the capsula fibrosa of the liver, the gall

ladder is included in the pleurohepatic cavity in that group. Dorsal and ventralulmonary ligaments are shown at the left. Note that the post-pulmonary septumnd the ductus Cuvieri encircle the developing lungs (after Perry, 1985).

& Neurobiology 171 (2010) 1–16

musculature, expanding and stabilizing the thoracic cavity. At thesame time, paired long, striated muscles (M. diaphragmaticus) thatare derived from the hypaxial body wall pull the liver caudally.This muscle group extends from the pelvic girdle and posteriorgastralia to the post-hepatic septum surrounding the abdominalcavity and liver (Gans and Clark, 1976; Farmer and Carrier, 2000;Kent and Carr, 2001; Kardong, 2002; Claessens, 2004a,b). Unlikethe mammalian diaphragm, the diaphragmaticus muscle is seg-mentally innervated: it is probably derived from the transversus(Duncker, 1978) or possibly the rectus system and therefore aroseseparately from the mammalian diaphragm and the M. diaphrag-maticus (M. striatum pulmonale) in turtles (Perry, 1978; Brainerd,1999). At the same time the M. ischiopubis rotates the kineticpubis down and back, expanding the abdominal cavity (Carrier andFarmer, 2000a,b). During expiration the mm. diaphragmaticus andischiopubis relax, and contraction of the abdominal and intercostalmuscles constricts the coelom and displaces the viscera, pushingthe liver cranially (Farmer and Carrier, 2000; Kardong, 2002).

Keith (1905) associated the rectus abdominis muscle, which inthe dogfish shark inserts on the ventral part of the pericardium,with a circulatory role, as its contraction would increase both thevolume of the pericardial space and the intercoelomic pressure,thereby contributing to the venous return to the heart. In crocodil-ians the contraction of the rectus is associated with expiration(Gans and Clark, 1976) and may also contribute to pelvic aspiration(Farmer and Carrier, 2000). Although these accessory muscles areassociated with normal breathing in crocodilians, a recent studyindicates that they may have arisen in an aquatic branch of thisancient group, in connection with the regulation of the centre ofbuoyancy (Uriona and Farmer, 2008).

Turtles, like mammals, have incorporated striated musculaturein the PPS. Turtle ribs are immobile, and the intercostal and rec-tus muscles do not develop. The lungs in most species are attacheddorsally to the carapace and held in place by the PPS. In trionychidand aquatic emydid species the PPS contains striated muscle (M.diaphragmaticus), which may be derived from the missing inter-costals (George and Shah, 1954). A respiratory function has not yetbeen demonstrated for this muscle (Shah, 1962; Perry, 1978). It par-tially or completely (in Lissemys punctatus, Shah, 1962) envelopsthe lungs, whereby a contraction of the musculature must serve toincrease the intrapulmonary pressure. Some species also possessstriated musculature (M. pulmonalis = M. striatum pulmonalis, vonHansemann, 1915) in the lung wall, deep to the M. diaphragmati-acus, if present. The transversus muscle is not reduced, originatesin the parietal peritoneum of the carapace, and inserts in the vis-ceral peritoneum, which is closely associated with the liver. Activeexpiration is accomplished by contraction of this muscle, push-ing the liver against the lungs (Gaunt and Gans, 1969; Gans andHughes, 1967). This action may be aided by contraction of the pec-toral muscles (McCutcheon, 1964). As the volume of the body cavitydecreases, the broad obliquus and serratus muscles are stretchedinward at the base of the hind- and forelimbs, respectively. Sub-sequent contraction of these muscles creates negative pressure inthe body cavity, and when the glottis is opened the animal inspires(Gaunt and Gans, 1969). Thus, turtles have what might be describedas an external diaphragm analogue that has no phylogenetic orontogenetic relationship to that of mammals. Nevertheless turtlesremain effective aspiration breathers in spite of their immobileribs and anecdotal accounts to the contrary (Mirwald and Perry,1989). In the relatively basal anuran group Discoglossidae, the so-called “diaphragmaticus” muscle described by Beddard (1895a,b)

and Keith (1905) may function as a pinch valve to prevent refluxof stomach content into the esophagus during breathing (Pickeringand Jones, 2002). In addition, the location of the ductus Cuvieri(Fig. 3A and B) at the base of the PPS (Uskow, 1883; Perry, 1985)and the close association of the transverse septum with the sinus

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enosus (Keith, 1905) suggests that a diaphragmatic muscle mayave been important in facilitating venous return to the heartGegenbaur, 1898). The observation that venous return is impededuring locomotion in the iguana, which lacks both a PPS and a PHSFarmer and Hicks, 2000), is also consistent with this hypothesis.

. The mammalian diaphragm

.1. General anatomy

“The chief characteristic of mammalian myology is theiaphragm, which, as such, is not more completely developed inan than in the Monotreme” (Owen, 1868). The diaphragm is a

ome-shaped structure, consisting of a central tendon (aponeu-osis) surrounded by a ring of predominantly radially orientedtriated muscle, the M. diaphragma (Fig. 4A and B). Except in patho-ogical conditions, the diaphragm completely separates the pairedleural cavities from the abdomen, hence its name (from the Greek��������, a wall or partition —���, across; ������, a wall).lato and Aristotle held that the diaphragm, by separating the tho-acic and abdominal cavities, protected the heart, viewed as the seatf the soul, from the emanations of the digestive process (Derennet al., 1994, 1995).

In general, the diaphragm is obliquely oriented in the body cav-

ty, the dorsal margin extending further caudally than the ventralne. The central tendon, which is perforated on its right side bylarge foramen for the vena cava, (Fig. 5) is a semi-lunar shape

n monotremes and chiropteroids, and cloverleaf shaped in pri-ates and ungulates. In insectivores, cats and rats the central

ig. 4. Human diaphragm. Part A is the ventral view of the hemisected torso. Notehat the esophagus is completely enclosed in crural muscle, whereas the aorta isnly partly enclosed and the vena cava perforates the central tendon. Part B, Poste-ior (inferior) view in supine posture. Note large central tendon (aponeurosis), andternocostal and lumbocostal trigona. Dotted lines indicate course of last two ribsafter Osmond, 1985).

Fig. 5. Comparative anatomy of diaphragms in echidna (Tachyglossus aculeatus),A; and in domestic rabbit, B; rat, C; dog, D; and cat, E in supine posture. Viewnot specified in source text. Note large central tendon in echidna, rabbit, dog andman, as compared with small central tendon in rat, mouse and cat, indicating func-

tional rather than systematic significance. Arrows indicate areas of local intenseacetylcholinesterase histochemical reaction in rabbit and rat, indicating possiblesystematic significance. All drawings represented in similar size for comparison(modified after Perry et al., 2000; Gordon et al., 1989).

tendon is crescent shaped and weakly developed (Owen, 1868;Broman, 1911; Nishi, 1938; Starck, 1982; Gordon et al., 1989; Perryet al., 2000) but is more extensive in monotremes, caviomorphrodents, humans, rabbits, dogs, perissodactyls and artiodactyls(Fig. 5). The extent of the central tendon changes with growth,the diaphragm being more muscular in children than in adults (LeDouble, 1897): this has been proposed as an explanation for thepresence of accessory muscular slips that can be found in variouslocations in the central tendon (Blair, 1923). Interestingly, the cen-tral tendon is reduced or lacking in certain species; for example,the polecat (Mammalia:Carnivora:Mustelus sp.), and the porpoise(Mammalia:Cetacea:Phocoenidae) (Le Double, 1897).

The muscular part of the diaphragm has crural and sterno-costal parts even in monotremes (Perry et al., 2000). The tendonsof the crural diaphragm can be separated from those of the verte-

bral column (e.g., in cats, dogs and guinea pigs) or can be joinedwith them (lemurs and primates). One branch is normally present,with two (crus mediale and laterale) in dolphins, some carnivoresand primates. A crus intermedium is also recognised in humans(Nishi, 1938; Sabotta and Becher, 1975). The crural diaphragm bears

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oramina for the esophagus and aorta (Fig. 4B). The sterno-costalart of the diaphragm originates on the inner surface of the ribage, from the most caudal rib to the xiphoid process of the ster-um, and inserts radially oriented in the central tendon. The sternalnd costal parts, and the costal and crural parts are separatedrom each other by triangular extensions of the central tendon, therigonum sternocostale and lumbocostale, respectively. The laterre well developed in monotremes (Fig. 5A) (Kyou-Jouffroy andessertisseur, 1971).

.2. Specialized diaphragms

In wallabies the diaphragm is oriented transversely to the bodyxis; in whales it turns sharply caudally and lies almost parallelo the long axis of the body (Nishi, 1938; Starck, 1982; Slijper,936). This is also the case in horses and elephants (Le Double,897; Brown et al., 1997). The most peculiar diaphragm, how-ver, is that of the Florida manatee Trichechus manatus latirostris.ere, separate half diaphragms lie in the frontal plane in the dorsalart of the body cavity (Fig. 6A and C). They have no attach-ent to the sternum, lie dorsal to heart, liver and the alimentary

anal and extend to the caudal end of the body cavity (Fig. 6B,ommel and Reynolds, 2000). The transverse septum separateshe heart from the liver as in all vertebrates (Ravn, 1899), butontains no muscle and does not form an integral part of theiaphragm. Rather, the transverse septum and the diaphragm liet right angles to each other. This peculiar morphology can be seens adaptation to an aquatic, low-energy life-style (Rommel andeynolds, 2000). Indeed, the lungs are distributed dorsally alonghe entire length of the body cavity, and thus keep the animaln the proper resting orientation while at the same time allow-ng it to change positions without shifting the position of the air

ass.

.3. The functions of the diaphragm

In general, the physiology of diaphragm is primarily consideredrom its inspiratory activity. However, the diaphragm does havedditional roles that indicate from an evolutionary point of view,hat inspiration may not have been the primary function of theiaphragm (Jones, 1913). The diaphragm is indeed a “separator”

ig. 6. Manatee (Trichechus manatus latirostris) in lateral (A) and transverse (C) view, anorizontal disposition of the two hemi-diaphragms, with the diaphragmatic muscle lying

& Neurobiology 171 (2010) 1–16

between the thoracic and the abdominal cavities. It is also a promi-nent agent of activities that are “expulsive” in nature and requirebuilding up high intra-abdominal pressures.

3.3.1. The diaphragm as an inspiratory muscle3.3.1.1. Historical reminder. The description of the mechanics ofdiaphragm contraction, namely a caudad movement – referred toas a “descent” in humans – of the diaphragmatic dome provokingan expansion of the lower rib cage and an outward movement ofthe anterior abdominal wall, can be dated back to Galen (Duchennede Boulogne, 1853; Derenne et al., 1995). This description was thenforgotten, and several different theories about the action and roleof the diaphragm proliferated (Derenne, 2004). The mechanics ofthe inspiratory action of the diaphragm and the effects of a bilat-eral section of the phrenic nerves were re-described at the end ofthe XVIIth century (Lower, 1665). At the beginning of the XIXthcentury, Magendie again identified the diaphragm as an impor-tant agent of inspiration (Magendie, 1817), and concluded that thecontraction of the diaphragm elevated the ribs, as did the contrac-tion of the intercostals. This view impugned the dominant beliefof the time, that the intercostal muscles were the sole agonists ofthe inspiratory increase in rib cage dimensions (see above, “costalbreathing”; von Haller, 1767; see review by De Troyer, 2005). AfterMagendie, the mechanical effects of the diaphragmatic contrac-tion on the rib cage were described by Ure (1819), Cloquet (1820,1825), Beau and Maissiat (1843), Duchenne de Boulogne (1853)– in this case with great refinement owing to the use of electri-cal stimulation of the phrenic nerves –, and Bert (1870). In themodern era, a host of studies have refined the description of theaction of the diaphragm qualitatively and quantitatively, in ani-mals and in humans, from observations conducted in health anddisease and from mathematical modeling (Ward and Macklem,1995; De Troyer and Loring, 1995; Whitelaw, 1995; Angelillo etal., 1997; Cluzel et al., 2000; Amancharla et al., 2001; Ricci et al.,2002).

