Decreased Delta/Beta ratio index as the sleep state-independent electrophysiological signature of sleep state misperception in Insomnia disorder: A focus on the sleep onset and the whole night.

PURPOSE: Sleep State Misperception (SSM) is described as the tendency of Insomnia Disorder (ID) patients to overestimate Sleep Latency (SL) and underestimate Total Sleep Time (TST). Literature exploring topographical components in ID with SSM is scarce and does not allow us to fully understand the potential mechanisms underlying this phenomenon. This study aims to evaluate the existence of sleep EEG topography alterations in ID patients associated with SSM compared to Healthy Controls (HC), focusing on two distinct periods: the Sleep Onset (SO) and the whole night. METHODS: Twenty ID patients (mean age: 43.5 ± 12.7; 7 M/13F) and 18 HCs (mean age: 41.6 ± 11.9; 8 M/10F) underwent a night of Polysomnography (PSG) and completed sleep diaries the following morning upon awakening. Two SSM indices, referring to the misperception of SL (SLm) and TST (TSTm), were calculated by comparing objective and subjective sleep indices extracted by PSG and sleep diary. According to these indices, the entire sample was split into 4 sub-groups: ID +SLm vs HC -SLm; ID +TSTm vs HC -TSTm. RESULTS: Considering the SO, the two-way mixed-design ANOVA showed a significant main effect of Groups pointing to a decreased delta/beta ratio in the whole scalp topography. Moreover, we found a significant interaction effect for the sigma and beta bands. Post Hoc tests showed higher sigma and beta power in anterior and temporo-parietal sites during the SO period in IDs +SLm compared to HC -SLm. Considering the whole night, the unpaired t-test revealed in IDs +TSTm significantly lower delta power during NREM, and lower delta/beta ratio index during NREM and REM sleep compared to HCs -TSTm. Finally, we found diffuse significant negative correlations between SSM indices and the delta/beta ratio during SO, NREM, and REM sleep. CONCLUSION: The main finding of the present study suggests that higher SL overestimation and TST underestimation are both phenomena related to diffuse cortical hyperarousal interpreted as a sleep state-independent electrophysiological correlate of the SSM, both during the SO and the whole night.

States of consciousness and interoceptive hypersensibility: A study in patients with insomnia disorder.

This exploratory study aimed to investigate the relationship between interoceptive sensibility and quality of consciousness in individuals with insomnia disorder, in order to understand how the modulation of internal states may contribute to modifying the experience of consciousness during sleep difficulties. A total of 37 patients with insomnia disorder (mean age = 46.05 ± 18.16) and 41 healthy good sleepers (mean age = 50.2 ± 12.99) underwent a psychometric sleep and interoceptive sensibility assessment, using Insomnia Severity Index (ISI), Pittsburgh Sleep Quality Index (PSQI), and Multidimensional Assessment of Interoceptive Awareness (MAIA). Moreover, patients with insomnia disorder also completed a quality of consciousness evaluation, using the Phenomenology of Consciousness Inventory (PCI). Patients with insomnia disorder exhibited heightened interoceptive sensibility, particularly in noticing body sensations (p < 0.0001) and emotional awareness (p = 0.032), along with diminished abilities in attention regulation (p = 0.040), not-worrying (p = 0.001), and trusting (p = 0.002). Furthermore, correlations between interoceptive sensibility and multiple aspects of the consciousness state during the insomnia night were identified. Specifically, higher emotional awareness was linked to a 2.49-fold increase in the likelihood of subjectively experiencing altered consciousness states during insomnia. The study sheds light on the relationship between interoceptive sensibility and the subjective state of consciousness during insomnia, emphasising the importance of exploring and considering interoception as part of the therapeutic process for insomnia disorder. Given the exploratory nature of the study and the increased risk of type-I error from numerous correlations, the results should be interpreted with caution. Further research is needed to validate and confirm their robustness.

Prenatal insomnia disorder may predict concurrent and postpartum psychopathology: A longitudinal study.

