Background: Patients with congenital heart disease (CHD) are at risk for the development of low cardiac output and other physiologic derangements, which could be detected early through continuous stroke volume (SV) measurement. Unfortunately, existing SV measurement methods are limited in the clinic because of their invasiveness (eg, thermodilution), location (eg, cardiac magnetic resonance imaging), or unreliability (eg, bioimpedance). Multimodal wearable sensing, leveraging the seismocardiogram, a sternal vibration signal associated with cardiomechanical activity, offers a means to monitoring SV conveniently, affordably, and continuously. However, it has not been evaluated in a population with significant anatomical and physiological differences (ie, children with CHD) or compared against a true gold standard (ie, cardiac magnetic resonance). Here, we present the feasibility of wearable estimation of SV in a diverse CHD population (N=45 patients). Methods and Results: We used our chest‐worn wearable biosensor to measure baseline ECG and seismocardiogram signals from patients with CHD before and after their routine cardiovascular magnetic resonance imaging, and derived features from the measured signals, predominantly systolic time intervals, to estimate SV using ridge regression. Wearable signal features achieved acceptable SV estimation (28% error with respect to cardiovascular magnetic resonance imaging) in a held‐out test set, per cardiac output measurement guidelines, with a root‐mean‐square error of 11.48 mL and R ² of 0.76. Additionally, we observed that using a combination of electrical and cardiomechanical features surpassed the performance of either modality alone. Conclusions: A convenient wearable biosensor that estimates SV enables remote monitoring of cardiac function and may potentially help identify decompensation in patients with CHD.

Objective: Variations in respiration patterns are a characteristic response to distress due to underlying neurorespiratory couplings. Yet, no work to date has quantified respiration pattern variability (RPV) in the context of traumatic stress and studied its functional neural correlates – this analysis aims to address this gap. Methods: Fifty human subjects with prior traumatic experiences (24 with posttraumatic stress disorder (PTSD)) completed a ∼3-hr protocol involving personalized traumatic scripts and active/sham (double-blind) transcutaneous cervical vagus nerve stimulation (tcVNS). High-resolution positron emission tomography functional neuroimages, electrocardiogram (ECG), and respiratory effort (RSP) data were collected during the protocol. Supplementing the RSP signal with ECG-derived respiration for quality assessment and timing extraction, RPV metrics were quantified and analyzed. Specifically, correlation analyses were performed using neuroactivity in selected limbic regions, and responses to active and sham tcVNS were compared. Results: The single-lag unscaled autocorrelation of respiration rate correlated negatively with left amygdala activity and positively with right rostromedial prefrontal cortex (rmPFC) activity for non-PTSD; it also correlated negatively with left and right insulae activity and positively with right rmPFC activity for PTSD. The single-lag unscaled autocorrelation of expiration time was greater following active stimulation for non-PTSD. Conclusion: Quantifying RPV is of demonstrable importance to assessing trauma-induced changes in neural function and tcVNS effects on respiratory physiology. Significance: This is the first demonstration of RPV's pertinence to traumatic stress- and tcVNS-induced neurorespiratory responses. The open-source processing pipeline elucidated herein uniquely includes both RSP and ECG-derived respiration signals for quality assessment, timing estimation, and RPV extraction.

Background: Transcutaneous cervical vagus nerve stimulation (tcVNS) is a promising alternative to implantable stimulation of the vagus nerve. With demonstrated potential in myriad applications, ranging from systemic inflammation reduction to traumatic stress attenuation, closed-loop tcVNS during periods of risk could improve treatment efficacy and reduce ineffective delivery. However, achieving this requires a deeper understanding of biomarker changes over time. Objective: The aim of the present study was to reveal the dynamics of relevant cardiovascular biomarkers, extracted from wearable sensing modalities, in response to tcVNS. Methods: Twenty-four human subjects were recruited for a randomized double-blind clinical trial, for whom electrocardiography and photoplethysmography were used to measure heart rate and photoplethysmogram amplitude responses to tcVNS, respectively. Modeling these responses in state-space, we (1) compared the biomarkers in terms of their predictability and active vs sham differentiation, (2) studied the latency between stimulation onset and measurable effects, and (3) visualized the true and model-simulated biomarker responses to tcVNS. Results: The models accurately predicted future heart rate and photoplethysmogram amplitude values with root mean square errors of approximately one-fifth the standard deviations of the data. Moreover, (1) the photoplethysmogram amplitude showed superior predictability (P=.03) and active vs sham separation compared to heart rate; (2) a consistent delay of greater than 5 seconds was found between tcVNS onset and cardiovascular effects; and (3) dynamic characteristics differentiated responses to tcVNS from the sham stimulation. Conclusions: This work furthers the state of the art by modeling pertinent biomarker responses to tcVNS. Through subsequent analysis, we discovered three key findings with implications related to (1) wearable sensing devices for bioelectronic medicine, (2) the dominant mechanism of action for tcVNS-induced effects on cardiovascular physiology, and (3) the existence of dynamic biomarker signatures that can be leveraged when titrating therapy in closed loop. Trial Registration: ClinicalTrials.gov NCT02992899; https://clinicaltrials.gov/ct2/show/NCT02992899 International Registered Report Identifier (IRRID): RR2-10.1016/j.brs.2019.08.002

