Stable Non-rapid Eye Movement Research Articles

Activation of Ventral Pallidum CaMKIIa-Expressing Neurons Promotes Wakefulness.

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.

State-dependent and region-specific alterations of cerebellar connectivity across stable human wakefulness and NREM sleep states

Sleep regulation and functioning may rely on systematic coordination throughout the whole brain, including the cerebellum. However, whether and how interactions between the cerebellum and other brain regions vary across sleep stages remain poorly understood. Here, using simultaneous EEG-fMRI recordings captured from 73 participants during wakefulness and non-rapid eye movement (NREM) sleep, we constructed cerebellar connectivity among intrinsic functional networks with intra-cerebellar, neocortical and subcortical regions. We uncovered that cerebellar connectivity exhibited sleep-dependent alterations: slight differences between wakefulness and N1/N2 sleep and greater changes in N3 sleep than other states. Region-specific cerebellar connectivity changes between N2 sleep and N3 sleep were also revealed: general breakdown of intra-cerebellar connectivity, enhancement of limbic-cerebellar connectivity and alterations of cerebellar connectivity with spatially specific neocortices. Further correlation analysis showed that functional connectivity between the cerebellar Control II network and regions (including the insula, hippocampus, and amygdala) correlated with delta power during N3 and beta power during N2 sleep. These findings systematically reveal altered cerebellar connectivity among intrinsic networks from wakefulness to deep sleep and highlight the potential role of the cerebellum in sleep regulation and functioning.

Multicomponent Analysis of Sleep Using Electrocortical, Respiratory, Autonomic and Hemodynamic Signals Reveals Distinct Features of Stable and Unstable NREM and REM Sleep.

A new concept of non-rapid eye movement (NREM) and rapid eye movement (REM) sleep is proposed, that of multi-component integrative states that define stable and unstable sleep, respectively, NREMS, NREMUS REMS, and REMUS. Three complementary data sets are used: obstructive sleep apnea (20), healthy subjects (11), and high loop gain sleep apnea (50). We use polysomnography (PSG) with beat-to-beat blood pressure monitoring, and electrocardiogram (ECG)-derived cardiopulmonary coupling (CPC) analysis to demonstrate a bimodal, rather than graded, characteristic of NREM sleep. Stable NREM (NREMS) is characterized by high probability of occurrence of the <1 Hz slow oscillation, high delta power, stable breathing, blood pressure dipping, strong sinus arrhythmia and vagal dominance, and high frequency CPC. Conversely, unstable NREM (NREMUS) has the opposite features: a fragmented and discontinuous <1 Hz slow oscillation, non-dipping of blood pressure, unstable respiration, cyclic variation in heart rate, and low frequency CPC. The dimension of NREM stability raises the possibility of a comprehensive integrated multicomponent network model of NREM sleep which captures sleep onset (e.g., ventrolateral preoptic area-based sleep switch) processes, synaptic homeostatic delta power kinetics, and the interaction of global and local sleep processes as reflected in the spatiotemporal evolution of cortical “UP” and “DOWN” states, while incorporating the complex dynamics of autonomic-respiratory-hemodynamic systems during sleep. Bimodality of REM sleep is harder to discern in health. However, individuals with combined obstructive and central sleep apnea allows ready recognition of REMS and REMUS (stable and unstable REM sleep, respectively), especially when there is a discordance of respiratory patterns in relation to conventional stage of sleep.

Effects of central apneas on sympathovagal balance and hemodynamics at night: impact of underlying systolic heart failure

BackgroundIncreased sympathetic drive is the key determinant of systolic heart failure progression, being associated with worse functional status, arrhythmias, and increased mortality. Central sleep apnea is highly prevalent in systolic heart failure, and its effects on sympathovagal balance (SVB) and hemodynamics might depend on relative phase duration and background pathophysiology.ObjectiveThis study compared the effects of central apneas in patients with and without systolic heart failure on SVB and hemodynamics during sleep.MethodsDuring polysomnography, measures of SVB (heart rate and diastolic blood pressure variability) were non-invasively recorded and analyzed along with baroreceptor reflex sensitivity and hemodynamic parameters (stroke volume index, cardiac index, total peripheral resistance index). Data analysis focused on stable non-rapid eye movement N2 sleep, comparing normal breathing with central sleep apnea in subjects with and without systolic heart failure.ResultsTen patients were enrolled per group. In heart failure patients, central apneas had neutral effects on SVB (all p > 0.05 for the high, low, and very low frequency components of heart rate and diastolic blood pressure variability). Patients without heart failure showed an increase in very low and low frequency components of diastolic blood pressure variability in response to central apneas (63 ± 18 vs. 39 ± 9%; p = 0.001, 43 ± 12 vs. 31 ± 15%; p = 0.002). In all patients, central apneas had neutral hemodynamic effects when analyzed over a period of 10 min, but had significant acute hemodynamic effects.ConclusionEffects of central apneas on SVB during sleep depend on underlying systolic heart failure, with neutral effects in heart failure and increased sympathetic drive in idiopathic central apneas.

