Ventilatory response to induced auditory arousals during NREM sleep.

What is the central question of this study? A transcranial magnetic stimulation (TMS)-induced twitch applied on isolated single breaths over the motor cortex somatotopic representation of the tongue briefly recruits submental muscles and improves airflow dynamics of flow-limited respiratory cycles without arousing sleep apnoea patients. However, the mechanical impact of the TMS-induced twitch applied during consecutive breathing cycles on airflow dynamics remains unknown. What is the main finding and what is its importance? Our results show that application of TMS with the stimulator output set at the sleep submental motor threshold intensity on consecutive respiratory cycles increases inspiratory flow and reduces the turbulent airflow component. These results indicate an improvement of airflow pattern after two single consecutive TMS-induced twitches without arousing sleep apnoea patients. Transcranial magnetic stimulation (TMS)-induced twitches applied on isolated breaths briefly recruit upper airway dilator muscles and improve airflow and inspiratory volume without arousing apnoeic patients from sleep, but the effects of applying such twitches consecutively on airflow dynamics is unknown. The objective of this study was to quantify the effects of five consecutive TMS-induced twitches applied on sleep-induced obstructive hypopnoeic breaths in 10 obstructive sleep apnoea patients. Submental muscle motor threshold (SUBMT) and motor-evoked potential were measured during wakefulness and sleep. The TMS-induced twitches were applied during stable non-rapid eye movement (NREM) sleep, at the beginning of inspiration of consecutive flow-limited respiratory cycles, with the stimulator output set at sleep SUBMT. Maximal inspiratory flow, inspiratory volume, inspiratory time, shifts of electroencephalogram frequency and pulse rate variability were assessed. During sleep, SUBMT increased (wakefulness, 25.3 ± 4.9%; NREM sleep, 27.0 ± 6.2%; P = 0.02). During each series of stimulations there was a rise in maximal inspiratory flow (from 306.7 ± 123.2 to 359.8 ± 154.1 ml s(-1); P = 0.0002) and in inspiratory volume (from 346.1 ± 128.1 to 414.9 ± 171.2 ml; P = 0.02) without differences in thoraco-abdominal efforts and inspiratory time. These responses were observed in the absence of arousals and ceased immediately after TMS interruption. Transcranial magnetic stimulation-induced cortical and/or autonomic arousal was observed in 30.2% of all series of stimulation. Consecutive twitch TMS of submental muscles may lead to arousals in a minority of patients but can be applied on consecutive respiratory cycles during sleep and can significantly improve maximal inspiratory flow and inspiratory volume of flow-limited cycles.

Cardiovascular Disease and Sleep Disordered Breathing: Are Children Vulnerable?

EEG beta power and heart rate variability describe the association between cortical and autonomic arousals across sleep.

The termination of obstructive respiratory events is typically associated with arousal from sleep. The ventilatory response to arousal may be an important determinant of subsequent respiratory stability/instability and therefore may be involved in perpetuating obstructive respiratory events. In healthy subjects arousal is associated with brief hyperventilation followed by more prolonged hypoventilation on return to sleep. This study was designed to assess whether elevated sleeping upper airway resistance (R(UA)) alters the ventilatory response to arousal and subsequent breathing on return to sleep in patients with obstructive sleep apnoea (OSA). Inspired minute ventilation (V(I)), R(UA) and end-tidal CO(2) pressure (P(ET,CO(2))) were measured in 22 patients (11 men, 11 women) with OSA (mean +/-s.e.m., apnoea-hypopnoea index (AHI) 48.9 +/- 5.9 events h(-1)) during non-rapid eye movement (NREM) sleep with low R(UA) (2.8 +/- 0.3 cmH(2)O l(-1) s; optimal continuous positive airway pressure (CPAP) = 11.3 +/- 0.7 cmH(2)O) and with elevated R(UA) (17.6 +/- 2.8 cmH(2)O l(-1) s; sub-optimal CPAP = 8.4 +/- 0.8 cmH(2)O). A single observer, unaware of respiratory data, identified spontaneous and tone-induced arousals of 3-15 s duration preceded and followed by stable NREM sleep. V(I) was compared between CPAP levels before and after spontaneous arousal in 16 subjects with tone-induced arousals in both conditions. During stable NREM sleep at sub-optimal CPAP, P(ET,CO(2)) was mildly elevated (43.5 +/- 0.8 versus 42.5 +/- 0.8 Torr). However, baseline V(I) (7.8 +/- 0.3 versus 8.0 +/- 0.3 l min(-1)) was unchanged between CPAP conditions. For the first three breaths following arousal, V(I) was higher for sub-optimal than optimal CPAP (first breath: 11.2 +/- 0.9 versus 9.3 +/- 0.6 l min(-1)). The magnitude of hypoventilation on return to sleep was not affected by the level of CPAP and both obstructive and central respiratory events were rare following arousal. Similar results occurred after tone-induced arousals which led to larger responses than spontaneous arousals. V(I) for the first breath following arousal under optimal CPAP was greater in men than women (11.0 +/- 0.4 versus 7.6 +/- 0.6 l min(-1)). These results demonstrate that the ventilatory response to arousal is influenced by pre-arousal airway resistance and gender. Whether this contributes to the perpetuation of respiratory events and the pathogenesis of OSA is unclear.

