twelve women ( median age , 56 y ; range , 46 - 69 y ; 9 white and 3 african american ) were enrolled in an ongoing , open - label , single - site feasibility study of hirrem for individuals with diverse psychophysiological conditions .
procedures were approved by the wake forest university health sciences institutional review board , and all participants provided a written informed consent form .
hot flash symptoms were reported by all participants and documented by use of a daily hot flash diary .
individuals with a history of known sleep apnea , restless legs / periodic leg movement disorder , seizure disorder , or severe hearing impairment ; a need for ongoing treatment with opiates , benzodiazepines , or antipsychotic medications ; or ongoing use of recreational drugs or alcohol were excluded . after meeting eligibility criteria , each participant completed a pre - hirrem visit for enrollment and data collection , a baseline hirrem assessment , a series of hirrem sessions , and a post - hirrem data collection visit .
procedures for the provision of hirrem have been discussed in detail previously.13 self - reported comorbidities before starting the hirrem sessions , each participant underwent a baseline hirrem assessment , which obtained information regarding brain electrical frequencies and amplitudes .
the baseline assessment consisted of very brief recordings of brainwaves obtained from at least six standard locations on the scalp ( f3/f4 , c3/c4 , p3/p4 , t3/t4 , fz / oz , and o1/o2 ) , with the recipient at rest and carrying out a task .
the assessment includes 1-minute recordings at each location with eyes closed , eyes partially open , and eyes open while performing a specific mental task appropriate for the location ( ie , recalling numbers , reading a passage , etc ) .
this assessment ( 45 min ) allows for identification of the relative balance between homologous brain regions and for the proportionation or distribution of amplitudes among different frequency bands at each location .
hirrem was received as a series of sessions lasting approximately 90 minutes ( range , 54 - 102 min ) , consisting of four to nine individualized protocols , and addressing multiple brain locations and frequencies .
some protocols were performed with eyes closed and some with eyes open , with the participant sitting or reclining comfortably in a chair .
the hirrem sessions were scheduled to maximize frequency and efficiency , with participants generally completing two sessions in half a day separated by a 20- to 30-minute break . because hirrem is a unique , individualized process for each recipient
, the specific protocols and session lengths vary between participants . certified hirrem technologists set session frequency and identified protocols ( a combination of sensor montage and specific software design to address multiple locations and frequency bands during each session ) to facilitate balance and proportionation between and within cortical regions , based on data from the initial assessment or the preceding hirrem sessions , as previously reported.15 during protocols , a proprietary mathematical algorithm selected the specific auditory tone to be reflected back to the participant by identifying the dominant frequency through high - resolution spectral analysis of noninvasively recorded real - time brain electrical activity .
the dominant frequency was translated into an auditory tone and presented bilaterally , simultaneously , to the participant through earphones ( creative ep-630 or sony stereo headphones mdr - ex58v ) with a delay of as little as 8 milliseconds .
the primary outcomes for this analysis included changes in hot flash scores from baseline to post - hirrem and serial values for the sum of high - frequency amplitudes at t3 and t4 .
secondary outcomes included self - report insomnia ( insomnia severity index [ isi ] ) and depression ( center for epidemiological studies  depression scale [ ces - d ] ) questionnaires at baseline and after the hirrem intervention .
hot flash diaries provide a valid and reliable approach to understanding a participant s experience of hot flashes.16 diaries measure the daily frequency ( number of hot flashes ) and severity of each hot flash .
hot flash severity categories are as follows : 1 , mild ; 2 , moderate ; 3 , severe ; 4 , very severe . the hot flash severity score for each day was calculated as the sum of the number of hot flashes within each severity category , multiplied by the severity score for that category , with the resulting sum divided by the total number of hot flashes .
participants were asked to complete a paper - and - pencil hot flash diary for up to 1 week before beginning the hirrem sessions to provide a more accurate reflection of the baseline pattern of hot flashes .
postintervention hot flash scores were derived from the final day of reporting available for each individual participant .
