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

Not Applicable

Completed

Conditions: Depression
Insomnia

Registration Number: NCT04424407

Lead Sponsor: Stanford University

Brief Summary: 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-amygdala 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.

Detailed Description: Not available

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 51

Inclusion Criteria

Ages 25-60
Subjective complaint of sleep disturbance for ≥ 3 months (ISI≥10)
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)

Study & Design

Study Type: INTERVENTIONAL

Study Design: SINGLE_GROUP

Primary Outcome Measures

Name	Time	Method
Change in Amygdala Activation During the Facial Expressions of Emotion Task (Conscious Condition) as Assessed by Functional Magnetic Resonance Imaging	Assessed at week 0 and week 11	The Conscious condition of the Facial Expressions of Emotion task measures supraliminal (without backward masking) emotional face processing. Amygdala activation while viewing threat-related emotional faces relative to neutral faces was quantified using functional magnetic resonance imaging (fMRI) as a marker of Emotion Regulation Network engagement. Blood-oxygenation level dependent (BOLD) signal change before and after CBT-I treatment was compared by modeling the activity of the amygdala while viewing emotional faces using generalized linear models, producing beta weights for each participant and timepoint. A positive beta-weight at pre-treatment means that the amygdala increased its activity in response to emotional faces, relative to neutral faces. A negative value for the change in amygdala activation means that average amygdala reactivity decreased following treatment. It is theorized that higher amygdala emotional reactivity is associated with worse outcomes.
Change in Amygdala Activation During the Facial Expressions of Emotion Task (Nonconscious Condition) as Assessed by Functional Magnetic Resonance Imaging	Assessed at week 0 and week 11	The Nonconscious condition of the Facial Expressions of Emotion task measures subliminal (with backward masking) emotional face processing. Amygdala activation while viewing threat-related emotional faces relative to neutral faces was quantified using fMRI as a marker of Emotion Regulation Network engagement. Blood-oxygenation level dependent (BOLD) signal change before and after CBT-I treatment was compared by modeling the activity of the amygdala while viewing emotional faces using generalized linear models, producing beta weights for each participant and timepoint. A positive beta-weight at pre-treatment means that the amygdala increased its activity in response to emotional faces, relative to neutral faces. A negative value for the change in amygdala activation means that average amygdala reactivity decreased following treatment. It is theorized that higher amygdala emotional reactivity is associated with worse outcomes.
Change in Amygdala Activation During the Emotion Regulation Scenes Task	Assessed at week 0 and week 11	Participants are asked to "look" or "decrease" their emotional response to negative and neutral valence images taken from the International Affective Picture System. Amygdala activation while viewing emotional scenes relative to neutral scenes, and while passively viewing emotional scenes relative to down-regulating emotion, was quantified using fMRI as a marker of Emotion Regulation Network engagement. Blood-oxygenation level dependent (BOLD) signal change before and after CBT-I treatment was compared by modeling the activity of the amygdala while viewing emotional scenes or while downregulating using generalized linear models, producing beta weights for each participant and timepoint. A positive beta-weight at pre-treatment means that the amygdala increased its activity in response to the task demands, and a negative value means that average amygdala reactivity decreased following treatment. It is theorized that higher amygdala emotional reactivity is associated with worse outcomes
Change in Amygdala-Medial Prefrontal Cortex Connectivity During the Facial Expressions of Emotion Task (Conscious Condition) as Assessed by Functional Magnetic Resonance Imaging	Assessed at week 0 and week 11	This outcome tested whether amygdala connectivity with regions of the mPFC was changed following treatment using psychophysiological interaction (PPI) analysis for this contrast/task. Regions of the mPFC include: dorsal anterior cingulate cortex (dACC), ventromedial prefrontal cortex (vmPFC), dorsomedial prefrontal cortex (dmPFC), subgenual anterior cingulate cortex (sgACC), pregenual anterior cingulate cortex (pACC). PPI analyses produce a beta weight for each participant at each timepoint, and represents the degree to which the connectivity of the amygdala and mPFC is modulated by task conditions. A positive value means average connectivity increases in the task-contrast, and a positive value for the change score means an increase in average connectivity following CBT-I treatment. It is theorized that higher amygdala connectivity is associated with better outcomes.
Change in Beck Depression Inventory (BDI)	Assessed at week 0 and week 11	This measure is of the Beck Depression Inventory-II total score after excluding one sleep item. 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 summed to create an overall score of 0 to 63. higher scores indicate greater levels of severity. The ranges for depression are: 0-13 minimal, 14-19 mild, 20-28 moderate, and 29-63 severe. A negative change score means that average depression symptom severity was reduced following CBT-I treatment.
Change in PSG Sleep Efficiency	Assessed at week 0 and week 11	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. A positive change score means average sleep efficiency increased following CBT-I treatment.

