The Importance of Sleep Stages and Arousals in Sleep Quality, Study notes of Neurobiology

Download The Importance of Sleep Stages and Arousals in Sleep Quality and more Study notes Neurobiology in PDF only on Docsity! 91Zakevicius M, Liesiene V, Griksiene R, Masaitiene R, Ruksenas O Sleep Sci. 2013;6(3):91-97 Arousals and macrostructure of sleep: importance of NREM stage 2 reconsidered ORIGINAL ARTICLE Despertar e macroestruturas do sono: importância de reconsiderar o estágio NREM Zakevicius Martynas1, Liesiene Vanda2, Griksiene Ramune1, Masaitiene Raminta3, Ruksenas Osvaldas1 Study carried out at Department of Neurobiology and Biophysics, Faculty of Natural Sciences, Vilnius University, Vilnius, Lithuania. 1 Department of Neurobiology and Biophysics, Faculty of Natural Sciences, Vilnius University, Vilnius, Lithuania. 2 Institute of Neuromedicine, Kaunas, Lithuania. 3 Sleep disorders laboratory, Vilnius Sapiegos Hospital, Vilnius, Lithuania. Corresponding author: Martynas Zakevicius. Department of Neurobiology and Biophysics, Vilnius Universit. M.K. Ciurlionio st. 21/27, 03101 Vilnius, Lithuania. Phone: +370 605 84 607. Fax: +370 5 239 8216. E-mail: martis54@gmail.com Received: February 26, 2013; Accepted: August 26, 2013. ABSTRACT Objectives: The sense of rest after sleep and its relation to various sleep parameters is still a debatable issue. The purpose of the present study was to analyse sleep fragmentation by scoring various arousals (microarousals (MA), vegetative (VA) and behavioural (BA) arousals) in all sleep stages and to evaluate their relation with subjective sleep quality without paying attention to the type of insomnia. Methods: The overnight sleep cycles of 60 subjects were analyzed according to their stage composition and arousals. Arousal indices (AI) were calculated for all types of arousals in all sleep stages and sleep cycles. The sleep quality was quantified using the Pittsburgh sleep quality index (PSQI). Results: AI differences between sleep cycles were not statistically significant. MAI value in total sleep time (TST) - 5.8 ± SD 4.1 - was the highest among all the three arousal types. Differences between AI in most sleep stages were statistically significant for all types of arousals. This suggests that human sleep development within a single sleep cycle is more important for the sleep quality than the changes between different sleep cycles. The highest AI scores for the three types of arousals were found in NREM stage 2. The strongest and significant correlation was between PSQI and MAI (r = 0.42; p = 0 .001). Conclusion: The density of microarousals is impor- tant for the subjective sleep quality. The highest values of MAI and other arousal types are found in NREM stage 2. The importance of this stage might be higher than thought before and especially in initial sleep cycles. Keywords: sleep, sleep arousals disorders, sleep stages. RESUMO Objetivos: O sentido de descanso após o sono e sua relação com vários parâmetros do sono ainda é uma questão discutível. O obje- tivo do presente estudo foi analisar a fragmentação do sono, mar- cando vários despertares (microdespertares (MA), vegetativas (VA) e comportamentais (BA) despertares) em todas as fases do sono e avaliar sua relação com a qualidade subjetiva do sono, sem prestar atenção ao tipo de insônia. Métodos: Os ciclos de sono durante a noite de 60 indivíduos foram analisados de acordo com a sua composição palco e despertares. Índices de excitação (AI) foram calculados para todos os tipos de despertares em todas as fases do sono e os ciclos do sono. A qualidade do sono foi quantifica- INTRODUCTION The overnight course of sleep is not a simple linear process, and it exhibits a very complex behavior which involves various areas of the central nervous system at different levels and at different times(1). The daily shifts from the wake state to NREM and REM sleep are under the control of interconnected processes, including the circadian timing of sleep onset, the homeostatic balance between wakefulness and sleep and the ultradian interaction between NREM and REM sleep(2). More recently, and especially to explain the clinical consequences of sleep disorders, the three processes of sleep regulation - circadian, homeostatic and ultradian - have been integrated by the definition of the arousal system(3). Arousals are transient episodes of cerebral activation during sleep which involves massively the cortex regulated by the interplay between cortical and subcortical neurons(3,4). Most authors consider arousals as a transient cortical activation in response to sleep disruptive events(5-7), but there are other studies indicating that Descritores: fases do sono, sono, transtornos do despertar do sono. da através do índice de qualidade do sono de Pittsburgh (PSQI). Resultados: Diferenças entre AI ciclos de sono não foram estatis- ticamente significativas. MAI valor no tempo total de sono (TST) - 5,8 ± SD 4.1 - foi o maior entre todos os três tipos de excitação. Diferenças entre AI na maioria dos estágios do sono foram estatis- ticamente