Non-invasive Vagus Nerve Stimulation Research Articles

Transcutaneous Vagus Nerve Stimulation (tVNS) Improves High-Confidence Recognition Memory but Not Emotional Word Processing.

Previous clinical research found that invasive vagus nerve stimulation (VNS) enhanced word recognition memory in epileptic patients, an effect assumed to be related to the activation of brainstem arousal systems. In this study, we applied non-invasive transcutaneous auricular VNS (tVNS) to replicate and extend the previous work. Using a single-blind, randomized, between-subject design, 60 healthy volunteers received active or sham stimulation during a lexical decision task, in which emotional and neutral stimuli were classified as words or non-words. In a subsequent recognition memory task (1 day after stimulation), participants' memory performance on these words and their subjective memory confidence were tested. Salivary alpha-amylase (sAA) levels, a putative indirect measure of central noradrenergic activation, were also measured before and after stimulation. During encoding, pleasant words were more accurately detected than neutral and unpleasant words. However, no tVNS effects were observed on task performance or on overall sAA level changes. tVNS also did not modulate overall recognition memory, which was particularly enhanced for pleasant emotional words. However, when hit rates were split based on confidence ratings reflecting familiarity- and recollection-based memory, higher recollection-based memory performance (irrespective of emotional category) was observed during active stimulation than during sham stimulation. To summarize, we replicated prior findings of enhanced processing and memory for emotional (pleasant) words. Whereas tVNS showed no effects on word processing, subtle effects on recollection-based memory performance emerged, which may indicate that tVNS facilitates hippocampus-mediated consolidation processes.

A Randomized Sham-Controlled Cross-Over Study on the Short-Term Effect of Non-Invasive Cervical Vagus Nerve Stimulation on Spinal and Supraspinal Nociception in Healthy Subjects.

The aim of the present study was to test the effects of vagus nerve stimulation (VNS) on the descending pain inhibition, quantified by the nociceptive flexor (RIII) reflex and the conditioned pain modulation (CPM) paradigm, and on supraspinal nociceptive responses, assessed by pain intensity and unpleasantness ratings and late somatosensory evoked potentials (SEPs), in healthy subjects. Non-invasive vagus nerve stimulation (nVNS) showed promising effects on headache and pain treatment. Underlying mechanisms are only incompletely understood but may include the activation of the descending pain inhibitory system and/or the modification of emotional responses to pain. Twenty-seven adult, healthy, and pain-free subjects participated in this double-blind cross-over study conducted at a university research center. They received 4minutes of cervical nVNS or sham stimulation in randomized order. RIII reflexes, pain ratings, and SEPs were assessed before, during, and 5, 15, 30, and 60minutes after nVNS/sham stimulation, followed by CPM testing. The primary outcome was the nVNS effect on the RIII reflex size. Three subjects were excluded after the preparatory session (before randomization), 1 subject was excluded after outlier analysis, leaving 23 for analysis. RIII reflex areas were 917.1±563.8µV×ms (mean±SD) before, 952.4±467.4µV×ms during and 929.2±484.0µV×ms immediately after nVNS and 858.4±489.2µV×ms before, 913.9±539.7µV×ms during and 862.4±476.0µV×ms after sham stimulation, revealing no differences between the immediate effects of nVNS and sham stimulation (F [3,66] =0.67, P=.574). There also were no effects of nVNS over sham on RIII reflex areas up to 60minutes after nVNS (F [1.7,37.4] =1.29, P=.283). Similarly, there was no statistically significant effect of nVNS on pain intensity ratings and thresholds, RIII reflex thresholds, late SEP amplitudes, and the CPM effect, compared to sham. Pain unpleasantness ratings statistically significantly decreased from 4.4±2.4 (NRS 0-10) to 4.1±2.5 during nVNS compared to sham stimulation (F [1,22] =8.74, P=.007), but there were no longer lasting effects (5-60minutes after stimulation). The present study does not support an acute effect of nVNS on descending pain inhibition, pain intensity perception or supraspinal nociception in healthy adults. However, there was a small effect on pain unpleasantness during nVNS, suggesting that nVNS may preferentially act on affective, not somatosensory pain components.

