Non-Invasive Electric and Magnetic Brain Stimulation for the Treatment of Fibromyalgia

Although fibromyalgia is defined by its core muscular nociceptive component, it also includes multiple dysfunctions that involve the musculoskeletal, gastrointestinal, immune, endocrine, as well as the central and peripheral nervous systems, amongst others. The pathogenic involvement of the nervous system and the numerous neurological and neuroinflammatory symptoms of this disease may benefit from neuromodulatory stimulation techniques that have been shown to be effective and safe in diverse nervous system pathologies. In this systematic review, we outline current evidence showing the potential of non-invasive brain stimulation techniques, such as therapeutic strategies in fibromyalgia. In addition, we evaluate the contribution of these tools to the exploration of the neurophysiological characteristics of fibromyalgia. Considering that the pathogenesis of this disease is unknown, these approaches do not aim to causally treat this syndrome, but to significantly reduce a range of key symptoms and thus improve the quality of life of the patients.


Introduction
The term fibromyalgia was introduced in 1976 [1] to replace the less precise terminology of fibromatosis that was previously used. The current criteria for the diagnosis of this syndrome are based on the definition of the American College of Rheumatology from 1990 (tender points or tenderness elicited by pressure of at least 11 of 18 specified body sites and widespread pain), which was updated by the American College of Rheumatology in 2010 and 2011 [2], and revised in 2016 [3] (generalized pain in at least four regions, symptoms present for at least 3 months, generalized pain index (GPI) ≥ 7, and severity of symptoms ≥ 5). Recent fibromyalgia prevalence studies estimate values between 0.2 and 6.6% in the general population, between 2.4 and 6.8 % in women, maximum values of headache, and several other poorly defined symptoms whose overlap has an unknown etiopathogenesis [5,6]. Because of this large number of overlapping symptoms, a multifactorial pathogenesis is discussed. Fibromyalgia thus seems to be an imprecise term, focused only on one of the multiple systems involved in the disease, and does not refer to its phenotype or its unknown etiopathogenesis [7]. This limited knowledge about the etiopathogenesis of the disease is one likely reason for the limited effectiveness of current symptomatic treatments, which have, at best, moderate therapeutic effects [6,8]. Until knowledge about the pathogenesis of this disease allows the development of a corrective causal treatment, the exploration of new effective and safe symptomatic therapeutic options is necessary to deal with the core symptoms of the disease.
In this systematic review, we focus on the involvement of the central nervous system in this syndrome and critically evaluate how non-invasive brain stimulation might be a useful method to explore the neurophysiological characteristics of fibromyalgia. Additionally, we highlight recent studies that point to the potential of non-invasive electric and magnetic brain stimulation [9,10] as a therapeutic approach to treat at least some of its neurological and neuroinflammatory symptoms [11], taking into account the apparent effectiveness of these methods to improve some physical indicators of health [12].

Methods
This review follows the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines.

Search Strategy and Selection Criteria
Our search focused on research studies about neurophysiological alterations in fibromyalgia as evaluated by transcranial magnetic stimulation, as well as studies investigating the effects of non-invasive magnetic or electric brain stimulation methods on fibromyalgia symptoms. We conducted a systematic search in PubMed and Web of Science databases using the following keyword combinations: "transcranial magnetic stimulation" OR "TMS" OR "rTMS" AND "fibromyalgia" OR "transcranial electric stimulation" OR "tES" AND "fibromyalgia" OR "transcranial direct current stimulation" OR "tDCS" AND "fibromyalgia" OR "transcranial alternating current stimulation" OR "tACS" AND "fibromyalgia" OR "transcranial random noise stimulation" OR "tRNS" AND "fibromyalgia" OR "transcutaneous vagus nerve stimulation" OR "tVNS" AND "fibromyalgia". The database search included publications from 2000 until January 2023. This search yielded a total of 572 results, as shown in the PRISMA flow diagram of Figure 1.
We selected research articles that met the following criteria: adult participants with fibromyalgia, studies with non-invasive electric and/or magnetic brain stimulation (openlabel, single or double-blind, with or without sham condition, and healthy participants, randomized or not randomized studies). The search was restricted to full-text original articles published in English. Fifty-four studies met these criteria and were included in this systematic review (Figure 1). Review and study protocol articles were only reported in the Discussion Section or to support general concepts, but they were not considered as research results.

