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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.

Non-invasive continuous blood pressure monitoring remains elusive. There has been extensive research using the photoplethysmographic (PPG) waveform for blood pressure estimation, but improvements in accuracy are still needed before clinical use. Here we explored the use of an emerging technique, speckle contrast optical spectroscopy (SCOS), for blood pressure estimation. SCOS provides measurements of both blood volume changes (PPG) and blood flow index (BFi) changes during the cardiac cycle, and thus provides a richer set of parameters compared to traditional PPG. SCOS measurements were taken on the finger and wrists of 13 subjects. We investigated the correlations between features extracted from both the PPG and BFi waveforms with blood pressure. Features from the BFi waveforms were more significantly correlated with blood pressure than PPG features (R = − 0.55, p = 1.1 × 10−4 for the top BFi feature versus R = − 0.53, p = 8.4 × 10−4 for the top PPG feature). Importantly, we also found that features combining BFi and PPG data were highly correlated with changes in blood pressure (R = − 0.59, p = 1.7 × 10−4). These results suggest that the incorporation of BFi measurements should be further explored as a means to improve blood pressure estimation using non-invasive optical techniques.

Maladaptation of the sympathetic nervous system contributes to the progression of cardiovascular disease and risk for sudden cardiac death, the leading cause of mortality worldwide. Axonal modulation therapy (AMT) directed at the paravertebral chain blocks sympathetic efferent outflow to the heart and maybe a promising strategy to mitigate excess disease-associated sympathoexcitation. The present work evaluates AMT, directed at the sympathetic chain, in blocking sympathoexcitation using a porcine model. In anesthetized porcine (n = 14), we applied AMT to the right T1-T2 paravertebral chain and performed electrical stimulation of the distal portion of the right sympathetic chain (RSS). RSS-evoked changes in heart rate, contractility, ventricular activation recovery interval (ARI), and norepinephrine release were examined with and without kilohertz frequency alternating current block (KHFAC). To evaluate efficacy of AMT in the setting of sympathectomy, evaluations were performed in the intact state and repeated after left and bilateral sympathectomy. We found strong correlations between AMT intensity and block of sympathetic stimulation-evoked changes in cardiac electrical and mechanical indices (r = 0.83–0.96, effect size d = 1.9–5.7), as well as evidence of sustainability and memory. AMT significantly reduced RSS-evoked left ventricular interstitial norepinephrine release, as well as coronary sinus norepinephrine levels. Moreover, AMT remained efficacious following removal of the left sympathetic chain, with similar mitigation of evoked cardiac changes and reduction of catecholamine release. With growth of neuromodulation, an on-demand or reactionary system for reversible AMT may have therapeutic potential for cardiovascular disease-associated sympathoexcitation. NEW & NOTEWORTHY Autonomic imbalance and excess sympathetic activity have been implicated in the pathogenesis of cardiovascular disease and are targets for existing medical therapy. Neuromodulation may allow for control of sympathetic projections to the heart in an on-demand and reversible manner. This study provides proof-of-concept evidence that axonal modulation therapy (AMT) blocks sympathoexcitation by defining scalability, sustainability, and memory properties of AMT. Moreover, AMT directly reduces release of myocardial norepinephrine, a mediator of arrhythmias and heart failure.

Stellate ganglia within the intrathoracic cardiac control system receive and integrate central, peripheral, and cardiopulmonary information to produce postganglionic cardiac sympathetic inputs. Pathological anatomical and structural remodeling occurs within the neurons of the stellate ganglion (SG) in the setting of heart failure. A large proportion of SG neurons function as interneurons whose networking capabilities are largely unknown. Current therapies are limited to targeting sympathetic activity at the cardiac level or surgical interventions such as stellectomy, to treat heart failure. Future therapies that target the stellate ganglion will require understanding of their networking capabilities to modify any pathological remodeling. We observe SG networking by examining cofluctuation and specificity of SG networked activity to cardiac cycle phases. We investigate network processing of cardiopulmonary transduction by SG neuronal populations in porcine with chronic pacing-induced heart failure and control subjects during extended in-vivo extracellular microelectrode recordings. We find that information processing and cardiac control in chronic heart failure by the SG, relative to controls, exhibits: i) more frequent, short-lived, high magnitude cofluctuations, ii) greater variation in neural specificity to cardiac cycles, and iii) neural network activity and cardiac control linkage that depends on disease state and cofluctuation magnitude.

