IMR Press / JIN / Volume 21 / Issue 4 / DOI: 10.31083/j.jin2104110
Open Access Review
Applications of transcranial magnetic stimulation in migraine: evidence from a scoping review
Show Less
1 IRCCS Centro Neurolesi Bonino Pulejo-Piemonte, 98124 Messina, Italy
2 Istituto Clinico Polispecialistico, C.O.T. Cure Ortopediche Traumatologiche s.p.a., 98124 Messina, Italy
3 AOU Policlinico “G. Martino”, Rehabilitation Unit, 98124 Messina, Italy
4 Ospedali Riuniti Villa Sofia-Cervello, Neurology Unit, 90146 Palermo, Italy
5 AOU Policlinico “G. Martino”, Stroke Unit, 98124 Messina, Italy
*Correspondence: salbro77@tiscali.it (Rocco Salvatore Calabrò)
Academic Editor: Rafael Franco
J. Integr. Neurosci. 2022 , 21(4), 110; https://doi.org/10.31083/j.jin2104110
Submitted: 15 December 2021 | Revised: 27 January 2022 | Accepted: 8 February 2022 | Published: 7 June 2022
(This article belongs to the Special Issue Migraine: from Bench to Clinical Practice)
Copyright: © 2022 The Author(s). Published by IMR Press.
This is an open access article under the CC BY 4.0 license.
Abstract

Transcranial magnetic stimulation (TMS), a non-invasive brain stimulation method, is trying to emerge as a migraine management strategy for both attack treatment and prevention. This scoping review presents 16 among single-pulse (to manage episodic and chronic migraine) and repetitive TMS randomized clinical trials (to manage chronic migraine). The works we reviewed suggest that TMS may be adopted as add-on therapy in those patients who are refractory to pharmacological therapy only with special arrangements for individualized treatment strategies or research. There are still limited clinical research programs and metaanalysis to promote routinely TMS employment, as TMS has been shown either to have no significant effects for any outcome or to be effective for migraine. These diverging conclusions depend on several biasing factors, including the lack of reliable, large, sham-controlled clinical trials, the dyshomogeneity in study designs (including the area of stimulation, the frequency of stimulation, the number of pulses, pulse intensity, and the number of sessions), patient selection criteria (migraine w/o aura, episodic and chronic migraine; TMS contraindication), and the lack of outcomes homogeneity and long-term real-world efficacy data. Therefore, in the future, it will be important to conduct larger randomized trials to confirm TMS usefulness in migraine management (acute attack and prophylactic treatment), identify those patients who may benefit from TMS, maybe independently of pharmacological treatments (i.e., using TMS as an alternative and not only as an add-on treatment). Otherwise, TMS will play a role in treating migraine only with special arrangements for individualized management strategies or research.

Keywords
transcranial magnetic stimulation (TMS)
migraine attack treatment
migraine prophylactic treatment
clinical trial
1. Introduction

Migraine is one of the primary headaches according to the International Classification of Headache Disorder third edition (ICHD-3) beta, affecting about 15% of the population and causing severe impairment of the quality of life [1]. Owing to its genetic, environmental, and hormonal basis, migraine has become one of the most common nervous system diseases worldwide [2].

The physiopathology of migraine is complex (including several biochemical cascades, the cortical spreading depression phenomenon, and an enhanced central sensitization) and still partially unknown [3]. This partial knowledge makes it challenging to find proficient treatments [3]. Furthermore, pharmacologic therapies to relieve symptoms and the prophylaxis of migraine are sometimes inefficacious and can foster the risk of medication overuse headaches in some individuals. For these reasons, non-pharmacological treatments have been the object of research. Among these, single-pulse (sTMS) and repetitive transcranial magnetic stimulation (rTMS) have been studied to be implemented as both acute and preventive migraine add-on treatment options [4, 5, 6, 7, 8]. The rationale of using TMS to treat and prevent migraine attacks resides in the capability of TMS to affect cortical excitability beneath and far beyond the site of TMS application, with relevant effects on brain signaling. This is fundamental because migraine is a neuronal network disorder, whose modulation through different mechanisms and in different sites could be significant for migraine management. Notably, it seems that magnetic pulses could inhibit the cortical spreading depression and the related thalamocortical signaling [9], consistently with the evidence that targeting some brain areas with TMS may interfere with pain [8], thus blocking migraine attack and contributing to reducing migraine pain and frequency [10]. Overall, there seems to be practical, promising effects of TMS in reducing migraine frequency and intensity, but there is still no clear evidence.

The present narrative syntheses aimed at identifying peer-reviewed works describing the TMS paradigms implemented in migraine treatment, focusing on the pros and cons of this approach in the clinical management of migraine.

2. Materials and methods
Research strategy

This literature review was developed according to the guidance for narrative syntheses [11, 12] and the Enhancing Transparency in Reporting the Synthesis of Qualitative Research (ENTREQ) reporting guidelines [13]. Our research focused on papers on TMS and migraine, using the research keywords “migraine” AND “transcranial magnetic stimulation”. Papers were searched from PubMed, MEDLINE, PeDro, Google Scholar, and Cochrane Database. We included peer-reviewed journal and English-written papers, regardless of the date of publication, if they described the clinical impact of TMS on migraine in adult humans. We included only pilot and/or randomized clinical trials to consider different aspects of migraine management. Papers were excluded if they did not fit into the study’s conceptual framework, focused on other headache types, or belonged to gray literature. The search strategies were drafted by A.N. and L.B. and further refined by R.S.C., who also solved any disagreements on article inclusion.

The first search returned 1005 papers (pruned from duplicates by A.N.). Two-hundred seventy-one articles were screened for eligibility using the abovementioned research keywords, main judgment criteria, and publication types. To this end, the papers were assessed, focusing on titles and abstracts. Therefore, 16 articles were included in the present review by a full-text assessment of the papers. All the reviewed studies are summarized in Table 1 (Ref. [14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29]). The flow diagram depicting the flow of information through the different phases of the review is reported in Fig. 1.

