The moderating effect of prefrontal response to sleep-related stimuli on the association between depression and sleep disturbance in insomnia disorder.

We investigated differences in brain activity in response to sleep-related pictures between chronic insomnia disorder (CID) patients and good sleepers (GS), and examined whether brain activity moderated the relationship between depressive symptoms and sleep disturbance in CID patients and GS. This study included 43 patients diagnosed with CID, based on the International Classification of Sleep Disorders-3, and 42 GS. The participants kept a sleep diary, underwent nocturnal polysomnography to measure sleep parameters, and completed self-report questionnaires to assess sleep and psychiatric symptoms. They underwent functional magnetic resonance imaging (fMRI) to examine differences in brain activity in response to sleep-related pictures compared to neutral pictures. A moderated moderation analysis was performed to investigate the moderating role of brain responses to sleep-related pictures in the association between depressive symptoms and sleep disturbance. Compared to GS, the brain responses to sleep-related stimuli were significantly lower in CID patients in the right lateral prefrontal cortex (LPFC) and dorsomedial prefrontal cortex (DMPFC). More severe depressive symptoms were significantly associated with longer sleep latency only when LPFC activity was low in CID patients, but not in GS. LPFC hypoactivity in response to sleep-related stimuli in CID patients could moderate the relationship between depression and sleep disturbance.

Neural activation underlying emotional interference of cognitive control in rotating shift workers: moderating effects of the prefrontal cortex response on the association between sleep disturbance and depressive symptoms.

STUDY OBJECTIVES: This study investigated the altered neural function involved in emotional interference and its role in linking sleep disturbance and depressive/anxiety symptoms in rotating shift workers. METHODS: Sixty rotating shift workers and 61 controls performed the emotional Stroop task in three blocks (emotional-related, sleep-related, and neutral words) during functional magnetic resonance imaging (fMRI) assessments. Sleep disturbance and depressive/anxiety symptoms were assessed using self-report measures and sleep diaries. Actigraphy was used to assess the sleep and circadian variables. fMRI scans were performed to compare brain activation during the emotional Stroop task. The proposed moderating models were tested using the PROCESS macro in SPSS software. RESULTS: A significant condition effect on reaction time was detected. Regardless of the group, reaction times were longer in the negative emotional word and sleep-related conditions than in the neutral word condition. Whole-brain analysis revealed that rotating shift workers show greater neural activation in the left dorsolateral prefrontal cortex (DLPFC) compared with controls while performing the emotional Stroop task with negative emotional words. Sleep disturbance was more strongly associated with depressive symptoms when activation of the left DLPFC was higher during the emotional Stroop task with negative words. CONCLUSIONS: The left DLPFC may play important roles in increased sensitivity to emotional information, possibly due to circadian misalignment, and has moderating effects on the association between sleep disturbance and depressive symptoms in rotating shift workers. These findings will help to identify possible brain regions where interventions can be performed to correct sleep and mood problems in rotating shift workers.

Negative and positive sleep state misperception in patients with insomnia: factors associated with sleep perception.

