Total REM Sleep Time Research Articles

0671 Identifying Disruptive Nocturnal Behaviors in Trauma Associated Sleep Disorder with Video-Polysomnography on Consecutive Nights

Abstract Introduction Trauma associated sleep disorder (TSD) manifests with trauma-related nightmares, disruptive nocturnal behaviors (DNB), and autonomic hyperactivity. Although patients with TSD frequently report DNB, events are infrequently identified during in-lab polysomnography (PSG), possibly due to a sense of safety imparted by a monitored environment. It is unknown if patients with TSD acclimate to the lab environment if studied on consecutive nights. Given the infrequent and potentially subtle nature of DNB and REM sleep abnormalities, the objective of this study was to compare self-reported and PSG characteristics from two consecutive nights of PSG in patients with TSD. Methods Individuals were initially screened for TSD with the Pittsburgh Sleep Quality Index Addendum. Those reporting trauma-related nightmares and DNB underwent a structured clinical interview to confirm the diagnosis. Patients with TSD completed 2 consecutive nights of attended in-lab PSG with post-PSG dream/nightmare questionnaire. Video-PSG analysis was performed including detailed review of movements, excluding epochs with sleep disordered breathing. REM sleep analysis included quantifying “any” electromyographic (EMG) activity as an objective measurement for REM without atonia. ANOVA was used for statistical analysis. Results We diagnosed 15 individuals (11 males; 14 service members, 1 Veteran; average age 32.2 years) with TSD. Traumatic exposures were combat-related in 40% and physical or sexual assault related in 60%. There was a significant difference between proximal limb movements on night 1 vs night 2 (1.0 ± 1.73 vs 10.3 ± 4.04; p=0.02). There was a significant difference in the amount of increased EMG tone using 3 second REM mini epochs between the 2 nights (153 ± 147.8 mini epochs vs 417 ± 35.1; p=0.04). No difference was detected between nights for vocalizations or sleep parameters including total REM sleep time and percentage. Nightmares were reported by 33% during their first night PSG vs 66% during their second PSG. Conclusion In patients with TSD, there was an increase in the number of proximal limb movements, total mini epochs of “any” REM EMG activity, and nightmares during the second night of consecutive in-lab PSG testing. More than one night of in-lab PSG evaluation is likely required to best characterize the severe nocturnal disruptions of TSD. Support (if any)

A novel GABAB receptor positive allosteric modulator, ASP8062, exerts analgesic effects in a rat model of fibromyalgia

The gamma-aminobutyric acid type B (GABAB) receptor agonist, the sodium salt of gamma-hydroxybutyrate (GHB), significantly improved pain, sleep disturbance and fatigue in fibromyalgia (FM) patients. However, the use of GABAB receptor agonists is limited by their undesirable side-effects. To clarify whether GABAB receptor positive allosteric modulator (PAM) approach would achieve analgesia with less side-effects than GABAB receptor agonist in FM, we investigated the potential of a novel GABAB receptor PAM, ASP8062, for FM treatment. We examined the in vitro profiles of ASP8062, the effects of a GABAB receptor PAM and an agonist on pain in a rat model of FM, and the sleep/wake cycle, EEG during sleep stages and motor coordination in rats. ASP8062 showed PAM activity on human and rat GABAB receptors. Oral administration of ASP8062 significantly reversed the decrease in muscle pressure threshold in reserpine-induced myalgia rats. The analgesic effects of ASP8062 were significantly blocked by a GABAB receptor antagonist. ASP8062 had a significant effect on motor coordination at a 1000-fold higher dose than the analgesic dose in rats. ASP8062 significantly decreased total REM sleep time and frequency of sleep interruptions, and increased the power in delta waves frequency during non-REM sleep in rats. ASP8062, a novel GABAB receptor PAM, has therapeutic potential to exert analgesic effects with less side-effects compared to GABAB receptor agonists in patients with FM.

Sleep disorders in NiemannPick disease type C, beyond cataplexy

PurposeThe aim of this study was to clinically characterize sleep disorders in a cohort of Niemann-Pick type C (NPC) patients, correlating these findings with disease features and polysomnographic (PSG) results. MethodsWe evaluated eight consecutive patients with molecular confirmation of NPC followed at the Hospital Geral de Fortaleza. Patients underwent a comprehensive neurological and sleep evaluation. Four participants underwent polysomnography and then performed the multiple sleep latency test. ResultsAll eight patients evaluated had sleep disorders. Four participants performed polysomnography followed by multiple sleep latency test. Chronic insomnia and Obstructive Sleep Apnea (OSA) were the most frequent sleep disorders (62,5%). Two patients were diagnosed with Restless Legs Syndrome (RLS) (25%) and two with probable REM sleep behavior disorder (RBD) (25%). All the patients who did polysomnography had reduced and/or disorganized sleep, with reduction on sleep efficiency, total sleep time and REM sleep time. ConclusionOur results suggest that sleep abnormalities in Niemann-Pick type C patients may be more prevalent than previously thought.