Stimulation of the vagus nerve reduces learning in a go/no-go reinforcement learning task

When facing decisions to approach rewards or to avoid punishments, we often figuratively go with our gut, and the impact of metabolic states such as hunger on motivation are well documented. However, whether and how vagal feedback signals from the gut influence instrumental actions is unknown. Here, we investigated the effect of non-invasive transcutaneous auricular vagus nerve stimulation (taVNS) vs. sham (randomized cross-over design) on approach and avoidance behavior using an established go/no-go reinforcement learning paradigm in 39 healthy human participants (23 female) after an overnight fast. First, mixed-effects logistic regression analysis of choice accuracy showed that taVNS acutely impaired decision-making, p = .041. Computational reinforcement learning models identified the cause of this as a reduction in the learning rate through taVNS (∆α = −0.092, pboot = .002), particularly after punishment (∆αPun = −0.081, pboot = .012 vs. ∆αRew =−0.031, pboot = .22). However, taVNS had no effect on go biases, Pavlovian response biases or response time. Hence, taVNS appeared to influence learning rather than action execution. These results highlight a novel role of vagal afferent input in modulating reinforcement learning by tuning the learning rate according to homeostatic needs.

A review on the alterations in the brain of persistent postural-perceptual dizziness patients and non-pharmacological interventions for its management.

Persistent postural perceptual dizziness (PPPD) is a relatively newer term, and this term is included in the International Classification of Diseases in its 11th revision. The typical features of PPPD include the presence of persistent dizziness, non-spinning vertigo, and unsteadiness, and these symptoms are exacerbated during upright posture, movement, or visual stimuli. Moreover, the structural changes have also been identified in the brains of PPPD patients, particularly in visual, vestibular, and limbic areas. These include a decrease in the volume and gyration of gray matter, a decrease in the blood flow to the cortex region, and alterations in the structural and functional connectivity, particularly in the visual-vestibular networks. Moreover, the impairment in sensory processing is restricted not only to the vestibular and visual regions; instead, there is a generalized impairment in the sensory processing, and thus, there is a multisensory dimension of sensory impairment. Selective serotonin uptake inhibitors and serotonin-norepinephrine reuptake inhibitors are the mainstay drugs for the management of PPPD patients. However, a significant proportion of PPPD patients do not show improvement in response to standard drug therapy. The employment of alternative and complementary treatment strategies, including vestibular rehabilitation therapy, cognitive behavioral therapy, and non-invasive vagal nerve stimulation, is effective in the management of PPPD patients. The present review discusses the alterations in the brains of PPPD patients along with the possible non-pharmacological treatment options in these types of patients.

P26 Inter-ictal molecular phenotyping of the neuro-immune axis in migraine patients under non-invasive cervical vagus nerve stimulation

P26 Inter-ictal molecular phenotyping of the neuro-immune axis in migraine patients under non-invasive cervical vagus nerve stimulation

Inhibition of Trigeminal Nociception by Non-invasive Vagus Nerve Stimulation: Investigating the Role of GABAergic and Serotonergic Pathways in a Model of Episodic Migraine.

