anatomy sleep upper way

1153

AbstractPatients with obstructive sleep apnea (OSA) develop repetitive pharyngeal airway closure during sleep. Sophisticated physi-ologic and imaging studies have significantly advanced our understanding of the anatomic risk factors for OSA and illu-minated the biomechanical mechanisms by which therapeutic interventions for this disorder such as continuous positive airway pressure, weight loss, oral appliances, and surgery increase upper airway caliber. Pharyngeal airway patency is maintained by a balance of forces between the activity of the upper airway muscles that dilate and stiffen the airway and negative intraluminal pressure. However, this balance can be disturbed by abnormalities in upper airway anatomy and neural control. Patients with OSA have been shown to have a narrowed, more collapsible pharyngeal airway. Sleep-related reduction in upper airway dilating muscle activity can lead to

(the caudal margin of the soft palate to the base of the epiglottis); and the hypopharynx, which includes the base of the tongue and epiglottis to the larynx (Fig. 101-1). The majority of patients with OSA manifest upper airway nar-rowing and closure during sleep in the retropalatal region, the retroglossal region, or both.1,2In order to evaluate airway closure in patients with OSA

it is important to understand how pharyngeal wall struc-tures mediate changes in airway size. The anterior wall of the oropharynx is formed primarily by the soft palate and tongue, and the posterior wall of the oropharynx is com-posed primarily of the superior, middle, and inferior con-strictor muscles. The lateral oropharyngeal walls are formed by several different structures including oropha-ryngeal muscles (hyoglossus, styloglossus, stylohyoid, sty-lopharyngeus, palatopharyngeus, palatoglossus, and the superior, middle, and inferior pharyngeal constrictors), lymphoid tissue (palatine tonsils), and adipose tissue (parapharyngeal fat pads). The mandibular rami bound all the structures that form the lateral pharyngeal walls (Figs. 101-2 and 101-3).

STATIC AND DYNAMIC PROPERTIES OF THE NORMAL PHARYNGEAL AIRWAYThe mechanical behavior of the pharyngeal airway under passive conditionsthat is, in the absence of pharyngeal muscle activitycan be described in terms of the relation-ship between cross-sectional airway area (A) and transmu-ral pressure (Ptm).3 As depicted in Figure 101-4A, transmural pressure is the difference between intraluminal pressure (PL) and tissue pressure (Pti):

P P Ptm L ti=

An increase in transmural pressure, caused either by more-positive intraluminal pressure or more-negative tissue

UPPER AIRWAY FUNCTION

The upper airway includes the extrathoracic trachea, larynx, pharynx, and nose. This chapter focuses on the pharynx because it is the site of upper airway narrowing and closure during sleep in patients with obstructive sleep apnea (OSA).The upper airway is a common pathway for digestive,

phonatory, and respiratory functions. Deglutition requires the closure of the pharyngeal airway, and phonation requires coordination of the larynx and nasopharynx, val-vular structures of the upper airway. As a conduit for airflow, however, pharyngeal patency is critical. With the exception of the upstream and downstream ends of the entire respiratory airway tract (the nares and the small intrapulmonary airways) the pharynx is the only collapsible segment of this anatomically defined system.Normally, the pharynx remains open at all times, except

during momentary closures associated with swallowing, regurgitation, eructation, and speech. Pharyngeal patency during wakefulness, with integration and coordination of its various physiologic functions, is in large part attribut-able to continual neuromuscular control by the central nervous. The sleep state is associated with a decrease in neuromotor output to pharyngeal muscles. When this occurs against the background of anatomic abnormalities of the upper airway, the pharyngeal airway can become severely narrowed or can close.

NORMAL UPPER AIRWAY ANATOMYThe upper airway has been separated into three regions: the nasopharynx, which includes the posterior margin of the nasal turbinates to the posterior margin of the hard palate; the oropharynx, subdivided into the retropalatal region (the posterior margin of the hard palate to the caudal margin of the soft palate) and the retroglossal region

Anatomy and Physiology of Upper Airway ObstructionRichard J. Schwab, John E. Remmers, and Samuel T. Kuna

Chapter

101greater negative intraluminal pharyngeal pressure that further narrows and completely closes the airway.We do not yet fully understand the pathogenesis of OSA, but

there are certain fundamental characteristics of airway closure in patients with OSA. Upper airway closure occurs in the oropharynx, usually in the retropalatal region, but it can occur in the retroglossal region or in both regions. There are often multiple sites of pharyngeal airway closure in patients with sleep apnea. Enlargement of the upper airway soft tissues structures are important risk factors for OSA. Pharyngeal airway patency is maintained by a balance between the action of the upper airway dilator muscles and negative intraluminal pressure. Abnormal upper airway anatomy and possibly abnormal neural control during sleep can lead to pharyngeal airway collapse in patients with OSA. This chapter reviews our current understanding of the underlying pathophysiology.

1154 PART II / Section 13 Sleep Breathing Disorders

cross-sectional area (see Figure 101-4B). This relationship is referred to as the tube law and describes the dependence of cross-sectional area on transmural pressure. The closing pressure (Pclose) is the transmural pressure when cross-sec-tional airway area reaches zero (i.e., complete obstruction), and the point at which the curve reaches a plateau is the maximum airway area. The slope of the line at any point in the relationship (A/Ptm) is the effective compliance at that particular transmural pressure. A number of mechani-cal factors (Box 101-1) influence the upper airway to cause it to be fully open, narrowed, or closed. These factors, classified as static and dynamic, interact with the tube law of the pharynx to determine, at any time, the cross-sectional area of the airway.

Static Factors Influencing Behavior of the Normal Pharyngeal AirwaySurface Adhesive ForcesClinical observations and studies in anesthetized animals indicate that surface adhesive forces between opposed luminal surfaces can contribute to airway patency and closure.4-6 During nasal breathing with the mouth closed, surface adhesive forces help maintain the soft palate in apposition to the base of the tongue and promote contact

pressure, distends and enlarges the airway area. Con-versely, a decrease in transmural pressure, caused either by more-negative intraluminal pressure or more-positive tissue pressure, narrows the airway.The mechanical characteristics at a particular region of

the passive pharynx are revealed in a plot demonstrating the relation between transmural pressure and intraluminal

A

B

C

DA

Soft palate

Airwaycenterline

Cervicalspine

Spinalcord

TongueHyoid

Mandible

Maxilla

B

Figure 101-1 A, Midsagittal magnetic resonance image (MRI) in a normal subject highlighting the four upper airway regions: the nasopharynx, which is defined from the nasal turbinates to the hard palate; the retropalatal (RP) oropharynx, extending from the hard palate to the caudal margin of the soft palate; the retroglossal (RG) region from the caudal margin of the soft palate to the base of the epiglottis; and the hypopharynx, which is defined from the base of the tongue to the larynx. B, This diagram demon-strates important midsagittal upper airway, soft tissue, and bone structures.

Teeth

Tongue

Softpalate

Subcutaneousfat

Spinalcord

Parapharyngealfat pad

Pharynageallateral wall

Parotid

MandibleAirway

Figure 101-2 Axial MRI in a normal subject in the retropalatal region. The tongue, soft palate, parapharyngeal fat pads (fat is white on MRI), lateral parapharyngeal walls (muscles between the airway and lateral parapharyngeal fat pads) and mandibular rami can all be visualized on this axial MRI.

Box 101-1 Mechanical Influences on the Passive Pharyngeal Airway

Static FactorsSurface adhesive forcesNeck and jaw positionTracheal tugGravity

Dynamic FactorsUpstream resistance in the nasal airway and pharynxBernoulli effectDynamic compliance

CHAPTER 101 Anatomy and Physiology of Upper Airway Obstruction 1155

Neck and Jaw PositionStudies indicate that neck flexion under passive conditions tends to close the airway, and neck extension acts to open it.7 The retropalatal and retroglossal regions of the pharyngeal airway are narrowed as the neck is flexed. Jaw position has also been documented to alter the size of the upper airway. Opening the jaw slightly can actu-ally increase the size of the pharynx by providing more room in the oral cavity for the tongue. This may be particularly important if the tongue is large relative to the oral cavity. However, progressive opening of the jaw leads to posterior movement of the genial tubercle of the mandible: The genial tubercle moves closer to the posterior pharyngeal wall because the mandibular condyle

Midsagittal MR sliceRetroglossal axial MR slice

Retropalatal axial MR slice

Figure 101-3 Midsagittal MRI in a normal subject depicting the midretropalatal (RP) and midretroglossal (RG) regions.

Ptm : Area ; Ptm : Area A B

"Tube law"

Area

Pl

Ptm = Pl PtiCompliance =

Pclose

Ptm

dPtm

Pti A

Ptm

dA

Figure 101-4 A, The concept of transmural pressure (Ptm) and a tube law of the pharynx are schematized. Ptm is defined as intra-luminal pressure (P1) minus surrounding tissue pressure (Pti). B, An increase in Ptm results in an increase in the cross-sectional area (A) in accordance with a tube law of the pharynx. The slope of the tube law represents compliance of the pharynx. Pclose, closing pressure; Pti, tissue pressure.

of the tongue with the mucosa of the oral cavity. Mouth opening potentially destabilizes the airway by freeing the mucosal attachments of the tongue and soft palate and allowing these now freely moving structures to relocate posteriorly and compromise the pharyngeal airway. Surface adhesive forces can also make restoration of airway patency more difficult and might explain why the pres-sure needed to open an already closed airway (opening pressure) is greater than the closing pressure. Although surface adhesive forces are an important determinant of airway patency, reduction in these forces by administer-ing surfactant to the upper airway mucosa results in only a relatively modest reduction in airway collapsibility during sleep.4


stiffen the upper airway.8,9 This action may be exerted through axial forces in the trachea, called tracheal tug. Increasing lung volume causes a caudal displacement of the intrathoracic trachea that, in turn, exerts caudally directed forces on the upper airway. The resulting passive axial tension in the pharyngeal wall tends to open the pharynx. There are at least four mechanisms by which caudal traction on the upper airway may improve airway patency (Fig. 101-6).10 As the upper airway is pulled toward the thorax, folding may be reduced in the walls of both the larynx and oropharynx. Second, stretching should stiffen the upper airway and make it more resistant to collapse. Caudal displacement of fat and other structures surrounding the pharynx can reduce extrinsic compression of the airway. Finally, caudal traction can improve airway patency through its mechanical effect on the hyoid apparatus.