An assessment of a simple clinical technique to estimate pharyngeal collapsibility in people with obstructive sleep apnea.

Quantification of upper airway collapsibility in obstructive sleep apnea (OSA) could help inform targeted therapy decisions. However, current techniques are clinically impractical. The primary aim of this study was to assess if a simple, novel technique could be implemented as part of a continuous positive airway pressure (CPAP) titration study to assess pharyngeal collapsibility. A total of 35 participants (15 female) with OSA (mean ± SD apnea-hypopnea index = 35 ± 19 events/h) were studied. Participants first completed a simple clinical intervention during a routine CPAP titration, where CPAP was transiently turned off from the therapeutic pressure for ≤5 breaths/efforts on ≥5 occasions during stable non-rapid eye movement (non-REM) sleep for quantitative assessment of airflow responses (%peak inspiratory flow [PIF] from preceding 5 breaths). Participants then underwent an overnight physiology study to determine the pharyngeal critical closing pressure (Pcrit) and repeat transient drops to zero CPAP to assess airflow response reproducibility. Mean PIF of breaths 3-5 during zero CPAP on the simple clinical intervention versus the physiology night were similar (34 ± 29% vs. 28 ± 30% on therapeutic CPAP, p = 0.2; range 0%-90% vs. 0%-95%). Pcrit was -1.0 ± 2.5 cmH2O (range -6 to 5 cmH2O). Mean PIF during zero CPAP on the simple clinical intervention and the physiology night correlated with Pcrit (r = -0.7 and -0.9, respectively, p < 0.0001). Receiver operating characteristic curve analysis indicated significant diagnostic utility for the simple intervention to predict Pcrit < -2 and < 0 cmH2O (AUC = 0.81 and 0.92), respectively. A simple CPAP intervention can successfully discriminate between patients with and without mild to moderately collapsible pharyngeal airways. This scalable approach may help select individuals most likely to respond to non-CPAP therapies.

Effect of acetazolamide on susceptibility to central sleep apnea in chronic spinal cord injury.

Spinal cord injury (SCI) is an established risk factor for central sleep apnea. Acetazolamide (ACZ), a carbonic anhydrase inhibitor, has been shown to decrease the frequency of central apnea by inducing mild metabolic acidosis. We hypothesized that ACZ would decrease the propensity to develop hypocapnic central apnea and decrease the apneic threshold. We randomized 16 participants with sleep-disordered breathing (8 SCI and 8 able-bodied controls) to receive ACZ (500 mg twice a day for 3 days) or placebo with a 1-wk washout before crossing over to the other drug arm. Study nights included polysomnography and determination of the hypocapnic apneic threshold and CO2 reserve using noninvasive ventilation. For participants with spontaneous central apnea, CO2 was administered until central apnea was abolished, and CO2 reserve was measured as the difference in end-tidal Pco2 () before and after. Steady-state plant gain, the response of end-tidal Pco2 to changes in ventilation, was calculated from and V̇e ratio during stable sleep. Controller gain, the response of ventilatory drive to changes in end-tidal Pco2, was defined as the ratio of change in V̇e between control and hypopnea to the ΔCO2 during stable non-rapid eye movement sleep. Treatment with ACZ for three days resulted in widening of the CO2 reserve (-4.0 ± 1.2 vs. -3.0 ± 0.7 mmHg for able-bodied, -3.4 ± 1.9 vs. -2.2 ± 2.2 mmHg for SCI, P < 0.0001), and a corresponding decrease in the hypocapnic apnea threshold (28.3 ± 5.2 vs. 37.1 ± 5.6 mmHg for able-bodied, 29.9 ± 5.4 vs. 34.8 ± 6.9 mmHg for SCI, P < 0.0001), respectively. ACZ significantly reduced plant gain when compared with placebo (4.1 ± 1.7 vs. 5.4 ± 1.8 mmHg/L min for able-bodied, 4.1 ± 2.0 vs. 5.1 ± 1.7 mmHg·L-1·min for SCI, P < 0.01). Acetazolamide decreased apnea-hypopnea index (28.8 ± 22.9 vs. 39.3 ± 24.1 events/h; P = 0.05), central apnea index (0.6 ± 1.5 vs. 6.3 ± 13.1 events/h; P = 0.05), and oxyhemoglobin desaturation index (7.5 ± 8.3 vs. 19.2 ± 15.2 events/h; P = 0.01) compared with placebo. Our results suggest that treatment with ACZ decreases susceptibility to hypocapnic central apnea due to decreased plant gain. Acetazolamide may attenuate central sleep apnea and improve nocturnal oxygen saturation, but its clinical utility requires further investigation in a larger sample of patients.NEW & NOTEWORTHY Tetraplegia is a risk factor for central sleep-disordered breathing (SDB) and is associated with narrow CO2 reserve (a marker of susceptibility to central apnea). Treatment with high-dose acetazolamide for 3 days decreased susceptibility to hypocapnic central apnea and reduced the frequency of central respiratory events during sleep. Acetazolamide may play a therapeutic role in alleviating central SDB in patients with cervical spinal cord injury, but larger clinical trials are needed.