While insomnia symptoms may be a risk factor for mental disturbances, few studies evaluated "Insomnia Disorder" and its relationship with perinatal psychopathology. Pregnant women were recruited during their last routine assessment before being hospitalized for delivery during the 3rd trimester at the Gynaecological Unit of the University Hospital of Ferrara and Udine, Italy, from January 2022 to January 2023. Our assessment included baseline evaluation (T0), and evaluations at 1 month (T1) and 3 months (T2) in the postpartum period, with specific questionnaires for insomnia disorder, such as Sleep Condition Indicator, mood and anxiety symptoms and psychosocial functioning, such as Edinburgh Postnatal Depression Scale, Mood Disorder Questionnaire, State-Trait Anxiety Inventory, Work and Social Adjustment Scale. At T0, 181 pregnant women were included. Insomnia disorder affected 22.3% at T0, 23.5% at T1 and 16.2% at T2. Women with insomnia disorder at baseline were significantly more affected by concurrent anxiety and depressive symptoms, had higher bipolar diathesis and poorer psychosocial functioning in the perinatal period. Prenatal insomnia disorder predicted anxiety (T0: odds ratio 4.44, p << 0.001; T1: odds ratio 4.009, p = 0.042) and depressive symptoms (T0: odds ratio 2.66, p = 0.015; T1: odds ratio 11.20, p = 0.001; T2: odds ratio 12.50 p = 0.049) in both the prenatal and postnatal period. It also predicted poor psychosocial function during the prenatal (odds ratio 3.55, p = 0.003) and postpartum periods (T1: odds ratio 2.33, p = 0.004). Insomnia disorder is emerging as an important prenatal factor that may contribute to concurrent and postpartum psychopathology.

First-night effect in insomnia disorder: a systematic review and meta-analysis of polysomnographic findings.

Polysomnographic studies have been performed to investigate the first-night effect in insomnia disorder. However, these studies have revealed discrepant findings. This meta-analysis aimed to summarise and quantify the characteristics of the first-night effect in insomnia disorder. We performed a systematic search of the PubMed, Medline, EMBASE, Web of Science and PsycINFO databases to identify studies published through October 2019. A total of 11,862 articles were identified, and seven studies with eight independent populations were included in the meta-analysis. A total of 639 patients with insomnia disorder and 171 healthy controls underwent more than 2 consecutive nights of in-laboratory polysomnography. Pooled results demonstrated that both variables of sleep continuity and sleep architecture, other than slow-wave sleep were significantly altered in the first-night effect in insomnia disorder. Furthermore, the results indicated that patients with insomnia disorder had a disruption of sleep continuity in the first-night effect, including increased sleep onset latency and reduced total sleep time, compared to healthy controls. Overall, the findings show that patients with insomnia disorder experience the first-night effect, rather than reverse first-night effect, and the profiles of the first-night effect in patients with insomnia are different from healthy controls. These indicate that an adaptation night is necessary when sleep continuity and sleep architecture is to be studied in patients with insomnia disorder. More well-designed studies with large samples are needed to confirm the results.

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.

Disentangling the complex landscape of sleep-wake disorders with data-driven phenotyping: A study of the Bernese center.

BACKGROUND AND PURPOSE: The diagnosis of sleep-wake disorders (SWDs) is challenging because of the existence of only few accurate biomarkers and the frequent coexistence of multiple SWDs and/or other comorbidities. The aim of this study was to assess in a large cohort of well-characterized SWD patients the potential of a data-driven approach for the identification of SWDs. METHODS: We included 6958 patients from the Bernese Sleep Registry and 300 variables/biomarkers including questionnaires, results of polysomnography/vigilance tests, and final clinical diagnoses. A pipeline, based on machine learning, was created to extract and cluster the clinical data. Our analysis was performed on three cohorts: patients with central disorders of hypersomnolence (CDHs), a full cohort of patients with SWDs, and a clean cohort without coexisting SWDs. RESULTS: A first analysis focused on the cohort of patients with CDHs and revealed four patient clusters: two clusters for narcolepsy type 1 (NT1) but not for narcolepsy type 2 or idiopathic hypersomnia. In the full cohort of SWDs, nine clusters were found: four contained patients with obstructive and central sleep apnea syndrome, one with NT1, and four with intermixed SWDs. In the cohort of patients without coexisting SWDs, an additional cluster of patients with chronic insomnia disorder was identified. CONCLUSIONS: This study confirms the existence of clear clusters of NT1 in CDHs, but mainly intermixed groups in the full spectrum of SWDs, with the exception of sleep apnea syndromes and NT1. New biomarkers are needed for better phenotyping and diagnosis of SWDs.

