A Fully Remote Randomized Trial of Transcranial Alternating Current Stimulation for the Acute Treatment of Major Depressive Disorder.

Objective: Major depressive disorder (MDD) is common, but current treatment options have significant limitations in terms of access and efficacy. This study examined the effectiveness of transcranial alternating current stimulation (tACS) for the acute treatment of MDD.Methods: We performed a triple-blind, fully remote, randomized controlled trial comparing tACS with sham treatment. Adults aged 21-65 years meeting DSM 5 criteria for MDD and having a score on the Beck Depression Inventory, Second Edition (BDI-II), between 20 and 63 were eligible to participate. Participants utilized tACS or sham treatment for two 20-minute treatment sessions daily for 4 weeks. The primary outcome was change in BDI-II score from baseline to the week 2 time point in an intent-to treat analysis, followed by analyses of treatment-adherent participants. Secondary analyses examined change at the week 1 and 4 time points, responder rates, subgroup analyses, other self-report mood measures, and safety. The study was conducted from April to October 2022.Results: A total of 255 participants were randomized to active or sham treatment. Improvement in intent-to-treat analysis was not statistically significant at week 2 (P= .056), but there were significant effects in participants with high adherence (P= .005). Significantly greater improvement at week 1 (P= .020) and greater response at week 4 (P= .028) occurred following tACS. Improvements were significantly larger for female participants. There were no significant effects on secondary mood measures. Side effects were minimal and mild.Conclusions: Rapid, clinically significant improvement in depression in adults with MDD was associated with tACS, particularly for women. Compared to other depression therapies, tACS has 3 key advantages: rapid, clinically significant treatment effect, the ability of patients to use the treatment on their own at home, and the rarity and low impact of adverse events.Trial Registration: ClinicalTrials.gov identifier: NCT05384041.

Resting-state functional connectivity changes in older adults with sleep disturbance and the role of amyloid burden.

Sleep and related disorders could lead to changes in various brain networks, but little is known about the role of amyloid ß (Aß) burden-a key Alzheimer's disease (AD) biomarker-in the relationship between sleep disturbance and altered resting state functional connectivity (rsFC) in older adults. This cross-sectional study examined the association between sleep disturbance, Aß burden, and rsFC using a large-scale dataset from the Alzheimer's Disease Neuroimaging Initiative (ADNI). Sample included 489 individuals (53.6% cognitively normal, 32.5% mild cognitive impairment, and 13.9% AD) who had completed sleep measures (Neuropsychiatric Inventory), PET Aß data, and resting-state fMRI scans at baseline. Within and between rsFC of the Salience (SN), the Default Mode (DMN) and the Frontal Parietal network (FPN) were compared between participants with sleep disturbance versus without sleep disturbance. The interaction between Aß positivity and sleep disturbance was evaluated using the linear regressions, controlling for age, diagnosis status, gender, sedatives and hypnotics use, and hypertension. Although no significant main effect of sleep disturbance was found on rsFC, a significant interaction term emerged between sleep disturbance and Aß burden on rsFC of SN (ß = 0.11, P = 0.006). Specifically, sleep disturbance was associated with SN hyperconnectivity, only with the presence of Aß burden. Sleep disturbance may lead to altered connectivity in the SN when Aß is accumulated in the brain. Individuals with AD pathology may be at increased risk for sleep-related aberrant rsFC; therefore, identifying and treating sleep problems in these individuals may help prevent further disease progression.

Neighborhood disadvantage is associated with sleep disturbance in a sample of trauma-exposed Veterans.

