High-Resolution, Relational, Resonance-Based, Electroencephalic Mirroring (HIRREM) for Vasomotor Symptoms (Hot Flashes) in Perimenopausal and Postmenopausal Women: A Randomized, Controlled Clinical Trial
Phase: NA
Conditions: Vasomotor Symptoms, Hot Flashes, Menopause
Sponsor: Wake Forest University Health Sciences

 
 
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HIRREM Hot Flashes Study 
NCT03512002 
03/23/2018 
 
 
 
 

 
 
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Title: 
High-resolution, Relational, Resonance-based, Electroencephalic Mirroring (HIRREM) for Vasomotor 
Symptoms in Perimenopausal and Postmenopausal Women: A Randomized Pilot Clinical Trial 
Principal Investigator: 
Charles H. Tegeler, MD1 
Department of Neurology 
Wake Forest School of Medicine 
Medical Center Boulevard 
Winston-Salem, NC  27157-1078 
E-mail: ctegeler@wakehealth.edu 
Phone: 336-716-7651 
Fax: 336-716-5813 
 
Co-Investigators: 
Sean L. Simpson, PhD2, Hossam A. Shaltout, PhD3, Christopher M. Miles, MD4 
Consultants: 
Lee Gerdes5    
Other Study Team Members:  
Catherine L. Tegeler1, Nancy C. Buchheimer1, Krystal D. Schmidt1, Lindsay J. Howard1, Emillee I. Garlin1, 
Kenzie L. Brown1  
 Affiliations: 
1. Department of Neurology, Wake Forest School of Medicine (WFSM) 
2. Department of Biostatistics, Division of Public Health Sciences, WFSM 
3. Hypertension and Vascular Research Center, WFSM 
4. Department of Family and Community Medicine, WFSM 
5. Brain State Technologies, LLC, Scottsdale, AZ 
Funding: The Susanne Marcus Collins Foundation, Inc. 
Key Words: neurotechnology, autonomic dysregulation, hyperarousal, brain electrical activity, HIRREM, 
acoustic stimulation, perimenopausal, postmenopausal, hot flashes, night sweats, vasomotor symptoms, 
allostasis 
 
 

 
 
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Abstract: 
Background:    
Up to 80% of women experience menopausal vasomotor symptoms during the perimenopause 
transition period, such as hot flashes, night sweats, and flushes, although they can vary between 
individuals.  These often last for more than 7 years for over half of women.  These symptoms are related 
to negative outcomes including depressed mood, reduced social quality of life, and decreased 
quantity/quality of sleep.  A common therapy used to address these symptoms is hormone replacement 
therapy (HRT), although there is concern with long term use and safety is unknown.  Noninvasive, non-
drug alternative interventions are needed.   
High-resolution, relational, resonance-based, electroencephalic mirroring (HIRREM®) is a closed-loop, 
allostatic, acoustic stimulation neurotechnology that uses software-guided algorithmic analysis to 
identify and translate selected brain frequencies into audible tones to support real-time self-
optimization of brain activity.  Pilot data shows that the use of HIRREM is associated with reduced 
symptoms of traumatic stress and anxiety, and improved autonomic cardiovascular regulation across 
heterogeneous cohorts, as well as reduced blood pressure in a small series with comorbid hypertension.  
This study will evaluate the use of HIRREM for those with hot flashes in a randomized clinical trial.   
Objective: The primary objective of this pilot study is to evaluate whether the addition of acoustic 
stimulation linked to brain activity (HIRREM), to continued current care, will reduce the frequency and 
severity of vasomotor symptoms experienced by perimenopausal and postmenopausal women.  
Methods: This will be a randomized, single site, pilot clinical trial, enrolling up to 40 women, who have at 
least 5 hot flashes per day (with at least one being categorized as moderate to severe), and who are not 
taking medications or supplements for management of hot flashes.  Participants will be randomly 
assigned to receive 8-16 sessions over a maximum of 4 weeks of acoustic stimulation linked to brain 
activity (HIRREM and continued current care, HCC) or will be assigned to a waitlist group (continued 
current care, CCC).  Both groups will continue their other current care throughout.  There will be pre- 
and post-intervention data collection to include physiological outcomes (BP, HR, and measures of 
autonomic cardiovascular regulation), as well as daily hot flash diaries, Hot Flash Related Daily 
Interference Scale (HFRDIS), the Menopause Rating Scale (MRS), symptom inventories for insomnia 
(Insomnia Severity Index, ISI; Pittsburgh Sleep Quality Index, PSQI; and the Epworth Sleepiness Score, 
ESS), depression (Center for Epidemiological Studies- Depression Scale, CES-D), anxiety (Generalized 
Anxiety Disorder-7, GAD-7), stress (Perceived Stress Scale, PSS), and a quality of life measure (Quality of 
Life Scale, QOLS), as well as drop stick reaction testing, and dynamometry for grip strength.  Measures 
will be collected at an enrollment visit (V1).  Both groups will then maintain a hot flash diary for 7-14 
days, after which the intervention will begin for the HCC group.  Post-intervention data collections will 
be obtained at 4-6 weeks (V2, primary outcome) and 12-14 weeks (V3) following completion of the 
intervention.  Follow up data collection for the CCC group will occur at 10-12 weeks (V2), and 18-20 
weeks (V3) after the V1 visit.  Both groups will maintain a hot flash diary for 1-2 weeks prior to the V2 
and V3 visits.  The primary outcome will be differential change in hot flash frequency and severity from 

 
 
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V1 to V2 between HCC and CCC, based on data from the hot flash daily diary.  Following V3, those in the 
CCC group will be offered the opportunity to cross over to receive a course of HCC within 3 months, and 
will continue to be followed for data collections at 4-6 weeks (V4), and 12-14 weeks (V5) after 
completing their crossover HIRREM sessions.  Additional mean contrasts will be constructed to evaluate 
the consistency of any benefit of HIRREM through subsequent visits beyond V3.  Comparisons of 
changes in all secondary outcomes will be assessed in a similar fashion. 
Importance: This study will explore the use of HIRREM for vasomotor symptoms associated with 
menopause in a randomized, clinical trial.  The study will confirm feasibility using a closed-loop, acoustic 
stimulation intervention for a randomized clinical trial in this population, and will also provide estimates 
of effect size, which might justify larger controlled trials.  A positive result would suggest that HIRREM 
might have benefit as a noninvasive, non-drug alternative for management of vasomotor symptoms.  
This, over and above the potential benefit from participating in a clinical trial, and interacting with the 
study personnel and the study environment.  The study will also help to identify the characteristics of 
subgroups that might experience differential effects/benefits from HIRREM.   
 