Table 1.Summary of the reviewed studies.
Setup Sample Study design Outcome
Session number and pulses, intensity and site of stimulation (n, age ± SD, gender)
Clarke 2006 [14] two sTMS 5 s apart* 42 EM (MA and MO) randomized both sTMS produced immediate, 24 h lasting, significant reduction in pain during the MA episode
41.43 ± 11.69 double-blind
36 females TMS-intensity controlled
Lipton 2010 [15] sTMS inion 164 EM (MA) randomized Significant lack of ma episodes up to 48 h compared to the sham group
39.4 ± 11 double-blind
65 females sham-controlled
O’Reardon 2007 [16] 10 Hz 3000p 120% AMT left DLPFC 2 MDD with CM case-report decrease in the number of headache days only following the real treatment
1 d 5 w × 6 w 51y female double-blind
66y male sham-controlled
Conforto 2014 [23] 32 × 10 Hz 1600p 110% RMT left DLPFC 18 CM randomized significant decrease in the number of headache days in both groups
3–4 w × 8 w 36.8 ± 11.9 double-blind
not reported sham-controlled
Teepker 2010 [17] 2 × 1 Hz 500p 100% RMT vertex 27 EM (MA-MO) randomized significant decrease of migraine attacks in both groups
1 d × 1 w 35.66 ± 10.23 double-blinded
22 females sham-controlled
Amin 2020 [19] 5 Hz 900p 100% RMT left DLPFC 33 EM (MA-MO) randomized significant decrease of headache days compared to the sham group
1 d × 1 w 34.8 ± 10.75 double-blinded
22 females sham-controlled
Sahu 2019 [20] 10 × iIbs #600p 80% AMT left DLPFC 41 EM (MA-MO) randomized significant reduction of migraine severity in the active group up to 12 weeks
2 d × 1 w 30.79 ± 8.26 double-blinded
31 females sham-controlled
Misra 2012 [21] 10 × 10 Hz 600p 70% RMT left M1 51 EM randomized significant reduction of headache days and migraine severity in both groups up to one month
3 w aged 16–61 double-blinded
45 females sham-controlled
Kalita 2021 [27] 10 × 10 Hz 600p 70% RMT left M1 83 CM randomized significant reduction of headache days in the rTMS + amitripty line group at 2 months; conversion of cm to em in 67% patients in the rTMS + amitriptyline group
3 w × 3 m 31.12 ± 9.39 double-blinded
w/o amitriptyline 25 mg/d 72 females sham-controlled
Kumar 2021 [24] 10 × 10 Hz 600p 70% RMT left M1 20 CM randomized significant reduction of migraine severity (mean vas rating and midas scoring) up to 1 month in the real group compared to the sham group
5 w × 2 w 33.5 ± 7.7 double-blinded
11 females sham-controlled
Shehata 2016 [25] 20 × 10 Hz 2000p 80% RMT left M1 29 CM open-label randomized significant reduction of migraine severity in both groups, with a lasting effect only in the rTMS + BTX-A group (up to 12 weeks)
3 w × 1 m w/o BTX-A 32.65 ± 7.82 sham-controlled
19 females
Kalita 2016 [22] 10 × 10 Hz 600p 70% RMT left M1 98 CM and chronic tension-type headache randomized significant reduction of headache days and severity in both groups, with a lasting effect in the real group
3-real vs. 1-real + 2-sham sessions 31.73 ± 8.56 double-blinded
79 females sham-controlled
Starling 2018 [29] preventive (4p 2 d every 15 min) and acute treatment (3p × 3 every 15 min for each attack) sTMS inion 263 EM (MA-MO) prospective, open label, observational study significant reduction of headache days; significant reduction in pain during the MA episode
aged 18–65
not reported
Brighina 2004 [26] 10 × 20 Hz 400p 90% AMT left DLPFC 11 CM randomized reduction of headache days and severity in the real group
3 w × 1 m 47 ± 7 double-blinded
7 females sham-controlled
Leahu 2021 [28] 13 × 67 Hz 140p 60% RMT swiping three pre-established tracks, followed by 33 × 67 Hz 15p 85% RMT multifocal 65 EM (MA-MO) randomized significant reduction of headache days and severity in real group
39.7 ± 11.6 double-blinded
52 females sham-controlled
Hammad 2021 [18] 2 × 1 Hz 500p 100% RMT vertex 65 EM (MA-MO) open label significant reduction in pain intensity, frequency and duration of migraine attacks
29.75 ± 4.94 Observational study
34 females
Legend: AMT, active motor threshold; BTX-A, botulinum toxin A; CM, chronic migraine; DLPFC, dorsolateral prefrontal cortex; EM, episodic migraine; HC, healthy controls; iTBS, intermittent theta-burst stimulation; m, month; M1, primary motor cortex; MA, migraine with aura; MDD, major depressive disorder; p, pulses; RMT, resting motor threshold; sTMS, single-pulse TMS; d, day; w, week; w/o, with or without; *, over the area of perceived pain or over the area of the brain generating the aura (2 paired-pulses soon after attack onset, other paired-pulses every 15 min until pain and symptoms resolve anyway up to 2 h); #, bursts of three stimuli at 50 Hz repeated at 5-Hz frequency each train lasting for 2 s with an inter-train interval of 8 s; VAS, Visual Analogue Scale; MIDAS, Migraine Disability Assessment.
Fig. 1.

The flow diagram depicts the flow of information through the different phases of the review. It maps out the number of records identified, included and excluded, and the reasons for exclusions.

3. Results

The available studies on TMS application to migraine can be grouped into (i) treating and (ii) preventing the migraine attack. Regarding the former group, sTMS was applied, whereas both sTMS and rTMS were used to prevent migraine attacks.

