Functional and Physiological Effects of High-resolution, Relational, Resonance-based, Electroencephalic Mirroring (HIRREM) for Neurological, Cardiovascular and Psychophysiological Disorders
Phase: NA
Conditions: Sleep Initiation and Maintenance Disorders, Anxiety, Post-Traumatic Stress Disorder, Hot Flashes, Headache, Traumatic Brain Injury, Post Concussion Symptoms
Sponsor: Wake Forest University Health Sciences

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
HIRREM Developmental Study 
04/20/2017 
Charles H Tegeler, MD 
NCT02709369 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
Functional and Physiological Effects of High-resolution, relational, resonance-based, electroencephalic 
mirroring (HIRREM) for Neurological, Cardiovascular and Psychophysiological Disorders 
 
Abnormal electroencephalographic (EEG) asymmetries have been reported in a variety of 
neurological, cardiovascular, and psychophysiological conditions including Attention Deficit 
Hyperactivity Disorder ADHD, anxiety, autism spectrum disorders, depression, dyslexia, Post-Traumatic 
Stress Disorder (PTSD), and traumatic brain injury (TBI).1,2,3,4,5,6,7,8,9,10,11,12  Many, if not all of these 
conditions are associated with autonomic imbalance and psychophysiological dysfunction manifested as 
low heart rate variability or other abnormal measures.13, 14, 15  It comes as no surprise that EEG 
asymmetry and autonomic perturbations occur concomitantly as Craig has posited a plausible theory for 
the anatomic lateralization of autonomic function within the brain.16  Aiming to balance EEG 
asymmetries using biofeedback has yielded positive results in the treatment of neurological and 
psychiatric conditions of interest such as ADHD, depression, anxiety, pain, substance abuse disorders, 
and TBI.17,18,19,20,21,22,23  Conventional EEG biofeedback (neurofeedback) employed in these studies utilizes 
operant conditioning to help individuals consciously learn to alter their brainwave activity, with the goal 
of ameliorating neurobehavioral symptoms.   Specific EEG frequencies and locations are targeted that 
are believed to influence specific cognitive domains.  The goal is to bring the individual’s brainwave 
activity within a range as defined by a control group or normative database.24  Recent evidence suggests 
the need to attain idiosyncratic set points for each patient rather than adjust to a single standard.25 
High-resolution, relational, resonance-based, electroencephalic mirroring (HIRREM®), can help achieve 
desired electrical balance in the brain in an individualized manner by functioning as a mirror for the 
brain to observe its own disequilibrium26. 
 
HIRREM is an innovative, noninvasive approach to facilitating greater self-regulatory capacity 
for, by, and through the human brain (Brain State Technologies, LLC, Scottsdale, AZ)(BST).  HIRREM may 
be conceived as a high-resolution electronic mirror that reflects the brain’s activity back to itself, in “real 
time.”  But rather than use light to reflect the brain’s changing visual appearance, as would a 
conventional household mirror, HIRREM instead uses sound to reflect the brain’s changing pattern of 
frequency-specific electrical activity.  In effect, HIRREM simply creates an opportunity for an individual 
to “listen to his or her own brain.” 
 
The HIRREM system uses unique sensors which are placed on the scalp and held in place using 
standard EEG conductive paste.  The sensors precisely measure and map the surface EEG frequencies 
and amplitudes of the brain throughout its major lobes.  The sensors utilize embedded computer chips 
that improve filtering of electromagnetic interference/artifact, allow collection of more precise 
frequency data, and thus demonstrate functional aspects of the brain in greater detail.  
 
The choice of the specific musical tone to be reflected back to the user is made through a 
mathematical algorithm which identifies the dominant frequency of the individual’s EEG spectrum in a 
floating middle range, in a given instant of time.  The dominant EEG frequency is translated to a musical 
tone whose frequency corresponds to the dominant EEG frequency.  The musical tone is played back to 
the individual through ear buds, with a delay of as little as 12 milliseconds.  Since the brain is a dynamic 
organ, with constantly changing frequencies, the subject hears a series of musical tones.  It appears that 
a phenomenon of resonance occurs between the musical tones being fed back, and the oscillating 
neural circuits in the subject’s brain.  The operational theory is that such resonance creates an 
opportunity for the brain to either dissipate or accrete neural energy in an extremely subtle, noninvasive 
way.  Neural-musical resonance may be a mechanism for auto-calibration of neural networks.   
 

