Randomized, controlled clinical trial of acoustic stimulation to reduce postconcussive symptoms.

OBJECTIVE: Effective interventions are needed to address postconcussive symptoms. We report the results of randomized, sham-controlled trial of Cereset Research™ Standard Operating Procedures (CR-SOP), a noninvasive, closed-loop, allostatic, acoustic stimulation neurotechnology previously shown to improve insomnia. METHODS: Military service members, veterans, or their spouses with persistent symptoms (Neurobehavioral Symptom Inventory [NSI] Score ≥23) after mTBI 3 months to 10 years ago, were randomized to receive 10 sessions of engineered tones linked to brainwaves (LB, intervention), or random engineered tones not linked to brainwaves (NL, sham control). The primary outcome was change in NSI, with secondary outcomes of heart rate variability and self-report measures of sleep, mood, and anxiety. RESULTS: Participants (n = 106, 22% female, mean age 37.1, 2.8 deployments, 3.8 TBIs) were randomized 1:1 to LB or NL, with no significant differences between groups at baseline. Among all study participants, the NSI declined from baseline 41.0 to 27.2 after (P < 0.0001), with gains largely sustained at 3 months (31.2) and 6 months (28.4). However, there were no significant differences between the LB (NSI declined from 39.9 at baseline to 28.2 post-intervention, 31.5 at 3 months, and 29.4 at 6 months) and NL (NSI declined from 41.5 at baseline to 26.2, 29.9, and 27.3, respectively. Similar patterns were observed for the PCL5 and PHQ-9 and there was no difference in HRV between groups. INTERPRETATION: Ten hours of acoustic stimulation while resting in a zero-gravity chair improves postconcussive symptoms. However, linking tones to brain electrical activity did not reduce symptoms more than random tones. REGISTRATION: ClinicalTrials.gov - NCT03649958.

Cereset Research Standard Operating Procedures for Insomnia: A Randomized, Controlled Clinical Trial.

Background: Interventions for insomnia that also address autonomic dysfunction are needed. Objective: We evaluate Cereset Research™ Standard Operating Procedures (CR-SOP) in a pilot randomized, controlled trial. CR-SOP is a less operator-dependent, more generalizable innovation of HIRREM®, a noninvasive, closed-loop, allostatic, acoustic stimulation neurotechnology demonstrated to improve insomnia and autonomic function. Methods: Adults with Insomnia Severity Index (ISI) scores of ≥8 were randomized to receive ten sessions of CR-SOP, with tones linked to brainwaves (LB, intervention), or a sham condition of random tones not linked to brainwaves (NL, control). Measures were collected at enrollment and 0-14 days and 4-6 weeks post-allocated intervention. The primary outcome was differential change in ISI from baseline to 4-6 weeks post-intervention. Secondary self-report measures assessed sleep quality65 and behavioral outcomes. Ten-minute recordings of heart rate and blood pressure were collected to analyze autonomic function (heart rate variability [HRV] and baroreflex sensitivity). Results: Of 22 randomized, 20 participants completed the allocated condition. Intention to treat analysis of change from baseline to the 4-6 week outcome demonstrated mean ISI score reduction of 4.69 points among controls (SE 1.40). In the intervention group, there was an additional 2.58 point reduction in ISI score (SE 2.13; total reduction of 7.27, P = .24). Sleep quality and some measures of autonomic function improved significantly among the intervention group compared to control. Conclusions: This pilot study compared use of a standardized, allostatic, acoustic neurotechnology intervention with a sham, active control condition. The magnitude of change in insomnia severity was clinically relevant and similar to the findings in a prior, fully powered trial, but the differential improvement observed was not statistically significant. Significant improvements were demonstrated in sleep quality and some autonomic function measures.

Rapid Implementation of Outpatient Teleneurology in Rural Appalachia: Barriers and Disparities.

OBJECTIVE: To describe rapid implementation of telehealth during the COVID-19 pandemic and assess for disparities in video visit implementation in the Appalachian region of the United States. METHODS: A retrospective cohort of consecutive patients seen in the first 4 weeks of telehealth implementation was identified from the Neurology Ambulatory Practice at a large academic medical center. Telehealth visits defaulted to video, and when unable, phone-only visits were scheduled. Patients were divided into 2 groups based on the telehealth visit type: video or phone only. Clinical variables were collected from the electronic medical record including age, sex, race, insurance status, indication for visit, and rural-urban status. Barriers to scheduling video visits were collected at the time of scheduling. Patient satisfaction was obtained by structured postvisit telephone call. RESULTS: Of 1,011 telehealth patient visits, 44% were video and 56% phone only. Patients who completed a video visit were younger (39.7 vs 48.4 years, p < 0.001), more likely to be female (63% vs 55%, p < 0.007), be White or Caucasian (p = 0.024), and not have Medicare or Medicaid insurance (p < 0.001). The most common barrier to scheduling video visits was technology limitations (46%). Although patients from rural and urban communities were equally likely to be scheduled for video visits, patients from rural communities were more likely to consider future telehealth visits (55% vs 42%, p = 0.05). CONCLUSION: Rapid implementation of ambulatory telemedicine defaulting to video visits successfully expanded video telehealth. Emerging disparities were revealed, as older, male, Black patients with Medicare or Medicaid insurance were less likely to complete video visits.

