Estimation of central blood pressure waveform from femoral blood pressure waveform by blind sources separation.

Background: Central blood pressure (cBP) is a better indicator of cardiovascular morbidity and mortality than peripheral BP (pBP). However, direct cBP measurement requires invasive techniques and indirect cBP measurement is based on rigid and empirical transfer functions applied to pBP. Thus, development of a personalized and well-validated method for non-invasive derivation of cBP from pBP is necessary to facilitate the clinical routine. The purpose of the present study was to develop a novel blind source separation tool to separate a single recording of pBP into their pressure waveforms composing its dynamics, to identify the compounds that lead to pressure waveform distortion at the periphery, and to estimate the cBP. The approach is patient-specific and extracts the underlying blind pressure waveforms in pBP without additional brachial cuff calibration or any a priori assumption on the arterial model. Methods: The intra-arterial femoral BPfe and intra-aortic pressure BPao were anonymized digital recordings from previous routine cardiac catheterizations of eight patients at the German Heart Centre Berlin. The underlying pressure waveforms in BPfe were extracted by the single-channel independent component analysis (SCICA). The accuracy of the SCICA model to estimate the whole cBP waveform was evaluated by the mean absolute error (MAE), the root mean square error (RMSE), the relative RMSE (RRMSE), and the intraclass correlation coefficient (ICC). The agreement between the intra-aortic and estimated parameters including systolic (SBP), diastolic (DBP), mean arterial pressure (MAP), and pulse pressure (PP) was evaluated by the regression and Bland-Altman analyses. Results: The SCICA tool estimated the cBP waveform non-invasively from the intra-arterial BPfe with an MAE of 0.159 ± 1.629, an RMSE of 5.153 ± 0.957 mmHg, an RRMSE of 5.424 ± 1.304%, and an ICC of 0.94, as well as two waveforms contributing to morphological distortion at the femoral artery. The regression analysis showed a strong linear trend between the estimated and intra-aortic SBP, DBP, MAP, and PP with high coefficient of determination R2 of 0.98, 0.99, 0.99, and 0.97 respectively. The Bland-Altman plots demonstrated good agreement between estimated and intra-aortic parameters with a mean error and a standard deviation of difference of -0.54 ± 2.42 mmHg [95% confidence interval (CI): -5.28 to 4.20] for SBP, -1.97 ± 1.62 mmHg (95% CI: -5.14 to 1.20) for DBP, -1.49 ± 1.40 mmHg (95% CI: -4.25 to 1.26) for MAP, and 1.43 ± 2.79 mmHg (95% CI: -4.03 to 6.90) for PP. Conclusions: The SCICA approach is a powerful tool that identifies sources contributing to morphological distortion at peripheral arteries and estimates cBP.

Mental and physiological wellbeing while rowing across the North Atlantic: a single-case study of subjective versus objective data.

Introduction: Unassisted rowing across the Atlantic Ocean is an extreme undertaking challenging the human body in every possible way. The reported rowing journey lasted for 42 days in a small vessel with 12 rowers, each rowing for 12 h a day, broken into 3 h shifts. This schedule disrupts the natural circadian cycle and autonomic balance, affecting subjective and objective wellbeing and sleep quality, that lack continuous empirical quantification. Methods: With a self-reported questionnaire and objective heart rate variability measurements every second day in a single female rower, we monitor evolutions of the subjective sleep quality and mental wellbeing as well as autonomic body control over the journey duration. We evaluate the hypothesis that extreme rowing impairs subjective and objective data in a similar way over time and that 3 h shifts diminish the circadian rhythm of the autonomic body control. Results: The sleep quality was mainly influenced by wake ups during sleep, while mental wellbeing was predominantly influenced by physical exhaustion. The perceived sleep quality and wellbeing dropped 2-3 days after the start with the rower not yet accommodated, in the middle of the journey with major wake ups, and again 5-6 days prior to the end with major exhaustion of the participant. Evolutions of the subjective perceptions diverge from that of the heart rate variability. The body's autonomic recovery during short sleep periods progressively decreases over the journey duration while the vagal activity rises and the sympathovagal balance shifts towards vagal tone. The shifts of 3 h weaken the circadian rhythm of the heart rate variability. Discussion: Our results demonstrate how human body meets extreme mental and physical exhaustion on the high seas. The gained physiological and psychological insights also offer a basis for effective preparation of undertakings involving extreme physical exhaustion and sleep deprivation.

