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.

Acceptance and Commitment Therapy, Combined with Bedtime Restriction, versus Cognitive Behavioral Therapy for Insomnia: A Randomized Controlled Pilot Trial.

INTRODUCTION: Cognitive behavioral therapy for insomnia (CBT-I) is the current first-line treatment for insomnia. However, rates of nonresponse and nonremission are high and effects on quality of life are only small to moderate, indicating a need for novel treatment developments. We propose that Acceptance and Commitment Therapy (ACT) addresses core pathophysiological pathways of insomnia. ACT therefore has the potential to improve treatment efficacy when combined with bedtime restriction, the most effective component of CBT-I. The aim of this study was to compare the efficacy of ACT for insomnia combined with bedtime restriction (ACT-I) and CBT-I in improving insomnia severity and sleep-related quality of life. METHODS: Sixty-three patients with insomnia disorder (mean age 52 years, 65% female, 35% male) were randomly assigned to receive either ACT-I or CBT-I in a group format. The primary outcomes were insomnia severity (Insomnia Severity Index) and sleep-related quality of life (Glasgow Sleep Impact Index). Outcomes were assessed before randomization (T0), directly after treatment (T1), and at 6-month follow-up (T2). RESULTS: The results indicated significant, large pre-to-post improvements in both groups, for both primary and secondary outcomes. Improvements were maintained at the 6-month follow-up. However, there was no significant group by time interactions in linear mixed models, indicating an absence of differential efficacy. On a subjective treatment satisfaction scale, patients in the ACT-I group indicated significantly greater satisfaction with their improvement of several aspects of health including their energy level and work productivity. CONCLUSIONS: The results suggest that ACT-I is feasible and effective, but not more effective than CBT-I for the improvement of insomnia severity and sleep-related quality of life. Future studies are needed to assess whether ACT-I is noninferior to CBT-I and to shed light on mechanisms of change in both treatments.

The European Insomnia Guideline: An update on the diagnosis and treatment of insomnia 2023.

Progress in the field of insomnia since 2017 necessitated this update of the European Insomnia Guideline. Recommendations for the diagnostic procedure for insomnia and its comorbidities are: clinical interview (encompassing sleep and medical history); the use of sleep questionnaires and diaries (and physical examination and additional measures where indicated) (A). Actigraphy is not recommended for the routine evaluation of insomnia (C), but may be useful for differential-diagnostic purposes (A). Polysomnography should be used to evaluate other sleep disorders if suspected (i.e. periodic limb movement disorder, sleep-related breathing disorders, etc.), treatment-resistant insomnia (A) and for other indications (B). Cognitive-behavioural therapy for insomnia is recommended as the first-line treatment for chronic insomnia in adults of any age (including patients with comorbidities), either applied in-person or digitally (A). When cognitive-behavioural therapy for insomnia is not sufficiently effective, a pharmacological intervention can be offered (A). Benzodiazepines (A), benzodiazepine receptor agonists (A), daridorexant (A) and low-dose sedating antidepressants (B) can be used for the short-term treatment of insomnia (≤ 4 weeks). Longer-term treatment with these substances may be initiated in some cases, considering advantages and disadvantages (B). Orexin receptor antagonists can be used for periods of up to 3 months or longer in some cases (A). Prolonged-release melatonin can be used for up to 3 months in patients ≥ 55 years (B). Antihistaminergic drugs, antipsychotics, fast-release melatonin, ramelteon and phytotherapeutics are not recommended for insomnia treatment (A). Light therapy and exercise interventions may be useful as adjunct therapies to cognitive-behavioural therapy for insomnia (B).

[Insomnia]. / Insomnie.

Patients with insomnia suffer from problems falling asleep and/or maintaining sleep. This has a negative effect on their daytime wellbeing and performance. Insomnia is primarily diagnosed by a detailed clinical history, supplemented by questionnaires and sleep diaries. Polysomnography may be necessary for the differential diagnosis of organic sleep disorders. Insomnia is a frequent comorbidity of most mental disorders and many physical diseases. It is treated according to guidelines with cognitive behavioural therapy for insomnia (CBT-I). CBT-I is offered in individual or group format as well as online-supported treatment. If behavioural therapy is not effective or not available, pharmacotherapy can be discussed.

