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Supplements Considerations in Non-Invasive Vagus Nerve Stimulation: Clinical Data and Expert Panel Recommendations
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Mechanism of Action of Non-Invasive Cervical Vagus Nerve Stimulation for the Treatment of Primary Headaches
Bruce Simon, PhD, and Justyna Blake, MSE
The Emerging Role of gammaCore in the Management of Cluster Headache: Expert Panel Recommendations
Stephen D. Silberstein, MD; Anne H. Calhoun, MD, FAHS; Christina Treppendahl, FNP-BC, AQH; David W. Dodick, MD; Alan M. Rapoport, MD; Avinash Mamidi, PharmD, BCPS; Peter Vargas, RPh; Thomas H. Ebert; Stewart J. Tepper, MD
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Mechanism of Action of Non-Invasive Cervical Vagus Nerve Stimulation for the Treatment of Primary Headaches

Bruce Simon, PhD, and Justyna Blake, MSE
Two minutes of nVNS rapidly (<5 minutes) decreased periorbital sensitivity for up to 3.5 hours. Previous work from this lab55 showed that glyceryl trinitrate (GTN), a nitric oxide donor that causes prolonged migraine-like headaches in migraineurs but not in healthy controls, causes a further decrease in sensitivity, which correlates with increased levels of extracellular glutamate in the trigeminal nucleus caudalis (TNC). High levels of glutamate in the TNC are a marker for increased trigeminal pain. Allodynic rats that received nVNS had only a 2-fold increase in extracellular glutamate after GTN compared with a nearly 8-fold increase in untreated animals. Even when nVNS was delayed until 2 hours after GTN treatment, the stimulation could still reverse the elevated levels of glutamate, bringing them back to naïve levels, which were maintained for the duration of the experiment. These data suggest that nVNS may treat headache pain by a direct, acute, inhibitory modulation of headache pain pathways that increase nerve activity in the TNC and therefore in its projections to the thalamus and the cortex where the perception of pain occurs.

Chen et al44 looked at the effects of iVNS and nVNS in a rat model of CSD. CSDs are waves of propagating neuronal depolarization thought to be the electrophysiological correlate of migraine aura, which are the visual disturbances reported by migraineurs that often precede headache. The frequency of continuous CSDs, induced by placing a potassium chloride-soaked cotton ball on the dura, or electrical thresholds, determined by measuring the minimal amount of injected current needed to induce a single CSD, are surrogates for cortical excitability. This model has been used to screen migraine drugs now used clinically. These drugs were shown to reduce CSD frequency and increase electrical thresholds, although many weeks of daily infusions were necessary.56

Chen et al44 showed that both iVNS and nVNS reduced CSD frequency by almost 50% and increased electrical thresholds by about 3-fold. Further, the effects of two 2-minute stimulations lasted more than 3 hours and were equally effective on CSDs in the ipsilateral or contralateral hemispheres. If indeed aura precedes and causes a subsequent headache, these results suggest nVNS may work preventively by reducing the frequency of aura and the resulting migraine headaches.

Akerman et al57 studied the effects of nVNS on the firing of trigeminocervical pain neurons in a rat model of migraine-like and cluster-like acute head pain. A single 2-minute dose of ipsilateral or contralateral VNS suppressed dural-evoked trigeminocervical neuronal firing, both spontaneous and noxious, within 15 minutes. This effect was dose dependent, with 2 doses of ipsilateral VNS prolonging suppression of ongoing spontaneous firing for up to 3 hours and of noxious dural-evoked responses for more than 2 hours. As in the previous study, both ipsilateral and contralateral stimulations were equally effective. To model the trigeminal-autonomic pathway implicated in CH, superior salivatory nucleus (SUS)-evoked trigeminocervical neuronal responses were studied. Two doses of VNS suppressed SUS responses for 2.5 hours. The degree of inhibition with VNS (between 20% and 50% for evoked responses) was similar to that found with other abortive headache treatments, including triptans, in the same model, suggesting a similar site of action.58 Consistent with clinical observations, VNS did not affect normal somatosensory nociceptive processing. Further experiments will be needed to determine if the inhibition of firing of trigeminocervical neurons is a direct effect of VNS-induced descending inhibition by release of inhibitory neurotransmitters, like gamma-aminobutyric acid or serotonin, or by an upstream effect on other targets involved in intracranial trigeminovascular nociceptive transmission.

A large body of literature describes the anti-inflammatory effects of VNS (referred to as the cholinergic anti-inflammatory pathway), pioneered by Kevin Tracey and colleagues.4 Stimulating appropriate efferent or afferent fibers of the VN inhibits splenic (and other organ) macrophage production of several inflammatory cytokines, including tumor necrosis factor-alpha (TNF-α), interleukin-1, and interleukin-6.4 A recent study in human rheumatoid arthritis patients with iVNS showed a reduction in disease symptom severity that paralleled changes in TNF-α and C-reactive protein, a measure of inflammation.18 nVNS has been shown to also activate this pathway in 2 human studies.59,60 In addition, Brock et al49 showed a sustained elevation of cardiac vagal tone (a measure of parasympathetic activity indicative of VN stimulation) that lasted up to 24 hours after a 2-minute treatment with gammaCore. A reduction in inflammation and an increase in vagal tone may also play a part in the mechanism by which VNS alleviates headache.


Non-invasive stimulation of the cervical branch of the vagus nerve is an exciting new teCHnology that may increase access to the clinical use of VNS by avoiding the need for surgical implantation of a stimulator and for the associated cost and morbidity. Preliminary clinical studies in various primary headache disorders are encouraging. Human studies and modeling have demonstrated that nVNS activates vagus nerve fibers similar to those implicated in the clinical benefits of iVNS. Continuing human and animal research will be necessary to further elucidate the MOA and to help define optimal signal parameters and treatment paradigms for headache and other disorders

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