Migraine is a prevalent neurological disease that is characterized by unpredictable episodic attacks of intense head pain. The underlying pathology involves sensitization and activation of the trigeminal system. Although non-invasive vagus nerve stimulation (nVNS) is recommended for the treatment of migraine, the abortive mechanism of action is not well-understood. The goal of this study was to compare the ability of nVNS and sumatriptan to inhibit trigeminal activation in two animal models of episodic migraine and to investigate the receptor mechanism of action of nVNS. Nocifensive head withdrawal response was investigated in adult male Sprague Dawley rats using von Frey filaments. To induce trigeminal nociceptor sensitization, complete Freund's adjuvant was injected in the trapezius muscle and trigeminal neurons were activated by exposure to a pungent odor or injection of the nitric oxide donor sodium nitroprusside. Some animals received nVNS or sumatriptan as treatment. Some animals were injected intracisternally with antagonists of GABAA, 5-HT3 or 5-HT7 receptors prior to nVNS since these receptors are implicated in descending modulation. While unsensitized animals exposed to the pungent odor or nitric oxide alone did not exhibit enhanced mechanical nociception, sensitized animals with neck muscle inflammation displayed increased trigeminal nocifensive responses. The enhanced nociceptive response to both stimuli was attenuated by nVNS and sumatriptan. Administration of antagonists of GABAA, 5-HT3, and 5-HT7 receptors in the upper spinal cord suppressed the anti-nocifensive effect of nVNS. Our findings suggest that nVNS inhibits trigeminal activation to a similar degree as sumatriptan in episodic migraine models via involvement of GABAergic and serotonergic signaling to enhance central descending pain modulation.

Efficacy of Non-invasive Vagus Nerve Stimulation for Treatment of Axial Spondyloarthritis Resistant to Biotherapies

Efficacy of Non-invasive Vagus Nerve Stimulation for Treatment of Axial Spondyloarthritis Resistant to Biotherapies

Mechanism of transcutaneous auricular vagus nerve stimulation on polycystic ovary syndrome

Non-invasive transcutaneous auricular vagus nerve stimulation (ta-VNS) is established on the basis of auricular acupuncture and the principle of vagus nerve stimulation (VNS). The results of the comparative study of 4 indications of VNS show that ta-VNS achieves almost the equivalent effect as VNS. Moreover, the ta-VNS is advantageous at safety, economy and portability. Regarding the clinical prevention and treatment of polycystic ovary syndrome (PCOS), it is still controversial for the effect of acupuncture and moxibustion therapy including auricular acupuncture. Moreover, it is the difficulty for the principle of acupoint selection and the treatment mechanism of this therapy to be in line with modern medicine. As neuroendocrine disease, PCOS and the ovary, its target organ are all associated with the vagus nerve. It is a new idea to introduce the ta-VNS in treatment of PCOS by regulating the reproductive and endocrinal disturbance of PCOS in terms of vagus nerve and improving the acupuncture and moxibustion therapy, such as the auricular acupuncture. In the paper, the potential mechanism of the ta-VNS in treatment of PCOS is presented: 1)the ta-VNS treats PCOS by improving insulin resistance; 2)the ta-VNS relieves PCOS-induced psychological disorders through the treatment of depression; 3)the ta-VNS is applicable in treatment of PCOS complications, such as hypertension and diabetes.

Noninvasive vagus nerve stimulation and the trigeminal autonomic reflex: An fMRI study.

The trigeminal autonomic reflex is a physiologic reflex that plays a crucial role in primary headache and particularly in trigeminal autonomic cephalalgias, such as cluster headache. Previous studies have shown that this reflex can be modulated by the vagus nerve, leading to an inhibition of the parasympathetic output of the reflex in healthy participants. The aim of the present study was to characterize neural correlates of the modulatory effect of noninvasive vagus nerve stimulation (nVNS) on the trigeminal autonomic reflex. Twenty-one healthy participants were included in a 2-day, randomized, single-blind, within-subject design. The reflex was activated inside the MRI scanner using kinetic oscillation stimulation placed in the left nostril, resulting in an increase in lacrimation. After the first fMRI session, the participants received either sham vagus nerve stimulation or nVNS outside the scanner and underwent a subsequent fMRI session. nVNS prompted an increase in activation of the left pontine nucleus and a decreased activation of the right parahippocampal gyrus. Psychophysiologic interaction analyses revealed an increased functional connectivity between the left pontine nucleus and the right hypothalamus and a decreased functional connectivity between the right parahippocampal gyrus and the bilateral spinal trigeminal nuclei (sTN). These findings indicate a complex network involved in the modulatory effect of nVNS including the hypothalamus, the sTN, the pontine nucleus, and the parahippocampal gyrus.

