An Asymmetrical Hypothesis for the NREM-REM Sleep Alternation-What Is the NREM-REM Cycle?

Since the discovery of rapid eye movement (REM) sleep (Aserinsky and Kleitman, 1953), sleep has been described as a succession of cycles of non-REM (NREM) and REM sleep episodes. The hypothesis of short-term REM sleep homeostasis, which is currently the basis of most credible theories on sleep regulation, is built upon a positive correlation between the duration of a REM sleep episode and the duration of the interval until the next REM sleep episode (inter-REM interval): the duration of REM sleep would therefore predict the duration of this interval. However, the high variability of inter-REM intervals, especially in polyphasic sleep, argues against a simple oscillator model. A new "asymmetrical" hypothesis is presented here, where REM sleep episodes only determine the duration of a proportional post-REM refractory period (PRRP), during which REM sleep is forbidden and the only remaining options are isolated NREM episodes or waking. After the PRRP, all three options are available again (NREM, REM, and Wake). I will explain why I think this hypothesis also calls into question the notion of NREM-REM sleep cycles.

Psychophysical evaluation of chemosensory functions 5 weeks after olfactory loss due to COVID-19: a prospective cohort study on 72 patients.

PURPOSE: To evaluate the evolution of chemosensation via extended psychophysical testing in patients who suffered from sudden chemosensory loss due to coronavirus disease 2019 (COVID-19). Additionally, this study sought to determine whether odor threshold testing provided additional information on olfactory loss due to COVID-19 compared to the more common odor identification testing. METHODS: Prospective cohort study of patients with sudden chemosensory loss since February 2020 and confirmed COVID-19 infection via RT-PCR or serology testing. Olfactory function was tested extensively using the "Sniffin Sticks" test battery. In addition, we screened gustatory perception and nasal cooling sensations using psychophysical tests. RESULTS: Seventy-two patients completed the study. After a mean of 37 days, 37% of patients showed olfactory dysfunction, 7% were dysgeusic, and 48% showed signs of low sensitivity for cooling sensation. A longer duration of anosmia before smell improvement was correlated with lower olfactory function at 5 weeks. Odor threshold detection was more affected by COVID-19 compared to odor identification. CONCLUSION: Five weeks after developing sudden chemosensory loss due to COVID-19, a high proportion of patients were dysosmic and showed signs of low nasal cooling sensitivity, whereas most of them had normal taste function. SARS-CoV-2 affected mainly odor thresholds, possibly suggesting that the major cause of loss of smell lies at the level of the olfactory neuroepithelium, rather than in the central nervous system.

Relationships between REM and NREM in the NREM-REM sleep cycle: a review on competing concepts.

Sixty-five years after the discovery of rapid eye movement (REM) sleep, the reasons why we sleep and why we need two states of sleep are still largely unclear. Moreover, the functional relationship between the two types of sleep remains the matter of much conjecture. Several questions come to mind. How does sleep regulation in monophasic and polyphasic animals compare? What are the circadian and homeostatic influences on both states? Are non-rapid eye movement (NREM) and REM states dependent on each other, or are they regulated independently? What about long-term and short-term regulation? In addition, what determines the number and duration of cycles per night? What roles are played by temperature and energy allocation? The evidence collected over the years regarding these questions is summarized here, trying to address each issue.

Sleep ultradian cycling: Statistical distribution and links with other sleep variables, depression, insomnia and sleepiness-A retrospective study on 2,312 polysomnograms.

