The Hierarchy of Coupled Sleep Oscillations Reverses with Aging in Humans.

A well orchestrated coupling hierarchy of slow waves and spindles during slow-wave sleep supports memory consolidation. In old age, the duration of slow-wave sleep and the number of coupling events decrease. The coupling hierarchy deteriorates, predicting memory loss and brain atrophy. Here, we investigate the dynamics of this physiological change in slow wave-spindle coupling in a frontocentral electroencephalography position in a large sample (N = 340; 237 females, 103 males) spanning most of the human life span (age range, 15-83 years). We find that, instead of changing abruptly, spindles gradually shift from being driven by slow waves to driving slow waves with age, reversing the coupling hierarchy typically seen in younger brains. Reversal was stronger the lower the slow-wave frequency, and starts around midlife (age range, ∼40-48 years), with an established reversed hierarchy between 56 and 83 years of age. Notably, coupling strength remains unaffected by age. In older adults, deteriorating slow wave-spindle coupling, measured using the phase slope index (PSI) and the number of coupling events, is associated with blood plasma glial fibrillary acidic protein levels, a marker for astrocyte activation. Data-driven models suggest that decreased sleep time and higher age lead to fewer coupling events, paralleled by increased astrocyte activation. Counterintuitively, astrocyte activation is associated with a backshift of the coupling hierarchy (PSI) toward a "younger" status along with increased coupling occurrence and strength, potentially suggesting compensatory processes. As the changes in coupling hierarchy occur gradually starting at midlife, we suggest there exists a sizable window of opportunity for early interventions to counteract undesirable trajectories associated with neurodegeneration.SIGNIFICANCE STATEMENT Evidence accumulates that sleep disturbances and cognitive decline are bidirectionally and causally linked, forming a vicious cycle. Improving sleep quality could break this cycle. One marker for sleep quality is a clear hierarchical structure of sleep oscillations. Previous studies showed that sleep oscillations decouple in old age. Here, we show that, rather, the hierarchical structure gradually shifts across the human life span and reverses in old age, while coupling strength remains unchanged. This shift is associated with markers for astrocyte activation in old age. The shifting hierarchy resembles brain maturation, plateau, and wear processes. This study furthers our comprehension of this important neurophysiological process and its dynamic evolution across the human life span.

Insomnia, poor sleep quality and perinatal suicidal risk: A systematic review and meta-analysis.

Suicidal risk in mothers is a public health priority. Risk factors include biological, psychological and psychosocial factors. Among the biological factors, the role of sleep disturbances as potential contributors to increased suicidal risk during the peripartum period is becoming apparent. To explore this further, we conducted a systematic review following the PRISMA criteria. Currently, 10 studies have examined the role of insomnia and poor sleep quality in suicidal risk during the peripartum period and have involved 807,760 women. The data showed that disturbed sleep and poor sleep quality increase the risk of suicidal ideation in both pregnant women with and without perinatal depression. The results of the meta-analysis indicated that insomnia and poor sleep quality increase the odds of suicidal risk in pregnant women by more than threefold (OR = 3.47; 95% CI: 2.63-4.57). Specifically, the odds ratio (OR) for poor sleep quality was 3.72 (95% CI: 2.58-5.34; p < 0.001), and for insomnia symptoms, after taking into account perinatal depression, was 4.76 (95% CI: 1.83-12.34; p < 0.001). These findings emphasise the importance of assessing and addressing sleep disturbances during the peripartum period to mitigate their adverse effects on peripartum psychopathology and suicidal risk.

Interactions between insomnia, sleep duration and emotional processes: An ecological momentary assessment of longitudinal influences combining self-report and physiological measures.