3.3.1.2. Mechanics of the inspiratory action of the diaphragm. Thedescription that follows mostly pertains to human physiology, butprovides a reasonable generalizable model. From a functional pointof view, the diaphragm forms an elliptical cylindroid (the muscleitself) capped by a quasi-flat dome (the central tendon). The cylin-

d in schematic lateral view (B), showing extreme dorsal position of lungs and thelaterally (after Rommel and Reynolds, 2000).

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rical, vertical part of the muscle is in contact with the inner facef the lower rib cage, over a “zone of apposition” that occupiesoughly one third of the total height of the rib cage. The lower ribsre therefore exposed to the abdominal pressure and not to theleural pressure (Mead, 1979; Urmey et al., 1988).

When the diaphragm contracts, its fibres shorten and theiaphragmatic dome descends over the abdominal content in aiston-like movement, without major change in shape (Boriek etl., 2005). The descent of the diaphragm expands the thoracic cav-ty by lengthening its craniocaudal axis, lowering pleural pressurend driving air into the lungs. Simultaneously, the abdominal vis-era are pushed caudally, and the abdominal pressure increases.his creates the outward motion of the abdominal wall that isharacteristic of “diaphragmatic inspirations”. The positive abdom-nal pressure so created applies an outwardly force to the internalace of the lower ribs (appositional force) (Loring and Mead, 1982;

ead and Loring, 1982) . At the same time, the shortening of theiaphragm fibres exerts a cranially oriented force on the loweribs (insertional force) (Loring and Mead, 1982; Mead and Loring,982). Because of the oblique orientation of the costovertebral joint,oth the appositional and the insertional forces provoke an upwardovement of the lower ribs. This increases the transversal dimen-

ion of the lower rib cage, and further increases the intrathoracicolume (De Troyer and Loring, 1995).

This mechanical sequence has important consequences: Firstly,he contraction of the diaphragm is unique in that it produces aall in pleural pressure that is synchronous with a rise in abdomi-al pressure. A “diaphragmatic” inspiration is therefore associatedith a caudal movement of the abdominal viscera that are pushed

way from the expanding lungs, which is mechanically beneficialnd improves on costal breathing alone. Indeed, the opposite occurshen inspiration is solely driven by the intercostal muscles: theegative pleural pressure produced by the expansion of the ribage is then transmitted to the abdominal cavity and tends to suckhe abdominal viscera within the thorax. This visceral movementpposes lung expansion and is in fact expiratory in nature. Thisxplains the paradoxical inward movement of the abdominal wallhat is characteristically observed during inspiration in patientsuffering from diaphragm paralysis (Kreitzer et al., 1978; Cohent al., 1982; Similowski et al., 2000).

Secondly, the mechanical output of a diaphragm contractionntimately depends on the geometry and mechanical characteris-ics of the rib cage and of the abdominal wall. Thus, lung volumeffects diaphragm efficiency through its inverse relationship withhe length of the muscle and with the surface of the zone of appo-ition: the higher the lung volume, the shorter the diaphragm andhe smaller the zone of apposition (Petroll et al., 1990; Gauthiert al., 1994; Pettiaux et al., 1997; Cluzel et al., 2000), which inurn leads to a reduced capacity to produce inspiration. Thereforebdominal compliance determines diaphragmatic performance. Inhe absence of abdominal muscle tone (as in tetraplegic or para-legic patients, or in patients with abdominal wall defects of anyrigin), the diaphragm looses its inspiratory effectiveness inde-endently of any change in intrinsic muscular properties, becausebdominal pressure cannot build up (hence a lesser expanding forces applied to the lower ribs) (Estenne and De Troyer, 1987).

Thirdly, the contraction of the diaphragm creates a vertical pres-ure gradient within the pleural space (D’Angelo et al., 1974; Urmeyt al., 1988). A common misunderstanding holds that pleural pres-ure is uniformly negative. In fact, the pleural pressure is actuallyositive in the part of the rib cage that is in contact with the

bdominal cavity, as a result of the transmission of the abdomi-al pressure (which pushes the ribs outward). Pleural pressure isegative only above the zone of apposition, in the upper part of theib cage (Urmey et al., 1988). This negative pressure, transmittedo the alveoli, drives inspiration. It also pulls the ribs inward caus-

& Neurobiology 171 (2010) 1–16 7

ing a detrimental distortion effect (Urmey et al., 1986; Ward et al.,1992; Chihara et al., 1996). The heterogeneity of pleural pressureover the thorax can easily be inferred from the precise descrip-tions provided by Galen (1956; translations by Furley and Wilkie1989), who observed the mechanics of the rib cage in living animalsafter paralysing all the other respiratory muscles through nerve ormuscle sections. Galen (1956) found that the contraction of thediaphragm only expanded the lower part of the rib cage, and wasassociated with a deflation of its upper portion. In humans, this canbe readily observed during isolated diaphragmatic contractions,either spontaneously in patients with low cervical quadriplegia(Mortola and Sant’Ambrogio, 1978; Urmey et al., 1986) or whenthey are provoked by phrenic nerve stimulation (Mead et al., 1984;Nochomovitz et al., 1983). The inspiratory-related expansions ofthe abomen and lower rib cage are then synchronous with aninward motion (“paradox”) of a large portion of the upper ribcage. Therefore, while isolated costal breathing is impeded by theinspiratory-related cephalad movement of the viscera, isolateddiaphragmatic breathing is impeded by the inspiratory-relatedparadoxical deflation of the upper rib cage.

Ultimately, it appears that an optimal inspiration requires,mechanistically speaking: (1) adequate rib cage physical proper-ties, including an abdominal wall tone that sufficiently opposesthe inspiration-related diaphragm descent for abdominal pres-sure to build-up; and (2) the combined action of the diaphragmand of the inspiratory intercostal muscles on the rib cage. Thisis exactly what occurs during normal inspiration, that involvesthe temporo-spatial distribution of neural commands to severalmuscle groups (Saboisky et al., 2007). Given the plesiomorphicnature of costal breathing (Gans, 1970, 1971) and its highly suc-cessful character as a ventilatory modality in birds – where the lowcompliance lungs are ventilated through external air sacs, whichalleviate the “abdominal viscera” issue –, it seems likely that thediaphragm inspiratory function initially evolved as an “aide” tocostal breathing, allowing, in addition, the development of lowcompliance lungs. Interestingly, as shown by phrenic nerve sectionexperiments, the loss of diaphragm function is not lethal, (Galen,1956; Lower, 1667; Duchenne de Boulogne, 1853). However, inhumans, it is associated with clinical features clearly illustrat-ing the importance of driving the viscera away from the lungs(paradoxical abdominal respiration, orthopnea) and with compen-satory changes in the neural breathing command. An increasedintercostal activity is associated with phrenic section in the dog(De Troyer, 1998). Resting minute ventilation is maintained at thecost of a faster, more superficial breathing pattern (Sokolowskaet al., 2003; Stradling et al., 1987). In some instances of humandiaphragm paralysis, central neural plasticity occurs that allowsthe inspiratory activity of extradiaphragmatic muscles to persistthroughout sleep (Arnulf et al., 2000; Bennett et al., 2004). Thisplasticity might explain why patients with bilateral diaphragmaticparalysis may exhibit a surprisingly conserved aerobic capacity(Hart et al., 2002). Of note, the contribution of the diaphragmto rib cage volume displacement is high during resting breath-ing, but it does not remain so when ventilatory requirements areincreased to meet exercise-related demands, or when mechanicalloads are imposed on the system. In such circumstances, extra-diaphragmatic inspiratory muscles account for the most part ofinspiratory pressure generation, while the diaphragm serves prin-cipally as a flow generator (Aliverti et al., 1997, 2002; Kenyon et al.,1997).

Whilst the main function of the diaphragm is producing ven-

tilation, particularly at rest, this may not have been the primarydriver in its evolution. Indeed the inspiratory role of the diaphragmmay represent an exaptation (Gould and Vrba, 1992). Hereafter weexamine the non-respiratory functions of the diaphragm from thisparticular angle.

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.3.2. The diaphragm as a ‘visceral organiser’The separation functions of the diaphragm were the first to

e recognised by scientists, as indicated by etymological consid-rations (see above). In developmental terms, the importance ofhis function is well illustrated by the consequences of congenitaliaphragm hernias on the development of the lungs. Congenitaliaphragm hernias are associated with a pulmonary hypoplasiahat is bilateral but predominates on the side of the hernia. Inumans, bronchial divisions stop around 10–12 weeks on the her-ia side and 2–4 weeks later on the other side, resulting in a reducedumber of alveoli, under-developed interalveolar septa and anbnormaly thick pulmonary interstitium (George et al., 1987; Bargyt al., 2006). This reduced and impaired gas exchange surface isssociated with vascular abnormalities, consisting in a rarefied andemodelled vascular bed (Levin, 1978; Shehata et al., 1999; Bargyt al., 2006), the regulation of which is profoundly disturbed (Deagausie et al., 2005; Shehata et al., 2006). The current view ishat a normal and complete diaphragmatic development facilitatesarmonious development of the cardiopulmonary system.

.3.2.1. The diaphragm and static mechanics of the thoracoabdominalomplex. In physiological terms, the role of the diaphragm as a vis-eral organizer can be considered from both a static and a dynamicoint of view. The physiological importance of the diaphragm inaintaining the position of the viscera is illustrated by the cranial

isplacement of the abdominal content associated with a herni-

ted (Fig. 7A) or paralysed diaphragm (Fig. 8). This displacementccurs immediately (as illustrated by hemidiaphragm elevationithin minutes after a phrenic lesion, Takasaki and Arai, 2001),

he diaphragm returning to its normal anatomical configuration ifts function is restored (Takasaki and Arai, 2001). Such a tempo-

ig. 7. Semi-schematic ventral view of a cat, showing effect of congenital centraliaphragmatic hernia. Note invasion of left pleural space by liver, stomach, intestinend spleen, impinging on the left lung and pushing the mediastinum to the right.he left kidney is also displaced cranially (after Plagens and JBradbury, 1930).

Fig. 8. Effect of unilateral diaphragmatic paralysis without hernia, showing cranialdisplacement of viscera. (A) Expiration and (B) inspiration.

ral dynamics indicates that the visceral organization function ofthe diaphragm has an active component, depending on its contrac-tile tone and not only on its structural elasticity (in other words,muscle atrophy and the corresponding loss in elasticity are notrequired for the cephalad visceral displacement to be observed).The diaphragmatic tonic activity (as opposed to its phasic, inspi-ratory activity) therefore contributes to increase and maintain thevolume of the thoracic cavity and, consequently of the lungs. Inthis, the diaphragm may serve a static mechanical purpose and con-tribute to lower lung compliance. Bilateral section of the phrenicnerves in dogs is indeed associated with a 30% acute reductionin dynamic lung compliance (Takeda et al., 1986) and with anincreased work of breathing in spite of unchanged minute ventila-tion. These observations are strikingly similar to observations madeafter the surgical resection of the post-hepatic septum of the tegulizard, Tupinambis merianae (Klein et al., 2003c). Removal of thePHS has major effects on the topology of the viscera and dramati-cally reduces the space available for the lungs. It also significantlyreduces resting lung volume and static lung compliance (Klein etal., 2003c). Although the PHS and the mammalian diaphragm arenot homologous, we suggest that the functional analogy betweenthe two structures is of great heuristic value in understanding theprimitive functions of the diaphragm.