serial values for the sums of high - frequency amplitudes ( 23 - 36 hz ) at t3/t4 ( v ) were evaluated by analysis of 1-minute epochs of brain electrical data recorded during the hirrem assessment at baseline and during the penultimate minute of the first four hirrem sessions and the last four hirrem sessions .
analysis focused on high - frequency amplitudes at the temporal regions ( sum of amplitudes at t3 and t4 ) owing to their proximity to underlying cortical regions implicated in autonomic regulation , with notation of change in values from baseline to the final hirrem session .
the isi is a seven - item survey that assesses the severity , nature , and impact of insomnia symptoms on quality of life in the previous 2 weeks.17 it is scored on a five - point likert scale from 0 ( no problem ) to 4 ( very severe problem ) on a composite score range from 0 to 28 .
composite scores can be stratified into the following clinical severities of insomnia : absent ( 0 - 7 ) , subthreshold ( 8 - 14 ) , moderate ( 15 - 21 ) , and severe ( 22 - 28).18 the internal consistency for isi was 0.74 , and a correlation with sleep diaries was also established.19 the ces - d is a 20-item survey that assesses affective depressive symptoms to screen for risk of depression.20 each question identifies a depressive symptom and is scored on a four - point likert scale from 0 ( rarely ; < 1 d / wk ) to 3 ( most or all of the time ; 5 - 7 d / wk ) .
participants were instructed to respond based on how they have felt during the past week .
the cumulative score ranges from 0 to 60 , with a score of 16 commonly used as a clinically relevant cutoff.21 its internal consistency varies by demographics , with  coefficients between 0.60 and 0.90 and with 3-month test - retest validity higher than 0.60.22,23 continuous blood pressure and heart rate data were acquired from noninvasive finger arterial pressure measurements for a minimum of 5 minutes while participants were in supine position .
systolic blood pressure and r - r interval files ( biopac acquisition software ; biopac systems , santa barbara , ca ) acquired at 1,000 hz were analyzed using nevrokard baroreflex sensitivity software ( medistar , ljubljana , slovenia ) for measures of baroreflex sensitivity ( as low - frequency and high - frequency  indices ; sequence baroreflex sensitivity ) , heart rate variability , and blood pressure variability as power of systolic blood pressure spectra calculated as low - frequency systolic arterial pressure and sd of the mean arterial pressure .
specific heart rate variability measures included the power of r - r interval spectra in low and high frequency ranges , the sd of beat - to - beat r - r interval , and the root mean square of successive beat - to - beat differences in r - r interval duration .
data are summarized as sample frequencies and median / interquartile ranges . changes from baseline to the post - hirrem data collection visit were evaluated using wilcoxon signed rank test . 
spaghetti  plots were used to illustrate longitudinal trajectories for the diary - based hot flash scores during the course of the hirrem intervention.24 all analyses were performed using the r statistical computing environment.25
before starting the hirrem sessions , each participant underwent a baseline hirrem assessment , which obtained information regarding brain electrical frequencies and amplitudes .
the baseline assessment consisted of very brief recordings of brainwaves obtained from at least six standard locations on the scalp ( f3/f4 , c3/c4 , p3/p4 , t3/t4 , fz / oz , and o1/o2 ) , with the recipient at rest and carrying out a task .
the assessment includes 1-minute recordings at each location with eyes closed , eyes partially open , and eyes open while performing a specific mental task appropriate for the location ( ie , recalling numbers , reading a passage , etc ) .
this assessment ( 45 min ) allows for identification of the relative balance between homologous brain regions and for the proportionation or distribution of amplitudes among different frequency bands at each location .
hirrem was received as a series of sessions lasting approximately 90 minutes ( range , 54 - 102 min ) , consisting of four to nine individualized protocols , and addressing multiple brain locations and frequencies .
some protocols were performed with eyes closed and some with eyes open , with the participant sitting or reclining comfortably in a chair .
