- Email: [email protected]
Clinical neurophysiology of apnea
Handbook of Clinical Neurology, Vol. 161 (3rd series) Clinical Neurophysiology: Diseases and Disorders K.H. Levin and P. Chauvel, Editors https://doi.org/10.1016/B978-0-444-64142-7.00059-X Copyright © 2019 Elsevier B.V. All rights reserved
Chapter 22
Clinical neurophysiology of apnea TINA WATERS AND REENA MEHRA* Sleep Center, Neurological Institute, Cleveland Clinic, Cleveland, OH, United States
Abstract Understanding the clinical neurophysiology of apnea generation encompasses discussion of the neuroanatomic aspects of central respiratory rhythm and pattern generation, including the central respiratory control networks, central and peripheral chemoreceptors, mechanisms of respiratory muscles, and sleep state dependent differences. Anatomical and functional links to apnea also involve central respiratory motor output recruited from the hypoglossal nerve, which has led to novel treatments for obstructive sleep apnea. Autonomic fluctuations occur in relation to sleep–wake and sleep states (i.e., REM vs NREM sleep), with both parasympathetic and sympathetic contributions. Finally, our understanding of the pathophysiology of obstructive sleep apnea now includes concepts of critical closing pressure of the upper airway, increased loop gain as reflected by high responsiveness to external perturbations, inadequate responsiveness of upper airway muscle recruitment, and reductions in arousal threshold leading to ventilatory instability. In turn, these concepts have led to the development of novel therapies such as hypoglossal nerve stimulation and targeting key culprit physiologic mechanisms specific to the individual.
BREATHING NEUROANATOMY Sleep apnea is a common sleep disorder. In the United States, 26% of individuals between 30 and 70 years of age may be afflicted (Peppard et al., 2013). Breathing involves key elements that are interconnected with multiple feedforward and feedback mechanisms. The aim is to provide oxygen to different body parts and to eliminate carbon dioxide resulting from cell metabolism. The four main anatomic elements of breathing are (1) brainstem neurons responsible for respiratory pattern generation, (2) sensory inputs relaying chemoreceptor information back to the brainstem control centers allowing for adjustments based on the underlying physiologic need, (3) respiratory motoneurons acting as the final common output for central nervous system control of respiratory muscles, and (4) respiratory and airway muscles controlling air flow in and out of the lungs (Fig. 22.1). These elements are influenced by the sleep– wake state of the system and the respiratory cycle. Malfunction of any of these elements can result in
abnormal breathing, which is more likely to emerge during sleep when compensatory stimuli during wake are absent. The central respiratory control network for pattern generation is located in the medulla and the pons. The medullary respiratory neurons consist of the dorsal and ventral respiratory groups (DRG and VRG). The pontine respiratory neurons consist of the pontine respiratory group (PRG) (Table 22.1). The DRG is located in the dorsomedial medulla, within the ventrolateral nucleus tractus solitarius (nTS), and contains predominantly inspiratory neurons (Rekling and Feldman, 1998; Duffin, 2004). The nTS is the key cardiorespiratory sensory integration site for afferent information coming from the phrenic, vagus, and glossopharyngeal nerves. It has multiple outputs, including the retrotrapezoid nucleus, which is part of the central chemoreception process, and the VRG (Rosin et al., 2006; Burke et al., 2015). The VRG, extending from the facial nucleus to the first cervical segment of the spinal cord, consists of multiple components: the pre-B€otzinger complex, the B€otzinger
*Correspondence to: Reena Mehra, MD, MS, 9500 Euclid Avenue, Cleveland, OH 44195, United States. Tel: +1-216-445-8072, E-mail: [email protected]
346
T. WATERS AND R. MEHRA
Fig. 22.1. The main elements of breathing include (1) a central respiratory control network consisting of multiple brainstem neurons responsible for respiratory pattern generation, (2) sensory inputs relaying chemoreceptor information to the control network to adjust breathing based on physiologic need, (3) respiratory motoneurons acting as the final common output for the central nervous system’s influence on respiratory muscles, and (4) respiratory and airway muscles that create air flow in and out of the lungs. Nucleus tractus solitaries (nTS), retroambigualis (RA). Reprinted with permission, Cleveland Clinic Center for Medical Art & Photography © 2017. All Rights Reserved.
complex, the nucleus ambiguous, the rostral retroambigualis nucleus, and the caudal retroambigualis nucleus. The VRG contains both inspiratory and expiratory neurons. The pre-B€ otzinger complex, composed of neurons with pacemaker-like properties that have a persistent respiratory rhythm, has projections via interneurons throughout the brainstem to other respiratory control sites, and acts on inspiratory neurons (Smith et al., 1991).
Opioid stimulation of mu-opioid receptors in the preB€otzinger complex are partially responsible for switching of pulmonary C-fiber-mediated rapid shallow breathing to apnea in experimental animal models (Zhang et al., 2012). The B€otzinger complex, adjacent to the preB€otzinger complex, consists of expiratory neurons that activate pathways for expiration and inhibit inspiratory respiratory motoneurons. The nucleus ambiguous has
CLINICAL NEUROPHYSIOLOGY OF APNEA
347
Table 22.1 Brainstem nuclei involved in central respiratory control with regard to their location, function, and impact on inspiratory or expiratory neurons
Rhythmicity Medulla DRG VRG
Pons PRG
nTS Pre-B€ otzinger complex B€otzinger complex Nucleus ambiguous Rostral retroambigualis Caudal retroambigualis
Parabrachialis medialis Parabrachialis lateralis Kőlliker-Fuse
Sensory integration
Inspiratory
Expiratory
Dorsal respiratory group (DRG), ventral respiratory group (VRG), pontine respiratory group (PRG), nucleus tractus solitaries (nTS).
both inspiratory and expiratory premotor neurons, and subregions within this nucleus provide respiratory motor output to the larynx and pharynx via vagal motoneurons. The rostral retroambigualis sends projections to inspiratory neurons, and the caudal retroambigualis projects to expiratory neurons. The VRG and DRG have bulbospinal respiratory premotoneurons projecting to spinal motoneurons that subsequently innervate breathing muscles (e.g., respiratory pump muscles and abdominal breathing muscles). They also contain propriobulbar neurons projecting to other medullary respiratory neurons but not to motoneurons. The hypoglossal, trigeminal, and facial motor nuclei act independently from the VRG and DRG, innervating pharyngeal muscles that maintain upper airway patency; their dysfunction plays a role in sleep apnea pathogenesis (Horner, 1996). The PRG includes the nucleus parabrachial medialis, the parabrachialis lateralis, and the K€ olliker-Fuse nucleus (Table 22.1) (Horner, 2017). The nucleus parabrachialis medialis controls expiratory neurons; the nucleus parabrachialis lateralis and the Kőlliker-Fuse nucleus control inspiratory neurons. The PRG acts to fine-tune the breathing patterns. Activation of the PRG can decrease inspiratory activity within the DRG, leading to reduced inspiratory time (Poon and Song, 2014). The sensory integration center in the nTS receives input from central chemoreceptors and peripheral chemoreceptors. The main peripheral chemoreceptors are the carotid bodies, lying at the bifurcation of the common carotid arteries. They respond to changes in oxygen, carbon dioxide, and hydrogen ion concentration. The second peripheral chemoreceptors are the aortic bodies located within the aortic arch (Dempsey and Smith, 2014).