In humans, the importance of the diaphragm in maintaininglung volume and minimizing work of breathing is well illustratedby the occurrence of orthopnea (namely the appearance or wors-

ening of dyspnea when going from the sitting or standing tothe supine posture) in patients with severe diaphragmatic dys-function (Wilcox and Pardy, 1989; Mier-Jedrzejowicz et al., 1988;Similowski et al., 2000). In the upright position, gravity keeps theabdominal viscera down and somewhat counterbalances the loss

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f diaphragm tone and elasticity. In the supine position, on theontrary, the content of the abdomen further migrates within thehorax, which is associated with a further reduction in lung volumethat counts among diagnostic criteria), hence further breathingifficulties. A supine reduction in intercostal muscle activity alsoontributes to this phenomenon (McCool et al., 1991). In strikingllustration of the role of gravity on lung volume and respiratoryensations in patients with diaphragm paralysis, immersion in theater reproduces the breathing pattern changes and the dyspnearovoked by the supine position (McCool et al., 1991; Schoenhofert al., 2004)

There are no available data that would allow one to quantify theespective contributions of muscle tone and muscle elasticity in theisceral organizing function of the diaphragm. This would involveomparing visceral topology and respiratory mechanics before andfter surgically removing the diaphragm (elastic membrane role)n animals having previously undergone a phrenic section (role of

uscle tone). There is, however, indirect information indicatinghat both factors are important. In animals with acute experimen-al unilateral diaphragm paralysis, the contraction of the intactemidiaphragm does not result in a cephalad movement of thebdominal content, because the paralyzed diaphragm is pulledownward by the healthy one through the central tendon (Scilliat al., 2004). Conversely, in patients with long-standing unilateraliaphragm paralysis – where the atrophy of the relevant hemidi-phragm is bound to result in a loss of its elasticity – the contractionf the healthy diaphragm results in a typical ascent of the para-yzed hemidiaphragm with an upward motion of the abdominalontent toward the thorax. This is particularly visible during sniffanoeuvres for example (Hitzenberger, 1927; Alexander, 1966).

.3.2.2. The diaphragm and dynamic mechanics of the thoracoab-ominal complex: locomotor–respiratory coupling. As in all classesf vertebrates (Perry and Carrier, 2006), there is ample evidenceor a locomotor–respiratory coupling in mammalians. Runninguadrupeds synchronize the locomotor and respiratory cycles atn integral ratio of one breath per one stride (Bramble and Carrier,983). Human runners also synchronize breathing and locomo-ion, at various integral or half-integral phase-locked patterns (4:1,:1, 2:1, 1:1, 5:2, and 3:2; Bramble and Carrier, 1983). This isbserved in both untrained and trained runners, but the latterxhibit more stable couplings across locomotor speeds (McDermottt al., 2003). Locomotor–respiratory coupling in humans also occursuring walking (Rassler and Kohl, 2000) and during other activi-ies such as rowing (Siegmund et al., 1999) or forearm sinusoidalracking (Ebert et al., 2000). The 1:1 ratio between locomotion andespiration is also observed during bipedal hopping in wallabies,hile cardiac frequency shows no such entrainment (Baudinette

t al., 1987).From the 1:1 locomotor–respiratory coupling observed during

opping in wallabies and running in quadrupeds, it has been pos-ulated that the primary determinants of airflow generation duringhese activities were inertial displacements of the abdominal vis-era generated by the locomotory forces. According to this view,scillations of the visceral mass drove pulmonary ventilation inde-endently of diaphragmatic contractions (Bramble and Jenkins,993). The large central tendon of the wallaby diaphragm has beenaken as an argument to support this contention (Baudinette et al.,987). Under this premise, the diaphragm was viewed as a dynamicisceral organizer, so to speak, the primary role of which was toodulate visceral kinetics during exercise (Bramble and Jenkins,

993).This theory has however been disproven by several studies con-

ucted in chronically instrumented dogs and horses (Ainsworth etl., 1996, 1997). These experiments provided evidence that, dur-ng exercise induced hyperpnea, each breath is determined by

& Neurobiology 171 (2010) 1–16 9

respiratory neuromuscular events, namely phasic diaphragmaticelectromyographic bursts corresponding to tidal shortenings ofthe diaphragm, themselves always synchronous with decreasesin esophageal pressure and the consequent inspiratory flowgeneration. Therefore, while locomotory-associated forces andlumbo-sacral flexion may assist with flow generation (Ainsworthet al., 1997), they are not the primary determinants of breath-ing during exercise, and also not the primary determinant of thelocomotor–respiratory coupling. The latter is more likely of neuralorigin, and may proceed from direct interactions between respi-ratory central pattern generator in the brainstem and locomotorpattern generators in the spinal cord (Perry and Carrier, 2006).It may also involve the afferent pathways of mechanoreceptors(Gozal and Simakajornboon, 2000). Indeed, in patients with con-genital central alveolar hypoventilation who have no automaticbreathing activity during sleep, passive ankle mobilization drivesventilation (Gozal and Simakajornboon, 2000). The hypothesis ofa neural locomotor–respiratory coupling is consistent with theleapfrogging of respiratory and locomotor faculties that is appar-ent throughout evolution and begins in non-craniate chordates tocontinue in water-breathing and air-breathing vertebrates (Perryand Carrier, 2006). Indeed, locomotion-respiratory synchroniza-tion exists in spite of very different breathing mechanisms. Ofnote, the contraction of the diaphragm during exercise in mammalsoccurs with such timing that it counteracts the inertial cepha-lad displacement of abdominal viscera induced by the locomotordynamics (Ainsworth et al., 1996, 1997) that is expiratory innature. During locomotion, the activity of the interosseous por-tions of the intercostals also becomes uncoupled from breathingand correlates with leg movements, as opposed to the activ-ity of the parasternal intercostals that is always associated withinspiration (Carrier, 1996). This exercise-related loss of intercostalmuscle efficiency makes the involvement of the diaphragm in thelocomotor–respiratory coupling all the more important.

3.3.2.3. The diaphragm and dynamic mechanics of the thoracoab-dominal complex: postural function of the diaphragm. In humans,the diaphragm is active during non-respiratory activities that chal-lenge trunk posture, such as weightlifting (Al-Bilbeisi and Mc Cool,2000), and, in a less intuitive manner, rapid upper limb movements(Hodges et al., 1997; Hodges and Gandevia, 2000a,b). Anticipatorycostal and crural diaphragmatic contractions occur before rapidflexions of the shoulder initiated in response to visual stimula-tions (Hodges et al., 1997). Repetitive fast upper limbs movementsinduce tonic expiratory diaphragm activity upon which is added aphasic modulation at the frequencies of both respiration and limbmovements (Hodges and Gandevia, 2000b). Similar phenomena areobserved for abdominal muscles – e.g. transversus abdominis –(Hodges et al., 1997; Hodges and Gandevia, 2000b) and for pelvicfloor muscles (Hodges et al., 2007). Of note, pelvic floor muscles arelinked to respiratory muscles through polysynaptic reflexes that aretriggered by expiratory – cough – or inspiratory – sniff – increasesin abdominal pressure (Chan et al., 2004).

The intra-abdominal pressure is increased during postural tasks(Hemborg et al., 1985). This is the result of activation of thediaphragm and of abdominal muscles, and also of pelvic muscles.The intra-abdominal pressure rise that occurs during lifting activ-ities seems to be correlated to a good coordination between themuscles surrounding the abdominal cavity (Hemborg et al., 1985).Of these, the diaphragm seems to be the most important determi-nant of the pressure level that is reached, which is also contributed

to by closure of the glottis. The rise in intra-abdominal pressure hasbeen shown to increase spinal stiffness and to reduce interverte-bral motion at the lumbar level (Shirley et al., 2003; Hodges et al.,2003) that should stabilize the trunk and optimize the efficiencyof this movement. Tension ruptures of the diaphragm following

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losed glottis efforts have been described (Matsevych, 2008) witheveral postulated mechanisms including the shearing of an over-tretched membrane, avulsion of the diaphragm from its points ofttachment, and sudden force transmission through viscera actings a viscous fluid.

The integration of the respiratory and postural functions of theiaphragm may depend on inputs summation at the level of theespiratory motoneurones, itself the result of pre-motoneuronaloordination. This is supported by the fact that the postural activ-ty of the diaphragm decreases when respiratory drive increasesHodges et al., 2001), which may attenuate the postural commandseaching the phrenic motoneurons (Hodges et al., 2001),

.3.3. Expulsive function of the diaphragmIn addition to its inspiratory and trunk stabilizing functions

described above) the diaphragm is activated during a variety ofctions of which the common objective is to extrude somethingrom the organism. Some of these actions can be expiratory in aim,nvolving the opening of the glottis and the expelling of air at aiven point of the corresponding motor sequence. Thus, antagonis-ic diaphragm activity can be demonstrated during coughing effortsGrelot and Milano, 1991; Estenne and Gorini, 1992), sneezingSieck and Fournier, 1989), voluntary forced expiration (Melissinost al., 1981), or laughing (Filippelli et al., 2001).

Other expulsive actions are non-respiratory, they involve alosed glottis and the prolonged co-contraction of the abdominaluscles (also of expiratory rib cage muscles) and of the diaphragm,behaviour that is referred to as “straining” (Iscoe, 1998). Strain-

ng is involved in defecation (Fukuda and Fukai, 1986a,b), vomitingAbe et al., 1993, 1994), micturition (Fukuda and Fukai, 1986a,b), orarturition (Higuchi et al., 1987). Depending on the expulsive taskonsidered the corresponding increases in abdominal pressure aressociated with changes in the activity of the gastro-esophageal,nal, and urethral sphincters. These changes depend, among otherhings, on the rate of rise of the abdominal pressure (Iscoe, 1998).or example, in human, rapid increases in abdominal pressure suchs during cough augment the activity of the anal sphincter therebyreventing incontinence, whereas slow increases, as occur in defe-ation, decrease or abolish its activity (Shafik, 1991).

It is interesting to note that non-ventilatory diaphragmatic con-ractions can correspond to very high levels of neural activationor, in other words, of motoneuron recruitment). In an anesthetizedat preparation, the transdiaphragmatic pressure produced duringuiet breathing amounted to 12% of the maximal value elicitedy bilateral supramaximal stimulation of the phrenic nerves. It

ncreased to 28% of this value when respiration was stimulatedy CO2, but remained below 50% during respiratory movementsccurring against complete airway occlusion. In contrast, the gageflex and sneezing produced maximal diaphragmatic activation,ith transdiaphragmatic pressures reaching or exceeding 100%

f the maximal stimulated pressure (Sieck and Fournier, 1989).athematical modelling has suggested that only a small fraction

f the transdiaphragmatic pressure acts to inflate the rib cageMacklem, 1979). Such observations lend support to the idea, pre-iously expounded by Jones (1913), that assisting inspiration mayot have been the primary function of the diaphragm.

Expulsive actions imply not only the production but also theaintenance over time of very high abdominal pressures. In

his regard, antagonistic co-contractions of the diaphragm opti-ize the synchronous contractions of the abdominal muscles, and

ice-versa. This involves at least two mechanisms. Firstly, the

ynchronous contraction of antagonistic muscles prevents theirespective shortening (Ait-Haddou et al., 2000), which keeps themithin a fixed zone of their length-tension relationship through-

ut the whole duration of the contraction. This explains why, forxample, trans-diaphragmatic pressures generated voluntarily in

& Neurobiology 171 (2010) 1–16

humans are higher during combined expulsive-Mueller manoeu-vres – where the contraction of the abdominal muscles preventsthe diaphragm from shortening – than during isolated Muellermanoeuvres – where this does not occur – (Laporta and Grassino,1985). Secondly, contracting the diaphragm synchronously withthe abdominal muscles during expulsive manoeuvres prevents anycephalad displacements of the abdominal content toward the tho-racic cavity. This, as discussed before, would be counterproductivein terms of pressure generation.

