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HEADACHE: Edited by Peter J. Goadsby

Neuromodulation in primary headaches: current evidence and integration into clinical practice

Rimmele, Florian; Jürgens, Tim P.

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Current Opinion in Neurology: June 2020 - Volume 33 - Issue 3 - p 329-337
doi: 10.1097/WCO.0000000000000820
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Neuromodulatory techniques have enlarged our armamentarium for the treatment of primary headaches. However, their role has recently been challenged by new compounds, such as monoclonal antibodies to calcitonin gen-related peptide and its receptor, gepants, and ditans, which have been proven effective in a large number of well designed, adequately powered randomized controlled trials. First reports on the use of neuromodulation techniques date back to Ancient Greece and Rome, where Dioscorides, Galen, and Scribonius Largus used electric eels and rays to treat headaches [1]. With the increasing availability of electricity in the 19th century, external application for headaches regained attention. The first commercially available battery-powered device for transcutaneous electrical nerve stimulation was introduced in 1919. It was not until 1967 neurostimulators were implanted for invasive pain therapy and not before the late 1990s that occipital nerve stimulation (ONS) was used in occipital headaches [2]. Deep brain stimulation (DBS) for the treatment of chronic cluster headache (CCH) was not established until 2001 [3]. Lately, noninvasive approaches have gained popularity over invasive methods. Both approaches targeting peripheral and central targets using either intermittent or continuous stimulation are currently applied in either acute or preventive stimulation (or both) (Fig. 1; Table 1). 

Invasive and noninvasive as well as peripheral and central methods of neuromodulation with their active agents. PAG, Periaqueductal gray; RVM, rostral ventral medulla; TMS, transcranial magnetic stimulation; TNC, trigeminal caudal nucleus; TCC, trigeminal cervical complex.
Table 1
Table 1:
Overview of relevant neuromodulating procedures in the treatment of headache and facial pain
Box 1
Box 1:
no caption available


These include ONS and sphenopalatine ganglion stimulation (SPGS).

Occipital nerve stimulation

Pathophysiological considerations

Peripheral (such as a frequency-dependent modulation of conduction velocity, segmental gating of nociceptive input, modulation of trigemino-cervical connectivity) and central effects (such as modulation of descending inhibitory networks and other parts of the ‘pain matrix’ by activation of ascending second-order neurons) have been discussed (see [4] for further details). Recent studies confirmed modulation of mechanically induced activity of central thalamic neurons (neuronal spike frequency and burst activity) by ONS in a rat model of chronic migraine [5] (Fig. 1). Migraine: A recent meta-analysis from 2018 [6▪] which included the Occipital nerve stimulation for the treatment of intractable chronic migrain headache study by Saper et al.[7] and another study on chronic migraine by Silberstein et al.[8] did not find any significant effects for the endpoints responder rate (reduction of headache days by ≥50%) and headache intensity. However, the reduction of headache days/month and migraine disability assessment scores was more pronounced with active ONS. Owing to a presumably high risk of systematic errors, scientific evidence was judged low. Chen et al.[9] reported similar findings in a metaanalysis from 2015 with significant differences between active ONS and placebo stimulation only for the number of days with prolonged headaches (≥4 h) of moderate to severe intensity. Due to the large number of device related adverse events and high rate of surgical revisions [8] the Conformité Européenne mark for ‘refractory chronic migraine’ was withdrawn by the notified body in 2011. Another system was not certified until 2018 for the indication ‘refractory chronic cluster headache’ in 2018. A prospective long-term open study on chronic migraine with an average follow-up of 9.4 years [10] initially included 37 patients with response to a prior occipital nerve block. Thirty-five responded to external occipital nerve stimulation and received a fully implanted system leading to reduction of pain intensity reduced by 4.9 points out of 10. Five patients were pain-free. Seven patients required explantation of the system. In an open, prospective study from the United Kingdom, 53 patients with refractory chronic migraine and a mean follow-up of 42 months reported a decrease of moderate to severe headache days by 8.51 per month (P < 0.001) [11]. An increasing body of evidence suggests that prior occipital interventions are predictive of therapeutic efficacy, such as occipital nerve blocks [12▪], occipital transcutaneous electrical nerve stimulation [13], and percutaneous electrical field stimulation [14▪].

