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This project is designed as a randomized controlled trial (RCT), with an active control group. Sleep and heart rate will be monitored at home for 1 week before and after the intervention. Questionnaires will be completed from home before, during and 8 weeks after the end of the Intervention. The Cognitive Behavioural Therapy for Insomnia, adapted for post-concussed individuals (CBT-pI) and control interventions, will be delivered on a digital online platform over an 8-week period. Participants in the control arm will be offered CBT-pI after the follow-up period. All intervention arms will be delivered as adjuncts to standard clinical care. All other treatments received during the intervention will be documented.
Background and Rationale
Up to 50% of individuals who sustain a concussion experience sleep disturbances. Poor sleep has been found predictive of poorer outcomes in post-concussion recovery. In Canada, insomnia constitutes a major burden upon public health. Insomnia not only impairs sleep quality but also exacerbates cognitive, emotional, and physiological post-concussion symptoms, including cardiovascular dysfunctions, such as elevated heart rate and sympathetic overactivation; thus, possibly leading to delayed recovery following a concussion. Furthermore, recent work in chronic insomnia identified increased levels of brain microstructure injury biomarkers previously linked to concussion. These disruptions can potentially interfere with brain-heart functions and delay post-concussion recovery. As such, treating insomnia may result in better post-concussion recovery, which may notably be observable through biomarkers linked to brain-heart health.
Cognitive-Behavioural Therapy treatment for insomnia (CBT-I) is the first line of treatment recommended for chronic primary insomnia sufferers. It combines multipronged strategies involving education and progressive personalized sleep manipulations to address the maladaptive cognitive and behavioural processes contributing to the maintenance of insomnia. Five distinct intervention components - stimulus control, time in bed restriction therapy, psychoeducation about sleep, cognitive therapy, and relaxation training - are included within the CBT-I framework. CBT-I has been found effective to address sleep issues emerging after a concussion, with documented benefits for post-concussion recovery. This may notably operate via the restoration of brain-heart functions since CBT-I enhances brain functions following concussions, may influence autonomic regulation by reducing hyperarousal and sympathetic overactivation, and improves cardiovascular outcomes.
One of the putative mechanisms of action of CBT-I resides in increased deep sleep due to enhanced sleep pressure. Deep sleep is a state characterized by high amplitude low frequency brain activity in the delta frequency range on the electroencephalogram (EEG). Recent discoveries highlight the role of deep sleep in autonomic regulation and healing processes. Post-concussion sleep has been associated with increased deep sleep. One may postulate that higher increases in delta activity driven by CBT-I may be associated with enhanced autonomic functions and post-concussion symptoms recovery.
The investigators recently expanded previous results suggesting that individuals with insomnia have low coherence between brain and heart activity. To the best of our knowledge, research has yet to investigate whether successful insomnia treatment, through CBT-I, restores brain-heart interactions, and how changes in brain, heart, and brain-heart interactions may relate to post-concussion symptoms recovery following CBT-I.
Study Objectives
Primary objective:
• Evaluate the efficacy of a digital CBT-I program adapted for post-concussion syndrome (CBT-pI) on insomnia symptoms (primary outcome) and biomarkers related to post-concussion brain-heart function (secondary outcomes)
Secondary objectives:
Methods
3.1. Contact Pathway Participants will be recruited through the 360 Concussion Care (360CC) clinic. The participants will be referred by clinicians at this clinic to members of the research team. Clinicians will identify patients they would like to refer to the study, request that these patients fill out the "Permission to be contacted form", and send this form to the research team. A research assistant will then contact the potential participant through email to send them a summary of the study and a link to complete an anonymous online screening form for the first set of eligibility criteria on a secured web platform (Qualtrics, www.qualtrics.com; license held via the University of Ottawa) and a unique identification code. The first question of this online form will ask participants to confirm their consent to take part in the screening process. This will be documented in the screening database. The second question of this online screening form will ask participants to insert their unique anonymous research screening code. This screening form will notably include items assessing neurologic and psychiatric history and medications, and will include the Sleep Condition Indicator (SCI), WHO-ASSIST item 2, Sleep Disorders Symptoms Checklist-25 (SDS-CL-25), and Epworth Sleepiness Scale. It should take between 10 and 15 minutes to complete.
