NCBI Bookshelf. A service of the National Library of Medicine, National Institutes of Health.

Duncan JR, Byard RW, editors. SIDS Sudden Infant and Early Childhood Death: The Past, the Present and the Future. Adelaide (AU): University of Adelaide Press; 2018 May.

Cover of SIDS Sudden Infant and Early Childhood Death

SIDS Sudden Infant and Early Childhood Death: The Past, the Present and the Future.

Show details

Chapter 27Sudden Infant Death Syndrome, Sleep, and the Physiology and Pathophysiology of the Respiratory Network

, PhD, , and , PhD.

Author Information

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 spontaneously arouse and move their head in response to a decrease in oxygen (hypoxia), and the subsequent build-up in carbon dioxide (hypercapnia). However, a vulnerable infant, perhaps one with abnormal serotonin expression in the brainstem or one who is regularly exposed to cigarette smoke, may have a blunted arousal response and fail to autoresuscitate during a hypoxic challenge. A vulnerable child will likely survive if they are never placed in a position in which these protective responses are required. This underscores the importance of placing a child prone on a firm mattress without excessive bedding. (Authors’ own work.).

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, pFL) 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 view of a mouse brainstem. Specifically, the preBötzinger Complex (preBötC) is responsible for controlling inspiration, the postinspiratory complex (PiCo) controls postinspiratory activity, and lateral parafacial neurons (pFL) control active expiration. The breathing networks functionally integrate with cardiac vagal neurons in the nucleus ambiguus (NA), referred to as cardiorespiratory coupling. Additionally, the nucleus tractus solitarius (NTS), located in the dorsal medulla, helps to co-ordinate respiratory and sympathetic responses to hypoxia. Grey shapes represent various motornuclei; VII N = facial motor nucleus. (Authors’ own work.).

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 responds by initiating an augmentation period typified by an increase in eupneic burst frequency and the generation of sighs. This period is followed by a secondary depressive phase in which gasps are generated. This response pattern of the preBötzinger complex is thought to be the neuronal correlate to the stereotypical hypoxic response observed in humans. (Authors’ own work.).

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...)

The preBötzinger complex and the raphe nucleus

The preBötC receives important inputs from other microcircuits in other brainstem regions, such as the raphe nucleus, which provides critical neuromodulatory drive to the preBötC. Among the neuromodulators released by the raphe is serotonin, which plays a critical role in stimulating respiratory activity via the 5-HT2A and NK1 receptors, respectively (139). Disturbances in both of these neuromodulators have been implicated in SIDS. It has been specifically hypothesized that a loss of serotonergic drive could lead to the loss of activity in neurons that are required for the generation of gasping or sighing (138, 70). This is a significant observation because sighing and gasping are important behaviors that contribute to the arousal response, as previously mentioned.

However, it is important to emphasize that the raphe nucleus is a microcircuit in itself. This means that the disturbances that have been associated with SIDS cannot be simply summarized as a lack of serotonergic drive. Indeed, too much serotonin, or a dysregulation of different serotonin receptor subtypes or the aminergic transport systems, could also play a role in compromising an arousal response. The raphe contains, for example, autoreceptors for serotonin (the 5-HT1A receptor subtype), which would respond to an increased serotonin concentration with a decreased serotonergic release. Thus, it is perhaps not surprising that different types of serotonergic abnormalities have been implicated in SIDS. Similarly, the raphe contains not only serotonin, but also substance P, a peptidergic neuromodulator which is also critical for respiratory and cardiorespiratory control.

Aside from the raphe, other modulatory nuclei are known to control the preBötC, which includes a variety of noradrenergic nuclei (140, 141), as well as areas releasing orexin or bombesin, which have been implicated in the generation of sighs (142, 143). Sighs are also controlled by cholinergic modulators, which have also been implicated in the control of sleep and wakefulness (135).

The preBötzinger complex and cardiorespiratory coupling

There is close co-ordination between neuronal circuits controlling the heart and breathing, which is evident in the “biphasic response” to hypoxia. During hypoxia, there is an initial increase in both the heart rate and respiratory rate (144-148). During this initial “augmentation phase” there is also the generation of sighs, which cause further transient increases in heart rate. The augmentation phase is followed by a depression phase during which respiration and heart rate decrease. The general heart rate decrease (bradycardia) is interrupted by transient periods of tachycardia that co-incide with the generation of gasps (71-73). Mechanistically, it is hypothesized that this cardiorespiratory coupling is mediated through an interaction between the preBötzC, the microcircuit controlling inspiration, and the anatomically proximate nucleus ambiguus, a nucleus that contains the cardiac vagal neurons that generate the parasympathetic control of the heart rate. Indeed, these cardiovagal neurons are located at the same level of the nucleus ambiguus as the preBötC (149, 150). It is hypothesized that during each inspiration, inhibitory inspiratory neurons within the preBötC inhibit cardiac vagal neurons in the nucleus ambiguus, which results in the disinhibition at the level of the heart, thus leading to an inspiratory-related heart rate increase. Any disturbance in this core interaction between the respiratory and the cardiac system will result in dysautonomia. Given that arousal is directly linked to the change in heart rate occurring during a sigh and gasp, we expect that a vulnerable infant is likely characterized by a disturbance of this core circuitry. One possible scenario is that in these infants cardiovagal neurons are not as excitable, which would lead to an increased heart rate and decreased cardiorespiratory coupling, all typical signs of dysautonomia (151, 152).

The postinspiratory complex — A “new kid on the block”

Postinspiration is a distinct phase of breathing that occurs just after an inspiration. It serves as a brake on the passive release of expiratory airflow and protects the larynx and upper airways from aspirating particulate matter and fluid (153). During the postinspiratory phase, laryngeal adductor muscles in the neck are activated and are involved in multiple non-ventilatory behaviors including swallowing, vocalization, and coughing. These behaviors must be tightly co-ordinated with breathing to prevent aspiration. Stimulating sensory laryngeal receptors activates a laryngeal adductor reflex comprising of a prolonged postinspiratory apnea and a dramatic decrease in heart rate (149). While this is normally cardioprotective, in vulnerable individuals exaggeration of the laryngeal adductor reflex can induce a fatal apnea due to prolonged glottal closure (154). This has been proposed as a possible cause of death for SIDS victims (155, 156).

A medullary population rostral to the preBötC was recently identified as an autonomous oscillator thought to control postinspiration (81) (Figure 27.2). This region, termed the PiCo, is also in close proximity to the nucleus ambiguus and has similar rhythm-generating characteristics to the preBötC. Postinspiratory vagal motor output, which innervates the larynx, can be recorded when PiCo neurons are optogenetically excited. Future studies will be necessary to elucidate the PiCo’s role in cardiorespiratory coupling, the co-ordination of postinspiratory behaviors, and the laryngeal adductor reflex.

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).

