Aberrant individual large-scale functional network connectivity and topology in chronic insomnia disorder with and without depression.

Insomnia is increasingly prevalent with significant associations with depression. Delineating specific neural circuits for chronic insomnia disorder (CID) with and without depressive symptoms is fundamental to develop precision diagnosis and treatment. In this study, we examine static, dynamic and network topology changes of individual large-scale functional network for CID with (CID-D) and without depression to reveal their specific neural underpinnings. Seventeen individual-specific functional brain networks are obtained using a regularized nonnegative matrix factorization technique. Disorders-shared and -specific differences in static and dynamic large-scale functional network connectivities within or between the cognitive control network, dorsal attention network, visual network, limbic network, and default mode network are found for CID and CID-D. Additionally, CID and CID-D groups showed compromised network topological architecture including reduced small-world properties, clustering coefficients and modularity indicating decreased network efficiency and impaired functional segregation. Moreover, the altered neuroimaging indices show significant associations with clinical manifestations and could serve as effective neuromarkers to distinguish among healthy controls, CID and CID-D. Taken together, these findings provide novel insights into the neural basis of CID and CID-D, which may facilitate developing new diagnostic and therapeutic approaches.

Alcohol Dependence Among Adult Males in Chengalpattu District, South India: A Mixed Methods Study.

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.

Altered cingulate gyrus subregions functional connectivity in chronic insomnia disorder with anxiety.

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.

Lectin YKL-40 Level and Telomere Length are Indicators of Insomnia Disorder.

OBJECTIVE: To explore the relationship between YKL-40 level, telomere length, and different subtypes of insomnia disorder. METHODS: A total of 145 individuals suffering from insomnia were enrolled and divided into four groups according to the insomniac subtypes: difficulty initiating sleep, early morning awakening, difficulty maintaining sleep, and mixed symptoms. Eighty healthy controls were also collected at the same time. Peripheral leukocyte genomic DNA was extracted, relative telomere lengths were measured using the real-time quantitative polymerase chain reaction method, and YKL-40 levels were determined using enzyme-linked immunoassay. Logistic regression modeling was used to analyze the correlation between different insomnia subtypes, YKL-40 level, and telomere length. RESULTS: People with telomere lengths in the lowest tertile were more likely to have trouble falling asleep (odds ratio (OR) 2.13, 95% confidence interval (CI) 1.22-3.63; p = 0.03) and had a higher frequency of mixed symptoms (OR 1.49, 95% CI 1.30-2.81; p = 0.04). People in the highest tertile of YKL-40 level had an increased chance of waking up early (OR 2.98, 95% CI 1.54-5.33; p = 0.01) and more mixed symptoms (OR 1.47, 95% CI 1.22-2.79; p = 0.02). Furthermore, using receiver operating characteristic curve analysis, the area under the curve of YKL-40 level and telomere length was 0.806 and 0.746, respectively. CONCLUSIONS: Telomere length in patients with difficulty initiating sleep and mixed symptoms was significantly shortened and the level of YKL-40 in people who have early morning awakening and mixed symptoms was significantly increased. Our findings provide the first evidence that leukocyte telomere length and YKL-40 level are individually linked to mixed symptoms.

The Abnormal N-Acetylaspartate to Creatine Ratio of the Right Putamen is Linked to Wakefulness in Patients with Insomnia Disorder.

Purpose: Converging evidence implicates the putamen in sleep-wake regulation. However, its role remains unclear. We hypothesized that metabolic abnormalities in the putamen are linked to insomnia disorder, which has not been previously addressed, and investigated putaminal N-acetylaspartate (NAA), choline (Cho), and creatine (Cr) in patients with insomnia disorder compared to healthy controls. Participants and Methods: In the present study, the concentrations of NAA, Cho, and Cr in the putamen of 23 patients with insomnia disorder and 18 healthy controls were determined using proton magnetic resonance spectroscopy. Sociodemographic, psychometric, and polysomnography data were obtained from all participants. Results: We found that the mean NAA/Cr ratio of the right putamen was significantly greater in the insomnia group compared to the control group and also greater than the left putamen within the insomnia group. The NAA/Cr ratio of the right putamen distinguished insomnia disorder from normal sleep with 78.3% sensitivity and 61.1% specificity. Furthermore, this ratio positively correlated with both objective and subjective insomnia severity and sleep quality. Conclusion: Our findings provide critical evidence for the dysfunctional putaminal metabolism of NAA/Cr in insomnia disorder, suggesting that the abnormal NAA/Cr ratio of the right putamen is linked to wakefulness in patients with insomnia disorder and may serve as a potential biomarker of insomnia disorder.