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.

Pre-ejection period (PEP), an indicator of sympathetic nervous system activity, is useful in psychophysiology and cardiovascular studies. Accurate PEP measurement is challenging and relies on robust identification of the timing of aortic valve opening, marked as the B point on impedance cardiogram (ICG) signals. The ICG sensitivity to noise and its waveform's morphological variability makes automated B point detection difficult, requiring inefficient and cumbersome expert visual annotation. In this article, we propose a machine learning-based automated algorithm to detect the aortic valve opening for PEP measurement, which is robust against noise and ICG morphological variations. We analyzed over 60 hr of synchronized ECG and ICG records from 189 subjects. A total of 3657 averaged beats were formed using our recently developed ICG noise removal algorithm. Features such as the averaged ICG waveform, its first and second derivatives, as well as high-level morphological and critical hemodynamic parameters were extracted and fed into the regression algorithms to estimate the B point location. The morphological features were extracted from our proposed "variable" physiologically valid search-window related to diverse B point shapes. A subject-wise nested cross-validation procedure was performed for parameter tuning and model assessment. After examining multiple regression models, Adaboost was selected, which demonstrated superior performance and higher robustness to five state-of-the-art algorithms that were evaluated in terms of low mean absolute error of 3.5 ms, low median absolute error of 0.0 ms, high correlation with experts' estimates (Pearson coefficient = 0.9), and low standard deviation of errors of 9.2 ms. For reproducibility, an open-source toolbox is provided.

Background Traumatic stress can have lasting effects on neurobiology and result in psychiatric conditions such as posttraumatic stress disorder (PTSD). We hypothesize that non-invasive cervical vagal nerve stimulation (nVNS) may alleviate trauma symptoms by reducing stress sympathetic reactivity. This study examined how nVNS alters neural responses to personalized traumatic scripts. Methods Nineteen participants who had experienced trauma but did not have the diagnosis of PTSD completed this double-blind sham-controlled study. In three sequential time blocks, personalized traumatic scripts were presented to participants immediately followed by either sham stimulation (n = 8; 0–14 V, 0.2 Hz, pulse width = 5s) or active nVNS (n = 11; 0–30 V, 25 Hz, pulse width = 40 ms). Brain activity during traumatic scripts was assessed using High Resolution Positron Emission Tomography (HR-PET) with radiolabeled water to measure brain blood flow. Results Traumatic scripts resulted in significant activations within the bilateral medial and orbital prefrontal cortex, premotor cortex, anterior cingulate, thalamus, insula, hippocampus, right amygdala, and right putamen. Greater activation was observed during sham stimulation compared to nVNS within the bilateral prefrontal and orbitofrontal cortex, premotor cortex, temporal lobe, parahippocampal gyrus, insula, and left anterior cingulate. During the first exposure to the trauma scripts, greater activations were found in the motor cortices and ventral visual stream whereas prefrontal cortex and anterior cingulate activations were more predominant with later script presentations for those subjects receiving sham stimulation. Conclusion nVNS decreases neural reactivity to an emotional stressor in limbic and other brain areas involved in stress, with changes over repeated exposures suggesting a shift from scene appraisal to cognitively processing the emotional event.

