5 phylogeny and animal models: an uninhibited survey phylogeny and animal models: an uninhibited...

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Phylogeny and Animal Models: An Uninhibited Survey

Todd D. Morgan Scripps Memorial Hospital, Encinitas, California, U.S.A.

John E. RemmersRespiratory Reasearch Group, University of Calgary, Calgary, Alberta, Canada

INTRODUCTION

This chapter examines human obstructive sleep apnea (OSA) in relation to air breathing in vertebrates. It begins by examining the origins of air breathing and showing that the neuromuscular factors that were responsible for air breathing in the earliest terrestrial vertebrates play a key role in modern sleep-disordered breathing in man. The chapter considers the evolution of the pharynx in prehuman species, documenting trends in the structure of the facial framework and pharyn-geal dimensions. We show that these trends in hominids underlie human speech but predispose Homo sapiens to sleep apnea. Finally, we review animal models of obstructive sleep apnea to discover why it is a uniquely human disorder. We label our survey uninhibited to emphasize its diversity of informational sources and to acknowledge the speculative nature of our discussion. As well, our lack of inhibi-tion reflects our exuberance for the topic, which we hope is shared by the reader.

TERRESTRIALITY AND EVOLUTION OF THE PHARYNX

Evolution underwent a major transition 400 million years ago when animal life moved from the sea onto land. For animals, this allowed access to a new, oxygen-rich convective media for ventilation of gas-exchange organs. The key and most fundamental aspect of this transition was the development of a lung and the means for ventilating it. Fish meet their aerobic demands by ventilating gills with water, a dense, viscous media with a limited capacity for carrying oxygen. The early terres-trial air breathers (Dipnoi) ventilated a lung, which was homologous with the highly partitioned mammalian lung (1). However, they used an oropharyngeal force pump to inflate their lung. This differed dramatically from the pumping mechanism, which was subsequently evolved in Amniota (Fig. 1). The lung fish, the modern descendant of one of the earliest air breathers, inflates the lung by first aspirating air into the oropharynx, then opening the pharynx and compressing the oropharyngeal gas, thereby inflating the lungs (2). The modern amphibia employs the same force pump mechanism (Fig. 2). Thus, from its inception, the oropharynx plays a funda-mental role in ventilating the lungs by providing the neuromuscular mechanism used for lung inflation (3). Thus, respiratory oscillators of the early tetrapods generated outputs that projected to cranial motoneurons, including hypoglossal motoneurons, and over from the hypoglossal nerve to oropharyngeal muscles (Fig. 2). Of great interest is that in mammals these same neural pathways convey rhythmic inspiratory activity to pharyngeal dilator muscles and ultimately play a key role in stabilizing the pharynx of humans during sleep.

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62 Morgan and Remmers

Development of an aspiration mechanism of lung inflation appeared in reptiles and was further perfected with the appearance of the diaphragm in the mammal (4). The development of the thorax allows inspiratory pump muscles to generate subatmospheric pressures that act directly on the surface of the lung. With the appearance of this method for inflating the lungs, the oropharynx was no longer used for gas pumping, and the single oropharynx of the amphibian (Fig. 3, left) was subdivided into three cavities, the nasal cavity, the oral cavity, and the pharynx in reptiles (Fig. 3, right) and in mammals (Fig. 4).

In reptiles, a rudimentary soft palate separates the nasal cavity from the pharynx (Fig. 3, right). In mammals, the soft palate is well developed and partitions the pharynx from the oral cavity or nasal cavity (Fig. 4). As we shall see, the inspi-ratory activation of pharyngeal dilators was maintained; rather than assisting with lung inflation by creating a positive intrapharyngeal pressure, the actions of these muscles serve to prevent collapse of the nares and pharynx by subatmospheric pressures in the nose and pharynx during aspirative inspiration.

What happened to the respiratory rhythmogenic process during the evolution of air breathing? Did the evolution of a vastly different ventilatory act, aspiration, require a new neural mechanism for generating tidal breathing? The answers to these questions hold interest for not only the neurobiologist. They also lend insight into motor control of the pharyngeal dilator muscles, and ultimately, to the genesis of obstructive sleep apnea. A paired coupled oscillator drives breathing in the frog and is comprised of a buccal oscillator and a lung oscillator (2). The rhythmogenic mechanisms and timing of respiratory events in mammals bear a striking resem-blance to those found in amphibia. As in the amphibian, paired coupled oscillators comprise the fundamental rhythmogenic mechanism driving breathing. As well, a preinspiratory (pre-I) oscillator displays a burst of activity prior to mechanical inspiration and it triggers activity in a second or inspiratory oscillator, the pre-Bötzinger (pre-Böt) oscillator, which activates inspiratory pump muscles (5).