Parametric characterization of the rat Hering-Breuer reflex evoked with implanted and non-invasive vagus nerve stimulation

Vagus nerve stimulation (VNS) has rapidly gained interest as a treatment for a variety of disorders. A number of methods have been employed to stimulate the vagus nerve, but the most common relies on a cuff electrode implanted around the cervical branch of the nerve. Recently, two non-invasive methods have increased in popularity: transcutaneous cervical VNS (tcVNS) and transcutaneous auricular VNS (taVNS). Despite promising clinical results, there has been little direct comparison of these methods to stimulation delivered via an implanted device. In this study, we directly compared both non-invasive strategies to stimulation with an implanted cuff electrode on activation of the Hering-Breuer (HB) reflex, a non-invasive biomarker of A-fiber activation in the vagus. Stimulation was delivered across a wide range of parameters using tcVNS, taVNS, and an implanted cuff electrode in female rats. Activation of the HB reflex, changes in heart rate, and neck muscle twitch force were recorded. Consistent with low thresholds reported in previous studies, we found that the threshold to activate the HB reflex using an implanted cuff electrode was 0.406 ± 0.066 mA. tcVNS was capable of activating the HB reflex, but the threshold was 34.18 ± 1.86 mA, over 15 fold higher than the stimulation intensity that caused twitching of the neck muscles (2.09 ± 0.16 mA). No activation of the HB reflex was observed with taVNS at any parameters. These results describe activation of the HB reflex with each strategy and provide initial evidence regarding differences in the activation of the vagus nerve with invasive and non-invasive methods.

Patient experience with non-invasive vagus nerve stimulator: gammaCore patient registry.

gammaCore is cleared by the FDA for acute and preventive treatment of cluster headache and the acute treatment of migraine in adults. Previously, only 2 treatments were approved for acute treatment of cluster headache while none were approved for preventive treatment. Following the initial FDA clearance, based on the ACT-1 and ACT-2 studies, a gammaCore Patient Registry (GPR) was designed to provide insights on the use of gammaCore and prescription patterns in the real-world setting and to characterize respective benefits and challenges during the acute treatment of episodic cluster headache. GPR was a prospective observational registry in which patients with episodic cluster headache (3rd edition of the International Classification of Headache Disorders criteria) who were prescribed gammaCore were invited to voluntarily enroll and provide information on their experiences between July 2017 and June 2018. Participants provided baseline information and were trained to self-administer treatment with gammaCore for cluster pain. Participants were also requested to record information for each cluster attack. Of the 182 patients who provided baseline demographic and cluster headache characteristics, 152 provided health index baseline data using EuroQol Health Index tool, 5-level format (EQ5D-5L) and 17 patients provided attack data on a total of 192 cluster headache attacks. The mean age was 49 years; 65% were male and 82% were white; the mean number of months of known diagnosis of cluster headache was 57; the mean number of attacks per cluster headache 4-week period was 14; and the mean pain score was 3.7 (0-4 scale) with a mean attack duration of 74 minutes. Sixty-seven percent of patients had used preventive treatments and 83% had used abortive treatments for cluster headaches; 25% of participants reported at least 1 comorbidity. The mean EQ5D-5L score (scale 0-1) was 0.83. Of the 192 cluster headache attacks reported, gammaCore was used in 116 (60%) attacks. Within this group, the mean pain score at the start of the attacks was 2.7, the mean number of stimulations used was 3.6, and the pain score after 30 minutes was 1.3. At 30 minutes, the pain of 81 (70%) attacks was reduced to none (27%) or mild (43%) (a pain score of 0 or 1) and in 94 (81%) attacks, patients experienced a reduction of at least 1 point in the pain score. This real-world observational evidence suggests that gammaCore adds clinically meaningful value to patients with episodic cluster headache by providing rapid pain relief and confirms that there is significant interest among prescribers in providing this new treatment and technology. This evidence further supports the need to redefine gammaCore as no longer investigational or experimental during considerations for reimbursement.

