Non-invasive neuromodulation alters neural activity through the stimulation of nerves and neural tissue.1 Neuromodulation therapies may provide an alternative treatment option to drug therapies for the treatment of migraine and cluster headache. During the 19th Congress of the International Headache Society (IHC 2019), Dr Simon Akerman (University of Maryland, USA), Dr Anna Andreou (Guy’s and St Thomas’ NHS Trust, United Kingdom) and Prof. David Yarnitsky (Rambam Medical Centre, Israel) discussed the role of non-invasive neuromodulation devices for the treatment of migraine and cluster headaches.

Dr Simon Akerman: Non-invasive vagus nerve stimulation (nVNS)

Dr Akerman began his presentation by describing clinical trial data evaluating the efficacy of nVNS for the treatment of migraine and cluster headache. In migraine, results of a randomized, sham-controlled trial are suggestive of effective pain relief and tolerability for the acute treatment of episodic migraine.2 In cluster headaches, pooled data from two randomized, sham-controlled trials showed that nVNS was effective in acute treatment for episodic cluster headache.3 It was noted that the efficacy of nVNS is yet to be determined for the preventive treatment of chronic migraine and cluster headache.

Dr Akerman discussed the mechanisms of action of nVNS, highlighting results of a preclinical migraine model that suggests nVNS engages dural-trigeminovascular mechanisms.4 Dr Akerman also described how nVNS engages cortical neurons, demonstrated by effects of cortical spreading depression (CSD). Dr Akerman concluded that via both direct and indirect effects, nVNS engages and modulates migraine and cluster headache-related descending trigeminal and ascending cortical responses.

Dr Anna Andreou: Single-pulse transcranial magnetic stimulation (sTMS)

As part of her presentation, Dr Andreou presented efficacy data for the treatment of migraine with sTMS. A randomized, sham-controlled trial in acute migraine with aura showed increased freedom from pain with sTMS compared with sham stimulation.5 In terms of preventive treatment for migraine, results of an open-label, observational study showed a significant mean reduction of headache days from baseline compared with a statistically-derived placebo estimate.6

“In the future, we may have a magnet in our phone to treat our headaches”
Dr Anna Andreou (Guy’s and St Thomas’ NHS Trust, United Kingdom)

Using data from animal models of migraine, Dr Andreou described how the mechanisms of action for sTMS affect both cortical and thalamic activity. In animal models of migraine with aura, sTMS was shown to block CSD frequency and increase the CSD threshold.7 Single neuron extracellular electrophysiology has shown that sTMS also modulates trigeminovascular neuronal activity within the thalamus7 and alters dopaminergic hypothalamic signaling.

Prof. David Yarnitsky: Non-cranial nerve stimulation

Prof. Yarnitsky discussed how patients with migraine are unable to suppress pain in the same way as people without migraine. This is supported by study findings that suggest patients with migraine have deficient conditioned pain modulation (CPM) compared with healthy controls.8,9 Prof. Yarnitsky described CPM an endogenous analgesia mechanism, in which conditioning stimulation inhibits pain in remote body regions.

Prof. Yarnitsky proceeded to describe remote electrical neuromodulation (REN), a novel acute migraine treatment in which upper arm peripheral nerves are stimulated to induce CPM. In a recent randomized, sham-controlled study, REN was shown to be more effective than sham stimulation in the treatment of episodic migraine pain.10 Prof. Yarnitsky concluded his presentation by emphasizing that although REN seems to be an effective and well-tolerated non-pharmacologic treatment for episodic migraine, the proposed mode of action for REN via CPM activation still needs to be proven through experimental research.


  1. Reuter U, et al. Non-invasive neuromodulation for migraine and cluster headache: a systematic review of clinical trials. Migraine 2019;90:796–804.
  2. Tassorelli C, et al. Noninvasive vagus nerve stimulation as acute therapy for migraine: The randomized PRESTO study. Neurology 2018;91:e364-e373.
  3. De Coo IF, et al. Differential efficacy of non-invasive vagus nerve stimulation for the acute treatment of episodic and chronic cluster headache: A meta-analysis. Cephalalgia 2019;39:967–977.
  4. Akerman S, et al. Vagus nerve stimulation suppresses acute noxious activation of trigeminocervical neurons in animal models of primary headache. Neurobiol Dis 2017;102:96–104.
  5. Lipton RB, et al. Single-pulse transcranial magnetic stimulation for acute treatment of migraine with aura: a randomised, double-blind, parallel-group, sham-controlled trial. Lancet Neurology 2010;9:373–380.
  6. Starling AJ, et al. A multicenter, prospective, single arm, open label, observational study of sTMS for migraine prevention (ESPOUSE Study). Cephalalgia 2018;38:1038–1048.
  7. Andreou AP, et al. Transcranial magnetic stimulation and potential cortical and trigeminothalamic mechanisms in migraine. Brain  2016;139:2002–2014.
  8. Sandrini G, et al. Abnormal modulatory influence of diffuse noxious inhibitory controls in migraine and chronic tension-type headache patients. Cephalalgia 2006;26;782–789.
  9. Nahman-Averbuch H, et al. Waning of “conditioned pain modulation”: a novel expression of subtle pronociception in migraine. Headache 2013;53:1104–1115.
  10. Yarnitsky D, et al. Remote Electrical Neuromodulation (REN) Relieves Acute Migraine: A Randomized, Double-Blind, Placebo-Controlled, Multicenter Trial. Headache 2019;doi: 10.1111/head.13551. [Epub ahead of print].