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Neural Control of the Upper Airway: Integrative Physiological Mechanisms and Relevance for Sleep Disordered Breathing

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Abstract

The various neural mechanisms affecting the control of the upper airway muscles are discussed in this review, with particular emphasis on structure‐function relationships and integrative physiological motor‐control processes. Particular foci of attention include the respiratory function of the upper airway muscles, and the various reflex mechanisms underlying their control, specifically the reflex responses to changes in airway pressure, reflexes from pulmonary receptors, chemoreceptor and baroreceptor reflexes, and postural effects on upper airway motor control. This article also addresses the determinants of upper airway collapsibility and the influence of neural drive to the upper airway muscles, and the influence of common drugs such as ethanol, sedative hypnotics, and opioids on upper airway motor control. In addition to an examination of these basic physiological mechanisms, consideration is given throughout this review as to how these mechanisms relate to integrative function in the intact normal upper airway in wakefulness and sleep, and how they may be involved in the pathogenesis of clinical problems such obstructive sleep apnea hypopnea. © 2012 American Physiological Society. Compr Physiol 2:479‐535, 2012.

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Figure 1. Figure 1.

A respiratory‐related decrease in pressure recorded in the isolated and sealed upper airway indicates the presence of a net dilating force acting on the upper airspace during inspiration. The upper airway is isolated between the nose and the area below the larynx by using a tight fitting face mask and blocking the nostrils, and an inflated balloon placed below the larynx. The animal breathes through a cuffed endotracheal tube attached to a pneumotachograph from which airflow and tidal volume (VT) are derived. Pressure within the upper airway segment (PUA) is measured via a catheter placed inside the nostril; tracheal pressure (PT) is also measured. The lower traces show upper airway pressure swings during breathing across states of wakefulness, slow wave sleep (SWS) and rapid eye movement (REM) sleep. Decreases in pressure in the isolated upper airspace indicate increased airway volume, whereas decreases in pressure indicate decreased airway volume. Note the lesser dilatation of the upper airspace during breathing in SWS, and the accompanying change in baseline pressure to more positive values indicating a smaller airspace compared to wakefulness. Also note the sporadic and erratic swings in upper airway pressure in REM sleep reflecting marked fluctuations in airway volume. Figure compiled from . The large voltage swings on the electroencephalogram (EEG) channel are associated with eye movements and muscle movement artifacts.

Figure 2. Figure 2.

Upper airway cross‐sectional area measured by cine computed tomography and plotted as a function of tidal volume in a normal subject and a patient with obstructive sleep apnea‐hypopnea (OSAH). Data are shown for the retropalatal airspace (i.e., posterior to the soft palate) and glossopharyngeal airspace (i.e., posterior to the tongue). Note that the upper airway is: (i) narrowest in the retropalatal airspace, (ii) narrower in the OSAH patient, and (iii) varies during the breathing cycle. Activation of pharyngeal muscles helps prevent airway narrowing during inspiration and airway size remains relatively constant. Solid lines with open symbols indicates inspiration (Insp), dashed lines with closed symbols indicates expiration (Exp), thin‐dotted line indicates the extrapolation between end inspiration and the beginning of expiration, and between end expiration and the beginning of inspiration. Data are plotted from values in .

Figure 3. Figure 3.

(A) The schema illustrates the lung and upper airway compartments of breathing. The upper airway is modeled as a collapsible tube with maximum flow () determined by upstream nasal pressure (PN) and resistance (RN). The collapsible segment of the upper airway is shown by the blue lines, with airflow into the lungs by the red arrows. (B) The relationship between and PN; airflow ceases in the collapsible segment of the upper airway at a critical value of airway pressure (PCRIT). Maximum flow is determined by: = (PNPCRIT)/RN. From the equation it can be seen that increases in PN lead to increases in in the upper airway. This effect is the basis for nasal continuous positive airway pressure therapy in OSAH. Also note that decreases in PN will decrease in the upper airway. The relationship described by the equation is linear for the upper airway such that 1/slope gives upstream resistance. (C) The PCRIT at which airflow ceases in the collapsible segment of the upper airway is progressively more positive (i.e., indicating a more easily collapsed upper airspace) from normal sleeping subjects, to snorers, to patients with hypopnea and OSAH. Of importance, therefore, subjects in whom the upper airway is closed, or nearly closed, at pressures near (or above) atmospheric are highly susceptible to OSAH and require upper airway muscle activation to permit adequate airflow. (D) Increased upper airway muscle activation (e.g., caused by reflexes, respiratory‐related, or tonic muscle activation) increases in the upper airway and decreases upper airway collapsibility by making PCRIT more negative. This effect is shown by going from a passive to an active upper airway (i.e., low to higher muscle tone, direction indicated by the blue arrow). In contrast, decreased upper airway muscle activity (e.g., caused by sleep‐related reductions in tonic motor activity, anesthesia, sedation, or alcohol) decreases in the upper airway and increases airway collapsibility. Data redrawn and modified from .

