Cereset Research Exploratory Study for Dementia Caregivers

Study Overview
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Brief Summary
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Caregivers of a person living with dementia (PLWD) experience high levels of prolonged stress that can lead to chronic problems with health, including increased risk of cardiovascular disease that is linked to autonomic dysregulation. Heart rate variability (HRV), measures of autonomic cardiovascular regulation, is decreased (worse) in caregivers of a person living with dementia. Autonomic function is linked to lateralization in the brain, and emerging neuromodulation methods that target lateralized signals in the brain, like Cereset (CR), may be able to improve heart rate variability. Therefore, this pilot study aims to test whether CR can improve HRV in caregivers of a person living with dementia experiencing stress, anxiety, or insomnia, as well as improve self-report measures of stress, sleep and caregiver burden.

Detailed Description
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Phase I: Intervention only pre-piloting: up to 5 adults; mirroring Phase II characteristics described below Phase II: 20 dementia caregivers experiencing symptoms of stress, anxiety or insomnia. Primary aims are to: 1) Evaluate the effect of CR to improve autonomic cardiovascular regulation measured as heart rate variability (HRV) and baroreflex sensitivity (BRS). Impact will be assessed based on changes in standard measures of HRV and BRS such as SDNN, rMSSD, HF Alpha, and Sequence ALL. This will also provide blood pressure values evaluated by an automated oscillometric blood pressure device. 2) Assess the effect of CR on self-reported symptom inventories of stress, anxiety, insomnia, and caregiver burden and distress. Insomnia as assessed by the Insomnia Severity Index (ISI). Behavioral outcomes such as depression (as assessed by the Center for Epidemiological Studies-Depression Scale, CES-D), anxiety (as evaluated by the GAD-7), traumatic stress (as assessed by the PCL-C), and stress (as assessed by the Perceived Stress Scale, PSS). Overall quality of life as evaluated using the QOLS measure. Caregiver burden and distress measured with the Zarit Caregiver Burden scale and the Neuropsychiatric Inventory Questionnaire (NPI-Q). Brief (4-item) caregiver self-efficacy scale.

Official Title
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Cereset Research for Dementia Caregivers: A Randomized, Placebo-Controlled Trial

Conditions
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Dementia Caregivers

Intervention / Treatment
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* Device: Cereset Research


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: participants must provide at least 10 hours of care a week to a person with a diagnosis of dementia (including Alzheimer's disease (early onset or late onset), frontotemporal dementia, Lewy body dementia, Parkinsonian dementia, and mixed dementias) participants must be willing to provide informed consent participants have no planned travel during the study period participants must be able to comply with basic instructions participants must be able to sit comfortably for up to 90 minutes, and attend up to three 60-minute intervention sessions each week during the 4-week intervention period participants must self report experiencing symptoms of stress, anxiety, or insomnia and meet threshold scores on one or more self-report inventories of these symptoms (Insomnia Severity Index (ISI, ≥ 8), the Perceived Stress Index (PSS, ≥ 14), or the Generalized Anxiety Disorder 7-item (GAD-7, ≥ 5) scale) Exclusion criteria: participants providing less than 10 hours a week of care to a person with dementia participants who are unable or unwilling to attend intervention sessions during the planned study period participants who are unable or unwilling to provide consent participants who are unable to sit comfortably for up to 75 minutes participants who are not exhibiting symptoms of stress, anxiety or insomnia participants with hearing impairment severe enough that they cannot perceive tones through ear buds participants anticipating ongoing use of alcohol or recreational drugs participants with known seizure disorder, or suicidal thoughts within the last 3 months participants who respond positively to a question about risk for suicide within the last 3 months will be excluded and receive a behavioral health resource list participants weighing more than 400 pounds (the weight limit of the chair used during intervention) participants currently enrolled in another intervention study prior use of neuromodulation, neurostimulation, deep brain stimulation, neurofeedback, biofeedback, alpha stim, Eye Movement Desensitization and Reprocessing (EMDR),or electroconvulsive therapy within the last month participants taking Medications that may affect the assessment of heart rate variability (beta blockers. Ongoing need for treatment with opiate, benzodiazepine, or anti-psychotic medications, anti-depressant medications (SSRI, or SNRI's), sleep medications such as zolpidem or eszopiclone, stimulants such as Adderall, Provigil, or Ritalin, or thyroid hormone)