Continuous updating of individual headache forecasting models using Bayesian methods.

OBJECTIVE: To illustrate the benefits of deploying individual headache forecasting models using continuous updating with Bayesian methods. BACKGROUND: The ability to reliably forecast headache attacks within an individual over time would enhance the study of attacks and allow preemptive treatment. However, deploying a suitable forecasting model in a clinical setting will likely involve several unique challenges related to heterogeneity in the predictor weights, limited or sparse data, and the need for a quick "warm-up." The use of Bayesian methods offers solutions to each of these specific challenges. METHODS: This was a post hoc analysis of a cohort study of individuals with episodic migraine attacks. Individuals completed daily diaries that allowed the estimation of several forecasting models, each using different types of ancillary information incorporated into formal prior probability distributions. An in silico analysis was conducted that mimicked the deployment of these models in a clinical-like setting where the parameters of the models were continuously updated and evaluated each day using root mean square error (RMSE). RESULTS: Individuals (N = 95) were followed for 50 days and contributed 3359 days of nonmissing diary data. During the observation period, there were 1293/3359 (38.5%) days with a headache attack. Self-reported baseline headache frequency was associated with the corresponding predicted probability of future attacks, r = 0.15-0.39. At Day 25, the correlation between baseline information and predicted attack likelihood was r = 0.29 (95% CI: 0.09-0.47). Additionally, the use of prior probability distributions for model parameters improved the model fit, especially early in the deployment of the models (e.g., Day 5 RMSE 0.45 vs. 0.43). Models using informative prior probability distributions outperformed the models estimated without this information during the first 42 days of observation, although performance became more similar as more data were collected. CONCLUSIONS: This analysis demonstrates the value of Bayesian methods in using additional available information to improve forecasting model performance, especially early in the deployment of a forecasting model. To obtain the full value of such models or to apply any model in clinical settings, a model with adequate discrimination and calibration will be needed.

Effects of an Allostatic Closed-Loop Neurotechnology (HIRREM) on Brain Functional Connectivity Laterality in Military-Related Traumatic Stress.

BACKGROUND AND PURPOSE: Brain asymmetries are reported in posttraumatic stress disorder, but many aspects of laterality and traumatic stress remain underexplored. This study explores lateralization changes in resting state brain network functional connectivity in a cohort with symptoms of military-related traumatic stress, associated with use of a closed-loop neurotechnology, HIRREM. METHODS: Eighteen participants (17 males, mean age 41 years [SD = 7]) received 19.5 (1.1) HIRREM sessions over 12 days. Whole brain resting magnetic resonance imaging was done pre- and post-HIRREM. Laterality of functional connectivity was assessed on a whole brain basis, and in six predefined networks or regions. Laterality of connectivity within networks or regions was assessed separately from laterality of connections between networks or regions. RESULTS: Before HIRREM, significant laterality effects of connection type (ipsilateral for either side, or contralateral in either direction) were observed for the whole brain, within networks or regions, and between networks or regions. Post-HIRREM, there were significant changes for within-network or within-region analysis in the motor network, and changes for between-network or between-region analyses for the salience network and the motor cortex. CONCLUSIONS: Among military service members and Veterans with symptoms of traumatic stress, asymmetries of network and brain region connectivity patterns were identified prior to usage of HIRREM. A variety of changes in lateralized patterns of brain connectivity were identified postintervention. These laterality findings may inform future studies of brain connectivity in traumatic stress disorders, with potential to point to mechanisms of action for successful intervention.

High-resolution, relational, resonance-based, electroencephalic mirroring (HIRREM) improves symptoms and autonomic function for insomnia: A randomized, placebo-controlled clinical trial.