OBJECTIVES: This study examined associations among neighborhood disadvantage, all-night respiratory sinus arrhythmia, fear of sleep, nightmare frequency, and sleep duration in a sample of trauma-exposed Veterans. METHODS: Participants completed baseline assessments and slept on a mattress actigraphy system for seven nights. Neighborhood disadvantage was assessed with the Area Deprivation Index, a census-based socioeconomic index. Differences between the least and most disadvantaged groups on the sleep variables were analyzed. RESULTS: Data were available from 37 Veterans. Residing in neighborhoods with greater disadvantage was associated with elevated fear of sleep and reduced sleep-period respiratory sinus arrhythmia. No significant differences were observed for nightmare frequency or sleep duration. A regression confirmed that neighborhood context had a significant effect on respiratory sinus arrhythmia, after controlling for other baseline sleep variables. CONCLUSIONS: In this sample of Veterans, sleep context may increase hypervigilance in turn serving as a mechanism by which trauma-induced sleep disruptions are maintained.

The relationship between alcohol- and sleep-related traits: Results from polygenic risk score and Mendelian randomization analyses.

STUDY OBJECTIVES: We investigated whether genetic risk for insomnia and sleep duration abnormalities are associated with AUD and alcohol consumption. We also evaluated the causal relationships between sleep- and alcohol-related traits. METHODS: Individual-level phenotype and genotype data from the Million Veteran Program were used. Polygenic risk scores (PRS) were computed using summary statistics from two recent discovery GWAS of insomnia (N= 453,379 European-ancestry (EA) individuals) and sleep duration (N= 446,118 EAs) and tested for association with lifetime AUD diagnosis (N= 34,658 EA cases) and past-year Alcohol Use Disorders Identification Test-Consumption scale scores (AUDIT-C, N= 200,680 EAs). Bi-directional two-sample Mendelian Randomization (MR) analyses assessed causal associations between the two sleep traits and the two alcohol-related traits. RESULTS: The insomnia PRS was positively associated with AUD at 2/9 PRS thresholds, with p<0.01 being the most significant (OR = 1.02, p = 3.48 × 10-5). Conversely, insomnia PRS was negatively associated with AUDIT-C at 6/9 PRS thresholds (most significant threshold being p = 0.001 (ß = -0.02, p = 5.6 × 10-8). Sleep duration PRS was positively associated with AUDIT-C at 2/9 PRS thresholds, with the most significant threshold being p = 1 × 10-6 (ß = 0.01, p = 0.0009). MR analyses supported a significant positive causal effect of insomnia on AUD (14 SNPs; ß = 104.14; SE = 16.19; p = 2.22 × 10-5), although with significant heterogeneity. MR analyses also showed that shorter sleep duration had a causal effect on the risk of AUD (27 SNPs; ß = -63.05; SE = 3.54; p = 4.55 × 10-16), which was robust to sensitivity analyses. CONCLUSION: The genetic risk for insomnia shows pleiotropy with AUD, and sleep continuity abnormalities have a causal influence on the development of AUD.

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.

Effect of sleep manipulations on intrusive memories after exposure to an experimental analogue trauma: A meta-analytic review.

Sleep plays an important role in memory processing and is disrupted in individuals with post-traumatic stress disorder (PTSD). A growing body of research has experimentally investigated how sleep - or lack thereof - in the early aftermath of a traumatic experience contributes to intrusive memory formation. The aim of this meta-analytic review was to examine the effects of various experimental sleep manipulations (e.g., sleep deprivation, daytime naps) on intrusive memories following exposure to an experimentally induced analogue traumatic event. Eight eligible studies were systematically identified through PsycInfo and PubMed and provided sufficient data to contribute to a meta-analysis of the effects of sleep versus wakefulness on intrusive memory frequency. Sleep was found to reduce intrusive memory frequency when compared to wakefulness at a small but significant effect size (Hedge's g = 0.29). There was no evidence of publication bias and heterogeneity of effect sizes across studies was moderate. Results suggest that sleep plays a protective role in the aftermath of exposure to a traumatic event with implications for early post-trauma intervention efforts.

Potential genetic and epigenetic mechanisms in insomnia: A systematic review.