Promoting long-term inhibition of human fear responses by non-invasive transcutaneous vagus nerve stimulation during extinction training

Inhibiting fear-related thoughts and defensive behaviors when they are no longer appropriate to the situation is a prerequisite for flexible and adaptive responding to changing environments. Such inhibition of defensive systems is mediated by ventromedial prefrontal cortex (vmPFC), limbic basolateral amygdala (BLA), and brain stem locus-coeruleus noradrenergic system (LC-NAs). Non-invasive, transcutaneous vagus nerve stimulation (tVNS) has shown to activate this circuit. Using a multiple-day single-cue fear conditioning and extinction paradigm, we investigated long-term effects of tVNS on inhibition of low-level amygdala modulated fear potentiated startle and cognitive risk assessments. We found that administration of tVNS during extinction training facilitated inhibition of fear potentiated startle responses and cognitive risk assessments, resulting in facilitated formation, consolidation and long-term recall of extinction memory, and prevention of the return of fear. These findings might indicate new ways to increase the efficacy of exposure-based treatments of anxiety disorders.

Update on noninvasive neuromodulation for migraine treatment-Vagus nerve stimulation.

Noninvasive neurostimulation methods are particularly suited for migraine treatment thanks to their most favorable adverse event profile. Among them, noninvasive vagus nerve stimulation (nVNS) has raised great hope because of the role the vagus nerve is known to play in pain modulation, inflammation and brain excitability. We will critically review the clinical studies performed for migraine attack treatment and migraine prevention with the GammaCore® device, which allows cervical vagus nerve stimulation. nVNS is effective for the abortive treatment of migraine attacks, although the effect size is modest and numbers-to-treat appear not superior to those of other noninvasive neurostimulation methods, and inferior to those of oral triptans. The effect of nVNS with the GammaCore® in migraine prevention is not superior to sham stimulation, except possibly in patients with high adherence to the treatment. Both in acute and preventive trials, nVNS was characterized by an outstanding tolerance and safety profile, like the other noninvasive neurostimulation techniques. In physiological animal and human studies, cervical nVNS was shown to generate somatosensory evoked responses, to modulate pain perception and several areas of the cerebral pain network, and to inhibit experimental cortical spreading depression, which are relevant effects for migraine therapy.

Future directions of stroke rehabilitation

Recently, in the field of stroke rehabilitation, some novel concepts and therapeutic interventions have been proposed. It seems that earlier mobilization for acute stroke patients could lead to better functional outcome. In addition, neural plasticity during acute phase of stroke is enhanced, which means that this phase of stroke could be the period when the patients are likely to respond to rehabilitation training. In the future, acute rehabilitation should be aggressively provided in stroke centers in Japan. Some interventions such as non-invasive brain stimulation, centrally-acting drugs and vagus nerve stimulation have been reported to enhance neural plasticity. If these interventions are introduced combined with rehabilitation training, compensatory mechanism for impaired neurological function could be facilitated, leading to further functional recovery. Some robotic devices to support joint movements of the limbs externally have been developed. Robot-assisted rehabilitation can improve the efficacy of rehabilitation training, especially when applied for gait training. Neurofeedback is a sophisticated training system applying real-time monitoring of brain activity with the use of functional neuroimaging. Neurofeedback can be introduced in order to remedy motor imagery of stroke patients even if motor function is severely impaired. Regenerative therapy is a promising therapeutic intervention and some institutions in Japan have already started to introduce this therapy for stroke patients. It is proposed that rehabilitation training should be provided following the introduction of regenerative therapy so that structural reorganization caused by the therapy could lead to beneficial functional reorganization of the damaged brain. With the aim of improving active motor functions of hemiparetic limbs, botulinum toxin injection for limb spasticity after stroke should be combined with rehabilitation training. If these concepts and interventions are introduced aggressively and more widely for stroke patients, it is expected that functional outcome of such patients could be generally improved.

