Impact of Insomnia Treatment on Brain Responses During Resting-state and Cognitive Tasks

Neural Responses and Connectivity During Rest, Memory Encoding and Emotional Stimulation in Chronic Insomnia, and Their Relationships With Insomnia Treatment: a Wait-list Controlled Randomized Trial of Cognitive-behavioural Therapy for Insomnia

Individuals with chronic insomnia have persistent difficulty falling and staying asleep, as well as complaints of altered daytime functioning that may be associated with cognitive impairments. The neural processes underlying these daytime complaints may involve abnormal activation of brain regions and neural networks involved in working memory, memory encoding and emotions. The goal of this study is to assess whether a psychological treatment for insomnia will reverse these abnormalities in brain responses to cognitive tasks and at rest. A secondary objective of the study is to characterize impairments in attentional processing and assess if the impairments can be reversed by the psychological treatment. We hypothesized that the psychological treatment for insomnia will lead to a normalization of the brain responses to working memory, declarative memory encoding, insomnia-related stimuli, and the functional connectivity within the default-mode and limbic networks.

Study Overview

• Status: Recruiting
• Conditions: Chronic Insomnia
• Intervention / Treatment: Behavioral: Cognitive-Behavioural therapy for insomnia (CBT-I)

Detailed Description

Study hypothesis

Brain responses associated with working memory task and declarative memory encoding will be decreased in chronic insomnia compared to good sleepers and, among individuals with chronic insomnia, cognitive-behavioral therapy for insomnia will lead to larger recovery in these brain responses, compared to a 3-month wait period.

Brain responses to emotional stimulation, especially to insomnia-related stimuli, will be increased in chronic insomnia compared to good sleepers, and, among individuals with chronic insomnia, cognitive-behavioral therapy for insomnia will lead to larger reduction in these brain responses, compared to a 3-month wait period.

Connectivity in the default-mode and limbic networks during resting-state will be increased in chronic insomnia compared to good sleepers, and, among individuals with chronic insomnia, cognitive-behavioral therapy for insomnia will lead to larger reduction in this connectivity, compared to a 3-month wait period.

• Study Type: Interventional
• Enrollment (Estimated): 120
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Thanh Dang-Vu, MD PhD; Phone Number: 3364 514-848-2424; Email: tt.dangvu@concordia.ca

Study Locations

• Canada
  • Quebec
    • Montréal, Quebec, Canada, H4B 1R6
      • Recruiting
      • Perform Center, Concordia University
      • Contact: Thanh Dang-Vu, MD PhD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 25 years to 65 years (Adult, Older Adult)
• Accepts Healthy Volunteers: Yes

Description

Inclusion Criteria:

80 participants with chronic primary insomnia (40 per group) 40 good sleepers

Exclusion Criteria:

1. Older than 65 y.o. or younger than 25 y.o.
2. Contraindication to the MRI scanning
3. Current neurological disorder
4. Past history of brain lesion
5. Major surgery (i.e., requiring general anesthesia) in the past 3 months
6. Untreated thyroid disorder
7. Chronic pain syndrome self-reported as interfering with sleep
8. Recent and severe infection in the past 3 months
9. Active cancer, or remitted cancer with cancer treatment within the last 2 years
10. Stroke
11. Myocardial infarct
12. Arterial bypass or angioplasty
13. Pacemaker
14. Heart failure causing limitation of ordinary physical activity
15. Renal insufficiency
16. Sleep apnea with an apnea-hypopnea index > 5/h
17. Restless legs syndrome with symptoms 3 days or more per week
18. Periodic limb movements during sleep with index > 15/h
19. REM-sleep behavior disorder
20. Narcolepsy and other central disorders of hypersomnolence
21. Sleepwalking more than once/month
22. Having worked on night shifts or rotating shifts for more than 2 weeks in the last 3 months or expecting to do so during the study period
23. Severe mental disorders: bipolar disorder (Type I), schizophrenia, anxiety disorders, major depressive disorder, current substance use disorder, current post-traumatic stress disorder
24. Current suicidality
25. Frequent alcohol consumption (>10 glasses/week) or use of cannabis (more than once a week) or illicit drugs (more than once a month)
26. Smoking cigarettes more than 10 cigarettes/day
27. Pregnant or breastfeeding women
28. Current psychotherapy or past cognitive-behavioural therapy for insomnia
29. Current use of medication for depression or anxiety
30. Unable to stop hypnosedative medications for at least 2 weeks prior to the first assessment
31. For good sleepers: insomnia symptoms more than 3 times/ week.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
No Intervention: Waitlist
Experimental: Immediate intervention	Behavioral: Cognitive-Behavioural therapy for insomnia (CBT-I); Participants with chronic primary insomnia are randomized into 2 groups with a 1:1 allocation ratio, after the completion of the pre-treatment assessment. Post-treatment and post-waitlist assessment occur after the 3-month treatment or waiting period. One group will receive the intervention immediately after the pre-treatment assessment and the other group will receive the intervention after a waiting period of 3 months. The intervention consists of manualized cognitive-behavioural therapy for insomnia. This treatment includes psychoeducation about sleep and circadian rhythms, stimulus control, sleep restriction, relaxation, and cognitive therapy. The therapy is administered individually. Participants meet for 8 sessions of 50 minutes spread over 12 weeks.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Functional magnetic resonance imaging (fMRI) to examine brain responses to working memory with increasing task difficulty	Functional magnetic resonance imaging (fMRI) will be used to look at changes in brain activations to working memory in individuals with chronic insomnia compared to good sleepers, as well as the modifications in these brain activations after cognitive-behavioral therapy for insomnia.	3 months
Functional magnetic resonance imaging (fMRI) to examine brain responses to declarative memory encoding	Functional magnetic resonance imaging (fMRI) will be used to look at changes in brain activations to declarative memory encoding in individuals with chronic insomnia compared to good sleepers, as well as the modifications in these brain activations after cognitive-behavioral therapy for insomnia.	3 months
Functional magnetic resonance imaging (fMRI) to examine brain responses to insomnia-related stimuli	Functional magnetic resonance imaging (fMRI) will be used to look at changes in brain activations to insomnia-related pictures in individuals with chronic insomnia compared to good sleepers, as well as the modifications in these brain activations after cognitive-behavioral therapy for insomnia.	3 months
Functional magnetic resonance imaging (fMRI) to examine functional connectivity within the default-mode and limbic networks at rest	Functional magnetic resonance imaging (fMRI) will be used to look at changes in resting state functional connectivity in individuals with chronic insomnia compared to good sleepers, as well as the modifications in this functional connectivity after cognitive-behavioral therapy for insomnia, with a focus on the default-mode and limbic networks.	3 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Insomnia Severity Index (ISI)	Self-reported insomnia severity	3 months and 1 year
Pittsburgh Sleep Quality Index (PSQI)	Self-reported sleep quality	3 months and 1 year
Total sleep time	Self-reported total sleep time from 14-day sleep diary	3 months and 1 year
Total sleep time	Total sleep time from 14-day actigraphy	3 months
Sleep latency	Self-reported sleep latency from 14-day sleep diary	3 months and 1 year
Sleep latency	Sleep latency from 14-day actigraphy	3 months
Wake-after-sleep-onset (WASO)	Self-reported duration of wake-after-sleep-onset from 14-day sleep diary	3 months and 1 year
Wake-after-sleep-onset (WASO)	Duration of wake-after-sleep-onset from 14-day actigraphy	3 months