Brain-derived neurotrophic factor genetic polymorphism rs6265 and creativity.

The protein brain-derived neurotrophic factor (BDNF) promotes neural plasticity of the central nervous system and plays an important role for learning and memory. A single nucleotide polymorphism (rs6265) at position 66 in the pro-region of the human BDNF gene, resulting in a substitution of the amino acid valine (val) with methionine (met), leads to attenuated BDNF secretion and has been associated with reduced neurocognitive function. Inhomogeneous results have been found regarding the effect of the BDNF genotype on behavior. We determined the BDNF genotype and performance on the Compound Remote Associate (CRA) task as a common measure of creativity in 76 healthy university students. In our main analyses, we did not find significant differences between met-carriers (n = 30) and non-met carriers (n = 46). In a secondary analysis, we found that met-carriers had a slower solution time (medium effect size) for items of medium difficulty. Our results suggest that met-carriers and non-met-carriers do not generally differ regarding their creativity, but non-met-carriers may have a certain advantage when it comes to moderately difficult problems. The wider literature suggests that both genetic variants come with advantages and disadvantages. Future research needs to sharpen our understanding of the disadvantages and, potentially, advantages met allele carriers may have.

Cognitive behavioural therapy for insomnia in inpatient psychiatric care: a systematic review.

Insomnia is highly prevalent among patients with psychiatric disorders. According to current guidelines, cognitive behavioural therapy for insomnia (CBT-I) represents the first-line treatment for chronic insomnia, also for patients with psychiatric comorbidity. While recent studies have demonstrated that CBT-I not only improves insomnia but also other health outcomes in patients with psychiatric disorders and comorbid insomnia in outpatient settings, the level of implementation and treatment potential of CBT-I in inpatient psychiatry is less clear. The objective of this systematic review is to present and discuss studies that have adapted CBT-I for inpatient psychiatric care. PubMed, Cumulative Index to Nursing and Allied Health Literature (CINAHL) and PsycINFO, were searched until June 2023. A total of 10 studies were identified, with the majority being non-randomised trials without comparison groups and small sample sizes. With preliminary character, studies report feasibility and potential efficacy in inpatient settings. Together, this review identifies a paucity of studies on CBT-I or derivates in inpatient psychiatry. Despite challenging in this setting, studies adapting CBT-I to the needs of severely ill patients and hospital settings might have the potential to improve mental health care.

[Insomnia in psychiatry and psychotherapy]. / Insomnie en psychiatrie et psychothérapie.

Insomnia disorder is characterized by disturbed sleep continuity and associated daytime impairment. Insomnia is frequent in patients with psychiatric disorders ; 30-40% fulfill the criteria for insomnia disorder as a comorbidity. According to current guidelines, cognitive behavioral therapy for insomnia (CBT-I) is the first-line treatment, comprising sleep education, bedtime restriction, relaxation and cognitive restructuring. Despite guideline recommendations, CBT-I is insufficiently implemented, and insomnia is frequently over-treated with hypnotics. 'Become your own SLEEPexpert' is a behavioral treatment program based on CBT-I with the aim of empowering patients to take care of their own sleep health.

L'insomnie est un trouble de la continuité du sommeil et des troubles diurnes associés. Les symptômes sont fréquents chez les patients souffrant de troubles psychiatriques ; 30 à 40 % d'entre eux remplissant les critères du trouble de l'insomnie en tant que comorbidité. Selon les directives internationales, la thérapie cognitivo-comportementale de l'insomnie (TCC-I) est le traitement de première intention, comprenant l'éducation, la restriction du temps passé au lit, la relaxation et la restructuration cognitive. Malgré les recommandations, la TCC-I n'est pas suffisamment mise en œuvre et l'insomnie est souvent surtraitée avec des hypnotiques. « Become your own SLEEPexpert ¼ est un programme comportemental basé sur la TCC-I, dont l'objectif est de permettre aux patients de prendre en charge leur propre santé du sommeil.

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 symptoms as risk factor for somatic disorders: An umbrella review of systematic reviews and meta-analyses.

