Circadian misalignment alters resting-state functional connectivity of the salience network in rotating shift workers.

STUDY OBJECTIVES: This study compared resting-state functional connectivity (rsFC) of the salience network (SN) between rotating shift workers (RSWs) and controls. Furthermore, we examined whether rsFC of the SN was correlated with sleep, emotion, cognition, and attention. METHODS: The 60 RSWs and 57 controls enrolled in this study completed self-report questionnaires and sleep diaries to assess subjective sleep quality, and polysomnography and actigraphy to evaluate objective sleep and 24-hour rest-activity rhythm parameters. The participants also underwent resting-state functional magnetic resonance imaging and structural T1 scans. We performed a seed-based rsFC analysis of the SN using the anterior cingulate cortex (ACC) and anterior insula (AI) as seed regions. Furthermore, AI and ACC rsFC were compared in RSWs and controls, and we analyzed correlations between rsFC and variables of interest showing significant group differences. RESULTS: Compared with controls, RSWs showed reduced rsFC between the ACC and right insula, and increased rsFC of the ACC with the left occipital lobe and right superior frontal gyrus extending to the supplementary motor area (SFG/SMA). Moreover, RSWs showed reduced rsFC between the right AI and right superior parietal lobule (SPL). Finally, rsFC between the ACC and right AI was correlated with 24-hour rest-activity rhythmicity. CONCLUSIONS: Although RSWs did not show sleep disturbance, emotional distress, cognitive impairment, or attention deficits, alterations of right insula, left occipital lobe, right SFG/SMA, and right SPL rsFC in the SN indicate that impairments in salience detection and top-down attentional control may emerge in shift workers over time.

Amygdala resting-state functional connectivity alterations in patients with chronic insomnia disorder: correlation with electroencephalography beta power during sleep.

STUDY OBJECTIVES: This study investigated alterations in resting-state functional connectivity (RSFC) and hyperarousal biomarkers in patients with chronic insomnia disorder (CID), compared with good sleepers (GS). We also examined the relationships between altered RSFC and hyperarousal biomarkers. METHODS: Fifty patients with CID and 52 GS completed self-reporting questionnaires, and then underwent polysomnography and resting-state functional magnetic resonance imaging. We analyzed RSFC in the amygdala (AMG) and anterior insula (aINS), which are core regions of the salience network that are likely to be involved in hyperarousal. We also analyzed electroencephalography (EEG) relative beta power and heart rate variability (HRV) parameters (e.g. low and high frequency) during sleep. We then tested between-group differences in the RSFC and hyperarousal biomarkers; we examined correlations of RSFC with EEG beta power and HRV. RESULTS: Compared with GS, patients with CID showed more negative RSFC between the right amygdala (R.AMG) and left supramarginal gyrus (L.SMG), but less positive RSFC between the left aINS and bilateral lateral prefrontal cortex. The R.AMG-L.SMG RSFC was negatively correlated with EEG beta power in central regions (C3: r = -0.336, p = 0.012; C4: r = -0.314, p = 0.024). CONCLUSIONS: Decreased RSFC between the R.AMG and L.SMG in patients with insomnia may reflect the difficulty in cortical top-down regulation of the AMG, indicating daytime hyperarousal. Individuals who experience hyperarousal during the daytime may also exhibit cortical hyperarousal during sleep, as indicated by increased EEG beta power.

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.

Cognitive Appraisal of Sleep and Brain Activation in Response to Sleep-Related Sounds in Healthy Adults.

Purpose: Sounds play important roles in promoting and disrupting sleep. How our brain processes sleep-related sounds and individual differences in processing sleep-related sounds must be determined to understand the role of sound in sleep. We investigated neural responses to sleep-related sounds and their associations with cognitive appraisals of sleep. Participants and Methods: Forty-four healthy adults heard sleep-related and neutral sounds during functional magnetic resonance imaging using a 3T scanner. They also completed the Dysfunctional Beliefs and Attitudes about Sleep (DBAS) questionnaire, which was used to assess cognitive appraisals of sleep. We conducted a voxel-wise whole-brain analysis to compare brain activation in response to sleep-related and neutral sounds. We also examined the association between the DBAS score and brain activity in response to sleep-related sounds (vs neutral sounds) using region of interest (ROI) and whole-brain correlation analyses. The ROIs included the anterior cingulate cortex (ACC), anterior insula (AI), and amygdala. Results: The whole-brain analysis revealed increased activation in the temporal regions and decreased activation in the ACC in response to sleep-related sounds compared to neutral sounds. The ROI and whole-brain correlation analyses showed that higher DBAS scores, indicating a negative appraisal of sleep, were significantly correlated with increased activation of the ACC, right medial prefrontal cortex, and brainstem in response to sleep-related sounds. Conclusion: These results indicate that the temporal cortex and ACC, which are implicated in affective sound processing, may play important roles in the processing of sleep-related sounds. The positive association between the neural responses to sleep-related sounds and DBAS scores suggest that negative and dysfunctional appraisals of sleep may be an important factor in individual differences in the processing of sleep-related sounds.