Intermittent, repetitive hypoxic episodes as observed in sleep apnea enhance carotid chemosensory activity and hypoxic ventilator response, which can perpetuate breathing instability. This response mediates increased sympathetic activation. Carotid body denervation appears to normalize increased blood pressure in experimental intermittent hypoxia models (Fung, 2014). The central chemoreception zone located on the ventral surface of the medulla contains the retrotrapezoid nucleus, which responds to the partial pressure of carbon dioxide and resultant hydrogen ion concentration in the cerebrospinal fluid. The central chemoreceptors have projections back to the nTS in the DRG. Compared with peripheral chemoreceptors, the central chemoreceptors respond more slowly (Dempsey and Smith, 2014). Other nTS inputs that influence the rate and depth of breathing include receptors in muscles and joints, stretch receptors in the lung, sensory receptors for pain, touch and temperature, limbic system activation from emotional stimulation, and the overall wakefulness drive to breathe. During inspiration, the central respiratory drive potential from the inspiratory DRG and VRG neurons is transmitted via monosynaptic connections to the phrenic and intercostal motoneurons (Duffin, 2004). During expiration, B€otzinger complex expiratory neurons project widespread inhibitory connections throughout the brainstem and spinal cord and inhibit the inspiratory premotoneurons and motoneurons (Horner, 2017). The spinal cord serves as the integrating center for different inputs to the respiratory motoneurons. There is a difference between the central neural control of spinal respiratory motoneurons and the control of pharyngeal motoneurons. Animal studies show that the source for the inspiratory drive to hypoglossal motoneurons is
348
T. WATERS AND R. MEHRA
different from that of phrenic motoneurons (Duffin, 2004). Hypoglossal motoneurons are stimulated from reticular neurons lateral to the hypoglossal motor nucleus, while phrenic motoneurons are stimulated from bulbospinal neurons from the DRG and VRG (Duffin, 2004). Hypoglossal motoneurons are not actively inhibited during expiration, unlike phrenic motoneurons, and thus their overall activation during breathing consists of an inspiratory drive and a continuous tonic drive that persists during expiration, even when the inspiratory activation is removed (Duffin, 2004). This tonic drive is most prominent during wakefulness and contributes to baseline airway size and patency; however, it is withdrawn during sleep, resulting in an airway more vulnerable to collapse (Horner, 1996; Lo et al., 2007). The muscles of respiration include inspiratory muscles, expiratory muscles, and upper airway muscles. As a result of the stimulation from central control, the diaphragm contracts during inspiration, increasing intrathoracic volume. Other muscles of inspiration include the external intercostal muscles elevating the ribs and expanding the thorax, and the accessory breathing muscles (the scalene and sternocleidomastoid). Expiration is usually a passive process; however, during forced expiration, the internal intercostal muscles and abdominal muscles (internal and external obliques, rectus abdominis, and transverse abdominis) can be recruited. The upper airway consists of 24 pairs of striated skeletal muscles extending from the nares to the larynx, divided into regions based on anatomic structures: nasopharynx, retropalatal oropharynx, retroglossal oropharynx, hypopharynx, and larynx. The pharyngeal muscles regulate the position of the soft palate, tongue, hyoid bone, and pharyngeal walls (Rowley and Badr, 2017). Upper airway patency is maintained by many stabilizing muscles, including the genioglossus, levator palatini, tensor palatini, and geniohyoid. Respiratory and upper airway muscle activity is influenced by the sleep–wake state and the inspiratory or expiratory phase of the respiratory cycle. Changes in muscle tone occur because of changes to the electrical properties and membrane potential of motoneurons as a result of varying degrees of excitatory and inhibitory inputs. Breathing is regular during NREM sleep but is irregular during REM sleep. During NREM sleep, the medullary respiratory activity of the VRG and DRG is decreased, and muscle tone is slightly reduced compared to wakefulness, resulting from slight hyperpolarization of the membrane potential. However, during REM sleep medullary respiratory activity is increased, and there is strong motoneuron hyperpolarization, resulting in robust tonic suppression of muscle activity (Eckert and Butler, 2017). This muscle suppression occurs as a result of postsynaptic inhibition and a reduction in the discharge of tonically active presynaptic excitatory neurons
(Chase and Morales, 2005). REM sleep is associated with this increased motoneuron inhibition, and there are also strong motor excitatory drives that occur that can overpower the inhibition, resulting in motoneuron discharges and muscle fiber contraction (Chase and Morales, 2005). Upper airway muscles can exhibit either tonic activity, independent of the phase of respiration, or phasic activity, occurring during one part of the respiratory cycle. Some of the upper airway muscles, including the genioglossus, can be classified as pharyngeal “dilators,” due to their phasic inspiratory activity, while others such as the tensor palatini, exert tonic activity with a presumed stiffening effect on the upper airway. Reductions of both the tonic and phasic activity are seen during NREM and REM sleep, resulting in upper airway narrowing and increased airway resistance (Horner, 1996; Rowley and Badr, 2017). During sleep, most of the inputs that can alter breathing are either absent or markedly downregulated, and chemical control is the dominant driver. At sleep onset and during stable sleep, chemosensitivity decreases and both respiratory pump muscle tone and upper airway muscle tone are reduced, leading to lowered minute ventilation and increased upper airway resistance (Eckert et al., 2009). Rapid eye movements during REM sleep are associated with further inhibition of upper airway dilator muscle activity, decreased tidal volume, and inhibition of protective upper airway reflexes (Eckert et al., 2007, 2009). The timing and magnitude of all these changes vary among individuals and can lead to sleep disordered breathing, especially during REM sleep, when obstructive sleep apnea (OSA) is known to be more prominent. Due to these sleep state-dependent alterations, there is an overall reduction of oxygen saturation by 1%–2% and rise in arterial pCO2 by 3–7 mmHg during sleep, with more pronounced changes during REM sleep (Douglas et al., 1982).
HYPOGLOSSAL NERVE ANATOMY Upper airway dilator muscles, particularly the genioglossus, contribute to stabilizing the upper airway during sleep. The hypoglossal nerve has become a target for stimulation therapy as an alternative treatment for OSA. Its lateral branches innervate the hyoglossus, styloglossus, and intrinsic inferior longitudinal retrusor muscles; the medial branch innervates the genioglossus and transverse and vertical intrinsic stiffener protrusor muscles. The lateral component of the nerve consists of multiple branches; the medial branch divides into its terminal fibers before entering the genioglossus muscle (Mu and Sanders, 2010; Bassiri Gharb et al., 2015). In total, the hypoglossal nerve gives off 50–60 branches
CLINICAL NEUROPHYSIOLOGY OF APNEA along its entire length (Heiser et al., 2016). The ideal location for stimulation excludes those branches supplying the retrusor muscles, allowing for maximum airway enlargement via tongue protrusion and mechanical coupling with the soft palate.
AUTONOMIC FUNCTION IN SLEEP AND OBSTRUCTIVE SLEEP APNEA Autonomic fluctuations are characteristic of wake–sleep transitions and change with sleep state. Overall, sleep is considered to be a cardio-protective state due to enhanced parasympathetic tone and overall reduction in sympathetic activation intrinsic to this state compared to wakefulness. During sleep, a reduction in heart rate and blood pressure occur in a state-dependent fashion. Sympathetic activation is reduced by more than half during NREM sleep compared to wakefulness, but is highest during REM sleep (Mancia, 1993; Somers et al., 1993). NREM sleep, which constitutes 80%–85% of the sleep time, is characterized by stability of the autonomic nervous system, reduction in metabolic demands, augmentation of baroreceptor gain and normal respiratory sinus arrhythmia as a result of coupling of respiratory and cardiorespiratory centers in the brain. Systemic vascular resistance, blood pressure, and heart rate oscillate markedly during REM sleep in concert with the phasic and tonic aspects inherent in REM sleep. Specifically, heart rate is reduced and reduction in heart rate variability has been observed in N1, N2, and N3 sleep as opposed to increased heart rate variability noted during REM sleep (Zemaityte et al., 1984). Bradycardia during sleep occurs primarily due to an enhanced parasympathetic state, whereas reduction in blood pressure appears to be mainly secondary to reduction in sympathetic activation, as evidenced by attenuation of hypotension by surgical sympathectomy (Baccelli et al., 1969); 24-h ambulatory blood pressure monitoring shows approximately 10% lower blood pressure during sleep compared to wakefulness. Heart rate variability (a marker of cardiac health and autonomic function) and respiratory sinus arrhythmia increase during sleep (Verrier and Josephson, 2009). Reduced metabolic demands and the reduction in hemodynamic parameters result in decreased cardiac demand with regard to preload, afterload, and myocardial oxygen consumption. Diurnal patterning of sudden cardiac death also differs in the normal physiologic state versus in the setting of sleep pathology, such as OSA. In the general population, the risk of sudden cardiac death peaks from 6 a.m. to noon, with a predilection for 6 a.m. to 9 a.m. morning hours. The cardio-protective nature of sleep and reduced nocturnal risk may be attributable to favorable hemodynamics, including dipping blood pressure profile. Morning sudden cardiac death vulnerability likely has a
349
multifactorial circadian physiologic basis, including enhanced sympathetic activation (Somers et al., 1993) related to REM-predominance during the latter part of the sleep cycle, increased circulating cortisol, enhanced hypercoagulability (Andreotti et al., 1988), altered electrophysiology (Bexton et al., 1986; Huikuri et al., 1995), and changes in baroreflex sensitivity (Legramante et al., 2003). In contrast, nocturnal predisposition to sudden cardiac death in OSA peaks from midnight to 6 a.m., is directly aligned with the severity of sleep apnea ascertained by the apnea hypopnea index, and confers an almost threefold higher risk compared to those without OSA (Gami et al., 2005). Elevation of sympathetic nerve activation has been observed in those with OSA compared to controls and likely contributes to increased sudden nocturnal cardiac death (Somers et al., 1995). This elevation of sympathetic activation in OSA also persists during the daytime (Somers et al., 1995). During the apneic phase, enhanced parasympathetic tone is associated with bradycardia, culminating in increasing respiratory effort against the obstructed airway and leading to an enhanced sympathetic response due to synergies of hypoxia and hypercapnia, associated with lack of sympathetic inhibition of normal lung inflation reflexes (Leung, 2009).
