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

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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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

Conditions
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Chronic Insomnia

Intervention / Treatment
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* Behavioral: Cognitive-Behavioural therapy for insomnia (CBT-I)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 80 participants with chronic primary insomnia (40 per group) 40 good sleepers Exclusion Criteria: Older than 65 y.o. or younger than 25 y.o. Contraindication to the MRI scanning Current neurological disorder Past history of brain lesion Major surgery (i.e., requiring general anesthesia) in the past 3 months Untreated thyroid disorder Chronic pain syndrome self-reported as interfering with sleep Recent and severe infection in the past 3 months Active cancer, or remitted cancer with cancer treatment within the last 2 years Stroke Myocardial infarct Arterial bypass or angioplasty Pacemaker Heart failure causing limitation of ordinary physical activity Renal insufficiency Sleep apnea with an apnea-hypopnea index > 5/h Restless legs syndrome with symptoms 3 days or more per week Periodic limb movements during sleep with index > 15/h REM-sleep behavior disorder Narcolepsy and other central disorders of hypersomnolence Sleepwalking more than once/month 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 Severe mental disorders: bipolar disorder (Type I), schizophrenia, anxiety disorders, major depressive disorder, current substance use disorder, current post-traumatic stress disorder Current suicidality Frequent alcohol consumption (>10 glasses/week) or use of cannabis (more than once a week) or illicit drugs (more than once a month) Smoking cigarettes more than 10 cigarettes/day Pregnant or breastfeeding women Current psychotherapy or past cognitive-behavioural therapy for insomnia Current use of medication for depression or anxiety Unable to stop hypnosedative medications for at least 2 weeks prior to the first assessment For good sleepers: insomnia symptoms more than 3 times/ week.

Ages Eligible for Study
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Minimum Age: 25 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: This study is a randomized controlled trial. Participants with chronic insomnia are randomized to either immediate cognitive-behavioural therapy or a 3-month wait-list period using a 1:1 allocation ratio. Randomization is conducted with block sizes of 4 participants. Randomization results are contained in sealed opaque envelopes that are opened in the presence of the participants after the completion of the pre-treatment assessment. A second assessment will be conducted after the treatment or waiting period. A follow-up assessment is conducted 12 months after the completion of the post-treatment assessment. A group of good sleepers, matched on age and gender with the insomniacs, will also be recruited and assessed at baseline only to provide a normative reference group.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Immediate intervention<br> | Behavioral: Cognitive-Behavioural therapy for insomnia (CBT-I)<br>* 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.<br>|
| No Intervention: Waitlist<br> | |

What is the study measuring?
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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 |