3.2. Ongoing Consent Procedure For participants found to be eligible after the screening, the research assistant will call participants to summarize the next steps of the study verbally and address any questions or concerns that participants may have. At which point, verbal consent will be obtained to conduct a structured interview using the Mini International Neuropsychiatric Interview (M.I.N.I) and the insomnia module of the SCID to determine the last set of eligibility criteria.
After this interview, eligible participants will be sent an electronic form containing the information and consent form (ICF) and will have as much time as the participant needs to read it at home before enrolling in the study. As part of that same electronic form, the participant will confirm consent by ticking consent boxes and entering their full name. This information will be stored in a consent database showing the participant's full name and consent date, which will be kept on restricted-access folders on the ROMHC's server in separate files than the research data. This online consent form was created based on published guidelines from peer-reviewed articles. Special care will be given to ensure that participants understand that their participation is entirely voluntary and that the participant can withdraw from the study at any stage (without any consequence on the treatment[s] they receive at the 360CC clinic or their relationship with any of the clinicians at the 360CC clinic).
At each follow-up assessment stage, participants will provide consent via an electronic form before completing the online assessment battery; thus, ongoing consent will be documented at each follow-up time point. The consent procedure will consist of the same process as outlined above - participants will confirm their consent electronically by ticking consent boxes and entering their full name. The investigators will store this information in the consent database.
3.3. Pre/post-intervention Assessments Eligible participants will receive the research equipment by mail and attend a video call appointment (on a secured uOttawa Zoom platform). Participants who are able and willing to come on-site will be invited to do this visit in person at the Sleep Research Unit of the ROMHC rather than over Zoom.
During this first appointment, a research assistant will instruct participants on how to use the study equipment. Participants will also be provided with a brief pre-recorded online video explaining how to use the equipment. The study equipment will include a digital sleep log (containing the core elements of the ''Consensus Sleep Diary'') on the study smartphone app to be filled for 14 days at four time points: baseline (before the intervention starts), post-intervention (after the last treatment week), follow-up 1 (1 month after treatment), and follow-up 2 (6 months after treatment). Participants may fill out the daily sleep log on paper to reduce screen time, if needed. During the last 7 nights of time points 1, 2 and 3, participants will wear. a portable EEG and heart rate headband device (InteraXon, Toronto, Canada). Participants will be informed that they will be able to contact the research assistant at any point throughout the study trial if the participant has any questions and/or concerns.
Participants will complete assessment questionnaires on a secured web-platform (Qualtrics, licensed to the University of Ottawa) at the four time points. These questionnaires should last about 20-30 minutes (see table 1) and will inquire about general demographic and clinical information (including all treatments received for sleep and post-concussion symptoms), sleep, daytime functioning, post-concussion symptoms, mental health, medication use, psychological treatments, and perceptions about the EEG headband. If required, patients can break this up into briefer sessions. The day after the last intervention session, the questionnaire pack will be supplemented by scales assessing treatment adherence and satisfaction (about 5 additional minutes). At the same four time points, participants will be invited to undergo brief cognitive testing on the same online app that will be used for the intervention.
3.4. Collating data from the 360 Concussion Care clinics By consenting to take part to the study, participants will consent for their data, collected as part of the 360 Concussion Care clinics (i.e., our recruitment site) and the TRANSENDENT Concussion Research Program that is taking place through the clinics, to be used in the current study. This consent will be obtained explicitly through the information and consent form. This includes: (1) autonomic measures (e.g. heart rate and blood pressure, tilt test results), (2) aerobic exercise tolerance (Buffalo Concussion Bike Test [BCBT/ Buffalo Concussion Treadmill Test (BCTT]), (3) pupillometry, (4) eye-tracking, (5) salivary fluid (i.e., micro[mi] RNAs) to assess physiological biomarkers of concussion symptomology (see description of relevance in paragraph below), (6) blood (i.e., inflammatory markers) to assess physiological biomarkers of concussion symptomology (see description of relevance in paragraph below, and (7) advanced neuroimaging (MRI), (8) results from questionnaires, diagnoses, and treatment plans (see TRANSCENDENT protocol paper).