Pre-ejection period (PEP) is an index of sympathetic nervous system activity that can be computed from electrocardiogram (ECG) and impedance cardiogram (ICG) signals, but sensitive to speech/motion artifact. We sought to validate an ICG noise removal method, three-stage ensemble-average algorithm (TEA), in data acquired from a clinical trial comparing active versus sham non-invasive vagal nerve stimulation (tcVNS) after standardized speech stress. We first compared TEA's performance versus the standard conventional ensemble-average algorithm (CEA) approach to classify noisy ICG segments. We then analyzed ECG and ICG data to measure PEP and compared group-level differences in stress states with each approach. We evaluated 45 individuals, of whom 23 had post-traumatic stress disorder (PTSD). We found that the TEA approach identified artifact-corrupted beats with intraclass correlation coefficient 0.99 compared to expert adjudication. TEA also resulted in higher group-level differences in PEP between stress states than CEA. PEP values were lower in the speech stress (vs. baseline rest) group using both techniques, but the differences were greater using TEA (12.1 ms) than CEA (8.0 ms). PEP differences in groups divided by PTSD status and tcVNS (active vs. sham) were also greater when using the TEA versus CEA method, although the magnitude of the differences was lower. In conclusion, TEA helps to accurately identify noisy ICG beats during speaking stress, and this increased accuracy improves sensitivity to group-level differences in stress states compared to CEA, suggesting greater clinical utility.

Neural control of the heart involves continuous modulation of cardiac mechanical and electrical activity to meet the organism’s demand for blood flow. The closed-loop control scheme consists of interconnected neural networks with central and peripheral components working cooperatively with each other. These components have evolved to cooperate control of various aspects of cardiac function, which produce measurable “functional” outputs such as heart rate and blood pressure. In this review, we will outline fundamental studies probing the cardiac neural control hierarchy. We will discuss how computational methods can guide improved experimental design and be used to probe how information is processed while closed-loop control is operational. These experimental designs generate large cardio-neural datasets that require sophisticated strategies for signal processing and time series analysis, while presenting the usual large-scale computational challenges surrounding data sharing and reproducibility. These challenges provide unique opportunities for the development and validation of novel techniques to enhance understanding of mechanisms of cardiac pathologies required for clinical implementation.

Transcutaneous electrical stimulation of the vagus nerve is believed to deliver afferent signaling to the brain that, in turn, yields downstream changes in peripheral physiology, including cardiovascular and respiratory parameters. While the effects of transcutaneous cervical vagus nerve stimulation (tcVNS) on these parameters have been studied broadly, little is known regarding the specific effects of tcVNS on exhalation time and the spontaneous respiration cycle. By understanding such effects, tcVNS could be used to counterbalance sympathetic hyperactivity following distress by enhancing vagal tone through parasympathetically favored modulation of inspiration and expiration – specifically, lengthened expiration relative to inspiration. We thus investigated the effects of tcVNS on respiration timings by decomposing the respiration cycle into inspiration and expiration times and incorporating state-of-the-art respiration quality assessment algorithms for respiratory effort belt and electrocardiogram derived respiration signals. This enabled robust estimation of respiration timings from quality measurements alone. We thereby found that tcVNS increases expiration time minutes after stimulation, compared to a sham control (N = 26). This suggests that tcVNS could counteract sympathovagal imbalance, given the relationship between expiration and heightened vagal tone.

Background: Posttraumatic stress disorder (PTSD) is a highly disabling condition associated with alterations in multiple neurobiological systems, including increases in inflammatory and sympathetic function, responsible for maintenance of symptoms. Treatment options including medications and psychotherapies have limitations. We previously showed that transcutaneous Vagus Nerve Stimulation (tcVNS) blocks inflammatory (interleukin (IL)-6) responses to stress in PTSD. The purpose of this study was to assess the effects of tcVNS on PTSD symptoms and inflammatory responses to stress. Methods: Twenty patients with PTSD were randomized to double blind active tcVNS (N=9) or sham (N=11) stimulation in conjunction with exposure to personalized traumatic scripts immediately followed by active or sham tcVNS and measurement of IL-6 and other biomarkers of inflammation. Patients then self administered active or sham tcVNS twice daily for three months. PTSD symptoms were measured with the PTSD Checklist (PCL) and the Clinician Administered PTSD Scale (CAPS), clinical improvement with the Clinical Global Index (CGI) and anxiety with the Hamilton Anxiety Scale (Ham-A) at baseline and one-month intervals followed by a repeat of measurement of biomarkers with traumatic scripts. After three months patients self treated with twice daily open label active tcVNS for another three months followed by assessment with the CGI. Results: Traumatic scripts increased IL-6 in PTSD patients, an effect that was blocked by tcVNS (p

