Stress Disorders, Post-Traumatic
Conditions
Keywords
PTSD, military, neurotechnology, HIRREM, allostasis, heart rate variability, baroreflex sensitivity, closed loop, acoustic stimulation, neural oscillations, autonomic, hyperarousal
Brief summary
The purpose of this study is to evaluate the effects associated with the use of in-office High-resolution, relational, resonance-based, electroencephalic mirroring (HIRREM) for participants with symptoms of military-related traumatic stress. This is a single site, non-randomized, open label pilot study. Outcome measures collected before, and after the intervention evaluate effects on self-reported symptoms, autonomic cardiovascular regulation, functional measures, blood and saliva biomarkers of stress and inflammation, and network connectivity on whole brain, rest MRI testing. Self-reported symptom outcomes will also be collected remotely at 1, 3, and 6 months after completion of intervention. The study will assess feasibility in this cohort, focused on the Special Operations community, will provide estimates of effect size, and durability of symptom changes, while providing important pilot data for future proposals and investigations.
Detailed description
This will be an open label, single site, pilot, clinical research study. Up to 40 active duty military personnel, or recent Veterans, age 18 or older, who have been diagnosed with PTSD, have received treatment for, are referred by military medical personnel for, or have active symptoms of military-related traumatic stress, with or without mild TBI, will be recruited to receive up to 24 HIRREM sessions over 2 weeks. For those who self-refer, and do not have a prior diagnosis or treatment for PTSD, active symptoms will be identified by a screening PCL-M score of 50 or greater. Recruitment of 40 participants will allow us to achieve the goal of 36 participants to complete the intervention, allowing for the possibility of dropouts. The primary outcome will be differential change in the PCL-M from baseline to completion of HIRREM sessions. Secondary measures include the Insomnia Severity Index (ISI), the Center for Epidemiological Studies Depression Scale (CES-D), an anxiety measure (GAD-7), a quality of life measure (EQ-5D), an autonomic symptom measure (Compass 31), and a daily sleep diary, as well as physiological measures including heart rate (HR), and blood pressure (BP), with calculation of heart rate variability measures (HRV), and baroreflex sensitivity (BRS). Functional measures will include reaction time (drop-stick paradigm), and grip strength (hydraulic dynamometer), and analysis of brain patterns. If there is a history of TBI, a Rivermead Post-Concussion Symptoms Questionnaire (RPQ) will be added. There will be pre- and post-intervention data collection for all measures (baseline, V1, and at completion of HIRREM sessions, V2). Self-report measures will also be repeated by phone at 1, 3, and 6 months after completion of sessions (V3, V4, and V5 respectively). The online sleep diary will be maintained from V1 until V3. A brainwave assessment will be obtained at V1.
Interventions
DEVICEHIRREM
HIRREM is a closed-loop, allostatic, acoustic stimulation neurotechnology intended to support auto-calibration of neural oscillations. The core technology is commercially available as a technique for relaxation. Scalp sensors monitor brain frequencies and amplitudes, and in real time, software algorithms translate specific frequencies into audible tones of varying pitch. These are reflected via earbuds in as little as 4-8 milliseconds. The in-office intervention for this study is administered as a series of up to twenty four, typically 1.5-2 hours sessions, comprised of 4-10 protocols (some eyes open, some eyes closed), lasting 6-40 minutes each, working at different scalp locations. Sessions are received over 12 days. Two sessions can be done in a half day. The intervention is received while comfortably seated in a zero gravity chair.
Sponsors
Brain State Technologies, LLC
Wake Forest University Health Sciences
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
Single site, non-randomized, single arm, open label design,with collection of outcome measures before, and at intervals after the intervention
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
Active duty military personnel, or recent veterans (Operation Enduring Freedom, Operation Iraqi Freedom, or Operation New Dawn), men and women, with a diagnosis of PTSD, or active symptoms suggesting PTSD as identified by a screening PCL-M score of 50 or greater, with or without traumatic brain injury (TBI), are eligible to participate in the study.