Data Extraction and Analysis
We analyzed the following information from the full-text articles: study population (fibromyalgia patients, patients with other clinical conditions, healthy controls), sample size (per group and total), study design (between-subjects with parallel groups, within subject-crossover, single case study, single-or double-blind, open-label study, randomized study, sham-controlled, longitudinal study), TMS-dependent neurophysiological measures of cortical excitability, TMS and tDCS protocols and stimulation parameters, cortical stimulation target, tDCS electrode position, the total number of stimulation sessions and duration, sessions per week, pain measures, questionnaires and other outcome measures, tasks, physiological measures, results reported, and adverse effects.

Results
The results of the selected studies were organized according to the stimulation method (TMS, rTMS, and tDCS). These data are shown in Tables 1-3.

Data Extraction and Analysis
We analyzed the following information from the full-text articles: study population (fibromyalgia patients, patients with other clinical conditions, healthy controls), sample size (per group and total), study design (between-subjects with parallel groups, within subject-crossover, single case study, single-or double-blind, open-label study, randomized study, sham-controlled, longitudinal study), TMS-dependent neurophysiological measures of cortical excitability, TMS and tDCS protocols and stimulation parameters, cortical stimulation target, tDCS electrode position, the total number of stimulation sessions and duration, sessions per week, pain measures, questionnaires and other outcome measures, tasks, physiological measures, results reported, and adverse effects.

Results
The results of the selected studies were organized according to the stimulation method (TMS, rTMS, and tDCS). These data are shown in Tables 1-3.

Nervous System Involvement in Fibromyalgia
Several of the multiple symptoms of fibromyalgia have an evident neurological contribution, such as headache, irritable bowel syndrome, allodynia, sleep disorders, fatigue, depression, anxiety, post-traumatic stress disorder, cognitive impairment, paresthesia, and neuropathic pain [62]. The last probably includes chronic central sensitization, a maladaptive plasticity mechanism of the brain in response to chronic pain [63]. This sensitization results in increased responsiveness to all kinds of stimuli with pain perception. Probable changes in gray matter volumes of the pain brain matrix have been shown in fibromyalgia patients by magnetic resonance imaging (MRI) [64], but evidence for systematic structural and functional alterations in the pain processing network is still limited. Likewise, the functional integrity of the descending pain-modulating system seems to be compromised in these patients [65], which could be a target for therapeutic interventions. In recent years, chronic pain in fibromyalgia has also been related to abnormal functioning of the C-fibers of spinal neurons of the dorsal horn [66,67], which may contribute to central sensitization as well [63]. Via transcranial magnetic stimulation (TMS), a distinctive dysfunction of intracortical excitation and inhibition processes has been identified in basic and clinical fibromyalgia studies (see below in the TMS section). This altered cortical activity pattern includes decreased intracortical inhibition and facilitation in the primary motor cortex (M1), and this dysfunctional excitability pattern suggests an altered basal neuronal plasticity state in the cerebral motor network that might be associated with some clinical symptoms modulated by the sensorimotor system, such as chronic and widespread pain, probably strengthened by maladaptive LTP-like plasticity of the pain matrix [13].
A possible direct or indirect involvement of the nervous system in the pathogenesis of fibromyalgia symptoms is also suggested by the fact that widespread pain in these patients may be relieved via psychoactive drugs with different pharmacodynamic properties, such as antidepressants (duloxetine, milnacipran, tricyclics), anxiolytics (benzodiazepines), muscle relaxants (cyclobenzaprine), and anticonvulsants (pregabalin) [68][69][70][71], which are however not analgesics in the strictest sense. The combination of neurological, psychological, and neuropsychiatric symptoms, as well as the moderate effects of available psychopharmacological therapies in fibromyalgia, encourage the further development of central nervous system interventions as adjuvant therapies in the treatment of this complex disease. Non-invasive brain stimulation could be one such intervention, considering its advantageous safety profile and effectiveness in the treatment of several neurological, neuropsychological, and neuropsychiatric disorders [72,73], including pain relief [74]. Moreover, brain stimulation with non-invasive methods is a useful tool for studying the cortical activity of fibromyalgia patients in basic studies [67], which could provide potential neurophysiological targets for neuromodulation therapies. In summary, evidence indicates that some fibromyalgia symptoms involve central nervous system mechanisms, mainly cortical plasticity alterations and central sensitization, and these perturbances of the nervous system may be tackled by non-invasive brain stimulation methods.
According to this background, in the following sections we show how non-invasive brain stimulation, particularly specific TMS protocols, may help to understand the pattern of cortical excitation and inhibition in fibromyalgia patients. We also analyze the level of evidence for the potential effectiveness of commonly used non-invasive brain stimulation methods to treat some of the most relevant nervous system-dependent fibromyalgia symptoms.