The objective of this umbrella review is to present a comprehensive summary of systematic reviews and meta-analyses on the longitudinal association between insomnia and the risk of developing somatic disorders. Pubmed, Medline, CINAHL, PsycInfo and PsycArticles were searched until 16 December 2022. Fourteen systematic reviews and meta-analyses met the inclusion criteria. Results suggest that insomnia symptoms (i.e. aspects of disturbed sleep continuity as a single symptom) convey a risk factor for cardiovascular diseases, hypertension and thyroid cancer. The presence of insomnia symptoms may also enhance the risk for obesity, cognitive decline and dementia-however, results are contradictory and not conclusive here. Results do not suggest an association between insomnia symptoms and mortality. No conclusions can be drawn regarding insomnia disorder because the reviews did not ensure a valid diagnosis. It remains unclear what proportion of participants with insomnia symptoms fulfil diagnostic criteria for insomnia disorder and/or suffer from an organic sleep disorder such as sleep-related breathing disorder. Moreover, most of the included reviews were assessed to have critically low confidence according to the AMSTAR-2 tool. Inconsistent definitions of insomnia and methodological unclarities further underline that results should be interpreted with caution. There is a need for future longitudinal studies that focus on a careful definition and differential diagnosis of both insomnia and the outcome.

Insomnia-A risk factor for mental disorders.

Longitudinal studies observed that individuals suffering from insomnia disorder have a higher vulnerability to develop symptoms of psychopathology compared with good sleepers. Particularly, insomnia disorder has been associated with an increased risk for depression. Previous studies indicate relatively stable effects; however, replication is needed as the last meta-analysis on the topic has been published 4 years ago. We conducted a replication of a previous systematic review and meta-analysis evaluating the longitudinal association between insomnia disorder and psychopathology, including original works published between 2018 and 2022. Literature search was conducted from April 2018 to August 2022 using key words identifying longitudinal studies that evaluate individuals with insomnia disorder compared with good sleepers at baseline, and the onset of all possible mental disorders at long-term follow-up. Only one work was added to the previous sample of studies published in 2019 looking at the longitudinal association between insomnia disorder and depression. Meta-analytic results confirmed the previous observation, with an even higher observed effect for the link between insomnia and depression. This again recognizes insomnia disorder as a possible transdiagnostic process in psychopathology, with consequent important clinical implications. Nevertheless, more longitudinal studies are needed evaluating the link between insomnia disorder and mental disorders.

The Effects of Cognitive Behavioral Therapy for Insomnia on Multidimensional Perfectionism.

Perfectionism is related to insomnia and objective markers of disturbed sleep. This study examined whether multidimensional perfectionism is related to dysfunctional beliefs about sleep, sleep-effort, pre-sleep arousal, and polysomnography-determined markers of sleep among individuals with insomnia. The effects of cognitive behavioral therapy for insomnia (CBT-I) on perfectionism was also examined. This was a secondary analysis of a randomized controlled trial on CBT-I. Forty-three insomnia patients were randomized to treatment (receiving CBT-I) or waitlist control groups. Sleep was recorded using polysomnography at baseline. Participants completed measures of perfectionism, dysfunctional beliefs about sleep, sleep-effort and pre-sleep arousal at baseline and posttreatment. Total perfectionism scores and doubts about action, concern over mistakes and personal standards were each significantly related to increased sleep effort, pre-sleep arousal and dysfunctional beliefs about sleep at baseline. Patients receiving treatment displayed increased total perfectionism scores posttreatment d = .49. In those receiving treatment, levels of organization d = .49 and parental expectations d = .47 were significantly increased posttreatment, relative to baseline. In line with the literature, our results confirm that perfectionism is related to insomnia. Here, insomnia was related to increased sleep effort, pre-sleep arousal and dysfunctional beliefs about sleep. The propensity to maintain a high standard of order and organization may be elevated following CBT-I, considering the treatment protocol expects patients to strictly adhere to a set of clearly defined rules. Levels of parental expectations may be increased following CBT-I since the patient-therapist-relationship may trigger implicit expectations in patients which are reminiscent of their relationship to their parents.