the hirrem sessions were scheduled to maximize frequency and efficiency , with participants generally completing two sessions in half a day separated by a 20- to 30-minute break . because hirrem is a unique , individualized process for each recipient
, the specific protocols and session lengths vary between participants . certified hirrem technologists set session frequency and identified protocols ( a combination of sensor montage and specific software design to address multiple locations and frequency bands during each session ) to facilitate balance and proportionation between and within cortical regions , based on data from the initial assessment or the preceding hirrem sessions , as previously reported.15 during protocols , a proprietary mathematical algorithm selected the specific auditory tone to be reflected back to the participant by identifying the dominant frequency through high - resolution spectral analysis of noninvasively recorded real - time brain electrical activity .
the dominant frequency was translated into an auditory tone and presented bilaterally , simultaneously , to the participant through earphones ( creative ep-630 or sony stereo headphones mdr - ex58v ) with a delay of as little as 8 milliseconds .
the primary outcomes for this analysis included changes in hot flash scores from baseline to post - hirrem and serial values for the sum of high - frequency amplitudes at t3 and t4 .
secondary outcomes included self - report insomnia ( insomnia severity index [ isi ] ) and depression ( center for epidemiological studies  depression scale [ ces - d ] ) questionnaires at baseline and after the hirrem intervention .
hot flash diaries provide a valid and reliable approach to understanding a participant s experience of hot flashes.16 diaries measure the daily frequency ( number of hot flashes ) and severity of each hot flash .
hot flash severity categories are as follows : 1 , mild ; 2 , moderate ; 3 , severe ; 4 , very severe . the hot flash severity score for each day was calculated as the sum of the number of hot flashes within each severity category , multiplied by the severity score for that category , with the resulting sum divided by the total number of hot flashes .
participants were asked to complete a paper - and - pencil hot flash diary for up to 1 week before beginning the hirrem sessions to provide a more accurate reflection of the baseline pattern of hot flashes .
postintervention hot flash scores were derived from the final day of reporting available for each individual participant .
serial values for the sums of high - frequency amplitudes ( 23 - 36 hz ) at t3/t4 ( v ) were evaluated by analysis of 1-minute epochs of brain electrical data recorded during the hirrem assessment at baseline and during the penultimate minute of the first four hirrem sessions and the last four hirrem sessions .
analysis focused on high - frequency amplitudes at the temporal regions ( sum of amplitudes at t3 and t4 ) owing to their proximity to underlying cortical regions implicated in autonomic regulation , with notation of change in values from baseline to the final hirrem session .
hot flash diaries provide a valid and reliable approach to understanding a participant s experience of hot flashes.16 diaries measure the daily frequency ( number of hot flashes ) and severity of each hot flash .
hot flash severity categories are as follows : 1 , mild ; 2 , moderate ; 3 , severe ; 4 , very severe . the hot flash severity score for each day was calculated as the sum of the number of hot flashes within each severity category , multiplied by the severity score for that category , with the resulting sum divided by the total number of hot flashes .
participants were asked to complete a paper - and - pencil hot flash diary for up to 1 week before beginning the hirrem sessions to provide a more accurate reflection of the baseline pattern of hot flashes .
postintervention hot flash scores were derived from the final day of reporting available for each individual participant .
serial values for the sums of high - frequency amplitudes ( 23 - 36 hz ) at t3/t4 ( v ) were evaluated by analysis of 1-minute epochs of brain electrical data recorded during the hirrem assessment at baseline and during the penultimate minute of the first four hirrem sessions and the last four hirrem sessions .
analysis focused on high - frequency amplitudes at the temporal regions ( sum of amplitudes at t3 and t4 ) owing to their proximity to underlying cortical regions implicated in autonomic regulation , with notation of change in values from baseline to the final hirrem session .
the isi is a seven - item survey that assesses the severity , nature , and impact of insomnia symptoms on quality of life in the previous 2 weeks.17 it is scored on a five - point likert scale from 0 ( no problem ) to 4 ( very severe problem ) on a composite score range from 0 to 28 .