Cardiovascular and psychiatric disorders are among the most commonly treated conditions worldwide. Research in neurocardiology, psychiatry, and epidemiology have defined bidirectional relationships between psychiatric disorders and heart disease, affirming the role of impaired autonomic nervous system, or dysautonomia in the prognosis and development in these disorders. These studies have fueled rapid clinical translation of experimental findings, with potential to complement existing pharmacological therapies. In this review, we comprehensively discuss the state-of-the-art investigations and novel treatment approaches for stress-related dysautonomias, emphasizing the effects of stress on the cardiac neuronal hierarchy. Increasing evidence suggests that autonomic modulation stands as an attractive therapeutic strategy in the treatment of dysautonomias that could complement existing therapies and possibly reduce the burden of drug-related side effects and treatment-resistant conditions. Further investigations regarding treatment optimization, selectivity, usability, and ethical concerns are required.

Human-computer interaction (HCI) technology, and the automatic classification of a person’s mental state, are of interest to multiple industries. In this work, the fusion of sensing modalities that monitor the oxygenation of the human prefrontal cortex (PFC) and cardiovascular physiology was evaluated to differentiate between rest, mental arithmetic and N-back memory tasks. A flexible headband to measure near-infrared spectroscopy (NIRS) for quantifying PFC oxygenation, and forehead photoplethysmography (PPG) for assessing peripheral cardiovascular activity was designed. Physiological signals such as the electrocardiogram (ECG) and seismocardiogram (SCG) were collected, along with the measurements obtained using the headband. The setup was tested and validated with a total of 16 human subjects performing a series of arithmetic and N-back memory tasks. Features extracted were related to cardiac and peripheral sympathetic activity, vasomotor tone, pulse wave propagation, and oxygenation. Machine learning techniques were utilized to classify rest, arithmetic, and N-back tasks, using leave-one-subject-out cross validation. Macro-averaged accuracy of 85%, precision of 84%, recall rate of 83%, and F1 score of 80% were obtained from the classification of the three states. Statistical analyses on the subject-based results demonstrate that the fusion of NIRS and peripheral cardiovascular sensing significantly improves the accuracy, precision, recall, and F1 scores, compared to using NIRS sensing alone. Moreover, the fusion significantly improves the precision compared to peripheral cardiovascular sensing alone. The results of this work can be used in the future to design a multi-modal wearable sensing system for classifying mental state for applications such as acute stress detection.

Objective Exacerbated autonomic responses to acute stress are prevalent in posttraumatic stress disorder (PTSD). The purpose of this study was to assess the effects of transcutaneous cervical VNS (tcVNS) on autonomic responses to acute stress in patients with PTSD. The authors hypothesized tcVNS would reduce the sympathetic response to stress compared to a sham device. Methods Using a randomized double-blind approach, we studied the effects of tcVNS on physiological responses to stress in patients with PTSD (n = 25) using noninvasive sensing modalities. Participants received either sham (n = 12) or active tcVNS (n = 13) after exposure to acute personalized traumatic script stress and mental stress (public speech, mental arithmetic) over a three-day protocol. Physiological parameters related to sympathetic responses to stress were investigated. Results Relative to sham, tcVNS paired to traumatic script stress decreased sympathetic function as measured by: decreased heart rate (adjusted β = −5.7%; 95% CI: ±3.6%, effect size d = 0.43, p, Highlights • We studied the effects of tcVNS on physiological responses to stress in patients with posttraumatic stress disorder (PTSD). • TcVNS modulates physiologic reactivity to acute traumatic and mental stress. • Peripheral autonomic measures could serve as real-time measures to evaluate the therapy response in longitudinal settings.

