Chapter 1

Physiology and neural control of breathing during sleep

L.C. McKay*, A. Atalla#," and M.J. Morrell#,"

Summary
Sleep represents a period of vulnerability to ventilatory irregularities, even in healthy individuals. Moreover, the presence of disease magnifies both the risk and the consequences of sleepdisordered breathing. Respiratory disorders during sleep are highly prevalent in the population but despite this the underlying mechanisms leading to breathing instability remain poorly understood because of the limitations related to studying humans and the lack of non-mammalian models that can mimic the complexity of this integrated, physiological system. In this chapter we have reviewed the present understanding of brainstem respiratory control in non-mammalian models and how this control is modulated during sleep. Although much remains to be resolved, animal models are invaluable for the understanding of human respiratory control and vice versa. In humans, the onset of sleep brings about a number of physiological changes that have also been reviewed, such as a reduction in alveolar ventilation and chemosensitivity, as well as an increase in upper airway resistance. Moreover, the concept of loop gain has been used to predict the response of the respiratory control system to the sleep-related changes and hence, stability of breathing. It is hoped that combining evidence from these different models and methodologies will increase understanding of the respiratory control during sleep. Likewise, being aware of the pathophysiological mechanisms that lead to, or present as, sleep-disorderd breathing will result in improved clinical management and inform more targeted therapies. Keywords: Apnoea, chemosensitivity, loop gain, respiratory control, sleep-disordered breathing, upper airway
*Institute of Neuroscience and Psychology, University of Glasgow, Glasgow, # National Heart and Lung Institute, Imperial College London, and " Academic Unit of Sleep and Ventilation, Royal Brompton Hospital, London, UK. Correspondence: A. Atalla, Unit of Sleep and Ventilation, Royal Brompton Hospital, Sydney Street, London, SW6 3NP, UK, E-mail a.atalla@imperial.ac.uk

Eur Respir Mon 2010. 50, 116. Printed in UK all rights reserved. Copyright ERS 2010. European Respiratory Monograph; ISSN: 1025-448x. DOI: 10.1183/1025448x.00023909

L.C. MCKAY ET AL.

reathing is a unique, essential and continuous behaviour in mammals, constantly adapting to changes in environmental and behavioural conditions in order to maintain blood gas homeostasis from birth until death. Understanding the neural and physiological mechanisms that control breathing is an important challenge. Failure to maintain a normal breathing pattern, as occurs in diseases such as sleep-disordered breathing (SDB) and congenital hypoventilation syndrome, leads to serious health problems, a diminished quality of life and even death. In the 12 yrs since the previous European Respiratory Monograph (ERM) great progress has been made in the understanding of the physiology of breathing. Animal and human data have produced a more complete view of central respiratory rhythm generation and how the neural outputs are modulated during sleep. In this chapter the current views on animal models of respiratory rhythm generation are discussed and translated into humans, with the aim of elucidating the neural mechanisms associated with respiratory disorders. The concept of loop gain has been used to describe the modulation of breathing during sleep and to provide an outline of how changes in the respiratory control system can initiate and perpetuate SDB. Taking this approach highlights the notion that one event begets another through a process of feedback and feed-forward mechanisms, and that during sleep the respiratory control system is uniquely dependent on these neural networks because there is a loss of wakefulness input. The individual factors that lead to the different types of SDB will be reviewed in detail later on in this edition of the ERM.

Neural control of breathing

The functional importance of the brainstem in respiratory control has long been established. However, the neural mechanisms underlying this control remain poorly understood. Much of what is known comes from non-primate mammalian models, which have greatly improved our knowledge of respiratory control and consequently of human respiratory disorders. This review outlines the current views of the neural control of breathing and how this control is modulated during sleep.