OBSTRUCTIVE SLEEP APNEA PATHOPHYSIOLOGY Both respiration and sleep are disturbed in sleep apnea. In spite of different pathophysiologies, recurrence of events is common to obstructive, central, and mixed sleep apneas. Oscillations in ventilation during sleep likely occur due to alterations in feedback control of breathing (Strohl et al., 1986; Strohl and Olson, 1987). There is reduction of upper airway muscle tone during sleep with depression of the activity of the upper airway muscles leading to increased upper airway resistance. Obstructive apnea during sleep occurs due to an imbalance of activity of the upper airway muscle and the chest wall muscles. During inspiration, upper airway obstruction may occur unless the negative pressure resulting from the chest wall muscle contraction is effectively counteracted by the force of the extrathoracic pharyngeal dilator muscles. The benefit of positive airway pressure (PAP) use in obstructive sleep apnea came from the observation that the upper airway can be obstructed by negative pressure applied to the nose (Sullivan et al., 1984). It was observed that application of nasal PAP served as a pneumatic splint to maintain upper airway patency and resulted in the improved sleep architecture and continuity (Sullivan et al., 1981). Physiologic concepts are now focusing on forces that either counteract or work together to predispose to upper airway collapse and apnea genesis. Principles are
350
T. WATERS AND R. MEHRA
emerging that will position the field for a personalized approach to the treatment of sleep-related breathing disorders. Physiologic processes that are being explored for treatment potential include (1) critical closing airway pressure (Pcrit), (2) responsiveness to disturbance resulting in perpetuation of apnea (or sensitivity of the ventilator control system), (3) recruitment of the airway muscles responsible for airway patency, and (4) arousal threshold during sleep (Eckert et al., 2013). Patients will be defined as having risk of OSA due to anatomic factors, anatomic and other contributing factors, or nonanatomic factors (Owens et al., 2015). It is becoming apparent that these factors do not operate alone. Treatment strategies will need to address multiple contributing factors.
Critical closing pressure of the upper airway Critical closing pressure (Pcrit) has historically been considered the gold-standard measurement of collapsibility of the upper airway. Although nonanatomic factors can influence OSA propensity, in the majority of patients with OSA, mechanical upper airway collapsibility plays an important role. Conceptually, this is based on the notion that, in those with OSA, the pharyngeal airway collapses during sleep like a Starling resistor (Schwartz et al., 1989; Gleadhill et al., 1991). When the downstream pressure in a Starling resistor drops below a key (or critical) level, a “choke point” or Pcrit occurs, preventing further decrements. Increased negative intraluminal pressure in the airway occurs during inspiration when the diaphragm generates negative pressure, reducing the airway size. Standard methods to measure Pcrit involve assessment while individuals are using CPAP, allowing for minimization of the role of pharyngeal dilator activity (Smith et al., 1988). Pcrit is then determined and defined as the estimated nasal pressure at which the passive upper airway collapses, resulting in cessation of airflow (Smith et al., 1988). An important assumption is that the level of CPAP applied results in minimization of the pharyngeal dilator activity and does not heavily influence the Pcrit measurement being obtained during the five breaths used to quantify this measure. In support of this, data from existing studies support the notion of progressive increases in Pcrit in healthy individuals, compared with snorers and those patients with OSA (Schwartz et al., 1988; Gleadhill et al., 1991). There are complexities in understanding the role of the Pcrit in OSA pathophysiology, given the interacting influences of other nonanatomic factors. Pcrit measurement is influenced by genioglossus (but not tensor palatine) activity, which declines from wakefulness to sleep, further declining from N3 to N2 sleep to REM sleep (Carberry et al., 2016). Furthermore, muscle efferent
output leading to mechanical changes in the airway are difficult to measure in the presence of edema (Strohl et al., 2012).
Loop gain The ability to maintain arterial oxygen and carbon dioxide concentrations within a narrow range is the result of tight regulation via multiple feedback loops, including chemoreceptors for oxygen and carbon dioxide, intrapulmonary stretch receptors, and respiratory muscle afferents. Ventilatory control can be conceptualized as a mechanical system regulated by multiple feedback loops (loop gain system). Such a system responds vigorously to an external stimulus, whereas a low loop gain system responds in a more muted fashion (White, 2005). The key components of loop gain are controller gain and plant gain. Controller gain is characterized by hypoxic and hypercapnic chemoresponsiveness, and plant gain by effectiveness of the respiratory system to clear CO2 given a specific level of ventilation. A high loop gain system reflects ventilatory instability and a destabilized system, whereas in a lower loop gain system a respiratory disturbance would result in a response, with quick resumption of ventilation. High loop gain systems can occur in situations in which there is a high controller gain that may be observed in individuals with higher chemosensitivity. Examples include high-altitude periodic breathing, central sleep apnea– Cheyne–Stokes respirations, idiopathic central sleep apnea, and OSA. For those with high loop gain, supplemental oxygen has been shown to reduce loop gain and thereby reduce OSA severity gain (Wellman et al., 2008); CPAP also can stabilize ventilation by reducing loop gain as the ventilatory response to CO2 decreases (Loewen et al., 2009; Salloum et al., 2010). Data support the utility of oral appliance therapy in those patients with OSA who have lower loop gain (Edwards et al., 2016).
Upper airway muscle recruitment Poor pharyngeal muscle responsiveness during sleep is another physiologic feature contributing to OSA. Inadequate responsiveness of the upper airway dilator muscles during sleep is recognized by minimal increase in EMG activity to negative pharyngeal pressure (Eckert et al., 2013). The inability to mount the necessary level of neural drive to the upper airway muscles during sleep in response to negative intraluminal airway pressure contributes to the pathogenesis of OSA. In one particular study, more than one-third of patients with OSA generated less than 0.1% increase in maximal genioglossal activity in response to a 1-cm water pressure decline in negative pharyngeal pressure, consistent with marked
CLINICAL NEUROPHYSIOLOGY OF APNEA compromise in responsiveness (Eckert et al., 2013). Suboptimal muscle responsiveness has been identified as a salient factor in many individuals with OSA, and data suggest a specific problem in effectiveness of the upper airway neural drive on mechanical opening of the airway ( Jordan et al., 2007; Patil et al., 2007). Some data also suggest that both increased mechanical loads and blunted neuromuscular responses are necessary for development of OSA (Patil et al., 2007).
Arousal threshold It is estimated that one-third of patients with OSA have a reduction in the arousal threshold, resulting in disruption of sleep and premature awakenings, preventing sufficient upper airway muscle recruitment to maintain upper airway patency (Eckert et al., 2013). Changes in sleep state may represent periods of vulnerability to ventilator stability. In fact, even though conventional wisdom in the treatment of OSA is to avoid medications such as sedative hypnotics that can theoretically result in reduction of upper airway muscle tone, recent literature has highlighted the notion that certain sedative hypnotic medications, such as eszopiclone, result in increases in the respiratory arousal threshold and improvement in OSA as defined by the apnea hypopnea index (Eckert et al., 2011). An important caveat is that for those patients who have severe oxygen desaturation accompanying OSA, hypnotics are contraindicated, given potential to prolong time to arousal, worsening hypoxemia and hypercapnia. A genetic predisposition may affect the intensity of cortical arousals and associated cardiovascular influences which evidence supports is consistent within individuals, however, heterogeneous within populations (Poon and Song, 2014).
CONCLUSION Breathing during wake and sleep involves preservation as well as adjustability of salient neuroanatomic and neural network pathways involving specific key respiratory networks: central and peripheral chemosensitivity, motoneurons, and upper airway muscle physiology. Critical closing pressure of the upper airway, altered loop gain, blunted responsiveness of upper airway muscle recruitment, and reductions in arousal threshold contributing to ventilatory instability are factors that either separately or in combination will play a role in the future individualized treatment of sleep apnea. Current management strategies that are “one approach fits all” are suboptimal. Scientific advancements have allowed for development of novel therapeutics targeting specific aspects of respiratory physiology, such as the hypoglossal nerve, the role of the mu receptors in the pre-B€ otzinger complex, and carotid body denervation.