Background: Vagal Nerve Stimulation (VNS) has been shown to be efficacious for the treatment of depression, but to date, VNS devices have required surgical implantation, which has limited widespread implementation. Methods: New noninvasive VNS (nVNS) devices have been developed which allow external stimulation of the vagus nerve, and their effects on physiology in patients with stress-related psychiatric disorders can be measured with brain imaging, blood biomarkers, and wearable sensing devices. Advantages in terms of cost and convenience may lead to more widespread implementation in psychiatry, as well as facilitate research of the physiology of the vagus nerve in humans. nVNS has effects on autonomic tone, cardiovascular function, inflammatory responses, and central brain areas involved in modulation of emotion, all of which make it particularly applicable to patients with stress-related psychiatric disorders, including posttraumatic stress disorder (PTSD) and depression, since dysregulation of these circuits and systems underlies the symptomatology of these disorders. Results: This paper reviewed the physiology of the vagus nerve and its relevance to modulating the stress response in the context of application of nVNS to stress-related psychiatric disorders. Conclusions: nVNS has a favorable effect on stress physiology that is measurable using brain imaging, blood biomarkers of inflammation, and wearable sensing devices, and shows promise in the prevention and treatment of stress-related psychiatric disorders.

Pituitary adenylate cyclase-activating peptide (PACAP) is a neuropeptide that plays a key role in the neurobiology of the stress response, and prior studies suggest that its function is dysregulated in post-traumatic stress disorder (PTSD). Transcutaneous cervical vagus nerve stimulation (tcVNS) acts through PACAP and other neurobiological systems to modulate stress responses and/or symptoms of PTSD. In this pilot study, we examined the effects of tcVNS on PACAP in a three day chronic stress laboratory paradigm involving serial traumatic and mental stress exposures in healthy individuals with a history of exposure to psychological trauma (n ​= ​18) and patients with PTSD (n ​= ​12). Methods A total of 30 subjects with a history of exposure to psychological trauma experience were recruited (12 with PTSD diagnosis) for a three-day randomized double-blinded study of tcVNS or sham stimulation. Subjects underwent a protocol that included both personalized trauma recall and non-personalized mental stressors (public speaking, mental arithmetic) paired to tcVNS or sham stimulation over three days. Blood was collected at baseline and multiple time points after exposure to stressors. Linear mixed-effects models were used to assess changes in PACAP over time (in response to stressors) and its relation to active tcVNS or sham stimulation. Results PACAP blood levels increased over the course of three days for both active tcVNS and sham groups. This increase was statistically-significant in the sham group at the end of the second (Cohen’s drm ​= ​0.35, p ​= ​0.04), and third days (drm ​= ​0.41, p ​= ​0.04), but not in the active tcVNS group (drm ​= ​0.21, drm ​= ​0.18, and p ​> ​0.20). Conclusion These pilot findings suggest tcVNS may attenuate this neurobiological stress-response. Larger studies are needed to investigate gender and interaction effects.

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. CLINICALTRIAL ClinicalTrials.gov NCT02992899; https://clinicaltrials.gov/ct2/show/NCT02992899 INTERNATIONAL REGISTERED REPORT RR2-10.1016/j.brs.2019.08.002

Da Costa originally described Soldier's Heart in the 19th Century as a syndrome that occurred on the battlefield in soldiers of the American Civil War. Soldier's Heart involved symptoms similar to modern day posttraumatic stress disorder (PTSD) as well as exaggerated cardiovascular reactivity felt to be related to an abnormality of the heart. Interventions were appropriately focused on the cardiovascular system. With the advent of modern psychoanalysis, psychiatric symptoms became divorced from the body and were relegated to the unconscious. Later, the physiology of PTSD and other psychiatric disorders was conceived as solely residing in the brain. More recently, advances in psychosomatic medicine led to the recognition of mind-body relationships and the involvement of multiple physiological systems in the etiology of disorders, including stress, depression PTSD, and cardiovascular disease, has moved to the fore, and has renewed interest in the validity of the original model of the Soldier's Heart syndrome.