Ages Eligible for Study
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Minimum Age: 18 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: Supportive Care
Allocation: Randomized
Intervention Model: Single Group Assignment
Interventional Model Description: Prior to the start of the randomized Phase II for the trial, a limited intervention-only pilot will be carried out with up to 5 participants (Phase I). The purpose of this is to confirm feasibility of cohort and identify challenges, intervention, and outcome assessment procedures to ensure they are optimized by the start of the randomized phase, and allow additional time to work towards any obstacles that arise with the placebo. Phase II will be a single-blind, randomized, pilot clinical trial that aims to enroll 20 participants who will be randomized to receive 6 sessions of CR intervention linked to brainwaves (INT) (n=10) or 6 sessions of sham control tones not linked to brainwaves (CON) (n=10). In this study, the tones not linked to brainwaves will be used as the control.
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Cereset Research<br>This will be the active intervention arm using 6 Cereset (CR) sessions and participants will continue current care. | Device: Cereset Research<br>* Cereset Research The upgraded platform for medical research using the HIRREM technology has been rebranded as Cereset Research® (CR). This system uses the same core technology and algorithms to echo brainwaves in real-time using audible tones, as with HIRREM. The CR system also includes 64-bit processing architecture for faster feedback, the use of 4 sensors, and the use of standard protocols (with flexibility regarding the length and sequencing of the standard protocols), all done with eyes closed. Four sensors are applied to the scalp at a time. However, only two sensors are actively echoing feedback. The software automatically switches from one sensor pair to the other when needed. This reduces the number of sensor placement changes needed, resulting in shorter session time and fewer interruptions.<br>|
| Sham Comparator: Control<br>Participants will have 6 CR sessions of sham control tones and also continue their current care. | Device: Cereset Research<br>* Cereset Research The upgraded platform for medical research using the HIRREM technology has been rebranded as Cereset Research® (CR). This system uses the same core technology and algorithms to echo brainwaves in real-time using audible tones, as with HIRREM. The CR system also includes 64-bit processing architecture for faster feedback, the use of 4 sensors, and the use of standard protocols (with flexibility regarding the length and sequencing of the standard protocols), all done with eyes closed. Four sensors are applied to the scalp at a time. However, only two sensors are actively echoing feedback. The software automatically switches from one sensor pair to the other when needed. This reduces the number of sensor placement changes needed, resulting in shorter session time and fewer interruptions.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Blood Pressure Measurements | BP measurements will be obtained using an automate oscillometric blood pressure device. Three samples will be obtained and the last two averaged to get the value that will be used as the reading for that visit. | Baseline; V2 (0-14 days after intervention completion; V3 (4-7 weeks following completion of the intervention) | 
| Change in Heart Rate (HR) | Continuous heart rate will be recorded while participant is breathing normally in seated position for 10 minutes using Faros 180 heart rate monitor (Bittium Corporation, Oulu, Finland). Beat to beat intervals (RRI) files will be generated at 1000 Hz via the data acquisition software. Files will be analyzed with Nevrokard HRV software (by Nevrokard Kiauta, d.o.o., Izola, Slovenia). Recordings will be visually inspected to ensure data quality (dropped beats or gross motion artifacts are excluded) and first 5 minutes of usable tracings will be analyzed. | Baseline; V2 (0-14 days after intervention completion; V3 (4-7 weeks following completion of the intervention) | 
| Change in Heart Rate Variability (HRV) | Measures of heart rate variability in frequency domain will be derived and measures integrated over specified frequency ranges (LF: 0.04-0.15 Hz; HF: 0.15-0.4 Hz). Power of RRI spectra in LF, HF range (LFRRI and HFRRI) and total power (TP) will be calculated in normalized units and ratio of LF/HF used as a measure of sympatho-vagal balance. | Baseline; V2 (0-14 days after intervention completion; V3 (4-7 weeks following completion of the intervention) | 
| Change in Baroreflex Sensitivity | BRS calculated by this method is based on quantification of sequences of at least three beats (n) in which Systolic Blood Pressure (SBP) consecutively increases (UP sequence) or decreases (DOWN sequence), which are accompanied by changes in the same direction of the beat-to-beat intervals (RRI) of subsequent beats (n+1). The software scans the RRI and SBP records, identifies sequences, and calculates linear correlation between RRI and SBP for each sequence. The mean of all individual regression coefficients (slopes), a measure of sequence BRS, is calculated for Sequence UP, DOWN and ALL (ms/mmHg). | Baseline; V2 (0-14 days after intervention completion; V3 (4-7 weeks following completion of the intervention) | 