Safety and Efficacy of Non-invasive Vagus Nerve Stimulation in the Treatment of Headache in Subarachnoid Hemorrhage

Safety and Efficacy of Non-invasive Vagus Nerve Stimulation in the Treatment of Headache in Subarachnoid Hemorrhage

Rationale and design for a randomized, single-center, double-blind, sham-controlled study of non-invasive vagus nerve stimulation for treatment of post-traumatic headache

ObjectiveEvaluate the efficacy and safety of non-invasive vagus nerve stimulation (nVNS) for the treatment of post-traumatic headache (PTH).BackgroundWorldwide, ∼69 million people per year sustain a traumatic brain injury (TBI), many of whom develop PTH. Clinicians often treat PTH with drugs approved for primary headache disorders, and many patients self-treat with over-the-counter agents but have inadequate pain relief. There has been little study of therapies for PTH, and safe, effective treatments are needed.Design/MethodsThis randomized, double-blind, sham-controlled, parallel-group pilot study is enrolling adults who present 1–4 weeks after a head injury, meet International Classification of Headache Disorders 3rd edition (ICHD-3) criteria for acute headache attributed to mild TBI, and have ≥2 headaches/week with a migraine or probable migraine phenotype. After a 2-week run-in period, subjects are randomly assigned (1:1 allocation) to receive daily preventive therapy and as-needed acute treatment with nVNS or a sham device. Preventive therapy consists of two 120-second stimulations 3 times daily. Acute treatment comprises 2 stimulations at headache onset and 2 stimulations 20 minutes after the start of initial treatment. Subjects are not to use acute rescue medication for 120 minutes post-treatment. One North American site will enroll ≤80 subjects. The expected duration is 12 months (enrollment, 9 months; participation, 14 weeks).ResultsThe primary effectiveness end point is decrease in pain (on a 7-point scale) 60 minutes post-treatment for all treated headache attacks. Secondary end points include decrease in the frequency of headache days between the run-in period and the last 2 weeks of the double-blind period and responder rates (ie, percentages of subjects with ≥50% decrease in attack frequency). The primary safety end point is the incidence of treatment-related serious adverse events.ConclusionsThis study will assess the efficacy and safety of nVNS as a novel therapy for PTH.

Acute vestibular migraine treatment with noninvasive vagus nerve stimulation.

To report on the benefits of noninvasive vagus nerve stimulation (nVNS) on acute vestibular migraine (VM) treatment. This was a retrospective chart review of patients with VM treated with nVNS in a single tertiary referral center between November 2017 and January 2019. Eighteen patients (16 women) were identified (mean age 45.7 [±14.8] years); 14 were treated for a VM attack and 4 for bothersome interictal dizziness consistent with persistent perceptual postural dizziness (PPPD). Patients graded the severity of vestibular symptoms and headache using an 11-point visual analog scale (VAS; 0 = no symptoms, 10 = worst ever symptoms) before and 15 minutes after nVNS. In those with acute VM, vertigo improved in 13/14 (complete resolution in 2, at least 50% improvement in 5). The mean vertigo intensity before nVNS was 5.2 (±1.6; median 6), and 3.1 (±2.2; median 3) following stimulation; mean reduction in vertigo intensity was 46.9% (±31.5; median 45%). Five experienced headache with the VM attack; all reported improvement following nVNS. Mean headache severity was 6 (±1.4; median 6) prior to treatment and 2.4 (±1.5; median 3) following nVNS; mean reduction in headache intensity was 63.3% (±21.7; median 50). All 4 treated with nVNS for interictal PPPD reported no benefit. Our study provides preliminary evidence that nVNS may provide rapid relief of vertigo and headache in acute VM, and supports further randomized, sham-controlled studies into nVNS in VM. This study provides Class IV evidence that for patients with acute VM, nVNS rapidly relieves vertigo and headache.