ObjectiveExacerbated autonomic responses to acute stress are prevalent in posttraumatic stress disorder (PTSD). The purpose of this study was to assess the effects of transcutaneous cervical VNS (tcVNS) on autonomic responses to acute stress in patients with PTSD. The authors hypothesized tcVNS would reduce the sympathetic response to stress compared to a sham device.MethodsUsing a randomized double-blind approach, we studied the effects of tcVNS on physiological responses to stress in patients with PTSD (n=25) using noninvasive sensing modalities. Participants received either sham or active tcVNS after exposure to acute personalized traumatic script stress and mental stress (public speech, mental arithmetic) over a three-day protocol. Physiological parameters related to sympathetic responses to stress were investigated.ResultsRelative to sham, tcVNS paired to traumatic script stress decreased sympathetic function as measured by: decreased heart rate (adjusted ß=-5.7%; 95% CI: ±3.6%, effect size d=0.43, pConclusiontcVNS attenuates sympathetic arousal associated with stress related to traumatic memories as well as mental stress in patients with PTSD, with effects persisting throughout multiple traumatic stress and stimulation testing days. These findings show that tcVNS has beneficial effects on the underlying neurophysiology of PTSD. Such autonomic metrics may also be evaluated in daily life settings in tandem with tcVNS therapy to provide closed-loop delivery and measure efficacy.ClinicalTrials.gov Registration # NCT02992899HighlightsWe studied the effects of tcVNS on physiological responses to stress in patients posttraumatic stress disorder (PTSD).tcVNS modulates physiologic reactivity to traumatic and mental stress in PTSD, and modulates autonomic tone when applied without acute stress.Repeated tcVNS enhances resilience in the face of repeated stress in PTSD as quantified by peripheral autonomic measures which potentially could serve as real-time measures to evaluate the therapy response in longitudinal settings.

Sympathetic nervous system (SNS) activity plays a significant role in cardiovascular control. Preejection period (PEP) is a noninvasive biomarker that reflects SNS activity. In this paper, unobtrusive estimation of PEP of the heart using ballistocardiogram (BCG) and electrocardiogram (ECG) signals is investigated. Although previous work has shown that the time intervals from ECG R-peak to BCG I and J peaks are correlated with PEP, relying on a single BCG beat can be prone to errors. An approach is proposed based on multiple regression and use of initial training data sets with a reference standard, impedance cardiography (ICG). For evaluation, healthy subjects were asked to stand on a force plate to record BCG and ECG signals. Regression coefficients were obtained using leave-one-out cross-validation and the true PEP values were obtained using ECG and ICG. Regression coefficients were averaged over two different recordings from the same subjects. The estimation performance was evaluated based on the data, via leave-one-out cross-validation. Multiple regression is shown to reduce the mean absolute error and the root mean square error, and has a reduced confidence interval compared with the models based on only a single feature. This paper shows that the fusion of multiple timing intervals can be useful for improved PEP estimation.

Transcutaneous cervical vagal nerve stimulation (tcVNS) devices are attractive alternatives to surgical implants, and can be applied for a number of conditions in ambulatory settings, including stress-related neuropsychiatric disorders. Transferring tcVNS technologies to at-home settings brings challenges associated with the assessment of therapy response. The ability to accurately detect whether tcVNS has been effectively delivered in a remote setting such as the home has never been investigated. We designed and conducted a study in which 12 human subjects received active tcVNS and 14 received sham stimulation in tandem with traumatic stress, and measured continuous cardiopulmonary signals including the electrocardiogram (ECG), photoplethysmogram (PPG), seismocardiogram (SCG), and respiratory effort (RSP). We extracted physiological parameters related to autonomic nervous system activity, and created a feature set from these parameters to: 1) detect active (vs. sham) tcVNS stimulation presence with machine learning methods, and 2) determine which sensing modalities and features provide the most salient markers of tcVNS-based changes in physiological signals. Heart rate (ECG), vasomotor activity (PPG), and pulse arrival time (ECG+PPG) provided sufficient information to determine target engagement (compared to sham) in addition to other combinations of sensors. resulting in 96% accuracy, precision, and recall with a receiver operator characteristics area of 0.96. Two commonly utilized sensing modalities (ECG and PPG) that are suitable for home use can provide useful information on therapy response for tcVNS. The methods presented herein could be deployed in wearable devices to quantify adherence for at-home use of tcVNS technologies.

