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Introduction Post-pandemic alcohol consumption is on the rise due to people starting to adapt themselves to the practice of consuming alcoholic beverages at home. In addition to the direct effects of intoxication and addiction, estimates suggest that alcohol contributes to approximately 20-30% of global cases of oesophagal cancer, liver cancer, cirrhosis of the liver, homicide, epilepsy, and motor vehicle accidents. In India, one-fifth of alcohol consumers were found to be alcohol dependent. The study was done with the primary objective of finding out the prevalence of alcohol dependence among alcohol users and exploring the reasons for alcohol dependence among alcohol users in an urban area of Chengalpattu District, Tamil Nadu. Methodology The study design is an explanatory sequential mixed-methods study. It was done among 624 adult male alcohol consumers in the Chennai district, selected by the cluster sampling method in a community setting. The Alcohol Use Disorders Identification Test (AUDIT) was used to diagnose alcohol dependence. Using the purposive sampling method, in-depth interviews were conducted among 24 alcohol-dependent people to explore and understand their experiences, identify common themes, and provide insights into the problem. Quantitative data were analysed using Statistical Package for Social Sciences (SPSS) version 26 (IBM Corp., Armonk, NY), and qualitative data were analysed using deductive content analysis using Qualcoder software. Results The mean age of the study participants was 38±7 years. Among current alcohol consumers, 16.9% (106/624) were found to be suffering from alcohol dependence. The significant predictors of alcohol dependence were found to be unskilled occupation (adjusted odds ratio [AOR] = 2.09), having suicidal ideation (AOR = 2.4), alcohol consumption by family members (AOR = 1.90), depression (AOR = 3.98), drinking pattern-affected interpersonal relationships (AOR = 2.29), and not receiving health education about alcohol use in school/college (AOR = 1.74). The major themes and codes identified among alcohol dependents were factors related to mental health, physical health, and social factors. Conclusion This study provides essential points of reference for policymakers and primary care physicians to develop prevention strategies for people to understand and overcome the problem of alcohol addiction, and it also sheds light on the burden of alcohol dependence and their lived experiences.

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BACKGROUND: Chronic insomnia disorder (CID) is commonly associated with mood disorders. The cingulate gyrus (CG) plays a critical role in the pathophysiology of CID and anxiety. However, the specific characteristics of altered brain networks in the CG in CID with anxiety remain unclear. This study aimed to investigate the characteristics of CG functional connectivity (FC) in CID with and without anxiety. METHODS: Resting-state functional magnetic resonance imaging was conducted on 92 CID and 36 healthy controls (HC). CID was divided into CID with anxiety (CID-A, N = 37) and CID without anxiety (CID-NA, N = 55) groups based on anxiety scores. Using the Human Brainnetome Atlas, the subregion CG FC network was constructed. RESULTS: Compared with HC, CID showed significantly decreased CG FC with the precuneus, middle frontal gyrus (MFG), and hippocampus, while showing significantly increased CG FC with the middle temporal gyrus (MTG)/superior temporal gyrus (STG). In contrast, CID-A showed significantly decreased CG FC with the salience network (insular, putamen) and default mode network (MTG/STG and inferior parietal lobule), while showing significantly increased CG FC with the thalamus and MFG compared to CID-NA. Further, CID-A and CID-NA could be classified with 84.21 % accuracy by using the CG FCs as features. Among these features, the CG FC with MFG, thalamus, and putamen had the highest contribution weights. CONCLUSION: This study revealed specific changes in the brain network of the CG subregion in CID-A. Understanding these CG FC alterations can help identify potential biomarkers specific to CID-A, which may be valuable for early detection and differentiation from other CID subtypes.

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Given the limitations of available studies, the objective of this study was to explore the role played by current and remitted major depression in the occurrence of comorbid insomnia disorder for apneic patients. Data from 1488 apneic patients were extracted from the medical reports of polysomnographic recordings available in the database of the Sleep Laboratory. The presence of comorbid insomnia disorder in these apneic patients was defined based on the diagnostic criteria of the American Academy of Sleep Medicine Work Group. The risk of comorbid insomnia disorder associated with current or remitted major depression in apneic patients was investigated using multivariate logistic regression models. After adjustment for the main confounding factors, multivariate logistic regression analyses revealed that remitted and current major depression were significantly associated with the occurrence of comorbid insomnia disorder in apneic patients. The findings of this study seem to indicate that comorbid insomnia disorder could be a residual symptom and a marker of major depression in apneic patients, which justifies the establishment of an adequate treatment for major depressive episodes and their potential residual symptoms to allow the better management of comorbid insomnia disorder and the better prevention of its potential negative consequences in this particular subpopulation.