351
REFERENCES Andreotti F, Davies GJ, Hackett DR et al. (1988). Major circadian fluctuations in fibrinolytic factors and possible relevance to time of onset of myocardial infarction, sudden cardiac death and stroke. Am J Cardiol 62: 635–637. Baccelli G, Guazzi M, Mancia G et al. (1969). Neural and non-neural mechanisms influencing circulation during sleep. Nature 223: 184–185. Bassiri Gharb B, Tadisina KK, Rampazzo A et al. (2015). Microsurgical anatomy of the terminal hypoglossal nerve relevant for neurostimulation in obstructive sleep apnea. Neuromodulation 18: 721–728. Bexton RS, Vallin HO, Camm AJ (1986). Diurnal variation of the QT interval—influence of the autonomic nervous system. Br Heart J 55: 253–258. Burke PG, Kanbar R, Basting TM et al. (2015). Statedependent control of breathing by the retrotrapezoid nucleus. J Physiol 593: 2909–2926. Carberry JC, Jordan AS, White DP et al. (2016). Upper airway collapsibility (Pcrit) and pharyngeal dilator muscle activity are sleep stage dependent. Sleep 39: 511–521. Chase MH, Morales FR (2005). Control of motoneurons during sleep. In: MH Kryger, T Roth, WC Dement (Eds.), Principles and practice of sleep medicine, fourth edn. WB Saunders, Philadelphia. Dempsey JA, Smith CA (2014). Pathophysiology of human ventilatory control. Eur Respir J 44: 495–512. Douglas NJ, White DP, Weil JV et al. (1982). Hypercapnic ventilatory response in sleeping adults. Am Rev Respir Dis 126: 758–762. Duffin J (2004). Functional organization of respiratory neurones: a brief review of current questions and speculations. Exp Physiol 89: 517–529. Eckert DJ, Butler JE (2017). Respiratory physiology: understanding the control of ventilation. In: MH Kryger, T Roth, WC Dement (Eds.), Principles and practice of sleep medicine, sixth edn. Elsevier, Philadelphia. Eckert DJ, McEvoy RD, George KE et al. (2007). Genioglossus reflex inhibition to upper-airway negativepressure stimuli during wakefulness and sleep in healthy males. J Physiol 581: 1193–1205. Eckert DJ, Malhotra A, Lo YL et al. (2009). The influence of obstructive sleep apnea and gender on genioglossus activity during rapid eye movement sleep. Chest 135: 957–964. Eckert DJ, Owens RL, Kehlmann GB et al. (2011). Eszopiclone increases the respiratory arousal threshold and lowers the apnoea/hypopnoea index in obstructive sleep apnoea patients with a low arousal threshold. Clin Sci (Lond) 120: 505–514. Eckert DJ, White DP, Jordan AS et al. (2013). Defining phenotypic causes of obstructive sleep apnea. Identification of novel therapeutic targets. Am J Respir Crit Care Med 188: 996–1004. Edwards BA, Andara C, Landry S et al. (2016). Upper-airway collapsibility and loop gain predict the response to oral appliance therapy in patients with obstructive sleep apnea. Am J Respir Crit Care Med 194: 1413–1422.
352
T. WATERS AND R. MEHRA
Fung ML (2014). Pathogenic roles of the carotid body inflammation in sleep apnea. Mediators Inflamm 2014, 354279. Gami AS, Howard DE, Olson EJ et al. (2005). Day-night pattern of sudden death in obstructive sleep apnea. N Engl J Med 352 (12): 1206–1214. Gleadhill IC, Schwartz AR, Schubert N et al. (1991). Upper airway collapsibility in snorers and in patients with obstructive hypopnea and apnea. Am Rev Respir Dis 143: 1300–1303. Heiser C, Thaler E, Boon M et al. (2016). Updates of operative techniques for upper airway stimulation. Laryngoscope 126 (Suppl. 7): S12–S16. Horner RL (1996). Motor control of the pharyngeal musculature and implications for the pathogenesis of obstructive sleep apnea. Sleep 19: 827–853. Horner RL (2017). Respiratory physiology: central neural control of respiratory neurons and motoneurons during sleep. In: MH Kryger, T Roth, WC Dement (Eds.), Principles and practice of sleep medicine, sixth edn. Elsevier, Philadelphia. Huikuri HV, Yli-Mayry S, Linnaluoto MK et al. (1995). Diurnal fluctuations in human ventricular and atrial refractoriness. Pacing Clin Electrophysiol: PACE 18: 1362–1368. Jordan AS, Wellman A, Heinzer RC et al. (2007). Mechanisms used to restore ventilation after partial upper airway collapse during sleep in humans. Thorax 62: 861–867. Legramante JM, Marciani MG, Placidi F et al. (2003). Sleeprelated changes in baroreflex sensitivity and cardiovascular autonomic modulation. J Hypertens 21: 1555–1561. Leung RS (2009). Sleep-disordered breathing: autonomic mechanisms and arrhythmias. Prog Cardiovasc Dis 51: 324–338. Lo YL, Jordan AS, Malhotra A et al. (2007). Influence of wakefulness on pharyngeal airway muscle activity. Thorax 62: 799–805. Loewen A, Ostrowski M, Laprairie J et al. (2009). Determinants of ventilatory instability in obstructive sleep apnea: inherent or acquired? Sleep 32: 1355–1365. Mancia G (1993). Autonomic modulation of the cardiovascular system during sleep. N Engl J Med 328: 347–349. Mu L, Sanders I (2010). Human tongue neuroanatomy: nerve supply and motor endplates. Clin Anat 23: 777–791. Owens RL, Edwards BA, Eckert DJ et al. (2015). An integrative model of physiological traits can be used to predict obstructive sleep apnea and response to non positive airway pressure therapy. Sleep 38: 961–970. Patil SP, Schneider H, Marx JJ et al. (2007). Neuromechanical control of upper airway patency during sleep. J Appl Physiol (1985) 102: 547–556. Peppard PE, Young T, Barnet JH et al. (2013). Increased prevalence of sleep-disordered breathing in adults. Am J Epidemiol 177: 1006–1014. Poon CS, Song G (2014). Bidirectional plasticity of pontine pneumotaxic postinspiratory drive: implication for a pontomedullary respiratory central pattern generator. Prog Brain Res 209: 235–254. Rekling JC, Feldman JL (1998). PreBotzinger complex and pacemaker neurons: hypothesized site and kernel for respiratory rhythm generation. Annu Rev Physiol 60: 385–405. Rosin DL, Chang DA, Guyenet PG (2006). Afferent and efferent connections of the rat retrotrapezoid nucleus. J Comp Neurol 499: 64–89.
Rowley JA, Badr MS (2017). Anatomy and physiology of upper airway obstruction. In: MH Kryger, T Roth, WC Dement (Eds.), Principles and practice of sleep medicine, sixth edn. Elsevier, Philadelphia. Salloum A, Rowley JA, Mateika JH et al. (2010). Increased propensity for central apnea in patients with obstructive sleep apnea: effect of nasal continuous positive airway pressure. Am J Respir Crit Care Med 181: 189–193. Schwartz AR, Smith PL, Wise RA et al. (1988). Induction of upper airway occlusion in sleeping individuals with subatmospheric nasal pressure. J Appl Physiol (1985) 64: 535–542. Schwartz AR, Smith PL, Wise RA et al. (1989). Effect of positive nasal pressure on upper airway pressure-flow relationships. J Appl Physiol (1985) 66: 1626–1634. Smith PL, Wise RA, Gold AR et al. (1988). Upper airway pressure-flow relationships in obstructive sleep apnea. J Appl Physiol (1985) 64: 789–795. Smith JC, Ellenberger HH, Ballanyi K et al. (1991). PreBotzinger complex: a brainstem region that may generate respiratory rhythm in mammals. Science 254: 726–729. Somers VK, Dyken ME, Mark AL et al. (1993). Sympatheticnerve activity during sleep in normal subjects. N Engl J Med 328: 303–307. Somers VK, Dyken ME, Clary MP et al. (1995). Sympathetic neural mechanisms in obstructive sleep apnea. J Clin Invest 96: 1897–1904. Strohl KP, Olson LG (1987). Concerning the importance of pharyngeal muscles in the maintenance of upper airway patency during sleep. An opinion. Chest 92: 918–920. Strohl KP, Cherniack NS, Gothe B (1986). Physiologic basis of therapy for sleep apnea. Am Rev Respir Dis 134: 791–802. Strohl KP, Butler JP, Malhotra A (2012). Mechanical properties of the upper airway. Compr Physiol 2: 1853–1872. Sullivan CE, Issa FG, Berthon-Jones M et al. (1981). Reversal of obstructive sleep apnoea by continuous positive airway pressure applied through the nares. Lancet 1: 862–865. Sullivan CE, Issa FG, Berthon-Jones M et al. (1984). Pathophysiology of sleep apnea. In: NA Saunders, CE Sullivan (Eds.), Sleep and breathing. Marcel Dekker, New York, pp. 299–364. Verrier RL, Josephson ME (2009). Impact of sleep on arrhythmogenesis. Circ Arrhythm Electrophysiol 2: 450–459. Wellman A, Malhotra A, Jordan AS et al. (2008). Effect of oxygen in obstructive sleep apnea: role of loop gain. Respir Physiol Neurobiol 162: 144–151. White DP (2005). Pathogenesis of obstructive and central sleep apnea. Am J Respir Crit Care Med 172: 1363–1370. Zemaityte D, Varoneckas G, Sokolov E (1984). Heart rhythm control during sleep. Psychophysiology 21: 279–289. Zhang Z, Zhang C, Zhuang J et al. (2012). Contribution of central mu-receptors to switching pulmonary C-fibersmediated rapid shallow breathing into an apnea by fentanyl in anesthetized rats. Brain Res 1469: 73–81.