The number of alternations between Non-Rapid Eye Movement (NREM) sleep and Rapid Eye Movement (REM) sleep in humans is usually considered to consist of 4-5 cycles of about 90 minutes duration per night. Previous studies by our group showed a normal distribution on 26 healthy human subjects. The present study retrospectively analyzes the polysomnograms of 2,312 unmedicated patients who were admitted for medical and/or psychiatric reasons in the Erasme University Hospital between 2003 and 2014. The normal distribution of the Number of Cycles and Mean Cycle Duration was confirmed. Q-Q plots were very close to linearity. This distribution allows the use of these variables in parametric comparisons. The Number of Cycles per night and the Mean Cycle Duration showed predominant links with REM sleep-related variables, such as the REM Latency, REM sleep duration, the REM/NREM sleep ratio. None of these variables was associated with the diagnosis of Major Depressive Disorder, nor the intensity of Depression as measured by the Beck Depression Inventory (short version). On the other hand, the diagnosis of Major Depressive Disorder was significantly associated with the Insomnia Severity Index and correlated with the intensity of depressive symptoms (Beck Depression Inventory).

Slow wave sleep in the chronically fatigued: Power spectra distribution patterns in chronic fatigue syndrome and primary insomnia.

OBJECTIVES: To investigate slow wave sleep (SWS) spectral power proportions in distinct clinical conditions sharing non-restorative sleep and fatigue complaints without excessive daytime sleepiness (EDS), namely the chronic fatigue syndrome (CFS) and primary insomnia (PI). Impaired sleep homeostasis has been suspected in both CFS and PI. METHODS: We compared perceived sleep quality, fatigue and sleepiness symptom-intensities, polysomnography (PSG) and SWS spectral power distributions of drug-free CFS and PI patients without comorbid sleep or mental disorders, with a good sleeper control group. RESULTS: Higher fatigue without EDS and impaired perceived sleep quality were confirmed in both patient groups. PSG mainly differed in sleep fragmentation and SWS durations. Spectral analysis revealed a similar decrease in central ultra slow power (0.3-0.79Hz) proportion during SWS for both CFS and PI and an increase in frontal power proportions of faster frequencies during SWS in PI only. The latter was correlated to affective symptoms whereas lower central ultra slow power proportions were related to fatigue severity and sleep quality impairment. CONCLUSIONS: In combination with normal (PI) or even increased SWS durations (CFS), we found consistent evidence for lower proportions of slow oscillations during SWS in PI and CFS. SIGNIFICANCE: Observing normal or increased SWS durations but lower proportions of ultra slow power, our findings suggest a possible quantitative compensation of altered homeostatic regulation.

Age distribution curve in psychiatric admissions inversely correlates with Life Satisfaction.

A strong inverse correlation was found between the age-distribution curve of psychiatric admissions and the U-bend Life Satisfaction curve. It may indicate that the peak of mental disorders at midlife reflects a less satisfactory period of life or, conversely, that the mental health load burdens of Life Satisfaction.

Dimensions of pure chronic fatigue: psychophysical, cognitive and biological correlates in the chronic fatigue syndrome.

OBJECTIVES: To investigate associated dimensions of fatigue regarding cognitive impairment, psychomotor performances, muscular effort power and circulating cytokine levels and their relations to symptom intensity in a sample of pure chronic fatigue syndrome (CFS) patients without overlapping objective sleepiness or sleep disorders. METHODS: 16 CFS patients were compared to 14 matched controls. We assessed structured symptom-scales, polysomnography, multiple sleep latency tests, attention (Zazzo-Cancellation ZCT, digit-symbol-substitution DSST), psychomotor vigilance and speed (PVT, finger tapping test, FTT), dynamometer handgrip force (tonic and phasic trials) and circulating cytokines (IFN-γ, IL-1b, IL-6, IL-8, IL-10, TNF-α). RESULTS: In addition to fatigue, CFS patients presented with higher affective symptom intensity and worse perceived sleep quality. Polysomnography showed more slow-wave sleep and microarousals in CFS but similar sleep time, efficiency and light-sleep durations than controls. Patients presented with impaired attention (DSST, ZCT), slower reaction times (PVT) but not with lower hit rates (FTT). Notwithstanding lower grip strength during tonic and phasic trials, CFS also presented with higher fatigability during phasic trials. Cytokine levels were increased for IL-1b, IL-8, IL-10 and TNF-α and fatigue intensity was correlated to grip strength and IL-8. CONCLUSIONS: In contrast to sleepiness, chronic fatigue is a more complex phenomenon that cannot be reduced to one single measured dimension (i.e., sleep propensity). Showing its relations to different measurements, our study reflects this multidimensionality, in a psychosomatic disorder such as CFS. To obtain objective information, routine assessments of fatigue should rule out sleepiness, combine aspects of mental and physical fatigue and focus on fatigability.