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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.

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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.

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BACKGROUND: Insomnia disorder (ID) is one of the most common sleep problems, usually accompanied by anxiety and depression symptoms. Functional magnetic resonance imaging (fMRI) study suggests that both poor sleep quality and negative emotion are linked to the dysregulation of brain network related to emotion processing in ID patients. Acupuncture therapy has been proven effective in improving sleep quality and mood of ID patients, but the involved neurobiological mechanism remains unclear. We aimed to investigate the modulation effect of acupuncture on resting-state functional connectivity (rsFC) of the emotional network (EN) in patients experiencing insomnia. METHODS: A total of 30 healthy controls (HCs) and 60 ID patients were enrolled in this study. Sixty ID patients were randomly assigned to real and sham acupuncture groups and attended resting-state fMRI scans before and after 4 weeks of acupuncture treatment. HCs completed an MRI/fMRI scan at baseline. The rsFC values within EN were calculated, and Hamilton Anxiety Scale (HAMA), Hamilton Depression Scale (HAMD), Pittsburgh Sleep Quality Index (PSQI), Hyperarousal Scale (HAS), and actigraphy data were collected for clinical efficacy evaluation. RESULTS: Resting-state FC analysis showed abnormalities in rsFC centered on the thalamus and dorsolateral prefrontal cortex within EN of ID patients compared to HCs. After real acupuncture treatment, rsFC of the anterior cingulate cortex, hippocampus, and amygdala were increased compared with the sham acupuncture group (p < 0.05, FDR corrected). In real acupuncture group, the rsFC value was decreased between left amygdala and left thalamus after 4 weeks of treatment compared with baseline. A trend of correlation was found that the increased rsFC value between the right amygdala and left hippocampus was positively correlated with the decreased HAMA scores across all ID patients, and the decreased left amygdala rsFC value with the left thalamus was negatively correlated with the increased sleep efficiency in the real acupuncture group. CONCLUSION: Our findings showed that real acupuncture could produce a positive effect on modulating rsFC within network related to emotion processing in ID patients, which may illustrate the central mechanism underlying acupuncture for insomnia in improving sleep quality and emotion regulation. TRIAL REGISTRATION: http://www.chictr.org.cn ., ChiCTR1800015282, 20/03/2018.

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STUDY OBJECTIVES: This study aimed to investigate the relationship between sleep-aiding music and sleep-related attentional bias based on electroencephalography (EEG) functional connectivity (FC) in patients with insomnia disorder (ID), to evaluate the effectiveness of music in aiding sleep. METHOD: This study included 30 participants, comprising 15 patients with ID and 15 healthy controls (HCs). Six types of music were selected for sleep aid, and a dot-probe task based on sleep-related attentional bias was utilized to collect behavioral and EEG data. Vigilance bias and disengagement bias were measured using reaction time and EEG FC. Differences in sleep-related attentional bias before and after the intervention of music were explored to evaluate the sleep-aiding effects and identify EEG biomarkers. RESULTS: Compared with HCs, patients with ID showed decreased sleep-related attentional bias of EEG FC between occipital-central and temporal-frontal lobes. Among the six types of music, International Standard Sleep Aid and Lullaby had a greater impact on decreasing vigilance bias in the ID group. Additionally, the International Standard Sleep Aid and Nature Sound were more effective in decreasing disengagement bias in the ID group. This study also examined the resting-state EEG FC of patients with ID before and after the intervention of music. The results showed that the FC in the temporal, frontal, and occipital lobes significantly differed before and after the intervention of music, especially with the use of International Standard Sleep Aid, Lullaby, and Alpha Sound Wave. However, it is worth noting that these three types of music showed no similarities in EEG FC, in contrast to the result of sleep-related attentional bias of EEG FC. CONCLUSION: This study found that the sleep-related attentional bias of EEG FC has more distinct characteristics when compared to resting-state EEG FC. The results suggest that the sleep-related attentional bias of EEG FC could be a potential biomarker for assessing the sleep-aiding effect of music interventions. International Standard Sleep Aid was the most effective for patients with ID among six types of sleep-aiding music. These findings could facilitate the development of personalized therapies for patients with ID. CLINICAL TRIALS REGISTRATION: Chinese Clinical Trial Register, http://www.chictr.org.cn, ID: ChiCTR2400081608.