STUDY OBJECTIVES: In the present study, factors associated with sleep perception were identified by comparing clinical characteristics and polysomnographic variables between insomnia patients with negative and positive sleep state misperception (NSSM and PSSM, respectively). METHODS: Self-reported and objective sleep measures were retrospectively collected, including the Pittsburgh Sleep Quality Index (PSQI), Beck Depression Inventory, and a questionnaire on "morning feeling" after nocturnal polysomnography in 150 patients with insomnia. Based on the misperception index (MI), participants were classified into NSSM (MI > 0, n = 115) and PSSM (MI < 0, n = 35) groups. RESULTS: The PSSM group had more N3 sleep on nocturnal polysomnography than the NSSM group (P = .002). The NSSM group showed a higher PSQI score (P < .001), longer self-reported sleep-onset latency (SOL) (P = .001), and a greater SOL discrepancy (P = .001). Self-reported feelings of tiredness and morning awakenings in the morning were higher in the NSSM group (P = .029 and P = .038). The MI negatively correlated with a proportion of N3 sleep (P = .005) and positively correlated with PSQI (P < .001), morning awakenings (P = .01), self-reported SOL (P < .001), and SOL discrepancy (P < .001) in patients with insomnia. Multiple regression analysis showed that N3 sleep, PSQI, and morning awakenings were significantly associated with MI in patients with insomnia. CONCLUSIONS: The proportion of slow-wave sleep and self-reported measures may be associated with perception of sleep in patients with insomnia. Objective and self-reported characteristics of patients with insomnia should be carefully evaluated and managed because they may influence the perception of sleep. CITATION: Yoon G, Lee MH, Oh SM, Choi J-W, Yoon SY, Lee YJ. Negative and positive sleep state misperception in patients with insomnia: factors associated with sleep perception. J Clin Sleep Med. 2022;18(7):1789-1795.

Life stress, sleep disturbance and depressive symptoms: The moderating role of prefrontal activation during emotion regulation.

OBJECTIVES: Evidence suggests that emotion regulation difficulty may play an important role in the association between life stress, sleep disturbance and depressive symptoms. We proposed two models depicting the possible moderating roles of prefrontal cortex activation during emotion regulation in the associations among these variables and tested them. We hypothesized that (1) the association between stress and sleep disturbance would differ across prefrontal cortex activation during emotion regulation (moderation model) and (2) the indirect effects of stress on depressive symptoms through sleep disturbance would depend on prefrontal cortex activation during emotion regulation (moderated mediation model). METHODS: Forty-eight healthy adults without sleep disorders based on nocturnal polysomnography participated in this study. They received functional magnetic resonance imaging scans while performing an emotion regulation task. They also completed questionnaires assessing life stress, sleep disturbance and depressive symptoms. The proposed models were tested using the PROCESS macro for SPSS. RESULTS: As hypothesized, there was a significant moderating effect of prefrontal cortex activation during emotion regulation on the association between life stress and sleep disturbance. Furthermore, right lateral prefrontal cortex activation had a moderating role in the indirect effect of life stress on depressive symptoms through sleep disturbance. CONCLUSION: These findings highlight the important role of prefrontal cortex function during emotion regulation in the associations between stress, sleep disturbance and depressive symptoms. Increasing lateral prefrontal cortex recruitment when regulating the emotional response to negative life events may be critical for the prevention and intervention of depression as well as sleep problems.

Negative life stress, sleep disturbance, and depressive symptoms: The moderating role of anterior insula activity in response to sleep-related stimuli.

BACKGROUND: This study investigated the effects of anterior insula (AI) activation on the association between stress and sleep disturbance as a neurobiological basis of the trait-like degree of sleep reactivity to stress. Additionally, it examined the effects of AI activity on the association between sleep disturbance and depression. METHODS: The participants were 48 adults. To assess AI activation in response to sleep-related stimuli (SS) compared to neutral stimuli (NS), we extracted mean AI parameter estimates for the SS-NS contrast. We examined whether the interaction between life stress and AI activation would predict sleep disturbance and whether the interaction between sleep disturbance and AI activation would predict depression. RESULTS: At higher levels of bilateral AI activation in response to SS, higher levels of stress were associated with greater sleep disturbance (left AI x stress: b = 1.07, SE = 0.44, p < 0.05; right AI x stress: b = 1.05, SE = 0.48, p < 0.05). In addition, at higher levels of right AI activation, higher levels of sleep disturbance were associated with more severe depressive symptoms (right AI x sleep disturbance: b = 2.55, SE = 1.10, p < 0.05). LIMITATION: This study assessed sleep quality and depressive symptoms based on self-reported questionnaires. CONCLUSION: This study revealed moderating effects of AI activation on the association between negative life stress and sleep disturbance. Additionally, AI activation strengthened the association between sleep disturbance and depression. AI activation may reflect a crucial etiological diathesis for insomnia and stress-related disorders.