Contributions of Non-Invasive Brain Stimulation
The two most frequently used non-invasive brain stimulation tools in fibromyalgia research (for both clinical and basic studies) are transcranial magnetic and electrical stimulation. Both approaches include different variants (i.e., with single, double, or repetitive magnetic pulses or with direct, alternating, random oscillatory, or pulsed current, to mention the most relevant magnetic and electric stimulation procedures), which are applied with different stimulation parameters (intensity, frequency, duration, etc.) and protocols (number of sessions, target area, in combination with other interventions, etc.).
Single and double-pulse TMS protocols are applied not for therapeutic purposes but for monitoring disease-related cortical excitability alterations and, thus, exploring pathophysiological features of fibromyalgia [14]. These tools may therefore facilitate the design of neuromodulation strategies aimed at minimizing or antagonizing possible dysfunctions of cortical excitability. For therapeutic purposes in the context of fibromyalgia, most clinical evidence is available for the application of repetitive transcranial magnetic stimulation (rTMS) and transcranial direct current stimulation (tDCS), both showing therapeutic effects with a moderate level of evidence [9,75]. rTMS consists of the application of repetitive magnetic pulses over the scalp with different frequencies. This TMS variant modulates the cortical activity and excitability beyond the end of the stimulation period, and specific stimulation frequencies induce excitability enhancement or reduction. Underlying mechanisms involve long-term potentiation (LTP) and long-term depression (LTD)-like plasticity processes. tDCS, on the other hand, consists of the application of weak direct currents (in the mA range) for a few minutes via electrodes (anode and cathode) placed on the scalp, which promotes polarity-dependent cortical excitability changes via the induction of subthreshold alterations of the resting membrane potential, and induction of LTP-and LTD-like plasticity. Under conventional protocols, anodal tDCS increases cortical excitability and cathodal tDCS reduces it. Some stimulation parameters, such as intensity and duration, may influence these effects in a non-linear way. Moreover, specific tDCS protocols, particularly those involving multiple sessions, have also shown the potential to induce prolonged neuroplastic and behavioral effects [73].
Transcranial alternating current stimulation (tACS) applies oscillatory sinusoidal, not tonic currents, with similar current strengths as tDCS, that entrain brain oscillations. It has been relatively rarely explored as a therapeutic tool to treat central nervous system activitydependent fibromyalgia symptoms. Only a recent study has reported effects so far [76], thus, evidence for its efficacy is limited at present [76,77]. Other non-invasive electrical brain stimulation techniques, such as transcranial random noise stimulation (tRNS), have also been explored in the context of fibromyalgia, but their effectiveness is unclear.
In the following sections, we provide details about the specific stimulation parameters and protocols applied via magnetic and electric brain stimulation methods, both in clinical and basic fibromyalgia studies, to present currently available knowledge about the usefulness of these brain stimulation techniques in the study of the neurobiology of fibromyalgia, and in the clinical context of this disease.