 

 
 
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Background: 
An estimated 22 million women are between the ages of 45 and 54 years, suggesting that they are 
entering or have begun the perimenopause transition.  Of these women, approximately 75% of them 
will experience vasomotor symptoms (hot flashes) due to the menopause transition, and 25% will seek 
medical treatment.  Around $4 billion is spent annually in the United States on medications to treat 
women going through menopause.  
As individuals go through the menopausal transition, their body begins to reduce the production of 
estrogen and progesterone.  Progesterone is a sleep-promoting hormone, so this can also lead to 
troubles sleeping or even insomnia. 
There is evidence that patients are at an elevated risk of coronary heart disease (CHD) when given 
standard oral doses of hormone therapy treatments, which are often used to manage symptoms 
associated with perimenopause (Huang , Sawaya, Vittinghoff, Lin, & Grady, 2009).  The risk increases for 
older postmenopausal individuals when compared to those who more recently went through the 
menopause transition.  Due to safety concerns surrounding the use of hormone therapy, there remains 
a need for safe, effective, relatively brief, non-pharmacological therapies to help manage symptoms in 
this population.   
Autonomic hyperarousal appears to play an etiological role related to vasomotor symptoms associated 
with menopause.  Use of non-pharmacological strategies such as biofeedback and slow abdominal 
breathing, EMG-biofeedback, and HRV-biofeedback, targeting downstream autonomic function are 
reportedly associated with improved autonomic function and reduced blood pressure in those with 
prehypertension (Chen, Sun, Wang, Lin, & Wang, 2016; Innes, Selfe, & Vishnu, 2010; Lin et al., 2012; 
Wang et al., 2010; Xu, Gao, Ling, & Wang, 2007).  Trials of mind-body, relaxation, behavioral, and 
complementary interventions have shown promise, possibly related to impact on autonomic 
hyperarousal (Avis, Legault, Russell, Weaver, & Danhauer, 2014; Befus et al., 2018; Guthrie et al., 2018; 
Innes et al., 2010; Stefanopoulou & Grunfeld, 2017). 
High-resolution, relational, resonance-based, electroencephalic mirroring (HIRREM®) was developed by 
Brain State Technologies, Scottsdale, AZ.  It is a commercially available, noninvasive, electroencephalic-
based method to facilitate client-unique relaxation and auto-calibration of cortical neural oscillations by 
reflecting auditory tones in near real time (Gerdes, Gerdes, Lee, & Tegeler, 2013).  HIRREM uses scalp 
sensors to observe brain frequencies and amplitudes in real time, and software-guided algorithmic 
analysis to identify and translate selected brain frequencies into audible tones to support real-time self-
optimization of brain activity.  The audible tones are reflected back to the recipient bilaterally, 
simultaneously, in 4-8 milliseconds, providing an opportunity for the recipient to, figuratively speaking, 
listen to the song the brain is playing right now.  This rapid updating regarding its pattern allows the 
brain a chance to, self-optimize, self-adjust, “relax,” and reset/get unstuck from what has been stuck 
stress/trauma response patterns.  The brain electrical patterns are typically observed to shift 
independently, with no conscious, cognitive activity required, no operant conditioning, and no learner in 
the loop, towards improved balance and reduced hyperarousal.   

 
 
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The mechanism of this effect remains to be fully understood, but may involve resonance between 
reflected tones and oscillating brain networks, much like a musical instrument tuning itself.  
Functionally, it may be that this acoustic stimulation facilitates kindling of sleep in neuronal units, which 
had previously been stuck in the “on” position due to stress responses (Krueger, Huang, Rector, & 
Buysse, 2013).  Better sleep is foundational for all health and healing.  A key aspect of observed 
beneficial effects may also be related to the observed improvement in downstream autonomic function, 
as evidenced by increased heart rate variability and baroreflex sensitivity, apparently associated with 
increased dynamic range and flexibility of autonomic responses managed by the brain.  
Since 2011, the HIRREM Research Program at WFSM has enrolled over 480 participants in five clinical 
studies to evaluate the effects and potential benefits of HIRREM.  Data have shown reduction in 
symptoms of insomnia, depression, stress/anxiety, military-related traumatic stress, hot flashes, and 
persisting symptoms after athletic concussion, associated with the use of HIRREM (C. L. Tegeler et al., 
2017).  Improved autonomic cardiovascular regulation has also been observed in those receiving 
HIRREM, including a cohort of adolescents with Postural Orthostatic Tachycardia Syndrome (J. E. 
Fortunato et al., 2016; J.E. Fortunato et al., 2013; C. Tegeler et al., 2014).  In addition, correlation has 
been reported between high frequency electrical brain pattern asymmetry scores at baseline, and 
measures of autonomic cardiovascular regulation (C.H. Tegeler, Shaltout, Tegeler, Gerdes, & Lee, 2015). 
Specific Relevant Pilot Data: 
12 women (median age 56 y; range, 46-69 y) were enrolled in an ongoing IRB approved study exploring a 
variety of neurological, cardiovascular, and psychological conditions, and were identified as also 
reporting co-morbid perimenopausal symptoms (C. H. Tegeler, Tegeler, Cook, Lee, & Pajewski, 2015).  
After an initial HIRREM assessment of brain frequencies and amplitudes, baseline data collection 
included symptom inventories for insomnia (ISI), depression (CES-D), and anxiety (GAD-7), along with 
physiological and functional measures.  Blood pressure and heart rate were continuously recorded while 
supine, with spontaneous breathing. Participants completed a hot flash diary for a median of 3.5 days 
(range, 1-11 d) before beginning their HIRREM sessions, and maintained through follow up data 
collection visits.  Subjects then received a median of 13 (range, 8-23) HIRREM sessions approximately 90 
minutes each (range, 54-102 min).  Sessions consisted of 4-9 protocols, from 6-30 minutes each, with up 
to two sessions per day, and were received over a median of 9.5 days (range, 4-32 d).  All measurements 
were repeated at the follow-up data collection visit at a median of 10 days (range, 0-20 d) after 
completing their final HIRREM session.   
Primary outcomes included hot flash frequency and severity, sleep and depressive symptoms.  High 
frequency (23-36 Hertz) amplitudes from bilateral temporal scalp recordings were measured at baseline 
and during serial sessions.  Median changes (range, p value) for hot flash frequency and severity were -
2.32 (-14 to 3, 0.050) and -1 (-3 to 0.8, 0.004), respectively.  Sleep and depression scores decreased by -
8.5 (-20 to -1, p = 0.022), and -5.5 (-32 to 8, p = 0.015) points, respectively.  Median amplitude in 
temporal high frequency brain electrical activity was 8.44 microvolts (µv, 6.27-16.66) at baseline and 
decreased a median of -2.96 µv (-11.05 to -0.65, p = 0.0005) by the final session. 

