A Novel, Cardiac-Derived Algorithm for Uterine Activity Monitoring in a Wearable Remote Device.

Background: Uterine activity (UA) monitoring is an essential element of pregnancy management. The gold-standard intrauterine pressure catheter (IUPC) is invasive and requires ruptured membranes, while the standard-of-care, external tocodynamometry (TOCO)'s accuracy is hampered by obesity, maternal movements, and belt positioning. There is an urgent need to develop telehealth tools enabling patients to remotely access care. Here, we describe and demonstrate a novel algorithm enabling remote, non-invasive detection and monitoring of UA by analyzing the modulation of the maternal electrocardiographic and phonocardiographic signals. The algorithm was designed and implemented as part of a wireless, FDA-cleared device designed for remote pregnancy monitoring. Two separate prospective, comparative, open-label, multi-center studies were conducted to test this algorithm. Methods: In the intrapartum study, 41 laboring women were simultaneously monitored with IUPC and the remote pregnancy monitoring device. Ten patients were also monitored with TOCO. In the antepartum study, 147 pregnant women were simultaneously monitored with TOCO and the remote pregnancy monitoring device. Results: In the intrapartum study, the remote pregnancy monitoring device and TOCO had sensitivities of 89.8 and 38.5%, respectively, and false discovery rates (FDRs) of 8.6 and 1.9%, respectively. In the antepartum study, a direct comparison of the remote pregnancy monitoring device to TOCO yielded a sensitivity of 94% and FDR of 31.1%. This high FDR is likely related to the low sensitivity of TOCO. Conclusion: UA monitoring via the new algorithm embedded in the remote pregnancy monitoring device is accurate and reliable and more precise than TOCO standard of care. Together with the previously reported remote fetal heart rate monitoring capabilities, this novel method for UA detection expands the remote pregnancy monitoring device's capabilities to include surveillance, such as non-stress tests, greatly benefiting women and providers seeking telehealth solutions for pregnancy care.

Novel uterine contraction monitoring to enable remote, self-administered nonstress testing.

BACKGROUND: The serial fetal monitoring recommended for women with high-risk pregnancies places a substantial burden on the patient, often disproportionately affecting underprivileged and rural populations. A telehealth solution that can empower pregnant women to obtain recommended fetal surveillance from the comfort of their own home has the potential to promote health equity and improve outcomes. We have previously validated a novel, wireless pregnancy monitor that can remotely capture fetal and maternal heart rates. However, such a device must also detect uterine contractions if it is to be used to robustly conduct remote nonstress tests. OBJECTIVE: This study aimed to describe and validate a novel algorithm that uses biopotential and acoustic signals to noninvasively detect uterine contractions via a wireless pregnancy monitor. STUDY DESIGN: A prospective, open-label, 2-center study evaluated simultaneous detection of uterine contractions by the wireless pregnancy monitor and an intrauterine pressure catheter in women carrying singleton pregnancies at ≥32 0/7 weeks' gestation who were in the first stage of labor (ClinicalTrials.gov Identifier: NCT03889405). The study consisted of a training phase and a validation phase. Simultaneous recordings from each device were passively acquired for 30 to 60 minutes. In a subset of the monitoring sessions in the validation phase, tocodynamometry was also deployed. Three maternal-fetal medicine specialists, blinded to the data source, identified and marked contractions in all modalities. The positive agreement and false-positive rates of both the wireless monitor and tocodynamometry were calculated and compared with that of the intrauterine pressure catheter. RESULTS: A total of 118 participants were included, 40 in the training phase and 78 in the validation phase (of which 39 of 78 participants were monitored simultaneously by all 3 devices) at a mean gestational age of 38.6 weeks. In the training phase, the positive agreement for the wireless monitor was 88.4% (1440 of 1692 contractions), with a false-positive rate of 15.3% (260/1700). In the validation phase, using the refined and finalized algorithm, the positive agreement for the wireless pregnancy monitor was 84.8% (2722/3210), with a false-positive rate of 24.8% (897/3619). For the subgroup who were monitored only with the wireless monitor and intrauterine pressure catheter, the positive agreement was 89.0% (1191/1338), with a similar false-positive rate of 25.4% (406/1597). For the subgroup monitored by all 3 devices, the positive agreement for the wireless monitor was significantly better than for tocodynamometry (P<.0001), whereas the false-positive rate was significantly higher (P<.0001). Unlike tocodynamometry, whose positive agreement was significantly reduced in the group with obesity compared with the group with normal weight (P=.024), the positive agreement of the wireless monitor did not vary across the body mass index groups. CONCLUSION: This novel method to noninvasively monitor uterine activity, via a wireless pregnancy monitoring device designed for self-administration at home, was more accurate than the commonly used tocodynamometry and unaffected by body mass index. Together with the previously reported remote fetal heart rate monitoring capabilities, this added ability to detect uterine contractions has created a complete telehealth solution for remote administration of nonstress tests.