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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.

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Insomnia is the second most prevalent psychiatric disorder worldwide, but the understanding of the pathophysiology of insomnia remains fragmented. In this study, we calculated the connectome gradient in 50 chronic insomnia disorder (CID) patients and 38 healthy controls (HC) to assess changes due to insomnia and utilized these gradients in a connectome-based predictive modeling (CPM) to predict clinical symptoms associated with insomnia. The results suggested that insomnia led to significant alterations in the functional gradients of some brain areas. Specifically, the gradient scores in the middle frontal gyrus, superior anterior cingulate gyrus, and right nucleus accumbens were significantly higher in the CID patients than in the HC group, whereas the scores in the middle occipital gyrus, right fusiform gyrus, and right postcentral gyrus were significantly lower than in the HC group. Further correlation analysis revealed that the right middle frontal gyrus is positively correlated with the self-rating anxiety scale (r=0.3702). Additionally, the prediction model built with functional gradients could well predict the sleep quality (r=0.5858), anxiety (r=0.6150), and depression (r=0.4022) levels of insomnia patients. This offers an objective depiction of the clinical diagnosis of insomnia, yielding a beneficial impact on the identification of effective biomarkers and the comprehension of insomnia.

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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.

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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.

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OBJECTIVES: This cross-sectional study aimed to evaluate sleep quality and perceived stress levels in Chinese patients with active minor recurrent aphthous stomatitis (MiRAS) lesions, as well as to investigate the potential relationship between sleep quality and perceived stress levels and the risk of MiRAS episodes. METHODS: The study population consisted of individuals recruited from a Chinese cohort who underwent medical and oral examinations from March 2022 to August 2023. All participants completed a set of uniform anonymous questionnaires, which included sociodemographic characteristics, clinical information, the Pittsburgh Sleep Quality Index (PSQI), the Insomnia Severity Index (ISI) and the Perceived Stress Scale (PSS-14). Statistical analysis was conducted using the independent sample t test, Mann-Whitney U test, Pearson's chi-square test and Pearson's correlation analysis. After adjusting for potential confounders (age, gender, marital status, and education level), multivariate logistic regression analyses were performed to assess the associations of sleep quality and perceived stress levels with the risk of MiRAS episodes. Additionally, restricted cubic spline curves were constructed to visualize these correlations. RESULTS: A total of 329 eligible volunteers participated in the study, comprising 122 Chinese MiRAS patients and 207 healthy controls without MiRAS. Compared to healthy participants, MiRAS patients exhibited significantly higher PSQI and ISI scores (p = 0.000). However, no statistically significant difference was observed between the two groups regarding PSS-14 scores or its two subscales (p > 0.05). Multiple regression analysis indicated that lower sleep quality was significantly associated with an increased risk of MiRAS episodes (p = 0.000), whereas no statistically significant relationship was found between perceived stress levels and the risk of MiRAS episodes (p > 0.05). CONCLUSION: Maintaining a regular bedtime and improving sleep quality may contribute to reducing the incidence and recurrence of MiRAS, while psychological intervention may be ineffective for MiRAS patients.

Recurrent aphthous stomatitis (RAS) is one of the most prevalent oral mucosal diseases, affecting approximately 20% of the general population, with prevalence rates ranging from 0.5% to 68% across different countries. MiRAS is classified as the most common type of RAS, accounting for about 85% of RAS patients. Previous studies have identified several potential predisposing factors, including trauma, psychological disorders, genetic susceptibility, immune dysregulation, hormonal imbalance, and microbial flora disorders. However, the definitive etiology of RAS remains unknown to date. This study assessed sleep quality and perceived stress levels in Chinese patients with active MiRAS lesions using standardized measures, including the Pittsburgh Sleep Quality Index (PSQI), Insomnia Severity Index (ISI), and Perceived Stress Scale (PSS-14). The results indicated that MiRAS patients had significantly higher PSQI and ISI scores compared to healthy controls, regardless of age, gender, marital status, or education level. However, no statistically significant difference was observed between the two groups concerning PSS-14 scores and its subscales. Furthermore, better sleep quality was found to be moderately associated with a reduced risk of MiRAS episodes, while perceived stress levels did not show a significant relationship with the risk. Findings from this study suggest that maintaining proper bedtime routines and improving sleep quality may help reduce both the incidence and recurrence rates of MiRAS.