 
 
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Table 1: Hot Flashes: Median (Ranges) Scores at Baseline and Final Day of HIRREM Sessions (*Hot flash 
score derived by multiplying frequency by worst severity score for each day) 
 
Baseline  
Final Day 
Change 
P value 
Hot Flash Frequency 
4.7 (1, 14) 
2 (0, 11) 
-2.32 (-14, 3) 
0.050 
Hot Flash Severity 
3 (1.2, 4) 
2 (0, 3) 
-1 (-3, 0.8) 
0.004 
Hot Flash Scorea 
9.08 (2, 42) 
3.5 (0, 17) 
-6.42 (-42, 3) 
0.011 
 
Table 2: Changes in clinical category for insomnia after HIRREM based on ISI scores 
Clinical Category by ISI Score 
Baseline  
(Percent of Total) 
Post-HIRREM (Percent of 
Total) 
No clinically significant insomnia (0-7) 
2 (16.67%) 
10 (83.33%) 
Subthreshold insomnia (8-14) 
4 (33.33%) 
0 
Moderate insomnia (15-21) 
3 (25.00%) 
2 (16.67%) 
Severe insomnia (22-28) 
3 (25.00%) 
0 
 
Figure 1 (A and B): Figure 1A: Changes in hot flash frequency over time.  The Y-axis indicates hot flash 
frequency.  The X-axis indicates the number of days since the start of the HIRREM sessions.  Each 
colored line represents an individual participant in the study.  Figure 1B: Changes in hot flash severity 
over time.  The Y-axis indicates hot flash severity (1 = mild, 2 = moderate, 3 = severe, 4 = very severe).  
The X-axis indicates the number of days since the start of HIRREM sessions.  Each colored line represents 
and individual participant in the study. 

 
 
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Figure 2 (A and B): Figure 2 (A and B): Example of observed changes in brain electrical pattern.  FFT 
spectral display of electroencephalic data with frequency (Hz, central Y-axis) plotted against 
transformed amplitude (µv, X-axis).  Data represents one minute of data from the T3/T4 montage with 
EC at the baseline assessment (4-A), and at the penultimate minute of the final session (4-B) for one 
participant, a 47 year old woman.  Note the change of amplitudes in the 23-36 Hz range (dark purple 
color), outlined by red boxes. 
 

 
 
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Hypothesis: 
The addition of acoustic stimulation linked to brain activity (HIRREM plus continued current care, HCC) 
will be associated with greater reduction in the frequency and severity of hot flashes experienced than 
that seen with continued current clinical care alone (CCC), among patients with perimenopausal and 
postmenopausal vasomotor symptoms.    
Research Design and Method:  
Objectives:  
Primary Objective: 
The primary objective of this pilot study is to evaluate whether the addition of acoustic stimulation 
linked to brain activity (HIRREM, HCC) to continued current clinical care, will reduce the frequency and 
severity of vasomotor symptoms, as compared with continued current clinical care (CCC) alone in 
patients with documented perimenopausal and postmenopausal vasomotor symptoms.  
Secondary Objectives:  
Evaluate whether the addition of HCC to continued current clinical care will result in greater differential 
changes in a variety of physiological, behavioral, and function outcome measures outlined below, as 
compared to CCC.    
1. Autonomic nervous system functions, as manifested by heart rate, HRV, and BRS.  We expect to 
see greater changes in autonomic activity and an improvement of sympatho-vagal balance in 
the HCC group.  This would be reflected as changes in heart rate, and an increase of HRV and 
BRS parameters such as the standard deviation of the R-R interval (SDRR), rMSSD, HF alpha, and 
Sequence Up, Down, or All. 
2. Reduction in menopause-related scales: Menopause Rating Scale (MRS) and Hot Flash Related 
Daily Interference Scale (HFRDIS).  We anticipate to see greater improvement in these 
symptoms in the HCC group. 
3. Behavioral outcomes such as insomnia (assessed by the Insomnia Severity Index, ISI; Pittsburgh 
Sleep Quality Index, PSQI; and the Epworth Sleepiness Score, ESS), depression (as assessed by 
the Center for Epidemiological Studies-Depression Scale, CES-D), anxiety (as evaluated by the 
GAD-7), and stress (as assessed by the Perceived Stress Scale, PSS).  We expect to see greater 
improvement in these symptom inventory scores in the HCC group. 
4. Overall quality of life as evaluated using the QOLS.  We hope to see greater improvement in 
overall quality of life scores in the HCC group.  
5. Functional performance evaluated using drop stick reaction testing.  We expect to see more 
improvement in the HCC group. 
6. Functional performance evaluated by grip strength, using a hand dynamometer.  We expect to 
see greater improvement of grip strength in the HCC group. 
Overview: 

