Suppression Of Slow-wave Sleep Research Articles

REM Sleep Preserves Affective Response to Social Stress-Experimental Study.

Sleep's contribution to affective regulation is insufficiently understood. Previous human research has focused on memorizing or rating affective pictures and less on physiological affective responsivity. This may result in overlapping definitions of affective and declarative memories and inconsistent deductions for how rapid eye movement sleep (REMS) and slow-wave sleep (SWS) are involved. Literature associates REMS theta (4-8 Hz) activity with emotional memory processing, but its contribution to social stress habituation is unknown. Applying selective sleep stage suppression and oscillatory analyses, we investigated how sleep modulated affective adaptation toward social stress and retention of neutral declarative memories. Native Finnish participants (N = 29; age, M = 25.8 years) were allocated to REMS or SWS suppression conditions. We measured physiological (skin conductance response, SCR) and subjective stress response and declarative memory retrieval thrice: before laboratory night, the next morning, and after 3 d. Linear mixed models were applied to test the effects of condition and sleep parameters on emotional responsivity and memory retrieval. Greater overnight increase in SCR toward the stressor emerged after suppressed SWS (intact REMS) relative to suppressed REMS (20.1% vs 6.1%; p = 0.016). The overnight SCR increase was positively associated with accumulated REMS theta energy irrespective of the condition (r = 0.601; p = 0.002). Subjectively rated affective response and declarative memory recall were comparable between the conditions. The contributions of REMS and SWS to habituation of social stress are distinct. REMS theta activity proposedly facilitates the consolidation of autonomic affective responses. Declarative memory consolidation may not have greater dependence on intact SWS relative to intact REMS.

Feasibility, efficacy, and functional relevance of automated auditory closed-loop suppression of slow-wave sleep in humans.

Slow-wave sleep (SWS) is a fundamental physiological process, and its modulation is of interest for basic science and clinical applications. However, automatised protocols for the suppression of SWS are lacking. We describe the development of a novel protocol for the automated detection (based on the whole head topography of frontal slow waves) and suppression of SWS (through closed-loop modulated randomised pulsed noise), and assessed the feasibility, efficacy and functional relevance compared to sham stimulation in 15 healthy young adults in a repeated-measure sleep laboratory study. Auditory compared to sham stimulation resulted in a highly significant reduction of SWS by 30% without affecting total sleep time. The reduction of SWS was associated with an increase in lighter non-rapid eye movement sleep and a shift of slow-wave activity towards the end of the night, indicative of a homeostatic response and functional relevance. Still, cumulative slow-wave activity across the night was significantly reduced by 23%. Undisturbed sleep led to an evening to morning reduction of wake electroencephalographic theta activity, thought to reflect synaptic downscaling during SWS, while suppression of SWS inhibited this dissipation. We provide evidence for the feasibility, efficacy, and functional relevance of a novel fully automated protocol for SWS suppression based on auditory closed-loop stimulation. Future work is needed to further test for functional relevance and potential clinical applications.

Peculiarities of neuroregulatory mechanisms of adaptation under alcohol dependence (experimental study)

Neurophysiological and biochemical markers of alcohol dependence were identified in a study conducted in laboratory rats at the systemic and molecular levels. It has been shown that long-term alcohol consumption is accompanied by an increase in dopamine levels in the ventral tegmental area and a decrease in GABA and BDNF levels in the hippocampus and serum and leads to attenuation of neocortex control of the limbic emotional-motivational system of the brain. Disturbance of the mechanisms of structural and functional organization of wake-sleep processes and regulation of emotional reactions, which is reflected in the suppression of slow-wave sleep, reduction of paradoxical sleep, inhibition of positive emotional centers, the development of anxiety and depression have been determined. Key words: alcohol dependence, sleep-wake, anxiety, depression, catecholamines, GABA, BDNF

Selective slow-wave sleep suppression affects glucose tolerance and melatonin secretion. The role of sleep architecture

