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Abstract

Introduction

Persistent idiopathic facial pain is a refractory and disabling condition of unknown mechanism and etiology. It has been suggested that persistent idiopathic facial pain patients have not only peripheral generators of pain, but also central nervous system changes that would contribute to the persistence of symptoms. We hypothesized that persistent idiopathic facial pain would have changes in brain cortical excitability as measured by transcranial magnetic stimulation compared to healthy controls.

Methods

Twenty-nine persistent idiopathic facial pain patients were compared to age- and sex-matched healthy controls and underwent cortical excitability measurements by transcranial magnetic stimulation applied to the cortical representation of the masseter muscle of both hemispheres. Single-pulse stimulation was used to measure the resting motor threshold and suprathreshold motor-evoked potentials. Paired-pulse stimulation was used to assess short intracortical inhibition and intracortical facilitation. Clinical pain and associated symptoms were assessed with validated tools.

Results

Spontaneous pain was found in 27 (93.1%) and provoked pain was found in two (6.9%) persistent idiopathic facial pain patients. The motor-evoked potentials at 120% and 140% were significantly lower for both hemispheres compared to controls. Persistent idiopathic facial pain patients had lower short-interval intracortical inhibition compared with controls. These changes were correlated with some aspects of quality of life, and higher mood symptoms. These neurophysiological alterations were not influenced by analgesic medication, as similar changes were observed in patients with or without central-acting drugs.

Conclusions

Persistent idiopathic facial pain is associated with changes in intracortical modulation involving GABAergic mechanisms, which may be related to certain aspects of the pathophysiology of this chronic pain condition.

Trial registration: NTC01746355.

Keywords

Persistent idiopathic facial pain cortical excitability chronic pain neuropathic pain transcranial magnetic stimulation atypical facial pain

Introduction

Chronic orofacial pain comprises a large number of differential diagnoses and affects 10% of the adult and 50% of the elderly population (1 –3). Atypical facial pain (currently called persistent idiopathic facial pain (PIFP)) (4) describes diffuse, poorly localized, uni- or bilateral pain that is most frequently located in the maxillary region without symptoms of classical neuralgias affecting the face (e.g. trigeminal or other orofacial pain conditions) (5,6). It is generally described as a deep, throbbing pain that is not usually associated with nerve injury or structural and functional alteration. Thus, the diagnosis of PIFP is based on the exclusion of other causes of pain and it has no pathognomonic signs or symptoms, which highlights its complex and challenging nature. Many PIFP patients undergo multiple invasive treatments (i.e. surgical procedures, dental restoration and extractions, medications), which are frequently unsuccessful for providing significant pain relief and can even cause superimposed nerve injuries, subsequently aggravating pain (7,8). The pathophysiology of PIFP remains unknown, and possible mechanisms include neuropathic, vascular, and psychogenic components, although the actual role of each of these components in an individual patient is always challenging to discern. To date, there is no evidence-based treatment for PIFP (9,10). This is in part due to the lack of objective neurophysiological, laboratory, or neuroimaging markers of the condition.

It has been proposed that not only peripheral but also central neuronal changes may play a role in the genesis of PIFP, and the presence of a neuropathic component has also been suggested (11 –14). Irrespective of the peripheral generator of pain, it has been suggested that PIFP would occur due to a central phenomenon/amplification driven by a peripherally originating process. Similar to what has been demonstrated in fibromyalgia (15), low-back pain (16), and peripheral neuropathic pain (17), we hypothesized that cortical excitability would be altered in PIFP, and it would be related to the presence of pain and associated symptoms.

Here, we aimed to investigate cortical excitability changes in PIFP compared to age- and gender-matched healthy volunteers using a comprehensive clinical and neurological cortical excitability battery, and we also sought to explore possible correlations with the clinical characteristics of PIFP patients.

Methods

The study was carried out at the Hospital das Clínicas da Universidade de São Paulo, Brazil. Our local Ethics Review Board approved the protocol. This study included the cortical excitability baseline assessment of patients with PIFP included in the clinical trial using repetitive transcranial magnetic stimulation (rTMS) to treat PIFP, registered as NTC01746355. All participants provided written informed consent before inclusion in the study.