 
 
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This will be a randomized, single site, pilot clinical trial.  Assuming a potential drop-out rate of 20%, up 
to 48 subjects will be enrolled to achieve a goal of having at least 40 subjects (20 per group) complete 
the study, per protocol.  Patients who have at least 5 hot flashes per day (with at least one being 
categorized as moderate to severe) will be eligible to participate.     
Those who have no other exclusions, are interested to participate, and provide informed consent will be 
randomly assigned to receive 8-16 sessions of in-office acoustic stimulation linked to brainwave activity 
(HCC), over a maximum of 4 weeks, while continuing their other current clinical care, or to continue 
their current clinical care alone (CCC).  There will be pre- and post-intervention data collection to include 
a daily hot flash diary (to be completed for 7-14 days by both groups) and many secondary outcome 
measures including completion of the MRS, HFRDIS, measures of autonomic cardiovascular regulation 
(continuous recording of BP and HR for calculation of measure of HRV and BRS), behavioral symptom 
outcomes (ISI, PSQI, ESS, CES-D, GAD-7, PSS), quality of life measure (QOLS), and function performance 
measures (drop stick reaction testing, and grip strength).  All measures will be collected at an enrollment 
visit (V1).  Both groups will then maintain a hot flash diary for 7-14 days, after which the intervention 
will begin for the HCC group.  Post-intervention data collections will include an intermediate post-
intervention visit (V2, primary outcome, 4-6 weeks after intervention completion for HCC, and 10-12 
weeks after V1 for CCC), and a final follow up visit (V3, 12-14 weeks following completion of the 
intervention for HCC, and 18-20 weeks after V1 for CCC).  Both groups will maintain a hot flash diary for 
1-2 weeks prior to the V2 and V3 visits.  The primary outcome will be reduction in frequency and 
severity of hot flashes score from V1 to V2.  Following V3, those in the CCC group will be offered the 
opportunity to receive a course of HCC within 3 months (will have another brainwave assessment 0-14 
days before beginning sessions), and will continue to be followed for data collections at 4-6 weeks (V4), 
and 12-14 weeks (V5) after completing their HIRREM sessions.   

 
 
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Hot Flash Study Flow Chart 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CCC Group Who Complete V1-V3 and Choose to Receive a Course of HCC 
V1 
Enrollment 
(up to 120 minutes) 
 
-Informed consent 
-Baseline outcome 
measures 
-Brainwave 
assessment with 
Technologist 
-Randomized 
-Keep daily hot flash 
diary for 7-14 days 
after 
 
HCC: 
8-16 sessions over 4 
weeks 
(90-120 minutes each) 
 
-Continue other 
current clinical care 
 
V2 
(up to 120 minutes) 
 
-Keep hot flash diary 
for 7-14 days before  
-Repeat outcome 
measures 
-Repeat brainwave 
assessment  
 
HCC: 
Within 4-6 weeks of 
final session 
 
CCC: 
10-12 weeks after V1 
 
V3 
(up to 45 minutes) 
 
-Keep hot flash diary 
for 7-14 days before  
-Repeat outcome 
measures 
-Study completed for 
HCC group 
-CCC group offered 
opportunity to receive 
HCC  
 
HCC: 
Within 12-14 weeks of 
final session 
 
CCC: 18-20 weeks 
after V1  
CCC:  
-Continue current 
clinical care 
 
 
HCC: 
 
Must begin crossover 
within 3 months of 
completing V3  
 
-Brainwave 
assessment 0-14 days 
before beginning 
sessions 
 
8-16 sessions linked to 
brain activity over 4 
weeks  
(90-120 minutes each) 
 
 
 
V4 
Within 4-6 weeks of 
final session 
(up to 120 minutes) 
 
-Keep hot flash diary 
for 7-14 days before  
-Repeat outcome 
measures 
-Repeat brainwave 
assessment 
 
V5 
Within 12-14 weeks of 
final session 
(up to 45 minutes) 
 
-Keep hot flash diary 
for 7-14 days before  
-Repeat outcome 
measures 
-Study completed 
 

 
 
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Participants/Subjects: 
Women ages 40 and older with self-reported perimenopausal and postmenopausal related vasomotor 
symptoms, who meet the following inclusion criteria and are interested to participate in the study will 
be recruited from the community by physician referral and advertisement.  Each subject must be able to 
provide an informed consent.  The criteria for inclusion will be those experiencing at least five hot 
flashes per day (with at least one being categorized as moderate to severe).  
Interested subjects will be informed with a more detailed description of the study, and the extent of 
their commitment, through phone calls or email communications.  If no exclusions are apparent from 
initial phone or email communications, potential participants will complete an online eligibility screening 
form, which will be reviewed by the study team.  If potential participants express continued interest in 
the project and have no major exclusions, they will be scheduled for an enrollment visit (V1) at which 
time an informed consent will be completed.  Those scheduled for an enrollment visit will also be 
provided a copy of Appendix B, Handout to Study Participants, and/or a welcome email with details. 
 As part of the informed consent process, study procedures, schedule for visits, and duration of 
participation will again be reviewed, and alternatives discussed, including the option to not enroll in this 
project, and follow up with their primary health care provider.   
After informed consent is obtained, randomization will be completed, baseline study measures 
obtained, and all participants will be instructed how to maintain a hot flash daily diary. 
Inclusion Criteria: 
Women, age 40 or older, with perimenopausal and postmenopausal related vasomotor symptoms 
(intact uterus and ovaries), who have at least 5 hot flashes per day (with at least one being categorized 
as moderate to severe), with what is reported to be a stable pattern for at least one month. 
Exclusion Criteria: 
Less than 5 hot flashes per day 
Does not experience at least 1 moderate to severe hot flash per day 
Unable, unwilling, or incompetent to provide informed consent 
Physically unable to come to the study visits, or to sit comfortably in a chair for up to two hours  
Known seizure disorder 
Known or potential pregnancy (females with last menstrual period less than one year from enrollment 
will be tested for pregnancy prior to randomization) 
Severe hearing impairment (because the subject will be using headphones during the interventions) 
Ongoing need for treatment with opiate, benzodiazepine, or anti-psychotic medications, anti-depressant 
medications such as SSRI, SNRI, or tricyclic, and sleep medications such as zolpidem or eszopiclone 
Use of pharmaceuticals for treatment of vasomotor symptoms or any type of hormone replacement 
therapy 