FURTHER READING Strohl KP, Redline S (1996). Recognition of obstructive sleep apnea. Am J Respir Crit Care Med 154: 279–289.
Chapter 22
Clinical neurophysiology of apnea TINA WATERS AND REENA MEHRA* Sleep Center, Neurological Institute, Cleveland Clinic, Cleveland, OH, United States
Abstract Understanding the clinical neurophysiology of apnea generation encompasses discussion of the neuroanatomic aspects of central respiratory rhythm and pattern generation, including the central respiratory control networks, central and peripheral chemoreceptors, mechanisms of respiratory muscles, and sleep state dependent differences. Anatomical and functional links to apnea also involve central respiratory motor output recruited from the hypoglossal nerve, which has led to novel treatments for obstructive sleep apnea. Autonomic fluctuations occur in relation to sleep–wake and sleep states (i.e., REM vs NREM sleep), with both parasympathetic and sympathetic contributions. Finally, our understanding of the pathophysiology of obstructive sleep apnea now includes concepts of critical closing pressure of the upper airway, increased loop gain as reflected by high responsiveness to external perturbations, inadequate responsiveness of upper airway muscle recruitment, and reductions in arousal threshold leading to ventilatory instability. In turn, these concepts have led to the development of novel therapies such as hypoglossal nerve stimulation and targeting key culprit physiologic mechanisms specific to the individual.
BREATHING NEUROANATOMY Sleep apnea is a common sleep disorder. In the United States, 26% of individuals between 30 and 70 years of age may be afflicted (Peppard et al., 2013). Breathing involves key elements that are interconnected with multiple feedforward and feedback mechanisms. The aim is to provide oxygen to different body parts and to eliminate carbon dioxide resulting from cell metabolism. The four main anatomic elements of breathing are (1) brainstem neurons responsible for respiratory pattern generation, (2) sensory inputs relaying chemoreceptor information back to the brainstem control centers allowing for adjustments based on the underlying physiologic need, (3) respiratory motoneurons acting as the final common output for central nervous system control of respiratory muscles, and (4) respiratory and airway muscles controlling air flow in and out of the lungs (Fig. 22.1). These elements are influenced by the sleep– wake state of the system and the respiratory cycle. Malfunction of any of these elements can result in
abnormal breathing, which is more likely to emerge during sleep when compensatory stimuli during wake are absent. The central respiratory control network for pattern generation is located in the medulla and the pons. The medullary respiratory neurons consist of the dorsal and ventral respiratory groups (DRG and VRG). The pontine respiratory neurons consist of the pontine respiratory group (PRG) (Table 22.1). The DRG is located in the dorsomedial medulla, within the ventrolateral nucleus tractus solitarius (nTS), and contains predominantly inspiratory neurons (Rekling and Feldman, 1998; Duffin, 2004). The nTS is the key cardiorespiratory sensory integration site for afferent information coming from the phrenic, vagus, and glossopharyngeal nerves. It has multiple outputs, including the retrotrapezoid nucleus, which is part of the central chemoreception process, and the VRG (Rosin et al., 2006; Burke et al., 2015). The VRG, extending from the facial nucleus to the first cervical segment of the spinal cord, consists of multiple components: the pre-B€otzinger complex, the B€otzinger
*Correspondence to: Reena Mehra, MD, MS, 9500 Euclid Avenue, Cleveland, OH 44195, United States. Tel: +1-216-445-8072, E-mail: [email protected]
346
T. WATERS AND R. MEHRA
Fig. 22.1. The main elements of breathing include (1) a central respiratory control network consisting of multiple brainstem neurons responsible for respiratory pattern generation, (2) sensory inputs relaying chemoreceptor information to the control network to adjust breathing based on physiologic need, (3) respiratory motoneurons acting as the final common output for the central nervous system’s influence on respiratory muscles, and (4) respiratory and airway muscles that create air flow in and out of the lungs. Nucleus tractus solitaries (nTS), retroambigualis (RA). Reprinted with permission, Cleveland Clinic Center for Medical Art & Photography © 2017. All Rights Reserved.
complex, the nucleus ambiguous, the rostral retroambigualis nucleus, and the caudal retroambigualis nucleus. The VRG contains both inspiratory and expiratory neurons. The pre-B€ otzinger complex, composed of neurons with pacemaker-like properties that have a persistent respiratory rhythm, has projections via interneurons throughout the brainstem to other respiratory control sites, and acts on inspiratory neurons (Smith et al., 1991).
Opioid stimulation of mu-opioid receptors in the preB€otzinger complex are partially responsible for switching of pulmonary C-fiber-mediated rapid shallow breathing to apnea in experimental animal models (Zhang et al., 2012). The B€otzinger complex, adjacent to the preB€otzinger complex, consists of expiratory neurons that activate pathways for expiration and inhibit inspiratory respiratory motoneurons. The nucleus ambiguous has
CLINICAL NEUROPHYSIOLOGY OF APNEA
347
Table 22.1 Brainstem nuclei involved in central respiratory control with regard to their location, function, and impact on inspiratory or expiratory neurons
Rhythmicity Medulla DRG VRG
Pons PRG
nTS Pre-B€ otzinger complex B€otzinger complex Nucleus ambiguous Rostral retroambigualis Caudal retroambigualis
Parabrachialis medialis Parabrachialis lateralis Kőlliker-Fuse
Sensory integration
Inspiratory
Expiratory
Dorsal respiratory group (DRG), ventral respiratory group (VRG), pontine respiratory group (PRG), nucleus tractus solitaries (nTS).
both inspiratory and expiratory premotor neurons, and subregions within this nucleus provide respiratory motor output to the larynx and pharynx via vagal motoneurons. The rostral retroambigualis sends projections to inspiratory neurons, and the caudal retroambigualis projects to expiratory neurons. The VRG and DRG have bulbospinal respiratory premotoneurons projecting to spinal motoneurons that subsequently innervate breathing muscles (e.g., respiratory pump muscles and abdominal breathing muscles). They also contain propriobulbar neurons projecting to other medullary respiratory neurons but not to motoneurons. The hypoglossal, trigeminal, and facial motor nuclei act independently from the VRG and DRG, innervating pharyngeal muscles that maintain upper airway patency; their dysfunction plays a role in sleep apnea pathogenesis (Horner, 1996). The PRG includes the nucleus parabrachial medialis, the parabrachialis lateralis, and the K€ olliker-Fuse nucleus (Table 22.1) (Horner, 2017). The nucleus parabrachialis medialis controls expiratory neurons; the nucleus parabrachialis lateralis and the Kőlliker-Fuse nucleus control inspiratory neurons. The PRG acts to fine-tune the breathing patterns. Activation of the PRG can decrease inspiratory activity within the DRG, leading to reduced inspiratory time (Poon and Song, 2014). The sensory integration center in the nTS receives input from central chemoreceptors and peripheral chemoreceptors. The main peripheral chemoreceptors are the carotid bodies, lying at the bifurcation of the common carotid arteries. They respond to changes in oxygen, carbon dioxide, and hydrogen ion concentration. The second peripheral chemoreceptors are the aortic bodies located within the aortic arch (Dempsey and Smith, 2014).