Single and Double Pulse TMS
Single and double-pulse TMS protocols are useful for exploring differences in cortical excitability between fibromyalgia patients, other pathologies, and healthy humans (Table 1). Particularly, TMS protocols tackling M1 as a model system for human cortical excitability indicate an alteration of intracortical inhibition [13], involving mainly reduced short-latency intracortical inhibition (SICI) in fibromyalgia patients, which suggests central disinhibition mechanisms in this syndrome [14,18,19]. However, reduced SICI has not been demonstrated in all studies [17]. A lower inhibitory control of the descending pain modulatory system (DPMS) was also revealed in fibromyalgia patients, in accordance with the observed reduced intracortical inhibition [17,20]. These disinhibition processes are related to higher levels of plasma BDNF [17,18,20]. On the other hand, reduced intracortical facilitation (ICF) has also been described in fibromyalgia [14], but this finding has not been as consistent as that observed with inhibitory processes. Although the specific pathophysiology of fibromyalgia that affects cortical excitability is not well understood [16], empirical results show that M1 stimulation via rTMS reduces pain intensity and modulates intracortical inhibition processes [25]. Further studies are needed to elucidate whether these cortical excitability alterations are a primary central mechanism of fibromyalgia and its relationship to chronic pain and other symptoms.

rTMS
The second general finding of TMS studies is related to the potential therapeutic effects of rTMS in fibromyalgia. Different rTMS protocols have been explored in clinical trials, and the results reveal moderate positive effects on pain, quality of life, anxiety, and depression [21,[23][24][25][26], as well as improvements of several other symptoms, such as catastrophizing [22], general activity and sleep disturbances [25], and physical and general fatigue [23]. All these were randomized, double-blind, and sham-controlled studies, except one, in which randomization was not reported [26], and targeted the left M1 or left DLPFC, with the exception of a single study targeting the dorsal anterior cingulate cortex (dACC) [26]. The number of sessions ranged between 10 and 16 when targeting M1 and between 10 and 20 when stimulating the DLPFC. The total sample size was between 30 and 49 in the M1 studies and between 20 and 26 in the DLPFC studies. The dACC study included a sample of 32 participants (Table 2).
Mechanistically, the long-lasting analgesic effect of rTMS in fibromyalgia has been linked to the stabilization of cortical inhibition and facilitation. Active, but not sham, facilitatory rTMS with 10 Hz over M1 has been shown to increase SICI and ICF, and reduce pain intensity in fibromyalgia patients [25]. This relation between improved intracortical excitability measures and reduced pain might be mediated by a re-establishment of the dysfunctional descending pain control system [17,20]. Alternatively, the analgesic effects of rTMS might depend on the inhibition of thalamic sensory nuclei induced by motor nuclei activation. The rTMS protocol with the best evidence with respect to its analgesic potential is high-frequency rTMS (with a frequency of 10 Hz) applied over the left M1 (80% intensity of the resting motor threshold, RMT) [21,25], which is also associated with significant improvements in the quality of life measures [22]. The analgesic effects of this protocol are moderate to high and are not limited to the intervention period, although the heterogeneity of the measured follow-up periods of the different studies makes definitive conclusions about the exact stability of effects difficult. rTMS (also with 10 Hz trains) over the left dorsolateral prefrontal cortex (DLPFC) at 120% RMT has shown moderate effects on pain intensity, fatigue, and depression, that continue for several weeks during the follow-up period [23,24], and 10 Hz rTMS, but not 1 Hz rTMS, at 110% of RMT over the dorsal anterior cingulate cortex (dACC) also induced strong pain intensity reductions lasting for 4 weeks after the last session [26]. In all of these studies, reported adverse effects were minor and transient (headache, neck pain, flashes, dizziness, nausea) ( Table 2).

