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Noninvasive Vagal Nerve Stimulation Effects on Anger Response

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Abstract

Non-invasive vagus nerve stimulation (n-VNS) devices offer non-surgical alternatives to implantable VNS therapy for possible treatment of autonomic nervous system disorders. In this work, we investigate the patient outcomes for n-VNS devices applied in tandem with traumatic stress. A total of 25 human subjects participated in a double-blind study, half undergoing active n-VNS and half undergoing sham stimulus. The protocol included audible delivery of neutral recordings (voice recordings about pleasant scenery) and traumatic stress recordings (personalized voice recordings based on prior traumatic experiences). Stimulation was administered immediately after the traumatic stress recordings. Patient outcomes were quantified with visual analog ratings of five mood dimensions: nervousness, anxiety, fear, anger, highness measured during baseline, after each neutral recording, and after each traumatic stress recording followed by n-VNS. Our results reveal that the sham group experienced significantly increased anger responses after hearing traumatic stressors, compared to baseline (p<0.05), whereas the active group did not show a significant anger response (p=0.18). These findings suggest that active n-VNS blocks adverse behavioral responses to reminders of traumatic stress. N-VNS may a useful intervention for stress-related psychiatric disorders.
AbstractNon-invasive vagus nerve stimulation (n-VNS)
devices offer non-surgical alternatives to implantable VNS
therapy for possible treatment of autonomic nervous system
disorders. In this work, we investigate the patient outcomes for
n-VNS devices applied in tandem with traumatic stress. A total
of 25 human subjects participated in a double-blind study, half
undergoing active n-VNS and half undergoing sham stimulus.
The protocol included audible delivery of neutral recordings
(voice recordings about pleasant scenery) and traumatic stress
recordings (personalized voice recordings based on prior
traumatic experiences). Stimulation was administered
immediately after the traumatic stress recordings. Patient
outcomes were quantified with visual analog ratings of five
mood dimensions: nervousness, anxiety, fear, anger, highness
measured during baseline, after each neutral recording, and
after each traumatic stress recording followed by n-VNS. Our
results reveal that the sham group experienced significantly
increased anger responses after hearing traumatic stressors,
compared to baseline (p<0.05), whereas the active group did not
show a significant anger response (p=0.18). These findings
suggest that active n-VNS blocks adverse behavioral responses
to reminders of traumatic stress. N-VNS may a useful
intervention for stress-related psychiatric disorders.
I. INTRODUCTION
Electrical stimulation of the vagus nerve, one of the major
components of the autonomic nervous system, has clinical
applications for a wide range of disorders [1]. Traditional
stimulation approaches involve surgically implanted vagus
nerve stimulation (VNS) devices that are expensive and
potentially lead to complications from the surgery.
Non-invasive VNS (n-VNS) has the potential to reduce the
shortcomings of implantable VNS. In prior work, we
presented physiological biomarkers of n-VNS that could
quantify the real-time response to acute treatment [2, 3]. In
our current study, we investigate the patient outcomes based
on visual analog scales that represent the current mood state.
II. METHODS
The data were obtained from a double-blind study held in
the Emory University School of Medicine with 25 human
subjects separated into active n-VNS (n = 12) and sham (n =
13) groups. The protocol included audible delivery of neutral
recordings (voice recordings about pleasant scenery to serve
as control) and traumatic stress recordings (personalized voice
recordings based on prior traumatic experiences). Traumatic
This work is based on material supported by the Defense Advanced
Research Projects Agency (DARPA), Arlington, VA, under Cooperative
Agreement N66001-16-2-4054.
N.Z. Gurel, O.T. Inan are with Inan Research Lab, School of Electrical
and Computer Engineering, Georgia Institute of Technology, Atlanta, GA,
30332 (corresponding author e-mail: nil@gatech.edu).
M.T. Wittbrodt, J.D. Bremner, A.J. Shah, V. Vaccarino are with Emory
School of Medicine and Rollins School of Public Health, Atlanta, GA,
30322.
stress recordings were immediately followed with stimulation
using noninvasive handheld devices with the same operation
and appearance (gammaCore). Sham or n-VNS was
administered to each subject six times throughout the session.
Visual analog ratings representing current mood in five
dimensions (nervousness, anxiety, fear, anger, highness) were
obtained during baseline, after each six neutral recordings, and
after each six traumatic stress recordings followed by
stimulation. Data were averaged across each interval and
dimension for each subject. For comparison of each dimension
between three intervals, analysis of variance methods
(Kruskal-Wallis) and post-hoc multiple comparisons (Tukeys
Honestly Significant Difference) were conducted.
III. RESULTS
Anger responses were significantly increased in the sham
group following traumatic scripts compared to baseline
(p=0.01, Figure 1). Anger was not significantly increased
within the active n-VNS group (p=0.18). No differences in
other scales were found between groups. Active n-VNS
blocks anger responses to reminders of traumatic events.
Given the known role of autonomic function in stress-related
behavioral responses including anger, the current findings are
consistent with our prior findings of reduced sympathetic
activity in response to stress [2].
REFERENCES
[1] D. Guiraud et al., "Vagus nerve stimulation: state of the art of
stimulation and recording strategies to address autonomic
function neuromodulation," J Neural Eng, vol. 13, no. 4, p.
041002, Aug 2016.
[2] N. Z. Gurel et al., "Abstract# 36: Toward Wearable Sensing
Enabled Closed-Loop Non-Invasive Vagus Nerve Stimulation: A
Study of Real-Time Physiological Biomarkers," Brain
Stimulation, vol. 12, no. 2, p. e13, August 2019.
[3] N. Z. Gurel et al., "Toward Closed-Loop Transcutaneous Vagus
Nerve Stimulation using Peripheral Cardiovascular Physiological
Biomarkers: A Proof-of-Concept Study," presented at the IEEE
15th International Conference on Wearable and Implantable
Body Sensor Networks (BSN), Las Vegas, NV, 2018.
Noninvasive Vagal Nerve Stimulation Effects on Anger Response
Nil Z. Gurel, Student Member, IEEE, Matthew T. Wittbrodt, Amit J. Shah, Viola Vaccarino, Omer T.
Inan, Senior Member, IEEE, and J. Douglas Bremner
Figure 1. Anger scores classified by device status. (Shades represent
68% confidence intervals, *p<0.05 from baseline to trauma)
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Conference Paper
Full-text available
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.
Article
Objective: Neural signals along the vagus nerve (VN) drive many somatic and autonomic functions. The clinical interest of VN stimulation (VNS) is thus potentially huge and has already been demonstrated in epilepsy. However, side effects are often elicited, in addition to the targeted neuromodulation. Approach: This review examines the state of the art of VNS applied to two emerging modulations of autonomic function: heart failure and obesity, especially morbid obesity. Main results: We report that VNS may benefit from improved stimulation delivery using very advanced technologies. However, most of the results from fundamental animal studies still need to be demonstrated in humans.
Bremner Figure 1. Anger scores classified by device status
  • Matthew T Ieee
  • Amit J Wittbrodt
  • Viola Shah
  • Omer T Vaccarino
  • Senior Inan
  • Member
  • J Ieee
  • Douglas
Noninvasive Vagal Nerve Stimulation Effects on Anger Response Nil Z. Gurel, Student Member, IEEE, Matthew T. Wittbrodt, Amit J. Shah, Viola Vaccarino, Omer T. Inan, Senior Member, IEEE, and J. Douglas Bremner Figure 1. Anger scores classified by device status. (Shades represent 68% confidence intervals, *p<0.05 from baseline to trauma)