Cluster headache

So far, no randomized, controlled studies have been published on the efficacy of ONS in cluster headaches. However, countless case series and open studies have been published on the effectiveness of ONS in patients with refractory and chronic progression. A systematic review from 2018 [6▪] based on eight earlier case series [15–22] reported a reduction of attacks frequency of 40–95%, responder rates from 20–92% and pain intensity of 17–60% with an average follow-up of was 18.5 months.

Sphenopalatine ganglion stimulation

Pathophysiological considerations

It remains ambiguous whether SPGS exerts its disruptive effects on the trigemino-parasympathic loop by blocking efferent parasympathic fibers or a rapid depletion of neurotransmitters (Table 1).


With the exception of one case series showing acute effectiveness, no further studies have been published for migraine [23].

Cluster headache

Based on numerous studies on interventions targeting the ganglion sphenopalatinum (SPG), a small pilot study (n = 5) using SPG stimulation reduced the pain effectively (≥50%) in 14 of 18 treated attacks (78%) [24]. This led to the development of an implantable microstimulator for intermittent stimulation. In a first multicenter study (pathway cluster headache-1) conducted in Europe in patients with refractory CCH (n = 32) active, subthreshold (below perception threshold) and sham stimulation [25]) led to a statistically significant reduction of pain using active stimulation (67.1%) compared with the control conditions (7.4 and 7.3%, P < 0.001). Furthermore, a significant reduction of attack frequency was also found. A long-term follow-up study showed sustained acute and preventive effects [26]. The pathway cluster headache-2 study in the United States (n = 93) revealed a relevant reduction in pain within 15 min in 62.46% of attacks over 992 attacks using active stimulation compared with an active control (P = 0.008) using transcutaneous electrical stimulation. Similarly, the weekly attack frequency was reduced by 2.9 (P = 0.03) [27▪▪] with active stimulation illustrating both acute and preventive therapeutic effects. Side-effects were transient, light to moderate, and related to implantation (trigeminal sensory disorders, postoperative pain, and swelling) in 73% of patients. As of April 19th, 2019, Autonomic Technologies, Inc. had stopped business and discontinued distribution and technical support. At present, there is no system available for SPGS.


Deep brain stimulation of the posterior hypothalamus is the only established approach for primary headaches.

Deep brain stimulation of the posterior hypothalamus

Pathophysiological considerations

The posterior hypothalamus has been found to play a pivotal role in the pathophysiology of cluster headache in clinical and hormonal studies as well as structural and functional imaging studies [28]. Imaging studies point to a functional modulation of pain processing networks [28]. Neurophysiological data studies did not reveal short-term changes of DBS, but lateralized neuroplastic changes after long-term stimulation [29] (Fig. 1).

Cluster headache

The first successful implantation in a medication-refractory patient dates back to 2001 [1,3]. The target coordinates lie between the posterior hypothalamus and the midbrain tegmentum. In the open phase of the only randomized, controlled study therapeutic effects were detectable in the experimental phase [30]. However, case series and prospective, open studies have reported effectiveness [31–33]. Although DBS is well tolerated by most patients over the course of years, it is associated with potentially serious side-effects because of its invasive nature [34], such as intracerebral hemorrhage, loss of consciousness, diplopia, and infections.


These include trigeminal, vagal, and extracranial targets.

Stimulation of the supraorbital and supratrochlear nerve

Pathophysiological considerations

Peripheral and central effects are discussed with special emphasis on the role of the trigemino-cervical complex and modulatory effects on the descending inhibitory systems [35]. Recent imaging studies suggest a relevant modulation of the anterior cingulate cortex [36] (Table 1).


In the tricentric ACME study [37▪▪] (n = 109) a significant absolute and relative reduction in pain intensity was found within 60 min (−59%) in the active compared with sham stimulation (−30%) (P < 0.001). The corresponding 50% responder rate was 63 versus 31% (P < 0.01). There were no serious side-effects and no device-related side-effects.

In 2013, transcutaneous stimulation of supraorbital and supratrochlear nerve (tSNS) had already shown efficacy in episodic migraine in the multicenter PREvention of MIgraine using the supraorbital transcutaneous stimulator CEfaly study (PREMICE study) [38] (n = 67; 20 min daily for 3 months). The number of headache days per month, decreased from 6.94 by 2.06 (P = 0.0023) with active, but only by 0.32 from 6.54 with sham stimulation (P = 0.608). However, comparing both groups statistical significance was missed by a narrow margin (P = 0.054). The 50% responder rate was 38 versus 12% (P = 0.014).