significantes para todos os tipos de despertares. Isto su- gere que o desenvolvimento de sono humano dentro de um único ciclo do sono é mais importante para a qualidade do sono do que as variações entre diferentes ciclos de sono. Os maiores escores de IA para os três tipos de despertares foram encontrados em fase NREM 2. A correlação mais forte e significativa foi entre PSQI e MAI (r = 0,42, p = 0, 001). Conclusão: A densidade de micro- despertares é importante para a qualidade subjectiva do sono. Os maiores valores de MAI e outros tipos de excitação são encontradas em fase NREM 2. A importância desta fase pode ser maior do que se pensava antes e, especialmente, nos ciclos iniciais do sono. Sleep Sci. 2013;6(3):91-97 92 Arousals and Sleep Quality arousals punctuate both REM and NREM sleep even in the absence of detectable disturbing stimuli(8,9). On the one hand, there are debates still going on about the nature and role of arousals in sleep, and on the other hand, there is a question about their role for the sleeper him/herself - how his/her sleep quality is affected by them. There are various stud- ies trying to evaluate a person’s sense of rest after the sleep in the morning, but researchers still disagree about what determines the sense of rest after the sleep(10). There are findings which showed that the subjective satisfaction after the sleep is not dependent on the overall sleep length(11). It was assumed that the amount of delta sleep is very important in sleep structure, but it wasn’t ex- actly confirmed and even people with sufficient amounts of deep sleep might feel unrested in the morning(5). A lot of attention is recently paid to the sleep integrity and the role of sleep fragmen- tation, which is characteristic of primary insomnia and could have an effect on the sleep’s restorative function(12,13). The aim of the present study was to analyze sleep fragmentation by scoring different type arousals in all sleep stages and cycles and to evaluate their relationship with the subjective sense of rest after the sleep without paying attention to the type of insomnia. MATERIAL AND METHODS Subjects The data analyzed in this study were collected from the all night polysomnographic (PSG) recordings of 60 subjects (30 men and 30 women) aged between 36 and 55 years (mean 46 ± SD 5.6 years). Subjects were recruited from clinical patients of the Sleep disorders laboratory at Vilnius Sapiegos hospital in Vilnius. All subjects were diagnosed with various sleep disorders. The only exclusion criteria were sleep apneas and heavy snoring problems. They had all night PSG study performed in the sleep disorders laboratory and woke up in the morning at their usual time. Before the study, patients had consultations with the doctor, filled out necessary questionnaires and provided written informed consents. All clinical experiments conformed to the principles outlined by the Declaration of Helsinki. Arousal scoring A monopolar derivation (C3-A2 or C4-A1) was used to score sleep stages(14) and arousals. Arousals were scored and arousal indices (AI) (the number of arousals per hour of sleep) were calculated in three major groups to represent different levels of cortical and somatovegetative activations: • Behavioural arousal (BA): reported in the Rechtshaffen and Kales manual(14) as a movement arousal described as any increase in electromyographic activity that is accompanied by a change in any other EEG channel. • Micro (cortical) arousal (MA): defined by the American sleep disorders association (ASDA) committee in 1992 as EEG arousal and characterized by transient desynchronized EEG patterns interrupting sleep. It reflects a brief awakening of the cerebral cortex regardless of any concomitant participation of the autonomic system or behavioral components(3). • Vegetative (autonomic) arousal (VA): identified when vegetative activation is associated with a transient EEG pattern different from a conventional ASDA arousal(15,16). The Pittsburgh Sleep Quality Index (PSQI) The Pittsburgh Sleep Quality Index (PSQI)(17) was developed to measure sleep quality during the previous month and to discriminate between good and poor sleepers. The PSQI has been used to measure sleep quality among truck drivers(18), to test the effects of a drug on sleep quality in a randomized placebo controlled trial(19) and others. Sleep quality is a complex phenomenon that involves several dimensions, each of which is covered by the PSQI. The covered domains include Subjective Sleep Quality, Sleep Latency, Sleep Duration, Habitual Sleep Efficiency, Sleep Disturbances, Use of Sleep Medications, and Daytime Dysfunction. The PSQI is designed to assess sleep quality during the past month and con- tains 19 self-rated questions and 5 questions rated by a bed part- ner or roommate (only the self-rated items are used in scoring the scale). Seven component scores that correspond to the domains listed previously are calculated and summed into a global score(17). A score of 5 and more indicates poor sleep quality; the higher the score, the worse the sleep