Exclusion criteria
* Unable, unwilling, or incompetent to provide informed consent * Physically unable to come to the study visits, or to sit in a chair for several hours * Known seizure disorder * Severe hearing impairment (because the subject will be using ear buds during HIRREM) * 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 * Anticipated and ongoing use of recreational drugs, alcohol, or energy drinks * Lack of internet or smart phone access (will maintain remote access daily sleep diary through 1 month post-HIRREM visit)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in PCL-M Score From Baseline to 12 Days | Data is collected at baseline and immediately following completion of the HIRREM intervention (up to 12 days later) | The PTSD Checklist (PCL) - Military (M) is a symptom checklist to measure stress severity due to a traumatic experience in military settings. The PCL-M measures the American Psychiatric Association's Diagnostic and statistical manual of mental disorders (DSM-IV) of PTSD symptoms based on traumatic life experience. Seventeen items are rated on a Likert scale from 1 (not at all) to 5 (extremely), with a total score ranging from 17 to 85. Higher scores suggest more PTSD symptoms. Primary outcome for this pilot study will be change in PCL-M score from baseline to the immediate post-intervention in-person data collection at the completion of the HIRREM intervention (up to 12 days later). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in Insomnia Severity Index (ISI) Score From Baseline to 12 Days | Data is collected at baseline and immediately following completion of the intervention (up to 12 days later) | 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. Secondary outcome with the ISI will be analyzed for change from baseline to the immediate post-HIRREM in person data collection. |
| Change in Generalized Anxiety Disorder-7 (GAD-7) Score From Baseline to 12 Days | Data is collected at baseline and immediately following completion of the intervention (up to 12 days later) | The Generalized Anxiety Disorder-7 (GAD-7) is a seven item screening tool for anxiety that is widely used in primary care. Each item is rated from 0 (not at all) to 3 (nearly every day). Scores range from 0 to 21 with higher scores suggesting more anxiety. Secondary outcome with the GAD-7 will be analyzed for change from baseline to the immediate post-HIRREM in person data collection. |
| Change in Rivermead Post-Concussion Symptoms Questionnaire (RPQ) Score From Baseline to 12 Days | Data is collected at baseline and immediately following completion of the intervention (up to 12 days later) | The Rivermead Post-Concussion Symptoms Questionnaire (RPQ) is a 16-item survey that assesses the severity of the most common post-concussion symptoms on a scale of 0 to 4, with a total score range from 0 to 64 (least to greatest symptom severity). Items are compared to levels before the head injury and are reported as a 24 hour recall. Secondary outcome with the RPQ will be analyzed for change from baseline to the immediate post-HIRREM in person data collection. |
| Change in EQ-5D Score From Baseline to 12 Days | Data is collected at baseline and immediately following completion of the intervention (up to 12 days later) | The EQ-5D is a brief, standardized measure of health status developed by the EuroQol Group, and is a paper and pencil survey providing a single index value for health status. Secondary outcome with the EQ-5D will be analyzed for change from baseline to the immediate post-HIRREM in person data collection. Global health rating question is reported (0-100, with 100 being in the best health possible). |
| Change in Heart Rate Variability Measure of SDNN From Baseline to 12 Days | Data is collected at baseline and immediately following completion of the intervention (up to 12 days later) | Secondary autonomic outcome with heart rate variability will be analyzed for change from baseline to the immediate post-HIRREM in person data collection. Heart rate variability is measured in the time domain as standard deviation 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. Higher SDNN values suggest better autonomic regulation. |
| Change in Baroreflex Sensitivity HF Alpha From Baseline to 12 Days | Data is collected at baseline and immediately following completion of the intervention (up to 12 days later) | 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 Baroreflex Sensitivity (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. Evaluation includes analysis for measures of spontaneous baroreflex sensitivity (BRS), in the frequency domain as high frequency (HF) alpha index (ms2). Secondary autonomic outcome with BRS will be analyzed for change from baseline to the immediate post-HIRREM in person data collection. Higher values in HF alpha suggest better autonomic regulation. |