Secondary Outcome Measures

Name	Time	Method
Change in Beck Scale of Suicidal Ideation Total Score	Assessed at week 0 and week 11	The Beck Scale of Suicidal Ideation (BSSI) is designed to assess the severity of suicidal ideation over the past week. The total score is derived from the sum of the first 19 items, creating an overall score ranging from 0 to 38. Scores of 0 are interpreted as no suicidal ideation, 1-8 as low levels, 9-16 as moderate levels, and 17-38 as high levels. A negative change score means an average reduction in suicidal ideation following CBT-I treatment.
Change in Columbia Suicide Severity Rating Scale	Assessed at week 0 and week 11	The Columbia Suicide Severity Rating Scale (CSSRS) 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. The CSSRS does not provide a numerical score but categorizes risk levels based on responses. We report the proportions of risk at each timepoint.
Change in Actigraph Sleep Onset Latency (SOL) as a Measure of Sleep Continuity	Assessed at week 0 and week 11	Sleep Onset Latency (SOL) is the time (minutes) from "lights out" to actually falling asleep (sleep onset).
Change in Actigraph Number of Arousals as a Measure of Sleep Continuity	Assessed at week 0 and week 11	Number of Arousals is determined by number of times of awakening as seen on the actigraph data.
Change in Actigraph Wake After Sleep Onset (WASO) as a Measure of Sleep Continuity	Assessed at week 0 and week 11	Wake After Sleep Onset (WASO) are periods of wakefulness occurring after sleep onset, before final awakening (sleep offset).
Change in Actigraph Total Sleep Time (TST) as a Measure of Sleep Continuity	Assessed at week 0 and week 11	Total Sleep Time (TST) is the total time spent asleep, from the start of sleep onset to sleep offset subtracting any periods of wakefulness.
Change in Actigraph Sleep Efficiency (SE) as a Measure of Sleep Continuity	Assessed at week 0 and week 11	Sleep Efficiency (SE) is calculated as TST divided by total time spent in bed, multiplied by 100.
Change in PSG Sleep Onset Latency (SOL) as a Measure of Sleep Architecture	Assessed at week 0 and week 11	Sleep onset latency is the time it takes to fall asleep, specifically the amount of time in minutes from "LightsOff", which is the time at which the participant started trying to sleep, to stage 1 sleep. A negative change score means it took less time to fall asleep following CBT-I treatment.
Change in PSG Number of Arousals as a Measure of Sleep Architecture	Assessed at week 0 and week 11	Number of Arousals is determined by number of times of awakening by EEG changes. A negative change score means on average there were fewer overnight arousals following CBT-I treatment.
Change in PSG Wake After Sleep Onset (WASO) as a Measure of Sleep Architecture	Assessed at week 0 and week 11	Wake After Sleep Onset (WASO) are periods of wakefulness occurring after sleep onset, before final awakening (sleep offset) measured by EEG changes. A negative change value means there was less WASO on average after CBT-I treatment.
Change in PSG Total Sleep Time (TST) as a Measure of Sleep Architecture	Assessed at week 0 and week 11	Total Sleep Time (TST) is the total time (minutes) spent asleep, from the start of sleep onset to sleep offset, subtracting any periods of wakefulness. TST includes stages N1, N2, N3, and REM sleep. A positive change score means the average TST increased following CBT-I.
Change in Sleep Physiology Measured by PSG	Assessed at week 0 and week 11	Fronto-central 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. A positive change score means there was an increase in absolute power in the specified frequency band following CBT-I treatment.
Change in Insomnia Severity Index (ISI) Scale Score	Assessed at week 0 and week 11	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), then summed to create an overall score of 0 to 28. 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. A negative change score means average insomnia symptoms improved following CBT-I treatment.
Change in 36-Item Short Form Survey (SF-36) Score	Assessed at week 0 and week 11	The SF-36 measures health-related quality of life based on eight domains: physical activity, social activities, limitations in activities due to physical health problems, bodily pain, general mental health, limitations in activities due to emotional problems, vitality, and general health perceptions. Items are recoded then averaged together to create each an average score for all items that the respondent answered. The eight subscales are then into two component summary t-scores (Mental and Physical Component Summary t-scores), each with a mean of 50 and a standard deviation of 10. A t-score higher than 50 means better mental or physical health than the general population, and a t-score below 50 means worse than the general population. Instructions for scoring these component scores recommends that they be set to missing if any subscales are missing. A positive change score means the Component Summary Score improved following CBT-I.
Change in Beck Anxiety Inventory (BAI)	Assessed at week 0 and week 11	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), then summed to create an overall score range of 0 to 63. 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. A negative change score means that average anxiety symptom severity was reduced following CBT-I treatment.
Change in Respiratory Sinus Arrhythmia (RSA)- Measured by PSG	Assessed at week 0 and week 11	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.