Rationale: Sleep-disordered breathing (SDB) occurring primarily during rapid eye movement (REM) sleep is a common clinical problem. The natural history of REM-related SDB and the associated cardiovascular sequelae of disease progression remain to be determined.Objectives: The objective of the current study was to describe the natural history of REM-related SDB, ascertain predictors of progression, and determine whether the evolution of REM-related SDB into non-REM (NREM) sleep is associated with incident cardiovascular events.Methods: Participants from the Sleep Heart Health Study with a baseline NREM apnea-hypopnea index (NREM-AHI) of <5 events/h and data from a follow-up sleep study along with information on incident cardiovascular disease were included in the study. Bivariate logistic regression was used to jointly model the predictors of disease progression based on the presence or absence of SDB during NREM and REM sleep using a cut-point of 5 events/h. Explanatory variables such as age, race, body mass index (BMI), change in BMI, and baseline REM-AHI were considered. Proportional hazards regression was then used to establish whether the development of SDB during NREM sleep was associated with incident cardiovascular disease.Results: The majority of the 1,908 participants included in the study did not develop SDB during NREM sleep. The likelihood of progression of SDB into NREM sleep did increase with higher baseline REM-AHI. BMI and an increase in BMI predicted progression of SDB in both NREM and REM sleep in men but not in women. There was a strong interdependence between developing a NREM-AHI of ≥5 events/h and worsening REM-AHI at follow-up with odds ratios of 6.01 and 4.47, in women and men, respectively. Moreover, the relative risk for incident cardiovascular events among those who developed a NREM-AHI of ≥5 events/h at the follow-up visit was elevated only in women with REM-related SDB at baseline.Conclusions: SDB during REM sleep is a relatively stable condition and does not progress in the majority of individuals. Progression of SDB into NREM sleep is associated with sex, weight, and age. SDB during REM and NREM sleep tends to develop concurrently. Finally, the development of SDB during NREM sleep is associated with incident cardiovascular events, but only in women with REM-related SDB at baseline.

The purpose of this study was to determine whether acutely raising carotid sinus pressure (Pcs) causes changes in upper airway resistance and/or electroencephalographic (EEG) frequency during wakefulness and non-rapid-eye-movement (NREM) sleep. Five dogs were chronically instrumented so that breathing, tracheal pressure, mouth pressure, EEG, and electrooculogram could be measured while pressure in the vascularly isolated carotid sinus was rapidly increased between 40 and 150 mmHg via an extracorporeal perfusion circuit. Dogs were studied during both wakefulness and NREM sleep. Multiple trials of increased Pcs were conducted in each dog. We observed that increasing Pcs 40-150 mmHg caused not only a reflex cardiovascular response but also a 15-40% decrease in minute ventilation. Raising Pcs caused no physiologically significant changes in upper airway resistance over the range of airway pressures and flow rates encountered during inspiration and expiration. Even dogs that demonstrated moderate to substantial sleep-induced increases in airway resistance did not consistently increase resistance during superimposed baroreceptor stimulation. Small increases in airway resistance were sometimes observed during baroreceptor stimulation, but this was not a consistent finding. Acute increases in Pcs did not cause measurable changes in EEG frequency during wakefulness or NREM sleep. We conclude that acute stimulation of the carotid sinus baroreceptors does not cause physiologically meaningful changes in upper airway resistance or EEG activity in awake or sleeping dogs.