Transcriptional signatures of cortical structural changes in chronic insomnia disorder.

Chronic insomnia disorder (CID) is a multidimensional disease that may influence various levels of brain organization, spanning the macroscopic structural connectome to microscopic gene expression. However, the connection between genomic variations and morphological alterations in CID remains unclear. Here, we investigated brain structural changes in CID patients at the whole-brain level and whether these link to transcriptional characteristics. Brain structural data from 104 CID patients and 102 matched healthy controls (HC) were acquired to examine cortical structural alterations using morphometric similarity (MS) analysis. Partial least squares (PLS) regression and transcriptome data from the Allen Human Brain Atlas were used to extract genomes related to MS changes. Gene-category enrichment analysis (GCEA) was used to identify potential molecular mechanisms behind the observed structural changes. We found that CID patients exhibited MS reductions in the parietal and limbic regions, along with enhancements in the temporal and frontal regions compared to HCs (pFDR < .05). Subsequently, PLS and GCEA revealed that these MS alterations were spatially correlated with a set of genes, especially those significantly correlated with excitatory and inhibitory neurons and chronic neuroinflammation. This neuroimaging-transcriptomic study bridges the gap between cortical structural changes and the molecular mechanisms in CID patients, providing novel insight into the pathophysiology of insomnia and targeted treatments.

Top-down and bottom-up alterations of connectivity patterns of the suprachiasmatic nucleus in chronic insomnia disorder.

The importance of the suprachiasmatic nucleus (SCN, also called the master circadian clock) in regulating sleep and wakefulness has been confirmed by multiple animal research. However, human studies of SCN in vivo are still nascent. Recently, the development of resting-state functional magnetic resonance imaging (fMRI) has made it possible to study SCN-related connectivity changes in patients with chronic insomnia disorder (CID). Hence, this study aimed to explore whether sleep-wake circuitry (i.e., communication between the SCN and other brain regions) is disrupted in human insomnia. Forty-two patients with CID and 37 healthy controls (HCs) underwent fMRI scanning. Resting-state functional connectivity (rsFC) and Granger causality analysis (GCA) were performed to find abnormal functional and causal connectivity of the SCN in CID patients. In addition, correlation analyses were conducted to detect associations between features of disrupted connectivity and clinical symptoms. Compared to HCs, CID patients showed enhanced rsFC of the SCN-left dorsolateral prefrontal cortex (DLPFC), as well as reduced rsFC of the SCN-bilateral medial prefrontal cortex (MPFC); these altered cortical regions belong to the "top-down" circuit. Moreover, CID patients exhibited disrupted functional and causal connectivity between the SCN and the locus coeruleus (LC) and the raphe nucleus (RN); these altered subcortical regions constitute the "bottom-up" pathway. Importantly, the decreased causal connectivity from the LC-to-SCN was associated with the duration of disease in CID patients. These findings suggest that the disruption of the SCN-centered "top-down" cognitive process and "bottom-up" wake-promoting pathway may be intimately tied to the neuropathology of CID.

Daridorexant treatment for chronic insomnia: a real-world retrospective single-center study.

