Scalable and reversible axonal neuromodulation of the sympathetic chain for cardiac control.

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.

Noninvasive Cervical Vagal Nerve Stimulation Alters Brain Activity During Traumatic Stress in Individuals With Posttraumatic Stress Disorder.

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.

Confederates in the Attic: Posttraumatic Stress Disorder, Cardiovascular Disease, and the Return of Soldier's Heart.

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.

Fusing Near-Infrared Spectroscopy with Wearable Hemodynamic Measurements Improves Classification of Mental Stress.

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.

Simultaneous photoplethysmography and blood flow measurements towards the estimation of blood pressure using speckle contrast optical spectroscopy.

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.

Effect of transcutaneous cervical vagus nerve stimulation on declarative and working memory in patients with Posttraumatic Stress Disorder (PTSD): A pilot study.

BACKGROUND: Posttraumatic stress disorder (PTSD) is associated with changes in multiple neurophysiological systems, including verbal declarative memory deficits. Vagus Nerve Stimulation (VNS) has been shown in preliminary studies to enhance function when paired with cognitive and motor tasks. The purpose of this study was to analyze the effect of transcutaneous cervical VNS (tcVNS) on attention, declarative and working memory in PTSD patients. METHODS: Fifteen PTSD patients were randomly assigned to active tcVNS (N = 8) or sham (N = 7) stimulation in a double-blinded fashion. Memory assessment tests including paragraph recall and N-back tests were performed to assess declarative and working memory function when paired with active/sham tcVNS once per month in a longitudinal study during which patients self-administered tcVNS/sham twice daily. RESULTS: Active tcVNS stimulation resulted in a significant improvement in paragraph recall performance following pairing with paragraph encoding for PTSD patients at two months (p < 0.05). It resulted in a 91 % increase in paragraph recall performance within group (p = 0.03), while sham tcVNS exhibited no such trend in performance improvement. In the N-back study, positive deviations in accuracy, precision and recall measures on different day visits (7,34,64,94) of patients with respect to day 1 revealed a pattern of better performance of the active tcVNS population compared to sham VNS which did not reach statistical significance. LIMITATIONS: Our sample size was small. CONCLUSIONS: These preliminary results suggest that tcVNS improves attention, declarative and working memory, which may improve quality of life and productivity for patients with PTSD. Future studies are required to confirm these results.

Transcutaneous vagal nerve stimulation modulates stress-induced plasma ghrelin levels: A double-blind, randomized, sham-controlled trial.

BACKGROUND: Transcutaneous cervical vagus nerve stimulation (tcVNS) has emerged as a potential treatment strategy for patients with stress-related psychiatric disorders. Ghrelin is a hormone that has been postulated to be a biomarker of stress. While the mechanisms of action of tcVNS are unclear, we hypothesized that tcVNS reduces the levels of ghrelin in response to stress. METHODS: Using a randomized double-blind approach, we studied the effects of tcVNS on ghrelin levels in individuals with a history of exposure to traumatic stress. Participants received either sham (n = 29) or active tcVNS (n = 26) after exposure to acute personalized traumatic script stress and mental stress challenges (public speech, mental arithmetic) over a three day period. RESULTS: There were no significant differences in the levels of ghrelin between the tcVNS and sham stimulation groups at either baseline or in the absence of trauma scripts. However, tcVNS in conjunction with personalized traumatic scripts resulted in lower ghrelin levels compared to the sham stimulation group (265.2 ± 143.6 pg/ml vs 478.7 ± 349.2 pg/ml, P = 0.01). Additionally, after completing the public speaking and mental arithmetic tests, ghrelin levels were found to be lower in the group receiving tcVNS compared to the sham group (293.3 ± 102.4 pg/ml vs 540.3 ± 203.9 pg/ml, P = 0.009). LIMITATIONS: Timing of ghrelin measurements, and stimulation of only left vagus nerve. CONCLUSION: tcVNS decreases ghrelin levels in response to various stressful stimuli. These findings are consistent with a growing literature that tcVNS modulates hormonal and autonomic responses to stress.

Stress-related dysautonomias and neurocardiology-based treatment approaches.

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.

Metrics of high cofluctuation and entropy to describe control of cardiac function in the stellate ganglion.

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 (HF). 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 HF. Future therapies that target the SG 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 HF and control subjects during extended in-vivo extracellular microelectrode recordings. We find that information processing and cardiac control in chronic HF 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.

Studying Cardiac Neural Network Dynamics: Challenges and Opportunities for Scientific Computing.

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.

Data-driven approach for automatic detection of aortic valve opening: B point detection from impedance cardiogram.

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.

Robust Estimation of Respiratory Variability Uncovers Correlates of Limbic Brain Activity and Transcutaneous Cervical Vagus Nerve Stimulation in the Context of Traumatic Stress.

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.

Validation of a new impedance cardiography analysis algorithm for clinical classification of stress states.

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.

Transcutaneous Cervical Vagus Nerve Stimulation Lengthens Exhalation in the Context of Traumatic Stress.

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.

Transcutaneous Cervical Vagus Nerve Stimulation Inhibits the Reciprocal of the Pulse Transit Time's Responses to Traumatic Stress in Posttraumatic Stress Disorder.

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.

Transcutaneous Cervical Vagal Nerve Stimulation in Patients with Posttraumatic Stress Disorder (PTSD): A Pilot Study of Effects on PTSD Symptoms and Interleukin-6 Response to Stress.

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<.05). Active tcVNS treatment for three months resulted in a 31% greater reduction in PTSD symptoms compared to sham treatment as measured by the PCL (p=0.013) as well as hyperarousal symptoms and somatic anxiety measured with the Ham-A p<0.05). IL-6 increased from baseline in sham but not tcVNS. Open label tcVNS resulted in improvements measured with the CGI compared to the sham treatment period p<0.05). CONCLUSIONS: These preliminary results suggest that tcVNS reduces inflammatory responses to stress, which may in part underlie beneficial effects on PTSD symptoms.

Application of Noninvasive Vagal Nerve Stimulation to Stress-Related Psychiatric Disorders.

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.

Digital Cardiovascular Biomarker Responses to Transcutaneous Cervical Vagus Nerve Stimulation: State-Space Modeling, Prediction, and Simulation.

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.

Automatic Detection of Target Engagement in Transcutaneous Cervical Vagal Nerve Stimulation for Traumatic Stress Triggers.

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.

Quantifying acute physiological biomarkers of transcutaneous cervical vagal nerve stimulation in the context of psychological stress.

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 < 0.01), decreased peripheral sympathetic function as measured by increased photoplethysmogram (PPG) amplitude (decreased vasoconstriction) by 47.9% (1.4-94.5%, p < 0.05), a 9% decrease in respiratory rate (-14.3 to -3.7%, p < 0.01). Similar effects were seen when tcVNS was applied after other stressors and in the absence of a stressor. CONCLUSION: Wearable sensing modalities are feasible to use in experiments in human participants, and tcVNS modulates cardiovascular and peripheral autonomic responses to stress.