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Mechanism Identified Whereby Vagus Nerve Stimulation Relieves Migraine Pain

Key findings

  • In a previous animal study, Massachusetts General Hospital researchers determined that vagus nerve stimulation (VNS) inhibits cortical spreading depression (CSD), the electrophysiological event underlying migraine aura and a putative headache trigger
  • Now, the researchers have found in an animal model that invasive VNS suppresses CSD susceptibility by activating visceral sensory afferents that project to the nucleus tractus solitarius (NTS) in the brain stem
  • Other experiments showed that the NTS is a critical relay for noninvasive VNS to suppress CSD susceptibility and norepinephrine and serotonin are important central mediators for noninvasive VNS suppression of cortical CSD susceptibility
  • Noninvasive VNS may have relevance for the prevention of migraine (not just treatment) and treatment of brain injury

When noninvasive vagus nerve stimulation (VNS) began to be tested by patients with intractable epilepsy and depression, a serendipitous finding was that it also improved migraine. In 2018, the Food and Drug Administration approved a vagus nerve stimulator for treatment of migraine pain in adults, but its mechanisms of action were unknown.

Massachusetts General Hospital researchers previously demonstrated that VNS inhibits cortical spreading depression (CSD), an intense depolarization wave widely accepted to be the electrophysiological event underlying migraine aura and possibly a trigger for headache (published in Pain).

80% of the vagus nerve is comprised of sensory afferent fibers that project to the nucleus tractus solitarius (NTS) bilaterally in the brain stem. VNS activates both the efferent and the afferent vagal fibers, and the researchers wondered whether its efficacy is attributable to the stimulation of these fibers.

Visiting grad student Andreia Morais, MSc, and Cenk Ayata, MD, a neurologist in the Department of Neurology and Department of Radiology at Mass General, and colleagues have now extended their research, finding that CSD suppression by VNS is mediated exclusively by central vagal afferents to the NTS that activate serotonergic and norepinephrinergic projections to the cortex. They published their observations in Pain.

Effects of Vagotomy

In male rats, the researchers cut the vagus nerve either distal or proximal to a surgically implanted VNS electrode. These procedures eliminated visceral motor efferents and sensory afferents, respectively, projecting to the NTS. Control mice had an electrode implanted but received no stimulation.

Susceptibility to CSD was evaluated 40 minutes after stimulation by determining the electrical threshold for CSD and the frequency of repetitive CSDs induced by dabbing potassium chloride (KCl) on the cortex. They found:

  • In the presence of an intact vagus nerve, invasive VNS (iVNS) elevated the electrical stimulation threshold of CSD induction more than twofold, reduced KCl-induced CSD frequency more than 20% and slowed CSD propagation compared with control animals
  • After distal vagotomy, the results were similar: iVNS increased the electrical CSD threshold more than twofold and decreased KCl-induced CSD frequency almost 20%
  • After proximal vagotomy, iVNS had no effect on electrical CSD threshold or KCl-induced CSD frequency

Effects of NTS Block

The researchers blocked neurotransmission to the NTS by injecting mice with lidocaine or CNQX, a glutamate receptor antagonist (vagal afferents to the NTS are glutamatergic). Both agents prevented noninvasive VNS (nVNS) from suppressing CSD susceptibility.

Effects of Serotonin and Norepinephrine Depletion

NTS neurons project to the locus coeruleus and dorsal raphe nucleus, which provide norepinephrine and serotonin innervation of the cortex, respectively. VNS stimulation leads to the release of these neurotransmitters.

The researchers used two neurotoxins, alone or together, to deplete norepinephrine and serotonin in the brain. Either toxin alone diminished CSD suppression by nVNS, and in combination, the toxins completely abolished the effect of nVNS on CSD susceptibility.

Clinical Importance of the Findings

This study describes a mechanism of action whereby VNS has a beneficial effect in migraine, especially migraine with aura, and also epilepsy and depression. Several antiepileptic and antidepressant drugs are commonly used to prevent migraines, and these data suggest that VNS should be evaluated as a prophylactic treatment as well.

VNS may also be relevant to the treatment of brain injury, where numerous CSDs occur over many days and may exacerbate the outcome.

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