ObjectivesOur study aimed to assess the impact of one night of slow-wave sleep (SWS) suppression on glucose tolerance, and explore whether melatonin plays a role in glucose tolerance impairment after SWS suppression. MethodsIn sum, 20 volunteers participated in two experimental sessions: a session with SWS suppression during one night's sleep and a session with a regular night's sleep (control). Each session included collecting seven salivary samples. The following morning, an oral glucose tolerance test (OGTT) was performed. ResultsSWS suppression effects depended on the individual blood glucose response to the OGTT. During the control session, ‘responders’ (N = 11), already presented with low glucose tolerance, which further declined after SWS suppression. ‘Non-responders’ (N = 9) experienced high glucose tolerance in both conditions. Among the responders, SWS suppression led to an increase in melatonin at the moment of awakening, while in non-responders melatonin increased during the first half of the night. In both conditions, responders were characterized by a shorter total sleep time (TST) and less rapid eye movement (REM) sleep. During SWS suppression, they had more non-rapid eye movement (NREM) stage 1 and longer nocturnal wakefulness. Responders and non-responders showed a comparable amount of SWS. ConclusionsThis study highlights three key findings: first, SWS suppression leads to an increase in salivary melatonin; second, melatonin's effect on glucose tolerance depends on its secretion timing; and third, durations of REM sleep and nocturnal awakenings, appear to play an important role in melatonin secretion and glucose tolerance, indicating the potential clinical relevance of these findings for type 2 diabetes risk assessment.

Effects Of Acute Suppression Of Slow-Wave Sleep On Young Men's Androgen Levels

Effects Of Acute Suppression Of Slow-Wave Sleep On Young Men's Androgen Levels

Slow-wave sleep and androgens: selective slow-wave sleep suppression affects testosterone and 17α-hydroxyprogesterone secretion

ObjectivesLevels of steroid hormones such as androgens and cortisol exhibit circadian variation, and their fluctuations are related to the sleep-wake cycle. Currently, the functional role of different stages of sleep in steroid hormone secretion remains unclear. The present study aims to explore the effect of slow-wave sleep (SWS) suppression on morning levels of cortisol and androgens. MethodsTwelve healthy male volunteers participated in two experimental sessions: a session with selective SWS suppression during night sleep and a session with regular night sleep (control). SWS suppression was achieved by stimulation using an acoustic tone. Salivary samples were collected in the morning immediately after awakening and again 40 min later. The samples were analysed by liquid chromatography-tandem mass spectrometry for testosterone, androstenedione (Ad), dehydroepiandrosterone (DHEA), 17α-hydroxyprogesterone (17-OHP), and cortisol. ResultsSWS suppression reduced overall SWS duration by 54.2% without significant changes in total sleep time and sleep efficiency. In the session with selective SWS suppression, the average level of morning testosterone was lower than in the control session (p = 0.017). Likewise, 17-OHP was lower in the SWS suppression condition (p = 0.011) whereas the ratio of DHEA/Ad was higher (p = 0.025). There were no significant differences between sessions in cortisol, Ad, or DHEA concentrations. ConclusionsThe effect of selective SWS suppression on morning levels of testosterone and 17-OHP points to the importance of SWS for the synthesis and secretion of androgens. These results suggest that chronic sleep problems, which lead to reduced SWS, increase the risk for the development of androgen deficiency in the long term.

Selective slow-wave sleep suppression affects the testosterone level at the next morning

Selective slow-wave sleep suppression affects the testosterone level at the next morning

Efficacy and safety of almorexant in adult chronic insomnia: a randomized placebo-controlled trial with an active reference

