Control of the cardiovascular and respiratory systems during sleep

doi:10.1016/j.autneu.2019.01.007

Autonomic Neuroscience

Volume 218, May 2019, Pages 54-63

https://doi.org/10.1016/j.autneu.2019.01.007 Get rights and content

Abstract

Sleep and arousal from sleep are associated with profound changes in cardiovascular and respiratory functions. Fluctuations of arterial blood pressure (ABP), heart rate (HR), and respiration occur both during non-rapid eye movement (NREM) and REM sleep and during transitions between sleep and behavioral arousal. These changes reflect complex, state-dependent interactions among several neuronal groups in the hypothalamus and brainstem. These neurons utilize the excitatory amino-acid L-glutamate or the inhibitory amino acid γ-aminobutyric acid (GABA) and are modulated in a state-dependent manner by inputs from cholinergic, monoaminergic, and hypothalamic orexin/hypocretin and melanin-concentrating hormone (MCH) neurons. These different neuronal populations mediate continuous interactions between cortical state and subcortical circuits modulating sympathetic and cardiovagal output, respiratory pattern, and chemosensitivity. Reciprocally, brainstem areas involved in these functions promote behavioral arousal in the setting of hypoxia, hypercapnia, or other stressors. Studies in rodents using optogenetic and other approaches for selective activation or inactivation of specific neuronal groups identified by their unique neurochemical markers, combined with recording of cortical activity, cardiovascular responses, and respiration, have provided new information on the brainstem mechanisms controlling arousal, wake-sleep cycle, cardiovascular and respiratory control (Luppi et al., 2017; Saper and Fuller, 2017; Scammell et al., 2017; Dampney, 2016; Del Negro et al., 2018; Guyenet, 2006; Guyenet and Abbott, 2013; Smith et al., 2013). These findings also provide further insight into the pathophysiology of sleep-related cardiovascular and respiratory disorders including sleep apnea, narcolepsy, congenital central hypoventilation syndrome, sudden infantile death syndrome, and sudden unexpected death in epilepsy.

Section snippets

Cardiovascular and respiratory phenomenology during sleep and wakefulness

The different stages or sleep are defined by distinct patterns of electrocortical activity reflected in the electroencephalogram (EEG) and associated changes in motor and autonomic functions. NREM sleep is associated with reduction of muscle tone, and different EEG patterns that define 3 stages; stage 1 (N1) at the beginning of sleep; stage 2 (N2) characterized by sleep spindles; and deep or stage 3 sleep (N3) characterized by low frequency (0.5–2 Hz) delta waves. NREM sleep is punctuated by

Control of arousal and sleep states

The changes in cardiovascular and respiratory functions during sleep reflect the influences of multiple neuronal cell groups that regulate arousal and transitions between sleep stages. These neurons are distributed in the basal forebrain, hypothalamus, and brainstem. Whereas medullary neurons mediate feedback cardiovascular and respiratory reflexes, inputs from more rostral areas involved in control of arousal and sleep-wake cycle provide a state-dependent, feedforward modulation of these

Mechanisms for cardiovascular control during sleep

Both during wakefulness and across sleep stages the control of ABP and HR occurs primarily at the level of the medulla and results from the interaction between feedback control via reflexes triggered by cardiovascular and respiratory afferents, and feedforward modulation by inputs primarily from the hypothalamus and PAG activated during different behavioral states (Dampney, 2016; Guyenet, 2006; Silvani and Dampney, 2013) (Fig. 2).

Brainstem respiratory circuits and sleep

The respiratory central pattern generator is located in the lower brainstem and includes several rhythm-generating components that drive downstream premotor neurons innervating spinal respiratory and cranial motoneurons (Del Negro et al., 2018; Smith et al., 2013). These pattern generators respond to stimuli from central and peripheral chemoreceptors that trigger ventilatory responses to maintain optimal alveolar ventilation and gas exchange (Nattie and Li, 2012). These central and peripheral

Integrated control of arousal, cardiovascular and respiratory control

The multiple interactions among neuronal groups controlling arousal, cardiovascular, and respiratory functions provide for an integration among these functions across behavioral states.