Previous studies indicated that further investigation is needed to understand how insomnia disorder interacts with emotional processes. The present study is an ecological momentary assessment evaluating the link between emotional and sleep alterations in patients with insomnia. Physiological (heart rate and heart rate variability) and subjective (sleep and emotions) indices were observed for 5 days in patients with insomnia disorder (n = 97), good sleepers under self-imposed sleep restriction (n = 41), and good sleepers with usual amount of sleep (n = 45). We evaluated differences in emotion regulation strategies and in valence and variability of emotional experiences. Over 5 days, patients with insomnia showed increased sleep and emotional difficulties compared with both control groups. Independent from group allocation, days with more negative emotions were associated with higher sleep alterations. Longer wake episodes at night and higher diurnal heart rate were associated with increased variations in emotion experienced during the day. Only in patients with insomnia, use of adaptive emotion regulation strategies was associated with higher sleep efficiency. Our data showed that alterations in sleep and emotional processes are closely linked. A combination of strategies targeting both sleep and emotional processes appears promising in the prevention and treatment of insomnia disorder.

Chronic insomnia, REM sleep instability and emotional dysregulation: A pathway to anxiety and depression?

The world-wide prevalence of insomnia disorder reaches up to 10% of the adult population. Women are more often afflicted than men, and insomnia disorder is a risk factor for somatic and mental illness, especially depression and anxiety disorders. Persistent hyperarousals at the cognitive, emotional, cortical and/or physiological levels are central to most theories regarding the pathophysiology of insomnia. Of the defining features of insomnia disorder, the discrepancy between minor objective polysomnographic alterations of sleep continuity and substantive subjective impairment in insomnia disorder remains enigmatic. Microstructural alterations, especially in rapid eye movement sleep ("rapid eye movement sleep instability"), might explain this mismatch between subjective and objective findings. As rapid eye movement sleep represents the most highly aroused brain state during sleep, it might be particularly prone to fragmentation in individuals with persistent hyperarousal. In consequence, mentation during rapid eye movement sleep may be toned more as conscious-like wake experience, reflecting pre-sleep concerns. It is suggested that this instability of rapid eye movement sleep is involved in the mismatch between subjective and objective measures of sleep in insomnia disorder. Furthermore, as rapid eye movement sleep has been linked in previous works to emotional processing, rapid eye movement sleep instability could play a central role in the close association between insomnia and depressive and anxiety disorders.

Digital cognitive behavioural therapy for insomnia reduces insomnia in nurses suffering from shift work disorder: A randomised-controlled pilot trial.

Insomnia is a primary symptom of shift work disorder, yet it remains undertreated. This randomised-controlled pilot trial examined the efficacy of a digital, guided cognitive behavioural therapy for insomnia adapted to shift work (SleepCare) in nurses with shift work disorder. The hypothesis was that SleepCare reduces insomnia severity compared with a waitlist control condition. A total of 46 unmedicated nurses suffering from shift work disorder with insomnia (age: 39.7 ± 12.1 years; 80.4% female) were randomised to the SleepCare group or the waitlist control group. The primary outcome measure was the Insomnia Severity Index. Other questionnaires on sleep, mental health and occupational functioning, sleep diary data and actigraphy data were analysed as secondary outcomes. Assessments were conducted before (T0), after the intervention/waitlist period (T1), and 6 months after treatment completion (T2). The SleepCare group showed a significant reduction in insomnia severity from T0 to T1 compared with the control condition (ß = -4.73, SE = 1.12, p < 0.001). Significant improvements were observed in sleepiness, dysfunctional beliefs about sleep, pre-sleep arousal, sleep effort, self-reported sleep efficiency and sleep onset latency. No significant effect was found in actigraphy data. Depressive and anxiety symptoms, cognitive irritation and work ability improved significantly. Overall, satisfaction and engagement with the intervention was high. SleepCare improved insomnia severity, sleep, mental health and occupational functioning. This is the first randomised-controlled trial investigating the efficacy of digital cognitive behavioural therapy for insomnia in a population suffering from shift work disorder with insomnia. Future research should further explore these effects with larger sample sizes and active control conditions.

Insomnia.