FIGURE 1 A cladogram depicting the phylogenetics of air breathing. Actinopterygii used a four-stroke mechanism to ventilate a lung that was probably not homologous with the modern lung. Dipnoi and Amphibia used a two-stroke force pump mechanism to ventilate a lung that was homolo-gous with the modern lung. Source: From Ref. 3.


Phylogeny and Animal Models: An Uninhibited Survey 63

FIGURE 2 Breathing in a frog. (A) Normal buccal breathing (left) and lung breathing (right). The former consists of tidal ventilation of the oropharynx and the latter consists of a large buccal dilation, opening of the larynx and compression of the oropharyngeal gas, forcing it into the lungs. (B) Efferent neurograms from cranial nerve (CN) V, and from the hypoglossal (H) nerve and illustrates buccal dila-tion (Bd) and buccal constriction (Bc) followed by a series of lung (L) inflations. Source: From Ref. 3.

FIGURE 3 Drawings of the nose and oropharynx. (A) The common oropharynx and rudimentary nasal cavity of the amphibian (frog). (B) A partitioning of the nose from the mouth by a hard palate in the reptile (alligator). Abbreviations: E, esophagus; H, hard palate; L, larynx; N, nose; O, oral cavity; P, pharynx; T, tongue; TR, trachea. Source: From Ref. 6.



FIGURE 4 Drawings of the upper airway configuration in mammals. (A) The linear airway of the dog. (B) The partially angulated airway of the ape with the mouth set more dorsally than in non-primates. (C) Human infant with retroplaced mouth. (D) Human adult with severely angulated airway and retroplaced tongue. Note: The velo-epiglottal overlap is present in all except for the adult human. Source: Visible Productions, 2001.

The pre-I burst appears to activate pharyngeal dilators, particularly the genioglos-sus, which is innervated by the hypoglossal nerve. The mechanical action of the muscles innervated by the main branch of the hypoglossal nerve has changed during evolution. The hyoid and larynx migrate caudally and the supraglottic airway becomes angulated during evolution of mammals. Another important development that appeared with evolution of the mammalian pharynx was the appearance of the epiglottis. Unlike other pharyngeal cartilages (e.g., larynx and hyoid) the epiglottis was not derived from the original branchial arch skeletal tissue. The epiglottis is thought to play a role in infant suckling, as nonsuckling, egg-laying mammals (duck-billed platypus and anteater) lack this structure (6). During suck-ling the epiglottis covers most of the ventral wall of the oropharynx and extends upward above the free margin of the soft palate. This means that milk can flow from the oral cavity around the lateral margins of the epiglottis and into the esophagus without contacting the larynx (Fig. 4), thereby allowing simultaneous breathing and swallowing. In other words, air can pass from the nose into the larynx, while milk is flowing from the oral cavity into the esophagus. Various authors have speculated that a mechanical linkage exists between the soft palate and the epiglottis. The evidence for this so-called “locking” of the two structures is highly inferential,



however. Nonetheless the overlap of the soft palate and epiglottis is a unique feature of the pharynx in all suckling mammals except for the human where it is present at birth but lost in childhood.

In summary, the first major advance in the evolution of air breathing was the development of the modern lung, and the second was the development of the thorax and the muscles for ventilating it using aspiration. Mammals and reptiles developed a compartmentalized cavity: the nose that allowed olfaction and conditioning of the inspirate, the mouth for mastication, and the pharynx for both airflow and alimenta-tion. As well, the pharynx took on the role in sound communication by modulating sound generated in the larynx. The fundamental role of the larynx, protector of the pulmonary airway, remained unchanged in all terrestrial air breathers.

EVOLUTIONARY PRESSURES INFLUENCE THE PHARYNXWalking, Talking, and Breathing: What Is the Problem?The advance of hominids through intellectual development, walking, and speech are paramount to the success of Homo sapiens. In this evolution, three factors have major implications for the upper airway and for breathing during sleep. These are: development of the brain, upright posture, and oral articulation. The location and function of the aero-digestive tract in our closest ancestors is well described within skeletal remains. By considering cranial base angles, the size and attachments of the hyoid, and the landmarks from which the larynx suspends, soft tissue models can be created that predict the acquisition of speech. In this section, we consider the possibility that an anatomic model for speech in prehistoric species provides insights for understanding of OSA as a uniquely human disease.