Prospective longitudinal investigation shows correlation of event-related potential to mild traumatic brain injury in adolescents.

STUDY DESIGN: Prospective longitudinal cohort study. BACKGROUND: Adolescent athletes may be more susceptible to the long-term effects of mild traumatic brain injury (mTBI). A diagnostic and prognostic neuromarker may optimize management and return-to-activity decision-making in athletes who experience mTBI. OBJECTIVE: Measure an event-related potential (ERP) component captured with electroencephalography (EEG), called processing negativity (PN), at baseline and post-injury in adolescents who suffered mTBI and determine their longitudinal response relative to healthy controls. METHODS: Thirty adolescents had EEG recorded during an auditory oddball task at a pre-mTBI baseline session and subsequent post-mTBI sessions. Longitudinal EEG data from patients and healthy controls (n= 77) were obtained from up to four sessions in total and processed using Brain Network Analysis algorithms. RESULTS: The average PN amplitude in healthy controls significantly decreased over sessions 2 and 3; however, it remained steady in the mTBI group's 2nd (post-mTBI) session and decreased only in sessions 3 and 4. Pre- to post-mTBI amplitude changes correlated with the time interval between sessions. CONCLUSION: These results demonstrate that PN amplitude changes may be associated with mTBI exposure and subsequent recovery in adolescent athletes. Further study of PN may lead to it becoming a neuromarker for mTBI prognosis and return-to-activity decision-making in adolescents.

A jugular vein compression collar prevents alterations of endogenous electrocortical dynamics following blast exposure during special weapons and tactical (SWAT) breacher training.

Exposure to explosive blasts places one at risk for traumatic brain injury, especially for special weapons and tactics (SWAT) and military personnel, who may be repeatedly exposed to blasts. In the current study, the effectiveness of a jugular vein compression collar to prevent alterations in resting-state electrocortical activity following a single-SWAT breacher training session was investigated. SWAT team personnel were randomly assigned to wear a compression collar during breacher training and resting state electroencephalography (EEG) was measured within 2 days prior to and two after breacher training. It was hypothesized that significant changes in brain dynamics-indicative of possible underlying neurodegenerative processes-would follow blast exposure for those who did not wear the collar, with ameliorated changes for the collar-wearing group. Using recurrence quantification analysis (RQA) it was found that participants who did not wear the collar displayed longer periods of laminar electrocortical behavior (as indexed by RQA's vertical max line measure) after breacher training. It is proposed that the blast wave exposure for the no-collar group may have reduced the number of pathways, via axonal disruption-for electrical transmission-resulting in the EEG signals becoming trapped in laminar states for longer periods of time. Longer laminar states have been associated with other electrocortical pathologies, such as seizure, and may be important for understanding head trauma and recovery.

Reduced dual-task gait speed is associated with visual Go/No-Go brain network activation in children and adolescents with concussion.