Background: Stress is associated with activation of the sympathetic nervous system, and can lead to lasting alterations in autonomic function and in extreme cases symptoms of posttraumatic stress disorder (PTSD). Vagal nerve stimulation (VNS) is a potentially useful tool as a modulator of autonomic nervous system function, however currently available implantable devices are limited by cost and inconvenience. Objective: The purpose of this study was to assess the effects of transcutaneous cervical VNS (tcVNS) on autonomic responses to stress. Methods: Using a double-blind approach, we investigated the effects of active or sham tcVNS on peripheral cardiovascular and autonomic responses to stress using wearable sensing devices in 24 healthy human participants with a history of exposure to psychological trauma. Participants were exposed to acute stressors over a three-day period, including personalized scripts of traumatic events, public speech, and mental arithmetic tasks. Results: tcVNS relative to sham applied immediately after traumatic stress resulted in a decrease in sympathetic function and modulated parasympathetic/sympathetic autonomic tone as measured by increased pre-ejection period (PEP) of the heart (a marker of cardiac sympathetic function) of 4.2 ms (95% CI 1.6–6.8 ms, p

BackgroundTranscutaneous 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.ObjectiveThe aim of the present study was to reveal the dynamics of relevant cardiovascular biomarkers, extracted from wearable sensing modalities, in response to tcVNS.MethodsTwenty-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.ResultsThe 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.ConclusionsThis 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 RegistrationClinicalTrials.gov NCT02992899; https://clinicaltrials.gov/ct2/show/NCT02992899International Registered Report Identifier (IRRID)RR2-10.1016/j.brs.2019.08.002

A non-invasive, soft, thermal modulation system was designed and evaluated for use in physiological experiments to assess neuro-vascular health. The system stimulates biomechanisms involved in thermoregulation by varying the temperature of the skin with a soft, fluidically-controlled thermal pad. The silicone-based thermal pad was strategically embedded with graphite particles to improve the base thermal conductivity. The temperature control mechanism was achieved by implementing a proportional-integral control loop with feedback from a thermistor in touch with the skin. To verify the system operation, physiological signals were collected from a human subject to monitor local blood volume changes and autonomic nervous system activity in response to temperature modulation. The mechanisms associated with thermoregulation were quantified by extracting features from the measured biosignals. This work compares the design of the soft, fluid-based system to a previous rigid design. The presented design reduces the mass of the on-body system and eliminates painful pressure on the skin, while inducing physiological modulation as shown by the bio-signal results. The system provides a wearable interface for a multitude of physiology experiments that could require temperature modulation.

Unobtrusive monitoring of physio-behavioral variables from animals can minimize variability in preclinical research and thereby maximize the potential for clinical translation. In this paper, we present the design, implementation, and validation of an instrumented nest providing continuous recordings of seismocardiogram (SCG) signals and skin temperature. SCG represents the chest-wall vibrations associated with the heartbeat, and can potentially provide a measure by which individual heartbeats can be detected without the need for electrodes or implantable devices. A non-contact electric field sensor placed in proximity to the animal in the nest was also used to detect respiratory dynamics. The setup was tested with a total of six anesthetized mice. To understand the effects of mouse positioning within the nest on signal quality, the error in heartbeat detection at different positions of the sensor on the body was quantified, with a simultaneously-obtained electrocardiogram (ECG) as the reference standard. At the optimal placement determined with this approach, multiple perturbations were performed such as pinching, changing ambient temperature, and norepinephrine injection to modulate physiology and assess measurement capability. Heartbeat intervals obtained from the ECG and SCG during the perturbations were correlated (R2=0.82) and were in agreement according to Bland-Altman methods (bias: 0.006ms, 95% confidence interval: [-3.79, 3.78]ms) suggesting that SCG can be reliably used for unobtrusive heartbeat detection. Accordingly, the setup can provide a means by which individual heartbeats – and thereby heart rate and heart rate variability indices – can be quantified without the need for any sensors to be attached to the body of the animal.