composite scores can be stratified into the following clinical severities of insomnia : absent ( 0 - 7 ) , subthreshold ( 8 - 14 ) , moderate ( 15 - 21 ) , and severe ( 22 - 28).18 the internal consistency for isi was 0.74 , and a correlation with sleep diaries was also established.19 the ces - d is a 20-item survey that assesses affective depressive symptoms to screen for risk of depression.20 each question identifies a depressive symptom and is scored on a four - point likert scale from 0 ( rarely ; < 1 d / wk ) to 3 ( most or all of the time ; 5 - 7 d / wk ) . participants were instructed to respond based on how they have felt during the past week .
the cumulative score ranges from 0 to 60 , with a score of 16 commonly used as a clinically relevant cutoff.21 its internal consistency varies by demographics , with  coefficients between 0.60 and 0.90 and with 3-month test - retest validity higher than 0.60.22,23 continuous blood pressure and heart rate data were acquired from noninvasive finger arterial pressure measurements for a minimum of 5 minutes while participants were in supine position .
systolic blood pressure and r - r interval files ( biopac acquisition software ; biopac systems , santa barbara , ca ) acquired at 1,000 hz were analyzed using nevrokard baroreflex sensitivity software ( medistar , ljubljana , slovenia ) for measures of baroreflex sensitivity ( as low - frequency and high - frequency  indices ; sequence baroreflex sensitivity ) , heart rate variability , and blood pressure variability as power of systolic blood pressure spectra calculated as low - frequency systolic arterial pressure and sd of the mean arterial pressure .
specific heart rate variability measures included the power of r - r interval spectra in low and high frequency ranges , the sd of beat - to - beat r - r interval , and the root mean square of successive beat - to - beat differences in r - r interval duration .
the isi is a seven - item survey that assesses the severity , nature , and impact of insomnia symptoms on quality of life in the previous 2 weeks.17 it is scored on a five - point likert scale from 0 ( no problem ) to 4 ( very severe problem ) on a composite score range from 0 to 28 .
composite scores can be stratified into the following clinical severities of insomnia : absent ( 0 - 7 ) , subthreshold ( 8 - 14 ) , moderate ( 15 - 21 ) , and severe ( 22 - 28).18 the internal consistency for isi was 0.74 , and a correlation with sleep diaries was also established.19
the ces - d is a 20-item survey that assesses affective depressive symptoms to screen for risk of depression.20 each question identifies a depressive symptom and is scored on a four - point likert scale from 0 ( rarely ; < 1 d / wk ) to 3 ( most or all of the time ; 5 - 7 d / wk ) . participants were instructed to respond based on how they have felt during the past week .
the cumulative score ranges from 0 to 60 , with a score of 16 commonly used as a clinically relevant cutoff.21 its internal consistency varies by demographics , with  coefficients between 0.60 and 0.90 and with 3-month test - retest validity higher than 0.60.22,23
continuous blood pressure and heart rate data were acquired from noninvasive finger arterial pressure measurements for a minimum of 5 minutes while participants were in supine position .
systolic blood pressure and r - r interval files ( biopac acquisition software ; biopac systems , santa barbara , ca ) acquired at 1,000 hz were analyzed using nevrokard baroreflex sensitivity software ( medistar , ljubljana , slovenia ) for measures of baroreflex sensitivity ( as low - frequency and high - frequency  indices ; sequence baroreflex sensitivity ) , heart rate variability , and blood pressure variability as power of systolic blood pressure spectra calculated as low - frequency systolic arterial pressure and sd of the mean arterial pressure .
specific heart rate variability measures included the power of r - r interval spectra in low and high frequency ranges , the sd of beat - to - beat r - r interval , and the root mean square of successive beat - to - beat differences in r - r interval duration .
changes from baseline to the post - hirrem data collection visit were evaluated using wilcoxon signed rank test . 
spaghetti  plots were used to illustrate longitudinal trajectories for the diary - based hot flash scores during the course of the hirrem intervention.24 all analyses were performed using the r statistical computing environment.25
participants had a median of 13 ( range , 8 - 23 ) hirrem sessions ( 90 min each ) administered for a median of 9.5 days ( range , 4 - 32 d ) .
all participants returned for a follow - up data collection visit at a median of 10 days ( range , 0 - 20 d ) after completion of their final hirrem session .
