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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.

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.

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.

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.