Closed-loop vagus nerve stimulation. Patient-tailored therapy or undirected treatment?

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 (<i>P</i>=.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. CLINICALTRIAL ClinicalTrials.gov NCT02992899; https://clinicaltrials.gov/ct2/show/NCT02992899 INTERNATIONAL REGISTERED REPORT RR2-10.1016/j.brs.2019.08.002

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

JMIR mhealth and uhealth ◽

10.2196/20488 ◽

2020 ◽

Vol 8 (9) ◽

pp. e20488 ◽

Cited By ~ 4

Author(s):

Asim H Gazi ◽

Nil Z Gurel ◽

Kristine L S Richardson ◽

Matthew T Wittbrodt ◽

Amit J Shah ◽

...

Keyword(s):

Heart Rate ◽

Vagus Nerve ◽

State Space ◽

Nerve Stimulation ◽

Vagus Nerve Stimulation ◽

Closed Loop ◽

Promising Alternative ◽

Wearable Sensing ◽

Space Modeling ◽

Mean Square Errors

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

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Vagus Nerve Stimulation Paired With Rehabilitative Training Enhances Motor Recovery After Bilateral Spinal Cord Injury to Cervical Forelimb Motor Pools

Neurorehabilitation and Neural Repair ◽

10.1177/1545968319895480 ◽

2020 ◽

Vol 34 (3) ◽

pp. 200-209 ◽

Cited By ~ 2

Author(s):

Michael J. Darrow ◽

Miranda Torres ◽

Maria J. Sosa ◽

Tanya T. Danaphongse ◽

Zainab Haider ◽

...

Keyword(s):

Spinal Cord ◽

Spinal Cord Injury ◽

Vagus Nerve ◽

Motor Neurons ◽

Nerve Stimulation ◽

Vagus Nerve Stimulation ◽

Closed Loop ◽

Neurological Injury ◽

Injury Model ◽

Cord Injury

Closed-loop vagus nerve stimulation (VNS) paired with rehabilitative training has emerged as a strategy to enhance recovery after neurological injury. Previous studies demonstrate that brief bursts of closed-loop VNS paired with rehabilitative training substantially improve recovery of forelimb motor function in models of unilateral and bilateral contusive spinal cord injury (SCI) at spinal level C5/6. While these findings provide initial evidence of the utility of VNS for SCI, the injury model used in these studies spares the majority of alpha motor neurons originating in C7-T1 that innervate distal forelimb muscles. Because the clinical manifestation of SCI in many patients involves damage at these levels, it is important to define whether damage to the distal forelimb motor neuron pools limits VNS-dependent recovery. In this study, we assessed recovery of forelimb function in rats that received a bilateral incomplete contusive SCI at C7/8 and underwent extensive rehabilitative training with or without paired VNS. The study design, including planned sample size, assessments, and statistical comparisons, was preregistered prior to beginning data collection ( https://osf.io/ysvgf/ ). VNS paired with rehabilitative training significantly improved recovery of volitional forelimb strength compared to equivalent rehabilitative training without VNS. Additionally, VNS-dependent enhancement of recovery generalized to 2 similar, but untrained, forelimb tasks. These findings indicate that damage to alpha motor neurons does not prevent VNS-dependent enhancement of recovery and provides additional evidence to support the evaluation of closed-loop VNS paired with rehabilitation in patients with incomplete cervical SCI.

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