Figure 4. Figure 4.

Schema to illustrate how a change in upper airway closing pressure can be affected by changes in airway size and/or wall stiffness. (A) Airway volume decreases in response to decreasing airway pressure, with airway closure occurring at some value of subatmospheric suction pressure (i.e., the closing pressure). At the closing pressure, a residual volume is present in the upper airway (i.e., above and below the collapsed segment). The slope of the change in pharyngeal pressure (δP) to change in pharyngeal volume (δV) yields an index of wall stiffness (i.e., compliance). (B) In the absence of a change in compliance, an increase in airway size (A→B) makes closing pressures more negative (A1→B1), that is, a less collapsible airway, whereas a decrease in airway size (A→C) makes closing pressures more positive (A1→C1), that is, a more collapsible airway. (C) In the absence of a change in airway size, a decrease in compliance makes closing pressures more negative and the airway less collapsible (A1→D), whereas increases in compliance make closing pressures more positive and the airway is more collapsible (A1→E). Analysis suggests that in response to an increase in upper airway muscle activity, a more subatmospheric closing pressure results from a predominant effect on airway size rather than wall stiffness, see text for further details. Figure Modified, with permission, from .

Figure 5. Figure 5.

Schema to show how converging tonic (nonrespiratory) and respiratory inputs to a motoneuron summate to produce the tonic and respiratory components of electromyographic activity. These premotor tonic and respiratory inputs can be excitatory or inhibitory, but in this figure they are shown as excitatory for simplicity. Panels A to D further show how changes in the tonic and respiratory components of respiratory muscle activity can result from independent changes in either tonic drives affecting tonic membrane potential (A‐C, e.g., as may occur upon transitions from wakefulness to sleep), or the magnitude of the respiratory drive potential (B vs. D, e.g., as may occur in sleep compared to wakefulness). Changes in respiratory drive potential at the motoneuron can result from decreases in the input from respiratory neurons, presynaptic modulation of that input and/or changes in input resistance of the motoneuron membrane per se [see for further details]. In the examples shown in A to D, respiratory drive is indicated as three depolarizing potentials, each associated with the generation of motoneuron action potentials when the membrane potential exceeds threshold (dashed line). Figure modified, with permission, from . As noted in the text, the results of studies recording single genioglossal motor units across sleep‐wake states , suggest that the organization of inputs to respiratory motoneurons is not as discrete as shown (for conceptual simplicity) in this figure. The tonic inputs to respiratory motoneurons themselves are likely to exhibit some respiratory modulation, and the respiratory‐related inputs are also likely to exist on a background tonic signal, all to varying degrees which will be different for different premotor inputs to different muscles, and which will vary depending on the respiratory and/or behavioral functions of those muscles.

Figure 6. Figure 6.

Schematic representation of the afferent innervation of the upper airway. Cranial nerves V, IX, X, and XI are shown. Note that the innervation of the supraglottic larynx is via the internal branch of the superior laryngeal nerve, whereas the subglottic larynx is via the recurrent laryngeal nerve. The glossopharyngeal nerve innervates the tonsillar fossa (not shown), the posterior aspect of the tongue and the posterior pharyngeal wall. Figure adapted, with permission, from .

Figure 7. Figure 7.