quality. Component scores range from 0 to 3 and global scores range from 0 to 21. Protocol All patients who took part in the study were patients of the Sleep disorders laboratory in Vilnius Sapiegos hospital. As part of their standard clinical assessment they completed the PSQI at their initial patient consultation and a clinical history was taken. An overnight sleep study was then performed using the electrophysiological recording equipment (SleepLab Applications from VIASYS® Respiratory Care Inc., Viasys Healthcare GmbH, Hoechberg, Germany) to measure 4 EEG leads (C3, C4, P3, P4 referenced to linked ears), an electrooculogram (EOG), an electromyogram (EMG), and an electrocardiogram (ECG). Also arterial oxygen saturation (SaO2) was determined, respiration was monitored with thermistors and thoracic movements, and tibialis electromyographic activ- ity was recorded using surface electrodes placed on the right and left legs. The sleep laboratory was equipped with video and sound recording devices for additional monitoring of body movements and sounds. All equipment was time synchronized. Subjects went to bed at their usual time and were asked to refrain from drinking beverages containing caffeine or alcohol in the previous afternoon and evening hours. In the morning they also awakened at their usual time. Sleep stages were visually scored according to standard criteria(14) using 30-second epochs, with the investigator blind to subject and experimental conditions. Standard sleep parameters were computed over the complete sleep time period, and all recordings were analyzed for sleep staging and arousal scoring with the Matrix Sleep Analysis SleepLab® for Windows (version 1.70.0.3) software package. 95Zakevicius M, Liesiene V, Griksiene R, Masaitiene R, Ruksenas O Sleep Sci. 2013;6(3):91-97 Table 3. Arousal indices in sleep stages. N1 N2 N3 N4 REM p F Significantly differing sleep stages Number of subjects 45 45 45 45 45 BAI 11.7 ± 9.3 19.0 ± 14.0 3.6 ± 4.0 0.7 ± 1.2 9.3 ± 9.4 < 0.05 2.275 1 > 3; 1 > 4; 2 > 1; 2 > 3; 2 > 4; 2 > REM; REM > 4 MAI 11.1 ± 11.0 25.1 ± 21.3 4.1 ± 5.0 0.2 ± 0.5 12.9 ± 11.1 < 0.0001 3.702 1 > 4; 2 > 1; 2 > 3; 2 > 4; 2 > REM; REM > 3; REM > 4 VAI 6.1 ± 6.7 15.8 ± 15.6 2.5 ± 3.6 0.3 ± 0.6 7.3 ± 6.9 < 0.01 5.369 2 > 1; 2 > 3; 2 > 4; 2 > REM BAI: Behavioural arousal index; MAI: Microarousal index; VAI: Vegetative arousal index; N1, N2, N3, N4: Stages 1, 2, 3, 4 of non-rapid eye movement sleep; REM: Rapid eye movement sleep; p: Significance of inter cycle differences; F: F-ratio variance; Average ± SD. Figure 2. Pittsburgh sleep quality index correlations with conventional sleep parameters (N = 51). W: Wake; N1, N2, N3, N4: Stages 1, 2, 3, 4 of NREM (non-rapid eye movement sleep); REM: Rapid eye movement sleep. Figure 3. Pittsburgh sleep quality index correlations with light sleep and deep sleep duration in different sleep cycles (N = 44). LS: Light sleep; DS: Deep sleep; REM: Rapid eye movement. AIs dynamics during the night is closely related to the duration of sleep stages in each sleep cycle. MAI corre- lations with PSQI increase from cycle to cycle, but it is not significant and is mainly related to increasing proportion of light sleep in each sleep cycle and especially N2. Correla- tions between BAI, VAI and PSQI become more negative over the night in parallel with decreasing amount of deep sleep in each sleep cycle (Figure 5). This negative trend Figure 4. Pittsburgh sleep quality index correlations with different type arousals in sleep cycles (N = 46). BAI: Behavioural arousal index; MAI: Microarousal index; VAI: Vegetative arousal index. Figure 5. Pittsburgh sleep quality index correlations with different type arousals in sleep cycles (N = 46). LS %: Percentage of light sleep; DS %: Percentage of deep sleep; BAI: Behavioural arousal index; MAI: Microarousal index; VAI: Vegetative arousal index; L: Left hand side axis; R: Right hand side axis. is similar to the negative correlations between PSQI and VAI in TST. That could be related to the maintenance and preparation of internal body functions before the morning time awakening. Not significant AI differences between sleep cycles (Table 2) and significant AI differences between sleep stages (Table 3) sug- gested that developments of human sleep within the single sleep cycle are more important for the sleep quality than the changes between sleep cycles. Factorial ANOVA confirmed that the sleep stage and the arousal type were significant factors for the AI values, whereas the sleep cycle was not (see above in Subjective sleep quality). Sleep Sci. 2013;6(3):91-97 96 Arousals and Sleep Quality The highest AI values were found in N2 stage and MAI in this stage was higher than the other two AIs (Table 3). On this basis, we suggest that not only the sleep stage proportions (the amount of deep sleep) are important to feel good after the sleep, but the microstructure of each stage, and especially N2, might be significant for that also. What is happening during N2 in the human body that we could think of its importance? The average cerebral metabolism and blood flow begin to decrease in N2 compared to wakefulness(26,27). Comparing the influence of high (34-37ºC) and low (21ºC) ambient temperatures on sleep, Haskell et al. pointed out that the durations of wakefulness and N1 sleep increased in cold exposure whereas the duration of N2 sleep decreased(28). They concluded that cold was more disruptive to sleep than heat. A similar observation has been reported by Palca et al.