References

1.
de Jonge GA, Engelberts AC, Koomen-Liefting AJ, Kostense PJ. Cot death and prone sleeping position in The Netherlands. Brit Med J. 1989;298(6675):722. https://doi​.org/10.1136/bmj.298.6675.722. [PMC free article: PMC1836032] [PubMed: 2496821]
2.
McGlashan ND. Sudden infant deaths in Tasmania, 1980-1986: A seven year prospective study. Soc Sci Med. 1989;29(8):1015-26. https://doi​.org/10.1016​/0277-9536(89)90059-2. [PubMed: 2814572]
3.
Chiodini BA, Thach BT. Impaired ventilation in infants sleeping facedown: Potential significance for sudden infant death syndrome. J Pediatr. 1993;123(5):686-92. https://doi​.org/10.1016​/S0022-3476(05)80841-8. [PubMed: 8229475]
4.
Kemp JS, Kowalski RM, Burch PM, Graham MA, Thach BT. Unintentional suffocation by rebreathing: A death scene and physiologic investigation of a possible cause of sudden infant death. J Pediatr. 1993;122(6):874-80. https://doi​.org/10.1016​/S0022-3476(09)90010-5. [PubMed: 8501562]
5.
Trachtenberg FL, Haas EA, Kinney HC, Stanley C, Krous HF. Risk factor changes for sudden infant death syndrome after initiation of Back-to-Sleep campaign. Pediatrics. 2012;129(4):630-8. https://doi​.org/10.1542/peds.2011-1419. [PMC free article: PMC3356149] [PubMed: 22451703]
6.
Berard A, Zhao JP, Sheehy O. Success of smoking cessation interventions during pregnancy. Am J Obstet Gynecol. 2016;215(5):611e1-e8. [PubMed: 27402053]
7.
Leung LW, Davies GA. Smoking cessation strategies in pregnancy. J Obstet Gynaecol Can. 2015;37(9):791-7. https://doi​.org/10.1016​/S1701-2163(15)30149-3. [PubMed: 26605448]
8.
Mage DT, Donner M. A unifying theory for SIDS. Int J Pediatr. 2009;2009:368270. [PMC free article: PMC2798085] [PubMed: 20049339]
9.
Paterson DS, Trachtenberg FL, Thompson EG, Belliveau RA, Beggs AH, Darnall R, et al. Multiple serotonergic brainstem abnormalities in sudden infant death syndrome. JAMA. 2006;296(17):2124-32. https://doi​.org/10.1001/jama.296.17.2124. [PubMed: 17077377]
10.
Paterson DS, Thompson EG, Kinney HC. Serotonergic and glutamatergic neurons at the ventral medullary surface of the human infant: Observations relevant to central chemosensitivity in early human life. Auton Neurosci. 2006;124(1-2):112-24. https://doi​.org/10.1016/j​.autneu.2005.12.009. [PubMed: 16458076]
11.
Rubens DD, Vohr BR, Tucker R, O’Neil CA, Chung W. Newborn oto-acoustic emission hearing screening tests: Preliminary evidence for a marker of susceptibility to SIDS. Early Hum Dev. 2008;84(4):225-9. https://doi​.org/10.1016/j​.earlhumdev.2007.06.001. [PubMed: 17614220]
12.
Carlin RF, Moon RY. Risk factors, protective factors, and current recommendations to reduce sudden infant death syndrome: A review. JAMA Pediatr. 2017;171(2):175-80. https://doi​.org/10.1001/jamapediatrics​.2016.3345. [PubMed: 27918760]
13.
van Norstrand DW, Ackerman MJ. Genomic risk factors in sudden infant death syndrome. Genome Med. 2010;2(11):86. https://doi​.org/10.1186/gm207. [PMC free article: PMC3016628] [PubMed: 21122164]
14.
Filiano JJ, Kinney HC. A perspective on neuropathologic findings in victims of the sudden infant death syndrome: The triple-risk model. Biol Neonate. 1994;65(3-4):194-7. https://doi​.org/10.1159/000244052. [PubMed: 8038282]
15.
Kinney HC, Thach BT. The sudden infant death syndrome. N Engl J Med. 2009;361(8):795-805. https://doi​.org/10.1056/NEJMra0803836. [PMC free article: PMC3268262] [PubMed: 19692691]
16.
Schechtman VL, Harper RM, Wilson AJ, Southall DP. Sleep state organization in normal infants and victims of the sudden infant death syndrome. Pediatrics. 1992;89(5 Pt 1):865-70. [PubMed: 1579396]
17.
Blair PS, Platt MW, Smith IJ, Fleming PJ, Group SSR. Sudden infant death syndrome and the time of death: Factors associated with night-time and day-time deaths. Int J Epidemiol. 2006;35(6):1563-9. https://doi​.org/10.1093/ije/dyl212. [PubMed: 17148463]
18.
Douglas NJ, White DP, Weil JV, Pickett CK, Zwillich CW. Hypercapnic ventilatory response in sleeping adults. Am Rev Respir Dis. 1982;126(5):758-62. [PubMed: 7149440]
19.
White DP. Pathogenesis of obstructive and central sleep apnea. Am J Respir Crit Care Med. 2005;172(11):1363-70. https://doi​.org/10.1164/rccm​.200412-1631SO. [PubMed: 16100008]
20.
Chamberlin NL, Eikermann M, Fassbender P, White DP, Malhotra A. Genioglossus premotoneurons and the negative pressure reflex in rats. J Physiol. 2007;579(Pt 2):515-26. https://doi​.org/10.1113/jphysiol​.2006.121889. [PMC free article: PMC2075396] [PubMed: 17185342]
21.
Fogel RB, Malhotra A, Pillar G, Edwards JK, Beauregard J, Shea SA, et al. Genioglossal activation in patients with obstructive sleep apnea versus control subjects. Mechanisms of muscle control. Am J Respir Crit Care Med. 2001;164(11):2025-30. https://doi​.org/10.1164/ajrccm​.164.11.2102048. [PubMed: 11739130]
22.
Horner RL. Impact of brainstem sleep mechanisms on pharyngeal motor control. Respir Physiol. 2000;119(2-3):113-21. https://doi​.org/10.1016​/S0034-5687(99)00106-1. [PubMed: 10722854]
23.
Susarla SM, Thomas RJ, Abramson ZR, Kaban LB. Biomechanics of the upper airway: Changing concepts in the pathogenesis of obstructive sleep apnea. Int J Oral Maxillofac Surg. 2010;39(12):1149-59. https://doi​.org/10.1016/j​.ijom.2010.09.007. [PubMed: 21030210]
24.
Wheatley JR, Mezzanotte WS, Tangel DJ, White DP. Influence of sleep on genioglossus muscle activation by negative pressure in normal men. Am Rev Respir Dis. 1993;148(3):597-605. https://doi​.org/10.1164/ajrccm/148.3.597. [PubMed: 8368629]
25.
Krous HF, Haas EA, Chadwick AE, Masoumi H, Stanley C. Intrathoracic petechiae in SIDS: A retrospective population-based 15-year study. Forensic Sci Med Pathol. 2008;4(4):234-9. https://doi​.org/10.1007​/s12024-008-9054-8. [PubMed: 19291444]