PHYSIOLOGY AND NEURAL CONTROL

Animal models of respiratory rhythm generation

Within the ventrolateral medulla, respiratory related pre-motor and propriobulbar neurones are located in a column extending from the facial nucleus to the upper spinal cord (fig. 1). When isolated, the neonatal rat brainstemspinal cord, which encompasses ventrolateral medullary respiratory neurones, reveals a remarkable property, it continues to generate a rhythmic, respiratory-like motor nerve output [1]. A bilateral cluster of ventrolateral medullary neurones, tzinger Complex (preBo tC), is essential for this rhythmogensis. Indeed, even known as the preBo tC can continue to produce a respiratory-like when isolated in a thin medullary slice the preBo tC neurons are anatomically distinguished from rhythm [2]. A critical subpopulation of preBo other respiratory neurones within the ventrolateral column by their high level of expression of the tC neurones are glutamatergic [6], and a subset neurokinin-1 receptor (NK1R) [35]. These preBo also express the m-opioid receptor [3] and somatostatin [6]. These properties facilitate the tC, allowing it to be specifically targeted in vivo. Bilateral anatomical delineation of the preBo tC NK1R-expressing neurones in the adult rat in vivo, by focal application of the ablation of preBo toxin saporin conjugated to substance P (a neuropeptide that binds to the NK1R), leads to a progressive and irreversible deterioration of breathing pattern [7, 8]. The significance of this finding for the neural control of breathing during sleep is that initially the respiratory disturbances (central apnoeas and hypopnoeas) occur only during rapid eye movement (REM) sleep, eventually progressing into non-REM sleep [8]. The central apnoeas and hypopnoeas then increase in severity and duration until breathing stops at sleep onset and a highly disrupted breathing pattern develops tC NK1R-expressing neurones during wakefulness [7, 8]. Interestingly, unilateral ablation of preBo also leads to SDB but unlike bilateral ablation, breathing during wakefulness is unaffected [9]. tC in maintaining a eupnoeic These in vitro and in vivo studies highlight a key role for the preBo breathing pattern during wakefulness and critically during sleep.

In healthy elderly people and in individuals who suffer from neurodegenerative diseases, such as motor neurone disease, it has been sug tC gested that a gradual loss of preBo NK1R-expressing neurones over time may explain why SDB is highly prevalent in these populations (see following chapters). Studies of human post mortem tissue have anatomically identified a cluster of NK1R-expressing neurones within the reticular formation of the caudal brainstem, presumed to be the tC [10, 11]. It is anticipated preBo that future studies will determine the relationship between any neurodegeneration in this area and the clinical occurrence of SDB (see following sections).

CB

LC NTS

VRC NA Ventral SO VII BC rVG LRN cVG

More recently, a second brainstem site involved in rhythm generation RTN/pFRG preBtC has been proposed. Ventral to the Caudal facial nucleus and rostral to the Figure 1. A parasagittal section through the medulla and caudal tC, there is a cluster of neupreBo pons highlighting the anatomical arrangement of respiratory rones called the retrotrapezoid nuneurones within the ventrolateral medulla. & %: ventrolateral respiracleus (RTN) in adults [1214] and tory column (VRC), including the Bo tzinger complex (BC), the parafacial respiratory group preBo tzinger complex (preBo tC), rostral ventral respiratory group (pFRG) in neonates [15] (fig. 1). (rVG) and caudal ventral respiratory group (cVG). & %: retrotrapezoid nucleus (RTN)/parafacial respiratory group (pFRG) and preBo tC, i.e. The anatomical boundaries and the regions discussed in this chapter. CB: cerebellum; LC: locus functional significance of these areas ceruleus; NTS: nucleus of the solitary tract; NA: nucleus ambiguus; are still under debate and appear to LRN: lateral reticular nucleus, VII: facial motor nucleus; SO: superior depend on the experimental condiolive. tions under which the studies are preformed, as well as the developmental stage being studied. The pFRG is located within the parafacial region in the neonatal rodent. Neurones within the pFRG have a pre-inspiratory discharge pattern [16, 17], which has led to the proposal that they have a primary role in rhythm generation by controlling the timing of inspiratory bursts [15]. Most of the pre-inspiratory bursting pFRG neurones can be anatomically identified by expression of the NK1R and the transcription factor Phox2b. In addition, these neurones are intrinsically sensitive to carbon dioxide and so may also have a role in chemosensitivity [18]. The pFRG neurones are opiate insensitive [19], a property that distinguishes them from the tC [19]. In en bloc opiate-sensitive, rhythm-generating inspiratory neurones within the preBo preparations [20] and in neonatal rats in vivo [21], opiates result in quantal slowing of inspiratory, but not expiratory, activity. Principally this means that inspiration becomes irregular by skipping breaths, whereas expiration continues rhythmically. These data have led to the suggestion that inspiration and expiration are separately controlled and that there are two respiratory generators: tC that drives inspiratory rhythm, and 2) neurones within the parafacial region that 1) the preBo drive expiratory rhythm [2123]. However, it should be noted that breathing in mammals at rest is driven by active inspiration, while expiration occurs passively unless there is a high respiratory drive, e.g. during exercise. If an expiratory oscillator is present, it may only become active during

L.C. MCKAY ET AL.

