Introduction

The identification of risk factors associated with sudden infant death syndrome (SIDS) has led to significant advances in the prevention of this tragic outcome. The discovery of the prone sleeping position and smoking as two of the major risk factors (1-5) led to worldwide awareness campaigns, such as, for example, the “Back to Sleep” campaign launched in the United States in 1996, and various smoking cessation campaigns (6, 7). These initiatives resulted in a dramatic reduction in the number of children succumbing to SIDS (5, 8). Unfortunately, SIDS still remains the number-one cause of death in infants under 1 year of age in many countries, despite epidemiological and pathological studies that continue to identify additional risk factors, such as hearing deficiencies, or various genetic alterations associated with SIDS (9-11, 12, 13). To parents and families, as well as some health professionals and researchers, the sheer number of suggested risk factors and gene mutations can also be bewildering.

The Triple Risk hypothesis by Dr Hannah Kinney and collaborators (14) can partly resolve this confusion. This hypothesis states that SIDS is caused by an incident in which not just one but three risk factors come together to bring an infant into a situation that leads to the sudden death. Specifically, it was proposed that those factors include [1] a vulnerable infant; [2] a critical period of development in homeostatic control; and [3] an exogenous stressor (14, 15). In other words, in the presence of two risk factors, namely being a vulnerable infant in a critical period of development, a third risk factor (e.g. an exogenous stressor) can become the ultimate cause that triggers an irreversible cascade of events leading to the sudden death.

The Triple Risk hypothesis also has important practical implications. The awareness campaigns have shown that it is possible to significantly reduce the risk of an infant being exposed to exogenous stressors. A potentially more challenging task is to identify the infant who is particularly vulnerable, which is clearly one of the major tasks for research. A better understanding of the characteristics of a vulnerable infant would facilitate the development of strategies that target a specific vulnerability. Similarly, it will be important for research to identify and recognize the specific developmental conditions that characterize the critical period for SIDS, especially if they are dysregulated, or to target the important developmental and homeostatic mechanisms to prevent the death. This chapter will describe how different risk factors can contribute to the sudden death, the failure to arouse, the specific conditions associated with sleep, and the neuronal networks controlling cardiorespiratory functions and how they contribute to the events leading to sudden death. In this context we will review the physiology and pathophysiology of important brainstem mechanisms that are critical for survival, but that can sometimes fail. Understanding how these brainstem mechanisms interact with endogenous and exogenous mechanisms can also facilitate understanding of the significance of a variety of risk factors known to contribute to SIDS.

Sleep and its Implications for SIDS

One of the developmental risk factors for SIDS is sleep, and indeed many SIDS victims die during the morning hours of sleep (16, 17). Infants at the age when SIDS occurs quite frequently spend most of their sleep in a stage known as rapid eye movement or REM sleep. This sleep stage is characterized by the dysregulation of various mechanosensory airway and chemosensory autonomous reflexes that are critical for survival (18, 19). A dysregulation of mechanosensory pathways could be detrimental, since these afferent inputs contribute to a phasic activation of the genioglossus (an extrinsic muscle in the tongue) during inspiration. The phasic activation is critical for keeping the upper airways open during the inspiratory phase and for preventing the pharynx from collapsing during REM sleep (20-24). A role of airway dysfunction and collapse during sleep has been implicated as one of the mechanisms contributing to SIDS (25, 26).

Aside from the effect of sleep on sensory pathways, we know that the release of neurotransmitters and neuromodulators also contributes to the potential complications associated with sleep. The activation of glutamatergic, glycinergic, and gamma-aminobutyric acid (GABA) ergic mechanisms, for example, inhibits premotor neurons projecting to the hypoglossus nucleus in the brainstem, which innervates the genioglossus (27-31). REM sleep is also characterized by decreased activity of neurons that release serotonin (5-HT) or norepinephrine (32). A decrease in activity of noradrenergic and serotonergic neurons (33-35) during REM sleep is particularly significant for understanding SIDS, since disturbances in serotonergic and noradrenergic mechanisms have been implicated as important factors that make a child vulnerable to SIDS (9, 36-39). The REM-specific alterations in reflexes and neuromodulatory control contribute to the vulnerability of an infant to stressors that would not be dangerous in wakefulness or for an older child that developed well-co-ordinated motor behaviors, which allow a child to better cope with dangerous situations occurring during sleep.