26.
Becher JC, Bhushan SS, Lyon AJ. Unexpected collapse in apparently healthy newborns — A prospective national study of a missing cohort of neonatal deaths and near-death events. Arch Dis Child Fetal Neonatal Ed. 2012;97(1):F30-4. https://doi​.org/10.1136/adc.2010.208736. [PubMed: 21715368]
27.
Chase MH, Soja PJ, Morales FR. Evidence that glycine mediates the postsynaptic potentials that inhibit lumbar motoneurons during the atonia of active sleep. J Neurosci. 1989;9(3):743-51. [PMC free article: PMC6569981] [PubMed: 2926479]
28.
Funk GD, Parkis MA, Selvaratnam SR, Walsh C. Developmental modulation of glutamatergic inspiratory drive to hypoglossal motoneurons. Respir Physiol. 1997;110(2-3):125-37. https://doi​.org/10.1016​/S0034-5687(97)00078-9. [PubMed: 9407606]
29.
Soja PJ, Morales FR, Baranyi A, Chase MH. Effect of inhibitory amino acid antagonists on IPSPs induced in lumbar motoneurons upon stimulation of the nucleus reticularis gigantocellularis during active sleep. Brain Res. 1987;423(1-2):353-8. https://doi​.org/10.1016​/0006-8993(87)90862-6. [PubMed: 3676812]
30.
Soja PJ, Lopez-Rodriguez F, Morales FR, Chase MH. The postsynaptic inhibitory control of lumbar motoneurons during the atonia of active sleep: Effect of strychnine on motoneuron properties. J Neurosci. 1991;11(9):2804-11. [PMC free article: PMC6575255] [PubMed: 1880550]
31.
Yamuy J, Fung SJ, Xi M, Morales FR, Chase MH. Hypoglossal motoneurons are postsynaptically inhibited during carbachol-induced rapid eye movement sleep. Neuroscience. 1999;94(1):11-15. https://doi​.org/10.1016​/S0306-4522(99)00355-3. [PubMed: 10613491]
32.
Funk GD, Zwicker JD, Selvaratnam R, Robinson DM. Noradrenergic modulation of hypoglossal motoneuron excitability: Developmental and putative state-dependent mechanisms. Arch Ital Biol. 2011;149(4):426-53. [PubMed: 22205594]
33.
Aston-Jones G, Bloom FE. Activity of norepinephrine-containing locus coeruleus neurons in behaving rats anticipates fluctuations in the sleep-waking cycle. J Neurosci. 1981;1(8):876-86. [PMC free article: PMC6564235] [PubMed: 7346592]
34.
Jacobs BL, Fornal CA. Activity of brain serotonergic neurons in the behaving animal. Pharmacol Rev. 1991;43(4):563-78. [PubMed: 1775508]
35.
Leung CG, Mason P. Physiological properties of raphe magnus neurons during sleep and waking. J Neurophysiol. 1999;81(2):584-95. [PubMed: 10036262]
36.
Kinney HC. Abnormalities of the brainstem serotonergic system in the sudden infant death syndrome: A review. Pediatr Dev Pathol. 2005;8(5):507-24. https://doi​.org/10.1007​/s10024-005-0067-y. [PubMed: 16222475]
37.
Duncan JR, Paterson DS, Hoffman JM, Mokler DJ, Borenstein NS, Belliveau RA, et al. Brainstem serotonergic deficiency in sudden infant death syndrome. JAMA. 2010;303(5):430-7. https://doi​.org/10.1001/jama.2010.45. [PMC free article: PMC3242415] [PubMed: 20124538]
38.
Ozawa Y, Obonai T, Itoh M, Aoki Y, Funayama M, Takashima S. Catecholaminergic neurons in the diencephalon and basal ganglia of SIDS. Pediatr Neurol. 1999;21(1):471-5. https://doi​.org/10.1016​/S0887-8994(99)00033-8. [PubMed: 10428433]
39.
Hilaire G. Endogenous noradrenaline affects the maturation and function of the respiratory network: Possible implication for SIDS. Auton Neurosci. 2006;126-7:320-31. https://doi​.org/10.1016/j​.autneu.2006.01.021. [PubMed: 16603418]
40.
Ramirez JM, Garcia AJ 3rd, Anderson TM, Koschnitzky JE, Peng YJ, Kumar GK, et al. Central and peripheral factors contributing to obstructive sleep apneas. Respir Physiol Neurobiol. 2013;189(2):344-53. https://doi​.org/10.1016/j​.resp.2013.06.004. [PMC free article: PMC3901437] [PubMed: 23770311]
41.
Bolton DP, Taylor BJ, Campbell AJ, Galland BC, Cresswell C. Rebreathing expired gases from bedding: A cause of cot death? Arch Dis Child. 1993;69(2):187-90. https://doi​.org/10.1136/adc.69.2.187. [PMC free article: PMC1029454] [PubMed: 8215518]
42.
Kemp JS, Thach BT. Sudden death in infants sleeping on polystyrene-filled cushions. N Engl J Med. 1991;324(26):1858-64. https://doi​.org/10.1056​/NEJM199106273242605. [PubMed: 2041551]
43.
Glogowska M, Richardson PS, Widdicombe JG, Winning AJ. The role of the vagus nerves, peripheral chemoreceptors and other afferent pathways in the genesis of augmented breaths in cats and rabbits. Respir Physiol. 1972;16(2):179-96. https://doi​.org/10.1016​/0034-5687(72)90050-3. [PubMed: 4644668]
44.
McGinty DJ, London MS, Baker TL, Stevenson M, Hoppenbrouwers T, Harper RM, et al. Sleep apnea in normal kittens. Sleep. 1979;1(4):393-412. [PubMed: 504878]
45.
Orem J, Trotter RH. Medullary respiratory neuronal activity during augmented breaths in intact unanesthetized cats. J Appl Physiol (1985). 1993;74(2):761-9. [PubMed: 8458793]
46.
Lijowska AS, Reed NW, Chiodini BA, Thach BT. Sequential arousal and airway-defensive behavior of infants in asphyxial sleep environments. J Appl Physiol (1985). 1997;83(1):219-28. [PubMed: 9216967]
47.
McNamara F, Wulbrand H, Thach BT. Characteristics of the infant arousal response. J Appl Physiol (1985). 1998;85(6):2314-21. [PubMed: 9843558]
48.
Thach BT, Lijowska A. Arousals in infants. Sleep. 1996;19(10 Suppl):S271-3. https://doi​.org/10.1093/sleep/19​.suppl_10.S271. [PubMed: 9085529]
49.
Anderson CA, Dick TE, Orem J. Respiratory responses to tracheobronchial stimulation during sleep and wakefulness in the adult cat. Sleep. 1996;19(6):472-8. https://doi​.org/10.1093/sleep/19.6.472. [PubMed: 8865504]
50.
Kahn A, Blum D, Rebuffat E, Sottiaux M, Levitt J, Bochner A, et al. Polysomnographic studies of infants who subsequently died of sudden infant death syndrome. Pediatrics. 1988;82(5):721-7. [PubMed: 3186351]