INTRODUCTION: Chronic insomnia disorder (CID) significantly impacts well-being and daily functioning. Daridorexant, a double orexin receptor blocker, has shown efficacy in randomized clinical trials and has been recently approved for the treatment of CID in adult patients. This retrospective observational study aimed to describe real-world data on daridorexant effectiveness and safety in adult patients with CID. METHODS: Consecutive patients initiating on-label daridorexant at the Sleep Medicine Centre, University Hospital of Rome Tor Vergata were enrolled. Baseline and 30-day follow-up (FU) evaluations included patients' and CID characteristics, comorbidities, and clinicians' and patients' subjective ratings of changes with the Clinical and Patient Global Impression-Improvement scores (CGI-Is and PGI-Is), as well as Insomnia Severity Index (ISI) scores in a subgroup of patients. RESULTS: Sixty-nine patients initiated 50-mg daily dosage. At FU, 58% of both patients and clinicians rated CID as improved on CGI-Is and PGI-Is, with no differences based on comorbidities, sex, or number of previous medications. No significant predictors of CGI-Is and PGI-Is improvement were identified. At FU, ISI scores (n = 24) significantly decreased from 18.25 ± 3.21 to 12.08 ± 6.12 (Z = 8.000; p < 0.001). Of these, eight patients (33.3%) had absence of insomnia symptoms, and no patients reported a worsening in ISI score categories. CONCLUSIONS: This study suggests daridorexant to be effective and safe in real-world CID treatment whether used as a first-ever treatment, switch, or add-on, as reflected by subjective and objective measures and the absence of serious treatment-related adverse events. Future research on larger cohorts should explore daridorexant potential across diverse patient characteristics.

Increased functional connectivity within the salience network in patients with insomnia.

BACKGROUND: Insomnia is a common sleep disorder with significant negative impacts on emotional states; however, the underlying mechanism of insomnia with comorbid emotional dysregulation remains largely unknown. The salience network (SN) plays an important role in both sleep and emotional regulation. The study aimed to explore the specific alterations in functional connectivity (FC) within the SN in insomnia patients. METHODS: A total of 30 eligible patients with insomnia disorder (ID group) and 30 healthy controls (HC group) underwent resting-state functional magnetic resonance imaging (fMRI) scanning and psychometric assessments. Differences in FC within the SN were examined using seed-based region-to-region connectivity analysis. RESULTS: Compared with healthy controls, patients with insomnia showed increased FC within the SN, mainly between the anterior cingulate cortex (ACC) and right superior frontal gyrus (SFG), the right SFG and right supramarginal gyrus (SMG), and between the right insular (INS) and left SMG (P<0.05). Additionally, significant correlations were observed between increased FC and the Hamilton Depression Rating Scale (HAMD), Pittsburgh Sleep Quality Index (PSQI), and Hamilton Anxiety Rating Scale (HAMA) scores (P<0.05, after Bonferroni correction). CONCLUSIONS: These results suggest that increased FC within the SN may be related to poor sleep quality and negative emotions, highlighting the importance of the SN in the pathophysiological mechanisms of insomnia with comorbid emotional dysregulation.

The insensitivity of sleep to an unfamiliar sleeping environment in patients with insomnia disorder.

BACKGROUND: Sleeping in an unfamiliar environment, such as a sleep laboratory, is thought to disturb sleep in healthy individuals and could express a hyperarousal state called the first night effect. Insomnia disorder (ID) is a highly prevalent health problem characterized by increased arousal during the night and daytime. Whether or not a similar phenomenon occurs in patients with ID is unclear. This study aimed to investigate the effect of an unfamiliar environment on the sleep of patients with ID. METHODS: In an unfamiliar sleep laboratory, polysomnographic recording testing was performed for two consecutive nights in patients with ID and age- and sex-matched healthy control subjects (HC). We collected sleep diaries and questionnaires regarding sleep, medical conditions, psychological status, and health history. Sleep continuity and architecture in both groups were compared and analyzed for two consecutive nights. RESULTS: Participants with ID (n = 39)  and HC (n = 35) demonstrated differentially poor sleep on laboratory adaptation after exposure to the sleep laboratory. Patients with ID had longer rapid eye movement (REM) latency on the first night than on the second sleep night. HC showed increased duration and percentage of N1, decreased duration and percentage of N3, and decreased REM percentage during initial nights compared to subsequent nights. The other sleep variables showed no differences between the first and second sleep nights in patients with ID and HC. CONCLUSIONS: An unfamiliar sleep environment does not aggravate the disruption of sleep continuity and sleep architecture but only affects the REM latency in patients with ID compared with HC.