Participants

Right-handed patients meeting the International Headache Society criteria for PIFP were included in the study (18). Age- and gender-matched healthy controls with no chronic pain and no use of psychotropics or analgesics in the previous 60 days were included in blocks of five participants per group. At the screening, all patients underwent physical examination by a pain specialist. The diagnostic protocol consisted of a standardized interview including medical and pain history and a clinical systematic evaluation of the cervical, cranial, facial, dental, and other oral structures as well as the following: a) patients’ referral, b) age and gender, c) pain duration, d) affected facial side, main trigeminal branches related to the painful area and associated signs, e) spontaneous pain description and f) medication use in the previous 60 days. Participants were excluded if they had any inflammatory or autoimmune disease, any concurrent chronic pain condition, or any psychiatric disorder and/or substance abuse/dependence. Contraindications for non-invasive neuromodulation were also used as exclusion criteria (19,20).

Clinical assessment

Patients were invited to answer the following questionnaires. The Brief Pain Inventory (BPI) was used to measure mean pain in the last 24 hours and the pain interference during daily activity (21,22). The short form of the McGill Pain Questionnaire (MPQ) was used to assess the characteristics and main descriptors of pain in three domains: Affective, sensory, and cognitive (23). Mood and anxiety symptoms were assessed by the self-administered 21-item Hospital Anxiety and Depression Scale (HADS) (24,25), and the pain catastrophizing scale (PCS) (26) was used to characterize catastrophizing thoughts and behavior. The douleur neuropathique-4 questionnaire (DN-4) was used to screen for pain of neuropathic characteristics (27,28), and the NPSI was employed to characterize neuropathic pain symptoms. The neuropathic pain symptoms inventory (NPSI) is a self-questionnaire designed to provide characterization of neuropathic pain symptoms in five domains (spontaneous superficial and deep pain; paroxysmal pain; evoked pain; and paresthesia/dysesthesia) and its temporal pattern (28,29). Quality of life (QoL) was assessed by the health survey quality-of-life questionnaire (SF-36), which is a general questionnaire (30).

Cortical excitability measurement by TMS

The participants underwent a single experimental session. The experimental session occurred in a laboratory at room temperature, and the participants were asked to remain as relaxed as possible. TMS was performed with a MagPROX100 machine (Magventure Tonika Elektronic, Farum, Denmark) using a circular-shaped coil (C-100 Magventure Tonika Elektronic, Farum), using the appropriate A/B side to reach the correct target in the motor cortex. Motor cortical excitability testing included the determination of rest motor threshold (RMT) (31); motor evoked potentials (MEPs); short-interval intracortical inhibition (SICI) at interstimulus intervals (ISI) of 2 ms and 4 ms; and intracortical facilitation (ICF) at ISI 10 ms and 15 ms. These were all tested in both hemispheres. The results of four trials were averaged for each ISI. MEP was recorded over the cortical representation of the masseter of the contralateral face with an EMG amplifier module (Tonika Elecktronic, Denmark) and surface electrodes (Skovlunde, Denmark), amplified (50–500 µV/division), filtered (20–2,000 Hz). The MEPs were recorded from masseter muscles, with participants keeping the mandible in a resting state sitting in a dental chair with head and neck support; the electrode was placed 2 cm below the mandible angle and the active electrode was placed over the lower third of the muscle belly within 4–5 cm of distance, the ground electrode was placed in the back neck (32). The measures performed by this trial were RMT considered as a motor-evoked potential of at least 50 µV in 5 out of 10 trials; positive responses were considered when the MEP amplitude measured ≥ 50 µV peak-to-peak, as well as motor-evoked potentials to 120% and 140% of RMT (33), as described earlier by Mhalla (15,34,35).

The paired-pulse paradigm was used to investigate facilitation and inhibition circuits in PIFP. The trial consisted of 80% of the output of the RMT value for a conditioning stimulus and 120% of the output of the RMT value for the test stimulus. After the hotspot and RMT were determined, paired-pulse responses were recorded as the average of four trials by each ISI (15,33).