Phylogeny reveals an elegant evolution of pharynx and its added complexity of function that mirrors brain growth and development of the human intellect. For articulate speech, we need a pharynx that has the length and flexibility necessary for sound modulation as well as the neural network necessary to respond to the brain’s instructions. The vocal tract anatomy related to speech and the origin of language is quite distinct issues; one relates to mechanical function, while the other involves reorganization of the brain. Great apes, for example, are capable of symbolic thought, but do not have the neuro-mechanical features required for articulation and speech (7). The neural origins of speech appear to arise from a region within the inferior frontal gyrus, termed “Broca’s area.” Broca’s area may be home to mirror neurons that enable mimicking behavior and may also have undetected synaptic influence over the higher functions of pharynx involving the interplay of symbolic thought, syntax, and cortical interpretation (Fig. 5 displays one version of early human phy-logeny). Homo erectus, a possible human ancestor alive two million years ago, had the expanded Broca’s area required for symbolic thought, as do all Homo genus lines. However, the anatomical fossil record fails to indicate that this species was capable of language. Hominids as far back as Homo heidelbergsis (600,000 years) ago displayed enough cranial base flexion and presumptive laryngeal length to have a potential for speech and, perhaps, OSA as well. However, no cultural evidence in the fossil record supports the acquisition of speech until 40,000 years ago, around the time when Cro Magnon (CM) displaced Neandertals in the Levant (8). In hindsight, CM brought with him the ultimate trump card: the aptitude and ability to finally fulfill the role of the pharynx in the communicative expression of associ-ated thoughts that would enhance creativity and survival. In other words, the



potential for speech appears to have long existed in hominids but the actual use of language occurred relatively recently. For Homo sapiens, language became an ineluc-table advantage over other species. Perhaps the length and collapsibility of the pharynx required for speech constituted a powerful countervailing disadvantage that limited the appearance of language until the ascendance of CM.

Cleverness was the ultimate Homo sapiens survival strategy, and this develop-ment was intrinsically related to the development of speech and language. However, the development of language and speech as driving forces in evolution has appar-ently outpaced the development of compensatory reflexes or anatomic safeguards for the pharynx during sleep. While reflexes generated from pharyngeal mechano-receptors effectively guard the patency of the pharynx driving wakefulness, these reflexes are lost or greatly suppressed during sleep (9). Thus, without a more linear airway, reinforced ventral pharynx, and the ligamentous “strutting effect” of the hyoid afforded to other vertebrates, hominids were left vulnerable to the night.

As shown in Figure 4, we speculate that three features of the pharynx in Homo sapiens allowed this characteristic function of walking and talking, but severely limited the ability to breathe during sleep. These are: severely angulated airflow path (upright posture), lack of velo-epiglottal overlap (pharyngeal length) and loss of hyoidal strutting (pharyngeal compliance).

Changes in the Craniofacial RelationshipsComparison of the chimpanzee and man reveals striking differences in the ratio of the horizontal oral length and the vertical pharyngeal height (Fig. 6). As well, the relationship between the cranial vault and the facial framework differs strikingly among nonhuman primates, hominids and Homo sapiens (Fig. 7). The facial bones can be seen to move dorsally as one compares the great apes, Australopithecus, H. sapiens, H. neandertalensis, and modern man. In essence, the facial structures (nasal, oral, and pharyngeal cavities) rotate dorsally in relation to the skull so that in

FIGURE 5 A proposed phylogenetic tree for hominids. A. Afarensis (reconstruction at right) is but one of many Australopithecine species known to science. Researchers disagree about exactly how these species are related to one another, but most presume that A. afarensis was a precursor to our own genus. Source: From Ref. 26.



Homo sapiens, they become positioned under the temporal and frontal bones rather than ventral to them (Fig. 7). This change can be quantitated as a decrease in the midsagittal angle between the line connecting the auditory meatus to the supra-orbital torus and a facial skeleton strut connecting the supraorbital torus to the postorbital bar (values presented in Fig. 7).

This rearrangement of the craniofacial relationship can also be assessed by the cranial base angle (CBA), the angle between precordal and postcordal planes. This is measured as the angle between a line connecting the centre of the sella turcica to the basion and the line from the centre of the sella turcica to the foramen cecum (Fig. 8, left). A decrease in the CBA is referred to as “flexing” of the cranial base. Leiberman and McCarthy (12) measured the CBA in mature Pan troglodytes and Homo sapiens to be 156° and 134°, respectively. This indicates flexion of the cranial base in humans compared to nonhuman primates, allowing less space for the facial framework. Also of interest are the CBA changes with development in these two species as shown in Figure 8 (right), the CBA decreases with age in Homo sapiens and increases in Pan troglodytes. During development the relative positioning of the cranium and the facial structures change in opposite directions in the two species, that is, during development in the human the cranial base flexes and in the nonhuman primate it extends.