 
 
Like any polished mirror, HIRREM is extremely precise, and also “non-judgemental.”  There is no 
operant conditioning, and no imparting of normative information by the HIRREM provider, that would 
aim to explicitly reward, inhibit, entrain, instruct, re-program, or in any other way to over-write the 
brain’s existing pattern of activity.  Thus, HIRREM is fundamentally different from other available 
technologies such as binaural beats, auditory or photic stimulation, “synchronization” and other “brain-
enhancement” methodologies.  
 
Based on information received from the licensor, HIRREM has been found to be an extremely 
safe procedure.  The licensors of HIRREM technology are not aware of any serious adverse events that 
have been associated with undergoing the HIRREM process, among over 50,000 individuals world-wide. 
On an anecdotal basis, individuals undergoing HIRREM may report an apparent “release of emotions” or 
paradoxical effects, especially initially, which can manifest as brief periods of increased awareness of 
emotional states, both positive and negative.  These experiences are typically transient, that is, lasting 
intermittently over the course of one to several days.  Based on our own experience with having 
enrolled over 400 subjects in HIRREM clinical research projects at Wake Forest School of Medicine, 
reflecting a total of over 4,000 HIRREM sessions, there have been no serious adverse events.  
Subthreshold changes in emotional symptomatology (not requiring additional clinical intervention or 
necessitating discontinuation of sessions) have been seen in an estimated 5-10% of subjects.   
The purpose of this study is to ascertain the functional and physiological effects of BWO using 
HIRREM as supplemental care in populations and individuals with a variety of neurological, 
cardiovascular, and psychophysiological diseases.  The scope of the conditions to be investigated is 
broad since it is the intention of this proposal to allow the recruitment of a wide variety of patients at 
the discretion of the investigators.  One goal is to allow investigators to identify patient cohorts which 
would be desirable for further study, some of which may not be intuitively obvious, using such data as 
the basis for pursuit of additional disease-specific projects, or funding opportunities.  Anecdotal 
evidence collected by BST has demonstrated efficacy of treatment for many diseases and disorders of 
interest including PTSD, TBI, insomnia, ADHD, substance abuse disorders, cardiovascular diseases, 
gastrointestinal disturbances, and others.  It is those conditions along with autism spectrum disorders, 
depression, dyslexia, anxiety disorders, migraines, hot flashes, and others, for which we seek to formally 
evaluate the functional and physiologic effects of HIRREM.   
As of this submission, two randomized clinical trials utilizing HIRREM have been completed at 
Wake Forest School of Medicine.  This includes a wait-list controlled pilot trial for insomnia (n=20), and a 
sham placebo controlled trial for migraine (n=30).  A manuscript has been published regarding the 
insomnia study, and one is being prepared related to the migraine work.  Results of the insomnia study 
showed significant reduction in the Insomnia Severity Index (ISI), with the effect persisting for one 
month following completion of the HIRREM intervention27.  There was also a significant decrease in 
symptoms of depression as identified by the CES-D scale.  A larger, confirmatory, placebo-controlled trial 
for insomnia will be launched shortly.   
 
There has also been analysis of several subsets of subjects from this ongoing research project.  A 
case series of subjects with symptoms of Post-Traumatic Stress Disorder (PTSD) was presented as a 
poster at the annual meeting of the International Society for Traumatic Stress Studies, and a manuscript 
has been submitted for possible publication.  This case series (n=10) showed significant improvements in 
the symptoms of PTSD (PCL-Civilian scale), sleep (ISI), and depression (CES-D).  An abstract based on 
analysis of outcomes for another case series (n=10) of subjects with physical trauma/TBI  was submitted 

 
 
for possible presentation at the 2013 meeting of the American Academy of Neurology (AAN),  showing 
significant improvements found in the ISI, CESD, and PCL-C scales.   
 
We anticipate that there will be beneficial effects on balance in the autonomic nervous system 
associated with HIRREM, and thus, believe that heart rate variability (HRV), which reflects balance in the 
autonomic signal to the heart, is a good objective measure, and represents a relevant outcome for this 
study, irrespective of the clinical condition.  To that end, an additional abstract was submitted for 
possible presentation at the 2013 AAN meeting.  This case series of consecutive subjects enrolled in the 
project, for a variety of clinical complaints (n=23), showed significant correlation between the brain 
pattern pre-HIRREM (temporal asymmetry at T3/T4) and a HRV parameter (RMS-SD).  This provides 
support for our understanding regarding lateralization of autonomic function in the HIRREM assessment 
of surface EEG data.     
 
Evidence of benefit for HIRREM in other conditions, prospectively gathered in a carefully  
monitored clinical environment through this proposal, can serve as a foundation for the pursuit of future 
randomized controlled pilot studies, and eventually larger randomized controlled clinical trials.  The 
ultimate goal of this line of study is the development of HIRREM as a noninvasive therapy for a variety of 
clinical conditions.   
 
