Enhanced amygdala-cingulate connectivity associates with better mood in both healthy and depressive individuals after sleep deprivation.

Sleep loss robustly disrupts mood and emotion regulation in healthy individuals but can have a transient antidepressant effect in a subset of patients with depression. The neural mechanisms underlying this paradoxical effect remain unclear. Previous studies suggest that the amygdala and dorsal nexus (DN) play key roles in depressive mood regulation. Here, we used functional MRI to examine associations between amygdala- and DN-related resting-state connectivity alterations and mood changes after one night of total sleep deprivation (TSD) in both healthy adults and patients with major depressive disorder using strictly controlled in-laboratory studies. Behavioral data showed that TSD increased negative mood in healthy participants but reduced depressive symptoms in 43% of patients. Imaging data showed that TSD enhanced both amygdala- and DN-related connectivity in healthy participants. Moreover, enhanced amygdala connectivity to the anterior cingulate cortex (ACC) after TSD associated with better mood in healthy participants and antidepressant effects in depressed patients. These findings support the key role of the amygdala-cingulate circuit in mood regulation in both healthy and depressed populations and suggest that rapid antidepressant treatment may target the enhancement of amygdala-ACC connectivity.

Insomnia Symptoms and Suicide-Related Ideation in U.S. Army Service Members.

Background: Insomnia has been identified as a key risk factor for suicide, though most studies have been limited to global measures of these constructs. The aim of the present study was to evaluate the link between insomnia symptoms and five different aspects of suicide-related ideation. Participants: 1,160 active U.S. Army service members (719 male; Mage = 31.2; SDage = 8.62). Methods: As part of an archival analysis, retrospectively assessed insomnia, depression, anxiety symptoms, as well as suicide-related ideation, were evaluated. Suicide-related ideation was assessed in terms of: thoughts of death, thoughts of suicide, suicidal plan, suicidal intent, and suicidal communication. Results: Subjects with clinically significant insomnia symptoms were 3.5 times more likely to report any suicide-related ideation, and approximately 3 times more likely to report thoughts of death and thoughts of suicide. More frequent nocturnal awakenings (i.e., waking up three or more times during a single night) were associated with a greater likelihood of reporting thoughts of death or suicide, whereas greater middle insomnia (i.e., waking up and having difficulty getting back to sleep) was associated with lower odds of experiencing thoughts of suicide, suicidal plan, and suicidal intent. Conclusions: A more refined delineation of insomnia and suicide-related ideation may serve to clarify the nature of the association, and potentially offer some clues as to the underlying mechanisms. With regard to potential clinical implications, the results support that careful assessment of insomnia symptoms, suicide-related ideation, and their respective subtypes, is important and may influence how we estimate risk for suicide.

Effects of slow-wave activity on mood disturbance in major depressive disorder.

BACKGROUND: Studies have demonstrated that decreases in slow-wave activity (SWA) predict decreases in depressive symptoms in those with major depressive disorder (MDD), suggesting that there may be a link between SWA and mood. The aim of the present study was to determine if the consequent change in SWA regulation following a mild homeostatic sleep challenge would predict mood disturbance. METHODS: Thirty-seven depressed and fifty-nine healthy adults spent three consecutive nights in the sleep laboratory. On the third night, bedtime was delayed by 3 h, as this procedure has been shown to provoke SWA. The Profile of Mood States questionnaire was administered on the morning following the baseline and sleep delay nights to measure mood disturbance. RESULTS: Results revealed that following sleep delay, a lower delta sleep ratio, indicative of inadequate dissipation of SWA from the first to the second non-rapid eye movement period, predicted increased mood disturbance in only those with MDD. CONCLUSIONS: These data demonstrate that in the first half of the night, individuals with MDD who have less SWA dissipation as a consequence of impaired SWA regulation have greater mood disturbance, and may suggest that appropriate homeostatic regulation of sleep is an important factor in the disorder.

An Integrated Model of Slow-Wave Activity and Neuroplasticity Impairments in Major Depressive Disorder.

PURPOSE OF REVIEW: In this review, we aim to integrate the most recent research highlighting alterations in sleep slow-wave activity (SWA), and impairments in neuroplasticity in major depressive disorder (MDD) into a novel model of disorder maintenance. RECENT FINDINGS: Sleep homeostasis has been shown to be impaired in MDD, with a subset of individuals also demonstrating impaired SWA. SWA is considered a marker of the homeostatic regulation of sleep, and is implicated in the downscaling of synaptic strength in the context of maintaining homeostatic plasticity. Individuals with MDD have been shown to exhibit impairments in both neural plasticity such as loss of dendritic branching, and synaptic plasticity such as decreased long-term potentiation-dependent learning and memory. Alterations in the homeostatic regulation of sleep, SWA, and synaptic plasticity in MDD suggest an underlying impairment in the modulation of synaptic strength. One candidate mechanism for this impairment is AMPA receptor trafficking.

