Non-invasive vagus nerve stimulation (nVNS) has recently been suggested as a potential therapy for traumatic brain injury (TBI). We previously demonstrated that nVNS inhibits cortical spreading depolarization, the electrophysiological event underlying migraine aura, and is relevant to TBI. Our past work also suggests a role for interleukin-1 beta (IL-1β) in cognitive deficits after closed head injury (CHI) in mice. We show that nVNS pre-treatment suppresses CHI-associated spatial learning and memory impairment and prevents IL-1β activation in injured neurons, but not endothelial cells. In contrast, nVNS administered 10 min after CHI was ineffective. These data suggest that nVNS prophylaxis might ameliorate neuronal dysfunction associated with CHI in populations at high risk for concussive TBI.

Introduction: Workers operating on high-speed roads (i.e., incident responders and emergency service workers) are at significant risk of being fatally injured while working. An identified gap in current prevention strategies is training focused on developing the skills of workers to effectively communicate and coordinate safety responses when operating on roads. Methods: This study discusses the development of a program designed to optimize communication and coordination of safety practices at the scene of an incident on a high-speed road. The program is referred to as ‘Safety in the Grey Zone.’ The goal of the study is to present the results from an evaluation on its implementation across 23 sessions involving 158 participants from 7 incident response agencies in 1 state in Australia. Results: The results of this study provide support for effectiveness in implementing the program as planned. The results also provide preliminary support for effectiveness of the program in achieving its learning outcomes as demonstrated by feedback received from participants following completion of the program. Conclusions: The findings of this study provide recommendations to consider in the program’s future roll-out, as well as suggestions for future evaluations to assess the program’s effectiveness in improving the safety of incident responders operating on high-speed roads.

Background Noninvasive vagus nerve stimulation (nVNS) has recently emerged as a promising therapy for migraine. We previously demonstrated that vagus nerve stimulation inhibits cortical spreading depression (CSD), the electrophysiological event underlying migraine aura and triggering headache; however, the optimal nVNS paradigm has not been defined. Methods Various intensities and doses of nVNS were tested to improve efficacy on KCl-evoked CSD frequency and electrical threshold of CSD in a validated rat model. Chronic efficacy was evaluated by daily nVNS delivery for four weeks. We also examined the effects of nVNS on neuroinflammation and trigeminovascular activation by western blot and immunohistochemistry. Results nVNS suppressed susceptibility to CSD in an intensity-dependent manner. Two 2-minute nVNS 5 min apart afforded the highest efficacy on electrical CSD threshold and frequency of KCl-evoked CSD. Daily nVNS for four weeks did not further enhance efficacy over a single nVNS 20 min prior to CSD. The optimal nVNS also attenuated CSD-induced upregulation of cortical cyclooxygenase-2, calcitonin gene-related peptide in trigeminal ganglia, and c-Fos expression in trigeminal nucleus caudalis. Conclusions Our study provides insight on optimal nVNS parameters to suppress CSD and suggests its benefit on CSD-induced neuroinflammation and trigeminovascular activation in migraine treatment.

Since the outbreak of the COVID-19 pandemic, races across academia and industry have been initiated to identify and develop disease modifying or preventative therapeutic strategies has been initiated. The primary focus has been on pharmacological treatment of the immune and respiratory system and the development of a vaccine. The hyperinflammatory state ("cytokine storm") observed in many cases of COVID-19 indicates a prognostically negative disease progression that may lead to respiratory distress, multiple organ failure, shock, and death. Many critically ill patients continue to be at risk for significant, long-lasting morbidity or mortality. The human immune and respiratory systems are heavily regulated by the central nervous system, and intervention in the signaling of these neural pathways may permit targeted therapeutic control of excessive inflammation and pulmonary bronchoconstriction. Several technologies, both invasive and non-invasive, are available and approved for clinical use, but have not been extensively studied in treatment of the cytokine storm in COVID-19 patients. This manuscript provides an overview of the role of the nervous system in inflammation and respiration, the current understanding of neuromodulatory techniques from preclinical and clinical studies and provides a rationale for testing non-invasive neuromodulation to modulate acute systemic inflammation and respiratory dysfunction caused by SARS-CoV-2 and potentially other pathogens. The authors of this manuscript have co-founded the International Consortium on Neuromodulation for COVID-19 to advocate for and support studies of these technologies in the current coronavirus pandemic.

