Vagus Nerve Stimulation Suppresses Cortical Spreading Depression -- a Trigger for Migraine

vagus nerve stimulation (VNS) was found to suppress cortical spreading depression (CSD2).

​According to a study led by scientists at Massachusetts General Hospital, Harvard Medical School1 published in the journal Pain, vagus nerve stimulation (VNS) was found to suppress cortical spreading depression (CSD2). CSDs are believed to be responsible for the aura, or visual disturbance, that frequently precedes some migraines, and have been a significant target for pharmaceutical development.

In this study, VNS was shown to raise the level of resistance to electrically and to chemically triggered CSDs by threefold.  More impressively, however, the researchers found that VNS suppressed CSD by this amount within 30 minutes of the first administration of the therapy, which is significantly superior to commonly used migraine prophylactic drugs that typically take several weeks to achieve comparable results.

This controlled animal study further showed, for the first time, that non-invasive vagus nerve (nVNS) stimulation was as effective as surgically implanted vagus nerve stimulation (iVNS) in significantly reducing CSDs by, up to 40%. The non-invasive VNS treatment, which involves the delivery of two brief 2-minute doses, was able to suppress CSDs for the full three-hour duration of the study, with no indication that the efficacy had yet diminished.

Interestingly, stimulating vagus on only one side of the neck was sufficient to suppress CSDs triggered on both sides of the brain suggesting that nVNS may be useful in treating unilateral or bilateral headaches, independent of which side of the neck is stimulated.

Dr. Cenk Ayata, the senior author, commented, “We have established that VNS reduces cerebral excitability as shown by CSD suppression, and that VNS has a strikingly rapid onset of action compared to traditional migraine prophylactic agents, such as topiramate and valproate. We also established that both the non-invasive hand held gammaCore device and surgically implanted device should be equally effective in reducing cortical spreading depression.”

Reducing CSD is a validated platform for screening pharmacological therapies for migraine with aura. The authors believe that VNS works through the modification of neurotransmitter levels and potentially an affect on local and circulating cytokines3.

Study details

The study had five groups of animals; non-invasive VNS; surgically implanted VNS; sham group – electrodes were implanted but never stimulated; femoral nerve stimulation group; and naïve animals. CSD was elicited by either a continuous topical KCI application or by electrical stimulation.

CSDs were then measured in all groups and it was found that VNS raised the electrical threshold to initiate a CSD more than threefold and reduced the frequency and speed of the continuous KCI-induced CSDs.

Blood pressure and heart rate were also continuously monitored and were only minimally and transiently affected by VNS.

1 Full list of authors and their hospitals.

2 CSD is a local disturbance in the brain cortex, a slowly propagating wave of depolarisation and suppression of electrical activity across the cortex.

3 Cytokines include a number of substances, such as interferon, interleukin, and growth factors, which are secreted by certain cells of the immune system and have an effect on other cells.


Notes to editors

Research funding. This work was funded in part by the American Heart Association (10SDG2610275, KEH; 10SDG2600218, IA), the Massachusetts General Hospital (Claflin Distinguished Award, KEH), and an unrestricted research gift from electroCore LLC. 

About electroCore

electroCore LLC, the New Jersey based bioelectric pharma company, is focused on developing non-invasive vagus nerve stimulation therapies (the gammaCore device) for the treatment of multiple conditions in neurology, psychiatry, gastroenterology, and respiratory fields. The company’s initial target is the treatment of primary headaches (migraine and cluster headache), and the associated chronic co-morbidities of gastric motility, psychiatric, sleep, and pain disorders that drive disproportionately large direct and indirect costs within the healthcare system and society.



On behalf of electroCore LLC

Simon Vane Percy
Vane Percy & Roberts
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