Objectives and Hypotheses:  
 
 
The primary objective of this proposal is to generate new hypotheses and data for future studies 
by evaluating the effect of HIRREM as supplemental care for subjects with a number of 
neurological, cardiovascular, and psychophysiological diseases.  The primary analytic outcome to 
determine the effect and feasibility of HIRREM is HRV as measured by standard outcomes 
collected using a BIOPAC device for continuous recording of heart rate and blood pressure.  This 
also allows calculation of mean arterial pressure and baroreceptor sensitivity.  We anticipate a 
decrease in sympathetic activity and an improvement in sympatho-vagal balance manifested as 
an increase in HRV parameters. 
 
 
Secondary objectives of this proposal  include evaluation of the effects of HIRREM on: 
 
o Autonomic nervous system functions, as manifested by blood pressure and heart rate.  
Another expected result of a decrease in sympathetic activity and an improvement of 
sympatho-vagal balance may be a decrease in heart rate and blood pressure. 
 
o Psycho-physiological functional outcomes as measured using  a standardized measure of 
health status the (EQ-5D) , the Center for Epidemiologic Studies Depression Scale (CES-
D), the GAD-7 measure of anxiety, the Insomnia Severity Index (ISI), and the PTSD Check 
List for civilians or military service members (PCL-C, or PCL-M, respectively.  We expect 
to see an improvement in these measures following HIRREM.   
 
o Metrics for specific disorders will be measured according to relevant currently accepted 
assessment tools.  Some of the conditions for which treatment is anticipated and the 
corresponding evaluation tools are in Appendix A.  We expect to see improvement in 
these measures. 
 

 
 
o Weight will be measured at the enrollment visit (V1), completion visit (V2) and follow-up 
visit (V3) to determine the potential impact of HIRREM on weight. 
 
o Reaction time will be measured using the clinical reaction time enrollment visit (V1), 
completion visit (V2) and follow-up visit (V3). 
 
 
Research Design and Methods:   
 
This protocol is an assessment of the functional and physiological effects of HIRREM on neurological, 
cardiovascular, and neurophysiological disorders.  It will be a non-randomized, open label, and 
unblinded before-and-after trial.  The intention of this protocol is to evaluate the effect of HIRREM on an 
objective, physiological common denominator (HRV), across a variety of relevant conditions, as well as 
changes in clinical symptoms scales, to generate hypotheses and pilot data for investigation in future 
proposals.  HIRREM will be offered as deemed potentially advantageous by the investigator.  Patients 
will be recruited to receive eight to twenty HIRREM sessions in addition to their usual care.  HIRREM 
sessions will be completed over a one month period.  Measurements for the primary and secondary 
outcomes will be obtained at the initial visit and after completion of HIRREM therapy.  A follow-up visit 
(V3)   will be performed four to eight weeks after the completion visit (V2).  This will consist of several 
representative questionnaires and surveys and a repeat of recording of blood pressure and heart rate 
using the BIOPAC device. 
 
1) Subjects Selection Criteria: 
 
Male and Female adults and children over the age of 11 years with a clinical diagnosis consistent 
with the aims of this proposal, who also meet the inclusion criteria outlined below and are 
interested in receiving HIRREM, will be enrolled.  Subjects will be recruited by physician referral, 
word of mouth, and through advertisement.  Physicians who want to inform prospective subjects 
about the availability of the research will be provided with copies of the IRB approved consent form 
and IRB approved ad which they may give to prospective subjects.  The physicians do not obtain 
subjects’ consent for the research or act as representatives of the investigators.  Physicians provide 
prospective subjects with information about contacting investigators for information or enrollment; 
and/or seek or obtain the prospective subjects’ permission for investigators to contact them. The 
participant must be able to provide informed consent.  
 
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 ADHD, Asperger 
Syndrome, chronic pain, dyslexia, depression, insomnia, migraines, PTSD, substance abuse 
disorder, TBI, and others. 
 
During the screening process a list of questions, Appendix D, shall be asked to evaluate 
eligibility, severity and related concerns to be considered for treatment. 
 

 
 
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 bilateral hearing impairment (treatment 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 investigator.   
 
Subjects with anticipated and ongoing use of recreational drugs except when deemed 
acceptable by the investigator. 
 