Randomized controlled study to evaluate the safety and clinical impact of percutaneous auricular vagus nerve stimulation in patients with severe COVID-19.

Introduction: A severe course of COVID-19 is characterized by a hyperinflammatory state resulting in acute respiratory distress syndrome or even multi-organ failure along a derailed sympatho-vagal balance. Methods: In this prospective, randomized study, we evaluate the hypothesis that percutaneous minimally invasive auricular vagus nerve stimulation (aVNS) is a safe procedure and might reduce the rate of clinical complications in patients with severe course of COVID-19. In our study, patients with SARS-CoV-2 infection admitted to the intensive care unit with moderate-to-severe acute respiratory distress syndrome, however without invasive ventilation yet, were included and following randomization assigned to a group receiving aVNS four times per 24 h for 3 h and a group receiving standard of care (SOC). Results: A total of 12 patients were included (six in the aVNS and six in the SOC group). No side effects in aVNS were reported, especially no significant pain at device placement or during stimulation at the stimulation site or significant headache or bleeding after or during device placement or lasting skin irritation. There was no significant difference in the aVNS and SOC groups between the length of stay in the intensive care unit and at the hospital, bradycardia, delirium, or 90-day mortality. In the SOC group, five of six patients required invasive mechanical ventilation during their stay at hospital and 60% of them venovenous extracorporeal membrane oxygenation, compared to three of six patients and 0% in the aVNS group (p = 0.545 and p = 0.061). Discussion: Vagus nerve stimulation in patients with severe COVID-19 is a safe and feasible method. Our data showed a trend to a reduction of progression to the need of invasive ventilation and venovenous extracorporeal membrane oxygenation which encourages further research with larger patient samples.

Handheld Device Measures Cardiovascular Effects of Cognitive and Physical Stress.

Stress is an increasing burden for our society and related to cardiovascular (CV) parameters and diseases. Effects of mental or physical stress were observed in CV parameters during task completion and recovery. These effects were measured using a novel handheld device, which can be incorporated in mHealth solutions.

Induced pain affects auricular and body biosignals: From cold stressor to deep breathing.

Pain affects every fifth adult worldwide and is a significant health problem. From a physiological perspective, pain is a protective reaction that restricts physical functions and causes responses in physiological systems. These responses are accessible for evaluation via recorded biosignals and can be favorably used as feedback in active pain therapy via auricular vagus nerve stimulation (aVNS). The aim of this study is to assess the significance of diverse parameters of biosignals with respect to their deflection from cold stressor to deep breathing and their suitability for use as biofeedback in aVNS stimulator. Seventy-eight volunteers participated in two cold pressors and one deep breathing test. Three targeted physiological parameters (RR interval of electrocardiogram, cardiac deflection magnitude Z AC of ear impedance signal, and cardiac deflection magnitude PPG AC of finger photoplethysmogram) and two reference parameters (systolic and diastolic blood pressures BP S and BP D) were derived and monitored. The results show that the cold water decreases the medians of targeted parameters (by 5.6, 9.3%, and 8.0% of RR, Z AC, and PPG AC, respectively) and increases the medians of reference parameters (by 7.1% and 6.1% of BP S and BP D, respectively), with opposite changes in deep breathing. Increasing pain level from relatively mild to moderate/strong with cold stressor varies the medians of targeted and reference parameters in the range from 0.5% to 6.0% (e.g., 2.9% for RR, Z AC and 6.0% for BP D). The physiological footprints of painful cold stressor and relaxing deep breathing were shown for auricular and non-auricular biosignals. The investigated targeted parameters can be used as biofeedback to close the loop in aVNS to personalize the pain therapy and increase its compliance.

Vagus Nerve Stimulation: A Personalized Therapeutic Approach for Crohn's and Other Inflammatory Bowel Diseases.