GravityGravity also has an important influence on pharyngeal airway patency and it is common for patients with OSA to have a higher apnea-hypopnea index in the supine than in the nonsupine position. When the patient is supine, gravity can help to narrow the pharyngeal airway by pulling the tongue and soft palate in a posterior direction.11

Dynamic Properties of the Normal Pharyngeal AirwayThe upper airway has also been modeled as behaving like a Starling resistor.12 Starling resistor describes a highly col-lapsible tube having infinite compliance (e.g., more floppy) at one transmural pressure and low compliance (e.g., more stiff) at transmural pressures that are above and below this pressure. The tube is completely closed at one luminal pressure and completely open at a higher luminal pressure. The luminal pressure at which the airway shifts from fully open to fully closed (i.e., the point of infinite compliance) is determined by the extramural pressure and is referred to as the critical pressure (Pcrit).

Maxilla

Genialtubercle

Mandibularcondyle

Hyoid

Sternum

Mentalprotuberance

Figure 101-5 Jaw opening results in a posterior and caudal displacement of the genial tubercle of the mandible, as well as the floating hyoid bone, through the many hyomandibular attachments. As a result, the anterior pharyngeal wall struc-tures such as the tongue and epiglottis move in a posterior direction, decreasing pharyngeal airway size. Neck flexion would have a similar effect on the hyoid, tongue, and epiglottis even without a change in the relationship between the mandi-ble and the maxilla.

Pharyngealunfolding

Reducedcompliance

Pharyngealdecompression

Hyoidretraction

Figure 101-6 Possible mechanisms that can explain how tracheal traction on the upper airway protects upper airway patency (From Van de Graaff WB. Thoracic influence on upper airway patency. J Appl Physiol 1988;65:2124-2131).

of the temporomandibular joint is considerably rostral to the plane of the mandible (Fig. 101-5). This posterior movement of the genial tubercle of the mandible with mouth opening causes the tongue and hyoid apparatus to move posteriorly, and thereby narrows the pharyngeal airway.

Tracheal TugIncreases in lung volume are thought to increase pharyn-geal cross-sectional area, reduce closing pressure, and


ute to further pressure drop across the collapsible airway segment. By contrast, progressive narrowing of the upstream pharyngeal segment produces progressively more negative inspiratory intraluminal pressures down-stream from the site of narrowing, regardless of inspiratory flow limitation, because of increased viscous energy losses in the narrowed region. If the cross-sectional area of the pharyngeal lumen decreases in some regions, the velocity of airflow is elevated in these regions. This increase in airflow velocity implies an increase in kinetic energy of the airstream and, hence, a decrease in distending pressure. This reduction in distending pressure allows further inspi-ratory narrowing according to the tube law of the pharynx.

Dynamic ComplianceDuring inspiration, the decrease in intraluminal pressure at any point in the upper airway interacts with the dynamic compliance of that segment of the upper airway.13 If intra-luminal pressure at the beginning of inspiration is a value that lies on the steep portion of the pressure-area relation-ship, the upper airway narrows as intraluminal pressure decreases during inspiration. The degree to which pharyn-geal cross-sectional area decreases depends on the dynamic compliance of the upper airway. This mechanical property also influences the likelihood of further airway collapse. Specifically, narrowing during inspiration due to a decrease in intraluminal pressure might decrease the area signifi-cantly which, in turn, increases the velocity of gas flowing through that segment. This results in further reductions in intraluminal pressure because of the conversion of static to kinetic energy with decreased distending pressure. Such a decline in luminal pressure, in turn, tends to further decrease airway area. This sequence describes dynamic narrowing of the upper airway, which is typically observed under normal conditions if the pharyngeal muscles are hypotonic. In early expiration (positive airway pressure due to chest wall recoil), airway caliber increases, and toward the end of expiration (reduction in positive airway pressure and the upper airway dilator muscles remain inactive), the airway narrows.1 Patients with OSA are at risk for airway closure at the end of expiration and in inspiration.

Ventilatory ControlAlterations in ventilatory control can also influence the upper airway and promote upper airway obstruction. In humans, arterial oxygen and carbon dioxide levels are tightly controlled by various feedback systems involving chemoreceptors, intrapulmonary receptors, and respira-tory muscle afferents. Because ventilatory control is regu-lated by feedback systems, these systems can become unstable (waxing and waning ventilation). Disturbances in these respiratory feedback systems are generally character-ized by an increase in loop gain, which can augment peri-odicities in breathing patterns and in some persons produces associated periodic upper airway obstruction. (See Chapter 100 for a complete description of loop gain.)

PHARYNGEAL MUSCLES

Activation of the Pharyngeal MusclesMany of the 20 or more skeletal muscles surrounding the pharyngeal airway are phasically activated during

Factors Influencing the Dynamic Properties of the Passive Pharyngeal AirwayUpstream Resistance within the Nasal AirwayInspiratory airflow through the nose results from a pres-sure drop between the nares and the nasopharynx, thereby creating a driving pressure. This driving pressure for inspi-ratory airflow is generated by reduction in nasopharyngeal pressure secondary to active contraction of the diaphragm and other inspiratory pump muscles. The nose has a rela-tively high resistance and the flow pattern is turbulent, characteristics that are enhanced when the nasal airway is narrowed by such conditions as mucosal congestion, nasal polyps, and turbinate hypertrophy. These factors increase nasal airway resistance during inspiration. This increase is nonlinear relative to inspiratory airflow such that as inspi-ratory airflow increases, there is disproportionately more negative nasopharyngeal intraluminal pressure generated. Nasopharyngeal pressure is effectively equivalent to the pharyngeal intraluminal pressure if the resistance within the pharynx is relatively low. All other things being equal, increases in nasal resistance produce a more-negative inspiratory swing in pharyngeal intraluminal pressure and consequently, as per the tube law, a reduction of pharyn-geal cross-sectional area. The extent to which the lumen narrows depends on regional airway compliance, that is, the relative compliance of each segment.

Upstream Resistance within the PharynxAs is the case with nasal resistance, a high resistance within the pharynx is associated with a more-negative intralumi-nal pressure in more caudal (more downstream) segments during inspiration. In other words, a narrowing at the retropalatal region is associated with a further decline in intraluminal pressure during inspiration at sites caudal to the retropalatal region, thereby increasing the tendency for closure in the retroglossal region and hypopharynx.

Bernoulli EffectTwo types of physical phenomena promote a reduction in intraluminal pressure as gas flows through a tube: loss of energy by work performed in overcoming flow-resistance aspects of the airway and the Bernoulli effect (the conver-sion of energy from static to kinetic caused by an increase in the velocity of airflow when cross-sectional airway area decreases). The first phenomenon relates to upstream resistance to airflow. Whenever gas flows through a resis-tance, potential energy is dissipated in overcoming friction and, consequently, intraluminal pressure decreases. The second phenomenon relates to acceleration of gas as it flows through a narrowed segment of a tube. Both phe-nomena contribute to decreasing pharyngeal intraluminal pressure during inspiration; therefore, both tend to narrow the pharynx during inspiration.Because pharyngeal pressure must fall below pressure at

the airway opening (nares or mouth) to generate inspira-tory airflow, nasal or other sites of upstream resistance contribute to the development of negative intraluminal pharyngeal pressure even in the absence of inspiratory flow limitation. However, once inspiratory flow limitation is present, the relatively rigid nasal passage does not contrib-


vated individually. Co-activation of the hyoid muscles is a particularly good example of this phenomenon (Fig. 101-8; see Fig. 101-7B). The hyoid bone in humans, unlike that in other mammals, does not articulate with any other bony or cartilaginous structure. The position of the hyoid bone is determined by the muscle attachments to this floating bony structure. Muscles inserting on the hyoid include the geniohyoid and genioglossus. Contraction of these muscles pulls the hyoid in a rostral and anterior direction. Strap muscles originating from the sternum (sternohyoid) and thyroid cartilage (thyrohyoid) also insert on the hyoid and pull it in a caudal direction. With simultaneous contraction of all four muscles, the resultant force vector acting on the hyoid is directed caudally and anteriorly. This combined effect moves the anterior pharyngeal wall outward, can stiffen the lateral pharyngeal walls, and promotes upper airway patency. Another example of coactivation of muscles and upper airway patency involves the tongue. Evidence indicates that simultaneous activation of the antagonistic protrudor and retractor tongue muscles, as occurs under hypercapnic and hypoxic conditions, has a synergistic effect in promoting upper airway patency.16The action of an upper airway muscle depends not only

on whether other muscles are simultaneously active but also on its lengthtension and forcevelocity characteris-tics at the time of activation. For instance, opening the mouth decreases genioglossus and geniohyoid muscle length, which can affect upper airway caliber. Similarly, neck flexion changes the position of the hyoid bone; alter-ing the anatomic relationships of a variety of muscles acting on this structure and shifting the vector of their forces in a more caudal direction. Other evidence suggests that a particular pharyngeal muscle can have different mechanical effects on the airway depending on the size of the airway at the time of muscle activation.17,18 The ability of a given muscle to produce different mechanical effects

inspiration, which helps to dilate the airway and stiffen the airway walls.14,15 As shown in Figure 101-7, the pharyngeal muscles have complex anatomic relationships that help regulate the position of the soft palate, tongue, hyoid appa-ratus, and posterolateral pharyngeal walls. Contraction of specific muscles within these groups can have antagonistic effects on the pharyngeal airway. For example, contraction of the palatal levator palatini muscle, along with the supe-rior pharyngeal constrictor, closes the retropalatal airway, but contraction of other palatal muscles, the palatopharyn-geus and glossopharyngeus, opens the airway in the retro-palatal region. Similarly, the extrinsic tongue muscles can have antagonistic effects; namely, the genioglossus and geniohyoid protrude the tongue and the hyoglossus and styloglossus retract it.In addition, pharyngeal muscles can have different

effects when activated in concert as opposed to when acti-

Tensorpalatini

Levatorpalatini

Genioglossus

Epiglottis

Mentalprotuberance

Geniohyoid

Hyoid bone

Thyrohyoid

Thyroidcartilage

Nasopharynx

Retropalatal oropharynx

Retroglossal oropharynx

Hypopharynx

Hyoglossus

GenioglossusMandible

Digastric

Hyoid bone

Thyrohyoid ligamentSternohyoid

Styloglossus

Superior pharyngealconstrictor

Digastric

Middlepharyngealconstrictor

Inferiorpharyngealconstrictor

Thyroidcartilage

B

A

Figure 101-7 A, Schematic diagram of upper airway anatomy. The tensor palatini moves the soft palate ventrally. The genio-glossus acts to displace the tongue ventrally. Coactivation of the muscles in the anterior pharyngeal wall such as the genio-hyoid and sternohoid act on the hyoid bone to move it ven-trally. B, Schematic diagram of upper airway muscles. Among the many upper airway muscles attaching to the floating hyoid bone are the genioglossus, geniohyoid, hyoglossus, middle pharyngeal constrictor, sternohyoid, and digastric.