Reductions in dead space ventilation with nasal high flow depend on physiological dead space volume: metabolic hood measurements during sleep in patients with COPD and controls.

Nasal high flow (NHF) reduces minute ventilation and ventilatory loads during sleep but the mechanisms are not clear. We hypothesised NHF reduces ventilation in proportion to physiological but not anatomical dead space.11 subjects (five controls and six chronic obstructive pulmonary disease (COPD) patients) underwent polysomnography with transcutaneous carbon dioxide (CO2) monitoring under a metabolic hood. During stable non-rapid eye movement stage 2 sleep, subjects received NHF (20 L·min-1) intermittently for periods of 5-10 min. We measured CO2 production and calculated dead space ventilation.Controls and COPD patients responded similarly to NHF. NHF reduced minute ventilation (from 5.6±0.4 to 4.8±0.4 L·min-1; p<0.05) and tidal volume (from 0.34±0.03 to 0.3±0.03 L; p<0.05) without a change in energy expenditure, transcutaneous CO2 or alveolar ventilation. There was a significant decrease in dead space ventilation (from 2.5±0.4 to 1.6±0.4 L·min-1; p<0.05), but not in respiratory rate. The reduction in dead space ventilation correlated with baseline physiological dead space fraction (r2=0.36; p<0.05), but not with respiratory rate or anatomical dead space volume.During sleep, NHF decreases minute ventilation due to an overall reduction in dead space ventilation in proportion to the extent of baseline physiological dead space fraction.

Heart rate phenotypes and clinical correlates in a large cohort of adults without sleep apnea.

BackgroundNormal sleep is associated with typical physiological changes in both the central and autonomic nervous systems. In particular, nocturnal blood pressure dipping has emerged as a strong marker of normal sleep physiology, whereas the absence of dipping or reverse dipping has been associated with cardiovascular risk. However, nocturnal blood pressure is not measured commonly in clinical practice. Heart rate (HR) dipping in sleep may be a similar important marker and is measured routinely in at-home and in-laboratory sleep testing.MethodsWe performed a retrospective cross-sectional analysis of diagnostic polysomnography in a clinically heterogeneous cohort of n=1047 adults without sleep apnea.ResultsWe found that almost half of the cohort showed an increased HR in stable nonrapid eye movement sleep (NREM) compared to wake, while only 13.5% showed a reduced NREM HR of at least 10% relative to wake. The strongest correlates of HR dipping were younger age and male sex, whereas the periodic limb movement index (PLMI), sleep quality, and Epworth Sleepiness Scale (ESS) scores were not correlated with HR dipping. PLMI was however significantly correlated with metrics of impaired HR variability (HRV): increased low-frequency power and reduced high-frequency power. HRV metrics were unrelated to sleep quality or the ESS value. Following the work of Vgontzas et al, we also analyzed the sub-cohort with insomnia symptoms and short objective sleep duration. Interestingly, the sleep–wake stage-specific HR values depended upon insomnia symptoms more than sleep duration.ConclusionWhile our work demonstrates heterogeneity in cardiac metrics (HR and HRV), the population analysis suggests that pathological signatures of HR (nondipping and elevation) are common even in this cohort selected for the absence of sleep apnea. Future prospective work in clinical populations will further inform risk stratification and set the stage for testing interventions.