INTRODUCTION: Effective insomnia interventions that also address autonomic dysregulation are lacking. We evaluate high-resolution, relational, resonance-based, electroencephalic mirroring (HIRREM® ), in a randomized, controlled clinical trial. HIRREM is a noninvasive, closed-loop, allostatic, acoustic stimulation neurotechnology, to support self-optimization of brain rhythms. METHODS: One hundred and seven adults (mean age 45.7, SD ± 5.6, 73 women), with Insomnia Severity Index (ISI) scores of ≥15, received ten, 90-min sessions of HIRREM, with tones linked to brainwaves (LB, 56), or random tones not linked to brainwaves (NL, 51), as an active, sham placebo. Outcomes were obtained at enrollment (V1), 1-7 days (V2), 8-10 weeks (V3), and 16-18 weeks (V4) after intervention. Primary outcome was differential change in ISI from V1 to V3. Secondary measures assessed depression (BDI), anxiety (BAI), quality of life (EQ-5D), and a sleep diary. Ten minute recordings of HR and BP allowed analysis of heart rate variability (HRV) and baroreflex sensitivity (BRS). RESULTS: Of 107 randomized, 101 completed the intervention. Intention-to-treat analysis (107) of change from V1 to V3 revealed a mean reduction of ISI in NL of -4.93 (SE ± 0.76) points, with additional, significant reduction of -2.05 points (0.74) in LB (total reduction of -6.98, p = .045). Additional reduction of -2.30 points (0.76) was still present in the LB at V4 (p = .058). Total ISI reduction from V1 to V4 was -5.90 points for NL and -7.93 points in LB. There were group differences (p < .05) for multiple HRV and BRS measures (rMSSD, SDNN, HF alpha, and Seq ALL), as well as total sleep time, sleep onset latency, and sleep efficiency. There were no serious adverse events. CONCLUSIONS: Results of this controlled clinical trial showed clinically relevant reduction of insomnia symptoms with HIRREM, over, and above an active, sham control, with associated, durable improvement in autonomic cardiovascular regulation.

Pilot Trial of a Noninvasive Closed-Loop Neurotechnology for Stress-Related Symptoms in Law Enforcement: Improvements in Self-Reported Symptoms and Autonomic Function.

BACKGROUND: Law enforcement officers have decreased life expectancy, attributed to work-related exposure to traumatic stress and circadian disruption. Autonomic dysregulation is reported with traumatic stress and chronic insomnia. OBJECTIVE: We explore potential benefits for reduced symptoms related to stress and insomnia and improved autonomic function associated with open label use of high-resolution, relational, resonance-based, electroencephalic mirroring (HIRREM®), in a cohort of sworn law enforcement personnel. METHODS: Closed-loop noninvasive therapies utilizing real-time monitoring offer a patient-centric approach for brain-based intervention. HIRREM® is a noninvasive, closed-loop, allostatic, neurotechnology that echoes specific brain frequencies in real time as audible tones to support self-optimization of brain rhythms. Self-report symptom inventories done before and after HIRREM included insomnia (ISI), depression (CES-D), traumatic stress (PCL-C), anxiety (GAD-7), perceived stress (PSS), and quality of life (EQ-5D). Ten-minute recordings of heart rate and blood pressure allowed analysis of baroreflex sensitivity (BRS) and heart rate variability (HRV). RESULTS: Fifteen participants (1 female), mean (SD) age 45.7 (5.6), received 12.2 (2.7) HIRREM sessions, over 7.9 in-office days. Data were collected at baseline, and at 22.8 (9.2), and 67.2 (14.1) days after intervention. All symptom inventories improved significantly (P < .01), with durability for 2 months after completion of the intervention. The use of HIRREM was also associated with significant increases (P < .001) in HRV measured as rMSSD and BRS measured by high-frequency alpha index. There were no serious adverse events or drop outs. CONCLUSION: These pilot data provide the first report of significant symptom reductions, and associated improvement in measures of autonomic cardiovascular regulation, with the use of HIRREM in a cohort of law enforcement personnel. Randomized clinical trials are warranted.

Functional Brain Network Changes Following Use of an Allostatic, Closed-Loop, Acoustic Stimulation Neurotechnology for Military-Related Traumatic Stress.