Example and group data (n = 10) showing reflex activation of the genioglossus (GG) muscle of the tongue following application of sudden onset subatmospheric pressure stimuli to the upper airway of normal human subjects via a face mask. Note the short latency (∼40 ms) of the GG response from the onset of the −15 cmH2O pressure pulse. The group data shows the magnitude of the GG responses to the stimuli of subatmospheric airway pressure in each experimental condition [glottis open, glottis closed (i.e., an “isolated” upper airway) and the control condition with the mouth and nose closed]. Fisher's least significant differences (P < 0.05) are shown between each pair of conditions [(a) glottis open vs. glottis closed; (b) glottis closed vs. control; and (c) glottis open vs. control). Note the dose‐dependent GG responses to the subatmospheric airway pressure stimuli, with significantly larger responses when the higher magnitude stimuli have access to both the upper and lower airways (see text for further details). Figure adapted, with permission, from .

Figure 8. Figure 8.

Example and group data showing the individuality of the magnitude of reflex genioglossus muscle responses to subatmospheric pressure stimuli in normal human subjects. The single reflex responses shown for two different female subjects of the same age illustrate that one has a consistently larger response to the same pressure stimulus than the other. The group data shows the repeatability of averaged responses within an individual (seven subjects) to subatmospheric (−25cm H2O) pressure pulses applied with the glottis open and closed (i.e., an isolated upper airway) on separate days. The number of points for each subject varies according to the number of times they visited the laboratory (multiple measurements of reflex response were measured on each visit, and the averaged response is shown). Subjects are ranked on the abscissa according to the “strength” of response in the glottis open condition. Statistical analysis of these data show that responses within an individual are more similar than those between individuals, suggesting that each subject has a characteristic strength of response (see text for further details). Figure adapted, with permission, from .

Figure 9. Figure 9.

Example showing reduced reflex genioglossus muscle response to application of subatmospheric pressure stimuli in a normal human subject in sleep. Note the increased latency and decreased magnitude of motor response in sleep compared to wakefulness. In this figure the first spike in the electromyogram trace, before the pressure stimulus, is an artifact due to triggering of the suction apparatus used to generate the pressure change. Figure adapted from .

Figure 10. Figure 10.

Representative examples to illustrate the major afferent nerves responsible for mediating reflex genioglossus (GG) muscle responses to subatmospheric pressure stimuli in normal human subjects. Reflex responses are shown for the control condition (saline application to areas indicated below), and anesthesia of the nasal, oral and/or laryngeal mucosae [the reader is referred to for details of the nerves targeted, anesthetics used, and the tests of sensory and motor function performed]. Overall, the trigeminal and superior laryngeal nerves mediate an important component of the reflex GG muscle responses elicited by exposure of the upper airway above the glottis to stimuli of subatmospheric pressure, with the glossopharyngeal nerves playing a less important role. Figure adapted, with permission, from .

Figure 11. Figure 11.

Schema to illustrate how changes in upper airway mucosal sensation and reflex neuromuscular compensatory responses (such as upper airway motor activation elicited by subatmospheric airway collapsing pressures) can be involved in the pathogenesis and natural history of obstructive sleep apnea hypopnea. Schema redrawn and adapted, with permission, from .

Figure 12. Figure 12.