51.
Bartlett D Jr. Origin and regulation of spontaneous deep breaths. Respir Physiol. 1971;12(2):230-8. https://doi​.org/10.1016​/0034-5687(71)90055-7. [PubMed: 5568463]
52.
Bell HJ, Haouzi P. The hypoxia-induced facilitation of augmented breaths is suppressed by the common effect of carbonic anhydrase inhibition. Respir Physiol Neurobiol. 2010;171(3):201-11. https://doi​.org/10.1016/j​.resp.2010.04.002. [PubMed: 20382275]
53.
Bell HJ, Haouzi P. Acetazolamide suppresses the prevalence of augmented breaths during exposure to hypoxia. Am J Physiol Regul Integr Comp Physiol. 2009;297(2):R370-81. https://doi​.org/10.1152/ajpregu​.00126.2009. [PubMed: 19494178]
54.
Cherniack NS, von Euler C, Glogowska M, Homma I. Characteristics and rate of occurrence of spontaneous and provoked augmented breaths. Acta Physiol Scand. 1981;111(3):349-60. https://doi​.org/10.1111/j​.1748-1716.1981.tb06747.x. [PubMed: 6797251]
55.
Hill AA, Garcia AJ 3rd, Zanella S, Upadhyaya R, Ramirez JM. Graded reductions in oxygenation evoke graded reconfiguration of the isolated respiratory network. J Neurophysiol. 2011;105(2):625-39. https://doi​.org/10.1152/jn.00237.2010. [PMC free article: PMC3059168] [PubMed: 21084689]
56.
Lieske SP, Thoby-Brisson M, Telgkamp P, Ramirez JM. Reconfiguration of the neural network controlling multiple breathing patterns: Eupnea, sighs and gasps. Nat Neurosci. 2000;3(6):600-7. https://doi​.org/10.1038/75776. [PubMed: 10816317]
57.
Burke PG, Abbott SB, Coates MB, Viar KE, Stornetta RL, Guyenet PG. Optogenetic stimulation of adrenergic C1 neurons causes sleep state-dependent cardiorespiratory stimulation and arousal with sighs in rats. Am J Respir Crit Care Med. 2014;190(11):1301-10. https://doi​.org/10.1164/rccm​.201407-1262OC. [PMC free article: PMC4315817] [PubMed: 25325789]
58.
Dunne KP, Fox GP, O’Regan M, Matthews TG. Arousal responses in babies at risk of sudden infant death syndrome at different postnatal ages. Ir Med J. 1992;85(1):19-22. [PubMed: 1568841]
59.
Kahn A, Groswasser J, Rebuffat E, Sottiaux M, Blum D, Foerster M, et al. Sleep and cardiorespiratory characteristics of infant victims of sudden death: A prospective case-control study. Sleep. 1992;15(4):287-92. https://doi​.org/10.1093/sleep/15.4.287. [PubMed: 1519001]
60.
Kato I, Scaillet S, Groswasser J, Montemitro E, Togari H, Lin JS, et al. Spontaneous arousability in prone and supine position in healthy infants. Sleep. 2006;29(6):785-90. https://doi​.org/10.1093/sleep/29.6.785. [PubMed: 16796217]
61.
McCulloch K, Brouillette RT, Guzzetta AJ, Hunt CE. Arousal responses in near-miss sudden infant death syndrome and in normal infants. J Pediatr. 1982;101(6):911-17. https://doi​.org/10.1016​/S0022-3476(82)80009-7. [PubMed: 7143167]
62.
Sawaguchi T, Kato I, Franco P, Sottiaux M, Kadhim H, Shimizu S, et al. Apnea, glial apoptosis and neuronal plasticity in the arousal pathway of victims of SIDS. Forensic Sci Int. 2005;149(2-3):205-17. https://doi​.org/10.1016/j​.forsciint.2004.10.015. [PubMed: 15749363]
63.
Haupt ME, Goodman DM, Sheldon SH. Sleep related expiratory obstructive apnea in children. J Clin Sleep Med. 2012;8(6):673-9. https://doi​.org/10.1164​/ajrccm-conference​.2012.185.1_MeetingAbstracts.A6664. [PMC free article: PMC3501664] [PubMed: 23243401]
64.
Porges WL, Hennessy EJ, Quail AW, Cottee DB, Moore PG, McIlveen SA, et al. Heart-lung interactions: The sigh and autonomic control in the bronchial and coronary circulations. Clin Exp Pharmacol Physiol. 2000;27(12):1022-7. https://doi​.org/10.1046/j​.1440-1681.2000.03370.x. [PubMed: 11117224]
65.
Weese-Mayer DE, Kenny AS, Bennett HL, Ramirez JM, Leurgans SE. Familial dysautonomia: Frequent, prolonged and severe hypoxemia during wakefulness and sleep. Pediatr Pulmonol. 2008;43(3):251-60. https://doi​.org/10.1002/ppul.20764. [PubMed: 18220270]
66.
Wulbrand H, McNamara F, Thach BT. The role of arousal related brainstem reflexes in causing recovery from upper airway occlusion in infants. Sleep. 2008;31(6):833-40. https://doi​.org/10.1093/sleep/31.6.833. [PMC free article: PMC2442409] [PubMed: 18548828]
67.
Thach BT. Graded arousal responses in infants: Advantages and disadvantages of a low threshold for arousal. Sleep Med. 2002;3 Suppl 2:S37-40. https://doi​.org/10.1016​/S1389-9457(02)00162-4. [PubMed: 14592377]
68.
Franco P, Szliwowski H, Dramaix M, Kahn A. Polysomnographic study of the autonomic nervous system in potential victims of sudden infant death syndrome. Clin Auton Res. 1998;8(5):243-9. https://doi​.org/10.1007/BF02277969. [PubMed: 9801844]
69.
Franco P, Verheulpen D, Valente F, Kelmanson I, de Broca A, Scaillet S, et al. Autonomic responses to sighs in healthy infants and in victims of sudden infant death. Sleep Med. 2003;4(6):569-77. https://doi​.org/10.1016​/S1389-9457(03)00107-2. [PubMed: 14607352]
70.
Pena F, Parkis MA, Tryba AK, Ramirez JM. Differential contribution of pacemaker properties to the generation of respiratory rhythms during normoxia and hypoxia. Neuron. 2004;43(1):105-17. https://doi​.org/10.1016/j​.neuron.2004.06.023. [PubMed: 15233921]
71.
Hunt CE. The cardiorespiratory control hypothesis for sudden infant death syndrome. Clin Perinatol. 1992;19(4):757-71. [PubMed: 1464189]
72.
Poets CF, Meny RG, Chobanian MR, Bonofiglo RE. Gasping and other cardiorespiratory patterns during sudden infant deaths. Pediatr Res. 1999;45(3):350-4. https://doi​.org/10.1203​/00006450-199903000-00010. [PubMed: 10088653]
73.
Harper RM, Kinney HC, Fleming PJ, Thach BT. Sleep influences on homeostatic functions: Implications for sudden infant death syndrome. Respir Physiol. 2000;119(2-3):123-32. https://doi​.org/10.1016​/S0034-5687(99)00107-3. [PubMed: 10722855]