 
 
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Use of supplements for improvement of vasomotor symptoms including but not limited to black cohosh, 
soy isoflavone extract, and red clover leaf extract 
Menopausal symptoms resulting from, or associated with surgery, chemotherapy, radiation, or use of 
other chemicals or medications   
Anticipated and ongoing use of recreational drugs, alcohol, or energy drinks 
Ongoing need for treatment with thyroid medications 
Weight is over the chair limit (285 pounds) 
Are enrolled in another research study that includes an active intervention 
Have previously received brainwave optimization (BWO), used a B2 or a B2v2 wearable device, or 
previously participated in a HIRREM research study 
 
Participants are encouraged to discuss their participation with their health care provider following 
completion of the study because HIRREM may alleviate some of the need for medications they were on 
previously.  Participants are requested to abstain from using any alcohol or recreational drugs during the 
intervention, and for at least six weeks following sessions since use of these substances may cause 
reversal or cessation of the benefits of HIRREM.  In addition, the participants are also advised to suspend 
chiropractic, cranial-sacral therapy, and bio-energy work during the intervention, and for at least six 
weeks following. 
Number of Subjects: 
As a pilot study, in a new cohort of participants, using a wait-list control, we are not able to calculate an 
accurate sample size.  In order to evaluate feasibility and effect size, and allowing for up to 20% drop 
outs, we will arbitrarily enroll up to 48 subjects to achieve a goal of having 40 subjects complete the 
study per protocol (estimated 20 per group). 
Number of HCC Sessions and Length of Study: 
All baseline measures, along with a brainwave assessment, will be obtained during an enrollment visit 
(V1).  The intervention will commence 7-14 days later.  Participants will receive 8 to 16 in-office 
intervention sessions over a maximum of 4 weeks.  HCC sessions will be about 1.5-2 hours in length.  All 
will receive a total of 6 sessions during the first three days of the intervention period.  Following the 
initial 6 sessions, some sessions may be arranged as singles (one per day), if needed due to schedule 
issues.   Participants will be encouraged to complete the remainder of the intervention sessions within 
two-three weeks, with a maximum of four weeks to complete the sessions.  If done as two sessions per 
half day, subject involvement will thus require 4-8 half days during the intervention period.   
At the primary post-intervention data collection visit, all measures will be repeated.  This visit will occur 
at 4-6 weeks after completion of the intervention for the HCC group, and 10-12 weeks after V1 for the 
CCC group.  A final data collection visit (V3) will occur 12-14 weeks after completion of the intervention 
for the HCC group, and 18-20 weeks after V1 for the CCC group, with repeat of the outcome measures, 
but no brainwave assessment.  At V3, official study involvement is complete for those in the HCC group, 
while those randomized to the CCC group will be offered an opportunity to be scheduled to receive a 

 
 
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course of HCC within 3 months.  Participants who cross over will have a brainwave assessment 0-14 days 
before starting sessions.  Those who opt to do so will receive a course of in-office acoustic stimulation 
linked to brainwaves, as described for the HCC group, and will continue to be followed for data 
collections at 4-6 weeks (V4), and 12-14 weeks (V5), as done during the initial intervention period, after 
completing their HCC sessions.   
Enrollment Visit: 
Informed consent is obtained, notification of group assignment is made, and all baseline measures are 
collected, including a brainwave assessment.  The V1 visit will require about 2 hours of time. 
Intervention Period: 
During the intervention period, subjects will receive in-office sessions of acoustic stimulation linked to 
brainwave activity (HIRREM, HCC), while relaxing in a zero gravity chair.  Sessions last about 1.5-2 hours, 
and two can be done in a half day, with a short break between sessions.  All subjects must receive the 
initial 6 sessions, two per day, on three consecutive days.  Thereafter, subjects are encouraged to get 
the complete all sessions within two to three weeks, and in no longer than 4 weeks, without going 
longer than 5 days between sessions.  Those assigned to the CCC group will continue with their current 
clinical care, including any life-style, non-pharmacological therapies that they may be employing. 
Post-Intervention Data Collection Visits: 
For participants in the HCC group, participants will return for a post-intervention data collection visit 
(V2, primary outcome) between 4-6 weeks after completion of the intervention.  This will occur at 10-12 
weeks after V1 for those in the CCC group.  All measures will be repeated, including a brainwave 
assessment.  This visit will require about 120 minutes.      
Between 12-14 weeks after completion of the intervention, participants in the HCC group will return for 
a final data collection visit (V3).  The V3 visit will be between 18-20 weeks after V1 for those in the CCC 
group.  All measures other than the brainwave assessment will be repeated for a final time.  This will 
complete the official study involvement for participants in the HCC group, while those in the CCC group 
will be offered an opportunity to be scheduled to receive a course of HCC, and this will be discussed.  
This visit will take about 45 minutes.   
High-resolution, relational, resonance-based, electroencephalic mirroring (HIRREM): 
High-resolution, relational, resonance-based, electroencephalic mirroring (HIRREM®) is a computer-
based technology created by Brain State Technologies, LLC, Scottsdale, AZ, designed to facilitate 
relaxation and auto-calibration of neural oscillations through reflecting back musical tones in near real 
time.   
 
