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.

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.

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.

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.

Coexistent extra- and intracranial stenosis, cervical atherosclerosis, and abnormal ankle brachial index in acute ischemic stroke.

BACKGROUND: There are limited data regarding abnormal ankle brachial index (ABI) with coexistent extracranial carotid stenosis (ECS), intracranial stenosis (ICS), and nonstenotic cervical atherosclerosis (CAS) in stroke, especially in Asia. METHODS: We studied the prevalence of ECS, ICS, CAS, and combined ECS and ICS in 756 Thai patients with acute ischemic stroke and correlated sites of atherosclerosis with stroke risk factors and abnormal ABI. RESULTS: The prevalence of ECS was 8.8%, ICS 52.6%, CAS 36.0%, abnormal ABI 18.8%, combined ECS and ICS 4.6%, combined ECS and abnormal ABI 2.8%, combined ICS and abnormal ABI 10.6%, and combined ECS, ICS, and abnormal ABI 1.6%. The prevalence of ECS, CAS, and combined ECS and ICS was higher in abnormal ABI compared to normal ABI (14.8% v 7.5% [P = .006]; 46.5% v 33.5% [P = .004], and 8.4% v 3.7% [P = .016], respectively). ECS was significantly correlated with history of coronary artery disease (CAD) and abnormal ABI; ICS with male gender, no alcohol use, and no atrial fibrillation; CAS with age ≥ 60 years, history of CAD and abnormal ABI; and combined ECS and ICS with history of CAD. CONCLUSIONS: The frequency of atherosclerosis, especially ICS, was high. Cervicocerebral atherosclerosis was higher in abnormal ABI. This suggests that ischemic stroke patients should be screened for ECS, CAS, ICS, and abnormal ABI, especially in specific subsets (age ≥ 60 years, male gender, and history of CAD). The improved identification of vascular lesions could allow for a more optimal choice of antithrombotics, neurointervention, and more aggressive control of risk factors, potentially improving prevention of disease progression and a decrease in recurrent vascular events.

Prevalence and association between risk factors, stroke subtypes, and abnormal ankle brachial index in acute ischemic stroke.

BACKGROUND: Abnormal ankle brachial index (ABI) identifies a stroke subgroup with high risk of subsequent stroke and other vascular events. There are few data regarding the prevalence of abnormal ABI in ischemic stroke in Asian countries. METHODS: We evaluated the prevalence of abnormal ABI in 747 Thai patients with ischemic stroke or transient ischemic attack and assessed the correlation of abnormal ABI with stroke risk factors and stroke subtypes. RESULTS: The prevalence of abnormal ABI (≤0.9) in ischemic stroke patients was 18.1%. Abnormal ABI in ischemic stroke patients was significantly correlated with female gender (odds ratio [OR], 1.61; confidence interval [CI], 1.09-2.40; P = .017), age ≥ 60 years (OR, 3.54; CI, 2.14-5.85; P < .001), and previous ischemic events, including coronary artery disease (OR, 2.55; CI, 1.47-4.43; P = .001), cerebrovascular disease (OR, 2.15; CI, 1.37-3.55; P = .002), and atrial fibrillation (OR, 1.71; CI, 1.03-2.82; P = .036). There was a significant difference in the prevalence of abnormal ABI among stroke subtypes (P < .001), which tended to be more frequent in those with large artery disease (20.4%), cardioembolic stroke (29.2%), and undetermined etiology (20.6%). CONCLUSIONS: An ABI examination should be considered in patients with ischemic stroke to facilitate the early detection and treatment of asymptomatic peripheral arterial disease and identification of excess risk for subsequent stroke or other vascular events.

Telestroke to improve acute stroke care in North Carolina.

Effective, albeit time-limited, treatment is available for acute ischemic stroke but is underutilized in North Carolina. There is a mismatch between stroke resources and expertise and the services available at many hospitals where patients seek initial care. Video telecommunications can improve access to stroke expertise and to potentially life-saving therapies.

Enhancing the effectiveness of community stroke risk screening: a randomized controlled trial.

Stroke risk factors are routinely assessed in community screening programs; however, the rate of patient follow-up for health care once risk factors are identified is known to be low. This study was conducted to test the effectiveness of a brief behavioral telephonic intervention in an ongoing community stroke prevention screening program on health care seeking for stroke risk. A total of 227 participants with 2 or more stroke risk factors were randomly allocated to either an attention control arm or a behavioral intervention arm. The control group received standard information on risk and advice, whereas the intervention group received a brief Health Belief Model telephonic intervention designed to motivate care-seeking. The effect of treatment on the participants who completed a health care visit for stroke risk concerns was assessed using logistic regression. Cox survival analysis was used to compare time to physician visit between the 2 groups. Participants in the intervention arm were 1.85 times more likely to visit a primary care physician than controls. At 3 months, 69.2% of subjects in the intervention arm and 52.9% of those in the controls arm reported a new primary care visit after screening (P = .02), with 56.0% in the intervention arm and 38.4% in the control arm reporting a primary care visit specifically to discuss the stroke screening results (P < .01). Our data indicate that the brief, low-cost, motivational intervention effectively promoted adherence to screening advice and merits further testing.

