Introduction

Sudden infant death syndrome (SIDS) has a complex and heterogeneous pathogenesis, with multiple abnormalities in a number of physiological functions and systems including neurological, cardiovascular, respiratory, gastrointestinal, nutritional, endocrine, metabolic, infectious, immunological, environmental, and genetic (1-7). Typically, without warning, an apparently healthy infant is found deceased sometime after being placed to sleep (8). There are many theories involving animal and human studies that have attempted to understand the pathophysiology of SIDS. Unfortunately, to date, there are no biomarkers available to aid in the prevention or definitive diagnosis of SIDS. The aim of much scientific research has been to determine the mechanisms of failure in SIDS infants that are undetectable prior to death and that remain just as unclear following death. While the precise cause of death in infants dying of SIDS has not been identified, there is considerable evidence that the syndrome results from a combination of circumstances involving [1] a cardiorespiratory challenge that occurs in [2] a neurologically compromised infant at [3] a specific period of postnatal development (3, 9, 10). The following chapter will focus on the failure of cardiorespiratory and autonomic control associated with neuropathology of the brainstem in SIDS.

An important step in understanding the complex pathophysiology of SIDS was the establishment of the Triple Risk Model, which successfully conceptualized the epidemiological, physiological, and neuropathological data associated with SIDS. The Triple Risk Model proposes three coinciding factors: [1] an underlying vulnerability of the infant; [2] a critical developmental period in homeostatic control that the infant is transitioning through; and [3] the application of an exogenous stressor/s such as an asphyxiating environment (11). The model implies that an infant may be most at risk of SIDS when all three factors are simultaneously present (8, 11). All three factors contribute to the risk of an adverse event that occurs suddenly in an otherwise “healthy” infant. Therefore, consideration of the Triple Risk Model is of key importance to SIDS research, with the model providing a foundation upon which researchers can build in the generation of research hypotheses.

Underlying Vulnerability and the Brainstem Hypothesis

Multiple neuropathologic studies in SIDS victims have supported the concept that SIDS infants are not entirely “normal” prior to death; instead these infants possess some form of underlying vulnerability exposing them to an increased risk for sudden death (3, 8). Interest in investigation of the brainstem in SIDS began with the findings of Naeye (12), who reported astrogliosis in this region in 50% of SIDS cases, with hypoxia thought to be the underlying cause. Further, research by Kinney et al. (13) showed reactive gliosis in one-fifth of cases. Building upon these observations, research was then directed towards investigation of neurotransmitters in brainstem respiratory related pathways, particularly those located in the medulla oblongata, which controls respiration, chemosensitivity, autonomic function, and arousal (9, 10, 14). As such, there is now sufficient evidence that SIDS, or a certain subset of SIDS, is associated with some form of underlying neural or systematic dysfunction in medullary homeostatic control. This dysfunction is thought to impair critical responses to life-threatening challenges such as hypoxia, hypercarbia, and asphyxia during a sleep period (3, 8, 14), hence the term “brainstem hypothesis”. This concept is based on evidence that the brainstem has a crucial role in respiratory, cardiac, and blood pressure control, as well as in central chemosensitivity, thermoregulation, and modulation of upper airway reflexes, particularly during sleep. Additionally, investigations of possible defects in medullary control, consistent with brainstem dysfunction in infants who subsequently died of SIDS, have implicated impaired autoresuscitation (gasping), abnormal respiratory patterning, and episodic obstructive apnea during sleep, autonomic dysfunction (episodic tachycardia/bradycardia, abnormal heart rate variability), and arousal deficits (3, 15-21).