FIGURE 6 Comparison of oral/pharyngeal dimensions in the chimpanzee and man from sagittal drawings. Note that in relation to the horizontal pharynx to incisor, the vertical laryngeal to oropha-ryngeal distance is much greater in modern man (left) than in the Neandertal (right) or chimpanzee (center). Source: Visible Productions, 2001.

FIGURE 7 Drawings of the skull and facial bones of the gorilla (G), Australopithecus africanus (A), H. neandertalensis (N), and Homo sapiens (H). The values indicating the angle from the base of the skull to the ante-rior facial bones decrease progressively with evolution of the human craniofacial structure documenting the downward and backward rotation of the facial framework. Source: From Ref. 23.



Changes in the Maxilla“Descent of larynx is attributable to upright posture in man” (10). Upright pos-ture matched a coordinated and (relatively) rapid rotation of growing forebrain upon a retreating facial framework while the nasal airway became diminished in size and function. Flexion of cranial base angle required compression of the maxilla, both in volume and surface area, effectively reducing paranasal sinus size and olfaction acuity.

The net effect of this change in maxilla creates the flatter and longer face that differentiates human appearance from primates. Further, this decrease in nose volume may increase in “upstream” resistance to airflow and further aggravate the potential for collapse in a newly acquired oropharynx. Later hominids were no longer obligate nose breathers and upon exertion they would transition to oral breathing. Potentially, this may have contributed to changes in mandibular posture, downward migration of tongue base and further descent of the hyoid. Increases in time spent mouth breathing implies a reduction in time spent with teeth in contact, negating the tongue’s postural influence upon the palate (Fig. 9). The upshot: a diminished potential for horizontal growth of the maxilla, narrowing of the palate and increasing facial height (Figs. 10 and 11). The most robust cephalometric predictors of OSA are related to this backward rotation of maxilla and mandible (11). Akin to this, Kushida described a morphometric formula for predicting OSA based on the constriction of horizontal growth, relating to the pala-tal distance between the first molars (12).

Oropharyngeal CompressionEvidence for a more recent continuing trend in facial height elongation is demon-strated, when we compare maxillae in prehistoric and modern skulls (Fig. 12). Note the considerable narrowing of the maxillary arch and posterior nasal aperture in modern specimens. Like other mammals that display only minute differences in

FIGURE 8 The measurement of the cranial base angle (CBA) in man is shown in the left panel. The right panel shows the CBA during development for the chimpanzee P. troglodytes (open symbols) and man H. sapiens (closed symbols). Note that the CBA is longer in the young chimpanzee than the human and that during development, the two diverge. Source: From Ref. 27.



occlusion within species, this prehistoric specimen displays a broad palatal arch with room for 32 aligned teeth. Constriction of maxillary horizontal growth and the modern “V” shaped dental arch may account for our modern struggle with malocclusion, dental caries and a constricted oropharyngeal inlet (Fig. 13). While an astute clinician may be inclined to blame a “foreshortened” mandible for the clinical observation of an overbite and crowded dentition, an underdeveloped maxilla is likely the root cause. In recent decades, modern orthodontic theory has shifted para-digmatically to allow an orthopedic “first phase” of treatment intended to create horizontal expansion of maxilla. Maxillary expansion devices help to compensate for horizontal growth that was lost to an imbalance of muscle forces, commonly tendered by underlying negative postural influences secondary to nasal airway constriction (Fig. 14). Perhaps early recognition of abnormal tongue posture can lead to intervention with maxillary expansion devices, in order to allow the full potential for horizontal growth of maxilla.

FIGURE 9 Closed mouth posture: the relationship of tongue, teeth, and buccina-tor muscles is shown in the coronal depic-tion of the mouth of modern humans; the tongue assumes a resting posture in prox-imity to the palate. The teeth are inter-posed between the tongue and buccinators, thereby allowing growth of the arch in rela-tion to the relative dilating (genioglossus) and compressive (buccinator) forces, cre-ating a “balance of forces.” Source: Courtesy of B. Palmer, DDS.

FIGURE 10 Open mouth posture: oral breathing drives the tongue downward and maxillary constriction occurs, increasing facial height. Source: B. Palmer, DDS.



LANGUAGE, SPEECH, AND BRAIN GROWTHAltricial Brain Growth in MammalsClimatic changes and a warming of the Earth following the Ice Age produced a transition from preponderant rain forests to drier tundra, and may have driven the advance of orthograde posture and bipedalism. As open spaces began to allow for nomadic travel and dispersal of species, hominids’ new strategy for survival would include entry into the carnivore guild. These new early foragers found an abundant, new calorie-rich food source in animal carcasses, and a new diet supplemented with

FIGURE 11 Dental models of a mouth breather. Source: B. Palmer, DDS.