High-speed roads present a considerable level of risk for frontline workers operating in these environments. To optimise safety, prevention activities need to target the key skills required to mitigate risk. The aim of this research was to explore the behavioural (compliance, participation, voice), motivational (safety motivation) and work demand (role clarity) factors that influence safety outcomes for incident responders working on high-speed roads. Safety outcomes included secondary incidents and near misses with passing vehicles. A total of 295 complete survey responses were received from six emergency service and incident response agencies in one Australian state. Data were analysed using structural equation modelling. The results showed that higher levels of safety voice, safety motivation and, role clarity were significantly associated with safer self-reported safety outcomes after controlling for the number of incidents attended. The findings from this study will be used to guide the development of a training program to improve the cognitive, behavioural and perceptual skills of incident responders operating on high-speed roads. Some insight into the structure and format of this program is provided.

Experimental and clinical data strongly support vagus nerve stimulation (VNS) as a novel treatment in migraine. Vagus nerve stimulation acutely suppresses cortical spreading depression (CSD) susceptibility, an experimental model that has been used to screen for migraine therapies. However, mechanisms underlying VNS efficacy on CSD are unknown. Here, we interrogated the central and peripheral mechanisms using VNS delivered either invasively (iVNS) or noninvasively (nVNS) in male Sprague-Dawley rats. Cortical spreading depression susceptibility was evaluated 40 minutes after the stimulation. iVNS elevated the electrical CSD threshold more than 2-fold and decreased KCl-induced CSD frequency by 22% when delivered to intact vagus nerve. Distal vagotomy did not alter iVNS efficacy (2-fold higher threshold and 19% lower frequency in iVNS vs sham). By contrast, proximal vagotomy completely abolished iVNS effect on CSD. Pharmacological blockade of nucleus tractus solitarius, the main relay for vagal afferents, by lidocaine or glutamate receptor antagonist CNQX also prevented CSD suppression by nVNS. Supporting a role for both norepinephrine and serotonin, CSD suppression by nVNS was inhibited by more than 50% after abrogating norepinephrinergic or serotonergic neurotransmission alone using specific neurotoxins; abrogating both completely blocked the nVNS effect. Our results suggest that VNS inhibits CSD through central afferents relaying in nucleus tractus solitarius and projecting to subcortical neuromodulatory centers providing serotonergic and norepinephrinergic innervation to the cortex.

Cortical spreading depolarization (SD) waves negatively affect neuronal survival and outcome after ischemic stroke. We here aimed to investigate the effects of vagus nerve stimulation (VNS) on SDs in a rat model of focal ischemia. To this end, we delivered non-invasive VNS (nVNS) or invasive VNS (iVNS) during permanent middle cerebral artery occlusion (MCAO), and found that both interventions significantly reduced the frequency of SDs in the cortical peri-infarct area compared to sham VNS, without affecting relative blood flow changes, blood pressure, heart rate or breathing rate. In separate groups of rats subjected to transient MCAO, we found that cortical stroke volume was reduced 72 h after transient MCAO, whereas stroke volume in the basal ganglia remained unchanged. In rats treated with nVNS, motor outcome was improved 2 days after transient MCAO, but was similar to sham VNS animals 3 days after ischemia. We postulate that VNS may be a safe and efficient intervention to reduce the clinical burden of SD waves in stroke and other conditions.

The mechanisms by which noninvasive vagal nerve stimulation (nVNS) affect central and peripheral neural circuits that subserve pain and autonomic physiology are not clear, and thus remain an area of intense investigation. Effects of nVNS vs sham stimulation on subject responses to five noxious thermal stimuli (applied to left lower extremity), were measured in 30 healthy subjects (n = 15 sham and n = 15 nVNS), with fMRI and physiological galvanic skin response (GSR). With repeated noxious thermal stimuli a group × time analysis showed a significantly (p < .001) decreased response with nVNS in bilateral primary and secondary somatosensory cortices (SI and SII), left dorsoposterior insular cortex, bilateral paracentral lobule, bilateral medial dorsal thalamus, right anterior cingulate cortex, and right orbitofrontal cortex. A group × time × GSR analysis showed a significantly decreased response in the nVNS group (p < .0005) bilaterally in SI, lower and mid medullary brainstem, and inferior occipital cortex. Finally, nVNS treatment showed decreased activity in pronociceptive brainstem nuclei (e.g. the reticular nucleus and rostral ventromedial medulla) and key autonomic integration nuclei (e.g. the rostroventrolateral medulla, nucleus ambiguous, and dorsal motor nucleus of the vagus nerve). In aggregate, noninvasive vagal nerve stimulation reduced the physiological response to noxious thermal stimuli and impacted neural circuits important for pain processing and autonomic output.