3.5. Experimental Conditions Following the pre-intervention assessment, participants will be randomly assigned to one of two arms: an active intervention (CBT-pI) or a control intervention (sleep hygiene), both of which will be delivered on the same digital infrastructure that could be accessed either via a mobile phone or computer (i.e. online app). Their account on this online app will not contain any identifiable information, only an anonymous research participant identification code.
Randomization and blinding:
The randomization process will be done by a computer-generated randomizer, stratified by sex. This will be managed by a research collaborator who will not be directly involved in clinical assessments or data processing. All researchers involved in clinical assessments or data processing will be blinded to the assignment of these different conditions.
Active Intervention:
The digital CBT-pI program is co-developed with lived experts with a history of post-concussion insomnia and is inspired from published recommendations and existing evidence-based CBT-pI programs. It includes four bi-weekly sessions lasting about 30-45 minutes covering all core elements of CBT-I, with some adaptations tailored to better serve people with post-concussion symptoms. For instance, the app design will account for light, sound, and visual field motion sensitivity (e.g. light enlarged text fonts on dark background colours, amber filters, sound processing to lower high pitch tones, minimized scrolling, and slow screen transitions). Participants will be advised to use a large font, reduce the brightness and white point on their screen and/or switch to night settings or add a colour filter to their phone of their choosing. Also, the traditional psychoeducation module will be supplemented with information about sleep changes following concussion (e.g. periods of hypersomnolence, circadian disruptions, and comorbid sleep-related respiratory disturbances often superimposed on insomnia), interactions between sleep and chronic pain, expected course of recovery, the benefits of improving sleep for memory, concentration and mood. As advised by our team members with lived experience, the active intervention arm will also include components of mindfulness-based self-compassion (https://self-compassion.org/) and "Soothe and Calm" Feldenkrais (https://www.feldenkraisaccess.com) videos.
Control Intervention:
The control condition will leverage a digital sleep hygiene program that will mirror the active intervention, as is commonly done in CBT-I trials since sleep hygiene is known to be ineffective to treat insomnia. It will be delivered over the same number/length of bi-weekly sessions using the same digital infrastructure as the CBT-PI program, which will be cloned, but the content will be changed. The content will consist of educational information regarding sleep stages, normal sleep architecture, and healthy sleep practices (e.g., reducing caffeine and alcohol, avoiding exercise and other physical activity just before bed, having a light snack before bed, and keeping the bedroom quiet, and at a comfortable temperature.
Monitoring during treatment:
As per standard procedures during CBT-I, participants will fill out a daily sleep log (containing the core elements of the ''Consensus Sleep Diary'') during the intervention. The Insomnia Severity Index questionnaire will be done at the end of each second week of the intervention, just before participants will do the treatment module. Both the sleep diary and the insomnia severity index questionnaires will be done directly on the digital intervention online app (i.e. on their smartphone or computer). Again, participants will also have the choice to complete these on paper if they prefer. Participants will receive a prompt via the app to remind them of doing the questionnaires and intervention modules.
Adherence will be monitored using sleep schedules documented on the sleep diary and time stamps on the app to track completion of each intervention module. Mid-way through the intervention, participants will be invited for a brief 10-15-minute check-in phone call with a research assistant to ensure the participant does not have any questions or roadblocks with the intervention.
3.6. Additional Post-Assessment Measures Participants will undergo a semi-structured exit interview via a secured Zoom link to gather further insights (about 20-30 minutes). This will aim to gather feedback on participants' experiences throughout the intervention and potential adaptations to better address challenges linked to insomnia treatment in the context of brain-heart function in concussed adults. The exit interview will be recorded (audio only) to enable accurate transcription. Once the transcription is completed, the recordings will be destroyed.