Slow-wave disruption enhances the accessibility of positive memory traces.

The purpose of this study was to explore the effects of slow-wave disruption on positive and negative word recognition in a sample of healthy control participants and those with major depressive disorder. Prior to sleep, participants learned a set of emotional and neutral words during an encoding task by responding whether or not the word described them. Following baseline sleep, participants underwent one night of selective slow-wave disruption by auditory stimuli. Accuracy and reaction time to a recognition word set, including both positive and negative words, was assessed in the morning. Repeated-measures ANOVA revealed a significant interaction between word valence and condition, with positive words recognized significantly faster than negative words after disruption, in only healthy control participants. There were no significant results in those with major depressive disorder, or with regard to accuracy. These results may add to the increasing body of literature suggesting a hedonic bias to positive stimuli following sleep disruption.

Examining the effects of sleep delay on depressed males and females and healthy controls.

Individuals with major depressive disorder typically exhibit sleep electroencephalograpy abnormalities which have been shown to vary by sex. Recent research has shown that depressed males display deficits in slow wave sleep and delta electroencephalograph (EEG) activity that are not apparent in depressed females. This may suggest that males and females with depression vary with respect to their homeostatic regulation of sleep. Utilizing archival data, the present study examined the effects of a 3-h sleep delay, which represents a mild sleep challenge, on slow wave activity in healthy controls and individuals with depression. All participants slept in the laboratory for three sequential nights. On the third night in the laboratory, the participants' bedtime was delayed by 3 h. Slow wave activity was calculated utilizing power spectral analysis and compared across groups. Following the sleep delay, males with depression exhibited the lowest slow wave activity compared to all other groups. These results may suggest that males with depression are at a greater risk for homeostatic dysregulation than females, and may require specialized intervention.

Does insomnia treatment prevent depression?

Rates of major depressive disorder (MDD) are increasing globally, in part due to the coronavirus disease 2019 pandemic, contributing to disease burden. It has long been known that insomnia is intricately connected with depression as indicated by greater depression severity and lower treatment response. Furthermore, insomnia is a significant risk factor for new-onset depression. Treatment of insomnia is thus a logical target for prevention of incidents and recurrent MDD. This systematic review sought to evaluate the current evidence for the preventive effects of insomnia treatment on depression onset. A database search yielded 186 studies, six of which met criteria for inclusion in this review. All of the studies utilized cognitive behavioral treatment for insomnia (CBT-I) as the target intervention and most delivered treatment via a digital platform. Four of the studies found significantly lower rates of MDD onset in those who received CBT-I compared to a control condition. The two remaining studies failed to confirm these effects in primary analyses but secondary analyses suggested evidence of a preventive effect. There was significant methodologic heterogeneity across studies in terms of sample selection, outcomes, and follow-up periods, limiting the ability to draw firm conclusions. The evidence overall is in the direction of insomnia treatment reducing the risk for onset of MDD, but further research is warranted.

The sleep homeostatic response to sleep deprivation in humans is heritable.

STUDY OBJECTIVES: Following sleep deprivation, increases in delta power have historically been used to index increases in sleep pressure. Research in mice has demonstrated that the homeostatic delta power response to sleep deprivation is heritable. Whether this is true in humans is unknown. In the present study, we used delta power and ORP, a novel measure of sleep depth, to investigate the effects of acute sleep deprivation on sleep depth and to assess the heritability of sleep homeostasis in humans. METHODS: ORP and delta power were examined during baseline and recovery sleep following 38 h of sleep deprivation in 57 monozygotic and 38 dizygotic same-sex twin pairs. Two complementary methods were used to estimate the trait heritability of sleep homeostasis. RESULTS: During recovery sleep, ORP was lower and delta power was higher than at baseline, indicating deeper sleep. However, at the end of the recovery night, delta power reached baseline levels but ORP demonstrated incomplete recovery. Both ORP and delta power showed a broad sense heritability of sleep homeostasis following sleep deprivation. The classical approach demonstrated an h2 estimate of 0.43 for ORP and 0.73 for delta power. Mixed-effect multilevel models showed that the proportion of variance attributable to additive genetic transmission was 0.499 (95% CI = 0.316-0.682; p < .0001) for ORP and 0.565 (95% CI = 0.403-0.726; p < .0001 for delta power. CONCLUSIONS: These results demonstrate that the homeostatic response to sleep deprivation is a heritable trait in humans and confirm ORP as a robust measure of sleep depth.

Antidepressant effects of acute sleep deprivation are reduced in highly controlled environments.