Area

Active

Passive

A

P1Pmus

P2 Ptm

Figure 101-8 Airway area under passive conditions (i.e., no muscle activation) can be increased by a rise in transmural pressure (Ptm). Such a change occurs with the application of a positive intraluminal pressure, such as with nasal continuous positive airway pressure (CPAP). Contraction of pharyngeal dila-tors shifts the passive curve up and to the left. The muscle contraction increases Ptm, and (P2-P1) now represents Pmus (muscle pressure).


muscles occurs in rapid eye movement (REM) sleep, par-ticularly in phasic REM.25,26 Thus, there is compelling evidence that the neural output to pharyngeal dilator muscles is decreased during sleep.

Sensory Modulation of Pharyngeal MusclesNeurosensory feedback from thoracic and upper airway receptors can modulate motor output to pharyngeal muscles.27 During NREM sleep and general anesthesia in animals, withdrawal of vagally mediated phasic volume feedback by tracheal occlusion during inspiration results in an immediate large augmentation in motor output to many upper airway and chest wall inspiratory pump muscles.28-30 Introduction of subatmospheric pressure into an isolated, sealed upper airway in spontaneously breath-ing tracheostomized animals precipitates neurally medi-ated muscle activation.31,32 It is believed that upper airway receptors located superficially in the airway wall mediate this reflex activation because it is not present following administration of topical anesthesia.33The majority of upper airway respiratory-related affer-

ents are located in the upper trachea and larynx and carried in the internal branch of the superior laryngeal nerve. Sensory information from the upper airway is also trans-mitted in the glossopharyngeal and trigeminal nerves.34 Both intrathoracic and upper airway sensory afferents can also reduce motor output to the thoracic inspiratory muscles, thereby increasing intraluminal pressure below the site of airway obstruction.35 The effects of this reflex on upper airway and respiratory pump muscles could rep-resent a powerful defense mechanism for maintaining upper airway patency during sleep. Presumably, neural reflex activation of pharyngeal muscles by upper airway and thoracic receptors would be initiated by upper airway obstruction and would tend to compensate for airway

may be due to changes in muscle fiber orientation with concomitant changes in airway size and shape. In addition, the timing of muscle activation relative to the phase of respiration may play a role in determining the mechanical effects of such activation.19The differing mechanical effects of the pharyngeal

muscles, depending on airway conditions at the time of activation, may help explain how pharyngeal muscles can play a role in such disparate functions as respiration, deglu-tition, and phonation. Rather than a separate set of muscles performing one particular function, activation of a given muscle can have diametrically different mechanical effects on the airway depending on what other muscles are simul-taneously active and on the precise anatomic configuration of the muscle at the time of activation.

Factors Modulating Pharyngeal Muscle ActivationActivation of pharyngeal muscles can alter the mechanical characteristics of the upper airway. The effect of pharyn-geal dilator muscle activation on the tube law of the pharynx is shown in Figure 101-8. Under active condi-tions, the pressurearea relationship is shifted upward and to the left. At any given transmural pressure, muscle activa-tion increases airway area and stiffens the airway, that is, decreases effective compliance. The effect of muscle acti-vation on the tube law is quantified by the term Pmus, the effective pressure exerted by muscle activation, equivalent to the change in transmural pressure required to yield the equivalent change in area on the passive curve (see Fig. 101-8). Under certain conditions, pharyngeal dilator muscles display bursts of inspiratory activity superimposed on tonic activity. Alcohol, sleep deprivation, anesthesia, and sedative-hypnotics suppress respiratory-related pha-ryngeal muscle activation.20 Additional factors that modu-late respiratory-related activity of pharyngeal airway motoneurons include changes in state, proprioceptive feedback, and chemical drive (Fig. 101-9).

Changes in StatePerhaps the most convincing evidence supporting the overall importance of neuromuscular activity on airway patency is that apneas and hypopneas occur during sleep. That modification of neuromuscular factors (e.g., decrease in genioglossus activity) by sleep is a normal physiologic phenomenon can be inferred from measurements of supra-glottic resistance, the airflow resistance extending from the nares to the region above the glottis in normal subjects in whom supraglottic resistance increases fourfold to fivefold with sleep onset (e.g., from 1 to 2 cm H2O/L/sec during wakefulness to 5 to 10 cm H2O/L/sec during sleep).21,22 Supraglottic airway resistance is abnormally high in OSA patients during wakefulness and increases even further with sleep onset. The decrease in upper airway caliber that occurs with sleep onset is explained by a state-dependent reduction in neural output to upper airway muscles, which causes a decrease in Pmus at one or more sites within the pharyngeal airway. EMG recordings of pharyngeal muscles, such as the genioglossus and tensor palatini, confirm this decrease in pharyngeal muscle activity during the transition from wakefulness to sleep.23,24 An even more pronounced reduction in motor output to pharyngeal

Pharyngealluminal area

Proprioceptors

0 100%

Dilatormuscle

tone

Centralbreathing

control

Upperairwaydrive

Airwaysuction

Inspiratorydrive

Peripheralchemoreceptors

Centralchemoreceptors

Figure 101-9 Balance of forces that sustain upper airway patency. The two major forces are airway suction pressure and upper airway muscle tone that dilates and stiffens the airway. These in turn are influenced by other factors.


normal subjects.45,46 Reduction in mandibular body length, in particular, has been shown to be an important risk factor for obstructive sleep apnea. In addition to craniofacial differences, enlargement of the upper airway soft tissue structures (tongue, lateral pharyngeal walls, soft palate, parapharyngeal fat pads) has also been demonstrated in patients with OSA compared to normal persons.42,43Imaging studies with computed tomography (CT) or

magnetic resonance imaging (MRI) have demonstrated increases in the cross-sectional area and dimensions of the soft palate, tongue, parapharyngeal fat pads, and lateral pharyngeal walls in patients with OSA.42,47 Figure 101-10A (a mid-sagittal MRI image) demonstrates narrowing of the upper airway and elongation of the soft palate and tongue in an OSA patient compared to a normal subject. Figure 101-10B (an axial MRI in the retropalatal region) demon-strates lateral airway narrowing in an OSA patient com-pared to a normal subject.A case-control study demonstrated that the volume of

the upper airway soft tissue structures (tongue, lateral pha-ryngeal walls, soft palate, parapharyngeal fat pads) (Fig. 101-11) was significantly greater in OSA patients than normal subjects.42 The volume of the lateral pharyngeal walls, tongue, and total soft tissue surrounding the upper airway remained significantly larger in OSA patients than in normal subjects after adjustments for co-variates includ-ing gender, age, ethnicity, craniofacial size, and fat sur-rounding the upper airway. This study demonstrated that increased volume of the lateral pharyngeal walls, tongue, and total upper airway soft tissue significantly increased the risk (increased odds ratios) for OSA even after adjust-ment for co-variates.42 There are several possible explana-tions for the enlargement of the upper airway soft tissue structures in OSA patients including edema, weight gain, muscle injury, gender, and genetic factors.

EdemaNegative pressure during airway closure or trauma from repeated apneic events can cause edema to the soft tissue structures surrounding the upper airway. This edema could increase the size of these soft tissue structures. The soft palate is especially at risk for developing edema because it can be tugged caudally and traumatized during apneas. Supporting the presence of pharyngeal soft tissue swelling in untreated OSA is the reported reduction in upper airway edema following treatment of these patients with CPAP therapy.48 Quantitative magnetic resonance mapping also suggests that there is more edema in the genioglossus muscles of OSA patients compared to normal subjects.47,49,50 Histologic studies have also shown that patients with OSA have increased edema in the uvula compared to normal subjects.51Additional support for the presence of upper airway

edema is the observation that OSA is commonly associated with conditions that result in fluid overload states such as congestive heart failure52 and kidney failure.53 It has been proposed that increased central venous pressure could increase edema in the upper airway structures.54 In support of this hypothesis, several studies have shown that applying lower body positive pressure with antishock trousers caused a fluid shift from the lower extremities, increasing central venous pressure. This resulted in increased neck

obstruction by dilating and stiffening the pharynx. However, evidence indicates that these neurally mediated reflexes to protect upper airway patency are blunted in sleeping humans.36Repetitive mechanical stress on pharyngeal airway struc-

tures from recurrent episodes of apnea and snoring on the upper airway appear to have neurosensory consequences. Evidence indicates that there is a sensory-neural abnor-mality in patients with sleep apnea with impaired upper airway sensation, which is partially reversible with continu-ous positive airway pressure (CPAP).37-39 In addition, studies have shown the importance of upper airway reflexes that increase upper airway caliber.36 These reflexes are activated by negative inspiratory pressure and may be attenuated by the sensory impairment of the upper airway. Repeated episodes of snoring and vibration at night have also been thought to lead to progressive local neuropa-thy.40,41 Both the upper airway sensory abnormalities and neuropathy could explain the progressive worsening of sleep apnea over time.

Chemical StimuliRespiratory-related phasic pharyngeal muscle activity, which can be absent during quiet breathing, usually appears under hypercapnic or hypoxic conditions.14 Under condi-tions of increased chemical drive, the majority of pharyn-geal muscles exhibit phasic inspiratory activity that dilates and stiffens the airway. Upper airway and phrenic motor neurons differ in their response to hypocapnia. Upper airway motor neurons appear to have a higher CO2 thresh-old for activation than respiratory pump muscles. With passive hyperventilation in a tracheotomized, vagotomized, anesthetized animal, phasic upper airway motor neuron activity disappears prior to phrenic activity. When the CO2 level is then allowed to rise, phasic activity first reappears in the phrenic nerve. Transmission of the resulting subat-mospheric intrathoracic pressure during inspiration into the pharyngeal airway, in the absence of simultaneous pha-ryngeal dilator muscle activation, increases the risk of pha-ryngeal airway narrowing and closure. Thus, cyclic changes in arterial CO2 around the CO2 threshold for activation of upper-airway motor neuron activity could lead to an imbal-ance of forces acting on the pharyngeal airway and favor closure.