Transcranial Direct Current Stimulation
We identified thirty-five studies reporting the use of tDCS to improve fibromyalgia symptoms (mainly pain intensity), and some of these studies correlated symptomatic improvements with changes in neurobiological measures. The specific protocols followed in each study and the respective results are shown in Table 3  .
There is no consensus about the optimal tDCS protocol to treat pain and other fibromyalgia symptoms. However, all studies reported significant effects of particular tDCS configurations on different fibromyalgia symptoms (from moderate to high), thus highlighting the potential of this non-invasive brain stimulation method to improve a variety of symptoms. Overall, these studies reveal that anodal tDCS applied over the left M1 (1/2 mA, 20 min, 1/5/10/15 sessions) [42,44,47,48,51,52], and to a lesser extent, over the DLPFC (1.5/2 mA, 20/30 min, 3/8/10/20/60 sessions) [27,31,34,36,39,41], has therapeutic effects on pain, with moderate to high levels of effectivity. With two exceptions [47,51] in the case of M1, and four in the case of the DLPFC stimulation [27,31,36,39], these studies were randomized, double-blind, and sham-controlled. The number of sessions of M1 tDCS ranged between 1 and 15, with 5 sessions being the most frequently used protocol. When targeting the DLPFC, the number of tDCS sessions ranged between 3 and 60, with greater variability in the number of sessions in this case, and without a common pattern of repetitions in these studies. The total sample size in the M1 studies was between 12 and 36, and between 20 and 58 in the DLPFC studies (Table 3).
In addition to measures of chronic pain, these studies assessed other characteristic symptoms of the disease, such as fatigue, quality-of-life related to pain, sleep disturbances, and cognitive and emotional functions. tDCS over M1 induced significant effects on these symptoms as well, although with a lower degree of effectiveness and evidence in relation to pain improvements [36]. Moreover, when symptomatic changes induced by anodal M1/DLPFC tDCS were contrasted with pre-and post-intervention physiological measures, some associations were found. Increased intracortical excitability as indexed by TMS, increased cortical activity as monitored by functional MRI (fMRI) in the rostral anterior cingulate cortex/ventromedial prefrontal cortex (rACC/vmPFC), reduced activity in the posterior insula, reduced serum BDNF and increased beta-endorphin levels, among other biological measures, were positively correlated with pain improvements [30,38,39,41,42]. No serious adverse effects were reported. Frequently reported side effects were the typical transient effects associated with tDCS, i.e., tingling, slight burning, and skin redness beneath the stimulation electrode.
In contrast to these largely consistent results, one study reported no significant effects of tDCS [49], as compared with the sham condition, on specific fibromyalgia symptoms, such as pain, fatigue, cognitive and sleep disturbances, and hyperalgesia. This double-blind study with four treatment groups (20 min of anodal tDCS, 2 mA stimulation intensity) conducted the intervention over the left M1, DLPFC, or the operculo-insular cortex, vs. sham stimulation, over 15 sessions, for 5 consecutive days per week. The return electrode was positioned over a typical contralateral region, the supraorbital area (Fp2 EEG electrode position), which is the most frequently used electrode placement for the cathodal return electrode in fibromyalgia studies. During the trial, the patients kept the usual medication of the two previous months. The primary outcome was pain intensity, and secondary outcomes were fatigue, mood, cognitive and sleep disturbances, and hyperalgesia measured by pressure pain threshold. Measurements were taken at 3-time points (before, immediately after treatment, and at 6 months follow-up). Thus, the tDCS parameters (intensity and density of current, session duration, number of sessions, etc.) and protocol in this study were comparable with those implemented in other studies, which reported significant effects of the intervention on these and other symptoms. Tentative explanations for this single negative effect may include the well-known inter-individual variability of tDCS effects (dependent on anatomical, physiological, behavioral, psychological, and other characteristics). Interestingly, the three active tDCS groups (anodal stimulation over the left M1, left DLPFC, and left operculo-insular cortex) showed a significantly larger improvement in the secondary outcome measures of anxiety and depression, compared with the sham condition, which reveals the effectiveness of tDCS at least for the treatment of affective symptoms in fibromyalgia also in this study. Taken together, evidence indicates that conventional protocols of anodal tDCS over the left M1 and DLPFC are an effective and safe neuromodulation approach with moderate effects on the core symptoms (pain, fatigue, poor quality of life, cognitive and mood alterations) of fibromyalgia.

