Chronic migraine is a primary multifactorial neurological disorder (Vos et al., 2016, 2017; James et al., 2018) which is common and incapacitating. It is defined by the occurrence of headache on 15 days or more per month, with at least 8 of these days having the characteristics of migraine, for more than 3 months (Arnold, 2018). It has an estimated prevalence of 13–18% of the world population and its pathophysiology seems to be more linked to abnormalities in the neural network of pain resulting from morphofunctional alterations in brain regions such as the dorsolateral prefrontal cortex (DLPFC), mesencephalic structures and the cingulate cortex (Marcus, 2003; Lipton et al., 2008). The increase in the frequency of the crises inherent to the pathology leads to a greater central sensitization, predisposing the sufferer to a “vicious cycle of pain” (Burstein, 2001; Chiapparini et al., 2010) and further predisposing them to potential negative repercussions in the biopsychosocial sphere in the face of the frequent association with absenteeism from work, anxiety, depression, sleep disorders and decreased socialization (Mercante et al., 2005; Stuginski-Barbosa and Speciali, 2011).

Therapeutic prophylaxis is strongly recommended in patients with severe and/or frequent impairment related to headache cephalalgy. The main treatment is still pharmacological, although most drugs are not very specific, and can trigger side effects which are not tolerable, and their excessive consumption predisposes the user to a diagnostic association with migraine due to the abusive use of drugs (Goadsby and Sprenger, 2010; Shukla and Sinh, 2010; Buse et al., 2012; Parra et al., 2015; Rocha et al., 2015; Shirahige et al., 2016). In this context, non-pharmacological therapies have been shown to be allied to lower drug consumption and frequency of headaches, with greater acceptance and safety compared to current therapy (Peres et al., 2011).

Mindfulness, whose core was possibly originated in meditative practices of ancient Taoism, Hinduism, and Buddhism, is the consciousness of intentional and non-judgmental attention to the present moment. Its exercise enables people to focus on present experiences, interrupting the trend of daily automation, as well as providing the cultivation of non-judging attitudes, emotions and pain (Andrasik et al., 2016). There have been substantial advances in the knowledge of the neural mechanisms related to mindfulness practices. Electroencephalographic (EEG) and functional magnetic resonance imaging (fMRI) studies suggest that mindfulness exercise induces changes in the brain “state,” including activations of the anterior cingulate cortex and the dorsomedial prefrontal cortex (Davidson et al., 2003; Hölzel et al., 2008; McCallion, 2017). Mindfulness-based interventions can produce similar effects to isolated medication for chronic migraine patients with a history of too much pharmacological use (Grazzi et al., 2017).

Thus, Mindfulness-based therapeutic interventions have been used as a single or co-adjuvant treatment for migraines (Day et al., 2014). This technique provides greater attentional and emotional self-regulation and self-perception (Gu et al., 2018), generating physical, mental and social well-being benefits, in addition to minimizing symptoms related to anxiety, stress, depression, and rumination, which are considered triggers for migraine attacks (Badran et al., 2017). Previous neuroimaging studies comparing experienced meditators to non-meditators point to the existence of a greater volume of the gray substance in the hippocampal and frontal cortex in regular practitioners (Luders et al., 2009; Chételat et al., 2017), which is also related to long-term changes in hippocampus functional topology (Lardone et al., 2018).

Transcranial direct-current stimulation (tDCS) is a neuromodulatory technique that enables greater pain control and a decrease in the clinical symptoms of migraine, as it can modulate the excitability and excessive cortical neural hyperresponsiveness inherent to this pathology and can be used, both in prophylaxis and in crisis intervention (Machado et al., 2009; Peres et al., 2011; Magis, 2015; Parra et al., 2015; Shirahige et al., 2016).