Doxepin is more effective than zolpidem in improving executive function in patients with insomnia disorder.

BACKGROUND : Insomnia disorder is associated with an impairment in cognitive performance. Doxepin and zolpidem have been found to be effective in improving sleep. In this study, we aimed to compare the effects of doxepin and zolpidem on sleep structure and executive function in patients with insomnia disorder. METHODS: Patients with primary insomnia were randomly assigned to receive doxepin 6 mg/day orally or zolpidem 5-10 mg/day orally. Polysomnography (PSG) and the Pittsburgh Sleep Quality Index (PSQI) were used at baseline and after the 8-week treatment to compare clinical efficacy in the two groups. Safety was assessed using the Treatment Emergent Symptom Scale (TESS). Executive function was evaluated using the Wisconsin sorting card test (WSCT). RESULTS: Of 120 patients enrolled in the study, 60 participants were assigned to each group. A total of 109 participants (53 in the doxepin group and 56 in the zolpidem group) completed the study. After treatment, the wake after sleep onset (WASO) and total sleep time (TST) values in the doxepin group were 80.3 ± 21.4 min and 378.9 ± 21.9 min, respectively, which were significantly better than those in the zolpidem group (132.9 ± 26.5 min and 333.2 ± 24.2 min, respectively; (P < 0.05)). The sleep onset latency (SOL) value in the zolpidem group (20.3 ± 4.7 min) was significantly better than that in the doxepin group (28.2 ± 5.6 min; P < 0.05). The sleep efficiency (SE) in the doxepin group was 77.8 ± 4.2%, which was significantly better than that in the zolpidem group (68.6 ± 5.0%; P < 0.05). The PSQI score of the doxepin group was 6.1 ± 1.1, which was significantly lower than that in the zolpidem group (7.9 ± 1.9; P < 0.05). The treatment adverse events in the doxepin group was 23.3%, which was significantly higher than that in the zolpidem group (13.3%; P < 0.05). The WSCT showed a significant improvement in persistent errors (PE), random errors (RE), and categories in the two groups after 8-week treatment, and the improvement in RE and the categories was more obvious in the doxepin group (P < 0.05). CONCLUSIONS: Both doxepin and zolpidem were found to be effective in improving sleep quality, but the effects exhibited different patterns. Doxepin improved executive function more effectively than zolpidem in patients with insomnia disorder.

Analysis of functional connectivity changes in attention networks and default mode networks in patients with depression and insomnia.

PURPOSE: Major Depressive Disorder (MDD) and Insomnia Disorder (ID) are prevalent psychiatric conditions often occurring concurrently, leading to substantial impairment in daily functioning. Understanding the neurobiological underpinnings of these disorders and their comorbidity is crucial for developing effective interventions. This study aims to analyze changes in functional connectivity within attention networks and default mode networks in patients with depression and insomnia. METHODS: The functional connectivity alterations in individuals with MDD, ID, comorbid MDD and insomnia (iMDD), and healthy controls (HC) were assessed from a cohort of 174 participants. They underwent rs-fMRI scans, demographic assessments, and scale evaluations for depression and sleep quality. Functional connectivity analysis was conducted using region-of-interest (ROI) and whole-brain methods. RESULTS: The MDD and iMDD groups exhibited higher Hamilton Depression Scale (HAMD) scores compared to HC and ID groups (P < 0.001). Both ID and MDD groups displayed enhanced connectivity between the left and right orbital frontal cortex compared to HC (P < 0.05), while the iMDD group showed reduced connectivity compared to HC and ID groups (P < 0.05). In the left insula, reduced connectivity with the right medial superior frontal gyrus was observed across patient groups compared to HC (P < 0.05), with the iMDD group showing increased connectivity compared to MDD (P < 0.05). Moreover, alterations in functional connectivity between the left thalamus and left temporal pole were found in iMDD compared to HC and MDD (P < 0.05). Correlation analyses revealed associations between abnormal connectivity and symptom severity in MDD and ID groups. CONCLUSIONS: Our findings demonstrate distinct patterns of altered functional connectivity in individuals with MDD, ID, and iMDD compared to healthy controls. These findings contribute to a better understanding of the pathophysiology of depression and insomnia, which could be used as a reference for the diagnosis and treatments of these patients.