Sleep phenotype in the Townes mouse model of sickle cell disease

PurposePatients with sickle cell disease (SCD) regularly experience abnormal sleep, characterized by frequent arousals and reduced total sleep time. However, obstructive sleep apnea syndrome (OSAS) is a common comorbidity of SCD, making it unclear whether the disease per se is impacting sleep, or sleep disruption is secondary to the presence of OSAS. Thus, we assessed sleep, independent of OSAS, using a mouse model of SCD.MethodsSleep was compared between 10-to-12-week-old Townes knockout-transgenic mice with the sickle cell phenotype SS (n = 6) and Townes mice with sickle cell trait AS (n = 6; control). The mice underwent chronic polysomnographic electrode implantation (4EEG/2EMG) to assess sleep architecture.ResultsThe SS mice had significantly lower hemoglobin concentration compared to control AS mice (7.3 ± 1.3 vs. 12.9 ± 1.7 g/dL; p < 0.01), consistent with the expected SCD phenotype. SS mice exhibited significantly decreased total NREM sleep time (45.0 ± 0.7 vs. 53.0 ± 1.3% 24 h sleep time; p < 0.01), but no change in total REM sleep time compared to the AS mice. The SS mice took longer to resume sleep after a wake period compared to the AS mice (3.2 ± 0.3 min vs. 1.9 ± 0.2 min; p < 0.05). Unexpectedly, SS mice experienced fewer arousals compared to AS mice (19.0 ± 0.9 vs. 23.3 ± 2.1 arousals/h of sleep; p = 0.031).ConclusionsThe presence of decreased total NREM sleep associated with reduced arousals, in the absence of OSAS, suggests a distinctive underlying sleep phenotype in a mouse model of SCD.

Neuroscience: Sleepy and dreamless mutant mice.

Sleep in mammals consists of non-rapid-eye-movement and rapid-eye-movement sleep. A large genetic screen reveals that these two sleep states are altered in mice by mutations dubbed Sleepy and Dreamless. See Article p.378 Although the molecular pathways regulating circadian rhythms have been extensively explored and catalogued, much less is known about the molecular mechanisms controlling and driving sleep homeostasis. Using a forward genetic screen, Hiromasa Funato et al. identify two mutations affecting sleep/wakefulness balance. The Sik3 protein kinase was shown to be essential for determining total wake time, and mutations in the cation channel NALCN modulated REM sleep episode duration and total REM sleep time.

Effects of a newly developed potent orexin-2 receptor-selective antagonist, compound 1 m, on sleep/wakefulness states in mice

Orexins (also known as hypocretins) play critical roles in the regulation of sleep/wakefulness states by activating two G-protein coupled receptors (GPCRs), orexin 1 (OX1R) and orexin 2 receptors (OX2R). In order to understand the differential contribution of both receptors in regulating sleep/wakefulness states we compared the pharmacological effects of a newly developed OX2R antagonist (2-SORA), Compound 1 m (C1 m), with those of a dual orexin receptor antagonist (DORA), suvorexant, in C57BL/6J mice. After oral administration in the dark period, both C1m and suvorexant decreased wakefulness time with similar efficacy in a dose-dependent manner. While C1m primarily increased total non-rapid eye movement (NREM) sleep time without affecting episode durations and with minimal effects on REM sleep, suvorexant increased both total NREM and REM sleep time and episode durations with predominant effects on REM sleep. Fos-immunostaining showed that both compounds affected the activities of arousal-related neurons with different patterns. The number of Fos-IR noradrenergic neurons in the locus coeruleus was lower in the suvorexant group as compared with the control and C1m-treated groups. In contrast, the numbers of Fos-IR neurons in histaminergic neurons in the tuberomamillary nucleus and serotonergic neurons in the dorsal raphe were reduced to a similar extent in the suvorexant and C1m groups as compared with the vehicle-treated group. Together, these results suggest that an orexin-mediated suppression of REM sleep via potential activation of OX1Rs in the locus coeruleus may possibly contribute to the differential effects on sleep/wakefulness exerted by a DORA as compared to a 2-SORA.