| Change in Baroreflex Sensitivity Sequence Up From Baseline to 12 Days | Data is collected at baseline and immediately following completion of the intervention (up to 12 days later) | 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 Baroreflex Sensitivity (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. Evaluation includes analysis for measures of spontaneous baroreflex sensitivity (BRS), in the time domain as frequency domain as BRS Sequence Up (ms/mmHg). Secondary autonomic outcome with BRS will be analyzed for change from baseline to the immediate post-HIRREM in person data collection. Higher values in Sequence Up suggest better autonomic regulation. |
| Change in Baroreflex Sensitivity Sequence Down From Baseline to 12 Days | Data is collected at baseline and immediately following completion of the intervention (up to 12 days later) | 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 Baroreflex Sensitivity (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. Evaluation includes analysis for measures of spontaneous baroreflex sensitivity (BRS), in the time domain as frequency domain as BRS Sequence Down (ms/mmHg). Secondary autonomic outcome with BRS will be analyzed for change from baseline to the immediate post-HIRREM in person data collection. Higher values in Sequence Down suggest better autonomic regulation. |
| Change in Baroreflex Sensitivity Sequence All From Baseline to 12 Days | Data is collected at baseline and immediately following completion of the intervention (up to 12 days later) | 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 Baroreflex Sensitivity (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. Evaluation includes analysis for measures of spontaneous baroreflex sensitivity (BRS), in the time domain as frequency domain as BRS Sequence All (ms/mmHg). Secondary autonomic outcome with BRS will be analyzed for change from baseline to the immediate post-HIRREM in person data collection. Higher values in Sequence All suggest better autonomic regulation. |
| Change in Center for Epidemiologic Studies Depression Scale (CES-D) Score From Baseline to 12 Days | Data is collected at baseline and immediately following completion of the intervention (up to 12 days later) | 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 suggest more depressive symptomatology. Secondary outcome with the CES-D will be analyzed for change from baseline to the immediate post-HIRREM in person data collection. |
| Change in Grip Strength From Baseline to 12 Days | Data is collected at baseline and immediately following completion of the intervention (up to 12 days later) | Grip strength will evaluated using a hydraulic hand dynamometer (Baseline Hydraulic Hand Dynamometer, ranges from 0 to 300 lbs). Both right and left hand will be evaluated, and the greatest force generated during three trials will be used for analysis. A higher score indicates stronger grip strength. |
| Change in Functional MRI From Baseline to 12 Days | Data is collected at baseline and immediately following completion of the intervention (up to 12 days later) | Anatomical and physiological brain imaging will be performed during a 1-hour imaging session at baseline and immediately following completion of the intervention. This will include imaging sequences such as high resolution structural scans. Brain network data will be collected using blood oxygenation level dependent (BOLD) scans. These scans will be collected under various states such as at rest. All images will be acquired using a 3 Tesla Siemens MRI scanner. Whole-brain network connectivity will be assessed using blood oxygenation level dependent (BOLD) imaging. Unit of measure is percentage of BOLD signal change. Community structure will be determined for each participant pre- and post-intervention. This project will focus on the community including the Default Mode Network (DMN). Participant strength of the community structure will be determined of the DMN. Permutation analysis will be used to evaluate significant pattern change in specific networks. |
| Change in Blood Biomarkers for Stress and Inflammation Score From Baseline to 12 Days | Data is collected at baseline and immediately following completion of the intervention (up to 12 days later) | Blood for a panel of biomarkers for stress will be collected at enrollment, and after completion of the intervention. The panel includes Ang II, Ang 1-7, Epinephrine, Norepinephrine, C-reactive protein, Vasopressin, IL-1, IL-6, and IL-10. |
| Salivary Biomarker Cortisol for Stress From Baseline to 12 Days | Salivary biomarker for stress will be obtained at baseline and immediately following completion of the intervention (up to 12 days) | Saliva for salivary biomarker Cortisol, for stress, will be collected at enrollment, and after completion of the intervention. |