Cluster headache

In the absence of controlled trials, only a small case series suggests effectiveness in cluster headache [39].

Transcutaneous vagal nerve stimulation

Pathophysiological considerations

Stimulation of cervical and auricular vagal branches is thought to modulate the trigemino-cervical complex relayed by vagal nuclei. A recent functional MRI study has revealed a complex central regulatory network modulated by cervical transcutaneous vagus nerve stimulation (tVNS) in humans. tVNS caused increased activity in the left pons nucleus and a reduced activity in the right parahippocampal gyrus. Furthermore, it led to a loss in functional connectivity between both spinal trigeminal nuclei and the right parahippocampal gyrus and a gain in functional connectivity between the left pons and the right hypothalamus [40▪▪] (Fig. 1).


Acute treatment

The multicenter PRESTO study [41▪▪] (bilateral stimulation for 120 s) in episodic migraine (n = 248) failed to showed significant differences for the primary endpoint (pain freedom at 120 min) with 30.4% for active versus 19.7% for sham stimulation (P = 0.067), unlike pain freedom at 30 and 60 min (12.7 versus 4.2%, P = 0.012; 21.0 versus 10.0%, P = 0.023). Fifty percent responder rates for pain reduction and freedom of pain 120 min after stimulation were significantly higher in the verum group (32.4 versus 18.2%, P = 0.02, and 47.6 versus 32.3%, P = 0.026).


Preventive treatment

The multicenter EVENT study [42] in chronic migraine (n = 59) showed that active or sham stimulation over two months did not change the number of headache days/month from baseline to month 2 (−1.4, P = 0.44; −0.2; P = 0.72). Only an analysis of responders yielded significant results with the inherent risk of a selection bias due study dropouts (n = 11) in the experimental phase. The side-effects were mainly transient and minor to moderate, the most frequent were pain and paresthesia in the face, gastrointestinal symptoms, and pharyngitis. The multicenter PREMIUM study [43▪] in episodic migraines with and without aura (n = 447) using active stimulation or active placebo on both sides of the neck for 120 s three times a day over a course of 12 weeks yielded no significant differences for the primary endpoint (reduction of migraine days per month) (2.26 versus 1.80, P = 0.15). The device-related side-effects were mild and transient [43▪].

Auricular tVNS [44] in chronic migraine (n = 46) revealed surprisingly that presumably active stimulation (25 Hz for 4 h/day in the external ear canal) was inferior to the putative sham condition (1 Hz) (−6.9 versus −3.3 days; P = 0.035). The rate of side-effects was considerably higher in the 25 Hz group (71 versus 50%). The most side-effects rated mild to moderate included slight localized pain, paraesthesia, pruritus, and cutaneous ulcerations.

Cluster headache

Acute treatment

In the multicenter Acute cluster headache treatment study (ACT1) study [45], 38 patients with episodic cluster headache (ECH) and 22 with CCH received 3 × 120 min of active cervical stimulation (25 Hz) and 47 with ECH and 26 with CCH sham stimulation (0.1 Hz). The primary endpoint (relevant improvement within 15 min) did not differ between both groups (26.7 versus 15.1%, P = 0.1). A subgroup analysis revealed significant effects for ECH (34.2 versus 10.6%; P = 0.008) whereas no significant changes were found for those with CCH (13.6 versus 23.1%; P = 0.48). Forty-eight percent of the study participants had at least one side-effect (mostly localized irritation of the stimulation site, skin irritation, dysgeusia).

In the ACT2 study, 48 patients were treated with active stimulation (14 ECH, 34 CCH) and 44 with placebo stimulation (13 ECH and 31 CCH) [46▪]. As in the ACT1 study, the primary endpoint (no pain within 15 min) was not achieved (13.5 versus 11.5%; P = 0.71). Similarly, significant differences were found in ECH only (48 versus 6%; P < 0.01).

Preventive treatment

In the open, randomized, and prospective PREVenti study stimulation (3 × 120 s/day at 25 Hz) and stable SOC (mostly verapamil) in CCH (n = 48) was more effective than SOC (n = 48) each over a period of four weeks [47] in reducing the average number of cluster attacks per week (−5.9 versus −2.1, P = 0.02). The rate of adverse events did not differ (52 or 49%) and included dizziness, headaches, nasopharyngitis, oropharyngeal, and neck pain.

Remote electrical neurostimulation

Pathophysiological considerations

REN is thought to convey its effects by conditioned pain modulation via activation of descending inhibition pathways (Fig. 1).