DIFFERENCES IN STATIC UPPER AIRWAY ANATOMY IN PATIENTS WITH SLEEP APNEA

Upper Airway AreaMost studies have shown that the pharyngeal airway cross-sectional area is smaller in patients with OSA compared to normal subjects.42-44 The airway narrowing has been shown to be primarily in the retropalatal region. The reduced size of the pharyngeal airway in patients with OSA compared to normal persons must be secondary to enlargement of the surrounding soft tissues or to reductions or changes to the craniofacial structures. Cephalometric studies have demonstrated reduction in mandibular body length (i.e., retrognathia), inferiorly positioned hyoid bone, and retro-position of the maxilla in patients with OSA compared to


OSA is related to fat deposition in the neck. Upper airway imaging studies in obese OSA patients have demonstrated increased subcutaneous adipose tissue as well as increased adipose tissue surrounding the airway (primarily enlarge-ment of the lateral parapharyngeal fat pads) (see Figs. 101-2, 101-10B, and 101-11).49 These studies suggest that obesity increases fat deposition in the lateral pharyngeal fat pads, which in turn has been hypothesized to displace the lateral walls and reduce upper airway size.Fat deposition within the tongue or soft palate may also

be important in increasing the size of the soft tissue struc-tures and reducing the caliber of the upper airway. Fat has been shown to be deposited in the uvula of patients with

circumference, pharyngeal airflow resistance, and upper airway collapsibility and reduced upper airway cross-sec-tional area.55-57b

Fat Distribution and Body WeightObesity is known to be an important risk factor for OSA.58 Although the relationship between obesity and OSA is not well understood, it appears that obesity decreases pharyn-geal airway size and increases airway collapsibility. Increased neck size, a better surrogate of upper airway fat distribution than body mass index (BMI), has been dem-onstrated to be an excellent predictor of OSA.59,60 It is thought that the increased neck size in obese patients with

MIDSAGITTAL MRI

NormalA ApneicAXIAL MRI

NormalB ApneicFigure 101-10 A, Midsagittal MRI of a normal subject (left) and a patient with sleep apnea (right). The upper airway is smaller and the soft palate is longer in the patient with sleep apnea. The amount of subcutaneous fat (white area at the back of the neck) is greater in the apneic than in the normal subject. B, Axial MRI in the retropalatal region of a normal subject (left) and a patient with sleep apnea (right). The upper airway is smaller (primarily narrowed in the lateral dimension) in the patient with sleep apnea. There is more subcutaneous fat in the patient with sleep apnea.


suggest that weight gain might predispose to OSA by increasing the size of the muscular soft tissue structures (tongue, soft palate, lateral pharyngeal walls) surrounding the upper airway in addition to the direct deposition of fat in the parapharyngeal fat pads. This hypothesis is sup-ported by data in obese nonapneic women that show that weight loss decreases the volume of the lateral pharyngeal walls and parapharyngeal fat pads (Fig. 101-12).70Other explanations for the relationship between obesity

and OSA include changes in upper airway compliance and alterations in the biomechanical relationships of the upper airway muscles.71 Thus although obesity has been shown to be an important risk factor for OSA, the specific effect of weight gain on the upper airway soft tissue structures is not entirely understood.

Upper Airway MyopathyIt has been hypothesized that patients with OSA have a primary myopathy that contributes to the enlargement of the upper airway soft tissue structures.72 OSA is thought to be associated with changes in the contractile properties of upper airway muscles. Several studies have shown an increase in type II fast-twitch fibers in the genioglossus

OSA, supporting the hypothesis that fat deposited outside of the parapharyngeal fat pads may be important in the pathogenesis of OSA.61,62 An autopsy study of tongue volume and percentage of fat content demonstrated that the percentage of fat in the tongue increases with increasing BMI.63 It has also been argued that the total amount of fat surrounding the upper airway may be a more important contributor to OSA than fat localized in a particular anatomic site. Tsuiki and coworkers have hypothesized that increased soft tissue volume, including fat deposition in the space bounded by the mandibular rami, increases tissue pressure that in turn would narrow the airway.64In addition to direct deposition of fat, weight gain can

also alter the muscular tissue surrounding the upper airway because it not only increases the amount of adipose tissue but also increases muscle mass.65,66 Approximately 25% of the increased weight in obese patients is secondary to fat-free tissue.66,67 In support of this, it has been shown there is a larger percentage of muscle in the uvula of patients with OSA compared to normal subjects.68,69 We do not know if this increased muscle mass is a consequence of the apnea itself or is related to obesity. Nonetheless, such data

Tongue Mandible

Normal subject

Parapharyngealfat pads

Soft palate Pharyngealwalls

Airway

TongueMandible

Patient with sleep apnea

Parapharyngealfat pads

Soft palate Pharyngealwalls

Airway

Figure 101-11 Volumetric reconstruction of axial MR images in a normal subject and patient with sleep apnea. The mandible is depicted in white, the tongue in red, the soft palate in blue, the lateral parapharyngeal fat pads in yellow, and the lateral-posterior pharyngeal walls in green. The airway is depicted in gray. The normal subject has a larger airway than the patient with sleep apnea. The tongue, soft palate, parapharyngeal fat pads, and lateral pharyngeal walls of the patient with sleep apnea are all larger than in the normal subject.

Preweight lossA Postweight loss

Preweight lossParapharyngeal

fat padsAirway

B Postweight loss

Figure 101-12 A, Axial MRIs of a normal subject, before and after weight loss in the retropalatal region. Airway area and lateral airway dimensions increase with weight loss. The thickness of lateral pharyngeal walls and the size of the parapharyngeal fat pads decrease with weight loss. B, Volumetric reconstructions of the upper airway soft tissues and craniofacial tissue before and after weight loss in a normal subject: soft palate (purple), tongue (orange/rust), lateral pharyngeal walls (green), parapharyngeal fat pads (yellow), and mandible (gray). The size of the upper airway increases with weight loss. The lateral pharyngeal walls and the parapharyngeal fat pads demonstrated the largest reductions in size with weight loss. Mandibular volume did not change with weight loss.

43

12

Phases 3 and 4 = Expiration

Phases 1 and 2 = Inspiration

Uppe

r airw

ay a

rea

Tidal volume

Figure 101-13 Diagram of the changes in upper airway area as a function of tidal volume during the respiratory cycle. Airway caliber is relatively constant in inspiration (phases 1 and 2), whereas airway size increases in early expiration (phase 3) and decreases in late expiration (phase 4).

pharyngeal soft tissue volume, all demonstrated significant levels of heritability after controlling for confounders. Enlarged retropalatal and retroglossal lateral pharyngeal walls, soft palate, and total soft tissue volume were all independently associated with an increased risk of having a sibling with OSA.79

DYNAMIC PHYSIOLOGIC CHANGES IN UPPER AIRWAY STRUCTURESAlthough we have gained important insights into the ana-tomic risk factors for OSA with static studies of the upper airway, examination of the dynamic behavior of the upper airway is also necessary to completely understand the pathogenesis of sleep-disordered breathing. CT, MRI, and nasopharyngoscopy have been used to examine dynamic changes in upper airway caliber and the surrounding soft tissue structures during the respiratory cycle.80,81Electron beam CT has been used to demonstrate that

upper airway size changes during four distinct phases of the respiratory cycle in normal persons and in patients with OSA (Fig. 101-13).80,82 During early inspiration (phase 1; see Fig. 101-13) there is a small increase in upper airway size, but during most of inspiration (phase 2; see Fig. 101-13) upper airway caliber remains relatively constant. The finding that upper airway caliber is rela-tively constant during inspiration while awake suggests a balance between the action of the upper airway dilator muscles to maintain airway size and the negative intralu-minal pressure, which promotes a decrease in airway size. During early expiration, upper airway caliber increases (phase 3; see Fig. 101-13) secondary to positive intralumi-nal pressure (the upper airway dilator muscles are not

muscle of OSA patients.41,73,74 Type II fibers are more likely to fatigue than type I fibers; therefore, the upper airway muscles in patients with OSA would be more susceptible to fatigue than those of normal subjects. The remodeling of the upper airway muscles in patients with OSA may be a primary or secondary phenomenonthat is, a conse-quence rather than the cause of apneas. Carrera and coworkers74 studied the structure and function of the genioglossus in OSA patients and normal subjects and demonstrated that the myopathy is a secondary phenom-enon. These investigators found increased type II fibers in the genioglossus muscle of OSA patients; however, these fiber changes in the genioglossus muscle were reversed with CPAP.

SexGender can have an important effect on the size of the upper airway soft tissue structures. Several studies have demonstrated that pharyngeal airway size is smaller in women than in men.68,75 In addition, studies have shown that neck circumference is smaller in women than in men,65 so it has been hypothesized that the size of the upper airway soft tissue structures (tongue, soft palate, lateral pharyngeal walls, lateral parapharyngeal fat pads) are also smaller in women than men.It has been shown that fat distribution is different in

women than men.66,67 In men, fat is deposited primarily in the upper body and trunk, whereas in women it is depos-ited primarily in the lower body and extremities.66,67 These gender-related differences in overall fat distribution suggest that the size of the lateral parapharyngeal fat pads may be greater in men than women. However, two studies have examined gender-related differences in upper airway soft tissue structures in normal subjects with MRI,69,76 and while both showed that the size of the tongue, soft palate, and total soft tissue were greater in normal men than women,69,76 neither found a significant between-gender difference in lateral pharyngeal fat pad size. These data suggest that gender might not have a significant effect on the amount of visceral (parapharygneal fat pads) neck fat but might have an important effect on the size of the other upper airway soft tissue structures.

Genetic FactorsGenetic factors play an important role in determining the size of the upper airway soft tissue structures (see Chapter 103.) Macroglossia has been shown to be a risk factor for OSA in patients with trisomy 21.77 Family aggregation of craniofacial anatomy (reduction in posterior airway space, increase in mandibular to hyoid distance, inferior hyoid placement) has been shown in patients with OSA.65,78 The data from these studies suggest that elements of craniofa-cial structure are likely inherited in OSA patients. In addi-tion to craniofacial structures, soft tissue structures are also heritable.79 Using volumetric MRI, and controlling for sex, ethnicity, age, craniofacial size, and visceral neck fat, the lateral pharyngeal walls, soft palate, genioglossus muscle, tongue volume, and total soft tissue volume have been shown to be enlarged in OSA patients and their siblings but not in normal subjects and their siblings. More impor-tantly, the volume of the lateral pharyngeal walls (retro-palatal and retroglossal) and tongue, as well as total


Site and Patterns of Pharyngeal ObstructionThe retropalatal region is the most common primary site of airway narrowing or closure during sleep in patients with OSA, although upper airway narrowing can also occur in the retroglossal region.88,89 However, most patients with OSA have more than one site of narrowing. Studies examining state-dependent changes in the upper airway also demonstrate that airway narrowing during sleep occurs in both the lateral and anterior-posterior dimen-sions (Fig. 101-15).

EFFECT OF TREATMENT OF OBSTRUCTIVE SLEEP ON UPPER AIRWAY CALIBERThe following sections review data on the effect of weight loss, CPAP, oral appliances, and surgery on upper airway size and the surrounding soft tissue and craniofacial struc-ture. The purpose of this section is to illustrate how these therapeutic interventions influence upper airway patho-physiology. Other chapters deal specifically with these therapies.

Weight LossWeight loss on the order of 5% to 10% has been shown to improve OSA and decrease the collapsibility of the airway.90-92 However, the mechanism by which weight loss improves OSA, increases the size of the upper airway, and changes the size and configuration of the upper airway soft-tissue structures (soft palate, tongue, parapharyngeal fat pads, lateral pharyngeal walls) is not known. It has been hypothesized that weight loss decreases the volume of the parapharyngeal fat pads, which, in turn, could increase the size of the upper airway. Alternatively, weight loss might decrease the size of the tongue or other upper airway soft tissue structures.