74.
Cherniack NS, Edelman NH, Lahiri S. The effect of hypoxia and hypercapnia on respiratory neuron activity and cerebral aerobic metabolism. Chest. 1971;59:Suppl:29S. https://doi​.org/10.1016​/S0012-3692(15)31576-2. [PubMed: 5575676]
75.
Pena F, Aguileta MA. Effects of riluzole and flufenamic acid on eupnea and gasping of neonatal mice in vivo. Neurosci Lett. 2007;415(3):288-93. https://doi​.org/10.1016/j​.neulet.2007.01.032. [PubMed: 17276002]
76.
Serdarevich C, Fewell JE. Influence of core temperature on autoresuscitation during repeated exposure to hypoxia in normal rat pups. J Appl Physiol (1985). 1999;87(4):1346-53. [PubMed: 10517762]
77.
Franco P, Szliwowski H, Dramaix M, Kahn A. Influence of ambient temperature on sleep characteristics and autonomic nervous control in healthy infants. Sleep. 2000;23(3):401-7. [PubMed: 10811384]
78.
Franco P, Scaillet S, Valente F, Chabanski S, Groswasser J, Kahn A. Ambient temperature is associated with changes in infants’ arousability from sleep. Sleep. 2001;24(3):325-9. https://doi​.org/10.1093/sleep/24.3.325. [PubMed: 11322716]
79.
Ramirez JM, Dashevskiy T, Marlin IA, Baertsch N. Microcircuits in respiratory rhythm generation: Commonalities with other rhythm generating networks and evolutionary perspectives. Curr Opin Neurobiol. 2016;41:53-61. https://doi​.org/10.1016/j​.conb.2016.08.003. [PMC free article: PMC5495096] [PubMed: 27589601]
80.
Smith JC, Ellenberger HH, Ballanyi K, Richter DW, Feldman JL. Pre-Botzinger complex: a brainstem region that may generate respiratory rhythm in mammals. Science. 1991;254(5032):726-9. https://doi​.org/10.1126/science.1683005. [PMC free article: PMC3209964] [PubMed: 1683005]
81.
Anderson TM, Garcia AJ 3rd, Baertsch NA, Pollak J, Bloom JC, Wei AD, et al. A novel excitatory network for the control of breathing. Nature. 2016;536(7614):76-80. https://doi​.org/10.1038/nature18944. [PMC free article: PMC5479418] [PubMed: 27462817]
82.
Janczewski WA, Feldman JL. Distinct rhythm generators for inspiration and expiration in the juvenile rat. J Physiol. 2006;570(Pt 2):407-20. https://doi​.org/10.1113/jphysiol​.2005.098848. [PMC free article: PMC1464316] [PubMed: 16293645]
83.
Pagliardini S, Janczewski WA, Tan W, Dickson CT, Deisseroth K, Feldman JL. Active expiration induced by excitation of ventral medulla in adult anesthetized rats. J Neurosci. 2011;31(8):2895-905. https://doi​.org/10.1523/JNEUROSCI​.5338-10.2011. [PMC free article: PMC3142740] [PubMed: 21414911]
84.
Ramanantsoa N, Hirsch MR, Thoby-Brisson M, Dubreuil V, Bouvier J, Ruffault PL, et al. Breathing without CO(2) chemosensitivity in conditional Phox2b mutants. J Neurosci. 2011;31(36):12880-8. https://doi​.org/10.1523/JNEUROSCI​.1721-11.2011. [PMC free article: PMC6623392] [PubMed: 21900566]
85.
Guyenet PG. Regulation of breathing and autonomic outflows by chemoreceptors. Compr Physiol. 2014;4(4):1511-62. https://doi​.org/10.1002/cphy.c140004. [PMC free article: PMC4794276] [PubMed: 25428853]
86.
Kumar NN, Velic A, Soliz J, Shi Y, Li K, Wang S, et al. Regulation of breathing by CO(2) requires the proton-activated receptor GPR4 in retrotrapezoid nucleus neurons. Science. 2015;348(6240):1255-60. https://doi​.org/10.1126/science.aaa0922. [PMC free article: PMC5171229] [PubMed: 26068853]
87.
Ruffault PL, D’Autreaux F, Hayes JA, Nomaksteinsky M, Autran S, Fujiyama T, et al. The retrotrapezoid nucleus neurons expressing Atoh1 and Phox2b are essential for the respiratory response to CO(2). Elife. 2015;4:e07051. https://doi​.org/10.7554/eLife.07051. [PMC free article: PMC4429526] [PubMed: 25866925]
88.
Guyenet PG, Bayliss DA. Neural control of breathing and CO2 homeostasis. Neuron. 2015;87(5):946-61. https://doi​.org/10.1016/j​.neuron.2015.08.001. [PMC free article: PMC4559867] [PubMed: 26335642]
89.
Stornetta RL, Rosin DL, Simmons JR, McQuiston TJ, Vujovic N, Weston MC, et al. Coexpression of vesicular glutamate transporter-3 and gamma-aminobutyric acidergic markers in rat rostral medullary raphe and intermediolateral cell column. J Comp Neurol. 2005;492(4):477-94. https://doi​.org/10.1002/cne.20742. [PubMed: 16228993]
90.
Fu W, Le Maitre E, Fabre V, Bernard JF, David Xu ZQ, Hokfelt T. Chemical neuroanatomy of the dorsal raphe nucleus and adjacent structures of the mouse brain. J Comp Neurol. 2010;518(17):3464-94. https://doi​.org/10.1002/cne.22407. [PubMed: 20589909]
91.
Mifflin SW. Arterial chemoreceptor input to nucleus tractus solitarius. Am J Physiol. 1992;263(2 Pt 2):R368-75. [PubMed: 1510176]
92.
Chitravanshi VC, Sapru HN. Chemoreceptor-sensitive neurons in commissural subnucleus of nucleus tractus solitarius of the rat. Am J Physiol. 1995;268(4 Pt 2):R851-8. [PubMed: 7733393]
93.
Machado BH. Neurotransmission of the cardiovascular reflexes in the nucleus tractus solitarii of awake rats. Ann N Y Acad Sci. 2001;940:179-96. https://doi​.org/10.1111/j​.1749-6632.2001.tb03676.x. [PubMed: 11458676]
94.
Accorsi-Mendonca D, Castania JA, Bonagamba LG, Machado BH, Leao RM. Synaptic profile of nucleus tractus solitarius neurons involved with the peripheral chemoreflex pathways. Neuroscience. 2011;197:107-20. https://doi​.org/10.1016/j​.neuroscience.2011.08.054. [PubMed: 21963868]
95.
Zoccal DB, Furuya WI, Bassi M, Colombari DS, Colombari E. The nucleus of the solitary tract and the coordination of respiratory and sympathetic activities. Front Physiol. 2014;5:238. https://doi​.org/10.3389/fphys.2014.00238. [PMC free article: PMC4070480] [PubMed: 25009507]
96.