| Change in Epigenetic Markers From Baseline to 12 Days | Blood for epigenetic markers will be obtained at baseline and immediately following completion of the intervention (up to 12 days) | DNA will be isolated from whole blood, collected in yellow-top Vacutainer tubes (ACD as the preservative), using the AutoPure LS system in the Genomics Center Core lab. DNA will be bisulfite-converted using the EZ DNA Methylation Gold kit (Zymo, Irvine, CA). To quantify DNA methylation at each site, investigators will use the HumanMethylationEPIC450 BeadChip (Illumina, Inc.). The methylation proportion for each site (beta value) is based on the ratio of the fluorescence intensity of the methylated versus the combined methylated & unmethylated probes, & will be determined with GenomeStudio (Illumina, Inc.). Ratio of 0 equals no methylation & ratio of 1 equals total (100%) methylation. Effects of DNA methylation for a specific site are dependent on function of the regulated gene(s). For some genes, increased level methylation from the intervention may be beneficial, while for others an increased level may be detrimental. There is no universal way to interpret change in DNA methylation. |
| Change in Sleep Latency Score From Baseline to 42 Days | Sleep diary data will be collected daily via online access from baseline to a month following completion of intervention (up to 42 days) | An online daily sleep diary to calculate sleep latency will be maintained from baseline, through the one month post-intervention remote data collection (roughly 42 days). Sleep latency is reported in minutes and a smaller score suggests falling asleep faster. |
| Change in C-reactive Protein for Stress and Inflammation Score From Baseline to 12 Days | Data is collected at baseline and immediately following completion of the intervention (up to 12 days later) | Blood for biomarker C-reactive protein for stress will be collected at enrollment, and after completion of the intervention. |
| Salivary Biomarker for Stress From Baseline to 12 Days | Salivary biomarker Alpha-Amylase for stress will be obtained at baseline and immediately following completion of the intervention (up to 12 days) | Saliva for salivary biomarker Alpha-Amylase, for stress, will be collected at enrollment, and after completion of the intervention. |
| Change in Drop Stick Reaction Time From Baseline to 12 Days | Data is collected at baseline and immediately following completion of the intervention (up to 12 days later) | Reaction testing is measured by a drop-stick apparatus that has been validated as a way to quantify the impact of athletic concussion on psychomotor performance. Following two practice trials, participants perform eight trials, and a mean distance value is calculated. Secondary functional outcome with drop-stick reaction time will be analyzed for changes in distance from baseline to the in person data collection immediately after completion of the intervention. A lower average indicates a faster reaction time. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| HIRREM This is the intervention, treatment arm that all participants receive in this open label, single arm trial. The intervention is High-resolution, relational, resonance-based, electroencephalic mirroring (HIRREM).
HIRREM: HIRREM is a closed-loop, allostatic, acoustic stimulation neurotechnology intended to support auto-calibration of neural oscillations. The core technology is commercially available as a technique for relaxation. Scalp sensors monitor brain frequencies and amplitudes, and in real time, software algorithms translate specific frequencies into audible tones of varying pitch. These are reflected via earbuds in as little as 4-8 milliseconds. The in-office intervention for this study is administered as a series of up to twenty four, typically 1.5-2 hours sessions, comprised of 4-10 protocols (some eyes open, some eyes closed), lasting 6-40 minutes each, working at different scalp locations. Sessions are received over 12 days. Two sessions can be done in a half day. The intervention is received while comfortably seated in a zero gravity chair. | 32 |
| Total | 32 |
Baseline characteristics
| Characteristic | HIRREM |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 0 Participants |
| Age, Categorical Between 18 and 65 years | 32 Participants |
| Age, Continuous | 40.72 years STANDARD_DEVIATION 6.4 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 26 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 5 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 4 Participants |
| Race (NIH/OMB) White | 27 Participants |
| Region of Enrollment United States | 32 participants |
| Sex: Female, Male Female | 1 Participants |
| Sex: Female, Male Male | 31 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 0 / 32 |
| other Total, other adverse events | 0 / 32 |
| serious Total, serious adverse events | 0 / 32 |
Outcome results
Primary
Change in PCL-M Score From Baseline to 12 Days
The PTSD Checklist (PCL) - Military (M) is a symptom checklist to measure stress severity due to a traumatic experience in military settings. The PCL-M measures the American Psychiatric Association's Diagnostic and statistical manual of mental disorders (DSM-IV) of PTSD symptoms based on traumatic life experience. Seventeen items are rated on a Likert scale from 1 (not at all) to 5 (extremely), with a total score ranging from 17 to 85. Higher scores suggest more PTSD symptoms. Primary outcome for this pilot study will be change in PCL-M score from baseline to the immediate post-intervention in-person data collection at the completion of the HIRREM intervention (up to 12 days later).