3.7. Deception and debriefing session This study involves a moderate level of deception. To minimize the placebo effect on the control condition, participants will be led to believe that this study will evaluate two different types of sleep interventions. The participant will not be informed that one is the first-line recommended treatment for insomnia (i.e. CBT-I) and the other is anticipated to yield no major benefit for chronic insomnia symptoms.
After participants complete the last follow-up measures, they will be contacted by a research assistant who will explain the deception component of the study and the reason behind it. Participants who were in the control condition will then be offered the active intervention.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Cognitive Behavioural Therapy for Insomnia | Active Comparator | Four bi-weekly sessions lasting about 30-45 minutes covering all core elements of CBT-I, with some adaptations tailored to better serve people with post-concussion symptoms. For instance, the app design will account for light, sound, and visual field motion sensitivity (e.g. light enlarged text fonts on dark background colors, amber filters, sound processing to lower high pitch tones, minimized scrolling, and slow screen transitions). Also, the traditional psychoeducation module will be supplemented with information about sleep changes following concussion, interactions between sleep and chronic pain, expected course of recovery, the benefits of improving sleep for memory, concentration and mood. |
|
| Placebo | Placebo Comparator | A digital sleep hygiene program will mirror the CBT-I intervention. It will be delivered over the same number/length of bi-weekly sessions using the same digital infrastructure as the CBT-PI program. The content will consist of educational information regarding sleep stages, normal sleep architecture, and healthy sleep practices (e.g., reducing caffeine and alcohol, avoiding exercise and other physical activity just before bed, having a light snack before bed, and keeping the bedroom quiet, and at a comfortable temperature). |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| CBT-pI | Behavioral | A digital CBT-pI program co-developed with lived experts with a history of post-concussion insomnia and inspired from published recommendations and existing evidence-based CBT-pI programs. |
| Measure | Description | Time Frame |
|---|---|---|
| Changes in insomnia symptoms | Changes in insomnia symptoms as indicated by the Insomnia Severity Index-7 (ISI-7) total score from pre-intervention to post-intervention. The ISI-7 is a 7 item questionnaire with total scores ranging from 0 to 28, with higher scores indicating more severe insomnia symptoms. | From baseline (week 0) to post-intervention (week 10) |
| Measure | Description | Time Frame |
|---|---|---|
| Satisfaction with treatment effectiveness as measured with the Modified Treatment Satisfaction Questionnaire for Medication | Satisfaction with treatment effectiveness, side effects, and convenience as rated on the Modified Treatment Satisfaction Questionnaire for Medication (mTSQM). The TSQM is a 14-item self-report scale with total scores ranging from 14-98, higher scores indicating greater treatment satisfaction. This questionnaire has been adapted for the purpose of this study: the term "medication" has been replaced by "intervention", and the term "condition" had been replaced by "symptoms of insomnia or depression". |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Role | Phone | Extension | |
|---|---|---|---|---|
| Rebecca Robillard | Contact | 613-722-6521 | 6279 | Rebecca.Robillard@uottawa.ca |
| Name | Affiliation | Role |
|---|---|---|
| Rebecca Robillard | University of Ottawa Institute of Mental Health Research at The Royal | Principal Investigator |
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| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 16453985 | Background | Zhang B, Wing YK. Sex differences in insomnia: a meta-analysis. Sleep. 2006 Jan;29(1):85-93. doi: 10.1093/sleep/29.1.85. | |
| 39613462 | Background | Zhang G, Wang S, Ma P, Pan J. Neurophysiology and Molecular Basis of Cognitive Behavioral Therapy for Patients with Insomnia: Implications for Non-Pharmacological Approaches. J Integr Neurosci. 2024 Oct 31;23(11):200. doi: 10.31083/j.jin2311200. |
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Sharing of data outside of the primary institution leading the study such as through collaboration will be arranged only after express agreement with the PI.