BACKGROUND AND PURPOSE: Post-traumatic stress disorder is associated with connectivity changes in the default mode, central executive, and salience networks, and other brain regions. This study evaluated changes in network connectivity associated with usage of High-resolution, relational, resonance-based electroencephalic mirroring (HIRREM® ; Brain State Technologies, Scottsdale, AZ), a closed-loop, allostatic, acoustic stimulation neurotechnology, for military-related traumatic stress. METHODS: Eighteen participants (17 males, mean age 41 years [SD = 7], 15 active duty) enrolled in an IRB approved pilot trial for symptoms of military-related traumatic stress. Participants received 19.5 (1.1) HIRREM sessions over 12 days. Symptoms, physiological and functional measures, and whole brain resting MRI were collected before and after HIRREM. Six whole brain functional networks were evaluated using summary variables and community structure of predefined networks. Pre to postintervention change was analyzed using paired-sample statistical tests. RESULTS: Postintervention, there was an overall increase in connectivity of the default mode network (P = .0094). There were decreases of community structure in both the anterior portion of the default mode (medial prefrontal cortex, P = .0097) and in the sensorimotor (P = .005) network. There were no statistically significant changes at the whole brain level, or in the central executive, salience, or other networks analyzed. Participants demonstrated significant improvements in clinical symptoms, as well as autonomic cardiovascular regulation, which have been reported previously. CONCLUSIONS: Use of closed-loop, allostatic, acoustic stimulation neurotechnology (HIRREM) was associated with connectivity changes in the default mode and sensorimotor networks, in directions that may have explained the subjects' clinical improvements.

Improvements in Heart Rate Variability, Baroreflex Sensitivity, and Sleep After Use of Closed-Loop Allostatic Neurotechnology by a Heterogeneous Cohort.

BACKGROUND: Heart rate variability (HRV) is an indicator of dynamic adaptability of the autonomic nervous system. Few interventions target upstream, cerebral cortex components of the heart-brain system for autonomic management. We report changes in HRV and baroreflex sensitivity (BRS), associated with use of a noninvasive, closed-loop, allostatic, computer-guided, acoustic stimulation neurotechnology. METHODS: Over 5 years, 220 subjects with heterogeneous neurological, cardiovascular, and psychophysiological conditions consecutively enrolled in a naturalistic, single-arm study exploring clinical effects associated with use of the neurotechnology. Of those, 202 completed the study protocol and 160 had recordings adequate to analyze HRV and BRS. Mean age was 44.0 (SD 19.4), with 130 women. Participants received a mean of 16.1 (5.2) sessions, over 24.2 days (23.3), with 9.5 (3.8) actual intervention days. Sessions included real-time analysis of brain electrical activity and software algorithm-guided translation of selected frequencies into patterns of acoustic stimulation (audible tones of variable pitch and timing), to facilitate auto-calibration of neural oscillations. Outcomes including 10-min supine, at-rest recordings of blood pressure and heart rate, and inventories for insomnia (ISI) and depression (CES-D or BDI-II), were obtained at baseline and 15.3 (16.7) days after the last session. RESULTS: Compared to baseline, significant increases (all p < 0.001) were observed for measures of HRV across all participants including the mean percentage change for SDNN 24.2% (SE 0.04), and RMSSD, 42.2% (0.08), and BRS [Sequence Up, 55.5% (0.09), Sequence Down, 77.6% (0.23), and Sequence All, 53.7% (0.07)]. Significant improvements were noted in SAP, MAP, and DAP, as well as natural log of HF, and total power. Self-reported ISI was reduced (ISI, -6.4 points, SD 5.6, p < 0.001). The proportion reporting clinically significant depressive symptoms reduced from 48.2% at baseline to 22.1% at follow-up. Linear regression showed that rightward asymmetry predicted lower SDNN (p = 0.02). Exploratory analysis showed a trend for improved balance of temporal lobe high-frequency amplitudes over the course of initial sessions. CONCLUSION: These findings indicate that use of a noninvasive, allostatic, closed-loop neurotechnology appears to have robust potential for public health efforts to support greater flexibility in autonomic cardiovascular regulation, through self-optimization of electrical activity at the level of the brain.

Forecasting Individual Headache Attacks Using Perceived Stress: Development of a Multivariable Prediction Model for Persons With Episodic Migraine.

OBJECTIVE: To develop and validate a prediction model that forecasts future migraine attacks for an individual headache sufferer. BACKGROUND: Many headache patients and physicians believe that precipitants of headache can be identified and avoided or managed to reduce the frequency of headache attacks. Of the numerous candidate triggers, perceived stress has received considerable attention for its association with the onset of headache in episodic and chronic headache sufferers. However, no evidence is available to support forecasting headache attacks within individuals using any of the candidate headache triggers. METHODS: This longitudinal cohort with forecasting model development study enrolled 100 participants with episodic migraine with or without aura, and N = 95 contributed 4626 days of electronic diary data and were included in the analysis. Individual headache forecasts were derived from current headache state and current levels of stress using several aspects of the Daily Stress Inventory, a measure of daily hassles that is completed at the end of each day. The primary outcome measure was the presence/absence of any headache attack (head pain > 0 on a numerical rating scale of 0-10) over the next 24 h period. RESULTS: After removing missing data (n = 431 days), participants in the study experienced a headache attack on 1613/4195 (38.5%) days. A generalized linear mixed-effects forecast model using either the frequency of stressful events or the perceived intensity of these events fit the data well. This simple forecasting model possessed promising predictive utility with an AUC of 0.73 (95% CI 0.71-0.75) in the training sample and an AUC of 0.65 (95% CI 0.6-0.67) in a leave-one-out validation sample. This forecasting model had a Brier score of 0.202 and possessed good calibration between forecasted probabilities and observed frequencies but had only low levels of resolution (ie, sharpness). CONCLUSIONS: This study demonstrates that future headache attacks can be forecasted for a diverse group of individuals over time. Future work will enhance prediction through improvements in the assessment of stress as well as the development of other candidate domains to use in the models.