A genome-wide methylation analysis of Chinese Han patients with chronic insomnia disorder.

BACKGROUND: As the most common sleep disorder, chronic insomnia disorder (CID) has become a global health burden to the public. However, it remains unclear about the pathogenesis of this disease. Epigenetic changes may provide important insights into the gene-environment interaction in CID. Therefore, this study was conducted to investigate the DNA methylation pattern in CID and reveal the epigenetic mechanism of this disease. METHODS: In this study, whole blood DNA was extracted from 8 CID patients (the CID group) and 8 healthy controls (the control group), respectively. Besides, genome-wide DNA methylation was detected by Illumina Human Methylation 850 K Beadchip. Moreover, the sleep quality and insomnia severity were evaluated by the Pittsburgh Sleep Quality Index (PSQI) and Insomnia Severity Index (ISI), respectively. RESULTS: A total of 369 differentially methylated positions (DMPs) and 23 differentially methylated regions (DMRs) were identified between the CID and control groups. LHX6 was identified as the most important differentially methylated gene (DMG). The Gene Ontology (GO) analysis results corroborated that DMPs were significantly enriched in 105 GO terms, including cell signaling, homogenous cell adhesion of plasma membrane adhesion molecules, nervous system development, cell adhesion, and calcium ion binding. In addition, it was demonstrated that DMPs were significantly enriched in the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways, including the hippo signaling pathway, Ras signaling pathway, and vitamin B6 metabolism. The DMR-related GO analysis results revealed the positive regulation of protein kinase activities. CONCLUSIONS: DNA methylation plays a critical role in the development of CID, and LHX6 is validated to be an important DMG.

Insomnia disorder characterized by probabilistic metastable substates using blood-oxygenation-level-dependent (BOLD) phase signals.

PURPOSE: From a clinical point of view, how to force a transition from insomnia brain state to healthy brain state by external driven stimulation is of great interest. This needs to define brain state of insomnia disorder as metastable substates. The current study was to identify recurrent substates of insomnia disorder in terms of probability of occurrence, lifetime, and alternation profiles by using leading eigenvector dynamics analysis (LEiDA) method. METHODS: We enrolled 32 patients with insomnia disorder and 30 healthy subjects. We firstly obtained the BOLD phase coherence matrix from Hilbert transform of BOLD signals and then extracted all the leading eigenvectors from the BOLD phase coherence matrix for all subjects across all time points. Lastly, we clustered the leading eigenvectors using a k-means clustering algorithm to find the probabilistic metastable substates (PMS) and calculate the probability of occurrence and associated lifetime for substates. RESULTS: The resulting 3 clusters were optimal for brain state of insomnia disorder and healthy brain state, respectively. The occurred probabilities of the PMS were significantly different between the patients with insomnia disorder and healthy subjects, with 0.51 versus 0.44 for PMS-1 (p < 0.001), 0.25 versus 0.27 for PMS-2 (p = 0.051), and 0.24 versus 0.29 for PMS-3 (p < 0.001), as well as the lifetime (in TR) of 36.65 versus 33.15 for PMS-1 (p = 0.068), 14.36 versus 15.43 for PMS-2 (p = 0.117), and 14.80 versus 16.34 for PMS-3 (p = 0.042). The values of the diagonal of the transition matrix were much higher than the probabilities of switching states, indicating the metastable nature of substates. CONCLUSION: The resulted probabilistic metastable substates hint the characteristic brain dynamics of insomnia disorder. The results may lay a foundation to help determine how to force a transition from insomnia brain state to healthy brain state by external driven stimulation.