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

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

Sleep, insomnia and mental health.

While sleep serves important regulatory functions for mental health, sleep disturbances, in particular insomnia, may favour a state of allostatic overload impairing brain neuroplasticity and stress immune pathways, hence contributing to mental disorders. In this framework, the aim of this work was to link current understanding about insomnia mechanisms with current knowledge about mental health dysregulatory mechanisms. The focus of the present work was on mood, anxiety, and psychotic disorders, which represent important challenges in clinical practice. Literature searches were conducted on clinical, neurobiological, and therapeutic implications for insomnia comorbid with these mental disorders. Given the complexity and heterogeneity of the existing literature, we ended up with a narrative review. Insomnia may play an important role as a risk factor, a comorbid condition and transdiagnostic symptom for many mental disorders including mood/anxiety disorders and schizophrenia. Insomnia may also play a role as a marker of disrupted neuroplasticity contributing to dysregulation of different neurobiological mechanisms involved in these different mental conditions. In this framework, insomnia treatment may not only foster normal sleep processes but also the stress system, neuroinflammation and brain plasticity. Insomnia treatment may play an important preventive and neuroprotective role with cognitive behavioural therapy for insomnia being the treatment with important new evidence of efficacy for insomnia, psychopathology, and indices of disrupted neuroplasticity. On the other hand, pharmacological pathways for insomnia treatment in these mental conditions are still not well defined. Therapeutic options acting on melatonergic systems and new therapeutic options acting on orexinergic systems may represents interesting pathways of interventions that may open new windows on insomnia treatment in mental disorders.

Cognitive behavioral therapy for insomnia in patients with mental disorders and comorbid insomnia: A systematic review and meta-analysis.

Almost 70% of patients with mental disorders report sleep difficulties and 30% fulfill the criteria for insomnia disorder. Cognitive behavioral therapy for insomnia (CBT-I) is the first-line treatment for insomnia according to current treatment guidelines. Despite this circumstance, insomnia is frequently treated only pharmacologically especially in patients with mental disorders. The aim of the present meta-analysis was to quantify the effects of CBT-I in patients with mental disorders and comorbid insomnia on two outcome parameters: the severity of insomnia and mental health. The databases PubMed, CINHAL (Ebsco) und PsycINFO (Ovid) were searched for randomized controlled trials on adult patients with comorbid insomnia and any mental disorder comparing CBT-I to placebo, waitlist or treatment as usual using self-rating questionnaires as outcomes for either insomnia or mental health or both. The search resulted in 1994 records after duplicate removal of which 22 fulfilled the inclusion criteria and were included for the meta-analysis. The comorbidities were depression (eight studies, 491 patients), post-traumatic stress disorder (PTSD, four studies, 216 patients), alcohol dependency (three studies, 79 patients), bipolar disorder (one study, 58 patients), psychosis (one study, 50 patients) and mixed comorbidities within one study (five studies, 189 patients). The effect sizes for the reduction of insomnia severity post treatment were 0.5 (confidence interval, CI, 0.3-0.8) for patients with depression, 1.5 (CI 1.0-1.9) for patients with PTSD, 1.4 (CI 0.9-1.9) for patients with alcohol dependency, 1.2 (CI 0.8-1.7) for patients with psychosis/bipolar disorder, and 0.8 (CI 0.1-1.6) for patients with mixed comorbidities. Effect sizes for the reduction of insomnia severity were moderate to large at follow-up. Regarding the effects on comorbid symptom severity, effect sizes directly after treatment were 0.5 (CI 0.1-0.8) for depression, 1.3 (CI 0.6-1.9) for PTSD, 0.9 (CI 0.3-1.4) for alcohol dependency in only one study, 0.3 (CI -0.1 - 0.7, insignificant) for psychosis/bipolar, and 0.8 (CI 0.1-1.5) for mixed comorbidities. There were no significant effects on comorbid symptoms at follow-up. Together, these significant, stable medium to large effects indicate that CBT-I is an effective treatment for patients with insomnia and a comorbid mental disorder, especially depression, PTSD and alcohol dependency. CBT-I is also an effective add-on treatment with the aim of improving mental health in patients with depression, PTSD, and symptom severity in outpatients with mixed diagnoses. Thus, in patients with mental disorders and comorbid insomnia, given the many side effects of medication, CBT-I should be considered as a first-line treatment.

