Application of Noninvasive Vagal Nerve Stimulation to Stress-Related Psychiatric Disorders

James Douglas Bremner, Nil Z Gurel, Matthew T Wittbrodt, Mobashir H Shandhi, Mark H Rapaport, Jonathon A Nye, Bradley D Pearce, Viola Vaccarino, Amit J Shah, Jeanie Park, Marom Bikson, Omer T Inan, James Douglas Bremner, Nil Z Gurel, Matthew T Wittbrodt, Mobashir H Shandhi, Mark H Rapaport, Jonathon A Nye, Bradley D Pearce, Viola Vaccarino, Amit J Shah, Jeanie Park, Marom Bikson, Omer T Inan

Abstract

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.

Keywords: PTSD; VNS; depressive disorders; inflammation; interferon; interleukin-6; posttraumatic; stress; stress disorders; sympathetic; vagal nerve stimulation; vagus nerve.

Conflict of interest statement

J.D.B. has research funding support from ElectroCore LLC who also donated devices used in the research reviewed here.

Figures

Figure 1
Figure 1
Model of effects of transcutaneous Vagal Nerve Stimulation (VNS) on physiological function. Stimulation of the vagus nerve in the neck as it passes through the carotid sheath (transcutaneous cervical VNS (tcVNS)) or in the ear (transcutaneous auricular VNS (taVNS)) activates the Nucleus Tractus Solitarius (NTS) in the brainstem, which has projections to other key brainstem nuclei containing cell bodies for neurotransmitters, including the locus coeruleus (LC), site of norepinephrine (NE), pedunculopontine nucleus (PPN) for acetylcholine (Ach), and raphe nucleus (RN) for serotonin (5-HT), and the reticular activating system (RAS). These regions, in turn, originate pathways to multiple brain areas involved in modulation of fear and emotion, as well as memory and neuroplasticity, including the anterior cingulate, hippocampus, amygdala, and cortex (including insula). Vagal efferents project to peripheral cardiovascular, autonomic, and inflammatory pathways. The vagus also projects information from the periphery back to the brain through afferents.
Figure 2
Figure 2
Study protocol undergoing since 2017. Physiological sensing data is collected continuously throughout three study days. The protocol timeline depicts neutral and trauma scripts, HR-PET scans (first day), mental stress tasks of public speech and mental arithmetic (second and third day), stimulation with active tcVNS or sham, and blood draws (all days).

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