Intermittent, repetitive hypoxic episodes as observed in sleep apnea enhance carotid chemosensory activity and hypoxic ventilator response, which can perpetuate breathing instability. This response mediates increased sympathetic activation. Carotid body denervation appears to normalize increased blood pressure in experimental intermittent hypoxia models (Fung, 2014). The central chemoreception zone located on the ventral surface of the medulla contains the retrotrapezoid nucleus, which responds to the partial pressure of carbon dioxide and resultant hydrogen ion concentration in the cerebrospinal fluid. The central chemoreceptors have projections back to the nTS in the DRG. Compared with peripheral chemoreceptors, the central chemoreceptors respond more slowly (Dempsey and Smith, 2014). Other nTS inputs that influence the rate and depth of breathing include receptors in muscles and joints, stretch receptors in the lung, sensory receptors for pain, touch and temperature, limbic system activation from emotional stimulation, and the overall wakefulness drive to breathe. During inspiration, the central respiratory drive potential from the inspiratory DRG and VRG neurons is transmitted via monosynaptic connections to the phrenic and intercostal motoneurons (Duffin, 2004). During expiration, B€otzinger complex expiratory neurons project widespread inhibitory connections throughout the brainstem and spinal cord and inhibit the inspiratory premotoneurons and motoneurons (Horner, 2017). The spinal cord serves as the integrating center for different inputs to the respiratory motoneurons. There is a difference between the central neural control of spinal respiratory motoneurons and the control of pharyngeal motoneurons. Animal studies show that the source for the inspiratory drive to hypoglossal motoneurons is
348
T. WATERS AND R. MEHRA
different from that of phrenic motoneurons (Duffin, 2004). Hypoglossal motoneurons are stimulated from reticular neurons lateral to the hypoglossal motor nucleus, while phrenic motoneurons are stimulated from bulbospinal neurons from the DRG and VRG (Duffin, 2004). Hypoglossal motoneurons are not actively inhibited during expiration, unlike phrenic motoneurons, and thus their overall activation during breathing consists of an inspiratory drive and a continuous tonic drive that persists during expiration, even when the inspiratory activation is removed (Duffin, 2004). This tonic drive is most prominent during wakefulness and contributes to baseline airway size and patency; however, it is withdrawn during sleep, resulting in an airway more vulnerable to collapse (Horner, 1996; Lo et al., 2007). The muscles of respiration include inspiratory muscles, expiratory muscles, and upper airway muscles. As a result of the stimulation from central control, the diaphragm contracts during inspiration, increasing intrathoracic volume. Other muscles of inspiration include the external intercostal muscles elevating the ribs and expanding the thorax, and the accessory breathing muscles (the scalene and sternocleidomastoid). Expiration is usually a passive process; however, during forced expiration, the internal intercostal muscles and abdominal muscles (internal and external obliques, rectus abdominis, and transverse abdominis) can be recruited. The upper airway consists of 24 pairs of striated skeletal muscles extending from the nares to the larynx, divided into regions based on anatomic structures: nasopharynx, retropalatal oropharynx, retroglossal oropharynx, hypopharynx, and larynx. The pharyngeal muscles regulate the position of the soft palate, tongue, hyoid bone, and pharyngeal walls (Rowley and Badr, 2017). Upper airway patency is maintained by many stabilizing muscles, including the genioglossus, levator palatini, tensor palatini, and geniohyoid. Respiratory and upper airway muscle activity is influenced by the sleep–wake state and the inspiratory or expiratory phase of the respiratory cycle. Changes in muscle tone occur because of changes to the electrical properties and membrane potential of motoneurons as a result of varying degrees of excitatory and inhibitory inputs. Breathing is regular during NREM sleep but is irregular during REM sleep. During NREM sleep, the medullary respiratory activity of the VRG and DRG is decreased, and muscle tone is slightly reduced compared to wakefulness, resulting from slight hyperpolarization of the membrane potential. However, during REM sleep medullary respiratory activity is increased, and there is strong motoneuron hyperpolarization, resulting in robust tonic suppression of muscle activity (Eckert and Butler, 2017). This muscle suppression occurs as a result of postsynaptic inhibition and a reduction in the discharge of tonically active presynaptic excitatory neurons
(Chase and Morales, 2005). REM sleep is associated with this increased motoneuron inhibition, and there are also strong motor excitatory drives that occur that can overpower the inhibition, resulting in motoneuron discharges and muscle fiber contraction (Chase and Morales, 2005). Upper airway muscles can exhibit either tonic activity, independent of the phase of respiration, or phasic activity, occurring during one part of the respiratory cycle. Some of the upper airway muscles, including the genioglossus, can be classified as pharyngeal “dilators,” due to their phasic inspiratory activity, while others such as the tensor palatini, exert tonic activity with a presumed stiffening effect on the upper airway. Reductions of both the tonic and phasic activity are seen during NREM and REM sleep, resulting in upper airway narrowing and increased airway resistance (Horner, 1996; Rowley and Badr, 2017). During sleep, most of the inputs that can alter breathing are either absent or markedly downregulated, and chemical control is the dominant driver. At sleep onset and during stable sleep, chemosensitivity decreases and both respiratory pump muscle tone and upper airway muscle tone are reduced, leading to lowered minute ventilation and increased upper airway resistance (Eckert et al., 2009). Rapid eye movements during REM sleep are associated with further inhibition of upper airway dilator muscle activity, decreased tidal volume, and inhibition of protective upper airway reflexes (Eckert et al., 2007, 2009). The timing and magnitude of all these changes vary among individuals and can lead to sleep disordered breathing, especially during REM sleep, when obstructive sleep apnea (OSA) is known to be more prominent. Due to these sleep state-dependent alterations, there is an overall reduction of oxygen saturation by 1%–2% and rise in arterial pCO2 by 3–7 mmHg during sleep, with more pronounced changes during REM sleep (Douglas et al., 1982).
HYPOGLOSSAL NERVE ANATOMY Upper airway dilator muscles, particularly the genioglossus, contribute to stabilizing the upper airway during sleep. The hypoglossal nerve has become a target for stimulation therapy as an alternative treatment for OSA. Its lateral branches innervate the hyoglossus, styloglossus, and intrinsic inferior longitudinal retrusor muscles; the medial branch innervates the genioglossus and transverse and vertical intrinsic stiffener protrusor muscles. The lateral component of the nerve consists of multiple branches; the medial branch divides into its terminal fibers before entering the genioglossus muscle (Mu and Sanders, 2010; Bassiri Gharb et al., 2015). In total, the hypoglossal nerve gives off 50–60 branches
CLINICAL NEUROPHYSIOLOGY OF APNEA along its entire length (Heiser et al., 2016). The ideal location for stimulation excludes those branches supplying the retrusor muscles, allowing for maximum airway enlargement via tongue protrusion and mechanical coupling with the soft palate.
AUTONOMIC FUNCTION IN SLEEP AND OBSTRUCTIVE SLEEP APNEA Autonomic fluctuations are characteristic of wake–sleep transitions and change with sleep state. Overall, sleep is considered to be a cardio-protective state due to enhanced parasympathetic tone and overall reduction in sympathetic activation intrinsic to this state compared to wakefulness. During sleep, a reduction in heart rate and blood pressure occur in a state-dependent fashion. Sympathetic activation is reduced by more than half during NREM sleep compared to wakefulness, but is highest during REM sleep (Mancia, 1993; Somers et al., 1993). NREM sleep, which constitutes 80%–85% of the sleep time, is characterized by stability of the autonomic nervous system, reduction in metabolic demands, augmentation of baroreceptor gain and normal respiratory sinus arrhythmia as a result of coupling of respiratory and cardiorespiratory centers in the brain. Systemic vascular resistance, blood pressure, and heart rate oscillate markedly during REM sleep in concert with the phasic and tonic aspects inherent in REM sleep. Specifically, heart rate is reduced and reduction in heart rate variability has been observed in N1, N2, and N3 sleep as opposed to increased heart rate variability noted during REM sleep (Zemaityte et al., 1984). Bradycardia during sleep occurs primarily due to an enhanced parasympathetic state, whereas reduction in blood pressure appears to be mainly secondary to reduction in sympathetic activation, as evidenced by attenuation of hypotension by surgical sympathectomy (Baccelli et al., 1969); 24-h ambulatory blood pressure monitoring shows approximately 10% lower blood pressure during sleep compared to wakefulness. Heart rate variability (a marker of cardiac health and autonomic function) and respiratory sinus arrhythmia increase during sleep (Verrier and Josephson, 2009). Reduced metabolic demands and the reduction in hemodynamic parameters result in decreased cardiac demand with regard to preload, afterload, and myocardial oxygen consumption. Diurnal patterning of sudden cardiac death also differs in the normal physiologic state versus in the setting of sleep pathology, such as OSA. In the general population, the risk of sudden cardiac death peaks from 6 a.m. to noon, with a predilection for 6 a.m. to 9 a.m. morning hours. The cardio-protective nature of sleep and reduced nocturnal risk may be attributable to favorable hemodynamics, including dipping blood pressure profile. Morning sudden cardiac death vulnerability likely has a
349
multifactorial circadian physiologic basis, including enhanced sympathetic activation (Somers et al., 1993) related to REM-predominance during the latter part of the sleep cycle, increased circulating cortisol, enhanced hypercoagulability (Andreotti et al., 1988), altered electrophysiology (Bexton et al., 1986; Huikuri et al., 1995), and changes in baroreflex sensitivity (Legramante et al., 2003). In contrast, nocturnal predisposition to sudden cardiac death in OSA peaks from midnight to 6 a.m., is directly aligned with the severity of sleep apnea ascertained by the apnea hypopnea index, and confers an almost threefold higher risk compared to those without OSA (Gami et al., 2005). Elevation of sympathetic nerve activation has been observed in those with OSA compared to controls and likely contributes to increased sudden nocturnal cardiac death (Somers et al., 1995). This elevation of sympathetic activation in OSA also persists during the daytime (Somers et al., 1995). During the apneic phase, enhanced parasympathetic tone is associated with bradycardia, culminating in increasing respiratory effort against the obstructed airway and leading to an enhanced sympathetic response due to synergies of hypoxia and hypercapnia, associated with lack of sympathetic inhibition of normal lung inflation reflexes (Leung, 2009).