Time frame: Data is collected at baseline and immediately following completion of the HIRREM intervention (up to 12 days later)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| HIRREM | Change in PCL-M Score From Baseline to 12 Days | -12.88 score on a scale | Standard Deviation 9.11 |
Secondary
Change in Baroreflex Sensitivity HF Alpha From Baseline to 12 Days
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 Baroreflex Sensitivity (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. Evaluation includes analysis for measures of spontaneous baroreflex sensitivity (BRS), in the frequency domain as high frequency (HF) alpha index (ms2). Secondary autonomic outcome with BRS will be analyzed for change from baseline to the immediate post-HIRREM in person data collection. Higher values in HF alpha suggest better autonomic regulation.
Time frame: Data is collected at baseline and immediately following completion of the intervention (up to 12 days later)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| HIRREM | Change in Baroreflex Sensitivity HF Alpha From Baseline to 12 Days | 9.43 ms2 | Standard Deviation 12.05 |
Secondary
Change in Baroreflex Sensitivity Sequence All From Baseline to 12 Days
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 Baroreflex Sensitivity (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. Evaluation includes analysis for measures of spontaneous baroreflex sensitivity (BRS), in the time domain as frequency domain as BRS Sequence All (ms/mmHg). Secondary autonomic outcome with BRS will be analyzed for change from baseline to the immediate post-HIRREM in person data collection. Higher values in Sequence All suggest better autonomic regulation.
Time frame: Data is collected at baseline and immediately following completion of the intervention (up to 12 days later)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| HIRREM | Change in Baroreflex Sensitivity Sequence All From Baseline to 12 Days | 5.75 ms/mmHg | Standard Deviation 8.21 |
Secondary
Change in Baroreflex Sensitivity Sequence Down From Baseline to 12 Days
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 Baroreflex Sensitivity (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. Evaluation includes analysis for measures of spontaneous baroreflex sensitivity (BRS), in the time domain as frequency domain as BRS Sequence Down (ms/mmHg). Secondary autonomic outcome with BRS will be analyzed for change from baseline to the immediate post-HIRREM in person data collection. Higher values in Sequence Down suggest better autonomic regulation.
Time frame: Data is collected at baseline and immediately following completion of the intervention (up to 12 days later)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| HIRREM | Change in Baroreflex Sensitivity Sequence Down From Baseline to 12 Days | 5.56 ms/mmHg | Standard Deviation 9.16 |
Secondary
Change in Baroreflex Sensitivity Sequence Up From Baseline to 12 Days
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 Baroreflex Sensitivity (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. Evaluation includes analysis for measures of spontaneous baroreflex sensitivity (BRS), in the time domain as frequency domain as BRS Sequence Up (ms/mmHg). Secondary autonomic outcome with BRS will be analyzed for change from baseline to the immediate post-HIRREM in person data collection. Higher values in Sequence Up suggest better autonomic regulation.
Time frame: Data is collected at baseline and immediately following completion of the intervention (up to 12 days later)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| HIRREM | Change in Baroreflex Sensitivity Sequence Up From Baseline to 12 Days | 7.46 ms/mmHg | Standard Deviation 12.33 |
Secondary
Change in Blood Biomarkers for Stress and Inflammation Score From Baseline to 12 Days
Blood for a panel of biomarkers for stress will be collected at enrollment, and after completion of the intervention. The panel includes Ang II, Ang 1-7, Epinephrine, Norepinephrine, C-reactive protein, Vasopressin, IL-1, IL-6, and IL-10.