Group data illustrating the effects of systemic administration of ethanol and vehicle (saline) on sleep‐wake regulation and respiratory motor activity in freely behaving rats. (A) The figure shows the effects of ethanol on the percent (%) amounts of active wakefulness (i.e., periods with movements and overt behaviours), quiet wakefulness (i.e., periods without any body movements), non‐REM sleep, and REM sleep. Values were obtained from the data collected in the first 2 h postethanol, that is, during the time when blood ethanol levels were significantly elevated to a physiologically relevant degree (see text). (B‐D) Effects of ethanol on electroencephalogram activity, showing the power of the signal in selected low (B) and high‐frequency bands (C), and postural (neck) muscle activity (D). Together, the data in A‐D are consistent with a sedating effect of ethanol. In contrast, there were no effects on respiratory network activity as judged by no change in the amplitude of diaphragm activity or respiratory rate (E‐F). (G‐I) The changes in the respiratory and tonic components of genioglossus (GG) muscle activity are similar to the effects on the postural muscle. For the correlations in panels H and J, the symbols •, ▾, and ▪ refer to wakefulness, non‐REM and REM sleep, respectively (symbols show 3 states per animal for 10 animals, overlap obscures some of the symbols). The correlations are indicated by the solid lines, with the 95% confidence intervals shown by the dashed lines. Some individual values for the reduction in GG activity with ethanol are negative because in these instances GG activity was increased compared to the vehicle controls. There were significant positive relationships between the level of respiratory and tonic GG activities recorded with vehicle within a rat, and the magnitude of decrease observed in response to ethanol (r = 0.627, P = 0.0002, and r = 0.701, P = 0.00002, respectively, for respiratory (H) and tonic (J) GG activities, Pearson product moment correlations). In general, therefore, the bigger the signal during the control condition, the larger depression effect with of ethanol. The lack of effect on tongue muscle activity with ethanol at the hypoglossal motor pool (see text) indicates that the GG and postural motor suppression following systemic administration was mediated via effects on state‐dependent/arousal‐related processes. Together, these data show that ethanol can suppress GG by primary influences on state‐dependent aspects of central nervous system function independent of effects on the respiratory network per se. The symbols indicate significant differences (P < 0.05) between ethanol and saline conditions (*) and the respective sleep‐wake states (#). Data are shown as mean + SEM (n = 10 rats). Figure adapted, with permission, from .

Figure 13. Figure 13.

The principle by which sedatives may allow increased pharyngeal dilator muscle tone during sleep by delaying the arousal response to increasing respiratory stimulation. In a given individual, a certain degree of upper airway muscle tone is necessary for adequate airflow and lung ventilation (indicated by dashed horizontal line). In some individuals, however, the level of upper airway muscle tone is below this level during sleep, resulting in hypopnea or upper airway obstruction. In response to the ensuing hypoventilation, the level of chemoreceptor‐mediated respiratory stimulation increases, leading to increased upper airway motor tone. In individuals with a low threshold for arousal from sleep, the increasing chemoreceptor stimulation can cause arousal from sleep before the required level of upper airway motor tone for adequate airflow is reached (condition A: Control). In this circumstance, the arousal from sleep coupled with arousal‐related heightened motor activity and chemoreceptor stimulation leads to excessive ventilation during the arousal, causing further predisposition to unstable breathing [see text and for further details]. In principle, delaying arousal from sleep with sedative hypnotics in an individual with an arousal‐related predisposition to unstable breathing can increase the chemical drive at which arousal occurs (condition B: Sedative). In this case, the level of upper airway motor tone achieved during sleep (i.e., before arousal occurs) is now higher than the required level for adequate airflow and stable breathing ensues (indicated by gray circle). Figure modified from .



Figure 1.

A respiratory‐related decrease in pressure recorded in the isolated and sealed upper airway indicates the presence of a net dilating force acting on the upper airspace during inspiration. The upper airway is isolated between the nose and the area below the larynx by using a tight fitting face mask and blocking the nostrils, and an inflated balloon placed below the larynx. The animal breathes through a cuffed endotracheal tube attached to a pneumotachograph from which airflow and tidal volume (VT) are derived. Pressure within the upper airway segment (PUA) is measured via a catheter placed inside the nostril; tracheal pressure (PT) is also measured. The lower traces show upper airway pressure swings during breathing across states of wakefulness, slow wave sleep (SWS) and rapid eye movement (REM) sleep. Decreases in pressure in the isolated upper airspace indicate increased airway volume, whereas decreases in pressure indicate decreased airway volume. Note the lesser dilatation of the upper airspace during breathing in SWS, and the accompanying change in baseline pressure to more positive values indicating a smaller airspace compared to wakefulness. Also note the sporadic and erratic swings in upper airway pressure in REM sleep reflecting marked fluctuations in airway volume. Figure compiled from . The large voltage swings on the electroencephalogram (EEG) channel are associated with eye movements and muscle movement artifacts.



Figure 2.