OBSTRUCTIVE SLEEP APNEA PATHOPHYSIOLOGY Both respiration and sleep are disturbed in sleep apnea. In spite of different pathophysiologies, recurrence of events is common to obstructive, central, and mixed sleep apneas. Oscillations in ventilation during sleep likely occur due to alterations in feedback control of breathing (Strohl et al., 1986; Strohl and Olson, 1987). There is reduction of upper airway muscle tone during sleep with depression of the activity of the upper airway muscles leading to increased upper airway resistance. Obstructive apnea during sleep occurs due to an imbalance of activity of the upper airway muscle and the chest wall muscles. During inspiration, upper airway obstruction may occur unless the negative pressure resulting from the chest wall muscle contraction is effectively counteracted by the force of the extrathoracic pharyngeal dilator muscles. The benefit of positive airway pressure (PAP) use in obstructive sleep apnea came from the observation that the upper airway can be obstructed by negative pressure applied to the nose (Sullivan et al., 1984). It was observed that application of nasal PAP served as a pneumatic splint to maintain upper airway patency and resulted in the improved sleep architecture and continuity (Sullivan et al., 1981). Physiologic concepts are now focusing on forces that either counteract or work together to predispose to upper airway collapse and apnea genesis. Principles are
350
T. WATERS AND R. MEHRA
emerging that will position the field for a personalized approach to the treatment of sleep-related breathing disorders. Physiologic processes that are being explored for treatment potential include (1) critical closing airway pressure (Pcrit), (2) responsiveness to disturbance resulting in perpetuation of apnea (or sensitivity of the ventilator control system), (3) recruitment of the airway muscles responsible for airway patency, and (4) arousal threshold during sleep (Eckert et al., 2013). Patients will be defined as having risk of OSA due to anatomic factors, anatomic and other contributing factors, or nonanatomic factors (Owens et al., 2015). It is becoming apparent that these factors do not operate alone. Treatment strategies will need to address multiple contributing factors.
Critical closing pressure of the upper airway Critical closing pressure (Pcrit) has historically been considered the gold-standard measurement of collapsibility of the upper airway. Although nonanatomic factors can influence OSA propensity, in the majority of patients with OSA, mechanical upper airway collapsibility plays an important role. Conceptually, this is based on the notion that, in those with OSA, the pharyngeal airway collapses during sleep like a Starling resistor (Schwartz et al., 1989; Gleadhill et al., 1991). When the downstream pressure in a Starling resistor drops below a key (or critical) level, a “choke point” or Pcrit occurs, preventing further decrements. Increased negative intraluminal pressure in the airway occurs during inspiration when the diaphragm generates negative pressure, reducing the airway size. Standard methods to measure Pcrit involve assessment while individuals are using CPAP, allowing for minimization of the role of pharyngeal dilator activity (Smith et al., 1988). Pcrit is then determined and defined as the estimated nasal pressure at which the passive upper airway collapses, resulting in cessation of airflow (Smith et al., 1988). An important assumption is that the level of CPAP applied results in minimization of the pharyngeal dilator activity and does not heavily influence the Pcrit measurement being obtained during the five breaths used to quantify this measure. In support of this, data from existing studies support the notion of progressive increases in Pcrit in healthy individuals, compared with snorers and those patients with OSA (Schwartz et al., 1988; Gleadhill et al., 1991). There are complexities in understanding the role of the Pcrit in OSA pathophysiology, given the interacting influences of other nonanatomic factors. Pcrit measurement is influenced by genioglossus (but not tensor palatine) activity, which declines from wakefulness to sleep, further declining from N3 to N2 sleep to REM sleep (Carberry et al., 2016). Furthermore, muscle efferent
output leading to mechanical changes in the airway are difficult to measure in the presence of edema (Strohl et al., 2012).
Loop gain The ability to maintain arterial oxygen and carbon dioxide concentrations within a narrow range is the result of tight regulation via multiple feedback loops, including chemoreceptors for oxygen and carbon dioxide, intrapulmonary stretch receptors, and respiratory muscle afferents. Ventilatory control can be conceptualized as a mechanical system regulated by multiple feedback loops (loop gain system). Such a system responds vigorously to an external stimulus, whereas a low loop gain system responds in a more muted fashion (White, 2005). The key components of loop gain are controller gain and plant gain. Controller gain is characterized by hypoxic and hypercapnic chemoresponsiveness, and plant gain by effectiveness of the respiratory system to clear CO2 given a specific level of ventilation. A high loop gain system reflects ventilatory instability and a destabilized system, whereas in a lower loop gain system a respiratory disturbance would result in a response, with quick resumption of ventilation. High loop gain systems can occur in situations in which there is a high controller gain that may be observed in individuals with higher chemosensitivity. Examples include high-altitude periodic breathing, central sleep apnea– Cheyne–Stokes respirations, idiopathic central sleep apnea, and OSA. For those with high loop gain, supplemental oxygen has been shown to reduce loop gain and thereby reduce OSA severity gain (Wellman et al., 2008); CPAP also can stabilize ventilation by reducing loop gain as the ventilatory response to CO2 decreases (Loewen et al., 2009; Salloum et al., 2010). Data support the utility of oral appliance therapy in those patients with OSA who have lower loop gain (Edwards et al., 2016).
Upper airway muscle recruitment Poor pharyngeal muscle responsiveness during sleep is another physiologic feature contributing to OSA. Inadequate responsiveness of the upper airway dilator muscles during sleep is recognized by minimal increase in EMG activity to negative pharyngeal pressure (Eckert et al., 2013). The inability to mount the necessary level of neural drive to the upper airway muscles during sleep in response to negative intraluminal airway pressure contributes to the pathogenesis of OSA. In one particular study, more than one-third of patients with OSA generated less than 0.1% increase in maximal genioglossal activity in response to a 1-cm water pressure decline in negative pharyngeal pressure, consistent with marked
CLINICAL NEUROPHYSIOLOGY OF APNEA compromise in responsiveness (Eckert et al., 2013). Suboptimal muscle responsiveness has been identified as a salient factor in many individuals with OSA, and data suggest a specific problem in effectiveness of the upper airway neural drive on mechanical opening of the airway ( Jordan et al., 2007; Patil et al., 2007). Some data also suggest that both increased mechanical loads and blunted neuromuscular responses are necessary for development of OSA (Patil et al., 2007).
Arousal threshold It is estimated that one-third of patients with OSA have a reduction in the arousal threshold, resulting in disruption of sleep and premature awakenings, preventing sufficient upper airway muscle recruitment to maintain upper airway patency (Eckert et al., 2013). Changes in sleep state may represent periods of vulnerability to ventilator stability. In fact, even though conventional wisdom in the treatment of OSA is to avoid medications such as sedative hypnotics that can theoretically result in reduction of upper airway muscle tone, recent literature has highlighted the notion that certain sedative hypnotic medications, such as eszopiclone, result in increases in the respiratory arousal threshold and improvement in OSA as defined by the apnea hypopnea index (Eckert et al., 2011). An important caveat is that for those patients who have severe oxygen desaturation accompanying OSA, hypnotics are contraindicated, given potential to prolong time to arousal, worsening hypoxemia and hypercapnia. A genetic predisposition may affect the intensity of cortical arousals and associated cardiovascular influences which evidence supports is consistent within individuals, however, heterogeneous within populations (Poon and Song, 2014).
CONCLUSION Breathing during wake and sleep involves preservation as well as adjustability of salient neuroanatomic and neural network pathways involving specific key respiratory networks: central and peripheral chemosensitivity, motoneurons, and upper airway muscle physiology. Critical closing pressure of the upper airway, altered loop gain, blunted responsiveness of upper airway muscle recruitment, and reductions in arousal threshold contributing to ventilatory instability are factors that either separately or in combination will play a role in the future individualized treatment of sleep apnea. Current management strategies that are “one approach fits all” are suboptimal. Scientific advancements have allowed for development of novel therapeutics targeting specific aspects of respiratory physiology, such as the hypoglossal nerve, the role of the mu receptors in the pre-B€ otzinger complex, and carotid body denervation.