OBJECTIVE: To investigate the association between dual-task gait performance and brain network activation (BNA) using an electroencephalography (EEG)-based Go/No-Go paradigm among children and adolescents with concussion. METHODS: Participants with a concussion completed a visual Go/No-Go task with collection of electroencephalogram brain activity. Data were treated with BNA analysis, which involves an algorithmic approach to EEG-ERP activation quantification. Participants also completed a dual-task gait assessment. The relationship between dual-task gait speed and BNA was assessed using multiple linear regression models. RESULTS: Participants (n = 20, 13.9 ± 2.3 years of age, 50% female) were tested at a mean of 7.0 ± 2.5 days post-concussion and were symptomatic at the time of testing (post-concussion symptom scale = 40.4 ± 21.9). Slower dual-task average gait speed (mean = 82.2 ± 21.0 cm/s) was significantly associated with lower relative time BNA scores (mean = 39.6 ± 25.8) during the No-Go task (ß = 0.599, 95% CI = 0.214, 0.985, p = 0.005, R2 = 0.405), while controlling for the effect of age and gender. CONCLUSION: Among children and adolescents with a concussion, slower dual-task gait speed was independently associated with lower BNA relative time scores during a visual Go/No-Go task. The relationship between abnormal gait behaviour and brain activation deficits may be reflective of disruption to multiple functional abilities after concussion.

The Effects of External Jugular Compression Applied during Head Impact Exposure on Longitudinal Changes in Brain Neuroanatomical and Neurophysiological Biomarkers: A Preliminary Investigation.

OBJECTIVES: Utilize a prospective in vivo clinical trial to evaluate the potential for mild neck compression applied during head impact exposure to reduce anatomical and physiological biomarkers of brain injury. METHODS: This project utilized a prospective randomized controlled trial to evaluate effects of mild jugular vein (neck) compression (collar) relative to controls (no collar) during a competitive hockey season (males; 16.3 ± 1.2 years). The collar was designed to mildly compress the jugular vein bilaterally with the goal to increase intracranial blood volume to reduce risk of brain slosh injury during head impact exposure. Helmet sensors were used to collect daily impact data in excess of 20 g (games and practices) and the primary outcome measures, which included changes in white matter (WM) microstructure, were assessed by diffusion tensor imaging (DTI). Specifically, four DTI measures: fractional anisotropy, mean diffusivity (MD), axial diffusivity, and radial diffusivity (RD) were used in the study. These metrics were analyzed using the tract-based Spatial Statistics (TBSS) approach - a voxel-based analysis. In addition, electroencephalography-derived event-related potentials were used to assess changes in brain network activation (BNA) between study groups. RESULTS: For athletes not wearing the collar, DTI measures corresponding to a disruption of WM microstructure, including MD and RD, increased significantly from pre-season to mid-season (p < 0.05). Athletes wearing the collar did not show a significant change in either MD or RD despite similar accumulated linear accelerations from head impacts (p > 0.05). In addition to these anatomical findings, electrophysiological network analysis of the degree of congruence in the network electrophysiological activation pattern demonstrated concomitant changes in brain network dynamics in the non-collar group only (p < 0.05). Similar to the DTI findings, the increased change in BNA score in the non-collar relative to the collar group was statistically significant (p < 0.01). Changes in DTI outcomes were also directly correlated with altered brain network dynamics (r = 0.76; p < 0.05) as measured by BNA. CONCLUSION: Group differences in the longitudinal changes in both neuroanatomical and electrophysiological measures, as well as the correlation between the measures, provide initial evidence indicating that mild jugular vein compression may have reduced alterations in the WM response to head impacts during a competitive hockey season. The data indicate sport-related alterations in WM microstructure were ameliorated by application of jugular compression during head impact exposure. These results may lead to a novel line of research inquiry to evaluate the effects of protecting the brain from sports-related head impacts via optimized intracranial fluid dynamics.