 

 
 
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Brainwave Assessment: 
This is the first step in the HIRREM process.  It occurs during the V1 enrollment visit, and will be 
performed on both groups.  The assessment creates a map of frequencies and amplitudes, and informs 
the choice of protocols for the initial HIRREM sessions.  Our pilot data also suggest that this information 
is also useful for correlating with autonomic function (HRV and BRS), and that changes can be observed 
in frequencies and amplitudes from pre- to post-HIRREM.  For the assessment, with the participant in a 
sitting position, sensors are sequentially placed over six areas of the scalp to record one minute epochs 
of data while the brain is at rest, or on task, with eyes open and with eyes closed.  For the assessment, 
measurements are taken at homologous regions of the bilateral hemispheres according to the 10-20 
International System at F3/F4, C3/C4, P3/P4, T3/T4, FZ/OZ, O1/O2, FP1/FP2, and CB1/CB2 with both 
eyes closed (EC; one minute), and eyes open (EO; one minute) conditions ("Report of the committee on 
methods of clinical examination in electroencephalography: 1957," 1958).  For EO assessments, subjects 
are given standardized tasks involving numerical digit recall (F3/F4), reading silently (C3/C4), math 
calculations (P3/P4), listening comprehension (T3/T4), and to relax with eyes open (O1/O2).  A sixth 
midline measurement is taken at FZ/OZ, with an EO task to count number of appearances of a specific 
word as they read a standardized printed passage. A seventh (FP1/FP2, given standardized tasks 
involving numerical digit recall), and eighth (CB1/CB2, relax with eyes open) location are also measured.  
The reference sensors are connected at A1/A2 and linked for assessments. The data are processed to 
identify patterns and imbalances of frequencies and amplitudes, which are used to generate specific 
protocols for the initial HIRREM session.  The assessment takes about 30-45 minutes to complete.  An 
assessment will be repeated at the V2 visit to allow comparison between brain patterns at baseline, and 
post-intervention, between the two groups.  
HIRREM Sessions: 
Participants assigned to both study groups will continue their current clinical care.  The HIRREM 
intervention group (HCC), will also receive a course of 8-16 in-office HIRREM sessions.  Each session 
requires about 1.5-2 hours, and will include between 3-10 individual protocols, working with different 
locations on the scalp.  Each protocol will typically last from 6-40 minutes.  For the sessions, with the 
subject comfortably at rest, sitting or reclining, the sensors are placed over the specific target areas on 
the scalp corresponding with brain regions/lobes to be observed.  Brainwaves are monitored in real 
time, and the dominant frequency within a chosen target frequency band, e.g. delta (0.5-3 Hz) is 
identified.  The dominant frequency is assigned an auditory tone which is played back to the subject via 
ear phones with as little as 4-8 millisecond second delay.  Thus, the subject listens to the energetic 
"song" being played in the brain from moment to moment, providing the brain with rapid updating 
about its frequencies, amplitudes, and patterns via an electronic/acoustic mirror of itself.   
Some sessions will occur with eyes closed, for which the subject will be instructed to relax.  Some 
sessions will occur with eyes open, during which the subject can read, or do other activities such as a 
word search, or just relax.   

 
 
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Although there are similarities to methods such as neurofeedback, or traditional biofeedback, HIRREM 
uses an algorithm-based observation for the brain to view itself, which provides an opportunity for 
subject-unique auto-calibration, self-adjustment, and movement towards a more balanced state, rather 
than operant conditioning designed to try to force the brain toward a standardized or ideal pattern of 
frequencies and amplitudes.  In addition, no active, conscious, cognitive involvement by the participant 
is needed to accomplish this process.   
The in-office HIRREM process is individualized for each recipient, such that the specific protocols chosen, 
the session length, and the total number of sessions are variable.  Technologists time sessions and 
choose protocols to facilitate an overall trend toward greater hemispheric symmetry and more optimal 
proportionation in frequency ranges, between and within cortical regions, based upon data from the 
initial assessment and the ensuing sessions (Gerdes et al., 2013).  Each participant in the HCC group will 
receive at least 8 sessions.  The final number of HIRREM sessions, which may be extended to as many as 
16, will depend on continuous review of brain patterns relative to progress towards improved balance 
and quieting of electrical amplitudes, as well as progress and stability of self-reported status regarding 
symptoms such as sleep and stress.   
Safety: 
Evidence to date indicates that the HIRREM intervention has potentially high benefit and low risk.  Based 
on experience reported by Brain State Technologies, garnered from provision of case management 
support, feedback from their clients, and feedback from the HIRREM provider community, as well as 
results from IRB-approved studies at WFSM (now over 480 participants to receive HIRREM), we are not 
aware of any serious adverse events resulting from HIRREM sessions.   
Non-serious, temporary, effects have been reported by participants in other studies.  This includes 
things such as the participant reporting being more aware of, or more affected by their feelings, or by 
those around them, changes in sleep, including dreams, emotions, or energy levels, or a feeling of 
fullness in the head or mild headache.  In the course of provision of HIRREM as part of five IRB-approved 
studies at WFSM, such non-serious, temporary effects have been estimated to occur in ten percent or 
less of participants.  Based on recent analysis of a placebo controlled trial of HIRREM for moderate to 
severe insomnia (n = 107), such non-serious, temporary adverse effects that were judged to go beyond 
the intensity, expression, or nature of pre-existing health conditions were reported during study 
participation by 10.7% in the HIRREM group, and 13.7% in the placebo group.  All episodes were brief, 
typically resolving in hours to 1-2 days, but at the most lasted less than one week.  Skin irritation at the 
site from the paste used to affix the sensors to the scalp was reported by a single participant (<1%) 
(personal communication).   
All HIRREM sessions are administered by Technologists who have been certified in the procedure, 
including guidelines for addressing any adverse effects that may occur.  In the event that any adverse 
effect is prolonged or intense, participants will be advised to see their primary care physician, or if 
needed, to see a mental health professional for additional evaluation or treatment.  It acute, and severe, 

 
 