3.1 Acute attack treatment

sTMS was initially applied as an alternating real and sham pulsed magnetic field to different scalp sites, including the occipital region, in 40 patients with headache (thus, not only migraine), with positive results in terms of headache frequency and intensity reduction [30]. The study by Pelka et al. [31] adopted a global magnetic field with good results in terms of attack interruption.

Other studies applied sTMS in 42 [14] and 164 patients with migraine (82 real sTMS and 82 sham sTMS) [15] over the painful area of the skull (in migraine without an aura) or over the occipital cortex (in migraine with aura) within one hour after the aura onset, achieving a reduction in headache intensity up to the complete headache abortion for 24 h in 32% of the patients reported. Only minor side effects (including headache, migraine, sinusitis, and paresthesia) were appreciable, without significant between-group differences.

Finally, 190 patients (59 individuals with episodic migraine with or without, and 131 with chronic migraine) who were provided with sTMS (according to [14] and [15]), participated in a 3-month telephone survey. The subjects reported a significant clinical improvement in 62% of patients, including the reduction in monthly headache days and attack duration in both episodic and chronic migraine, in addition to a reduction in disability [32].

3.2 Prophylactic treatment: rTMS

rTMS has been implemented only for a prophylactic action on migraine. A first double-blind study with real and sham rTMS on two patients with migraine and major depression reported the disappearance of migraine [16]. High-frequency (20 Hz) rTMS over the left dorsolateral prefrontal cortex (DLPFC) in six chronic migraine patients compared to five sham-rTMS patients was shown to be effective for prophylaxis of migraine, including attack frequency, headache index, and the number of acute medications. On the contrary, lower frequency rTMS (10 Hz over the left DLPFC [33], or 1 Hz rTMS over the vertex [17]) were ineffective. On the contrary, an open-label observational study employing 1 Hz rTMS over the vertex obtained a significant reduction in pain intensity, frequency and, and the duration of migraine attacks [18].

Two other studies applying 5 Hz [19] and intermittent theta-burst [20] stimulation of the left DLPFC showed partially positive data in the primary outcome (i.e., reduction of headache-days per month).

Instead, a single session of high-frequency rTMS (600 pulses at 10 Hz) over the left primary motor cortex (M1) reduced the number of headache days per month (of about 3 days), the migraine attack intensity, the quality of life impairment, and the painkiller intake, particularly within the first two weeks after the paradigm application in a chronic migraine sample [21]. Notably, providing the patients with three of these sessions was not significantly superior to the single session [22]. An 8-week, high-frequency rTMS protocol over left DLPFC in chronic migraine individuals was feasible and safe, but inferior to sham rTMS to decrease the number of headache days. Thus, M1 stimulation with rTMS seems a more promising target than the DLPFC does [23]. In a double-blind, parallel-group, randomized clinical trial employing neuronavigated TMS, the researchers delivered 600 pulses at 70% of resting motor threshold patterned in 10 trains at 10 Hz with an inter-train interval of 60 s in a daily session to the left M1. This paradigm was repeated 5 days per week, over two consecutive weeks. The authors found a significant, one-month lasting reduction in the mean pain rating scale, headache frequency, and Migraine Disability Assessment questionnaire in the real rTMS group [24].

High-frequency rTMS (10 Hz, 2000 pulses per session) over the left M1 was not superior to botulinum toxin-A injection up to 8 weeks post-treatment, but it was less effective at 12 weeks [25]. A 20 Hz-rTMS study over left M1 was shown to reduce attack frequency, headache index, and the number of abortive pills used for up to 2 months [26]. Lastly, high-frequency rTMS has been reported effective in converting chronic migraine to episodic migraine, particularly when combined with amitriptyline, compared to rTMS alone [27].

On the sidelines, we report on a deep TMS study aimed at relieving pain in chronic migraine patients. The authors reported that high-frequency deep TMS of both DLPFCs was more effective than the standard pharmacological treatment alone in reducing the frequency and intensity of migraine attacks, drug overuse, and depressive symptoms, thus resulting as a potentially helpful add-on strategy in chronic migraine [34].

An innovative approach described in a randomized, double-blinded, sham-controlled study employing swiping and, soon then, multifocal-spot high-frequency rTMS in episodic migraine patients significantly reduced headache days and severity [28].

3.3 Prophylactic treatment: sTMS

sTMS has also been studied as a preventative treatment. In a multi-center, prospective, open-label, observational study, 217 patients were provided with daily sTMS treatment for 3 months (3 consecutive pulses as needed for acute therapy, with the possibility to add other two pulse-sequences if pain relief was not achieved within 15 min; 4 pulses twice daily were instead delivered as a preventative therapy). It was found a mean reduction of about three headache days from baseline versus placebo and a reduction in acute medication use and disability [29].

Forty-two migraine patients with both migraine with aura and migraine without an aura were provided with paired-pulse sTMS (at either 50% or 30% of the maximum stimulator output) soon after attack onset. The percentage of patients complaining of migraine relief, mainly those among migraine with aura, increased with increasing stimulation rounds, suggesting a cumulative effect of sTMS, which was used to treat episodic migraine [14].

Finally, we mention a prospective, open-label, observational study pilot study carried out on twelve adolescents (12–17 years old, mean age 15 ± 1.5 years, 14 females) with episodic or chronic migraine [35]. Patients were provided with four single pulses over the inion twice a day (two pairs of two pulses separated by 15 min intervals) for 12 weeks, with further pulses available for acute treatment. The authors found that the stimulation strategy was feasible, well-tolerated, and acceptable as a non-pharmacologic preventive treatment. Even though the efficacy remains to be assessed in larger trials, the authors found a significant reduction in headache days per month (about 5 days) and in Migraine Disability Assessment score (about –36).