The neural mechanisms that govern diaphragmatic contractionsduring expulsive maneuvers are complex (see Iscoe, 1998). Verybriefly, straining is a coordinated behaviour that arises from a ros-tral pontine structure, possibly the Kölliker-Fuse nucleus (Fukudaand Fukai, 1986b). It can be elicited, in decerebrated dogs, by dis-tension of the rectum, vagina or bladder or by stimulation of pelvicafferents (Fukuda and Fukai, 1986a,b). Stimulation of vaginal affer-ents in pregnant rats also elicits this response, leading to expulsionof the fetus (Higuchi et al., 1987). Interestingly, in humans, theactive participation of the diaphragm to coughing efforts is pre-served in quadriplegic patients who have paralyzed abdominalmuscles, indicating that the cough-related diaphragm contractionsdo not result from reflexes triggered by abdominal muscle contrac-tions (Estenne and Gorini, 1992).

The importance of the diaphragm in expulsive manoeuvresis supported by anecdotal clinical observations. Firstly, patientssuffering from severe diaphragmatic weakness often report mic-turitional or defecating difficulties (Duchenne de Boulogne, 1853;T. Similowski, personal observations). This is in line with the accu-mulation of faeces in the rectum that is observed in the horseafter phrenic section (Jones, 1913). Conversely, diaphragm pacingin quadriplegics is associated with easier fecal exoneration (T. Sim-ilowski, personal observations). Secondly, there are occasional casereports of diaphragm ruptures occurring during expulsive effortssuch as those described as a result of coughing (Kallay et al., 2000),vomiting (Lee et al., 2006), or during parturition (Hamoudi et al.,2004). Among expulsive behaviors, parturition involves the mostintense, prolonged, and repeated efforts during which the abdomi-nal muscles and the diaphragm undergo sustained co-contractions.This is particularly true in humans, where the dimensions of thefetus head and of the birth canal are almost identical, hence therequirement for high intra-abdominal pressures in addition to theuterine contractions. The human diaphragm appears to be of partic-ular importance during labor. During the early XIXth century, Jones(1913) – who held it that the primitive function of the diaphragmwas to generate high intra-abdominal tensions with the abdomi-nal muscles acting as “resisters” to optimize its action – reportedhaving observed “many cases [of] multiple hematomata of thediaphragm in women who have died either in childbirth or afterconfinement”. In the more recent and readily accessible literature, afew cases of parturition-related diaphragmatic ruptures have beenreported (Dave et al., 1973; Hill and Heller, 1996; Hamoudi et al.,2004). Perhaps more significantly, the occurrence of diaphragmfatigue during normal human labour has been described throughelectromyographic evidence (Nava et al., 1992). From an evolution-ary point of view, it could be hypothesized that the development ofa muscular diaphragm early in the mammalian lineage contributedto allow mammals to bear and deliver living offspring. Furthermore,the expulsive function of the diaphragm could be considered as anexaptation favouring the evolution of head size in humans (andthus of the “disproportionate” human brain).

4. Origin of the mammalian diaphragm

Despite comparative anatomical and embryological research,the exact anatomical origin of the diaphragm muscle is unclear.There are two groups of plausible explanations: One group, the

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muscular hypothesis”, maintains that the diaphragm is primar-ly muscular, and originates by the lung invading the spaceetween the rib cage and the existing body wall musculature.he central tendon would therefore be a secondary result causedy muscle atrophy (Broman, 1911). The other group of expla-ations, the “membranous” hypotheses, favours a muscle-freeembranous diaphragm that becomes secondarily muscular-

zed.Within the muscular hypothesis the classical view holds that

he muscular component is derived from the rectus abdominissee Starck, 1982). In support of this theory is the observationhat the rectus abdominis in Rana is innervated by a branch ofhe second spinal nerve, and that this nerve also innervates thediaphragm” in Xenopus (Beddard, 1895a,b; Keith, 1905). The impli-ation is as follows: if the amphibian “diaphragm” is homologouso the mammalian one, then both are actually part of the rectusbdominis system (henceforth referred to as the rectus system).he second spinal nerve in anurans, however, also innervates hypo-ranchial muscles (Gaupp et al., 1899; Ravn, 1899; Uskow, 1883)nd thus, the amphibian (and possibly mammalian) diaphragmay also be affiliated with that group. Furthermore, the hypo-

ranchial and rectus groups can intergrade broadly. Snapper et al.1974) confirmed that the amphibian diaphragm is active duringreathing. However, its possible function in filling the lungs withir remains unclear. Another view (Gräper, 1928a,b) is that theuscle of the diaphragm is derived from the transversus, rather

han from the rectus. Whilst attractive from the point of viewf explaining the reduction in mammals of a transversus thoracistriangularis sterni) muscle, this hypothesis does not adequatelyxplain the innervation of the diaphragm from cervical segments3–C7 (mostly C4 and C5) rather than from more posterior seg-ents.The “membranous hypothesis” theory of diaphragm origin is

ased entirely on the embryological origin of the diaphragm from arimarily muscle-free dorsal extension of the pleuroperitoneal foldPPF), with some participation of the cranial nephric fold (Wolfel,907) (Fig. 3A) (Goodrich, 1930; Duncker, 1978; Perry, 1985). This

mplies that the diaphragmatic musculature either migrates inrom another source (rectus, transversus or more than one source)r differentiates in situ (Körner, 1939; Lessertisseur, 1968; Brink,956). In anesthetized dogs, De Troyer et al. (1981) have shownhat stimulating the costal part of the diaphragm without co-timulation of its crural part resulted in increased dimensions ofhe rib cage. Stimulating the crural part of the muscle, however,ecreased these dimensions. Based upon this radical physiolog-

cal distinction they concluded that the diaphragm was in factwo separate muscles. Among their arguments, they emphasizedhat the crural and the sterno-costal parts have different embry-logical origins, suggesting that the crural part may be axial inrigin and that the costal part may develop from myoblasts orig-nating in the lateral body walls. Whereas early embryologicaltudies (Gaupp et al., 1899; Giglio-Tos, 1894; Ravn, 1899; Uskow,883), and recent molecular developmental data (Greer et al., 1999;abiuk et al., 2003) attribute the origin of the membranous partf the diaphragm to separate parts of the pleuroperitoneal fold,hey do not confirm the origin of its muscular part from axial,ectus or transversus groups. Instead the totality of the diaphrag-atic muscle appears to originate in undifferentiated cervical

omites and to migrate into the PPF. In addition c-met null mutantice, in which axial muscle develops normally but muscles that

epend on migration do not, demonstrate that no part of the

iaphragm becomes muscularized (Bladt et al., 1995; Yang et al.,996). Therefore, a separate axial origin of the crural diaphragmppears unlikely and furthermore from an embryological point ofiew, the diaphragm appears to be a single muscle rather thanwo.

& Neurobiology 171 (2010) 1–16 11

4.1. Embryological development

Embryologically both the lungs and the diaphragm in mammalsoriginate in the cervical region of the fetus where the pleuroperi-toneal fold is located initially. This is anterior to their ultimatelocation in the thorax. The lungs accompany the oesophagus andin the 8-mm rabbit embryo extend past the primordial diaphragminto the pleuroperitoneal space (Uskow, 1883). Later, pleural spacesform through desquamation of the inner layer of the pleuroperi-cardial membrane and transverse septum ventrally and caudallyrespectively, and the lateral mesoderm laterally. It is possible there-fore that the ‘diaphragm’ may have originally been a part of thebody wall and has access to developing somatic muscle blastemes.The separate pleural spaces then join and expand to form thedefinitive right and left pleural cavities as the embryo stretches. Abroad attachment of the diaphragm to the pericardium (pars affixa)remains in some species, including man, whereas in others (rabbit,pig, rat) this attachment is reduced (Uskow, 1883). Simultaneously,stretching of the embryo and differentiation of the neck pull thelungs forward, and the diaphragm closes behind them, draggingthe phrenic nerves with it from their cervical origin (Uskow, 1883;Goodrich, 1930). These data are consistent, in part, with the modelof Brink (1956) suggesting that a partial diaphragm was presentin Permian therapsids as a perforated membrane in which smoothmuscle became replaced in situ by striated muscle. The presence ofsuch a smooth muscle containing, but not homologous perforatedmembrane (PHS) has been demonstrated in the tegu lizard (Kleinet al., 2003a,b,c).

Two facts, however, speak against the hypothesis that diaphrag-matic smooth muscle was replaced by striated muscle or was evenpresent in the first place in therapsids. First, the functional tran-sition from gastralia to diaphragm must have taken place earlyin therapsid evolution, since although gastralia were widespreadin “pelycosaurs”, they have been reported in a single, anomod-ont therapsid group (Romer, 1956; Brinkman, 1981). Secondly,although striated-to-smooth muscle transitions in the same organ(e.g., esophagus) are well known (Patt and Patt, 1969; Fawcett,1994), it is unlikely that this was the case for the diaphragm. Ifthe source of the smooth muscle were esophageal, peritoneal ormesenterial, one would expect vagal-visceral rather than cervical-somatic innervation. Therefore, it is more likely that striated muscleand associated innervation were already present in the primordialdiaphragm during its phylogenetic origin in basal therapsids.

4.2. Original function of the diaphragm and one scenario for itsorigin

In light of the long, separate evolution of Synapsida and thus ofthe Mammalia which evolved within this group, amphibian mod-els of a functional explanation for origin of the diaphragm appearrelevant. In the relatively basal anuran group Discoglossidae, the so-called “diaphragmaticus” muscle described by Beddard (1895a,b)and Keith (1905) may function as a pinch valve to prevent refluxof stomach content into the esophagus during breathing (Pickeringand Jones, 2002). In addition, the location of the ductus Cuvieri(Fig. 3) at the base of the PPS (Uskow, 1883; Perry, 1985) and theclose association of the transverse septum with the sinus venosus(Keith, 1905) suggests that a diaphragmatic muscle may have beenimportant in facilitating venous return to the heart (Gegenbaur,1898). Interestingly, recent human data indicate that diaphragm

pacing has beneficial haemodynamic effects in patients with heartfailure (Roos et al., 2009). The observation that venous return isimpeded during locomotion in the iguana, which lacks both a PPSand a PHS (Farmer and Hicks, 2000), is also consistent with thishypothesis.

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One problem inherent in the amphibian model of diaphrag-atic origin in mammals however, is that all Lissamphibia are

ighly derived. The neck of a frog is very short and a distinct neckegion from which the diaphragmatic muscle in mammals mayave originated was lacking in the common basal tetrapod ancestorf Lissamphibia and amniotes (Clack, 2002). Therefore, the anuranquivalent of the mammalian cervical vertebrae from which thehrenic nerve roots emanate is unclear. As in ontogeny, the evolu-ion of the neck region may have been coupled to the displacementf the lungs and diaphragm to the thorax.

At this point the diaphragm may have taken the role of dynam-cally stabilizing the liver and other viscera. Indeed, the diaphragmoes prevent movements of the abdominal viscera into the thoracicavity (see Figs. 7 and 8) (Plagens and JBradbury, 1930). Geneti-ally determined diaphragm defects in animals (posterior defectsn mice with Couptf2 and Wtl genes alterations; anterior defectsn slit3 knockout mice and Gata4 null carrier mice; musculariza-ion defects in c-Met null mice and Fog2 hypomorphs: see Pober,008) and in humans (in the context of congenital diaphragm her-ia) are all associated with an invasion of the thoracic cavity byhe liver and abdominal viscera, leading to various degrees of lungypoplasia and compression that can be lethal (Yuan et al., 2003).