Restoration of abnormal sleep EEG power in patients with insomnia disorder after 1Hz rTMS over left DLPFC.

Introduction: Hyperarousal has been a significant pathophysiological theory related to insomnia disorder (ID), characterized by excessive cortical activation and abnormal electroencephalogram (EEG) power during daytime or sleep. However, there is currently insufficient attention to the EEG power during rapid eye movement (REM) sleep and different stages of non-rapid eye movement (NREM) sleep. Additionally, whether the abnormal sleep EEG power in ID patients can be restored by repetitive transcranial magnetic stimulation (rTMS) remains unclear. Methods>: Data of 26 ID patients and 26 healthy controls (HCs) were included in the current observational study. The comparisons of relative power between patients and HCs at baseline in each band of each sleep stage and the changes in patients before and after rTMS treatment were performed. The correlations between relative power and behavioral measures of the patients were also investigated. Results: Abnormalities in sleep EEG relative power in the delta, beta and gamma bands of the patients were observed in NREM2, NREM3 and REM sleep. Correlations were identified between relative power and behavioral measures in ID group, primarily encompassing sleep efficiency, sleep onset latency and depression scores. Post-treatment improvements in relative power of the delta and beta band were observed in NREM2 sleep. Discussion: The relative power of sleep EEG exhibited a significant correlation with sleep measures in ID patients, and demonstrated notable differences from HCs across the delta, beta, and gamma frequency bands. Furthermore, our findings suggest that rTMS treatment may partially ameliorate relative power abnormalities in patients with ID.

Expanded gray matter atrophy with severity stages of adult comorbid insomnia and sleep apnea.

OBJECTIVE: To investigate gray matter volume (GMV) changes in patients with comorbid insomnia and sleep apnea (COMISA) of differing severity and relationships between GMV alterations and clinical measures. METHODS: Thirty-four COMISA patients and 24 healthy controls (HC) were recruited. All patients underwent structural MRI and completed measures related to respiration, sleep, mood, and cognition. COMISA patients were further divided into a mild and moderate COMISA (MC) and a severe COMISA (SC) group. Changes in GMV of COMISA patients were investigated via VBM. The voxel-wise differences in GMV were compared between HC group and COMISA group. Analysis of covariance (ANCOVA) was performed on individual GMV maps in MC, SC, and HC groups to further investigate effects of different stages of COMISA severity on GMV. Partial correlation analysis was then performed to analyze relationships between altered GMV and clinical measures. RESULTS: GMV atrophy was mainly located in the temporal lobes and fusiform gyrus in COMISA group. The post-hoc analysis of the ANCOVA revealed temporal lobes and fusiform gyrus atrophy in MC and SC groups compared to HC and the temporal lobe atrophy was expanded in SC group based on cluster size. Moreover, the SC group showed GMV atrophy of the right amygdala compared to both MC and HC groups. Partial correlation analysis revealed positive relationships between the GMV and mood-and cognitive-related measures and negative correlation between GMV and respiration measure. CONCLUSIONS: Our findings showed GMV atrophy expansion from temporal lobe to limbic system (right amygdala) as severity stages increase in COMISA patients. These findings contribute to our understanding of neurobiological mechanisms underlying different stages of severity in COMISA patients.

Sleep-aiding music therapy for insomnia: Exploring EEG functional connectivity of sleep-related attentional bias.

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.

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.

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.

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.

Acupuncture modulates emotional network resting-state functional connectivity in patients with insomnia disorder: a randomized controlled trial and fMRI study.

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.

Risk of Comorbid Insomnia Disorder Associated with Major Depression in Apneic Patients: A Cross-Sectional Study.

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.

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.

Functional connectome gradient predicts clinical symptoms of chronic insomnia disorder.

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.

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.

Sleep quality and perceived stress levels in Chinese patients with minor recurrent aphthous stomatitis: a cross-sectional questionnaire-based survey.

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.

Dose-response of daridorexant in insomnia disorder: An analysis of Phase 2 and 3 studies.

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.

Functional MRI-based biomarkers of insomnia with objective short sleep duration phenotype.

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.

Effectiveness of repetitive transcranial magnetic stimulation for insomnia disorder on fear memory extinction: study protocol for a randomised controlled trial.

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.