Background and objectivesThe orally active dual OX1R and OX2R antagonist, almorexant, targets the orexin system for the treatment of primary insomnia. This clinical trial assessed the effect of almorexant on sleep maintenance and other sleep endpoints, and its safety and tolerability in adults. Patients and methodsProspective, randomized, double-blind, placebo-controlled, active referenced trial in male and female adults aged 18–64 years with chronic, primary insomnia. Patients were randomized 1:1:1:1 to receive placebo, almorexant 100 mg, almorexant 200 mg, or zolpidem 10 mg (active reference) for 16 days. Primary efficacy assessments were objective (polysomnography-measured) and subjective (patient-recorded) wake time after sleep onset (WASO). Further sleep variables were also evaluated. ResultsFrom 709 randomized patients, 707 (mean age 45.4 years; 61.7% female) received treatment and 663 (93.8%) completed the study. A significant decrease versus placebo in median objective WASO was observed with almorexant 200 mg at the start and end of randomized treatment (−26.8 min and −19.5 min, respectively; both p < 0.0001); subjective WASO also decreased over the two-week treatment period (p = 0.0006). Objective and subjective total sleep time (TST) were increased with almorexant 200 mg (p < 0.0001). Almorexant 200 mg significantly reduced objective and subjective latency to persistent sleep and latency to sleep onset at initiation of therapy, and provided longer duration of sleep stages with no suppression of slow-wave sleep. No impaired next-day performance, rebound insomnia, or withdrawal effects were observed. Adverse events were similar with almorexant and placebo. ConclusionAlmorexant reduced time to sleep onset and maintained sleep without residual effects on next-day performance or safety concerns. This study provides further support for the role of the endogenous orexin system in insomnia disorder. ClinicalTrials.gov registrationNCT00608985.

Effect of Slow Wave Sleep Disruption on Metabolic Parameters in Adolescents.

Cross-sectional studies report a correlation between slow wave sleep (SWS) duration and insulin sensitivity (SI) in children and adults. Suppression of SWS causes insulin resistance in adults but effects in children are unknown. This study was designed to determine the effect of SWS fragmentation on SI in children. Fourteen pubertal children (11.3-14.1 y, body mass index 29(th) to 97(th) percentile) were randomized to sleep studies and mixed meal (MM) tolerance tests with and without SWS disruption. Beta-cell responsiveness (Φ) and SI were determined using oral minimal modeling. During the disruption night, auditory stimuli (68.1 ± 10.7/night; mean ± standard error) decreased SWS by 40.0 ± 8.0%. SWS fragmentation did not affect fasting glucose (non-disrupted 76.9 ± 2.3 versus disrupted 80.6 ± 2.1 mg/dL), insulin (9.2 ± 1.6 versus 10.4 ± 2.0 μIU/mL), or C-peptide (1.9 ± 0.2 versus 1.9 ± 0.1 ng/mL) levels and did not impair SI (12.9 ± 2.3 versus 10.1 ± 1.6 10(-4) dL/kg/min per μIU/mL) or Φ (73.4 ± 7.8 versus 74.4 ± 8.4 10(-9) min(-1)) to a MM challenge. Only the subjects in the most insulin-sensitive tertile demonstrated a consistent decrease in SI after SWS disruption. Pubertal children across a range of body mass indices may be resistant to the adverse metabolic effects of acute SWS disruption. Only those subjects with high SI (i.e., having the greatest "metabolic reserve") demonstrated a consistent decrease in SI. These results suggest that adolescents may have a unique ability to adapt to metabolic stressors, such as acute SWS disruption, to maintain euglycemia. Additional studies are necessary to confirm that this resiliency is maintained in settings of chronic SWS disruption.

Selective slow wave sleep but not rapid eye movement sleep suppression impairs morning glucose tolerance in healthy men

Shortened nocturnal sleep impairs morning glucose tolerance. The underlying mechanism of this effect is supposed to involve a reduced fraction of slow wave sleep (SWS). However, it remains unanswered if impaired glucose tolerance occurs due to specific SWS reduction or a general disturbance of sleep. Sixteen healthy men participated in three experimental conditions in a crossover design: SWS suppression, rapid eye movement (REM)-sleep disturbance, and regular sleep. Selective sleep stage disturbance was performed by means of an acoustic tone (532Hz) with gradually rising sound intensity. Blood concentrations of glucoregulatory parameters were measured upon an oral glucose tolerance test the next morning. Our data show that morning plasma glucose and serum insulin responses were significantly increased after selective SWS suppression. Moreover, SWS suppression reduced postprandial insulin sensitivity up to 20%, as determined by Matsuda Index. Contrastingly, disturbed REM-sleep did not affect glucose homeostasis. We conclude that specifically SWS reduction is critically involved in the impairment of glucose tolerance associated with disturbed sleep. Therefore, glucose metabolism in subjects predisposed to reduced SWS (e.g. depression, aging, obstructive sleep apnea, pharmacological treatment) should be thoroughly monitored.