Functioning as a visceral organizer and stabilizer may have beennstrumental in allowing the concomitance of respiration and loco-

otion, later optimized to allow rapid, but above all sustained,ocomotion. The diaphragm may have developed gradually as the

ammalian lung evolved its alveolar structure and decreased itsompliance. By analogy, numerous reptiles have high-complianceungs and also lack special internal coelomic septation (Broman,904; Perry and Duncker, 1978; Klein and Owerkowicz, 2005), butegus, which have the lowest lung compliance of any lizard mea-ured to date, possess a nearly complete PHS. It thus appears thatmuscular septum is the prerequisite for the evolution of dense,omogeneous, low-compliance lungs (Perry and Duncker, 1980).

n addition, the development of a phasic diaphragmatic inspiratoryctivity would have increased the efficiency of costal breathing,ot only by preventing the abdominal content to be aspired in thehorax during inspiration, but also by pushing this content awayrom the expanding lungs, and by enhancing the expansion of theower rib cage. The inspiratory action of the diaphragm is thus inti-

ately linked to its visceral organization function, insofar as fort to be optimal the abdominal content must act as a resister tots descent. This was purported as early as by Galen (1956, 1989),e-discovered theoretically by Magendie (1817) and fully demon-trated by Duchenne de Boulogne (1853). Of note and in support ofhis mechanism, the first use of x-rays to study diaphragm actionevealed surprisingly little caudal displacement of the liver (Fick,898).

In connection with this “secondary” breathing function inncreasing thoracic volume and optimizing costal breathing, theiaphragm evolved as an inspiratory muscle, under neuronal con-rol that temporally coordinates the activity of all respiratory

uscles and prevents rib cage distortion. Indeed, whilst the lowerib cage is exposed to positive pressure, the upper part expe-iences negative pressure due to the action of the parasternalntercostals and scalenes during quiet breathing, and of other

uscles including the sternocleidomastoid when respiration isugmented.

The question remains as to how therapsids breathed. Gastraliare dermal bones that in numerous Paleozoic tetrapods, thero-od dinosaurs, crocodilians, and Sphenodon cover the belly wall

etween the posterior margin of the sternum and the pelvic girdleRomer, 1956, 1966; Maurer, 1896). Kinetic gastralia in theropodinosaurs may have played an important role during respirationClaessens, 2004a,b; Codd et al., 2008). Furthermore, Perry (1983)uggested that fixed gastralia may have served a similar function

& Neurobiology 171 (2010) 1–16

to the diaphragm by controlling paradoxical (inward) belly wallmovement and concomitant visceral displacement in other groups.These structures, which were ancestral in tetrapods, have becomelost repeatedly (Claessens, 2004a,b). In such cases, either the respi-ratory system has an extremely high compliance (birds, snakes andsome lizards) or they have become replaced by internal septation(crocodilians, tegu lizards), which also controls visceral movement.Gastralia are reduced or absent in therapsids but are well developedin their “pelycosaur” sister group Sphenacodontidae. In additionmany mammal-like cynodont therapsids possessed a true lumbarregion, in which ribs were lacking (Thrinaxodon) or reduced. Thisled Brink (1956) to speculate that these animals also possessed afunctional diaphragm. The question remains, how the diaphragmcould have arisen in therapsids and what its function might havebeen.

One possible scenario is that Pelycosaurs may have possessedan undivided pleuro-peritoneal cavity, with large, high-compliancelungs dorsal to the liver as in most modern lizards. The primi-tive diaphragm (PPS; also present in archosaurs, varanoid lizardsand chameleons) may have functioned in regulation of venousreturn or regurgitation of stomach contents, as explained in thefrog model and gastralia controlled unproductive belly wall move-ment. As therapsids became more aerobically active (indicated bytheir more cursorial limb structure and flexible trunk in cynodonts)the lung surface area increased and lung compliance decreased. It isnow possible to envision a positive feedback loop in which the PPSincreases in importance for controlling visceral movement, therebyincreasing breathing efficiency and making the gastralia obsolete.The reduction of the gastralia contributed to flexibility of the trunkand locomotor efficiency thereby reinforcing the locomotor func-tions of the protodiaphragm. The new, more cursorial therapsidscould catch smaller prey and/or acquired heterodont dentitionthat aided in reduction of bolus size. Alternatively other therap-sid lineages evolved herbivory. The perforations in the diaphragmwere therefore no longer necessary to accommodate very largeswallowed prey and the diaphragm closed. The new capabilityof generating high negative thoracic pressures could now sup-port low-compliance lungs, allowing further reduction in lungvolume and a simultaneous increase in surface area. These animalscould now support a constant high metabolic rate, which evolvedtogether with the fur, facial musculature and other mammaliantraits.

The highly derived broncho-alveolar lungs of mammals haveextremely low inflation compliance compared with those of “rep-tiles” (Perry and Duncker, 1978, 1980). Lung compliance is equalto or less than the compliance of the body wall in most mammals(Mortola, 1987) and the situation is more pronounced in small andnewborn animals than in large ones. Therefore, the lungs would notbe inflatable if they were simply suspended by the pulmonary liga-ments in an undivided pleuro-peritoneal cavity as in many lizards.The apparent correlation between the lack of development of thecentral tendon and the degree of separation of the crura from thevertebra in carnivores deserves further study in relation to theuse of spinal flexion in locomotion in different species (Alexander,1989).

The role of the diaphragm as an exaptation in allowing theproduction of very high abdominal pressure has been seen as cru-cial in the later evolution of vivipary in placental mammals andin the production of large and/or precocial young (Jones, 1913).This could have played a major role in the evolution of large –disproportionate – brains in humans. In its role as a visceral orga-

nizer and as an inspiratory muscle the diaphragm has been crucialto the evolution of mammals as high-performance homeotherms(Perry and Duncker, 1980). Investigations into the origin of themammalian diaphragm clearly demonstrate that despite the gapof almost a century between the early basic comparative anatom-

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cal and embryological studies and the modern molecular work,ontinuity can be found.

In conclusion, it remains unclear which muscles in earlyetrapods might have corresponded to the mammalian diaphragm.he hypothesis of migration from an already fully differentiatedectus abdominis or transversus thoracis group seems remote, andhe most likely answer is that the ‘pre-diaphragm’ was either aypobranchial muscle or “none of the above”.

cknowledgments

The authors acknowledge the financial support of J.R.C. and.F.P. through the DFG Graduiertenkolleg “Evolution und Biodiver-ität in Zeit und Raum” (DFG 721/1), S.F.P. through DFG FOR533,

.K. through the DAAD/CAPES Probral Program and Graduierten-örderung des Landes Nordrhein-Westfalen, J.R.C. through theBSRC (BB/G011388/1) and The Leverhulme Trust (F/00 120/BH)nd T.S. through the Association pour le Développement et’Organisation de la Recherche en Pneumologie (ADOREP), Paris,rance. We are grateful to Marion Schlich for assistance with illus-rations, Klaus Völker for assistance in literature research.

eferences

be, T., Kusuhara, N., Katagiri, N., Tomita, T., Easton, P.A., 1993. Differential functionof the costal and crural diaphragm during emesis in canines. Respir. Physiol. 91,183–193.

be, T., Kieser, T.M., Tomita, T., Easton, P.A., 1994. Respiratory muscle function duringemesis in awake canines. J. Appl. Physiol. 76, 2552–2560.

insworth, D.M., Smith, C.A., Henderson, K.S., Dempsey, J.A., 1996. Breathing duringexercise in dogs—passive or active? J. Appl. Physiol. 81, 586–595.

insworth, D.M., Smith, C.A., Eicker, S.W., Ducharme, N.G., Henderson, K.S., Snedden,K., Dempsey, J.A., 1997. Pulmonary–locomotory interactions in exercising dogsand horses. Respir. Physiol. 110, 287–294.

it-Haddou, R., Binding, P., Herzog, W., 2000. Theoretical considerations oncocontraction of sets of agonistic and antagonistic muscles. J. Biomech. 33,1105–1111.

l-Bilbeisi, F., Mc Cool, C.F., 2000. Diaphragm recruitment during non-respiratoryactivities. Am. J. Respir. Crit. Care. Med. 162, 456–459.

lexander, C., 1966. Diaphragm movements and the diagnosis of diaphragmaticparalysis. Clin. Radiol. 17, 79–83.

lexander, R.M., 1989. On the synchronization of breathing with running in walla-bies (Macropus spp.) and horses (Equus caballus). J. Zool. Lond. 218, 69–85.

liverti, A., Cala, S.J., Duranti, R., Ferrigno, G., Kenyon, C.M., Pedotti, A., Scano, G.,Sliwinski, P., Macklem, P.T., Yan, S., 1997. Human respiratory muscle actionsand control during exercise. J. Appl. Physiol. 83, 1256–1269.

liverti, A., Iandelli, I., Duranti, R., Cala, S.J., Kayser, B., Kelly, S., Misuri, G., Pedotti, A.,Scano, G., Sliwinski, P., 2002. Respiratory muscle dynamics and control duringexercise with externally imposed expiratory flow limitation. J. Appl. Physiol. 92,1953–1963.

mancharla, M.R., Rodarte, J.R., Boriek, A.M., 2001. Modeling the kinematics of thecanine midcostal diaphragm. Am. J. Physiol. 280, R588–597.

ngelillo, M., Boriek, A.M., Rodarte, J.R., Wilson, T.A., 1997. Theory of diaphragmstructure and shape. J. Appl. Physiol. 83, 1486–1491.

rnulf, I., Similowski, T., Salachas, F., Garma, L., Mehiri, S., Attali, V., Behin-Bellhesen,V., Meininger, V., Derenne, J.P., 2000. Sleep disorders and diaphragmatic functionin patients with amyotrophic lateral sclerosis. Am. J. Respir. Crit. Care. Med. 161,849–856.

abiuk, R.P., Zhang, W., Clugston, R., Allan, D.W., Greer, J.J., 2003. Embryologicalorigins and development of the rat diaphragm. J. Comp. Neurol. 455, 477–487.

argy, F., Beaudoin, S., Barbet, P., 2006. Fetal lung growth in congenital diaphrag-matic hernia. Fetal Diagn. Ther. 21, 39–44.

audinette, R.V., Gannon, B.J., Runciman, W.B., Wells, S., Love, J.B., 1987. Do car-diorespiratory frequencies show entrainment with hopping in the Tammarwallaby? J. Exp. Biol. 129, 251–263.

ayle, F., 1688. Dissertation sur quelques points de physique et de médecine. Fouchacand Bely, publishers, Toulouse, France.

eau, J.H.S., Maissiat, J.H., 1843. Recherches sur le mécanisme des mouvementsrespiratoires (deuxième article). Arch. Générales de Médecine 4, 265–295.

eddard, F.E., 1895a. On some points the anatomy of Pipa americana. Proc. Zool. Soc.Lond. 53, 827–841.

eddard, F.E., 1895b. On the diaphragm and muscular anatomy of Xenopus. Proc.

Zool. Soc. Lond. 53, 841–846.

ennett, J.R., Dunroy, H.M.A., Corfield, D.R., Simonds, A.K., Polkey, M.I., Morrell, M.J.,2004. Respiratory muscle activity during REM sleep in patients with diaphragmparalysis. Neurology 62, 134–137.

ert, P., 1870. Lecons, sur la Physiologie Comparée de la Respiration Professées auMuséum d’histoire Naturelle. JB Baillière, Publisher, Paris, France, pp. 345, 353.

& Neurobiology 171 (2010) 1–16 13

Bladt, F., Riethmacher, D., Isenmann, S., Aguzzi, A., Birchmeier, C., 1995. Essentialrole for the c-met receptor in the migration of myogenic precursor cells into thelimb bud. Nature 376, 768–771.

Blair, D.M., 1923. A study of the central tendon of the diaphragm. J. Anat. 57, 203–215.Boriek, A.M., Hwang, W., Trinh, L., Rodarte, J.R., 2005. Shape and tension distribution

of the active canine diaphragm. Am. J. Physiol. 288, R1021–1027.Brainerd, E.L., 1999. New perspectives on the evolution of lung ventilation mecha-

nisms in vertebrates. Exp. Biol. 4, 11–28.Brainerd, E.L., Ditelberg, J.S., Bramble, D.M., 1993. Lung ventilation in salamanders

and the evolution of vertebrate air-breathing mechanisms. Biol. J. Linn. Soc. 43,163–183.

Bramble, D.M., Carrier, D.R., 1983. Running and breathing in mammals. Science 219,251–256.