Inflammatory bowel diseases, including Crohn's disease and ulcerative colitis, are incurable autoimmune diseases characterized by chronic inflammation of the gastrointestinal tract. There is increasing evidence that inappropriate interaction between the enteric nervous system and central nervous system and/or low activity of the vagus nerve, which connects the enteric and central nervous systems, could play a crucial role in their pathogenesis. Therefore, it has been suggested that appropriate neuroprosthetic stimulation of the vagus nerve could lead to the modulation of the inflammation of the gastrointestinal tract and consequent long-term control of these autoimmune diseases. In the present paper, we provide a comprehensive overview of (1) the cellular and molecular bases of the immune system, (2) the way central and enteric nervous systems interact and contribute to the immune responses, (3) the pathogenesis of the inflammatory bowel disease, and (4) the therapeutic use of vagus nerve stimulation, and in particular, the transcutaneous stimulation of the auricular branch of the vagus nerve. Then, we expose the working hypotheses for the modulation of the molecular processes that are responsible for intestinal inflammation in autoimmune diseases and the way we could develop personalized neuroprosthetic therapeutic devices and procedures in favor of the patients.

Percutaneous Auricular Vagus Nerve Stimulation Reduces Inflammation in Critical Covid-19 Patients.

Covid-19 is an infectious disease associated with cytokine storms and derailed sympatho-vagal balance leading to respiratory distress, hypoxemia and cardiovascular damage. We applied the auricular vagus nerve stimulation to modulate the parasympathetic nervous system, activate the associated anti-inflammatory pathways, and reestablish the abnormal sympatho-vagal balance. aVNS is performed percutaneously using miniature needle electrodes in ear regions innervated by the auricular vagus nerve. In terms of a randomized prospective study, chronic aVNS is started in critical, but not yet ventilated Covid-19 patients during their stay at the intensive care unit. The results show decreased pro-inflammatory parameters, e.g. a reduction of CRP levels by 32% after 1 day of aVNS and 80% over 7 days (from the mean 151.9 mg/dl to 31.5 mg/dl) or similarly a reduction of TNFalpha levels by 58.1% over 7 days (from a mean 19.3 pg/ml to 8.1 pg/ml) and coagulation parameters, e.g. reduction of DDIMER levels by 66% over 7 days (from a mean 4.5 µg/ml to 1.5 µg/ml) and increased anti-inflammatory parameters, e.g. an increase of IL-10 levels by 66% over 7 days (from the mean 2.7 pg/ml to 7 pg/ml) over the aVNS duration without collateral effects. aVNS proved to be a safe clinical procedure and could effectively supplement treatment of critical Covid-19 patients while preventing devastating over-inflammation.

Auricular vagus nerve stimulator for closed-loop biofeedback-based operation.

Auricular vagus nerve stimulation (aVNS) is a novel neuromodulatory therapy used for treatment of various chronic systemic disorders. Currently, aVNS is non-individualized, disregarding the physiological state of the patient and therefore making it difficult to reach optimum therapeutic outcomes. A closed-loop aVNS system is required to avoid over-stimulation and under-stimulation of patients, leading to personalized and thus improved therapy. This can be achieved by continuous monitoring of individual physiological parameters that serve as a basis for the selection of optimal aVNS settings. In this work we developed a novel aVNS hardware for closed-loop application, which utilizes cardiorespiratory sensing using embedded sensors (and/or external sensors), processes and analyzes the acquired data in real-time, and directly governs settings of aVNS. We show in-lab that aVNS stimulation can be arbitrarily synchronized with respiratory and cardiac phases (as derived from respiration belt, electrocardiography and/or photo plethysmography) while mimicking baroreceptor-related afferent input along the vagus nerve projecting into the brain. Our designed system identified > 90% of all respiratory and cardiac cycles and activated stimulation at the target point with a precision of ± 100 ms despite the intrinsic respiratory and heart rate variability reducing the predictability. The developed system offers a solid basis for future clinical research into closed-loop aVNS in favour of personalized therapy.

Integrated Platform for the Management of Chronic Low Back Pain.

BACKGROUND: Chronic low back pain is a global health problem having a tremendous effect on the quality of life of patients. OBJECTIVES: An online therapy management system (TMS) is developed for comprehensive management of chronic low back pain patients. METHODS: A smartphone and a web app are built based on the Keep-In-Touch Telehealth Platform. The smartphone app allows entering patient reported outcomes and connection to third party devices to monitor physiological data and parameters of therapy. RESULTS: The TMS has been realized and a wearable auricular vagus nerve stimulation device has been integrated. The TMS is currently evaluated in a randomized clinical trial.