FIGURE 12 Comparison of palate width in hominid (left) and modern humans (right). Source: B. Palmer, DDS.



bone marrow fat and protein, which enabled accelerated brain growth that maternal lactation alone could not support. Changes in weaning patterns of early hominids advanced a unique pattern of altricial-type of brain growth not seen in mammals (13). A further increase in the size of the human infant brain is dependent on a con-tinuation of fetal brain growth, which can only be supported by a transition to adult foods at an earlier age. A new diet supplemented with bone marrow fat and protein enabled a “secondarily altricial” pattern of brain growth that maternal lactation alone could not support, while “buffing up” neural mass and adding weight atop the cervical spine.

FIGURE 13 Comparison of a broad (top) versus a narrow upper dental arch (bottom). Source: B. Palmer, DDS.

FIGURE 14 Maxillary expansion devices correct for lost horizontal growth, increasing size of choanae and nasal airway.



Infant energy requirements begin to exceed milk production levels in the second half of the first year. An average woman can produce 1000 mL/day of milk that provides 487 kcal/day and is relatively low in protein when compared to bovine. Despite the risks to child survival, selection pressure may have favored early weaning and a shift toward adult foods in order to support the child during a critical time in neurological development, enabling full potential for brain size and intellect.

For example, brain size of P. troglodytes and humans at birth are both about one-third of their adult size. However, in terms of absolute size, the chimpanzee brain would only need to grow about 300 mL more to reach adult volume, whereas the human brain would grow to 900 mL; both brains reach their final growth poten-tial at six to seven years. This advanced pattern of human brain growth is “expen-sive,” in that developing children must devote as much as 80% of their basal metabolic rate to the brain, as compared to 25% for adults (14). Despite this adaptive risk to early survival and an altered mortality rate for young adults, who are now competing with carnivores for prey (15), foraging hominids began to leave their offspring with groups to hunt and procure a rich food source.

Brain growth in size and weight may have driven concomitant postural changes needed to satisfy a new cranial “balancing act.” Spinal mechanics, notably cervical spine curvature, are adapted from head posture and favor upright stance, bipedal-ism, and horizontal vision. Unlike other mammals, who remained quadrupeds, upright posture would drive changes in cervical spine, relocate the tongue base to the pharynx and influence the development of a new compartment, oropharynx.

Cerebral Control Over PharynxIn addition to the tasks of respiration and deglutition, speaking humans would require exquisite neural control to manage the pharyngeal airway in this motor act. Control of voluntary respirations and speech are closely held within the frontal lobes of the brain—the most recent evolutionary development. The first step toward managing a common aero-digestive tract requires relay of afferent information related to pharyngeal contents. Indeed, the pharyngeal mucosa and its juxtaposed layers of interwoven and specialized muscle fibers are innervated with extremely dense terminal nerve branches (Fig. 15). Banding patterns of these fibers and their variety and types of motor endplates allude to specialization within constrictors and the upper esophageal sphincter in humans. Further, the presence within these muscle groups of unusual myosin heavy chain isomers, including low-tonic and alpha-cardiac types, has been demonstrated (16). The appearance of multiple iso-mers within the pharynx and some other cranial muscles is thought to be associated with unique functional requirements that require precise control.

Acquisition of Speech Predisposes to Obstructive Sleep ApneaUnderstandably, anthropological studies focus primarily on the “vocal tract” rather than respiratory control and speech-related behaviors. Our goal is to surmise and infer functional behavior from studies of fossils. During hominid evolution, the descent of the hyoid/larynx, rotation of the facial framework, and flexion of cranial base angle together lead to progressive pharyngeal constriction and the suscepti-bility to OSA. We speculate that these changes are principally related to the devel-opment of the motor act of speaking. A variety of models have been proposed to define the characteristics of the pharynx required for acquisition of speech.



Debate continues as to whether early hominids, and particularly Neandertals, had the pharyngeal height necessary to form essential vowel sounds. Is there a predictive value and correlation between the collapsibility of the pharynx in OSA and proposed models for the predicted acquisition of speech? By performing skull base reconstructions of H. neandertalensis from La Chapelle-aux-Saints, Lieberman and Crelin (17) predicted a position and length for larynx that was not compatible with the accepted requirements for speech (Fig. 7). In their model comparing Neandertals, chimpanzee and the human infant, they advanced the hypothesis that an anatomic basis for speech, based on a minimum laryngeal descent, precluded all three species from producing the essential vowel sounds (i) (a) (u) due to reduced pharyngeal space.