Non-invasive Vagus Nerve Stimulation in Acute Ischemic Stroke

Non-invasive Vagus Nerve Stimulation in Acute Ischemic Stroke

Exploration of the Impact of Brief Noninvasive Vagal Nerve Stimulation on EEG and Event-Related Potentials

The primary objective of this study was to explore the impact of noninvasive Vagal Nerve Stimulation (nVNS) on brain electrophysiology, as assessed through spontaneous resting-state EEG and stimulus-driven event-related potentials (ERPs). A hand-held transcutaneous stimulator was placed on the neck over the main branch of the left vagus (active condition) or more laterally over neck muscles (sham condition), with two 120-sec long bursts of stimulation applied over a five-minute period. For each of eight neurotypical subjects, prior to stimulation, and then again beginning at 15, 120, and 240 min post-stimulation, ten minutes of background EEG data were collected, along with a series of ERPs-N100 auditory sensory-gating; the N1/P2 loudness dependent auditory evoked responses (LDAER); mismatch negativity; P300a; and P300b. Each subject participated in active and sham stimulation sessions. Brief nVNS had a significant (p < 0.05), and in some cases prolonged (>2 hours), impact on the spontaneous EEG (decreased theta and alpha, and increased beta and gamma), and on sensory gating, LDAER, and P300b evoked responses. Based on prior literature, these specific observations may reflect nVNS-induced modulation of particular neurotransmitter systems including those for GABA (gamma power and frequency); acetylcholine (sensory gating); serotonin (LDAER); and noradrenaline (P300b). Brief nVNS leads to changes in a sub-set of resting-state and event-related electrophysiologic indices of brain activity. These changes are believed to be mediated by vagal afferent projections to the nucleus of the solitary tract, which in turn regulates several neurotransmitter systems through known direct and indirect neuroanatomic pathways.

The Effects of Noninvasive Vagus Nerve Stimulation on Fatigue and Immune Responses in Patients With Primary Sjögren’s Syndrome

Primary Sjögren's syndrome (pSS) sufferers have rated chronic fatigue as the most important symptom needing improvement. Emerging data suggest that stimulation of the vagus nerve can modulate immunological responses. The gammaCore device (electroCore), developed to stimulate the cervical vagus nerve noninvasively, was used to assess the effects of vagus nerve activation on immune responses and clinical symptoms of pSS. Fifteen female pSS subjects used the nVNS device twice daily a 26-day period. At baseline, blood was drawn before and after application of the gammaCore device for 90 sec over each carotid artery. The following fatigue-related outcome measures were collected at baseline, day 7 and day 28: EULAR patient reported outcome index, profile of fatigue (Pro-F), visual analogue scale of abnormal fatigue, and Epworth sleepiness scale (ESS). Whole blood samples were stimulated with 2 ng/mL lipopolysaccharide (LPS) and the supernatant levels of IFNγ, IL12-p70, TNFα, MIP-1α, IFNα, IL-10, IL-1β, IL-6, and IP-10 were measured at 24 hours. In addition, clinical hematology and flow cytometric profiles of whole blood immune cells were analyzed. Pro-F and ESS scores were significantly reduced across all three visits. LPS-stimulated production of IL-6, IL-1β, IP-10, MIP-1α, and TNFα were significantly reduced over the study period. Patterns of NK- and T-cell subsets also altered significantly over the study period. Interestingly, lymphocyte counts at baseline visit correlated to the reduction in fatigue score. The vagus nerve may play a role in the regulation of fatigue and immune responses in pSS and nVNS may reduce clinical symptoms of fatigue and sleepiness. However, a sham-controlled follow-up study with a larger sample size is required to confirm the findings.