Clinical, hemispheric, and autonomic changes associated with use of closed-loop, allostatic neurotechnology by a case series of individuals with self-reported symptoms of post-traumatic stress.

BACKGROUND: The objective of this pilot study was to explore the use of a closed-loop, allostatic, acoustic stimulation neurotechnology for individuals with self-reported symptoms of post-traumatic stress, as a potential means to impact symptomatology, temporal lobe high frequency asymmetry, heart rate variability (HRV), and baroreflex sensitivity (BRS). METHODS: From a cohort of individuals participating in a naturalistic study to evaluate use of allostatic neurotechnology for diverse clinical conditions, a subset was identified who reported high scores on the Posttraumatic Stress Disorder Checklist (PCL). The intervention entailed a series of sessions wherein brain electrical activity was monitored noninvasively at high spectral resolutions, with software algorithms translating selected brain frequencies into acoustic stimuli (audible tones) that were delivered back to the user in real time, to support auto-calibration of neural oscillations. Participants completed symptom inventories before and after the intervention, and a subset underwent short-term blood pressure recordings for HRV and BRS. Changes in temporal lobe high frequency asymmetry were analyzed from baseline assessment through the first four sessions, and for the last four sessions. RESULTS: Nineteen individuals (mean age 47, 11 women) were enrolled, and the majority also reported symptom scores that exceeded inventory thresholds for depression. They undertook a median of 16 sessions over 16.5 days, and 18 completed the number of sessions recommended. After the intervention, 89% of the completers reported clinically significant decreases in post-traumatic stress symptoms, indicated by a change of at least 10 points on the PCL. At a group level, individuals with either rightward (n = 7) or leftward (n = 7) dominant baseline asymmetry in temporal lobe high frequency (23-36 Hz) activity demonstrated statistically significant reductions in their asymmetry scores over the course of their first four sessions. For 12 individuals who underwent short-term blood pressure recordings, there were statistically significant increases in HRV in the time domain and BRS (Sequence Up). There were no adverse events. CONCLUSION: Closed-loop, allostatic neurotechnology for auto-calibration of neural oscillations appears promising as an innovative therapeutic strategy for individuals with symptoms of post-traumatic stress. TRIALS REGISTRATION: ClinicalTrials.gov #NCT02709369 , retrospectively registered on March 4, 2016.

Successful use of closed-loop allostatic neurotechnology for post-traumatic stress symptoms in military personnel: self-reported and autonomic improvements.

BACKGROUND: Military-related post-traumatic stress (PTS) is associated with numerous symptom clusters and diminished autonomic cardiovascular regulation. High-resolution, relational, resonance-based, electroencephalic mirroring (HIRREM®) is a noninvasive, closed-loop, allostatic, acoustic stimulation neurotechnology that produces real-time translation of dominant brain frequencies into audible tones of variable pitch and timing to support the auto-calibration of neural oscillations. We report clinical, autonomic, and functional effects after the use of HIRREM® for symptoms of military-related PTS. METHODS: Eighteen service members or recent veterans (15 active-duty, 3 veterans, most from special operations, 1 female), with a mean age of 40.9 (SD = 6.9) years and symptoms of PTS lasting from 1 to 25 years, undertook 19.5 (SD = 1.1) sessions over 12 days. Inventories for symptoms of PTS (Posttraumatic Stress Disorder Checklist - Military version, PCL-M), insomnia (Insomnia Severity Index, ISI), depression (Center for Epidemiologic Studies Depression Scale, CES-D), and anxiety (Generalized Anxiety Disorder 7-item scale, GAD-7) were collected before (Visit 1, V1), immediately after (Visit 2, V2), and at 1 month (Visit 3, V3), 3 (Visit 4, V4), and 6 (Visit 5, V5) months after intervention completion. Other measures only taken at V1 and V2 included blood pressure and heart rate recordings to analyze heart rate variability (HRV) and baroreflex sensitivity (BRS), functional performance (reaction and grip strength) testing, blood and saliva for biomarkers of stress and inflammation, and blood for epigenetic testing. Paired t-tests, Wilcoxon signed-rank tests, and a repeated-measures ANOVA were performed. RESULTS: Clinically relevant, significant reductions in all symptom scores were observed at V2, with durability through V5. There were significant improvements in multiple measures of HRV and BRS [Standard deviation of the normal beat to normal beat interval (SDNN), root mean square of the successive differences (rMSSD), high frequency (HF), low frequency (LF), and total power, HF alpha, sequence all, and systolic, diastolic and mean arterial pressure] as well as reaction testing. Trends were seen for improved grip strength and a reduction in C-Reactive Protein (CRP), Angiotensin II to Angiotensin 1-7 ratio and Interleukin-10, with no change in DNA n-methylation. There were no dropouts or adverse events reported. CONCLUSIONS: Service members or veterans showed reductions in symptomatology of PTS, insomnia, depressive mood, and anxiety that were durable through 6 months after the use of a closed-loop allostatic neurotechnology for the auto-calibration of neural oscillations. This study is the first to report increased HRV or BRS after the use of an intervention for service members or veterans with PTS. Ongoing investigations are strongly warranted. TRIAL REGISTRATION: NCT03230890 , retrospectively registered July 25, 2017.