Continuous Positive Airway PressureAlthough CPAP suppresses upper airway muscle activity, it increases airway caliber by establishing a positive trans-mural pressure along the entire pharyngeal airway, func-tioning as a pneumatic splint.93 Initially it was thought that CPAP increased the caliber of the upper airway by anteri-orly displacing the tongue and soft palate. However, CT and MRI studies have shown that the dilation of the upper airway with CPAP is greater in the lateral dimension than in anterior-posterior dimension.1,94 Progressive increases in CPAP (up to 15 cm H2O) not only increase airway caliber in the lateral dimension but also significantly increase airway volume (threefold increase) and airway area in the retropalatal and retroglossal regions (Fig. 101-16).

Oral AppliancesOral mandibular advancement devices are also used to treat patients with OSA.95 These devices increase the pos-terior airway space.96 However, the specific biomechanical mechanisms that explain the increase in airway caliber with these devices are not well understood. Furthermore there is no gold standard oral appliance, and the many

phasically active during expiration). Upper airway caliber is largest in early expiration.80,82 At the end of expiration (phase 4; see Fig. 101-13), however, there is a large reduc-tion in upper airway caliber.It has been hypothesized that the end of expiration is a

vulnerable time for upper airway narrowing or collapse due to the absence of both phasic upper airway dilator muscle activity (phases 1 and 2, during inspiration) and positive intraluminal pressure (phase 3, early expiration) during this phase of the respiratory cycle. In these inves-tigations, pharyngeal area was smallest at the end of expira-tion.80,82 The finding that upper airway caliber is smallest at the end of expiration may have important implications with regard to the timing of sleep-induced upper airway closure. Apneas and hypopneas during sleep are thought to occur during inspiration secondary to negative intralu-minal pressure generated by chest wall contraction.83 However, studies examining airway resistance have dem-onstrated that airway closure in patients with OSA can occur during both expiration and inspiration.84,85 Studies using nasopharygoscopy and measurement of closing pres-sure have also shown that airway closure during sleep occurs during expiration and that subatmospheric intralu-minal pressure was not required for pharyngeal closure.86,87 These data indicate that the upper airway is vulnerable to collapse at the end of expiration in addition to collapse during inspiration.

OBSTRUCTION OF THE PHARYNX DURING SLEEP

Periodic and Nonperiodic Obstruction of the Pharynx during SleepA typical polygraphic recording from a patient displaying periodic pharyngeal occlusion during sleep is shown in Figure 101-14A. Periods during which airflow is absent are interspersed with somewhat briefer periods during which airflow is present. During the periods of pharyngeal occlu-sion, arterial oxygen saturation drops progressively and the magnitude of respiratory fluctuations in the esophageal pressure recording progressively increases. The apneic episodes terminate with an arousal that is associated with a large burst of submental electromyographic (EMG) activity.Sustained nonocclusive narrowing of the pharyngeal

lumen can also produce a relatively stable elevation of respiratory resistance associated with sustained arterial oxygen desaturation and repetitive, large inspiratory efforts associated with chin muscle activation (see Fig. 101-14B). As is the case with periodic occlusion, the location of the airway narrowing can be localized to the pharynx by mea-suring airflow and supraglottic pressure, which can reveal upper airway resistance exceeding 75 cm H2O/L/sec. This tracing also provides insight into a consequence of a col-lapsible pharyngeal tube (i.e., inspiratory flow limitation). Note that despite a progressively larger driving pressure (as reflected by abnormally negative esophageal pressure) during an inspiratory effort, airflow remains constant, indicating increasing resistance during inspiration, pre-sumably resulting from the progressive reduction of the pharyngeal lumen.


A

B

EOG

EEG(C4A1)

500 cc

1L/secV

V

SaO2

Peso 10 cm H2O

EOGEMG(submental)

RESPabd

MIC5 sec

100%90%80%

EOG

EEG(C4A1)

V 1L/sec

V

SaO2

Peso 10 cm H2O

ECGEMG(submental)

RESPabd

MIC5 sec

100%90%80%

500 cc

Figure 101-14 A, A typical tracing derived from a patient with severe obstructive sleep apnea. Bioelectric measurements (top three channels) indicate that the patient is in light sleep between periods of arousals associated with activation of the submental electromyogram (EMG). Arterial oxygen saturation (SaO2) decreases periodically and increases after onset of airflow ( V). Esophageal pressure (Peso) and abdominal motion (RESPabd) show continuous respiratory efforts. EEG, electroencephalogram; EKG, electrocar-diogram; EOG, electrooculogram; MIC, microphone; V, volume. B, A typical tracing derived from a patient with obstructive sleep hypopnea. A submental electromyogram (EMG) indicates rhythmical bursting of pharyngeal inspiratory muscles. SaO2 reveals stable mild hypoxemia. Airflow demonstrates flow limitation during inspiration. Despite a progressively larger driving pressure during an inspiratory effort (time between dashed vertical lines), flow remains constant, which indicates increasing resistance during inspiration, presumably resulting from progressive narrowing of the pharyngeal lumen. The thickened tracing at this time results from high-frequency oscillation in airflow caused by snoring. EEG, electroencephalogram; EOG, electrooculogram; MIC, microphone; Peso, esophageal pressure; RESPabd, abdominal motion; SaO2, arterial oxygen saturation; V, volume; V, airflow.

commercially available appliances have different mecha-nisms of action due to their differences in design. It has been hypothesized that mandibular repositioning devices increase airway size more in the retroglossal than in the retropalatal region because these devices advance the man-

dible and pull the tongue forward. However recent studies have shown that mandibular repositioning devices increase airway size in the retropalatal as well as the retroglossal region.97,98 The increase in retropalatal airway area is predominantly in the lateral dimension,98 suggesting that


the mechanism of action of oral appliances may be more complex than simply pulling the tongue and soft palate forward.

Upper Airway SurgeryUvulopalatopharyngoplasty (UPPP) is the most common surgical procedure for patients with OSA.99 During a UPPP the tonsils (if present), uvula, distal margin of the soft palate, and any excessive pharyngeal tissue are removed. The success rate of UPPP partially depends on the site of airway closure.88,100,101 Patients with retro-palatal obstruction have better results after UPPP than those with retroglossal obstruction. Unfortunately, the success rate in patients undergoing UPPP surgery is only 50%, which is an unacceptably high failure rate. More-favorable results with UPPP have been demonstrated if the surgery reduces the critical closing pressure.102 Thus far, the biomechanical changes in the upper airway soft tissue structures that underlie the efficacy, or lack of effi-cacy, of UPPP have not been identified.1,49,103 Nonetheless, preliminary studies with MRI have demonstrated that in patients who have undergone UPPP, the airway remains small in the nonresected portion of the soft palate, and the airway enlarges in the resected portion of the soft palate (Fig. 101-17).104 Computed tomography studies have also demonstrated increased width of the soft palate after UPPP.105 Persistent upper airway narrowing in the nonresected portion of the soft palate after UPPP might explain why UPPP has not been more successful in treat-ing patients with OSA.1,49,103,104

INTERACTION OF ANATOMIC AND NEUROLOGIC FACTORS ON PHARYNGEAL AIRWAY CLOSURE DURING SLEEP: A SCHEMATIC MODELThe overall balance of airway pressure and Pmus generated by upper airway muscles for normal persons and patients with OSA is depicted in Figure 101-18, where a balance beam depicts the counteracting effects of luminal pressure and pharyngeal Pmus, and the angle of equilibrium indicates the pharyngeal luminal area.106 The position of the fulcrum is determined by the mechanical characteristics of the upper airway. In awake normal persons (see Fig. 101-18A), equal values of negative luminal pressure and Pmus result in a widely dilated upper airway because the anatomy of the upper airway favors patency; that is, the fulcrum is to the left of center. In contrast, an anatomic abnormality (increase in the size of the upper airway soft tissue struc-tures or a reduction in the length of the mandible) in patients with OSA moves the pivot position of the balance to the right of center (see Fig. 101-18B). Under these conditions, even in the presence of increased upper airway muscle activity and normal intraluminal airway pressure (as may be present during wakefulness), the pharyngeal airway is still smaller than normal. The effect of sleep on these equilibriums under normal conditions and in obstruc-tive sleep apnea is shown in Figure 101-18C and D.In a normal subject, sleep is associated with a decrease

in pharyngeal luminal area because of a sleep-induced

Wakefulness Sleep

Figure 101-15 MRI in the retropalatal region of a normal subject during wakefulness and sleep. Airway area is smaller during sleep in this normal subject. The state-dependent change in airway caliber is a result of decreases in the lateral and anteriorposterior airway dimensions. Thickening of the lateral pharyngeal walls is demonstrated during sleep.

NasopharynxRetropalatal

Retroglossal

Hypopharynx

A

B

0 cm H2O

CPAP = 0 cm H2O CPAP = 15 cm H2O

5 cm H2O 10 cm H2O 15 cm H2O

Figure 101-16 A, Volumetric reconstruction of the upper airway with progressively greater continuous positive airway pressure (CPAP) (0 to 15 cm H2O) settings in a normal subject. There are significant increases in upper airway volume in the retropalatal and retroglossal regions with higher levels of CPAP. B, Axial MRI in a normal subject at two levels of CPAP (0 and 15 cm H2O) in the retropalatal region. Airway area is signifi-cantly greater at 15 cm H2O. The airway enlargement is pre-dominantly in the lateral dimension. Airway enlargement with CPAP results in thinning of the lateral pharyngeal walls, although the parapharyngeal fat pads are not displaced.


of airway occlusion in patients with obstructive sleep apnea, and the latter as the anatomic hypothesis.