Acute treatment

In a crossover pilot study, 71 patients were included treating 299 attacks with stimulation REN at the upper arm starting within 20 min after onset of an attack for 20 min with varying pulse widths (100, 150, and 200 μs). Sixty-four percent of participants reported a reduction of pain of at least 50% with active stimulation compared with 26% (P = 0.005) using sham stimulation [48▪]. Earlier stimulation yielded better outcomes. In a confirmatory multicenter study (n = 202) active stimulation applied to the upper arm for 30–45 min within 1 h after attack onset [49▪▪] led to pain relief within 2 h in 66.7 versus 38.8% using active sham stimulation (P < 0.0001). Tolerability did not differ between both groups (P = 0.499).


Recent systematic reviews and metaanalyses suggest favorable effects of transcranial magnetic stimulation over transcranial direct current stimulation (tDCS) regarding various endpoints (such as headache frequency, duration, and intensity) [50▪] with excitatory stimulation of the primary motor cortex (M1) considered most effective [51▪]. However, high-quality studies using standardized protocols are lacking.

Pathophysiological considerations

Transcranial magnetic stimulation and tDCS convey their effects by activation of a top-down cascade directly involving parts of the ‘pain matrix’ and other higher order structures such as M1 which modulate downstream targets involved in headache pathophysiology (Fig. 1).

Transcranial magnetic stimulation


Acute treatment

Migraine patients experiencing a visual aura during 30% of their attacks followed by moderate-to-severe headaches in at least 90% received two occipital single pulses within 1 h after aura onset [52]. After 2 h, 39% from the verum group reported pain freedom compared with 22% from the sham group (P = 0.0179). Side-effects included sinusitis and paraesthesia.

Preventive treatment with single pulses

In the multicenter, prospective, open ESPOUSE study [53], repeat single pulses in migraines without and without aura (n = 132) reduced headache days significantly (−2.75 days) in week 9–12 which was statistically significant (P < 0.001) compared with a ‘statistical placebo’ (two randomized, controlled clinical trials with topiramate for migraines, and the PREMICE).

Preventive treatment with repetitive transcranial magnetic stimulation

Trials on rTMS efficacy [54–57] and metaanalyses [50▪,58,59] yielded heterogeneous results attributable to different stimulation paradigms, including target region, stimulation frequency, and intensity. As there is no portable rTMS device, its use in a routine clinical setting remains difficult.

Cluster headache

Apart from a ‘naturalistic’ study [60] (n = 19) with 10–20 min treatments for two weeks with a significant reduction of attack frequency solid evidence is missing.

Transcranial direct current stimulation


A metaanalysis from 2016 did not find any significant effects for the endpoints pain intensity, migraine attacks, use of painkillers, and side-effects [58]. In a double-blind study [61] on refractory chronic migraine (n = 13), active stimulation (three times a week for four weeks) over M1 or the dorsolateral prefrontal cortex (DLPFC) at 2 mA for 20 min significantly lower HIT-6 scores after DLPFC stimulation were found compared with M1 and sham stimulation. Small group sizes were problematic (n = 3–6). Occipital cathodic tDCS in menstrual migraine (n = 16) for 20 min with 2 mA on each of the five days leading to expected menstruation [62] did not reduce the number of attacks compared with sham stimulation. The most frequent side-effect was paresthesia. Again, sample size was low.

Cluster headache

Only uncontrolled data [63▪] on refractory CCH (n = 31) are available showing that active tDCS for 20 min over the anterior cingular cortex at 2 mA on a daily basis for four to eight weeks leads to a decrease in attack frequency of 35% (P < 0.001).


Based on the regulatory limitations (Table 2) and the evidence shown above (Table 3), it is difficult to integrate neuromodulatory approaches into established treatment algorithms for migraine and cluster headache.

Table 2
Table 2:
Currently available neuromodulatory systems which have been tested in published randomized controlled trials with CE mark and/or FDA clearance
Table 3
Table 3:
Effectiveness of the individual neuromodulating methods in the acute and preventive treatment of migraines and cluster headache



With limited positive data suggesting acute efficacy in acute treatment for tVNS, preventive use in chronic migraine was disappointing [42]. Acute tSNS is supported by a positive study, whereas the trial on preventive effects did not formally meet its endpoint. Single-pulse TMS has shown acute efficacy in migraine with aura only. No clear recommendations can be given for the other approaches. In the absence of comparative studies and the limited evidence of combined use with conventional pharmaceuticals [64▪], the role noninvasive neuromodulation in current algorithms is unclear and should be based upon the patients’ preference. They may be considered in case of contraindications, failure of conventional pharmaceuticals, polypharmacy, and pregnancy or breastfeeding.