Insomnia is a stress-related sleep disorder conceptualised within a diathesis-stress framework, which it is thought to result from predisposing factors interacting with precipitating stressful events that trigger the development of insomnia. Among predisposing factors genetics and epigenetics may play a role. A systematic review of the current evidence for the genetic and epigenetic basis of insomnia was conducted according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) system. A total of 24 studies were collected for twins and family heritability, 55 for genome-wide association studies, 26 about candidate genes for insomnia, and eight for epigenetics. Data showed that insomnia is a complex polygenic stress-related disorder, and it is likely to be caused by a synergy of genetic and environmental factors, with stress-related sleep reactivity being the important trait. Even if few studies have been conducted to date on insomnia, epigenetics may be the framework to understand long-lasting consequences of the interaction between genetic and environmental factors and effects of stress on the brain in insomnia. Interestingly, polygenic risk for insomnia has been causally linked to different mental and medical disorders. Probably, by treating insomnia it would be possible to intervene on the effect of stress on the brain and prevent some medical and mental conditions.

Persistent Ventral Anterior Cingulate Cortex and Resolved Amygdala Hyper-responses to Negative Outcomes After Depression Remission: A Combined Cross-sectional and Longitudinal Study.

BACKGROUND: Major depressive disorder (MDD) is a highly prevalent mood disorder affecting more than 300 million people worldwide. Biased processing of negative information and neural hyper-responses to negative events are hallmarks of depression. This study combined cross-sectional and longitudinal experiments to explore both persistent and resolved neural hyper-responses to negative outcomes from risky decision making in patients with current MDD (cMDD) and remitted MDD (rMDD). METHODS: A total of 264 subjects participated in the cross-sectional study, including 117 patients with medication-naïve, first-episode current depression; 45 patients with rMDD with only 1 episode of depression; and 102 healthy control subjects. Participants completed a modified balloon analog risk task during functional magnetic resonance imaging. In the longitudinal arm of the study, 42 patients with cMDD were followed and 26 patients with rMDD were studied again after 8 weeks of antidepressant treatment. RESULTS: Patients with cMDD showed hyper-responses to loss outcomes in multiple limbic regions including the amygdala and ventral anterior cingulate cortex (vACC). Amygdala but not vACC hyperactivity correlated with depression scores in patients with cMDD. Furthermore, amygdala hyperactivity resolved while vACC hyperactivity persisted in patients with rMDD in both cross-sectional and longitudinal studies. CONCLUSIONS: These findings provide consistent evidence supporting differential patterns of amygdala and vACC hyper-responses to negative outcomes during depression remission. Amygdala hyperactivity may be a symptomatic and state-dependent marker of depressive neural responses, while vACC hyperactivity may reflect a persistent and state-independent effect of depression on brain function. These findings offer new insights into the neural underpinnings of depression remission and prevention of depression recurrence.

Sleep Disturbances Associated With Posttraumatic Stress Disorder.

Sleep disturbances, namely insomnia and recurrent nightmares, are ubiquitous following trauma exposure and are considered hallmarks of posttraumatic stress disorder (PTSD). Other sleep disorders frequently co-occur with PTSD. This article describes research examining sleep problems most common in PTSD, including prevalence and clinical characteristics. Sleep disturbances are often robust to trauma-focused treatment; thus, evidence for psychological and pharmacological interventions for insomnia and nightmares in PTSD are discussed. Given the high prevalence of sleep problems in PTSD, more work is needed to empirically study putative mechanisms linking trauma exposure and sleep, as well as how to best target these symptoms in patients with PTSD.

The association of polysomnographic sleep on posttraumatic stress disorder symptom clusters in trauma-exposed civilians and veterans.