BACKGROUND: Numerous studies summarized in a recent meta-analysis have shown sleep deprivation rapidly improves depressive symptoms in approximately 50 % of individuals with major depressive disorder (MDD), however those studies were typically conducted in clinical settings. Here we investigated the effects of sleep deprivation utilizing a highly controlled experimental approach. METHODS: 36 antidepressant-free individuals with MDD and 10 healthy controls (HC) completed a 5 day/4-night protocol consisting of adaptation, baseline, total sleep deprivation (TSD), and recovery phases. Light was kept consistently dim (≤50 lx), meals were regulated, and activity was restricted. In-the-moment mood was assessed using a modified Hamilton Rating Scale for Depression (HRSD) at screening and each morning following the experimental nights. RESULTS: Day of study had a significant effect on mood in both groups. Post-hoc analyses revealed that significant effects were attributed to mood improvement in the MDD group following study initiation prior to beginning TSD, and in the HC group following recovery sleep, but were not due to mood improvement in the MDD group during TSD. No further improvement in mood occurred during 36 h of TSD. LIMITATIONS: Strict eligibility requirements may limit generalizability. The requirement to be medication free may have biased toward a less severely depressed sample. CONCLUSIONS: Results revealed that individuals with moderate MDD can experience a significant reduction in depressive symptoms upon entering a highly controlled laboratory environment. Environmental effects on mood can be substantial and need to be considered.

Treatment of Insomnia with Zaleplon in HIV+ Significantly Improves Sleep and Depression.

More than 50% of individuals who are HIV positive report insomnia, which can reduce HIV treatment adherence, impair quality of life, and contribute to metabolic dysfunction. Major depressive disorder is also highly comorbid in this population, leading to further impairment. There is evidence that treating insomnia may improve not only sleep, but depression and metabolic function, as well. The present study aimed to examine the effects of pharmacotherapeutic treatment of insomnia on sleep, depression, and metabolic functioning in individuals with HIV. 20 individuals with asymptomatic seropositive HIV and comorbid insomnia and depression were administered zaleplon for 6 weeks. Insomnia severity was assessed using the Insomnia Severity Index and Epworth Sleepiness Scale, and depression severity was assessed using the Quick Inventory of Depression, both prior to treatment and 6 weeks post treatment. Metabolomic changes were assessed using a comprehensive platform measuring ~2000 lipid features and polar metabolites. Linear mixed effects models demonstrated that 6 weeks of treatment with zaleplon significantly improved symptoms of both insomnia and depression. Metabolomic analyses also demonstrated that changes in insomnia severity were associated with significant changes in key branched chain amino acid metabolites. Our results show that improvement in insomnia is associated with reduced depressive symptoms and beneficial metabolomic changes. Additionally, changes in key branched chain amino acid metabolites following treatment may serve as useful biomarkers of treatment response.

Spindles are highly heritable as identified by different spindle detectors.

STUDY OBJECTIVES: Sleep spindles, a defining feature of stage N2 sleep, are maximal at central electrodes and are found in the frequency range of the electroencephalogram (EEG) (sigma 11-16 Hz) that is known to be heritable. However, relatively little is known about the heritability of spindles. Two recent studies investigating the heritability of spindles reported moderate heritability, but with conflicting results depending on scalp location and spindle type. The present study aimed to definitively assess the heritability of sleep spindle characteristics. METHODS: We utilized the polysomnography data of 58 monozygotic and 40 dizygotic same-sex twin pairs to identify heritable characteristics of spindles at C3/C4 in stage N2 sleep including density, duration, peak-to-peak amplitude, and oscillation frequency. We implemented and tested a variety of spindle detection algorithms and used two complementary methods of estimating trait heritability. RESULTS: We found robust evidence to support strong heritability of spindles regardless of detector method (h2 > 0.8). However not all spindle characteristics were equally heritable, and each spindle detection method produced a different pattern of results. CONCLUSIONS: The sleep spindle in stage N2 sleep is highly heritable, but the heritability differs for individual spindle characteristics and depends on the spindle detector used for analysis.

An Integrated Sleep and Reward Processing Model of Major Depressive Disorder.

Major depressive disorder with comorbid sleep disturbance has been associated with negative outcomes, including lower rates of treatment response and a greater likelihood of depressive relapse compared to those without sleep disturbance. However, little, if any, research has been conducted to understand why such negative treatment outcomes occur when sleep disturbance is present. In this conceptual review, we argue that the relationship of sleep disturbance and negative treatment outcomes may be mediated by alterations in neural reward processing in individuals with blunted trait-level reward responsivity. We first briefly characterize sleep disturbance in depression, discuss the nature of reward processing impairments in depression, and summarize the sleep/reward relationship in healthy human subjects. We then introduce a novel Integrated Sleep and Reward model of the course and maintenance of major depressive disorder and present preliminary evidence of sleep and reward interaction in unipolar depression. Finally, we discuss limitations of the model and offer testable hypotheses and directions for future research.