Recent studies raise doubt on stimulating pathophysiologically relevant cranial structures only, as demonstrated by REN [48▪,65], which is more feasible for longer stimulation in daily life.

Cluster headache

tVNS has shown efficacy in acute treatment of ECH [45,46▪] and preventive treatments in addition to standard treatment in CCH [47]. There is insufficient evidence for the remaining procedures. tVNS should especially be considered in cases of contraindications to or overuse of triptans.



In the absence of an approved method and ambiguous data from controlled trials, ONS seems acceptable only in highly refractory cases. Beforehand, noninvasive neuromodulation, minimally invasive procedures (occipital nerve blocks), monoclonal antibodies, and multimodal treatment approaches [66] should have been tried and failed.

Cluster headache

With a Conformité Européenne-marked system available, ONS is the method of choice in CCH if tVNS and occipital nerve blocks have failed. Data on the monoclonal antibodies fremanezumab and galcanezumab are positive only for galcanezumab in ECH with approved by the FDA [67–69]. Following the manufacturer's insolvency, SPGS is currently unavailable.


One major shortcoming is the limited number of well-designed and adequately powered trials. Effective blinding is difficult in peripheral approaches given the induction of paresthesia in the receptive field. Alleged ‘active placebo’ paradigms have been used successfully in some trials [27▪▪] but emerged as equally or even more effective than the putative ‘active stimulation’ in others [44,70▪▪]. Thus, additional inactive placebo conditions or more preceding research is necessary.

The manufacturer's closure of business had profound reverberations for patients with SPGS. This illustrates the need for compulsory backup plans (including repositories for essential technical equipment) for any implanted device in the future.


Neuromodulation is a helpful addition with noninvasive procedures being used increasingly. The integration into established treatment algorithms is difficult. The limited number of sufficiently powered randomized controlled trials and the lack of head-to-head studies with conventional preventives remain relevant methodological limitations.



Financial support and sponsorship


Conflicts of interest

F.R. has received honoraria from Novartis and Pharm Allergan. T.P.J. has received honoraria from Hormosan Pharma, Lilly, Novartis, Teva, Pharm Allergan, Autonomic Technologies and Sanofi (to TPJ).


Papers of particular interest, published within the annual period of review, have been highlighted as:


1. Fraunberger F. Das Experiment in der Physik: Ausgewählte Beispiele aus der Geschichte. Berlin: Springer-Verlag; 2013.
2. Weiner RL, Reed KL. Peripheral neurostimulation for control of intractable occipital neuralgia. Neuromodulation 1999; 2:217–221.
3. Leone M, Franzini A, Bussone G. Stereotactic stimulation of posterior hypothalamic gray matter in a patient with intractable cluster headache. N Engl J Med 2001; 345:1428–1429.
4. Jürgens TP, Leone M. Pearls and pitfalls: neurostimulation in headache. Cephalalgia 2013; 33:512–525.
5. Walling I, Smith H, Gee LE, et al. Occipital nerve stimulation attenuates neuronal firing response to mechanical stimuli in the ventral posteromedial thalamus of a rodent model of chronic migraine. Neurosurgery 2017; 81:696–701.
6▪. Cadalso RT, Daugherty J, Holmes C, et al. Efficacy of electrical stimulation of the occipital nerve in intractable primary headache disorders: a systematic review with meta-analyses. J Oral Facial Pain Headache 2018; 32:40–52.
7. Saper JR, Dodick DW, Silberstein SD, et al. Occipital nerve stimulation for the treatment of intractable chronic migraine headache: ONSTIM feasibility study. Cephalalgia 2011; 31:271–285.
8. Silberstein SD, Dodick DW, Saper J, et al. Safety and efficacy of peripheral nerve stimulation of the occipital nerves for the management of chronic migraine: results from a randomized, multicenter, double-blinded, controlled study. Cephalalgia 2012; 32:1165–1179.
9. Chen YF, Bramley G, Unwin G, et al. Occipital nerve stimulation for chronic migraine: a systematic review and meta-analysis. PLoS One 2015; 10:e0116786.
10. Rodrigo D, Acin P, Bermejo P. Occipital nerve stimulation for refractory chronic migraine: results of a long-term prospective study. Pain Physician 2017; 20:E151–E159.
11. Miller S, Watkins L, Matharu M. Long-term outcomes of occipital nerve stimulation for chronic migraine: a cohort of 53 patients. J Headache Pain 2016; 17:68.
12▪. Miller S, Watkins L, Matharu M. Predictors of response to occipital nerve stimulation in refractory chronic headache. Cephalalgia 2018; 38:1267–1275.
13. Nguyen JP, Nizard J, Kuhn E, et al. A good preoperative response to transcutaneous electrical nerve stimulation predicts a better therapeutic effect of implanted occipital nerve stimulation in pharmacologically intractable headaches. Neurophysiol Clin 2016; 46:69–75.
14▪. Kinfe TM, Pintea B, Roeske S, et al. Percutaneous nerve field stimulation (PENS) of the occipital region as a possible predictor for occipital nerve stimulation (ONS) responsiveness in refractory headache disorders? A feasibility study. Cephalalgia 2016; 36:779–789.
15. Mueller OM, Gaul C, Katsarava Z, et al. Occipital nerve stimulation for the treatment of chronic cluster headache: lessons learned from 18 months experience. Centr Eur Neurosurg 2011; 72:84–89.
16. Mueller O, Diener HC, Dammann P, et al. Occipital nerve stimulation for intractable chronic cluster headache or migraine: a critical analysis of direct treatment costs and complications. Cephalalgia 2013; 33:1283–1291.
17. Strand NH, Trentman TL, Vargas BB, Dodick DW. Occipital nerve stimulation with the Bion® microstimulator for the treatment of medically refractory chronic cluster headache. Pain Physician 2011; 14:435–440.
18. Magis D, Allena M, Bolla M, et al. Occipital nerve stimulation for drug-resistant chronic cluster headache: a prospective pilot study. Lancet Neurol 2007; 6:314–321.
19. Magis D, Gerardy PY, Remacle JM, Schoenen J. Sustained effectiveness of occipital nerve stimulation in drug-resistant chronic cluster headache. Headache 2011; 51:1191–1201.
20. Burns B, Watkins L, Goadsby PJ. Treatment of medically intractable cluster headache by occipital nerve stimulation: long-term follow-up of eight patients. Lancet 2007; 369:1099–1106.
21. Burns B, Watkins L, Goadsby PJ. Treatment of intractable chronic cluster headache by occipital nerve stimulation in 14 patients. Neurology 2009; 72:341–345.
22. Fontaine D, Christophe Sol J, Raoul S, et al. Treatment of refractory chronic cluster headache by chronic occipital nerve stimulation. Cephalalgia 2011; 31:1101–1105.
23. Tepper SJ, Rezai A, Narouze S, et al. Acute treatment of intractable migraine with sphenopalatine ganglion electrical stimulation. Headache 2009; 49:983–989.
24. Ansarinia M, Rezai A, Tepper SJ, et al. Electrical stimulation of sphenopalatine ganglion for acute treatment of cluster headaches. Headache 2010; 50:1164–1174.