Subjects are encouraged to discuss their participation with their healthcare provider following 
completion of HIRREM since some of their symptoms and conditions may be alleviated and 
therefore no longer require the same type or dosage of medication.  Throughout the course of/ 
and for three weeks following treatment subjects will be requested to abstain from the 
consumption of alcohol or use of recreational drugs since the effects of these substances may 
cause reversal or cessation of the benefits of HIRREM.  Additionally, subjects will be asked to 
discontinue chiropractic practices, cranial-sacral therapy, and bio-energy work during treatment 
and for the three weeks following treatment.  Other instructions and requests may be given to 
the patient and will be contingent upon the condition(s) being treated and will be at the 
discretion of the investigator.   
 
2) Number of Subjects: 
 
This protocol is submitted with the intention of uncovering potential for future research and as such 
the aim is for three hundred subjects to be enrolled and receive HIRREM.  This cohort will provide 
data across a variety of conditions, which can be used to generate estimates of effect size, and serve 
as pilot data in proposals for future studies. 
 
3) Number of HIRREM Sessions and Length of Study: 
 
All baseline measures will have been collected during the enrollment visit.  The period of active 
HIRREM will begin with an initial assessment to map the patterns of frequencies and amplitudes in 
the brain.  Participants will typically then receive eight to twenty HIRREM sessions over a one month 
period.  Based on objective data regarding brain patterns, evidence of progress with balancing of 
frequencies and quieting of amplitudes, along with clinical progress, HIRREM may be extended 
beyond 20 sessions.  Participants may be given a brief break of one to two weeks before returning 
for additional sessions.  HIRREM sessions typically are 1.5 hours in length.  Participants may receive 
two HIRREM sessions during a half day period, and thus will spend an average of five half days 
getting HIRREM during the month.  There will then be a post-HIRREM data collection visit (V2) no 
longer than two weeks after completion of the HIRREM during which outcome measures will be 
repeated and a follow-up visit (V3) 4-8 weeks after (V2).   
 
 
 

 
 
a. Enrollment Visit:  
 
Informed consent obtained, brief medical history obtained (Appendix B), and collection of 
baseline measures.  This will occur prior to the start of HIRREM and will require about 45-60 
minutes of time. When possible the completed medical history form may be requested and 
received prior to the enrollment visit. 
 
b. Initial Half Day Session: 
 
On the first day of HIRREM, the participant will have an assessment (about 60 minutes) to 
determine the pattern of frequencies and amplitudes in his/her brain which may be 
followed by the first and possibly second HIRREM sessions.  
 
c. Remaining HIRREM Sessions: 
 
Participants may receive two HIRREM sessions in a half day period for an anticipated 
average total of 10 HIRREM sessions per participant, with five half days spent during the 
month of HIRREM.  Participants may receive up to 20 HIRREM sessions over the course of 
ten visits.  In the event this is deemed appropriate and necessary, and for the benefit of the 
subject, (see above) the number of HIRREM sessions may be extended.  
 
d. Treatment Completion Visit:  
 
Participants will return for a study completion visit no longer than two weeks following 
completion of the HIRREM sessions, when post-intervention measures will be obtained.  
This visit will take 45-60 minutes. 
 
e. Follow-Up Visit: 
 
Follow-up visit will be scheduled for 4 -8 weeks after V2 treatment completion visit.  Post 
intervention measures will be repeated.  
 
 
4) High Resolution, Relational, Resonance-Based, Electroencephalic Mirroring (HIRREM) 
 
HIRREM is an EEG-based, noninvasive technology to facilitate relaxation and auto-calibration 
of neural oscillations. 
 
a. Brain Pattern Assessment  
 
This is the first step in the process, occurring prior to the active HIRREM sessions.  The 
assessment is to create a map of the frequencies and amplitudes in the brain.  With the 
participant in a sitting or slightly reclined position, sensors are sequentially placed over 
seven areas of the scalp, and measurements are taken with eyes closed (1 minute), eyes 
partially open (1 minute), and eyes open (1 minute).  For eyes closed, subjects are asked to 
rest and relax quietly.  For eyes open, subjects are given standardized tasks such as 
numerical digit recall, reading silently, calculations, or listening comprehension.  This allows 

 
 
evaluation of the brain pattern with the brain at rest, and at task.  The data are processed to 
identify patterns and imbalances, which will then be used to generate specific protocols for 
the HIRREM sessions that follow.  The mapping takes up to 60 minutes to complete. 
 
b. HIRREM Session 
 
Each HIRREM session requires about 90-120 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 addressed.  Frequencies and amplitudes 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 a musical note, which is played back to the subject via ear 
buds within 12-25 milliseconds.  Thus, the subject listens to the energetic "song" being 
played in the brain from moment to moment, providing the brain with a mirror of itself, and 
its energetic function.  Although similar to methods such as neurofeedback, HIRREM uses an 
algorithm-based observation for the brain to view itself, which results in spontaneous 
movement toward a more balanced state of function, rather than operant conditioning 
designed to try to force the brain towards a standardized or ideal pattern of energetics and 
function.  No active involvement by the participant is needed to accomplish this energetic 
balancing.  Correction of brain imbalances associated with persistent autonomic responses 
may then lead to resolution of symptoms which had been associated with the same.    
 