Objective: Posttraumatic stress disorder (PTSD) is a disabling condition affecting a large segment of the population; however, current treatment options have limitations. New interventions that target the neurobiological alterations underlying symptoms of PTSD could be highly beneficial. Transcutaneous cervical (neck) vagal nerve stimulation (tcVNS) has the potential to represent such an intervention. The goal of this study was to determine the effects of tcVNS on neural responses to reminders of traumatic stress in PTSD. Methods: Twenty-two participants were randomized to receive either sham (n = 11) or active (n = 11) tcVNS stimulation in conjunction with exposure to neutral and personalized traumatic stress scripts with high-resolution positron emission tomography scanning with radiolabeled water for brain blood flow measurements. Results: Compared with sham, tcVNS increased brain activations during trauma scripts (p < .005) within the bilateral frontal and temporal lobes, left hippocampus, posterior cingulate, and anterior cingulate (dorsal and pregenual), and right postcentral gyrus. Greater deactivations (p < .005) with tcVNS were observed within the bilateral frontal and parietal lobes and left thalamus. Compared with tcVNS, sham elicited greater activations (p < .005) in the bilateral frontal lobe, left precentral gyrus, precuneus, and thalamus, and right temporal and parietal lobes, hippocampus, insula, and posterior cingulate. Greater (p < .005) deactivations were observed with sham in the right temporal lobe, posterior cingulate, hippocampus, left anterior cingulate, and bilateral cerebellum. Conclusions: tcVNS increased anterior cingulate and hippocampus activation during trauma scripts, potentially indicating a reversal of neurobiological changes with PTSD consistent with improved autonomic control. Trial Registration: No. NCT02992899.

Opioid Use Disorder (OUD) is a serious public health problem, and the behavioral and physiological effects of opioid withdrawal can be a major impediment to recovery. Medication for OUD is currently the mainstay of treatment; however, it has limitations and alternative approaches are needed. The purpose of this study was to assess the effects of transcutaneous cervical vagus nerve stimulation (tcVNS) on behavioral and physiological manifestations of acute opioid withdrawal. Patients with OUD undergoing acute opioid withdrawal were randomly assigned to receive double blind active tcVNS (N = 10) or sham stimulation (N = 11) while watching neutral and opioid cue videos. Subjective opioid withdrawal, opioid craving, and anxiety were measured using a Visual Analogue Scale (VAS). Distress was measured using the Subjective Units of Distress Scale (SUDS), and pain was measured using the Numerical Rating Scale (NRS) for pain. Electrocardiogram signals were measured to compute heart rate. The primary outcomes of this initial phase of the clinical trial (ClinicalTrials.gov NCT04556552) were heart rate and craving. tcVNS compared to sham resulted in statistically significant reductions in subjective opioid withdrawal (p = .047), pain (p = .045), and distress (p = .004). In addition, tcVNS was associated with lower heart rate compared to sham (p = .026). Craving did not significantly differ between groups (p = .11). tcVNS reduces behavioral and physiological manifestations of opioid withdrawal, and should be evaluated in future studies as a possible non-pharmacologic, easily implemented approach for adjunctive OUD treatment.

Research has shown that transcutaneous cervical vagus nerve stimulation (tcVNS) yields downstream changes in peripheral physiology in individuals afflicted with posttraumatic stress disorder (PTSD). While the cardiovascular effects of tcVNS have been studied broadly in prior work, the specific effects of tcVNS on the reciprocal of the pulse transit time (1/PTT) remain unknown. By quantifying detectable effects, tcVNS can be further evaluated as a counterbalance to sympathetic hyperactivity during distress – specifically, we hypothesized that tcVNS would inhibit 1/PTT responses to traumatic stress. To investigate this, the electrocardiogram (ECG), photoplethysmogram (PPG), and seismocardiogram (SCG), were simultaneously measured from 24 human subjects suffering from PTSD. Implementing state-of-the-art signal quality assessment algorithms, relative changes in the pulse arrival time (PAT) and the pre-ejection period (PEP) were estimated solely from signal segments of sufficient quality. Thereby computing relative changes in 1/PTT, we find that tcVNS results in reduced 1/PTT responses to traumatic stress and the first minute of stimulation, compared to a sham control (corrected p < 0.05). This suggests that tcVNS induces inhibitory effects on blood pressure (BP) and/or vasoconstriction, given the established relationship between 1/PTT and these parameters.Clinical Relevance— Relative changes in 1/PTT are induced by varying vasomotor tone and/or BP – it has therefore piqued considerable interest as a potential surrogate of continuous BP. Studying its responses to tcVNS thus furthers understanding of tcVNS-induced cardiovascular modulation. The positive effects detailed herein suggest a potential role for tcVNS in the long-term management of PTSD.