Upper airway cross‐sectional area measured by cine computed tomography and plotted as a function of tidal volume in a normal subject and a patient with obstructive sleep apnea‐hypopnea (OSAH). Data are shown for the retropalatal airspace (i.e., posterior to the soft palate) and glossopharyngeal airspace (i.e., posterior to the tongue). Note that the upper airway is: (i) narrowest in the retropalatal airspace, (ii) narrower in the OSAH patient, and (iii) varies during the breathing cycle. Activation of pharyngeal muscles helps prevent airway narrowing during inspiration and airway size remains relatively constant. Solid lines with open symbols indicates inspiration (Insp), dashed lines with closed symbols indicates expiration (Exp), thin‐dotted line indicates the extrapolation between end inspiration and the beginning of expiration, and between end expiration and the beginning of inspiration. Data are plotted from values in .



Figure 3.

(A) The schema illustrates the lung and upper airway compartments of breathing. The upper airway is modeled as a collapsible tube with maximum flow () determined by upstream nasal pressure (PN) and resistance (RN). The collapsible segment of the upper airway is shown by the blue lines, with airflow into the lungs by the red arrows. (B) The relationship between and PN; airflow ceases in the collapsible segment of the upper airway at a critical value of airway pressure (PCRIT). Maximum flow is determined by: = (PNPCRIT)/RN. From the equation it can be seen that increases in PN lead to increases in in the upper airway. This effect is the basis for nasal continuous positive airway pressure therapy in OSAH. Also note that decreases in PN will decrease in the upper airway. The relationship described by the equation is linear for the upper airway such that 1/slope gives upstream resistance. (C) The PCRIT at which airflow ceases in the collapsible segment of the upper airway is progressively more positive (i.e., indicating a more easily collapsed upper airspace) from normal sleeping subjects, to snorers, to patients with hypopnea and OSAH. Of importance, therefore, subjects in whom the upper airway is closed, or nearly closed, at pressures near (or above) atmospheric are highly susceptible to OSAH and require upper airway muscle activation to permit adequate airflow. (D) Increased upper airway muscle activation (e.g., caused by reflexes, respiratory‐related, or tonic muscle activation) increases in the upper airway and decreases upper airway collapsibility by making PCRIT more negative. This effect is shown by going from a passive to an active upper airway (i.e., low to higher muscle tone, direction indicated by the blue arrow). In contrast, decreased upper airway muscle activity (e.g., caused by sleep‐related reductions in tonic motor activity, anesthesia, sedation, or alcohol) decreases in the upper airway and increases airway collapsibility. Data redrawn and modified from .



Figure 4.

Schema to illustrate how a change in upper airway closing pressure can be affected by changes in airway size and/or wall stiffness. (A) Airway volume decreases in response to decreasing airway pressure, with airway closure occurring at some value of subatmospheric suction pressure (i.e., the closing pressure). At the closing pressure, a residual volume is present in the upper airway (i.e., above and below the collapsed segment). The slope of the change in pharyngeal pressure (δP) to change in pharyngeal volume (δV) yields an index of wall stiffness (i.e., compliance). (B) In the absence of a change in compliance, an increase in airway size (A→B) makes closing pressures more negative (A1→B1), that is, a less collapsible airway, whereas a decrease in airway size (A→C) makes closing pressures more positive (A1→C1), that is, a more collapsible airway. (C) In the absence of a change in airway size, a decrease in compliance makes closing pressures more negative and the airway less collapsible (A1→D), whereas increases in compliance make closing pressures more positive and the airway is more collapsible (A1→E). Analysis suggests that in response to an increase in upper airway muscle activity, a more subatmospheric closing pressure results from a predominant effect on airway size rather than wall stiffness, see text for further details. Figure Modified, with permission, from .



Figure 5.