c. Safety 
 
Based on information received from the sponsor, HIRREM has been found to be an 
extremely safe procedure.  With over 50,000 individuals receiving HIRREM clinically, there 
have been no serious adverse events reported.  Participants may or may not experience 
improvement.  Participants will be closely monitored for any adverse effects of HIRREM.  It 
is common for individuals undergoing HIRREM to report “release of emotions,” which can 
manifest as brief periods of increased awareness of emotional states, both positive and 
negative.  These experiences are typically transient, that is, lasting intermittently over the 
course of one to several days.  Based on our own experience with having enrolled over 400 
subjects in HIRREM clinical research projects at Wake Forest School of Medicine, 
representing a total of over 4,000 HIRREM sessions, there have been no serious adverse 
events.  Subthreshold changes in emotional symptomatology (not requiring additional 
clinical intervention or necessitating discontinuation of sessions) have been seen in an 
estimated 5-10% of subjects.  All HIRREM sessions are administered by Technologists who 
have been certified in this procedure.  Their training included protocols for addressing 
emotional releases that may occur.  If emotional releases are more prolonged, or more 
intense, subjects will be referred to a mental health professional for additional evaluation or 
treatment. 
 
 
5) Data Collection and Process 
 
A series of measures will be collected at the enrollment visit and the post-HIRREM data collection 
visits.   

 
 
 
a. Primary Data Sets: Heart Rate Variability (HRV) Measurement 
i. HRV Data Acquisition:   
 
Baroreflex sensitivity (BRS) for control of HR, heart rate variability (HRV) and blood pressure 
variability (BPV): Continuous BP and HR are acquired from noninvasive finger arterial pressure 
measurements and ECG for a minimum of 8 minutes in subjects lying down quietly. SBP and 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 
(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 their squared-coherence 
modulus is computed if coherence is >0.5 as reported (16). 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 (17). 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 (18, 19). HRV is 
determined by computing the standard deviation of beat-to-beat interval (SDRR) 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).  
 
ii. HRV 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 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, pNN50, VLF, LF, HF, TP, 
LF/HF, sample asymmetry, sample entropy, and coherence.  All of the algorithms for 
computation of these parameters are derived from information or source code from 
the Physionet archive (Goldberger).  Data are saved to Excel spreadsheets for 
further statistical analysis by study team members. 
 
b. Blood Pressure (BP) 
 

 
 
Blood pressure (BP) measurements will be taken with a finger cuff on two fingers of the left 
hand while lying down on an examination table. 
 
c. Neuropsychological and Psycho-Physiological Function: 
 
i. The Center for Epidemiologic Studies Depression Scale (CES-D) is a standard paper 
and pencil depression scale which will help to assess this co-morbidity. 
ii. 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.  
iii. The Generalized Anxiety Disorder-7 (GAD-7) is a seven item screening tool for 
anxiety that is widely used in primary care.   
iv. The Insomnia Severity Index (ISI) is a seven parameter measure of insomnia.    
v. Post Traumatic Stress Disorder (PTSD) (Civilian and Military) is a checklist to 
measure stress severity due to a traumatic experience 
vi. Nausea /Dizziness Severity Scale is a screening tool to measure symptoms related to 
stomach problems 
 
d. Disorder Specific Metrics 
 
i. These may vary across subjects depending on the underlying condition.  The table in 
Appendix A contains some of the conditions to be included and the corresponding 
assessment tools to measure the effects of HIRREM.  This list is not exhaustive and 
other conditions may be added at the discretion of the investigator.  In the event a 
patient with an unlisted condition is enrolled a currently accepted assessment 
technique will be employed to collect both initial and final data. 
 
e. Weight 
 
i. This will be measured using a standard scale. 
 
f. Reaction Time 
 
Reaction time testing will be measured by the clinical reaction time apparatus.  It is 
constructed from a meter stick covered in the 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 is converted to reaction.  This 
simple clinical measure has been evaluated by Eckner et al and demonstrated utility in 
testing comparable to computerized testing methods.33 
 
 
g. T3/T4 Asymmetry 
 
The proprietors of HIRREM have repeatedly observed that EEG asymmetries in the temporal 
lobes (specifically at T3 and T4 in the 10-20 International System for EEG correspond to 
autonomic dysfunction.  When T4 signals are dominant to T3 signals a sympathetic state is 
favored which is manifested as symptoms of anxiety, cardiovascular over-drive, and 