Neural HypothesisThere is no evidence at present to indicate the existence of a primary neural abnormality in patients with OSA, but this might simply reflect our inability to quantify and compare changes from wakefulness to sleep across popula-tions of OSA patients and normal persons. Genioglossus muscle activity during wakefulness is reported to be greater in patients with OSA than that seen in normal persons.107,108 Such neuromuscular compensation can help preserve airway patency during wakefulness. Loss of pharyngeal muscle activity at sleep onset induces pharyngeal narrow-ing that becomes more severe as intraluminal pressure falls during inspiration. Whether the level of neuromuscular activation associated with the sleep state in patients with OSA is abnormally reduced or reflects a normal sleep-related loss of activity remains a question. Evidence sug-gests, however, that the response of the genioglossus to hypercapnia in normal subjects is attenuated following sleep deprivation.108 A similar reduction in motor output to pharyngeal muscles in patients with OSA resulting from their sleep fragmentation might further reduce pharyngeal muscle activation. In addition, there may be sensorineural abnormalities in the upper airway that propagate sleep apnea.37-41

Anatomic HypothesisThe finding of higher pharyngeal closing pressures in paralyzed, anesthetized patients with OSA compared to normal persons provides strong evidence that independent of neuromuscular factors, structural changes in the upper airway contribute significantly to the pathogenesis of OSA.106 In addition, it has been demonstrated that the volume of the tongue, lateral pharyngeal walls, and total soft tissue were not only larger in OSA patients than in normal persons but also that volumetric enlargement of these structures significantly increased the risk for OSA.42 Thus abnormalities in upper airway anatomy are clearly important in the pathogenesis of OSA.

decrease in upper airway muscle activity and a persistence of subatmospheric luminal pressure during inspiration. This means that the upper airway narrows during sleep compared to wakefulness but remains patent. However, patients with OSA develop significant airway narrowing and closure during sleep because the sleep-induced loss of upper airway activity occurs against the background of an anatomic impairment.Although there is no doubt that sleep is associated with

a decrease in pharyngeal muscle activity in normal subjects and OSA patients, a fundamental question regarding the pathogenesis of OSA is if the reduced motor output con-stitutes a key abnormality or if it occurs against the back-ground of an abnormally narrow passive pharynx that constitutes the principal pathogenic alteration. The former can be referred to as the neural hypothesis of the pathogenesis

Clinical Pearl

It is important to understand upper airway anatomy and why the upper airway collapses in patients with sleep apnea. Numerous factors including edema, obesity, and genetics can alter upper airway anatomy. There are many anatomic risk factors for sleep apnea including macroglossia, lateral peritonsillar narrow-ing, elongation of the uvula, narrowing of the hard palate, and retrognathia. These anatomic risk factors need to be sought when patients are being evaluated for sleep apnea. Factors that reduce upper airway muscle tone (alcohol, sedatives, narcotics, hypnotics) also need to be considered in the evaluation of sleep apnea.

A

B

Pre-UPPP Post-UPPP

Pre-UPPP

Uvula

Post-UPPP

Figure 101-17 A, Midsagittal MRI in a patient with sleep apnea before and after an uvulopalatopharyngoplasty. The uvula is shorter after the uvulopalatopharyngoplasty. However, the airway remains narrow in the region where the soft palate is not resected. B, Axial MRI before and after uvulopalatopharyn-goplasty in the region where the uvula was resected. Airway caliber increases substantially after the uvulopalatopharyngo-plasty in this region of the airway.


9. Stanchina ML, Malhotra A, Fogel RB, et al. The influence of lung volume on pharyngeal mechanics, collapsibility, and genioglossus muscle activation during sleep. Sleep 2003;26(7):851-856.

10. Van de Graaff WB. Thoracic influence on upper airway patency. J Appl Physiol 1988;65(5):2124-2131.

11. Isono S, Tanaka A, Nishino T. Lateral position decreases collaps-ibility of the passive pharynx in patients with obstructive sleep apnea. Anesthesiology 2002;97(4):780-785.

12. Patil SP, Schneider H, Schwartz AR, Smith PL. Adult obstructive sleep apnea: pathophysiology and diagnosis. Chest 2007;132(1): 325-337.

13. Isono S, Feroah TR, Hajduk EA, et al. Interaction of cross-sectional area, driving pressure, and airflow of passive velopharynx. J Appl Physiol 1997;83:851-859.

14. Series F. Upper airway muscles awake and asleep. Sleep Med Rev 2002;6:229-242.

15. Jordan AS, White DP. Pharyngeal motor control and the pathogen-esis of obstructive sleep apnea. Respir Physiol Neurobiol 2008;160(1):1-7.

16. Fregosi RF. Influence of tongue muscle contraction and dynamic airway pressure on velopharyngeal volume in the rat. J Appl Physiol 2008;104(3):682-693.

17. Kuna ST, Vanoye CR. Mechanical effects of pharyngeal constrictor activation on pharyngeal airway function. J Appl Physiol 1999; 86:411-417.

A B

C D

Awake

NormalPharyngealluminal area

Airwaypressure

UA muscleactivities

Airwaypressure

UA muscleactivities

Normal

0 100%

OSAPharyngealluminal area

Airwaypressure

UA muscleactivities

Normal OSA

0 100%As

leep


Normal

0 100%


Airwaypressure

UA muscleactivities

Normal OSA

0 100%

Figure 101-18 Schematic model explaining pharyngeal airway patency, showing upper airway (UA) muscle activities and airway pressure on either side of a fulcrum that represents the intrinsic mechanical properties of the passive upper airway (i.e., upper airway anatomy). The fulcrum of sleep apneic subjects (B and D) is suggested to be to the right side of normal subjects (A and C). OSA, obstructive sleep apnea (From Isono S, Remmers JE, Tanaka A, et al. Anatomy of pharynx in patients with obstructive sleep apnea and in normal subjects. J Appl Physiol 1997;82:1319-1326.)

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2. Thakkar K, Yao M. Diagnostic studies in obstructive sleep apnea. Otolaryngol Clin North Am 2007;40(4):785-805.

3. Isono S, Morrison DL, Launois SH, et al. Static mechanics of the velopharynx of patients with obstructive sleep apnea. J Appl Physiol 1993;75:148-154.

4. Kirkness JP, Madronio M, Stavrinou R, et al. Relationship between surface tension of upper airway lining liquid and upper airway collapsibility during sleep in obstructive sleep apnea hypopnea syndrome. J Appl Physiol 2003;95(5):1761-1766.

5. Kirkness JP, Madronio M, Stavrinou R, et al. Surface tension of upper airway mucosal lining liquid in obstructive sleep apnea/hypopnea syndrome. Sleep 2005;28(4):457-463.

6. Verma M, Seto-Poon M, Wheatley JR, et al. Influence of breathing route on upper airway lining liquid surface tension in humans. J Physiol 2006;574(Pt. 3):859-866.

7. Isono S, Tanaka A, Tagaito Y, et al. Influences of head positions and bite opening on collapsibility of the passive pharynx. J Appl Physiol 2004;97(1):339-346.

8. Tagaito Y, Isono S, Remmers JE, et al. Lung volume and collaps-ibility of the passive pharynx in patients with sleep-disordered breathing. J Appl Physiol 2007;103(4):1379-1385.

CoverFront MatterPrinciples and Practice of SLEEP MEDICINEISBN: 9781416066453CopyrightDedicationPoetryContributorsForewordPrefaceAcknowledgmentsAbbreviations

Part I - Principles of Sleep MedicineSection 1 - Normal Sleep and Its VariationsHistory of Sleep Physiology and MedicineAbstractSLEEP AS A PASSIVE STATETHE ELECTRICAL ACTIVITY OF THE BRAINTHE ASCENDING RETICULAR SYSTEMEARLY OBSERVATIONS OF SLEEP PATHOLOGYSIGMUND FREUD AND THE INTERPRETATION OF DREAMSCHRONOBIOLOGYTHE DISCOVERY OF REM SLEEPALL-NIGHT SLEEP RECORDINGS AND THE BASIC SLEEP CYCLEREM SLEEP IN ANIMALSTHE DUALITY OF SLEEPPREMONITIONS OF SLEEP MEDICINESLEEP-ONSET REM PERIODS AND CATAPLEXYTHE NARCOLEPSY CLINIC: A FALSE STARTEUROPEAN INTERESTBENZODIAZEPINES AND HYPNOTIC EFFICACY STUDIESTHE DISCOVERY OF SLEEP APNEAITALIAN SYMPOSIABIRTH PANGSTHE EARLY DEVELOPMENT OF SLEEP MEDICINE CLINICAL PRACTICECLINICAL SIGNIFICANCE OF EXCESSIVE DAYTIME SLEEPINESSFURTHER DEVELOPMENT OF SLEEP MEDICINETHE TURN OF THE CENTURY AND BEYONDREFERENCES

Normal Human Sleep:AbstractSLEEP DEFINITIONSSLEEP ONSETDefinition of Sleep OnsetElectromyogramElectrooculogramElectroencephalogram

Behavioral Concomitants of Sleep OnsetSimple Behavioral TaskVisual ResponseAuditory ResponseOlfactory ResponseResponse to Meaningful StimuliHypnic Myoclonia

Memory Near Sleep OnsetLearning and Sleep

PROGRESSION OF SLEEP ACROSS THE NIGHTPattern of Sleep in a Normal Young AdultFirst Sleep CycleNREM-REM Cycle

Distribution of Sleep Stages across the NightLength of SleepGeneralizations about Sleep in the Normal Young AdultFactors Modifying Sleep Stage DistributionAgePrior Sleep HistoryCircadian RhythmsTemperatureDrug IngestionPathologyNarcolepsySleep Apnea SyndromesSleep Fragmentation

Acknowledgments

REFERENCES

Normal AgingAbstractSLEEP ARCHITECTUREPercentage of Time Spent in Each Sleep StageArousals during SleepComorbiditiesSlow-Wave Sleep

CIRCADIAN RHYTHMS IN AGINGCAUSES AND CONSEQUENCES OF POOR SLEEP IN OLD AGECausesPotential Consequences

RESTLESS LEGS SYNDROME AND PERIODIC LIMB MOVEMENTS IN SLEEPSLEEP-DISORDERED BREATHINGRisk FactorsOutcomes

WHY DO OLDER PEOPLE NAP?BASIC SCIENCE CONSIDERATIONSSUMMARYAcknowledgment

REFERENCES

Daytime Sleepiness and AlertnessAbstractINTRODUCTIONEPIDEMIOLOGY OF SLEEPINESSSleepiness in Limited Populations or Populations of ConvenienceSleepiness in Representative PopulationsRisk Factors for Sleepiness

NATURE OF SLEEPINESSPhysiological Need StateNeural Substrates of Sleepiness

ASSESSMENT OF SLEEPINESSQuantifying SleepinessRelation of Sleepiness to Behavioral FunctioningClinical Assessment of Sleepiness

DETERMINANTS OF SLEEPINESSQuantity of SleepQuality of SleepCircadian RhythmsCNS DrugsSedating Drug EffectsAlerting Drug Effects

Influence of Basal SleepinessCNS Pathologies

CLINICAL AND PUBLIC HEALTH SIGNIFICANCE OF SLEEPINESSREFERENCES

Acute Sleep DeprivationAbstractTOTAL SLEEP DEPRIVATIONBehavioral EffectsSleep/Circadian InfluencesArousal InfluencesActivityBright lightNoiseTemperaturePostureDrugsMotivation or InterestGroup EffectsRepeated Periods of Sleep Loss

Individual CharacteristicsAgeSensitivity to Sleep LossPersonality and Psychopathology