Conclusions

Recent experimental findings provide a pathophysiological basis for combined cardiovascular and respiratory abnormalities functions in sleep-related disorders, including development of hypertension in patients with obstructive sleep apnea and increased cardiovascular risk in patients with narcolepsy. These disorders are further discussed in other reviews in this Issue and only few examples will be briefly mentioned here to emphasize the interactions among sleep, cardiovascular, and respiratory

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Sleep disruptions experienced by patients with obstructive sleep apnea (OSA) can lead to excessive daytime sleepiness (EDS) and significantly impact patients’ quality of life. EDS may persist despite use of continuous positive airway pressure (CPAP) therapy. Small molecules that target the orexin system, which has a known role in sleep-wake regulation, show therapeutic potential for the treatment of EDS in patients with hypersomnia. This randomized, placebo-controlled, phase 1b study aimed to investigate the safety of danavorexton, a small-molecule orexin-2 receptor agonist, and its effects on residual EDS in patients with OSA.
Adults with OSA aged 18–67 years with adequate CPAP use were randomized to one of six treatment sequences of single IV infusions of danavorexton 44 mg, danavorexton 112 mg, and placebo. Adverse events were monitored throughout the study. Pharmacodynamic assessments included maintenance of wakefulness test (MWT), Karolinska Sleepiness Scale (KSS), and the psychomotor vigilance test (PVT).
Among 25 randomized patients, 16 (64.0%) had treatment-emergent adverse events (TEAEs) and 12 (48.0%) had TEAEs considered related to treatment, all mild or moderate. Seven patients (28.0%) had urinary TEAEs: three, seven, and none while taking danavorexton 44 mg, danavorexton 112 mg, and placebo, respectively. There were no deaths or TEAEs leading to discontinuation. Improvements in mean MWT, KSS, and PVT scores were observed with danavorexton 44 mg and 112 mg vs placebo. These findings show that danavorexton can improve subjective and objective measures of EDS in patients with OSA and residual EDS despite adequate CPAP use.
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Physiological regulation can be defined as the integrated neural control mechanism underlying somatic, autonomic, and neuroendocrine activity. Such an integration occurs mostly at hypothalamic level. Physiological regulation is intrinsically heterogeneous between non-rapid eye movement (NREM) and rapid eye movement (REM) sleep. During NREM sleep, it is aimed at the maintenance of body homeostasis at a low level of energy expenditure. During REM sleep, the cardiorespiratory instability and the thermoregulatory impairment are indicative of a derangement of the integrative neural regulation of physiological functions. However, the finding that osmoregulation is maintained during REMS suggests that this derangement does not affect the whole hypothalamus.
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Orexin neurons can also be directly activated as central respiratory chemoreceptors (CRCs) by the increase of pCO2 in the CNS [186], and abundant evidence suggests that they can activate neurons related to cardiopulmonary regulation including the LC and DRN to promote respiration. Therefore, orexin neurons play an important role in coordinating arousal and respiratory chemical reflexes through the monoaminergic neurons in the brainstem [66,183,186–188]. In summary, orexin may play an indirect role in SUDEP by regulating the monoaminergic nervous system.
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Only the brainstem tegmentum, cerebellum and hippocampus were identified in both maps. The most basic breathing control takes place in the brainstem and deep brain structures (Smith and Lee-Chiong, 2008; Benarroch, 2019; Bosch et al., 2017). Therefore, it is likely that breathing variations are coupled to fMRI signal in deep brain systems in both conscious and unconscious states.
After falling asleep, the brain needs to detach from waking activity and reorganize into a functionally distinct state. A functional MRI (fMRI) study has recently revealed that the transition to unconsciousness induced by propofol involves a global decline of brain activity followed by a transient reduction in cortico-subcortical coupling. We have analyzed the relationships between transitional brain activity and breathing changes as one example of a vital function that needs the brain to readapt. Thirty healthy participants were originally examined. The analysis involved the correlation between breathing and fMRI signal upon loss of consciousness. We proposed that a decrease in ventilation would be coupled to the initial decline in fMRI signal in brain areas relevant for modulating breathing in the awake state, and that the subsequent recovery would be coupled to fMRI signal in structures relevant for controlling breathing during the unconscious state. Results showed that a slight reduction in breathing from wakefulness to unconsciousness was distinctively associated with decreased activity in brain systems underlying different aspects of consciousness including the prefrontal cortex, the default mode network and somatosensory areas. Breathing recovery was distinctively coupled to activity in deep brain structures controlling basic behaviors such as the hypothalamus and amygdala. Activity in the brainstem, cerebellum and hippocampus was associated with breathing variations in both states. Therefore, our brain maps illustrate potential drives to breathe, unique to wakefulness, in the form of brain systems underlying cognitive awareness, self-awareness and sensory awareness, and to unconsciousness involving structures controlling instinctive and homeostatic behaviors.
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Interestingly, experimental studies also suggest a possible link between the alteration of the OX system and respiration dysfunctions in PWS. In particular, studies on mouse models with OX deficiency [125–130] reported both a modulatory effect of the hypothalamic OX system on respiratory activity [127,128,131] and an increase of spontaneous sleep apneas, especially in REM sleep [129]. On the other hand, it has been shown that repetitive breathing cessations, resulting in hypoxia/hypercapnia (H/H), may inhibit and damage orexinergic neurons [130].
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ReviewControl of the cardiovascular and respiratory systems during sleep

