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

Abstract

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

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

“…These findings suggest that tcVNS may target the underlying neurobiology of PTSD, in particular noradrenergic and peripheral sympathetic nervous system function. The findings are consistent with our prior studies showing a decrease in sympathetic nervous system activity when tcVNS is paired with traumatic reminders in traumatized individuals ( Gazi et al, 2020 ; Gurel et al, 2020a ; Gurel et al, 2020b ; Gurel et al, 2020e ), as well as numerous studies showing nVNS (taVNS) blocks peripheral sympathetic nervous system function and startle reflex ( Bretherton et al, 2019 ; Clancy et al, 2014 ; Lamb et al, 2017 ). Symptoms of hyperarousal reduced by tcVNS in this study include increased attention and vigilance, being on guard, poor concentration and sleep.…”

“…We showed that tcVNS blocks IL-6 and IFNγ response to traumatic script stress in PTSD ( Bremner et al, 2020a ) and blocks the rise in Pituitary Adenylate Cyclase Activating Peptide (PACAP) over three days of stressful tasks in traumatized subjects with and without PTSD ( Gurel et al, 2020c ). We also previously reported that tcVNS in traumatized healthy human subjects with and without PTSD blocked peripheral sympathetic and enhanced parasympathetic responses both at baseline and in response to both personalized traumatic scripts and mental stressors ( Gazi et al, 2020 ; Gurel et al, 2020a ; Gurel et al, 2020b ; Gurel et al, 2018 ; Gurel et al, 2020d ; Gurel et al, 2020e ) and modulated brain response to traumatic scripts ( Wittbrodt et al, 2020 ), and other studies reported that tcVNS blocked sympathetic function in healthy subjects ( Brock et al, 2017 ; Lerman et al, 2019 ) while taVNS blocked sympathetic function in healthy human subjects ( Badran et al, 2018b ; Bretherton et al, 2019 ; Clancy et al, 2014 ) and patients with co-morbid mild Traumatic Brain Injury (mTBI) and PTSD ( Lamb et al, 2017 ). This work replicated findings in healthy subjects using implanted VNS ( Schomer et al, 2014 ).…”

A method to quantify autonomic nervous system function in healthy, able-bodied individuals

“…Future work may also include other tests, such as a cognitive aptitude assessment, social stress test or mental arithmetic (Bauerly et al, 2019 ; Duschek et al, 2009 ; Gurel et al, 2020a ; Tornatzky & Miczek, 1993 ), that can induce more central nervous system mediated responses and, therefore, increase the utility of EDA, pupil diameter, and other recorded modalities. Recent work has also shown that biomarkers, like HR and PPG amplitude, can be used to predict responses to transcutaneous cervical vagus nerve stimulation (tcVNS) and model dynamic characteristics of an adapting ANS (Gazi et al, 2020 ). While it is unclear how this may scale for other conditions or interventions, modeling biomarker responses can be applied to continuously monitoring vital-sensing devices to calculate real-time risk scores and further comprehensive index values related to autoimmune health.…”

A method to quantify autonomic nervous system function in healthy, able-bodied individuals

“…Future work may also include other tests, such as a cognitive aptitude assessment, social stress test or mental arithmetic (Tornatzky & Miczek, 1993; Duschek et al, 2009; Bauerly et al, 2019; Gurel et al, 2020), that can induce more central nervous system mediated responses and, therefore, increase the utility of EDA, pupil diameter, and other recorded modalities. Recent work has also shown that biomarkers, like heart rate and PPG amplitude, can be used to predict responses to transcutaneous cervical vagus nerve stimulation (tcVNS) and model dynamic characteristics of an adapting ANS (Gazi et al, 2020). While it is unclear how this may scale for other conditions or interventions, modeling biomarker responses can be applied to continuously monitoring vital-sensing devices to calculate real-time risk scores and further comprehensive index values related to autoimmune health…”