Non-REM sleep EEG power distribution in fatigue and sleepiness.

OBJECTIVES: The aim of this study is to contribute to the sleep-related differentiation between daytime fatigue and sleepiness. METHODS: 135 subjects presenting with sleep apnea-hypopnea syndrome (SAHS, n=58) or chronic fatigue syndrome (CFS, n=52) with respective sleepiness or fatigue complaints and a control group (n=25) underwent polysomnography and psychometric assessments for fatigue, sleepiness, affective symptoms and perceived sleep quality. Sleep EEG spectral analysis for ultra slow, delta, theta, alpha, sigma and beta power bands was performed on frontal, central and occipital derivations. RESULTS: Patient groups presented with impaired subjective sleep quality and higher affective symptom intensity. CFS patients presented with highest fatigue and SAHS patients with highest sleepiness levels. All groups showed similar total sleep time. Subject groups mainly differed in sleep efficiency, wake after sleep onset, duration of light sleep (N1, N2) and slow wave sleep, as well as in sleep fragmentation and respiratory disturbance. Relative non-REM sleep power spectra distributions suggest a pattern of power exchange in higher frequency bands at the expense of central ultra slow power in CFS patients during all non-REM stages. In SAHS patients, however, we found an opposite pattern at occipital sites during N1 and N2. CONCLUSIONS: Slow wave activity presents as a crossroad of fatigue and sleepiness with, however, different spectral power band distributions during non-REM sleep. The homeostatic function of sleep might be compromised in CFS patients and could explain why, in contrast to sleepiness, fatigue does not resolve with sleep in these patients. The present findings thus contribute to the differentiation of both phenomena.

Ultra-slow delta power in chronic fatigue syndrome.

The role of sleep in patients diagnosed with chronic fatigue syndrome is not fully understood. Studies of polysomnographic and quantitative sleep electroencephalographic (EEG) measures have provided contradictory results, with few consistent findings in patients with Chronic Fatigue Syndrome (CFS). For the most part, it appears that delta EEG activity may provide the best discrimination between patients and healthy controls. A closer examination of delta activity in the very slow end of the frequency band is still to be considered in assessing sleep in CFS. The present preliminary study compared absolute and relative spectral power in conventional EEG bands and ultra-slow delta (0.5-0.8Hz) between 10 young female patients with the CFS and healthy controls without psychopathology. In absolute measures, the ultra-slow delta power was lower in CFS, about one-fifth that of the control group. Other frequency bands did not differ between groups. Relative ultra-slow delta power was lower in patients than in controls. CFS is associated with lower ultra-slow (0.5-0.8Hz) delta power, underscoring the importance of looking beyond conventional EEG frequency bands. From a neurophysiological standpoint, lower ultra-slow wave power may indicate abnormalities in the oscillations in membrane potential or a failure in neural recruitment in those with CFS.

Neurocognitive determinants of novelty and sensation-seeking in individuals with alcoholism.

AIM: Sober alcoholic abusers exhibit personality traits such as novelty-seeking (NS) and sensation-seeking, which overlap to a limited extent. In parallel, they also show impaired executive and decision-making processes. However, little is known about the specific and common cognitive processes associated with NS and sensation-seeking personality traits in detoxified sober alcoholic abusers. METHODS: In these present studies, we have investigated the relationships between executive functioning/central executive of working memory (pre-potent response inhibition, manipulation stored in working memory), and decision-making under uncertainty and NS/sensation-seeking traits in such alcoholics. RESULTS: Compared with healthy controls (n = 30, mean age = 40.2), and in agreement with previous studies, alcoholics (n = 30, mean age = 40.4) showed higher levels of both NS and sensation-seeking traits. Alcoholics were also disadvantaged with respect to (a) gambling tasks, as reported previously, and (b) a poor ability to manipulate information stored in working memory and inhibit pre-potent responses. Most importantly, regression analyses and mediation analyses measures showed that poor response inhibition and decision-making were associated with high NS behaviour. In addition, impaired decision-making and manipulation of stored information in working memory were associated with a high sensation-seeking trait. CONCLUSIONS: Overall, these results support the existence of specific links between cognitive executive functioning, decision-making under uncertainty and NS/sensation-seeking personality traits in individuals with alcoholism.