Insomnia is highly prevalent in clinical practice, occurring in up to 50% of primary care patients. Insomnia can present independently or alongside other medical conditions or mental health disorders and is a risk factor for the development and exacerbation of these other disorders if not treated. In 2016, the American College of Physicians recommended that insomnia be specifically targeted for treatment. The recommended first-line treatment for insomnia, whether the underlying cause has been identified or not, is cognitive behavioural therapy for insomnia (CBT-I). Currently, there is no global consensus regarding which pharmacological treatment has the best efficacy or risk-benefit ratio. Both CBT-I and pharmacological intervention are thought to have similar acute effects, but only CBT-I has shown durable long-term effects after treatment discontinuation. Administering a combined treatment of CBT-I and medication could decrease the latency to treatment response, but might diminish the durability of the positive treatment effects of CBT-I.

Hyperarousal in insomnia disorder: Current evidence and potential mechanisms.

Insomnia disorder is among the most frequent mental disorders, making research on its aetiology and pathophysiology particularly important. A unifying element of many aetiological and pathophysiological models is that they support or even centre on the role of some form of hyperarousal. In this theoretical review, we aim to summarise the current evidence on hyperarousal in insomnia. Hyperarousal is discussed as a state of relatively increased arousal in physiological, cortical and cognitive-emotional domains. Regarding physiological hyperarousal, there is no conclusive evidence for the involvement of autonomous variables such as heart rate and heart rate variability, whereas recent evidence points to a pathophysiological role of neuroendocrine variables. In addition, current literature supports a central involvement of cortical arousal, that is, high-frequency electroencephalographic activity. An increasingly important focus in the literature is on the role of other microstructural sleep parameters, especially the existence of microarousals during sleep. Beyond that, a broad range of evidence exists supporting the role of cognitive-emotional hyperarousal in the form of insomnia-related thought and worries, and their concomitant emotional symptoms. Besides being a state marker of insomnia, hyperarousal is considered crucial for the predisposition to insomnia and for the development of comorbid mental disorders. Thus, beyond presenting evidence from cross-sectional studies on markers of hyperarousal in insomnia, hypotheses about the mechanisms of hyperarousal are presented. Nevertheless, longitudinal studies are needed to further elucidate the mechanism of hyperarousal throughout the course of the disorder, and future studies should also focus on similarities and differences in hyperarousal across different diagnostic entities.

Sleep quality in persons with mental disorders: Changes during inpatient treatment across 10 diagnostic groups.

Sleep disturbances have been documented across a range of mental disorders, particularly depression. However, studies that have examined sleep quality in large samples of different diagnostic groups and that report how sleep quality changes during inpatient treatment have been scarce. This retrospective, observational study examined changes in sleep quality during inpatient treatment at a psychosomatic hospital in Germany from admission to discharge as a function of 10 diagnostic groups. Data of 11,226 inpatients were analysed who completed the Pittsburgh Sleep Quality Index as part of the routine diagnostic assessment at admission and discharge. All diagnostic groups showed impaired sleep quality (Pittsburgh Sleep Quality Index score > 5). Patients with trauma-related disorders had the lowest sleep quality and patients with obsessive-compulsive disorder had the highest sleep quality. While sleep quality significantly improved in each diagnostic group, changes differed in size, with patients with trauma-related disorders showing the smallest improvement and patients with eating disorders showing the largest improvement. The current study documents impaired sleep quality in inpatients with mental disorders and shows that sleep problems are a transdiagnostic feature in this population. Results also resonate with earlier suggestions that sleep disturbances represent a key feature of trauma-related disorders in particular and the need for trauma-specific sleep interventions. Although sleep quality significantly improved during disorder-specific inpatient treatment in all diagnostic groups, average scores were still clinically elevated at discharge. Thus, a future avenue would be to examine whether adding sleep-specific treatment elements fosters both short- and long-term success in the treatment of mental disorders.

Cognitive behavioural therapy to treat stress and insomnia: A randomized wait list-controlled trial of two online courses.