Bramble, D.M., Jenkins Jr., F.A., 1993. Mammalian locomotor–respiratory inte-gration: implications for diaphragmatic and pulmonary design. Science 262,235–240.

Brink, A.S., 1956. Speculations on some advanced mammalian characteristics in thehigher mammalian-like reptiles. Palaeont. Afr. 4, 77–96.

Brinkman, D., 1981. The structure and relationships of the Dromasours (Reptilia:Therapsid). Breviora 465, 1–34.

Broman, I., 1904. Die Entwicklungsgeschichte der Bursa omentalis und ähnlicherRezessbildungen bei den Wirbeltieren. Entw. -Gesch. Monogr. I, 446–523.

Broman, I., 1911. Ergebnisse der Anatomie und Entwicklungsgeschichte. 20: pagenumbers not available.

Brown, R.E., Butler, J.P., Godleski, J.J., Loring, S.H., 1997. The elephant’s respiratorysystem: adaptations to gravitational stress. Resp. Physiol. 102, 177–194.

Byerly, T., 1925. The myology of Sphenodon punctatum. Univ. Iowa. Stud. Nat. Hist.11, 1–51.

Carrier, D.R., 1996. Function of the intercostal muscles in trotting dogs: ventilationor locomotion? J. Exp. Biol. 199, 1455–1465.

Carrier, D.R., Farmer, C.G., 2000a. The evolution of pelvic aspiration in archosaurs.Paleobiology 26, 271–293.

Carrier, D.R., Farmer, C.G., 2000b. The integration of ventilation and locomotion inarchosaurs. Amer. Zool. 40, 87–100.

Chan, C.L., Ponsford, S., Swash, M., 2004. The anal reflex elicited by cough andsniff: validation of a neglected clinical sign. J Neurol. Neurosurg. Psychiatry 75,1449–1451.

Chihara, K., Kenyon, C.M., Macklem, P.T., 1996. Human rib cage distortability. J. Appl.Physiol. 81, 437–447.

Clack, J.A., 2002. Gaining Ground. The Origin and Evolution of Tetrapods. IndianaUniversity Press, Bloomington, Indiana.

Claessens, L.P.A.M., 2004a. Dinosaur gastralia; origin, morphology, and function. J.Vert. Paleo 24 (1), 89–106.

Claessens, L.P.A.M., 2004b. Archosaurian respiration and the pelvic girdle aspirationbreathing of crocodyliforms. Proc. R. Soc. 271, 1461–1465.

Cloquet, J., 1820. De l’influence des Efforts sur les Organes Enfermés dans la cavitéThoracique. Méquignon-Marvis Publisher, Paris, France.

Cloquet, J., 1825. Muscle diaphragm. Manuel d’anatomie descriptive du corpshumain, représentée en planches lithographiées. Béchet Jeune Publisher, Paris,France, pp. 162–167.

Cluzel, P., Similowski, T., Chartrand-Lefebvre, C., Zelter, M., Derenne, J.P., Grenier,P.A., 2000. Diaphragm and chest wall: assessment of the inspiratory pump withMR imaging-preliminary observations. Radiology 215, 574–583.

Codd, J.R., Boggs, D.F., Perry, S.F., Carrier, D.R., 2005. Activity of three muscles asso-ciated with the uncinate processes of the giant Canada goose (Branta canadensismaximus). J. Exp. Biol. 208 (5), 849–857.

Codd, J.R., Manning, P.L., Perry, S.F., Norell, M.A., 2008. Avian-like breathing mechan-ics in maniraptoran dinosaurs. Proc. R. Soc. B 275, 157–161.

Cohen, C.A., Zagelbaum, G., Gross, D., Roussos, C., Macklem, P.T., 1982. Clinical man-ifestations of inspiratory muscle fatigue. Am. J. Med. 73, 308–316.

D’Angelo, E., Sant’Ambrogio, G., Agostoni, E., 1974. Effect of diaphragm activity orparalysis on distribution of pleural pressure. J. Appl. Physiol. 37, 311–315.

Dave, K.S., Bekassy, S.M., Wooler, G.H., Ionescu, M.I., 1973. Spontaneous” rupture ofthe diaphragm during delivery. Br. J. Surg. 60, 666–668.

De Lagausie, P., De Buys-Roessingh, A., Ferkdadji, L., Saada, J., Aisenfisz, S., Martinez-Vinson, C., Fund, X., Cayuela, J.M., Peuchmaur, M., Mercier, J.C., Berrebi, D., 2005.Endothelin receptor expression in human lungs of newborns with congenitaldiaphragmatic hernia. J. Pathol. 205, 112–118.

Derenne, J.P., Debru, A., Grassino, A.E., Whitelaw, W.A., 1994. The earliest history ofdiaphragm physiology. Eur. Respir. J. 7, 2234–2240.

Derenne, J.P., Debru, A., Grassino, A.E., Whitelaw, W.A., 1995. History of diaphragmphysiology: the achievements of Galen. Eur. Respir. J. 8, 154–216.

Derenne, J.P, 2004. Respiration. Extrait du premier “Dictionnaire culturel en langueFrancaise”, éditions Le Robert. [Respiration. Extract from the first “Cultural Dic-tionary in the French Language” from Robert’s Dictionary]. Revue des MaladiesRespiratoires 21 (9), S7–S24.

De Troyer, A., 2005. Respiratory action of the intercostal muscles. Physiol. Rev. 85,717–756.

De Troyer, A., Loring, S.H., 1995. Actions of the respiratory muscles. In: Roussos, C.(Ed.), The Thorax, Part B. Lung Biology in Health and Disease Series Volume 85.

Marcel Dekker, New York, USA, pp. 535–564.

De Troyer, A., 1998. The canine phrenic-to-intercostal reflex. J. Physiol. 508, 919–927.De Troyer, A., Sampson, M., Sigrist, S., Macklem, P.T., 1981. The diaphragm: two

muscles. Science 213, 237–238.Duchenne de Boulogne, G., 1853. Recherches Electro-physiologiques Pathologiques

et Thérapeutiques sur le Diaphragme. Typographie Félix Malteste et Ce, Paris.

1 ology

D

E

E

E

F

F

F

FF

F

F

G

G

G

G

G

G

G

G

G

G

G

G

G

G

G

G

G

G

G

G

G

H

HH

v

H

4 S.F. Perry et al. / Respiratory Physi

uncker, H.R., 1978. Coelom-Gliederung der Wirbeltiere - Funktionelle Aspekte.Verh. Anat. Ges. 72, 91–112.

bert, D., Rassler, B., Hefter, H., 2000. Coordination between breathing and forearmmovements during sinusoidal tracking. Eur. J. Appl. Physiol. 81, 288–296.

stenne, M., De Troyer, A., 1987. Mechanism of the postural dependence of vitalcapacity in tetraplegic subjects. Am. Rev. Respir. Dis. 135, 367–371.

stenne, M., Gorini, M., 1992. Action of the diaphragm during cough in tetraplegicsubjects. J. Appl. Physiol. 72, 1074–1080.

armer, C.G., Carrier, D.R., 2000. Pelvic aspiration in the American alligator (Alligatormississippiensis). J. Exp. Biol. 203, 1679–1687.

armer, C.G., Hicks, J.W., 2000. Circulatory impairment induced by exercise in thelizard Iguana iguana. J. Exp. Biol. 203, 2691–2697.

awcett, D.W., 1994. Bloom and Fawcett. A Textbook of Histology, 11th ed. Chapman& Hall, New York, London.

ick, R., 1898. Ueber die Atemmuskeln, vol. 14. Anatomischer Anzeiger, pp. 178–181.ilippelli, M., Pellegrino, R., Iandelli, I., Misuri, G., Rodarte, J.R., Duranti, R., Brusasco,

V., Scano, G., 2001. Respiratory dynamics during laughter. J. Appl. Physiol. 90,1441–1446.

ukuda, H., Fukai, K., 1986a. Postural change and straining induced by distensionof the rectum, vagina and urinary bladder of decerebrate dogs. Brain Res. 380,276–286.

ukuda, H., Fukai, K., 1986b. Location of the reflex centre for straining elicitedby activation of pelvic afferent fibres of decerebrate dogs. Brain Res. 380,287–296.

alen, 1956. On Anatomical Procedures (De Anatomicis Administrationibus). BookVIII, Chap. 8. Kuhn. Translated with an introduction and notes by C. Singer.London, Oxford University Press, 690 pp.

alen, 1989. On the Causes of Breathing (De Causis Respirationis). Galen on Res-piration and the Arteries. Translations by D.J. Furley and J.S. Wilkie. Princeton,Princeton University Press.

ans, C., 1970. Respiration in early tetrapods—the frog is a red herring. Evolution24, 723–734.

ans, C., 1971. Strategy and sequence in the evolution of external gas exchangers ofectothermal vertebrates. Form Funct. 3, 61–104.

ans, C., Clark, B., 1976. Studies on ventilation of Caiman crocodilus (Crocodilia:Reptilia). Resp. Physiol. 26, 285–301.

ans, C., Hughes, G.M., 1967. The mechanism of lung ventilation in the tortoiseTestudo graeca Linné. J. Exp. Biol. 47, 1–20.

aunt, A.S., Gans, C., 1969. Mechanics of respiration in the snapping turtle, Chelydraserpentina (Linné). J. Morphol. 128, 195–228.

aupp, E., Ecker, A., Wiedersheim, R., 1899. Anatomie des Frosches auf Grundeigener Untersuchungen durchaus neu Bearbeitet. Zweite Abtheilung. Lehrevom Nerven- und Gefässsystem. Zweite Auflage. Friedrich Vieweg und Sohn.Braunschweig.

authier, A.P., Verbanck, S., Estenne, M., Segebarth, C., Macklem, P.T., Paiva, M., 1994.Three-dimensional reconstruction of the in vivo human diaphragm shape atdifferent lung volumes. J. Appl. Physiol. 76, 495–506.

egenbaur, C., 1898. Vergleichende Anatomie der Wirbelthiere mit Berücksichti-gung der Wirbellosen. Leipzig Engelmann.

eorge, D.K., Cooney, T.P., Chiu, B.K., Thurlbeck, W.M., 1987. Hypoplasia and imma-turity of the terminal lung unit (acinus) in congenital diaphragmatic hernia. Am.Rev. Respir. Dis. 136, 947–950.

eorge, J.C., Shah, R.V., 1954. The occurrence of a striated outer muscular sheathin the lungs of Lissemys punctata granosa Schoepff. J. Anim. Morphol. Physiol. 1,13–16.

iglio-Tos, E., 1894. Sull’ omologia tra il diaframma degli anfibe anuri e quello deimammiferi. Atti della R. Academia delle Scienze di Torino, 29.

oodrich, E.S., 1930. Studies on the Structure and Development of Vertebrates.Macmillan, London, New York.

ordon, D.C., Hammond, C.G.M., Fisher, J.T., Richmond, F.J.R., 1989. Muscle fiberarchitecture, innervation and histochemistry in the diaphragm of the cat. J.Morphol. 201, 131–143.

ould, S.J., Vrba, E.S., 1992. Exaptation—a missing term in the science of form. Pale-obiology 8, 4–15.

ozal, D., Simakajornboon, N., 2000. Passive motion of the extremities modifies alve-olar ventilation during sleep in patients with congenital central hypoventilationsyndrome. Am. J. Respir. Crit. Care. Med. 162, 1747–1751.

räper, L., 1928a. Lungen, Pleurahöhlen und Zwerchfell bei den Amphibien undWarmblütern. Gegenb. Morphol. 60, 78–105.

räper, L., 1928b. Zwerchfell, Lunge und Pleurahöhlen in der Tierreihe. Anat. Anz.66, 71–77.

reer, J.J., Allen, D.W., Martin-Caraballo, M., Lemke, M., 1999. An overview of phrenicnerve and diaphragm muscle development in the perinatal rat. J. Appl. Physiol.86 (3), 779–786.

relot, L., Milano, S., 1991. Diaphragmatic and abdominal muscle activity duringcoughing in the decerebrate cat. Neuroreport 2, 165–168.

aller, von A., 1767. Primae Lineae Physiologiae, 1767, translated by W.Cullen. Edin-burgh: Elliot, 1786.

amberger, G.E., 1749. De Respirationis Mechanismo et Usu Genuino. Jena.amoudi, D., Bouderka, M.A., Benissa, N., Harti, A., 2004. Diaphragmatic rupture

during labor. Int. J. Obstet. Anesth. 13, 284–286.on Hansemann, D., 1915. Die Lungenatmung der Schildkröten. In: Sitzungsbericht

der königlich preussischen Akademie der Wissenschaften zu Berlin. with plateIII + IV. Berlin, pp. 661–672.

art, N., Nickol, A.H., Cramer, D., Ward, S.P., Lofaso, F., Pride, N.B., Moxham, J.,Polkey, M.I., 2002. Effect of severe isolated unilateral and bilateral diaphragm

& Neurobiology 171 (2010) 1–16

weakness on exercise performance. Am. J. Respir. Crit. Care Med. 165,1265–1270.

