A Novel Use of a Sleep Intervention to Target the Emotion Regulation Brain Network to Treat Depression and Anxiety

Study Overview
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Brief Summary
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Several lines of evidence suggest that unhealthy sleep patterns contribute to depressive symptoms through disruption of brain networks that regulate emotional functions. However, we do not yet know to what degree the emotion regulation brain network is modified by the restoration of sleep, or whether the degree to which a sleep intervention modifies these neural targets mediates reductions in other depressive symptoms including suicidality. The overall aim is to test the efficacy of an established sleep intervention (Cognitive Behavioral Therapy for Insomnia (CBT-I)) in reducing depressive symptoms through improving emotion regulation brain function in individuals with elevated depressive symptoms and clinically meaningful sleep disturbance. In this study, we will assess feasibility of recruitment and retention as well as target engagement. Target engagement is defined as the treatment effect on increasing mPFC-amygala connectivity, and/or decreasing amygdala reactivity during emotion reactivity and regulation paradigms. Participants will be 70 adults experiencing at least moderate sleep disturbances and who also have elevated anxious and/or depressive symptoms. Emotion distress and sleep disruption will be assessed prior to, and weekly while receiving six Cognitive Behavioral Therapy for Insomnia (CBT-I) across a period of 8 weeks. CBT-I improves sleep patterns through a combination of sleep restriction, stimulus control, mindfulness training, cognitive therapy targeting dysfunctional beliefs about sleep, and sleep hygiene education. Using fMRI scanning, emotion regulation network neural targets will be assayed prior to and following completion of CBT-I treatment.

Official Title
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A Novel Use of a Sleep Intervention to Target the Emotion Regulation Brain Network to Treat Depression and Anxiety

Conditions
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Insomnia, Depression

Intervention / Treatment
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* Behavioral: Cognitive Behavioral Therapy for Insomnia


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Ages 25-60 Subjective complaint of sleep disturbance for ≥ 3 months (ISI>15) Subjective complaint of depression (BDI≥14) and not at imminent risk for suicide, as measured by CSSRS assessment Fluent and literate in English Written informed consent. Reside within 60 miles of Stanford University Exclusion Criteria: Presence of other sleep or circadian rhythm disorders Medications that would significantly impact sleep, alertness, or mood >14 alcoholic drinks per week or >4 drinks per occasion General medical condition, disease or neurological disorder that interferes with the assessments or outpatient participation Substance abuse or dependence Mild traumatic brain injury Severe impediment to vision, hearing and/or hand movement, likely to interfere with the ability to follow study protocols Pregnant or breast feeding Current or lifetime history of bipolar disorder or psychosis Current or or expected cognitive behavior therapy or other evidence-based psychotherapies for another condition Received CBT-I within the past year Acute or unstable chronic illness Current exposure to trauma, or exposure to trauma within the past 3 months Working a rotating shift that overlaps with 2400h. Presence of suicidal ideations representing imminent risk as determined by the empirically-supported, standardized suicide risk assessment to the exclusion criteria Individuals who are not CPAP adherent or have untreated OSA of moderate severity or worse (AHI ≥ 15)

