Cereset Research Exploratory Study

Study Overview
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Brief Summary
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The purpose of this study is to evaluate the use of Cereset Research to improve autonomic function in participants with symptoms of stress, anxiety, or insomnia.

Detailed Description
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The primary objective of this open label exploratory study is to evaluate the effect of CR to improve autonomic cardiovascular regulation in participants with symptoms of stress, anxiety, or insomnia. The secondary objective is to evaluate the effect of CR on a variety of self-reported symptom inventories. Tertiary objectives are to explore the impact of selected medications on outcomes associated with use of CR, the effect size in subgroups of participants who also report specific co-morbid symptoms or conditions of interest, and any unexpected challenges or barriers for working with the same. The latter includes those with TBI, PTSD, hypertension, hot flashes, chronic pain, or prior stroke. Methods: This will be a single site, open label, pilot clinical trial, enrolling people aged 11 or older, who have self-reported symptoms of stress, anxiety, or insomnia, and meet a threshold score on self-reported inventories. Up to 150 participants will be enrolled. Participants will receive between 6 and 12 sessions of audible tones echoing current brainwave activity (CR). Participants will continue their other current care throughout the study. There will be pre- and post-intervention data collection of physiological outcomes (BP, HR, and measures of autonomic cardiovascular regulation assessed by heart rate variability and baroreflex sensitivity), which will alse serve as the primary outcome. Secondary outcomes to be collected include symptom inventories for insomnia (Insomnia Severity Index, ISI; Pittsburgh Sleep Quality Index, PSQI), depression (Center for Epidemiological Studies- Depression Scale, CES-D), anxiety (Generalized Anxiety Disorder-7, GAD-7), stress (Perceived Stress Scale, PSS), traumatic stress (PTSD Checklist for civilians, PCL-C, or military, PCL-M), , and overall quality of life (QOLS). Other secondary outcome inventories will be collected for physical activity (International Physical Activity Questionnaire, IPAQ-SF), and physical activity satisfaction questions, as well. Participants who also self-report having specific co-morbid symptoms or conditions of interest may complete additional condition-specific outcome measures. All measures will be collected at an enrollment visit (V1), and the intervention will begin 0-14 days thereafter. Mean contrasts will be used to compare the changes in measures of autonomic cardiovascular regulation from V1 to V3, the primary outcome, as well as for secondary outcomes. Linear mixed models, which can accommodate within-subject correlations due to repeated assessments over time, will be used to generate point estimates for effect size along with 95% confidence intervals.

Official Title
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Cereset Research Exploratory Study

Conditions
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Neurological Diseases or Conditions, Cardiovascular Conditions After Birth, Psychophysiologic Disorders

Intervention / Treatment
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* Device: Active CR


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Subjects must have the ability to comply with basic instructions and be able to sit still comfortably with the sensor leads attached Subjects experiencing symptoms of stress, anxiety, or insomnia, who meet threshold scores on one or more self-reported inventories for the same. This includes the Insomnia Severity Index (ISI, ≥ 8), the Perceived Stress Index (PSS, ≥ 14), or the Generalized Anxiety Disorder 7-item (GAD-7, ≥ 5) scale. Exclusion Criteria: Unable, unwilling, or incompetent to provide informed consent/assent. Physically unable to come to the study visits, or to sit comfortably in a chair for up to 1.5 hours. Severe hearing impairment (because the subject will be using ear buds during CR). Anticipated and ongoing use of alcohol or recreational drugs. Weight is over the chair limit (285 pounds). Currently in another active intervention research study. Prior use of HIRREM, Brainwave Optimization, Cereset, or a wearable configuration of the same (B2, or B2v2). Prior use of electroconvulsive therapy (ECT). Prior use of transcranial magnetic stimulation (TMS), transcranial direct current stimulation (TDCS), alpha stimulation, neurofeedback, biofeedback, or deep brain stimulation (DBS) within one month before enrollment. Known seizure disorder.

