HIRREM Developmental Study

• ClinicalTrials.gov Identifier: NCT02709369
• Recruitment Status: Completed
• First Posted: March 16, 2016
• Results First Posted: December 24, 2019
• Last Update Posted: December 24, 2019
• Sponsor: Wake Forest University Health Sciences
• Information provided by (Responsible Party): Wake Forest University Health Sciences

Study Description

Brief Summary:

The purpose of this study is to explore the functional and physiological effects associated with the use of High-resolution, relational, resonance-based, electroencephalic mirroring (HIRREM), as supplemental care, for symptoms of neurological, cardiovascular, and neuropsychological disorders. This is a non-randomized, open label, and unblinded before-and-after trial, evaluating the effect of HIRREM on an objective, physiological common denominator (heart rate variability, HRV), across a variety of relevant conditions, as well as changes in clinical symptoms inventories, to generate hypotheses and pilot data for investigation in future proposals.

Condition or disease	Intervention/treatment	Phase
Sleep Initiation and Maintenance Disorders; Anxiety; Post-Traumatic Stress Disorder; Hot Flashes; Headache; Traumatic Brain Injury; Post Concussion Symptoms	Device: HIRREM	Not Applicable

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 300 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Functional and Physiological Effects of High-resolution, Relational, Resonance-based, Electroencephalic Mirroring (HIRREM) for Neurological, Cardiovascular and Psychophysiological Disorders
• Actual Study Start Date: August 23, 2011
• Actual Primary Completion Date: October 25, 2018
• Actual Study Completion Date: October 25, 2018

Arms and Interventions

Arm

Intervention/treatment

Experimental: Active HIRREM; This is a single site, single-arm, open-label, developmental study. Participants are recruited to receive eight to twenty sessions of High-resolution, relational, resonance-based electroencephalic mirroring (HIRREM), in addition to their usual care.

Device: HIRREM; HIRREM is a noninvasive, closed-loop, allostatic, acoustic stimulation neuro-technology to facilitate recipient-unique relaxation, auto-calibration, and self-optimization of cortical neural oscillations by reflecting auditory tones in near real time. After an initial HIRREM assessment, evaluating patterns of brain electrical rhythms, subjects get a series of 90-120 minute HIRREM sessions, including 5 to 9 individualized protocols. A protocol is a combination of sensor montage and specific software design, during which dominant brain frequencies, recorded at high spectral resolutions, are translated to audible tones, and reflected back via earphones with as little as 8 milliseconds delay. Protocols are received sitting or reclining in a chair, some with eyes open, others eyes closed.

Outcome Measures

Primary Outcome Measures :

1. Heart Rate Variability Standard Deviation of NN Intervals (SDNN) [ Time Frame: Baseline/Enrollment visit ]
   Heart rate variability is measured in the time domain as standard deviation of beat-to-beat interval
2. Heart Rate Variability (SDNN) [ Time Frame: Up to 2 weeks after the intervention is completed ]
   Heart rate variability is measured in the time domain as standard deviation of beat-to-beat interval
3. Baroreflex Sensitivity High Frequency (HF) Alpha [ Time Frame: Baseline/Enrollment visit ]
   Analysis is conducted on the first complete 5-minute epoch that is considered to be acceptable for analysis using Nevrokard Baroreflex Sensitivity (BRS) software.
4. Baroreflex Sensitivity High Frequency (HF) Alpha [ Time Frame: Up to two weeks after the intervention is completed ]
   Analysis is conducted on the first complete 5-minute epoch that is considered to be acceptable for analysis using Nevrokard Baroreflex Sensitivity (BRS) software.
5. Baroreflex Sensitivity Sequence Up [ Time Frame: Baseline/Enrollment visit ]
   Analysis is conducted on the first complete 5-minute epoch that is considered to be acceptable for analysis using Nevrokard Baroreflex Sensitivity (BRS) software.
6. Baroreflex Sensitivity Sequence Up [ Time Frame: Up to two weeks after the intervention is completed ]
   Analysis is conducted on the first complete 5-minute epoch that is considered to be acceptable for analysis using Nevrokard Baroreflex Sensitivity (BRS) software.
7. Baroreflex Sensitivity Sequence Down [ Time Frame: Baseline/Enrollment visit ]
   Analysis is conducted on the first complete 5-minute epoch that is considered to be acceptable for analysis using Nevrokard Baroreflex Sensitivity (BRS) software.
8. Baroreflex Sensitivity Sequence Down [ Time Frame: Up to two weeks after the intervention is completed ]
   Analysis is conducted on the first complete 5-minute epoch that is considered to be acceptable for analysis using Nevrokard Baroreflex Sensitivity (BRS) software.
9. Baroreflex Sensitivity Sequence All [ Time Frame: Baseline/Enrollment visit ]
   Analysis is conducted on the first complete 5-minute epoch that is considered to be acceptable for analysis using Nevrokard Baroreflex Sensitivity (BRS) software.
10. Baroreflex Sensitivity Sequence All [ Time Frame: Up to 2 weeks after the intervention is completed ]
    Analysis is conducted on the first complete 5-minute epoch that is considered to be acceptable for analysis using Nevrokard Baroreflex Sensitivity (BRS) software.