Hemborg, B., Moritz, U., Lowing, H., 1985. Intra-abdominal pressure and trunk mus-cle activity during lifting. IV. The causal factors of the intra-abdominal pressurerise. Scand. J. Rehabil. Med. 17, 25–38.

Higuchi, T., Uchide, K., Honda, K., Negoro, H., 1987. Pelvic neurectomy abolishes thefetus-expulsion reflex and induces dystocia in the rat. Exp. Neurol. 96, 443–455.

Hill, R., Heller, M.B., 1996. Diaphragmatic rupture complicating labor. Ann. Emerg.Med. 27, 522–524.

Hitzenberger, K., 1927. Das Zwerchfell im Gesunden und Kranken Zustand. Springer,Vienna.

Hochstetter, F., 1906. Über die Entwicklung der Scheidewandbildungen in derLeibeshöhle der Krokodile. Wiss. Ergebn. Bd. IV.

Hodges, P.W., Butler, J.E., McKenzie, D.K., Gandevia, S.C., 1997. Contraction of thehuman diaphragm during rapid postural adjustments. J. Physiol. 505, 539–548.

Hodges, P.W., Gandevia, S.C., 2000a. Changes in intra-abdominal pressure duringpostural and respiratory activation of the human diaphragm. J. Appl. Physiol.89, 967–976.

Hodges, P.W., Gandevia, S.C., 2000b. Activation of the human diaphragm during arepetitive postural task. J. Physiol. 522 (1), 165–175.

Hodges, P.W., Heijnen, I., Gandevia, S.C., 2001. Postural activity of the diaphragmis reduced in humans when respiratory demand increases. J. Physiol. 537,999–1008.

Hodges, P., Kaigle Holm, A., Holm, S., Ekstrom, L., Cresswell, A., Hansson, T.,Thorstensson, A., 2003. Intervertebral stiffness of the spine is increased byevoked contraction of transversus abdominis and the diaphragm: in vivo porcinestudies. Spine 28, 2594–2601.

Hodges, P.W., Sapsford, R., Pengel, L.H., 2007. Postural and respiratory functions ofthe pelvic floor muscles. Neurourol. Urodyn. 26, 362–371.

Iscoe, S., 1998. Control of abdominal muscles. Prog. Neurobiol. 56, 433–506.Johanson, Z., 2003. Placoderm branchial and hypobranchial muscles and origins in

jawed vertebrates. J. Vert. Paleo. 23 (4), 735–749.Jones, F.W., 1913. The functional history of the coelom and the diaphragm. J. Anat.

Physiol. 47, 282–318.Kallay, N., Crim, L., Dunagan, D.P., Kavanagh, P.V., Meredith, P., Haponik, E.F., 2000.

Massive left diaphragmatic separation and rupture due to coughing during anasthma exacerbation. South Med. J. 93, 729–731.

Kardong, K.V., 2002. The Respiratory System. In: Vertebrates, Comparative Anatomy,Function, Evolution. McGraw-Hill Publishing, New York, pp. 421.

Keith, A., 1905. The nature of the mammalian diaphragm and pleural cavities. J. Anat.Physiol. 39, 243–284.

Kent, G.C., Carr, R.K., 2001. Respiratory System. In: Comparative Anatomy of theVertebrates, 9th ed. McGraw Hill, New York, pp. 157.

Kenyon, C.M., Cala, S.J., Yan, S., Aliverti, A., Scano, G., Duranti, R., Pedotti, A., Macklem,P.T., 1997. Rib cage mechanics during quiet breathing and exercise in humans.J. Appl. Physiol. 83, 1242–1255.

Klein, W., Abe, A.S., Andrade, D.V., Perry, S.F., 2003a. Structure of the posthepaticseptum and its influence on visceral topology in the tegu lizard, Tupinambismerianae (Teiidae:Reptilia). J. Morphol. 258, 151–157.

Klein, W., Abe, A.S., Perry, S.F., 2003b. Static lung compliance and body pressuresin Tupinambis merianae with and without post-hepatic septum. Resp. Physiol.Neurobiol. 135, 73–86.

Klein, W., Abe, A.S., Andrade, D.V., Perry, S.F., 2003c. Role of the post-hepatic septumon breathing during locomotion in Tupinambis merianae (Reptilia: Teiidae). J.Exp. Biol. 206, 2135–2143.

Klein, W., Böhme, W., Perry, S.F., 2000. The mesopneumonia and the post-hepaticseptum of the Teiioidea (Reptilia: Squamata). Acta Zoologica. 81, 109–119.

Klein, W., Owerkowicz, T., 2005. Function of intracolomic septa in lung ventila-tion of amniotes: lessons from lizards Physiol. Biochem. Zool. 79 (6), 1019–1032.

Klein, W., Reuter, C., Böhme, W., Perry, S.F., 2005. Lungs and mesopneumonia inscincomorph lizards (Reptilia: Squamata). Org. Divers. Evol. 5, 47–57.

Körner, F., 1939. Über die Muskularisierung des Zwerchfells. Z. Anat. Entw. 109,282–292.

Kreitzer, S.M., Feldman, N.T., Saunders, N.A., Ingram Jr., R.H., 1978. Bilateral diaphrag-matic paralysis with hypercapnic respiratory failure. A physiologic assessment.The Am. J. Med. 65, 89–95.

Kyou-Jouffroy, F., Lessertisseur, J., 1971. Particulaités musculaires des monotremes.Musculature postcranienne. In: P.P. Grassé (ed.). Traité de Zoologie, vol 16(3),pp. 733–836.

Laporta, D., Grassino, A., 1985. Assessment of transdiaphragmatic pressure inhumans. J. Appl. Physiol. 58, 1469–1476.

Le Double, A.F., 1897. Diaphragme. In: Traité des variations du système musculairede l’homme et leur signification au point de vue de l’anthropologie zoologique,vol. 1, Schleicher Frères publishers, Paris, France, pp. 297–309.

Lee, H.Y., Yoo, S.M., Song, I.S., Yu, H., Kim, Y.S., Lee, J.B., Shon, D.S., 2006. Sponta-neous diaphragmatic rupture after vomiting: rapid diagnosis on multiplanarreformatted multidetector CT. J. Thorac Imag. 21, 54–56.

Lessertisseur, J., 1968. Mammifères, Système musculaire. Musculature hyposoma-tique. In: Grassé, P.P. (Ed.), Traité de Zoologie. Masson, Paris.

Levin, D.L., 1978. Morphologic analysis of the pulmonary vascular bed in congenitalleft-sided diaphragmatic hernia. J. Pediatr. 92, 805–809.

Loring, S.H., Mead, J., 1982. Action of the diaphragm on the rib cage inferred from aforce-balance analysis. J. Appl. Physiol. 53, 756–760.

Lower, R., 1667. An account of making a dog draw his breath like a wind-brokenhorse. Phil. Trans. R. Soc. Lon 29, 197–199.

ology

L

L

M

M

M

M

M

M

M

M

M

M

M

M

M

M

M

N

N

N

O

O

O

P

P

P

P

P

P

P

P

P

P

P

P

P

S.F. Perry et al. / Respiratory Physi

umholt, J.P., Johansen, K., Maloiy, G.M.O., 1975. Is the aestivating lungfish the firstvertebrate with sectional breathing? Nature 275, 787–788.

umholt, J.P., 1993. Breathing in the aestivating African lungfish, Protopterusamphibius. In: Sing, B.R. (Ed.), Advances in Fish Research, vol. 1. Narendra Pub-lishing House, Delhi, pp. 17–34.

acklem, P.T., 1979. A mathematical and graphical analysis of inspiratory muscleaction. Resp. Physiol. 18, 153–171.

agendie, 1817. Précis élémentaire de Physiologie, Tome second. Méquignon-Marvis Publisher, Paris, France.

atsevych, O.Y., 2008. Blunt diaphragmatic rupture: four year’s experience. Hernia12, 73–78.

aurer, F., 1896. Die ventrale Rumpfmuskulatur einiger Reptilien. Festschrift zum8. Gebortstag von Carl Gegenbauer. Engelmann, Leipzig, pp. 1–76.

cCool, F.D., Tzelepis, G.E., Mead, J., 1991. Absence of a hemidiaphragm: mechanicalimplications. Lung 169, 87–96.

cCutcheon, F.H., 1964. Organ systems in adaption: the respiratory system. In: Dill,D.B., Adolph, E.F., Wilber, C.G. (Eds.), Handbook of Physiology. Amer. Physiol.Soc., Washington, DC, pp. 167–191.

cDermott, W.J., van Emmerik, R.E., Hamill, J., 2003. Running training and adap-tive strategies of locomotor–respiratory coordination. Eur. J. Appl. Physiol. 89,435–444.

ead, J., 1979. Functional significance of the area of apposition of diaphragm to ribcage. Am. Rev. Respir. Dis. 119, 31–32.

ead, J., Loring, S.H., 1982. Analysis of volume displacement and length changes ofthe diaphragm during breathing. J. Appl. Physiol. 53, 750–755.

ead, J., Banzett, R.B., Lehr, J., Loring, S.H., O’Cain, C.F., 1984. Effect of posture onupper and lower rib cage motion and tidal volume during diaphragm pacing.Am. Rev. Respir. Dis. 130, 320–321.

elissinos, C.G., Bruce, E.N., Goldman, M.D., Elliott, E., Mead, J., 1981. Pattern ofdiaphragmatic activity during forced expiratory vital capacity. J. Appl. Physiol.51, 1515–1525.

ier-Jedrzejowicz, A., Brophy, C., Moxham, J., Green, M., 1988. Assessment ofdiaphragm weakness. Am. Rev. Respir. Dis. 137, 877–883.

irwald, M., Perry, S.F., 1989. Wie atmen Schildkröten wirklich? Ein leider nicht nurhistorischer Rückblick. Tier Mus. 1, 64–66.

ortola, J.P., 1987. Dynamics of breathing in newborn mammals. Physiol. Rev. 67,187–242.

ortola, J.P., Sant’Ambrogio, G., 1978. Motion of the rib cage and the abdomen intetraplegic patients. Clin. Sci. Mol. Med. 54, 25–32.

ava, S., Zanotti, E., Ambrosino, N., Fracchia, C., Scarabelli, C., Rampulla, C., 1992.Evidence of acute diaphragmatic fatigue in a “natural” condition. The diaphragmduring labor. Am. Rev. Respir. Dis. 146, 1226–1230.

ishi, S., 1938. Muskelsystem. II. Muskeln des Rumpfes. In: L. Bolk, E. Göppert,E. Kallius, W. Lubosch (eds.). Handbuch der vergleichenden Anatomie derWirbeltiere, pp. 351–446.

ochomovitz, M.L., Dimarco, A.F., Mortimer, J.T., Cherniack, N.S., 1983. Diaphragmactivation with intramuscular stimulation in dogs. Am. Rev. Respir. Dis. 127,325–329.