Background: Primary Sjögren's syndrome (pSS) sufferers have rated physical and mental fatigue ('brain fog') as the most important symptoms needing improvement. Previous data from our group suggest that stimulation of the vagus nerve can invoke immunological responses and concurrently an improvement of patient reported symptoms of fatigue1. Objectives: This follow up study uses the gammaCore device (electroCore) and a sham device to assess the effects of non-invasive vagus nerve stimulation (nVNS) on patient reported symptoms of fatigue in pSS. In addition, neurocognitive tests were used to assess the effect of nVNS on short term memory, executive function and attention. Methods: 40 pSS participants were assigned to use active (n = 20) or sham (n = 20) nVNS devices. Participants and research staff were blinded to the active/sham device assignment. The participants were instructed to use the device twice daily for a study period of 56 days. The following patient reported measures of fatigue and neuropsychological tests were collected at baseline and day 56; Profile of Fatigue (PRO-F, Physical and Mental), visual analogue scale (VAS) of abnormal fatigue, trail making, Digit Symbol Substitution Test (DSST), Stroop test and digit span. 7 subjects were excluded from the analysis due to withdrawal from the study. Changes in fatigue and test scores from baseline to day 56 were compared between devices using t-tests. Results: Physical fatigue was significantly reduced between baseline and day 56 in the active group but not the placebo group (p = 0.047) The mean reduction in physical fatigue was 30% and 6% for the active and sham arms respectively (Figure 1). In both the active and sham subject groups there were no significant changes in the patient reported mental fatigue or neuropsychological test scores. Conclusion: This sham controlled scientific study of vagus nerve stimulation in pSS suggests nVNS may improve patient reported symptoms of physical fatigue, which is consistent with our published data. There were no improvements in the neurosychological test scores which is consistent with no improvements in patient reported mental fatigue. nVNS has been shown to activate the anti-inflammatory reflex, therefore assessment of peripheral inflammatory markers may help our understanding of nVNS, inflammation and fatigue. Reference [1] Tarn, J., Legg, S., Mitchell, S., Simon, B. & Ng, W.-F. The Effects of Noninvasive Vagus Nerve Stimulation on Fatigue and Immune Responses in Patients With Primary Sjögren's Syndrome. Neuromodulation49, 844 (2018). Disclosure of Interests: Jessica Tarn: None declared, Victoria Macrae: None declared, Sheryl Mitchell: None declared, Bruce Simon Shareholder of: Bruce Simon is an employee and shareholder of electroCore., Peter Gallagher: None declared, John-Paul Taylor: None declared, Stuart Watson: None declared, Mark Baker: None declared, Stephen Rushton: None declared, Andrew Blamire: None declared, Julia Newton: None declared, Wan Fai Ng: None declared