Yet not only REM, but also the other sleep stage, namely deep sleep or “slow wave sleep” (SWS), can be challenging to an infant. Specifically, the neuromodulatory milieu during SWS can facilitate the generation of central apneas — that is, periods of breathing cessation that are caused by the central nervous system (40). Indeed, apneas are common in infants, in particular those born prematurely.

Perhaps not surprisingly, healthy children have evolved protective mechanisms that help to overcome dangerous situations which frequently occur during sleep. For example, a child sleeping in a prone position can face a situation in which it breathes into a pillow. This situation, referred to as “rebreathing”, will quickly lead to decreased levels of oxygen (hypoxia) and increased levels of carbon dioxide (CO₂, hypercapnia) (3, 4, 41, 42) (Figure 27.1).

Figure 27.1:

The failure to arouse in the presence of a hypoxic challenge can lead to SIDS. Placing an infant in the prone position to sleep increases the risk of the child rebreathing into a pillow or other bedding. Healthy infants employ protective mechanisms to (more...)

In response to these conditions, a healthy infant will arouse, and as long as the infant can avoid rebreathing by moving its head into a safe position, it will survive. However, two principle scenarios could lead to an infant’s death. First, if the healthy infant cannot escape this situation (e.g. if the infant is covered by heavy blankets), this natural arousal response will not be effective and the infant will suffocate. It should be expected that a suffocation event should not have a gender bias, and could affect male and female infants with a similar likelihood. Alternatively, if the infant is not healthy and/or vulnerable due to various potential risk factors including a genetic brainstem abnormality and/or living in a smoking environment, this vulnerable infant may not arouse and may die in situations that would arouse a healthy infant. It is, for example, conceivable that an infant with a serotonin-abnormality might have a blunted arousal response, which becomes significant if challenged during REM sleep when serotonergic neurons are less active. However, this vulnerable infant would survive if it was never put into a challenging condition that requires those protective arousal responses. These considerations could explain, for example, why a “Back to Sleep” campaign could result in such a dramatic reduction in SIDS deaths, because it reduced the number of vulnerable infants being challenged by the prone sleeping position.

The Arousal Response

The protective responses leading to arousal have been well studied and they point toward mechanisms that are deeply rooted within the brainstem. These responses are very stereotypic and begin with the generation of a sigh, sometimes also called an “augmented breath”. The generation of sighs is followed by increased somatic activity, heart rate change, and often also a sleep state transition (43-45). Thach and colleagues performed a series of experiments on healthy, sleeping infants to demonstrate that arousal from a variety of stimuli begins with a sigh, followed by trashing movements, eye opening, and the repositioning of the head (46-48). Interestingly, these investigators also observed that spontaneous arousals begin with the generation of a sigh (48, 49).

Additionally, studies suggest that infants that succumb to SIDS exhibit a lower frequency of sighs during sleep in contrast to age-matched controls (50). For our understanding of the events leading to SIDS, it is important to emphasize that sighs are very sensitive to changes in blood gases, in particular hypoxia (51-56). As will be described below, this chemical sensitivity seems to be mediated centrally within the lower brainstem in the ventrolateral medulla (56). More recently it has been demonstrated that the mechanisms linking the sigh with arousal involve a close association between the neurons controlling the sigh and the so-called C1-neurons, noradrenergic neurons that mediate arousal, and changes in cortical states (57). These are important considerations for understanding the events leading to SIDS, since we know from prospective studies that spontaneous and induced arousals from sleep are reduced in infants who died of SIDS (16, 58-62).

An important aspect of this behavioral sequence is the coupling between the respiratory behavior and heart rate control. During the inspiratory phase of the sigh, heart rate increases, which is followed by a heart rate decrease during the expiratory phase of the sigh (47, 63-66). Thach and colleagues observed that the larger the heart rate change during the sigh, the more likely it was that an infant would arouse (48, 67). Again, this is a critical finding for understanding the events leading to SIDS, since decreased heart rate variability during the sigh was characteristic for infants that later died of SIDS (50, 68, 69).