Study Objectives: Self-reported sleep disturbance has been established as a risk factor and predictor for posttraumatic stress disorder (PTSD); however, less is known about the relationship between objective sleep and PTSD symptom clusters, and the specific role of hyperarousal. The present study examined the relationships between sleep continuity and architecture on PTSD symptom clusters. Methods: Participants underwent two in-laboratory sleep studies to assess sleep continuity and architecture. They also completed the Clinician-Administered PTSD-IV scale and the Structured Clinical Interview for the DSM-IV to assess for PTSD diagnosis and other psychiatric disorders. Results: Sleep continuity (i.e. total sleep time, sleep efficiency percent, wake after sleep onset, sleep latency) was significantly related to PTSD Cluster B (reexperiencing) symptom severity (R 2 = .27, p < .001). Sleep architecture, specifically Stage N1 sleep, was significantly associated with PTSD Cluster B (t = 2.98, p = .004), C (Avoidance; t = 3.11, p = .003), and D (Hyperarosual; t = 3.79, p < .001) symptom severity independently of Stages N2, N3, and REM sleep. REM sleep variables (i.e. REM latency, number of REM periods) significantly predicted Cluster D symptoms (R 2 = .17, p = .002). Conclusions: These data provide evidence for a relationship between objective sleep and PTSD clusters, showing that processes active during Stage N1 sleep may contribute to PTSD symptomatology in civilians and veterans. Further, these data suggest that arousal mechanisms active during REM sleep may also contribute to PTSD hyperarousal symptoms.This paper is part of the War, Trauma, and Sleep Across the Lifespan Collection. This collection is sponsored by the Sleep Research Society.

Insomnia in the Older Adult.

Although insomnia is not a normal part of the aging process, its prevalence increases with age. Factors such as medications and medical and psychiatric disorders can increase the risk for insomnia. In order to diagnose insomnia, it is important for older adults to complete comprehensive sleep and health histories. Cognitive behavioral therapy for insomnia, which includes stimulus control, sleep restriction, sleep hygiene, and cognitive therapy, is the recommended first-line treatment of insomnia and is more effective that medications for the long-term management of insomnia. Medications such as benzodiazepines and antidepressants should be avoided for the treatment of insomnia in older adults.

Trauma type as a risk factor for insomnia in a military population.

BACKGROUND: This study evaluated whether lifetime traumatic stress compared to deployment-related traumatic stress differentially affected the likelihood of insomnia in military personnel. METHODS: Data were obtained from the Army Study to Assess Risk and Resilience in Servicemembers (unweighted N = 21,499; weighted N = 670,335; 18-61 years; 13.5% Female). DSM-5 criteria were applied to the Brief Insomnia Questionnaire to determine past month insomnia diagnostic status. A lifetime stress survey was used to assess traumatic stress encountered outside of the military, and a deployment-related stress survey assessed for various types of deployment-related traumatic stress. RESULTS: Adjusting for sex and psychiatric disorders, lifetime traumatic stress increased the prevalence for insomnia among those who endorsed combat death of close friend or relative, 1.021 (95% CI, 1.02-1.02), followed by those who reported other experiences that put them at risk of death or serious injury, 1.013 (95% CI, 1.01-1.01), whereas deployment-related traumatic stress showed that the prevalence for insomnia was highest for those who reported being sexually assaulted or raped, 1.059 (95% CI, 1.04-1.08), followed by those who endorsed being hazed or bullied by one or more members of their unit 1.042 (95% CI, 1.04-1.05). LIMITATIONS: The cross-sectional nature of the assessment limits causal inferences and there was no clinician determined diagnosis for insomnia. CONCLUSION: Findings suggest that traumas over both one's lifetime and during deployment are associated with a higher prevalence for insomnia among Army soldiers. Results highlight the importance of considering both lifetime and deployment traumas into mental health assessment and treatment for active-duty soldiers.

Daily steps and depressive symptoms: A longitudinal evaluation of patients with major depressive disorder in the precision medicine in mental health care study.