4. Discussion

The works we reviewed were carried out in adults aged 18–65 with primary or secondary headaches provided with TMS compared to sham/placebo or alternative standard of care. Headache frequency and duration, medication use, anxiety, quality of Life, and function improved following TMS in about 50% of enrolled patients, but this did not seem statistically different from sham treatment. This limited evidence suggests that TMS may be adopted as add-on therapy in those patients who are refractory to pharmacological treatments only in specific research or clinical contexts. There are still limited clinical research programs and metaanalysis that would lead to a different conclusion. Some reviews and meta-analyses concluded that TMS has no significant effects for any outcome [7, 8, 36], whereas other reviews proposed that TMS is effective for migraine, although admitting that there is still insufficient evidence to promote its large-scale use in clinical settings [4, 5, 6, 37]. These diverging conclusions depend on several biasing factors, including the lack of reliable, large, sham-controlled clinical trials, the dyshomogeneity in study designs (including the area of stimulation, the frequency of stimulation, the number of pulses, pulse intensity, and the number of sessions), patient selection criteria variability (migraine w/o aura, episodic and chronic migraine, absolute contraindication for TMS application), and the lack of outcomes homogeneity and long-term real-world efficacy data. Therefore, we have at first to summarize the pros and cons of TMS in migraine management to achieve a balanced conclusion on TMS usefulness in migraine.

4.1 Potential benefits

The data from our literature review indicate that TMS can consistently reduce the number of migraine days per month, mitigate the intensity and duration of migraine attacks for several days after TMS application, up to one month, interrupt migraine attack quickly, and improve the quality of life. In addition, TMS is safe and well-tolerated, also considering that the majority of trials employed subthreshold stimulation intensities, as only mild light-headedness, tinnitus, dizziness, paresthesia, tinnitus, scalp discomfort, and worsening of migraine have been reported [38]. Furthermore, the more specific theoretical mechanisms of action of TMS, the reversibility of any potential side effects, and the minimal-risk options for drug interaction (i.e., a prophylactic pharmacologic therapy seems not to influence the efficacy of rTMS) are other strength points [39].

Although such non-invasive neuromodulation devices are relatively expensive, TMS seems cost-effective in some cases (e.g., cheaper than botulinum toxin-A for chronic migraine treatment, cheaper than the whole, complex pharmacological management of chronic migraine) [40, 41, 42, 43, 44, 45, 46].

4.2 Current limitations

The effectiveness of TMS in managing migraine critically depends on the stimulation paradigm employed. Migraine reduction improves while increasing the number and intensity of stimuli, suggesting a cumulative effect of TMS stimuli consistently with neuroplasticity principles [47]; however, this is not an absolute rule as sham TMS outperformed real TMS in some clinical trials. There is also a consistent variability in the number of sessions (ranging from one to 12), the overall number of pulses, and the number of pulses per session (from 600 to more than 20000). Another critical factor is the stimulation target. TMS seems more effective when applied to the M1 than to the DLPFC or the vertex [48], although the research of TMS over the DLPFC is growing [49].

Furthermore, TMS efficacy is significantly influenced by the stimulation frequency selection. The number of migraine attacks and days did not differ significantly between real and sham low-frequency rTMS [17]. Conversely, high-frequency rTMS often promoted more evident migraine improvement. The greater efficacy of high-frequency rTMS may lie in its capability to engage several functionally connected brain networks through a spatial summation process [50]. Furthermore, the high-frequency stimulation may have a temporal resolution sufficient to interfere more with the network connectivity (i.e., the migrainous brain is hyperexcitable between attacks), which is related to migraine attack generation.

Patients’ selection is another factor limiting judgement on TMS usefulness in migraine management. Indeed, most of the available clinical trials enrolled female-dominated samples of patients who were refractory to pharmacological therapy, thus limiting the generalizability of the present findings to the entire migraine population [51]. Furthermore, patients with episodic migraine complained of at least four episodes a month. The number of patients with migraine with aura was exiguous. Finally, most studies enrolled episodic and chronic sufferers without differences in improvement, although chronic migraine seems to respond better to rTMS than episodic migraine does [21].

This issue, together with the lack of reliable, large, sham-controlled clinical trials (actually, the reviewed clinical trials were all randomized but lacked random sequence generation or concealed allocation) and the relatively high costs of the devices, limit the widespread use and clinical applications of noninvasive neuromodulation therapies.

4.3 Neurophysiological rationale for TMS in migraine

A non-negligible problem related to the large-scale clinical use of TMS in migraine is the not yet complete knowledge of TMS mechanisms of action in migraine concerning both the prophylactic treatment (mainly rTMS) and the acute phase treatment (sTMS). However, a solid rationale for adopting TMS to manage migraine remains.

Migraine patients’ cortical excitability and connectivity are largely abnormal and intimately correlated with migraine attack pathogenesis [52]. Furthermore, migraineurs’ brain shows an abnormal responsivity to TMS pulses as suggested by high-amplitude motor evoked potentials [53], lower phosphene threshold [54, 55, 56], high sensitivity of M1 to light exposure during both the pre-ictal and ictal phases of migraine [57, 58]. This baseline hyperexcitability concerns the M1 and DLPFC, which play a significant role as pain modulators, and the secondary somatosensory cortex. Furthermore, the baseline activity of such brain areas, which seems largely abnormal in chronic pain conditions [59, 60], has been proposed to tune other pain-associated neural areas [61]. Similarly, thermal pain measures and cold and heat pain threshold are largely abnormal in migraineurs compared to healthy controls, suggesting a reduced intracortical inhibition and a hypofunction of inhibitory pain modulation mechanisms [62]. All these issues justify the potentially positive response of patients with migraine with or without aura to rTMS, which has been estimated putatively capable of reverting the mentioned above (mal) adaptive plasticity in chronic pain conditions [63, 64]. Contemporarily, these baseline alterations may explain some of the paradoxical responses of the M1 in migraine to both inhibitory (low-frequency) or facilitatory (high-frequency) rTMS paradigms [65, 66, 67, 68, 69], explaining the reason why sham-rTMS was often superior to real-rTMS. However, over and above that, high-frequency rTMS carries a high potential of inducing a placebo effect, which can be usefully leveraged to enhance patients’ coping strategies [70]. Furthermore, rTMS over sensorimotor and premotor regions seems to entrain various biochemical mechanisms related to pain control, including plasma β-endorphins, vasoactive neuropeptides, predominantly calcitonin gene-related peptide, substance P, and neurokinin A [71]. However, it remains uncertain how long the effects of TMS last, although applying more stimuli in structured patterns may increase the duration of the aftereffects [47].