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participants will be referred to the Emergency Department.  There are no anticipated additional risks 
associated with continuation of current clinical care.      
Other Data Collection, Measures, and Process: 
A series of measures will be collected at the enrollment visit (V1), as well as at three post-intervention 
period visits for all participants.  Those in the CCC group, who choose to receive HCC within 3 months, 
will also have an additional two post-interventions data collection visits.    
Demographics: 
Demographic information will include embedded elements to allow calculation of the Charlson 
Comorbidity Index Score (Charlson et al., 2008).   
Autonomic cardiovascular Regulation [Blood Pressure (BP), Heart Rate (HR), Heart Rate Variability (HRV), 
Baroreflex Sensitivity (BRS), and Blood Pressure Variability (BPV)]: 
Continuous BP and HR are acquired from noninvasive finger arterial pressure measurements and ECG 
for a minimum of 10 minutes in subjects lying down quietly, supine.  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 of BRS, HRV and BPV as follows:  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).  A Hanning window is 
applied and the squared-coherence modulus is computed if coherence is >0.5 as reported.  The square-
root of the ratio of RRI’s and SBP powers is computed to calculate LF, HF alpha indices, which reflect BRS 
(16).  Power of RRI spectra in LF, HF range (LFRRI and HFRRI) are calculated in normalized units and the 
ratio of LFRRI/HFRRI is used as a measure of sympathovagal balance.  Power of SBP spectra calculated as 
LFSAP is used as a measure of BPV.  Sequence Method.  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.  If the correlation coefficient 
exceeds a pre-set critical value (0.85), the regression coefficient (slope) is calculated and accepted.  The 
mean of all individual regression coefficients (slopes), a measure of sequence BRS, is then calculated for 
Sequence UP, DOWN and TOTAL.  Time-Domain Analysis.  Three time-domain parameters are used for 
hemodynamic variability.  HRV is determined by computing the standard deviation of normal to normal 
intervals (SDNN), and the root mean square of successive beat-to-beat differences in R-R interval 
duration (rMSSD).  BPV is the standard deviation of the mean arterial pressure (SDMAP). 
HRV and BRS Data Processing and Interpretation: 
Heart rate is measured as beat-to-beat intervals (RRI) recorded by pulse-wave recording, and will be 
analyzed using custom software developed by Matlab.  Data can be loaded and viewed, and a subset of 

 
 
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the data can be selected to avoid artifacts during device placement or removal.  Outlier identification is 
performed by determining all IBIs which demonstrate a 30% difference from the mean of the previous 
four samples.  Such outliers are removed from the data set.  HRV statistics that are generated include 
mean, variance, SDNN, rMSSD, VLF, LF, HF, TP, LF/HF, sample asymmetry, sample entropy, and 
coherence ("Heart rate variability: standards of measurement, physiological interpretation and clinical 
use. Task Force of the European Society of Cardiology and the North American Society of Pacing and 
Electrophysiology," 1996).  All of the algorithms for computation of these parameters are derived from 
information or source code from the Physionet archive.  Data are saved to Excel spreadsheets for further 
statistical analysis by study team members. 
Menopause -related symptoms: 
Hot flash diaries provide a valid and reliable approach to understanding a participant’s experience of hot 
flashes and night sweats (Sloan et al., 2001).  An adapted hot flash daily diary that includes daytime and 
nighttime frequency and severity will be included.  Categories are mild (1), moderate (2), severe (3), and 
very severe (4).  Data will be used to calculate a hot flash severity score for each day as the sum number 
of hot flashes within each severity category multiplied by the severity score of that category, with the 
resulting sum divided by the total number of hot flashes.  Participants will be asked to keep a 7-14 day 
daily hot flash diary after V1, and then 7-14 days before each subsequent data collection visit.  
Hot Flash Related Daily Interference Scale (HFRDIS) is a 10 item measure to capture the daily impact of 
vasomotor symptoms in a variety of domains within the past week.  These domains include work, social 
activities, leisure activities, sleep, mood, concentration, relation with others, sexuality, enjoyment of life, 
and overall quality of life.  Items are scored from 1 (not at all) to 10 (extremely) (Carpenter, 2001).      
The Menopause Rating Scale (MRS) is a survey that generates a score between 0 and 44 based on the 
individual’s symptom severity rankings (Research, 2008).  There are 11 symptoms listed related to 
perimenopause that are each assigned a score of 0 to 4 by the individual.  A score of 0 indicates none, 1 
is mild, 2 is moderate, 3 is severe, and 4 is very severe.  After completion, the individual’s score is tallied 
to create an overall score.  Scores from 0-4 are considered zero to little, scores from 5-8 are considered 
mild, scores from 9-16 are moderate, and scores 17 or greater are considered severe.  
Insomnia:  
The severity of insomnia symptoms is measured using three self-report symptom inventories with each 
data collection visit (Appendix A).  This includes the Insomnia Severity Index (ISI), the Pittsburgh Sleep 
Quality Index (PSQI), and the Epworth Sleepiness Score (ESS).  The ISI is a 7 question measure, with 
responses from 0-4 for each question, yielding scores ranging from 0-28 (Bastien, Vallieres, & Morin, 
2001; C.M. Morin, Belleville, Belanger, & Ivers, 2011; C. M. Morin et al., 2009).  The PSQI is a 19 item 
inventory that assesses sleep quality over a 1-month time interval (Buysse, Reynolds, Monk, Berman, & 
Kupfer, 1989).  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.  The ESS measures a person’s general level of daytime sleepiness, or 
their average sleep propensity in daily life.  The simple questionnaire is based on retrospective reports 

 
 
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of the likelihood of dozing off or falling asleep in a variety of different situations.  Rated on a 4-point 
scale (0-3), it evaluates their usual chances of dozing off or falling asleep while engaged in eight different 
activities.  The ESS score (the sum of 8 item scores, 0-3) can range from 0 to 24 (Johns, 1991). 
Behavioral and Psycho-physiological function: 
Depression:  
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 (Radloff, 1977).  Scores range from 0-60, with a score of 16 commonly used 
as a clinically relevant cut-off (SmarrK.L., 2003). 
Anxiety: 
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 
(Spitzer, Kroenke, Williams, & Lowe, 2006). 
Stress: 
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 (Cohen, Kamarck, & Mermelstein, 1983). 
Quality of Life: 
Quality of Life: 
The Quality of Life Scale (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) (Carol S. Burckhardt & 
Anderson, 2003; C. S. Burckhardt, Woods, Schultz, & Ziebarth, 1989; Offenbächer, Sauer, Kohls, Waltz, & 
Schoeps, 2012). 
Alcohol Intake Screening: 
The AUDIT-C is a short, 3-item alcohol screening for hazardous drinkers or active alcohol use disorders.  
This measure consists of 3 questions to assess an individual’s alcohol use.  Each question has five 
possible answers ranging from of 0-4 with a total scoring scale of 0-12.  A total score of 3 or more in 
women and a score of four or more in men is suggestive of hazardous drinking or active alcohol use 
disorders.  This form is modified from the longer, 10-item AUDIT instrument (Bradley et al., 2003; 
Bradley et al., 2007; Bush, Kivlahan, McDonell, Fihn, & Bradley, 1998).  