Brain Network Activation Analysis Utilizing Spatiotemporal Features for Event Related Potentials Classification.

The purpose of this study was to introduce an improved tool for automated classification of event-related potentials (ERPs) using spatiotemporally parcellated events incorporated into a functional brain network activation (BNA) analysis. The auditory oddball ERP paradigm was selected to demonstrate and evaluate the improved tool. Methods: The ERPs of each subject were decomposed into major dynamic spatiotemporal events. Then, a set of spatiotemporal events representing the group was generated by aligning and clustering the spatiotemporal events of all individual subjects. The temporal relationship between the common group events generated a network, which is the spatiotemporal reference BNA model. Scores were derived by comparing each subject's spatiotemporal events to the reference BNA model and were then entered into a support vector machine classifier to classify subjects into relevant subgroups. The reliability of the BNA scores (test-retest repeatability using intraclass correlation) and their utility as a classification tool were examined in the context of Target-Novel classification. Results: BNA intraclass correlation values of repeatability ranged between 0.51 and 0.82 for the known ERP components N100, P200, and P300. Classification accuracy was high when the trained data were validated on the same subjects for different visits (AUCs 0.93 and 0.95). The classification accuracy remained high for a test group recorded at a different clinical center with a different recording system (AUCs 0.81, 0.85 for 2 visits). Conclusion: The improved spatiotemporal BNA analysis demonstrates high classification accuracy. The BNA analysis method holds promise as a tool for diagnosis, follow-up and drug development associated with different neurological conditions.

Preliminary evidence of reduced brain network activation in patients with post-traumatic migraine following concussion.

Post-traumatic migraine (PTM) (i.e., headache, nausea, light and/or noise sensitivity) is an emerging risk factor for prolonged recovery following concussion. Concussions and migraine share similar pathophysiology characterized by specific ionic imbalances in the brain. Given these similarities, patients with PTM following concussion may exhibit distinct electrophysiological patterns, although researchers have yet to examine the electrophysiological brain activation in patients with PTM following concussion. A novel approach that may help differentiate brain activation in patients with and without PTM is brain network activation (BNA) analysis. BNA involves an algorithmic analysis applied to multichannel EEG-ERP data that provides a network map of cortical activity and quantitative data during specific tasks. A prospective, repeated measures design was used to evaluate BNA (during Go/NoGo task), EEG-ERP, cognitive performance, and concussion related symptoms at 1, 2, 3, and 4 weeks post-injury intervals among athletes with a medically diagnosed concussion with PTM (n = 15) and without (NO-PTM) (n = 22); and age, sex, and concussion history matched controls without concussion (CONTROL) (n = 20). Participants with PTM had significantly reduced BNA compared to NO-PTM and CONTROLS for Go and NoGo components at 3 weeks and for NoGo component at 4 weeks post-injury. The PTM group also demonstrated a more prominent deviation of network activity compared to the other two groups over a longer period of time. The composite BNA algorithm may be a more sensitive measure of electrophysiological change in the brain that can augment established cognitive assessment tools for detecting impairment in individuals with PTM.

Clinically Effective Treatment of Fibromyalgia Pain With High-Definition Transcranial Direct Current Stimulation: Phase II Open-Label Dose Optimization.