participants maintained the hot flash diary for a median of 3.5 days ( range , 1 - 11 d ) before starting the hirrem sessions .
the median change in hot flash severity score was 0.97 ( range , 3.00 to 1.00 ; p = 0.015 ) .
figure 1a , b illustrates changes in hot flash severity score for each individual participant during the period of her diary recordings .
general inspection shows that much of the benefits associated with hirrem accrued quickly , within the first 7 days of the beginning of the intervention .
changes in hot flash ( hf ) severity scores across time as a percentage of baseline score for the entire cohort ( a ) and with focus on the 0% to 150% range that included most participants ( b ) .
the x axis indicates the number of days since the start of high - resolution , relational , resonance - based , electroencephalic mirroring ( hirrem ) sessions .
the median total t3/t4 high - frequency amplitude was 8.44 v ( range , 6.27 - 16.66 v ) at baseline , decreasing by a median of 2.96 v ( range , 11.05 to 0.65 ; p = 0.0005 ) by the final hirrem session .
figure 2a , b provides an example ( from one study participant ) of the type of changes generally seen in high - frequency amplitudes , with initially high amplitudes in high - frequency ranges ( fig .
a , b : fast fourier transform spectral display of electroencephalic data with frequency ( hz ; central y axis ) plotted against transformed amplitude ( v ; x axis ) .
data represent 1 minute of data from the t3/t4 montage with eyes closed at baseline assessment ( a ) and at the penultimate minute of the final session ( b ) for one participant ( a woman aged 47 y ) .
note the change in amplitudes in the range 23 to 36 hz ( dark purple ) outlined by red boxes .
symptom scales for insomnia and depression saw a decrease in median scores post - hirrem . at baseline
, participants had a median isi score of 16 ( range , 4 - 27 ) and a median decrease of 8.5 ( range , 20 to 1 ; p = 0.022 ) .
ten of 12 participants reported at least subthreshold insomnia ( isi score 8 ) at baseline .
eight of these 10 participants reported no insomnia post - hirrem ( table 2 ) .
changes in clinical category for insomnia after hirrem , by isi score baseline ces - d scores showed a median value of 14 ( range , 3 - 36 ) with a median change of 5.5 ( range , 32 to 8 ; p = 0.015 ) .
six of 12 participants reported clinically relevant depressive symptoms ( ces - d score 16 ) at baseline .
four of these six participants reported depressive symptoms below the clinically relevant threshold post - hirrem .
one participant who reported subthreshold depressive symptoms at baseline ( ces - d score , 11 ) indicated clinically relevant symptoms of depression after the intervention ( ces - d score , 19 ) .
in this open - label study , use of hirrem by perimenopausal and postmenopausal women was associated , on average , with significant reductions in hot flash frequency and severity , decreased symptoms of insomnia and depression , and decreased amplitudes in the high - frequency range of brain electrical activity , as measured from bilateral temporal scalp recordings .
interpretation of our findings is limited by the sample size of the study , the absence of a control group , and the lack of long - term follow - up .
a current model for the genesis of vasomotor symptoms focuses on changes in the thermoregulatory neutral zone , as defined by the hypothalamus.26 in this model , vasomotor symptoms result from a narrowing between the upper limits and the lower limits of body temperature , producing sweating and shivering , respectively .
narrowing of the thermoregulatory neutral zone is in turn explained as a consequence of the changing rhythms of ovarian steroid circulation and their influence on neurotransmitter activity in the hypothalamus , serotonergic system , and noradrenergic system.12 noradrenergic systems are demonstrated to contribute to hot flashes .
injection of yohimbine , an 2 antagonist that increases norepinephrine availability , produces increased vasomotor symptoms.27 in contrast , noradrenergic reuptake inhibitors have been shown to be efficacious for reducing vasomotor symptoms , suggesting that  restoring  norepinephrine levels is a way to stabilize thermoregulatory mechanisms.11 these divergent effects seem to be further confirmation of the  brain adaptation  model for menopausal symptoms in that the role of brain norepinephrine in vasomotor symptoms may lie not on its absolute excess or deficiency but on irregular fluctuations in the dynamics of its availability and activity .