Co-ordination of brain and heart oscillations during non-rapid eye movement sleep.

Oscillatory activities of the brain and heart show a strong variation across wakefulness and sleep. Separate lines of research indicate that non-rapid eye movement (NREM) sleep is characterised by electroencephalographic slow oscillations (SO), sleep spindles, and phase-amplitude coupling of these oscillations (SO-spindle coupling), as well as an increase in high-frequency heart rate variability (HF-HRV), reflecting enhanced parasympathetic activity. The present study aimed to investigate further the potential coordination between brain and heart oscillations during NREM sleep. Data were derived from one sleep laboratory night with polysomnographic monitoring in 45 healthy participants (22 male, 23 female; mean age 37 years). The associations between the strength (modulation index [MI]) and phase direction of SO-spindle coupling (circular measure) and HF-HRV during NREM sleep were investigated using linear modelling. First, a significant SO-spindle coupling (MI) was observed for all participants during NREM sleep, with spindle peaks preferentially occurring during the SO upstate (phase direction). Second, linear model analyses of NREM sleep showed a significant relationship between the MI and HF-HRV (F = 20.1, r2  = 0.30, p < 0.001) and a tentative circular-linear correlation between phase direction and HF-HRV (F = 3.07, r2  = 0.12, p = 0.056). We demonstrated a co-ordination between SO-spindle phase-amplitude coupling and HF-HRV during NREM sleep, presumably related to parallel central nervous and peripheral vegetative arousal systems regulation. Further investigating the fine-graded co-ordination of brain and heart oscillations might improve our understanding of the links between sleep and cardiovascular health.

Augmentation of Psychotherapy with Neurobiological Methods: Current State and Future Directions.

BACKGROUND: Psychotherapy and pharmacotherapy are first-line treatments for mental disorders. Despite recent improvements, only approximately 50% of the patients reach sustained remission, indicating a need for novel developments. The main concept put forward in this systematic review and hypothesis article is the targeted co-administration of defined neurobiological interventions and specific psychotherapeutic techniques. METHODS: We conducted a systematic literature search for randomized controlled trials comparing the efficacy of augmented psychotherapy to psychotherapy alone. RESULTS: Thirty-five trials fulfilled the inclusion criteria. The majority (29 trials) used augmentation strategies such as D-cycloserine, yohimbine, or sleep to enhance the effects of exposure therapy for anxiety disorders. Fewer studies investigated noninvasive brain stimulation with the aim of improving cognitive control, psychedelic compounds with the aim of enhancing existentially oriented psychotherapy, and oxytocin to improve social communication during psychotherapy. Results demonstrate small augmentation effects for the enhancement of exposure therapy - however, some of the studies found negative results. Other methods are less thoroughly researched, and results are mixed. CONCLUSIONS: This approach provides an open matrix for further research and has the potential to systematically guide future studies.

Shaping the slow waves of sleep: A systematic and integrative review of sleep slow wave modulation in humans using non-invasive brain stimulation.

The experimental study of electroencephalographic slow wave sleep (SWS) stretches over more than half a century and has corroborated its importance for basic physiological processes, such as brain plasticity, metabolism and immune system functioning. Alterations of SWS in aging or pathological conditions suggest that modulating SWS might constitute a window for clinically relevant interventions. This work provides a systematic and integrative review of SWS modulation through non-invasive brain stimulation in humans. A literature search using PubMed, conducted in May 2020, identified 3220 studies, of which 82 fulfilled inclusion criteria. Three approaches have been adopted to modulate the macro- and microstructure of SWS, namely auditory, transcranial electrical and transcranial magnetic stimulation. Our current knowledge about the modulatory mechanisms, the space of stimulation parameters and the physiological and behavioral effects are reported and evaluated. The integration of findings suggests that sleep slow wave modulation bears the potential to promote our understanding of the functions of SWS and to develop new treatments for conditions of disrupted SWS.