1499 – Neurodynamic patterns of sleep disturbances related to posttraumatic stress disorder in war veterans

Sleep disturbances are important features of posttraumatic stress disorder (PTSD), however, data characterizing PTSD sleep phenomena are limited. Detailed clinical description of sleep function and its study with the use of modern instrumental methods is important for timely and differential diagnosis of mental disorders in PTSD patients. 21 war veterans fighting in “hot spots were observed during treatment in the specialized department of psychological rehabilitation, Samara Regional Clinical Hospital for War Veterans. After clinical interview the overnight polysomnography “Sagura-2000” (PSG) was performed. Sleep disorders in PTSD patients are characterized by the complex of subjective, clinical and neurophysiological symptoms: 1. Superficial sleep (restless, lack of deep sleep); 2. Increased motor activity during sleep (number of activations of the paradoxical phase of sleep to those of deep sleep); 3. Nightmares; 4. Specific (defensive) movements during sleep; 5. Frequent nocturnal awakening (increased number and duration of awakenings); 6. The excess of REM sleep. PSG identified the most frequently related nightmares neurodynamic phenomena: 1. Deficiency of the deep sleep (stages 3 and 4 NREM); 2. Up to 70% of the time NREM takes stage 2 sleep; 3. The increase in motor and EEG activations; 4. The number of activations of the REM than those of NREM; 5. The increase in total REM sleep time; 6. Increasing episodes of REM sleep. Further studies are required to clarify polysomnographic sleep changes, in particular, role of REM sleep dysregulation and treatment of sleep disorders in PTSD. Study was supported by Russian Humanitarian Scientific Foundation (???? 12-36-01155)

Effect of Ethanol on Sleep-Awake State in Sleep-Disturbed Rats

The present study was undertaken to investigate the effect of ethanol on the sleep-wake cycle in normal rats and sleep-disturbed rats. In normal rats, no significant difference was observed by ethanol in sleep latency, total awake time and total non-rapid eye movement (NREM) sleep time, except for total REM sleep time. On the other hand, in sleep-disturbed rats, ethanol at doses of 1 and 2 g/kg caused significant decreases in sleep latency and total wake time, and an increase in total NREM sleep time. In addition, ethanol showed a significant increase in delta activity in the sleep-disturbed model rat, different from triazolam. These results suggested that ethanol had not only a hypnotic but also a sleep-maintaining effect in sleep-disturbed rats at reasonable blood ethanol concentrations.

Studies on Somnolence in the Daytime Caused by Drugs Used for Neuropathic Pain

In the present study, the characteristics of the sleep features of amitriptyline, mexiletine, and N-(4-tertiarybutylphenyl)-4-(3-cholorphyridin-2-yl)tetrahydropyradine-1(2H)-carbox-amide (BCTC) were studied. Electrodes were chronically implanted into the frontal cortex and the dorsal neck muscles of rats for electroencephalogram (EEG) and electromyogram (EMG) measurements, respectively. EEG and EMG were recorded with an electroencephalograph, and SleepSign ver. 2.0. was used for sleep–wake state analysis. Recordings were performed from 11:00 to 17:00. Amitriptyline caused significant decreases in sleep latency and total wake time and an increase in total non-rapid eye movement (non-REM) sleep time. Mexiletine caused a significant decrease in sleep latency, but no significant effect was observed in total wake time and total non-REM sleep time. On the other hand, BCTC, which is an antagonist of transient receptor potential vaniloid 1 (TRPV1), showed no significant effect on sleep latency, total wake time, total non-REM sleep time, and total REM sleep time. From these results, it can be concluded that a TRPV1 antagonist may become a useful drug for neuropathic pain without sedative side effects in the daytime, different from amitriptyline and mexiletine.

Changes of Sleep Patterns in Rats with Chronic Constriction Injury under Aversive Conditions

In the present study, we investigated the changes of sleep parameters in rats with chronic constriction injury (CCI) under aversive conditions. The electroencephalogram (EEG) in the frontal cortex of CCI rats and electromyogram (EMG) were measured over 6 h by placing rats on sandpaper as an aversive condition, to compare with rats placed on sawdust. Six days after CCI surgery, the rats exhibited significant mechanical allodynia, and also had neuropathic pain. When rats were placed on sawdust, no significant difference was observed between the CCI group and sham-operated control group in sleep latency, total waking time, total non-REM sleep time and total REM sleep time. On the other hand, when CCI rats were placed on sandpaper, a significant increase was observed in sleep latency and total waking time compared with the sham group; however, no significant difference was observed in the total non-REM sleep time and total REM sleep time between these two groups. These results indicate that an important factor of sleep disturbance in CCI rats is not only damage to the nerves but also being under aversive conditions. In addition, it was found that CCI rats placed on sandpaper as an aversive condition can serve as a new sleep disturbance model.