A Preliminary Study of the Effectiveness of an Allostatic, Closed-Loop, Acoustic Stimulation Neurotechnology in the Treatment of Athletes with Persisting Post-concussion Symptoms.

BACKGROUND: Effective interventions are needed for individuals with persisting post-concussion symptoms. High-resolution, relational, resonance-based, electroencephalic mirroring (HIRREM®) is an allostatic, closed-loop, acoustic stimulation neurotechnology, designed to facilitate relaxation and self-optimization of neural oscillations. METHODS: Fifteen athletes (seven females, mean age 18.1 years, SD 2.6) with persisting post-concussion symptoms received 18.7 (SD 6.0) HIRREM sessions over a mean of 29.6 (SD 23.2) days, including 11.3 (SD 4.6) in office days. Pre- and post-HIRREM measures included the Rivermead Post-Concussion Symptoms Questionnaire (RPQ, n = 12), the Insomnia Severity Index (ISI, n = 15), the Center for Epidemiologic Studies Depression Scale (CES-D, n = 10), short-term blood pressure and heart rate recordings for measures of autonomic cardiovascular regulation (n = 15), and reaction time by the drop-stick method (n = 7). All participants were asked about their physical activity level and sports participation status at their post-HIRREM data collection visit and 1 to 3 months afterward. RESULTS: At the post-HIRREM visit, subjects reported improvements in all three inventories (RPQ mean change 19.7, SD 11.4, Wilcoxon p = 0.001; ISI mean change -4.1, SD 4.1, Wilcoxon p = 0.003; CES-D mean change -12.0, SD 10.0, Wilcoxon p = 0.004), including statistically significant reductions in 14 of the 16 individual items of the RPQ. There were also statistically significant improvements in baroreflex sensitivity, heart rate variability in the time domain (SDNN), and drop-stick reaction testing (baseline mean distance of 23.8 cm, SD 5.6, decreased to 19.8 cm, SD 4.6, Wilcoxon p = 0.016). Within 3 months of the post-HIRREM data collection, all 15 had returned to full exercise and workouts, and ten had returned to full participation in their athletic activity. CONCLUSIONS: The use of HIRREM by a series of athletes with persisting post-concussion symptoms was associated with a range of improvements including, for the majority, return to full participation in their sport. The findings do not appear to be consistent with constituents of the placebo effect. A larger controlled trial is warranted.

Carotid Intima-media Thickness Measurements: Relations with Atherosclerosis, Risk of Cardiovascular Disease and Application in Randomized Controlled Trials.

Advances in the field of carotid ultrasound have been incremental, resulting in a steady decrease in measurement variability. Improvements in edge detection algorithms point toward increasing automation of CIMT measurements. The major advantage of CIMT is that it is completely noninvasive and can be repeated as often as required. It provides a continuous measure since all subjects have a measurable carotid wall. It is also relatively inexpensive to perform, and the technology is widely available. A graded relation between raising LDL cholesterol and increased CIMT is apparent. Increased CIMT has been shown consistently to relate the atherosclerotic abnormalities elsewhere in the arterial system. Moreover, increased CIMT predicts future vascular events in both populations from Caucasian ancestry and those from Asian ancestry. Furthermore, lipid­lowering therapy has been shown to affect CIMT progression within 12­18 months in properly designed trials with results congruent with clinical events trials. In conclusion, when one wants to evaluate the effect of a pharmaceutical intervention that is to be expected to beneficially affect atherosclerosis progression and to reduce CV event risk, the use of CIMT measurements over time is a valid, suitable, and evidence­based choice.