P-1349 - A bad night's sleep impairs morning glucose tolerance in humans: role of slow wave sleep

Introduction Short nocturnal sleep impairs morning glucose tolerance, and this effect is thought to involve the lack of slow-wave sleep (SWS). Objectives So far, it has not been examined in humans whether the influence of poor sleep on morning glucose tolerance may emerge when non-SWS sleep is lacking. Aims To compare the influence of one night of slow-wave sleep suppression (SWSS) with that of one night of non-SWS suppression (NSWSS) on morning glucose tolerance in humans. Methods 16 normal-weight students [age 20–30 years] participated in a counterbalanced fashion in three experimental conditions: regular sleep, SWSS, and NSWSS. The suppression of sleep was performed by means of an acoustic tone (562 Hz) with gradually rising intensity. Glucoregulatory parameters were measured upon an oral glucose tolerance test (OGTT) the next morning. Results Following the oral glucose load, the serum insulin and plasma glucose responses were significantly greater after the nocturnal suppression of SWS, as compared with those after NSWSS and regular sleep, respectively ( P P > 0.27). Conclusions One night of SWSS is linked to an impaired glucoregulatory response to an oral glucose load. Since NSWSS, compared to regular sleep, did not influence the postprandial serum insulin and plasma glucose response, our data suggest that lacking slow wave sleep may be the driving force that underlies the association between poor sleep and impaired daytime glucose tolerance.

Do differences in sleep architecture exist between persons with type 2 diabetes and nondiabetic controls?

It has been shown previously that the suppression of slow-wave sleep (SWS) markedly reduced insulin sensitivity and led to an impairment of glucose tolerance. We hypothesized that a decreased amount of SWS is a feature peculiar to subjects with type 2 diabetes. A retrospective case-control study analyzed polysomnographic recordings and covariate data of 22 type 2 diabetic and 22 nondiabetic subjects [n = 44; 8 women, 36 men, aged 57.5 +/- 5.5 years, body mass index (BMI) 33.8 +/- 5.9 kg/m(2), apnea-hypopnea index (AHI) 29.6 +/- 22.2 episodes/hr] matched individually for sex, race, age, BMI, and severity of sleep-related breathing disorders (SRBD). We assessed differences in sleep architecture between the study group and the control group. Primary end points included the percentage of total sleep time spent in each sleep stage. Despite similar age and severity of SRBD, subjects with type 2 diabetes demonstrated a significantly decreased amount of SWS (3.9 +/- 5.95% vs 8.4 +/- 4.57%; p = 0.012), increased percentage time in rapid eye movement sleep (24.1 +/- 12.14% vs 13.8 +/- 6.96%; p = 0.005), and higher arousal index (44.3 +/- 19.53/hr vs 35.7 +/- 12.67/hr; p = 0.037) compared to nondiabetic controls. After adjustment for sex, BMI, AHI, and smoking, age and presence of type 2 diabetes were independent predictors of the decreased SWS percentage (p = 0.001). Variables in this model accounted for 34% of the variance in the SWS percentage in our cohort. Results demonstrated distinct differences in sleep architecture in our cohort with decreased amounts of SWS in type 2 diabetes. These findings suggest that polysomnographic recognition of altered sleep architecture may be partially implicated in the early detection of persons with type 2 diabetes.

Serotonin 5-HT2A receptor antagonists in the treatment of insomnia: present status and future prospects

Benzodiazepine (BZD) and non-BZD hypnotics improve sleep induction and sleep maintenance. BZD induces a further reduction of slow wave sleep (SWS) and rapid eye movement (REM) sleep, whereas SWS and REM values remain decreased during non-BZD administration. There is evidence indicating that the nonselective serotonin 5-HT(2A/2C) receptor antagonists, ritanserin, ketanserin, seganserin and ICI-169369, the selective 5-HT(2A) receptor antagonist eplivanserin and the 5-HT(2A) receptor inverse agonist pimavanserin, increase SWS in subjects with normal sleep. In addition, it has been shown that prior administration of ritanserin prevents the nitrazepam-induced suppression of SWS in normal subjects. Of note, ritanserin also induced an increase of SWS in poor sleepers, patients with chronic primary insomnia and psychiatric patients with a generalized anxiety disorder or a mood disorder. The 5-HT(2A) receptor inverse agonist APD-125 gave rise to a similar effect in patients with chronic primary insomnia. Thus, presently available evidence tends to indicate that the association of a 5-HT(2A) receptor antagonist or a 5-HT(2A) receptor inverse agonist with a BZD or a non-BZD hypnotic could be a valid alternative to normalize SWS in patients with primary or comorbid insomnia.