Although the link between sigh and arousal is the first line of defense against a hypoxic situation, it is not the last chance to arouse. While sighs are evoked by even slight changes in hypoxia, severe hypoxic conditions will lead to the activation of gasps, which are also associated with heart rate changes and arousal in healthy infants (70). Like the generation of the sigh as the first line of defense, the generation of gasping also follows a very stereotypic transition from normal breathing, also referred to as “eupnea” (71-73). Gasping consists of isolated, rapid inspiratory efforts that are not followed by expirations (71, 72, 74, 75), but like sighs are associated with rapid heart rate changes (73). In some children who died of SIDS, gasping was apparently not associated with heart rate changes, or the number of gasps was very low and ineffective at triggering autoresuscitation (72). Exogenous stressors can further aggravate the situation, such as increased ambient temperature, one of the risk factors for SIDS, which decreases oxygen saturation, increases arousal threshold, and decreases gasping (76-78). Failure to arouse from gasping will result in irreversible events, leading to severe hypoxic damage in the brain, heart failure, and ultimately death.

In conclusion, the defense against a hypoxic exposure follows a two-stage stereotypic sequence of events. At the first sign of hypoxia, sighs are initiated that are followed by movements and arousal. If the arousal is unsuccessful and the hypoxic conditions become more severe, gasps are initiated that are the second and last step to autoresuscitate. However, once gasping occurs any abnormality in the autoresuscitation response will quickly be fatal, as the infant’s breathing will cease, followed shortly by cessation of their heartbeat.

The Control of Breathing and Heart Rate, and the Concept of Brainstem Microcircuits

Ultimately any death is caused by a loss of cardiorespiratory control that results in the cessation of breathing and heartbeat. The cardiorespiratory system is controlled by the central nervous system in specific brainstem regions located within the ventrolateral medulla. An emerging concept is that each of these brainstem regions has specialized roles in controlling breathing and heartbeat. Indeed, we refer to each of these regions as a “microcircuit” that is imbued with cellular properties, synaptic and intrinsic membrane properties that generate a specific aspect of cardiorespiratory control (79). Among the microcircuits that have been identified are three networks that each control one particular phase of breathing: the preBötzinger complex (preBötC) which controls inspiration (80), the postinspiratory complex (PiCo) which controls postinspiratory activity (81), and a subset of the parafacial respiratory group (lateral parafacial, pF_L) controlling active expiration (82, 83) (Figure 27.2).

Figure 27.2:

Breathing control networks are located in the ventral brainstem. Distinct microcircuits in the ventral lateral medulla of the brainstem are thought to individually control the three phases of breathing. This figure illustrates a schematic from sagittal (more...)

Other brainstem areas are specialized to control heartbeat; they include the nucleus ambiguus (NA), a nucleus that contains cardiac vagal neurons and exerts parasympathetic control of the heart, and the retrotrapezoidal nucleus (RTN), containing Phox-2B neurons, which have a strong influence on sympathetic control of the heart. The RTN neurons are also critical for sensing CO₂ (84-88). A second area that has also been implicated in the control of CO₂ sensing is the raphe nucleus, which contains GABAergic and serotonergic neurons (89, 90). The nucleus tractus solitarius (NTS), in the dorsal medulla, receives important peripheral sensory information (e.g. from the carotid body), which is very sensitive to changes in blood oxygen levels (91-94). Recent findings suggest that the neurons of the NTS are essential for the processing and co-ordination of respiratory and sympathetic responses to hypoxia (95). Furthermore, various noradrenergic nuclei, such as the C1 region, are critical for the control of arousal and the sleep-wake cycle, as mentioned above. Functional cardiorespiratory control requires the tight and operative co-ordination between these important lower brainstem microcircuits.

There are many additional important microcircuits that also play critical roles in the homeostatic regulation of breathing and the heart. These can be found not only in the medulla and the pons, but also in the cerebellum, neocortex, hippocampus, amygdala, the hypothalamus, and the periaqueductal gray (PAG) (96-103). Each of these areas has specific roles in the control of breathing and heart rate, but it would exceed the scope of this chapter to discuss all possible interactions of the respiratory network. Suffice to say, respiration is probably one of the most integrated behaviors of all. Indeed, the cerebellum and hippocampus in particular have been implicated in SIDS as well as in sudden unexplained death in childhood (104-109).

The preBötzinger complex and the control of inspiration

Perhaps the best-understood microcircuit controlling breathing is the so-called preBötC, a well-defined brainstem region known to be critical for the generation of inspiration (80, 110, 111). Lesioning of this microcircuit leads to the cessation of breathing (112-115). A variety of disorders associated with breathing abnormalities and death, such as Multiple Systems Atrophy (MSA), have been associated with pathological abnormalities within the preBötC (110). Indeed, as early as 1976 Naeye described pathological abnormalities in the form of astrogliosis in SIDS victims in areas that overlap with those now known to co-localize with the preBötC (116).