Secondary Outcome Measures :

1. Center for Epidemiologic Studies Depression Scale (CES-D) [ Time Frame: enrollment visit/baseline ]
   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 the presence of more symptomatology.
2. Center for Epidemiologic Studies Depression Scale (CES-D) [ Time Frame: 1-2 weeks after intervention is completed ]
   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 the presence of more symptomatology.
3. Center for Epidemiologic Studies Depression Scale (CES-D) [ Time Frame: 4-8 weeks after completion of the intervention ]
   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 the presence of more symptomatology.
4. Euro Quality of Life--Five Dimension (EQ-5D) [ Time Frame: enrollment visit/baseline ]
   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. The score reported is current health status which ranges from 0 to 100 with a higher score denoting a better outcome.
5. Euro Quality of Life--Five Dimension (EQ-5D) [ Time Frame: 1-2 weeks after the intervention is completed ]
   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. The score reported is current health status which ranges from 0 to 100 with a higher score denoting a better outcome.
6. Euro Quality of Life--Five Dimension (EQ-5D) [ Time Frame: 4-8 weeks after completion of the intervention ]
   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. The score reported is current health status which ranges from 0 to 100 with a higher score denoting a better outcome.
7. Generalized Anxiety Disorder-7 (GAD-7) [ Time Frame: enrollment visit/baseline ]
   The Generalized Anxiety Disorder-7 (GAD-7) is a seven item screening tool for anxiety that is widely used in primary care. Scores range from 0 to 21 with higher scores suggesting anxiety.
8. Generalized Anxiety Disorder-7 (GAD-7) [ Time Frame: 1-2 weeks after the intervention is completed ]
   The Generalized Anxiety Disorder-7 (GAD-7) is a seven item screening tool for anxiety that is widely used in primary care. Scores range from 0 to 21 with higher scores suggesting anxiety.
9. Generalized Anxiety Disorder-7 (GAD-7) [ Time Frame: 4-8 weeks after completion of the intervention ]
   The Generalized Anxiety Disorder-7 (GAD-7) is a seven item screening tool for anxiety that is widely used in primary care. Scores range from 0 to 21 with higher scores suggesting anxiety.
10. Insomnia Severity Index (ISI) [ Time Frame: enrollment visit/baseline ]
    The ISI measures the severity of insomnia symptoms. The ISI is a 7 question measure, with responses from 0-4 for each question, yielding scores ranging from 0-28 where lower scores denote a healthier sleep quality.
11. Insomnia Severity Index (ISI) [ Time Frame: 1-2 weeks after the intervention is completed ]
    The ISI measures the severity of insomnia symptoms. The ISI is a 7 question measure, with responses from 0-4 for each question, yielding scores ranging from 0-28 where lower scores denote a healthier sleep quality.
12. Insomnia Severity Index (ISI) [ Time Frame: 4-8 weeks after completion of the intervention ]
    The ISI measures the severity of insomnia symptoms. The ISI is a 7 question measure, with responses from 0-4 for each question, yielding scores ranging from 0-28 where lower scores denote a healthier sleep quality.
13. Posttraumatic Stress Disorder Checklist (PCL-C) [ Time Frame: enrollment visit/baseline ]
    The PCL - Civilian (C) is a symptom checklist to measure stress severity due to a traumatic experience, in civilian settings. 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.
14. Posttraumatic Stress Disorder Checklist (PCL) [ Time Frame: 1-2 weeks after the intervention is completed ]
    The PCL - Civilian (C) is a symptom checklist to measure stress severity due to a traumatic experience, in civilian settings. 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.
15. Posttraumatic Stress Disorder Checklist (PCL) [ Time Frame: 4-8 weeks after completion of the intervention ]
    The PCL - Civilian (C) is a symptom checklist to measure stress severity due to a traumatic experience, in civilian settings. 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.
16. Rivermead Post-Concussion Symptoms Questionnaire (RPQ) [ Time Frame: enrollment visit/baseline ]
    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 with 64 denoting the greatest symptom severity.
17. Rivermead Post-Concussion Symptoms Questionnaire (RPQ) [ Time Frame: 1-2 weeks after the intervention is completed ]
    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 with a higher score denoting the greatest symptom severity.
18. Rivermead Post-Concussion Symptoms Questionnaire (RPQ) [ Time Frame: 4-8 weeks after completion of the intervention ]
    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 with 64 denoting the greatest symptom severity.
19. Drop Stick Reaction Testing [ Time Frame: enrollment visit/baseline ]
    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. Better reaction time is denoted by a lower score. The scores range from 0 to 100.
20. Drop Stick Reaction Testing [ Time Frame: 1-2 weeks after the intervention is completed ]
    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. Better reaction time is denoted by a lower score. The scores range from 0 to 100.
21. Drop Stick Reaction Testing [ Time Frame: 4-8 weeks after completion of the intervention ]
    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. Better reaction time is denoted by a lower score. The scores range from 0 to 100.