Other Non-Invasive Neuromodulation Methods
The effects of other non-invasive neuromodulation techniques on fibromyalgia symptoms have been explored to a lesser extent. Despite limited evidence for the effectiveness of transcutaneous electrical nerve stimulation (TENS) [78] and transcutaneous spinal cord stimulation (tSCS) for fibromyalgia [79] or peripheral neuropathic pain symptoms [80], other approaches seem to provide more promising results.
Since the parasympathetic vagus nerve is involved in neurovegetative and inflammatory processes, this cranial nerve is considered a target for neuromodulation in fibromyalgia patients. Invasive [81] and non-invasive [82][83][84] methods of vagal nerve stimulation have been shown to be effective in different neurological disorders. In this vein, non-invasive transcutaneous vagus nerve stimulation (tVNS) is a promising therapeutic approach because of its safety and efficacy profile [85]. Particularly, transcutaneous stimulation of the auricular and cervical branches of the vagal nerve induces modulatory effects on the activity of this nerve [86,87], with therapeutic impact in several pathologies [86,88]. Thus, the sympathetic and inflammatory dysregulation that appears to underlie fibromyalgia might be tackled non-invasively by tVNS [85], and some studies indeed suggest therapeutic effects of tVNS on pain and quality of life in patients with fibromyalgia [84,89].
Other attempts to treat fibromyalgia symptoms by neuromodulation were motivated by the observation of abnormal slow cortical alpha oscillations in these patients. For modulating such altered oscillations, the effects of tACS (35 cm 2 electrode size, intensity ranging from 1 to 2 mA, 30 min per session, 10 sessions, 5 times a week), followed by 60 min of physical rehabilitative exercise, was evaluated in a randomized, crossover (with a washout period of 4 weeks) study [76]. Patients showing a higher spectral power of low frequencies at baseline (theta, delta, alpha1) were stimulated with beta-tACS at 30 Hz, and patients with a higher spectral power of fast frequencies (beta, alpha2) were stimulated with theta-tACS at 4 Hz. In each patient, one electrode was positioned over the scalp area showing the highest spectral power difference with respect to healthy controls, and the other electrode was positioned over the ipsilateral mastoid. The effects on pain and cognitive symptoms were compared in all patients with those induced by tRNS, a noninvasive electric brain stimulation technique in which random oscillations are applied in a frequency band up to 600 Hz. The tRNS parameters set in this study were: alternating current with random amplitude and frequency, within the range of 1-2 mA and 0-100 Hz, respectively. Despite this a priori likely ineffective tRNS protocol, both methods improved symptoms after interventions, but, since this study did not include a conventional sham control, these results are of limited value [77]. However, preliminary data suggest that a stimulation protocol with 10 sessions (5 consecutive days per week for 2 weeks) of tRNS (electrodes positioned over the M1 and the right supra-orbital regions, 1.5 mA current intensity randomly oscillating in the frequency range of 101-640 Hz, for 10 min per session) is an effective approach to improve pain and Fibromyalgia Impact Questionnaire (FIQ) scores, as well as depression and anxiety symptoms in fibromyalgia patients [90]. This protocol also resulted in improved cognitive symptoms, which suggests that the application of randomly changing alternating currents might be an effective method to modulate cortical excitability via the induction of electric fields less dependent on neural orientation, as compared to the tonic fields induced by tDCS [90].

Discussion
In this systematic review, we highlight the usefulness of single and double-pulse TMS to explore the neurophysiological dynamics of fibromyalgia, particularly with respect to cortical excitatory and inhibitory activity, and we critically review the therapeutic application of two main interventions in this field, rTMS and tDCS. We also present the first results of emerging tES protocols, such as tACS and tRNS.