351
REFERENCES Andreotti F, Davies GJ, Hackett DR et al. (1988). Major circadian fluctuations in fibrinolytic factors and possible relevance to time of onset of myocardial infarction, sudden cardiac death and stroke. Am J Cardiol 62: 635–637. Baccelli G, Guazzi M, Mancia G et al. (1969). Neural and non-neural mechanisms influencing circulation during sleep. Nature 223: 184–185. Bassiri Gharb B, Tadisina KK, Rampazzo A et al. (2015). Microsurgical anatomy of the terminal hypoglossal nerve relevant for neurostimulation in obstructive sleep apnea. Neuromodulation 18: 721–728. Bexton RS, Vallin HO, Camm AJ (1986). Diurnal variation of the QT interval—influence of the autonomic nervous system. Br Heart J 55: 253–258. Burke PG, Kanbar R, Basting TM et al. (2015). Statedependent control of breathing by the retrotrapezoid nucleus. J Physiol 593: 2909–2926. Carberry JC, Jordan AS, White DP et al. (2016). Upper airway collapsibility (Pcrit) and pharyngeal dilator muscle activity are sleep stage dependent. Sleep 39: 511–521. Chase MH, Morales FR (2005). Control of motoneurons during sleep. In: MH Kryger, T Roth, WC Dement (Eds.), Principles and practice of sleep medicine, fourth edn. WB Saunders, Philadelphia. Dempsey JA, Smith CA (2014). Pathophysiology of human ventilatory control. Eur Respir J 44: 495–512. Douglas NJ, White DP, Weil JV et al. (1982). Hypercapnic ventilatory response in sleeping adults. Am Rev Respir Dis 126: 758–762. Duffin J (2004). Functional organization of respiratory neurones: a brief review of current questions and speculations. Exp Physiol 89: 517–529. Eckert DJ, Butler JE (2017). Respiratory physiology: understanding the control of ventilation. In: MH Kryger, T Roth, WC Dement (Eds.), Principles and practice of sleep medicine, sixth edn. Elsevier, Philadelphia. Eckert DJ, McEvoy RD, George KE et al. (2007). Genioglossus reflex inhibition to upper-airway negativepressure stimuli during wakefulness and sleep in healthy males. J Physiol 581: 1193–1205. Eckert DJ, Malhotra A, Lo YL et al. (2009). The influence of obstructive sleep apnea and gender on genioglossus activity during rapid eye movement sleep. Chest 135: 957–964. Eckert DJ, Owens RL, Kehlmann GB et al. (2011). Eszopiclone increases the respiratory arousal threshold and lowers the apnoea/hypopnoea index in obstructive sleep apnoea patients with a low arousal threshold. Clin Sci (Lond) 120: 505–514. Eckert DJ, White DP, Jordan AS et al. (2013). Defining phenotypic causes of obstructive sleep apnea. Identification of novel therapeutic targets. Am J Respir Crit Care Med 188: 996–1004. Edwards BA, Andara C, Landry S et al. (2016). Upper-airway collapsibility and loop gain predict the response to oral appliance therapy in patients with obstructive sleep apnea. Am J Respir Crit Care Med 194: 1413–1422.
352
T. WATERS AND R. MEHRA
Fung ML (2014). Pathogenic roles of the carotid body inflammation in sleep apnea. Mediators Inflamm 2014, 354279. Gami AS, Howard DE, Olson EJ et al. (2005). Day-night pattern of sudden death in obstructive sleep apnea. N Engl J Med 352 (12): 1206–1214. Gleadhill IC, Schwartz AR, Schubert N et al. (1991). Upper airway collapsibility in snorers and in patients with obstructive hypopnea and apnea. Am Rev Respir Dis 143: 1300–1303. Heiser C, Thaler E, Boon M et al. (2016). Updates of operative techniques for upper airway stimulation. Laryngoscope 126 (Suppl. 7): S12–S16. Horner RL (1996). Motor control of the pharyngeal musculature and implications for the pathogenesis of obstructive sleep apnea. Sleep 19: 827–853. Horner RL (2017). Respiratory physiology: central neural control of respiratory neurons and motoneurons during sleep. In: MH Kryger, T Roth, WC Dement (Eds.), Principles and practice of sleep medicine, sixth edn. Elsevier, Philadelphia. Huikuri HV, Yli-Mayry S, Linnaluoto MK et al. (1995). Diurnal fluctuations in human ventricular and atrial refractoriness. Pacing Clin Electrophysiol: PACE 18: 1362–1368. Jordan AS, Wellman A, Heinzer RC et al. (2007). Mechanisms used to restore ventilation after partial upper airway collapse during sleep in humans. Thorax 62: 861–867. Legramante JM, Marciani MG, Placidi F et al. (2003). Sleeprelated changes in baroreflex sensitivity and cardiovascular autonomic modulation. J Hypertens 21: 1555–1561. Leung RS (2009). Sleep-disordered breathing: autonomic mechanisms and arrhythmias. Prog Cardiovasc Dis 51: 324–338. Lo YL, Jordan AS, Malhotra A et al. (2007). Influence of wakefulness on pharyngeal airway muscle activity. Thorax 62: 799–805. Loewen A, Ostrowski M, Laprairie J et al. (2009). Determinants of ventilatory instability in obstructive sleep apnea: inherent or acquired? Sleep 32: 1355–1365. Mancia G (1993). Autonomic modulation of the cardiovascular system during sleep. N Engl J Med 328: 347–349. Mu L, Sanders I (2010). Human tongue neuroanatomy: nerve supply and motor endplates. Clin Anat 23: 777–791. Owens RL, Edwards BA, Eckert DJ et al. (2015). An integrative model of physiological traits can be used to predict obstructive sleep apnea and response to non positive airway pressure therapy. Sleep 38: 961–970. Patil SP, Schneider H, Marx JJ et al. (2007). Neuromechanical control of upper airway patency during sleep. J Appl Physiol (1985) 102: 547–556. Peppard PE, Young T, Barnet JH et al. (2013). Increased prevalence of sleep-disordered breathing in adults. Am J Epidemiol 177: 1006–1014. Poon CS, Song G (2014). Bidirectional plasticity of pontine pneumotaxic postinspiratory drive: implication for a pontomedullary respiratory central pattern generator. Prog Brain Res 209: 235–254. Rekling JC, Feldman JL (1998). PreBotzinger complex and pacemaker neurons: hypothesized site and kernel for respiratory rhythm generation. Annu Rev Physiol 60: 385–405. Rosin DL, Chang DA, Guyenet PG (2006). Afferent and efferent connections of the rat retrotrapezoid nucleus. J Comp Neurol 499: 64–89.
Rowley JA, Badr MS (2017). Anatomy and physiology of upper airway obstruction. In: MH Kryger, T Roth, WC Dement (Eds.), Principles and practice of sleep medicine, sixth edn. Elsevier, Philadelphia. Salloum A, Rowley JA, Mateika JH et al. (2010). Increased propensity for central apnea in patients with obstructive sleep apnea: effect of nasal continuous positive airway pressure. Am J Respir Crit Care Med 181: 189–193. Schwartz AR, Smith PL, Wise RA et al. (1988). Induction of upper airway occlusion in sleeping individuals with subatmospheric nasal pressure. J Appl Physiol (1985) 64: 535–542. Schwartz AR, Smith PL, Wise RA et al. (1989). Effect of positive nasal pressure on upper airway pressure-flow relationships. J Appl Physiol (1985) 66: 1626–1634. Smith PL, Wise RA, Gold AR et al. (1988). Upper airway pressure-flow relationships in obstructive sleep apnea. J Appl Physiol (1985) 64: 789–795. Smith JC, Ellenberger HH, Ballanyi K et al. (1991). PreBotzinger complex: a brainstem region that may generate respiratory rhythm in mammals. Science 254: 726–729. Somers VK, Dyken ME, Mark AL et al. (1993). Sympatheticnerve activity during sleep in normal subjects. N Engl J Med 328: 303–307. Somers VK, Dyken ME, Clary MP et al. (1995). Sympathetic neural mechanisms in obstructive sleep apnea. J Clin Invest 96: 1897–1904. Strohl KP, Olson LG (1987). Concerning the importance of pharyngeal muscles in the maintenance of upper airway patency during sleep. An opinion. Chest 92: 918–920. Strohl KP, Cherniack NS, Gothe B (1986). Physiologic basis of therapy for sleep apnea. Am Rev Respir Dis 134: 791–802. Strohl KP, Butler JP, Malhotra A (2012). Mechanical properties of the upper airway. Compr Physiol 2: 1853–1872. Sullivan CE, Issa FG, Berthon-Jones M et al. (1981). Reversal of obstructive sleep apnoea by continuous positive airway pressure applied through the nares. Lancet 1: 862–865. Sullivan CE, Issa FG, Berthon-Jones M et al. (1984). Pathophysiology of sleep apnea. In: NA Saunders, CE Sullivan (Eds.), Sleep and breathing. Marcel Dekker, New York, pp. 299–364. Verrier RL, Josephson ME (2009). Impact of sleep on arrhythmogenesis. Circ Arrhythm Electrophysiol 2: 450–459. Wellman A, Malhotra A, Jordan AS et al. (2008). Effect of oxygen in obstructive sleep apnea: role of loop gain. Respir Physiol Neurobiol 162: 144–151. White DP (2005). Pathogenesis of obstructive and central sleep apnea. Am J Respir Crit Care Med 172: 1363–1370. Zemaityte D, Varoneckas G, Sokolov E (1984). Heart rhythm control during sleep. Psychophysiology 21: 279–289. Zhang Z, Zhang C, Zhuang J et al. (2012). Contribution of central mu-receptors to switching pulmonary C-fibersmediated rapid shallow breathing into an apnea by fentanyl in anesthetized rats. Brain Res 1469: 73–81.
FURTHER READING Strohl KP, Redline S (1996). Recognition of obstructive sleep apnea. Am J Respir Crit Care Med 154: 279–289.