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BACKGROUND: Insomnia disorder with objective short sleep duration (ISS) phenotype is a more serious biological subtype than insomnia with objective normal sleep duration (INS) phenotype, and the neuroimaging data is helpful to understand the pathophysiology of the ISS phenotype. This study was to compare the amplitude of low-frequency fluctuation (ALFF), regional homogeneity (ReHo), and functional connectivity (FC) between the ISS phenotype and the INS phenotype. METHODS: In this cross-sectional study, 55 patients with insomnia disorder were recruited, and 22 of them were defined as the ISS phenotype by the objective cardiopulmonary coupling (CPC) technique. The blood oxygen level-dependent (BOLD) sequences of all participants were obtained using the 3.0 T magnetic resonance imaging system. We analyzed and compared the ALFF, ReHo, and FC between the ISS phenotype and the INS phenotype. We also conducted Pearson's correlation analysis between significant neuroimaging biomarkers and the CPC parameters. RESULTS: The differences were not significant in ALFF (PFWE-corr＞0.05) or ReHo (PFWE-corr＞0.05) between the ISS phenotype and the INS phenotype. For the FC analysis, the ISS phenotype had a Hub-node of the left inferior occipital gyrus (IOG.L), with significantly decreased connections (p＜0.001) in the bilateral occipital, parietal, and temporal regions. The significant FCs were closely related to sleep parameters. CONCLUSION: The left inferior occipital gyrus (IOG.L), as a Hub-node with decreased functional connections, may be a potential fMRI-based biomarker of the ISS phenotype.

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OBJECTIVE: Daridorexant is approved for the treatment of insomnia at two dose levels (25 and 50 mg). Dose-efficacy and -safety response relationships were evaluated using Phase 2 and 3 data. METHODS: Data (N = 2153) from one Phase 2 (daridorexant 5, 10, 25, 50 mg, placebo once daily for 1 month) and two Phase 3 studies (daridorexant 10 and 25 or 25 and 50 mg, placebo once daily for 3 months) were pooled. Dose-response analyses at 1 month of double-blind treatment were performed using a linear regression and a two-stage meta-analysis approach. Efficacy endpoints were polysomnography-derived wake after sleep onset, latency to persistent sleep (LPS), self-reported total sleep time and the Insomnia Daytime Symptoms and Impacts Questionnaire total score (only Phase 3 data for the latter). Safety endpoints were the incidence of total adverse events (AEs) and AEs corresponding to somnolence/fatigue. RESULTS: Dose-responses for all efficacy endpoints were significant in the observed dose range (both statistical approaches, p < 0.01). All dose-response relationships were linear except for LPS (two-stage meta-analysis) which showed a change in slope above 10 mg without reaching a plateau. No significant dose-response was observed for any AE (both approaches, p > 0.05). The incidence of AEs corresponding to somnolence/fatigue was low at all doses and, without linear assumption (two-stage meta-analysis) there was no dose-dependency (p = 0.369). CONCLUSIONS: The data support the use of 50 mg as the preferred daridorexant dose in patients with insomnia disorder to provide the greatest opportunity for efficacy with no increased risk for AEs, including somnolence/fatigue, compared to lower doses.

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BACKGROUND: Fear memory extinction is closely related to insomnia. Repetitive transcranial magnetic stimulation (rTMS) is safe and effective for treating insomnia disorder (ID), and it has been shown to be an efficient method for modulating fear extinction. However, whether rTMS can improve fear extinction memory in ID patients remains to be studied. In this study, we specifically aim to (1) show that 1 Hz rTMS stimulation could improve fear extinction memory in ID patients and (2) examine whether changes in sleep mediate this impact. METHODS AND DESIGN: We propose a parallel group randomised controlled trial of 62 ID participants who meet the inclusion criteria. Participants will be assigned to a real rTMS group or a sham rTMS group. The allocation ratio will be 1:1, with 31 subjects in each group. Interventions will be administered five times per week over a 4-week period. The assessments will take place at baseline (week 0), post-intervention (week 4), and 8-week follow-up (week 8). The primary outcome measure of this study will be the mean change in the Pittsburgh Sleep Quality Index (PSQI) scores from baseline to post-intervention at week 4. The secondary outcome measures include the mean change in skin conductance response (SCR), fear expectation during fear extinction, Insomnia Severity Index (ISI), Zung Self-Rating Anxiety Scale (SAS), and the Zung Self-Rating Depression Scale (SDS). DISCUSSION: This study will be the first examination of the impact of rTMS on fear memory extinction in ID patients. TRIAL REGISTRATION: Chinese Clinical Trials Register ChiCTR2300076097. Registered on 25 September 2021.