periods of high respiratory drive or when there is inspiratory depression, e.g. during apnoea. The functional implication of these findings is not yet understood. The pre-inspiratory discharge pattern recorded from neonatal pFRG neurones has never been observed in adult rodent preparations. In adults, neurones within the parafacial region are known as the RTN, a group of glutamatergic, chemosensory interneurones that can be anatomically identified by expression of the NK1R and Phox2b [2427]. Focal acidification of RTN neurones in vivo increases ventilation during wakefulness; however, during sleep there is no ventilatory response [28]. This differs from putative chemosensory neurones within the medullary raphe, which appear to have a greater response to focal carbon dioxide stimulation during sleep compared with wakefulness [29]. Central chemosensitivity remains a highly debated subject because there are many types of neurone that contribute to the chemoresponse and, in addition, the relative contribution of these neurones alters depending on the state of arousal [30, 31]. RTN neurones differ from pFRG neurones in that they are not rhythmically active but since they share the same anatomical markers and are both chemosensitive it is likely that they are the same group of cells, or that they overlap [24, 25]. Recent evidence from a transgenic mouse model has shown that developmental disruption of Phox2b-positive RTN neurones leads to a loss in carbon dioxide/pH sensitivity and lethal respiratory abnormalities at birth [32, 33]. This is of clinical interest because mutations in humans of the homeobox gene PHOX2B, which encodes the transcription factor Phox2b, causes congenital central hypoventilation syndrome (CCHS), a relatively rare genetic disorder with life threatening symptoms that include respiratory arrest during sleep and a reduced or blunted chemoresponse [3439]. Recently a study carried out in human post mortem tissue has identified a cluster of Phox2b-positive and NK1R-expressing neurones under the facial motor nucleus [40], which is presumed to be the site of the human RTN. Further histological studies will determine if these Phox2b-positive neurones are deficient in CCHS patients.

PHYSIOLOGY AND NEURAL CONTROL

Medullary deficits and SDB in humans

Translating observations from animal models of respiratory control to humans is challenging, especially since little is known of the mechanisms underlying respiratory rhythm generation in humans. Lesion deficit models provide some insights into neural respiratory control when there is underlying neuronal damage, presumably of specific brainstem nuclei involved in rhythm tC and/or the RTN. Deficits in generating circuitry and/or chemosensitivity, e.g. the preBo respiratory control are evident in patients with lesions of the bulbospinal pathway [41, 42] or with medullary damage [43, 44], including unilateral, rostrolateral meduallary lesions [45] and syringobulbia (brainstem symptoms or magnetic resonance imaging (MRI) evidence of medullary syrinx) [46]. In all these patients, respiratory motor output appears to be maintained adequately during wakefulness; however, during sleep breathing patterns are severely disrupted by the occurrence of apnoeas and severe hypopnoeas [45, 46]. As previously mentioned, SDB is common in patients with some neurodegenerative diseases, e.g. motor neurone disease [4749], multiple systems atrophy [5053] and Parkinsons disease [54 56], and it has been reported that these patients often die during sleep [49, 53, 56]. In addition, patients with multiple systems atrophy or Parkinsons disease have impaired chemosensitivity [57, 58]. Analyses of post mortem brain tissue from patients with multiple systems atrophy or Parkinsons disease have shown that NK1R-expressing neurones are significantly depleted within tC [10, the ventrolateral medulla [59], which presumably includes the presumptive human preBo 11]. These post mortem analyses have also highlighted a reduction of glutamatergic, serotonergic, putative chemosensory neurones in the brainstem of patients with multiple systems atrophy [60]. Taken together, these results suggest that neuronal loss within the brainstem, including the tC and chemosensitive sites, may have important clinical implications presumptive human preBo in the development of sleep apnoea, such that screening for SDB in high-risk patient groups may be recommended.

Breathing during sleep

Measurements of breathing in awake humans within a laboratory are influenced by volitional factors, i.e. emotional and behavioural adaptations to the laboratory environment and equipment (e.g. face masks). These influences can lead to variability in breathing during wakefulness and an over or under estimation of the sleep-related reduction in breathing [6164].

Wake-to-sleep changes in breathing

The transition from wakefulness to non-REM sleep is associated with changes in breathing pattern described in the seminal studies by BULOW [65]. A sleep-related reduction in minute ventilation of 0.40.9 L?min-1 (611%) occurs during non-REM stage II sleep and of 0.6 L?min-1 (810%) during non-REM stage IV sleep, compared with wakefulness [6569]. The reduction in minute ventilation occurs as a result of tidal volume decreasing by approximately 12%; respiratory frequency is either increased slightly, or unaffected [6569]. The ventilatory changes occur almost immediately at sleep onset (see following section), with the reduction in tidal volume being significantly correlated with a slowing of electroencephalogram (EEG) frequency, particularly in older people [70, 71]. The concurrent reduction in alveolar ventilation is associated with an increase in the alveolar carbon dioxide tension (PA,CO2) from ,2.0 to 6.5 mmHg [62, 63, 72], which is accompanied by a decrease in both carbon dioxide production (of 8.5%) and oxygen consumption (of 12.3%) [73]. A small sleep-related reduction in arterial oxygen saturation (Sa,O2) also occurs during non-REM stage IV sleep (Sa,O2 96.5 %), compared with wakefulness (Sa,O2 97.3%) [69].