Schema to show how converging tonic (nonrespiratory) and respiratory inputs to a motoneuron summate to produce the tonic and respiratory components of electromyographic activity. These premotor tonic and respiratory inputs can be excitatory or inhibitory, but in this figure they are shown as excitatory for simplicity. Panels A to D further show how changes in the tonic and respiratory components of respiratory muscle activity can result from independent changes in either tonic drives affecting tonic membrane potential (A‐C, e.g., as may occur upon transitions from wakefulness to sleep), or the magnitude of the respiratory drive potential (B vs. D, e.g., as may occur in sleep compared to wakefulness). Changes in respiratory drive potential at the motoneuron can result from decreases in the input from respiratory neurons, presynaptic modulation of that input and/or changes in input resistance of the motoneuron membrane per se [see for further details]. In the examples shown in A to D, respiratory drive is indicated as three depolarizing potentials, each associated with the generation of motoneuron action potentials when the membrane potential exceeds threshold (dashed line). Figure modified, with permission, from . As noted in the text, the results of studies recording single genioglossal motor units across sleep‐wake states , suggest that the organization of inputs to respiratory motoneurons is not as discrete as shown (for conceptual simplicity) in this figure. The tonic inputs to respiratory motoneurons themselves are likely to exhibit some respiratory modulation, and the respiratory‐related inputs are also likely to exist on a background tonic signal, all to varying degrees which will be different for different premotor inputs to different muscles, and which will vary depending on the respiratory and/or behavioral functions of those muscles.



Figure 6.

Schematic representation of the afferent innervation of the upper airway. Cranial nerves V, IX, X, and XI are shown. Note that the innervation of the supraglottic larynx is via the internal branch of the superior laryngeal nerve, whereas the subglottic larynx is via the recurrent laryngeal nerve. The glossopharyngeal nerve innervates the tonsillar fossa (not shown), the posterior aspect of the tongue and the posterior pharyngeal wall. Figure adapted, with permission, from .



Figure 7.

Example and group data (n = 10) showing reflex activation of the genioglossus (GG) muscle of the tongue following application of sudden onset subatmospheric pressure stimuli to the upper airway of normal human subjects via a face mask. Note the short latency (∼40 ms) of the GG response from the onset of the −15 cmH2O pressure pulse. The group data shows the magnitude of the GG responses to the stimuli of subatmospheric airway pressure in each experimental condition [glottis open, glottis closed (i.e., an “isolated” upper airway) and the control condition with the mouth and nose closed]. Fisher's least significant differences (P < 0.05) are shown between each pair of conditions [(a) glottis open vs. glottis closed; (b) glottis closed vs. control; and (c) glottis open vs. control). Note the dose‐dependent GG responses to the subatmospheric airway pressure stimuli, with significantly larger responses when the higher magnitude stimuli have access to both the upper and lower airways (see text for further details). Figure adapted, with permission, from .



Figure 8.

Example and group data showing the individuality of the magnitude of reflex genioglossus muscle responses to subatmospheric pressure stimuli in normal human subjects. The single reflex responses shown for two different female subjects of the same age illustrate that one has a consistently larger response to the same pressure stimulus than the other. The group data shows the repeatability of averaged responses within an individual (seven subjects) to subatmospheric (−25cm H2O) pressure pulses applied with the glottis open and closed (i.e., an isolated upper airway) on separate days. The number of points for each subject varies according to the number of times they visited the laboratory (multiple measurements of reflex response were measured on each visit, and the averaged response is shown). Subjects are ranked on the abscissa according to the “strength” of response in the glottis open condition. Statistical analysis of these data show that responses within an individual are more similar than those between individuals, suggesting that each subject has a characteristic strength of response (see text for further details). Figure adapted, with permission, from .



Figure 9.

Example showing reduced reflex genioglossus muscle response to application of subatmospheric pressure stimuli in a normal human subject in sleep. Note the increased latency and decreased magnitude of motor response in sleep compared to wakefulness. In this figure the first spike in the electromyogram trace, before the pressure stimulus, is an artifact due to triggering of the suction apparatus used to generate the pressure change. Figure adapted from .



Figure 10.

Representative examples to illustrate the major afferent nerves responsible for mediating reflex genioglossus (GG) muscle responses to subatmospheric pressure stimuli in normal human subjects. Reflex responses are shown for the control condition (saline application to areas indicated below), and anesthesia of the nasal, oral and/or laryngeal mucosae [the reader is referred to for details of the nerves targeted, anesthetics used, and the tests of sensory and motor function performed]. Overall, the trigeminal and superior laryngeal nerves mediate an important component of the reflex GG muscle responses elicited by exposure of the upper airway above the glottis to stimuli of subatmospheric pressure, with the glossopharyngeal nerves playing a less important role. Figure adapted, with permission, from .



Figure 11.