BACKGROUND: Although the benefits of exercise on Major Depressive Disorder (MDD) are well established, longitudinal studies of objectively measured activity in clinical populations are needed to establish specific guidelines for exercise by persons with moderate-to-severe depression. This study examines the association between objectively assessed daily step count and depressive symptoms over a 24-week follow- up period in outpatients receiving treatment for moderate-to-severe depression. METHODS: Participants were US Veterans with MDD enrolled in the Precision Medicine in Mental Health Care study (PRIME Care), a pragmatic, multi-site, randomized, controlled trial that examines the utility of genetic testing in the context of pharmacotherapy for MDD. Participants were a subset (N = 66) enrolled in actigraphy (using GT9X ActiGraph) monitoring component of the trial. Daily steps were examined as a predictor of depressive symptoms over 4-, 8-, 12-, 18-, and 24-weeks. RESULTS: On average, participants took 3,460 (±1,768) steps per day. In generalized linear mixed models, an increase in 1,000 steps per day was associated with a 0.6-point decrease in depressive symptom severity at the subsequent follow-up assessment. LIMITATIONS: Activity monitoring was observational and causal inferences cannot be made between daily steps and subsequent depressive symptom severity. Results may not generalize to non-treatment-seeking populations. CONCLUSIONS: Study findings provide an initial metric for persons with clinically significant MDD, of whom most do not get sufficient daily activity. The findings can inform future trials aimed at determining how much daily activity is needed to improve symptoms in individuals with MDD.

Treatment of a patient with a circadian sleep-wake disorder using a combination of melatonin and metoprolol.

CITATION: Circadian rhythm sleep-wake disorders result from the lack of synchronization between endogenous circadian rhythms and daily environmental or behavioral cycles. Current treatment of circadian rhythm sleep-wake disorders relies on strengthening normal zeitgebers, or temporal cues, through the combination of strict behavioral modification, controlled light exposure, and supplemental melatonin or melatonin receptor agonists. These therapies can be difficult to maintain and are supported with only limited clinical outcome data. The effectiveness of exogenous melatonin, in particular, may be reduced by the patient's continued production of endogenous melatonin with a temporal pattern that is not conducive to the desired sleep schedule. Here we describe the case of a single, sighted patient with a circadian rhythm sleep-wake disorder who benefited from the combined use of a beta blocker to suppress endogenous melatonin secretion along with the timed administration of exogenous melatonin. We suggest that the positive results obtained justify further study of this mechanism-guided approach. CITATION: Gehrman PR, Anafi RC. Treatment of a patient with a circadian sleep-wake disorder using a combination of melatonin and metoprolol. J Clin Sleep Med. 2021;17(10):2121-2124.

Insomnia: Sex differences and age of onset in active duty Army soldiers.

BACKGROUND: The prevalence of insomnia symptoms, insomnia diagnostic status, and age of onset compared by sex is understudied within the military population. METHOD: Data were examined from the All Army Study to Assess Risk and Resilience in Service members (N = 21,294; 18-61 years; 11.7% female and 87.6% male). Participants were given a self-administered version of the Composite International Diagnostic Interview Screening Scales to assess psychopathology and cognitive deficits, and the Brief Insomnia Questionnaire for insomnia disorder assessment. Participants identified the age they first experienced sleep problems for 1 month or longer as part of the self-administered questionnaire. RESULTS: Among this sample of Army soldiers, 22.8% met insomnia diagnostic status (22.0% of males and 28.4% of females). A binary logistic regression model revealed that insomnia diagnostic status was associated with female soldiers (OR = 1.26, P< .001, 95% CI = 1.13-1.41) compared to male soldiers, even when accounting for sociodemographic variables and mental health disorders. No significant sex differences emerged at insomnia symptom level or sleep problem age of onset. CONCLUSION: This study highlights the importance of examining insomnia by sex in active-duty populations. Results suggest that female active duty soldiers experience insomnia at a higher rate than their male counterparts, which may be driven by reports of daytime impairment. Given this information, more specific clinical recommendations on assessing and treating insomnia could be provided, especially when considering readiness for military duty.

Hyperarousal and Insomnia in Survivors of Cancer.