Mechanisms of respiratory control at sleep onset

Sleep onset is associated with a loss of the so called wakefulness drive to breathe [74]. The loss of this drive, together with changes in chemosensitivity and the sleep-related reduction in metabolism result in the blood gas changes described previously. The term wakefulness drive to breathe was first used by FINK [74] to describe the influence of cerebral activity during wakefulness on the regulation of breathing. Loss or impairment of this drive may explain, in part, why respiratory control is compromised during sleep. The precise neural substrates supporting the wakefulness drive to breathe are uncertain but are likely to include supra-brainstem structures. Recent brain imaging studies have shown that the primary and sensory cortices, basal ganglia and thalamic nuclei are implicated in volitional and behavioural control [7580]. In addition, brain imaging has identified many regions associated with carbon dioxide stimulated respiratory control, including the limbic system, basal ganglia, thalamus and brainstem [78, 8183]. Although these brain imaging studies provide a greater understanding of the neural basis of respiratory control during wakefulness, none have specifically investigated the changes in the neural control of breathing that occur at sleep onset, due, in part, to the challenges of carrying out such investigations in humans during sleep initiation.
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Stability of the respiratory control system

The wake-to-sleep changes in the neural control of breathing, described previously, occur in the context of a feedback system. The ability to maintain stable breathing during sleep onset is a function of how the respiratory control system responds to ventilatory perturbations which occur at this time. Loop gain is an engineering concept that has been used as a global measure of ventilatory stability. It is composed of the net effect of the actions from various physiological components that modulate breathing, e.g. chemosensitvity. As with all feedback systems, a high level of sensitivity carries a greater risk of instability, whereas a low or blunted sensitivity may leave a system unable to respond adequately or appropriately when required. In the respiratory control system it follows that if the feedback system is oversensitive the response to an apnoea may be greater in magnitude than that of the initial perturbation. This situation would

predispose the respiratory system to instability because the feedback loop would magnify the initial insult. Conversely, if the response to the initial perturbation is smaller in magnitude then the effect of the perturbation will be dampened without any system overshoot. In summary, the magnitude of the loop gain influences the ability of the respiratory system to maintain stable breathing during sleep.

Loop gain in healthy people and patients with obstructive sleep apnoea
Loop gain can be quantified numerically as the ratio between the respiratory response to a perturbation and the perturbation itself. A loop gain .1.0 describes a respiratory system where the response is greater than the insult and so is prone to instability. A loop gain ,1.0 describes a system where an insult will be dampened or smoothed out by a response smaller than the insult itself. WELLMAN et al. [84] found that loop gain was low (,0.78) in healthy adult males and females (aged 2248 yrs), with no significant difference between sexes. The same group also investigated loop gain in a healthy elderly population (aged 715 yrs) [85] and found loop gain to be low when compared with younger subjects. These data show that loop gain does not increase with age, as might be predicted if loop gain were to be used as a marker for the higher prevalence of SDB in older adults. Indeed, the age-related increase in SDB is more likely to be caused by changes in upper airway anatomy and physiology. Nevertheless, the measurement of loop gain in patients with obstructive sleep apnoea (OSA) may be a useful characteristic that could identify individuals predisposed to apnoea, due to ventilatory instability rather than closure of the upper airway per se [86, 87].