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Background: Chronic insomnia disorder (CID) is usually associated with Generalized Anxiety Disorder (GAD), which may change brain structure and function. However, the possible brain markers, imaging characteristics, and pathophysiology are unknown. Objective: To look at the probable brain markers, imaging characteristics, and pathogenesis of CID in combination with GAD. Methods: A total of 57 patients with CID concomitant GAD and 57 healthy controls (HC) were enrolled. Voxel-based morphometry (VBM) and functional connectivity (FC) were utilized to measure gray matter volume (GMV) and functional changes. Correlation analysis was utilized to identify relationships between brain changes and clinical characteristics. Results: Patients had decreased GMV in the left cerebellum, right cerebellar peduncle, and left insula; increased FC between the left cerebellum and right angular gyrus, as well as between the left insula and anterior left cingulate gyrus; and decreased FC in several areas, including the left cerebellum with the middle left cingulate gyrus and the left insula with the left superior postcentral gyrus. These brain changes related to CID and GAD. These data could be used to identify relevant brain markers, imaging features, and to better understand the etiology. Conclusion: The intensity of insomnia in patients was strongly related to the severity of anxiety. The lower GMV in the cerebellum could be interpreted as an imaging characteristic of CID. Reduced GMV in the insula, as well as aberrant function in the cingulate gyrus and prefrontal lobe, may contribute to the pathophysiology of CID and GAD. Abnormal function in the postcentral gyrus and angular gyrus may be associated with patients' clinical complaints.

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OBJECTIVES: Appraise the evidence for daridorexant 50 mg and 25 mg versus placebo when treating chronic insomnia disorder in terms of number needed to treat (NNT), number needed to harm (NNH), and likelihood to be helped or harmed (LHH). METHODS: NNT, NNH, and LHH were calculated from a 3-month pivotal Phase 3 study (N = 930; randomized 1:1:1 to daridorexant 50 mg, daridorexant 25 mg, or placebo once nightly). Wakefulness after sleep onset, latency to persistent sleep, self-reported total sleep time, Insomnia Daytime Symptoms and Impacts Questionnaire (IDSIQ), and Insomnia Severity Index were used for the NNT efficacy analysis. NNH safety analysis was performed using rates of adverse events (AEs) occurring in >1% of the participants in any arm. LHH was assessed for all NNT estimates, contrasting them with NNH estimates for somnolence, headache, and fatigue AEs. RESULTS: NNT estimates for daridorexant 50 mg versus placebo were <10 for clinically meaningful thresholds across all outcomes. NNT estimates for daridorexant 25 mg versus placebo were not as robust as those observed for daridorexant 50 mg, with many values exceeding 10. NNH estimates for daridorexant 50 mg and 25 mg versus placebo did not show a statistically significant treatment difference except for falls, where NNH was negative for the daridorexant 50 mg group (-44 [95% CI -328; -21]; rate of falls was greater with placebo than for daridorexant 50 mg). All LHH ratios at Months 1 and 3 were >1 (except for daridorexant 25 mg for the IDSIQ alert/cognition domain), indicating that patients were more likely to respond to daridorexant 50 mg and 25 mg than to experience an AE of somnolence, headache, or fatigue. CONCLUSION: Daridorexant 50 mg and 25 mg have a favorable benefit-risk ratio over 3 months. Daridorexant 50 mg demonstrated more robust (lower) NNT estimates versus placebo than daridorexant 25 mg.