Serotonergic System in the Central Nucleus of Amygdala Mediates Cannabidiol- Induced Sleep Alteration

Cannabidiol (CBD) is one of the psycho-inactive constituents of marijuana, the Cannabis sativa. The pharma- cological property of CBD, especially the anxiolytic effect, is significant in the therapeutic purposes. The central nucleus of amygdala (CeA) plays a key role in the anxiety and its related behavioral responses (e.g. sleep-wake activity), and sero- tonin is one of the major mediators. However, the sleep-wake effect of CBD remains unclear. This study was designed to elucidate the effects of CBD on sleep-wake alteration and the involvement of serotonin in the CeA. Administrations of 5- hydroxytryptamine (5-HT), 5-HT1A receptor partial agonist (buspirone), 5-HT2 antagonist (ritanserin), cannabinoid CB1 receptor agonist (ACEA), or CB1 antagonist (AM-251) were employed to elucidate the action of CBD on CeA presynaptic CB1 receptors, serotonergic activity and the subsequent sleep alteration. We found that microinjection of CBD into the CeA prior to the beginning of the light period dose-dependently decreased slow wave sleep (SWS) with limited effect on rapid eye movement sleep (REMS). CBD-induced SWS suppression during the light period could be mimicked by admin- istering serotonin into the CeA. Buspirone and ritanserin dose-dependently blocked CBD-induced SWS decrease. Fur- thermore, administration of AM-251 exhibits similar effect as that of CBD on sleep-wake activity, and the CBD-induced SWS decrease was partially blocked by ACEA. These observations suggest that CBD acting on the CeA neurons de- creases SWS during the light phase, which is at least partially mediated by the consequence of antagonizing presynaptic CB1 receptors, enhancing serotonin release from the presynaptic terminals and subsequently acting on the postsynaptic 5- HT2 receptors.

Slow-wave sleep and the risk of type 2 diabetes in humans.

There is convincing evidence that, in humans, discrete sleep stages are important for daytime brain function, but whether any particular sleep stage has functional significance for the rest of the body is not known. Deep non-rapid eye movement (NREM) sleep, also known as slow-wave sleep (SWS), is thought to be the most "restorative" sleep stage, but beneficial effects of SWS for physical well being have not been demonstrated. The initiation of SWS coincides with hormonal changes that affect glucose regulation, suggesting that SWS may be important for normal glucose tolerance. If this were so, selective suppression of SWS should adversely affect glucose homeostasis and increase the risk of type 2 diabetes. Here we show that, in young healthy adults, all-night selective suppression of SWS, without any change in total sleep time, results in marked decreases in insulin sensitivity without adequate compensatory increase in insulin release, leading to reduced glucose tolerance and increased diabetes risk. SWS suppression reduced delta spectral power, the dominant EEG frequency range in SWS, and left other EEG frequency bands unchanged. Importantly, the magnitude of the decrease in insulin sensitivity was strongly correlated with the magnitude of the reduction in SWS. These findings demonstrate a clear role for SWS in the maintenance of normal glucose homeostasis. Furthermore, our data suggest that reduced sleep quality with low levels of SWS, as occurs in aging and in many obese individuals, may contribute to increase the risk of type 2 diabetes.