Despite promising preliminary results in treating fibromyalgia (FM) pain, no neuromodulation technique has been adopted in clinical practice because of limited efficacy, low response rate, or poor tolerability. This phase II open-label trial aims to define a methodology for a clinically effective treatment of pain in FM by establishing treatment protocols and screening procedures to maximize efficacy and response rate. High-definition transcranial direct current stimulation (HD-tDCS) provides targeted subthreshold brain stimulation, combining tolerability with specificity. We aimed to establish the number of HD-tDCS sessions required to achieve a 50% FM pain reduction, and to characterize the biometrics of the response, including brain network activation pain scores of contact heat-evoked potentials. We report a clinically significant benefit of a 50% pain reduction in half (n = 7) of the patients (N = 14), with responders and nonresponders alike benefiting from a cumulative effect of treatment, reflected in significant pain reduction (P = .035) as well as improved quality of life (P = .001) over time. We also report an aggregate 6-week response rate of 50% of patients and estimate 15 as the median number of HD-tDCS sessions to reach clinically meaningful outcomes. The methodology for a pivotal FM neuromodulation clinical trial with individualized treatment is thus supported. ONLINE REGISTRATION: Registered in Clinicaltrials.gov under registry number NCT01842009. PERSPECTIVE: In this article, an optimized protocol for the treatment of fibromyalgia pain with targeted subthreshold brain stimulation using high-definition transcranial direct current stimulation is outlined.

Brain Network Activation as a Novel Biomarker for the Return-to-Play Pathway Following Sport-Related Brain Injury.

Children and adolescent athletes are at a higher risk for concussion than adults, and also experience longer recovery times and increased associated symptoms. It has also recently been demonstrated that multiple, seemingly mild concussions may result in exacerbated and prolonged neurological deficits. Objective assessments and return-to-play criteria are needed to reduce risk and morbidity associated with concussive events in these populations. Recent research has pushed to study the use of electroencephalography as an objective measure of brain injury. In the present case study, we present a novel approach that examines event-related potentials via a brain network activation (BNA) analysis as a biomarker of concussion and recovery. Specifically, changes in BNA scores, as indexed through this approach, offer a potential indicator of neurological health as the BNA assessment qualitatively and quantitatively indexes the network dynamics associated with brain injury. Objective tools, such as these support accurate and efficient assessment of brain injury and may offer a useful step in categorizing the temporal and spatial changes in brain activity following concussive blows, as well as the functional connectivity of brain networks, associated with concussion.

Brain Network Activation (BNA) reveals scopolamine-induced impairment of visual working memory.

The overarching goal of this event-related potential (ERP) study was to examine the effects of scopolamine on the dynamics of brain network activation using a novel ERP network analysis method known as Brain Network Activation (BNA). BNA was used for extracting group-common stimulus-activated network patterns elicited to matching probe stimuli in the context of a delayed matching-to-sample task following placebo and scopolamine treatments administered to healthy participants. The BNA extracted networks revealed the existence of two pathophysiological mechanisms following scopolamine, disconnection, and compensation. Specifically, weaker frontal theta and parietal alpha coupling was accompanied with enhanced fronto-centro-parietal theta activation relative to placebo. In addition, using the characteristic BNA network of each treatment as well as corresponding literature-guided selective subnetworks as combined biomarkers managed to differentiate between individual responses to each of the treatments. Behavioral effects associated with scopolamine included delayed response time and impaired response accuracy. These results indicate that the BNA method is sensitive to the effects of scopolamine on working memory and that it may potentially enable diagnosis and treatment assessment of dysfunctions associated with cholinergic deficiency.

Interactions between stimulus-specific adaptation and visual auditory integration in the forebrain of the barn owl.

Neural adaptation and visual auditory integration are two well studied and common phenomena in the brain, yet little is known about the interaction between them. In the present study, we investigated a visual forebrain area in barn owls, the entopallium (E), which has been shown recently to encompass auditory responses as well. Responses of neurons to sequences of visual, auditory, and bimodal (visual and auditory together) events were analyzed. Sequences comprised two stimuli, one with a low probability of occurrence and the other with a high probability. Neurons in the E tended to respond more strongly to low probability visual stimuli than to high probability stimuli. Such a phenomenon is known as stimulus-specific adaptation (SSA) and is considered to be a neural correlate of change detection. Responses to the corresponding auditory sequences did not reveal an equivalent tendency. Interestingly, however, SSA to bimodal events was stronger than to visual events alone. This enhancement was apparent when the visual and auditory stimuli were presented from matching locations in space (congruent) but not when the bimodal stimuli were spatially incongruent. These findings suggest that the ongoing task of detecting unexpected events can benefit from the integration of visual and auditory information.