Test Characteristics and TypesLength of TestKnowledge of ResultsTest PacingProficiency LevelDifficulty or ComplexityMemory RequirementExecutive FunctionSubjective (versus Objective) MeasuresEEG Measures

Summary

PHYSIOLOGIC EFFECTS OF SLEEP DEPRIVATIONNeurologic ChangesImaging StudiesClinical EEG

Autonomic ChangesBiochemical ChangesGene StudiesClinical ChangesImmune FunctionPainWeight Control and InsulinExercise

Summary

SLEEP FRAGMENTATIONExperimental Sleep FragmentationSleep Disorders and Fragmentation

RECOVERY SLEEPPerformance EffectsEEG EffectsRelationship between EEG and Psychomotor Performance Recovery Effects

CONCLUSIONSAcknowledgementsREFERENCES

Chronic Sleep DeprivationAbstractINCIDENCE OF CHRONIC SLEEP RESTRICTIONTHEORETICAL PERSPECTIVES ON SLEEP NEED AND SLEEP DEBTBasal Sleep NeedCore Sleep versus Optional SleepAdaptation to Sleep RestrictionTwo-Process Model Predictions of Sleep Restriction

EFFECTS OF CHRONIC SLEEP RESTRICTIONSleep ArchitectureSleep PropensityWaking ElectroencephalogramCognitive EffectsDriving PerformanceSubjective Sleepiness and MoodIndividual Differences in Responses to Chronic Sleep Restriction

PHYSIOLOGIC EFFECTSEndocrine and Metabolic EffectsImmune and Inflammatory EffectsCardiovascular Effects

AcknowledgmentsREFERENCES

Section 2 - Sleep Mechanisms and PhylogenyNeural Control of Sleep in MammalsAbstractDIVERSE BRAIN REGIONS MODULATE WAKING AND NREM SLEEPIsolated ForebrainDiencephalonThalamusLower Brainstem

RETICULAR ACTIVATING SYSTEM AND DELINEATION OF AROUSAL SYSTEMSWAKE-ON, REM-OFF AROUSAL SYSTEMSSerotoninNorepinephrineHistamineOrexin

WAKE-ON, REM-ON AROUSAL SYSTEMSAcetylcholineDopamineGlutamate

SLEEP-PROMOTING MECHANISMSA POA Sleep-Promoting Systemc-Fos Mapping

THE ORCHESTRATION OF SLEEP BY THE POA HYPNOGENIC SYSTEMTHALAMICCORTICAL INTERACTIONS AND THE GENERATION OF THE SLEEP EEGSleep SpindlesDelta WavesSlow Oscillations

INTEGRATION OF CIRCADIAN RHYTHMS AND SLEEPTHE POA, THERMOREGULATION, AND CONTROL OF SLEEPHIERARCHICAL CONTROL MODELSLEEP-PROMOTING NEUROCHEMICAL AGENTSAdenosineProinflammatory CytokinesProstaglandin D2Growth HormoneReleasing HormoneSleep as Detoxification or Protection from Oxidative Stress

SUMMARYAcknowledgmentsREFERENCES

REM Sleep*AbstractCHARACTERISTICS OF REM SLEEPREM GENERATION MECHANISMSTechnical ConsiderationsInactivation of Neurons by Lesions, Inhibition, Antisense Administration, or Genetic ManipulationActivation of Neurons by Electrical or Chemical Stimulation, Gene Activation, or Ion Channel ManipulationObservation of Neuronal ActivitySummary

Transection StudiesLocalized Lesion StudiesStimulation StudiesNeuronal Activity, Transmitter ReleaseMedial Brainstem Reticular FormationCholinergic Cell GroupsCells with Activity Selective for REM SleepMonoamine-Containing CellsOther Cholinergic Cells in Lateral Pontine RegionsFos Labeling

CONTROL OF MUSCLE TONENARCOLEPSY AND HYPOCRETINTHE FUNCTIONS OF REM SLEEPREFERENCES

Phylogeny of Sleep RegulationAbstractSLEEP REGULATION IN MAMMALSThe Origins and Definition of Sleep HomeostasisSleep Duration and Sleep IntensityDaily Time Course of Slow-Wave Activity and Its Sleep-Wake DependenceIs REM Sleep Homeostatically Regulated?The Waking EEG Reflects Homeostatic MechanismsCircadian versus Homeostatic Aspects of Sleep RegulationSpecial FeaturesHerbivores: Cows and Horses, Ruminants and NonruminantsSleep Regulation: Unihemispheric Sleep and Regional Aspects of Sleep

Sleep and HibernationOther Measures for Sleep Regulation: Sleep or Rest Consolidation

SLEEP REGULATION IN NONMAMMALIAN VERTEBRATESBirdsReptilesAmphibians and Fish

SLEEP REGULATION IN INVERTEBRATESOUTLOOKREFERENCES

Sleep in Animals:AbstractADAPTIVE INACTIVITYQUANTITATIVE ANALYSES OF THE CORRELATES OF SLEEP DURATIONTHE DIVERSITY OF SLEEPSLEEP IN MONOTREMESREINDEERBIRDSWALRUSSLEEP IN CETACEANS (DOLPHINS AND WHALES)SLEEP IN OTARIIDS (EARED SEALS)SLEEP REBOUNDCONCLUSIONAcknowledgmentREFERENCES

Section 3 - Genetics of SleepIntroductionREFERENCES

Circadian Clock GenesAbstractTHE MAMMALIAN CELLULAR CIRCADIAN CLOCKCIRCADIAN CLOCK PROPERTIES AND CLOCK GENESPOSITIVE ELEMENTSClockBmal1

NEGATIVE ELEMENTSPeriod GenesCryptochromes

MODULATORS OF PeriodTimelessCasein Kinase 1

MODULATORS OF Bmal1Rev-erb and ROR

MODULATORS OF CryFbxl3Other bHLH-PAS Family MembersDec1 and Dec2

OUTPUT REGULATIONClockProkineticin 2Transforming Growth Factor VPAC2Cardiomyotrophin-like Cytokine

INPUT REGULATIONMelanopsinRab3a

CONCLUSIONSREMAINING QUESTION: CLOCK GENES AS SLEEP GENES?Acknowledgements

REFERENCES

Genetics of Sleep in a Simple Model Organism:AbstractDROSOPHILA AS A MODEL SYSTEM FOR GENETICSDROSOPHILA AS A MODEL FOR STUDIES OF SLEEPDROSOPHILA CIRCADIAN BEHAVIOR REVEALS CONSERVED MECHANISMS BETWEEN FLIES AND HUMANSCELLULAR AND MOLECULAR BASIS OF DROSOPHILA SLEEPSPECIFIC NEURAL CIRCUITS ARE IMPORTANT FOR SLEEPWAKE REGULATIONGENETICS AND PHARMACOLOGY OF SLEEP: WHICH MOLECULES REGULATE SLEEP?Circadian Clock PathwayStress and Immune PathwaysMembrane ExcitabilityGrowth Factors and Signal TransductionArousal Neurotransmitters: Monoaminergic Arousal PathwaysSleep Neurotransmitters: GABA and Adenosine Sleep Pathways

WHICH GENES ARE REGULATED BY SLEEPWAKE?SUMMARYREFERENCES

Genetic Basis of Sleep in RodentsAbstractGENE EXPRESSION, mRNAs, AND MICROARRAY STUDIESIDENTIFICATION OF ALLELES THAT INFLUENCE SLEEP OR SLEEP-RELATED TRAITSMUTAGENESIS AND KNOCKOUTSHigh-Throughput ScreeningTargeted Gene DeletionGenetic Regulation of HomeostasisGenetic Regulation of Circadian Rhythm

REFERENCES

Genetic Basis of Sleep in Healthy HumansAbstractEVIDENCE FOR GENOTYPE-DEPENDENT DIFFERENCES IN DIURNAL PREFERENCE, SLEEP TIMING, SLEEP DURATION, SLEEP ARCHITECTURE, AND SLEEP EEGGENES CONTRIBUTING TO HUMAN MORNINGNESSEVENINGNESS AND TIMING OF SLEEPCandidate GenesGenome-Wide Association Study

GENES CONTRIBUTING TO HABITUAL SLEEP DURATIONGENES CONTRIBUTING TO SLEEP ARCHITECTURESlow-Wave Sleep and REM SleepThe Sleep EEG: Among the Most Heritable Traits in Humans

GENES CONTRIBUTING TO THE SLEEP EEGGENETIC BASIS OF SLEEPWAKE REGULATION: INTERACTION BETWEEN HOMEOSTATIC AND CIRCADIAN SYSTEMSCONCLUDING REMARKSAcknowledgements

REFERENCES

Genetics of Sleep and Sleep Disorders in HumansAbstractGENETIC STUDIES OF HUMAN SLEEP: METHODOLOGICAL LIMITATIONSGENETIC FACTORS UNDERLYING THE CIRCADIAN CLOCK AND CIRCADIAN RHYTHM DISORDERSGENETIC FACTORS REGULATING EEG AND THE SLEEP HOMEOSTATGENETICS OF NARCOLEPSYHeritabilityHuman Leukocyte Antigen in NarcolepsyHypocretin Deficiency in NarcolepsyNon-HLA, Non-Hypocretin Genes in Narcolepsy

GENETICS OF RESTLESS LEGS SYNDROMEHeritabilityRLS Linkage StudiesGenome-Wide AssociationsMEIS1 as a Candidate and Its SymptomatologyBTBD9 as a Candidate and Its SymptomatologyLBXCOR as a Candidate and SymptomatologyPTPRD and Nitric Oxide Synthase as Candidates in RLS

GENETICS OF OTHER HYPERSOMNIAS, INSOMNIA, AND PARASOMNIASAUTOSOMAL DOMINANT FRONTAL LOBE EPILEPSYGENETICS OF OBSTRUCTIVE SLEEP APNEACONGENITAL CENTRAL HYPOVENTILATION SYNDROMESLEEP DISORDERS IN ASSOCIATION WITH OTHER GENETIC DISORDERSCONCLUSION

REFERENCES

Section 4 - Physiology in SleepRelevance of Sleep Physiology for Sleep Medicine CliniciansAbstractREFERENCES

What Brain Imaging Reveals about Sleep Generation and MaintenanceAbstractFUNCTIONAL SEGREGATION AND INTEGRATION DURING NORMAL HUMAN SLEEPNONRAPID EYE MOVEMENT SLEEPPROCESSING OF EXTERNAL STIMULI DURING NREM SLEEPRAPID EYE MOVEMENT SLEEPReorganization of Regional Brain Function during REM Sleep: Relation with Dream CharacteristicsBrain Imaging and Other Characteristic Features of REM Sleep