Daridorexant, a dual orexin receptor antagonist, is a new treatment for chronic insomnia disorder. This analysis examined the effect and safety of daridorexant 50 and 25 mg, using data from a 3-month Phase 3 study (NCT03545191) to measure 'number needed to treat' (NNT) and 'number needed to harm' (NNH).NNT estimates how many patients need to be treated over a specific period to see one more beneficial response. Estimates versus placebo <10 indicate an effective treatment. Daridorexant 50 mg estimates were <10 for all objective and subjective measurements of insomnia assessed in this analysis, including evaluation of daytime functioning. NNT estimates for daridorexant 25 mg versus placebo were not as robust as daridorexant 50 mg, with values >10.NNH is calculated in the same way as NNT but estimates harmful outcomes rather than benefits. Estimates versus placebo >10 means the treatment is reasonably well tolerated.Using NNT and NNH, the 'likelihood to be helped or harmed' (LHH) ratio was calculated, determining how more likely a patient is to benefit versus experiencing harm from a treatment (LHH of >1 denotes a positive benefit­risk ratio). Both daridorexant doses had a favorable benefit­risk ratio over 3 months with LHH > 1.This analysis supports daridorexant 50 mg as the optimal dose to treat insomnia in adults, offering improved effectiveness compared with daridorexant 25 mg, with a similarly good safety profile.

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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.

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Objectives: To examine serum concentrations of neurotensin, pannexin-1 and sestrin-2, and their correlations with subjective and objective sleep quality and cognitive function in the patients with chronic insomnia disorder (CID). Methods: Sixty-five CID patients were enrolled continuously and fifty-six good sleepers in the same period were served as healthy controls (HCs). Serum levels of neurotensin, pannexin-1 and sestrin-2 were measured by enzyme-linked immunosorbent assays. Sleep quality was assessed with the Pittsburgh Sleep Quality Index (PSQI) and polysomnography, and mood was evaluated by 17-item Hamilton Depression Rating Scale. General cognitive function was assessed with the Chinese-Beijing Version of Montreal Cognitive Assessment and spatial memory was evaluated by Blue Velvet Arena Test (BVAT). Results: Relative to the HCs, the CID sufferers had higher levels of neurotensin (t=5.210, p<0.001) and pannexin-1 (Z=-4.169, p<0.001), and lower level of sestrin-2 (Z=-2.438, p=0.015). In terms of objective sleep measures, pannexin-1 was positively associated with total sleep time (r=0.562, p=0.002) and sleep efficiency (r=0.588, p=0.001), and negatively with wake time after sleep onset (r=-0.590, p=0.001) and wake time (r=-0.590, p=0.001); sestrin-2 was positively associated with percentage of rapid eye movement sleep (r=0.442, p=0.016) and negatively with non-rapid eye movement sleep stage 2 in the percentage (r=-0.394, p=0.034). Adjusted for sex, age and HAMD, pannexin-1 was still associated with the above objective sleep measures, but sestrin-2 was only negatively with wake time (r=-0.446, p=0.022). However, these biomarkers showed no significant correlations with subjective sleep quality (PSQI score). Serum concentrations of neurotensin and pannexin-1 were positively associated with the mean erroneous distance in the BVAT. Adjusted for sex, age and depression, neurotensin was negatively associated with MoCA score (r=-0.257, p=0.044), pannexin-1 was positively associated with the mean erroneous distance in the BVAT (r=0.270, p=0.033). Conclusions: The CID patients had increased neurotensin and pannexin-1 and decreased sestrin-2 in the serum levels, indicating neuron dysfunction, which could be related to poor sleep quality and cognitive dysfunction measured objectively.

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BACKGROUND: Cognitive behavioral therapy for insomnia (CBT-I) is among the recommended non-pharmacological treatments for patients with insomnia. While there are multiple reports on the effects of CBT-I treatment, few studies evaluating the factors associated with the treatment response to CBT-I have been reported. The present study aimed to confirm the effects of CBT-I in patients with insomnia and to examine the clinico-demographic factors that can predict the outcomes of CBT-I in these patients. METHODS: Overall, 62 patients were included in the present study. To confirm the effectiveness of CBT-I, we compared the pre- and post-CBT-I therapy values of several sleep parameters. Furthermore, to identify the clinico-demographic factors that could be predictive of the treatment response to CBT-I, we performed generalized linear model (GLM) analysis. RESULTS: The values of several sleep parameters were significantly lower after treatment than at baseline. The results of the GLM analysis revealed that sex and occupation were significantly associated with the treatment response to CBT-I. CONCLUSIONS: The present results suggest that several clinico-demographic factors should be considered in the treatment of patients with insomnia.