Auditory and multisensory responses in the tectofugal pathway of the barn owl.

A common visual pathway in all amniotes is the tectofugal pathway connecting the optic tectum with the forebrain. The tectofugal pathway has been suggested to be involved in tasks such as orienting and attention, tasks that may benefit from integrating information across senses. Nevertheless, previous research has characterized the tectofugal pathway as strictly visual. Here we recorded from two stations along the tectofugal pathway of the barn owl: the thalamic nucleus rotundus (nRt) and the forebrain entopallium (E). We report that neurons in E and nRt respond to auditory stimuli as well as to visual stimuli. Visual tuning to the horizontal position of the stimulus and auditory tuning to the corresponding spatial cue (interaural time difference) were generally broad, covering a large portion of the contralateral space. Responses to spatiotemporally coinciding multisensory stimuli were mostly enhanced above the responses to the single modality stimuli, whereas spatially misaligned stimuli were not. Results from inactivation experiments suggest that the auditory responses in E are of tectal origin. These findings support the notion that the tectofugal pathway is involved in multisensory processing. In addition, the findings suggest that the ascending auditory information to the forebrain is not as bottlenecked through the auditory thalamus as previously thought.

Multisensory enhancement in the optic tectum of the barn owl: spike count and spike timing.

Temporal and spatial correlations between auditory and visual stimuli facilitate the perception of unitary events and improve behavioral responses. However, it is not clear how combined visual and auditory information is processed in single neurons. Here we studied responses of multisensory neurons in the barn owl's optic tectum (the avian homologue of the superior colliculus) to visual, auditory, and bimodal stimuli. We specifically focused on responses to sequences of repeated stimuli. We first report that bimodal stimulation tends to elicit more spikes than in the responses to its unimodal components (a phenomenon known as multisensory enhancement). However, this tendency was found to be history-dependent; multisensory enhancement was mostly apparent in the first stimulus of the sequence and to a much lesser extent in the subsequent stimuli. Next, a vector-strength analysis was applied to quantify the phase locking of the responses to the stimuli. We report that in a substantial number of multisensory neurons responses to sequences of bimodal stimuli elicited spike trains that were better phase locked to the stimulus than spike trains elicited by stimulating with the unimodal counterparts (visual or auditory). We conclude that multisensory enhancement can be manifested in better phase locking to the stimulus as well as in more spikes.

Stimulus-specific adaptations in the gaze control system of the barn owl.

Abrupt orientation to novel stimuli is a critical, memory-dependent task performed by the brain. In the present study, we examined two gaze control centers of the barn owl: the optic tectum (OT) and the arcopallium gaze fields (AGFs). Responses of neurons to long sequences of dichotic sound bursts comprised of two sounds differing in the probability of appearance were analyzed. We report that auditory neurons in the OT and in the AGFs tend to respond stronger to rarely presented sounds (novel sounds) than to the same sounds when presented frequently. This history-dependent phenomenon, known as stimulus-specific adaptation (SSA), was demonstrated for rare sound frequencies, binaural localization cues [interaural time difference (ITD) and level difference (ILD)] and sound amplitudes. The manifestation of SSA in such a variety of independent acoustic features, in the midbrain and in the forebrain, supports the notion that SSA is involved in sensory memory and novelty detection. To track the origin of SSA, we analyzed responses of neurons in the external nucleus of the inferior colliculus (ICX; the source of auditory input to the OT) to similar sequences of sound bursts. Neurons in the ICX responded stronger to rare sound frequencies, but did not respond differently to rare ITDs, ILDs, or sound amplitudes. We hypothesize that part of the SSA reported here is computed in high-level networks, giving rise to novelty signals that modulate tectal responses in a context-dependent manner.