Ages Eligible for Study
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Minimum Age: 25 Years
Maximum Age: 60 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Interventional Model Description: This is a single-armed trial. All participants will receive Cognitive Behavioral Therapy for Insomnia
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Other: CBT-I<br> | Behavioral: Cognitive Behavioral Therapy for Insomnia<br>* Participants will meet with a psychologist once a week for six weeks to complete a brief CBT-I intervention. Cognitive Behavioral Therapy for Insomnia consists of a cognitive therapy and a behavioral therapy. The cognitive therapy is designed to identify incorrect ideas about sleep, challenge their validity, and replace them with correct information. This therapy tries to reduce worry, anxiety, and fear that one won't sleep by providing accurate information about sleep. The behavioral therapy increases sleep quality by limiting excessive time spent in bed to increase homeostatic sleep drive and sleep consolidation.<br>* Other names: CBT-I;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Emotion Regulation Network brain activation as assessed by functional magnetic resonance imaging | During functional magnetic resonance imaging the Emotion Regulation Network will be engaged by emotional tasks, and circuit activation will be quantified by blood flow in regions of interest. | Assessed at week 0 and week 11 | 
| Change in Emotion Regulation Network brain connectivity as assessed by functional magnetic resonance imaging | During functional magnetic resonance imaging the Emotion Regulation Network will be engaged by emotional tasks, and circuit connectivity will be quantified by the correlation of the blood flow between regions of interest. | Assessed at week 0 and week 11 | 
| Change in Beck Depression Inventory | This measure is of the Beck Depression Inventory-II total score after excluding one sleep item. The average item score for the remaining 20 items will be multiplied by 21 (the original number of items), to create a modified depression scale that maintains the original range (ranges: 0-13 minimal, 14-19 mild, 20-28 moderate, and 29-63 severe). The BDI-II is a 21-item self-report scale with high validity and reliability that assesses the severity of depression symptoms. The depression items consist of: sadness, pessimism, past failure, loss of pleasure, guilty feelings, punishment feelings, self-dislike, self-criticalness, suicidal thoughts or wishes, crying, agitation, loss of interest, indecisiveness, worthlessness, loss of energy, irritability, changes in appetite, concentration difficulty, tiredness or fatigue, and loss of interest in sex. Items are scored from 0 to 3, and higher scores indicate greater levels of severity. | Assessed at week 0 and week 11 | 
| Change in PSG Sleep Efficiency | Sleep efficiency (SE) is the percentage of total time in bed actually spent sleeping. Based on the overnight PSG sleep recording, SE will be calculated as the total time (minutes) spent asleep (sum of Stages N1, N2, N3, and REM) divided by the total time (minutes) in bed, and multiplied by 100. | Assessed at week 0 and week 11 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Columbia Suicide Severity Rating Scale | The Columbia Suicide Severity Rating Scale is a 12-item checklist that was designed to quantify the severity of suicidal ideation and behavior. It is composed of two parts. The first six questions ask about suicidal ideation and behavior in the past month while the last six questions ask about suicidal ideation and behavior since the last visit. The CSSRS has been proven to be reliable and valid. It has also been shown to have high sensitivity and specificity to the different suicidal behavior classifications. | Assessed at week 0 and week 11 | 
| Change in Actigraph Sleep Onset Latency (SOL) as a Measure of Sleep Continuity | Sleep Onset Latency (SOL) is the time (minutes) from lights out to actually falling asleep (sleep onset). | Assessed at week 0 and week 11 | 
| Change in Actigraph Number of Arousals as a Measure of Sleep Continuity | Number of Arousals is determined by number of times of awakening as seen on the actigraph data. | Assessed at week 0 and week 11 | 
| Change in Actigraph Wake After Sleep Onset (WASO) as a Measure of Sleep Continuity | Wake After Sleep Onset (WASO) are periods of wakefulness occurring after sleep onset, before final awakening (sleep offset). | Assessed at week 0 and week 11 | 
| Change in Actigraph Total Sleep Time (TST) as a Measure of Sleep Continuity | Total Sleep Time (TST) is the total time spent asleep, from the start of sleep onset to sleep offset subtracting any periods of wakefulness. | Assessed at week 0 and week 11 | 