The components of loop gain

PHYSIOLOGY AND NEURAL CONTROL

Loop gain is the product of controller, plant and feedback gains (fig. 2). The term controller gain describes the chemosensitivity of the respiratory control system (see Sleep-related changes in chemosensitivity section). Plant gain describes the efficiency with which ventilation removes carbon dioxide from the body; therefore, any factor interfering in this process will tend to increase plant gain and have a destabilising effect on respiratory control. Reduced lung volumes, a low cardiac output or impairment in the gas transfer surface may all contribute to a high plant gain [88]. Feedback gain describes the interval between a change in PA,CO2 in the lungs and the transmission of that change to the chemoreceptors which elicit a response. It is comprised of circulatory delay and is characteristic of all systems incorporating feedback and so is not, in and of itself, pathological. The ventilatory instability now well described in patients with heart failure and CheyneStokes respiration (CSR) was thought to be related almost exclusively to this component of loop gain. While circulatory delay is a pathophysiologically plausible cause for the cyclical pattern of ventilation seen in classical CSR, it is important to note that data to support this assumption is lacking. In a canine model circulation time had to be increased far beyond that which occurs physiologically in heart failure patients in order to provoke CSR [89]. The lung to ear circulation time, which is inversely correlated with cardiac output [90], is well correlated with the CSR/central sleep apnoea (CSA) cycle length [91], and in particular the duration of the hyperpnoea, but not the apnoea component of the CSR cycle [90]. Taken together, these data suggest that there are factors, in addition to circulation time, which influence the length of the apnoea, at least in heart failure patients with central SDB.

Modelling loop gain in CSA

Mathematical modelling allows an analysis of the individual components contributing to loop gain and permits an examination of the role played by each factor in isolation, in a way that is often not possible with in vivo testing in the laboratory [9294]. One such model from MANISTY et al. [94] found that independently increasing chemosensitvity and mean carbon dioxide, increased loop gain and so destabilised breathing. These findings appear to be contrary to experimental evidence

Controller gain The ventilatory response to a change in carbon dioxide Contributing factors: Hypercapnic ventilatory response Cerebrovascular reactivity Loop gain The product of controller plant and feedback gains

Feedback gain Dissipates and delays the change in carbon dioxide by mixing with blood between alveoli and the chemoreceptors Contributing factors: Reduction in cardiac output Prolonged circulation time Increased cardiac chamber size Circulating blood volume

Plant gain The efficiency with which ventilation removes carbon dioxide from the body Contributing factors: Transfer factor (DL,CO) Metabolic rate Lung volumes Cardiac output: low output causing pulmonary and reduced DL,CO

Figure 2. Simplified chemical feedback loop illustrating the concept of loop gain as a product of controller,
plant and feedback gains, and their contributing factors. Loop gain can be used to predict the response of the respiratory control system to changes in ventilation during sleep and so determine the stability of breathing during sleep. DL,CO: diffusing capacity of the lung for carbon monoxide. Adapted and reproduced from [84] with permission from the publisher.

which suggests that the proximity of the eupnoeic carbon dioxide to the apnoeic threshold (see Hypocapnicapnoeic threshold section) is a key factor in inducing respiratory instability. This may be because their theoretical model failed to incorporate the fact that a high PA,CO2 per se (induced physiologically via hypoventilation) can increase plant gain, reduce carbon dioxide reserve and promote instability, due of the shape of the metabolic hyperbole (specifically at high PA,CO2 less ventilation is required to promote instability; fig. 3a). This concept has been shown experimentally by NAKAYAMA et al. [95] who used acetazolamide and sodium hydrogen carbonate to lower and raise carbon dioxide without changing controller gain, and caused instability with a very narrow carbon dioxide reserve.

Sleep-related changes in chemosensitivity

Central and peripheral chemoreceptor responses are key components of the neural control of breathing during sleep and profoundly influence controller gain. Changes in arterial carbon dioxide tension (Pa,CO2) bring about changes in cerebral spinal fluid pH, which elicit a central chemoreceptor response resulting in an appropriate change in ventilation. Cerebral blood flow is exceptionally sensitive to carbon dioxide levels which serves to moderate the stimulation of the central chemoreceptors. The cerebral blood flow response to carbon dioxide, quantified by measurement of hypercapnic cerebral vascular reactivity is reduced in non-REM sleep and upon waking in comparison to day time wakefulness in healthy subjects [96, 97]; this equates to a reduction in controller gain (fig 2). More recent evidence suggests that patients with OSA have blunted hypercapnic cerebral vascular reactivity, which could in turn exacerbate respiratory instability by reducing controller gain and thus exaggerating the accumulation of Pa,CO2 at central chemoreceptors during an apnoea [98], although conversely it could also dampen the subsequent hyperventilation. The hypercapnic ventilatory response (HCVR) is used to describe the relationship between a given carbon dioxide load and the resultant ventilatory response, and is also a reflection of controller gain. It is well documented that ventilatory sensitivity to carbon dioxide fluctuates with the circadian

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a) 12 10 8 VA min 6 4 2 0 b) 12 10 8 VA min 6 4 2 0 20 25 30 35 40 PA,CO2 Torr 45 50 55 Hyperventilation Hypoventilation

rhythm [99] and is reduced, along with the ventilatory sensitivity to oxygen [66, 100], during non-REM sleep. These physiological changes result in sleep being a time of permissive hypercapnia, where an arousal from sleep brings about a fall in carbon dioxide to waking levels (fig. 4). Upon resumption of sleep this relative hypocapnoea may be a cause of ventilatory instability because of its proximity to the apnoeic threshold [73, 101, 102]. The HCVR is variable both within and between individuals. It is influenced by both sex [103] and age [104], with older people having a lower HCVR than younger people [104]. However, the wake-to-sleep reduction in HCVR is similar in both age groups [105]. Therefore, it seems unlikely that the increased prevalence of SDB in older people is caused by changes in the controller gain.