Data analysis

Demographical and clinical characteristics of the groups were reported using mean ± standard deviation for continuous variables and frequency (%) for categorical variables. To identify any differences between the clinical characteristics of the groups, we used two-tailed tests. The Gaussian distribution of the data was verified using the Shapiro–Wilk test. A separate mixed-model analysis was conducted for each primary outcome. Restricted maximum likelihood estimation and type-3 tests of fixed effects were also used. The model contained fixed-effects terms for group (patients vs. controls), region (hemisphere; left vs. right), group region interaction (affected side vs. non-affected side), and a psychotropic treatment interaction (use of psychotropic vs. no use of psychotropic). The presence of relationships between clinical data and cortical excitability values were explored, and only high and moderate correlations (r > 0.4) were reported. Pearson’s correlation test for multiple comparisons was used. Results were considered significant if p < 0.05. The sample size was calculated using G*Power 3.1 software (36) for the main clinical trial, including an F-test ANOVA with the following specifications: Repeated measure within-between interaction, number of groups: 2; number of measurements: 5; nonsphericity ɛ = 1, α probability of error = 0.05; and effect size f(U) = 0.8, adding 29 patients. Analyses were performed with SPSS 20.0 (SPSS Inc., Chicago, IL).

Results

Clinical characteristics of participants

Thirty-eight patients were screened for participation. Nine were excluded eight did not fulfill the IHS criteria for PIFP and one declined to participate in the study. Twenty-nine patients (55.1% female, mean age 55.7 ± 12.1 years) meeting the inclusion criteria and twenty-eight healthy volunteers (57.1% female, mean age 50.6 ± 12.1 years) were included in the study. The clinical characteristics of the patients are displayed in Table 1. The mean pain duration was 13.5 ± 11.0 years, and the most commonly used descriptors were burning (48.3%); heavy (37.9%); throbbing (34.5%); electric shock-like (13.8%); and continuous ongoing pain (13.8%) (from the MPQ). The DN-4 was positive ( ≥ 4) in 22 (75.9%) patients, and the mean NPSI score was 43.5 ± 20.4/100. Pain occurred on a daily basis in 25 patients (86.2%) and twice a week in four (13.8%) patients. Spontaneous pain was reported by 27 (93.1%), while evoked pain was predominant in two (6.9%) PIFP patients. Pain occurred more frequently on the left side in 16 (55.2%), and pain was bilateral in seven (24.1%) patients. Twenty-two patients (75.9%) were under pain psychotropic medications. The most frequent drugs were tricyclic antidepressants (n = 12); opioids (n = 4); neuroleptics (n = 6); anticonvulsants (n = 17); selective serotonin and norepinephrine reuptake inhibitors (SSNRIs) (n = 2); selective serotonin reuptake inhibitors (SSRIs) (n = 5); benzodiazepines (n = 2) (Table 1). Table 2 shows the medication quantification score (MQS) of the PIFP subjects.

Table 1.

General demographics and pain characteristics of participants.

		Patients with PIFP (n = 29)	Healthy volunteers (n = 28)	p
Age (years)		55.7 ± 12.1	50.6 ± 12.1	0.259^a
Gender	Male	13 (44.8%)	12 (42.9%)	0.744^b
Female	16 (55.2%)	16 (57.1%)
Side of pain	Right	6 (20.7%)	–	0.876
Side of pain	Left	16 (55.2%)	–	0.876
Bilateral	7 (24.1%)	–
Pain duration (years)		13.5 ± 11.0	–
Mean pain intensity (VAS/100 mm)		82 ± 15	–
BPI item 5 (“average pain”)		6.7 ± 2.0	–
BPI item 3 (“worst pain”)		8.1 ± 1.6	–
BPI item 4 (“least pain”)		4.9 ± 2.5	–
BPI item 6 (right now)		5.9 ± 3.1	–
Pain during assessment (% with VAS > 0)		27 (93.1%)	–
DN-4		5.0 ± 2.3	–
Positive DN-4 (≥4)		22 (75.8%)
NPSI		43.5 ± 20.4	–
BPI	Interference (0–70)	38.1 ± 20.1	–
HADS	Anxiety	9.4 ± 5.1	–
HADS	Depression	8.6 ± 4.9	–
Total score	18.1 ± 9.5	–
PCS		31.4 ± 12.7	–
MPQ	Sensitive	15.4 ± 6.35	–
MPQ	Affective	8.8 ± 3.5	–
Total score	24.3 ± 9.1	–
SF-36	Physical functioning	63.7 ± 27.6	–
	Role physical	41.3 ± 43.9	–
	Bodily pain	37.0 ± 23.4	–
	General health	60.1 ± 12.0	–
	Vitality	46.3 ± 22.7	–
	Social functioning	50.4 ± 39.3	–
	Role emotional	32.1 ± 39.3	–
Mental health	46.2 ± 25.3	–
Medication	Tricyclic antidepressant	12 (41.4%)	–
	Opioids	4 (13.8%)	–
	Neuroleptics	6 (20.7%)	–
	Anticonvulsants	17 (58.6%)	–
	Selective serotonin and norepinephrine reuptake inhibitor (SSNRIS)	2 (6.9%)	–
Selective serotonin reuptake inhibitor (SSRIS)	5 (17.2%)	–
	Benzodiazepines	2 (6.9%)	–
	Nonsteroidal anti-inflammatory drugs (NSAIDS)	1 (3.4%)	–
Muscle relaxants	0 (0%)	–