Studies have shown that the combination of mindfulness practice and tDCS seems to have a synergistic effect in reducing osteoarthritis pain (Ahn et al., 2019), in improving the working memory in individuals without neurological comorbidities (Hunter et al., 2018) and the positive affective experience in university students (Robinson et al., 2019). For example, improvements in parameters such as attentional inhibition, cognition and executive function skills were observed in a study associating mindfulness practice and tDCS of the left DLPFC of patients with refractory depression compared to conventional pharmacological treatment (Monnart et al., 2019). A recent study demonstrated that tDCS can improve mindfulness skills learning by an intervention program based on this technique in a group of adults with history of chronic pain (McCallion et al., 2020).

In view of the above, this study aimed to associate mindfulness practice with left DLPFC anodal tDCS as a prophylactic synergistic therapy in painful symptoms of patients diagnosed with chronic migraine. Specifically, we aim to increase the level of full attention of these patients with their potential benefits in order to minimize pain, decrease the degree of inability to perform activities of daily living and the negative impact of this clinical condition on patients' daily lives.

This study was approved by the Institution's Ethics Committee, conducted in accordance with the 1964 Helsinki Declaration and registered on the Clinical Trials platform (www.clinicaltrials.org) (NCT04219345). Written and informed consent was obtained from all participants.

In this study, it was observed that the active current group showed an increase in the level of full attention and improvements in the inability to perform activities of daily living and in the impact of the participants' headache. The sham group was also benefited, but with smaller effect sizes than the active group. However, only the inability to perform activities of daily living showed significant differences in the comparison between both groups in the post-treatment.

Since both groups performed mindfulness practices, this would be a possible explanation for the improvement in the results of all outcomes in the sham group. The use of mindfulness as a therapeutic practice has been shown in previous studies to be safe and viable in adults with chronic migraine (Wells et al., 2014), demonstrating to reduce functional disability and suffering related to migraine (Smitherman et al., 2015), promoting greater awareness, de-identification with self, greater optimism related to sensations and feelings (Feuille and Pargament, 2015), reducing relapses by minimizing triggers that trigger crises such as anxiety and tension, increasing resilience to stress and the effective regulation of heart rate (Azam et al., 2016), in addition to improving the perception of pain intensity and quality (Bakhshani et al., 2016). Another justification would be the performance of the placebo effect, which according to the definition found in the literature is “the favorable result that derives from the patient's positive expectations and not from the physiological mechanism of the treatment itself” (Teixeira, 2008).

This study proved to be favorable to the hypothesis that mindfulness practice and tDCS in the left DLPFC can be combined for synergistic effects in reducing pain symptoms and in expanding the level of full attention of chronic migraineurs, since the groups with active current showed better results than simulated current. According to previous studies, such occurrence stems from the neuroplasticity provided by tDCS, which increases the brain's ability to reorganize in response to other clinical interventions (Ahn et al., 2019), as well as facilitating neural activity patterns in progress (Hunter et al., 2018). According to previous studies, mindfulness and tDCS seem to having complementary mechanisms of action enabling to minimize rumination, which is a relevant causal factor for depression and also a potential trigger for migraine attacks (Azam et al., 2016; Monnart et al., 2019). A clinical trial associating mindfulness with tDCS in healthy individuals concluded that meditation sessions are positively reinforced (in quality of mindfulness levels) with the use of this neuromodulation tool (Badran et al., 2017). However, there is a study with alcohol patients undergoing treatment which found no evidence of synergism between mindfulness and tDCS with regard to improving the symptoms of this clinical condition (Witkiewitz et al., 2019).

All participants in the present study were female. It was initially thought to select representatives of both genders, however, as the demand for volunteers was massive among women and because the pathology under evaluation is predominant in this gender (Domingues et al., 2009; Queiroz et al., 2009; Cauás et al., 2010), we chose to select only female participants. The influence of female hormonal factors is considered to be potentially relevant in the pathophysiology of migraine (Parra et al., 2015) and this exclusive female selection can be considered a limiting factor, since it is not known whether the results of tDCS therapy could differ in males.