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.

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.

Neural correlates of emotional reactivity and regulation in traumatized North Korean refugees.

Refugees often report heightened emotional reactivity and emotion regulation difficulties and are at high risk for mental health problems. Given that refugees are repeatedly exposed to traumatic events that may cause changes in the brain, the present study examined neural correlates of emotional reactivity and regulation and their associations with refugee features (e.g., cumulative trauma) and the severity of psychiatric symptoms (e.g., post-traumatic stress disorder [PTSD]) in North Korean (NK) refugees. Forty NK refugees with trauma exposure and varying levels of psychopathology and 41 healthy South Korean (SK) controls without trauma exposure participated in this study. They performed an emotion regulation task during a functional magnetic resonance imaging (fMRI) assessment. Region of interest (ROI), whole brain, and generalized psychophysiological interaction (gPPI) analyses were conducted. NK refugees with trauma exposure and varying levels of psychopathology showed increased activation in response to negative socio-affective pictures in regions involved in affective processing, including the amygdala and hippocampus, relative to healthy SK controls without trauma exposure. They also exhibited greater prefrontal cortex (PFC) activation, amygdala-PFC functional connectivity (FC), and hippocampal-PFC FC during emotion regulation. More severe PTSD symptoms were associated with greater hippocampal response to negative pictures (vs. neutral pictures) in NK refugees. This study provides neuroscientific evidence for neural alterations in association with emotional reactivity and regulation in traumatized refugees. These findings may contribute to a better mechanistic understanding of emotional reactivity and regulation in refugees and suggest potential ways to address the emotional and mental problems of traumatized refugees.

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 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.

Thermal and Optical Performance of Glass Cloth Reinforced Organic-Inorganic Hybrid Polymer Composite Film.

Recently there has been considerable interest in flexible display as the next-generation display. The flexible plastic has been recommended as a strong candidate for substrate, but these plastic substrates have many problems to provide the comparable properties of dimensional stability, thermal stability, and solvent resistance to glass in order to apply conventional thin film transistor technology to flexible display. Then in this study, a glass cloth reinforced polymer (GCRP) composite was prepared. To improve the thermal property, glass cloth with an excellent coefficient of thermal expansion (CTE) for reinforcement and organic-inorganic hybrid nanomaterial with polyhedral oligomeric silsesquioxane (POSS) material having excellent heat resistance were introduced to ensure the excellent properties like transmittance, haze, yellow index, thermal stability and chemical resistance. The optical property of GCRP composite was measured by using a spectrophotometer and the CTE of GCRP composite was observed by thermomechanical analysis (TMA).

Topical cannabinoid receptor 1 agonist attenuates the cutaneous inflammatory responses in oxazolone-induced atopic dermatitis model.

BACKGROUND: Even with the widespread clinical use of cannabinoid receptor (CBR) stimulating compounds, such as palmitoylethanolamine, the role of CBR agonists on inflammatory skin diseases is not yet fully understood. This study was performed to investigate the effects of CBR agonists on skin inflammation, using acute and chronic inflammation animal models. METHODS: The effectiveness of the newly synthesized cannabinoid receptor 1 (CB1R) agonists was determined using in vitro assays. Markers for epidermal permeability barrier function and skin inflammation were measured, and histological assessments were performed for evaluation. RESULTS: Topical application of CB1R-specific agonist significantly accelerated the recovery of epidermal permeability barrier function and showed anti-inflammatory activity in both acute and chronic inflammation models. Histological assessments also confirmed the anti-inflammatory effects, which is consistent with previous reports. CONCLUSIONS: All of the results suggest that topical application of CB1R-specific agonist can be beneficial for alleviating the inflammatory symptoms in chronic skin diseases, including atopic dermatitis.

Sphingosine kinase 1 activation enhances epidermal innate immunity through sphingosine-1-phosphate stimulation of cathelicidin production.