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.

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.

A multicenter evaluation of the ABCD2 score's accuracy for predicting early ischemic stroke in admitted patients with transient ischemic attack.

STUDY OBJECTIVE: We evaluate, in admitted patients with transient ischemic attack, the accuracy of the ABCD(2) (age [A], blood pressure [B], clinical features [weakness/speech disturbance] [C], transient ischemic attack duration [D], and diabetes history [D]) score in predicting ischemic stroke within 7 days. METHODS: At 16 North Carolina hospitals, we enrolled a prospective, nonconsecutive sample of admitted patients with transient ischemic attack and with no stroke history, presenting within 24 hours of transient ischemic attack symptom onset. We conducted a medical record review to determine ischemic stroke outcomes within 7 days. According to a modified Rankin Scale Score, strokes were classified as disabling (>2) or nondisabling (< or =2). RESULTS: During a 35-month period, we enrolled 1,667 patients, of whom 373 (23%) received a diagnosis of an ischemic stroke within 7 days. Eighteen percent (69/373) of all strokes were disabling. We were unable to calculate an ABCD(2) score in 613 patients (37%); however, our imputed analysis indicated this did not significantly alter results. The discriminatory power of the ABCD(2) score was modest for ischemic stroke in 7 days (c statistic 0.59), and fair for disabling ischemic stroke within 7 days (c statistic 0.71). Patients characterized as low risk according to ABCD(2) score (< or =3) were at low risk for experiencing a disabling stroke within 7 days, with a negative likelihood ratio of 0.16 (95% confidence interval [CI] 0.04 to 0.64) with missing values excluded and 0.34 (95% CI 0.15 to 0.76) when missing values were imputed. CONCLUSION: Our analysis suggests the best application of the ABCD(2) score may be to identify patients at low risk for an early disabling ischemic stroke. Further study of the ability to determine an ABCD(2) score in all patients is needed, along with validation in a large, consecutive population of patients with transient ischemic attack.

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.

Early diffusion weighted MRI as a negative predictor for disabling stroke after ABCD2 score risk categorization in transient ischemic attack patients.

BACKGROUND AND PURPOSE: The prognostic value early diffusion-weighted magnetic resonance imaging (DWMRI) adds in the setting of transient ischemic attack (TIA), after risk stratification by a clinical score, is unclear. The purpose of this study is to evaluate, after ABCD2 score risk categorization in admitted TIA patients, whether negative DWMRI performed within 24 hours of symptom onset improves on the identification of patients at low risk for experiencing a disabling stroke within 90 days. METHODS: At 15 North Carolina hospitals, we enrolled a prospective nonconsecutive sample of admitted TIA patients. We excluded patients not undergoing a DWMRI within 24 hours of admission and patients for whom a dichotomized (< or = or >3) ABCD2 score could not be calculated. We conducted a medical record review to determine disabling ischemic stroke outcomes within 90 days. RESULTS: Over 35 months, 944 TIA patients met inclusion criteria, of whom 4% (n=41) had a disabling ischemic stroke within 90 days. In analyses stratified by low versus moderate/high ABCD2 score, the combination of a low risk ABCD2 score and a negative early DWMRI had excellent sensitivity (100%, 95% CI 34 to 100) for identifying low-risk patients. In patients classified as moderate to high risk, a negative early DWMRI predicted a low risk of disabling ischemic stroke within 90 days (sensitivity 92%, 95% CI 80 to 97; NLR 0.11, 95% CI 0.04 to 0.32). CONCLUSIONS: After risk stratification by the ABCD2 score, early DWMRI enhances the prediction of a low risk for disabling ischemic stroke within 90 days. Further study is warranted in a large, consecutive TIA population of early DWMRI as a sensitive negative predictor for disabling stroke within 90 days.

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.

Predictors of time from hospital arrival to initial brain-imaging among suspected stroke patients: the North Carolina Collaborative Stroke Registry.