Brainstem Respiratory Network

Respiration is both a spontaneous and an autonomic physiological function crucial for survival. Respiratory drive plays a critical role in homeostatic control by regulating blood oxygen, carbon dioxide (CO₂), and pH levels (22), and it is controlled by rhythmic respiratory signals generated by extensive neural networks located in the medulla oblongata (23, 24). Excitatory amino acids are considered the primary source of neurochemical signals in the generation of respiratory rhythm and inspiratory drive to spinal and cranial motoneurons (25), with basic respiratory rhythm pattern modulated by multiple amine and peptide neurotransmitter and neuromodulator systems (22). Breathing must be constantly adapted to suit metabolic demand and is therefore a highly integrative process. Breathing behaviors are exerted via the integration of multiple respiratory neurons concentrated in the ventral respiratory column, including the prebotzinger (PBC) and botzinger complexes, retrotrapezoid nucleus, parafacial respiratory group, kolliker fuse, and some cortical and cerebellar networks (26, 27). Respiratory rhythm and inspiratory and expiratory motor patterns emerge from the dynamic interactions between these structural and functional components (26).

The core of breathing rhythm generation is the PBC (see Chapter 27). Identified physiologically as an essential part of the medullary respiratory and rhythm-generating network in mammals by Smith et al. in 1991¹, the PBC is well established as a critical region for the generation and co-ordination of respiratory rhythm and breathing cessation (28-30). Three types of respiratory rhythmic control are identified as originating in the PBC — eupnea, sighs, and gasping (10, 31) — and the region is particularly sensitive to hypoxia (31, 32). Lesioning of the PBC results in cessation of breathing in experimental animals (33, 34), and pacemaker neurons within the PBC are postulated to have a role in the control of breathing as a contingency system that may be activated when normal respiratory rhythmogenesis fails (35, 36). Therefore, the structure and function of the PBC is of considerable importance with regards to brainstem respiratory control and failure of such a system in SIDS.

Although well described anatomically in experimental animals, the precise location of the PBC in the human brainstem has remained unclear. However, distinct cytoarchitectural characteristics of neighboring nuclei and fiber tracts, in addition to markers for interneurons of the PBC, may be utilized to help localize the region. Interneurons of the PBC have been shown to express high levels of the tachykinin NK1 receptor (NK1R) (24) and somatostatin (37). Stornetta et al. (37) and Schwarzacher et al. (38) utilized these characteristics to identify a circumscribed region of the ventrolateral medulla containing a high number of NK1R and somatostatin-immunoreactive neurons indicative of the PBC region in experimental animals, and deduced that this region could be the presumptive human homologue (38).

Respiratory Defense Mechanisms and Arousal Failure

Exposure to respiratory challenges occurs frequently during infancy; however, these can usually be overcome because of highly evolved protective respiratory defense mechanisms (36). These mechanisms involve complex feedback pathways at several neuroanatomic levels and are controlled by different underlying neural pathways and neurochemical actions to produce an integrated response (9).

Under normal conditions, increased blood CO₂ levels (hypercapnia) or decreased oxygen levels (hypoxia) stimulate an infant to produce respiratory and motor defense mechanisms, including sighs, thrashing, eye opening, head lifting or tilting, and cries, to trigger arousal (39, 40). Arousal from sleep then successfully overcomes the respiratory challenge and restores the network to the normal “eupneic” breathing state (10, 40). This arousal response to harmful stimuli is a key feature of breathing control development in newborns (41), protecting the infant from prolonged respiratory distress (36); thus any interruption or depression of arousal will have significant implications on the normal response to respiratory challenges (40). In the event of arousal failure, the normal breathing state shifts to gasping, which is a strong indicator of exposure to hypoxia. If oxygen becomes available during gasping, recovery from the respiratory challenge is still possible by “autoresuscitation”, where complete and rapid return of function of all organs is achieved (36). Gasping and autoresuscitation are, however, the final defenses in overcoming respiratory challenges, and failure of both results in an inability to restore blood oxygen levels with the loss of drive of heart rate (9, 36, 39, 40, 42). A “challenged” infant will therefore experience further respiratory distress, failing to overcome respiratory challenge, and will rapidly succumb to death (10).