Multitask fMRI and machine learning approach improve prediction of differential brain activity pattern in patients with insomnia disorder.

We investigated the differential spatial covariance pattern of blood oxygen level-dependent (BOLD) responses to single-task and multitask functional magnetic resonance imaging (fMRI) between patients with psychophysiological insomnia (PI) and healthy controls (HCs), and evaluated features generated by principal component analysis (PCA) for discrimination of PI from HC, compared to features generated from BOLD responses to single-task fMRI using machine learning methods. In 19 patients with PI and 21 HCs, the mean beta value for each region of interest (ROIbval) was calculated with three contrast images (i.e., sleep-related picture, sleep-related sound, and Stroop stimuli). We performed discrimination analysis and compared with features generated from BOLD responses to single-task fMRI. We applied support vector machine analysis with a least absolute shrinkage and selection operator to evaluate five performance metrics: accuracy, recall, precision, specificity, and F2. Principal component features showed the best classification performance in all aspects of metrics compared to BOLD response to single-task fMRI. Bilateral inferior frontal gyrus (orbital), right calcarine cortex, right lingual gyrus, left inferior occipital gyrus, and left inferior temporal gyrus were identified as the most salient areas by feature selection. Our approach showed better performance in discriminating patients with PI from HCs, compared to single-task fMRI.

The seasonal pattern of restless legs syndrome in a sample from the Korean Health Insurance Review and Assessment Service national database.

STUDY OBJECTIVES: To assess the seasonality of restless legs syndrome (RLS) using data from the Korean national health insurance database. METHODS: We retrospectively reviewed a randomly selected sample representing 3% of the national health insurance claims database in South Korea. From this sample, we obtained the monthly numbers of patients with RLS and diagnoses from 2009 to 2016, along with prescriptions for monthly dopamine agonists and clonazepam for patients with RLS from 2009 to 2013. Total dopamine agonist and clonazepam doses were converted to levodopa-equivalent doses, and the monthly cumulative prescription dose was calculated. Cosinor analysis was used to evaluate the seasonal pattern of each variable. RESULTS: This study included 11,466 patients with RLS and their diagnoses and 4,887 prescriptions for dopamine agonists and clonazepam. There were significant seasonal patterns in the numbers of patients with RLS (P < .001) and diagnoses (P < .001), both of which peaked in August. The magnitude of the greatest difference in the number of patients with RLS between August (highest) and February (lowest) was 29.96% (95% confidence interval, 24.03-100.80), and that of the number of RLS diagnoses was 39.56% (95% confidence interval, 31.24-47.89). The cumulative prescription dose of medication showed no significant seasonality. CONCLUSIONS: Our findings suggest that the prevalence of RLS is seasonally affected, with an increase during summer.

Association of heart rate variability with REM sleep without atonia in idiopathic REM sleep behavior disorder.

STUDY OBJECTIVES: Idiopathic rapid eye movement sleep behavior disorder (iRBD), characterized by rapid eye movement sleep without atonia (RSWA) and dream-enactment behavior, has been suggested to be a predictor of α-synucleinopathies. Autonomic instability, represented by heart rate variability, is a common characteristic of both iRBD and α-synucleinopathies. Previous studies reported that RSWA was associated with autonomic dysfunction and was a possible predictor of phenoconversion. Therefore, we sought to compare heart rate variability between iRBD and control groups and explore the relationship between heart rate variability and RSWA in patients with iRBD. METHODS: Nocturnal polysomnographic data on 47 patients (28 men, 19 women) diagnosed with iRBD based on video-polysomnography and 26 age-matched and sex-matched controls were reviewed. The first 5-minute epoch with a stable electrocardiogram lead II on video-polysomnography was selected from stage N2, wake, and rapid eye movement. For quantification of RSWA, tonic activity was analyzed from the submentalis electromyogram and phasic activity from the submentalis and bilateral anterior tibialis electromyogram channels. RESULTS: Compared to the control group, the iRBD group showed significant reductions in the standard deviation of the R-R intervals, the root mean square of successive R-R interval differences, and high-frequency values. Quantified tonic activity was inversely correlated with normalized low-frequency values and low-frequency/high-frequency ratios and positively correlated with normalized high-frequency values. CONCLUSIONS: This study implied decreased cardiac autonomic function in patients with iRBD, which showed parasympathetic predominance. Heart rate variability of the patients with iRBD in this study was associated with quantified tonic RSWA, which was previously reported to be a possible predictor of phenoconversion.