Movement DisordersVolume 34, Issue 6 p. 917-918 Letters: New Observations Noninvasive vagus nerve stimulation improves gait and reduces freezing of gait in Parkinson's disease Banashree Mondal MSc, Banashree Mondal MSc Department of Neurology and Ram Gopal Chamaria Medical Research Centre (RGC), Institute of Neurosciences, Kolkata, IndiaSearch for more papers by this authorSupriyo Choudhury MD, Supriyo Choudhury MD Department of Neurology and Ram Gopal Chamaria Medical Research Centre (RGC), Institute of Neurosciences, Kolkata, IndiaSearch for more papers by this authorBruce Simon PhD, Bruce Simon PhD ElectroCore LLC, Basking Ridge, New Jersey, USASearch for more papers by this authorMark R. Baker FRCP, Mark R. Baker FRCP Department of Neurology, Royal Victoria Infirmary, Newcastle upon Tyne, UK Department of Clinical Neurophysiology, Royal Victoria Infirmary, Newcastle, UK Institute of Neurosciences, Newcastle University, Newcastle upon Tyne, UKSearch for more papers by this authorHrishikesh Kumar DM, Corresponding Author Hrishikesh Kumar DM rishi_medicine@yahoo.com Department of Neurology and Ram Gopal Chamaria Medical Research Centre (RGC), Institute of Neurosciences, Kolkata, IndiaCorrespondence to: Dr. Hrishikesh Kumar, Department of Neurology, Institute of Neurosciences, Kolkata, 185/1 AJC Bose Road, Kolkata, West Bengal, India 700017; E-mail: rishi_medicine@yahoo.comSearch for more papers by this author Banashree Mondal MSc, Banashree Mondal MSc Department of Neurology and Ram Gopal Chamaria Medical Research Centre (RGC), Institute of Neurosciences, Kolkata, IndiaSearch for more papers by this authorSupriyo Choudhury MD, Supriyo Choudhury MD Department of Neurology and Ram Gopal Chamaria Medical Research Centre (RGC), Institute of Neurosciences, Kolkata, IndiaSearch for more papers by this authorBruce Simon PhD, Bruce Simon PhD ElectroCore LLC, Basking Ridge, New Jersey, USASearch for more papers by this authorMark R. Baker FRCP, Mark R. Baker FRCP Department of Neurology, Royal Victoria Infirmary, Newcastle upon Tyne, UK Department of Clinical Neurophysiology, Royal Victoria Infirmary, Newcastle, UK Institute of Neurosciences, Newcastle University, Newcastle upon Tyne, UKSearch for more papers by this authorHrishikesh Kumar DM, Corresponding Author Hrishikesh Kumar DM rishi_medicine@yahoo.com Department of Neurology and Ram Gopal Chamaria Medical Research Centre (RGC), Institute of Neurosciences, Kolkata, IndiaCorrespondence to: Dr. Hrishikesh Kumar, Department of Neurology, Institute of Neurosciences, Kolkata, 185/1 AJC Bose Road, Kolkata, West Bengal, India 700017; E-mail: rishi_medicine@yahoo.comSearch for more papers by this author First published: 14 March 2019 https://doi.org/10.1002/mds.27662Citations: 22 Funding agency: Noninvasive vagus nerve stimulation devices were provided by Dr. Bruce Simon (Electrocore [Basking Ridge, New Jersey]). Other research costs were covered by the research fund of Institute of Neurosciences, Kolkata. Relevant conflicts of interests/financial disclosures: Nothing to report. Correction added on March 21, 2019, after first online publication. The funding agency information for this article concerning the Institute of Neurosciences has been updated. Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinkedInRedditWechat No abstract is available for this article.Citing Literature Volume34, Issue6June 2019Pages 917-918 RelatedInformation

Chronically activated microglia contribute to the development of neurodegenerative diseases such as Alzheimer's disease (AD) by the release of pro-inflammatory mediators that compromise neuronal function and structure. Modulating microglia functions could be instrumental to interfere with disease pathogenesis. Previous studies have shown anti-inflammatory effects of acetylcholine (ACh) or norepinephrine (NE), which mainly activates the -receptors on microglial cells. Non-invasive vagus nerve stimulation (nVNS) is used in treatment of drug-resistant depression, which is a risk factor for developing AD. The vagus nerve projects to the brainstem's locus coeruleus from which noradrenergic fibers reach to the Nucleus Basalis of Meynert (NBM) and widely throughout the brain. Pilot studies showed first signs of cognitive-enhancing effects of nVNS in AD patients. In this study, the effects of nVNS on mouse microglia cell morphology were analyzed over a period of 280min by 2-photon laser scanning invivo microscopy. Total branch length, average branch order and number of branches, which are commonly used indicators for the microglial activation state were determined and compared between young and old wild-type and amyloid precursor protein/presenilin-1 (APP/PS1) transgenic mice. Overall, these experiments show strong morphological changes in microglia, from a neurodestructive to a neuroprotective phenotype, following a brief nVNS in aged animals, especially in APP/PS1 animals, whereas microglia from young animals were morphologically unaffected.

OBJECTIVES:To develop the first high-resolution, multi-scale model of cervical non-invasive vagus nerve stimulation (nVNS) and to predict vagus fiber type activation, given clinically relevant rheobase thresholds. METHODS:An MRI-derived Finite Element Method (FEM) model was developed to accurately simulate key macroscopic (e.g., skin, soft tissue, muscle) and mesoscopic (cervical enlargement, vertebral arch and foramen, cerebral spinal fluid [CSF], nerve sheath) tissue components to predict extracellular potential, electric field (E-Field), and activating function along the vagus nerve. Microscopic scale biophysical models of axons were developed to compare axons of varying size (Aα-, Aβ- and Aδ-, B-, and C-fibers). Rheobase threshold estimates were based on a step function waveform. RESULTS:Macro-scale accuracy was found to determine E-Field magnitudes around the vagus nerve, while meso-scale precision determined E-field changes (activating function). Mesoscopic anatomical details that capture vagus nerve passage through a changing tissue environment (e.g., bone to soft tissue) profoundly enhanced predicted axon sensitivity while encapsulation in homogenous tissue (e.g., nerve sheath) dulled axon sensitivity to nVNS. CONCLUSIONS:These findings indicate that realistic and precise modeling at both macroscopic and mesoscopic scales are needed for quantitative predictions of vagus nerve activation. Based on this approach, we predict conventional cervical nVNS protocols can activate A- and B- but not C-fibers. Our state-of-the-art implementation across scales is equally valuable for models of spinal cord stimulation, cortex/deep brain stimulation, and other peripheral/cranial nerve models.