This randomized, wait list-controlled trial aimed to evaluate the efficacy of the cognitive behavioural therapy-based online e-learning course stressfit for better stress management and the cognitive behavioural therapy for insomnia-based online course SweetDreams for coping with insomniac problems. The course modules offer state of the art psychoeducation and cognitive behavioural strategies concerning different aspects of stress, sleep and insomnia. They provide practice-oriented exercises for self-reflection, as well as a variety of evidence-based methods and measures to increase self-efficacy when dealing with stress or insomnia. Study participants were randomly assigned to the three test conditions stressfit, SweetDreams or a wait list. Participants filled in questionnaires on a wide range of scales relevant to stress and insomnia at three points in time (before, 4 weeks after, and 3 months after the treatment). Of the 588 participants in total, data from 347 participants (59%) were finally included in the data analyses. Data analyses showed that both courses yielded significant positive effects compared with the wait list condition 4 weeks and to some degree 3 months after completion in relation to insomnia symptoms, physical and psychological wellbeing, life satisfaction and general health (General Health Questionnaire), as well as on satisfaction with and effectiveness of coping with stress and sleep disorders. In conclusion, SweetDreams and stressfit proved to be feasible and effective online cognitive behavioural therapy (for insomnia) tools to reduce insomnia and stress symptoms on a broad variety of scales at the 4-weeks measurement point as well as at the 3-months follow-up.

Insomnia and REM sleep instability.

In this narrative review, we give an overview of the concept of rapid eye movement sleep instability and its reported implications in the context of insomnia. The term rapid eye movement sleep instability was coined to describe the observation of a modified rapid eye movement quality in insomnia, characterized by an increased tendency of perceiving rapid eye movement sleep as wake, a small but consistent rapid eye movement sleep reduction and an increased rapid eye movement sleep arousal index. Current research highlights relationships that are transdiagnostic in nature, corresponding to the known interaction of insomnia with many psychiatric disorders, and showing relationships to chronic stress and anxiety disorders.

How to deal with sleep problems during heatwaves: practical recommendations from the European Insomnia Network.

Heatwaves are occurring more frequently and are known to affect particularly night-time temperatures. We review here literature on how night-time ambient temperature changes affect body temperature and sleep quality. We then discuss how these temperature effects impact particularly vulnerable populations such as older adults, children, pregnant women, and those with psychiatric conditions. Several ways of dealing with sleep problems in the context of heatwaves are then suggested, adapted from elements of cognitive behavioural therapy for insomnia, with more specific advice for vulnerable populations. By better dealing with sleep problems during heatwaves, general health effects of heatwaves may be more limited. However, given the sparse literature, many links addressed in this review on sleep problems affected by temperature changes should be the focus of future research.

Cognitive behavioural therapy for insomnia disorder: Extending the stepped care model.

Despite cognitive behaviour therapy for insomnia (CBT-I) being the first-line intervention for the disorder, it is often not readily available to patients in need. The stepped care model (SCM) represents an approach to facilitating efficient and wide-ranging provision of evidence-based care to those with insomnia. The SCM reflects a pyramid of therapeutics based on CBT-I gradually increasing in clinical intensity and addressing clinical complexity. By applying CBT-I through the SCM it is hoped that the treatment gap can be bridged such that not only more patients can be reached, but that clinical resource can be more effectively distributed, with patients receiving more tailored care as needed. Nevertheless, this should not be done at the risk of a lower quality of care being offered, and high-standard training for clinicians and scrutiny of non-clinician led interventions remains important. As national health laws within European countries have substantial differences, the application of the SCM as it relates to the treatment of insomnia may be challenged by contrasting interpretations. In order that the SCM is appropriately implemented: (a) only evidence-based CBT-I treatments should be promoted within the model; (b) clinicians involved in SCM should be suitably qualified to offer CBT in general, and have appropriate further training in CBT-I; (c) professionals involved in interventions not included in the SCM, but related to it, such as preventive and educational programmes, diagnostic procedures, and pharmacological treatments, should also have good knowledge of the SCM in order to promote correct allocation to the appropriate interventional step.