The Moderating Effect of Sleep Disturbance on the Association of Stress with Impulsivity and Depressed Mood.

OBJECTIVE: This study was performed to investigate the associations of life event stress with impulsivity, anxiety, and depressed mood as a function of the presence of a sleep disturbance. METHODS: In total, 214 participants (age 38.96±10.53 years; 111 females) completed self-report questionnaires, including the Life Experience Survey (LES), Pittsburgh Sleep Quality Index (PSQI), Barratt's Impulsivity Scale (BIS), Beck Anxiety Inventory (BAI), and Beck Depression Inventory (BDI). The presence of a sleep disturbance was defined as a PSQI score >5. RESULTS: In total, 127 participants presented with a sleep disturbance (age 39.33±10.92 years; 64 females), whereas the remaining 87 did not (age 38.43±9.97 years; 47 females). Negative LES scores were significantly correlated with BIS (r=0.22, p=0.001), BAI (r=0.46, p< 0.001), and BDI (r=0.51, p<0.001) scores, and PSQI scores were significantly correlated with BAI (r=0.49, p<0.001) and BDI (r=0.60, p< 0.001) scores. Moderation analysis revealed statistically significant interactions between negative LES scores and the presence of a sleep disturbance on BIS (p=0.044) and BDI (p=0.014) but not on BAI (p=0.194) scores. CONCLUSION: The findings of the present study suggest that life event stress has varying degrees of influence on mental health, especially impulsivity and depressed mood, depending on the presence or absence of a sleep disturbance.

Effect of Closed-Loop Vibration Stimulation on Heart Rhythm during Naps.

Sleep plays a primary function for health and sustains physical and cognitive performance. Although various stimulation systems for enhancing sleep have been developed, they are difficult to use on a long-term basis. This paper proposes a novel stimulation system and confirms its feasibility for sleep. Specifically, in this study, a closed-loop vibration stimulation system that detects the heart rate (HR) and applies -n% stimulus beats per minute (BPM) computed on the basis of the previous 5 min of HR data was developed. Ten subjects participated in the evaluation experiment, in which they took a nap for approximately 90 min. The experiment comprised one baseline and three stimulation conditions. HR variability analysis showed that the normalized low frequency (LF) and LF/high frequency (HF) parameters significantly decreased compared to the baseline condition, while the normalized HF parameter significantly increased under the -3% stimulation condition. In addition, the HR density around the stimulus BPM significantly increased under the -3% stimulation condition. The results confirm that the proposed stimulation system could influence heart rhythm and stabilize the autonomic nervous system. This study thus provides a new stimulation approach to enhance the quality of sleep and has the potential for enhancing health levels through sleep manipulation.

Human Heart Rhythms Synchronize While Co-sleeping.