A human anti-neuronal autoantibody against GABA B receptor induces experimental autoimmune agrypnia

In the serum and cerebrospinal fluid of a patient with recurrent acute episodes of respiratory crises, autonomic symptoms and total insomnia (agrypnia), we identified a novel anti-neural complement fixing antibody directed against GABA B receptor (GABA BR). Patient purified IgG recognized a band of approximately 110 kDa on protein extracts of mouse cerebellum, cortex and brainstem and immunolabelled cultured Chinese hamster ovary (CHO) cells, transfected with human GABA BR1 and rat GABA BR2 receptors. Western blot analysis of transfected CHO homogenates showed the same band using both patient purified IgG and anti-GABA BR1 antibody. In order to verify the pathogenic role of these purified antibodies, we injected patient IgG intrathecally into cisterna magna of C57BL/6 mice pre-implanted with EEG electrodes and we observed severe ataxia followed by breathing depression and total suppression of slow wave sleep, as evidenced by EEG recording, in a dose-dependent manner. Immunohistochemistry on brain sections of mice injected with patient IgG showed the simultaneous presence of bound human IgG and C5b-9 deposits on Purkinje cells and cerebellar granular layer. After incubation with anti-GABA BR antibody, a marked reduction of receptor immunostaining was found with relative sparing of neuronal architecture. In conclusion we recognized an anti-neuronal autoantibody directed against GABA BR that is associated with autoimmune agrypnia and we showed that our patient purified IgG was able to induce in mice experimental autoimmune agrypnia characterized by a complex neurological syndrome affecting several CNS functions.

Dopaminergic Control of Sleep–Wake States

Dopamine depletion is involved in the pathophysiology of Parkinson's disease, whereas hyperdopaminergia may play a fundamental role in generating endophenotypes associated with schizophrenia. Sleep disturbances are known to occur in both schizophrenia and Parkinson's disease, suggesting that dopamine plays a role in regulating the sleep-wake cycle. Here, we show that novelty-exposed hyperdopaminergic mice enter a novel awake state characterized by spectral patterns of hippocampal local field potentials that resemble electrophysiological activity observed during rapid-eye-movement (REM) sleep. Treatment with haloperidol, a D2 dopamine receptor antagonist, reduces this abnormal intrusion of REM-like activity during wakefulness. Conversely, mice acutely depleted of dopamine enter a different novel awake state characterized by spectral patterns of hippocampal local field potentials that resemble electrophysiological activity observed during slow-wave sleep (SWS). This dopamine-depleted state is marked by an apparent suppression of SWS and a complete suppression of REM sleep. Treatment with D2 (but not D1) dopamine receptor agonists recovers REM sleep in these mice. Altogether, these results indicate that dopamine regulates the generation of sleep-wake states. We propose that psychosis and the sleep disturbances experienced by Parkinsonian patients result from dopamine-mediated disturbances of REM sleep.

P326 Experimental suppression of slow wave sleep without change in total sleep time is associated with decreased glucose tolerance and insulin sensitivity, and increased daytime sympathetic activity

P326 Experimental suppression of slow wave sleep without change in total sleep time is associated with decreased glucose tolerance and insulin sensitivity, and increased daytime sympathetic activity

Effect of frequent brief awakenings from nonREM sleep on the nonREM-REM sleep cycle.

In the framework of a selective sleep deprivation study, eight young men were repeatedly awakened during 3 nights from nonREM sleep (nonREMS). The mean number of awakenings per night was 27.4, 29.5 and 32.8. In order to avoid excessive suppression of slow wave sleep, no awakening occurred in the first nonREMS episode. Compared to baseline, cycle 2 was significantly prolonged in all 3 nights, and cycle 3 in night 3 only. However, after subtracting the waking intervals, the differences from baseline was eliminated. The results show that the mechanisms underlying sleep cycle control keep track of sleep time and disregard epochs of waking.

Recovery within day-time sleep after slow wave sleep suppression

Six subjects had their SWS activity suppressed by acoustic stimulation during a day-time (11.00 h) recovery sleep after a 4 h night sleep (03.00–07.00 h). Sleep was disturbed for a period corresponding to 90% of the duration of a preceding undisturbed baseline sleep (also at 11.00 h and preceded by a 4 h night sleep) and thereafter allowed to continue undisturbed until spontaneous awakening. The results showed that SWS and EEG power density were significantly reduced during suppression and that full recovery occurred before spontaneous awakening. The disturbed sleep was significantly longer than the baseline sleep. The increase in duration consisted mainly of SWS, stage 2 and REM. The results suggest that the suppression of SWS activity caused a need for an extension of sleep in order to allow recovery.