Other Outcome Measures:

1. Heart Rate Variability Standard Deviation of NN Intervals (SDNN) [ Time Frame: 4-8 weeks after completion of the intervention ]
   Heart rate variability is measured in the time domain as standard deviation of beat-to-beat interval
2. Baroreflex Sensitivity High Frequency (HF) Alpha [ Time Frame: 4-8 weeks after completion of the intervention ]
   Analysis is conducted on the first complete 5-minute epoch that is considered to be acceptable for analysis using Nevrokard Baroreflex Sensitivity (BRS) software.
3. Baroreflex Sensitivity Sequence Up [ Time Frame: 4-8 weeks after completion of the intervention ]
   Analysis is conducted on the first complete 5-minute epoch that is considered to be acceptable for analysis using Nevrokard Baroreflex Sensitivity (BRS) software.
4. Baroreflex Sensitivity Sequence Down [ Time Frame: 4-8 weeks after completion of the intervention ]
   Analysis is conducted on the first complete 5-minute epoch that is considered to be acceptable for analysis using Nevrokard Baroreflex Sensitivity (BRS) software.
5. Baroreflex Sensitivity Sequence All [ Time Frame: 4-8 weeks after completion of the intervention ]
   Analysis is conducted on the first complete 5-minute epoch that is considered to be acceptable for analysis using Nevrokard Baroreflex Sensitivity (BRS) software.

Eligibility Criteria

• Ages Eligible for Study: 11 Years and older (Child, Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

• Male and female adults and children aged 11 years and older.
• Subjects who are over the age of 18 must be able to give informed consent. Children must be able to sign an assent form and have a signed parental permission form.
• Subjects must have the ability to comply with basic instructions and be able to sit still comfortably with the sensor leads attached.
• Subjects previously diagnosed with a neurologic, cardiovascular, or psychophysiological disease such as attention deficit hyperactivity disorder, Asperger Syndrome, chronic pain, dyslexia, depression, insomnia, migraines, anxiety, PTSD, substance abuse disorder, traumatic brain injury, and others.

Exclusion Criteria:

• Subjects who fail to meet inclusion criteria.
• Subjects who are unable, unwilling, or incompetent to provide informed consent, assent and/or parental permission.
• Subjects physically unable to come to the study visits.
• Subjects with a known seizure disorder.
• Subjects with severe bilateral hearing impairment (HIRREM requires the use of headphones).
• Subjects receiving ongoing treatment with opiate, benzodiazepine, anti-psychotic or sleep medications, as well as some anti-depressants or stimulants, except those cases deemed acceptable by the principal investigator.
• Subjects with anticipated and ongoing use of recreational drugs except when deemed acceptable by the principal investigator.

Contacts and Locations

Locations

United States, North Carolina

Department of Neurology, Wake Forest School of Medicine

Winston-Salem, North Carolina, United States, 27157

Sponsors and Collaborators

Wake Forest University Health Sciences

Investigators

• Principal Investigator: Charles H Tegeler, MD; Wake Forest University Health Sciences

  Study Documents (Full-Text)

Documents provided by Wake Forest University Health Sciences:

Study Protocol and Statistical Analysis Plan  [PDF] April 20, 2017

More Information

Publications of Results:

Lee SW, Gerdes L, Tegeler CL, Shaltout HA, Tegeler CH. A bihemispheric autonomic model for traumatic stress effects on health and behavior. Front Psychol. 2014 Aug 1;5:843. doi: 10.3389/fpsyg.2014.00843. eCollection 2014.