25. Schoenen J, Jensen RH, Lantéri-Minet M, et al. Stimulation of the sphenopalatine ganglion (SPG) for cluster headache treatment: pathway CH-1: a randomized, sham-controlled study. Cephalalgia 2013; 33:816–830. doi:10.1177/0333102412473667.
26. Jürgens TP, Barloese M, May A, et al. Long-term effectiveness of sphenopalatine ganglion stimulation for cluster headache. Cephalalgia 2017; 37:423–434.
27▪▪. Goadsby PJ, Sahai-Srivastava S, Kezirian EJ, et al. Safety and efficacy of sphenopalatine ganglion stimulation for chronic cluster headache: a double-blind, randomised controlled trial. Lancet Neurol 2019; 18:1081–1090.
28. Hoffmann J, May A. Diagnosis, pathophysiology, and management of cluster headache. Lancet Neurol 2018; 17:75–83.
29. Jürgens TP, Leone M, Proietti-Cecchini A, et al. Hypothalamic deep-brain stimulation modulates thermal sensitivity and pain thresholds in cluster headache. Pain 2009; 146:84–90.
30. Leone M. Deep brain stimulation in headache. Lancet Neurol 2006; 5:873–877.
31. Leone M, Franzini A, Proietti Cecchini A, Bussone G. Success, failure, and putative mechanisms in hypothalamic stimulation for drug-resistant chronic cluster headache. Pain 2013; 154:89–94.
32. Seijo-Fernandez F, Saiz A, Santamarta E, et al. Long-term results of deep brain stimulation of the mamillotegmental fasciculus in chronic cluster headache. Stereotact Funct Neurosurg 2018; 96:215–222.
33. Akram H, Miller S, Lagrata S, et al. Optimal deep brain stimulation site and target connectivity for chronic cluster headache. Neurology 2017; 89:2083–2091.
34. Schoenen J, Di Clemente L, Vandenheede M, et al. Hypothalamic stimulation in chronic cluster headache: a pilot study of efficacy and mode of action. Brain 2005; 128:940–947.
35. Lauritsen CG, Silberstein SD. Rationale for electrical parameter determination in external trigeminal nerve stimulation (eTNS) for migraine: a narrative review. Cephalalgia 2019; 39:750–760.
36. Russo A, Tessitore A, Esposito F, et al. Functional changes of the perigenual part of the anterior cingulate cortex after external trigeminal neurostimulation in migraine patients. Front Neurol 2017; 8:282.
37▪▪. Chou DE, Shnayderman Yugrakh M, Winegarner D, et al. Acute migraine therapy with external trigeminal neurostimulation (ACME): a randomized controlled trial. Cephalalgia 2019; 39:3–14.
38. Schoenen J, Vandersmissen B, Jeangette S, et al. Migraine prevention with a supraorbital transcutaneous stimulator: a randomized controlled trial. Neurology 2013; 80:697–704.
39. Haane DY, Koehler PJ. Nociception specific supraorbital nerve stimulation may prevent cluster headache attacks: serendipity in a blink reflex study. Cephalalgia 2014; 34:920–926.
40▪▪. Möller M, Mehnert J, Schroeder CF, et al. Noninvasive vagus nerve stimulation and the trigeminal autonomic reflex: an fMRI study. Neurology 2020; 94:e1085–e1093.
41▪▪. Tassorelli C, Grazzi L, de Tommaso M, et al. Noninvasive vagus nerve stimulation as acute therapy for migraine: the randomized PRESTO study. Neurology 2018; 91:e364–e373.
42. Silberstein SD, Calhoun AH, Lipton RB, et al. Chronic migraine headache prevention with noninvasive vagus nerve stimulation: the EVENT study. Neurology 2016; 87:529–538.
43▪. Diener HC, Goadsby PJ, Ashina M, et al. Noninvasive vagus nerve stimulation (nVNS) for the preventive treatment of episodic migraine: the multicentre, double-blind, randomised, sham-controlled PREMIUM trial. Cephalalgia 2019; 39:1475–1487.
44. Straube A, Ellrich J, Eren O, et al. Treatment of chronic migraine with transcutaneous stimulation of the auricular branch of the vagal nerve (auricular t-VNS): a randomized, monocentric clinical trial. J Headache Pain 2015; 16:543.
45. Silberstein SD, Mechtler LL, Kudrow DB, et al. Non-invasive vagus nerve stimulation for the acute treatment of cluster headache: findings from the randomized, double-blind, sham-controlled ACT1 study. Headache 2016; 56:1317–1332.
46▪. Goadsby PJ, de Coo IF, Silver N, et al. Noninvasive vagus nerve stimulation for the acute treatment of episodic and chronic cluster headache: a randomized, double-blind, sham-controlled ACT2 study. Cephalalgia 2018; 38:959–969.
47. Gaul C, Diener HC, Silver N, et al. Noninvasive vagus nerve stimulation for PREVention and acute treatment of chronic cluster headache (PREVA): a randomised controlled study. Cephalalgia 2016; 36:534–546.
48▪. Yarnitsky D, Volokh L, Ironi A, et al. Nonpainful remote electrical stimulation alleviates episodic migraine pain. Neurology 2017; 88:1250–1255.