How many hours do you sleep? A comparison of subjective and objective sleep duration measures in a sample of insomnia patients and good sleepers.

Our objective was to assess the agreement and linear relationships amongst multiple measures of sleep duration in a sample of patients with insomnia disorder and good sleeper controls. We retrospectively analysed data from 123 patients with insomnia disorder and 123 age- and gender-matched good sleeper controls who completed a simple subjective habitual sleep duration question (Pittsburgh Sleep Quality Index), a sleep diary (5-14 days), 2 nights of polysomnography, and two corresponding morning subjective estimates of sleep duration. Descriptive statistics, linear regression analyses and Bland-Altman plots were used to describe the relationship and (dis)agreement between sleep duration measures. Relationships between polysomnography and the simple question as well as between polysomnography and sleep diary were weak to non-existent. Subjective measures and polysomnography did not agree. Sleep duration measured with the Pittsburgh Sleep Quality Index or sleep diary was about 2 hr above or up to 4 hr below polysomnography-measured sleep duration. Patients with insomnia disorder, on average, reported shorter sleep duration compared with polysomnography, while good sleeper controls, on average, reported longer sleep duration compared with polysomnography. The results suggest that subjective and objective measures apparently capture different aspects of sleep, even when nominally addressing the same value (sleep duration). They disagree in both patients with insomnia disorder and good sleeper controls, but in different directions. Studies assessing sleep duration should take into account both the investigated population and the assessment method when interpreting results. Future studies should continue to investigate possible psychological and physiological correlates of sleep (mis)perception.

On the relationship between EEG spectral analysis and pre-sleep cognitive arousal in insomnia disorder: towards an integrated model of cognitive and cortical arousal.

According to the hyperarousal model, insomnia is characterised by increased arousal in the cortical, cognitive, and physiological domains. However, the interaction between these arousal domains is poorly understood. The present observational case-control study aimed to investigate cortical arousal during the night, pre-sleep cognitive arousal and the relationship between these two domains. A total of 109 patients with insomnia disorder (ID) and 109 age-and gender matched healthy controls were investigated on two sleep laboratory nights. Electroencephalographic (EEG) spectral power during non-rapid eye movement (NREM) and REM sleep was analysed as a measure of cortical arousal. In addition, patients completed the Pre-Sleep Arousal Scale (PSAS), which consists of two subscales, one for cognitive arousal (PSAS-CA) and one for self-reported somatic arousal (PSAS-SA). The relationship between the subscale scores and EEG spectral power was calculated by multi- and univariate analyses of variance. During NREM and REM sleep, patients with ID showed significantly increased spectral power in the EEG gamma band. In addition, patients with ID showed significantly increased scores on both subscales of the PSAS. The PSAS-CA score was significantly associated with increased NREM and REM gamma power, whereas PSAS-SA was associated with decreases in NREM and REM gamma power. Consistent with our hypothesis, patients with ID showed increased cortical and cognitive arousal. Moreover, there was an association between these two arousal domains, which may indicate that cortical arousal during the night is (at least in part) elicited by pre-sleep worry and rumination.

Potential genetic and epigenetic mechanisms in insomnia: A systematic review.

Insomnia is a stress-related sleep disorder conceptualised within a diathesis-stress framework, which it is thought to result from predisposing factors interacting with precipitating stressful events that trigger the development of insomnia. Among predisposing factors genetics and epigenetics may play a role. A systematic review of the current evidence for the genetic and epigenetic basis of insomnia was conducted according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) system. A total of 24 studies were collected for twins and family heritability, 55 for genome-wide association studies, 26 about candidate genes for insomnia, and eight for epigenetics. Data showed that insomnia is a complex polygenic stress-related disorder, and it is likely to be caused by a synergy of genetic and environmental factors, with stress-related sleep reactivity being the important trait. Even if few studies have been conducted to date on insomnia, epigenetics may be the framework to understand long-lasting consequences of the interaction between genetic and environmental factors and effects of stress on the brain in insomnia. Interestingly, polygenic risk for insomnia has been causally linked to different mental and medical disorders. Probably, by treating insomnia it would be possible to intervene on the effect of stress on the brain and prevent some medical and mental conditions.