DN-4: neuropathic pain questionnaire 4; NPSI: neuropathic pain symptoms inventory; BPI: brief pain inventory; HADS: hospital anxiety and depression scale; PCS: pain catastrophizing scale; MPQ: McGill pain questionnaire; SF-36: health survey quality-of-life questionnaire.

Student’s t test; ^bChi-square test; significance level is 0.05.

Table 2.

Pain characteristics of patients with and without psychotropic analgesics.

		Patients with psychotropic treatment mean ± SD (n = 22)	Patients without psychotropic treatment Mean ± SD (n = 7)	p**
Age (years)		55.0 ± 13.0	58.0 ± 9.1	0.259^a
Gender	Male	9 (40.9%)	4 (57.1%)	0.744^b
	Female	13 (59.1%)	3 (42.9%)
Side of pain	Right	5 (22.7%)	1 (14.3%)	0.876^b
Side of pain	Left	12 (54.5%)	4 (57.1%)	0.876^b
Bilateral	5 (22.7%)	2 (28.6%)
Pain duration (years)		12.3 ± 10.9	17.1 ± 11.4	0.331
Mean pain intensity (VAS)		6.7 ± 1.7	6.7 ± 2.8	0.938
DN-4		5.2 ± 2.2	4.4 ± 2.9	0.302
NPSI		45.5 ± 16.8	37.1 ± 29.8	0.251
BPI	Interference	41.5 ± 18.7	27.5 ± 21.9	0.092
HADS	Anxiety	9.9 ± 5.2	8.1 ± 5.2	0.487
HADS	Depression	8.8 ± 4.9	8.1 ± 5.3	0.780
Total score	18.7 ± 9.4	16.2 ± 10.3	0.524
PCS		30.5 ± 11.8	34.2 ± 15.8	0.367
MPQ	Sensitive	15.2 ± 5.5	16.0 ± 8.8	0.898
MPQ	Affective	9.0 ± 3.3	8.2 ± 4.3	0.795
Total score	24.3 ± 8.1	24.2 ± 12.5	0.959
SF-36	Physical functioning	67.5 ± 24.9	52.1 ± 34.2	0.220
	Role physical	40.9 ± 45.9	42.8 ± 40.0	0.808
	Bodily pain	38.9 ± 24.0	31.0 ± 21.9	0.591
	General health	60.0 ± 11.9	60.1 ± 13.2	0.858
	Vitality	47.7 ± 22.9	42.1 ± 23.4	0.506
	Social functioning	48.8 ± 32.0	55.3 ± 36.6	0.678
	Role emotional	33.3 ± 39.8	28.5 ± 40.4	0.761
Mental health	43.8 ± 26.2	53.7 ± 22.1	0.371
Medication Quantification Scale		2.18 ± 0.85 (1–3)	0.14 ± 0.37 (0–1)	0.0001

DN-4: neuropathic pain questionnaire 4; NPSI: neuropathic pain symptoms inventory; BPI: brief pain inventory; HADS: hospital anxiety depression scale; PCS: pain catastrophizing scale; MPQ: McGill pain questionnaire; SF-36: health survey quality-of-life questionnaire.

Kruskal-Wallis test; ^bChi-square test; **Mann-Whitney U test; significance level is 0.05.

Cortical excitability

The cortical excitability (CE) data from the PIFP patients were similar and had no significant side-to-side differences (p > 0.455) (Figure 1). The CE data did not differ between patients (n = 22) using psychotropics compared with those not taking these drugs (n = 7) (p > 0.882) (Supplementary Table 1). Also, the CE data did not correlate with the numbers of drugs taken by the patients.

Figure 1.