PHYSIOLOGY AND NEURAL CONTROL

Figure 3. Diagrammatic representation of the relationship between

alveolar ventilation (VA) and alveolar carbon dioxide tension (PA,CO2) at a fixed resting carbon dioxide production of 250 mL?min-1. a) The effect of a change in plant gain where alveolar hyperventilation reduces PA,CO2 and displaces the eupnoeic set point to the left on this curve, the shape of which means that a relatively greater change in ventilation is required to drive PA,CO2 below the hypocapnic apnoeic threshold (????????). Conversely, when the PA,CO2 is high (a right shift on the curve) a relatively smaller change in ventilation is required to reach the apnoeic threshold. b) Demonstrates how a change in the ventilatory response to carbon dioxide (controller gain: bc) alters the carbon dioxide reserve, i.e. the proximity of the eupnoeic carbon dioxide ($) to the apnoeic threshold (#). A reduction in the hypercapnic ventilatory response (above eupnoea: b???c) would require a relatively bigger change in ventilation to drive PA,CO2 below the hypocapnic apnoeic threshold, compared to a brisker hypercapnic ventilatory response (b??????c). Adapted and reproduced from [73] with permission from the publisher.

Hypocapnicapnoeic threshold

It has been shown experimentally that apnoea can be induced during sleep when Pa,CO2 is decreased by 2 4 mmHg below eupnoeic values, i.e. to approximately the waking Pa,CO2 level [106108]. Conversely, it has been known for many years that if the same experiment is performed during wakefulness, hypocapnia may promote increases or decreases in respiratory motor output [61], presumably reflecting wakefulness and/ or volitional inputs to the central neural respiratory controller that are not present during sleep (see Mechanisms of respiratory control at sleep onset section). Removal of these inputs at the wakesleep transition unmasks a highly sensitive hypocapnic-dependent apnoeic threshold (fig. 5). The proximity of the sleeping eupnoeic Pa,CO2 to the hypocapnicapnoeic threshold is a factor that will increase the propensity to develop central SDB. This has been shown experimentally in patients with heart failure in whom the sleep-related increase in Pa,CO2 is relatively small [102]; however, it is important to remember that hypocapnoea per se is not a source of respiratory instability [73]. Considered in the context of the metabolic hyperbole (fig. 3), alveolar hyperventilation reduces PA,CO2 and displaces the eupnoeic set point to the left on this curve, the shape of which means that a relatively greater change in ventilation is required to drive PA,CO2 below the hypocapnic apnoeic threshold. Conversely, when the PA,CO2 is high the shape of this curve

dictates that a relatively smaller change in ventilation is required to reach the apnoeic threshold, increasing plant gain and reducing the carbon dioxide reserve (fig. 3a). This model assumes that chemosensitivity (controller gain) above and below the apnoeic threshold is similar (fig. 3b).

C4A1 O1A2 Right EOG Left EOG Chin EMG Effort sum RC effort Abdom effort

The role for peripheral chemoreceptors

Figure 4. A 7-min epoch of a polysomnogram illustrating a cortical The focus of this chapter has been arousal and the subsequent increase in ventilation (shown clearly on the role of the central chemothe effort sum trace) and resulting decrease in end-tidal carbon receptors in the neural control of dioxide tension tension (PET,CO2) The resumption of sleep is followed breathing, with the notion that by the emergence of periodic breathing and accompanying fluctuations in PET,CO2. C4A1/O1A2: electroencephalograms from the C4A1 changes in Pa,CO2 bring about and O1A2 reference points (international 1020 system of electrode changes in cerebral spinal fluid placement); EOG: electroocculogram; EMG: electromyogram; RC: pH that cause the central cheribcage (thoracic effort); Abdom: abdominal effort; Sum: abdomimoreceptors to respond. There is, nal+ribcage movements; Sa,O2: arterial oxygen saturation. however, state-of-the-art evidence pointing to an interaction between peripheral and central chemoreceptors, which cannot be ignored. SMITH et al. [109] have carried out a comprehensive review on this subject. This interaction is not the traditional interdependence between Pa,CO2 and arterial oxygen tension levels observed within the carotid body, but rather a more controversial suggestion that the carotid chemoreceptors exert a modulatory influence on the central chemoreceptors [110]. The finding that the peripheral chemoreceptors were obligatory to cause a hypocapnic induced apnoea in a sleeping dog model supports this notion [111]. Indeed without participation from the carotid bodies the functionally isolated central chemoreceptors do not produce central apnoeas during sleep, even in the face of substantial hypocapnia [112].