Adherence to sleep restriction therapy - An evaluation of existing measures.

Sleep restriction, a key element of cognitive behavioural therapy for insomnia, involves considerable behavioural changes in patients' lives, leading to side-effects like increased daytime sleepiness. Studies on sleep restriction rarely report adherence, and when assessed it is often limited to the average number of therapy sessions attended. This study aims to systematically evaluate different measures of adherence to cognitive behavioural therapy for insomnia and their relationship with treatment outcome. This is a secondary analysis of data from a randomized controlled trial investigating cognitive behavioural therapy for insomnia (Johann et al. (2020) Journal of Sleep Research, 29, e13102). The sample included 23 patients diagnosed with insomnia according to DSM-5 criteria who underwent 8 weeks of cognitive behavioural therapy for insomnia. The following adherence measures based on sleep diary data were used: number of sessions completed; deviations from agreed time in bed; average percentage of patients deviating from bedtime by 15, 30 or 60 min; variability of bedtime and wake-up time; change in time in bed from pre- to post-assessment. Treatment outcome was assessed using the Insomnia Severity Index. Multiple regression models were employed, and insomnia severity was controlled for. Results showed that none of the adherence measures predict insomnia severity. Baseline insomnia severity, dysfunctional thoughts and attitudes about sleep, depression or perfectionism did not predict adherence. The limited variance in the outcome parameter due to most patients benefiting from treatment and the small sample size may explain these findings. Additionally, using objective measures like actigraphy could provide a better understanding of adherence behaviour. Lastly, the presence of perfectionism in patients with insomnia may have mitigated adherence problems in this study.

Comparative short-term safety and efficacy of hypnotics: A quantitative risk-benefit analysis.

Several professional societies have provided recommendations for prescribing medications for insomnia. None has provided an integrative analysis that concurrently quantifies safety and efficacy (e.g., risk-benefit ratios). This represents an important gap for informing clinician decision-making. Accordingly, the aim of the present review is to provide such an analysis for five classes of sleep-promoting medications. Adverse event data values were extracted from the most recent FDA-approved package inserts and converted to an integer before being placebo-adjusted and standardized as a rate per 1000 (AEr). Efficacy data, pre-to-post self-reported data for active and placebo conditions were acquired from pivotal trials identified in "white papers" and systematic reviews/meta-analyses. Weighted effect sizes were calculated for subjective sleep latency, wake time after sleep onset and total sleep time, and then were averaged by medication class for each sleep continuity variable. Overall efficacy was represented by a single variable, SWT (sleep latency + wake time after sleep onset + total sleep time). Risk-benefit was represented using a simple ratio value. For safety, it was found that melatonin receptor agonists had the lowest adverse event rate (AEr = 43.1), and non-benzodiazepine benzodiazepine receptor agonists had the highest rate (AEr = 255.0). For efficacy, it was found that the pre-to-post placebo adjusted effect sizes were largest for benzodiazepines (effect size = 1.94) and smallest for melatonin receptor agonists (effect size = 0.109). For risk-benefit, histamine antagonist had the most favourable profile (risk-benefit = 69.5), while melatonin receptor agonist had the least favourable profile (risk-benefit = 395.7). Overall, the combined metric for risk-benefit suggests that treatment with a histamine antagonist is optimal and potentially represents the best first-line therapy for the medical management of insomnia.

Associations between insomnia symptoms and functional connectivity in the UK Biobank cohort (n = 29,423).