Sleep efficiency	Self-reported sleep efficiency from 14-day sleep diary	3 months and 1 year
Sleep efficiency	Sleep efficiency from 14-day actigraphy	3 months
Diagnosis of insomnia disorder	A trained interviewer evaluates the presence of an insomnia disorder using the SCID-V	3 months and 1 year
PSG total sleep time	Total sleep time from overnight polysomnography	3 months
PSG sleep latency	Sleep latency from overnight polysomnography	3 months
PSG wake-after-sleep-onset (WASO)	Duration of wake-after-sleep-onset from overnight polysomnography	3 months
PSG sleep efficiency	Sleep efficiency from overnight polysomnography	3 months
Sleep stage durations (N1, N2, N3, REM)	Durations of each sleep stage from overnight polysomnography	3 months
Arousal index	Number of EEG arousals per hour from overnight polysomnography	3 months
Spindle density	Number of sleep spindles per minute of stage N2-N3 sleep from overnight polysomnography	3 months
Dim light melatonin onset (DLMO)	Objective measure of central circadian timing (dim light melatonin onset; DLMO) will be obtained from hourly evening saliva samples	3 months
Cortisol	Cortisol will be assessed using salivary samples collected at bedtime, awakening and 45 minutes after awakening	3 months
Heart rate variability	Heart rate variability will be measured using the electrocardiogram leads during the overnight assessments	3 months
Blood pressure	Blood pressure is assessed using an oscillometer measurement of systolic and diastolic blood pressure in the morning following the overnight assessments	3 months
Circulating interleukin-6	Markers will be quantified using blood sample during the overnight assessments	3 months
Circulating tumor necrosis factor-alpha	Markers will be quantified using blood sample during the overnight assessments	3 months
Circulating C-reactive protein	Markers will be quantified using blood sample during the overnight assessments	3 months
Circulating neurotrophic factor BDNF	Markers will be quantified using blood sample during the overnight assessments	3 months
Beck Depression Inventory (BDI)		3 months and 1 year
State-Trait Inventory for Cognitive and Somatic Anxiety (STICSA)		3 months and 1 year
Sahlgrenska Academy Self-reported Cognitive Impairment Questionnaire (SASCI-Q, adapted version)	Questionnaire assessing self-reported (subjective) memory complaints. Total score ranges from 29 to 203 (higher score reflects more self-reported cognitive complaints).	3 months and 1 year
Work and Social Adjustment Scale (WSAS)	Self-reported measure assessing perceived functional impairment associated with insomnia. Total score ranges from 0 to 40 (lower score reflects less impairment).	3 months and 1 year
The Implicit Positive and Negative Affect Test (IPANAT)		3 months and 1 year
Beliefs and Attitudes about Sleep (DBAS)		3 months and 1 year
Daytime Insomnia Symptom Response Scale (DISRS)	Self-report measures assessing sleep-related rumination	3 months and 1 year
Attention	Attention will be assessed using computerized divided attention and multitasking tasks assessed in the evening and morning of the overnight assessments	3 months
Gray matter volume (GMV)	Brain morphometric measure from MRI	3 months
Cortical thickness	Brain morphometric measure from MRI	3 months
White matter integrity (fractional anisotropy, mean diffusivity)	Brain measure from MRI	3 months
GABA	GABA concentration from Magnetic Resonance Spectroscopy (in the anterior cingulate cortex)	3 months
Trier Inventory for Chronic Stress - short form		3 months and 1 year
Subjective happiness scale	Self-reported measure of global subjective happiness. Total score ranges from 4 to 28 (higher score reflects greater happiness).	3 months and 1 year
Temporal experience of pleasure scale (adapted version)	Self-reported measure of anticipatory and consummatory facets of pleasure. Total score ranges from 18 to 52 (higher score reflects greater pleasure).	3 months and 1 year
Fatigue symptom inventory		3 months and 1 year
Positive and Negative Affect Schedule		3 months and 1 year
Munich Chronotype Questionnaire (MCTQ)	Questionnaire on self-reported sleep habits, assessing individual chronotype (e.g., early type, normal type late type).	3 months and 1 year

Collaborators and Investigators

• Sponsor: Concordia University, Montreal
• Collaborators: Canadian Institutes of Health Research (CIHR)
• Investigators: Principal Investigator: Thanh Dang-Vu, MD PhD, Concordia University, Montreal

Study record dates

Study Major Dates

• Study Start (Actual): July 30, 2019
• Primary Completion (Estimated): July 30, 2024
• Study Completion (Estimated): July 30, 2025

Study Registration Dates

• First Submitted: July 12, 2019
• First Submitted That Met QC Criteria: July 17, 2019
• First Posted (Actual): July 18, 2019

Study Record Updates

• Last Update Posted (Estimated): February 7, 2024
• Last Update Submitted That Met QC Criteria: February 5, 2024
• Last Verified: February 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Mental Disorders; Nervous System Diseases; Sleep Disorders, Intrinsic; Dyssomnias; Sleep Wake Disorders; Sleep Initiation and Maintenance Disorders
• Other Study ID Numbers: 30011416

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No