The effect of sleep on the upper airway

Sleep is associated with a reduction in both efferent activity to the thoracic muscles and a reduction in hypoglossal motor output to the upper airway muscles. In young, nonobese people, who do not snore, the sleep-related reduction in neural drive results in a relatively small increase in total pulmonary resistance of ,3 cmH2O?L-1?s-1 [63], whereas in people who snore the increase can be 20 times greater, e.g. between ,970 cmH2O?L-1?s-1 [113115]. The change in upper airway resistance occurs almost simultaneously with the wake-to-sleep transition in the EEG frequencies [116] and is accompanied by a decrease in ventilation [117, 118]. Upper airway patency is, therefore, compromised in sleep and this is the mechanistic basis for obstructive SDB. More recent studies of the mechanisms of OSA have tried to quantify the relative contribution of ventilatory instability (as measured by loop gain) and upper airway susceptibility (as measured by pharyngeal closing pressure) to airway collapse, as a means of phenotyping patients [119]. In patients with a more collapsible airway the correlation between loop gain and apnoea/hypopnoea index (AHI) is poor. However, in those with an intermediate closing pressure, i.e. near atmospheric, there is a significant correlation between AHI and loop gain. These data support the notion that even in patients with clinically significant obstructive SDB ventilatory instability is likely to play a role.

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a)

Subject awake Onset at start of trace of sleep

Arousal from sleep

Upper airway load compensation during sleep

The sleep related increase in upper airway resistance presents a mechanical load to the upper airway that has to be overcome during sleep if stable breathing is to be maintained. Experimentally, if a mechanical load is imposed on the upper airway during wakefulness the ventilatory response is highly variable [120]. Minute ventilation is usually maintained by an immediate prolongation of inspiratory time coupled with an increase in inspiratory muscle activity [120124]. In contrast, during sleep the application of a ventilatory load typically results in a significant fall in tidal volume and minute ventilation [120125]. Any compensation to such a respiratory load may occur as a result of increased chemostimulation, or be due to mechanoreceptors and reflex mechanisms. During sleep the ability to elicit such compensation is protective and is key to maintaining airway patency. The process of mechanical compensation will be dealt with in more detail in subsequent chapters. In brief, negative pressure reflexes have been demonstrated in response to deformation of the upper airway, resulting in augmented hypoglossal nerve activity and subsequent genioglossus electromyogram (EMG) activity that stiffens the airway and reduces the propensity to closure [126]. Conversely, application of an upper airway load can also reduce central respiratory motor output, which means that negative intrathoracic pressure or collapsing pressure is diminished and the airway is less likely to narrow or close [127, 128]. This latter property may lead to a reflex inhibition of phrenic nerve activity during the collapse and deformation of the upper airway, such as occurs during CSA.

Pmask cmH2O PET,CO2 PET,O2

VT 1L 30 0 6% 0% AIR 10% b) Pre-2 1st missed breath

EEG 50 v

10 s 2nd missed Post-1 breath

Post-2 Post-3

PHYSIOLOGY AND NEURAL CONTROL

Cir cu de lator lay y

7.416 (40.9)

7.414 (41.1)

7.414 (41.1) 7.408 (42.0)

pHa 7.415 units Pa,CO2 41.0 mmHg

7.400 (43.0)

7.409 (41.8)