The ventral pallidum (VP) is involved in the regulation of a variety of behaviors such as motor, reward, and behavioral motivation, and the ability to perform these functions properly is dependent on a high degree of wakefulness. It is unknown whether VP CaMKIIa-expression (VPCaMKIIa) neurons also have a role in sleep-wake regulation and related neuronal circuit mechanisms. In the present experiment, we first used in vivo fiber photometry to find the population activity of VPCaMKIIa neurons which increased during the transitions from non-rapid-eye movement (NREM) sleep to wakefulness and NREM sleep to rapid-eye-movement (REM) sleep, with decreased during the transitions from wakefulness to NREM sleep. Then chemogenetic activation of VPCaMKIIa neurons induced an increase in wakefulness that lasted for 2h. Mice that were exposed to short-term optogenetic stimulation woke up quickly from stable NREM sleep, and long-term optogenetic stimulation maintained wakefulness. In addition, optogenetic activation of the axons of VPCaMKIIa neurons in the lateral habenula (LHb) also facilitated the initiation and maintenance of wakefulness and mediated anxiety-like behavior. Finally, the method of chemogenetic inhibition was employed to suppress VPCaMKIIa neurons, and yet, inhibition of VPCaMKIIa neuronal activity did not result in an increase in NREM sleep and a decrease in wakefulness. Overall, our data illustrate that the activation of VPCaMKIIa neurons is of great importance for promoting wakefulness.

Don’t Let Your Patients Lose Sleep Over Insomnia

Non-REM-sleep instability in recurrent sleepwalking in pre-pubertal children

Sleep stage classification plays a pivotal role in effective diagnosis and treatment of sleep related disorders. Traditionally, sleep scoring is done manually by trained sleep scorers. The analysis of electroencephalogram (EEG) signals recorded during sleep by clinicians is tedious, time-consuming and prone to human errors. Therefore, it is clinically important to score sleep stages using machine learning techniques to get accurate diagnosis. Several studies have been proposed for automated detection of sleep stages. However, these studies have employed only healthy normal subjects (good sleepers). The proposed study focuses on the automated sleep-stage scoring of subjects suffering from seven different kind of sleep disorders such as insomnia, bruxism, narcolepsy, nocturnal frontal lobe epilepsy (NFLE), periodic leg movement (PLM), rapid eye movement (REM) behavioural disorder and sleep-disordered breathing as well as normal subjects. The open source physionet’s cyclic alternating pattern (CAP) sleep database is used for this study. The EEG epochs are decomposed into sub-bands using a new class of optimized wavelet filters. Two EEG channels, namely F4-C4 and C4-A1, combined are used for this work as they can provide more insights into the changes in EEG signals during sleep. The norm features are computed from six sub-bands coefficients of optimal wavelet filter bank and fed to various supervised machine learning classifiers. We have obtained the highest classification performance using an ensemble of bagged tree (EBT) classifier with 10-fold cross validation. The CAP database comprising of 80 subjects is divided into ten different subsets and then ten different sleep-stage scoring tasks are performed. Since, the CAP database is unbalanced with different duration of sleep stages, the balanced dataset also has been created using over-sampling and under-sampling techniques. The highest average accuracy of 85.3% and Cohen’s Kappa coefficient of 0.786 and accuracy of 92.8% and Cohen’s Kappa coefficient of 0.915 are obtained for unbalanced and balanced databases, respectively. The proposed method can reliably classify the sleep stages using single or dual channel EEG epochs of 30 s duration instead of using multimodal polysomnography (PSG) which are generally used for sleep-stage scoring. Our developed automated system is ready to be tested with more sleep EEG data and can be employed in various sleep laboratories to evaluate the quality of sleep in various sleep disorder patients and normal subjects.