Ages Eligible for Study
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Minimum Age: 11 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Supportive Care
Intervention Model: Single Group Assignment
Interventional Model Description: This will be a single site, open label, pilot clinical trial, enrolling people aged 11 or older, who have self-reported symptoms of stress, anxiety, or insomnia, and meet a threshold score on self-reported inventories. Up to 100 participants will be enrolled so as to gather pilot data that will help inform regarding effect size, and dosing to support future cohort-specific randomized trials. Participants will receive between 6 and 12 intervention sessions of Cereset Research consisting of audible tones echoing current brainwave activity.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Experimental: Active CR<br>For this single arm, open label, exploratory trial this will be the intervention arm using active CR. | Device: Active CR<br>* 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 Heart Rate Variability | Heart rate variability is measured in the time domain as standard deviation of beat-to-beat interval (SDNN, milliseconds). For calculation of SDNN, the R-R intervals are visually inspected, and data considered as artifact is manually removed. Heart rate are acquired from 10 minute recordings of noninvasive finger arterial pressure measurements and ECG with participants lying quietly, supine. Systolic BP and beat to beat, RR intervals files generated via the data acquisition system (BIOPAC acquisition system and Acknowledge 4.2 software, Santa Barbara, CA), at 1000 Hz, are analyzed using Nevrokard BRS software (Nevrokard BRS, Medistar, Ljubljana, Slovenia). Analysis is conducted on the first complete 5-minute epoch that is considered to be acceptable for analysis. | Baseline, V2 (0-14 days after final session), and V3 (4-6 weeks after V2) | 
| Change in Baroreflex Sensitivity | BRS calculated by this method is based on quantification of sequences of at least three beats (n) in which SBP consecutively increases (UP sequence) or decreases (DOWN sequence), which are accompanied by changes in the same direction of the 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). Blood pressure and heart rate are acquired from 10 minute recordings of noninvasive finger arterial pressure measurements and ECG with participants lying quietly, supine. Systolic BP and beat to beat, RR intervals files generated via the data acquisition system (BIOPAC acquisition system and Acknowledge 4.2 software, Santa Barbara, CA), at 1000 Hz, are analyzed using Nevrokard BRS software (Nevrokard BRS, Medistar, Ljubljana, Slovenia). | Baseline, V2 (0-14 days after final session), and V3 (4-6 weeks after V2) | 
| Change in Blood Pressure | 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 final session), and V3 (4-6 weeks after V2) | 
| Change in 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). | Baseline, V2 (0-14 days after final session), and V3 (4-6 weeks after V2) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Insomnia Severity Index (ISI) | The severity of insomnia symptoms is measured using the ISI with each data collection visit. The ISI is a 7 question measure, with responses from 0-4 for each question, yielding scores ranging from 0-28. Higher scores indicate the strength of the insomnia severity. | Baseline, V2 (0-14 days after final session), and V3 (4-6 weeks after V2) | 
| Change in Pittsburgh Sleep Quality Index (PSQI) | The PSQI is a 19 item inventory that assesses sleep quality over a 1-month time interval. Items are weighted on a 0-3 interval scale. A global PSQI score is calculated by totaling the seven component scores, providing an overall score ranging from 0 to 21, where lower scores denote a healthier sleep quality. | Baseline, V2 (0-14 days after final session), and V3 (4-6 weeks after V2) | 
| Change in Center for Epidemiologic Studies Depression Scale (CES-D) | The 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. Higher scores indicate the presence of more symptomatology. | Baseline, V2 (0-14 days after final session), and V3 (4-6 weeks after V2) | 
| Change in Generalized Anxiety Disorder-7 (GAD-7) | The GAD-7 is a seven item screening tool for anxiety that is widely used in primary care. Scores range from 0-21. A lower score denotes a lower level of anxiety. | Baseline, V2 (0-14 days after final session), and V3 (4-6 weeks after V2) | 
| Change in Perceived Stress Scale (PSS) | The 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. Scores range from 0-40. A lower score denotes a lower level of perceived stress. | Baseline, V2 (0-14 days after final session), and V3 (4-6 weeks after V2) | 
| Change in 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 final session), and V3 (4-6 weeks after V2) | 
| Change in PTSD Checklist for Civilians (PCL-C) | The 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 related to civilians. 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. | Baseline, V2 (0-14 days after final session), and V3 (4-6 weeks after V2) | 
| Change in International Physical Activity Questionnaire (IPAQ-SF) | This is a four item questionnaire asking about physical activity in the last 7 days. Scores are calculated and categorized as low, moderate, or high. A higher score denotes more physical activity. | Baseline, V2 (0-14 days after final session), and V3 (4-6 weeks after V2) | 
| Change in HIRREM Physical Activity Satisfaction Questions | This is a four item questionnaire asking about the participants level of satisfaction with their physical activity. Responses range from 0-6 for each question, yielding scores ranging from 0-24. Higher scores denote a higher level of satisfaction. | Baseline, V2 (0-14 days after final session), and V3 (4-6 weeks after V2) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Autonomic Dysregulation, Hyperarousal, Brain electrical activity, Allostasis, HIRREM, Cereset Research, Insomnia, Anxiety, Stress, Neurotechnology