In this study, we did not exclude patients who were receiving previous pain control medication (only analgesics and/or non-steroidal anti-inflammatory drugs) and we did not perform specific analyzes with regard to the quantity and type of drug in each of the groups as outcome predictors, which is therefore a limitation. However, we selected participants using stable doses of pain medications and an approximate amount between them for at least 2 months before the intervention. We also asked them not to modify this use during the treatment period.

Adherence to home practices of mindfulness was monitored by filling in individual tables with the schedule performed and if there was an interruption with a later restart, as previously instructed. However, some participants claimed to sporadically forget filling in some exercises (maximum of three annotation gaps in the table of four participants), despite having informed that they performed the practice on the non-registration days. Four participants reported difficulty in home training (deconcentrating, not finding an adequate place to listen to the audios at home or not identifying with the tool), with three dropouts from the study due to inadequacy to exercise mindfulness. The absence of notes in the table provided can be considered a limitation, since it makes it difficult to assess adherence to this activity to complement the intervention associated with tDCS.

Some methodological aspects can also be considered limiting, such as the small size of the groups, which can decrease the statistical power to detect minor effects. In addition, the subjects were recruited from a service specialized within a tertiary institution, so they may not be representative of the general chronic migraine population. Another point would be the limitations of tDCS power found in the literature in relation to intra and interindividual variables (Boros et al., 2008; Cunningham et al., 2015). Thus, strategies were adopted in order to systematize the process in each stimulation session, such as standardization of the electrode size and the use of coordinates to locate the target region (left DLPFC).

Although the proportion of adverse effects was equivalent in both groups (Table 2) and this occurrence was compatible with that already mentioned in similar literature (Vecchio et al., 2016; Andrade et al., 2017), there was 40% more drowsiness in the sham current group. We speculate that the synergism between mindfulness and tDCS in the active stimulation group minimized the sleepiness of the full current group, since the literature demonstrates that the combination of cognitive training with brain stimulation seems to be conducive to the current neural activity patterns associated with control and regulation of attention (Clark and Parasuraman, 2014; Hunter et al., 2018).

It is indicated that future studies evaluate other stimulation parameters, such as intensity and polarity of the stimulation. Therefore, computational models (meaning models which predict current flow in the target areas) can be useful to refine the design of future studies, thus optimizing the effects of stimulation and providing specific information about the inter-individual differences that may influence tDCS effects on migraine. The inclusion of three more arms in the study (one with active tDCS only, another with tDCS sham only, and another with only mindfulness practice) can be useful to provide greater reliability in assessing the synergism of combination therapy and in more accurate conclusions about the placebo effect.

Despite the limitations discussed, the results of this study provide the first therapeutic evidence of the practice of mindfulness associated with anodic tDCS of the left DLPFC with its consequent increase in the level of full attention and its analgesic benefits in the clinical symptoms of patients with chronic migraine. It is hoped that this study will encourage further research on the interaction between tDCS and mindfulness training to reduce the negative effects of chronic migraine, including EEG recording, assessment of anxiety and sleep quality.

The original contributions presented in the study are included in the article/supplementary materials, further inquiries can be directed to the corresponding author/s.

The studies involving human participants were reviewed and approved by Comitê de Ética em Pesquisa—Centro de Ciências da Saúde—Federal of University Paraíba. The patients/participants provided their written informed consent to participate in this study.

SA and LP have designed the study and managed all stages of the design and writing process. LP has performed the data analysis and has written the first draft of the manuscript. LL has contributed to the interpretation and review of the data. EA, PB, JS, and JF have operationalized tDCS. LH and AL have written the last draft of the manuscript. All authors have contributed to the revision of the manuscript, read, and approved the submitted version.

This study was financed in part by the Coordination for the Improvement of Higher Education Personnel—Brazil (CAPES)—Finance Code 001.

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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