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| ID | Term |
|---|---|
| D007319 | Sleep Initiation and Maintenance Disorders |
| D038223 | Post-Concussion Syndrome |
| ID | Term |
|---|---|
| D020919 | Sleep Disorders, Intrinsic |
| D020920 | Dyssomnias |
| D012893 | Sleep Wake Disorders |
| D009422 | Nervous System Diseases |
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| Sleep Hygiene | Behavioral | This condition will leverage a digital sleep hygiene program that will mirror the CBT-I intervention |
|
| 10 weeks |
| Satisfaction with treatment effectiveness as measured by the Modified Treatment Satisfaction Scale | Perceived perceived symptom improvements as well as overall treatment satisfaction as measured by the Modified Treatment Satisfaction Scale (TSS). The TSS is a 7 item questionnaire with total scores ranging from 7 to 35, with higher scores indicating greater treatment satisfaction. In the present study, the TSS was adapted for insomnia to measure symptom improvement in key areas including insomnia, energy level, work productivity, coping, life enjoyment, hopefulness, self-esteem, and mood. | 10 weeks |
| Changes in insomnia symptoms | Changes in insomnia symptoms as indicated by the Insomnia Severity Index-7 (ISI-7) total score from pre-intervention to the first follow-up time point after the end of the intervention. The ISI-7 is a 7 item questionnaire with total scores ranging from 0 to 28, with higher scores indicating more severe insomnia symptoms. | From baseline (week 0) to the first follow-up (week 14) |
| Changes in insomnia symptoms | Changes in insomnia symptoms as indicated by the Insomnia Severity Index-7 (ISI-7) total score from pre-intervention to the last follow-up time point after the end of the intervention. The ISI-7 is a 7 item questionnaire with total scores ranging from 0 to 28, with higher scores indicating more severe insomnia symptoms. | From baseline (week 0) to the last follow-up (week 34) |
| Treatment acceptability as measured by the Treatment Acceptability/Adherence Scale | Adherence to CBT-I guidelines and perceived helpfulness of treatment guidelines as rated on the Treatment Acceptability/Adherence Scale (TAAS). The TAAS is a 10-item questionnaire with total scores ranging from 10-70, higher scores indicating greater treatment acceptability and adherence. | 10 weeks |
| Portable electroencephalogram (EEG) feedback | Assessing the perceptions on using portable electroencephalogram (EEG) using the Questionnaire on Perceptions about Portable EEG using a scale on how the information from the sleep headband aligned with own perceptions from 1 (not at all) to 11 (very much). | From baseline (week 0) to post-intervention (week 10) |
| Assess feedback of potential adaptations linked to insomnia treatment | A semi-structured exit interview via a secured Zoom link to gather further insights (about 20-30 minutes). This will aim to gather feedback on participants' experiences throughout the intervention and potential adaptations to better address challenges linked to insomnia treatment in the context of brain-heart function in concussed adults. | 10 weeks |
| Changes in EEG-based sleep latency | Changes in EEG-based sleep onset latency from pre- to post-intervention. | From baseline (week 0) to follow-up (week 14) |
| Changes in EEG-based latency to REM sleep | Changes in EEG-based latency to REM sleep from pre- to post-intervention. | From baseline (week 0) to follow-up (week 14) |
| Changes in EEG-based total sleep time | Changes in EEG-based total sleep time from pre- to post-intervention. | From baseline (week 0) to follow-up (week 14) |
| Changes in EEG-based slow wave activity | Changes in the amount of slow wave activity (spectral power in the delta frequency range) from pre- to post-intervention. | From baseline (week 0) to follow-up (week 14) |
| Changes in EEG-based slow wave sleep | Changes in the amount of slow wave sleep measured with the EEG headband from pre- to post-intervention. | From baseline (week 0) to follow-up (week 14) |
| Changes in EEG power spectra | Changes in global EEG power spectrum as measured by the EEG headband from pre- to post-intervention. | From baseline (week 0) to follow-up (week 14) |
| Changes in the density of sleep slow waves | Changes in the density of sleep slow waves (number of slow wave per minute of NREM sleep) measured by the EEG headband (Muse S Athena) from pre- to post-intervention. | From baseline (week 0) to follow-up (week 14) |