Time frame: Data is collected at baseline and immediately following completion of the intervention (up to 12 days later)
Population: Due to funding limitations, only 15 people received biomarker measures. One sample was unable to be used, so n=14 is presented.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| HIRREM | Change in Blood Biomarkers for Stress and Inflammation Score From Baseline to 12 Days | Ang II (pg/ml) | -0.50 pg/ml | Standard Deviation 23.17 |
| HIRREM | Change in Blood Biomarkers for Stress and Inflammation Score From Baseline to 12 Days | Ang 1-7 (pg/ml) | 5.11 pg/ml | Standard Deviation 16.94 |
| HIRREM | Change in Blood Biomarkers for Stress and Inflammation Score From Baseline to 12 Days | Epinephrine (pg/ml) | -5.87 pg/ml | Standard Deviation 20.66 |
| HIRREM | Change in Blood Biomarkers for Stress and Inflammation Score From Baseline to 12 Days | Norepinephrine (pg/ml) | -29.98 pg/ml | Standard Deviation 165.88 |
| HIRREM | Change in Blood Biomarkers for Stress and Inflammation Score From Baseline to 12 Days | Vasopressin (pg/ml) | -0.19 pg/ml | Standard Deviation 0.77 |
| HIRREM | Change in Blood Biomarkers for Stress and Inflammation Score From Baseline to 12 Days | IL-1 (pg/ml) | -0.20 pg/ml | Standard Deviation 0.07 |
| HIRREM | Change in Blood Biomarkers for Stress and Inflammation Score From Baseline to 12 Days | IL-6 (pg/ml) | -0.06 pg/ml | Standard Deviation 0.21 |
| HIRREM | Change in Blood Biomarkers for Stress and Inflammation Score From Baseline to 12 Days | IL-10 (pg/ml) | -0.09 pg/ml | Standard Deviation 0.22 |
Secondary
Change in Center for Epidemiologic Studies Depression Scale (CES-D) Score From Baseline to 12 Days
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 suggest more depressive symptomatology. Secondary outcome with the CES-D will be analyzed for change from baseline to the immediate post-HIRREM in person data collection.
Time frame: Data is collected at baseline and immediately following completion of the intervention (up to 12 days later)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| HIRREM | Change in Center for Epidemiologic Studies Depression Scale (CES-D) Score From Baseline to 12 Days | -13.69 units on a scale | Standard Deviation 9.24 |
Secondary
Change in C-reactive Protein for Stress and Inflammation Score From Baseline to 12 Days
Blood for biomarker C-reactive protein for stress will be collected at enrollment, and after completion of the intervention.
Time frame: Data is collected at baseline and immediately following completion of the intervention (up to 12 days later)
Population: Due to funding limitations, only 15 people received biomarker measures. One sample was unable to be used, so n=14 is presented.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| HIRREM | Change in C-reactive Protein for Stress and Inflammation Score From Baseline to 12 Days | -0.10 mg/dl | Standard Deviation 0.19 |
Secondary
Change in Drop Stick Reaction Time From Baseline to 12 Days
Reaction testing is measured by a drop-stick apparatus that has been validated as a way to quantify the impact of athletic concussion on psychomotor performance. Following two practice trials, participants perform eight trials, and a mean distance value is calculated. Secondary functional outcome with drop-stick reaction time will be analyzed for changes in distance from baseline to the in person data collection immediately after completion of the intervention. A lower average indicates a faster reaction time.