 
 
hyperarousal.  When T3 signals are excessively dominant to T4 signals a parasympathetic 
state is favored which is manifested as symptoms of emotional numbness, cardiovascular 
underactivity, GI dysfunction, and under-arousal.   Lateralization of autonomic activity is not 
a novel finding, it is in accord with a number of previously published studies which support a 
hypothesis of autonomic lateralization posited by Craig and previously discussed.16,28-32  
Utilization of HIRREM at T3 and T4 has demonstrated success in ameliorating symptoms 
associated with autonomic disruption.  EEG balance at T3 and T4 is indicative of autonomic 
balance and benefit according to BST. 
 
Our preliminary data demonstrate correlation between a T3/T4 temporal asymmetry score 
and objective physiological changes reflective of autonomic signaling to the heart at the 
baseline assessment.  Comparison of such activity at T3 and T4 over time will provide 
objective physiological outcome data regarding the effect of HIRREM on autonomic balance 
and function.    
 
6) Statistical Analysis 
 
Data will be analyzed using the most recent versions of SAS (SAS Institute, Inc., Cary, NC).  Prior to 
performing analyses related to the hypotheses, histograms and descriptive statistics will be 
computed to examine the characteristics and distributions of the data.  As detailed below, analytical 
methods will be conducted through generalized linear models that allow specification of appropriate 
distribution as well as various covariance types to ensure that inference tests can be interpreted 
conventionally.  If required, nonparametric equivalents to the proposed methods will be used to 
analyze variables not well characterized by standard distributions.  Unless otherwise stated, all 
relevant analyses will be two-tailed and p < 0.05 will be used to determine statistical significance. 
Because this proposal is designed to estimate effect sizes for future pilot and definitive trials, care 
will be taken to provide point estimates of effect size for each outcome along with corresponding 
95% CI.  
 
This primary objective of this protocol is to evaluate the effect of HIRREM in neurological, 
cardiovascular, and psychophysiological disorders as measured by standard HRV parameters.  Also, a 
variety of secondary outcomes will assess the impact on functional and physiological measures (BP 
and HR), a number of standard disorder specific clinical measures, and subjective psycho-
physiological outcomes.  The primary analysis will be examining group differences on the post-
HIRREM measure while controlling for baseline levels (i.e., group treated as a fixed effect, with 
baseline scores entered as a covariate in a generalized model assuming a normal distribution and 
identity link).  Changes in all secondary measures will be indexed using the GLM using the repeated 
measurements within each individual.  The groups will be comprised of a collection of individuals 
from within the study with a common clinical disorder, although exploratory analysis will also 
evaluate for common effects in consecutively enrolled subjects.   
 
Human Subjects Protection: 
 
1) Consent and Assent 
 
Written informed consent, or assent and parental permission will be obtained by the research staff 
from each competent subject.  
 

 
 
2) 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.  To help ensure subject privacy 
and confidentiality, only a unique study identifier 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, 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. 
 
3) 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.  No reference to any 
individual participant will appear in reports, presentations, or publications that may arise from the 
study. 
 
4) Reporting of Unanticipated Problems, Adverse Events of 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 appropriate.

 
 
 
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Appendix A:  Examples of Disease Specific Assessment Tools 
 
 
Condition 
Assessment Tool 
Traumatic Brain Injury 
Rivermead Post-Concussion Symptoms 
Questionnaire 
Headache 
Daily Headache Diary 
Hot Flashes 
Daily Diary for Hot Flashes 
Mild Cognitive Impairment 
Montreal Cognitive Assessment (MoCA) 
 

 
 
 
Appendix B: Medical History Form 
Medical History Form 
 
First Name:  
_________________________  
 
Date: 
_________________________ 
 
1. Please check whether you have the following medical problems/health history: 
 
 
Yes 
No 
Year of onset 
If yes, please explain 
High Blood Pressure 
 
 
 
 
Stroke 
 
 
 
 
Seizure/Epilepsy 
 
 
 
 
Heart Attack 
 
 
 
 
Heart Arrhythmia 
 
 
 
 
Lipid Disorder/High Cholesterol 
 
 
 
 
Diabetes 
 
 
 
 
Cancer 
 
 
 
 
Thyroid Disorder 
 
 
 
 
Fibromyalgia 
 
 
 
 
Other Chronic Pain 
 
 
 
 
Chronic Fatigue 
 
 
 
 
Headaches 
 
 
 
 
Migraines 
 
 
 