(a) and (b) Results of patients with PIFP (black columns) and healthy controls (gray columns) for rest motor threshold (RMT) measures for the right and left hemispheres, expressed as a percentage of output the intensity of the machine. (c) and (d) Results of patients with PIFP (black columns) and healthy controls (gray columns) of the suprathreshold of motor-evoked potential (MEP) amplitude at 120% of RMT measured for both hemispheres. (e) and (f) Results of patients with PIFP (black columns) and healthy controls (gray columns) of the suprathreshold of motor-evoked potential (MEP) amplitude at 140% of the output of RMT measured for the right and left hemispheres.

Neurophysiological measurements of RMT and MEPs

RMT was similar on both hemispheres of the PIFP patients compared with healthy controls (Figure 1(a) and (b)). The MEPs at 120% and 140% RMT were both significantly lower on both hemispheres in the PIFP patients compared with controls (Figure1(c); (d); (e) and (f)). The changes in RMT and MEP in the PIFP patients were not related to modifications in SICI and ICF. The mixed-model measures analysis revealed no significant main effects of group (F_1,108 = 0.585; raw p = 0.446); region (F_1,108 = 0.251; raw p = 0.617); group x region interaction effect (F_1,108 = 0.406; raw p = 0.525); or region x treatment psychotropic interaction effect (F_1,108 = 0.006; raw p = 0.938), suggesting that the use of psychotropics did not influence CE results in a significant manner.

Intracortical inhibition and facilitation assessed by the paired-pulse technique

Patients with PIFP had significantly impaired SICI (i.e. defective inhibition – higher values of SICI) compared to controls in both hemispheres (Figure 2). The alterations in SICI were similar in patients with and without drug treatments. The mixed-model measures analysis revealed significant main effects of group (F_1,108 = 56.987; raw p = 0.0001) and region (F_1,108 = 4.895; raw p = 0.029); no significant effects of the group x region interaction effect (F_1,108 = 0.500; raw p = 0.481); and no significant effects of the region x treatment psychotropic interaction effect (F_1,108 = 0.068; raw p = 0.795).

Figure 2.

((a) and (b)) Results of patients with PIFP (black columns) and healthy controls (gray columns) for short intracortical inhibition (SICI) expressed as the mean of inhibition of the test response. ((c) and (d)) Results of patients with PIFP (black columns) and healthy controls (gray columns) for intracortical facilitation (ICF) expressed as the mean of the facilitation of the test response.

ICF values were not different between groups (Figure 2(c) and (d)), and the ICF did not significantly differ between patients with and without psychotropic treatment. The mixed-model measures analysis confirmed the non-existence of significant main effects of group (F_1,108 = 2.037; raw p = 0.156) and region (F_1,108 = 0.991; raw p = 0.322) and no significant effects associated with the group x region interaction effect (F_1,108 = 0.078; raw p = 0.781) or the region x treatment psychotropic interaction effect (F_1,108 = 0.168; raw p = 0.682).

Correlation analyses

No significant correlations were found between MEP amplitude and SICI values and clinical pain characteristics. There was a positive correlation between RMT and PCS (rho = 0.453; p = 0.016) and ICF and depression subscores of the HAD scale (rho = 0.443, p = 0.021), and there was a negative correlation between the SF-36 item role ‘emotional’ and ICF values in PIFP patients (rho = −0.406; p = 0.002).

Discussion

To our knowledge, this is the first study to use TMS to evaluate cortical excitability in PIFP patients. Our results support the hypothesis that PIFP patients have significant alterations in cortical neurophysiological parameters of cortical excitability compared to healthy individuals. Patients with PIFP presented decreased MEP values – despite normal RMT – as well as defective SICI. This suggests PIFP patients have changes in neuronal membrane excitability related to ion channels as well as defective intracortical GABAergic interneuron activity in the intermediate layers of the M1.

Previous studies have assessed CE changes in other chronic pain conditions. Fibromyalgia patients are known to have elevated RMT, MEP (120% and 140%), and lower ICI and ICF values compared to healthy individuals, while patients with CRPS presented bilateral reductions in ICI. Limb amputees presented reduced ICI and increased ICF in the hemisphere contralateral to the amputation (15,37), and neuropathic pain patients presented defective SICI in the painful limb (38), which could be restored to normal values after an effective treatment (39). Here, we found that both MEP and SICI results were reduced in PIFP patients, and these changes occurred bilaterally and in a symmetric manner, irrespective of the asymmetric presentation of face pain in most patients. This is interesting when one takes into consideration that at least one-third of each side of the face receives bilateral outputs from M1 and that the proprioception inputs from jaw muscles (i.e. the masseter muscle assessed here) project to both hemispheres.