Initial treatment choices for long-term remission of chronic insomnia disorder in adults: a systematic review and network meta-analysis.

BACKGROUND: We aimed to evaluate the comparative efficacy and acceptability of cognitive behavioral therapy for insomnia (CBT-I), pharmacotherapy, and their combination in the long and short terms among adults with chronic insomnia disorder. METHODS: We searched multiple databases to December 27, 2023. We included trials in hypnotic-free adults with chronic insomnia comparing at least two of CBT-I, pharmacotherapy, or their combination. We assessed the confidence in evidence using CINeMA. The primary outcome was long-term remission. Secondary outcomes included all-cause dropout and self-reported sleep continuity measures in the long term, and the same outcomes in the short term. We performed frequentist random-effects network meta-analyses (CRD42024505519). FINDINGS: We identified 13 trials including 823 randomized participants (mean age, 47.8 years; 60% women). CBT-I was more beneficial than pharmacotherapy in the long term (median duration, 24 weeks [range, 12 to 48 weeks]; remission odds ratio, 1.82 [95% confidence interval (CI), 1.15-2.87]; [certainty of evidence: high]), while there was weaker evidence of benefit of combination against pharmacotherapy (1.71 [95% CI, 0.88-3.30: moderate]) and no clear difference of CBT-I against combination (1.07 [95% CI, 0.63-1.80: moderate]). CBT-I was associated with fewer dropouts than pharmacotherapy. Short-term outcomes favored CBT-I over pharmacotherapy except total sleep time. Given the average long-term remission rate in the pharmacotherapy-initiating arms of 28%, CBT-I resulted in a long-term remission rate of 41% (95% CI, 31%-53%) and combination 40% (95% CI, 25%-56%). INTERPRETATION: The current study found that starting with CBT-I for chronic insomnia leads to better outcomes than pharmacotherapy. Combination may be better than pharmacotherapy alone, but unlikely to be worth the additional burden over CBT-I alone.

The role of ascending arousal network in patients with chronic insomnia disorder.

The ascending arousal system plays a crucial role in individuals' consciousness. Recently, advanced functional magnetic resonance imaging (fMRI) has made it possible to investigate the ascending arousal network (AAN) in vivo. However, the role of AAN in the neuropathology of human insomnia remains unclear. Our study aimed to explore alterations in AAN and its connections with cortical networks in chronic insomnia disorder (CID). Resting-state fMRI data were acquired from 60 patients with CID and 60 good sleeper controls (GSCs). Changes in the brain's functional connectivity (FC) between the AAN and eight cortical networks were detected in patients with CID and GSCs. Multivariate pattern analysis (MVPA) was employed to differentiate CID patients from GSCs and predict clinical symptoms in patients with CID. Finally, these MVPA findings were further verified using an external data set (32 patients with CID and 33 GSCs). Compared to GSCs, patients with CID exhibited increased FC within the AAN, as well as increased FC between the AAN and default mode, cerebellar, sensorimotor, and dorsal attention networks. These AAN-related FC patterns and the MVPA classification model could be used to differentiate CID patients from GSCs with 88% accuracy in the first cohort and 77% accuracy in the validation cohort. Moreover, the MVPA prediction models could separately predict insomnia (data set 1, R2  = .34; data set 2, R2  = .15) and anxiety symptoms (data set 1, R2  = .35; data set 2, R2  = .34) in the two independent cohorts of patients. Our findings indicated that AAN contributed to the neurobiological mechanism of insomnia and highlighted that fMRI-based markers and machine learning techniques might facilitate the evaluation of insomnia and its comorbid mental symptoms.

Effects on resting-state EEG phase-amplitude coupling in insomnia disorder patients following 1 Hz left dorsolateral prefrontal cortex rTMS.