The preBötC was first anatomically defined by its rich staining for the neurokinin receptor NK1, a receptor that is targeted by endogenously released substance P (117). Another marker was somatostatin, as described by Stornetta et al. (118). With the advance of molecular and genetic techniques, it became possible to identify the neurons critical for the generation of inspiration based on a transcription factor, Dbx1 (119, 120). These Dbx1 neurons seem to be critical for the generation of inspiration (119, 121). A subset of Dbx1 neurons located more dorsal to, and partially overlapping with, the preBötC form the premotor neurons that innervate the hypoglossal nucleus (121, 122). The identification of these neurons allowed the optogenetic manipulation of these neurons, which clearly demonstrated their role in the generation of inspiratory activity and breathing in general (123, 124). However, the preBötC also contains inhibitory neurons, which are important not only for the generation of inspiration, but also for the afferent control of the preBötC (125, 126).

Important for the role of the preBötC in the events leading to SIDS is its ability to reconfigure into different states. Under normal baseline conditions, the preBötC contributes to the generation of normal breathing (also referred to as eupnea). However, the preBötC also spontaneously generates sighs. It is interesting to note that babies sigh every few minutes, and even more frequently right after birth (127, 128). Adult humans continue to sigh in a regular manner, but not as frequently as infants (129, 130, 131). An interesting mechanistic question is how the same neuronal circuitry in the preBötC can generate at the same time both the fast eupneic breathing rhythm and the slow, yet very regular sigh rhythm. Lieske et al. 2000 demonstrated that the majority of neurons in this microcircuit are activated during both eupneic and sigh activity. What seems to drive these differences are cellular mechanisms that differentially control sighs versus eupneic activity (132, 133). It has, for example, been demonstrated that sighs are exquisitely sensitive to a specific calcium channel subtype (P/Q-type channel) that is critical for glutamatergic, i.e. excitatory, synaptic transmission (132). It is noteworthy that mutating this particular channel subtype in an animal model does not affect normal breathing, but abolishes the ability to sigh. These animals ultimately die, which is interesting in the context of SIDS (134). Another aspect worth considering is that eupneic and sigh activity are differentially modulated by neuromodulators that are differentially expressed in sleep. Acetylcholine acting on muscarinic receptors activates sighs but inhibits eupneic activity (135). Serotonin and substance P, which have both been implicated in SIDS, activate sighs (136, 137). However, to what extent a disturbance in serotonin and substance P, as demonstrated for SIDS, also affects the ability to sigh, remains unknown.

The preBötC also reconfigures in response to hypoxia. Even following isolation, this microcircuit responds to reduced oxygen levels with an initial augmentation and the generation of sighs, followed by a secondary depression and the generation of gasps (Figure 27.3). Thus, the stereotypic response to hypoxia as described above has, to a certain extent, a neuronal correlate within this small neuronal network. Much has been learned about the neurons involved in the generation of the gasps in the preBötC and its underlying cellular mechanisms (70, 138).

Figure 27.3:

The isolated preBötzinger complex network reconfigures in response to hypoxia. During normal oxygenation, the preBötzinger complex autonomously generates a rhythmic, fictive eupneic pattern of activity. When exposed to hypoxia, the network (more...)

Conclusions

In conclusion, we have come a long way from identifying the critical risk factors contributing to SIDS to now understanding how these risk factors contribute to pathological changes in the cardiorespiratory response to exogenous stressors such as hypoxia or hypercapnia. Associated with these pathophysiological changes are changes in brainstem anatomy and pathology, as highlighted in Chapter 26. We have also learned how developmental changes in the control of the respiratory system and sleep structure may contribute to the developmental window that characterizes SIDS. These insights suggest that there will not be a unifying explanation for SIDS. Although it is likely that final common pathways involving brainstem dysfunction will lead to the cessation of breathing and heart rate, in the end a multitude of genetic, environmental, behavioral, and metabolic factors will ultimately contribute to SIDS. Thus, every individual will likely have a unique personal history that comes with a unique personal combination of risk factors. New technological advances in genetic screening, management of big data, and the increased ability to measure and monitor physiological states offer unique opportunities that will hopefully help to better identify the individual at risk to succumb to SIDS. These approaches combined will ultimately help to prevent SIDS and thus lower the SIDS risk world-wide.

Acknowledgement

This publication was supported by grants from the National Institute of Health (PO1HL090554; R01 HL 126523-01), and by the SIDS Fellowship Funds (John Kahan).

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