Given the cross-sectional nature of the present study, one cannot draw cause-and-effect relationships between findings, and the actual driving force behind CE changes in PIFP patients cannot be determined. One could hypothesize that excessive nociceptive inputs (e.g. tooth extraction, local infection) could trigger the central changes described here, and this could lead to central plastic changes that would perpetuate pain in predisposed patients, in whom maladaptive plasticity would occur. Thus, pain would persist despite the resolution of the initial nociceptive insult, thus leading to a state of low/absent oral or facial lesion (as seen in PIFP) coexisting with chronic pain.

PIFP diagnosis is based on the exclusion of other etiologies of orofacial pain, and frequently requires extensive diagnostic workup. However, the correct diagnosis would benefit from a deeper clinical characterization of PIFP patients, which is currently scarce in the literature. Here we also provided a comprehensive characterization of several aspects of pain in these patients (2,40) with validated tools. We found several characteristics of neuropathic pain in our sample, and this could be used in the future to more effectively subgroup PIFP patients into different phenotypes.

Cortical excitability is usually based on the MEPs of the first dorsal interosseous muscle (FDI) (20). Here, we measured CE’s effects over the masseter muscles after stimulating the M1 representation of the face, which provided a more accurate representation of central changes in facial pain patients. This has certainly provided more accurate information concerning the respective central changes in PIFP, although it has also been argued that M1 changes related to pain could be present diffusely in this cortical area and are not necessarily restricted to the M1 region and homologous to the contralateral painful body area (15).

One limitation of this study is that we did not include other potentially useful CE measurements such as cortical silent period measurements, which could provide more insights into PIFP physiology. We followed a set of CE measures that have been previously been explored in other chronic pain syndromes. Another limitation of this study is that a significant proportion of patients used centrally acting drugs. While it is known that many of these drugs may affect CE measurements (41), we could not find differences in the CE parameters of PIFP patients who took psychotropics compared to those who did not. This lack of influence of analgesic psychotropic intake on CE results has been reported previously (15,42) in other pain syndromes such as fibromyalgia. It has been argued that changes in CE brought about by pain itself were so intense that those caused by a heterogeneous group of medications would be overshadowed and would not be sufficiently robust to impact the results (33). Another point is the role of concurrent pain during neurophysiological assessments on CE results. While the presence of pain is likely to influence CE values compared to pain-free situations, all our patients were experiencing pain during the assessment, as shown by the brief pain inventory pain intensity scores. It would be interesting to evaluate chronic pain patients in the future both under current pain and after pain relief in order to dissect which aspects of CE changes could be attributed to the occurrence of pain per se and which would be related to broader, long-lasting effects of central plastic changes related to chronic pain.

In conclusion, PIFP patients had significant pain with neuropathic components and expressed changes in MEP amplitudes and intra-cortical inhibition, suggesting a defective GABAergic alteration in this pain syndrome. In contrast to what has been reported in fibromyalgia and peripheral neuropathic pain syndromes, we did not find significant correlations between SICI changes and clinical features of patients; therefore, these results should be explored in future studies with larger samples.

Article highlights

Persistent idiopathic facial pain patients have alterations in cortical excitability compared with healthy controls.

Changes in cortical excitability in persistent idiopathic facial pain were not influenced by central acting medications and correlated with associated symptoms such as mood and catastrophism.

Pain with neuropathic components was frequent in PIFP.

Supplemental Material

Supplementary table -Supplemental material for Altered cortical excitability in persistent idiopathic facial pain

Supplemental material, Supplementary table for Altered cortical excitability in persistent idiopathic facial pain by Ricardo Galhardoni, Daniel Ciampi de Andrade, Mariana YT Puerta, Andre R Brunoni, Bruna LR Varotto, José TT de Siqueira, Manoel J Teixeira and Silvia RDT Siqueira in Cephalalgia

Footnotes

Acknowledgements

RG would like to acknowledge Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq) for supporting this study, process number: 141192/2012-7. ARB is awarded by NARSAD (YI 2013/20493), CNPq (2013/470904) and São Paulo Research State Foundation (FAPESP, 2012/20911-5) grants.

Declaration of conflicting interests

The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The authors disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: The authors received financial support for the research from Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq) and Pain Center of Departmet of Neurology of University of Sao Paulo, Brazil.

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