Despite burgeoning evidence for cortical hyperarousal in insomnia disorder, the existing results on electroencephalography spectral features are highly heterogeneous. Phase-amplitude coupling, which refers to the modulation of the low-frequency phase to a high-frequency amplitude, is probably a more sensitive quantitative measure for characterizing abnormal neural oscillations and explaining the therapeutic effect of repetitive transcranial magnetic stimulation in the treatment of patients with insomnia disorder. Sixty insomnia disorder patients were randomly divided into the active and sham treatment groups to receive 4 weeks of repetitive transcranial magnetic stimulation treatment. Behavioral assessments, resting-state electroencephalography recordings, and sleep polysomnography recordings were performed before and after repetitive transcranial magnetic stimulation treatment. Forty good sleeper controls underwent the same assessment. We demonstrated that phase-amplitude coupling values in the frontal and temporal lobes were weaker in Insomnia disorder patients than in those with good sleeper controls at baseline and that phase-amplitude coupling values near the intervention area were significantly enhanced after active repetitive transcranial magnetic stimulation treatment. Furthermore, the enhancement of phase-amplitude coupling values was significantly correlated with the improvement of sleep quality. This study revealed the potential of phase-amplitude coupling in assessing the severity of insomnia disorder and the efficacy of repetitive transcranial magnetic stimulation treatment, providing new insights on the abnormal physiological mechanisms and future treatments for insomnia disorder.

Complementary and alternative treatments for insomnia disorder: a systematic umbrella review.

Insomnia is a common disorder and cognitive behavioural therapy for insomnia (CBT-I) is recommended as first-line treatment. However, CBT-I is not widely distributed and infrequently available while medication is not indicated for long-term use. To close this evident gap in supply, alternative treatments could be utilised. High-quality research on this topic is scarce, and there is currently no comprehensive publication on the effectiveness of alternative treatments. To address this pressing question, we systematically summarised the existing research on alternative treatments for insomnia. A comprehensive search of systematic reviews and (network) meta-analyses of randomised controlled trials investigating the efficacy of alternative treatments compared to waiting-list control or placebo in adults with insomnia disorder with or without comorbidities was conducted in PubMed, MEDLINE, PsycInfo, and PsycArticles on December 6, 2022, yielding 391 records. Finally, 15 eligible studies were included. Evidence on acupuncture, exogenous melatonin, mind-body interventions and exercise, repetitive transcranial magnetic stimulation (rTMS), valerian, and light exposure was found. Acupuncture, rTMS and mind-body exercises significantly improved sleep quality and insomnia severity but effects on objectively assessed outcomes were inconclusive. Melatonin led to a reduction in both self-reported and objectively assessed sleep onset latency. Light exposure and valerian did not significantly improve sleep outcomes. Overall, the quality of studies was rated as low. Results indicate that alternative treatments are effective mostly on subjective outcomes. However, evidence on the efficacy of some intervention types is sparse and there is a need for high-quality original studies. Future research could investigate whether combining different alternative treatment aspects with CBT-I improves individual treatment.

Tailoring cognitive behavioural therapy for insomnia across contexts, conditions, and individuals: What do we know, where do we go?

Cognitive behavioural therapy for insomnia (CBT-I) is considered the front-line treatment for insomnia. Despite the demonstrated effectiveness of CBT-I, it is necessary to consider how CBT-I may be tailored to different individuals. The purpose of the present review is to provide a summary of literature on tailoring CBT-I to different individuals and provide directions for future research. This review focused on the following domains of adaptation: (i) tailoring CBT-I components to individuals with comorbid mental or physical health conditions such as comorbid depression and pain; (ii) adapting CBT-I delivery for different contexts in which individuals exist, such as inpatient, educational, and different social/cultural settings, (iii) adapting CBT-I to specific individuals via case-formulation in clinical settings. We highlight current gaps in the exploration of tailored CBT-I, including a lack of research methodology to evaluate tailored interventions, a need for the integration of ongoing individualised assessment to inform treatment, and the necessary involvement of consumers and stakeholders throughout the research and treatment development process. Together, this review showed abundant adaptations in CBT-I already exist in the literature. Future research is needed in understanding when and how to apply adaptations in CBT-I and evaluate the benefits of these adaptations.