Cognitive impairment in fatigue and sleepiness associated conditions.

Although relating to very different concepts, sleepiness and fatigue are often confounded. However, both fatigue-associated conditions such as the chronic fatigue syndrome (CFS) and sleepiness-associated conditions such as the sleep apnea-hypopnea syndrome (SAHS) are associated with cognitive impairment with impaired attention, concentration and memory performances. Fifteen pure CFS patients, without primary sleep disorders or clinically relevant sleepiness, were compared to 15 untreated SAHS patients, without clinically relevant fatigue, and to 16 healthy controls of similar age. The auditory verbal learning test (AVLT), digit span, digit symbol and finger tapping test (FTT) were used as cognitive and behavioural measures. In addition we assessed daytime EEG spectral power and P300 evoked potentials. With exception for the digit span, all tests showed lower performances in patient groups. Recall on the AVLT did not differ between the two patient groups, but the digit and symbol spans showed more severe impairment in SAHS patients. Psychomotor performance on the FTT presented with slower hit rates in SAHS than in CFS. EEG theta power was highest in CFS patients. P300 latencies and amplitudes did not differ between groups. Fatigue- and sleepiness-associated conditions can both present with significant and objective impairment of cognitive functioning and behavioural motor performance. In our sample cognitive impairment and psychomotor performance were worse when associated to sleepiness in SAHS than with fatigue in CFS.

Clinical complaints of daytime sleepiness and fatigue: how to distinguish and treat them, especially when they become 'excessive' or 'chronic'?

Chronic daytime fatigue and excessive daytime sleepiness (EDS) are potentially invalidating and also common complaints in primary care and general neurological practice. The lack of distinction in the clinical use of terms like fatigue and sleepiness is an important issue. Although these semiological concepts present fundamental differences from physiological and pathological points of view, general medical literature still often confuses both symptoms. The objective of the present review is to contribute to the clinical distinction between fatigue and sleepiness and describe available measurement tools and respective treatment options. We found that sleepiness and fatigue both present with semiological multidimensionality and clinical complexity. Although relating to different underlying concepts, they can show overlapping features and several clinical conditions can present with both complaints simultaneously. Existing specific assessment tools are sometimes underutilised, causing EDS and fatigue to continue to be confounded. The blurring contributions of several studies are mainly due to the fact that typically only one of these two clinical dimensions is investigated. Despite consensus on objective sleepiness measures, simple and validated objective fatigue assessments are generally lacking and seem elusive. Causal and symptomatic treatment options exist predominantly for sleepiness-associated conditions. Although comprehension of sleepiness and its underlying physiology has seemed to improve over time, descriptions of common pathways of fatigue remain relatively incomplete. Clinical research and practice should systematically investigate both conditions with adequate measurement tools. Behavioural medicine is certainly underestimated, especially in the management of chronic daytime fatigue.

Do 'sleepy' and 'tired' go together? Rasch analysis of the relationships between sleepiness, fatigue and nonrestorative sleep complaints in a nonclinical population sample.