Effects of repetitive transcranial magnetic stimulation of upper airway muscles during sleep in obstructive sleep apnea patients

We tested the hypothesis that stimulating the genioglossus by repetitive transcranial magnetic stimulation (rTMS) during the ascendant portion of the inspiratory flow of airflow-limited breaths would sustain the recruitment of upper airway dilator muscles over time and improve airway dynamics without arousing obstructive sleep apnea (OSA) patients. In a cross-sectional design, nine OSA patients underwent a rTMS trial during stable non-rapid eye movement (NREM) sleep. Submental muscle motor threshold (SUB) and motor-evoked potential were evaluated during wakefulness and sleep. During NREM sleep, maximal inspiratory flow, inspiratory volume, inspiratory time, shifts of electroencephalogram frequency, and pulse rate variability were assessed under three different stimulation paradigms completed at 1.2 sleep SUB stimulation output: 1) 5Hz-08 (stimulation frequency: 5 Hz; duration of train stimulation: 0.8 s); 2) 25Hz-02 (stimulation frequency: 25 Hz; duration of train stimulation: 0.2 s); and 3) 25Hz-04 (stimulation frequency: 25 Hz; duration of train stimulation: 0.4 s). SUB increased during NREM sleep (wakefulness: 23.8 ± 6.1%; NREM: 26.8 ± 5.2%; = 0.001). Two distinct airflow patterns were observed in response to rTMS: with and without initial airflow drops, without other airflow variables change regardless the stimulation paradigm applied. Finally, rTMS-induced cortical and/or autonomic arousal were observed in 36, 26, and 35% of all delivered rTMS trains during 5Hz-08, 25Hz-02, and 25Hz-04 stimulation paradigms, respectively. In conclusion, rTMS does not provide any airflow improvement of flow-limited breaths as seen with nonrepetitive TMS of upper airway dilator muscles. However, rTMS trains were free of arousals in the majority of cases.

Cardiac autonomic function during sleep: Effects of alcohol dependence and evidence of partial recovery with abstinence

Chronic alcoholism is associated with the development of cardiac and peripheral autonomic nervous system (ANS) pathology. The aim of the present study was to evaluate the extent to which recovery in ANS function could be demonstrated over the first 4 months of abstinence. Fifteen alcoholics (7 women) were studied on three occasions: within a month of detoxification, at approximately 2 months post-detox, and at 4 months post-detox. Thirteen control subjects (6 women) were also studied on three occasions with inter-study intervals matching those of the alcoholics. Six alcoholics relapsed, 48.7 ± 27.9 days following the initial PSG session. ANS function was assessed in the first part of stable non-rapid eye movement sleep. Frequency-domain power spectral analysis of heart rate variability (HRV) produced variables including: heart rate (HR), total power (TP; an index representing total HR variability), High Frequency power (HFa; an index reflecting cardiac vagal modulation), HF proportion of total power (HFprop sympathovagal balance), and HF peak frequency (HFpf; an index reflecting respiration rate). Overall, high total and high frequency variability and low sympathovagal balance and myocardial contractility are considered as desired conditions to promote cardiovascular health. At initial assessment, alcoholics had a higher HR (p < 0.001) and respiratory rate (p < 0.01), and lower vagal activity (HFa; p < 0.01) than controls. Alcoholics showed evidence of recovery in HR (p = 0.039) and HFa (p = 0.031) with 4 months of abstinence. Alcoholics with higher TP at the initial visit showed a greater improvement in TP from the initial to the 4 month follow-up session (r = 0.75, p < 0.05). Alcoholics showed substantial recovery in HR and vagal modulation of HRV with 4 months of abstinence, with evidence that the extent of recovery in HRV may be partially determined by the extent of alcohol dependence-related insult to the cardiac ANS system. These data support other studies showing recovery in a number of ANS, central nervous system, and behavioral domains with abstinence, even in those with long-term dependence.