49▪▪. Yarnitsky D, Dodick DW, Grosberg BM, et al. Remote electrical neuromodulation (REN) relieves acute migraine: a randomized, double-blind, placebo-controlled, multicenter trial. Headache 2019; 59:1240–1252.
50▪. Stilling JM, Monchi O, Amoozegar F, Debert CT. Transcranial magnetic and direct current stimulation (TMS/tDCS) for the treatment of headache: a systematic review. Headache 2019; 59:339–357.
51▪. Feng Y, Zhang B, Zhang J, Yin Y. Effects of noninvasive brain stimulation on headache intensity and frequency of headache attacks in patients with migraine: a systematic review and meta-analysis. Headache 2019; 59:1436–1447.
52. Lipton RB, Dodick DW, Silberstein SD, et al. Single-pulse transcranial magnetic stimulation for acute treatment of migraine with aura: a randomised, double-blind, parallel-group, sham-controlled trial. Lancet Neurol 2010; 9:373–380.
53. Starling AJ, Tepper SJ, Marmura MJ, et al. A multicenter, prospective, single arm, open label, observational study of sTMS for migraine prevention (ESPOUSE Study). Cephalalgia 2018; 38:1038–1048.
54. Brighina F, Piazza A, Vitello G, et al. rTMS of the prefrontal cortex in the treatment of chronic migraine: a pilot study. J Neurol Sci 2004; 227:67–71.
55. Teepker M, Hötzel J, Timmesfeld N, et al. Low-frequency rTMS of the vertex in the prophylactic treatment of migraine. Cephalalgia 2010; 30:137–144.
56. Misra UK, Kalita J, Bhoi SK. High-rate repetitive transcranial magnetic stimulation in migraine prophylaxis: a randomized, placebo-controlled study. J Neurol 2013; 260:2793–2801.
57. Kalita J, Laskar S, Bhoi SK, Misra UK. Efficacy of single versus three sessions of high rate repetitive transcranial magnetic stimulation in chronic migraine and tension-type headache. J Neurol 2016; 263:2238–2246.
58. Shirahige L, Melo L, Nogueira F, et al. Efficacy of noninvasive brain stimulation on pain control in migraine patients: a systematic review and meta-analysis. Headache 2016; 56:1565–1596.
59. Lan L, Zhang X, Li X, et al. The efficacy of transcranial magnetic stimulation on migraine: a meta-analysis of randomized controlled trails. J Headache Pain 2017; 18:86.
60. Hodaj H, Alibeu JP, Payen JF, Lefaucheur JP. Treatment of chronic facial pain including cluster headache by repetitive transcranial magnetic stimulation of the motor cortex with maintenance sessions: a naturalistic study. Brain Stimul 2015; 8:801–807.
61. Andrade SM, de Brito Aranha RE, de Oliveira EA, et al. Transcranial direct current stimulation over the primary motor vs prefrontal cortex in refractory chronic migraine: a pilot randomized controlled trial. J Neurol Sci 2017; 378:225–232.
62. Wickmann F, Stephani C, Czesnik D, et al. Prophylactic treatment in menstrual migraine: a proof-of-concept study. J Neurol Sci 2015; 354:103–109.
63▪. Magis D, D’Ostilio K, Lisicki M, et al. Anodal frontal tDCS for chronic cluster headache treatment: a proof-of-concept trial targeting the anterior cingulate cortex and searching for nociceptive correlates. J Headache Pain 2018; 19:72.
64▪. Jiang L, Yuan DL, Li M, et al. Combination of flunarizine and transcutaneous supraorbital neurostimulation improves migraine prophylaxis. Acta Neurol Scand 2019; 139:276–283.
65. Rapoport AM, Lin T, Tepper SJ. Remote electrical neuromodulation (REN) for the acute treatment of migraine. Headache 2020; 60:229–234.
66. Kropp P, Meyer B, Dresler T, et al. Relaxation techniques and behavioural therapy for the treatment of migraine: guidelines from the German Migraine and Headache Society. Schmerz 2017; 31:433–447.
67. Teva provides update on clinical trial of fremanezumab for use in chronic cluster headache [date unknown]. [Accessed 9 April 2020].
68. Dodick DW, Goadsby PJ, Lucas C, et al. Phase 3 randomized, placebo-controlled study of galcanezumab in patients with chronic cluster headache: results from 3-month double-blind treatment. Cephalalgia 2020. 333102420905321doi:10.1177/0333102420905321 [Online ahead of print].
69. Goadsby PJ, Dodick DW, Leone M, et al. Trial of galcanezumab in prevention of episodic cluster headache. N Engl J Med 2019; 381:132–141.
70▪▪. Schroeder CF, Möller M, May A. nVNS sham significantly affects the trigeminal-autonomic reflex: a randomized controlled study. Neurology 2019; 93:e518–e521.

cluster headache; migraine; occipital nerve stimulation; supraorbital nerve stimulation; transcranial magnetic stimulation; vagus nerve stimulation

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