Time frame: Data is collected at baseline and immediately following completion of the intervention (up to 12 days later)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| HIRREM | Change in Drop Stick Reaction Time From Baseline to 12 Days | -3.86 cm | Standard Deviation 6.64 |
Secondary
Change in Epigenetic Markers From Baseline to 12 Days
DNA will be isolated from whole blood, collected in yellow-top Vacutainer tubes (ACD as the preservative), using the AutoPure LS system in the Genomics Center Core lab. DNA will be bisulfite-converted using the EZ DNA Methylation Gold kit (Zymo, Irvine, CA). To quantify DNA methylation at each site, investigators will use the HumanMethylationEPIC450 BeadChip (Illumina, Inc.). The methylation proportion for each site (beta value) is based on the ratio of the fluorescence intensity of the methylated versus the combined methylated & unmethylated probes, & will be determined with GenomeStudio (Illumina, Inc.). Ratio of 0 equals no methylation & ratio of 1 equals total (100%) methylation. Effects of DNA methylation for a specific site are dependent on function of the regulated gene(s). For some genes, increased level methylation from the intervention may be beneficial, while for others an increased level may be detrimental. There is no universal way to interpret change in DNA methylation.
Time frame: Blood for epigenetic markers will be obtained at baseline and immediately following completion of the intervention (up to 12 days)
Population: Only a subset of the main cohort had this testing done due to limited funds.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| HIRREM | Change in Epigenetic Markers From Baseline to 12 Days | -.00038 ratio of methylation | Standard Deviation 0.006003 |
Secondary
Change in EQ-5D Score From Baseline to 12 Days
The EQ-5D is a brief, standardized measure of health status developed by the EuroQol Group, and is a paper and pencil survey providing a single index value for health status. Secondary outcome with the EQ-5D will be analyzed for change from baseline to the immediate post-HIRREM in person data collection. Global health rating question is reported (0-100, with 100 being in the best health possible).
Time frame: Data is collected at baseline and immediately following completion of the intervention (up to 12 days later)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| HIRREM | Change in EQ-5D Score From Baseline to 12 Days | 9.59 score on a scale | Standard Deviation 12.35 |
Secondary
Change in Functional MRI From Baseline to 12 Days
Anatomical and physiological brain imaging will be performed during a 1-hour imaging session at baseline and immediately following completion of the intervention. This will include imaging sequences such as high resolution structural scans. Brain network data will be collected using blood oxygenation level dependent (BOLD) scans. These scans will be collected under various states such as at rest. All images will be acquired using a 3 Tesla Siemens MRI scanner. Whole-brain network connectivity will be assessed using blood oxygenation level dependent (BOLD) imaging. Unit of measure is percentage of BOLD signal change. Community structure will be determined for each participant pre- and post-intervention. This project will focus on the community including the Default Mode Network (DMN). Participant strength of the community structure will be determined of the DMN. Permutation analysis will be used to evaluate significant pattern change in specific networks.
Time frame: Data is collected at baseline and immediately following completion of the intervention (up to 12 days later)
Population: Due to funding limitations, only 18 received fMRI scans.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| HIRREM | Change in Functional MRI From Baseline to 12 Days | -0.012 % blood oxygenation level dep (BOLD) | Standard Deviation 0.034 |
Secondary
Change in Generalized Anxiety Disorder-7 (GAD-7) Score From Baseline to 12 Days
The Generalized Anxiety Disorder-7 (GAD-7) is a seven item screening tool for anxiety that is widely used in primary care. Each item is rated from 0 (not at all) to 3 (nearly every day). Scores range from 0 to 21 with higher scores suggesting more anxiety. Secondary outcome with the GAD-7 will be analyzed for change from baseline to the immediate post-HIRREM in person data collection.
Time frame: Data is collected at baseline and immediately following completion of the intervention (up to 12 days later)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| HIRREM | Change in Generalized Anxiety Disorder-7 (GAD-7) Score From Baseline to 12 Days | -6.69 score on a scale | Standard Deviation 4.72 |
Secondary
Change in Grip Strength From Baseline to 12 Days
Grip strength will evaluated using a hydraulic hand dynamometer (Baseline Hydraulic Hand Dynamometer, ranges from 0 to 300 lbs). Both right and left hand will be evaluated, and the greatest force generated during three trials will be used for analysis. A higher score indicates stronger grip strength.