Regarding migraine with aura, TMS is proposed to challenge the spread of cortical spreading depolarization, particularly when applied over the occipital cortex [72]. High-intensity TMS pulses may inhibit the cortical spreading depolarization by activating inhibitory GABAB fibers in the upper cortical layers [39]. Another contribution to TMS efficacy in migraine with aura may come from a blocking action onto the activity of third-order neurons in the VPM thalamic nucleus, potentially through reverberant cortico-thalamocortical loops [9]. Lastly, cortical TMS may modulate thalamus and hypothalamus activity by entraining motor cortex projections to the medial thalamus and the anterior cingulate/orbitofrontal cortices, with relevant consequences on endogenous painkiller mechanisms [71].

4.4 Study limitations

Our analysis has some limitations to acknowledge. First, we included only published clinical trials. It is thus necessary to be cautious when making conclusions that come from synthesizing evidence. Even though randomized, double-blind, controlled clinical trials provide reliable results, we had to include only 16 trials in this analysis, thus likely limiting us from achieving any different outcome for TMS employment in migraine management. Furthermore, all studies in the analysis presented lots of heterogeneity, including lack of grouping by migraine severity, sexuality, age, paradigm setup, and migraine pharmacological treatment.

Moreover, the patients enrolled in the studies came from general hospitals or major institutions, which somehow limits data generalizability. Lastly, we did not assess of quality bias or blinding validity in the included trials. However, this type of assessment may be challenging and unreliable, as a quantitative synthesis could be hard to perform consistently with the significant heterogeneity in headache type studied, protocol stimulation parameters, location and duration of treatment, and outcome measures.

5. Conclusions and future perspectives

To summarize, there is no robust evidence to suggest the application of TMS in migraine due to the few available randomized trials, nearly all with a sham arm but mostly underpowered. Therefore, these data cannot be generalized to all migraine patients [73, 74, 75]. Furthermore, the response rate for TMS seems to be not superior to that of the preventive drug treatment [76]. However, there are several promising data on the prophylactic role of TMS in migraine, as also recognized by the FDA, which approved some TMS devices for the migraine attack treatment. For these reasons, it is trying to reduce the costs of non-invasive brain stimulation related to the underlying engineering and biotechnology research [74].

Therefore, more randomized controlled trials are required to clarify the migraine pathophysiology (particularly the cortical spreading depression and the thalamocortical cross-talk) [77], possibly adopting simultaneously or deferred functional neuroimaging and neurophysiological studies methods, and analyze the safety of long-term or frequent use of TMS. Furthermore, a better pathophysiological knowledge could be important to identify the best migraine candidate o non-invasive brain stimulation. Finally, the potential interaction between non-invasive brain modulation and the newly available drugs for treating and preventing migraine attacks, including ditans, calcitonin gene-related peptide monoclonal antibodies, and gepants is still to be seen. In this regard, it will be very important to conduct larger, properly blinded, and controlled trials to confirm TMS usefulness in migraine management (acute attack treatment and/or prophylactic treatment) maybe independently of pharmacological treatments, i.e., using TMS as an alternative and not only as an add-on treatment. In this way, the patients who may benefit from TMS could also be identified. We, therefore, advise that now TMS should be used only in specific research or clinical contexts until proven otherwise.

Abbreviations

CGRP, calcitonin gene-related peptide; CSD, cortical spreading depression; DLPFC, dorsolateral prefrontal cortex; EM, episodic migraine; M1, primary motor cortex; MA, migraine with aura; MEP, motor evoked potentials; MO, migraine without an aura; rTMS, repetitive transcranial magnetic stimulation; sTMS, single pulse transcranial magnetic stimulation; TMS, transcranial magnetic stimulation.

Author contributions

AN and LB conceived and designed the review; LB performed the research; AN analyzed the data; AM and AI supervised the procedures; AN wrote the paper; RSC reviewed and validated the paper.

Ethics approval and consent to participate

Not applicable.

Acknowledgment

Not applicable.

Funding

This research received no external funding.

Conflict of interest

The authors declare no conflict of interest. RSC is serving as one of the Editorial Board members/Guest editors of this journal. We declare that RSC had no involvement in the peer review of this article and has no access to information regarding its peer review. Full responsibility for the editorial process for this article was delegated to RF.

