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.

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.

Cardiovascular pathophysiology from the cardioneural perspective and its clinical applications.

Coronary heart disease and psychological stress factors such as depression are prevalent and associated with high morbidity/mortality; they are also challenging to manage, especially when treated in isolation of each other. Recent advances support an integrated approach to their management that is built on a foundation of an extensive, multi-component network of neurological structures. In this review, we describe this extensive cardioneural network that encompasses the heart, brain, spinal cord, and ganglia throughout the body, and then discuss ambulatory and laboratory-based non-invasive measures of this network that both measure psychological stress and heart disease severity. Lastly, we discuss their potential transformative clinical and public health applications, and also possible cardioneural interventions such as exercise and biofeedback.

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.

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.

Hypoglossal Nerve Stimulation and Heart Rate Variability: Analysis of STAR Trial Responders.

OBJECTIVE: Hypoglossal nerve stimulation represents a novel therapy for the treatment of moderate-severe obstructive sleep apnea; nonetheless, its cardiovascular effects are not known. We examine the effects of hypoglossal nerve stimulation on heart rate variability, a measure of autonomic function. STUDY DESIGN: Substudy of the STAR trial (Stimulation Therapy for Apnea Reduction): a multicenter prospective single-group cohort. SETTING: Academic and private practice centers in the United States and Europe. SUBJECTS AND METHODS: A subset of responder participants (n = 46) from the STAR trial was randomized to therapy withdrawal or therapy maintenance 12 months after surgery. Heart rate variability analysis included standard deviation of the R-R interval (SDNN), low-frequency power of the R-R interval, and high-frequency power of the R-R interval. Analysis was performed by sleep with 5-minute sliding window epochs during baseline, 12 months, and the maintenance/withdrawal period. RESULTS: A significant improvement from baseline to 12 months in heart rate variability was seen for SDNN and low frequency across all sleep stages. SDNN analysis demonstrated no change in the wake period (mean ± SD: 0.042 ± 0.01 vs 0.077 ± 0.07, P = .19). Reduction in SDNN was correlated to improvement in apnea-hypopnea index ( r = 0.39, P = .03). In the therapy withdrawal group, no significant changes in SDNN were seen for N1/N2, N3, or rapid eye movement sleep. CONCLUSION: Hypoglossal nerve stimulation therapy appears to reduce heart rate variability during sleep. This reduction was not affected by a 1-week withdrawal period. Larger prospective studies are required to better understand the effect of hypoglossal nerve stimulation on autonomic dysfunction in obstructive sleep apnea.

Cardiovascular endpoints for obstructive sleep apnea with twelfth cranial nerve stimulation (CARDIOSA-12): Rationale and methods.

OBJECTIVES/HYPOTHESIS: To determine the effect of therapeutic levels of hypoglossal nerve stimulation therapy (HGNS), compared to subtherapeutic levels of HGNS, on 24-hour ambulatory blood pressure, sympathetic activity, and vascular function. STUDY DESIGN: Double-blind, sham-controlled, randomized crossover trial of 10-week duration at a university medical center METHODS: The target enrollment is 60 randomly assigned subjects. Interventions are active versus sham (subtherapeutic) HGNS therapy. RESULTS: The primary outcome is 24-hour ambulatory systolic blood pressure. Secondary outcomes include 24-hour ambulatory diastolic blood pressure, nocturnal systolic and diastolic pressure, muscle sympathetic nerve activity, pre-ejection period, flow-mediated dilation, and pulse wave velocity. CONCLUSIONS: The Cardiovascular Endpoints for Obstructive Sleep Apnea With Twelfth Cranial Nerve Stimulation study is designed to examine obstructive sleep apnea and test the effects of HGNS on the cardiovascular system through a sham-controlled trial in patients with moderate-severe obstructive sleep apnea. LEVEL OF EVIDENCE: 1 Laryngoscope, 2635-2643, 2018.

Attitudes of inner city patients with cardiovascular disease towards meditation.

OBJECTIVES: Meditation is a stress reduction intervention that is of potential benefit to patients with cardiovascular disease, but its interest in inner city cardiology patients is unknown. We surveyed patients at an inner city cardiology clinic about their interest in learning meditation and the impact of stress on their lifestyles. METHODS: A survey was distributed to 215 consecutive patients in an inner city cardiology clinic. Chi-square tests were used to compare those interested and not interested in meditation. RESULTS: Of the 215 surveys, 54 were excluded because of 2 or more missing responses, leaving 161 for analysis. The mean age was 61 (+/- 16.5) years; 59% were female, 37% were black non-Hispanic, and 34% were Hispanic, and 18% were white. Overall, 46% expressed interest in learning meditation, and 64% agreed that less stress would facilitate living a healthy lifestyle. In subgroup analysis, the highest levels of interest in meditation classes occurred in patients who were younger than 65 years old (69% interested) and those who agreed that less stress would facilitate living a healthy lifestyle (71% interested). CONCLUSION: Many of the patients at an inner city cardiology clinic may have interest in learning meditation. Given the effects of stress in this population, clinical trials involving meditation are warranted.