BACKGROUND: The ceramide metabolite, sphingosine-1-phosphate (S1P), regulates multiple cellular functions in keratinocytes (KC). We recently discovered that production of a key innate immune element, cathelicidin antimicrobial peptide (CAMP), is stimulated via a NF-κB-dependent mechanism that is activated by S1P when S1P is generated by sphingosine kinase (SPHK) 1. OBJECTIVE: We investigated whether pharmacological modulation of SPHK1 activity, using a novel synthetic SPHK1 activator, (S)-methyl 2-(hexanamide)-3-(4-hydroxyphenyl) propanoate (MHP), stimulates CAMP expression. METHODS: MHP-mediated changes in both S1P and CAMP downstream mediators were analyzed in normal cultured human KC by qRT-PCR, Western immunoblot, ELISA, confocal microscopy for immunohistochemistry, HPLC and ESI-LC/MS/MS, and microbial pathogen invasion/colonization in a human epidermal organotypic model. RESULTS: Treatment with MHP directly activated SPHK1 and increased cellular S1P content in normal cultured human KC. Because MHP did not inhibit S1P lyase activity, which hydrolyses S1P, augumented S1P levels could be attributed to increased synthesis rather than blockade of S1P degradation. Next, we found that exogenous MHP significantly stimulated CAMP mRNA and protein production in KC, increases that were significantly suppressed by siRNA directed against SPHK1, but not by a scrambled control siRNA. NF-κB activation, assessed by nuclear translocation of NF-κB, occurred in cells following incubation with MHP. Conversely, pretreatment with a specific inhibitor of SPHK1 decreased MHP-induced nuclear translocation of NF-κB, and significantly attenuated the MHP-mediated increase in CAMP production. Finally, topical MHP significantly suppressed invasion of the virulent Staphylococcus aureus into murine skin explants. CONCLUSION: MHP activation of SPHK1, a target enzyme of CAMP production, can stimulate innate immunity.

Protease activity enhances production of thymic stromal lymphopoietin and basophil accumulation in flaky tail mice.

Epidermal barrier abnormality due to filaggrin deficiency is an important predisposing factor in the development of atopic dermatitis (AD). In addition, the expression of thymic stromal lymphopoietin (TSLP) in keratinocytes (KCs), induced by barrier disruption, can promote type 2 helper T-cell polarization. Protease activity, including protease-activated receptor-2 (PAR-2), is also known to be involved in epidermal barrier function in AD. However, to our knowledge, the relationship between protease activity and filaggrin deficiency from the perspective of AD has not been elucidated. Flaky tail (Flg(ft)) mice, known to have a mutation in the filaggrin gene, were used to assess the role of protease in KCs in the steady state and the mite-induced AD-like skin inflammation model. In the steady state, the expression and activity levels of endogenous proteases, kallikreins 5, 7, and 14, in the skin and TSLP were higher in Flg(ft) than in control mice. In addition, activation of PAR-2 by its agonist induced the production of TSLP in KCs of Flg(ft) mice, which was abrogated by a newly developed PAR-2 antagonist. Application of the PAR-2 antagonist improved symptoms and basophil accumulation in Flg(ft) mice treated with mite extracts. These results suggest that possibly through the PAR-2 activation in KCs, filaggrin deficiency induces TSLP production and basophil accumulation, which play important roles in the establishment of AD.

Protease-activated receptor-2 mediates the expression of inflammatory cytokines, antimicrobial peptides, and matrix metalloproteinases in keratinocytes in response to Propionibacterium acnes.

Propionibacterium acnes (P. acnes) has been known to produce various exogenous proteases, however, their role in acne pathogenesis remains largely unknown. Proteases elicit cellular responses, at least in part, via proteinase-activated receptor-2 (PAR-2), which is known to mediate inflammation and immune response. In this study, we investigated whether proteases from P. acnes could activate PAR-2 on keratinocytes and induce pro-inflammatory cytokines, antimicrobial peptides (AMPs), and matrix metalloproteinases (MMPs) via PAR-2 signaling. We examined PAR-2 expression and protease activity in acne lesions using immunofluorescence staining and in situ zymography. The effect of the culture supernatant of P. acnes on Ca(2+) signaling in immortalized keratinocytes (HaCaT) was measured using a fluorescence method. HaCaT cells were treated with P. acnes strain ATCC 6919 culture supernatant, with or without pretreatment with serine protease inhibitor or selective PAR-2 antagonist and the gene expression of pro-inflammatory cytokines, AMPs, and MMPs was detected using real-time reverse transcription-polymerase chain reaction. We found that the protease activity and PAR-2 expression were increased in acne lesions. The P. acnes culture supernatant induced calcium signaling in keratinocytes via PAR-2 and stimulated the mRNA expression of interleukin (IL)-1α, -8, tumor necrosis factor (TNF)-α, human beta defensin (hBD)-2, LL-37, MMP-1, -2, -3, -9, and -13 in keratinocytes, which was significantly inhibited by serine protease inhibitor as well as selective PAR-2 specific antagonist. These results indicate that PAR-2 plays an important role in the pathogenesis of acne by inducing inflammatory mediators in response to proteases secreted from P. acnes.