References
[1]
Straube A, Andreou A. Primary headaches during lifespan. Journal of Headache and Pain. 2019; 20: 35.
[2]
Global, regional, and national incidence, prevalence, and years lived with disability for 301 acute and chronic diseases and injuries in 188 countries, 1990–2013: a systematic analysis for the global burden of disease study 2013. Lancet. 2015; 386: 743–800.
[3]
Goadsby PJ, Holland PR, Martins-Oliveira M, Hoffmann J, Schankin C, Akerman S. Pathophysiology of Migraine: a Disorder of Sensory Processing. Physiological Reviews. 2017; 97: 553–622.
[4]
Clark O, Mahjoub A, Osman N, Surmava A, Jan S, Lagman-Bartolome AM. Non-invasive neuromodulation in the acute treatment of migraine: a systematic review and meta-analysis of randomized controlled trials. Neurological Sciences. 2022; 43: 153–165.
[5]
Evers S. Non-Invasive Neurostimulation Methods for Acute and Preventive Migraine Treatment-A Narrative Review. Journal of Clinical Medicine. 2021; 10: 3302.
[6]
Burch R. Preventive Migraine Treatment. Continuum. 2021; 27: 613–632.
[7]
Lambru G, Res JM, Biloshytska M, Andreou A. Noninvasive Neuromodulation in Headache: an Update. Neurology India. 2021; 69: S183–S193.
[8]
Blech B, Starling AJ. Noninvasive Neuromodulation in Migraine. Current Pain and Headache Reports. 2020; 24: 78.
[9]
Andreou AP, Holland PR, Akerman S, Summ O, Fredrick J, Goadsby PJ. Transcranial magnetic stimulation and potential cortical and trigeminothalamic mechanisms in migraine. Brain. 2016; 139: 2002–2014.
[10]
Holland PR, Schembri C, Fredrick J, Goadsby PJ. Transcranial magnetic stimulation for the treatment of migraine aura? Cephalalgia. 2009; 29: 22.
[11]
Popay J, Roberts H, Sowden A, Petticrew M, Arai L, Rodgers M, et al. Guidance on the Conduct of Narrative Synthesis in Systematic Reviews. In A. P. f. t. E.M. Programme (Ed.) Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA). 2006.
[12]
Moher D, Liberati A, Tetzlaff J, Altman DG. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. Annals of Internal Medicine. 2009; 151: 264–269.
[13]
Tong A, Flemming K, McInnes E, Oliver S, Craig J. Enhancing transparency in reporting the synthesis of qualitative research: ENTREQ. BMC Medical Research Methodology. 2012; 12: 181.
[14]
Clarke BM, Upton ARM, Kamath MV, Al-Harbi T, Castellanos CM. Transcranial magnetic stimulation for migraine: clinical effects. Journal of Headache and Pain. 2006; 7: 341–346.
[15]
Lipton RB, Dodick DW, Silberstein SD, Saper JR, Aurora SK, Pearlman SH, 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.
[16]
O’Reardon JP, Fontecha JF, Cristancho MA, Newman S. Unexpected Reduction in Migraine and Psychogenic Headaches Following rTMS Treatment for Major Depression: a Report of Two Cases. CNS Spectrums. 2007; 12: 921–925.
[17]
Teepker M, Hötzel J, Timmesfeld N, Reis J, Mylius V, Haag A, et al. Low-frequency rTMS of the vertex in the prophylactic treatment of migraine. Cephalalgia. 2009; 30: 137–144.
[18]
Hammad AB, Elsharkawy RE, Abdel Azim GS. Repetitive transcranial magnetic stimulation as a prophylactic treatment in migraine. Egyptian Journal of Neurology, Psychiatry and Neurosurgery. 2021; 57: 5.
[19]
Amin R, Emara T, Ashour S, Hemeda M, Salah Eldin N, Hamed S, et al. The role of left prefrontal transcranial magnetic stimulation in episodic migraine prophylaxis. Egyptian Journal of Neurology, Psychiatry and Neurosurgery. 2020; 56: 19.
[20]
Sahu AK, Sinha VK, Goyal N. Effect of adjunctive intermittent theta-burst repetitive transcranial magnetic stimulation as a prophylactic treatment in migraine patients: a double-blind sham-controlled study. Indian Journal of Psychiatry. 2019; 61: 139–145.
[21]
Misra UK, Kalita J, Bhoi SK. High frequency repetitive transcranial magnetic stimulation (rTMS) is effective in migraine prophylaxis: an open labeled study. Neurological Research. 2012; 34: 547–551.
[22]
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. Journal of Neurology. 2016; 263: 2238–2246.
[23]
Conforto AB, Amaro E, Gonçalves AL, Mercante JP, Guendler VZ, Ferreira JR, et al. Randomized, proof-of-principle clinical trial of active transcranial magnetic stimulation in chronic migraine. Cephalalgia. 2014; 34: 464–472.
[24]
Kumar A, Mattoo B, Bhatia R, Kumaran S, Bhatia R. Neuronavigation based 10 sessions of repetitive transcranial magnetic stimulation therapy in chronic migraine: an exploratory study. Neurological Sciences. 2021; 42: 131–139.
[25]
Shehata HS, Esmail EH, Abdelalim A, El-Jaafary S, Elmazny A, Sabbah A, et al. Repetitive transcranial magnetic stimulation versus botulinum toxin injection in chronic migraine prophylaxis: a pilot randomized trial. Journal of Pain Research. 2016; 9: 771–777.
[26]
Brighina F, Piazza A, Vitello G, Aloisio A, Palermo A, Daniele O, et al. RTMS of the prefrontal cortex in the treatment of chronic migraine: a pilot study. Journal of the Neurological Sciences. 2004; 227: 67–71.
[27]
Kalita J, Kumar S, Singh VK, Misra UK. A Randomized Controlled Trial of High Rate rTMS Versus rTMS and Amitriptyline in Chronic Migraine. Pain Physician. 2021; 24: E733–E741.
[28]
Leahu P, Bange M, Ciolac D, Scheiter S, Matei A, Gonzalez-Escamilla G, et al. Increased migraine-free intervals with multifocal repetitive transcranial magnetic stimulation. Brain Stimulation. 2021; 14: 1544–1552.