Time frame: Data is collected at baseline and immediately following completion of the intervention (up to 12 days later)
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| HIRREM | Change in Grip Strength From Baseline to 12 Days | Right Hand | 1.74 lbs | Standard Deviation 13.25 |
| HIRREM | Change in Grip Strength From Baseline to 12 Days | Left Hand | 1.94 lbs | Standard Deviation 11.19 |
Secondary
Change in Heart Rate Variability Measure of SDNN From Baseline to 12 Days
Secondary autonomic outcome with heart rate variability will be analyzed for change from baseline to the immediate post-HIRREM in person data collection. Heart rate variability is measured in the time domain as standard deviation 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. Higher SDNN values suggest better autonomic regulation.
Time frame: Data is collected at baseline and immediately following completion of the intervention (up to 12 days later)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| HIRREM | Change in Heart Rate Variability Measure of SDNN From Baseline to 12 Days | 9.43 ms | Standard Deviation 17.43 |
Secondary
Change in Insomnia Severity Index (ISI) Score From Baseline to 12 Days
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. Secondary outcome with the ISI will be analyzed for change from baseline to the immediate post-HIRREM in person data collection.
Time frame: Data is collected at baseline and immediately following completion of the intervention (up to 12 days later)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| HIRREM | Change in Insomnia Severity Index (ISI) Score From Baseline to 12 Days | -6.31 score on a scale | Standard Deviation 5.03 |
Secondary
Change in Rivermead Post-Concussion Symptoms Questionnaire (RPQ) Score From Baseline to 12 Days
The Rivermead Post-Concussion Symptoms Questionnaire (RPQ) is a 16-item survey that assesses the severity of the most common post-concussion symptoms on a scale of 0 to 4, with a total score range from 0 to 64 (least to greatest symptom severity). Items are compared to levels before the head injury and are reported as a 24 hour recall. Secondary outcome with the RPQ will be analyzed for change from baseline to the immediate post-HIRREM in person data collection.
Time frame: Data is collected at baseline and immediately following completion of the intervention (up to 12 days later)
Population: Two participants did not have history of concussion and did not complete measure.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| HIRREM | Change in Rivermead Post-Concussion Symptoms Questionnaire (RPQ) Score From Baseline to 12 Days | -10.70 score on a scale | Standard Deviation 11.71 |
Secondary
Change in Sleep Latency Score From Baseline to 42 Days
An online daily sleep diary to calculate sleep latency will be maintained from baseline, through the one month post-intervention remote data collection (roughly 42 days). Sleep latency is reported in minutes and a smaller score suggests falling asleep faster.
Time frame: Sleep diary data will be collected daily via online access from baseline to a month following completion of intervention (up to 42 days)
Population: Due to initial funding, only the first 18 participants received the sleep diary.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| HIRREM | Change in Sleep Latency Score From Baseline to 42 Days | 36.01 minutes | Standard Deviation 27.24 |
Secondary
Salivary Biomarker Cortisol for Stress From Baseline to 12 Days
Saliva for salivary biomarker Cortisol, for stress, will be collected at enrollment, and after completion of the intervention.
Time frame: Salivary biomarker for stress will be obtained at baseline and immediately following completion of the intervention (up to 12 days)
Population: One participant had a bad file for salivary amylase (n=14).
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| HIRREM | Salivary Biomarker Cortisol for Stress From Baseline to 12 Days | 0.04 ug/dl | Standard Deviation 0.13 |
Secondary
Salivary Biomarker for Stress From Baseline to 12 Days
Saliva for salivary biomarker Alpha-Amylase, for stress, will be collected at enrollment, and after completion of the intervention.
Time frame: Salivary biomarker Alpha-Amylase for stress will be obtained at baseline and immediately following completion of the intervention (up to 12 days)
Population: One participant had a bad file for salivary amylase (n=14).
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| HIRREM | Salivary Biomarker for Stress From Baseline to 12 Days | 15.00 (U/ml) | Standard Deviation 16.66 |