A new model for predicting total pharyngeal height and basis for speech proposed by Boe et al. (18) in 2002, contrasts with the previous findings of Lieberman and Crelin. New reconstructions of La Chapelle-aux-Saints and of a newer specimen of Neandertal, La Ferrassie 1, which had an intact hyoid show that the Neandertal skull base did not differ significantly from modern humans, leading to the supposition that there has been little or no change in the position or shape of hyoid in the last 60,000 years of evolution. Based on cephalometric land-marks, Boe et al. were able to develop a laryngeal height index from palatal distance and laryngeal height. Application of their model to Neandertal and young humans predicts that Neandertals were capable of speech. However, if we assume that a measurement of laryngeal height mirrors the modern cephalometric measures, we conclude that the speech predisposition of Neandertals is low, based on this phonetic/ anatomic model (Fig. 6).

The hyoid bone may provide an important clue regarding the collapsibility of the pharynx in hominids. In nonhuman mammals, a complete, “strutted” hyoid provides a mechanical anchoring of the epiglottis, and, thereby, of the ventral wall of the pharynx in the presence of substantial velo-epiglottal over-lap. This provides pharyngeal stabilization in the absence of neuromuscular reflex control of pharyngeal muscles during sleep. By contrast, the “floating” hyoid of the human implies that the position of the ventral pharyngeal wall depends principally on neuromuscular forces. Although this provides for a highly compliant pharynx, a requirement for speech and tone modulation, it

FIGURE 15 Cricopharyngeus muscle with multiple innervations and motor endplates to muscle fibers. Source: From Ref. 16.



also allows the opportunity for easy collapse of the pharynx during sleep when muscular forces acting on the hyoid are greatly reduced. Thus, we are fairly bequeathed a new fate (sleep apnea) that squares our debt to unparalleled suc-cess as a species provided by speech and language.

Two hyoid bones have been found in hominids. The more ancient one (3,300,000 years old), a spectacularly well-preserved child skeleton of Australopithecus afarensis reveals a large, cup-shaped hyoid (25). As shown in Figure 16, the dimen-sions and shape of this hyoid are compatible with an ape-like hyoid and differ clearly from modern man. This suggests that A. afarensis had pharyngeal air sacks and a noncompliant pharynx, consistent with an apelike pharynx and vocal system. The second hyoid specimen is from a 60,000-year old Neanderthal skeleton and is an incomplete or “floating hyoid.”

Life History and Emergence of Obstructive Sleep ApneaWhat about neural control of pharynx during nocturnal breathing? Snoring was not an evolutionary advantage for Homo sapiens, albeit, some predators may have been alarmed by the world record of 112 decibels (19). One may argue that as life history changed for our immediate ancestors, we had no need to guard against OSA. A least until lifespan (only recently) increased beyond 40 to 50 years. Thus, the need to develop protective reflexes would be gratuitous and conspicuously absent in all upright hominids. Despite a lack of safeguards for our nocturnal respirations, a fur-ther descent of hyoid and expansion of oropharynx, along with the acquisition of the cortical equipment needed for speech, allowed a significant intellectual leap ahead of rival species.

The natural history of a disease may, or may not, impact evolutionary selec-tion processes depending on the timing and emergence of clinical symptoms or death. Assuming that early hominids lived no more than a few decades at best, and assuming a body habitus comprised of predominately lean muscle, little evolution-ary pressure might be brought to bear with regard to OSA. Indeed, selection may have favored the male with a deeper voice (lower hyoid) and robust, threatening tones. Alternatively, even with a lifespan beyond 50 years, if OSA was not an issue

FIGURE 16 Logarithmic plot of hyoid height versus depth for G. gorilla, P. troglodytes, H. sapiens, and the fossil from A. afarensis. Note that the shape of the A. afarensis hyoid is ape-like and differs substan-tially from the hyoid of modern man. Source: From Ref. 28.



during childbearing years, there would be no selective pressure for the inheritance of protective guards against pharyngeal collapse.

ANIMAL MODELS OF OBSTRUCTIVE SLEEP APNEAObesity and Bony AbnormalitiesAnimal models of human disease have often provided interesting insights into mechanisms of, or, therapy for the disorder in the human counterpart. Since obesity play a key role in the pathogenesis of human OSA, one might a priori assume that an obese animal would exhibit OSA. Surprisingly, this has not proven to be the case. As we shall see, this puzzling failure of obesity to produce OSA is a clue to one of the features of the pharynx in the human that is pivotal in the genesis of the human illness.