Brannan S, Liotti M, Egan G, Shade R, Madden L, Robillard R, et al. Neuroimaging of cerebral activations and deactivations associated with hypercapnia and hunger for air. Proc Natl Acad Sci USA. 2001;98(4):2029-34. https://doi​.org/10.1073/pnas.98.4.2029. [PMC free article: PMC29376] [PubMed: 11172070]
97.
Burdakov D, Karnani MM, Gonzalez A. Lateral hypothalamus as a sensor-regulator in respiratory and metabolic control. Physiol Behav. 2013;121:117-24. https://doi​.org/10.1016/j​.physbeh.2013.03.023. [PMC free article: PMC5767108] [PubMed: 23562864]
98.
Chamberlin NL, Saper CB. Topographic organization of respiratory responses to glutamate microstimulation of the parabrachial nucleus in the rat. J Neurosci. 1994;14(11 Pt 1):6500-10. [PMC free article: PMC6577246] [PubMed: 7965054]
99.
Liotti M, Brannan S, Egan G, Shade R, Madden L, Abplanalp B, et al. Brain responses associated with consciousness of breathlessness (air hunger). Proc Natl Acad Sci USA. 2001;98(4):2035-40. https://doi​.org/10.1073/pnas.98.4.2035. [PMC free article: PMC29377] [PubMed: 11172071]
100.
Masaoka Y, Sugiyama H, Katayama A, Kashiwagi M, Homma I. Slow breathing and emotions associated with odor-induced autobiographical memories. Chem Senses. 2012;37(4):379-88. https://doi​.org/10.1093/chemse/bjr120. [PubMed: 22230171]
101.
Nattie E, Li A. Respiration and autonomic regulation and orexin. Prog Brain Res. 2012;198:25-46. https://doi​.org/10.1016​/B978-0-444-59489-1.00004-5. [PMC free article: PMC4405125] [PubMed: 22813968]
102.
Ramirez JM, Doi A, Garcia AJ 3rd, Elsen FP, Koch H, Wei AD. The cellular building blocks of breathing. Compr Physiol. 2012;2(4):2683-731. https://doi​.org/10.1002/cphy.c110033. [PMC free article: PMC3684023] [PubMed: 23720262]
103.
Subramanian HH, Holstege G. Stimulation of the midbrain periaqueductal gray modulates preinspiratory neurons in the ventrolateral medulla in the rat in vivo. J Comp Neurol. 2013;521(13):3083-98. https://doi​.org/10.1002/cne.23334. [PMC free article: PMC3761193] [PubMed: 23630049]
104.
Cruz-Sanchez FF, Lucena J, Ascaso C, Tolosa E, Quinto L, Rossi ML. Cerebellar cortex delayed maturation in sudden infant death syndrome. J Neuropathol Exp Neurol. 1997;56(4):340-6. https://doi​.org/10.1097​/00005072-199704000-00002. [PubMed: 9100664]
105.
Lavezzi AM, Ottaviani G, Mauri M, Matturri L. Alterations of biological features of the cerebellum in sudden perinatal and infant death. Curr Mol Med. 2006;6(4):429-35. https://doi​.org/10.2174​/156652406777435381. [PubMed: 16900666]
106.
Calton MA, Howard JR, Harper RM, Goldowitz D, Mittleman G. The cerebellum and SIDS: Disordered breathing in a mouse model of developmental cerebellar purkinje cell loss during recovery from hypercarbia. Front Neurol. 2016;7:78. https://doi​.org/10.3389/fneur.2016.00078. [PMC free article: PMC4865515] [PubMed: 27242661]
107.
Kinney HC, Cryan JB, Haynes RL, Paterson DS, Haas EA, Mena OJ, et al. Dentate gyrus abnormalities in sudden unexplained death in infants: Morphological marker of underlying brain vulnerability. Acta Neuropathol. 2015;129(1):65-80. https://doi​.org/10.1007​/s00401-014-1357-0. [PMC free article: PMC4282685] [PubMed: 25421424]
108.
Kinney HC, Chadwick AE, Crandall LA, Grafe M, Armstrong DL, Kupsky WJ, et al. Sudden death, febrile seizures, and hippocampal and temporal lobe maldevelopment in toddlers: A new entity. Pediatr Dev Pathol. 2009;12(6):455-63. https://doi​.org/10.2350/08-09-0542.1. [PMC free article: PMC3286023] [PubMed: 19606910]
109.
Hefti MM, Kinney HC, Cryan JB, Haas EA, Chadwick AE, Crandall LA, et al. Sudden unexpected death in early childhood: General observations in a series of 151 cases: Part 1 of the investigations of the San Diego SUDC Research Project. Forensic Sci Med Pathol. 2016;12(1):4-13. https://doi​.org/10.1007​/s12024-015-9724-2. [PMC free article: PMC4752958] [PubMed: 26782961]
110.
Schwarzacher SW, Rub U, Deller T. Neuroanatomical characteristics of the human pre-Botzinger complex and its involvement in neurodegenerative brainstem diseases. Brain. 2011;134(Pt 1):24-35. https://doi​.org/10.1093/brain/awq327. [PubMed: 21115469]
111.
Ramirez JM. The human pre-Botzinger complex identified. Brain. 2011;134(Pt 1):8-10. https://doi​.org/10.1093/brain/awq357. [PMC free article: PMC3009844] [PubMed: 21186262]
112.
Tan W, Janczewski WA, Yang P, Shao XM, Callaway EM, Feldman JL. Silencing preBotzinger complex somatostatin-expressing neurons induces persistent apnea in awake rat. Nat Neurosci. 2008;11(5):538-40. https://doi​.org/10.1038/nn.2104. [PMC free article: PMC2515565] [PubMed: 18391943]
113.
Ramirez JM, Schwarzacher SW, Pierrefiche O, Olivera BM, Richter DW. Selective lesioning of the cat pre-Botzinger complex in vivo eliminates breathing but not gasping. J Physiol. 1998;507(Pt 3):895-907. https://doi​.org/10.1111/j​.1469-7793.1998.895bs.x. [PMC free article: PMC2230836] [PubMed: 9508848]
114.
Wenninger JM, Pan LG, Klum L, Leekley T, Bastastic J, Hodges MR, et al. Large lesions in the pre-Botzinger complex area eliminate eupneic respiratory rhythm in awake goats. J Appl Physiol (1985). 2004;97(5):1629-36. https://doi​.org/10.1152/japplphysiol​.00953.2003. [PubMed: 15247161]
115.
McKay LC, Janczewski WA, Feldman JL. Sleep-disordered breathing after targeted ablation of preBotzinger complex neurons. Nat Neurosci. 2005;8(9):1142-4. https://doi​.org/10.1038/nn1517. [PMC free article: PMC2819071] [PubMed: 16116455]
116.
Naeye RL, Ladis B, Drage JS. Sudden infant death syndrome. A prospective study. Am J Dis Child. 1976;130(11):1207-10. https://doi​.org/10.1001/archpedi​.1976.02120120041005. [PubMed: 984002]
117.