Human physiological systems have a major role in maintenance of internal stability. Previous studies have found that these systems are regulated by various types of interactions associated with physiological homeostasis. However, whether there is any interaction between these systems in different individuals is not well-understood. The aim of this research was to determine whether or not there is any interaction between the physiological systems of independent individuals in an environment where they are connected with one another. We investigated the heart rhythms of co-sleeping individuals and found evidence that in co-sleepers, not only do independent heart rhythms appear in the same relative phase for prolonged periods, but also that their occurrence has a bidirectional causal relationship. Under controlled experimental conditions, this finding may be attributed to weak cardiac vibration delivered from one individual to the other via a mechanical bed connection. Our experimental approach could help in understanding how sharing behaviors or social relationships between individuals are associated with interactions of physiological systems.

Decreased regional brain activity in response to sleep-related sounds after cognitive behavioral therapy for psychophysiological insomnia.

AIM: Patients with psychophysiological insomnia (PI) experience hyperarousal, especially as a reaction to sound stimuli. In the current study, we explored brain activity changes in response to sleep-related sounds (SS) in patients with insomnia after cognitive behavioral therapy for insomnia (CBT-I). METHODS: In 14 drug-free PI patients, regional brain activity in response to SS, and to white noise sound (NS) as neutral stimuli, was investigated before and after individual CBT-I using functional magnetic resonance imaging. Blood oxygen level-dependent (BOLD) signals to SS and NS were compared before and after CBT-I. In addition, the association between clinical improvement after CBT-I and changes in brain activity in response to SS and NS was analyzed. RESULTS: Compared with baseline, regional brain activity in response to SS after CBT-I decreased in the left middle temporal and left middle occipital gyrus. In regression analysis, a reduction in the Dysfunctional Beliefs and Attitudes about Sleep (DBAS) Scale score after CBT-I was associated with decrease in brain activity in response to SS in both thalami. However, brain activity in response to NS showed no BOLD signal changes and no association with DBAS change. CONCLUSION: Cortical hyperactivity, which may cause hyperarousal in PI, was found to decrease after CBT-I. CBT-I targeting changes in beliefs and attitudes about sleep may induce its therapeutic effects by reducing thalamic brain activity in response to sleep-related stimuli.

The association between obstructive sleep apnea during REM sleep and autonomic dysfunction as measured by heart rate variability.

PURPOSE: To determine the effect of obstructive sleep apnea (OSA) during rapid eye movement (REM) sleep on autonomic dysfunction using heart rate variability (HRV) analysis. METHODS: The medical records of adults who underwent nocturnal polysomnography at the Sleep and Chronobiology Center at Seoul National University Hospital were retrospectively reviewed. HRV parameters (mean RR interval, the standard deviation of all normal RR intervals [SDNN], square root of the mean squared differences of adjacent RR intervals [RMSSD], normalized low frequency [LF], normalized high frequency [HF], and the ratio of LF to HF [LF/HF]) were measured in 5-min electrocardiogram recordings obtained during W, N2, and R sleep stages. Comparisons were made among the control (apnea-hypopnea index (AHI < 15 and AHI during REM sleep (AHIREM) < 15, n = 27), REM-associated OSA (AHI < 15 and AHIREM ≥ 15, n = 27), and OSA (AHI ≥ 15, n = 27) groups. The groups were matched for age, sex, and body mass index. RESULTS: No significant differences were observed between the control and the REM-associated OSA groups for any of the HRV parameters. In contrast, compared with controls, the OSA group showed significantly lower normalized HF (p = 0.031) and higher LF/HF (p = 0.018) in stage W and a significantly shorter mean RR interval (p = 0.046) and lower RMSSD (p = 0.034) in stage N2. CONCLUSIONS: Our findings suggest that OSA during REM sleep is not a major contributor to autonomic dysfunction.

Trends in prescriptions for sedative-hypnotics among Korean adults: a nationwide prescription database study for 2011-2015.