TMS and Cortical Neurophysiology in Fibromyalgia
Regarding exploration of the neurophysiological pattern of fibromyalgia, single and double pulse TMS has shown to be a useful tool to explore intracortical and cortico-spinal excitability characteristics of patients, which may help to define a profile of central nervous system biomarkers of this disease [14,91]. One such biomarker identified in fibromyalgia is reduced intracortical inhibition, particularly SICI, as indexed by TMS measures. This cortical disinhibition is also related to dysfunctions in the descending pain-modulating system [75]. Cortical excitability alterations in fibromyalgia are, however, not limited to reduced SICI, since reduced ICF has also been reported [13,14]. Different non-invasive brain stimulation methods with the potential to modulate cortical excitability have been explored in clinical trials with fibromyalgia patients. The results of these studies reveal that rTMS and tDCS indeed induce neuromodulatory effects and, through neural mechanisms not yet fully understood, reduce pain intensity in these patients [25,91,92].

Therapeutic Effects of Non-Invasive Brain Stimulation on Fibromyalgia Symptoms
The exploration of new approaches for the treatment of fibromyalgia is important, due to the limited effectiveness of current pharmacological and physical therapies to face the symptoms of this syndrome. Although the etiopathogenesis of fibromyalgia is unknown, some critical symptoms are apparently related to dysfunctions of the nervous system. These alterations could potentially be tackled by different techniques of non-invasive neuromodulation. The results of the reviewed clinical studies reveal that electric and magnetic brain stimulation are safe neuromodulation methods (with slight and transient side effects) for the treatment of fibromyalgia, and they suggest that their overall effectiveness in improving pain intensity, fatigue, and quality of life is moderate (Tables 2 and 3). As brain stimulation targets, M1 and DLPFC (mainly over the left hemisphere) had similar pain-reducing effects in separate studies, although the available evidence for therapeutic potential is somewhat stronger in the case of M1 stimulation.

tDCS
Repetitive sessions of anodal tDCS applied over the left M1 have shown to be effective in significantly reducing pain intensity when compared to sham [29,30,33,[38][39][40]42,47,[52][53][54]. Meta-analyses of respective clinical studies came to similar results on pain and also described beneficial effects on affective and cognitive symptoms and quality of life [92][93][94]. The partially heterogeneous effects shown in these studies [11] may be due to the heterogeneity of experimental designs (number of tDCS sessions, crossover studies, parallel groups, follow-up periods, and others), protocols (current intensity, additional interventions, and others), and outcome measures (VAS, HPT, VNS, LF-MPQ, SF-MPQ, NRS, PCP-S, PPT, WPI, and others) ( Table 3). The main evidence for the effectiveness of tDCS in fibromyalgia is based on protocols that include multiple sessions (five as the most frequently applied number of sessions) of anodal tDCS applied over the left M1, under conventional current intensities and stimulation duration (1/2 mA, 20 min) [42,47]. Most of these studies, but not all, included randomization, double-blinding and a sham control. Similar protocols targeting the DLPFC also show significant therapeutic effects on pain and emotions, although the effect size here is medium overall [44]. All analyzed studies showed a good safety profile of tDCS in fibromyalgia patients, regardless of the number of sessions, current intensity, and cortical target (Table 3). Other non-invasive electric stimulation tools, such as tVNS, tACS, and tRNS, are currently being explored as potential therapeutic approaches in fibromyalgia. Evidence for a relevant treatment effect of these protocols is very limited at present [95], although preliminary results are similarly promising.