Several strains of obese rodents exist and these have been examined for the presence of OSA. These studies have failed to find OSA. Another species known to become obese is the pig, and while one initial report of sleep apnea in obese pigs appeared to reveal OSA (20), subsequent investigations failed to confirm this find-ing (21). The one confirmed example of OSA in nonhuman species is the English bulldog. This animal experiences apnea, shown to be obstructive, during rapid eye movement (REM) sleep. The distinctive feature of this animal is its brachiocephalic “retropositioning,” which results in dorsal placement of the maxilla and mandible. The consequence of this bony “malformation” is a reduction in oral volume and narrowing of the retropalatal space. While awake and during non-rapid eye move-ment (NREM) sleep, activation of various pharyngeal dilators maintain a patent airway. This activity is eliminated during REM sleep and OSA results. In summary, the English bulldog appears to be the only naturally occurring animal model of OSA. In this model, OSA results from bony malformations that include underdevel-opment of the maxilla and/or mandible. A striking finding relates to what does not exist, that is, obese nonhuman mammals do not experience OSA.

While the massively obese Vietnamese potbelly pig does not have OSA, it displays features of the “Pickwickian syndrome,” that is, daytime somnolence, respiratory failure, and, probably, cardiac failure aptly dubbed by one wag, the “pig-wickian syndrome.” While these animals do not display sleep apnea, their breathing during sleep fits the pattern of high upper airway resistance (HUAR), wherein inspiratory flow limitation occurs during consecutive breaths for pro-longed periods (Fig. 17). This leads to alveolar hypoventilation during both REM and NREM sleep.

Why the obese pig displays HUAR and not OSA is probably explained by observations of the mechanics of the passive pharynx. To evaluate this, lean and obese pigs were studied under general anesthesia and with complete muscular paralysis (Fig. 18). The observed static pressure-area relationships of the passive pharynx revealed several dramatic findings, as shown in Figure 18. First, the closing pressure in lean and fat pigs was in the range of −15 to −20 cmH2O, much lower than that observed for normal humans (−2 to −4 cmH2O) and for patients with OSA (+2 to +4 cmH2O). This means that a higher transmural pressure is required in order to completely close the pharynx in the pig, even the obese pig, than in humans.

Another feature that distinguishes the pig from the human pharynx is the shape of the pressure–area relationship, the pig being linear and the human being exponential. This means that in the pressure range 2–4 cmH2O above closing pressure, the passive pharynx of the pig is much less compliant than its human



counterpart. A region of high compliance allows dynamic collapse of the pharynx and allows the development of inspiratory flow limitation in the human.

The second distinctive anatomic feature of humans is the nonarticulated or “floating” hyoid. The pig and other mammals have a U-shaped hyoid that attaches dorsally. Together, these two features could stabilize the pharynx in nonhuman mammals. Dorsal movement of the hyoid is prevented by strutting, and through the aryepiglottic ligament, this limits dorsal rotation of the epiglottis, thereby stabi-lizing the oropharynx and velopharynx through the velo-epiglottal overlap.

Rhesus Monkey Model of Nasal Constriction“Elimination of nasal airway interferences followed by a change from oral to nasal res-piration may result in improvement of certain aspect of facial and dental deviations” (22). The first attempt to investigate the relationship between nasal obstruction

FIGURE 17 Tracings from an obese unanesthetized Vietnamese pot-bellied pig. Airflow (L/sec) and transpulmonary pressure (cmH2O) are recorded while awake, and in nonrapid eye movement (NREM) and rapid eye movement (REM) sleep. Note that no apnea is recorded but that resist-ance is high in all conditions and inspiratory flow limitation appears during REM sleep. Source: From Ref. 29.



and aberrant facial development made only casual reference to OSA. However, this early work did provide evidence for a link between the influence of environmental factors upon tongue posture and, as a corollary, the final position of jaws, dentoal-veolar structures, and by the nature of their juxtaposition, the upper airway.

In studies using the developing rhesus monkey as a model for obstructed nasal breathing, Harvold and others have observed and shown significant changes in normal respiratory physiology and functional form (22). Findings demonstrate compensatory recruitment of accessory muscles and a significant influence upon tongue posture that led to disruption of the natural balance between buccinators and genioglossus upon the developing alveolar arches, leading to malocclusion and downward mandibular posture. Compared to controls, changes in subjects with nasal airway occlusion consistently demonstrated increased facial height, posterior rotation of the mandible and malocclusions. It was postulated that differences in the degree of aberrant change may be explained by which muscles were recruited by each subject and how they were used for deviant respiration. Following removal of the obstruction, some monkey subjects did not reacquire normal posture and facial form. Similar changes are seen in children that display habitual mouth breathing posture and are at high risk of sleep-disordered breathing. Changes in these monkey subjects closely mimic reports from orthodontic literature dating back to the 1950s, when Brash described unfavorable changes in craniofacial growth in mouth breathing children (23).