(29). For naked subjects exposed for five consecutive nights at 21oC cold exposure increased wakefulness and decreased N2 sleep without any change in other sleep stages. That shows that sleep disruption might be expressed as the reduction in N2 sleep. The increase in slow wave activity during NREM sleep is associated with low adrenocorticotropic activity and low sympathetic activity, whereas N2 clearly reveals its hormonal and autonomic duality, depending on whether it prepares for deep sleep or REM sleep(30). It could be that sleep disorders might result from an alteration of the autonomic nervous system activity, or from inadequate coupling between endocrine, autonomic, and EEG ultradian rhythms(31). In healthy nocturnal young subjects, oral administration of exogenous melatonin before going to bed increased N2 amount significantly, with slight hypothermic action(32). The effect of a high melatonin dose (80 mg p.o.), when tested in subjects with insomnia induced by exposure to recorded traffic noise, was a reduction of sleep latency and of the number of awakening episodes and the increase of N2 sleep and sleep efficiency(33). Administration of 3-mg dose of melatonin during 14 nights to elderly patients with chronic primary insomnia brought about a significant reduction in WASO while TST and SE increased, with an increase of N2 stage(34). It turns out that pharmaceutical im- provement of sleep influences mostly N2 stage. Individuals who learn a new task have a significantly higher density of sleep spindles, which is one of the markers of N2 stage, than those in a control group(35) and the improvement of performance after a period of sleep is correlated with the percentage of N2 sleep(36). From all these findings we can see that N2 stage is associated and correlated with good sleep quality and sleep disruptive conditions make the most impact on N2 stage also. That and recent findings about sleep mechanism disruptions and its possible connection with some pathologies (from cognitive to metabolic defects)(37,38) raise new thoughts. Stabilization of sleep and especially in NREM stage 2 might help to reduce symptoms of these pathologies and give way for other specialists to intervene more effectively with their therapy. Moreover, the importance of this stage gets new meaning in the light with emerging concepts of sleep-wake cycle regulation and transition from NREM to REM sleep and vice versa, which usually is happening through NREM stage 2(39,40). In summary, it can be concluded that microarousal density is important for the subjective sense of rest after the sleep. The highest values of MAI and other arousal types are found in NREM stage 2. That is why we point out that the importance of this stage might be higher than anticipated and especially in initial sleep cycles. It is well known that during N2 essential changes in thalamo-cortical circuits take place andtemporary deafferentation of sensory influx to cortex occurs. It is assumed that this creates special conditions for cortical restorative processes. The stability of N2 defines how deep sleep which is responsible for the meta- bolic restoration unrolls. If during this stage everything goes well in the brain and sleep is undisrupted, then deep sleep plays its role and sleep quality is good, but if something goes wrong in this stage, e.g. sleep is fragmented by microarousals, and then sleep quality becomes poorer. There are a few limitations in our study that we would like to point out. First off all - age. Subjects’ age in this study varied from 35 to 55 years and this might have had some impact on the study results. It would be useful to collect a larger group of subjects in a narrower age range. The second is the type of sleep disorders. We wanted to see if there is any relation between the sleep microstructure in terms of arousals and the subjective sense of rest after the sleep without paying attention to the type of a sleep disorder. But a different type of a sleep disorder might have variable effects on the sleep microstructure and then on the sense of rest. Even though we analysed the data from patients who had various sleep disorders, we think that general concept that sleep fragmentation has a negative impact on sleeper’s sense of rest after the sleep applies for both people with and without sleep disorders. ACKNOWLEDGMENTS We thank the staff of the Sleep disorders laboratory at Vilnius Sapiegos hospital for letting us use their equipment. Authors’ contribution: MZ, RM, VL, OR conceived the study aims and design, contributed to the systematic review and data extraction. 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