SIDS infants also have a markedly reduced ability to turn their faces or to lift their heads away from a dangerous micro-environment, in addition to their inability to produce adequate respiratory musculature activity (43, 44). This suggests that there is an underlying flaw in the control of such mechanisms at the neural and subcellular levels. Studies of infants on monitors who eventually succumbed to SIDS have provided indirect evidence for a sleep-related impairment or a delayed maturation of these defense mechanisms (17, 18). Future SIDS victims from these studies exhibited decreased spontaneous and induced arousals during sleep (18, 45), had altered sleep patterns (20), and had significantly more obstructive and mixed apneas that were associated with altered autonomic responses (18, 21, 45-47). Gasping has also been identified as a common feature of recordings in future SIDS infants, with reports of unusual repeated double and triple gasps that were either completely ineffective or had minimal effects on increasing heart rate (15, 19). Other studies have indicated that SIDS may not always be sudden, but rather that death may be preceded by episodic cycles of tachycardia, bradycardia, or apnea in the hours, to days, before the lethal event (8). This is further supported by markers of chronic tissue hypoxia (48-50), including brainstem gliosis, β-amyloid precursor protein deposition, and apoptosis (12, 13, 51-53).

Possible Multi-Neurotransmitter Homeostatic Network Dysfunction

Neurochemicals are the mediators of sensory, motor, integrative, and modulatory processing in the respiratory network, including multiple inhibitory and excitatory neurotransmitters and neuromodulators (32, 54). Specifically, in regions of the brainstem involved in the control of respiration, notably the PBC, raphe magnus, and raphe obscurus of the medulla, neurotransmitter amino acids including glutamate, gamma-Aminobutyric acid (GABA), taurine, and glycine, as well as the neurotransmitters serotonin, dopamine, and substance P (SP), and the neuromodulator adenosine are found (55). The respiratory system is controlled by the balance and specific actions of these neurotransmitter and neuromodulator systems, which have diverse roles in regulating the amplitude and frequency of central rhythm generation and respiratory output (32, 56, 57). This is achieved through interaction with motoneurons, sensory neurons, and neurons of the central nervous system (CNS).

Neurotransmitters are expressed in a state-dependent manner and are centrally involved in reconfiguring the respiratory network under normal conditions; they are also involved with the homeostatic response to changes in oxygen and CO₂ levels during various states of breathing (55, 57). This occurs through modifying the membrane and synaptic properties of rhythm-generating neurons (58), and by altering their activity during different states, particularly hypoxia (55). Actions of neurochemicals are determined by the concurrent modulation and interaction with one another (29), and any deficiencies in one will be immediately compensated for by the action of others (29, 57). Following the deprivation of a specific modulatory input over a prolonged period, rhythmic activity is restored by the respiratory network functioning in an independent neuromodulator manner (31, 59). Therefore varying networks likely adapt to changes in neurotransmitter and neuromodulator expression by altering the concentration of other endogenously released neurochemicals (58).

As noted, the underlying vulnerability in SIDS infants is thought to be characterized by abnormalities in multiple neurotransmitter networks in the medulla oblongata which control critical homeostatic mechanisms. Indeed, abnormalities in various brainstem neurochemicals, including catecholamines, neuropeptides, indole amines (predominantly serotonin and its receptors), amino acids (predominantly glutamate), growth factors including brain-derived neurotropic growth factor (BDNF), and some cytokine systems, have been reported in infants who died of SIDS (Table 26.1) (60-79).

Table 26.1:

Previously published research investigating multiple neurotransmitter and receptor network abnormalities within the brainstem in post-mortem human infant brain tissues in SIDS.

Observations of abnormal neurochemicals across the medullary network may be the primary defect in SIDS responsible for failure of protective mechanisms to counteract homeostatic imbalances that impinge upon a sleeping infant. While the “multi-transmitter” hypothesis for SIDS acknowledges that neurochemical abnormalities are not limited to one system, it has yet to be established how abnormalities in individual systems may influence one another, or what the impact of dysfunction in a particular neurotransmitter might be on other systems within the same, or closely associated, medullary nuclei. This chapter will focus on abnormalities in the monoamine serotonin 5-hydroxytryptamine (5-HT) and neuropeptide substance P (SP) networks within the medulla in SIDS, due to their relationship with cardiorespiratory centers, given that both systems are at the forefront of current investigations into brainstem dysfunction in SIDS.