Experience-Dependent Modifications of Regional Brain Function during NREM and REM SleepBRAIN IMAGING AND NEURAL CORRELATES OF SLEEPWAKE CYCLE REGULATION

BRAIN IMAGING AND NEURAL CORRELATES OF HUMAN SLEEP DEPRIVATIONFUNCTIONAL NEUROIMAGING IN SLEEP DISORDERSInsomnia and Brainstem and Hypothalamic Arousal NetworksInsomnia, Disorders of Emotion, and Limbic and Paralimbic Arousal NetworksInsomnia, Disorders of Emotion, and Neocortical Arousal NetworksREM Sleep in DepressionFatal Familial Insomnia

SUMMARYAcknowledgements

REFERENCES

Cardiovascular Physiology:AbstractSLEEP-STATE CONTROL OF CARDIOVASCULAR FUNCTIONCARDIORESPIRATORY INTERACTIONSCentral MechanismsCardiorespiratory Homeostasis

SLEEP STATEDEPENDENT CHANGES IN HEART RHYTHMHeart Rate SurgesHeart Rhythm Pauses

CORONARY ARTERY BLOOD FLOW REGULATION DURING SLEEPIMPACT OF SLEEP ON ARRHYTHMOGENESISCentral Nervous System Sites Influencing Cardiac Electrical StabilityAutonomic Factors in Arrhythmogenesis during Sleep

SUMMARYAcknowledgments

REFERENCES

Cardiovascular Physiology:AbstractINTRODUCTIONTHE CARDIOVASCULAR AUTONOMIC NERVOUS SYSTEM: DEFINITION AND FUNCTIONSArterial BaroreflexCardiopulmonary ReflexesThe Chemoreflexes

MEASURES TO EXPLORE AUTONOMIC CHANGES DURING SLEEP AND THEIR PHYSIOLOGICAL SIGNIFICANCEHeart Rate, Arterial Blood Pressure, and Their VariabilityBaroreflex SensitivityPreejection PeriodMicroneurographic Recording of Sympathetic Nerve ActivityPeripheral Arterial Tone and Pulse Transit TimeSystemic Catecholamines

SLEEP RELATED CARDIOVASCULAR AUTONOMIC CHANGESDayNight Changes in Neural Circulatory ControlPhysiologic Responses to NREM and REM SleepRR Variability and EEG CouplingAutonomic Responses Associated with Arousal from Sleep and from Periodic Leg MovementsArousalsPeriodic Leg Movements during Sleep

IMPACT OF AGING ON NEURAL CIRCULATORY RESPONSE TO NORMAL SLEEPEFFECTS OF DISORDERED SLEEP AND PRIMARY AUTONOMIC DYSFUNCTION ON DAYNIGHT AUTONOMIC CHANGESEffects of Sleep Loss and Sleep Disorders on Nighttime BPLoss of Diurnal Variation in Autonomic Function in Diabetes Mellitus: What Comes First?

SYMPATHETIC ACTIVATION IN OBSTRUCTIVE SLEEP APNEASUMMARYREFERENCES

Respiratory Physiology:AbstractRESPIRATORY NEUROBIOLOGY: BASIC OVERVIEWMedullary Respiratory Neurons and MotoneuronsPre-Btzinger ComplexNeuronal Connections

SLEEP NEUROBIOLOGY: BASIC OVERVIEWWakefulnessNREM SleepREM Sleep

CONTROL OF RESPIRATORY MOTONEURONSDETERMINANTS OF RESPIRATORY MOTONEURON ACTIVITYTonic and Respiratory-Related Inputs to Respiratory MotoneuronsElectrical Properties of MotoneuronsPresynaptic ModulationTonic and Respiratory-Related Activity in Respiratory Muscle

NEUROMODULATION OF RESPIRATORY MOTONEURONS ACROSS SLEEPWAKE STATESExcitatory Influences across SleepWake StatesInhibitory Influences across SleepWake States

CONTROL OF RESPIRATORY NEURONSRespiratory Neurons Vary in the Strength of Their Relationship to BreathingRespiratory Neuron Activity in NREM SleepRespiratory Neuron Activity in REM SleepNeuromodulation of Respiratory Neurons across SleepWake States

AcknowledgmentsREFERENCES

Respiratory Physiology:AbstractINTRODUCTIONChemical InformationMechanical InformationInformation from Higher Central Nervous System Centers

PHYSIOLOGY OF VENTILATORY CONTROL DURING SLEEPHypoxic Ventilatory Response during SleepAdult Human BeingsAdult Animals

Hypercapnic Ventilatory Response during SleepAdult Human BeingsAdult Animals

Ventilatory Response to Chemical Stimuli: Conclusions

ADDED RESISTANCE AND AIRWAY OCCLUSION DURING SLEEPAdult Human BeingsAnimals

AROUSAL RESPONSESIsocapnic HypoxiaHypercapniaAdded ResistanceBronchial IrritationVentilatory Response to Arousal

CONTROL OF BREATHING RHYTHM DURING SLEEPHuman BeingsAnimals

UPPER AIRWAYOPENING MUSCLES DURING SLEEPFACTORS INFLUENCING RESPIRATORY CONTROL DURING SLEEPDecreased Basal Metabolic RateCerebral Blood FlowMetabolism RelationshipNeurological Changes during SleepNeuromechanical FactorsChest-Abdominal MovementReduced Functional Residual Capacity

Increased Airflow Resistance

CLINICAL SEQUELAE OF ABNORMAL VENTILATORY RESPONSESREFERENCES

Normal Physiology of the Upper and Lower AirwaysAbstractANATOMY AND PHYSIOLOGYRespiratory MusclesElastic Forces and Lung VolumesBreathing Cycle and Minute VentilationResistance

EFFECTS OF OBESITY AND BODY POSTURE ON LUNG VOLUMESEFFECTS OF SLEEP ON LUNG VOLUMEEFFECTS OF SLEEP ON BREATHING PATTERN AND BLOOD GASESUpper AirwayCollapsing ForcesDilating Forces

EFFECTS OF SLEEP ON UPPER AIRWAY MUSCLE ACTIVITYFACTORS INFLUENCING STABILIZING AND COLLAPSING FORCESCONCLUSION

REFERENCES

Respiratory Physiology:AbstractPHYSIOLOGIC ADJUSTMENT TO HIGH ALTITUDEIncreased VentilationSleep Disturbances

PERIODIC BREATHINGMechanismsRoles of Hypoxia and HypocapniaThe Apneic ThresholdRole of Decreased PCO2 versus Increased pH in the Generation of ApneaChemosensory MechanismsRole of SleepInfluence of Altitude AcclimatizationConsequences of Periodic BreathingRelationship of Sleep Disturbance and Periodic Breathing to Altitude SyndromesLiving High, Training Low

TREATMENTCarbonic Anhydrase InhibitorsBenzodiazepinesOther Agents

SLEEP AT HIGH ALTITUDE AFTER LONG-TERM ADAPTATIONCONCLUSIONSREFERENCES

Sleep and Host DefenseAbstractINTRODUCTIONTHE ACUTE PHASE RESPONSE AND HOST DEFENSESLEEP CHANGES AFTER INFECTIOUS CHALLENGEViral ChallengeBacterial Challenge

SLEEP LOSS EFFECTS ON IMMUNE FUNCTIONSLEEP AND IMMUNITY SHARE COMMON REGULATORY MOLECULESAcknowledgmentsREFERENCES

Endocrine Physiology in Relation to Sleep and Sleep DisturbancesAbstractMODULATION OF ENDOCRINE FUNCTION BY SLEEPWAKE HOMEOSTASIS AND CIRCADIAN RHYTHMICITYTHE GROWTH HORMONE AXISTHE CORTICOTROPIC AXISTHE THYROID AXISPROLACTIN SECRETIONTHE GONADAL AXISGLUCOSE REGULATIONSLEEP AND APPETITE REGULATIONWATER AND ELECTROLYTE BALANCE DURING SLEEPCHRONIC SLEEP RESTRICTION: IMPACT ON ENDOCRINE AND METABOLIC FUNCTIONLaboratory StudiesEpidemiologic Studies

REDUCED SLEEP QUALITY AND SLEEP DISORDERS: IMPACT ON ENDOCRINE AND METABOLIC FUNCTIONExperimental Reduction of Sleep QualityStudies in Population and Clinic-Based SamplesInsomnia

OSAAGE-RELATED SLEEP ALTERATIONS: IMPLICATIONS FOR ENDOCRINE FUNCTIONGH AxisProlactin SecretionPituitary-Adrenal AxisPituitary-Gonadal Axis

SLEEP DISTURBANCES IN METABOLIC AND ENDOCRINE DISORDERSObesityType 2 DiabetesPolycystic Ovary Syndrome

REFERENCES

Gastrointestinal Physiology in Relation to SleepABSTRACTINTRODUCTIONHISTORICAL ASPECTSGASTRIC FUNCTION DURING WAKE AND SLEEPAcid Secretion

GASTRIC MOTOR FUNCTION DURING SLEEPSWALLOWING AND ESOPHAGEAL FUNCTIONINTESTINAL MOTILITY DURING SLEEPSLEEP, ABDOMINAL PAIN, AND IRRITABLE BOWEL SYNDROMEEFFECT OF INTESTINAL MOTILITY ON SLEEPCOLONIC AND ANORECTAL FUNCTION DURING SLEEPCONCLUSIONSREFERENCES

Body Temperature, Sleep, and HibernationAbstractINTRODUCTIONCIRCADIAN REGULATION OF CORE BODY TEMPERATURERELATIONSHIP BETWEEN THE SLEEP REGULATORY AND THE THERMOREGULATORY SYSTEMCo-variation of Sleep and Thermophysiological VariablesBaseline ConditionsChanged Circadian Conditions

Intervention Studies in HumansChanging TemperaturesChanging Sleep Pressure

Intervention Studies in RodentsChanging TemperatureChanging Sleep PressureBrain Temperature, EEG, and Thermo- sensitive Neurons

HIBERNATIONThermoregulation and Metabolic Rate ReductionTorpor and Sleep

REFERENCES

Memory Processing in Relation to SleepAbstractMEMORY SYSTEMS AND MEMORY CONSOLIDATIONMETHODS FOR STUDYING THE ROLE OF SLEEP FOR MEMORY CONSOLIDATIONPosttraining Sleep DeprivationPosttraining Sleep ModificationsWithin-Sleep Stimulations

SLEEP AND DECLARATIVE MEMORYSemantic MemoryEpisodic MemoryEmotion in Episodic Memory

SLEEP AND NONDECLARATIVE MEMORIESSleep and Perceptual LearningSleep and Motor LearningSleep and PerceptualMotor LearningSleep and Priming

SLEEP-DEPENDENT MECHANISMS OF BRAIN P

anatomy sleep upper way

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