Asthma is a debilitating and life-threatening disorder resulting in 2 million emergency room visits each year and 500,000 hospital admissions. Asthma is characterized, in part, by smooth muscle contraction, which narrows the airways in a response to a variety of stimuli, including neural input, allergens, and irritants. Several animal models, including swine and guinea pig models, have demonstrated that electrically stimulating the vagus nerve can reduce bronchoconstriction by as much as 70%. Human clinical trials with both percutaneously inserted electrodes and a transcutaneously applied electrical signal have improved forced expiratory volume in 1 s (FEV1) and work of breathing (WOB) in patients experiencing acute asthma exacerbations. Although further blinded clinical studies are necessary, there clearly exists value in vagus nerve stimulation (VNS) as an alternate treatment for bronchoconstriction.

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.

Background: Vagus nerve stimulation (VNS) significantly reduces infarct volume in rat models of cerebral ischemia, but the mechanism of this protective effect remains open. Hypothesis: This study tested the hypothesis that non-invasive VNS (nVNS), during transient middle cerebral artery occlusion (MCAO), protects the blood-brain barrier (BBB), leading to reduced infarct size in ischemic brain. Methods: Spontaneous hypertensive rats (SHRs) were subjected to a 90 min MCAO. nVNS treated rats received 5 stimulations (duration: 2 min; every 10 min) on the skin overlying the cervical vagus nerve in the neck beginning 30 min after MCAO onset. Control rats received the same stimulations on the quadriceps femoris muscle. Twenty-four hours after MCAO onset, MRI and immunohistochemistry (IHC) were performed for analyses of infarct size and BBB leakage. Results: Compared with the control group, anatomic MRI T2-weighted images showed significantly smaller infarct sizes in the nVNS group. Dynamic contrast-enhanced (DCE)-MRI showed a significantly decreased BBB transfer rate (Ki map) in the lesion area in the nVNS group, which was spatially correlated with the attenuation of the infarct size. Furthermore, significantly lower serum IgG leakage, visualized by IHC, was seen in the ischemic hemisphere in nVNS treated rats. nVNS also protected vascular tight junction proteins from disruption in microvessels, and reduced expression of matrix metalloproteinases2/9 in reactive astrocytes surrounding the compromised vessels in the ischemic hemispheres. Conclusion: Our data suggest that the neuroprotective role of a series of nVNS administrations during MCA occlusion, spatially correlates with protection of BBB integrity from damage and reduction of infarct extent induced by ischemic stroke. (C) 2018 The Author(s). Published by Elsevier Inc.

OBJECTIVES: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). METHODS: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. RESULTS: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). CONCLUSIONS: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.

Vagus nerve stimulation (VNS) has been reported to be effective in the abortive treatment of both migraine and cluster headache. Using validated animal models of acute dural-intracranial (migraine-like) and trigeminal-autonomic (cluster-like) head pain we tested whether VNS suppresses ongoing and nociceptive-evoked firing of trigeminocervical neurons to explain its abortive effects in migraine and cluster headache. Unilateral VNS was applied invasively via hook electrodes placed on the vagus nerve. A single dose of ipsilateral or contralateral VNS, to trigeminal recording and dural-stimulating side, suppressed ongoing spontaneous and noxious dural-evoked trigeminocervical neuronal firing. This effect was dose-dependent, with two doses of ipsilateral VNS prolonging suppression of ongoing spontaneous firing (maximally by ~60%) for up to three hours, and dural-evoked (Aδ-fiber; by ~22%, C-fiber: by ~55%) responses for at least two hours. Statistically, there was no difference between ipsilateral and contralateral groups. Two doses of VNS also suppressed superior salivatory nucleus-evoked trigeminocervical neuronal responses (maximally by ~22%) for 2.5 h, to model nociceptive activation of the trigeminal-autonomic pathway. VNS had no effect on normal somatosensory cutaneous facial responses throughout. These studies provide a mechanistic rationale for the observed benefits of VNS in the abortive treatment of migraine and cluster headache. In addition, they further validate these preclinical models as suitable approaches to optimize therapeutic efficacy, and provide an opportunity to hypothesize and dissect the neurobiological mechanisms of VNS in the treatment of primary headaches.