 
Tinnitus (ringing in the ears) 
 
 
 
 
Vertigo/Dizziness 
 
 
 
 
Stress/Anxiety Disorder 
 
 
 
 
Post-Traumatic Stress Disorder 
 
 
 
 
Depression 
 
 
 
 

 
 
Insomnia 
 
 
 
 
Hot Flashes  
 
 
 
 
ADD/ADHD 
 
 
 
 
Autism Spectrum 
Disorder/Asperger’s 
 
 
 
 
Learning Disability/Dyslexia 
 
 
 
 
Impaired Memory/Mild Cognitive 
Impairment 
 
 
 
 
Sports-Related Concussion 
 
 
 
 
Traumatic Brain Injury/Head Injury 
 
 
 
 
Difficult Birth (Premature, 
Induced, C-Section, etc.) 
 
 
 
 
Other 
 
 
 
 
 
 
 
 
 
 
 
 
Any Surgery 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
2. Please list your prescribed medications (those taken regularly and PRN/as-needed/rescue) and 
duration taking them (for how long, how many times per week/month, or last dose). 
 
Medication 
Dose 
Time of day taken 
Duration taking this 
 
 
 
 
 
 
 
 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
3. Please list any over the counter medication, supplements, vitamins, herbs, etc. that you take 
(those taken regularly and PRN/as-needed/rescue) and duration taking them (for how long, how 
many times per week/month, or last dose). 
 
Name 
Dose 
Time of day taken 
Duration taking this 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Initial HIRREM Screening 
 
Name:   
_________________________ Email address:  
_________________________  
Address: 
_________________________ Telephone number(s):  _________________________ 
 
 
_________________________  
 
 
_________________________ 
Date of birth: 
_________________________ Gender:  
 
_________________________ 
Referred by:  
_________________________ Date screened:  
_________________________ 
 
 
 
Primary complaint: 
 
_____________________________________________________________________________________
_____________________________________________________________________________________ 
_____________________________________________________________________________________ 

 
 
 
Secondary complaints:  
_____________________________________________________________________________________
_____________________________________________________________________________________ 
_____________________________________________________________________________________ 
 
 
 
 
Other medical problems:  
_____________________________________________________________________________________
_____________________________________________________________________________________ 
_____________________________________________________________________________________ 
 
 
 
Medications (prescriptions, PRN/as-needed/rescue medicines, over the counter, supplements, vitamins, 
herbs, etc.) and duration taking them (for how long, how many times per week/month, or last dose): 
_____________________________________________________________________________________
_____________________________________________________________________________________ 
_____________________________________________________________________________________
_____________________________________________________________________________________ 
_____________________________________________________________________________________ 
 
 
 
  
 
 
  
Comments: 
_____________________________________________________________________________________
_____________________________________________________________________________________ 
_____________________________________________________________________________________
_____________________________________________________________________________________ 
_____________________________________________________________________________________  
_____________________________________________________________________________________
_____________________________________________________________________________________ 
_____________________________________________________________________________________
_____________________________________________________________________________________ 
_____________________________________________________________________________________  

 
 
Secondary HIRREM Screening 
 
Name:   
_________________________  
Date of birth:  _________________________ 
Date screened: _________________________  
Race: 
 
_________________________ 
 
Who is your primary care physician/contact number? 
_____________________________________________________________________________________ 
 
Do you see any  other health care providers regularly or use any integrated/complimentary therapies 
(acupuncture, yoga, massage, healing touch, etc.)? 
_____________________________________________________________________________________ 
_____________________________________________________________________________________ 
 
Please list an emergency contact, the relation, and a phone number. 
_____________________________________________________________________________________ 
 
General questions: 
1. Do you consume alcohol? 
 
 
 
□ Yes 
 
□ No 
a. If so, how much? 
____________________________________________________ 
b. If so, how often? 
____________________________________________________ 
c. If so, what type? 
____________________________________________________ 
2. Do you consume caffeine (coffee, tea, energy drinks, chocolate, etc.)? 
□ Yes 
 
□ No 
a. If so, how much? 
____________________________________________________ 
b. If so, how often? 
____________________________________________________ 
c. If so, what type? 
____________________________________________________ 
3. Are you a: 
 
 
 □ Current smoker 
□ Ex-smoker 
□ Never smoked 
a. If you have ever smoked, how much?  _______________________________________ 
b. If you have ever smoked, how often?  
_______________________________________ 
c. If you have ever smoked, what type? 
_______________________________________ 
4. Do you have a history of addiction (substance abuse, shopping, etc.)? _____________________ 
5. Were you in the military?  
 