| Change in Actigraph Sleep Efficiency (SE) as a Measure of Sleep Continuity | Sleep Efficiency (SE) is calculated as TST divided by total time spent in bed, multiplied by 100. | Assessed at week 0 and week 11 | 
| Change in PSG Sleep Onset Latency (SOL) as a Measure of Sleep Architecture | Sleep Onset Latency (SOL) is the time (minutes) from lights out or start of total recording time, to actually falling asleep as indicated by EEG changes. | Assessed at week 0 and week 11 | 
| Change in PSG Number of Arousals as a Measure of Sleep Architecture | Number of Arousals is determined by number of times of awakening by EEG changes. | Assessed at week 0 and week 11 | 
| Change in PSG Wake After Sleep Onset (WASO) as a Measure of Sleep Architecture | Wake After Sleep Onset (WASO) are periods of wakefulness occurring after sleep onset, before final awakening (sleep offset) measured by EEG changes. | Assessed at week 0 and week 11 | 
| Change in PSG Total Sleep Time (TST) as a Measure of Sleep Architecture | Total Sleep Time (TST) is the total time (minutes) spent asleep, from the start of sleep onsetto sleep offset, subtracting any periods of wakefulness. TST includes stages N1, N2, N3, and REM sleep. | Assessed at week 0 and week 11 | 
| Change in PSG Sleep Efficiency (SE) as a Measure of Sleep Architecture | Sleep Efficiency (SE) is calculated as TST divided by total time spent in bed, multiplied by 100. Duration of non-rapid eye movement (NREM) sleep includes stages N1, N2, and N3, and is measured in minutes. The duration of sleep outside of those stages that is associated with specific EEG stages is REM sleep. | Assessed at week 0 and week 11 | 
| Change in Sleep Physiology measured by PSG | Topographical EEG power spectral density analysis associated with sleep stages will be calculated in the Delta (0.5-Hz), Theta (4-7Hz), Alpha (7-11Hz), Sigma (12-15Hz), Beta-1 (15-20Hz), Beta-2 (20-35Hz) and Gamma (35-45Hz) bands, according to published methods. | Assessed at week 0 and week 11 | 
| Change in Insomnia Severity Index (ISI) Scale Score | Subjective ratings of sleep disturbance and insomnia severity will be assessed with the Insomnia Severity Index. The Insomnia Severity Index (ISI) is a 7-item self-report measure of insomnia type, severity, and impact on functioning. The items consist of severity of sleep onset, sleep maintenance, early morning awakenings, sleep dissatisfaction, interference with daytime functioning, noticeability of sleep problems by others, and distress caused by sleep difficulties. Items are scored from 0 to 4 (0 = no problem, 4 = very severe problem). Score ranges of insomnia are: 0-7 absent, 8-14 sub-threshold, 15-21 moderate, and 22-28 severe. The ISI has good validity and reliability. | Assessed at week 0 and week 11 | 
| Change in Social and Occupational Functioning Assessment Scale (SOFAS) | The SOFAS is a clinician-rated, global rating scale of overall level of current functioning based on social and occupational functioning. The scoring considers impairments in functioning directly related to physical and/or mental impairments. Scores range from 0 - 100, with lower scores indicating lower levels of functioning. | Assessed at week 0 and week 11 | 
| Change in World Health Organization quality of life assessment (WHOQoL) | The WHOQOL-BRIEF is a 26-item brief version of the WHOQOL, that measures quality of life based on six domains: physical health, psychological state, level of independence, social relations, environment, and spirituality/religion/personal beliefs. Four general items about subjective overall QOL and health are also included. Only domain and general item scores are calculated in the WHOQOL-BREF. Items are scored on scales of 1 to 5, and higher scores indicate higher quality of life. | Assessed at week 0 and week 11 | 
| Change in Beck Anxiety Inventory | The BAI is a 21-item self-report scale that assesses the severity of anxiety symptoms. Items are scored from 0 to 3 (0 = not at all, 3 = severe). Higher scores indicate greater levels of severity, and the ranges for anxiety levels are: 0-9 normal to minimal, 10-18 mild to moderate, 19-29 moderate to severe, and 30-63 severe. The BAI consists of two factors: somatic and cognitive. | Assessed at week 0 and week 11 | 
| Change in Respiratory Sinus Arrhythmia (RSA)- measured by PSG | RSA is the phenomenon of an increased heart rate during inhalation and a decreased heart rate during exhalation. Since these fluctuations are controlled mainly by vagal influences on the heart, RSA serves as a reliable metric for measuring parasympathetic activity. RSA has been proven to be a reliable measure of emotion regulation and emotional responding in numerous studies. | Assessed at week 0 and week 11 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Insomnia, Depression, Anxiety, CBT-I, Cognitive Behavioral Therapy for Insomnia