An increasing number of studies harness resting-state fMRI functional connectivity analysis to investigate the neurobiological mechanisms of insomnia. The results to date are inconsistent and the detection of minor and widely distributed alterations in functional connectivity requires large sample sizes. The present study investigated associations between insomnia symptoms and resting-state functional connectivity at the whole-brain level in the largest sample to date. This cross-sectional analysis used resting-state imaging data from the UK Biobank, a large scale, population-based biomedical database. The analysis included 29,423 participants (age: 63.1 ± 7.5 years, 54.3% female), comprising 9210 with frequent insomnia symptoms and 20,213 controls without. Linear models were adjusted for relevant clinical, imaging, and socio-demographic variables. The Akaike information criterion was used for model selection. Multiple comparisons were corrected using the false discovery rate with a significance level of q < 0.05. Frequent insomnia symptoms were associated with increased connectivity within the default mode network and frontoparietal network, increased negative connectivity between the default mode network and the frontoparietal network, and decreased connectivity between the salience network and a node of the default mode network. Furthermore, frequent insomnia symptoms were associated with altered functional connectivity between nodes comprising sensory areas and the cerebellum. These functional alterations of brain networks may underlie dysfunctional affective and cognitive processing in insomnia and contribute to subjectively and objectively impaired sleep. However, it must be noted that the item that was used to assess frequent insomnia symptoms in this study did not assess all the characteristics of clinically diagnosed insomnia.

No alterations in potential indirect markers of locus coeruleus-norepinephrine function in insomnia disorder.

The norepinephrine locus coeruleus system (LC NE) represents a promising treatment target in patients with insomnia disorder (ID) due to its well understood links to arousal and sleep regulation. However, consistent markers of LC NE activity are lacking. This study measured three potential indirect markers of LC NE activity - REM sleep, P3 amplitude during an auditory oddball paradigm (as a marker of phasic LC activation), and baseline pupil diameter (as a marker of tonic LC activation). The parameters were then combined in a statistical model and tested to compare LC NE activity between 20 subjects with insomnia disorder (13 female; age 44.2 ± 15.1 year) and 20 healthy, good sleeping controls (GSC; 11 female; age 45.4 ± 11.6 year). No group differences regarding the primary outcome parameters were detected. Specifically, insomnia disorder did not display the hypothesised changes in markers of LC NE function. While increased LC NE function remains an interesting speculative pathway for hyperarousal in insomnia disorder, the investigated markers do not appear closely related to each other and fail to discriminate between insomnia disorder and good sleeping controls in these samples.

Current models of insomnia disorder: a theoretical review on the potential role of the orexinergic pathway with implications for insomnia treatment.

Insomnia disorder is considered as a stress-related disorder associated with hyperarousal, stress and emotion dysregulation and the instability of the 'flip-flop' switch system. The orexinergic system is well known for its key role in sleep and arousal processes but also in the allostatic system regulating stress and emotions and may thus be of major interest for insomnia and its treatment. Accordingly, we discuss the potential role of orexins on sleep processes, brain systems modulating stress and emotions with potential implications for insomnia pathophysiology. We reviewed available data on the effect of dual orexin receptor antagonists (DORAs) on sleep and brain systems modulating stress/emotions with implications for insomnia treatment. We present our findings as a narrative review. Few data in animals and humans have reported that disrupted sleep and insomnia may be related to the overactivation of orexinergic system, while some more consistent data in humans and animals reported the overactivation of orexins in response to acute stress and in stress-related disorders. Taken together these findings may let us hypothesise that an orexins overactivation may be associated with stress-related hyperarousal and the hyperactivation of arousal-promoting systems in insomnia. On the other hand, it is possible that by rebalancing orexins with DORAs we may regulate both sleep and allostatic systems, in turn, contributing to a 'switch off' of hyperarousal in insomnia. Nevertheless, more studies are needed to clarify the role of the orexin system in insomnia and to evaluate the effects of DORAs on sleep, stress and emotions regulating systems.