OBJECTIVE: The lack of distinction in the clinical use of terms like fatigue and sleepiness is an important issue. While both fatigue and sleepiness can potentially be associated with nonrestorative sleep (NRS) complaints, their relationships are still poorly described. We propose to use Rasch analysis-based methods to study the interrelations of fatigue, sleepiness and NRS. METHODS: 150 subjects (mean age = 39.3 years, range = 18-65) from a community sample underwent a structured computer-assisted web interview. We assessed demographic data, sleep habits, and subjective fatigue with the Fatigue Severity Scale (FSS), global and situational sleepiness with the Epworth Sleepiness (ESS) and the Stanford Sleepiness Scales, respectively, and affective symptoms with the Hospital Anxiety and Depression Scale. Dimensionality, measurement invariance and common person equating were investigated to study the FSS, ESS and their relations to NRS. RESULTS: NRS was linked to shorter habitual sleep duration and to higher scores on psychometric scales. Both sleepiness and daytime fatigue were positively correlated to each other and to the intensity of affective symptoms. Rasch analyses showed both the ESS and FSS to measure unidimensional concepts of sleepiness and fatigue, respectively. In contrast to the FSS, the ESS only showed partial invariance to an NRS complaint. Common person equating suggests that, despite similar Rasch-derived agreeability scores, fatigue and sleepiness (as measured by the FSS and ESS) nevertheless designate distinct constructs. CONCLUSION: NRS complaints can simultaneously present with higher daytime fatigue and sleepiness levels but the associative relationships between fatigue and sleepiness remain relatively unaffected by NRS. Although participants might not present adequate differentiation, fatigue and sleepiness seem to relate to different underlying concepts.

High slow-wave sleep and low-light sleep: chronic fatigue syndrome is not likely to be a primary sleep disorder.

The status of chronic fatigue syndrome (CFS) is still under debate. Mainstream views still often consider it as an undetected primary sleep disorder or as the psychosomatic expression of a related anxiety or depression syndrome. Both primary sleep disorder and CFS are often related to unrefreshing sleep and affective daytime symptoms. The present study compares nonrapid eye movement sleep distribution between patients with a primary sleep disorder and "pure" CFS patients without sleep or mood disorders. Intensity measures of affective symptoms are also analyzed. Sleep variables of 32 pure CFS (mean age, 41.9 +/- 8.7 years; 25 women), 30 Sleep Apnea Hypopnea Syndrome patients (mean age, 43.7 +/- 6.7 years; 13 women), and 14 healthy controls (mean age, 40.2 +/- 7.6 years; 9 women) were compared. Related affective symptoms were assessed using the self-reported Zung anxiety and depression scales. The study confirms previous reports on increased slow-wave sleep in CFS patients. Both patient groups showed similar sleep duration and efficiency. Sleep efficiency was lower in both patient groups compared with controls. CFS patients showed a higher microarousal index than controls. Anxiety, but not depression symptoms were more intense in the CFS group. The distribution of nonrapid eye movement sleep in CFS differs sizeably from what can be observed in a primary sleep disorder.

Relationships between the number of ultradian cycles and key sleep variables in outpatients with major depressive disorder.

The regulation of the alternation between rapid eye movement sleep (REMS) and non-rapid eye movement sleep (NREMS) is still a matter of much debate. It is also an important topic for psychiatric research, since both sleep components show anomalies in Major Depressive Disorders (MDD) and related syndromes. In previous studies on healthy controls, we showed preferential links of the number of ultradian cycles with REMS-related variables rather than with NREMS-related variables. REMS Latency (RL), for example, was shown to be inversely related to the number of cycles. The present study replicates these analyses in a group of 29 patients with MDD (age range: 23-56; 16 females), after two adaptation nights. Results showed significant correlations between the number of cycles and REMS, and between the number of cycles and RL, whereas correlations with NREMS were not significant. This indirectly supports regulation hypotheses considering REMS as the main focus of the oscillation, inhibiting and interrupting NREMS. Also, when the RL is shorter, there are more ultradian cycles than when the RL is long. This adds an interesting element in the elucidation of the physiological meaning of anomalies of RL.

Are patients with chronic fatigue syndrome just 'tired' or also 'sleepy'?