 
 
□ Yes 
 
□ No 
 
a. If so, how many deployments/years did you serve?  
__________________________ 
6. Have you ever had any physical or emotional trauma (accidents, head injuries, childhood events, 
traumatic events, bad relationships, abuse)? 
 
□ Yes 
 
□ No 
7. What is your marital status? 
 
 
 
□ Married 
□ Divorced 
□ Single 
 
 
 
 
 
 
 
□  Widowed 
□ Other 
8. Do you have any children? 
 
 
 
□ Yes 
 
□ No 
a. If so, how many and what age?   
_______________________________________ 
b. Have you ever lost a child? 
 
 
□ Yes 
 
□ No 
Sleep 
1. How do you usually sleep?   
 
 
 
________________________________ 

 
 
a. Do you have any trouble falling asleep? □ Yes 
 
□ No 
b. Do you have any trouble staying asleep? 
□ Yes 
 
□ No 
c. Do you wake up rested? 
 
□ Yes 
 
□ No 
 
Headaches/Migraines 
1. Do you have headaches?  
 
 
 
□ Yes 
 
□ No 
d. If so, how many per week/month? 
 
________________________________  
e. If so, how long have you had them? 
 
________________________________ 
f. If so, do you do anything to alleviate them? 
________________________________ 
2. Did headaches occur from a concussion/TBI?  
 
□ Yes 
 
□ No 
3. Do you have migraines?  
 
 
 
□ Yes 
 
□ No 
a. If so, how many per week/month? 
 
________________________________ 
b. If so, how long have you had them? 
 
________________________________ 
c. If so, do you do anything to alleviate them? 
________________________________ 
Concussion/Traumatic brain injury (TBI) 
1. Have you ever had any concussions or TBIs? 
 
□ Yes 
 
□ No 
a. Was there more than one concussion or TBI? 
________________________________ 
b. If so, how many and what kind?  
 
________________________________ 
c. If so, when did it occur/what was the cause? 
________________________________ 
d. If so, did you lose consciousness? 
 
________________________________ 
e. If so, did you have to go to the hospital? 
________________________________ 
f. Were you hospitalized?  If so, for how long? 
________________________________ 
g. Did the injury require brain surgery or drainage of blood or fluid from in or around the 
brain?  
 
h. Have you ever had any other head injuries? 
________________________________ 
PTSD 
1. Do you have post-traumatic stress disorder?  
 
□ Yes 
 
□ No 
2. How long have you had PTSD symptoms? 
 
________________________________ 
3. Have you seen a physician for this? 
 
 
□ Yes 
 
□ No 
4. Do you have a formal diagnosis of PTSD?  
 
□ Yes 
 
□ No 
a. If so, when was the diagnosis made? 
 
________________________________ 
5. If you were in the military, in your opinion, did the traumatic event most responsible for your 
PTSD occur as part of your military service or did it occur as part of civilian life? 
□ Military 
□ Civilian 
a. If military, was it related to a blast injury?  
□ Yes 
 
□ No 
 
ADHD 
1. Do you have difficulty with focus and concentration?  
□ Yes 
 
□ No 
2. How long have you had these symptoms? 
 
________________________________ 
3. Have you seen a physician for this? 
 
 
□ Yes 
 
□ No 
a. Did you have a formal evaluation? 
 
□ Yes 
 
□ No 

 
 
b. Did a physician give you Adderall? 
 
□ Yes 
 
□ No 
4. Do you have a formal diagnosis of ADD/ADHD?   
□ Yes 
 
□ No 
a. If so, when was the diagnosis made? 
 
________________________________ 
 
Hot Flashes 
1. Do you have hot flashes? 
 
 
 
□ Yes 
 
□ No 
a. What is the frequency per day/week? 
 
 ________________________________ 
2. Do they occur during the day, night, or both? 
 
□ Day  
□ Night  
□ Both  
a. How severe are they?  
 
 
□ Mild  
□ Moderate 
 
□ Severe 
□ Very Severe   
 
Key: mild - sensation of heat w/o perspiration 
 
moderate - sensation of heat w/perspiration and able to continue activity 
 
severe - sensation of heat w/sweating causing you to stop activity or disrupting your sleep 
very severe - sensation of heat w/severe sweating, disrupting activity or requiring a change of sheets or clothes 
Comments: 
_____________________________________________________________________________________
_____________________________________________________________________________________
_____________________________________________________________________________________
_____________________________________________________________________________________
_____________________________________________________________________________________  
_____________________________________________________________________________________
_____________________________________________________________________________________
_____________________________________________________________________________________
_____________________________________________________________________________________
_____________________________________________________________________________________