rTMS
As with anodal tDCS, excitatory stimulation with rTMS at 10 Hz over the left M1 significantly reduces pain intensity [25], improves cognitive and emotional functions [21], and impacts on some physiological measures [22]. Although the exact mechanism is unknown, the analgesic effects of sensory-motor non-invasive electrical and magnetic brain stimulation might be related to neuromodulatory actions on pain processing [75]. According to the proposed mechanisms of non-invasive brain stimulation in chronic pain control [96,97], the analgesic effects of these methods on fibromyalgia patients may well depend on the modulation of thalamic-cortical connectivity and resulting pain perception reduction. Complementarily, a somatosensory cortex inhibition triggered by M1 stimulation might also contribute to pain reduction in these patients. Consistent with these hypothesized mechanisms, recent meta-analyses support the effectiveness of high-frequency rTMS over the left M1 to reduce fibromyalgia-related pain after the intervention, with short-and long-term therapeutic effects [9,98]. Similar rTMS protocols over the DLPFC are also effective and safe for treating pain in these patients [34]. The effects on pain reported after DLPFC stimulation might depend on its potential to regulate the emotional evaluation of pain [95]. The design of the clinical rTMS studies targeting M1 or DLPFC followed quality standards, including randomization, double-blinding, and sham-control, and included more than ten stimulation sessions and medium sample size in general. Fatigue and emotional symptoms have also been addressed in a few of these studies [23], but evidence to determine which rTMS protocols might be most effective and which cortical areas should be targeted for the treatment of these symptoms is missing. Moreover, similar to tDCS, rTMS-related beneficial effects on chronic pain not caused by fibromyalgia have also been described, and this intervention has been shown to be safe for pain treatment in general [99]. This TMS method is usually associated with minimal side effects, mainly headache and stimulation discomforts, all of them transient.

Future Directions and Limitations
With regard to future directions of research, the available data are promising regarding the possibility of implementing non-invasive brain stimulation protocols in the treatment of, at least, pain symptoms in patients with fibromyalgia. However, it is still necessary to develop standardized stimulation protocols that induce longer-lasting effects and address various symptoms, in this case perhaps, through specific procedures based on the cortical target with the greatest clinical evidence (M1 and DLPDFC), the optimal stimulation method (tDCS or rTMS) and protocol, and personalization of treatment. Potential interactions with other therapies, including pharmacological treatment, are uncertain, and due to the impact these may have on the effects of brain stimulation, these interactions should be systematically analyzed in future research. On the other hand, non-invasive brain stimulation approaches in the clinical context require considerable expertise and assistance in the hospital setting, which makes access to these therapies difficult at present for certain treatments. In this connection, tailored stimulation through home-based tDCS might facilitate the treatment of symptoms related to the central nervous system in this disease [41], although this potential advantage also needs to be systematically explored.

Conclusions
Non-invasive neuromodulation procedures, particularly rTMS and tDCS, have developed as effective and safe alternatives, or adjuvant treatments, for patients with fibromyalgia. However, so far, proof of concept studies have been primarily conducted, and protocols have to be systematically explored in future studies to improve the efficacy and feasibility of these methods for the clinical therapy of fibromyalgia. Firstly, stimulation protocols should be standardized regarding optimal dosage, number of sessions, and brain target. Secondly, interindividual variability in response to brain stimulation might require personalized procedures, which also should be tailored to specific symptoms, considering the wide range of dysfunctions in fibromyalgia. This personalization of treatment may help to optimize respective interventions and thus promote the maintenance of therapeutic effects over time. Thirdly, interactions with other therapies and their possible adjunctive effects are unknown, and this is one of the critical factors to be investigated due to the complexity of this disease. Fibromyalgia patients are usually under polypharmacotherapy [100], and this makes it difficult to analyze the drug interactions in each case with the effects of different techniques and stimulation protocols.
Although non-invasive brain stimulation appears to be effective for the treatment of fibromyalgia, rTMS and tDCS effects might not be specific to the symptoms of this pathology. Thus, rTMS protocols described in clinical fibromyalgia studies have shown similar effectiveness for relieving rheumatic [101,102] and post-stroke [103] pain. Likewise, the therapeutic effects of electric brain stimulation also do not seem to be restricted to fibromyalgia, as pain improvements after tDCS interventions have been described in patients with different pain syndromes (trigeminal neuralgia, poststroke pain syndrome, back pain, and fibromyalgia) [104]. This suggests that the clinical improvement induced by non-invasive neuromodulation is at present mainly due to a primary effect on central pain processing, which is also affected in other chronic pain pathologies.