Automatic scoring of sleep stages and cortical arousals using two electrodes on the forehead: validation in healthy adults

Accuracy and limitations of automatic scoring of sleep stages and electroencephalogram arousals from a single derivation (Fp1 -Fp2 ) were studied in 29 healthy adults using a portable wireless polysomnographic recorder. All recordings were scored five times: twice by a referent scorer who viewed the standard polysomnographic montage and observed the American Academy of Sleep Medicine rules (referent scoring and blind rescoring); and once by the same scorer who viewed only the Fp1 -Fp2 signal (alternative scoring), by another expert from the same institution, and by the algorithm. Automatic, alternative and independent expert scoring were compared with the referent scoring on an epoch-by-epoch basis. The algorithm's agreement with the reference (81.0%, Cohen's κ=0.75) was comparable to the inter-rater agreement (83.3%, Cohen's κ=0.78) or agreement between the referent scoring and manual scoring of the frontopolar derivation (80.7%, Cohen's κ=0.75). Most misclassifications by the algorithm occurred during uneventful wake/sleep transitions, whereas cortical arousals, rapid eye movement and stable non-rapid eye movement sleep were detected accurately. The algorithm yielded accurate estimates of total sleep time, sleep efficiency, sleep latency, arousal indices and times spent in different stages. The findings affirm the utility of automatic scoring of stages and arousals from a single frontopolar derivation as a method for assessment of sleep architecture in healthy adults.

Alternative approaches to treatment of Central Sleep Apnea.

Divergent approaches to treatment of hypocapnic central sleep apnea syndromes reflect the difficulties in taming a hyperactive respiratory chemoreflex. As both sleep fragmentation and a narrow CO2 reserve or increased loop gain drive the disease, sedatives (to induce longer periods of stable non-rapid eye movement (NREM) sleep and reduce the destabilizing effects of arousals in NREM sleep) and CO2-based stabilization approaches are logical. Adaptive ventilation reduces mean hyperventilation yet can induce ventilator-patient dyssynchrony, while enhanced expiratory rebreathing space (EERS, dead space during positive pressure therapy) and CO2 manipulation directly stabilize respiratory control by moving CO2 above the apnea threshold. Carbonic anhydrase inhibition can provide further adjunctive benefits. Provent and Winx may be less likely to trigger central apneas or periodic breathing in those with a narrow CO2 reserve. An oral appliance can meaningfully reduce positive pressure requirements and thus enable treatment of complex apnea. Novel pharmacological approaches may target mediators of carotid body glomus cell excitation, such as the balance between gas neurotransmitters. In complex apnea patients, single mode therapy is not always successful, and multi-modality therapy might need to be considered. Phenotyping of sleep apnea beyond conventional scoring approaches is the key to optimal management.

Vagal withdrawal during hot flashes occurring in undisturbed sleep

Little is known about the impact of hot flashes on cardiac autonomic regulation, particularly vagal control. Therefore, we assessed the cardiac autonomic profile associated with physiological hot flashes occurring in undisturbed sleep. Eleven perimenopausal women (45-56 y) had overnight laboratory recordings of polysomnography, electrocardiography, and skin conductance. Eighteen hot flashes that occurred in stable non-rapid eye movement sleep undisturbed by arousals were analyzed. Heart rate variability measures were obtained for three consecutive 2-minute windows starting from 4 minutes before (baseline and preflash periods) to 2 minutes after the onset of hot flashes (hot flash period). Heart rate increased by, on average, 4 beats/minute with the occurrence of a hot flash compared with both baseline (P < 0.001) and preflash (P < 0.001). High-frequency power was reduced, reflecting a decrease in vagal activity, at the onset of a hot flash compared with baseline (P < 0.001) and preflash (P < 0.001). There was no change in sympathovagal balance with the onset of a hot flash. The magnitude of the hot flash (ie, skin conductance amplitude) was associated with increased heart rate (r = 0.78, P < 0.001) and decreased vagal tone (r = -0.56, P = 0.014). Physiological hot flashes per se, recorded during undisturbed sleep periods and independent of any arousals, are associated with increased heart rate and decreased cardiac autonomic vagal activity. These data support the hypothesis that the parasympathetic branch of the autonomic nervous system is involved in the cardiac response to a hot flash.