Use of an allostatic neurotechnology by adolescents with postural orthostatic tachycardia syndrome (POTS) is associated with improvements in heart rate variability and changes in temporal lobe electrical activity.

Autonomic dysregulation and heterogeneous symptoms characterize postural orthostatic tachycardia syndrome (POTS). This study evaluated the effect of high-resolution, relational, resonance-based, electroencephalic mirroring (HIRREM(®)), a noninvasive, allostatic neurotechnology for relaxation and auto-calibration of neural oscillations, on heart rate variability, brain asymmetry, and autonomic symptoms, in adolescents with POTS. Seven subjects with POTS (three males, ages 15-18) underwent a median of 14 (10-16) HIRREM sessions over 13 (8-17) days. Autonomic function was assessed from 10-min continuous heart rate and blood pressure recordings, pre- and post-HIRREM. One-minute epochs of temporal high-frequency (23-36 Hz) brain electrical activity data (T3 and T4, eyes closed) were analyzed from baseline HIRREM assessment and subsequent sessions. Subjects rated autonomic symptoms before and after HIRREM. Four of seven were on fludrocortisone, which was stopped before or during their sessions. Heart rate variability in the time domain (standard deviation of the beat-to-beat interval) increased post-HIRREM (mean increase 51%, range 10-143, p = 0.03), as did baroreflex sensitivity (mean increase in high-frequency alpha 65%, range -6 to 180, p = 0.05). Baseline temporal electrical asymmetry negatively correlated with change in asymmetry from assessment to the final HIRREM session (p = 0.01). Summed high-frequency amplitudes at left and right temporal lobes decreased a median of 3.8 µV (p = 0.02). There was a trend for improvements in self-reported symptoms related to the autonomic nervous system. Use of HIRREM was associated with reduced sympathetic bias in autonomic cardiovascular regulation, greater symmetry and reduced amplitudes in temporal lobe high-frequency electrical activity, and a trend for reduced autonomic symptoms. Data suggest the potential for allostatic neurotechnology to facilitate increased flexibility in autonomic cardiovascular regulation, possibly through more balanced activity at regions of the neocortex responsible for autonomic management. Clinical trial registry "Tilt Table with Suspected postural orthostatic tachycardia syndrome (POTS) Subjects," Protocol Record: WFUBAHA01.

A groundwork for allostatic neuro-education.

We propose to enliven educational practice by marrying a conception of education as guided human development, to an advanced scientific understanding of the brain known as allostasis (stability through change). The result is a groundwork for allostatic neuro-education (GANE). Education as development encompasses practices including the organic (homeschooling and related traditions), cognitive acquisition (emphasis on standards and testing), and the constructivist (aimed to support adaptive creativity for both learner and society). Allostasis views change to be the norm in biology, defines success in contexts of complex natural environments rather than controlled settings, and identifies the brain as the organ of central command. Allostatic neuro-education contrasts with education focused dominantly on testing, or neuroscience based on homeostasis (stability through constancy). The GANE perspective is to view learners in terms of their neurodevelopmental trajectories; its objective is to support authentic freedom, mediated by competent, integrated, and expansive executive functionality (concordant with the philosophy of freedom of Rudolf Steiner); and its strategy is to be attuned to rhythms in various forms (including those of autonomic arousal described in polyvagal theory) so as to enable experiential excitement for learning. The GANE presents a variety of testable hypotheses, and studies that explore prevention or mitigation of the effects of early life adversity or toxic stress on learning and development may be of particular importance. Case studies are presented illustrating use of allostatic neurotechnology by an adolescent male carrying diagnoses of Asperger's syndrome and attention-deficit hyperactivity disorder, and a grade school girl with reading difficulties. The GANE is intended as a re-visioning of education that may serve both learners and society to be better prepared for the accelerating changes of the 21st century.

Rightward dominance in temporal high-frequency electrical asymmetry corresponds to higher resting heart rate and lower baroreflex sensitivity in a heterogeneous population.