Figure 5. Traces illustrating the effect of sleep onset on breathing. a) Tracings from a healthy subject illustrating the effect of transition from a to h activity on ventilation. Two a breaths are followed by a h breath and associated apnoea. Proportional assist ventilation maintains waking levels of carbon dioxide tension despite the onset of sleep. b) A schematic diagram of the data from (a) illustrating the relationship between tidal volume (VT) arterial pH (pHa; measured using a rapidly adapting intra-arterial electrode) and arterial carbon dioxide tension (Pa,CO2) before, during and after a h breath (values of pHa and Pa,CO2 are an average of 12 h breaths in this subject). Breathing stops during h activity when Pa,CO2 is 41.1 mmHg (below the apnoeic threshold). There is no significant change in pHa or Pa,CO2 until the end of the h breath, when mean pHa (7.408 units) is significantly lower and Pa,CO2 higher (42 mmHg), than during the pre-2 breath (7.415 units and 40.9 mmHg, respectively). Breathing resumes when Pa,CO2 reaches 42 mmHg. Note that the levels of Pa,CO2 that were sufficient to maintain breathing during wakefulness (40.9 mmHg), are insufficient during sleep due to the loss of the wakefulness drives to breath and changes in chemosensitivity. EEG: electroencephalogram; Pmask: mask pressure; PET,CO2: end-tidal carbon dioxide tension; PET,O2: end-tidal oxygen tension. Adapted and reproduced from [108] with permission from the publisher.

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Upper airway calibre during sleep

Upper airway imaging has shown that that the size of the pharyngeal airway lumen is reduced in sleep compared with wakefulness [129, 130]. Moreover, the typical pattern of inspiratory and expiratory airway narrowing seen in healthy people during non-REM sleep is exacerbated in people who snore or who have a mild degree of SDB [131]. During inspiration the airway lumen narrows substantially [132]; however, this inspiratory narrowing does not appear to be the critical determinant of airway closure. Rather, the progressive narrowing during the mid-to-late expiratory period determines the cross-sectional area of the airway lumen at end expiration, which is in turn linked to airway closure during the subsequent obstructive apnoea [133]. Remarkably, narrowing and even collapse of the upper airway has also been shown to occur during central sleep apnoea, when intrathoracic pressure does not become more negative [134]. This (passive) collapse of the upper airway will lead to the reflex inhibition of phrenic nerve activity (as described previously), which would prolong the apnoea.

Breathing during REM sleep

REM sleep is a particular time of vulnerability for the respiratory control system with both inhibition of respiratory muscles and damped chemosensitivity. In particular, the REM-related muscle atonia and lack of upper airway reflexes are likely to contribute to the increased prevalence of airway obstruction and sleep disordered breathing in REM.

Changes in respiratory control during REM sleep

REM sleep is associated with a 515% reduction in ventilation compared with wakefulness [135, 136] and respiratory rate is more variable; notably during phasic REM, which is associated with an increase in respiratory frequency and a fall in tidal volume. Moreover, upper airway compliance increases and the airway becomes more susceptible to collapse. Upper airway reflex mechanisms also appear to be absent during REM sleep [137, 138]. In addition, there is a sleep associated decrease in the activity of neurones that release serotonin, norepinephrine and histamine, all of which have roles in arousal [139]. This is significant since in the rodent, serotonin and norepinephrine have been tC neurones [140142]; thus, any decrease in their release would disfacilitate shown to excite preBo tC neuronal activity, possibly rendering breathing during sleep more vulnerable. In cats, there preBo is also evidence of a REM endogenous excitatory drive to the respiratory system, which may also account for the irregularities of breathing seen in this state [143].
L.C. MCKAY ET AL.

Chemosensitivity during REM sleep

The ventilatory response to hypercapnia and hypoxia are reduced during REM sleep, specifically during phasic REM when respiratory motor output is reduced and variable in response to a rising chemoreceptor sensory input [66, 100, 144]. However, as previously, there is now some evidence for an REM-related increase in respiratory motor output, although the significance of this is unclear [143]. During REM sleep the respiratory motor output is not systematic and progressive over the length of the apnoea as it is in non-REM sleep. Nevertheless the reduced chemoresponsiveness (controller gain) may act to stabilise breathing during REM sleep by reducing the post-apnoea hyperventilation and ensuing hypocapnia; thus preventing Pa,CO2 falling below the hypocapnic apnoeic threshold [145]. Phasic REM can lead to a reduction in diaphragm EMG due to the premature termination of inspiration, coincident with the REM. The postural muscle atonia may also increase chest wall compliance and cause distortion during inspiratory efforts, thereby compromising neuralmechanical coupling. Finally, REM events can cause fractionation of diaphragmatic EMG activity during inspiration [146], which reduce the diaphragmatic EMG and pressure responses during airway occlusion in REM sleep. If the fractionations also reduce sensory input from the chest wall

11

they may, in turn, prolong obstructive apnoeas during REM sleep by delaying the cortical arousal that occurs to end the apnoeic period [147]; although it has previously been shown that the arousal response in REM sleep is similar to that which occurs in non-REM sleep [148].

Statement of Interest
M.J. Morrell is a co-applicant on a grant from ResMed UK in excess of 5,000.

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