BACKGROUND: Cancer survivors are prone to insomnia due to the physical and psychological sequelae of cancer and treatment. Individuals with insomnia may present symptoms of hyperarousal. Cancer survivors with insomnia and trait hyperarousal may require different clinical treatments than patients with insomnia without trait hyperarousal. To our knowledge, no study has examined these factors previously. This study examined the relation between insomnia and trait hyperarousal in cancer survivors. METHODS: The sample included 160 individuals with previous cancer diagnoses who met DSM-5 criteria for insomnia disorder. Measures were collected with cross-sectional batteries of questionnaires, including the Insomnia Severity Index (ISI) and Hyperarousal Scale (HAS). This study is based on baseline data collected in a randomized clinical trial comparing CBT-I to acupuncture for cancer survivors with insomnia (Garland, Gehrman, Barg, Xie, & Mao, 2016). RESULTS: Hyperarousal was positively associated with insomnia (ISI total score) in bivariate correlations (r = .350, p < .01) and linear regressions (F = 22.06, p < .001). In bivariate correlations, hyperarousal was related to perceptions about the consequences of disturbed sleep rather than reported sleep patterns. For example, hyperarousal was positively related to reported satisfaction (r = .159, p < .05) and worry about sleep (r = .415, p < .01), but not to falling asleep, staying asleep, or awakening too early. In regressions, younger age, insomnia duration, and worry about sleep were uniquely associated with hyperarousal when adjusting for insomnia (B = 0.200, B = 0.177, B = -0.182, p < .05). CONCLUSIONS: Hyperarousal is associated with psychological appraisal of insomnia rather than reported sleep pattern. Younger age and longer duration of insomnia are associated with trait hyperarousal. These findings suggest targeting trait hyperarousal with amplified psychological treatment may lead to more personalized, effective treatment for insomnia.

Heritability of sleep duration and quality: A systematic review and meta-analysis.

Epidemiological and interventional research has highlighted sleep as a potentially modifiable risk factor associated with poor physical and mental health. Emerging evidence from (behavioral) genetic research also shows that sleep characteristics are under strong genetic control. With this study we aimed to meta-analyze the literature in this area to quantify the heritability of sleep duration and sleep quality in the general population. We conducted a systematic literature search in five online databases on January 24th 2020. Two authors independently screened 5644 abstracts, and 160 complete articles for the inclusion criteria of twin studies from the general population reporting heritability statistics on sleep duration and/or quality, and written in English. We ultimately included 23 papers (19 independent samples: 45,328 twins between 6 mo and 88 y) for sleep duration, and 13 papers (10 independent samples: 39,020 twins between 16 and 95 y) for sleep quality. Collectively, we showed that 46% of the variability in sleep duration and 44% of the variability in sleep quality is genetically determined. The remaining variation in the sleep characteristics can mostly be attributed to the unique environment the twins experience, although the shared environment seemed to play a role for the variability of childhood sleep duration. Meta-analyzed heritability estimates for sleep duration, however, varied substantially with age (17% infancy, 20-52% childhood, 69% adolescence and 42-45% adulthood) and reporter (8% parent-report, 38-52% self-report). Heritability estimates for actigraphic and Polysomnography (PSG)-estimated sleep were based on few small samples, warranting more research. Our findings highlight the importance of considering genetic influences when aiming to understand the underlying mechanisms contributing to the trajectories of sleep patterns across the lifespan.

Sleep classification from wrist-worn accelerometer data using random forests.

Accurate and low-cost sleep measurement tools are needed in both clinical and epidemiological research. To this end, wearable accelerometers are widely used as they are both low in price and provide reasonably accurate estimates of movement. Techniques to classify sleep from the high-resolution accelerometer data primarily rely on heuristic algorithms. In this paper, we explore the potential of detecting sleep using Random forests. Models were trained using data from three different studies where 134 adult participants (70 with sleep disorder and 64 good healthy sleepers) wore an accelerometer on their wrist during a one-night polysomnography recording in the clinic. The Random forests were able to distinguish sleep-wake states with an F1 score of 73.93% on a previously unseen test set of 24 participants. Detecting when the accelerometer is not worn was also successful using machine learning ([Formula: see text]), and when combined with our sleep detection models on day-time data provide a sleep estimate that is correlated with self-reported habitual nap behaviour ([Formula: see text]). These Random forest models have been made open-source to aid further research. In line with literature, sleep stage classification turned out to be difficult using only accelerometer data.