Medullary Serotonergic System

There is substantial evidence for multiple neural mechanisms contributing to the fatal event in SIDS. However, the most compelling and reproducible research to date is focused on the hypothesis that SIDS is due to a developmental disorder of medullary serotonergic and related neurotransmitter systems that occurs prenatally but exerts its effects in the postnatal period (9, 72, 80, 81).

Monoaminergic pathways represent a key component of the reticular activating system within the mammalian brain and are involved in multiple physiological functions (82). Serotonin (5-HT) is one of several biologic monoamines located in specific axon terminals that are widely distributed throughout the CNS (83). The 5-HT system is spread throughout the brainstem; however, it is primarily situated in the medulla oblongata where it is referred to as the “medullary 5-HT system” (84-86). The system comprises two core domains, caudal and rostral, which are distinct in their anatomic location, development, functions, and connectivity. The caudal domain projects to the cerebellum and spinal cord and is critical for respiratory and autonomic output. The rostral domain projects to the cerebral cortex, thalamus, hypothalamus, basal ganglia, hippocampus, and amygdala and mediates arousal, cognition, mood, motor activity, and cerebral blood flow (85, 87). The 5-HT system is recognized as a key regulator of the brain’s homeostatic control systems, including upper airway control, ventilation and gasping, autonomic control, thermoregulation, chemosensitivity, arousal, and hypoxia-induced plasticity (8, 84, 85).

Serotonin plays a fundamental role in the control and modulation of breathing (23, 56), exhibiting both inhibitory and excitatory effects (57) and acting via a large array of receptors that function to facilitate diverse respiratory effects (88, 89). The synaptic projections of 5-HT neurons are present across all major respiratory nuclei including the PBC, and arise from the midline raphe pallidus and raphe obscurus (90). Several neurotransmitters and neuropeptides are released by 5-HT neurons and directly enhance the excitability of multiple neuron subsets within the respiratory network (85). Serotonergic terminals also contain SP and thyrotropin-releasing hormone (TRH), and receptors for 5-HT, SP, and TRH are localized on neurons across the major respiratory nuclei (91). Activation of these receptors in vitro provokes modulatory effects on respiratory neurons to enhance their excitability and activity of the respiratory network. There is also considerable evidence recognizing 5-HT neurons as putative central respiratory chemoreceptors that assist in the detection of CO₂ and the implementation of ventilatory responses in order to maintain circulatory homeostasis (92).

It is well established that the exogenous release of 5-HT exerts complex modulatory effects on respiratory drive, as observed in in vivo preparations (23, 93). Peña and Ramirez (2002)² demonstrated that bursting respiratory neurons rely on endogenously released 5-HT acting on 5-HT_2A receptors, and that blockage of these receptors abolishes the critical bursting property of neurons in order to generate normal breathing. Doi and Ramirez (57) found that 5-HT increased and subsequently decreased bursting frequency in pre-inspiratory and inspiratory neurons, highlighting its important modulatory effects. Furthermore, inhibition of 5-HT medullary raphe and extra raphe neurons has been reported to decrease ventilatory sensitivity to C02 and also results in alterations to cardiovascular variables and sleep cycling (94). These observations reinforce the importance of neuromodulators such as 5-HT in adjusting ionic conductance crucial for regulating pacemaker and network properties of the rhythm-generating network.