[29]
Starling AJ, Tepper SJ, Marmura MJ, Shamim EA, Robbins MS, Hindiyeh N, et al. A multicenter, prospective, single arm, open label, observational study of sTMS for migraine prevention (ESPOUSE Study). Cephalalgia. 2018; 38: 1038–1048.
[30]
Grünner O. Cerebral use of a pulsating magnetic field in neuropsychiatry patients with long-term headache. Klinische Neurophysiologie. 1985; 16: 227–230. (In German)
[31]
Pelka RB, Jaenicke C, Gruenwald J. Impulse magnetic-field therapy for migraine and other headaches: a double-blind, placebo-controlled study. Advances in Therapy. 2001; 18: 101–109.
[32]
Bhola R, Kinsella E, Giffin N, Lipscombe S, Ahmed F, Weatherall M, et al. Single-pulse transcranial magnetic stimulation (sTMS) for the acute treatment of migraine: evaluation of outcome data for the UK post market pilot program. Journal of Headache and Pain. 2015; 16: 535.
[33]
Conforto A, Gonçalves AL, Mercante J, Guendler V, Amaro Jr E, Moraes M, et al. Effects of repetitive transcranial magnetic stimulation in chronic migraine: A pilot study. Cephalalgia. 2011; 31: 94.
[34]
Rapinesi C, Del Casale A, Scatena P, Kotzalidis GD, Di Pietro S, Ferri VR, et al. Add-on deep Transcranial Magnetic Stimulation (dTMS) for the treatment of chronic migraine: a preliminary study. Neuroscience Letters. 2016; 623: 7–12.
[35]
Irwin SL, Qubty W, Allen IE, Patniyot I, Goadsby PJ, Gelfand AA. Transcranial Magnetic Stimulation for Migraine Prevention in Adolescents: a Pilot Open-Label Study. Headache. 2018; 58: 724–731.
[36]
Shirahige L, Melo L, Nogueira F, Rocha S, Monte-Silva K. Efficacy of Noninvasive Brain Stimulation on Pain Control in Migraine Patients: a Systematic Review and Meta-Analysis. Headache. 2016; 56: 1565–1596.
[37]
Zhu S, Marmura MJ. Non-Invasive Neuromodulation for Headache Disorders. Current Neurology and Neuroscience Reports. 2016; 16: 2–11.
[38]
Dodick DW, Schembri CT, Helmuth M, Aurora SK. Transcranial magnetic stimulation for migraine: a safety review. Headache. 2010; 50: 1153–1163.
[39]
Almaraz AC, Dilli E, Dodick DW. The Effect of Prophylactic Medications on TMS for Migraine Aura. Headache. 2010; 50: 1630–1633.
[40]
Brüggenjürgen B, Baker T, Bhogal R, Ahmed F. Cost impact of a non-invasive, portable device for patient self-administration of chronic migraine in a UK National Health Service setting. SpringerPlus. 2016; 5: 1249.
[41]
Mwamburi M, Liebler EJ, Tenaglia AT. Cost-effectiveness of gammaCore (non-invasive vagus nerve stimulation) for acute treatment of episodic cluster headache. American Journal of Managed Care. 2017; 23: S300–S306.
[42]
Wong HT, Ahmed F. Clinical and Cost Effectiveness of Neuromodulation Devices in the Treatment of Headaches: Focus on Non-invasive Therapies. In Lambru G, Lanteri-Minet M (eds.) Neuromodulation in headache and facial pain management: Principles, rationale and clinical data (pp. 241–257). Springer: Berlin. 2020.
[43]
Andreou AP, Trimboli M, Al-Kaisy A, Murphy M, Palmisani S, Fenech C, et al. Prospective real-world analysis of OnabotulinumtoxinA in chronic migraine post-National Institute for Health and Care Excellence UK technology appraisal. European Journal of Neurology. 2018; 25: 1069–e83.
[44]
Andreou AP, Fuccaro M, Lambru G. The role of erenumab in the treatment of migraine. Therapeutic Advances in Neurological Disorders. 2020; 13: 1756286420927119.
[45]
Lambru G, Hill B, Murphy M, Tylova I, Andreou AP. A prospective real-world analysis of erenumab in refractory chronic migraine. Journal of Headache and Pain. 2020; 21: 61.
[46]
Lambru G, Andreou AP, Guglielmetti M, Martelletti P. Emerging drugs for migraine treatment: an update. Expert Opinion on Emerging Drugs. 2018; 23: 301–318.
[47]
Barker AT, Shields K. Transcranial Magnetic Stimulation: Basic Principles and Clinical Applications in Migraine. Headache. 2017; 57: 517–524.
[48]
Hulla R, Liegey-Dougall A. A systematic review of high-frequency transcranial magnetic stimulation on motor cortex areas as a migraine preventive treatment. Cephalalgia Reports. 2019; 2: 2515816319889971.
[49]
Mohamad Safiai NI, Amir NA, Basri H, Inche Mat LN, Hoo FK, Yusof Khan AHK, et al. Effectiveness and tolerability of repetitive transcranial magnetic stimulation for preventive treatment of episodic migraine: a single-centre, randomised, double-blind, sham-controlled phase 2 trial (Magnet-EM). Trials. 2020; 21: 923.
[50]
Garcia JO, Grossman ED, Srinivasan R. Evoked potentials in large-scale cortical networks elicited by TMS of the visual cortex. Journal of Neurophysiology. 2011; 106: 1734–1746.
[51]
Lambru G, Lanteri-Minet M. Neuromodulation in Headache and Facial Pain Management: Principles, Rationale and Clinical Data. Springer Nature: Berlin. 2019.
[52]
Burke MJ, Joutsa J, Cohen AL, Soussand L, Cooke D, Burstein R, et al. Mapping migraine to a common brain network. Brain. 2020; 43: 541–553.
[53]
Cosentino G, Fierro B, Vigneri S, Talamanca S, Palermo A, Puma A, et al. Impaired glutamatergic neurotransmission in migraine with aura? Evidence by an input-output curves transcranial magnetic stimulation study. Headache. 2011; 51: 726–733.
[54]