Complex Sleep Apnea

Complex sleep apnea currently refers to the emergence and persistence of central apneas and hypopneas following the application of positive airway pressure therapy in patients with obstructive sleep apnea. However, this narrow definition is an "outcome" and does not capture the spectrum of pathological activation of the respiratory chemoreflex in sleep apnea. The International Classification of Sleep Disorders - 3rd edition recognizes the phenomenon of Treatment-Related Central Sleep Apnea, but the phenotype is usually evident prior to onset of therapy. The key polysomnographic characteristics of chemoreflex modulated and mediated sleep apnea are nonrapid eye movement (NREM) dominance of respiratory events, short (<30seconds) or long (>60seconds) cycle time with a self-similar metronomic timing, and spontaneous improvement during rapid eye movement (REM) sleep. Thus, the majority of chemoreflex effects go unrecognized due to the bias toward obstructive sleep apnea's current scoring criteria. Any treatment of apparently obstructive sleep apnea, including surgery and oral appliances, can expose chemoreflex-driven instabilities. As both sleep fragmentation and a narrow CO2 reserve or increased loop gain drive the disease, sedatives (to induce longer periods of stable NREM sleep and reduce the destabilizing effects of arousals in NREM sleep) and CO2-based stabilization approaches are logical. Adaptive ventilation reduces mean hyperventilation yet can induce ventilator-patient desynchrony, while enhanced expiratory rebreathing space (EERS, dead space during positive pressure therapy) and CO2 manipulation directly stabilize respiratory control by moving CO2 above the apnea threshold. Carbonic anhydrase inhibition can provide further adjunctive benefits. Novel pharmacological approaches may target mediators of carotid body hypoxic sensitization, such as the balance between gas neurotransmitters. In complex apnea patients, single mode therapy is unlikely to be successful, and the power of multi-modality therapy should be harnessed for optimal outcomes.

Autonomic regulation across phases of the menstrual cycle and sleep stages in women with premenstrual syndrome and healthy controls.

To investigate the influence of menstrual cycle phase and the presence of severe premenstrual symptoms on cardiac autonomic control during sleep, we performed heart rate variability (HRV) analysis during stable non-rapid eye movement (NREM) and REM sleep in 12 women with severe premenstrual syndrome and 14 controls in the mid-follicular, mid-luteal, and late-luteal phases of the menstrual cycle. Heart rate was higher, along with lower high frequency (HF) power, reflecting reduced vagal activity, and a higher ratio of low frequency (LF) to high frequency power, reflecting a shift to sympathetic dominance, in REM sleep compared with NREM sleep in both groups of women. Both groups of women had higher heart rate during NREM and REM sleep in the luteal phase recordings compared with the mid-follicular phase. HF power in REM sleep was lowest in the mid-luteal phase, when progesterone was highest, in both groups of women. The mid-luteal phase reduction in HF power was also evident in NREM sleep in control women but not in women with PMS, suggesting some impact of premenstrual syndrome on autonomic responses to the hormone environment of the mid-luteal phase. In addition, mid-luteal phase progesterone levels correlated positively with HF power and negatively with LF/HF ratio in control women in NREM sleep and with the LF/HF ratio during REM sleep in both groups of women. Our findings suggest the involvement of female reproductive steroids in cardiac autonomic control during sleep in women with and without premenstrual syndrome.

Consecutive transcranial magnetic stimulation twitches reduce flow limitation during sleep in apnoeic patients

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.

Acute upper airway muscle and inspiratory flow responses to transcranial magnetic stimulation during sleep in apnoeic patients