smond, D.G., 1985. Functional anatomy of the chest wall. In: Roussos, C.C., Mack-lem, P.T. (Eds.), The Thorax. Part A, Vol. 29 Lung Biology in Health and Disease.M. Dekker, NY, pp. 199–233.

wen, R., 1868. On the Anatomy of Vertebrates, Vol. III. Mammals. Longmans, Green& Co, London.

werkowicz, T., Farmer, C.G., Hicks, J.W., 1999. Contribution of gular pumping tolung ventilation in monitor lizards. Science 284, 1661–1663.

att, D.I., Patt, G.R., 1969. Comparative Vertebrate Histology. New York, Evanston-Harper & Row, London.

erry, S.F., 1985. Functional anatomy of the chest wall: Evolutionary aspects. In: C.Roussos, P.T. Macklem (Eds.). The Thorax. Part A, Vol. 29 of Lenfant C (Exec Ed)Lung Biology in Health and Disease. M. Dekker, NY.

erry, S.F., 1978. Quantitative anatomy of the lungs of the red-eared turtle, Pseude-mys scripa elegans. Respir. Physiol. 35, 245–262.

erry, S.F., 1983. Reptilian Lungs. Functional anatomy and evolution. Adv. Anat.Embryol. Cell. Biol 79, 1–81.

erry, S.F., 1989. Mainstreams in the evolution of vertebrate respiratory structures.In: King, A.S., McLelland, J. (Eds.), Form and Function in Birds, vol. 4. AcademicPress, London, pp. 1–59.

erry, S.F., Carrier, D.R., 2006. The coupled evolution of breathing and locomotion asa game of leapfrog. Physiol. Biochem. Zool. 79, 997–999.

erry, S.F., Duncker, H.-R., 1978. Lung architecture, volume and static mechanics infive species of lizards. Respir. Physiol. 34, 61–81.

erry, S.F., Duncker, H.-R., 1980. Interrelationship of static mechanical factors andanatomical structure in lung evolution. J. Comp. Physiol. 138, 321–334.

erry, S.F., Sander, M., 2004. Reconstructing the evolution of the respiratory appa-ratus in tetrapods. Respir. Physiol. Neurobiol. 144, 125–139.

erry, S.F., Schmitz, A., Anderse, N., Wallau, B.R., Nicol, S., 2000. Descriptive studyof the diaphragm and lungs in the short-nosed echidna Tachyglossus aculeatus(Mammalia: Monotremata). J. Morphol. 243, 247–255.

etroll, W.M., Knight, H., Rochester, D.F., 1990. Effect of lower rib cage expan-sion and diaphragm shortening on the zone of apposition. J. Appl. Physiol. 68,

484–488.

ettiaux, N., Cassart, M., Paiva, M., Estenne, M., 1997. Three-dimensional reconstruc-tion of human diaphragm with the use of spiral computed tomography. J. Appl.Physiol. 82, 998–1002.

ickering, M., Jones, J.F., 2002. The diaphragm: two physiological muscles in one. J.Anat. 201, 305–312.

& Neurobiology 171 (2010) 1–16 15

Plagens, G., JBradbury, J.T., 1930. A case of congenital hernia through the left centrallinea semilunaris of the diaphragm (cat). Anat. Rec. 46, 259–271.

Pober, B.R., 2008. Genetic aspects of human congenital diaphragmatic hernia. Clin.Genet. 74, 1–15.

Rassler, B., Kohl, J., 2000. Coordination-related changes in the rhythms of breathingand walking in humans. Eur. J. Appl. Physiol. 82, 280–288.

Ravn, E., 1899. Ueber die Entwickelung des Septum transversum. Anat. Anz. 15,528–534.

Ricci, S.B., Cluzel, P., Constantinescu, A., Similowski, T., 2002. Mechanical model ofthe inspiratory pump. J. Biomech. 35, 139–145.

Romer, A.S., 1956. The Osteology of the Reptiles, Illinois. University of Chicago Press,Chicago.

Romer, A.S., 1966. Vertebrate Paleontology, Illinois. University of Chicago Press,Chicago.

Romer, A.S., 1978. The Vertebrate Body, 5th ed. Saunders Publishing, New York.Rommel, S., Reynolds, J.E., 2000. Diaphragm structure and function in the Florida

manatee (Trichechus manatus latirostris). Anat. Rec. 259, 41–51.Roos, M., Kobza, R., Jamshidi, P., Bauer, P., Resink, T., Schlaepfer, R., Stulz, P.,

Zuber, M., Erne, P., 2009. Improved cardiac performance through pacing-induceddiaphragmatic stimulation: a novel electrophysiological approach in heart fail-ure management. Europace 11, 191–199.

Saboisky, J.P., Gorman, R.B., De Troyer, A., Gandevia, S.C., Butler, J.E., 2007. Differ-ential activation among five human inspiratory motoneuron pools during tidalbreathing. J. Appl. Physiol. 102, 772–780.

Sabotta, J., Becher, H., 1975. Atlas of Human Anatomy. In: Vol. 1. Regions, Skeleton,Ligaments, Joints, Muscles. 9th English Edition. München. Urban and Schwarzen-berg, p. 163.

Scillia, P., Cappello, M., De Troyer, A., 2004. Determinants of diaphragm motion inunilateral diaphragmatic paralysis. J. Appl. Physiol. 96, 96–100.

Schoenhofer, B., Koehler, D., Polkey, M.I., 2004. Influence of immersion in wateron muscle function and breathing pattern in patients with severe diaphragmweakness. Chest 125, 2069–2074.

Shafik, A., 1991. Straining puborectalis reflex: description and significance of a “new”reflex. Anat. Rec. 229, 281–284.

Shah, R.V., 1962. A comparative study of the respiratory muscles in Chelonia. Brevo-ria 161, 1–6.

Shehata, S.M., Tibboel, D., Sharma, H.S., Mooi, W.J., 1999. Impaired structural remod-elling of pulmonary arteries in newborns with congenital diaphragmatic hernia:a histological study of 29 cases. J. Pathol. 189, 112–118.

Shehata, S.M., Sharma, H.S., Mooi, W.J., Tibboel, D., 2006. Pulmonary hypertensionin human newborns with congenital diaphragmatic hernia is associated withdecreased vascular expression of nitric-oxide synthase. Cell. Biochem. Biophys.44, 147–155.

Shirley, D., Hodges, P.W., Eriksson, A.E., Gandevia, S.C., 2003. Spinal stiffness changesthroughout the respiratory cycle. J. Appl. Physiol. 95, 1467–1475.

Sieck, G.C., Fournier, M., 1989. Diaphragm motor unit recruitment during ventilatoryand nonventilatory behaviors. J. Appl. Physiol. 66, 2539–2545.

Siegmund, G.P., Edwards, M.R., Moore, K.S., Tiessen, D.A., Sanderson, D.J., McKenzie,D.C., 1999. Ventilation and locomotion coupling in varsity male rowers. J. Appl.Physiol. 87, 233–242.

Similowski, T., Attali, V., Bensimon, G., Salachas, F., Mehiri, S., IArnulf, I.,Lacomblez, L., Zelter, M., Meininger, V., Derenne, J.P., 2000. Diaphragmaticdysfunction and dyspnoea in amyotrophic lateral sclerosis. Eur. Respir. J. 15,332–337.

Slijper, E.J., 1936. Die Cetaceen vergleichend anatomisch und systematisch. CapitaZool. 6/7, 1-590.

Snapper, J.R., Tenney, S.M., McCann, F.V., 1974. Observations on the amphibian“diaphragm”. Comp. Biochem. Physiol. 49A, 223–230.

Sokolowska, B., Jozwik, A., Pokorskim, M., 2003. A fuzzy-classifier system to distin-guish respiratory patterns evolving after diaphragm paralysis in the cat. Jpn. J.Physiol. 53, 301–307.

Starck, D., 1982. Vergleichende Anatomie der Wirbeltiere. Vol 3. Heidelberg SpringerVerlag, Germany, pp. 51-56.

Stradling, J.R., Kozar, L.F., Dark, J., Kirby, T., Amdrey, S.M., Phillipson, E.A., 1987. Effectof acute diaphragm paralysis on ventilation in awake and sleeping dogs. Am. Rev.Respir. Dis. 136, 633–637.

Takasaki, Y., Arai, T., 2001. Transient right phrenic nerve palsy associated with cen-tral venous catheterization. Brit. J. Anaes. 87 (3), 510–511.

Takeda, R., Remmers, J.E., JBaker, J.P., Madden, K.P., Farber, J.P., 1986. Postsynap-tic potentials of bulbar respiratory neurons of the turtle. Respir. Physiol. 64,149–160.

Tickle, P.G., Ennos, A.R., Lennox, L.E., Perry, S.F., Codd, J.R., 2007. Func-tional significance of the uncinate processes in birds. J. Exp. Biol. 210,3955–3961.

Ure, T., 1819. An Account of some experiments made on the body of a criminal imme-diately after execution, with physiological and practical observations. Quart. J.Sci. Arts 12, 283–295.

Uriona, T.J., Farmer, C.G., 2008. Recruitment of the diaphragmaticus, ischiopubisand other respiratory muscles to control pitch and roll in the American alligator(Alligator mississippiensis). J. Exp. Biol. 211, 1141–1147.

Urmey, W.F., Loring, S., Mead, J., Slutsky, A.S., Sarkarati, M., Rossier, A., Brown, R.,1986. Upper and lower rib cage deformation during breathing in quadriplegics.J. Appl. Physiol. 60, 618–622.

Urmey, W.F., De Troyer, A., Kelly, K.B., Loring, S.H., 1988. Pleural pressure increasesduring inspiration in the zone of apposition of diaphragm to rib cage. J. Appl.Physiol. 65, 2207–2212.

1 ology

U

W

W

W

W

6 S.F. Perry et al. / Respiratory Physi

skow, N., 1883. Ueber die Entwicklung des Zwerchfells, des Pericardiums und desCoeloms. Arch mikr. Anat. 22, 143–212.

ard, M.E., Macklem, P.T., 1995. Kinematics of the chest wall. In: Roussos, C. (Ed.),The Thorax, Part B. Lung Biology in Health and Disease Series, vol. 85. MarcelDekker, New York, USA, pp. 515–534.

ard, M.E., Ward, J.W., Macklem, P.T., 1992. Analysis of human chest wallmotion using a two-compartment rib cage model. J. Appl. Physiol. 72, 1338–

1347.

hitelaw, W.A., 1995. Topography of the diaphragm. In: Roussos, C. (Ed.), The Tho-rax, Part B. Lung Biology in Health and Disease Series, vol. 85. Marcel Dekker,New York, USA, pp. 587–616.

ilcox, P.G., Pardy, R.L., 1989. Diaphragmatic weakness and paralysis. Lung 167,323–341.

& Neurobiology 171 (2010) 1–16

Wilson, T.A., De Troyer, A., 2004. The two mechanisms of intercostal muscle actionon the lung. J. Appl. Physiol. 96, 483–488.

Wolfel, K., 1907. Beiträge zur Entwickelung des Zwerchfells und des Magens beiWiederkäuern. Anat. Anz. 30, 233–270.

Yang, X.M., Vogan, K., Gross, P., Park, M., 1996. Expression of the met receptor tyro-sine kinase in muscle progenitor cells in somites and limbs is absent in Splotchmice. Devel. 122, 2163–2171.

Yuan, W., Yi, R., Babiuk, R.P., Greer, J.J., Wu, J.Y., Ornitz, D.M., 2003. A genetic modelfor a central (septum transversum) congenital diaphragmatic hernia in micelacking Slit3. Proc. Nat. Acad. Sci. U.S.A. 100 (9), 5217–5222.

Zimmer, K., 1935. Beitrage zur Mechanik der Atmung bei den Vögeln in Stand undFlug. Aufgrund anatomischer-physiologisher und experimenteller Studien. Zoo-logica 88, 1–69.