It is presently unclear whether chronic fatigue syndrome (CFS) patients exhibit daytime sleepiness in addition to fatigue. Both, fatigue, such as that seen in CFS patients, and excessive daytime sleepiness, such as in sleep apnea-hypopnea syndrome (SAHS), remain poorly understood. Both daytime conditions are generally related to unrefreshing sleep and show affective symptoms. This study's objective was to contribute to the understanding of the relationship between fatigue and sleepiness in CFS patients not co-morbid for primary sleep or psychiatric disorders. We compared 16 untreated CFS patients (mean age 32.8, all females) with 13 untreated SAHS (mean age 47.7, all females) patients and 12 healthy controls (mean age 32.2, all females). Objective sleepiness was measured using multiple sleep latency tests (MSLT). Subjective sleepiness and fatigue were assessed with the Epworth Sleepiness Scale and the Fatigue Severity Scale, respectively. Mean Sleep Latency (SL) on the MSLT was significantly shorter in SAHS patients than in CFS patients and CFS patients showed significantly shorter mean SL than matched controls but within normal range. Subjective sleepiness was greatest in SAHS patients and subjective fatigue was highest in CFS patients. Affective symptoms showed highest intensities in CFS patients. While higher than the control group on all measures, compared to SAHS, the CFS group had higher subjective fatigue and lower subjective and objective sleepiness. Despite possible overlap in symptoms and signs of both daytime conditions, our data indirectly support the clinical distinction between fatigue and sleepiness.

Sleep quality perception in the chronic fatigue syndrome: correlations with sleep efficiency, affective symptoms and intensity of fatigue.

BACKGROUND/AIMS: One of the core symptoms of the chronic fatigue syndrome (CFS) is unrefreshing sleep and a subjective sensation of poor sleep quality. Whether this perception can be expressed, in a standardized questionnaire as the Pittsburgh Sleep Quality Index (PSQI), has to our knowledge never been documented in CFS. Furthermore, correlations of subjective fatigue, PSQI, affective symptoms and objective parameters such as sleep efficiency are poorly described in the literature. METHODS: Using a cross-sectional paradigm, we studied subjective measures like PSQI, Fatigue Severity Scale scores and intensity of affective symptoms rated by the Hamilton Depression and Anxiety scales as well as objective sleep quality parameters measured by polysomnography of 28 'pure' (no primary sleep and no psychiatric disorders) CFS patients compared to age- and gender-matched healthy controls. RESULTS: The PSQI showed significantly poorer subjective sleep quality in CFS patients than in healthy controls. In contrast, objective sleep quality parameters, like the Sleep Efficiency Index (SEI) or the amount of slow-wave sleep did not differ significantly. Subjective sleep quality showed a correlation trend with severity of fatigue and was not correlated with the intensity of affective symptoms in CFS. CONCLUSION: Our findings indicate that a sleep quality misperception exists in CFS or that potential nocturnal neurophysiological disturbances involved in the nonrecovering sensation in CFS are not expressed by sleep variables such as the SEI or sleep stage distributions and proportions.

Major depression in males: effects of age, severity and adaptation on sleep variables.

Sleep abnormalities have been repeatedly demonstrated in major depression. However, the respective influences of age, severity, adaptation and gender have never been clearly disentangled. In a retrospective study, full polysomnograms of 67 male depressive patients and 67 carefully age-matched male healthy control subjects were analyzed. The usual differences associated with the sleep of depressed patients were observed. However, in contrast to most reports, REMS was also found to be reduced; although no comparisons between sexes can be made in this all-male study, one interpretation of this finding is that reduction of REMS is a marker of male depression. Age was found to influence most sleep variables, but not the order of their association with depression. Depression severity was found to be associated with Wake After Sleep Onset (WASO), REMS, and Non-REMS (NREMS). No residual adaptation effect was observed. One of the main markers of depression was in fact the absence of sleep, whether observed as long delays prior to entering sleep, or excessive intermittent awakenings. This sleep reduction affected both REMS and NREMS, in comparable percentages. This supports the hypothesis of a hyperarousal possibly linked to stress.