hirrem helps the brain to self - optimize activity patterns toward more flexibly adaptive and recipient - unique set points , in contrast to pharmacological agents that stabilize the brain by clamping neurotransmitters at relatively fixed activity levels .
the findings from this study are consistent with the idea that hirrem may support symptom reduction by facilitating shifts in brain electrical activity patterns toward adaptively lower amplitudes in the high - frequency range . increased amplitudes in the high - frequency range of brain electrical activity
are observed not only in menopause14 but also in insomnia.28 we did not find changes in autonomic cardiovascular control , although such changes may be more reliably detected by recording autonomic activity in direct association with a hot flash event , as has been performed by others.29 the speed with which clinical changes were reported by study participants stands in contrast with other studies of relaxation techniques , in which benefits were typically not measured or demonstrated for at least 4 weeks after the start of the intervention.7 the rapidity of benefits in the current study was similar to our observations in a clinical trial of hirrem for individuals with insomnia13 and , preliminarily , may offer further evidence that self - optimization of brain activity at the cortex could be a viable  upstream  approach to achieving health objectives .
the current feasibility results do not allow for an evaluation of the duration of effects .
prior studies showed a persistent reduction in symptoms of insomnia at 1 month after hirrem completion13 and a clinically relevant reduction in probability of headache at 2 months after hirrem completion in a cohort with episodic migraine.30 future controlled trials should include a delay in collection of primary outcomes to allow for resolution of placebo effect and to assess duration of benefits .
recent null findings from studies of  alternative  techniques for reducing menopausal symptoms have led to a sense of frustration.31 the data from this exploratory study suggest that hirrem merits further study in controlled trials with longer follow - up to support the brain adaptation process undergone by women in menopause .
 abstractobjectiveincreased amplitudes in high - frequency brain electrical activity are reported with menopausal hot flashes . 
 we report outcomes associated with the use of high - resolution , relational , resonance - based , electroencephalic mirroring  a noninvasive neurotechnology for autocalibration of neural oscillations  by women with perimenopausal and postmenopausal hot flashes.methodstwelve women with hot flashes ( median age , 56 y ; range , 46 - 69 y ) underwent a median of 13 ( range , 8 - 23 ) intervention sessions for a median of 9.5 days ( range , 4 - 32 ) . 
 this intervention uses algorithmic analysis of brain electrical activity and near real - time translation of brain frequencies into variable tones for acoustic stimulation . 
 hot flash frequency and severity were recorded by daily diary . 
 primary outcomes included hot flash severity score , sleep , and depressive symptoms . 
 high - frequency amplitudes ( 23 - 36 hz ) from bilateral temporal scalp recordings were measured at baseline and during serial sessions . 
 self - reported symptom inventories for sleep and depressive symptoms were collected.resultsthe median change in hot flash severity score was 0.97 ( range , 3.00 to 1.00 ; p = 0.015 ) . sleep and depression scores decreased by 8.5 points ( range , 20 to 1 ; p = 0.022 ) and 5.5 points ( range , 32 to 8 ; p = 0.015 ) , respectively . 
 the median sum of amplitudes for the right and left temporal high - frequency brain electrical activity was 8.44 v ( range , 6.27 - 16.66 ) at baseline and decreased by a median of 2.96 v ( range , 11.05 to 0.65 ; p = 0.0005 ) by the final session.conclusionshot flash frequency and severity , symptoms of insomnia and depression , and temporal high - frequency brain electrical activity decrease after high - resolution , relational , resonance - based , electroencephalic mirroring . 
 larger controlled trials with longer follow - up are warranted . 
METHODS
HIRREM process
Primary outcome measures
Hot flash diaries
High-frequency amplitudes
Secondary outcome measures
Insomnia Severity Index
Center for Epidemiological StudiesDepression Scale
Autonomic cardiovascular control
Statistical analysis
RESULTS
DISCUSSION
CONCLUSIONS