Gray PA, Rekling JC, Bocchiaro CM, Feldman JL. Modulation of respiratory frequency by peptidergic input to rhythmogenic neurons in the preBotzinger complex. Science. 1999;286(5444):1566-8. https://doi​.org/10.1126/science​.286.5444.1566. [PMC free article: PMC2811082] [PubMed: 10567264]
118.
Stornetta RL, Rosin DL, Wang H, Sevigny CP, Weston MC, Guyenet PG. A group of glutamatergic interneurons expressing high levels of both neurokinin-1 receptors and somatostatin identifies the region of the pre-Botzinger complex. J Comp Neurol. 2003;455(4):499-512. https://doi​.org/10.1002/cne.10504. [PubMed: 12508323]
119.
Gray PA, Hayes JA, Ling GY, Llona I, Tupal S, Picardo MC, et al. Developmental origin of preBotzinger complex respiratory neurons. J Neurosci. 2010;30(44):14883-95. https://doi​.org/10.1523/JNEUROSCI​.4031-10.2010. [PMC free article: PMC3056489] [PubMed: 21048147]
120.
Bouvier J, Thoby-Brisson M, Renier N, Dubreuil V, Ericson J, Champagnat J, et al. Hindbrain interneurons and axon guidance signaling critical for breathing. Nat Neurosci. 2010;13(9):1066-74. https://doi​.org/10.1038/nn.2622. [PubMed: 20680010]
121.
Wang X, Hayes JA, Revill AL, Song H, Kottick A, Vann NC, et al. Laser ablation of Dbx1 neurons in the pre-Botzinger complex stops inspiratory rhythm and impairs output in neonatal mice. Elife. 2014;3:e03427. https://doi​.org/10.7554/eLife.03427. [PMC free article: PMC4129438] [PubMed: 25027440]
122.
Revill AL, Vann NC, Akins VT, Kottick A, Gray PA, Del Negro CA, et al. Dbx1 precursor cells are a source of inspiratory XII premotoneurons. Elife. 2015;4:e12301. https://doi​.org/10.7554/eLife.12301. [PMC free article: PMC4764567] [PubMed: 26687006]
123.
Vann NC, Pham FD, Hayes JA, Kottick A, Del Negro CA. Transient suppression of Dbx1 preBotzinger interneurons disrupts breathing in adult mice. PLoS One. 2016;11(9):e0162418. https://doi​.org/10.1371/journal​.pone.0162418. [PMC free article: PMC5017730] [PubMed: 27611210]
124.
Koizumi H, Mosher B, Tariq MF, Zhang R, Koshiya N, Smith JC. Voltage-dependent rhythmogenic property of respiratory pre-Botzinger complex glutamatergic, Dbx1-derived, and somatostatin-expressing neuron populations revealed by graded optogenetic inhibition. eNeuro. 2016;3(3). [PMC free article: PMC4891766] [PubMed: 27275007]
125.
Winter SM, Fresemann J, Schnell C, Oku Y, Hirrlinger J, Hulsmann S. Glycinergic interneurons are functionally integrated into the inspiratory network of mouse medullary slices. Pflugers Arch. 2009;458(3):459-69. https://doi​.org/10.1007​/s00424-009-0647-1. [PMC free article: PMC2691554] [PubMed: 19238427]
126.
Sherman D, Worrell JW, Cui Y, Feldman JL. Optogenetic perturbation of preBotzinger complex inhibitory neurons modulates respiratory pattern. Nat Neurosci. 2015;18(3):408-14. https://doi​.org/10.1038/nn.3938. [PMC free article: PMC4340826] [PubMed: 25643296]
127.
Fleming PJ, Goncalves AL, Levine MR, Woollard S. The development of stability of respiration in human infants: Changes in ventilatory responses to spontaneous sighs. J Physiol. 1984;347:1-16. https://doi​.org/10.1113/jphysiol​.1984.sp015049. [PMC free article: PMC1199430] [PubMed: 6707950]
128.
Hoch B, Bernhard M, Hinsch A. Different patterns of sighs in neonates and young infants. Biol Neonate. 1998;74(1):16-21. https://doi​.org/10.1159/000014006. [PubMed: 9657665]
129.
Vlemincx E, van Diest I, De Peuter S, Bresseleers J, Bogaerts K, Fannes S, et al. Why do you sigh? Sigh rate during induced stress and relief. Psychophysiology. 2009;46(5):1005-13. https://doi​.org/10.1111/j​.1469-8986.2009.00842.x. [PubMed: 19497009]
130.
Vlemincx E, Taelman J, De Peuter S, van Diest I, van den Bergh O. Sigh rate and respiratory variability during mental load and sustained attention. Psychophysiology. 2011;48(1):117-20. https://doi​.org/10.1111/j​.1469-8986.2010.01043.x. [PubMed: 20536901]
131.
Vlemincx E, Abelson JL, Lehrer PM, Davenport PW, van Diest I, van den Bergh O. Respiratory variability and sighing: A psychophysiological reset model. Biol Psychol. 2013;93(1):24-32. https://doi​.org/10.1016/j​.biopsycho.2012.12.001. [PubMed: 23261937]
132.
Lieske SP, Ramirez JM. Pattern-specific synaptic mechanisms in a multifunctional network. I. Effects of alterations in synapse strength. J Neurophysiol. 2006;95(3):1323-33. https://doi​.org/10.1152/jn.00505.2004. [PubMed: 16492944]
133.
Lieske SP, Ramirez JM. Pattern-specific synaptic mechanisms in a multifunctional network. II. Intrinsic modulation by metabotropic glutamate receptors. J Neurophysiol. 2006;95(3):1334-44. https://doi​.org/10.1152/jn.00506.2004. [PubMed: 16492945]
134.
Koch H, Caughie C, Elsen FP, Doi A, Garcia AJ 3rd, Zanella S, et al. Prostaglandin E2 differentially modulates the central control of eupnoea, sighs and gasping in mice. J Physiol. 2015;593(1):305-19. https://doi​.org/10.1113/jphysiol​.2014.279794. [PMC free article: PMC4293069] [PubMed: 25556802]
135.
Tryba AK, Pena F, Lieske SP, Viemari JC, Thoby-Brisson M, Ramirez JM. Differential modulation of neural network and pacemaker activity underlying eupnea and sigh-breathing activities. J Neurophysiol. 2008;99(5):2114-25. https://doi​.org/10.1152/jn.01192.2007. [PMC free article: PMC3860370] [PubMed: 18287547]
136.
Doi A, Ramirez JM. State-dependent interactions between excitatory neuromodulators in the neuronal control of breathing. J Neurosci. 2010;30(24):8251-62. https://doi​.org/10.1523/JNEUROSCI​.5361-09.2010. [PMC free article: PMC3606074] [PubMed: 20554877]
137.
Pena F, Ramirez JM. Substance P-mediated modulation of pacemaker properties in the mammalian respiratory network. J Neurosci. 2004;24(34):7549-56. https://doi​.org/10.1523/JNEUROSCI​.1871-04.2004. [PMC free article: PMC6729648] [PubMed: 15329402]
138.