Descent of Hyoid: Chimpanzees Mirror Human OntogenyTheories of speech physiology and the evolution of language in Homo species hold as a prerequisite the possession of adequate supraglottic space to produce sibilant and vowel sounds with enough resonance and force to form words. The “unique-ness” of the human oropharynx and our laryngeal ratio of 1:1, provide the platform necessary for these functions. But comparisons using magnetic resonance imaging (MRI) to study young chimpanzees in their early developmental stages have shown a similarity to humans with the brief appearance of an oropharynx, which may hold a clue as to why a common ancestor of extant hominids found an evolutionary path toward flatter faces, a descending hyoid and eventually, sleep-disordered breathing. However, it is unlikely that the acquisition of speech drove the secondary descent of

FIGURE 18 Pressure-area relationships of the passive pharynx are derived from data on humans and pigs and illustrate the differ-ences in shape between the two species as well as the differences in effect from obesity. Abbreviation: OSA, obstructive sleep apnea.



hyoid in humans. Rather, postural shifts along with progressive curvature of the cervical spine compelled the dynamic descent of the pharynx and our final suscep-tibility to OSA.

In nonhuman mammals, the distance from incisors to velum (horizontal growth) is always greater than distance from velum to glottis (vertical growth) (Fig. 6). The greater the ratio becomes, the more we depart from potential for a collapsible pharynx. In humans and chimpanzees alike, early development depicts similarities between species in the development of upper airway anatomy. During early infancy, both species display similar growth patterns in both of these dimensions, with an apparent shift in growth during late infancy that empha-sizes laryngeal descent in humans, and horizontal growth of the oral cavity in chimpanzees (24).

In 2006, Nishimura (24) studied three chimpanzee subjects during their early development with sagittal tomographic images across ages four months to five years in order to identify cephalometric landmarks that corresponded to human land-marks in a similar study by Lieberman et al. in 2001 (25) spanning one month to 13.9 years of age in children. Dental emergence was used to adjust chronological age between the two species. In early infancy, these chimpanzees displayed a rapid growth and laryngeal descent that mimicked human growth pattern, decreasing vocal tract ratio in both species. Thereafter, the direction of change in the ratio increases in chimpanzees, where a dominant growth in palatal length continues until adulthood. Humans continue to grow in the vertical dimension of larynx throughout later infancy, childhood, and puberty, permanently separating the larynx into its three distinctive compartments—velopharynx, oropharynx, and hypopharynx. The brief emergence of an analogous oropharynx in chimpanzees, however, may lend clues to a common evolutionary thread between species, lending credibility to pos-tural pressure as a driving force toward pharyngeal elongation, and a case for descent of the larynx and hyoid prior to divergence of the human from the chimpanzee lineage. Or, at least, that descent of the larynx is not “unique” to human lineage.

In all other mammalian species, the hyoid remains firmly strutted to the laryngeal skeleton and thus precludes the formation of a collapsible segment. At what point then, did a “floating” hyoid become incorporated within the complex functional matrix of the larynx and become a competitive advantage for extant hominids? Cephalometric studies have demonstrated that a clear predisposition for OSA is found with a greater mandibular plane to hyoid bone (MP-H) distance, a measure of hyoid descent. Separation of the velum from epiglottis carries with it profound hazards and must command new levels of cerebral and functional control over the pharynx in order to ensure species survival. Therefore, early human species must have found any associated advantages, such as orthograde posture, to be paramount long before the advent of sophisticated articulation and language. A yet undiscovered common ancestor to distant hominids may hold the key to under-standing how modern species came to acquire and appreciate a vulnerable airway.

CONCLUSIONS

The first terrestrial air breathers developed novel techniques to process oxygen in a new environment that allowed for an explosion of successful quadruped species. The evolution and development of the respiratory tract in land animals demanded precise control over an inflating mechanism, a nasal/oral cavity, and most recently, a highly partitioned pharynx. Phylogeny allows us to draw comparisons and define



the differences among many species that display specialized form and function, whereas natural selection favors traits that secure survival and propagation of spe-cies. The elongation and increased flexibility of the pharynx in early man ushered in speech, but the birth of syntax and language would call upon our uniquely human capacity to combine symbolism and abstract thoughts together, ultimately sum-moning the question... “What if?” Cleverness in scrimmage with other species engendered a foundation for life extension. However, these advances concealed a dark side that tends to “only come out at night” in the form of pharyngeal obstruc-tion during sleep. Despite our unique susceptibility to OSA and its burgeoning expression in recent history, the utility of our collapsible pharynx has, somehow, outweighed all other selection pressures in species Homo sapiens. Will future evolu-tion find us further uninhibited … and drowsy?

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