Serotonin enhancing drugs, including L-tryptophan and, more recently, fluoxetine and paroxetine, have been tested as pharmacologic treatments for sleep apnea syndrome. Although some patients have demonstrated reduced apnea expression after treatment with these compounds, this improvement has been restricted to nonrapid eye movement (NREM) sleep, with some patients showing no improvement. This study reports the effects of mirtazapine, an antidepressant with 5-HT(1) agonist as well as 5-HT(2) and 5-HT(3) antagonist effects, on sleep and respiration in an established animal model of central apnea. We studied nine adult male Sprague-Dawley rats chronically instrumented for sleep staging. In random order on separate days, rats were recorded after intraperitoneal injection of: (1) saline, (2) 0.1 mg/kg +/- mirtazapine (labeled as Remeron), (3) 1 mg/kg mirtazapine, or (4) 5 mg/ kg mirtazapine. With respect to saline injections, mirtazapine at all three doses reduced apnea index during NREM sleep by more than 50% (p < 0.0001) and during REM sleep by 60% (p < 0.0001) for at least 6 h. In association with this apnea suppression normalized inspiratory minute ventilation increased during all wake/sleep states (p < 0.001 for each state). The duration of NREM sleep was unaffected by any dose of mirtazapine (p = 0.42), but NREM EEG delta power was increased by more than 30% at all doses (p = 0.04), indicating improved NREM sleep consolidation after mirtazapine injection. We conclude that mirtazapine, over a 50-fold dose range, significantly reduces central apnea expression during NREM and REM sleep in the rat. The efficacy of this compound to suppress apnea in all sleep stages most probably arises from its mixed agonist/antagonist profile at serotonin receptors. The implications of these findings for the management of sleep apnea syndrome must be verified by appropriate clinical trials.

Slow oscillations are electrical potential oscillations with a spectral peak frequency of ∼0.8 Hz, and hallmark the electroencephalogram during slow-wave sleep. Recent studies have indicated a causal contribution of slow oscillations to the consolidation of memories during slow-wave sleep, raising the question to what extent such oscillations can be induced by external stimulation. Here, we examined whether slow oscillations can be effectively induced by rhythmic acoustic stimulation. Human subjects were examined in three conditions: (i) with tones presented at a rate of 0.8 Hz ('0.8-Hz stimulation'); (ii) with tones presented at a random sequence ('random stimulation'); and (iii) with no tones presented in a control condition ('sham'). Stimulation started during wakefulness before sleep and continued for the first ∼90 min of sleep. Compared with the other two conditions, 0.8-Hz stimulation significantly delayed sleep onset. However, once sleep was established, 0.8-Hz stimulation significantly increased and entrained endogenous slow oscillation activity. Sleep after the 90-min period of stimulation did not differ between the conditions. Our data show that rhythmic acoustic stimulation can be used to effectively enhance slow oscillation activity. However, the effect depends on the brain state, requiring the presence of stable non-rapid eye movement sleep.

Sleep apnea syndromes are more common in men than in women. The ventilatory response to arousal from sleep may be an important determinant of respiratory stability/instability and could contribute to this sex difference. We therefore compared changes in ventilation, end-tidal carbon dioxide (CO2), upper airway resistance, heart rate, and finger photoplethysmogram pulse wave amplitude after both spontaneous and tone-induced arousal from non-rapid eye movement sleep in 13 men and 13 women. At sleep onset, ventilation fell and both upper airway resistance and end-tidal CO2 rose, but these changes were not different between sexes. Spontaneous arousal (duration, 6.6 +/- 0.2 seconds) resulted in a biphasic ventilatory response consisting of brief hyperventilation (5 seconds) followed by prolonged hypoventilation (30-40 seconds) on resumption of sleep. The biphasic ventilatory response was greater in men than in women and did not appear to be explained by different wake-to-sleep increments in end-tidal CO2 or upper airway resistance between sexes. Peripheral vasoconstriction with arousal was also greater in men than in women. Ventilatory responses were more marked after tone-induced versus spontaneous arousals and when subjects slept supine compared with the left lateral position. These results suggest that male sex and supine position are associated with greater ventilatory instability after arousal from sleep.