Tryba AK, Pena F, Ramirez JM. Gasping activity in vitro: A rhythm dependent on 5-HT2A receptors. J Neurosci. 2006;26(10):2623-34. https://doi​.org/10.1523/JNEUROSCI​.4186-05.2006. [PMC free article: PMC6675157] [PubMed: 16525041]
139.
Pena F, Ramirez JM. Endogenous activation of serotonin-2A receptors is required for respiratory rhythm generation in vitro. J Neurosci. 2002;22(24):11055-64. [PMC free article: PMC6758407] [PubMed: 12486201]
140.
Viemari JC, Garcia AJ 3rd, Doi A, Ramirez JM. Activation of alpha-2 noradrenergic receptors is critical for the generation of fictive eupnea and fictive gasping inspiratory activities in mammals in vitro. Eur J Neurosci. 2011;33(12):2228-37. https://doi​.org/10.1111/j​.1460-9568.2011.07706.x. [PMC free article: PMC3652413] [PubMed: 21615559]
141.
Viemari JC, Garcia AJ 3rd, Doi A, Elsen G, Ramirez JM. Beta-Noradrenergic receptor activation specifically modulates the generation of sighs in vivo and in vitro. Front Neural Circuits. 2013;7:179. https://doi​.org/10.3389/fncir.2013.00179. [PMC free article: PMC3824105] [PubMed: 24273495]
142.
Li A, Nattie E. Antagonism of rat orexin receptors by almorexant attenuates central chemoreception in wakefulness in the active period of the diurnal cycle. J Physiol. 2010;588(Pt 15):2935-44. https://doi​.org/10.1113/jphysiol​.2010.191288. [PMC free article: PMC2956908] [PubMed: 20547681]
143.
Li P, Janczewski WA, Yackle K, Kam K, Pagliardini S, Krasnow MA, et al. The peptidergic control circuit for sighing. Nature. 2016;530(7590):293-7. https://doi​.org/10.1038/nature16964. [PMC free article: PMC4852886] [PubMed: 26855425]
144.
Bamford OS, Schuen JN, Carroll JL. Effect of nicotine exposure on postnatal ventilatory responses to hypoxia and hypercapnia. Respir Physiol. 1996;106(1):1-11. https://doi​.org/10.1016​/0034-5687(96)00051-5. [PubMed: 8946572]
145.
Horne RS, Sly DJ, Cranage SM, Chau B, Adamson TM. Effects of prematurity on arousal from sleep in the newborn infant. Pediatr Res. 2000;47(4 Pt 1):468-74. https://doi​.org/10.1203​/00006450-200004000-00010. [PubMed: 10759153]
146.
Nock ML, Difiore JM, Arko MK, Martin RJ. Relationship of the ventilatory response to hypoxia with neonatal apnea in preterm infants. J Pediatr. 2004;144(3):291-5. https://doi​.org/10.1016/j​.jpeds.2003.11.035. [PubMed: 15001929]
147.
Horne RS, Parslow PM, Harding R. Postnatal development of ventilatory and arousal responses to hypoxia in human infants. Respir Physiol Neurobiol. 2005;149(1-3):257-71. https://doi​.org/10.1016/j​.resp.2005.03.006. [PubMed: 15876558]
148.
Hehre DA, Devia CJ, Bancalari E, Suguihara C. Brainstem amino acid neurotransmitters and ventilatory response to hypoxia in piglets. Pediatr Res. 2008;63(1):46-50. https://doi​.org/10.1203/PDR​.0b013e31815b4421. [PubMed: 18043517]
149.
Mendelowitz D. Advances in parasympathetic control of heart rate and cardiac function. News Physiol Sci. 1999;14:155-61. [PubMed: 11390842]
150.
Neff RA, Simmens SJ, Evans C, Mendelowitz D. Prenatal nicotine exposure alters central cardiorespiratory responses to hypoxia in rats: Implications for sudden infant death syndrome. J Neurosci. 2004;24(42):9261-8. https://doi​.org/10.1523/JNEUROSCI​.1918-04.2004. [PMC free article: PMC6730089] [PubMed: 15496661]
151.
Carroll MS, Kenny AS, Patwari PP, Ramirez JM, Weese-Mayer DE. Respiratory and cardiovascular indicators of autonomic nervous system dysregulation in familial dysautonomia. Pediatr Pulmonol. 2012;47(7):682-91. https://doi​.org/10.1002/ppul.21600. [PubMed: 22170819]
152.
Garcia AJ 3rd, Koschnitzky JE, Dashevskiy T, Ramirez JM. Cardiorespiratory coupling in health and disease. Auton Neurosci. 2013;175(1-2):26-37. https://doi​.org/10.1016/j​.autneu.2013.02.006. [PMC free article: PMC3683976] [PubMed: 23497744]
153.
Dutschmann M, Jones SE, Subramanian HH, Stanic D, Bautista TG. The physiological significance of postinspiration in respiratory control. Prog Brain Res. 2014;212:113-30. https://doi​.org/10.1016​/B978-0-444-63488-7.00007-0. [PubMed: 25194196]
154.
Wang X, Guo R, Zhao W, Pilowsky PM. Medullary mediation of the laryngeal adductor reflex: A possible role in sudden infant death syndrome. Respir Physiol Neurobiol. 2016;226:121-7. https://doi​.org/10.1016/j​.resp.2016.01.002. [PubMed: 26774498]
155.
Leiter JC, Bohm I. Mechanisms of pathogenesis in the sudden infant death syndrome. Respir Physiol Neurobiol. 2007;159(2):127-38. https://doi​.org/10.1016/j​.resp.2007.05.014. [PubMed: 17644048]
156.
Thach BT. Some aspects of clinical relevance in the maturation of respiratory control in infants. J Appl Physiol (1985). 2008;104(6):1828-34. https://doi​.org/10.1152/japplphysiol​.01288.2007. [PubMed: 18420716]
© 2018 The Contributors, with the exception of which is by Federal United States employees and is therefore in the public domain.

This work is licenced under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0) License. To view a copy of this licence, visit http://creativecommons.org/licenses/by-nc-nd/4.0 or send a letter to Creative Commons, 444 Castro Street, Suite 900, Mountain View, California, 94041, USA. This licence allows for the copying, distribution, display and performance of this work for non-commercial purposes providing the work is clearly attributed to the copyright holders. Address all inquiries to the Director at the above address.

Bookshelf ID: NBK513387PMID: 30035952

Views

  • PubReader
  • Print View
  • Cite this Page
  • PDF version of this title (46M)

Related information

  • PMC
    PubMed Central citations
  • PubMed
    Links to PubMed

Similar articles in PubMed

See reviews...See all...

Recent Activity

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

See more...