| Blood Pressure Variability | Systolic BP and beat to beat, RR intervals (RRI) files generated via the data acquisition system (BIOPAC acquisition system and software, Santa Barbara, CA) at 1000 Hz are analyzed using Nevrokard SA-BRS software (by Nevrokard Kiauta, d.o.o., Izola, Slovenia) for measures BPV.Frequency Method. Power spectral densities of SBP and RRI oscillations are computed by 512 points Fast Fourier Transform (FFT) and integrated over specified frequency ranges (LF: 0.04-0.15 Hz; HF: 0.15-0.4 Hz). | V3 (4-7 weeks following completion of the intervention) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Severity of Insomnia (ISI) | The ISI is a 7 question, self-reported measure to evaluate symptoms of insomnia, with responses from 0-4 for each question, yielding scores ranging from 0-28. Lower scores represent better outcomes. | Baseline, V2 (0-14 days after intervention completion, and V3 (4-7 weeks following completion of the intervention) | 
| Center for Epidemiologic Studies Depression Scale (CES-D) | The Center for Epidemiologic Studies Depression Scale (CES-D) is a depression scale, which will help to assess this co-morbidity. CES-D is a 20-item survey assessing affective depressive symptomatology to screen for risk of depression. Scores range from 0-60, with a score of 16 commonly used as a clinically relevant cut-off. The higher the score, the more suggestive of depressive symptoms. | Baseline, V2 (0-14 days after intervention completion, and V3 (4-7 weeks following completion of the intervention) | 
| Generalized Anxiety Disorder-7 (GAD-7) scores | The Generalized Anxiety Disorder-7 (GAD-7) is a seven-item screening tool for anxiety that is widely used in primary care. GAD-7 is a brief, reliable and valid measure of assessing generalized anxiety disorder. A score of 10 or greater on the GAD-7 represents a reasonable cut point for identifying cases. Cut points of 5, 10, and 15 might be interpreted as representing mild, moderate, and severe levels of anxiety. | Baseline, V2 (0-14 days after intervention completion, and V3 (4-7 weeks following completion of the intervention) | 
| PTSD Checklist for civilians (PCL-C) | The PTSD Checklist for civilians (PCL-C), measures the American Psychiatric Association's Diagnostic and statistical manual of mental disorders (DSM-IV) Criteria B, C, & D of PTSD symptoms based on traumatic life experience either in civilian life. Seventeen items are rated on a Likert scale with a composite score range of 17 to 85. A score of 44 or higher correlates with probability of civilian-related PTSD. Higher scores suggest more traumatic stress. | Baseline, V2 (0-14 days after intervention completion, and V3 (4-7 weeks following completion of the intervention) | 
| Perceived Stress Scale (PSS) | The Perceived Stress Scale (PSS) is a ten-item psychological instrument for measuring the perception of stress. It is a measure of the degree to which situations in one's life are appraised as stressful. Items were designed to tap how unpredictable, uncontrollable, and overloaded respondents find their lives. The scale, with answers rated from 0-4, also includes a number of direct queries about current levels of experienced stress. Total scores range from 0-40. A lower score denotes a lower level of perceived stress. | Baseline, V2 (0-14 days after intervention completion, and V3 (4-7 weeks following completion of the intervention) | 
| Quality of Life Scale (QOLS) | The QOLS is a 16-item scale that was modified from a 15-item scale used in chronic disease patients. Topics include different components of daily life such as relationships, community engagement, personal fulfillment, and recreation. Each item is scaled from 1 to 7 and a sum score is calculated to represent higher levels of satisfaction in life (range is 16-112). | Baseline, V2 (0-14 days after intervention completion, and V3 (4-7 weeks following completion of the intervention) | 
| Caregiver Burden (Zarit) | The Zarit caregiver burden scale scoring system uses a five point scale. Responses can range from zero (which means never) to four (which means nearly always). A screening tool of this type can help identify challenges in a way that is less personal and threatening to the caregiver and the care recipient. | Baseline, V2 (0-14 days after intervention completion, and V3 (4-7 weeks following completion of the intervention) | 
| Caregiver Distress (NPI-Q) | Caregiver distress will be assessed using the Neuropsychiatric Inventory Questionnaire (NPI-Q) and an adaptation of the 22-item Impact of Events Scale-Revised (IES-R) for caregiving. Higher total scores (each question being 0-4 points) equal higher amounts of distress. The rationale for assessing only symptom severity on the NPI-Q is the finding that symptom severity is more strongly correlated with caregiver distress (i.e., more clinically significant) than how often the symptom occurs. The total NPI-Q severity score represents the sum of individual symptom scores and ranges from 0 to 36. | Baseline, V2 (0-14 days after intervention completion, and V3 (4-7 weeks following completion of the intervention) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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caregiver, caregiving, stress, anxiety, insomnia, neurotechnology, autonomic dysregulation, hyperarousal, brain electrical activity, allostasis, Alzheimer's, dementia, neuromodulation, acoustic stimulation, heart rate variability, High-resolution relational resonance-based electroencephalic mirroring HIRREM, Cereset Research