| Change in the amplitude of sleep slow waves | Change in the amplitude of sleep slow waves (in uV) measured by the EEG headband (Muse S Athena) from pre- to post-intervention. | From baseline (week 0) to follow-up (week 14) |
| Change in the rate of ascending phase of sleep slow waves | Changes in the rate of ascending phase of sleep slow waves (uV/s) measured by the EEG headband (Muse S Athena) from pre- to post-intervention. | From baseline (week 0) to follow-up (week 14) |
| Change in the rate of descending phase of sleep slow waves | Changes in the rate of descending phase of sleep slow waves (uV/s) measured by the EEG headband (Muse S Athena) from pre- to post-intervention. | From baseline (week 0) to follow-up (week 14) |
| Changes in heart rate | Changes in heart rate measures including beats per minutes and heart rate variability from pre- to post-intervention. | From baseline (week 0) to follow-up (week 14) |
| Changes in executive function, visual and motor abilities | Assessed by the digital Jewels A task to measure executive function, visual and motor abilities. This task will be measured in seconds (s), a faster time indicates a better score. | From baseline (week 0) to the last follow-up (week 34) |
| Changes in visuospatial and working memory | Assessed by the digital Spatial Span task to measure visuospatial and working memory. This task will be measured in amount of sequences correctly completed, more sequences correctly completed indicates a better score. | From baseline (week 0) to the last follow-up (week 34) |
| Changes in attention and inhibition | Assessed by the digital Pop the Bubbles task to measure attention and inhibition. This task will be measured with the amount of bubbles popped in a certain amount of seconds (s), more bubbles popped within the time frame indicates a better score. | From baseline (week 0) to the last follow-up (week 34) |
| Changes in associative and visual memory | Assessed by the digital Funny Memory task that measures associative and visual memory. This task will be measured in seconds (s), the less time it takes to recall an image indicates a better score. | From baseline (week 0) to the last follow-up (week 34) |
| Changes in executive function, set-shifting, visual and motor abilities | Assessed by the digital Jewels B task that measures executive function, set-shifting, visual and motor abilities. This task will be measured in seconds (s), a faster time indicates a better score. | From baseline (week 0) to the last follow-up (week 34) |
| Changes in attentional control, conflict resolution, and selective attention | Assessed by the digital Flanker task that measures attentional control, conflict resolution, and selective attention. This task will be measured in total trials completed, more trials completed with less errors indicates a better score. | From baseline (week 0) to the last follow-up (week 34) |
| Changes in subjective pre-sleep arousal | Changes in subjective pre-sleep arousal as rated on the Pre-Sleep Arousal Scale (PSAS) from pre- to post-intervention. The PSAS is a 16-item questionnaire with total scores ranging from 16 to 80, with higher scores indicating greater cognitive and somatic pre-sleep arousal. | From baseline (week 0) to post-intervention (week 10) |
| Changes in subjective dysautonomia | Assessed using the Composite Autonomic Symptom Score 31 (Compass-31) questionnaire that includes 31 questions that assesses the severity and frequency of autonomic symtoms in the past year. | From baseline (week 0) to last follow-up (week 34) |
| Changes in anxiety symptoms | Assessed using the General Anxiety Disorder-7 (GAD-7) questionnaire which evaluates the severity off anxiety symptoms. This 7 item questionnaire assesses the severity of anxiety symptoms over the past 2 weeks from "not at all" to "nearly every day". | From baseline (week 0) to follow-up (week 34) |
| Changes in beliefs about sleep | Assessed by the Dysfunctional Beliefs About Sleep (DBAS-16) questionnaire. This 16 item questionnaire assesses beliefs about sleep from 0 (strongly disagree) to 10 (strongly agree). | From baseline (week 0) to post-intervention (week 10) |
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| D001523 |
| Mental Disorders |
| D001924 | Brain Concussion |
| D016489 | Head Injuries, Closed |
| D006259 | Craniocerebral Trauma |
| D020196 | Trauma, Nervous System |
| D014947 | Wounds and Injuries |
| D014949 | Wounds, Nonpenetrating |