Abstract

Section snippets

Cardiovascular and respiratory phenomenology during sleep and wakefulness

Control of arousal and sleep states

Mechanisms for cardiovascular control during sleep

Brainstem respiratory circuits and sleep

Integrated control of arousal, cardiovascular and respiratory control

Conclusions

Neurosci. Lett.

Brain Res. Bull.

Exp. Neurol.

Neuroscience

Neuroscience

Curr. Opin. Neurobiol.

Brain Res.

Auton. Neurosci.

Respir. Physiol. Neurobiol.

Neuron

Brain Res.

Respir. Physiol. Neurobiol.

Curr. Opin. Neurobiol.

Sleep Med.

Sleep Med. Rev.

Brain Res.

Neuroscience

Prog. Brain Res.

Prog. Brain Res.

Brain Res.

Respir. Physiol. Neurobiol.

Brain Res.

Curr. Opin. Neurobiol.

Curr. Opin. Neurobiol.

Neuron

Neuron

Sleep Med.

Trends Neurosci.

Brain Res.

Respir. Physiol. Neurobiol.

C1 neurons excite locus coeruleus and A5 noradrenergic neurons along with sympathetic outflow in rats

J. Physiol.

Optogenetic stimulation of c1 and retrotrapezoid nucleus neurons causes sleep state-dependent cardiorespiratory stimulation and arousal in rats

Hypertension

Neuronal discharge of preoptic/anterior hypothalamic thermosensitive neurons: relation to NREM sleep

Am. J. Phys.

The GABAergic parafacial zone is a medullary slow wave sleep-promoting center

Nat. Neurosci.

A novel excitatory network for the control of breathing

Nature

Evaluating the physiological significance of respiratory sinus arrhythmia: looking beyond ventilation-perfusion efficiency

J. Physiol.

Vestibular nuclei: activity of single neurons during natural sleep and wakefulness

Science

The orexinergic neurons receive synaptic input from C1 cells in rats

J. Comp. Neurol.

Pathophysiology of REM sleep behaviour disorder and relevance to neurodegenerative disease

Brain

Cholinergic modulation of the parafacial respiratory group

J. Physiol.

State-dependent control of breathing by the retrotrapezoid nucleus

J. Physiol.

Topographic organization of cardiovascular responses to electrical and glutamate microstimulation of the parabrachial nucleus in the rat

J. Comp. Neurol.

Topographic organization of respiratory responses to glutamate microstimulation of the parabrachial nucleus in the rat

J. Neurosci.

Postural baroreflex stimuli may affect EEG arousal and sleep in humans

J. Appl. Physiol.

Functional link between the hypocretin and serotonin systems in the neural control of breathing and central chemosensitivity

J. Neurophysiol.

Serotonergic neurons in the nucleus raphe obscurus contribute to interaction between central and peripheral ventilatory responses to hypercapnia

Pflugers Arch.

A role for the lateral parabrachial nucleus in cardiovascular function and fluid homeostasis

Front. Physiol.

Functional organization of central pathways regulating the cardiovascular system

Physiol. Rev.

Central mechanisms regulating coordinated cardiovascular and respiratory function during stress and arousal

Am. J. Phys. Regul. Integr. Comp. Phys.

Central neural control of the cardiovascular system: current perspectives

Adv. Physiol. Educ.

Review
Control of the cardiovascular and respiratory systems during sleep