A comparison between left ventricular ejection time measurement methods during physiological changes induced by simulated microgravity.

NEW FINDINGS: What is the central question of this study? First, we validated easy-to-use oscillometric left ventricular ejection time (LVET) against echocardiographic LVET. Second, we investigated progression of left ventricular ejection time index (LVETI), pre-ejection period index (PEPI), total electromechanical systole index (QS2I) and PEP/LVET ratio during 60 days of head-down tilt (HDT). What is the main finding and its importance? The LVETosci and LVETecho showed good agreement in effect direction. Hence, LVETosci might be useful to evaluate cardiovascular responses during space flight. Moreover, the approach might be useful for individual follow-up of patients with altered ejection times. Furthermore, significant effects of 60 days of HDT were captured by measurements of LVETI, PEPI, QS2I and PEP/LVET ratio. ABSTRACT: Systolic time intervals that are easy to detect might be used as parameters reflecting cardiovascular deconditioning. We compared left ventricular ejection time (LVET) measured via ultrasound Doppler on the left ventricular outflow tract with oscillometrically measured LVET, measured at the brachialis. Furthermore, we assessed the progression of the left ventricular ejection time index (LVETI), the pre-ejection period index (PEPI), the Weissler index (PEP/LVET) and the total electromechanical systole index (QS2I) during prolonged strict head-down tilt (HDT) bed rest, including 16 male and eight female subjects. Simultaneous oscillometric and echocardiographic LVET measurements showed significant correlation (r = 0.53 with P = 0.0084 before bed rest and r = 0.73 with P < 0.05 on the last day of bed rest). The shortening of LVET during HDT bed rest measured with both approaches was highly concordant in their effect direction, with a concordance rate of 0.96. Our results also demonstrated a significant decrease of LVETI (P < 0.0001) and QS2I (P = 0.0992) and a prolongation of PEPI (P = 0.0049) and PEP/LVET (P = 0.0003) during HDT bed rest over 60 days. Four days after bed rest, LVETI recovered completely to its baseline value. Owing to the relationship between shortening of LVETI and heart failure progression, the easy-to-use oscillometric method might not only be a useful way to evaluate the cardiovascular system during space flights, but could also be of high value in a clinical setting.

Case Report: Auricular vagus nerve stimulation possibly alleviates COVID-19 disease on a high-risk patient.

Introduction: SARS-CoV-2 is a highly contagious virus that was identified as the cause of COVID-19 disease in early 2020. The infection is clinically similar to interstitial pneumonia and acute respiratory distress syndrome (ARDS) and often shows cardiovascular damage. Patients with cardiovascular risk factors are more prone to COVID-19 disease and their sequelae. Due to the anti-inflammatory effect and the improvement in pulmonary function, auricular vagus nerve stimulation (aVNS) therapy might alleviate a COVID-19 infection. Patient and Methods: A high-risk patient with cardiovascular diseases and Implantable Cardioverter Defibrillator (ICD), type 2 diabetes and peripheral arterial disease IV, according to Rutherford`s classification, became infected with COVID-19. The patient underwent wound surgery because of an infected necrosis with a methicillin-resistant Staphylococcus aureus (MRSA) of his small toe and was already on aVNS therapy to relieve his leg pain and improve microcirculation. AVNS was performed with the AuriStim device (Multisana GmbH, Austria), which stimulates vagally innervated regions of the auricle by administering electrical stimulation via percutaneous electrodes for 6 weeks. Results: The multimorbid high-risk patient, who was expected to go through a severe course of the COVID-19 disease, showed hardly any symptoms during ongoing aVNS therapy, while other family members, being much younger and healthy suffered from a more serious course with headache, pneumonia and general weakness. Conclusion: The auricular vagus nerve stimulation is a clinically tested and safe procedure and might represent an alternative and effective way of treating COVID-19 disease. Nevertheless, due to several limitations of this case report, randomized controlled studies are needed to evaluate the efficacy of aVNS therapy on COVID-19 disease.

Visualization of Complex Processes in Cardiovascular System during Electrical Auricular Vagus Nerve Stimulation.