BACKGROUND AND PURPOSE: We examined patient demographic and hospital characteristics and clinical predictors of delay time from hospital arrival until CT among 20 374 patients enrolled in the North Carolina Collaborative Stroke Registry (January 2005 to April 2008). METHODS: Delay time was log-transformed in linear regression analyses and dichotomized (25 minutes) in logistic regression analyses to correspond to a 1999 National Institute of Neurological Disorders and Stroke guideline. RESULTS: In multiple linear regression analyses, prehospital delay time, mode of transport, race, gender, presumptive diagnosis, time of day of arrival, weekday versus weekend arrival, and hospital type (defined by Joint Commission Primary Stroke Center certification and teaching status) were significantly associated with CT delay. In analyses of 3549 patients arriving within 2 hours of symptom onset, time of day of arrival and weekday versus weekend arrival were no longer significant. Among patients arriving within 2 hours of symptom onset, the strongest independent predictors of meeting the National Institute of Neurological Disorders and Stroke (NINDS) guideline were arrival by emergency medical services versus other modes of transportation (odds ratio, 95% CI=2.3 [1.9, 2.8]) and a presumptive diagnosis of transient ischemic attack versus unspecified stroke type (odds ratio, 95% CI=0.4 [0.3, 0.5]). CONCLUSIONS: Most patients do not arrive to the hospital in a timely manner and cannot be considered for time-dependent therapies. Among those that do, disparities exist in time to receipt of CT scan, suggesting room for improvement in hospital-level stroke systems of care.

Torcetrapib and carotid intima-media thickness in mixed dyslipidaemia (RADIANCE 2 study): a randomised, double-blind trial.

BACKGROUND: Patients with mixed dyslipidaemia have raised triglycerides, low high-density lipoprotein (HDL) cholesterol, and high low-density lipoprotein (LDL) cholesterol. Augmentation of HDL cholesterol by inhibition of the cholesteryl ester transfer protein (CETP) could benefit these patients. We aimed to investigate the effect of the CETP inhibitor, torcetrapib, on carotid atherosclerosis progression in patients with mixed dyslipidaemia. METHODS: We did a randomised double-blind trial at 64 centres in North America and Europe. 752 eligible participants completed an atorvastatin-only run-in period for dose titration, after which they all continued to receive atorvastatin at the titrated dose. 377 of these patients were randomly assigned to receive 60 mg of torcetrapib per day and 375 to placebo. We made carotid ultrasound images at baseline and at 6-month intervals for 24 months. The primary endpoint was the yearly rate of change in the maximum intima-media thickness of 12 carotid segments. Analysis was restricted to 683 patients who had at least one dose of treatment and had at least one follow-up carotid intima-media measurement; they were analysed as randomised. Mean follow-up for these patients was 22 (SD 4.8) months. This trial is registered with ClinicalTrials.gov, number NCT00134238. FINDINGS: The change in maximum carotid intima-media thickness was 0.025 (SD 0.005) mm per year in patients given torcetrapib with atorvastatin and 0.030 (0.005) mm per year in those given atorvastatin alone (difference -0.005 mm per year, 95% CI -0.018 to 0.008, p=0.46). Patients in the combined-treatment group had a 63.4% relative increase in HDL cholesterol (p<0.0001) and an 17.7% relative decrease in LDL cholesterol (p<0.0001), compared with controls. Systolic blood pressure increased by 6.6 mm Hg in the combined-treatment group and 1.5 mm Hg in the atorvastatin-only group (difference 5.4 mm Hg, 95% CI 4.3-6.4, p<0.0001). INTERPRETATION: Although torcetrapib substantially raised HDL cholesterol and lowered LDL cholesterol, it also increased systolic blood pressure, and did not affect the yearly rate of change in the maximum intima-media thickness of 12 carotid segments. Torcetrapib showed no clinical benefit in this or other studies, and will not be developed further.

Indications for carotid artery surgery and stent: the role of carotid ultrasound.

Carotid artery disease is the most frequently identified cause of ischemic stroke and is mostly due to atherosclerotic disease. Landmark trials have demonstrated that surgical intervention in cases of high-grade carotid stenosis can reduce the risk of subsequent stroke. Endovascular approaches continue to be evaluated in ongoing trials. Careful patient selection is critical if the potential benefits of carotid revascularization are to be realized. Ultrasound is a safe, accurate, readily available method to evaluate carotid artery disease. The degree of stenosis is the parameter most frequently used to make decisions about therapeutic approaches. Plaque characteristics may also be useful for identifying high-risk patients. Microembolic signals detected by transcranial Doppler ultrasound can identify cerebral embolization before or after carotid intervention. This review discusses the current clinical role of carotid ultrasound in the selection of patients for the two most frequently used carotid interventions: carotid endarterectomy or carotid angioplasty and stenting.