Characteristic changes in sleep patterns during pregnancy in rats

The purpose of this study was to evaluate changes in sleep patterns during pregnancy. We uninterrupted recorded electroencephalogram (EEG), electromyogram (EMG), and brain temperature (Tbr) throughout pregnancy in rats. The duration of non-rapid eye movement (non-REM) sleep decreased after day 5 of pregnancy associated with an inverse increase in the number of non-REM sleep episodes. Thus, the amount of total non-REM sleep time remained constant throughout pregnancy. The amount of total REM sleep time decreased on day 17 of pregnancy after which the reduced state was sustained. That was mainly due to a decrease in the number of REM sleep episodes. Brain temperature (Tbr) gradually decreased as pregnancy advanced, reaching its lowest value 3 days before delivery. These observations provide a better understanding of the sleep patterns during pregnancy, and useful information for investigation of mechanisms of sleep regulation during pregnancy.

Inhibition of REM sleep by ipsapirone, A 5HT1A agonist, in normal volunteers

In order to test the hypothesis that serotonergic mechanisms inhibit REM sleep via a 5HT1A receptor, we administered placebo and ipsapirone (10 and 20 mg by mouth 15 min before bedtime) to ten normal volunteers in a double blind fashion. Ipsapirone is a relatively selective 5HT1A receptor agonist. As predicted, ipsapirone prolonged REM latency and Mean Latency to Eye Movements (M-LEM), a measure of time between onset of REM sleep and the first eye movement of the REM period, and REM% at both doses compared with placebo. It also reduced sleep efficiency and total REM sleep time at the highest dose. These results support the hypothesis that systemic stimulation of 5HT1A receptors prolong REM latency and inhibit REM sleep.

Sleep and heart rate circadian rhythm in depression: the necessity to separate.

In order to determine whether a decrease in the amplitude of heart rate circadian rhythm (HRCR) could represent a chronobiological marker of depression and to answer the question of the possible role of this alteration in the reduction of rapid eye movement sleep latency (REM latency) observed in depression, 22 major depressed patients (DSM III R, Montgomery Asberg Depression Rating Scale) and 11 healthy volunteers entered this study, which included the simultaneous recordings of sleep and heart rate (HR) during two consecutive 24-h periods. After a smoothing procedure, the HR data, obtained from a portable device providing mean HR/min, were computed with the single cosinor method for the classical circadian parameters. We also determined the cosinor fitting index (CFI = percentage to fit). When studied as a single group and compared to the control group, the depressed patients, who had difficulties in sleep initiation and whose REM latencies were within normal limits, were characterized by a dampening of the amplitude HRCR and of the day-night HR difference. This was linked to a lesser increase of HR during the day and a reduced decrease at night. No significant phase modification of HRCR was observed in this group of depressives. In a second step, the depressives were divided into a depressed arrhythmic group (DAG, CFI < 50%, 11 patients) and a depressed rhythmic group (DRG, CFI > 50%, 11 patients) who did not differ on MADRS scores. Even though the amplitude of HRCR was reduced in the DAG only, with HR higher at night and lower during the daytime than for controls, both DAG and DRG significantly differed from controls on those items related to sleep induction and maintenance. In the DAG only was there a tendency toward a reduction of total sleep time and REM sleep time while REM latency was normal. This finding suggests that sleep problems are not responsible for the differences in HRCR parameters between the two depressed groups. These differences in HR and sleep parameters between two groups of similarly depressed patients also suggest that a short REM latency does not systematically imply a disruption of all circadian clocks.

Arousal induced by injection of triazolam into the dorsal raphe nucleus of rats.

In order to explore the possible sites at which benzodiazepines alter sleep, we have performed sleep studies following administration of 0.5 microgram of triazolam into the dorsal raphe nucleus of rats. Triazolam significantly increased sleep latency and decreased non-rapid eye movement (REM) sleep, with an effect greatest in the first 2 hours after injection. Total REM sleep time was not significantly affected, although there was a modest trend toward reduction in the first 2 hours. In contrast to the decreased sleep resulting from injection into the dorsal raphe nucleus, triazolam did not significantly alter sleep in animals in whom it was injected into surrounding areas. Similarly, the low dose employed in this study did not significantly affect sleep when injected into the lateral ventricle. These data are reminiscent of studies showing transient decreases in sleep following lesions of the dorsal raphe nucleus.

Effect of recurrent stimulation of the brain stem reticular formation on REM sleep in cats

A study was carried out in cats prepared for chronic sleep recordings of the effect of recurrent stimulation of the pontine reticular formation, REM sleep-deprivation and the interaction of both on the total REM sleep time and the mean number and duration of REM periods. During the three different experimental situations it was possible to observe a regularization in the occurrence of REM periods, as well as an increase of the total REM sleep time and mean duration of REM periods. There was a significant increase in the number of REM periods only when pontine reticular formation and REM sleep deprivation were interacted. These findings support the concept that REM sleep is an active process and that REM periods soon after stimulation of the pontine region are closely related to the stimulus.