OBJECTIVE: Explore potential use of a temporal lobe electrical asymmetry score to discriminate between sympathetic and parasympathetic tendencies in autonomic cardiovascular regulation. METHODS: 131 individuals (82 women, mean age 43.1, range 13-83) with diverse clinical conditions completed inventories for depressive (CES-D or BDI-II) and insomnia-related (ISI) symptomatology, and underwent five-minute recordings of heart rate and blood pressure, allowing calculation of heart rate variability and baroreflex sensitivity (BRS), followed by one-minute, two-channel, eyes-closed scalp recordings of brain electrical activity. A temporal lobe high-frequency (23-36 Hz) electrical asymmetry score was calculated for each subject by subtracting the average amplitude in the left temporal region from amplitude in the right temporal region, and dividing by the lesser of the two. RESULTS: Depressive and insomnia-related symptomatology exceeding clinical threshold levels were reported by 48% and 50% of subjects, respectively. Using a cutoff value of 5% or greater to define temporal high-frequency asymmetry, subjects with leftward compared to rightward asymmetry were more likely to report use of a sedative-hypnotic medication (42% vs. 22%, P = 0.02). Among subjects with asymmetry of 5% or greater to 30% or greater, those with rightward compared to leftward temporal high-frequency asymmetry had higher resting heart rate (≥5% asymmetry, 72.3 vs. 63.8, P = 0.004; ≥10%, 71.5 vs. 63.0, P = 0.01; ≥20%, 72.2 vs. 64.2, P = 0.05; ≥30%, 71.4 vs. 64.6, P = 0.05). Subjects with larger degrees of rightward compared to leftward temporal high-frequency asymmetry had lower baroreflex sensitivity (≥40% asymmetry, 10.6 vs. 16.4, P = 0.03; ≥50% asymmetry, 10.4 vs. 16.7, P = 0.05). CONCLUSION: In a heterogeneous population, individuals with rightward compared to leftward temporal high-frequency electrical asymmetry had higher resting heart rate and lower BRS. Two-channel recording of brain electrical activity from bilateral temporal regions appears to hold promise for further investigation as a means to assess cortical activity associated with autonomic cardiovascular regulation.

Reduction in menopause-related symptoms associated with use of a noninvasive neurotechnology for autocalibration of neural oscillations.

OBJECTIVE: Increased 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. METHODS: Twelve 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. RESULTS: The 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 µV (range, 6.27-16.66) at baseline and decreased by a median of -2.96 µV (range, -11.05 to -0.65; P = 0.0005) by the final session. CONCLUSIONS: Hot 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.

Transcranial Doppler Sonography: Atypical Dicrotic Pulse Waveforms in a Man with HIV Infection and Severe Cardiomyopathy.

A 27-year-old human immunodeficiency virus--positive man presented with abdominal pain. Computed tomography of the abdomen revealed large right pleural effusion, pericardial effusion and marked ascites with diffuse intra- and extraperitoneal lymphadenopathy. Echocardiography showed severely reduced left ventricular systolic function. After drainage of pleural and pericardial fluid, the patient developed severe hypotension and hypoxic respiratory failure. Extra- and intracranial neurovascular sonography demonstrated low carotid artery flow volume and dicrotic pulse waveforms in all vessels insonated bilaterally. This case report demonstrates an atypical dicrotic waveform pattern of transcranial Doppler in advanced ventricular dysfunction with shock.

A bihemispheric autonomic model for traumatic stress effects on health and behavior.

A bihemispheric autonomic model (BHAM) may support advanced understanding of traumatic stress effects on physiology and behavior. The model builds on established data showing hemispheric lateralization in management of the autonomic nervous system, and proposes that traumatic stress can produce dominant asymmetry in activity of bilateral homologous brain regions responsible for autonomic management. Rightward and leftward dominant asymmetries are associated with sympathetic high arousal or parasympathetic freeze tendencies, respectively, and return to relative symmetry is associated with improved autonomic regulation. Autonomic auto-calibration for recovery (inverse of Jacksonian dissolution proposed by polyvagal theory) has implications for risk behaviors associated with traumatic life stress. Trauma-induced high arousal may be associated with risk for maladaptive behaviors to attenuate arousal (including abuse of alcohol or sedative-hypnotics). Trauma-induced freeze mode (including callous-unemotional trait) may be associated with low resting heart rate and risk for conduct disorders. The model may explain higher prevalence of leftward hemispheric abnormalities reported in studies of violence. Implications of the BHAM are illustrated through case examples of a military special operations officer with history of traumatic brain injury and post-traumatic stress disorder, and a university student with persisting post-concussion symptoms. Both undertook use of a noninvasive closed-loop neurotechnology - high-resolution, relational, resonance-based, electroencephalic mirroring - with ensuing decrease in hemispheric asymmetry, improvement in heart rate variability, and symptom reduction. Finally, the BHAM aligns with calls for researchers to use brain-behavioral constructs (research domain criteria or RDoC, proposed by the National Institutes of Mental Health) as building blocks for assessment and intervention in mental health science.