Tegeler CH, Tegeler CL, Cook JF, Lee SW, Pajewski NM. Reduction in menopause-related symptoms associated with use of a noninvasive neurotechnology for autocalibration of neural oscillations. Menopause. 2015 Jun;22(6):650-5. doi: 10.1097/GME.0000000000000422.

Tegeler CH, Shaltout HA, Tegeler CL, Gerdes L, Lee SW. Rightward dominance in temporal high-frequency electrical asymmetry corresponds to higher resting heart rate and lower baroreflex sensitivity in a heterogeneous population. Brain Behav. 2015 Jun;5(6):e00343. doi: 10.1002/brb3.343. Epub 2015 May 1.

Fortunato JE, Tegeler CL, Gerdes L, Lee SW, Pajewski NM, Franco ME, Cook JF, Shaltout HA, Tegeler CH. Use of an allostatic neurotechnology by adolescents with postural orthostatic tachycardia syndrome (POTS) is associated with improvements in heart rate variability and changes in temporal lobe electrical activity. Exp Brain Res. 2016 Mar;234(3):791-8. doi: 10.1007/s00221-015-4499-y. Epub 2015 Dec 8.

Tegeler CH, Tegeler CL, Cook JF, Lee SW, Gerdes L, Shaltout HA, Miles CM, Simpson SL. A Preliminary Study of the Effectiveness of an Allostatic, Closed-Loop, Acoustic Stimulation Neurotechnology in the Treatment of Athletes with Persisting Post-concussion Symptoms. Sports Med Open. 2016 Dec;2(1):39. doi: 10.1186/s40798-016-0063-y. Epub 2016 Sep 14.

Other Publications:

Gerdes L, Gerdes P, Lee SW, H Tegeler C. HIRREM: a noninvasive, allostatic methodology for relaxation and auto-calibration of neural oscillations. Brain Behav. 2013 Mar;3(2):193-205. doi: 10.1002/brb3.116. Epub 2013 Jan 14.

Tegeler CH, Kumar SR, Conklin D, Lee SW, Gerdes L, Turner DP, Tegeler CL, C Fidali B, Houle TT. Open label, randomized, crossover pilot trial of high-resolution, relational, resonance-based, electroencephalic mirroring to relieve insomnia. Brain Behav. 2012 Nov;2(6):814-24. doi: 10.1002/brb3.101. Epub 2012 Oct 28.

Tegeler CH, Lee SW, Shaltout HA. Significance of right anterior insula activity for mental health intervention. JAMA Psychiatry. 2014 Mar;71(3):336. doi: 10.1001/jamapsychiatry.2013.3507. No abstract available.

Gerdes L, Tegeler CH, Lee SW. A groundwork for allostatic neuro-education. Front Psychol. 2015 Aug 17;6:1224. doi: 10.3389/fpsyg.2015.01224. eCollection 2015.

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Tegeler CH, Cook JF, Tegeler CL, Hirsch JR, Shaltout HA, Simpson SL, Fidali BC, Gerdes L, Lee SW. Clinical, hemispheric, and autonomic changes associated with use of closed-loop, allostatic neurotechnology by a case series of individuals with self-reported symptoms of post-traumatic stress. BMC Psychiatry. 2017 Apr 19;17(1):141. doi: 10.1186/s12888-017-1299-x.

• Responsible Party: Wake Forest University Health Sciences
• ClinicalTrials.gov Identifier: NCT02709369
• Other Study ID Numbers: IRB00017651
• First Posted: March 16, 2016
• Results First Posted: December 24, 2019
• Last Update Posted: December 24, 2019
• Last Verified: November 2018

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No
• Plan Description: Data will be shared in publications and presentations. No plan to formally make individual participant data available for this exploratory study

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: Yes

Keywords provided by Wake Forest University Health Sciences:

HIRREM; Neuro-technology; Closed-loop; Acoustic stimulation; Allostatic; heart rate variability; baroreflex sensitivity; traumatic brain injury; sports concussion; PTSD; hot flashes; headache; insomnia

Additional relevant MeSH terms:

Brain Injuries; Brain Injuries, Traumatic; Sleep Initiation and Maintenance Disorders; Post-Concussion Syndrome; Disease; Headache; Hot Flashes; Stress Disorders, Traumatic; Stress Disorders, Post-Traumatic; Pathologic Processes; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Craniocerebral Trauma; Trauma, Nervous System; Wounds and Injuries; Trauma and Stressor Related Disorders; Mental Disorders; Pain; Neurologic Manifestations; Sleep Disorders, Intrinsic; Dyssomnias; Sleep Wake Disorders; Brain Concussion; Head Injuries, Closed; Wounds, Nonpenetrating