The role of arousals in sleep is gaining interest among both basic researchers and clinicians. In the last 20 years increasing evidence shows that arousals are deeply involved in the pathophysiology of sleep disorders. The nature of arousals in sleep is still a matter of debate. According to the conceptual framework of the American Sleep Disorders Association criteria, arousals are a marker of sleep disruption representing a detrimental and harmful feature for sleep. In contrast, our view indicates arousals as elements weaved into the texture of sleep taking part in the regulation of the sleep process. In addition, the concept of micro-arousal (MA) has been extended, incorporating, besides the classical low-voltage fast-rhythm electroencephalographic (EEG) arousals, high-amplitude EEG bursts, be they like delta-like or K-complexes, which reflects a special kind of arousal process, mobilizing parallely antiarousal swings. In physiologic conditions, the slow and fast MA are not randomly scattered but appear structurally distributed within sleep representing state-specific arousal responses. MA preceded by slow waves occurs more frequently across the descending part of sleep cycles and in the first cycles, while the traditional fast type of arousals across the ascending slope of cycles prevails during the last third of sleep. The uniform arousal characteristics of these two types of MAs is supported by the finding that different MAs are associated with an increasing magnitude of vegetative activation ranging hierarchically from the weaker slow EEG types (coupled with mild autonomic activation) to the stronger rapid EEG types (coupled with a vigorous autonomic activation). Finally, it has been ascertained that MA are not isolated events but are basically endowed with a periodic nature expressed in non-rapid eye movement (NREM) sleep by the cyclic alternating pattern (CAP). Understanding the role of arousals and CAP and the relationship between physiologic and pathologic MA can shed light on the adaptive properties of the sleeping brain and provide insight into the pathomechanisms of sleep disturbances. Functional significance of arousal in sleep, and particularly in NREM sleep, is to ensure the reversibility of sleep, without which it would be identical to coma. Arousals may connect the sleeper with the surrounding world maintaining the selection of relevant incoming information and adapting the organism to the dangers and demands of the outer world. In this dynamic perspective, ongoing phasic events carry on the one hand arousal influences and on the other elements of information processing. The other function of arousals is tailoring the more or less stereotyped endogenously determined sleep process driven by chemical influences according to internal and external demands. In this perspective, arousals shape the individual course of night sleep as a variation of the sleep program.

1. Bursts of sympathetic activity in muscle nerves are phase-locked to the cardiac cycle by the sinoaortic baroreflexes. Acoustic arousal from non-rapid eye movement (NREM) sleep reduces the normally invariant interval between the R-wave of the electrocardiogram (ECG) and the peak of the corresponding sympathetic burst; however, the effects of other forms of sleep disruption (i.e. spontaneous arousals and apnoea-induced arousals) on this temporal relationship are unknown. 2. We simultaneously recorded muscle sympathetic nerve activity in the peroneal nerve (intraneural electrodes) and the ECG (surface electrodes) in seven healthy humans and three patients with sleep apnoea syndrome during NREM sleep. 3. In seven subjects, burst latencies were shortened subsequent to spontaneous K complexes (1.297 +/- 0.024 s, mean +/- s. e.m.) and spontaneous arousals (1.268 +/- 0.044 s) compared with latencies during periods of stable NREM sleep (1.369 +/- 0.023 s). In six subjects who demonstrated spontaneous apnoeas during sleep, apnoea per se did not alter burst latency relative to sleep with stable electroencephalogram (EEG) and breathing (1.313 +/- 0.038 vs. 1.342 +/- 0.026 s); however, following apnoea-induced EEG perturbations, burst latencies were reduced (1.214 +/- 0.034 s). 4. Arousal-induced reduction in sympathetic burst latency may reflect a temporary diminution of baroreflex buffering of sympathetic outflow. If so, the magnitude of arterial pressure perturbations during sleep (e.g. those caused by sleep disordered breathing and periodic leg movements) may be augmented by arousal.