Serotonergic abnormalities have been reported across multiple SIDS data-sets from varying ethnic, social, and cultural backgrounds (65, 72, 95, 96). These abnormalities involve raphe, extra raphe, and ventral (arcuate) populations of the brainstem containing 5-HT neurons and their projection sites, such as the dorsal motor nucleus of the vagus and the nucleus of the solitary tract (86). Abnormalities identified include alterations in 5-HT receptor binding patterns (5-HT_1A and 5-HT_2A receptors) (65, 95, 97-99), reduced brainstem levels of 5-HT and tryptophan hydroxylase (TPH2, the rate limiting enzyme-regulating 5-HT synthesis) (72), decreased binding to the 5-HT transporter relative to 5-HT cell density (14, 65), increased 5-HT cell number and density of 5-HT neurons, morphological immaturity of 5-HT neurons (3, 65), and reductions in the level of the 14-3-3 signal transduction family of proteins in regions of the medulla oblongata critically involved in the regulation of homeostatic function (Table 26.2) (100). Given the complex role of 5-HT within the medulla, associated abnormalities are likely responsible for impaired reflexes and responses of critical autonomic respiratory defense mechanisms to exogenous stressors such as hypoxia (9, 14, 101).

Table 26.2:

Previously published research investigating serotonin in post-mortem human infant brain tissue in SIDS.

While medullary 5-HT abnormalities are the most prominent findings in SIDS research to date, the precise pathogenesis remains unknown, with uncertainty as to whether these abnormalities are associated with the primary event in SIDS or are instead an epiphenomenon. However, it is most likely that the evolution of 5-HT abnormalities is multifactorial, involving a combination of environmental and genetic risk factors (80).

Substance P

The neuropeptide SP has also been shown to play an integral role in the modulation of homeostatic function in the medulla, including regulation of respiratory rhythm generation (24, 28, 32), integration of cardiovascular control (102), modulation of the baroreceptor reflex (103), and mediation of the chemoreceptor reflex in response to hypoxia (104, 105). Given the extensive role of SP across multiple homeostatic systems, a number of human conditions have been associated with an altered SP/NK1R system within the CNS (106); therefore it is not unreasonable to hypothesize that abnormalities in SP neurotransmission might also result in autonomic dysfunction during sleep and contribute to SIDS deaths. The role of SP in the pathogenesis of SIDS has been previously explored in a number of studies; however, SP expression in SIDS has been variable, even with respect to the normative distributions of SP and its receptor in the human infant brainstem. Among these studies are reports of increased SP immunoreactivity (64, 107-110), lowered expression of SP in fibers and tracts (111), and reports of no change in SP receptor binding density (112, 113) within various brainstem nuclei in SIDS cases compared to controls (Table 26.3).

Table 26.3:

Previously published research investigating substance P in post-mortem human infant brain tissue in SIDS.

The definition of SIDS that has been used in these studies has, however, been a significant confounding factor, as many studies either do not cite a definition or provide explanations as to how cases were classified (114-116). SIDS cases that had extended post-mortem intervals have also been included in analyses in some studies. These factors may explain the differences observed among study results and may unfortunately preclude meaningful comparisons. However, recent work by Bright has identified a significant developmental abnormality of SP and NK1R binding in multiple medullary nuclei related to cardiorespiratory function and autonomic control in SIDS cases compared to controls (117). This research provides support for the hypothesis that abnormalities in a multi-neurotransmitter network, and not simply abnormalities in one neurotransmitter system i.e. 5-HT, underlie the pathogenesis of SIDS deaths. Abnormalities were detected not only in brainstem nuclei that were involved in responses to hypoxia, but also in areas that controlled head and neck movement. The latter findings may explain why SIDS infants are unable to lift their heads out of challenging environments.

Experimental animal studies have contributed to the understanding of a potential functional relationship between 5-HT and SP neurotransmission across brainstem-mediated homeostatic control. As noted, the actions of neurotransmitters are determined by the concurrent modulation and interaction with one another, and so deficiencies in one will likely be immediately compensated for by the actions of others (29). Thus, with respect to the pathogenesis of SIDS, the presence of medullary 5-HT dysfunction within critical brainstem regions such as the raphe nuclei may stimulate a compensatory response by SP or may have adverse affects on SP neurotransmission within the same medullary nuclei. Withdrawal or alteration of the combination of 5-HT and SP-mediated homeostatic control within the developing infant brainstem could therefore contribute additively to network dysfunction in a subset of SIDS cases. This may explain the inability of a SIDS infant to execute appropriate responses to life-threatening challenges during sleep.