The analysis of human physiological systems from the point of view of complex systems theory remains a very ambitious task. The complexity of the problem often encourages the use of innovative mathematical methods analyzing the processes that take place in space and time. The main goal of this paper is to visualize the cardiovascular system during auricular vagus nerve stimulation (aVNS) using the matrix differences to evaluate the dynamic signal interfaces by cointegrating the initial signal data into the matrices during each case. Algebraic relationships between RR/JT and JT/QRS cardiac intervals are used not only to track the cardiovascular changes during aVNS but also to characterize individual features of the person during the transit through the therapy. This paper presents the computational techniques that can visualize the complex dynamical processes taking place in the cardiovascular system using the electrical aVNS therapy. Four healthy volunteers participated in two verum and two placebo experiments. We discovered that the body's reaction to the stimulation was very different in each of the cases, but the presented techniques opened new possibilities for a novel interpretation of the dynamics of the cardiovascular system.

Cardiovagal Baroreflex Hysteresis Using Ellipses in Response to Postural Changes.

The cardiovagal branch of the baroreflex is of high clinical relevance when detecting disturbances of the autonomic nervous system. The hysteresis of the baroreflex is assessed using provoked and spontaneous changes in blood pressure. We propose a novel ellipse analysis to characterize hysteresis of the spontaneous respiration-related cardiovagal baroreflex for orthostatic test. Up and down sequences of pressure changes as well as the working point of baroreflex are considered. The EuroBaVar data set for supine and standing was employed to extract heartbeat intervals and blood pressure values. The latter values formed polygons into which a bivariate normal distribution was fitted with its properties determining proposed ellipses of baroreflex. More than 80% of ellipses are formed out of nonoverlapping and delayed up and down sequences highlighting baroreflex hysteresis. In the supine position, the ellipses are more elongated (by about 46%) and steeper (by about 4.3° as median) than standing, indicating larger heart interval variability (70.7 versus 47.9 ms) and smaller blood pressure variability (5.8 versus 8.9 mmHg) in supine. The ellipses show a higher baroreflex sensitivity for supine (15.7 ms/mmHg as median) than standing (7 ms/mmHg). The center of the ellipse moves from supine to standing, which describes the overall sigmoid shape of the baroreflex with the moving working point. In contrast to regression analysis, the proposed method considers gain and set-point changes during respiration, offers instructive insights into the resulting hysteresis of the spontaneous cardiovagal baroreflex with respiration as stimuli, and provides a new tool for its future analysis.

Bursted auricular vagus nerve stimulation alters heart rate variability in healthy subjects.

Objective.Recent research suggests that percutaneous auricular vagus nerve stimulation (pVNS) beneficially modulates the autonomic nervous system (ANS). Bursted pVNS seems to be efficient for nerve excitation. Bursted pVNS effects on cardiac autonomic modulation are not disclosed yet.Approach.For the first time, the present study evaluates the effect of pVNS on cardiac autonomic modulation in healthy subjects (n = 9) using two distinct bursted stimulation patterns (biphasic and triphasic stimulation) and heart rate variability analysis (HRV). Stimulation was delivered via four needle electrodes in vagally innervated regions of the right auricle. Each of the two bursted stimulation patterns was applied twice in randomized order over four consecutive stimulation sessions per subject.Main results.Bursted pVNS did not change heart rate, blood pressure, and inflammatory parameters in study subjects. pVNS significantly increased the standard deviation of heart inter-beat intervals, from 46.39 ± 10.4 ms to 63.46 ± 22.47 ms (p < 0.05), and the total power of HRV, from 1475.7 ± 616.13 ms2to 3190.5 ± 2037.0 ms2(p < 0.05). The high frequency (HF) power, the low frequency (LF) power, and theLF/HFratio did not change during bursted pVNS. Both stimulation patterns did not show any significant differences in cardiac autonomic modulation. Stimulation intensity to reach a tingling sensation was significantly lower in triphasic compared to biphasic stimulation (p< 0.05). Bursted stimulation was well tolerated.Significance.Bursted pVNS seems to affect cardiac autonomic modulation in healthy subjects, with no difference between biphasic and triphasic stimulation, the latter requiring lower stimulation intensities. These findings foster implementation of more efficient pVNS stimulation.

3D Camera and Pulse Oximeter for Respiratory Events Detection.