Transcranial magnetic stimulation (TMS) can activate the corticobulbar system and briefly recruit upper airway dilator muscles, improving the inspiratory airflow dynamics of flow-limited respiratory cycles during sleep. The purpose of this investigation was to quantify the effects of TMS-induced twitches applied during sleep on flow-limited respiratory cycles in 14 obstructive sleep apnoea patients. Submental muscle motor threshold (SUB(MT)) and motor-evoked potential (SUB(MEP)) were examined during wakefulness and sleep. The TMS-induced twitches were applied during stable non-rapid eye movement (NREM) sleep, during non-consecutive flow-limited respiratory cycles at the beginning of inspiration, with intensities varying from sleep SUB(MT) up to maximal stimulation without arousal. Maximal inspiratory flow, inspiratory volume, shifts of electroencephalogram frequency and pulse rate variability were assessed. Cortical and/or autonomic arousal after TMS was observed in only 13.8% of all twitches applied. The SUB(MT) increased during NREM sleep (wakefulness, 24.8 ± 9.3%; and NREM sleep, 28.3 ± 9.5%; P = 0.003). Augmenting stimulator output from SUB(MT) to maximal stimulation before arousal enhanced SUB(MEP) peak-to-peak amplitude (from 0.09 ± 0.05 to 0.4 ± 0.3 mV; P = 0.005) with a concomitant rise in maximal inspiratory flow (from 376.2 ± 107.9 to 411.9 ± 109.3 ml s(-1); P = 0.008) and inspiratory volume (from 594.8 ± 189.2 to 663.7 ± 203.1 ml; P = 0.001) in all but one patient. Corticobulbar excitability of submental muscles decreases during NREM sleep. Brief recruitment of submental muscles with TMS during sleep improves upper airway mechanics without arousing patients from sleep.

Induction of slow oscillations by rhythmic acoustic stimulation

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.

A Moderate Increase of Physiological CO2 in a Critical Range during Stable NREM Sleep Episode: A Potential Gateway to REM Sleep

Sleep is characterized as rapid eye movement (REM) and non-rapid eye movement (NREM) sleep. Studies suggest that wake-related neurons in the basal forebrain, posterior hypothalamus and brainstem, and NREM sleep-related neurons in the anterior-hypothalamic area inhibit each other, thus alternating sleep–wakefulness. Similarly, pontine REM-ON and REM-OFF neurons reciprocally inhibit each other for REM sleep modulation. It has been proposed that inhibition of locus coeruleus (LC) REM-OFF neurons is pre-requisite for REM sleep genesis, but it remains ambiguous how REM-OFF neurons are hyperpolarized at REM sleep onset. The frequency of breathing pattern remains high during wake, slows down during NREM sleep but further escalates during REM sleep. As a result, brain CO2 level increases during NREM sleep, which may alter REM sleep manifestation. It has been reported that hypocapnia decreases REM sleep while hypercapnia increases REM sleep periods. The groups of brainstem chemosensory neurons, including those present in LC, sense the alteration in CO2 level and respond accordingly. For example, one group of LC neurons depolarize while other hyperpolarize during hypercapnia. In another group, hypercapnia initially depolarizes but later hyperpolarizes LC neurons. Besides chemosensory functions, LC REM-OFF neurons are an integral part of REM sleep executive machinery. We reason that increased CO2 level during a stable NREM sleep period may hyperpolarize LC neurons including REM-OFF, which may help initiate REM sleep. We propose that REM sleep might act as a sentinel to help maintain normal CO2 level for unperturbed sleep.

Sustained hyperoxia stabilizes breathing in healthy individuals during NREM sleep.

The present study was designed to determine whether hyperoxia would lower the hypocapnic apneic threshold (AT) during non-rapid eye movement (NREM) sleep. Nasal noninvasive mechanical ventilation was used to induce hypocapnia and subsequent central apnea in healthy subjects during stable NREM sleep. Mechanical ventilation trials were conducted under normoxic (room air) and hyperoxic conditions (inspired PO(2) > 250 Torr) in a random order. The CO(2) reserve was defined as the minimal change in end-tidal PCO(2) (PET(CO(2))) between eupnea and hypocapnic central apnea. The PET(CO(2)) of the apnea closest to eupnea was designated as the AT. The hypocapnic ventilatory response was calculated as the change in ventilation below eupnea for a given change in PET(CO(2)). In nine participants, compared with room air, exposure to hyperoxia was associated with a significant decrease in eupneic PET(CO(2)) (37.5 ± 0.6 vs. 41.1 ± 0.6 Torr, P = 0.001), widening of the CO(2) reserve (-3.8 ± 0.8 vs. -2.0 ± 0.3 Torr, P = 0.03), and a subsequent decline in AT (33.3 ± 1.2 vs. 39.0 ± 0.7 Torr; P = 001). The hypocapnic ventilatory response was also decreased with hyperoxia. In conclusion, 1) hyperoxia was associated with a decreased AT and an increase in the magnitude of hypocapnia required for the development of central apnea. 2) Thus hyperoxia may mitigate the effects of hypocapnia on ventilatory motor output by lowering the hypocapnic ventilatory response and lowering the resting eupneic PET(CO(2)), thereby decreasing plant gain.