A preliminary investigation of the role of slow-wave activity in modulating waking EEG theta as a marker of sleep propensity in major depressive disorder.

BACKGROUND: Both EEG slow-wave activity (SWA) during sleep and EEG theta activity during waking have been shown to increase with extended waking, and decrease following sleep, suggesting that both are markers of sleep propensity. In individuals with major depressive disorder (MDD), however, altered patterns of SWA have been noted, suggesting that sleep homeostasis is dysregulated. This study aimed to examine if slow-wave disruption would alter sleep propensity differently in healthy controls (HC) and those with MDD. METHODS: 25 individuals (13 diagnosed with MDD and 12 HC) participated. Following one night of adaptation sleep, participants underwent one night of baseline sleep, and one night of selective slow-wave disruption by auditory stimuli. In the evening, before sleep, and in the morning following sleep, waking EEG was recorded from participants in an upright position, with eyes open. RESULTS: Repeated measures ANOVA revealed a significant three-way interaction, such that AM theta activity was significantly lower following slow-wave disruption in those with MDD, but not in HC. Additionally, SWA was not correlated with theta activity in MDD. LIMITATIONS: These data are based on a relatively small sample size of unmedicated individuals with MDD. CONCLUSIONS: These data may suggest that SWA plays a differential role in the homeostatic regulation of sleep in HC, and in MDD, and provide additional evidence that the presence of SWA may be maladaptive in MDD.

Social rhythm regularity moderates the relationship between sleep disruption and depressive symptoms in veterans with post-traumatic stress disorder and major depressive disorder.

Approximately 50% to 80% of individuals with posttraumatic stress disorder (PTSD) also meet criteria for major depressive disorder (MDD). Sleep disturbance is a major concern in both PTSD and MDD, and is associated with poor treatment response, poor functional outcome and increased suicide risk. Social rhythm regularity, or the consistency of daily habitual behaviors, is theoretically linked to circadian rhythms and may be disturbed in both PTSD and MDD. The present study examined the relationship between social rhythm regularity, sleep disruption and MDD and PTSD symptoms in a sample of veterans with comorbid PTSD and MDD. Baseline data were obtained from 56 male veterans who met DSM-IV criteria for PTSD and MDD. Veterans completed the Social Rhythm Metric (SRM), a self-report questionnaire that assesses the regularity of routines by determining how regularly individuals completed 17 different types of activities. In a linear regression model, increased minutes awake after sleep onset (WASO) was a significant predictor of increased depression scores on the Hamilton Rating Scale for Depression (p < .05). SRM scores did not significantly predict depressive symptoms, however the interaction of WASO and SRM significantly predicted depressive symptoms (p = <.05), with significant relationships found at SRM scores less than 3.62. Neither minutes awake after sleep onset, SRM scores, nor their interaction was associated with PTSD symptom severity. Social and possibly circadian rhythm regularity may represent a risk or resilience factor for individuals with comorbid PTSD and MDD. Findings highlight the importance of exploring the interactions of sleep and social/circadian rhythms in depression in order to inform continued treatment development.

Neurophysiological correlates of suicidal ideation in major depressive disorder: Hyperarousal during sleep.

BACKGROUND: Suicide is a major public health concern, and a barrier to reducing the suicide rate is the lack of objective predictors of risk. The present study considers whether quantitative sleep electroencephalography (EEG) may be a neurobiological correlate of suicidal ideation. METHODS: Participants included 84 (45 female, mean age=26.6) adults diagnosed with major depressive disorder (MDD). The item that measures thoughts of death or suicide on the Quick Inventory of Depressive Symptomatology (QIDS) was used to classify 47 participants as low suicidal ideation (24 females, mean age=26.1) and 37 as high suicidal ideation (21 females, mean age=27.3). Data were obtained from archival samples collected at the University of Michigan and University of Texas Southwestern Medical Center between 2004 and 2012. Sleep EEG was quantified using power spectral analysis, and focused on alpha, beta, and delta frequencies. RESULTS: Results indicated that participants with high compared to low suicidal ideation experienced 1) increased fast frequency activity, 2) decreased delta activity, and 3) increased alpha-delta sleep after adjusting for age, sex, depression, and insomnia symptoms. LIMITATIONS: Limitations include the exclusion of imminent suicidal intent, a single suicidal ideation item, and cross-sectional archival data. CONCLUSIONS: This is one of the first studies to provide preliminary support that electrophysiological brain activity during sleep is associated with increased suicidal ideation in MDD, and may point toward central nervous system (CNS) hyperarousal during sleep as a neurobiological correlate of suicidal ideation.