Neurotransmitters and the Critical Development Period

Development of respiratory control is complex and begins early in gestation, with the respiratory network continually undergoing extensive refinement and adjustment after birth to reach adult levels of maturity. Humans experience a long gestation and prolonged period of postnatal maturation, and therefore infants are vulnerable to the interaction of a number of environmental factors, both prenatally and postnatally, that may expose them to harmful stimuli, including hypoxia, hyperoxia, and/or potential toxins (118, 119). In addition, during development there is an enhanced sensitivity to CO₂ which is thought to be, in part, mediated by the transition from fetal to neonatal patterns of breathing (120). Postnatal developmental changes in networks generating respiratory rhythm are likely to occur concurrently across several brainstem nuclei and, therefore, must be well synchronized to prevent any interruption of breathing (22, 121). Adverse events during this “critical period of development” may result in long-term alterations to the structure and function of the respiratory network, including dysfunction of the ventilatory response to a hypoxic challenge (122-124). Alterations during this period are likely to have a greater effect on respiratory control and maturity than insults later in life (122, 124, 125).

At birth a cascade of neurotransmitters and transcriptional factors are activated and there is increasing evidence that these neurotransmitters, neuromodulators, and their receptors function as developmental signals. These signals are important for the maturation of synapses and formation of neuronal networks, by modulating plasticity of brain circuits (121, 126). Shortly after birth, the respiratory system operates under “alert” conditions, defined by increased excitability in central respiratory networks (127), with a switch in dominance from inhibitory to excitatory neurotransmission (54, 128, 129). The various neurochemicals expressed within the respiratory network have been identified to either increase their expression with age (e.g. glutamate, serotonin, norepinephrine, thyrotropin-releasing hormone) or decrease in expression (e.g. GABA, 5-HT1A receptor, SP, NK1R, somatostatin) with age (54).

Animal studies have provided some insight into what may constitute a critical period in the development of the respiratory network. Wong-Riley and Liu (54) reported that the end of the second postnatal week was the most dynamic in the development of brainstem respiratory control in rat pups. However, at postnatal day 12, a dramatic shift occurred, where a transient dominance of inhibitory over excitatory neurotransmission was observed, in addition to multiple neurochemical and physiological adjustments and switches being simultaneously orchestrated. During this period rat pups had a reduced ability to respond to hypoxia and experienced multifaceted development and adjustment of the respiratory system in order for them to successfully transition from neonatal to adult forms of ventilatory control (125).

Extrapolating from animal studies to that of the developing human infant respiratory network has its challenges; however, these studies assist in potentially explaining why 90% of SIDS deaths occur in the first six months of life (3). The peak incidence in SIDS at 2 to 4 months of age (8, 14) may constitute a period of major brainstem respiratory network development in which an infant’s abilities to respond and overcome respiratory insults are diminished. Although abnormalities in neurochemicals and their systems, such as that of the medullary 5-HT network in SIDS, are thought to originate during prenatal development (9), the effects of these abnormalities may only present after birth during the early postnatal period (14). However, exactly when changes in the expression and activity of neurotransmitters and neuromodulators occur in the developing human brain is not known at present, nor the extent to which these changes may impact on normal respiration and contribute to increased vulnerability of a SIDS infant. It is unlikely that a critical developmental period ends abruptly; rather, it is likely to taper off gradually. Therefore, identifying when neurochemical switches occur in the human infant brainstem in particular is necessary to fully understand the critical developmental period and potential abnormalities during this time frame.

Conclusions

Neuropathological investigations have identified significant abnormalities in the development and function of homeostatic networks in the brainstems of SIDS infants. However, there is a need to broaden the scope of SIDS neuropathology research in order to investigate the interaction of multiple neurotransmitters in the brainstems of infants, in addition to further developing animal models. This will be the challenge of the future in order to prevent SIDS deaths from occurring.

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Footnotes

1

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.

2

Peña F, Ramirez JM. Endogenous activation of serotonin-2A receptors is required for respiratory rhythm generation in vitro. J Neurosci. 2002;22(24):11055-64.