Naeije G, Fogang Y, Ligot N, Mavroudakis N. Occipital transcranial magnetic stimulation discriminates transient neurological symptoms of vascular origin from migraine aura without headache. Neurophysiologie Clinique. 2017; 47: 269–274.
[55]
Brighina F, Piazza A, Daniele O, Fierro B. Modulation of visual cortical excitability in migraine with aura: effects of 1 Hz repetitive transcranial magnetic stimulation. Experimental Brain Research. 2002; 145: 177–181.
[56]
Palermo A, Fierro B, Giglia G, Cosentino G, Puma AR, Brighina F. Modulation of visual cortex excitability in migraine with aura: Effects of valproate therapy. Neuroscience Letters. 2009; 467: 26–29.
[57]
Aurora SK, Ahmad BK, Welch KM, Bhardhwaj P, Ramadan NM. Transcranial magnetic stimulation confirms hyperexcitability of occipital cortex in migraine. Neurology. 1998; 50: 1111–1114.
[58]
Aurora SK, Cao Y, Bowyer SM, Welch KM. The occipital cortex is hyperexcitable in migraine: experimental evidence. Headache. 1999; 39: 469–476.
[59]
Dasilva AF, Mendonca ME, Zaghi S, Lopes M, Dossantos MF, Spierings EL, et al. TDCS-induced analgesia and electrical fields in pain-related neural networks in chronic migraine. Headache. 2012; 52: 1283–1295.
[60]
Mhalla A, de Andrade DC, Baudic S, Perrot S, Bouhassira D. Alteration of cortical excitability in patients with fibromyalgia. Pain. 2010; 149: 495–500.
[61]
Castillo Saavedra L, Mendonca M, Fregni F. Role of the primary motor cortex in the maintenance and treatment of pain in fibromyalgia. Medical Hypotheses. 2014; 83: 332–336.
[62]
Uglem M, Omland PM, Engstrøm M, Gravdahl GB, Linde M, Hagen K, et al. Non-invasive cortical modulation of experimental pain in migraine. Clinical Neurophysiology. 2016; 127: 2362–2369.
[63]
Fregni F, Freedman S, Pascual-Leone A. Recent advances in the treatment of chronic pain with non-invasive brain stimulation techniques. Lancet Neurology. 2007; 6: 188–191.
[64]
Naro A, Milardi D, Russo M, Terranova C, Rizzo V, Cacciola A, et al. Non-invasive Brain Stimulation, a Tool to Revert Maladaptive Plasticity in Neuropathic Pain. Frontiers in Human Neuroscience. 2016; 10: 376.
[65]
Conforto AB, Moraes MS, Amaro E, Young WB, Lois LA, Gonçalves AL, et al. Increased variability of motor cortical excitability to transcranial magnetic stimulation in migraine: a new clue to an old enigma. Journal of Headache and Pain. 2012; 13: 29–37.
[66]
Brighina F, Giglia G, Scalia S, Francolini M, Palermo A, Fierro B. Facilitatory effects of 1 Hz rTMS in motor cortex of patients affected by migraine with aura. Experimental Brain Research. 2005; 161: 34–38.
[67]
Cosentino G, Di Marco S, Ferlisi S, Valentino F, Capitano WM, Fierro B, et al. Intracortical facilitation within the migraine motor cortex depends on the stimulation intensity. a paired-pulse TMS study. Journal of Headache and Pain. 2018; 19: 65.
[68]
Brighina F, Cosentino G, Vigneri S, Talamanca S, Palermo A, Giglia G, et al. Abnormal facilitatory mechanisms in motor cortex of migraine with aura. European Journal of Pain. 2011; 15: 928–935.
[69]
Conte A, Barbanti P, Frasca V, Iacovelli E, Gabriele M, Giacomelli E, et al. Differences in short-term primary motor cortex synaptic potentiation as assessed by repetitive transcranial magnetic stimulation in migraine patients with and without aura. Pain. 2010; 148: 43–48.
[70]
Granato A, Fantini J, Monti F, Furlanis G, Musho Ilbeh S, Semenic M, et al. Dramatic placebo effect of high frequency repetitive TMS in treatment of chronic migraine and medication overuse headache. Journal of Clinical Neuroscience. 2019; 60: 96–100.
[71]
Zardouz S, Shi L, Leung A. A feasible repetitive transcranial magnetic stimulation clinical protocol in migraine prevention. SAGE Open Medical Case Reports. 2016; 4: 2050313X16675257.
[72]
Hansen JM, Baca SM, Vanvalkenburgh P, Charles A. Distinctive anatomical and physiological features of migraine aura revealed by 18 years of recording. Brain. 2013; 136: 3589–3595.
[73]
Martelletti P, Jensen RH, Antal A, Arcioni R, Brighina F, de Tommaso M, et al. Neuromodulation of chronic headaches: position statement from the European Headache Federation. Journal of Headache and Pain. 2013; 14: 86.
[74]
U.S. Food and Drug Administration De Novo Summary (K130556). 2013. Available at: https://www.accessdata.fda.gov/cdrh_docs/reviews/k130556.pdf (Accessed: 5 March 2013).
[75]
National Institute for Health and Care Excellence (NICE) Transcranial magnetic stimulation for treating and preventing migraine. Interventional procedures guidance. 2014. Available at: https://www.nice.org.uk/guidance/ipg477/resources/transcranial-magnetic-stimulation-for-treating-and-preventing-migraine-pdf-1899869936447941 (Accessed: 23 January 2014).
[76]
Magis D, Schoenen J. Advances and challenges in neurostimulation for headaches. Lancet Neurology. 2012; 11: 708–719.
[77]
Tepe N, Filiz A, Dilekoz E, Akcali D, Sara Y, Charles A, et al. The thalamic reticular nucleus is activated by cortical spreading depression in freely moving rats: prevention by acute valproate administration. European Journal of Neuroscience. 2015; 41: 120–128.
Publisher’s Note: IMR Press stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Share
Back to top