OBJECTIVE: The purpose of this study was to derive a respiratory movement signal from a 3D time-of-flight camera and to investigate if it can be used in combination with SpO2 to detect respiratory events comparable to polysomnography (PSG) based detection. METHODS: We derived a respiratory signal from a 3D camera and developed a new algorithm that detects reduced respiratory movement and SpO2 desaturation to score respiratory events. The method was tested on 61 patients' synchronized 3D video and PSG recordings. The predicted apnea-hypopnea index (AHI), calculated based on total sleep time, and predicted severity were compared to manual PSG annotations (manualPSG). Predicted AHI evaluation, measured by intraclass correlation (ICC), and severity classification were performed. Furthermore, the results were evaluated by 30-second epoch analysis, labelled either as respiratory event or normal breathing, wherein the accuracy, sensitivity, specificity and Cohen's kappa were calculated. RESULTS: The predicted AHI scored an ICC r = 0.94 (0.90 - 0.96 at 95% confidence interval, p < 0.001) compared to manualPSG. Severity classification scored 80% accuracy, with no misclassification by more than one severity level. Based on 30-second epoch analysis, the method scored a Cohen's kappa = 0.72, accuracy = 0.88, sensitivity = 0.80, and specificity = 0.91. CONCLUSION: Our detection method using SpO2 and 3D camera had excellent reliability and substantial agreement with PSG-based scoring. SIGNIFICANCE: This method showed the potential to reliably detect respiratory events without airflow and respiratory belt sensors, sensors that can be uncomfortable to patients and susceptible to movement artefacts.

Measuring Arterial Stiffness in a Head-Down Tilt Bed Rest Study: A Multisensor Approach.

Arterial stiffness is an important indicator for vascular aging and an independent predictor for cardiovascular diseases. During space flights or simulated space flights by prolonged head-down tilt bed rest, major cardiovascular alterations occur. However, the changes in arterial stiffness are not fully understood yet. Thus, we aimed to develop a setup for the measurement of arterial stiffness during prolonged head-down tilt bed rest, which incorporates several combinations of biosignals and measurement locations for the determination of pulse transit times. By performing measurements using this setup on female and male subjects, we intend to deepen the understanding of changes in arterial stiffness during prolonged head-down tilt bed rest. This work describes and visualizes the complete setup as well as our measurement protocols and algorithms used. The result section shows the successful recording of baseline signals before the bed rest study and visualizes the synchronized recordings of pulse waves measured on different sides of the body. Thus, it is feasible to use the presented setup in bed rest studies.

Non-invasive Auricular Vagus Nerve Stimulation as a Potential Treatment for Covid19-Originated Acute Respiratory Distress Syndrome.

Background: Covid-19 is an infectious disease caused by an invasion of the alveolar epithelial cells by coronavirus 19. The most severe outcome of the disease is the Acute Respiratory Distress Syndrome (ARDS) combined with hypoxemia and cardiovascular damage. ARDS and co-morbidities are associated with inflammatory cytokine storms, sympathetic hyperactivity, and respiratory dysfunction. Hypothesis: In the present paper, we present and justify a novel potential treatment for Covid19-originated ARDS and associated co-morbidities, based on the non-invasive stimulation of the auricular branch of the vagus nerve. Methods: Auricular vagus nerve stimulation activates the parasympathetic system including anti-inflammatory pathways (the cholinergic anti-inflammatory pathway and the hypothalamic pituitary adrenal axis) while regulating the abnormal sympatho-vagal balance and improving respiratory control. Results: Along the paper (1) we expose the role of the parasympathetic system and the vagus nerve in the control of inflammatory processes (2) we formulate our physiological and methodological hypotheses (3) we provide a large body of clinical and preclinical data that support the favorable effects of auricular vagus nerve stimulation in inflammation, sympatho-vagal balance as well as in respiratory and cardiac ailments, and (4) we list the (few) possible collateral effects of the treatment. Finally, we discuss auricular vagus nerve stimulation protective potential, especially in the elderly and co-morbid population with already reduced parasympathetic response. Conclusions: Auricular vagus nerve stimulation is a safe clinical procedure and it could be either an effective treatment for ARDS originated by Covid-19 and similar viruses or a supplementary treatment to actual ARDS therapeutic approaches.