This live demonstration presents a wearable system for neuro-vascular health assessment. The system is comprised of three key subcomponents: 1) a soft, fluid-driven thermal modulation pad, 2) a portable case containing electrical and mechanical hardware, and 3) off-board biosignal processing and power units. The soft thermal modulation pad (the only component that interfaces with the user) contains fluid channels, embedded temperature sensors, and a flexible protoboard, encased in graphite-based silicone. The pad induces fluid-based heating or cooling of the hand, and is connected to the portable case through inlets and outlets. The portable case contains electrical and mechanical actuation (temperature modulation, fluid flow), sensing, and control circuitry, none of which is in contact with the user. Components include Peltier tiles, temperature and flow rate sensors, fluid pump, reservoir, control circuitry, heat sinks, cooling fans, and a microcontroller. All components in the case are enclosed with a laser-cut acrylic sheet to shield them from outside world, except for the fluid reservoir (to be filled with water before use) and toggle switches. Separate from the portable case and the pad are a data acquisition system, photoplethysmography (PPG) sensor to be worn on the hand, a laptop for visualization of the data, and a power supply. To enable closed-loop temperature control, the current and voltage flowing through the Peltier tiles are controlled with a custom algorithm implemented on the microcontroller. Biosignals involved with thermoregulation are collected. PPG measures the changes in blood volume pulse at the collected location; the amplitude of the PPG signal reflects the change in dilation or constriction of the vasculature [1].

BackgroundThe autonomic response to acute emotional stress can be highly variable, and pathological responses are associated with increased risk of adverse cardiovascular events. We evaluated the autonomic response to stress reactivity of young healthy subjects and aging subjects with coronary artery disease to understand how the autonomic stress response differs with aging.MethodsPhysiologic reactivity to arithmetic stress in a cohort of 25 young, healthy subjects (< 30 years) and another cohort of 25 older subjects (> 55 years) with CAD was evaluated using electrocardiography, impedance cardiography, and arterial pressure recordings. Stress-related changes in the pre-ejection period (PEP), which measures sympathetic activity, and high frequency heart rate variability (HF HRV), which measures parasympathetic activity, were analyzed as primary outcomes.ResultsMental stress reduced PEP in both groups (pDiscussionPEP decreases with stress regardless of health and age status, implying increased sympathetic function. Its decline with stress may be attenuated in CAD. The HF HRV (parasympathetic) stress reactivity is more variable and attenuated in younger individuals; perhaps this is related to a protective parasympathetic reflex.Trial registrationClinicalTrials.gov Identifier: NCT02657382.

Transcutaneous vagus nerve stimulation (t-VNS) is a promising technology for modulating brain function and possibly treating disorders of the central nervous system. While handheld devices are available for t-VNS, stimulation efficacy can only be quantified using expensive imaging or blood biomarker analyses. Additionally, the parameters and "dosage" recommendations for t-VNS are typically fixed, as there are limited biomarkers that can assess downstream effects of the stimulation outside of clinical settings. In this proof-of-concept study, we evaluated non-invasive peripheral cardiovascular measurements as physiological biomarkers of t-VNS efficacy. Specifically, we hypothesized two physiological biomarkers: (1) the pre-ejection period (PEP) of the heart — a parameter closely linked to sympathetic tone — and (2) the amplitude of peripheral photoplethysmogram (PPG) waveforms — representing changes in vasomotor tone and thus parasympathetic / sympathetic activation. A total of six healthy human subjects participated in the multi-day study, half each undergoing active or sham t-VNS stimulus. The three subjects receiving t-VNS had no decrease in PEP and an increase in PPG amplitude following t-VNS, while the subjects receiving sham stimulus had a decrease in PEP and no change in PPG amplitude. When combined with mental stress (a traumatic script being read back to the subjects), the group with t-VNS had no decrease in PEP and only a slight decrease in PPG amplitude following stimulus, while the group receiving sham stimulus had a decrease in PEP and also a slight decrease in PPG amplitude. These studies suggest that PEP and PPG amplitude measures may provide non-invasive physiological biomarkers of t-VNS efficacy, including in the presence of mental stress.