PURPOSE: This study investigated prescriptions for sedative-hypnotics via data obtained from the Health Insurance Review and Assessment (HIRA) service. METHODS: Data on sedative-hypnotic prescriptions from the HIRA service of the Republic of Korea were analyzed from 2011 to 2015. We included prescriptions for subjects > 18 years of age from hospitals and community healthcare centers. In addition, subgroup analyses with a subsample restricted to prescriptions from patients with diagnostic codes F510 (nonorganic insomnia) or G470 (insomnia) were performed. After analyzing the number of prescriptions by individual pharmacy items, the prescription codes were grouped as: (1) benzodiazepines; (2) non-benzodiazepines, including zolpidem; (3) antidepressants; and (4) antipsychotics. We calculated the monthly percent change in the number of prescriptions by drug group using Joinpoint regression. RESULTS: Among the sedative-hypnotic groups, benzodiazepines were the most commonly prescribed drugs in Korea during the study period. As a single sedative-hypnotic item, zolpidem was the most frequently prescribed medication for patients with insomnia. Prescriptions for all groups of sedative-hypnotics increased significantly during the study period. When stratified by age group, antipsychotic prescriptions increased significantly by 0.19-0.21% per month among men and women aged 50-59 years and > 70 years. Prescriptions for antidepressants in 30-39-year-old men increased significantly by 0.20%. CONCLUSIONS: Benzodiazepine prescriptions as well as those for antipsychotics and antidepressants to treat insomnia increased during 2011-2015 in Korea. Monitoring the use of sedative-hypnotics at the national level is necessary, especially in the elderly population.

Cancer-Stimulated CAFs Enhance Monocyte Differentiation and Protumoral TAM Activation via IL6 and GM-CSF Secretion.

Purpose: M2-type TAMs are increasingly implicated as a crucial factor promoting metastasis. Numerous cell types dictate monocyte differentiation into M2 TAMs via a complex network of cytokine-based communication. Elucidating critical pathways in this network can provide new targets for inhibiting metastasis. In this study, we focused on cancer cells, CAFs, and monocytes as a major node in this network.Experimental Design: Monocyte cocultures with cancer-stimulated CAFs were used to investigate differentiation into M2-like TAMs. Cytokine array analyses were employed to discover the CAF-derived regulators of differentiation. These regulators were validated in primary CAFs and bone marrow-derived monocytes. Orthotopic, syngeneic colon carcinoma models using cotransplanted CAFs were established to observe effects on tumor growth and metastasis. To confirm a correlation with clinical evidence, meta-analyses were employed using the Oncomine database.Results: Our coculture studies identify IL6 and GM-CSF as the pivotal signals released from cancer cell-activated CAFs that cooperate to induce monocyte differentiation into M2-like TAMs. In orthotopic, syngeneic colon carcinoma mouse models, cotransplanted CAFs elevated IL6 and GM-CSF levels, TAM infiltration, and metastasis. These pathologic effects were dramatically reversed by joint IL6 and GM-CSF blockade. A positive correlation between GM-CSF and IL6 expression and disease course was observed by meta-analyses of the clinical data.Conclusions: Our studies indicate a significant reappraisal of the role of IL6 and GM-CSF in metastasis and implicate CAFs as the "henchmen" for cancer cells in producing an immunosuppressive tumor ecological niche. Dual targeting of GM-CSF and IL6 is a promising new approach for inhibiting metastasis. Clin Cancer Res; 24(21); 5407-21. ©2018 AACR.

Preliminary Study on Quantitative Sleep EEG Characteristics in Patients with Schizophrenia.

We used quantitative electroencephalography (EEG) spectral analysis to compare activity in the bilateral frontal, central, and occipital areas in nine patients with schizophrenia and ten healthy control subjects during standard nocturnal polysomnography. Patients with schizophrenia had longer sleep latency than controls. In N2 sleep, the patients had significantly lower 0.5-1 Hz power and higher theta power in the left frontal region, and higher beta power in the left occipital region than did control subjects. In N3 sleep, the patients with schizophrenia had significantly higher alpha power in the left occipital region than did controls. These findings show distinctive EEG sleep patterns in patients with schizophrenia, which may reflect brain dysfunction or medication effects.