Schema to illustrate how changes in upper airway mucosal sensation and reflex neuromuscular compensatory responses (such as upper airway motor activation elicited by subatmospheric airway collapsing pressures) can be involved in the pathogenesis and natural history of obstructive sleep apnea hypopnea. Schema redrawn and adapted, with permission, from .



Figure 12.

Group data illustrating the effects of systemic administration of ethanol and vehicle (saline) on sleep‐wake regulation and respiratory motor activity in freely behaving rats. (A) The figure shows the effects of ethanol on the percent (%) amounts of active wakefulness (i.e., periods with movements and overt behaviours), quiet wakefulness (i.e., periods without any body movements), non‐REM sleep, and REM sleep. Values were obtained from the data collected in the first 2 h postethanol, that is, during the time when blood ethanol levels were significantly elevated to a physiologically relevant degree (see text). (B‐D) Effects of ethanol on electroencephalogram activity, showing the power of the signal in selected low (B) and high‐frequency bands (C), and postural (neck) muscle activity (D). Together, the data in A‐D are consistent with a sedating effect of ethanol. In contrast, there were no effects on respiratory network activity as judged by no change in the amplitude of diaphragm activity or respiratory rate (E‐F). (G‐I) The changes in the respiratory and tonic components of genioglossus (GG) muscle activity are similar to the effects on the postural muscle. For the correlations in panels H and J, the symbols •, ▾, and ▪ refer to wakefulness, non‐REM and REM sleep, respectively (symbols show 3 states per animal for 10 animals, overlap obscures some of the symbols). The correlations are indicated by the solid lines, with the 95% confidence intervals shown by the dashed lines. Some individual values for the reduction in GG activity with ethanol are negative because in these instances GG activity was increased compared to the vehicle controls. There were significant positive relationships between the level of respiratory and tonic GG activities recorded with vehicle within a rat, and the magnitude of decrease observed in response to ethanol (r = 0.627, P = 0.0002, and r = 0.701, P = 0.00002, respectively, for respiratory (H) and tonic (J) GG activities, Pearson product moment correlations). In general, therefore, the bigger the signal during the control condition, the larger depression effect with of ethanol. The lack of effect on tongue muscle activity with ethanol at the hypoglossal motor pool (see text) indicates that the GG and postural motor suppression following systemic administration was mediated via effects on state‐dependent/arousal‐related processes. Together, these data show that ethanol can suppress GG by primary influences on state‐dependent aspects of central nervous system function independent of effects on the respiratory network per se. The symbols indicate significant differences (P < 0.05) between ethanol and saline conditions (*) and the respective sleep‐wake states (#). Data are shown as mean + SEM (n = 10 rats). Figure adapted, with permission, from .



Figure 13.

The principle by which sedatives may allow increased pharyngeal dilator muscle tone during sleep by delaying the arousal response to increasing respiratory stimulation. In a given individual, a certain degree of upper airway muscle tone is necessary for adequate airflow and lung ventilation (indicated by dashed horizontal line). In some individuals, however, the level of upper airway muscle tone is below this level during sleep, resulting in hypopnea or upper airway obstruction. In response to the ensuing hypoventilation, the level of chemoreceptor‐mediated respiratory stimulation increases, leading to increased upper airway motor tone. In individuals with a low threshold for arousal from sleep, the increasing chemoreceptor stimulation can cause arousal from sleep before the required level of upper airway motor tone for adequate airflow is reached (condition A: Control). In this circumstance, the arousal from sleep coupled with arousal‐related heightened motor activity and chemoreceptor stimulation leads to excessive ventilation during the arousal, causing further predisposition to unstable breathing [see text and for further details]. In principle, delaying arousal from sleep with sedative hypnotics in an individual with an arousal‐related predisposition to unstable breathing can increase the chemical drive at which arousal occurs (condition B: Sedative). In this case, the level of upper airway motor tone achieved during sleep (i.e., before arousal occurs) is now higher than the required level for adequate airflow and stable breathing ensues (indicated by gray circle). Figure modified from .

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Richard L. Horner. Neural Control of the Upper Airway: Integrative Physiological Mechanisms and Relevance for Sleep Disordered Breathing. Compr Physiol 2012, 2: 479-535. doi: 10.1002/cphy.c110023