 
 
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Functional Measures: 
Reaction Testing: 
Reaction testing will be evaluated by a drop-stick, clinical reaction time apparatus.  It is constructed 
from a meter stick covered in friction tape with gradations.  The modified meter stick is fixed to a 
weighted rubber cylinder.  The apparatus is placed between the thumb and index finger of the subject 
and released at a random time during a countdown.  The subject catches the apparatus and the distance 
fallen (cm) is converted to reaction.  Following two practice trials, subjects perform eight trials, and a 
mean distance value is used for analysis.  This is repeated with a second set of 8 trials later during the 
enrollment visit, and the mean distance value from the second trial will be used as the baseline value.  
Use of the average distance from the second set of trials will be used as the baseline value so as to avoid 
the impact of learning effect for this test.  This simple clinical measure has been evaluated by Eckner et 
al, and demonstrated utility in testing comparable to computerized testing methods (Eckner, Kutcher, & 
Richardson, 2010).  Our pilot data demonstrate improved reaction testing associated with use of 
HIRREM for athletes with persisting post-concussion symptoms (C. H. Tegeler et al., 2016). 
Grip Strength: 
Grip strength will be evaluated using a hydraulic hand dynamometer (Baseline Hydraulic Hand 
Dynamometer).  The mean value of the greatest force generated during three trials will be used for 
analysis (Roberts et al., 2011). 
Statistical Analysis: 
Continuous variables will be summarized with standard descriptive statistics, such as quartiles, means, 
and standard deviations, while categorical variables will be summarized with percentages and 
frequencies.  LMMs will be employed to contrast longitudinal changes in systolic and diastolic blood 
pressure between the HCC and NCC groups.  Mean contrasts will be used to compare the changes in 
blood pressure between groups from V1 to V3, our primary test of efficacy.  Comparisons of changes in 
all secondary outcomes will be assessed in a similar fashion.  Assumption and computation diagnostics 
will be assessed for all model fits (Cheng, Edwards, Maldonado-Molina, Komro, & Muller, 2010) and 
model adjustments and outcome variable transformations will be made as necessary.  Data will be 
analyzed using SAS v9.4 (SAS Institute, Inc., Cary, NC) or the R Statistical Computing Environment. 
Participant Compensation: 
Participants will receive up to $100 compensation for time, travel, and inconvenience related to study 
visits.  Subjects who do not complete the entire study will receive a prorated portion of this amount 
($25 per visit for completion of each of the three data collection visits, and $25 for completion of the 
daily hot flash diaries).   
Human Subjects Protection: 
Consent: 

 
 
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Written informed consent will be obtained by the research staff from each competent subject. 
Confidentiality and Privacy: 
Confidentiality will be protected by collecting only information needed to assess study outcomes, 
minimizing to the fullest extent possible the collection of any information that could directly identify 
subjects, and maintaining all study information in a secure manner.  Per institutional policy, all research 
study participants will be assigned a hospital MRN number, if none already exists.  To help ensure 
subject privacy and confidentiality, only a unique study identifier and first name will appear on the data 
collection form.  Any collected patient identifying information corresponding to the unique study 
identifier will be maintained on a separate master log.  The master log will be kept secure, on a 
separate, limited access user group on a shared network drive, with access limited to designated study 
personnel.  Following data collection subject identifying information will be destroyed at the earliest 
opportunity, consistent with data validation and study design, producing an anonymous analytical data 
set.  Data access will be limited to study staff.  Data and records will be kept locked and secured, with 
any computer data password protected.  No reference to any individual participant will appear in 
reports, presentations, or publications that may arise from the study. 
Brain State Technologies, LLC (BST) may assist with brain pattern analysis.  To accomplish this, BST is to 
be provided with the first 8 characters from the randomly generated, 36 alpha numeric character 
identifier that the HIRREM software generates for each participant’s brain frequency and amplitude 
data, along with the participant’s age and gender, which are believed important for understanding brain 
patterns.  No other participant-specific information is provided.   
Data and Safety Monitoring: 
The principal investigator will be responsible for the overall monitoring of the data and safety of study 
participants.  The principal investigator will be assisted by other members of the study staff. 
Any collected patient identifying information corresponding to the unique study identifier will be 
maintained on a separate master log.  The master log will be kept secure, with access limited to 
designated study personnel.  Following data collection subject identifying information will be destroyed 
at the earliest opportunity, consistent with data validation and study design, producing an anonymous 
analytical data set.  Data access will be limited to study staff.  Data and records will be kept locked and 
secured, with any computer data password protected.   
Reporting of Unanticipated Problems, Adverse Events, or Deviations: 
Any unanticipated problems, serious and unexpected adverse events, deviations or protocol changes 
will be promptly reported by the principal investigator or designated member of the research team to 
the IRB and sponsor or appropriate government agency if necessary. 
 
 

 
 
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Appendices 
A: 
Hot Flash Daily Diary 
Hot Flash Related Daily Interference Scale (HFRDIS)  
Menopause Rating Scale (MRS) 
Insomnia Severity Index (ISI) 
Pittsburgh Sleep Quality Index (PSQI) 
Epworth Sleepiness Score (ESS) 
Center for Epidemiological Studies Depression Scale (CES-D) 
Generalized Anxiety Disorder 7-Item (GAD-7) 
Perceived Stress Scale (PSS) 
Quality of Life Scale (QOLS) 
AUDIT-C 
 
B: 
Handout for Study Participants 
 
C: 
Medical History/Screening Form  
 
 
 

 
 
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